INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KETRUDA® (KEYTRUDA®)

Composition:

Active substance: pembrolizumab;

1 ml of concentrate contains 25 mg of pembrolizumab;

1 vial (4 ml) of concentrate contains 100 mg of pembrolizumab.

Excipients: L-histidine, L-histidine monohydrochloride monohydrate, polysorbate 80, sucrose, water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear to slightly opalescent, colorless to light yellow solution. A liquid practically free from visible particles, pH 5.2–5.8.

Pharmacotherapeutic group. Antineoplastic agents. Monoclonal antibodies. PD-1/PD-L1 inhibitors (programmed cell death protein 1/programmed death-ligand 1). Pembrolizumab. ATC code L01FF02.

Pharmacological properties.

Pembrolizumab is an antibody that blocks the programmed death receptor-1 (PD-1). Pembrolizumab is a humanized monoclonal IgG4 kappa antibody with an approximate molecular weight of 149 kDa. Pembrolizumab is produced in recombinant Chinese hamster ovary cells.

Pharmacodynamics

Based on dose/exposure–response relationships, there were no clinically meaningful differences in efficacy and safety when pembrolizumab was administered at a dose of 200 mg or 2 mg/kg every 3 weeks, regardless of cancer type. Observations in adult patients with melanoma and solid tumors receiving pembrolizumab at doses of 200 mg or 2 mg/kg every 3 weeks and 400 mg every 6 weeks showed no differences in efficacy and safety based on dose/exposure–response relationships. The dose/exposure–response relationship for efficacy and safety of pembrolizumab administered at 400 mg every 6 weeks in patients with classical Hodgkin lymphoma or mediastinal large B-cell lymphoma has not been fully characterized.

Mechanism of action

Binding of PD-1 ligands (PD-L1 and PD-L2) to the PD-1 receptor on T-cells inhibits T-cell proliferation and cytokine production. PD-1 ligand activation occurs in some tumors, and signaling through this pathway may contribute to suppression of active T-lymphocyte immune surveillance of tumors. Pembrolizumab is a monoclonal antibody that binds to PD-1 receptors and blocks their interaction with PD-L1 and PD-L2, thereby releasing PD-1–mediated immune inhibition, including antitumor immune responses. In syngeneic mouse tumor models, PD-1 blockade resulted in reduced tumor growth.

Pharmacokinetics

Pharmacokinetics (PK) of pembrolizumab were analyzed using population PK modeling based on concentration data collected from 2993 patients with various malignancies who received pembrolizumab at doses of 1 to 10 mg/kg once every 2 weeks or 2 to 10 mg/kg once every 3 weeks, or 200 mg once every 3 weeks.

Steady-state concentrations of pembrolizumab are reached by Week 16 with repeated administration every 3 weeks, and systemic accumulation increases by a factor of 2.1. Maximum concentration (Cmax), minimum concentration (Cmin), and area under the plasma concentration–time curve relative to the steady-state concentration–time curve (AUCss) of pembrolizumab increase proportionally with dose over the range of 2 to 10 mg/kg once every 3 weeks.

Distribution

The geometric mean (CV %) of the steady-state volume of distribution is 6.0 L (20 %).

Elimination

Pembrolizumab clearance (CV %) is approximately 23 % lower [geometric mean, 195 mL/day (40 %)] at steady state compared to after the first dose [252 mL/day (37 %)]; this time-dependent reduction in clearance is not considered clinically significant. The terminal half-life (t1/2) is 22 days (32 %).

Special patient groups

The following factors have no clinically significant effect on pembrolizumab clearance: age (range: 15 to 94 years), sex, race (89 % Caucasian), renal impairment (glomerular filtration rate (GFR) ≥ 15 mL/min/1.73 m²), mild to moderate hepatic impairment (total bilirubin ≤ 3 times the upper limit of normal (ULN) and any level of AST), or tumor burden. The effect of severe hepatic impairment (total bilirubin > 3 times ULN or any level of AST) on the pharmacokinetics of pembrolizumab is unknown.

Pediatric patients: pembrolizumab concentrations at a body weight-based dose of 2 mg/kg once every 3 weeks in children (from 10 months to 17 years of age) are comparable to those in adults receiving the same dose.

Immunogenicity

The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods make it difficult to meaningfully compare the ADA incidence described in this section with ADA incidence in other studies, including studies of Keytruda® or other pembrolizumab products.

Low levels of pembrolizumab may interfere with electrochemiluminescence (ECL) assay results; therefore, an analysis of a subset of patients treated with Keytruda® and with pembrolizumab concentrations below the drug tolerance level was conducted for ADA testing.

In clinical studies of Keytruda® administered at 2 mg/kg once every 3 weeks, 200 mg once every 3 weeks, or 10 mg/kg once every 2 or 3 weeks, treatment-induced anti-pembrolizumab antibodies were detected in 27 (2.1 %) of 1289 evaluable patients, of whom 6 (0.5 %) had neutralizing antibodies to pembrolizumab. No clinically significant impact of ADA on the pharmacokinetics of pembrolizumab or on the risk of infusion-related reactions was observed. Due to the low incidence of ADA, their impact on the efficacy of Keytruda® is unknown.

Preclinical data

Carcinogenesis, mutagenesis, impairment of fertility

Studies on the potential carcinogenicity or genotoxicity of pembrolizumab have not been conducted.

Fertility studies with pembrolizumab have not been performed. In 1-month and 6-month repeat-dose toxicity studies in monkeys, no marked effects on reproductive organs in males or females were observed; however, most animals in these studies were not sexually mature.

Toxicological and/or pharmacological animal studies

In animal studies, inhibition of the PD-1/PD-L1 signaling pathway resulted in increased severity of certain infections and inflammatory responses.

In mice infected with Mycobacterium tuberculosis and with blocked PD-1, a marked decrease in survival rate was observed compared to control wild-type mice, correlating with increased bacterial proliferation and inflammatory response in these animals.

Blockade of PD-1 using anti-PD-1 antibodies in primates has also been shown to exacerbate M. tuberculosis infection in rhesus macaques.

In mice with blocked PD-1 and PD-L1, as well as in mice receiving a PD-L1–blocking antibody, reduced survival was also observed following infection with lymphocytic choriomeningitis virus.

Administration of pembrolizumab in chimpanzees with naturally occurring hepatitis B infection led to significant increases in serum ALT, AST, and GGT levels in 2 out of 4 animals, which persisted for at least 1 month after discontinuation of pembrolizumab.

Clinical Characteristics.

Indications.

Melanoma

Keytruda® is indicated for the treatment of patients with unresectable or metastatic melanoma.

Keytruda® is indicated as adjuvant therapy in adults and children (aged 12 years and older) with stage IIB, IIC, or III melanoma following complete resection.

Non-Small Cell Lung Cancer (NSCLC)

Keytruda® in combination with pemetrexed and a platinum agent is indicated as first-line therapy for patients with metastatic non-squamous NSCLC without epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) gene rearrangements.

Keytruda® in combination with carboplatin and paclitaxel or protein-bound paclitaxel is indicated as first-line therapy for patients with metastatic squamous NSCLC.

Keytruda® as monotherapy is indicated as first-line therapy for patients with NSCLC whose tumors express PD-L1 [Tumor Proportion Score (TPS) ≥ 1%], as confirmed by a validated test, in the absence of EGFR or ALK genomic aberrations, and in cases of:

• Stage III disease when patients are not candidates for surgical resection or definitive chemoradiation, or
• metastatic disease.

Keytruda® as monotherapy is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥ 1%), as confirmed by a validated test, following disease progression during or after platinum-based chemotherapy. For patients with EGFR or ALK genomic aberrations, Keytruda® may be administered after progression on targeted therapy in accordance with standard treatment guidelines for these aberrations.

Keytruda® is indicated for the treatment of patients with resectable NSCLC (tumors ≥ 4 cm or lymph node positive) in combination with platinum-based chemotherapy as neoadjuvant treatment, followed by continued use as monotherapy for adjuvant treatment after surgery.

Keytruda® as monotherapy is indicated for adjuvant treatment following resection and platinum-based chemotherapy in adult patients with stage IB (T2a ≥ 4 cm), II, or IIIA NSCLC.

Head and Neck Squamous Cell Carcinoma (HNSCC)

Keytruda® in combination with platinum and fluorouracil (FU) is indicated as first-line therapy for patients with metastatic or unresectable, recurrent HNSCC.

Keytruda® as monotherapy is indicated as first-line therapy for patients with metastatic or unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥ 1], as confirmed by a validated test.

Keytruda® is indicated as monotherapy for the treatment of patients with recurrent or metastatic HNSCC that has progressed on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma (cHL)

Keytruda® is indicated for the treatment of adults with recurrent or refractory classical Hodgkin lymphoma (cHL).

Keytruda® is indicated for the treatment of children with refractory cHL or cHL that has relapsed after two or more prior lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma (PMBCL)

Keytruda® is indicated for the treatment of adults and children with refractory primary mediastinal large B-cell lymphoma (PMBCL) or those with relapsed PMBCL after two or more prior lines of therapy.

Limitation of use: Keytruda® is not recommended for patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

Keytruda® in combination with enfortumab vedotin is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma.

Keytruda® as monotherapy is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma:

• who are not eligible for any platinum-containing chemotherapy, or
• who have disease progression during or after platinum-containing chemotherapy, or within 12 months after neoadjuvant or adjuvant platinum-containing chemotherapy.

Keytruda® as monotherapy is indicated for the treatment of patients with high-risk non-muscle-invasive bladder cancer unresponsive to Bacillus Calmette-Guérin (BCG) therapy, with carcinoma in situ with or without papillary tumors, who are not candidates for (or decline) cystectomy.

Cancers with High Microsatellite Instability or Mismatch Repair Deficiency

Keytruda® is indicated for the treatment of adults and children with unresectable or metastatic solid tumors that are microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), as confirmed by a validated test, that have progressed following prior treatment and for whom there are no satisfactory alternative treatment options.

High Microsatellite Instability or Mismatch Repair Deficiency in Patients with Colorectal Cancer

Keytruda® is indicated for the treatment of patients with unresectable or metastatic colorectal cancer (CRC) that is microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), as confirmed by a validated test.

Gastric Cancer

Keytruda® in combination with trastuzumab, fluoropyrimidine-, and platinum-containing chemotherapy is indicated as first-line treatment for adults with locally advanced unresectable or metastatic HER2-positive adenocarcinoma of the stomach or gastroesophageal junction (GEJ) whose tumors express PD-L1 [Combined Positive Score (CPS) ≥ 1], as confirmed by a validated test.

Keytruda® in combination with fluoropyrimidine- and platinum-containing chemotherapy is indicated as first-line treatment for adults with locally advanced unresectable or metastatic HER2-negative adenocarcinoma of the stomach or gastroesophageal junction (GEJ).

Esophageal Cancer

Keytruda® is indicated for the treatment of patients with locally advanced or metastatic carcinoma of the esophagus or gastroesophageal junction (GEJ) (tumor center located 1–5 cm above GEJ) that is not amenable to surgical resection or definitive chemoradiation:

• in combination with platinum- or fluoropyrimidine-based chemotherapy, or
• as monotherapy following one or more prior lines of systemic therapy in patients with squamous histology whose tumors express PD-L1 (CPS ≥ 10), as confirmed by a validated test.

Cervical Cancer

Keytruda® in combination with chemoradiation is indicated for the treatment of patients with cervical cancer stage III–IVA according to FIGO 2014.

Keytruda® in combination with chemotherapy, with or without bevacizumab, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥ 1), as confirmed by a validated test.

Keytruda® as monotherapy is indicated for the treatment of patients with recurrent or metastatic cervical cancer that has progressed during or after chemotherapy, when tumors express PD-L1 (CPS ≥ 1), as confirmed by a validated test.

Hepatocellular Carcinoma (HCC)

Keytruda® is indicated for the treatment of patients with hepatocellular carcinoma (HCC) secondary to hepatitis B who have received prior systemic therapy other than a regimen containing PD-1/PD-L1 inhibitors.

Biliary Tract Cancer

Keytruda® in combination with gemcitabine and cisplatin is indicated for the treatment of patients with locally advanced unresectable or metastatic biliary tract cancer (BTC).

Merkel Cell Carcinoma

Keytruda® is indicated for the treatment of adults and children with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC).

Renal Cell Carcinoma

Keytruda® in combination with axitinib is indicated as first-line therapy for the treatment of adults with advanced renal cell carcinoma (RCC).

Keytruda® is indicated as adjuvant therapy in patients with RCC at intermediate or high risk of recurrence following nephrectomy or following nephrectomy and resection of metastatic lesions.

Endometrial Carcinoma

Keytruda® in combination with carboplatin and paclitaxel, followed by continued use of Keytruda® as monotherapy, is indicated for the treatment of adult patients with primary advanced or recurrent endometrial carcinoma.

Keytruda® as monotherapy is indicated for the treatment of adult patients with advanced endometrial carcinoma that is MSI-H or dMMR, as confirmed by a validated test, who have disease progression following prior systemic therapy in any setting and who are not candidates for surgery or radiation (see section "Dosage and Administration").

Cancers with High Tumor Mutational Burden (TMB-H)

Keytruda® is indicated for the treatment of adults and children with unresectable or metastatic solid tumors with high tumor mutational burden (TMB-H) [≥ 10 mutations per megabase (mut/Mb)], as confirmed by a validated test (see section "Dosage and Administration"), that have progressed following prior treatment and for whom there are no satisfactory alternative treatment options.

Limitation of use: The safety and efficacy of Keytruda® in children with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma (cSCC)

Keytruda® is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not amenable to surgical or radiation therapy.

Triple-Negative Breast Cancer (TNBC)

Keytruda® is indicated for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant therapy, followed by continued use as adjuvant monotherapy after surgery.

Keytruda® in combination with chemotherapy is indicated for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥ 10), as confirmed by a validated test (see section "Dosage and Administration").

Classical Hodgkin Lymphoma and Primary Mediastinal Large B-Cell Lymphoma in Adults: Additional Dosing Regimen of 400 mg Every 6 Weeks

Keytruda® is indicated for use at the additional recommended dose of 400 mg every 6 weeks in classical Hodgkin lymphoma and primary mediastinal large B-cell lymphoma in adults (see sections "Indications", "Dosage and Administration"). This indication was approved under the accelerated approval pathway based on pharmacokinetic data, exposure-response relationships for efficacy and safety (see section "Pharmacological Properties"). Continued approval for this dosing regimen may depend on verification and description of clinical benefit in confirmatory trials.

Contraindications.

Severe hypersensitivity to the active substance (pembrolizumab) or to any of the excipients of the medicinal product (see section "Composition").

Interaction with Other Medicinal Products and Other Forms of Interaction.

Formal pharmacokinetic interaction studies between pembrolizumab and other medicinal products have not been conducted. Since pembrolizumab is eliminated from the systemic circulation via catabolism, metabolic interactions with other drugs are not expected.

Concomitant use of systemic corticosteroids or other immunosuppressants prior to initiation of pembrolizumab therapy should be avoided due to the potential impact on the pharmacodynamic activity and efficacy of pembrolizumab. However, systemic corticosteroids or other immunosuppressants may be administered after initiation of pembrolizumab to manage immune-mediated adverse reactions (see section "Special Warnings and Precautions for Use").

Corticosteroids may also be used as premedication when Keytruda® is administered in combination with chemotherapy, to prevent vomiting and/or to mitigate chemotherapy-related adverse reactions.

Special precautions.

Severe and fatal immune-mediated adverse reactions

Keytruda® is a monoclonal antibody belonging to a class of agents that bind either to programmed death receptor-1 (PD-1) or to PD-ligand 1 (PD-L1), thereby blocking the PD-1/PD-L1 pathway, releasing inhibition of the immune response, potentially breaking peripheral tolerance and causing immune-mediated adverse reactions. Important immune-mediated adverse reactions listed in the "Special precautions" section may not include all possible severe and fatal immune-mediated adverse reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and may affect more than one organ system simultaneously. Immune-mediated adverse reactions may occur at any time after initiation of treatment with PD-1/PD-L1 blocking antibodies. Although immune-mediated adverse reactions typically occur during treatment with PD-1/PD-L1 blocking antibodies, they may also manifest after discontinuation of PD-1/PD-L1 blocking antibodies.

Early detection and management of immune-mediated adverse reactions are critical to ensure the safe use of PD-1/PD-L1 blocking antibodies. Patients should be closely monitored for symptoms and signs that may represent clinically significant immune-mediated adverse reactions. Liver enzymes, creatinine, and thyroid function should be assessed at baseline and periodically during treatment. In patients with TNBC who received Keytruda® as neoadjuvant therapy, serum cortisol levels should be monitored at baseline, prior to surgery, and as clinically indicated.

If immune-mediated adverse reactions are suspected, appropriate investigations should be performed to exclude alternative etiologies, including infection. Prompt medical management, including specialist consultation if necessary, should be initiated.

Administration of Keytruda® should be withheld or permanently discontinued depending on severity (see section "Dosage and administration"). If interruption or discontinuation of Keytruda® is required, systemic corticosteroid therapy (1–2 mg/kg/day of prednisone or equivalent) should be initiated until adverse reactions improve to Grade 1 or lower. After improvement to Grade 1 or lower, tapering of corticosteroids should be initiated and continued for at least one month. Consideration should be given to the use of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroids.

Recommendations for managing toxicities that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-mediated pneumonitis

Keytruda® may cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have previously received thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving Keytruda®, including fatal cases (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) adverse reactions. Systemic corticosteroids were required in 67% (63/94) of patients with pneumonitis. Pneumonitis led to permanent discontinuation of Keytruda® in 1.3% (36) of patients and interruption of Keytruda® in 0.9% (26) of patients. All patients who had treatment interrupted resumed Keytruda® after symptom improvement; among them, 23% experienced a recurrence of pneumonitis. Pneumonitis resolved in 59% of the 94 patients.

In clinical trials involving 389 adult patients with cHL receiving Keytruda® as monotherapy, pneumonitis occurred in 31 (8%) patients, including Grade 3–4 pneumonitis in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). The frequency of pneumonitis was similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of Keytruda® in 21 (5.4%) patients. Among patients who developed pneumonitis, 42% interrupted treatment with Keytruda®, 68% discontinued treatment, and 77% recovered.

Immune-mediated colitis

Keytruda® may cause immune-mediated colitis, which may be accompanied by diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, repeat infectious workup should be considered to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving Keytruda®, including Grade 4 adverse reactions (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%). Systemic corticosteroids were required in 69% (33/48) of patients with colitis. Additional immunosuppressive therapy was needed in 4.2% of patients. Colitis led to permanent discontinuation of Keytruda® in 0.5% (15) of patients and interruption of Keytruda® in 0.5% (13) of patients. All patients who had treatment interrupted resumed Keytruda® after symptom improvement; among them, 23% experienced a recurrence of colitis. Colitis resolved in 85% of the 48 patients.

Hepatotoxicity and immune-mediated hepatitis

Keytruda® as monotherapy

Keytruda® may cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving Keytruda®, including Grade 4 adverse reactions (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%). Systemic corticosteroids were required in 68% (13/19) of patients with hepatitis. Eleven percent of these patients required additional immunosuppressive therapy. Hepatitis led to permanent discontinuation of Keytruda® in 0.2% (6) of patients and interruption of Keytruda® in 0.3% (9) of patients. All patients who had treatment interrupted resumed Keytruda® after symptom improvement; none experienced a recurrence of hepatitis. Hepatitis resolved in 79% of the 19 patients.

Keytruda® with axitinib

The combination of Keytruda® with axitinib may cause hepatic toxicity with a higher than expected frequency of Grade 3 and 4 elevations in ALT and AST levels compared to Keytruda® monotherapy. Liver enzymes should be monitored before initiation and periodically throughout treatment. More frequent monitoring of liver enzymes is required compared to monotherapy with these agents. In case of elevated liver enzymes, administration of Keytruda® and axitinib should be discontinued and consideration given to initiating corticosteroid therapy if necessary (see section "Dosage and administration").

With the combination of Keytruda® and axitinib, Grade 3 and 4 elevations in ALT (20%) and AST (13%) were observed. Systemic corticosteroids were administered to 59% of patients with elevated ALT. ALT levels decreased to Grade 0–1 in 94% of patients with ALT ≥3 times ULN (Grades 2–4, n=116). Among 92 patients who were rechallenged with Keytruda® (n=3), axitinib (n=34), or both (n=55), recurrence of ALT ≥3 times ULN occurred in 1 patient receiving Keytruda®, 16 patients receiving axitinib, and 24 patients receiving both Keytruda® and axitinib. All patients with recurrent ALT ≥3 ULN subsequently recovered.

Immune-mediated endocrinopathies

Adrenal insufficiency

Keytruda® may cause primary or secondary adrenal insufficiency. Symptomatic treatment, including replacement hormone therapy as clinically indicated, should be initiated for Grade 2 or higher adrenal insufficiency. Administration of Keytruda® should be withheld or permanently discontinued depending on severity (see section "Dosage and administration").

Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving Keytruda®, including Grade 4 adverse reactions (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%). Systemic corticosteroids were required in 77% (17/22) of patients with adrenal insufficiency; most remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of Keytruda® in <0.1% (1) of patients and permanent discontinuation of further Keytruda® treatment in 0.3% (8) of patients. All patients who had treatment interrupted resumed Keytruda® after symptom improvement.

Hypophysitis

Keytruda® may cause immune-mediated hypophysitis. Hypophysitis may present with acute symptoms related to systemic effects such as headache, photophobia, or visual field defects. Hypophysitis may lead to hypopituitarism. Replacement hormone therapy should be initiated as indicated. Administration of Keytruda® should be withheld or permanently discontinued depending on severity (see section "Dosage and administration").

Hypophysitis occurred in 0.6% (17/2799) of patients receiving Keytruda®, including Grade 4 adverse reactions (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%). Systemic corticosteroids were required in 94% (16/17) of patients with hypophysitis; most remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of Keytruda® in 0.1% (4) of patients and interruption of Keytruda® in 0.3% (7) of patients. All patients who had treatment interrupted resumed Keytruda® after symptom improvement.

Thyroid disorders

Keytruda® may cause immune-mediated thyroid disorders. Thyroiditis may occur with or without endocrinopathy. Hypothyroidism may follow hyperthyroidism. Hormone replacement therapy should be initiated for hypothyroidism or medical management of hyperthyroidism initiated as clinically indicated. Administration of Keytruda® should be withheld or permanently discontinued depending on severity (see section "Dosage and administration").

Thyroiditis occurred in 0.6% (16/2799) of patients receiving Keytruda®, including Grade 2 cases (0.3%). No patient discontinued Keytruda® due to thyroiditis. Administration of Keytruda® was interrupted in <0.1% (1) of patients.

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving Keytruda®, including Grade 3 (0.1%) and Grade 2 (0.8%). Hyperthyroidism led to permanent discontinuation of Keytruda® in <0.1% (2) of patients and interruption of Keytruda® in 0.3% (7) of patients. All patients who had treatment interrupted resumed Keytruda® after symptom improvement.

Hypothyroidism occurred in 8% (237/2799) of patients receiving Keytruda®, including Grade 3 (0.1%) and Grade 2 (6.2%). Hypothyroidism led to permanent discontinuation of Keytruda® in <0.1% (1) of patients and interruption of Keytruda® in 0.5% (14) of patients. All patients who had treatment interrupted resumed Keytruda® after symptom improvement. Most patients with hypothyroidism required long-term thyroid hormone replacement therapy.

The incidence of new-onset or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving Keytruda® as monotherapy or in combination with platinum and 5-FU, including Grade 3 hypothyroidism (0.3%). The incidence of new-onset or worsening hypothyroidism was higher in 389 patients with cHL (17%) receiving Keytruda® as monotherapy, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism.

Type 1 diabetes mellitus, which may present with diabetic ketoacidosis

Patients should be monitored for the development of hyperglycemia or other signs and symptoms of diabetes. Insulin therapy should be initiated as clinically indicated. Administration of Keytruda® should be withheld or discontinued depending on severity (see section "Dosage and administration").

Type 1 diabetes mellitus occurred in 0.2% (6/2799) of patients receiving Keytruda®. Type 1 diabetes led to permanent discontinuation in <0.1% (1) of patients and interruption of Keytruda® in <0.1% (1) of patients. All patients who had treatment interrupted resumed Keytruda® after symptom improvement. All patients with type 1 diabetes required long-term insulin therapy.

Immune-mediated nephritis and renal dysfunction

Keytruda® may cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving Keytruda®, including Grade 4 adverse reactions (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%). Systemic corticosteroids were required in 89% (8/9) of patients with nephritis. Nephritis led to permanent discontinuation of Keytruda® in 0.1% (3) of patients and interruption of Keytruda® in 0.1% (3) of patients. All patients who had treatment interrupted resumed Keytruda® after symptom improvement; none experienced a recurrence of nephritis. Nephritis resolved in 56% of the 9 patients.

Immune-mediated dermatologic adverse reactions

Keytruda® may cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, DRESS (drug reaction with eosinophilia and systemic symptoms), and toxic epidermal necrolysis (TEN), has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be sufficient for managing mild to moderate non-exfoliative rashes. Administration of Keytruda® should be withheld or discontinued depending on severity (see section "Dosage and administration").

Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving Keytruda®, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients with immune-mediated dermatologic adverse reactions. Immune-mediated dermatologic adverse reactions led to permanent discontinuation of Keytruda® in 0.1% (2) of patients and interruption of Keytruda® in 0.6% (16) of patients. All patients who had treatment interrupted resumed Keytruda® after symptom improvement; 6% experienced a recurrence of immune-mediated dermatologic adverse reactions. Immune-mediated dermatologic adverse reactions resolved in 79% of the 38 patients.

Other immune-mediated adverse reactions

The following clinically significant immune-mediated adverse reactions, occurring at a frequency of <1% (unless otherwise specified) in patients receiving Keytruda® or reported with other PD-1/PD-L1 blocking antibodies, are listed below. Some of these adverse reactions have been reported to be severe or fatal.

Cardiovascular system: myocarditis, pericarditis, vasculitis.

Nervous system: meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy.

Eyes: uveitis, iritis, and other inflammatory toxicities affecting the eyes may occur. Some cases may be associated with retinal detachment. Various degrees of visual impairment, including blindness, may occur. If uveitis occurs in combination with other immune-mediated adverse reactions, Vogt-Koyanagi-Harada-like syndrome should be considered, as this may require systemic steroid treatment to reduce the risk of permanent vision loss.

Gastrointestinal tract: pancreatitis, including elevated serum amylase and lipase, gastritis, duodenitis, exocrine pancreatic insufficiency.

Hepatobiliary system: sclerosing cholangitis.

Musculoskeletal and connective tissue: myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica.

Endocrine system: hypoparathyroidism.

Hematologic/immune disorders: hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, rejection of other transplants (including corneal grafts).

Complications of allogeneic HSCT

Fatal and other serious complications may occur in patients who have undergone allogeneic hematopoietic stem cell transplantation (HSCT) either before or after treatment with PD-1/PD-L1 blocking antibodies. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning, and steroid-requiring febrile syndrome (without established infectious cause). These complications may occur regardless of the interval between PD-1/PD-L1 blockade and allogeneic HSCT.

Patients should be closely monitored for transplant-related complications and managed promptly. The benefits and risks of treatment with PD-1/PD-L1 blocking antibodies before or after allogeneic HSCT should be carefully considered.

Infusion-related reactions

Keytruda® may cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, reported in 0.2% of 2799 patients receiving this medicinal product. Patients should be monitored for signs and symptoms of infusion-related reactions such as chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. Infusion should be interrupted or slowed for mild (Grade 1) or moderate (Grade 2) infusion reactions. Infusion should be discontinued and Keytruda® permanently discontinued in the event of severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions (see section "Dosage and administration").

Increased mortality in patients with multiple myeloma when Keytruda® is added to a thalidomide analogue and dexamethasone

In two randomized clinical trials in patients with multiple myeloma, adding Keytruda® to a thalidomide analogue plus dexamethasone, for which PD-1 or PD-L1 blocking antibodies are not indicated, resulted in increased mortality. Treatment of patients with multiple myeloma with PD-1 or PD-L1 blocking antibodies in combination with a thalidomide analogue and dexamethasone is not recommended outside of controlled clinical trials.

Embryo-fetal toxicity

Due to its mechanism of action, Keytruda® may cause harm to the fetus when administered to pregnant women. In animal models, the PD-1/PD-L1 signaling pathway has been shown to be important for maintaining pregnancy by inducing maternal immune tolerance to fetal tissues.

Women should be advised of the potential risk to the fetus. Women of reproductive potential should be advised to use effective contraception during treatment with Keytruda® and for 4 months after the last dose.

Use during pregnancy or breastfeeding.

Pregnancy

Summary of risks

Due to its mechanism of action, Keytruda® may cause harm to the fetus when administered to pregnant women. There are no human data available regarding the risk of embryo-fetal toxicity. In animal models, the PD-1/PD-L1 signaling pathway is important for maintaining pregnancy by inducing maternal immune tolerance to fetal tissues. Human IgG4 immunoglobulins are known to cross the placenta; therefore, transmission of pembrolizumab from mother to developing fetus is possible. Pregnant women should be advised of the potential risk to the fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Data

Animal data

Reproductive toxicity studies in animals have not been conducted with Keytruda® to evaluate its effects on fertility or embryo-fetal development. Evaluation of the impact of the PD-1 pathway on reproductive function based on published data indicates that a central function of the PD-1/PD-L1 pathway is to maintain pregnancy by supporting maternal immune tolerance to the fetus. In a mouse pregnancy model, blockade of the PD-L1 signaling pathway disrupted fetal tolerance and led to increased fetal loss; thus, potential risks of using Keytruda® during pregnancy include increased rates of abortion or stillbirth. As reported in publications, no developmental abnormalities related to PD-1 pathway blockade were observed in offspring of these animals; however, immune-mediated disorders occurred in PD-1 knockout mice. Due to its mechanism of action, pembrolizumab may increase the risk of immune-mediated disorders or alter normal immune responses in the fetus.

Breastfeeding

There are no data on the presence of pembrolizumab in human or animal breast milk, or on its effects on the breastfed child or milk production. Maternal IgG is known to be present in human breast milk. The consequences of local effects on the gastrointestinal tract and limited systemic exposure of Keytruda® on the breastfed child are unknown. Due to the potential for serious adverse reactions in breastfed children, women are advised not to breastfeed during treatment with Keytruda® and for 4 months after the last dose.

Fertility in women and men

Pregnancy testing

Women of reproductive potential should have a pregnancy test performed before starting treatment with Keytruda® (see subsection "Pregnancy").

Contraception

Keytruda® may cause harm to the fetus when administered to a pregnant woman (see section "Special precautions", subsection "Pregnancy"). Women of reproductive potential are advised to use effective contraception during treatment with Keytruda® and for 4 months after the last dose.

Effect on ability to drive and use machines.

Pembrolizumab may have a minimal effect on the ability to drive and use machines. Fatigue has been reported after administration of pembrolizumab.

Administration and Dosage

Only qualified physicians experienced in cancer treatment should prescribe and monitor therapy.

Patient selection for monotherapy

Patient selection for treatment with KEYTRUDA® as monotherapy is based on positive PD-L1 expression in:

• Stage III NSCLC, if patients are not candidates for surgical resection or definitive chemoradiation therapy;
• metastatic NSCLC;
• first-line treatment of metastatic or unresectable, recurrent HNSCC;
• metastatic urothelial carcinoma;
• previously treated recurrent locally advanced or metastatic esophageal carcinoma;
• recurrent or metastatic cervical cancer with disease progression during or after chemotherapy.

Tumor MSI or MMR status should be evaluated using a validated test.

For MSI-H/dMMR indications, select patients for treatment with KEYTRUDA® as monotherapy based on MSI-H/dMMR status in tumor specimens.

For the TMB-H indication, select patients for treatment with KEYTRUDA® as monotherapy based on TMB-H status in tumor specimens.

Since subclonal dMMR mutations and microsatellite instability may develop in high-grade gliomas during temozolomide therapy, testing for TMB-H, MSI-H, and dMMR is recommended in primary tumor specimens obtained prior to initiation of temozolomide chemotherapy in patients with high-grade gliomas.

Patient selection for combination therapy

Patients are selected for treatment with KEYTRUDA® in combination with chemotherapy and trastuzumab based on positive PD-L1 expression (CPS ≥1) in locally advanced unresectable or metastatic HER2-positive gastric adenocarcinoma or gastroesophageal junction (GEJ) adenocarcinoma.

Patients are selected for treatment with KEYTRUDA® in combination with chemotherapy, with or without bevacizumab, based on positive PD-L1 expression in persistent, recurrent, or metastatic cervical cancer.

Patient selection for treatment with KEYTRUDA® in combination with chemotherapy is based on positive PD-L1 expression in:

• locally recurrent unresectable or metastatic TNBC.

Recommended Doses

Table 1. Recommended Doses

* 30-minute intravenous infusion

† Refer to the prescribing information for the combination drugs for recommended dosing information, if necessary.

‡ When axitinib is used in combination with KEYTRUDA, dose escalation of axitinib above the initial dose of 5 mg may be considered at intervals of six weeks or longer.

§ Patients who experience disease progression or unacceptable toxicity related to KEYTRUDA during neoadjuvant therapy in combination with chemotherapy should not receive adjuvant monotherapy with KEYTRUDA.

Dose modifications

Dose reduction of KEYTRUDA is not recommended. In general, administration of KEYTRUDA should be withheld in cases of severe (Grade 3) immune-mediated adverse reactions. Discontinue KEYTRUDA permanently in cases of life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions requiring systemic immunosuppressive therapy, or inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks after initiating steroid therapy.

Dose modifications for KEYTRUDA in the event of adverse reactions requiring management different from these general recommendations are summarized in Table 2.

Table 2. Recommended dose modifications for adverse reactions

* Based on the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0

† Resumption of drug administration in patients with complete or partial normalization of condition (grade 0 to 1) after corticosteroid tapering. Permanently discontinue therapy if there is no complete or partial resolution or inability to reduce prednisone dose to 10 mg per day or less (or equivalent) within 12 weeks after initiation of steroid treatment.

‡ If AST and ALT are less than or equal to ULN at baseline, discontinue or permanently discontinue administration of KEYTRUDA® based on hepatitis recommendations in the absence of liver involvement.

ALT – alanine aminotransferase, AST – aspartate aminotransferase, DRESS – drug reaction with eosinophilia and systemic symptoms, SJS – Stevens-Johnson syndrome, TEN – toxic epidermal necrolysis, ULN – upper limit of normal

Table 3 presents dosage modifications that differ from those described above for KEYTRUDA® or from the prescribing information for the drug administered in combination.

Table 3. Recommendations for dose modification in the event of adverse reactions associated with combination therapy including KEYTRUDA®

* Consider corticosteroid therapy

† Based on the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.

Consider re-administration of a single agent or sequential re-administration of both agents after recovery. If retreatment with axitinib is undertaken, dose reduction should be considered according to axitinib dosing guidelines.

ALT – alanine aminotransferase, AST – aspartate aminotransferase, ULN – upper limit of normal

Preparation for intravenous infusion

• Visually inspect the concentrate for infusion solution for particulate matter and discoloration. The solution should be from clear to slightly opalescent and colorless to pale yellow. Discard the vial if visible particles are present.
• Dilute the Ketruda® concentrate solution prior to intravenous administration.
• Withdraw the required volume (see section "Administration and dosage") of Ketruda® from the vial and transfer it into an intravenous infusion bag or vial containing 0.9% sodium chloride injection or 5% dextrose injection. Mix the diluted solution gently by inverting the bag (or vial). Do not shake. The final concentration of the diluted solution should be between 1 mg/mL and 10 mg/mL.
• Destroy any unused portion remaining in the vial.

Any unused product or waste material should be disposed of in accordance with local requirements.

Storage of diluted solution

The product does not contain a preservative.

Store the diluted Ketruda® 100 mg/4 mL solution in the vial:

• At room temperature for no more than 6 hours from the time of dilution. This time includes storage at room temperature and the duration of infusion.
• In a refrigerator at 2–8°C for no more than 96 hours from the time of dilution.

If the solution has been refrigerated, allow it to reach room temperature before administration. Do not shake.

Discard after 6 hours at room temperature or after 96 hours under refrigeration. Do not freeze.

Administration method

• Administer the diluted solution intravenously over 30 minutes using an infusion set containing a sterile, pyrogen-free, low protein-binding, in-line or add-on filter with a pore size of 0.2 to 5 microns.
• Do not administer other medicinal products simultaneously through the same infusion set.

Elderly patients

Among 3,781 patients with melanoma, NSCLC, HNSCC, or urothelial carcinoma who received Ketruda® in clinical trials, 48% were aged 65 years and older, and 17% were aged 75 years and older. Overall, no differences in safety or efficacy were observed between elderly patients and younger patients.

Among 389 adult patients with cHL who received Ketruda® in clinical trials, 46 (12%) were aged 65 years and older. In patients aged 65 years and older, the incidence of serious adverse reactions was higher (50%) compared to patients under 65 years of age (24%). The clinical trials of Ketruda® in cHL did not include a sufficient number of patients aged 65 years and older to determine whether their response differs from younger patients.

Among 506 adult patients with stage IB (T2a ≥ 4 cm), II, or IIIA NSCLC following complete resection and platinum-based chemotherapy who received Ketruda® in the KEYNOTE-091 trial, 242 (48%) were aged 65 years and older. Overall, no differences in safety or efficacy outcomes were observed between elderly and younger patients.

Among 596 adult patients with TNBC who received Ketruda® in combination with paclitaxel, protein-bound paclitaxel, or gemcitabine and carboplatin in the KEYNOTE-355 trial, 137 (23%) were aged 65 years and older. Overall, no differences in safety or efficacy were observed between elderly and younger patients.

Among 564 patients with locally advanced or metastatic urothelial cancer who received Ketruda® in combination with enfortumab vedotin, 44% (n = 247) were aged 65–74 years and 26% (n = 144) were aged 75 years and older. No overall differences in safety or efficacy were observed between patients aged 65 years and older and younger patients. However, in patients aged 75 years and older receiving Ketruda® in combination with enfortumab vedotin, a higher frequency of fatal adverse reactions was observed compared to younger patients. The incidence of fatal adverse reactions was 4% in patients under 75 years of age and 7% in patients aged 75 years and older.

Among 432 patients randomized to receive Ketruda® in combination with axitinib in the KEYNOTE-426 trial, 40% were aged 65 years and older. No overall differences in safety or efficacy were reported between patients aged ≥65 years and younger patients.

Among 292 adult patients with FIGO 2014 stage III–IVA cervical cancer who received Ketruda® in combination with chemoradiotherapy (CRT) in the KEYNOTE-A18 trial, 42 (14%) were aged 65 years and older. No overall differences in safety or efficacy were observed between elderly and younger patients.

Pediatric population

The safety and efficacy of Ketruda® as monotherapy have been established in pediatric patients with melanoma, cHL, PMBCL, MCC, MSI-H or dMMR tumors, and TMB-H cancer. The use of Ketruda® in pediatric patients for these indications is supported by adequate and well-controlled studies in adults, supplemented by pharmacokinetic and safety data in pediatric patients (see sections "Adverse Reactions" and "Pharmacological Properties").

In the KEYNOTE-051 trial, 173 pediatric patients (65 children aged 6 months to 12 years and 108 adolescents aged 12 to 17 years) with advanced melanoma, lymphoma, or PD-L1-positive solid tumors received Ketruda® at a dose of 2 mg/kg every 3 weeks. The median duration of treatment was 2.1 months (range: 1 day to 25 months). Adverse reactions observed in pediatric patients at a frequency ≥10% higher than in adults included pyrexia (33%), vomiting (29%), headache (25%), abdominal pain (23%), lymphopenia (13%), and leukopenia (11%). Laboratory abnormalities observed in pediatric patients at a frequency ≥10% higher than in adults included leukopenia (31%), neutropenia (28%), thrombocytopenia (22%), and grade 3 anemia (17%).

The safety and efficacy of Ketruda® in pediatric patients for other approved indications have not been established (see section "Indications").

Overdose

There is no information on pembroli­zumab overdose.

In the event of overdose, patients should be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment should be initiated.

Adverse Reactions

Because clinical trials are conducted under varying conditions, the incidence rates of adverse reactions observed in one clinical trial cannot be directly compared to those in other trials and may not reflect the rates observed in clinical practice.

The data in the "Use in Specific Populations" section include information on exposure to KEYTRUDA® administered as monotherapy to 2799 patients in three randomized, open-label, active-controlled clinical trials (KEYNOTE-002, KEYNOTE-006, and KEYNOTE-010), of whom 912 had melanoma and 682 had NSCLC, as well as in one single-arm trial (KEYNOTE-001), in which 655 patients had melanoma and 550 had NSCLC.

In addition to these data from 2799 patients, certain subsections of the "Use in Specific Populations" section describe adverse reactions observed with KEYTRUDA® monotherapy in a non-randomized, open-label, multicohort trial (KEYNOTE-012), in a non-randomized, open-label, single-cohort trial (KEYNOTE-055), and in two randomized, open-label, active-controlled trials (monotherapy arms of KEYNOTE-040 and KEYNOTE-048), which included 909 patients with HNSCC; in two non-randomized, open-label trials (KEYNOTE-013 and KEYNOTE-087) and one randomized, open-label, active-controlled clinical trial (KEYNOTE-204) involving 389 patients with cHL; in a randomized, open-label, active-controlled trial (combination therapy arm of KEYNOTE-048) involving 276 patients with HNSCC; in combination with axitinib in a randomized, active-controlled trial (KEYNOTE-426) involving 429 patients with RCC; and during postmarketing use.

In all trials, KEYTRUDA® was administered at doses of 2 mg/kg intravenously every 3 weeks, 10 mg/kg intravenously every 2 weeks, 10 mg/kg intravenously every 3 weeks, or 200 mg intravenously every 3 weeks. Forty-one percent (41%) of the 2799 patients received the drug for 6 months or longer, and 21% received it for 12 months or longer.

Melanoma

Melanoma previously untreated with ipilimumab

The safety of KEYTRUDA® in patients with unresectable or metastatic melanoma who had not previously received ipilimumab and who had received no more than one prior systemic therapy was evaluated in KEYNOTE-006. KEYNOTE-006 was a multicenter, open-label, active-controlled trial in which patients were randomized (1:1:1) to receive KEYTRUDA® at a dose of 10 mg/kg every 2 weeks (n = 278) or every 3 weeks (n = 277) until disease progression or unacceptable toxicity, or to receive ipilimumab at a dose of 3 mg/kg every 3 weeks for up to 4 doses unless discontinued earlier due to disease progression or unacceptable toxicity (n = 256). Patients with autoimmune disease, conditions requiring systemic corticosteroids or other immunosuppressants, a history of interstitial lung disease, or active infection requiring treatment, including HIV or hepatitis B or C, were excluded from the trials.

The median duration of exposure to KEYTRUDA® was 5.6 months (range: 1 day to 11.0 months) and was similar in both treatment groups. Fifty-one percent (51%) and 46% of patients in the every-2-week and every-3-week dosing groups, respectively, received KEYTRUDA® for ≥ 6 months. No patient received treatment beyond 1 year.

Study participants had the following characteristics: median age 62 years (range: 18 to 89); 60% male; 98% White; 32% had elevated baseline lactate dehydrogenase (LDH); 65% had M1c stage disease; 9% had a history of brain metastases; approximately 36% of patients had previously received systemic therapy, including BRAF inhibitors (15%), chemotherapy (13%), and immunotherapy (6%).

In KEYNOTE-006, the adverse reaction profile was similar between the every-2-week and every-3-week dosing regimens; therefore, safety findings are presented in a pooled analysis (n = 555) of both KEYTRUDA® treatment groups. Adverse reactions leading to permanent discontinuation of KEYTRUDA® occurred in 9% of patients. The adverse reactions leading to permanent discontinuation in more than one patient were: colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and heart failure (0.4%). Adverse reactions leading to interruption of KEYTRUDA® occurred in 21% of patients; the most frequent reaction (≥ 1%) was diarrhea (2.5%).

Tables 4 and 5 summarize individual adverse reactions and laboratory abnormalities, respectively, observed in patients receiving KEYTRUDA® in KEYNOTE-006.

Table 4. Individual* adverse reactions occurring in ≥ 10% of patients receiving KEYTRUDA® in KEYNOTE-006

* Adverse reactions that occurred with equal or higher frequency compared to the ipilimumab group

† Grades according to NCI CTCAE v4.0

‡ Includes rash, erythematous rash, follicular rash, generalized rash, macular rash, maculopapular rash, papular rash, pruritic rash, exfoliative rash

§ Includes hypopigmentation of the skin

Other clinically important adverse reactions occurring in ≥ 10% of patients receiving KTRUDA®: diarrhea (26%), nausea (21%), and pruritus (17%).

Table 5. Individual* laboratory abnormalities from baseline occurring in ≥ 20% of patients with melanoma treated with KTRUDA® in KEYNOTE-006

*Adverse reactions that occurred at the same or higher frequency compared to the ipilimumab group

† Frequency is based on the number of patients with baseline test results and at least one result during the study: Keytruda® (range: 520 to 546 patients) and ipilimumab (range: 237 to 247 patients); hypertriglyceridemia: Keytruda® n = 429 and ipilimumab n = 183; hypercholesterolemia: Keytruda® n = 484 and ipilimumab n = 205.

‡ Grades according to NCI CTCAE v4.0

Other laboratory test abnormalities observed in ≥ 20% of patients treated with Keytruda®: worsening of hypoalbuminemia (27% all grades; 2.4% grades 3–4), increased ALT levels (23% all grades; 3.1% grades 3–4), and increased alkaline phosphatase levels (21% all grades; 2% grades 3–4).

Ipilimumab-refractory melanoma

The safety of Keytruda® in patients with unresectable or metastatic melanoma who had disease progression after treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor, was evaluated in KEYNOTE-002. KEYNOTE-002 was a multicenter, partially blinded (to Keytruda® dose), randomized (1:1:1), active-controlled study involving 528 patients who received Keytruda® at a dose of 2 mg/kg (n = 178) or 10 mg/kg (n = 179) every 3 weeks or investigator’s choice chemotherapy (n = 171), which included dacarbazine (26%), temozolomide (25%), paclitaxel and carboplatin (25%), paclitaxel (16%), and carboplatin (8%). Patients with autoimmune disease, severe immune-mediated toxicity associated with prior ipilimumab use defined as grade 4 toxicity or grade 3 toxicity requiring corticosteroids (more than 10 mg/day of prednisone or equivalent) for more than 12 weeks, medical conditions requiring systemic corticosteroids or other immunosuppressants, a history of interstitial lung disease, or active infection requiring treatment, including HIV or hepatitis B or C, were excluded from the study.

The median duration of exposure to Keytruda® at a dose of 2 mg/kg every 3 weeks was 3.7 months (range: 1 to 16.6 months), and at a dose of 10 mg/kg every 3 weeks was 4.8 months (range: 1 to 16.8 months). Keytruda® at a dose of 2 mg/kg was received by 36% of patients for ≥ 6 months and 4% for ≥ 12 months. In the 10 mg/kg Keytruda® group, 41% of patients received the drug for ≥ 6 months and 6% for ≥ 12 months.

Study participants had the following characteristics: median age 62 years (range: 15 to 89); 61% male; 98% Caucasian; 41% had elevated baseline lactate dehydrogenase (LDH) levels; 83% had stage M1c disease; approximately 73% of patients had received two or more prior systemic therapies for progressive disease or metastases (100% had received ipilimumab and 25% a BRAF inhibitor), and 15% had a history of brain metastases.

In KEYNOTE-002, the safety profile was similar for the 2 mg/kg and 10 mg/kg doses; therefore, safety findings are presented in a combined analysis (n = 357) of both Keytruda® treatment groups.

Adverse reactions leading to complete discontinuation of Keytruda® occurred in 12% of patients. The most frequent reactions (≥ 1%) were deterioration in general health status (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). Adverse reactions leading to treatment interruption occurred in 14% of patients; the most frequent (≥ 1%) were dyspnea (1%), diarrhea (1%), and maculopapular rash (1%).

Tables 6 and 7 summarize adverse reactions and laboratory abnormalities, respectively, observed in patients treated with Keytruda® in KEYNOTE-002.

Table 6. Individual* adverse reactions occurring in ≥ 10% of patients receiving Keytruda® in KEYNOTE-002

* Adverse reactions occurring at the same or higher frequency compared to the chemotherapy group

† Chemotherapy: dacarbazine, temozolomide, carboplatin plus paclitaxel, or carboplatin

‡ Grades according to NCI CTCAE v4.0

§ Includes rash, erythematous rash, generalized rash, macular rash, maculopapular rash, papular rash, pruritic rash

Other clinically important adverse reactions occurring in patients treated with Keytruda®: fatigue (43%), nausea (22%), decreased appetite (20%), vomiting (13%), and peripheral neuropathy (1.7%).

Table 7. Individual* laboratory abnormalities from baseline occurring in ≥ 20% of patients with melanoma treated with Keytruda® in KEYNOTE-002

* Adverse reactions that occurred with equal or greater frequency compared to the chemotherapy group

† Frequency is based on the number of patients with baseline test results and at least one result during the study: KEYTRUDA® (range: 320 to 325 patients) and chemotherapy (range: 154 to 161 patients); hypertriglyceridemia: KEYTRUDA® n = 247 and chemotherapy n = 116; decreased bicarbonate levels: KEYTRUDA® n = 263 and chemotherapy n = 123.

‡ Grades according to NCI CTCAE v4.0

Other laboratory test abnormalities observed in ≥ 20% of patients treated with KEYTRUDA®: anemia (44% all grades; 10% grades 3–4), lymphopenia (40% all grades; 9% grades 3–4).

Adjuvant therapy of stage IIB or IIC melanoma after resection

In 969 patients with stage IIB or IIC melanoma enrolled in the KEYNOTE-716 study who received KEYTRUDA®, the median duration of exposure to KEYTRUDA® was 9.9 months (range: 0 to 15.4 months). Patients with autoimmune disease or medical conditions requiring immunosuppression, or mucosal or ocular melanoma, were not included. Adverse reactions observed in patients with stage IIB or IIC melanoma were similar to those observed in 1011 patients with stage III melanoma from the KEYNOTE-054 study or in 2799 patients with melanoma or NSCLC who received KEYTRUDA® as monotherapy.

Adjuvant therapy of stage III melanoma after resection

The safety of KEYTRUDA® as monotherapy was evaluated in a randomized (1:1), double-blind study, KEYNOTE-054, in which 1019 patients with completely resected stage IIIA (lymph node metastases >1 mm), IIIB, or IIIC melanoma received 200 mg of KEYTRUDA® administered as an intravenous infusion every 3 weeks (n = 509) or placebo (n = 502) for up to 1 year. Patients with active autoimmune disease or medical conditions requiring immunosuppression, or mucosal or ocular melanoma, were not included in the study. Seventy-six percent of patients received KEYTRUDA® for 6 months or longer.

Study participants had the following characteristics: median age 54 years (range: 19 to 88); 25% were aged 65 years or older; 62% were male; 94% had ECOG PS 0 and 6% had ECOG PS 1. Sixteen percent had stage IIIA, 46% had stage IIIB, 18% had stage IIIC (positive in 1–3 lymph nodes), and 20% had stage IIIC (positive in ≥4 lymph nodes).

Two patients receiving KEYTRUDA® died from causes other than disease progression; the causes of death were drug reaction with eosinophilia and systemic symptoms and autoimmune myositis with respiratory failure. Serious adverse reactions were observed in 25% of patients receiving KEYTRUDA®. Adverse reactions leading to permanent discontinuation of KEYTRUDA® occurred in 14% of patients receiving KEYTRUDA®; the most frequent (≥1%) were: pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Adverse reactions leading to interruption of KEYTRUDA® administration occurred in 19% of patients; the most frequent reactions (≥1%) were diarrhea (2.4%), pneumonitis (2%), increased ALT (1.4%), arthralgia (1.4%), increased AST (1.4%), dyspnea (1%), and fatigue (1%).

Tables 8 and 9 summarize the adverse reactions and laboratory abnormalities, respectively, observed in patients receiving KEYTRUDA® in KEYNOTE-054.

Table 8. Individual* adverse reactions occurring in ≥10% of patients receiving KEYTRUDA® in KEYNOTE-054

* Adverse reactions that occurred at an equal or higher frequency compared to the placebo group

† Grading according to NCI CTCAE v4.03

Table 9. Individual* laboratory abnormalities from baseline occurring in ≥ 20% of melanoma patients treated with KEYTRUDA® in KEYNOTE-054

* Laboratory abnormalities occurring at the same or higher frequency compared to the placebo group

† Frequency is based on the number of patients with baseline test results and at least one on-study result: KEYTRUDA® (range: 503 to 507 patients) and placebo (range: 492 to 498 patients).

‡ Grades according to NCI CTCAE v4.03

NSCLC

First-line treatment of metastatic non-squamous NSCLC in combination with pemetrexed and a platinum agent

The safety of KEYTRUDA® in combination with pemetrexed and a platinum agent (either carboplatin or cisplatin) was evaluated in KEYNOTE-189, a multicenter, double-blind, randomized (2:1), active-controlled study involving patients with previously untreated metastatic non-squamous NSCLC whose tumors lacked genomic aberrations in EGFR or ALK. A total of 607 patients received KEYTRUDA® 200 mg, pemetrexed, and a platinum agent every 3 weeks for 4 cycles, followed by KEYTRUDA® and pemetrexed (n = 405), or placebo, pemetrexed, and a platinum agent every 3 weeks for 4 cycles, followed by placebo and pemetrexed (n = 202). Patients with autoimmune disease requiring systemic therapy within 2 years prior to initiation of treatment in this study, patients with medical conditions requiring immunosuppressive therapy, or patients who received more than 30 Gy of thoracic radiation within the previous 26 weeks were excluded from the study.

The median duration of treatment with KEYTRUDA® 200 mg every 3 weeks was 7.2 months (range: 1 day to 20.1 months). In the KEYTRUDA® group, 60% of patients received KEYTRUDA® for ≥ 6 months. Carboplatin was administered to 72% of patients.

Study participants had the following characteristics: median age 64 years (range: 34 to 84); 49% were aged 65 years and older; 59% were male; 94% were White, and 3% were Asian; 18% had a history of brain metastases.

Treatment with KEYTRUDA® was discontinued due to adverse reactions in 20% of patients. The most frequent adverse reactions leading to permanent discontinuation of KEYTRUDA® were pneumonitis (3%) and acute kidney injury (2%). Adverse reactions leading to interruption of KEYTRUDA® occurred in 53% of patients; the most frequent adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA® (≥ 2% of patients) were neutropenia (13%), asthenia/fatigue (7%), anemia (7%), thrombocytopenia (5%), diarrhea (4%), pneumonia (4%), increased blood creatinine (3%), dyspnea (2%), febrile neutropenia (2%), upper respiratory tract infection (2%), increased alanine aminotransferase (ALT) (2%), and pyrexia (2%).

Tables 10 and 11 summarize the adverse reactions and laboratory abnormalities observed in patients receiving KEYTRUDA® in KEYNOTE-189, respectively.

Table 10. Adverse reactions occurring in ≥ 20% of patients in KEYNOTE-189

* Severity grading based on NCI CTCAE criteria, v4.03

† Includes asthenia and fatigue

‡ Includes genital rash, rash, generalized rash, macular rash, maculopapular rash, papular rash, pruritic rash, and pustular rash

Table 11. Laboratory abnormalities compared to baseline occurring in ≥ 20% of patients in KEYNOTE-189

* Frequency is based on the number of patients with baseline and at least one on-study test result: Keytruda®/pemetrexed/platinum agent (range: 381 to 401 patients) and placebo/pemetrexed/platinum agent (range: 184 to 197 patients).

† Grading according to NCI CTCAE v4.03

First-line treatment of metastatic squamous NSCLC with chemotherapy using carboplatin and paclitaxel or protein-bound paclitaxel

The safety of Keytruda® in combination with carboplatin and paclitaxel or protein-bound paclitaxel, at the investigator’s choice, was evaluated in KEYNOTE-407, a multicenter, double-blind, randomized (1:1), placebo-controlled trial involving 558 patients with previously untreated metastatic squamous NSCLC. Safety data were available for the first 203 patients who received Keytruda® plus chemotherapy (n = 101) or placebo plus chemotherapy (n = 102).

Patients were excluded from the study if they had autoimmune disease requiring systemic therapy within the preceding 2 years; had a condition requiring immunosuppressive therapy; or had received thoracic radiation with doses exceeding 30 Gy within the prior 26 weeks.

The median duration of Keytruda® treatment was 7 months (range: 1 day to 12 months). In the Keytruda® treatment group, 61% of patients received Keytruda® for ≥ 6 months. Overall, 139 of 203 patients (68%) received paclitaxel and 64 patients (32%) received protein-bound paclitaxel, both in combination with carboplatin.

Study participants had the following characteristics: median age 65 years (range: 40 to 83); 52% were aged 65 years or older; 78% were male; 83% were White, and 9% had a history of brain metastases.

Keytruda® was discontinued due to adverse reactions in 15% of patients, with no single type of adverse reaction reported in the majority of patients. Adverse reactions leading to interruption of Keytruda® occurred in 43% of patients; the most frequent (≥ 2%) were thrombocytopenia (20%), neutropenia (11%), anemia (6%), asthenia (2%), and diarrhea (2%). The most common (≥ 2%) serious adverse reactions were febrile neutropenia (6%), pneumonia (6%), and urinary tract infection (3%).

Adverse reactions observed in the KEYNOTE-407 trial were similar to those documented in KEYNOTE-189, except that in KEYNOTE-407, the Keytruda® plus chemotherapy group had higher incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) compared to the placebo plus chemotherapy group.

Previously untreated NSCLC

The safety of Keytruda® was investigated in KEYNOTE-042, a multicenter, open-label, randomized (1:1), active-controlled trial involving 1251 patients with PD-L1 expressing, previously untreated stage III NSCLC not amenable to surgical resection or definitive chemoradiation, or metastatic NSCLC. Patients received 200 mg of Keytruda® every 3 weeks (n = 636) or investigator’s choice chemotherapy (n = 615), consisting of pemetrexed and carboplatin followed by optional pemetrexed (n = 312) or paclitaxel and carboplatin followed by optional pemetrexed (n = 303), administered once every 3 weeks. Patients with EGFR or ALK gene mutations; autoimmune disease requiring systemic therapy within 2 years of treatment initiation; medical conditions requiring immunosuppression; or who received more than 30 Gy of thoracic radiation within the prior 26 weeks were excluded from the study.

The median duration of Keytruda® exposure was 5.6 months (range: 1 day to 27.3 months). Forty-eight percent of patients in the Keytruda® 200 mg group received the drug for ≥ 6 months.

Study participants had the following characteristics: median age 63 years (range: 25 to 90); 45% were aged 65 years or older; 71% were male; 64% were White, 30% were Asian, and 2% were Black. Nineteen percent were of Hispanic or Latino ethnicity.

Eighty-seven percent had metastatic disease (Stage IV), 13% had Stage III disease (2% Stage IIIA and 11% Stage IIIB), and 5% had brain metastases at baseline.

Keytruda® was discontinued due to adverse reactions in 19% of patients. The most frequent adverse reactions leading to permanent discontinuation of Keytruda® were pneumonitis (3.0%), death from unknown causes (1.6%), and pneumonia (1.4%). Adverse reactions leading to interruption of Keytruda® occurred in 33% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption (≥ 2%) were pneumonitis (3.1%), pneumonia (3.0%), hypothyroidism (2.2%), and increased ALT (2.0%). The most common (≥ 2%) serious adverse reactions were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%).

Tables 12 and 13 summarize adverse reactions and laboratory abnormalities, respectively, observed in patients receiving Keytruda® in KEYNOTE-042.

Table 12. Adverse reactions occurring in ≥ 10% of patients in KEYNOTE-042

* Grades according to NCI CTCAE v4.03

† Includes fatigue and asthenia

‡ Includes rash, generalized rash, macular rash, maculopapular rash, papular rash, pruritic rash, and pustular rash

Table 13. Laboratory abnormalities occurring in ≥ 20% of patients in KEYNOTE-042 compared with baseline

* Frequency is based on the number of patients with baseline test results and at least 1 post-baseline result during the study: KEYTRUDA® (range: 598 to 610 patients) and chemotherapy (range: 588 to 597 patients); elevated INR: KEYTRUDA® n = 203 and chemotherapy n = 173.

† Grading according to NCI CTCAE v4.03

Patients previously treated for NSCLC

The safety of KEYTRUDA® was evaluated in KEYNOTE-010 (a multicenter, open-label, randomized [1:1:1] controlled trial) in patients with metastatic NSCLC who had disease progression on or after platinum-containing chemotherapy and, if EGFR or ALK positive genetic aberration, had received prior therapy targeted at such aberrations. A total of 991 patients received KEYTRUDA® at a dose of 2 mg/kg (n = 339) or 10 mg/kg (n = 343) every 3 weeks, or docetaxel (n = 309) at a dose of 75 mg/m² every 3 weeks.

Patients with autoimmune disease, medical conditions requiring systemic corticosteroids or other immunosuppressants, or patients who had received more than 30 Gy of thoracic radiation within the previous 26 weeks were excluded from the study.

The median duration of treatment with KEYTRUDA® at a dose of 2 mg/kg every 3 weeks was 3.5 months (range: 1 day to 22.4 months), and at a dose of 10 mg/kg every 3 weeks was 3.5 months (range: 1 day to 20.8 months).

The data presented below reflect exposure to KEYTRUDA® at a dose of 2 mg/kg in 31% of patients who received the drug for ≥ 6 months. In the group receiving KEYTRUDA® at 10 mg/kg, 34% of patients received the drug for ≥ 6 months.

Study participants had the following characteristics: median age of 63 years (range: 20 to 88 years); 42% were aged 65 years or older; 61% were male; 72% were Caucasian; 21% were of Asian descent; 8% had locally advanced disease; 91% had metastatic disease; and 15% had a history of brain metastases. Twenty-nine percent had received two or more prior regimens for advanced or metastatic disease.

In the KEYNOTE-010 study, the safety profile was similar with the 2 mg/kg and 10 mg/kg doses; therefore, safety results are presented in a combined analysis (n = 682). Treatment was discontinued due to adverse reactions in 8% of patients. The most frequent adverse reaction leading to complete discontinuation of KEYTRUDA® was pneumonitis (1.8%). Adverse reactions leading to interruption of KEYTRUDA® occurred in 23% of patients; the most common (≥ 1%) were: diarrhea (1%), fatigue (1.3%), pneumonitis (1%), increased liver enzymes (1.2%), decreased appetite (1.3%), and pneumonitis (1%).

Tables 14 and 15 summarize the adverse reactions and laboratory abnormalities, respectively, observed in patients treated with KEYTRUDA® in KEYNOTE-010.

Table 14. Individual* adverse reactions occurring in ≥ 10% of patients receiving KEYTRUDA® in KEYNOTE-010

* Adverse reactions occurring at the same or higher frequency compared to the docetaxel group

† Grades according to NCI CTCAE v4.0

‡ Includes rash, erythematous rash, macular rash, maculopapular rash, papular rash, pruritic rash

Other clinically important adverse reactions occurring in patients receiving KTRUDA®: fatigue (25%), diarrhea (14%), asthenia (11%), and pyrexia (11%).

Table 15. Individual* laboratory abnormalities from baseline occurring in ≥ 20% of NSCLC patients treated with KTRUDA® in KEYNOTE-010

*Adverse reactions that occurred at the same or higher frequency compared to the docetaxel group.

† Frequency is based on the number of patients who had baseline test results and at least one result during the study: Keytruda® (range: 631 to 638 patients) and docetaxel (range: 274 to 277 patients).

‡ Grades according to NCI CTCAE v4.0

Other laboratory abnormalities observed in ≥ 20% of patients treated with Keytruda®: hyperglycemia (44% all grades; 4.1% grades 3–4), anemia (37% all grades; 3.8% grades 3–4), hypertriglyceridemia (36% all grades; 1.8% grades 3–4), lymphopenia (35% all grades; 9% grades 3–4), hypoalbuminemia (34% all grades; 1.6% grades 3–4), and hypercholesterolemia (20% all grades; 0.7% grades 3–4).

Neoadjuvant and adjuvant therapy in resectable NSCLC

The safety of Keytruda® in combination with neoadjuvant platinum-based chemotherapy followed by surgical intervention and continuation of adjuvant monotherapy with Keytruda® after surgery was evaluated in a multicenter, randomized (1:1), double-blind, placebo-controlled trial, KEYNOTE-671, in patients with previously untreated, resectable NSCLC stage II, IIIA, or IIIB (N2) according to AJCC 8th edition classification. Patients with autoimmune disease requiring systemic therapy within 2 years of treatment or with medical conditions requiring immunosuppression were excluded from the study.

The median duration of exposure to Keytruda® 200 mg every 3 weeks was 10.9 months (range: 1 day to 18.6 months). Characteristics of the study population: median age 64 years (range: 26 to 83 years), 45% were aged 65 years and older, 7% were aged 75 years and older, 71% were male, 61% were White, 31% were Asian, 2% were Black, 4% race not specified, 9% were of Hispanic or Latino ethnicity.

Adverse reactions observed in patients with resectable NSCLC who received Keytruda® in combination with platinum-based chemotherapy as neoadjuvant therapy followed by continuation of Keytruda® as adjuvant monotherapy were generally similar to those observed in other clinical trials of patients with various tumor types receiving Keytruda® in combination with chemotherapy.

Neoadjuvant phase of KEYNOTE-671 study

Overall, 396 patients received at least one dose of Keytruda® in combination with platinum-based chemotherapy as neoadjuvant therapy, and 399 patients received at least one dose of placebo in combination with platinum-based chemotherapy as neoadjuvant therapy.

Serious adverse reactions were observed in 34% of patients receiving Keytruda® in combination with platinum-based chemotherapy as neoadjuvant therapy; the most frequent (≥ 2%) serious adverse reactions were pneumonia (4.8%), venous thromboembolism (3.3%), and anemia (2%). Fatal adverse reactions occurred in 1.3% of patients, including death from unknown cause (0.8%), sepsis (0.3%), and immune-mediated lung disease (0.3%).

Complete discontinuation of any study drug due to an adverse reaction was reported in 18% of patients receiving Keytruda® in combination with platinum-based chemotherapy as neoadjuvant therapy; the most frequent (≥ 1%) adverse reactions leading to complete discontinuation of any study drug were acute kidney injury (1.8%), interstitial lung disease (1.8%), anemia (1.5%), neutropenia (1.5%), and pneumonia (1.3%).

Among the 396 patients who received neoadjuvant therapy with Keytruda® and the 399 patients who received placebo, surgery was not performed in 6% (n = 25) and 4.3% (n = 17), respectively, due to adverse reactions. The most frequent (≥ 1%) adverse reaction leading to cancellation of surgery in the Keytruda® group was interstitial lung disease (1%).

Among 325 patients who received Keytruda® and underwent surgery, surgery was delayed in 3.1% (n = 10) due to adverse reactions (surgical treatment more than 8 weeks after the last cycle of neoadjuvant therapy if the patient received fewer than 4 cycles of neoadjuvant therapy, or more than 20 weeks after the first dose of neoadjuvant therapy if the patient received 4 cycles of neoadjuvant therapy). Among 317 patients who received placebo and underwent surgery, surgery was delayed in 2.5% (n = 8) due to adverse reactions.

Among 325 patients who received Keytruda® and underwent surgery, 7% (n = 22) did not receive adjuvant therapy due to adverse reactions. Among 317 patients who received placebo, 3.2% (n = 10) did not receive adjuvant therapy due to adverse reactions.

Adjuvant phase of KEYNOTE-671 study

Overall, 290 patients in the Keytruda® group and 267 patients in the placebo group received at least one dose of adjuvant therapy.

Serious adverse reactions occurred in 14% of patients receiving Keytruda® monotherapy as adjuvant therapy; the most frequent serious adverse reaction was pneumonia (3.4%). One fatal adverse reaction occurred due to pulmonary hemorrhage. Adjuvant therapy with Keytruda® was completely discontinued due to an adverse reaction in 12% of patients; the most frequent (≥ 1%) adverse reactions leading to complete discontinuation of adjuvant therapy with Keytruda® were diarrhea (1.7%), interstitial lung disease (1.4%), increased AST levels (1%), and musculoskeletal pain (1%).

Adjuvant therapy in resectable NSCLC

The safety of Keytruda® as monotherapy was evaluated in KEYNOTE-091, a multicenter, randomized (1:1), triple-blind, placebo-controlled trial in patients who underwent complete resection of stage IB (T2a ≥ 4 cm), II, or IIIA NSCLC; adjuvant chemotherapy of up to 4 cycles was optional. Overall, 1161 patients received Keytruda® 200 mg (n = 580) or placebo (n = 581) every 3 weeks. Patients were excluded from the study if they had active autoimmune disease, were on chronic immunosuppressive therapy, or had a history of interstitial lung disease or pneumonitis.

The median duration of Keytruda® treatment was 11.7 months (range: 1 day to 18.9 months). Sixty-eight percent of patients in the Keytruda® group received Keytruda® for ≥ 6 months.

Adverse reactions observed in KEYNOTE-091 were generally similar to those observed in other NSCLC patients receiving Keytruda® as monotherapy, except for hypothyroidism (21%) and hyperthyroidism (11%). Two fatal adverse reactions occurred due to myocarditis.

HNSCC

First-line therapy for metastatic or unresectable, recurrent HNSCC

The safety of Keytruda® as monotherapy and in combination with platinum (cisplatin or carboplatin) and fluorouracil chemotherapy was evaluated in KEYNOTE-048, a multicenter, open-label, randomized (1:1:1) active-controlled trial in patients with previously untreated, recurrent or metastatic HNSCC. Patients with autoimmune disease or medical conditions requiring systemic corticosteroids or other immunosuppressants were excluded from the study. Overall, 576 patients received Keytruda® 200 mg once every 3 weeks as monotherapy (n = 300) or in combination with platinum and 5-FU (n = 276) every 3 weeks for 6 cycles followed by Keytruda® monotherapy, compared to 287 patients who received weekly cetuximab in combination with platinum and 5-FU every 3 weeks for 6 cycles followed by cetuximab.

The median duration of exposure to Keytruda® was 3.5 months (range: 1 day to 24.2 months) in the Keytruda® monotherapy group and 5.8 months (range: 3 days to 24.2 months) in the combination therapy group. Seventeen percent of patients in the Keytruda® monotherapy group and 18% of patients in the combination therapy group received the drug for ≥ 12 months. Fifty-seven percent of patients who received Keytruda® in combination with chemotherapy initiated treatment with carboplatin.

Keytruda® was discontinued due to adverse reactions in 12% of patients in the Keytruda® monotherapy group. The most frequent adverse reactions leading to complete discontinuation of Keytruda® were sepsis (1.7%) and pneumonia (1.3%). Adverse reactions leading to interruption of Keytruda® occurred in 31% of patients; the most common adverse reactions leading to interruption of Keytruda® (≥ 2%) were pneumonia (2.3%), pneumonitis (2.3%), and hyponatremia (2%).

Keytruda® was discontinued due to adverse reactions in 16% of patients in the combination therapy group. The most frequent adverse reactions leading to complete discontinuation of Keytruda® were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). Adverse reactions leading to interruption of Keytruda® occurred in 45% of patients; the most common adverse reactions leading to interruption of Keytruda® were neutropenia (14%), thrombocytopenia (10%), anemia (6%), pneumonia (4.7%), and febrile neutropenia (2.9%).

Tables 16 and 17 summarize the adverse reactions and laboratory abnormalities, respectively, observed in patients treated with Keytruda® in KEYNOTE-048.

Table 16. Adverse reactions occurring in ≥ 10% of patients treated with Keytruda® in KEYNOTE-048

* NCI CTCAE v4.0 grading

† Includes fatigue, asthenia

‡ Includes diarrhea, colitis, hemorrhagic diarrhea, microscopic colitis

§ Includes dermatitis, acneiform dermatitis, allergic dermatitis, bullous dermatitis, contact dermatitis, exfoliative dermatitis, drug eruption, erythema, erythema multiforme, rash, erythematous rash, generalized rash, macular rash, maculopapular rash, pruritic rash, seborrheic dermatitis

¶ Includes cough, productive cough

Includes dyspnea, dyspnea on exertion

Ϸ Includes pneumonia, atypical pneumonia, bacterial pneumonia, staphylococcal pneumonia, aspiration pneumonia, lower respiratory tract infection, pulmonary infection, Pseudomonas pulmonary infection

β Includes peripheral sensory neuropathy, peripheral neuropathy, hypoesthesia, dysesthesia

α Includes back pain, musculoskeletal chest pain, musculoskeletal pain, myalgia

Table 17. Laboratory abnormalities occurring at ≥ 20% in patients treated with KEYTRUDA® in KEYNOTE-048 compared to baseline

* Frequency is based on the number of patients with baseline assessments and at least 1 post-baseline assessment during the study: Pembrolizumab/chemotherapy (range: 235 to 266 patients), Pembrolizumab (range: 241 to 288 patients), Cetuximab/chemotherapy (range: 249 to 282 patients).

† Grading according to NCI CTCAE v4.0

Previously treated recurrent or metastatic HNSCC

In KEYNOTE-012, which included 192 patients with squamous cell carcinoma of the head and neck, the median duration of treatment with Pembrolizumab was 3.3 months (range: 1 day to 27.9 months). Patients with autoimmune diseases or medical conditions requiring immunosuppressive therapy were excluded from KEYNOTE-012.

Study participants had the following characteristics: median age 60 years (range: 20 to 84); 35% were aged 65 years or older; 83% were male; 77% were White; 15% were Asian; 5% were Black. 61% of patients had received two or more prior therapies for recurrent or metastatic disease, and 95% had previously received radiotherapy. Baseline ECOG PS was 0 (30%) or 1 (70%), and 86% had M1 disease stage.

Pembrolizumab was discontinued due to adverse reactions in 17% of patients. Serious adverse reactions occurred in 45% of patients receiving Pembrolizumab. The most common adverse reactions occurring in at least 2% of patients were: pneumonia, dyspnea, confusion, vomiting, pleural effusion, and respiratory failure. The frequency of adverse reactions, including serious adverse reactions, was similar across dose groups (10 mg/kg every 2 weeks or 200 mg every 3 weeks); therefore, safety data are presented in a pooled analysis. The most common adverse reactions (occurring in ≥20% of patients) were fatigue, decreased appetite, and dyspnea.

Adverse reactions observed in patients with HNSCC were generally similar to those seen in 2799 patients with melanoma or NSCLC who received Pembrolizumab as monotherapy, except for a higher frequency of facial swelling (10% of all grades; 2.1% of grades 3–4) and hyperthyroidism or worsening hypothyroidism (see section "Special Warnings and Precautions").

Relapsed or refractory cHL

KEYNOTE-204

The safety of Pembrolizumab was evaluated in KEYNOTE-204. Adults with relapsed or refractory cHL received Pembrolizumab 200 mg intravenously every 3 weeks (n = 148) or brentuximab vedotin (BV) 1.8 mg/kg intravenously every 3 weeks (n = 152). Eligibility criteria included: absolute neutrophil count (ANC) ≥ 1000/μL, platelet count ≥ 75,000/μL, liver transaminases ≤ 2.5 times the upper limit of normal (ULN), bilirubin ≤ 1.5 times ULN, and ECOG performance status of 0 or 1. Patients were excluded if they had active non-infectious pneumonitis, history of steroid-treated pneumonitis, active autoimmune disease, medical condition requiring immunosuppression, or allogeneic HSCT within the past 5 years. The median duration of Pembrolizumab therapy was 10 months (range: 1 day to 2.2 years), with 68% of patients receiving at least 6 months of therapy and 48% receiving at least 1 year of therapy.

Serious adverse reactions occurred in 30% of patients receiving Pembrolizumab. Serious adverse reactions in ≥1% of patients included pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney injury, febrile neutropenia, and sepsis. Three patients (2%) died from causes other than disease progression: two from complications following allogeneic HSCT and one from unknown cause.

Treatment with Pembrolizumab was permanently discontinued due to adverse reactions in 14% of patients; 7% discontinued due to pneumonitis. Treatment was interrupted due to adverse reactions in 30% of patients. Adverse reactions leading to interruption in ≥3% of patients included upper respiratory tract infection, pneumonitis, increased transaminases, and pneumonia.

Thirty-eight percent of patients experienced an adverse reaction requiring systemic corticosteroid therapy.

Table 18 summarizes adverse reactions in KEYNOTE-204.

Table 18. Adverse reactions occurring in ≥10% of patients with cHL treated with Pembrolizumab in KEYNOTE-204

* Grades according to NCI CTCAE v4.0

† Adverse reactions in the BV group were only Grade 3

‡ Includes acute sinusitis, nasopharyngitis, pharyngitis, pharyngotonsillitis, rhinitis, sinusitis, bacterial sinusitis, tonsillitis, upper respiratory tract infection, viral upper respiratory tract infection

§ Includes arthralgia, back pain, bone pain, musculoskeletal discomfort, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, limb pain

¶ Includes diarrhea, gastroenteritis, colitis, enterocolitis

Includes abdominal discomfort, abdominal pain, upper abdominal pain, lower abdominal pain

Þ Includes fatigue, asthenia

β Includes acneiform dermatitis, atopic dermatitis, allergic dermatitis, contact dermatitis, exfoliative dermatitis, psoriasiform dermatitis, eczema, rash, erythematous rash, follicular rash, maculopapular rash, papular rash, pruritic rash, toxic skin rash

à Includes cough, productive cough

è Includes pneumonitis, interstitial lung disease

ð Includes dyspnea, exertional dyspnea, wheezing

ø Includes dysesthesia, hypoesthesia, peripheral neuropathy, paresthesia, peripheral motor neuropathy, peripheral sensory-motor neuropathy, peripheral sensory neuropathy, polyneuropathy

ý Includes headache, migraine, tension headache

Clinically significant adverse reactions occurring in < 10% of patients who received KEYTRUDA® included herpes infection (9%), pneumonia (8%), oropharyngeal pain (8%), hyperthyroidism (5%), hypersensitivity (4.1%), infusion reactions (3.4%), confusion (2.7%), and uveitis, myocarditis, thyroiditis, febrile neutropenia, sepsis, and worsening of tumor symptoms (each occurring in 1.4%).

Table 19 summarizes laboratory abnormalities in KEYNOTE-204.

Table 19. Laboratory abnormalities (≥ 15%) from baseline occurring in patients with cHL in KEYNOTE-204

* Frequency of each test is based on the number of patients with both baseline and at least one on-study laboratory measurement in the KEYTRUDA® study (range: 143 to 148 patients) and BV study (range: 146 to 152 patients); hypomagnesemia: KEYTRUDA® n = 53 and BV n = 50.

† Grading based on NCI CTCAE v4.0

KEYNOTE-087

In the KEYNOTE-087 study, the median duration of therapy with KEYTRUDA® received by 210 patients in total was 8.4 months (range: 1 day to 15.2 months). Serious adverse reactions occurred in 16% of patients receiving KEYTRUDA®. Serious adverse reactions occurring in ≥1% of patients included pneumonia, pneumonitis, pyrexia, dyspnea, graft-versus-host disease (GVHD), and herpes zoster. Two patients died from causes other than disease progression; one due to GVHD following subsequent allogeneic HSCT, and the other due to septic shock.

Discontinuation of KEYTRUDA® due to an adverse reaction occurred in 5% of patients, and interruption due to an adverse reaction occurred in 26%. Fifteen percent of patients had an adverse reaction requiring systemic corticosteroid therapy. Tables 20 and 21 summarize adverse reactions and laboratory abnormalities in KEYNOTE-087, respectively.

Table 20. Adverse Reactions (≥10%) occurring in patients with cHL who received KEYTRUDA® in KEYNOTE-087

* Grades according to NCI CTCAE v4.0

† Includes fatigue, asthenia

‡ Includes cough, productive cough

§ Includes dyspnea, dyspnea on exertion, wheezing

¶ Includes back pain, myalgia, bone pain, musculoskeletal pain, limb pain, chest musculoskeletal pain, musculoskeletal discomfort, neck pain

Includes diarrhea, gastroenteritis, colitis, enterocolitis

Þ Includes rash, maculopapular rash, drug eruption, eczema, asteatotic eczema, dermatitis, acneiform dermatitis, contact dermatitis, erythematous rash, macular rash, papular rash, pruritic rash, seborrheic dermatitis, psoriasiform dermatitis

β Includes peripheral neuropathy, peripheral sensory neuropathy, hypoesthesia, paresthesia, dysesthesia, polyneuropathy

Clinically significant adverse reactions occurring in < 10% of patients treated with KEYTRUDA® included: infusion-related reactions (9%), hyperthyroidism (3%), pneumonitis (3%), uveitis and myositis (each occurring in 1%), as well as myelitis and myocarditis (each occurring in 0.5%).

Table 21. Individual laboratory abnormalities (≥ 15%) compared to baseline values observed in cHL patients treated with KEYTRUDA® in KEYNOTE-087

* Frequency is based on the number of patients with baseline test results and at least 1 result during the study: Keytruda® (range: 208 to 209 patients).

† Grades according to NCI CTCAE v4.0

‡ Includes increased levels of ALT or AST

Hyperbilirubinemia was observed in less than 15% of patients enrolled in the KEYNOTE-087 study (10% all grades, 2.4% grades 3–4).

PMBCL

In the KEYNOTE-170 study of 53 patients with PMBCL, the median duration of treatment with Keytruda® was 3.5 months (range: 1 day to 22.8 months). Serious adverse reactions occurred in 26% of patients. Serious adverse reactions observed in 2% or more patients included: arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), exudative pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of starting treatment.

Discontinuation of Keytruda® due to an adverse reaction occurred in 8% of patients, and treatment interruption occurred in 15%. Twenty-five percent of patients experienced an adverse reaction requiring systemic therapy with corticosteroids.

Tables 22 and 23 summarize adverse reactions and laboratory abnormalities, respectively, occurring in patients treated with Keytruda® in KEYNOTE-170.

Table 22. Adverse reactions (≥ 10%) occurring in PMBCL patients treated with Keytruda® in KEYNOTE-170

* Grades according to NCI CTCAE v4.0

† Includes arthralgia, back pain, myalgia, musculoskeletal pain, limb pain, musculoskeletal chest pain, bone pain, neck pain, non-cardiac chest pain

‡ Includes nasopharyngitis, pharyngitis, rhinorrhea, rhinitis, sinusitis, upper respiratory tract infection

§ Includes fatigue, asthenia

¶ Includes allergic cough, cough, productive cough

Includes diarrhea, gastroenteritis

Þ Includes abdominal pain, upper abdominal pain

β Includes atrial fibrillation, sinus tachycardia, supraventricular tachycardia, tachycardia

Clinically significant adverse reactions occurring in < 10% of patients who received Keytruda® in KEYNOTE-170 included hypothyroidism (8%), hyperthyroidism and pericarditis (each 4%), as well as thyroiditis, pericardial effusion, pneumonitis, arthritis, and acute kidney injury (each 2%).

Table 23. Laboratory abnormalities (≥ 15%) from baseline occurring in PMBCL patients treated with Keytruda® in KEYNOTE-170

* The frequency of abnormalities for each parameter was calculated based on the number of patients who had the corresponding laboratory test performed both at baseline and at least once during the study: the pembrolizumab treatment group (range: 44 to 48 patients).

† Grading according to NCI CTCAE v4.0

‡ Includes increased concentrations of AST or ALT

Urothelial carcinoma

Patients with urothelial carcinoma, in combination with enfortumab vedotin

The safety of pembrolizumab in combination with enfortumab vedotin was evaluated in KEYNOTE-A39 in patients with locally advanced or metastatic urothelial carcinoma. A total of 440 patients received 200 mg of pembrolizumab on Day 1 and 1.25 mg/kg of enfortumab vedotin on Days 1 and 8 of each 21-day cycle, compared with 433 patients who received gemcitabine on Days 1 and 8 and investigator’s choice of cisplatin or carboplatin on Day 1 of each 21-day cycle. In patients receiving pembrolizumab and enfortumab vedotin, the median duration of exposure to pembrolizumab was 8.5 months (range: 9 days to 28.5 months).

Fatal adverse reactions occurred in 3.9% of patients receiving pembrolizumab in combination with enfortumab vedotin, including acute respiratory failure (0.7%), pneumonia (0.5%), and pneumonitis/interstitial lung disease (ILD) (0.2%).

Serious adverse reactions occurred in 50% of patients receiving pembrolizumab in combination with enfortumab vedotin. Serious adverse reactions occurring in ≥ 2% of these patients were rash (6%), acute kidney injury (5%), pneumonitis/ILD (4.5%), urinary tract infection (3.6%), diarrhea (3.2%), pneumonia (2.3%), pyrexia (2%), and hyperglycemia (2%).

Pembrolizumab was discontinued in 27% of patients. The most frequent adverse reactions (≥ 2%) leading to complete discontinuation of pembrolizumab were pneumonitis/ILD (4.8%) and rash (3.4%).

Pembrolizumab was interrupted in 61% of patients. The most frequent adverse reactions (≥ 2%) leading to interruption of pembrolizumab were rash (17%), peripheral neuropathy (7%), COVID-19 (5%), diarrhea (4.3%), pneumonitis/ILD (3.6%), neutropenia (3.4%), fatigue (3%), increased alanine aminotransferase levels (2.7%), hyperglycemia (2.5%), pneumonia (2%), and pruritus (2%).

Tables 24 and 25 summarize adverse reactions and laboratory abnormalities, respectively, that occurred in patients treated with pembrolizumab in combination with enfortumab vedotin in KEYNOTE-A39.

Table 24. Adverse reactions (≥ 20%, all grades) occurring in patients receiving pembrolizumab in combination with enfortumab vedotin in KEYNOTE-A39

* NCI CTCAE v4.03 grades

† Includes multiple terms

Clinically relevant adverse reactions (< 20 %) include pyrexia (18 %), dry skin (17 %), vomiting (12 %), pneumonitis/interstitial lung disease (10 %), hypothyroidism (10 %), blurred vision (6 %), infusion site extravasation (2 %), and myositis (0.5 %).

Table 25. Individual laboratory parameter changes from baseline occurring in ≥ 20 % of patients in KEYNOTE-A39

* The frequency of changes for each parameter is based on the number of patients for whom both baseline and at least one on-study result were available for the KEYTRUDA® study (range: 407 to 439 patients)

† NCI CTCAE v4.03 grades

Patients with urothelial cancer who are not candidates for cisplatin-based therapy, in combination with enfortumab vedotin

The safety of KEYTRUDA® in combination with enfortumab vedotin was evaluated in KEYNOTE-869 in patients with locally advanced or metastatic urothelial cancer who were not candidates for cisplatin-based chemotherapy. Overall, 121 patients received 200 mg of KEYTRUDA® on Day 1 and 1.25 mg/kg of enfortumab vedotin on Day 1 and Day 8 of each 21-day cycle. The median duration of exposure to KEYTRUDA® was 6.9 months (range: 1 day to 29.6 months). Fatal adverse reactions occurred in 5% of patients who received KEYTRUDA® in combination with enfortumab vedotin, including sepsis (1.6%), bullous dermatitis (0.8%), myasthenia gravis (0.8%), and pneumonitis (0.8%). Serious adverse reactions occurred in 50% of patients who received KEYTRUDA® and enfortumab vedotin. Serious adverse reactions in ≥ 2% of patients who received KEYTRUDA® in combination with enfortumab vedotin included acute kidney injury (7%), urinary tract infection (7%), urosepsis (5%), hematuria (3.3%), pneumonia (3.3%), pneumonitis (3.3%), sepsis (3.3%), anemia (2.5%), diarrhea (2.5%), hypotension (2.5%), myasthenia gravis (2.5%), myositis (2.5%), and urinary retention (2.5%). Treatment with KEYTRUDA® was discontinued in 32% of patients. The most frequent adverse reactions (≥ 2%) leading to permanent discontinuation of KEYTRUDA® were pneumonitis (5%), peripheral neuropathy (5%), rash (3.3%), and myasthenia gravis (2.5%). Treatment with KEYTRUDA® was interrupted in 69% of patients. The most frequent adverse reactions (≥ 2%) leading to interruption of KEYTRUDA® were peripheral neuropathy (22%), rash (17%), neutropenia (7%), fatigue (6%), diarrhea (5%), increased lipase (5%), acute kidney injury (3.3%), increased ALT (2.5%), and COVID-19 (2.5%).

Tables 26 and 27 summarize the adverse reactions and laboratory abnormalities, respectively, that occurred in patients receiving KEYTRUDA® in combination with enfortumab vedotin in KEYNOTE-869.

Table 26. Adverse Reactions Occurring in ≥ 20% of Patients Receiving KEYTRUDA® in Combination with Enfortumab Vedotin in KEYNOTE-869

* NCI CTCAE v4.03 grades

† Includes bullae, conjunctivitis, dermatitis, bullous dermatitis, generalized exfoliative dermatitis, erythema, erythema multiforme, exfoliative rash, hand-foot syndrome, pemphigoid, rash, erythematous rash, macular rash, maculopapular rash, papular rash, pruritic rash, bullous rash, skin desquamation, and stomatitis

‡ Includes dysesthesia, hypoesthesia, muscle weakness, paresthesia, peripheral motor neuropathy, peripheral sensory-motor neuropathy, peripheral sensory neuropathy, and gait disturbance

Clinically significant adverse reactions (< 20%) include vomiting (19.8%), pyrexia (18%), hypothyroidism (11%), pneumonitis/interstitial lung disease (10%), myositis (3.3%), myasthenia gravis (2.5%), and infusion site extravasation (0.8%).

Table 27. Individual laboratory abnormalities from baseline occurring in ≥ 20% of patients in KEYNOTE-869

* The frequency of changes in each laboratory parameter is based on the number of patients for whom both baseline and at least one on-study laboratory measurement were available during the study of KEYTRUDA® (range: 114 to 121 patients)

† Grades according to NCI CTCAE v4.03

Patients with urothelial carcinoma ineligible for cisplatin

The safety of KEYTRUDA® was evaluated in KEYNOTE-052, a single-arm trial involving 370 patients with locally advanced or metastatic urothelial carcinoma who were ineligible for cisplatin-containing chemotherapy. Patients with autoimmune disease or conditions requiring systemic corticosteroids or other immunosuppressive therapy were excluded from the study.

Patients received KEYTRUDA® at a dose of 200 mg every 3 weeks until unacceptable toxicity or disease progression (clinically or radiographically) occurred.

The median duration of KEYTRUDA® treatment was 2.8 months (range: 1 day to 15.8 months).

KEYTRUDA® was discontinued due to adverse reactions in 11% of patients. Eighteen patients (5%) died from causes unrelated to disease progression. Sepsis leading to death occurred in five patients (1.4%) receiving KEYTRUDA® treatment, and fatal pneumonia occurred in three patients (0.8%). Adverse reactions leading to interruption of KEYTRUDA® occurred in 22% of patients; the most frequent (≥1%) were: increased liver enzymes, diarrhea, urinary tract infection, acute kidney injury, fatigue, arthralgia, and pneumonia. Serious adverse reactions occurred in 42% of patients. The most frequent serious adverse reactions (≥2%) were: urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis.

Immune-mediated adverse reactions requiring systemic glucocorticoids occurred in 8% of patients; 8% of patients received hormonal therapy due to immune-mediated adverse reactions, and 5% required at least one dose of ≥40 mg of a corticosteroid (prednisone equivalent).

Table 28 summarizes adverse reactions observed in patients treated with KEYTRUDA® in KEYNOTE-052.

Table 28. Adverse reactions occurring in ≥10% of patients receiving KEYTRUDA® in KEYNOTE-052

* Grades according to NCI CTCAE v4.0

† Includes fatigue, asthenia

‡ Includes back pain, bone pain, chest musculoskeletal pain, musculoskeletal pain, myalgia, neck pain, limb pain, spinal pain

§ Includes diarrhea, colitis, enterocolitis, gastroenteritis, frequent bowel movements

¶ Includes abdominal pain, pelvic pain, flank pain, lower abdominal pain, tumor pain, bladder pain, liver pain, suprapubic pain, abdominal discomfort, upper abdominal pain

Includes autoimmune hepatitis, hepatitis, toxic hepatitis, hepatic injury, increased transaminases, hyperbilirubinemia, increased plasma bilirubin, increased ALT, increased AST, increased liver enzyme levels, increased liver function test results

Þ Includes dermatitis, bullous dermatitis, eczema, erythema, rash, macular rash, maculopapular rash, pruritic rash, pustular rash, skin reaction, acneiform dermatitis, seborrheic dermatitis, hand-foot syndrome (hand-foot erythrodysesthesia), generalized rash

β Includes peripheral edema, peripheral swelling

Urothelial carcinoma previously treated

The safety of KEYTRUDA® was evaluated in KEYNOTE-045, a multicenter, open-label, randomized (1:1), active-controlled trial involving 266 patients with locally advanced or metastatic urothelial carcinoma who had received prior platinum-containing chemotherapy. Patients with autoimmune disease or conditions requiring systemic corticosteroids or other immunosuppressants were excluded from the study. The median duration of exposure was 3.5 months (range: 1 day to 20 months) in patients receiving KEYTRUDA® and 1.5 months (range: 1 day to 14 months) in patients receiving chemotherapy.

KEYTRUDA® was discontinued in 8% of patients due to adverse reactions. The most frequent adverse reaction leading to complete discontinuation of KEYTRUDA® was pneumonitis (1.9%). Adverse reactions leading to interruption of KEYTRUDA® occurred in 20% of patients; the most frequent (≥1%) adverse reactions were urinary tract infection (1.5%), diarrhea (1.5%), and colitis (1.1%).

Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA®. The most frequent serious adverse reactions (≥2%) in patients treated with KEYTRUDA® were urinary tract infection, pneumonia, anemia, and pneumonitis.

Tables 29 and 30 summarize adverse reactions and laboratory abnormalities, respectively, observed in patients receiving KEYTRUDA® in KEYNOTE-045.

Table 29. Adverse reactions occurring in ≥10% of patients receiving KEYTRUDA® in KEYNOTE-045

* Chemotherapy: paclitaxel, docetaxel, or vinflunine

† Grades according to NCI CTCAE v4.0

‡ Includes asthenia, fatigue, malaise, lethargy

§ Includes back pain, myalgia, bone pain, musculoskeletal pain, limb pain, chest musculoskeletal pain, musculoskeletal discomfort, neck pain

¶ Includes maculopapular rash, genital rash, erythematous rash, papular rash, pustular rash, erythema, drug eruption, eczema, asteatotic eczema, contact dermatitis, acneiform dermatitis, dermatitis, seborrheic keratosis, lichenoid keratosis

Includes diarrhea, gastroenteritis, colitis, enterocolitis

Þ Includes cough, productive cough

ß Includes dyspnea, dyspnea on exertion, wheezing

à Includes blood in urine, hematuria, chromaturia

Table 30. Laboratory abnormalities compared to baseline occurring in ≥ 20% of patients with urothelial carcinoma treated with KEYTRUDA® in KEYNOTE-045

* Frequency is based on the number of patients who had a baseline test result and at least 1 result during the study: Keytruda® (range: 240 to 248 patients) and chemotherapy (range: 238 to 244 patients); decreased phosphate levels: Keytruda® n = 232 and chemotherapy n = 222.

† Grades according to NCI CTCAE v4.0

High-risk non–muscle-invasive bladder cancer with no response to BCG therapy

The safety of Keytruda® was evaluated in a multicenter, open-label, single-arm trial, KEYNOTE-057, which included 148 patients with high-risk non–muscle-invasive bladder cancer, including 96 patients with carcinoma in situ with or without papillary tumors who had no response to BCG therapy. Patients received Keytruda® at a dose of 200 mg every three weeks until development of unacceptable toxicity, persistent or recurrent high-risk non–muscle-invasive bladder cancer, disease progression, or for up to 24 months in the absence of disease progression.

The median duration of exposure to Keytruda® was 4.3 months (range: 1 day to 25.6 months).

Treatment with Keytruda® was discontinued in 11% of patients due to adverse reactions. The most common adverse reaction (>1%) leading to permanent discontinuation of Keytruda® was pneumonitis (1.4%). Adverse reactions leading to temporary interruption of Keytruda® occurred in 22% of patients; the most frequent (≥2%) were diarrhea (4%) and urinary tract infection (2%). Serious adverse reactions occurred in 28% of patients receiving Keytruda®. The most common serious adverse reactions (≥2%) in patients receiving Keytruda® were pneumonia (3%), ischemic heart disease (2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and urinary tract infection (2%).

Tables 31 and 32 summarize adverse reactions and laboratory abnormalities, respectively, in patients who received Keytruda® in the KEYNOTE-057 trial.

Table 31. Adverse Reactions Occurring in ≥10% of Patients Receiving Keytruda® in KEYNOTE-057

* Grades according to NCI CTCAE v4.03

† Includes asthenia, increased fatigue, malaise

‡ Includes peripheral edema, peripheral swelling

§ Includes diarrhea, gastroenteritis, colitis

¶ Includes maculopapular rash, rash, erythematous rash, pruritic rash, pustular rash, erythema, eczema,asteatotic eczema, lichenoid keratosis, urticaria, dermatitis

Includes back pain, myalgia, musculoskeletal pain, limb pain, musculoskeletal chest pain, neck pain

Þ Includes cough, productive cough

Table 32. Laboratory abnormalities compared to baseline occurring in ≥ 20% of patients with high-risk non-muscle-invasive bladder cancer who did not respond to BCG therapy and received Keytruda® in KEYNOTE-057

* Frequency of each test was determined by the number of patients who had baseline laboratory testing and at least one test during the study: KEYTRUDA® (range: 124 to 147 patients).

† Grading according to NCI CTCAE v4.03

Microsatellite instability-high or mismatch repair deficient cancer

The safety of KEYTRUDA® was evaluated in 504 patients with MSI-H or dMMR cancers enrolled in KEYNOTE-158, KEYNOTE-164, and KEYNOTE-051. The median duration of exposure to KEYTRUDA® was 6.2 months (range: 1 day to 53.5 months). Adverse reactions observed in patients with MSI-H or dMMR cancers were similar to those observed in patients with other solid tumors receiving KEYTRUDA® as monotherapy.

Microsatellite instability-high or mismatch repair deficiency in patients with colorectal cancer

In 153 patients with MSI-H or dMMR CRC enrolled in the KEYNOTE-177 study who received KEYTRUDA®, the median duration of treatment with KEYTRUDA® was 11.1 months (range: 1 day to 30.6 months). Patients with autoimmune disease or medical conditions requiring immunosuppression were excluded from the study. Adverse reactions observed in patients with MSI-H or dMMR CRC were similar to those in 2799 patients with melanoma or NSCLC who received KEYTRUDA® as monotherapy.

Gastric cancer

First-line therapy of locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma

The safety of KEYTRUDA® was evaluated in 433 patients with HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma enrolled in KEYNOTE-811, including 217 patients who received KEYTRUDA® 200 mg, trastuzumab, and either CAPOX (n = 189) or FP (n = 28) every 3 weeks, compared to 216 patients who received placebo, trastuzumab, and either CAPOX (n = 187) or FP (n = 29) every 3 weeks. The median duration of exposure to KEYTRUDA® was 5.8 months (range: 1 day to 17.7 months). Characteristics of the study population: median age 63 years (range: 19 to 84 years), 43% of patients were aged 65 years or older; 81% were male; 58% were White, 35% Asian, and 0.9% Black; 44% had ECOG performance status 0 and 56% had ECOG performance status 1. Treatment with KEYTRUDA® or placebo was discontinued due to adverse reactions in 6% of patients in each group. The most common adverse reaction leading to permanent discontinuation of KEYTRUDA® was pneumonitis (1.4%). Adverse reactions leading to interruption of KEYTRUDA® occurred in 58% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA® (≥ 2%) were neutropenia (18%), thrombocytopenia (12%), diarrhea (6%), anemia (3.7%), hypokalemia (3.7%), fatigue/asthenia (3.2%), decreased appetite (3.2%), increased AST (2.8%), increased blood bilirubin (2.8%), pneumonitis (2.8%), increased ALT (2.3%), and vomiting (2.3%). In the KEYTRUDA® group compared to placebo, there was a ≥ 5% difference in the incidence of diarrhea (53% vs. 44%) and nausea (49% vs. 44%) between patients receiving KEYTRUDA® compared to those receiving standard therapy alone. There were no clinically meaningful differences between groups in the incidence of grade 3–4 toxicity. A ≥ 5% difference in incidence was observed for increased ALT levels (34% vs. 29%) and increased creatinine levels (20% vs. 10%) between patients receiving KEYTRUDA® and those receiving standard therapy. There were no clinically meaningful differences between groups in the incidence of grade 3–4 toxicity.

First-line therapy of locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma

The safety of KEYTRUDA® was evaluated in 1572 patients with HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma enrolled in KEYNOTE-859, including 785 patients who received KEYTRUDA® 200 mg with either FP (n = 106) or CAPOX (n = 674) every 3 weeks, compared to 787 patients who received placebo with either FP (n = 107) or CAPOX (n = 679) every 3 weeks.

The median duration of exposure to KEYTRUDA® was 6.2 months (range: 1 day to 33.7 months).

Serious adverse reactions occurred in 45% of patients receiving KEYTRUDA®. Serious adverse reactions occurring in > 2% of patients included pneumonia (4.1%), diarrhea (3.9%), hemorrhage (3.9%), and vomiting (2.4%). Fatal adverse reactions occurred in 8% of patients receiving KEYTRUDA®, including infection (2.3%) and thromboembolism (1.3%).

Treatment with KEYTRUDA® was permanently discontinued due to adverse reactions in 15% of patients. Adverse reactions leading to permanent discontinuation of KEYTRUDA® in ≥ 1% of patients were infections (1.8%) and diarrhea (1.0%).

Treatment with KEYTRUDA® was interrupted due to adverse reactions in 65% of patients. Adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA® (≥ 2%) included neutropenia (21%), thrombocytopenia (13%), diarrhea (5.5%), fatigue (4.8%), infection (4.8%), anemia (4.5%), increased AST (4.3%), increased ALT (3.8%), increased blood bilirubin (3.3%), decreased white blood cell count (2.2%), nausea (2.0%), palmar-plantar erythrodysesthesia syndrome (2.0%), and vomiting (2.0%).

Tables 33 and 34 summarize the adverse reactions and laboratory abnormalities, respectively, observed in patients treated with KEYTRUDA® in KEYNOTE-859.

Table 33. Adverse reactions occurring in ≥ 20% of patients treated with KEYTRUDA® in KEYNOTE-859

Table 34. Changes in laboratory parameters from baseline occurring in ≥ 20% of patients receiving KEYTRUDA® in KEYNOTE-859

Esophageal cancer

First-line therapy for the treatment of locally advanced unresectable or metastatic esophageal/gastroesophageal junction cancer

The safety of KEYTRUDA® in combination with cisplatin and fluorouracil (FU) chemotherapy was evaluated in KEYNOTE-590. This was a multicenter, double-blind, randomized (1:1), placebo-controlled, first-line trial in patients with metastatic or locally advanced carcinoma of the esophagus or gastroesophageal junction (tumor center located 1–5 cm above the gastroesophageal junction) who were not candidates for surgical resection or definitive chemoradiotherapy. A total of 740 patients received KEYTRUDA® at a dose of 200 mg (n = 370) or placebo (n = 370) every 3 weeks for up to 35 cycles, in combination with cisplatin for up to 6 cycles and FU for up to 35 cycles.

The median duration of exposure to KEYTRUDA® was 5.7 months (range: 1 day to 26 months) in the combination therapy group and 5.1 months (range: 3 days to 27 months) in the chemotherapy group.

Discontinuation of KEYTRUDA® due to adverse reactions occurred in 15% of patients. The most common adverse reactions leading to discontinuation of KEYTRUDA® (≥1%) were pneumonitis (1.6%), acute kidney injury (1.1%), and pneumonia (1.1%). Adverse reactions leading to interruption of KEYTRUDA® occurred in 67% of patients. The most common adverse reactions leading to discontinuation of KEYTRUDA® (≥2%) were neutropenia (19%), fatigue/asthenia (8%), leukopenia (5%), pneumonia (5%), decreased appetite (4.3%), anemia (3.2%), increased blood creatinine (3.2%), stomatitis (3.2%), malaise (3.0%), thrombocytopenia (3%), pneumonitis (2.7%), diarrhea (2.4%), dysphagia (2.2%), and nausea (2.2%).

Tables 35 and 36 summarize the adverse reactions and laboratory abnormalities observed in patients receiving KEYTRUDA® in the KEYNOTE-590 study, respectively.

Table 35. Adverse reactions occurring in ≥20% of patients receiving KEYTRUDA® in KEYNOTE-590

* NCI CTCAE v4.03 grading

† One case of diarrhea with fatal outcome was reported in each treatment arm.

‡ Includes asthenia, fatigue

Table 36. Laboratory abnormalities occurring in ≥ 20% of patients with esophageal cancer treated with KEYTRUDA® in KEYNOTE-590, compared to baseline values

* Frequency is based on the number of patients with baseline laboratory results and at least 1 result during the study: KEYTRUDA®/cisplatin/5-FU (range: 345 to 365 patients) and placebo/cisplatin/5-FU (range: 330 to 358 patients).

† Graded according to NCI CTCAE v4.03

Previously treated recurrent locally advanced or metastatic esophageal cancer

Among 314 patients with esophageal cancer enrolled in KEYNOTE-181 and who received KEYTRUDA®, the median duration of exposure to KEYTRUDA® was 2.1 months (range: 1 day to 24.4 months). Patients with autoimmune disease or medical conditions requiring immunosuppression were not included in the study. Adverse reactions observed in patients with esophageal cancer were similar to those in 2799 patients with melanoma or NSCLC who received KEYTRUDA® as monotherapy.

Cervical cancer

Cervical cancer FIGO 2014 stage III–IVA with chemoradiotherapy

The safety of KEYTRUDA® in combination with chemoradiotherapy (cisplatin plus external beam radiation therapy [EBRT] followed by brachytherapy [BT]) was evaluated in KEYNOTE-A18, a placebo-controlled, randomized (1:1), multicenter, double-blind trial involving 594 women with cervical cancer FIGO 2014 stage III–IVA. Two hundred ninety-two women received KEYTRUDA® in combination with chemoradiotherapy, and 302 women received placebo in combination with chemoradiotherapy.

The median duration of exposure to KEYTRUDA® was 12.1 months (range: 1 day to 27 months).

Fatal adverse reactions occurred in 1.4% of women who received KEYTRUDA® in combination with chemoradiotherapy, including one case (0.3%) each of colonic perforation, urosepsis, sepsis, and vaginal bleeding.

Serious adverse reactions occurred in 30% of women who received KEYTRUDA® in combination with chemoradiotherapy. Serious adverse reactions occurring in ≥1% of women included urinary tract infection (2.7%), urosepsis (1.4%), and sepsis (1%).

Treatment with KEYTRUDA® was discontinued due to adverse reactions in 7% of women. The most frequent adverse reaction (≥1%) leading to permanent discontinuation was diarrhea (1%).

Adverse reactions that led to interruption of KEYTRUDA® occurred in 43% of women; the most common adverse reactions leading to interruption of KEYTRUDA® (≥2%) included anemia (8%), COVID-19 (6%), positive SARS-CoV-2 test (3.1%), neutropenia (2.7%), diarrhea (2.7%), urinary tract infection (2.7%), and increased ALT (2.4%).

Tables 37 and 38 summarize adverse reactions and laboratory abnormalities observed in women receiving KEYTRUDA® in KEYNOTE-A18.

Table 37. Adverse reactions occurring in ≥10% of women with cervical cancer FIGO 2014 stage III–IVA treated with KEYTRUDA® in KEYNOTE-A18

* Grades according to NCI CTCAE v5.0

† Includes urinary tract infection, Pseudomonas urinary tract infection, acute pyelonephritis, cystitis, Escherichia urinary tract infection

‡ Includes fatigue, asthenia

§ Includes hypothyroidism, autoimmune hypothyroidism

¶ Includes erythema multiforme, dermatitis, drug eruption, eczema, rash, skin desquamation, bullous dermatitis, maculopapular rash, lichen planus, dyshidrotic eczema, acneiform dermatitis

Table 38. Laboratory abnormalities worsening from baseline in ≥ 20% of patients with FIGO 2014 stage III–IVA cervical cancer who received KITRUDA® in KEYNOTE-A18

* The frequency of laboratory parameter changes is based on the number of patients who had both baseline and at least one post-baseline laboratory measurement for each parameter: Keytruda® + chemoradiotherapy (range: 286 to 291 patients) and placebo + chemoradiotherapy (range: 298 to 300 patients).

† Grades according to NCI CTCAE v5.0

Persistent, recurrent, or metastatic cervical cancer

The safety of Keytruda® in combination with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab, was evaluated in KEYNOTE-826. This was a multicenter, double-blind, randomized (1:1), placebo-controlled first-line therapy study involving patients with persistent, recurrent, or metastatic cervical cancer who had not received prior chemotherapy except when administered concurrently as a radiosensitizer. A total of 616 patients, regardless of tumor PD-L1 expression, received Keytruda® 200 mg plus chemotherapy with or without bevacizumab (n = 307) every 3 weeks or placebo plus chemotherapy with or without bevacizumab (n = 309) every 3 weeks. The median duration of exposure to Keytruda® was 9.9 months (range: 1 day to 26 months). Fatal adverse reactions occurred in 4.6% of patients receiving Keytruda® in combination with chemotherapy with or without bevacizumab, including 3 cases of hemorrhage, 2 cases of sepsis, 2 cases of unknown cause, and one case each of acute myocardial infarction, autoimmune encephalitis, cardiac arrest, cerebrovascular accident, femoral fracture with perioperative pulmonary embolism, intestinal perforation, and pelvic infection. Serious adverse reactions were observed in 50% of patients receiving Keytruda® and chemotherapy with or without bevacizumab. Serious adverse reactions occurring in ≥ 3% of patients included febrile neutropenia (6.8%), urinary tract infection (5.2%), anemia (4.6%), acute kidney injury (3.3%), and sepsis (3.3%). Keytruda® was discontinued due to adverse reactions in 15% of patients. The most frequent adverse reaction leading to complete discontinuation of Keytruda® (≥ 1%) was colitis (1%). Adverse reactions leading to interruption of Keytruda® occurred in 66% of patients; the most frequent adverse reactions or laboratory abnormalities leading to interruption of Keytruda® (≥ 2%) were thrombocytopenia (15%), neutropenia (14%), anemia (11%), increased ALT (6%), leukopenia (5%), fatigue/asthenia (4.2%), urinary tract infection (3.6%), increased AST (3.3%), pyrexia (3.3%), diarrhea (2.6%), acute kidney injury (2.6%), increased blood creatinine (2.6%), colitis (2.3%), decreased appetite (2.0%), and cough (2.0%). Among patients who received treatment with Keytruda®, chemotherapy, and bevacizumab (n = 196), the most common (≥ 20%) adverse reactions were peripheral neuropathy (62%), alopecia (58%), anemia (55%), fatigue/asthenia (53%), nausea (41%), neutropenia (41%), diarrhea (39%), hypertension (35%), thrombocytopenia (35%), constipation (31%), arthralgia (31%), vomiting (30%), urinary tract infection (27%), rash (26%), leukopenia (24%), hypothyroidism (22%), and decreased appetite (21%).

Tables 39 and 40 summarize the adverse reactions and laboratory parameter changes, respectively, observed in patients treated with Keytruda® in the KEYNOTE-826 study.

Table 39. Adverse reactions occurring in ≥ 20% of patients treated with Keytruda® in KEYNOTE-826

* Chemotherapy (paclitaxel and cisplatin or paclitaxel and carboplatin)

† Grades according to NCI CTCAE v4.0

‡ Includes peripheral neuropathy, peripheral sensory neuropathy, peripheral motor neuropathy, peripheral sensory-motor neuropathy, paresthesia

§ Includes rash, maculopapular rash, erythematous rash, macular rash, papular rash, pruritic rash, pustular rash

¶ Includes fatigue, asthenia

Table 40. Laboratory abnormalities occurring in ≥ 20% of patients who received KEYTRUDA® in KEYNOTE-826 compared with baseline values

* Frequency is based on the number of patients with baseline laboratory results and at least 1 result during the study: KEYTRUDA® plus chemotherapy (range: 297 to 301 patients) and placebo plus chemotherapy (range: 299 to 302 patients).

† Chemotherapy (paclitaxel and cisplatin or paclitaxel and carboplatin)

‡ Grades according to NCI CTCAE v4.0

Previously treated recurrent or metastatic cervical cancer

In 98 patients with cervical cancer enrolled in cohort E of the KEYNOTE-158 study, the median duration of treatment with KEYTRUDA® was 2.9 months (range: 1 day to 22.1 months). Patients with autoimmune disease or medical conditions requiring immunosuppression were not included in the study.

Treatment with KEYTRUDA® was discontinued due to adverse reactions in 8% of patients. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA®. The most frequently reported serious adverse reactions were anemia (7%), fistula (4.1%), hemorrhage (4.1%), and infections [excluding urinary tract infections (UTIs)] (4.1%).

Tables 41 and 42 summarize adverse reactions and laboratory abnormalities, respectively, observed in patients receiving KEYTRUDA® in KEYNOTE-158.

Table 41. Adverse reactions occurring in ≥ 10% of patients with cervical cancer in KEYNOTE-158

* Grades according to NCI CTCAE v4.0

† Includes asthenia, fatigue, somnolence, malaise

‡ Includes chest pain, tumor pain, dysesthesia, dysuria, ear pain, gum pain, groin pain, lymph node pain, oropharyngeal pain, generalized pain, skin pain, pelvic pain, radicular pain, pain at stoma site, toothache

§ Includes peripheral edema, peripheral swelling

¶ Includes arthralgia, back pain, musculoskeletal pain, skeletal pain, myalgia, myositis, neck pain, non-cardiac chest pain, limb pain

Includes colitis, diarrhea, gastroenteritis

Þ Includes abdominal discomfort, abdominal distension, abdominal pain, lower abdominal pain, upper abdominal pain

ß Includes epistaxis, hematuria, hemoptysis, metrorrhagia, rectal bleeding, uterine hemorrhage, vaginal hemorrhage

à Includes bacterial pyelonephritis, acute pyelonephritis, urinary tract infection, bacterial urinary tract infection, pyelonephritis due to Pseudomonas aeruginosa, urosepsis

è Includes cellulitis, Clostridium difficile infection, device-related infection, empyema, erysipelas, herpes virus infection, neoplasm-related infection, infection NOS, influenza, lower respiratory tract infection, lung infection, oral candidiasis, fungal infection of the mouth, osteomyelitis, Pseudomonas infection, respiratory tract infection, dental abscess, upper respiratory tract infection, uterine abscess, vulvovaginal candidiasis

ð Includes dermatitis, drug eruption, eczema, erythema, hand-foot syndrome, rash, generalized rash, maculopapular rash

Table 42. Laboratory abnormalities occurring at ≥ 20% of patients with cervical cancer in KEYNOTE-158 compared to baseline

* The frequency of each laboratory parameter abnormality was calculated based on the number of patients who had the corresponding laboratory test performed both at baseline and at least once during the study: the pembrolizumab treatment group (range: 76 to 79 patients).

† Grading according to NCI CTCAE v4.0

Other laboratory abnormalities occurring in ≥ 10% of patients treated with pembrolizumab included hypophosphatemia (19% all grades; 6% grades 3–4), increased international normalized ratio (INR) (19% all grades; 0% grades 3–4), hypercalcemia (14% all grades; 2.6% grades 3–4), decreased platelet count (14% all grades; 1.3% grades 3–4), prolonged activated partial thromboplastin time (aPTT) (14% all grades; 0% grades 3–4), hypoglycemia (13% all grades; 1.3% grades 3–4), decreased white blood cell count (13% all grades; 2.6% grades 3–4), and hyperkalemia (13% all grades; 1.3% grades 3–4).

Hepatocellular Carcinoma (HCC)

Previously Treated HCC

The safety of pembrolizumab was evaluated in a multicenter, double-blind, randomized, placebo-controlled trial, KEYNOTE-394, which included patients with previously treated HCC. Patients were randomized (2:1) to receive either pembrolizumab 200 mg (n = 299) or placebo (n = 153) intravenously every 3 weeks for up to 35 cycles.

The median duration of exposure was 3.3 months (range: 1 day to 27.3 months) in the pembrolizumab group and 2.2 months (range: 1 day to 15.5 months) in the placebo group. Treatment with pembrolizumab was permanently discontinued due to adverse reactions in 13% of patients. The most common adverse reaction leading to permanent discontinuation of pembrolizumab was ascites (2.3%). Adverse reactions leading to interruption of pembrolizumab treatment occurred in 26% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of pembrolizumab (≥ 2%) were increased blood bilirubin levels (9%), increased AST (5%), and increased ALT (2%).

Tables 43 and 44 summarize the adverse reactions and laboratory parameter abnormalities observed in patients receiving pembrolizumab in KEYNOTE-394.

Table 43. Adverse Reactions Occurring in ≥ 10% of Patients with HCC Treated with Pembrolizumab in KEYNOTE-394

* Grades according to NCI CTCAE v4.03

† Includes dermatitis, allergic dermatitis, bullous dermatitis, rash, erythematous rash, maculopapular rash, pustular rash, and blisters.

Table 44. Laboratory test abnormalities from baseline occurring in ≥ 20% of HCC patients treated with KEYTRUDA® in KEYNOTE-394

* The frequency of changes in each parameter is based on the number of patients for whom both baseline values and at least one laboratory measurement during the study of KEYTRUDA® were available (range: 223 to 297 patients) and placebo (range: 144 to 151 patients).

† Grades according to NCI CTCAE v4.03

Biliary Tract Cancer (BTC)

The safety of KEYTRUDA® in combination with gemcitabine and cisplatin was evaluated in a multicenter, double-blind, randomized, placebo-controlled trial, KEYNOTE-966, in patients with locally advanced unresectable or metastatic BTC who had not received prior systemic therapy for advanced disease. A total of 1063 patients received KEYTRUDA® 200 mg plus gemcitabine and cisplatin chemotherapy (n = 529) or placebo plus gemcitabine and cisplatin chemotherapy (n = 534) every 3 weeks.

The median duration of exposure to KEYTRUDA® was 6 months (range: 1 day to 28 months).

In 15% of patients, KEYTRUDA® was discontinued due to adverse reactions. The most frequent adverse reaction leading to complete discontinuation of KEYTRUDA® (≥ 1%) was pneumonitis (1.3%).

Adverse reactions leading to interruption of KEYTRUDA® administration occurred in 55% of patients. The most common adverse reactions or laboratory parameter changes leading to interruption of KEYTRUDA® (≥ 2%) were decreased neutrophil count (18%), decreased platelet count (10%), anemia (6%), decreased white blood cell count (4%), pyrexia (3.8%), fatigue (3.0%), cholangitis (2.8%), increased ALT levels (2.6%), increased AST levels (2.5%), and biliary tract obstruction (2.3%).

In the KEYTRUDA® plus chemotherapy group compared to the placebo plus chemotherapy group, a ≥ 5% difference in the incidence of adverse reactions was observed between patients receiving KEYTRUDA® and those receiving placebo for the following adverse reactions: pyrexia (26% vs. 20%), rash (21% vs. 13%), pruritus (15% vs. 10%), and hypothyroidism (9% vs. 2.6%). No clinically significant differences in the incidence of grade 3–4 toxicity between the groups were observed.

A ≥ 5% difference in the frequency of laboratory parameter changes was observed between patients receiving KEYTRUDA® plus chemotherapy and those receiving placebo plus chemotherapy for decreased lymphocyte count (69% vs. 61%). No clinically significant differences in the incidence of grade 3–4 toxicity between the groups were observed.

Merkel Cell Carcinoma (MCC)

In 150 patients with MCC enrolled in KEYNOTE-017 and KEYNOTE-913, the median duration of treatment with KEYTRUDA® was 6.3 months (range: 1 day to 28 months).

Patients with autoimmune disease or medical conditions requiring immunosuppression were not included in the studies. Adverse reactions observed in patients with Merkel cell carcinoma were similar to those in 2799 patients with melanoma or NSCLC who received KEYTRUDA® as monotherapy. Laboratory abnormalities (grade 3–4 severity) observed at higher frequency included elevated lipase (17%).

Renal Cell Carcinoma (RCC)

The safety of KEYTRUDA® in combination with axitinib was evaluated in KEYNOTE-426. Patients with conditions requiring systemic corticosteroids or other immunosuppressants, or with a history of severe autoimmune diseases, except for type 1 diabetes, vitiligo, Sjögren's syndrome, and hypothyroidism stable on hormone replacement therapy, were excluded from the study. Patients received KEYTRUDA® 200 mg intravenously every 3 weeks and axitinib 5 mg orally twice daily or sunitinib 50 mg once daily for 4 weeks, followed by no treatment for 2 weeks. The median duration of combination therapy with KEYTRUDA® and axitinib was 10.4 months (range: 1 day to 21.2 months).

Study participants had the following characteristics: median age 62 years (range: 30 to 89); 40% were aged 65 years or older; 71% were male; 80% were White; and 80% had a Karnofsky Performance Status (KPS) of 90–100 and 20% had a KPS of 70–80.

Fatal adverse reactions occurred in 3.3% of patients receiving KEYTRUDA® in combination with axitinib. These included 3 cases of cardiac arrest, 2 cases of pulmonary embolism, and 1 case each of heart failure, death from unknown cause, myasthenia gravis, myocarditis, Fournier's gangrene, multiple myeloma, pleural effusion, pneumonitis, and respiratory failure.

Serious adverse reactions occurred in 40% of patients receiving KEYTRUDA® in combination with axitinib. Serious adverse reactions in ≥ 1% of patients receiving KEYTRUDA® plus axitinib included hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%).

Treatment was permanently discontinued due to adverse reactions in 31% of patients: 13% of patients receiving only KEYTRUDA®, 13% receiving only axitinib, and 8% receiving both drugs. The most common serious adverse reactions (> 1%) leading to complete discontinuation of KEYTRUDA®, axitinib, or the combination included hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and stroke (1.2%).

Adverse reactions leading to temporary discontinuation or dose reduction, excluding temporary discontinuation of KEYTRUDA® due to infusion-related reactions, occurred in 76% of patients receiving KEYTRUDA® in combination with axitinib, including discontinuation of KEYTRUDA® in 50% of patients. Axitinib was discontinued in 64% of patients, and dose reduction occurred in 22% of patients. The most common adverse reactions (> 10%) leading to discontinuation of KEYTRUDA® were hepatotoxicity (14%) and diarrhea (11%), while the most common adverse reactions (> 10%) leading to discontinuation or dose reduction of axitinib were hepatotoxicity (21%), diarrhea (19%), and hypertension (18%).

The most common adverse reactions (≥ 20%) in patients receiving KEYTRUDA® and axitinib included diarrhea, fatigue/asthenia, hypertension, hypothyroidism, decreased appetite, hepatotoxicity, palmar-plantar erythrodysesthesia, nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation.

Twenty-seven percent (27%) of patients receiving KEYTRUDA® in combination with axitinib received daily doses of oral prednisone equivalent to ≥ 40 mg for the treatment of immune-mediated adverse reactions.

Tables 45 and 46 summarize adverse reactions and laboratory abnormalities, respectively, occurring in at least 20% of patients who received KEYTRUDA® and axitinib in KEYNOTE-426.

Table 45. Adverse Reactions Occurring in ≥ 20% of Patients Receiving KEYTRUDA® and Axitinib in KEYNOTE-426

* Grades according to NCI CTCAE v4.03

† Includes diarrhea, colitis, enterocolitis, gastroenteritis, enteritis, hemorrhagic enterocolitis

‡ Includes hypertension, increased blood pressure, hypertensive crisis, labile hypertension

§ Includes increased ALT, increased AST, autoimmune hepatitis, increased blood bilirubin, drug-induced liver injury, increased liver enzymes, liver function test abnormality, hepatitis, fulminant hepatitis, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, immune-mediated hepatitis, increased liver function tests, liver injury, transaminase elevation

¶ Includes rash, butterfly rash, dermatitis, acneiform dermatitis, atopic dermatitis, bullous dermatitis, contact dermatitis, exfoliative rash, genital rash, erythematous rash, generalized rash, macular rash, maculopapular rash, papular rash, pruritic rash, seborrheic dermatitis, skin depigmentation, skin desquamation, perineal rash

Table 46. Laboratory abnormalities compared to baseline occurring in ≥ 20% of patients receiving KEYTRUDA® and axitinib in KEYNOTE-426

* Frequency is based on the number of patients with baseline and at least one post-baseline test result in the study: KEYTRUDA®/axitinib (range: 342 to 425 patients) or sunitinib (range: 345 to 422 patients).

† Graded according to NCI CTCAE v4.03

‡ Adjusted for albumin

§ Two patients with Grade 3 prolonged activated partial thromboplastin time (aPTT) also had reported adverse reactions of hepatotoxicity.

Adjuvant Treatment of RCC

The safety of KEYTRUDA® as monotherapy was evaluated in KEYNOTE-564, a randomized (1:1), double-blind, placebo-controlled trial involving 984 patients who underwent nephrectomy for RCC and received either 200 mg of KEYTRUDA® administered as an intravenous infusion every three weeks (n = 488) or placebo (n = 496) for up to one year. The median duration of exposure to KEYTRUDA® was 11.1 months (range: 1 day to 14.3 months). Patients with active autoimmune disease or medical conditions requiring immunosuppression were excluded from the study. Serious adverse reactions occurred in 20% of patients receiving KEYTRUDA®. Serious adverse reactions (≥1%) included acute kidney injury, adrenal insufficiency, pneumonia, colitis, and diabetic ketoacidosis (each 1%). Fatal adverse reactions occurred in 0.2% of patients receiving KEYTRUDA®, including one case of pneumonia. Discontinuation of KEYTRUDA® due to adverse reactions occurred in 21% of patients; the most frequent (≥1%) were increased ALT (1.6%), colitis (1%), and adrenal insufficiency (1%). Interruption of KEYTRUDA® due to adverse reactions occurred in 26% of patients; the most frequent (≥1%) were increased AST (2.3%), arthralgia (1.6%), hypothyroidism (1.6%), diarrhea (1.4%), increased ALT (1.4%), fatigue (1.4%), rash, decreased appetite, and vomiting (each 1%).

Tables 47 and 48 list adverse reactions and laboratory abnormalities observed in patients receiving KEYTRUDA® in the KEYNOTE-564 study, respectively.

Table 47. Individual* adverse reactions occurring in ≥10% of patients receiving KEYTRUDA® in the KEYNOTE-564 study

* Adverse reactions occurring at the same or higher frequency compared to the placebo group

† Grades according to NCI CTCAE v4.0

‡ Includes arthralgia, back pain, myalgia, arthritis, limb pain, neck pain, musculoskeletal pain, musculoskeletal stiffness, spinal pain, musculoskeletal chest pain, bone pain, musculoskeletal discomfort

§ Includes asthenia, fatigue

¶ Includes rash, maculopapular rash, papular rash, exfoliative skin conditions, lichen planus, erythematous rash, eczema, macular rash, acneiform dermatitis, dermatitis, pruritic rash, Stevens-Johnson syndrome, asteatotic eczema, hand-foot syndrome

Includes diarrhea, colitis, enterocolitis, frequent defecation, enteritis

Þ Includes abdominal pain, lower abdominal pain, upper abdominal pain, abdominal discomfort, gastrointestinal pain

ß Includes upper respiratory tract cough syndrome, productive cough, cough

à Includes tension headache, headache, sinus headache, migraine with aura

è Includes increased alanine aminotransferase levels, increased aspartate aminotransferase levels, increased blood bilirubin levels, drug-induced liver injury, increased liver enzymes, liver function abnormalities, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, immune-mediated hepatitis, increased liver function tests, increased transaminase levels, increased gamma-glutamyl transferase levels, increased conjugated bilirubin levels

ð Includes acute kidney injury, increased blood creatinine levels, renal failure, kidney function impairment, oliguria, decreased glomerular filtration rate, toxic nephropathy

Table 48. Individual* laboratory abnormalities from baseline occurring in ≥ 20% of melanoma patients treated with KEYTRUDA® in KEYNOTE-564

* Laboratory abnormalities occurring at the same or higher frequency compared to the placebo group

† Frequency is based on the number of patients with baseline laboratory test results and at least one on-study result: KEYTRUDA® (range: 440 to 449 patients) and placebo (range: 461 to 469 patients); elevated INR: KEYTRUDA® n = 228 and placebo n = 254.

‡ Grades according to NCI CTCAE v4.03

Endometrial Carcinoma

Advanced or recurrent endometrial carcinoma

The safety of KEYTRUDA® in combination with chemotherapy (paclitaxel and carboplatin) was evaluated in KEYNOTE-868, a randomized (1:1), multicenter, double-blind, placebo-controlled trial in patients with advanced or recurrent endometrial carcinoma. Overall, 759 patients received KEYTRUDA® 200 mg every 3 weeks in combination with chemotherapy for 6 cycles, followed by KEYTRUDA® 400 mg every 6 weeks for 14 cycles (n = 382), or placebo with chemotherapy for 6 cycles followed by placebo for 14 cycles (n = 377). The median duration of exposure to KEYTRUDA® was 5.6 months (range: 1 day to 24.0 months).

Serious adverse reactions occurred in 35% of patients who received KEYTRUDA® in combination with chemotherapy, compared to 19% of patients who received placebo with chemotherapy.

Fatal adverse reactions occurred in 1.6% of patients who received KEYTRUDA® in combination with chemotherapy, including COVID-19 (0.5%) and cardiac arrest (0.3%).

In 14% of patients, KEYTRUDA® was discontinued due to adverse reactions. Chemotherapy dose reductions were required in 29% of patients receiving KEYTRUDA® in combination with chemotherapy, compared to 23% of patients receiving placebo with chemotherapy. There were no clinically meaningful differences in the discontinuation or interruption of chemotherapy between the study groups.

Adverse reactions observed in patients receiving KEYTRUDA® and chemotherapy were generally similar to those observed with monotherapy with KEYTRUDA® or chemotherapy alone, except for rash (33% all grades; 2.9% grade 3–4).

Monotherapy for the treatment of advanced endometrial carcinoma with MSI-H or dMMR

In 90 patients with MSI-H or dMMR endometrial carcinoma included in the KEYNOTE-158 trial who received KEYTRUDA® as monotherapy, the median duration of treatment with KEYTRUDA® was 8.3 months (range: 1 day to 26.9 months). Adverse reactions observed in patients with endometrial carcinoma were similar to those observed in 2799 patients with melanoma or NSCLC who received KEYTRUDA® as monotherapy.

Tumor Mutational Burden-High (TMB-H) Cancer

The safety of KEYTRUDA® was evaluated in 105 patients with TMB-H cancer included in the KEYNOTE-158 trial. The median duration of treatment with KEYTRUDA® was 4.9 months (range: 0.03 to 35.2 months). Adverse reactions observed in patients with TMB-H cancer were similar to those observed in patients with other solid tumors who received KEYTRUDA® as monotherapy.

Cutaneous Squamous Cell Carcinoma (cSCC)

In 159 patients with advanced cSCC (recurrent, metastatic, or locally advanced disease) included in the KEYNOTE-629 trial who received KEYTRUDA®, the median duration of treatment with KEYTRUDA® was 6.9 months (range: 1 day to 28.9 months). Patients with autoimmune disease or medical conditions requiring systemic immunosuppressive therapy, including corticosteroids, were excluded from the trial. Adverse reactions observed in patients with recurrent or metastatic cSCC or locally advanced cSCC were similar to those observed in 2799 patients with melanoma or NSCLC who received KEYTRUDA® as monotherapy. Laboratory abnormalities (grade 3–4) observed at high frequency included lymphopenia (10%) and decreased sodium levels (10%).

Triple-Negative Breast Cancer (TNBC)

Neoadjuvant and adjuvant treatment of high-risk early-stage TNBC

The safety of KEYTRUDA® in combination with neoadjuvant chemotherapy (carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide), followed by surgery and continued adjuvant treatment with KEYTRUDA® as monotherapy, was evaluated in KEYNOTE-522, a multicenter, randomized (2:1), double-blind, placebo-controlled trial in patients with newly diagnosed, previously untreated, high-risk early-stage TNBC.

A total of 778 patients in the KEYTRUDA® group received at least one dose of KEYTRUDA® in combination with neoadjuvant chemotherapy, followed by adjuvant treatment with KEYTRUDA® after surgery, compared to 389 patients who received at least one dose of placebo in combination with neoadjuvant chemotherapy, followed by adjuvant placebo after surgery.

The median duration of exposure to KEYTRUDA® 200 mg every 3 weeks was 13.3 months (range: 1 day to 21.9 months).

Fatal adverse reactions occurred in 0.9% of patients receiving KEYTRUDA®, including one case each of acute adrenal insufficiency, autoimmune encephalitis, hepatitis, pneumonia, pneumonitis, pulmonary embolism, sepsis with multi-organ dysfunction syndrome, and myocardial infarction. Serious adverse reactions were observed in 44% of patients receiving KEYTRUDA®.

Serious adverse reactions occurring in ≥ 2% of patients receiving KEYTRUDA® included febrile neutropenia (15%), pyrexia (3.7%), anemia (2.6%), and neutropenia (2.2%).

KEYTRUDA® was discontinued due to adverse reactions in 20% of patients. The most frequent adverse reactions (≥ 1%) leading to permanent discontinuation of KEYTRUDA® were increased ALT (2.7%), increased AST (1.5%), and rash (1%). Adverse reactions leading to interruption of KEYTRUDA® occurred in 57% of patients. The most frequent adverse reactions leading to interruption of KEYTRUDA® (≥ 2%) were neutropenia (26%), thrombocytopenia (6%), increased ALT (6%), increased AST (3.7%), anemia (3.5%), rash (3.2%), febrile neutropenia (2.8%), leukopenia (2.8%), upper respiratory tract infection (2.6%), pyrexia (2.2%), and fatigue (2.1%).

Tables 49 and 50 summarize the adverse reactions and laboratory abnormalities observed in patients receiving KEYTRUDA® in the KEYNOTE-522 trial.

Table 49. Adverse Reactions Occurring in ≥ 20% of Patients Receiving KEYTRUDA® in KEYNOTE-522

* Chemotherapy: carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide

† Grades according to NCI CTCAE v4.0

‡ Includes asthenia, fatigue

§ Includes aphthous ulcer, cheilitis, lip pain, lip ulcer, mouth ulcer, mucosal inflammation, oral mucosal erythema, oral pain, stomatitis, tongue blister, tongue ulcer

¶ Includes abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, abdominal tenderness

Includes dermatitis, acneiform dermatitis, allergic dermatitis, bullous dermatitis, exfoliative dermatitis generalized, drug-induced rash, eczema, incision site rash, injection site rash, rash, erythematous rash, follicular rash, macular rash, maculopapular rash, morbilliform rash, papular rash, pruritic rash, pustular rash, rubelliform rash, exfoliative dermatitis, skin toxicity, toxic skin eruption, urticaria, vasculitic rash, viral rash

Þ Includes peripheral neuropathy, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy

ß Includes cough, productive cough, upper respiratory tract cough syndrome

Table 50. Laboratory abnormalities compared to baseline occurring in ≥ 20% of patients receiving Keytruda® in KEYNOTE-522

* Frequency is based on the number of patients with baseline test results and at least 1 result during the study: Keytruda® in combination with chemotherapy followed by Keytruda® monotherapy (range: 759 to 777 patients) and placebo in combination with chemotherapy followed by placebo (range: 378 to 389 patients).

† Chemotherapy: carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide

† Grading according to NCI CTCAE v4.0

Locally recurrent unresectable or metastatic TNBC

The safety of Keytruda® in combination with paclitaxel, protein-bound paclitaxel, or gemcitabine and carboplatin was evaluated in a multicenter, double-blind, randomized (2:1), placebo-controlled trial, KEYNOTE-355, in patients with locally recurrent unresectable or metastatic TNBC who had not received prior chemotherapy for metastatic disease. Overall, 596 patients (including 34 patients from the initial safety run-in phase) received Keytruda® 200 mg every 3 weeks in combination with paclitaxel, protein-bound paclitaxel, or gemcitabine and carboplatin.

The median duration of Keytruda® treatment was 5.7 months (range: 1 day to 33.0 months).

Fatal adverse reactions occurred in 2.5% of patients receiving Keytruda® in combination with chemotherapy, including cardiac arrest and respiratory arrest (0.7%) and septic shock (0.3%).

Serious adverse reactions were observed in 30% of patients receiving Keytruda® in combination with paclitaxel, protein-bound paclitaxel, or gemcitabine and carboplatin. Serious adverse reactions occurring in ≥ 2% of patients included pneumonia (2.9%), anemia (2.2%), and thrombocytopenia (2%).

Keytruda® was discontinued due to adverse reactions in 11% of patients. The most common adverse reactions leading to permanent discontinuation of Keytruda® (≥ 1%) were increased ALT levels (2.2%), increased AST levels (1.5%), and pneumonitis (1.2%). Adverse reactions leading to interruption of Keytruda® therapy occurred in 50% of patients. The most common adverse reactions leading to interruption of Keytruda® therapy (≥ 2%) were neutropenia (22%), thrombocytopenia (14%), anemia (7%), increased ALT levels (6%), leukopenia (5%), increased AST levels (5%), decreased white blood cell count (3.9%), and diarrhea (2%).

Tables 51 and 52 summarize adverse reactions and laboratory abnormalities in patients who received Keytruda® in KEYNOTE-355.

Table 51. Adverse reactions occurring in ≥ 20% of patients receiving Keytruda® with chemotherapy in KEYNOTE-355

* NCI CTCAE v4.03 grading
† Includes fatigue and asthenia
‡ Includes rash, maculopapular rash, pruritic rash, pustular rash, macular rash, papular rash, butterfly rash, erythematous rash, eyelid rash
§ Includes cough, productive cough, upper respiratory tract cough syndrome
¶ Includes headache, migraine, tension headache

Table 52. Laboratory abnormalities occurring at ≥ 20% of patients with baseline shift during treatment with KEYTRUDA® in combination with chemotherapy in KEYNOTE-355

* The frequency of each test is based on the number of patients who had baseline test results and at least 1 test result during the study with KEYTRUDA® + chemotherapy (range: 566 to 592 patients) and placebo + chemotherapy (range: 269 to 280 patients).

† Grades according to NCI CTCAE v4.03

Adverse reactions observed in clinical trials or reported from post-marketing experience

The following adverse reactions have been reported in clinical trials or during the post-marketing period: eosinophilia, immune thrombocytopenic purpura, hypophysitis, adrenal insufficiency, thyroiditis, diabetes mellitus, epilepsy, lethargy, Guillain-Barré syndrome, myasthenic syndrome, meningitis (aseptic), dry eye sensation, hypertension, dry mouth, pancreatitis, small intestine perforation, hair color changes, dry skin, Stevens-Johnson syndrome, toxic epidermal necrolysis, arthritis, Vogt-Koyanagi-Harada syndrome, hemophagocytic lymphohistiocytosis, tenosynovitis, influenza-like illness, chills, increased amylase levels, gastrointestinal ulcer, glomerulonephritis, vasculitis, sclerosing cholangitis, non-infectious cystitis, gastritis, optic neuritis, and celiac disease.

Reporting of adverse reactions

Reporting of adverse reactions after drug registration is of significant importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Incompatibilities

Since compatibility studies with other medicinal products have not been conducted, KEYTRUDA® must not be mixed with other medicinal products, except as specified in the section "Dosage and administration".

Shelf life

Unopened vial

2 years.

Storage of diluted solution

The diluted product should be used immediately. The diluted solution must not be frozen.

If not used immediately, diluted solutions of KEYTRUDA® may be stored at room temperature for a total of up to 6 hours.

Diluted solutions of KEYTRUDA® may also be stored in a refrigerator at 2 to 8 °C; however, the total time from dilution of KEYTRUDA® to completion of infusion must not exceed 96 hours.

When stored in the refrigerator, vials and/or intravenous infusion bags should be allowed to reach room temperature before administration.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions

Store in a refrigerator at 2 to 8 °C. Do not freeze. Store in the original packaging, protected from light and out of reach of children.

Packaging

4 mL of concentrate for solution for infusion in a 10 mL vial made of colorless type I glass, containing 100 mg of pembrolizumab.

1 vial per carton.

Prescription category

Prescription only.

Manufacturer

Merck Sharp & Dohme B.V., the Netherlands

Manufacturer's location and address of place of business

Waarderweg 39, 2031 BN Haarlem, the Netherlands

INSTRUCTIONS

for medical use of the medicinal product

KEYTRUDA®

(KEYTRUDA®)

Composition:

Active substance: pembrolizumab;

1 ml of concentrate contains 25 mg of pembrolizumab;

1 vial (4 ml) of concentrate contains 100 mg of pembrolizumab.

Excipients: L-histidine, L-histidine monohydrochloride monohydrate, polysorbate 80, sucrose, water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: a clear to slightly opalescent, colorless to pale yellow solution. A liquid practically free from visible particles, pH 5.2–5.8.

Pharmacotherapeutic group. Antineoplastic agents. Monoclonal antibodies. PD-1/PD-L1 (programmed death-1/programmed death-ligand 1) inhibitors. Pembrolizumab. ATC code L01FF02.

Pharmacological Properties

Pembrolizumab is an antibody that blocks the programmed death receptor-1 (PD-1). Pembrolizumab is a humanized monoclonal IgG4 kappa antibody with an approximate molecular weight of 149 kDa. Pembrolizumab is produced in recombinant Chinese hamster ovary cells.

Pharmacodynamics

Based on dose/exposure-response and safety relationships, there are no clinically meaningful differences in efficacy and safety when pembrolizumab is administered at a dose of 200 mg or 2 mg/kg every 3 weeks, regardless of cancer type. Observations in adult patients with melanoma receiving pembrolizumab at doses of 200 mg every 3 weeks or 400 mg every 6 weeks, and in patients with solid tumors, showed no differences in efficacy and safety based on dose/exposure-response relationships. The dose/exposure-response relationship regarding efficacy and safety of pembrolizumab administered at 400 mg every 6 weeks in patients with classical Hodgkin lymphoma or mediastinal large B-cell lymphoma has not been fully characterized.

Mechanism of Action

Binding of PD-1 ligands (PD-L1 and PD-L2) to the PD-1 receptor expressed on T-cells inhibits T-cell proliferation and cytokine production. PD-1 ligand activation occurs in some tumors, and signaling through this pathway may contribute to suppression of active T-lymphocyte antitumor immunity. Pembrolizumab is a monoclonal antibody that binds to PD-1 receptors and blocks their interaction with PD-L1 and PD-L2, thereby releasing PD-1-mediated inhibition of immune responses, including antitumor immune responses. In syngeneic mouse tumor models, blockade of PD-1 activity resulted in reduced tumor growth.

Pharmacokinetics

The pharmacokinetics (PK) of pembrolizumab were analyzed using population PK modeling based on concentration data collected from 2993 patients with various malignancies who received pembrolizumab at doses ranging from 1 to 10 mg/kg once every 2 weeks or 2 to 10 mg/kg once every 3 weeks, or 200 mg once every 3 weeks.

Steady-state concentrations of pembrolizumab are reached by Week 16 with repeated administration every 3 weeks, and systemic accumulation increases by a factor of 2.1. Maximum concentration (Cmax), minimum concentration (Cmin), and area under the plasma concentration-time curve, relative to the steady-state concentration-time curve (AUCss) of pembrolizumab, increase proportionally with dose over the range of 2 to 10 mg/kg once every 3 weeks.

Distribution

The geometric mean (CV %) of the steady-state volume of distribution is 6.0 L (20%).

Elimination

The clearance of pembrolizumab (CV %) is approximately 23% lower [geometric mean, 195 mL/day (40%)] at steady state compared to after the first dose [252 mL/day (37%)]; this time-dependent decrease in clearance is not considered clinically significant. The terminal half-life (t1/2) is 22 days (32%).

Special Patient Groups

The following factors have no clinically important effect on pembrolizumab clearance: age (range: 15 to 94 years), sex, race (89% Caucasian), renal impairment (glomerular filtration rate (GFR) ≥ 15 mL/min/1.73 m²), mild to moderate hepatic impairment (total bilirubin ≤ 3 times the upper limit of normal (ULN) and any level of AST), or tumor burden. The effect of severe hepatic impairment (total bilirubin > 3 times ULN or any level of AST) on the pharmacokinetics of pembrolizumab is unknown.

Pediatric patients: pembrolizumab concentrations at a body weight-based dose of 2 mg/kg once every 3 weeks in pediatric patients (from 10 months to 17 years of age) are comparable to those in adults receiving the same dose.

Immunogenicity

The observed incidence of antibody formation to the drug (anti-drug antibodies, ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods make meaningful comparisons of ADA incidence across studies described in this section, as well as with other studies including those of Keytruda® or other pembrolizumab products, not feasible.

Low levels of pembrolizumab may interfere with electrochemiluminescent (ECL) assay results; therefore, analysis of ADA was performed in a subgroup of patients treated with Keytruda® who had pembrolizumab concentrations below the drug tolerance level.

In clinical studies of Keytruda® administered at 2 mg/kg once every 3 weeks, 200 mg once every 3 weeks, or 10 mg/kg once every 2 or 3 weeks, treatment-induced anti-pembrolizumab antibodies were detected in 27 (2.1%) of 1289 evaluable patients, of whom 6 (0.5%) patients had neutralizing antibodies to pembrolizumab. No clinically significant impact of ADA on the pharmacokinetics of pembrolizumab or on the risk of infusion-related reactions was observed. Due to the low incidence of ADA formation, their impact on the efficacy of Keytruda® is unknown.

Preclinical Data

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies on the potential carcinogenicity or genotoxicity of pembrolizumab have not been conducted.

Fertility studies with pembrolizumab have not been conducted. In 1-month and 6-month repeat-dose toxicity studies in monkeys, no marked effects on reproductive organs in males or females were observed; however, most animals in these studies were not sexually mature.

Toxicological and/or Pharmacological Studies in Animals

In animal studies, inhibition of the PD-1/PD-L1 signaling pathway led to increased severity of certain infections and inflammatory responses.

In mice infected with Mycobacterium tuberculosis, blockade of PD-1 was associated with markedly reduced survival compared to control wild-type mice, correlating with increased bacterial proliferation and inflammatory response in these animals.

Blockade of PD-1 using anti-PD-1 antibodies in primates has also been shown to exacerbate M. tuberculosis infection in rhesus macaques.

In mice with blocked PD-1 and PD-L1, as well as in mice treated with a PD-L1 blocking antibody, reduced survival was also observed following infection with lymphocytic choriomeningitis virus.

Administration of pembrolizumab in chimpanzees with naturally occurring hepatitis B infection resulted in significant increases in serum ALT, AST, and GGT levels in 2 out of 4 animals, which persisted for at least 1 month after discontinuation of pembrolizumab.

Clinical Characteristics.

Indications.

Melanoma

Ketruda® is indicated for the treatment of patients with unresectable or metastatic melanoma.

Ketruda® is indicated for adjuvant therapy in adults and children (aged 12 years and older) with stage IIB, IIC, or III melanoma following complete resection.

Non-Small Cell Lung Cancer (NSCLC)

Ketruda® in combination with pemetrexed and a platinum-containing agent is indicated as first-line therapy for patients with metastatic non-squamous NSCLC without epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) gene mutations.

Ketruda® in combination with carboplatin and paclitaxel or protein-bound paclitaxel is indicated as first-line therapy for patients with metastatic squamous NSCLC.

Ketruda® as monotherapy is indicated as first-line therapy for patients with NSCLC whose tumors express PD-L1 [Tumor Proportion Score (TPS) ≥ 1%], confirmed by a validated test, in the absence of EGFR or ALK genomic aberrations, and in cases of:

• Stage III disease when patients are not candidates for surgical resection or definitive chemoradiation, or
• Metastatic disease.

Ketruda® as monotherapy is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥ 1%), confirmed by a validated test, whose disease has progressed during or after platinum-based chemotherapy. For patients with EGFR or ALK genomic aberrations, Ketruda® may be administered after progression on targeted therapy in accordance with standard treatment guidelines for these aberrations.

Ketruda® is indicated for the treatment of patients with resectable NSCLC (tumors ≥ 4 cm or lymph node positive) in combination with platinum-based chemotherapy as neoadjuvant treatment, followed by continued use as monotherapy for adjuvant treatment after surgery.

Ketruda® as monotherapy is indicated for adjuvant treatment following resection and platinum-based chemotherapy in adult patients with stage IB (T2a ≥ 4 cm), II, or IIIA NSCLC.

Head and Neck Squamous Cell Carcinoma (HNSCC)

Ketruda® in combination with platinum and fluorouracil (FU) is indicated as first-line therapy for patients with metastatic or unresectable, recurrent HNSCC.

Ketruda® as monotherapy is indicated as first-line therapy for patients with metastatic or unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥ 1], confirmed by a validated test.

Ketruda® as monotherapy is indicated for the treatment of patients with recurrent or metastatic HNSCC whose disease has progressed on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

Ketruda® is indicated for the treatment of adults with relapsed or refractory classical Hodgkin lymphoma (cHL).

Ketruda® is indicated for the treatment of children with refractory cHL or cHL that has relapsed after two or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma (PMBCL)

Ketruda® is indicated for the treatment of adults and children with refractory primary mediastinal large B-cell lymphoma (PMBCL) or those with relapsed PMBCL after two or more prior therapies.

Use limitation: Ketruda® is not recommended for the treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

Ketruda® in combination with enfortumab vedotin is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma.

Ketruda® as monotherapy is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma:

• Who are not eligible for any platinum-containing chemotherapy, or
• Whose disease has progressed during or after platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.

Ketruda® as monotherapy is indicated for the treatment of patients with high-risk non-muscle-invasive bladder cancer without muscle invasion who are unresponsive to Bacillus Calmette-Guérin (BCG) therapy, with carcinoma in situ with or without papillary tumors, and who are not eligible for (or decline) cystectomy.

Cancers with High Microsatellite Instability or Mismatch Repair Deficiency

Ketruda® is indicated for the treatment of adults and children with unresectable or metastatic solid tumors with high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR), confirmed by a validated test, that have progressed following prior treatment and for whom no satisfactory alternative treatment options are available.

High Microsatellite Instability or Mismatch Repair Deficiency in Patients with Colorectal Cancer

Ketruda® is indicated for the treatment of patients with unresectable or metastatic colorectal cancer (CRC) with high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR), confirmed by a validated test.

Gastric Cancer

Ketruda® in combination with trastuzumab, fluoropyrimidine-, and platinum-containing chemotherapy is indicated as first-line treatment for adults with locally advanced unresectable or metastatic HER2-positive gastric adenocarcinoma or gastroesophageal junction (GEJ) adenocarcinoma, when tumors express PD-L1 [Combined Positive Score (CPS) ≥ 1], confirmed by a validated test.

Ketruda® in combination with fluoropyrimidine- and platinum-containing chemotherapy is indicated as first-line treatment for adults with locally advanced unresectable or metastatic HER2-negative gastric adenocarcinoma or GEJ adenocarcinoma.

Esophageal Cancer

Ketruda® is indicated for the treatment of patients with locally advanced or metastatic esophageal carcinoma or gastroesophageal junction (GEJ) carcinoma (tumor center located 1–5 cm above GEJ) that is not amenable to surgical resection or definitive chemoradiation:

• In combination with platinum- or fluoropyrimidine-based chemotherapy, or
• As monotherapy following one or more prior lines of systemic therapy in patients with squamous histology, when tumors express PD-L1 (CPS ≥ 10), confirmed by a validated test.

Cervical Cancer

Ketruda® in combination with chemoradiation is indicated for the treatment of patients with cervical cancer stage III–IVA according to FIGO 2014.

Ketruda® in combination with chemotherapy, with or without bevacizumab, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS ≥ 1), confirmed by a validated test.

Ketruda® as monotherapy is indicated for the treatment of patients with recurrent or metastatic cervical cancer who have disease progression during or after chemotherapy, when tumors express PD-L1 (CPS ≥ 1), confirmed by a validated test.

Hepatocellular Carcinoma

Ketruda® is indicated for the treatment of patients with hepatocellular carcinoma (HCC) secondary to hepatitis B who have received prior systemic therapy other than a regimen containing PD-1/PD-L1 inhibitors.

Biliary Tract Cancer

Ketruda® in combination with gemcitabine and cisplatin is indicated for the treatment of patients with locally advanced unresectable or metastatic biliary tract cancer (BTC).

Merkel Cell Carcinoma

Ketruda® is indicated for the treatment of adults and children with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC).

Renal Cell Carcinoma

Ketruda® in combination with axitinib is indicated as first-line therapy for the treatment of adults with advanced renal cell carcinoma (RCC).

Ketruda® is indicated for adjuvant therapy in patients with RCC at moderate or high risk of recurrence following nephrectomy or following nephrectomy and resection of metastatic lesions.

Endometrial Carcinoma

Ketruda® in combination with carboplatin and paclitaxel, followed by continued use of Ketruda® as monotherapy, is indicated for the treatment of adult patients with primary advanced or recurrent endometrial carcinoma.

Ketruda® as monotherapy is indicated for the treatment of adult patients with advanced endometrial carcinoma that is MSI-H or dMMR, confirmed by a validated test, who have disease progression following prior systemic therapy in any setting and who are not candidates for surgery or radiation (see section "Dosage and Administration").

Cancers with High Tumor Mutational Burden (TMB-H)

Ketruda® is indicated for the treatment of adults and children with unresectable or metastatic solid tumors with high tumor mutational burden (TMB-H) [≥ 10 mutations per megabase (mut/Mb)], confirmed by a validated test (see section "Dosage and Administration), whose disease has progressed following prior treatment and for whom no satisfactory alternative treatment options are available.

Use limitation: The safety and efficacy of Ketruda® in children with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

Ketruda® is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not amenable to surgical or radiation therapy.

Triple-Negative Breast Cancer

Ketruda® is indicated for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant therapy, followed by continued use as adjuvant monotherapy after surgery.

Ketruda® in combination with chemotherapy is indicated for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥ 10), confirmed by a validated test (see section "Dosage and Administration").

Classical Hodgkin Lymphoma in Adults and Primary Mediastinal Large B-Cell Lymphoma in Adults: Additional Dosing Schedule of 400 mg Every 6 Weeks

Ketruda® is indicated for use at the additional recommended dose of 400 mg every 6 weeks in classical Hodgkin lymphoma and primary mediastinal large B-cell lymphoma in adults (see sections "Indications" and "Dosage and Administration"). This indication was approved under accelerated approval based on pharmacokinetic data, exposure-response relationships for efficacy and safety (see section "Pharmacological Properties"). Continued approval for this dosing regimen may depend on verification and description of clinical benefit in confirmatory trials.

Contraindications.

Severe hypersensitivity to the active substance (pembrolizumab) or to any of the excipients of the medicinal product (see section "Composition").

Interaction with Other Medicinal Products and Other Forms of Interaction.

Formal pharmacokinetic interaction studies between pembrolizumab and other medicinal products have not been conducted. Since pembrolizumab is eliminated from the bloodstream via catabolism, metabolic interactions with other drugs are not expected.

Concomitant use of systemic corticosteroids or other immunosuppressants should be avoided prior to initiation of pembrolizumab therapy due to potential impact on the pharmacodynamic activity and efficacy of pembrolizumab. However, systemic corticosteroids or other immunosuppressants may be administered after initiation of pembrolizumab to manage immune-mediated adverse reactions (see section "Special Warnings and Precautions for Use").

Corticosteroids may also be used as premedication when Ketruda® is administered in combination with chemotherapy, for prevention of nausea and vomiting and/or to alleviate chemotherapy-related side effects.

Special precautions.

Severe and fatal immune-mediated adverse reactions

Keytruda® is a monoclonal antibody belonging to the class of drugs that bind either to programmed death receptor-1 (PD-1) or to PD-ligand 1 (PD-L1), thereby blocking the PD-1/PD-L1 pathway, releasing inhibition of the immune response, potentially disrupting peripheral tolerance, and causing immune-mediated adverse reactions. Important immune-mediated adverse reactions listed in the "Special precautions" section may not include all possible severe and fatal immune-mediated adverse reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and may affect more than one organ system simultaneously. Immune-mediated adverse reactions may occur at any time after initiation of treatment with PD-1/PD-L1 blocking antibodies. Although immune-mediated adverse reactions typically occur during treatment with PD-1/PD-L1 blocking antibodies, they may also manifest after discontinuation of PD-1/PD-L1 blocking antibodies.

Early detection and management of immune-mediated adverse reactions are critical to ensure the safe use of PD-1/PD-L1 blocking antibodies. Patients should be closely monitored for symptoms and signs that may represent clinical manifestations of major immune-mediated adverse reactions. Liver enzymes, creatinine, and thyroid function should be assessed at baseline and periodically during treatment. In patients with TNBC who received Keytruda® as neoadjuvant therapy, serum cortisol levels should be monitored at baseline, prior to surgery, and as clinically indicated.

In case of suspected immune-mediated adverse reactions, appropriate investigations should be performed to exclude alternative etiologies, including infection. Prompt medical evaluation should be provided, including specialist consultation if necessary.

Administration of Keytruda® should be withheld or permanently discontinued depending on severity (see section "Dosage and administration"). If interruption or discontinuation of Keytruda® is required, systemic corticosteroid therapy (1–2 mg/kg/day of prednisone or equivalent) should be initiated until adverse reactions improve to grade 1 or lower. After improvement to grade 1 or lower, tapering of corticosteroids should be initiated and continued for at least 1 month. Consideration should be given to the use of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroids.

Recommendations for managing toxicities that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-mediated pneumonitis

Keytruda® may cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have previously received thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving Keytruda®, including fatal cases (0.1%), grade 4 (0.3%), grade 3 (0.9%), and grade 2 (1.3) adverse reactions. Systemic corticosteroids were required in 67% (63/94) of patients with pneumonitis. Pneumonitis led to permanent discontinuation of Keytruda® in 1.3% (36) of patients and interruption of Keytruda® in 0.9% (26) patients. All patients whose treatment was interrupted resumed Keytruda® after symptom improvement; among them, 23% experienced pneumonitis recurrence. Pneumonitis resolved in 59% of the 94 patients.

In clinical trials involving 389 adult patients with cHL receiving Keytruda® as monotherapy, pneumonitis occurred in 31 (8%) patients, including grade 3–4 pneumonitis in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). The frequency of pneumonitis was similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of Keytruda® in 21 (5.4%) patients. Among patients who developed pneumonitis, 42% interrupted treatment with Keytruda®, 68% discontinued treatment with Keytruda®, and 77% recovered.

Immune-mediated colitis

Keytruda® may cause immune-mediated colitis, which may be accompanied by diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In case of corticosteroid-refractory colitis, repeat infectious workup should be considered to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving Keytruda®, including grade 4 (<0.1%), grade 3 (1.1%), and grade 2 (0.4%) adverse reactions. Systemic corticosteroids were required in 69% (33/48) of patients with colitis. Additional immunosuppressive therapy was needed in 4.2% of patients. Colitis led to permanent discontinuation of Keytruda® in 0.5% (15) of patients and interruption of Keytruda® in 0.5% (13) patients. All patients whose treatment was interrupted resumed Keytruda® after symptom improvement; among them, 23% experienced colitis recurrence. Colitis resolved in 85% of the 48 patients.

Hepatotoxicity and immune-mediated hepatitis

Keytruda® as monotherapy

Keytruda® may cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving Keytruda®, including grade 4 (<0.1%), grade 3 (0.4%), and grade 2 (0.1%) adverse reactions. Systemic corticosteroids were required in 68% (13/19) of patients with hepatitis. Eleven percent of these patients required additional immunosuppressive therapy. Hepatitis led to permanent discontinuation of Keytruda® in 0.2% (6) patients and interruption of Keytruda® in 0.3% (9) patients. All patients whose treatment was interrupted resumed Keytruda® after symptom improvement; none experienced hepatitis recurrence. Hepatitis resolved in 79% of the 19 patients.

Keytruda® with axitinib

The use of Keytruda® in combination with axitinib may cause hepatic toxicity with a higher than expected frequency of grade 3 and 4 increases in ALT and AST levels compared to Keytruda® monotherapy. Liver enzymes should be monitored before initiation and periodically throughout treatment. More frequent monitoring of liver enzymes is required compared to monotherapy with these agents. In case of elevated liver enzymes, administration of Keytruda® and axitinib should be interrupted and corticosteroids considered if necessary (see section "Dosage and administration").

When Keytruda® was used in combination with axitinib, grade 3 and 4 elevations in ALT (20%) and AST (13%) were observed. Systemic corticosteroids were administered to 59% of patients with elevated ALT. ALT levels decreased to grade 0–1 in 94% of patients with ALT ≥ 3 times ULN (grades 2–4, n=116). Among 92 patients who resumed treatment with Keytruda® (n=3), axitinib (n=34), or combination therapy (n=55), recurrence of ALT ≥ 3 times ULN occurred in 1 patient receiving Keytruda®, 16 patients receiving axitinib, and 24 patients receiving both Keytruda® and axitinib. All patients with recurrent ALT ≥ 3 times ULN subsequently recovered.

Immune-mediated endocrinopathies

Adrenal insufficiency

Keytruda® may cause primary or secondary adrenal insufficiency. For grade 2 or higher adrenal insufficiency, symptomatic management including hormone replacement therapy as clinically indicated should be initiated. Administration of Keytruda® should be withheld or permanently discontinued depending on severity (see section "Dosage and administration").

Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving Keytruda®, including grade 4 (<0.1%), grade 3 (0.3%), and grade 2 (0.3%) adverse reactions. Systemic corticosteroids were required in 77% (17/22) of patients with adrenal insufficiency; most remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of Keytruda® in <0.1% (1) of patients and discontinuation of further Keytruda® use in 0.3% (8) patients. All patients whose treatment was interrupted resumed Keytruda® after symptom improvement.

Hypophysitis

Keytruda® may cause immune-mediated hypophysitis. Hypophysitis may present with acute symptoms related to systemic effects such as headache, photophobia, or visual field defects. Hypophysitis may lead to hypopituitarism. Hormone replacement therapy should be initiated as indicated. Administration of Keytruda® should be withheld or permanently discontinued depending on severity (see section "Dosage and administration").

Hypophysitis occurred in 0.6% (17/2799) of patients receiving Keytruda®, including grade 4 (<0.1%), grade 3 (0.3%), and grade 2 (0.2%) adverse reactions. Systemic corticosteroids were required in 94% (16/17) of patients with hypophysitis; most remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of Keytruda® in 0.1% (4) patients and interruption of Keytruda® in 0.3% (7) patients. All patients whose treatment was interrupted resumed Keytruda® after symptom improvement.

Thyroid dysfunction

Keytruda® may cause immune-mediated thyroid disorders. Thyroiditis may occur with or without endocrinopathy. Hypothyroidism may follow hyperthyroidism. Hormone replacement therapy should be initiated for hypothyroidism or medical management of hyperthyroidism initiated as clinically indicated. Administration of Keytruda® should be withheld or permanently discontinued depending on severity (see section "Dosage and administration").

Thyroiditis occurred in 0.6% (16/2799) of patients receiving Keytruda®, including grade 2 cases (0.3%). No patient discontinued Keytruda® due to thyroiditis. Administration of Keytruda® was interrupted in <0.1% (1) of patients.

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving Keytruda®, including grade 3 (0.1%) and grade 2 (0.8%). Hyperthyroidism led to permanent discontinuation of Keytruda® in <0.1% (2) patients and interruption of Keytruda® in 0.3% (7) patients. All patients whose treatment was interrupted resumed Keytruda® after symptom improvement.

Hypothyroidism occurred in 8% (237/2799) of patients receiving Keytruda®, including grade 3 (0.1%) and grade 2 (6.2%). Hypothyroidism led to permanent discontinuation of Keytruda® in <0.1% (1) patient and interruption of Keytruda® in 0.5% (14) patients. All patients whose treatment was interrupted resumed Keytruda® after symptom improvement. Most patients with hypothyroidism required long-term thyroid hormone replacement therapy.

The incidence of new-onset or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving Keytruda® as monotherapy or in combination with platinum and 5-FU, including grade 3 hypothyroidism (0.3%). The incidence of new-onset or worsening hypothyroidism was higher in 389 patients with cHL (17%) receiving Keytruda® as monotherapy, including grade 1 (6.2%) and grade 2 (10.8%) hypothyroidism.

Type 1 diabetes mellitus, which may present with diabetic ketoacidosis

Patients should be monitored for the development of hyperglycemia or other signs and symptoms of diabetes. Insulin therapy should be initiated as clinically indicated. Administration of Keytruda® should be withheld or permanently discontinued depending on severity (see section "Dosage and administration").

Type 1 diabetes mellitus occurred in 0.2% (6/2799) of patients receiving Keytruda®. Type 1 diabetes led to permanent discontinuation in <0.1% (1) patient and interruption of Keytruda® in <0.1% (1) patient. All patients whose treatment was interrupted resumed Keytruda® after symptom improvement. All patients with type 1 diabetes required long-term insulin therapy.

Immune-mediated nephritis and renal dysfunction

Keytruda® may cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving Keytruda®, including grade 4 (<0.1%), grade 3 (0.1%), and grade 2 (0.1%) adverse reactions. Systemic corticosteroids were required in 89% (8/9) of patients with nephritis. Nephritis led to permanent discontinuation of Keytruda® in 0.1% (3) patients and interruption of Keytruda® in 0.1% (3) patients. All patients whose treatment was interrupted resumed Keytruda® after symptom improvement; none experienced nephritis recurrence. Nephritis resolved in 56% of the 9 patients.

Immune-mediated dermatologic adverse reactions

Keytruda® may cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, DRESS (drug reaction with eosinophilia and systemic symptoms), and toxic epidermal necrolysis (TEN), has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be sufficient for managing mild to moderate non-exfoliative rash. Administration of Keytruda® should be withheld or discontinued depending on severity (see section "Dosage and administration").

Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving Keytruda®, including grade 3 (1%) and grade 2 (0.1%) adverse reactions. Systemic corticosteroids were required in 40% (15/38) of patients with immune-mediated dermatologic adverse reactions. Immune-mediated dermatologic adverse reactions led to permanent discontinuation of Keytruda® in 0.1% (2) patients and interruption of Keytruda® in 0.6% (16) patients. All patients whose treatment was interrupted resumed Keytruda® after symptom improvement; 6% experienced recurrence of immune-mediated dermatologic adverse reactions. Immune-mediated dermatologic adverse reactions resolved in 79% of the 38 patients.

Other immune-mediated adverse reactions

The following clinically significant immune-mediated adverse reactions were observed at a frequency of <1% (unless otherwise specified) in patients receiving Keytruda® or reported with other PD-1/PD-L1 blocking antibodies. Some of these adverse reactions have been severe or fatal.

Cardiac/vascular system: myocarditis, pericarditis, vasculitis.

Nervous system: meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy.

Eyes: uveitis, iritis, and other inflammatory ocular toxicities may occur. Some cases may be associated with retinal detachment. Various degrees of visual impairment, including blindness, may occur. If uveitis occurs in combination with other immune-mediated adverse reactions, Vogt-Koyanagi-Harada-like syndrome should be considered, as this may require systemic steroid treatment to reduce the risk of permanent vision loss.

Gastrointestinal tract: pancreatitis, including elevated serum amylase and lipase, gastritis, duodenitis, exocrine pancreatic insufficiency.

Hepatobiliary system: sclerosing cholangitis.

Musculoskeletal and connective tissue: myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), rheumatic polymyalgia.

Endocrine system: hypoparathyroidism.

Hematologic/immune disorders: hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, rejection of other transplants (including corneal transplants).

Complications of allogeneic HSCT

Fatal and other serious complications may occur in patients who have undergone allogeneic hematopoietic stem cell transplantation (HSCT) either before or after treatment with PD-1/PD-L1 blocking antibodies. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning, and steroid-requiring febrile syndrome (without established infectious cause). These complications may occur regardless of the time interval between PD-1/PD-L1 blockade and allogeneic HSCT.

Patients should be closely monitored for transplant-related complications and managed promptly. The benefits and risks of treatment with PD-1/PD-L1 blocking antibodies before or after allogeneic HSCT should be carefully considered.

Infusion-related reactions

Keytruda® may cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, reported in 0.2% of 2799 patients receiving this medicinal product. Patients should be monitored for signs and symptoms of infusion-related reactions such as chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. Infusion should be interrupted or the rate slowed in case of mild (grade 1) or moderate (grade 2) infusion-related reactions. Infusion should be discontinued and Keytruda® permanently discontinued in case of severe (grade 3) or life-threatening (grade 4) infusion-related reactions (see section "Dosage and administration").

Increased mortality in patients with multiple myeloma when Keytruda® is added to a thalidomide analogue and dexamethasone

In two randomized clinical trials in patients with multiple myeloma, adding Keytruda® to a thalidomide analogue plus dexamethasone, for which PD-1 or PD-L1 blocking antibodies are not indicated, resulted in increased mortality. Treatment of patients with multiple myeloma using PD-1 or PD-L1 blocking antibodies in combination with a thalidomide analogue and dexamethasone is not recommended outside controlled clinical trials.

Embryo-fetal toxicity

Due to its mechanism of action, Keytruda® may have adverse effects on the fetus when administered to pregnant women. In animal models, the PD-1/PD-L1 signaling pathway has been shown to be important for maintaining pregnancy by inducing maternal immune tolerance to fetal tissues.

Women should be advised of the potential risk to the fetus. Women of reproductive potential should be advised to use effective contraception during treatment with Keytruda® and for 4 months after the last dose.

Use during pregnancy or breastfeeding.

Pregnancy

Risk summary

Due to its mechanism of action, Keytruda® may have adverse effects on the fetus when administered to pregnant women. There are no available human data on the risk of embryo-fetal toxicity. In animal models, the PD-1/PD-L1 signaling pathway is important for maintaining pregnancy by inducing maternal immune tolerance to fetal tissues. Human IgG4 immunoglobulins are known to cross the placenta; therefore, transfer of pembrolizumab from mother to developing fetus is possible. Pregnant women should be advised of the potential risk to the fetus.

In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Data

Animal reproduction studies

Reproductive toxicity studies with Keytruda® in animals to evaluate its effects on fertility and fetal development have not been conducted. Evaluation of the impact of the PD-1 pathway on reproductive function based on published data indicates that a central function of the PD-1/PD-L1 pathway is maintenance of pregnancy through induction of maternal immune tolerance to fetal tissues. In a mouse pregnancy model, blockade of the PD-L1 signaling pathway disrupted fetal tolerance and led to increased fetal loss; thus, potential risks of Keytruda® use during pregnancy include increased rates of abortion or stillbirth. According to published reports, no developmental abnormalities related to PD-1 pathway blockade were observed in offspring of these animals; however, immune-mediated disorders occurred in PD-1 knockout mice. Due to its mechanism of action, the effect of pembrolizumab on the fetus may increase the risk of immune-mediated disorders or altered normal immune responses.

Breastfeeding

There are no data on the presence of pembrolizumab in human or animal milk, or on its effects on the breastfed child or milk production. Maternal IgG is known to be present in human milk. The local effects of Keytruda® on the gastrointestinal tract and limited systemic effects in the breastfed child are unknown. Due to the potential for serious adverse reactions in breastfed children, women are advised not to breastfeed during treatment with Keytruda® and for 4 months after the last dose.

Fertility in women and men

Pregnancy testing

Women of reproductive potential should have a pregnancy test performed before starting treatment with Keytruda® (see subsection "Pregnancy").

Contraception

Keytruda® may harm the fetus when administered to a pregnant woman (see section "Special precautions", subsection "Pregnancy"). Women of reproductive potential are advised to use effective contraception during treatment with Keytruda® and for 4 months after the last dose.

Effect on ability to drive and use machines.

Pembrolizumab may have a minor influence on the ability to drive and use machines. Fatigue has been reported after administration of pembrolizumab.

Administration and Dosage

Only qualified physicians experienced in cancer treatment should prescribe and monitor therapy.

Patient Selection for Monotherapy

Patient selection for treatment with KEYTRUDA® as monotherapy is based on positive PD-L1 expression in:

• Stage III NSCLC, if patients are not candidates for surgical resection or definitive chemoradiation;
• metastatic NSCLC;
• first-line treatment of metastatic or unresectable, recurrent HNSCC;
• metastatic urothelial carcinoma;
• previously treated recurrent locally advanced or metastatic esophageal cancer;
• recurrent or metastatic cervical cancer with disease progression during or after chemotherapy.

The tumor MSI or MMR status should be assessed using a validated test.

For MSI-H/dMMR indications, select patients for treatment with KEYTRUDA® as monotherapy based on MSI-H/dMMR status in tumor specimens.

For the TMB-H indication, select patients for treatment with KEYTRUDA® as monotherapy based on TMB-H status in tumor specimens.

Since subclonal dMMR mutations and microsatellite instability may develop in high-grade gliomas during temozolomide therapy, testing for TMB-H, MSI-H, and dMMR is recommended in primary tumor samples obtained prior to initiation of temozolomide chemotherapy in patients with high-grade gliomas.

Patient Selection for Combination Therapy

Patients should be selected for treatment with KEYTRUDA® in combination with chemotherapy and trastuzumab based on positive PD-L1 expression (CPS ≥1) in locally advanced unresectable or metastatic HER2-positive adenocarcinoma of the stomach or gastroesophageal junction (GEJ).

Patients should be selected for treatment with KEYTRUDA® in combination with chemotherapy, with or without bevacizumab, based on positive PD-L1 expression in persistent, recurrent, or metastatic cervical cancer.

Patient selection for treatment with KEYTRUDA® in combination with chemotherapy is based on positive PD-L1 expression in:

• locally recurrent unresectable or metastatic TNBC.

Recommended Doses

Table 1. Recommended Doses

* 30-minute intravenous infusion

† Refer to the prescribing information for the combination drugs for recommended dosing information, if necessary.

‡ When axitinib is used in combination with KEYTRUDA, dose escalation of axitinib above the starting dose of 5 mg may be considered at intervals of six weeks or longer.

§ Patients who experience disease progression or unacceptable toxicity associated with KEYTRUDA during neoadjuvant therapy in combination with chemotherapy should not receive adjuvant monotherapy with KEYTRUDA.

Dosage Modifications

Dose reduction of KEYTRUDA is not recommended. In general, withhold KEYTRUDA for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue KEYTRUDA for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions requiring systemic immunosuppressive therapy, or inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating steroids.

Changes in KEYTRUDA dosing for adverse reactions requiring management different from these general recommendations are described in Table 2.

Table 2. Recommended Dosage Modifications for Adverse Reactions

* Based on the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0

† Reinitiate treatment in patients who achieve complete or partial resolution (Grade 0 to 1) following corticosteroid tapering. Permanently discontinue therapy if complete or partial resolution is not achieved or if the prednisone dose cannot be reduced to 10 mg per day or less (or equivalent) within 12 weeks after initiation of steroid treatment.

‡ If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue KEYTRUDA® based on hepatitis management guidelines in the absence of liver involvement.

ALT – alanine aminotransferase, AST – aspartate aminotransferase, DRESS – drug reaction with eosinophilia and systemic symptoms, SJS – Stevens-Johnson syndrome, TEN – toxic epidermal necrolysis, ULN – upper limit of normal

Table 3 presents dose modifications different from those described above for KEYTRUDA® or as specified in the prescribing information for the drug administered in combination.

Table 3. Dose modification recommendations for adverse reactions associated with combination therapy including KEYTRUDA®

* Consider corticosteroid therapy

† Based on the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.

Consider re-administration of a single agent or sequential re-administration of both agents after recovery. If retreatment with axitinib is undertaken, dose reduction should be considered according to axitinib prescribing information.

ALT – alanine aminotransferase, AST – aspartate aminotransferase, ULN – upper limit of normal

Preparation for intravenous infusion

• Visually inspect the concentrate for infusion solution for the presence of particulate matter and discoloration. The solution should be from clear to slightly opalescent and colorless to light yellow. Discard the vial if visible particles are observed.
• Dilute the KeYtruda^® concentrate solution before intravenous administration.
• Withdraw the required volume (see section "Dosage and administration") of KeYtruda^® from the vial and transfer it into an intravenous infusion bag or bottle containing 0.9% sodium chloride injection or 5% dextrose injection. Mix the diluted solution gently by inverting the bag (or vial). Do not shake. The final concentration of the diluted solution should be between 1 mg/mL and 10 mg/mL.
• Destroy any unused portion of the drug remaining in the vial.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Storage of the diluted solution

The product does not contain a preservative.

Store the diluted KeYtruda^® 100 mg/4 mL solution in the vial:

• At room temperature for no more than 6 hours after dilution. This time includes storage of the diluted solution at room temperature and the duration of infusion.
• In a refrigerator at 2–8 °C for no more than 96 hours after dilution.

If the solution has been refrigerated, allow it to reach room temperature before administration. Do not shake.

Discard after 6 hours at room temperature or after 96 hours of refrigeration. Do not freeze.

Method of administration

• Administer the diluted solution intravenously over 30 minutes using an infusion set containing a sterile, non-pyrogenic, low protein-binding in-line or add-on filter with a pore size of 0.2 to 5 microns.
• Do not co-administer other medicinal products through the same infusion line.

Elderly patients

Among 3781 patients with melanoma, NSCLC, HNSCC, or urothelial carcinoma who received KeYtruda^® in clinical studies, 48% were aged 65 years and older, and 17% were aged 75 years and older. Overall, no differences in safety or effectiveness were observed between elderly patients and younger patients.

Among 389 adult patients with cHL who received KeYtruda^® in clinical studies, 46 (12%) were aged 65 years and older. The incidence of serious adverse reactions was higher in patients aged 65 years and older (50%) compared to patients younger than 65 years (24%). The clinical studies of KeYtruda^® in cHL did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients.

Among 506 adult patients with stage IB (T2a ≥ 4 cm), II, or IIIA NSCLC who received KeYtruda^® after complete resection and platinum-based chemotherapy in the KEYNOTE-091 study, 242 (48%) were aged 65 years and older. Overall, no differences in safety or efficacy outcomes were observed between elderly and younger patients.

Among 596 adult patients with TNBC who received KeYtruda^® in combination with paclitaxel, protein-bound paclitaxel, or gemcitabine and carboplatin in the KEYNOTE-355 study, 137 (23%) were aged 65 years and older. Overall, no differences in safety or effectiveness were observed between elderly and younger patients.

Among 564 patients with locally advanced or metastatic urothelial cancer who received KeYtruda^® in combination with enfortumab vedotin, 44% (n = 247) were aged 65–74 years and 26% (n = 144) were aged 75 years and older. No overall differences in safety or efficacy were observed between patients aged 65 years and older and younger patients. In patients aged 75 years and older receiving KeYtruda^® in combination with enfortumab vedotin, a higher incidence of fatal adverse reactions was observed compared to younger patients. The incidence of fatal adverse reactions was 4% in patients younger than 75 years and 7% in patients aged 75 years and older.

Among 432 patients randomized to receive KeYtruda^® in combination with axitinib in the KEYNOTE-426 study, 40% were aged 65 years and older. No overall differences in safety or effectiveness were reported between patients aged ≥65 years and younger patients.

Among 292 adult patients with FIGO 2014 stage III–IVA cervical cancer who received KeYtruda^® in combination with chemoradiotherapy (CRT) in the KEYNOTE-A18 study, 42 (14%) were aged 65 years and older. No overall differences in safety and efficacy were observed between elderly and younger patients.

Children

The safety and efficacy of KeYtruda^® as monotherapy have been established in children with melanoma, cHL, PMBCL, MCC, MSI-H or dMMR tumors, and TMB-H cancer. The use of KeYtruda^® in children for these indications is supported by adequate and well-controlled studies in adults, supplemented by pharmacokinetic and safety data in children (see sections "Adverse reactions" and "Pharmacological properties").

In the KEYNOTE-051 study, 173 children (65 children aged 6 months to 12 years and 108 children aged 12 to 17 years) with advanced melanoma, lymphoma, or PD-L1-positive solid tumors received KeYtruda^® at a dose of 2 mg/kg every 3 weeks. The median duration of treatment was 2.1 months (range: 1 day to 25 months). Adverse reactions observed in children at a frequency ≥10% higher than in adults included pyrexia (33%), vomiting (29%), headache (25%), abdominal pain (23%), lymphocyte count decreased (13%), and leukocyte count decreased (11%). Laboratory abnormalities observed in children at a frequency ≥10% higher than in adults included leukopenia (31%), neutropenia (28%), thrombocytopenia (22%), and grade 3 anemia (17%).

The safety and efficacy of KeYtruda^® in children for other registered indications have not been established (see section "Indications").

Overdose

There is no information on pembrolizumab overdose.

In the event of an overdose, patients should be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment should be initiated.

Adverse Reactions

Because clinical trials are conducted under widely varying conditions, the incidence of adverse reactions observed in clinical trials of one drug cannot be directly compared with those of other drugs, and may not reflect the incidence of adverse reactions observed in clinical practice.

The data in the section "Clinical Studies" include information on exposure to KEYTRUDA® administered as monotherapy to 2799 patients in three randomized, open-label, active-controlled clinical trials (KEYNOTE-002, KEYNOTE-006, and KEYNOTE-010), of whom 912 had melanoma and 682 had NSCLC, as well as in one single-arm trial (KEYNOTE-001), in which 655 patients had melanoma and 550 had NSCLC.

In addition to these data from 2799 patients, certain subsections of the "Clinical Studies" section describe adverse reactions observed with KEYTRUDA® monotherapy in a non-randomized, open-label, multicohort trial (KEYNOTE-012), in a non-randomized, open-label, single-cohort trial (KEYNOTE-055), and in two randomized, open-label, active-controlled trials (monotherapy arms of KEYNOTE-040 and KEYNOTE-048) involving 909 patients with HNSCC; in two non-randomized, open-label trials (KEYNOTE-013 and KEYNOTE-087) and one randomized, open-label, active-controlled clinical trial (KEYNOTE-204) involving 389 patients with cHL; in the combination therapy arm of a randomized, open-label, active-controlled trial (KEYNOTE-048) involving 276 patients with HNSCC; in combination with axitinib in a randomized, active-controlled trial (KEYNOTE-426) involving 429 patients with RCC; and during post-marketing use.

In all trials, KEYTRUDA® was administered intravenously at doses of 2 mg/kg every 3 weeks, 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 200 mg every 3 weeks. Forty-one percent (41%) of the 2799 patients received the drug for 6 months or longer, and 21% received it for 12 months or longer.

Melanoma

Melanoma without prior ipilimumab treatment

The safety of KEYTRUDA® in patients with unresectable or metastatic melanoma who had not received prior ipilimumab treatment and who had received no more than one prior systemic therapy was evaluated in KEYNOTE-006. KEYNOTE-006 was a multicenter, open-label, active-controlled trial in which patients were randomized (1:1:1) to receive KEYTRUDA® at a dose of 10 mg/kg every 2 weeks (n = 278) or 10 mg/kg every 3 weeks (n = 277) until disease progression or unacceptable toxicity, or to receive ipilimumab at a dose of 3 mg/kg every 3 weeks for up to 4 doses unless discontinued earlier due to disease progression or unacceptable toxicity (n = 256). Patients with autoimmune disease, conditions requiring systemic corticosteroids or other immunosuppressants, history of interstitial lung disease, or active infection requiring treatment, including HIV or hepatitis B or C, were excluded from the trials.

The median duration of exposure to KEYTRUDA® was 5.6 months (range: 1 day to 11.0 months) and was similar in both treatment groups. Fifty-one percent (51%) and 46% of patients received KEYTRUDA® at 10 mg/kg every 2 weeks or every 3 weeks, respectively, for ≥ 6 months. No patient received treatment beyond 1 year.

Study participants had the following characteristics: median age of 62 years (range: 18 to 89); 60% male; 98% White; 32% had elevated baseline lactate dehydrogenase (LDH) levels; 65% had M1c stage disease; 9% had a history of brain metastases; approximately 36% of patients had received prior systemic therapy, including BRAF inhibitors (15%), chemotherapy (13%), and immunotherapy (6%).

In KEYNOTE-006, the adverse reaction profile was similar between the every-2-weeks and every-3-weeks dosing regimens; therefore, safety findings are presented in a combined analysis (n = 555) of both KEYTRUDA® treatment groups. Adverse reactions leading to permanent discontinuation of KEYTRUDA® occurred in 9% of patients. Adverse reactions leading to permanent discontinuation in more than 1 patient were: colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and heart failure (0.4%). Adverse reactions leading to temporary interruption of KEYTRUDA® occurred in 21% of patients; the most common reaction (≥ 1%) was diarrhea (2.5%).

Tables 4 and 5 summarize the individual adverse reactions and laboratory abnormalities, respectively, observed in patients treated with KEYTRUDA® in KEYNOTE-006.

Table 4. Individual* adverse reactions occurring in ≥ 10% of patients treated with KEYTRUDA® in KEYNOTE-006

* Adverse reactions occurring at the same or higher frequency compared to the ipilimumab group

† Grades according to NCI CTCAE v4.0

‡ Includes rash, erythematous rash, follicular rash, generalized rash, macular rash, maculopapular rash, papular rash, pruritic rash, exfoliative rash

§ Includes hypopigmentation of the skin

Other clinically important adverse reactions occurring in ≥ 10% of patients receiving KITRUDA®: diarrhea (26%), nausea (21%), and pruritus (17%).

Table 5. Individual* laboratory abnormalities from baseline occurring in ≥ 20% of patients with melanoma treated with KITRUDA® in KEYNOTE-006

*Adverse reactions that occurred with equal or higher frequency compared to the ipilimumab group

† Frequency is based on the number of patients with baseline test results and at least 1 result during the study: Keytruda® (range: 520 to 546 patients) and ipilimumab (range: 237 to 247 patients); hypertriglyceridemia: Keytruda® n = 429 and ipilimumab n = 183; hypercholesterolemia: Keytruda® n = 484 and ipilimumab n = 205.

‡ Grades according to NCI CTCAE v4.0

Other laboratory test abnormalities observed in ≥ 20% of patients treated with Keytruda®: worsening of hypoalbuminemia (27% all grades; 2.4% grades 3–4), increased ALT levels (23% all grades; 3.1% grades 3–4), and increased alkaline phosphatase levels (21% all grades; 2% grades 3–4).

Ipilimumab-refractory melanoma

The safety of Keytruda® in patients with unresectable or metastatic melanoma who had disease progression after treatment with ipilimumab and, if BRAF V600 mutation-positive, a BRAF inhibitor, was evaluated in KEYNOTE-002. KEYNOTE-002 was a multicenter, partially blinded (to Keytruda® dose), randomized (1:1:1), active-controlled trial involving 528 patients who received Keytruda® at a dose of 2 mg/kg (n = 178) or 10 mg/kg (n = 179) every 3 weeks or investigator’s choice chemotherapy (n = 171), which included dacarbazine (26%), temozolomide (25%), paclitaxel and carboplatin (25%), paclitaxel (16%), and carboplatin (8%). Patients with autoimmune disease, severe immune-mediated toxicity associated with prior ipilimumab use defined as grade 4 toxicity or grade 3 toxicity requiring corticosteroids (more than 10 mg/day prednisone or equivalent dose) for more than 12 weeks, medical conditions requiring systemic corticosteroids or other immunosuppressants, history of interstitial lung disease, or active infection requiring treatment, including HIV or hepatitis B or C, were excluded from the study.

The median duration of exposure to Keytruda® at a dose of 2 mg/kg every 3 weeks was 3.7 months (range: 1 to 16.6 months), and at a dose of 10 mg/kg every 3 weeks was 4.8 months (range: 1 to 16.8 months). Keytruda® at a dose of 2 mg/kg was administered to 36% of patients for ≥ 6 months and to 4% of patients for ≥ 12 months. In the 10 mg/kg Keytruda® group, 41% of patients received the drug for ≥ 6 months and 6% for ≥ 12 months.

Study participants had the following characteristics: median age of 62 years (range: 15 to 89); 61% male; 98% Caucasian; 41% had elevated baseline lactate dehydrogenase (LDH) levels; 83% had M1c stage disease; approximately 73% of patients had received 2 or more prior systemic therapies for progressive disease or metastases (100% had received ipilimumab and 25% a BRAF inhibitor), and 15% had a history of brain metastases.

In KEYNOTE-002, the adverse reaction profile was similar between the 2 mg/kg and 10 mg/kg doses; therefore, safety findings are presented in a combined analysis (n = 357) of both Keytruda® treatment groups.

Adverse reactions leading to complete discontinuation of Keytruda® occurred in 12% of patients. The most frequent reactions (≥ 1%) were worsening general health condition (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). Adverse reactions leading to treatment interruption occurred in 14% of patients; the most frequent (≥ 1%) were dyspnea (1%), diarrhea (1%), and maculopapular rash (1%).

Tables 6 and 7 summarize the adverse reactions and laboratory abnormalities observed in patients treated with Keytruda® in KEYNOTE-002, respectively.

Table 6. Individual* adverse reactions occurring in ≥ 10% of patients receiving Keytruda® in KEYNOTE-002

* Adverse reactions that occurred with equal or greater frequency compared to the chemotherapy treatment group

† Chemotherapy: dacarbazine, temozolomide, carboplatin plus paclitaxel, or carboplatin

‡ Grades according to NCI CTCAE v4.0

§ Includes rash, erythematous rash, generalized rash, macular rash, maculopapular rash, papular rash, pruritic rash

Other clinically significant adverse reactions observed in patients treated with KEYTRUDA®: fatigue (43%), nausea (22%), decreased appetite (20%), vomiting (13%), and peripheral neuropathy (1.7%).

Table 7. Individual* laboratory abnormalities from baseline occurring in ≥ 20% of melanoma patients treated with KEYTRUDA® in KEYNOTE-002

* Adverse reactions that occurred with equal or greater frequency compared to the chemotherapy group

† Frequency is based on the number of patients with baseline test results and at least one result during the study: KEYTRUDA® (range: 320 to 325 patients) and chemotherapy (range: 154 to 161 patients); hypertriglyceridemia: KEYTRUDA® n = 247 and chemotherapy n = 116; decreased bicarbonate level: KEYTRUDA® n = 263 and chemotherapy n = 123.

‡ Grades according to NCI CTCAE v4.0

Other laboratory test abnormalities observed in ≥ 20% of patients treated with KEYTRUDA®: anemia (44% all grades; 10% grades 3–4), lymphopenia (40% all grades; 9% grades 3–4).

Adjuvant treatment of stage IIB or IIC melanoma after resection

In 969 patients with stage IIB or IIC melanoma enrolled in the KEYNOTE-716 study who received KEYTRUDA®, the median duration of exposure to KEYTRUDA® was 9.9 months (range: 0 to 15.4 months). Patients with autoimmune disease or medical conditions requiring immunosuppression, or mucosal or ocular melanoma, were not included. Adverse reactions observed in patients with stage IIB or IIC melanoma were similar to those observed in 1011 patients with stage III melanoma from the KEYNOTE-054 study or in 2799 patients with melanoma or NSCLC who received KEYTRUDA® as monotherapy.

Adjuvant treatment of stage III melanoma after resection

The safety of KEYTRUDA® as monotherapy was evaluated in a randomized (1:1), double-blind study, KEYNOTE-054, in which 1019 patients with completely resected stage IIIA (lymph node metastases > 1 mm), IIIB, or IIIC melanoma received 200 mg of KEYTRUDA® as an intravenous infusion every 3 weeks (n = 509) or placebo (n = 502) for 1 year. Patients with active autoimmune disease or medical conditions requiring immunosuppression, or mucosal or ocular melanoma, were not included in the study. Seventy-six percent of patients received KEYTRUDA® for 6 months or longer.

Study participants had the following characteristics: median age 54 years (range: 19 to 88); 25% were aged 65 years or older; 62% were male; 94% had ECOG PS 0 and 6% had ECOG PS 1. Sixteen percent had stage IIIA, 46% had stage IIIB, 18% had stage IIIC (positive in 1–3 lymph nodes), and 20% had stage IIIC (positive in ≥ 4 lymph nodes).

Two patients receiving KEYTRUDA® died from causes other than disease progression; the causes of death were drug reaction with eosinophilia and systemic symptoms (DRESS) and autoimmune myositis with respiratory failure. Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA®. Adverse reactions leading to permanent discontinuation of KEYTRUDA® occurred in 14% of patients; the most frequent (≥ 1%) were: pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Adverse reactions leading to interruption of KEYTRUDA® occurred in 19% of patients; the most frequent reactions (≥ 1%) were: diarrhea (2.4%), pneumonitis (2%), increased ALT (1.4%), arthralgia (1.4%), increased AST (1.4%), dyspnea (1%), and fatigue (1%).

Tables 8 and 9 summarize the adverse reactions and laboratory abnormalities observed in patients receiving KEYTRUDA® in KEYNOTE-054.

Table 8. Individual* adverse reactions occurring in ≥ 10% of patients receiving KEYTRUDA® in KEYNOTE-054

* Adverse reactions occurring at the same or higher frequency compared to the placebo group

† Grading according to NCI CTCAE v4.03

Table 9. Individual* laboratory abnormalities from baseline occurring in ≥ 20% of melanoma patients treated with KITRUDA® in KEYNOTE-054

* Laboratory abnormalities occurring at the same or higher frequency compared to the placebo group

† Frequency based on the number of patients with baseline test results and at least one post-baseline result during the study: KEYTRUDA® (range: 503 to 507 patients) and placebo (range: 492 to 498 patients).

‡ Grades according to NCI CTCAE v4.03

NSCLC

First-line treatment of metastatic non-squamous NSCLC in combination with pemetrexed and a platinum agent

The safety of KEYTRUDA® in combination with pemetrexed and investigator’s choice platinum agent (either carboplatin or cisplatin) was evaluated in KEYNOTE-189, a multicenter, double-blind, randomized (2:1), active-controlled trial in patients with previously untreated metastatic non-squamous NSCLC whose tumors lacked genomic aberrations in EGFR or ALK. A total of 607 patients received KEYTRUDA® 200 mg, pemetrexed, and a platinum agent every 3 weeks for 4 cycles, followed by KEYTRUDA® and pemetrexed (n = 405), or placebo, pemetrexed, and a platinum agent every 3 weeks for 4 cycles, followed by placebo and pemetrexed (n = 202). The study excluded patients with autoimmune disease requiring systemic therapy within 2 years prior to study initiation; patients with conditions requiring immunosuppressive therapy; or patients who received more than 30 Gy of thoracic radiation within the prior 26 weeks.

The median duration of treatment with KEYTRUDA® 200 mg every 3 weeks was 7.2 months (range: 1 day to 20.1 months). In the KEYTRUDA® group, 60% of patients received KEYTRUDA® for ≥ 6 months. Carboplatin was administered to 72% of patients.

Study participants had the following characteristics: median age 64 years (range: 34 to 84); 49% were aged 65 years or older; 59% were male; 94% were White, and 3% were Asian; 18% had a history of brain metastases.

Treatment with KEYTRUDA® was discontinued due to adverse reactions in 20% of patients. The most frequent adverse reactions leading to permanent discontinuation of KEYTRUDA® were pneumonitis (3%) and acute kidney injury (2%). Adverse reactions leading to interruption of KEYTRUDA® occurred in 53% of patients; the most frequent adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA® (≥ 2% of patients) were neutropenia (13%), asthenia/fatigue (7%), anemia (7%), thrombocytopenia (5%), diarrhea (4%), pneumonitis (4%), increased blood creatinine (3%), dyspnea (2%), febrile neutropenia (2%), upper respiratory tract infection (2%), increased alanine aminotransferase (ALT) (2%), and pyrexia (2%).

Tables 10 and 11 summarize adverse reactions and laboratory abnormalities, respectively, observed in patients treated with KEYTRUDA® in KEYNOTE-189.

Table 10. Adverse reactions occurring in ≥ 20% of patients in KEYNOTE-189

* Severity grading based on NCI CTCAE criteria, v4.03

† Includes asthenia and fatigue

‡ Includes genital rash, rash, generalized rash, macular rash, maculopapular rash, papular rash, pruritic rash, and pustular rash

Table 11. Laboratory abnormalities compared to baseline occurring in ≥ 20% of patients in KEYNOTE-189

* Frequency is based on the number of patients with both baseline and at least one post-baseline assessment: KEYTRUDA®/pemetrexed/platinum (range: 381 to 401 patients) and placebo/pemetrexed/platinum (range: 184 to 197 patients).

† Grades according to NCI CTCAE v4.03

First-line treatment of metastatic squamous NSCLC with chemotherapy using carboplatin and paclitaxel or protein-bound paclitaxel

The safety of KEYTRUDA® in combination with carboplatin and paclitaxel or protein-bound paclitaxel, at the investigator’s choice, was evaluated in KEYNOTE-407, a multicenter, double-blind, randomized (1:1), placebo-controlled trial involving 558 patients with previously untreated metastatic squamous NSCLC. Safety data were available for the first 203 patients who received KEYTRUDA® plus chemotherapy (n = 101) or placebo plus chemotherapy (n = 102).

Patients with autoimmune disease requiring systemic therapy within the past 2 years, patients with medical conditions requiring immunosuppressive treatment, or patients who received thoracic radiation with more than 30 Gy within the prior 26 weeks were excluded from the study.

The median duration of KEYTRUDA® treatment was 7 months (range: 1 day to 12 months). In the KEYTRUDA® treatment group, 61% of patients received KEYTRUDA® for ≥ 6 months. Overall, 139 of 203 patients (68%) received paclitaxel and 64 patients (32%) received protein-bound paclitaxel, each in combination with carboplatin.

Study participants had the following characteristics: median age 65 years (range: 40 to 83 years); 52% were aged 65 years or older; 78% were male; 83% were White, and 9% had a history of brain metastases.

KEYTRUDA® was discontinued due to adverse reactions in 15% of patients, with no single type of adverse reaction occurring in the majority of patients. Adverse reactions leading to interruption of KEYTRUDA® occurred in 43% of patients; the most frequent (≥ 2%) were thrombocytopenia (20%), neutropenia (11%), anemia (6%), asthenia (2%), and diarrhea (2%). The most common (≥ 2%) serious adverse reactions were febrile neutropenia (6%), pneumonia (6%), and urinary tract infection (3%).

Adverse reactions observed in KEYNOTE-407 were similar to those documented in KEYNOTE-189, except that in KEYNOTE-407, the KEYTRUDA® plus chemotherapy group had higher incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) compared to the placebo plus chemotherapy group.

Previously untreated NSCLC

The safety of KEYTRUDA® was investigated in KEYNOTE-042, a multicenter, open-label, randomized (1:1), active-controlled trial involving 1251 patients with PD-L1 expressing, previously untreated stage III NSCLC if patients were not candidates for surgical resection or definitive chemoradiation, or metastatic NSCLC. Patients received 200 mg of KEYTRUDA® every 3 weeks (n = 636) or investigator’s choice chemotherapy (n = 615), consisting of pemetrexed and carboplatin followed by optional pemetrexed (n = 312) or paclitaxel and carboplatin followed by optional pemetrexed (n = 303), administered once every 3 weeks. Patients with EGFR or ALK mutations; patients with autoimmune disease requiring systemic therapy within 2 years of treatment; patients whose medical condition required immunosuppression; or patients who received more than 30 Gy of thoracic radiation within the prior 26 weeks were excluded from the study.

The median duration of KEYTRUDA® exposure was 5.6 months (range: 1 day to 27.3 months). Forty-eight percent of patients in the 200 mg KEYTRUDA® group received the drug for ≥ 6 months.

Study participants had the following characteristics: median age 63 years (range: 25 to 90); 45% were aged 65 years or older; 71% were male; 64% were White, 30% were Asian, and 2% were Black. Nineteen percent were of Hispanic or Latino ethnicity.

Eighty-seven percent had metastatic disease (Stage IV), 13% had Stage III disease (2% Stage IIIA and 11% Stage IIIB), and 5% had received treatment for brain metastases at study baseline.

KEYTRUDA® was discontinued due to adverse reactions in 19% of patients. The most frequent adverse reactions leading to permanent discontinuation of KEYTRUDA® were pneumonitis (3.0%), death due to unknown causes (1.6%), and pneumonia (1.4%). Adverse reactions leading to interruption of KEYTRUDA® occurred in 33% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA® (≥ 2%) were pneumonitis (3.1%), pneumonia (3.0%), hypothyroidism (2.2%), and increased ALT (2.0%). The most common (≥ 2%) serious adverse reactions were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%).

Tables 12 and 13 summarize the adverse reactions and laboratory abnormalities, respectively, observed in patients treated with KEYTRUDA® in KEYNOTE-042.

Table 12. Adverse reactions occurring in ≥ 10% of patients in KEYNOTE-042

| Adverse Reaction | KEYTRUDA® (n = 636) | Chemotherapy (n = 615) | |------------------|---------------------|------------------------| | Fatigue | 47% | 44% | | Nausea | 39% | 48% | | Constipation | 34% | 30% | | Diarrhea | 31% | 24% | | Musculoskeletal pain | 29% | 23% | | Decreased appetite | 28% | 25% | | Rash | 27% | 18% | | Cough | 26% | 24% | | Dyspnea | 25% | 27% | | Peripheral neuropathy | 24% | 19% | | Arthralgia | 22% | 17% | | Vomiting | 22% | 27% | | Abdominal pain | 21% | 17% | | Headache | 20% | 15% | | Hypothyroidism | 19% | 5% | | Insomnia | 18% | 14% | | Back pain | 17% | 15% | | Pyrexia | 17% | 10% | | Hypokalemia | 16% | 13% | | Hypoalbuminemia | 15% | 12% | | Hypomagnesemia | 15% | 11% | | Hypocalcemia | 14% | 10% | | Anemia | 14% | 17% | | Hypophosphatemia | 13% | 9% | | Upper respiratory tract infection | 13% | 10% | | Sinusitis | 12% | 8% | | Pneumonia | 12% | 14% | | Pleural effusion | 11% | 13% | | Bronchitis | 11% | 8% | | Dysgeusia | 11% | 7% | | Hypertension | 11% | 9% | | Hypoglycemia | 10% | 6% | | Hypothyroidism (laboratory abnormality) | 10% | 3% | | Hyperthyroidism | 10% | 2% | | Infusion-related reactions | 10% | 3% |

Note: Frequencies are based on all grades unless otherwise specified. Adverse reactions are listed by MedDRA preferred terms.

* Grades according to NCI CTCAE v4.03

† Includes fatigue and asthenia

‡ Includes rash, generalized rash, macular rash, maculopapular rash, papular rash, pruritic rash, and pustular rash

Table 13. Laboratory abnormalities compared with baseline occurring in ≥ 20% of patients in KEYNOTE-042

* Frequency is based on the number of patients with baseline test results and at least one post-baseline result during the study: KEYTRUDA® (range: 598 to 610 patients) and chemotherapy (range: 588 to 597 patients); elevated INR: KEYTRUDA® n = 203 and chemotherapy n = 173.

† Grades according to NCI CTCAE v4.03

Patients previously treated for NSCLC

The safety of KEYTRUDA® was evaluated in KEYNOTE-010 (a multicenter, open-label, randomized (1:1:1), active-controlled study) involving patients with advanced NSCLC who had disease progression on or after platinum-based chemotherapy and, if EGFR or ALK genetic aberrations were present, had received targeted therapy for these aberrations. A total of 991 patients received KEYTRUDA® at a dose of 2 mg/kg (n = 339) or 10 mg/kg (n = 343) every 3 weeks, or docetaxel (n = 309) at 75 mg/m² every 3 weeks.

Patients with autoimmune disease, medical conditions requiring systemic corticosteroids or other immunosuppressants, or patients who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were excluded from the study.

The median duration of treatment with KEYTRUDA® at 2 mg/kg every 3 weeks was 3.5 months (range: 1 day to 22.4 months), and at 10 mg/kg every 3 weeks was 3.5 months (range: 1 day to 20.8 months).

The data presented below reflect exposure to KEYTRUDA® at a dose of 2 mg/kg in 31% of patients who received the drug for ≥ 6 months. In the group receiving KEYTRUDA® at 10 mg/kg, 34% of patients received treatment for ≥ 6 months.

Study participants had the following baseline characteristics: median age 63 years (range: 20 to 88 years); 42% were aged 65 years or older; 61% were male; 72% were White; 21% were Asian; 8% had locally advanced disease; 91% had metastatic disease; and 15% had a history of brain metastases. Twenty-nine percent had received two or more prior regimens for advanced or metastatic disease.

In KEYNOTE-010, the safety profile was similar between the 2 mg/kg and 10 mg/kg doses; therefore, safety results are presented in a combined analysis (n = 682). Treatment was discontinued due to adverse reactions in 8% of patients. The most frequent adverse reaction leading to permanent discontinuation of KEYTRUDA® was pneumonitis (1.8%). Adverse reactions leading to interruption of KEYTRUDA® occurred in 23% of patients; the most frequent (≥ 1%) were: diarrhea (1%), fatigue (1.3%), pneumonitis (1%), increased liver enzymes (1.2%), decreased appetite (1.3%), and pneumonitis (1%).

Tables 14 and 15 summarize the adverse reactions and laboratory abnormalities, respectively, observed in patients treated with KEYTRUDA® in KEYNOTE-010.

Table 14. Individual* adverse reactions occurring in ≥ 10% of patients treated with KEYTRUDA® in KEYNOTE-010

* Adverse reactions that occurred at an equal or greater frequency compared to the docetaxel group

† Grades according to NCI CTCAE v4.0

‡ Includes rash, erythematous rash, macular rash, maculopapular rash, papular rash, pruritic rash

Other clinically important adverse reactions occurring in patients receiving KITRUDA®: fatigue (25%), diarrhea (14%), asthenia (11%), and pyrexia (11%).

Table 15. Individual* laboratory abnormalities from baseline occurring in ≥ 20% of patients with NSCLC receiving KITRUDA® in KEYNOTE-010

*Adverse reactions that occurred at the same or higher frequency compared to the docetaxel group.

† Frequency is based on the number of patients with baseline test results and at least one result during the study: KEYTRUDA® (range: 631 to 638 patients) and docetaxel (range: 274 to 277 patients).

‡ Grades according to NCI CTCAE v4.0

Other laboratory abnormalities observed in ≥ 20% of patients during treatment with KEYTRUDA®: hyperglycemia (44% all grades; 4.1% grades 3–4), anemia (37% all grades; 3.8% grades 3–4), hypertriglyceridemia (36% all grades; 1.8% grades 3–4), lymphopenia (35% all grades; 9% grades 3–4), hypoalbuminemia (34% all grades; 1.6% grades 3–4), and hypercholesterolemia (20% all grades; 0.7% grades 3–4).

Neoadjuvant and adjuvant therapy in resectable NSCLC

The safety of KEYTRUDA® in combination with neoadjuvant platinum-based chemotherapy followed by surgical intervention and continuation of adjuvant monotherapy with KEYTRUDA® after surgery was evaluated in a multicenter, randomized (1:1), double-blind, placebo-controlled trial, KEYNOTE-671, involving patients with previously untreated, resectable NSCLC stage II, IIIA, or IIIB (N2) according to the AJCC 8th edition classification. Patients with autoimmune disease requiring systemic therapy within 2 years of treatment or with medical conditions requiring immunosuppression were excluded from the study.

The median duration of exposure to KEYTRUDA® 200 mg every 3 weeks was 10.9 months (range: 1 day to 18.6 months). Characteristics of the study population: median age 64 years (range: 26 to 83 years), 45% were aged 65 years or older, 7% were aged 75 years or older, 71% were male, 61% were White, 31% were Asian, 2% were Black, 4% race not specified, 9% were of Hispanic or Latino ethnicity.

Adverse reactions observed in patients with resectable NSCLC who received KEYTRUDA® in combination with platinum-based chemotherapy as neoadjuvant therapy and continued with adjuvant monotherapy with KEYTRUDA® were generally similar to those observed in other clinical trials in patients with various tumor types receiving KEYTRUDA® in combination with chemotherapy.

Neoadjuvant phase of KEYNOTE-671

Overall, 396 patients received at least one dose of KEYTRUDA® in combination with platinum-based chemotherapy as neoadjuvant therapy, and 399 patients received at least one dose of placebo in combination with platinum-based chemotherapy as neoadjuvant therapy.

Serious adverse reactions occurred in 34% of patients receiving KEYTRUDA® in combination with platinum-based chemotherapy as neoadjuvant therapy; the most frequent (≥ 2%) serious adverse reactions were pneumonia (4.8%), venous thromboembolism (3.3%), and anemia (2%). Fatal adverse reactions occurred in 1.3% of patients, including death from unknown cause (0.8%), sepsis (0.3%), and immune-mediated lung disease (0.3%).

Discontinuation of any study drug due to an adverse reaction was reported in 18% of patients receiving KEYTRUDA® in combination with platinum-based chemotherapy as neoadjuvant therapy; the most frequent (≥ 1%) adverse reactions leading to complete discontinuation of any study drug were acute kidney injury (1.8%), interstitial lung disease (1.8%), anemia (1.5%), neutropenia (1.5%), and pneumonia (1.3%).

Among the 396 patients who received neoadjuvant therapy with KEYTRUDA® and the 399 patients who received placebo, surgery was not performed in 6% (n = 25) and 4.3% (n = 17), respectively, due to adverse reactions. The most frequent (≥ 1%) adverse reaction leading to cancellation of surgery in the KEYTRUDA® group was interstitial lung disease (1%).

Among the 325 patients who received KEYTRUDA® and underwent surgery, 3.1% (n = 10) had surgery delayed (surgical treatment more than 8 weeks after the last neoadjuvant cycle if the patient received fewer than 4 neoadjuvant cycles, or more than 20 weeks after the first neoadjuvant dose if the patient received 4 neoadjuvant cycles) due to adverse reactions. Among the 317 patients who received placebo and underwent surgery, 2.5% (n = 8) had surgery delayed due to adverse reactions.

Among the 325 patients who received KEYTRUDA® and underwent surgery, 7% (n = 22) did not receive adjuvant therapy due to adverse reactions. Among the 317 patients who received placebo, 3.2% (n = 10) did not receive adjuvant therapy due to adverse reactions.

Adjuvant phase of KEYNOTE-671

Overall, 290 patients in the KEYTRUDA® group and 267 patients in the placebo group received at least one dose of adjuvant therapy.

Serious adverse reactions occurred in 14% of patients receiving monotherapy with KEYTRUDA® as adjuvant therapy; the most frequent serious adverse reaction was pneumonia (3.4%). One fatal adverse reaction occurred due to pulmonary hemorrhage. Adjuvant therapy with KEYTRUDA® was completely discontinued due to an adverse reaction in 12% of patients; the most frequent (≥ 1%) adverse reactions leading to complete discontinuation of adjuvant therapy with KEYTRUDA® were diarrhea (1.7%), interstitial lung disease (1.4%), increased AST levels (1.0%), and musculoskeletal pain (1.0%).

Adjuvant therapy in resectable NSCLC

The safety of KEYTRUDA® as monotherapy was evaluated in KEYNOTE-091. This was a multicenter, randomized (1:1), triple-blind, placebo-controlled trial involving patients who underwent complete resection of stage IB (T2a ≥ 4 cm), II, or IIIA NSCLC; adjuvant chemotherapy with up to 4 cycles was optional. Overall, 1161 patients received KEYTRUDA® 200 mg (n = 580) or placebo (n = 581) every 3 weeks. Patients were excluded from the study if they had active autoimmune disease, were on chronic immunosuppressive therapy, or had a history of interstitial lung disease or pneumonitis.

The median duration of treatment with KEYTRUDA® was 11.7 months (range: 1 day to 18.9 months). Sixty-eight percent of patients in the KEYTRUDA® group received KEYTRUDA® for ≥ 6 months.

Adverse reactions observed in KEYNOTE-091 were generally similar to those observed in other NSCLC patients receiving KEYTRUDA® as monotherapy, except for hypothyroidism (21%) and hyperthyroidism (11%). Two fatal adverse reactions occurred due to myocarditis.

HNSCC

First-line therapy for metastatic or unresectable, recurrent HNSCC

The safety of KEYTRUDA® as monotherapy and in combination with platinum (cisplatin or carboplatin) and fluorouracil chemotherapy was evaluated in KEYNOTE-048. This was a multicenter, open-label, randomized (1:1:1), active-controlled trial involving patients with previously untreated, recurrent or metastatic HNSCC. Patients with autoimmune disease or medical conditions requiring systemic corticosteroids or other immunosuppressants were excluded from the study. Overall, 576 patients received KEYTRUDA® 200 mg once every 3 weeks as monotherapy (n = 300) or in combination with platinum and 5-FU (n = 276) every 3 weeks for 6 cycles, followed by KEYTRUDA® monotherapy, compared to 287 patients who received weekly cetuximab in combination with platinum and 5-FU every 3 weeks for 6 cycles, followed by cetuximab.

The median duration of exposure to KEYTRUDA® was 3.5 months (range: 1 day to 24.2 months) in the monotherapy group and 5.8 months (range: 3 days to 24.2 months) in the combination therapy group. Seventeen percent of patients in the monotherapy group and 18% of patients in the combination therapy group received the drug for ≥ 12 months. Fifty-seven percent of patients who received KEYTRUDA® in combination with chemotherapy initiated treatment with carboplatin.

Treatment with KEYTRUDA® was discontinued due to adverse reactions in 12% of patients in the monotherapy group. The most frequent adverse reactions leading to complete discontinuation of KEYTRUDA® were sepsis (1.7%) and pneumonia (1.3%). Adverse reactions leading to interruption of KEYTRUDA® occurred in 31% of patients; the most common adverse reactions leading to interruption of KEYTRUDA® (≥ 2%) were pneumonia (2.3%), pneumonitis (2.3%), and hyponatremia (2%).

Treatment with KEYTRUDA® was discontinued due to adverse reactions in 16% of patients in the combination therapy group. The most frequent adverse reactions leading to complete discontinuation of KEYTRUDA® were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). Adverse reactions leading to interruption of KEYTRUDA® occurred in 45% of patients; the most common adverse reactions leading to interruption of KEYTRUDA® were neutropenia (14%), thrombocytopenia (10%), anemia (6%), pneumonia (4.7%), and febrile neutropenia (2.9%).

Tables 16 and 17 summarize the adverse reactions and laboratory abnormalities, respectively, observed in patients treated with KEYTRUDA® in KEYNOTE-048.

Table 16. Adverse reactions occurring in ≥ 10% of patients treated with KEYTRUDA® in KEYNOTE-048

* NCI CTCAE v4.0 grades

† Includes fatigue, asthenia

‡ Includes diarrhea, colitis, hemorrhagic diarrhea, microscopic colitis

§ Includes dermatitis, acneiform dermatitis, allergic dermatitis, bullous dermatitis, contact dermatitis, exfoliative dermatitis, drug eruption, erythema, erythema multiforme, rash, erythematous rash, generalized rash, macular rash, maculopapular rash, pruritic rash, seborrheic dermatitis

¶ Includes cough, productive cough

Includes dyspnea, dyspnea on exertion

Ϸ Includes pneumonia, atypical pneumonia, bacterial pneumonia, staphylococcal pneumonia, aspiration pneumonia, lower respiratory tract infection, lung infection, pseudomonal lung infection

β Includes peripheral sensory neuropathy, peripheral neuropathy, hypoesthesia, dysesthesia

α Includes back pain, musculoskeletal chest pain, musculoskeletal pain, myalgia

Table 17. Laboratory abnormalities compared to baseline occurring in ≥ 20% of patients treated with KEYTRUDA® in KEYNOTE-048

* Frequency is based on the number of patients with baseline assessments and at least 1 post-baseline assessment during the study: Pembrolizumab®/chemotherapy (range: 235 to 266 patients), Pembrolizumab® (range: 241 to 288 patients), cetuximab/chemotherapy (range: 249 to 282 patients).

† Grading according to NCI CTCAE v4.0

Previously treated recurrent or metastatic HNSCC

In 192 patients with squamous cell carcinoma of the head and neck enrolled in KEYNOTE-012, the median duration of treatment with Pembrolizumab® was 3.3 months (range: 1 day to 27.9 months). Patients with autoimmune diseases or medical conditions requiring immunosuppressive therapy were excluded from KEYNOTE-012.

Study participants had the following characteristics: median age 60 years (range: 20 to 84); 35% were aged 65 years or older; 83% were male; 77% were White; 15% were Asian; 5% were Black. 61% of patients had received 2 or more prior therapies for recurrent or metastatic disease, and 95% had previously received radiotherapy. Baseline ECOG PS was 0 (30%) or 1 (70%), and 86% had M1 stage disease.

Pembrolizumab® was discontinued due to adverse reactions in 17% of patients. Serious adverse reactions occurred in 45% of patients receiving Pembrolizumab®. The most common adverse reactions occurring in at least 2% of patients were: pneumonia, dyspnea, confusion, vomiting, pleural effusion, and respiratory failure. The frequency of adverse reactions, including serious adverse reactions, was similar across dose groups (10 mg/kg every 2 weeks or 200 mg every 3 weeks); therefore, safety data are presented in a pooled analysis. The most common adverse reactions (occurring in ≥20% of patients) were fatigue, decreased appetite, and dyspnea.

Adverse reactions observed in patients with HNSCC were generally similar to those in 2799 patients with melanoma or NSCLC receiving Pembrolizumab® as monotherapy, except for a higher incidence of facial swelling (10% all grades; 2.1% grades 3–4) and hyperthyroidism or worsening hypothyroidism (see section "Special warnings and precautions").

Recurrent or refractory cHL

KEYNOTE-204

The safety of Pembrolizumab® was evaluated in KEYNOTE-204. Adults with recurrent or refractory cHL received Pembrolizumab® 200 mg intravenously every 3 weeks (n = 148) or brentuximab vedotin (BV) 1.8 mg/kg intravenously every 3 weeks (n = 152). Eligibility criteria included: absolute neutrophil count (ANC) ≥ 1000/μL, platelet count ≥ 75,000/μL, liver transaminases ≤ 2.5 times the upper limit of normal (ULN), bilirubin ≤ 1.5 times ULN, and ECOG performance status of 0 or 1. Patients were excluded if they had active non-infectious pneumonitis, prior steroid-treated pneumonitis, active autoimmune disease, medical conditions requiring immunosuppression, or allogeneic stem cell transplantation within the previous 5 years. The median duration of treatment with Pembrolizumab® was 10 months (range: 1 day to 2.2 years), with 68% of patients receiving at least 6 months of therapy and 48% receiving at least 1 year of therapy.

Serious adverse reactions occurred in 30% of patients receiving Pembrolizumab®. Serious adverse reactions in ≥1% of patients included pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney injury, febrile neutropenia, and sepsis. Three patients (2%) died from causes other than disease progression: two from complications following allogeneic stem cell transplantation and one from an unknown cause.

Treatment with Pembrolizumab® was permanently discontinued due to adverse reactions in 14% of patients; 7% discontinued due to pneumonitis. Treatment was interrupted due to adverse reactions in 30% of patients. Adverse reactions requiring interruption of Pembrolizumab® in ≥3% of patients included upper respiratory tract infection, pneumonitis, increased transaminases, and pneumonia.

Thirty-eight percent of patients experienced an adverse reaction requiring systemic corticosteroid therapy.

Table 18 summarizes adverse reactions in KEYNOTE-204.

Table 18. Adverse reactions occurring in ≥10% of patients with cHL treated with Pembrolizumab® in KEYNOTE-204

* Grades according to NCI CTCAE v4.0

† Adverse reactions in the BV group were only Grade 3

‡ Includes acute sinusitis, nasopharyngitis, pharyngitis, pharyngotonsillitis, rhinitis, sinusitis, bacterial sinusitis, tonsillitis, upper respiratory tract infection, viral upper respiratory tract infection

§ Includes arthralgia, back pain, bone pain, musculoskeletal discomfort, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, non-cardiac chest pain, limb pain

¶ Includes diarrhea, gastroenteritis, colitis, enterocolitis

Includes abdominal discomfort, abdominal pain, upper abdominal pain, lower abdominal pain

Þ Includes fatigue, asthenia

β Includes acneiform dermatitis, atopic dermatitis, allergic dermatitis, contact dermatitis, exfoliative dermatitis, psoriasiform dermatitis, eczema, rash, erythematous rash, follicular rash, maculopapular rash, papular rash, pruritic rash, toxic skin rash

à Includes cough, productive cough

è Includes pneumonitis, interstitial lung disease

ð Includes dyspnea, dyspnea on exertion, wheezing

ø Includes dysesthesia, hypoesthesia, peripheral neuropathy, paresthesia, peripheral motor neuropathy, peripheral sensory-motor neuropathy, peripheral sensory neuropathy, polyneuropathy

ý Includes headache, migraine, tension headache

Clinically significant adverse reactions occurring in < 10% of patients who received Keytruda® included herpes infection (9%), pneumonia (8%), oropharyngeal pain (8%), hyperthyroidism (5%), hypersensitivity (4.1%), infusion-related reactions (3.4%), confusion (2.7%), and the following adverse reactions: uveitis, myocarditis, thyroiditis, febrile neutropenia, sepsis, and worsening of tumor symptoms (each occurring in 1.4%).

Table 19 summarizes laboratory parameter abnormalities in KEYNOTE-204.

Table 19. Laboratory parameter abnormalities (≥ 15%) from baseline occurring in patients with cHL in KEYNOTE-204

* The frequency of each test is based on the number of patients who had both baseline and at least one on-study laboratory measurement in the KEYTRUDA® study (range: 143 to 148 patients) and BV study (range: 146 to 152 patients); hypomagnesemia: KEYTRUDA® n = 53 and BV n = 50.

† Graded according to NCI CTCAE v4.0

KEYNOTE-087

In the KEYNOTE-087 study, the median duration of therapy with KEYTRUDA® among 210 patients was 8.4 months (range: 1 day to 15.2 months). Serious adverse reactions occurred in 16% of patients receiving KEYTRUDA®. Serious adverse reactions occurring in ≥1% of patients included pneumonia, pneumonitis, pyrexia, dyspnea, graft-versus-host disease (GVHD), and herpes zoster. Two patients died from causes other than disease progression; one due to GVHD following subsequent allogeneic HSCT and one due to septic shock.

Discontinuation of KEYTRUDA® due to an adverse reaction occurred in 5% of patients, and interruption due to an adverse reaction occurred in 26%. Fifteen percent of patients had an adverse reaction requiring systemic corticosteroid therapy. Tables 20 and 21 summarize adverse reactions and laboratory abnormalities, respectively, in KEYNOTE-087.

Table 20. Adverse reactions (≥10%) occurring in patients with cHL receiving KEYTRUDA® in KEYNOTE-087

* Grades according to NCI CTCAE v4.0

† Includes fatigue, asthenia

‡ Includes cough, productive cough

§ Includes dyspnea, dyspnea on exertion, wheezing

¶ Includes back pain, myalgia, bone pain, musculoskeletal pain, limb pain, chest musculoskeletal pain, musculoskeletal discomfort, neck pain

Includes diarrhea, gastroenteritis, colitis, enterocolitis

Þ Includes rash, maculopapular rash, drug eruption, eczema, asteatotic eczema, dermatitis, acneiform dermatitis, contact dermatitis, erythematous rash, macular rash, papular rash, pruritic rash, seborrheic dermatitis, psoriasiform dermatitis

β Includes peripheral neuropathy, peripheral sensory neuropathy, hypoesthesia, paresthesia, dysesthesia, polyneuropathy

Clinically significant adverse reactions occurring in < 10% of patients treated with KEYTRUDA® included: infusion-related reactions (9%), hyperthyroidism (3%), pneumonitis (3%), uveitis and myositis (each 1%), as well as myelitis and myocarditis (each 0.5%).

Table 21. Individual laboratory abnormalities (≥ 15%) from baseline occurring in cHL patients treated with KEYTRUDA® in KEYNOTE-087

* Frequency is based on the number of patients with baseline test results and at least 1 result during the study: Keytruda® (range: 208 to 209 patients).

† Grading according to NCI CTCAE v4.0

‡ Includes increased levels of ALT or AST

Hyperbilirubinemia was observed in less than 15% of patients enrolled in the KEYNOTE-087 study (10% all grades, 2.4% grades 3–4).

PMBCL

In the KEYNOTE-170 study of 53 patients with PMBCL, the median duration of treatment with Keytruda® was 3.5 months (range: 1 day to 22.8 months). Serious adverse reactions occurred in 26% of patients. Serious adverse reactions observed in 2% or more patients included: arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), exudative pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of starting treatment.

Discontinuation of Keytruda® due to an adverse reaction occurred in 8% of patients, and treatment interruption occurred in 15%. Twenty-five percent of patients experienced an adverse reaction requiring systemic corticosteroid therapy.

Tables 22 and 23 summarize adverse reactions and laboratory abnormalities, respectively, observed in patients treated with Keytruda® in KEYNOTE-170.

Table 22. Adverse Reactions (≥ 10%) Occurring in Patients with PMBCL Receiving Keytruda® in KEYNOTE-170

* Grades according to NCI CTCAE v4.0

† Includes arthralgia, back pain, myalgia, musculoskeletal pain, limb pain, musculoskeletal chest pain, bone pain, neck pain, non-cardiac chest pain

‡ Includes nasopharyngitis, pharyngitis, rhinorrhea, rhinitis, sinusitis, upper respiratory tract infection

§ Includes fatigue, asthenia

¶ Includes allergic cough, cough, productive cough

Includes diarrhea, gastroenteritis

Þ Includes abdominal pain, upper abdominal pain

β Includes atrial fibrillation, sinus tachycardia, supraventricular tachycardia, tachycardia

Clinically significant adverse reactions occurring in < 10% of patients who received Keytruda® in KEYNOTE-170 included hypothyroidism (8%), hyperthyroidism and pericarditis (each 4%), as well as thyroiditis, pericardial effusion, pneumonitis, arthritis, and acute kidney injury (each 2%).

Table 23. Laboratory abnormalities (≥ 15%) occurring from baseline in patients with PMBCL treated with Keytruda® in KEYNOTE-170

* The frequency of abnormalities for each parameter was calculated based on the number of patients who had the corresponding laboratory test performed both at baseline and at least once during the study: the pembrolizumab treatment group (range: 44 to 48 patients).

† Grades according to NCI CTCAE v4.0

‡ Includes increased concentrations of AST or ALT

Urothelial carcinoma

Patients with urothelial carcinoma, in combination with enfortumab vedotin

The safety of pembrolizumab in combination with enfortumab vedotin was evaluated in KEYNOTE-A39 in patients with locally advanced or metastatic urothelial carcinoma. Overall, 440 patients received 200 mg of pembrolizumab on Day 1 and 1.25 mg/kg of enfortumab vedotin on Days 1 and 8 of each 21-day cycle, compared with 433 patients who received gemcitabine on Days 1 and 8 and investigator’s choice of cisplatin or carboplatin on Day 1 of each 21-day cycle. In patients receiving pembrolizumab and enfortumab vedotin, the median duration of exposure to pembrolizumab was 8.5 months (range: 9 days to 28.5 months).

Fatal adverse reactions occurred in 3.9% of patients receiving pembrolizumab in combination with enfortumab vedotin, including acute respiratory failure (0.7%), pneumonia (0.5%), and pneumonitis/interstitial lung disease (ILD) (0.2%).

Serious adverse reactions occurred in 50% of patients receiving pembrolizumab in combination with enfortumab vedotin. Serious adverse reactions occurring in ≥2% of patients receiving pembrolizumab in combination with enfortumab vedotin were rash (6%), acute kidney injury (5%), pneumonitis/ILD (4.5%), urinary tract infection (3.6%), diarrhea (3.2%), pneumonia (2.3%), pyrexia (2%), and hyperglycemia (2%).

Pembrolizumab was permanently discontinued in 27% of patients. The most frequent adverse reactions (≥2%) leading to permanent discontinuation of pembrolizumab were pneumonitis/ILD (4.8%) and rash (3.4%).

Pembrolizumab was interrupted in 61% of patients. The most frequent adverse reactions (≥2%) leading to interruption of pembrolizumab were rash (17%), peripheral neuropathy (7%), COVID-19 (5%), diarrhea (4.3%), pneumonitis/ILD (3.6%), neutropenia (3.4%), fatigue (3%), increased alanine aminotransferase levels (2.7%), hyperglycemia (2.5%), pneumonia (2%), and pruritus (2%).

Tables 24 and 25 summarize adverse reactions and laboratory parameter changes, respectively, that occurred in patients treated with pembrolizumab in combination with enfortumab vedotin in KEYNOTE-A39.

Table 24. Adverse reactions (≥20%, all grades) occurring in patients receiving pembrolizumab in combination with enfortumab vedotin in KEYNOTE-A39

* Grades according to NCI CTCAE v4.03

† Includes multiple terms

Clinically significant adverse reactions (< 20%) include pyrexia (18%), dry skin (17%), vomiting (12%), pneumonitis/interstitial lung disease (10%), hypothyroidism (10%), blurred vision (6%), extravasation at infusion site (2%), and myositis (0.5%).

Table 25. Individual laboratory parameter changes from baseline occurring in ≥ 20% of patients in KEYNOTE-A39

* The frequency of changes in each parameter is based on the number of patients for whom both baseline test results and at least one on-study result were available for KEYTRUDA® (range: 407 to 439 patients)

† Grading according to NCI CTCAE v4.03

Patients with urothelial cancer ineligible for cisplatin-containing chemotherapy, in combination with enfortumab vedotin

The safety of KEYTRUDA® in combination with enfortumab vedotin was evaluated in KEYNOTE-869 in patients with locally advanced or metastatic urothelial cancer who were ineligible for platinum-based chemotherapy. Overall, 121 patients received 200 mg of KEYTRUDA® on Day 1 and 1.25 mg/kg of enfortumab vedotin on Days 1 and 8 of each 21-day cycle. The median duration of exposure to KEYTRUDA® was 6.9 months (range: 1 day to 29.6 months). Fatal adverse reactions occurred in 5% of patients receiving KEYTRUDA® in combination with enfortumab vedotin, including sepsis (1.6%), bullous dermatitis (0.8%), myasthenia gravis (0.8%), and pneumonitis (0.8%). Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA® and enfortumab vedotin. Serious adverse reactions occurring in ≥ 2% of patients receiving KEYTRUDA® in combination with enfortumab vedotin included acute kidney injury (7%), urinary tract infection (7%), urosepsis (5%), hematuria (3.3%), pneumonia (3.3%), pneumonitis (3.3%), sepsis (3.3%), anemia (2.5%), diarrhea (2.5%), hypotension (2.5%), myasthenia gravis (2.5%), myositis (2.5%), and urinary retention (2.5%). In 32% of patients, KEYTRUDA® was discontinued permanently. The most frequent adverse reactions (≥ 2%) leading to permanent discontinuation of KEYTRUDA® were pneumonitis (5%), peripheral neuropathy (5%), rash (3.3%), and myasthenia gravis (2.5%). KEYTRUDA® was interrupted in 69% of patients. The most frequent adverse reactions (≥ 2%) leading to interruption of KEYTRUDA® were peripheral neuropathy (22%), rash (17%), neutropenia (7%), fatigue (6%), diarrhea (5%), increased lipase (5%), acute kidney injury (3.3%), increased ALT (2.5%), and COVID-19 (2.5%).

Tables 26 and 27 summarize adverse reactions and laboratory test abnormalities, respectively, that occurred in patients receiving KEYTRUDA® in combination with enfortumab vedotin in KEYNOTE-869.

Table 26. Adverse reactions occurring in ≥ 20% of patients receiving KEYTRUDA® in combination with enfortumab vedotin in KEYNOTE-869

* Grades according to NCI CTCAE v4.03

† Includes blister, conjunctivitis, dermatitis, bullous dermatitis, generalized exfoliative dermatitis, erythema, erythema multiforme, exfoliative rash, hand-foot syndrome, pemphigoid, rash, erythematous rash, macular rash, maculopapular rash, papular rash, pruritic rash, bullous rash, skin desquamation, and stomatitis

‡ Includes dysesthesia, hypoesthesia, muscle weakness, paresthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy, peripheral sensory neuropathy, and gait disturbance

Clinically significant adverse reactions (< 20%) include vomiting (19.8%), pyrexia (18%), hypothyroidism (11%), pneumonitis/IPF (10%), myositis (3.3%), myasthenia gravis (2.5%), and infusion site extravasation (0.8%).

Table 27. Individual laboratory abnormalities occurring at ≥ 20% of patients compared to baseline in KEYNOTE-869

* The frequency of changes in each laboratory parameter is based on the number of patients for whom both baseline and at least one on-study laboratory measurement were available during the study of KEYTRUDA® (range: 114 to 121 patients)

† Grading according to NCI CTCAE v4.03

Patients with urothelial carcinoma who are not eligible for cisplatin

The safety of KEYTRUDA® was evaluated in KEYNOTE-052, a single-arm trial involving 370 patients with locally advanced or metastatic urothelial carcinoma who were not eligible for cisplatin-containing chemotherapy. Patients with autoimmune diseases or conditions requiring systemic corticosteroids or other immunosuppressive therapy were excluded from the study.

Patients received KEYTRUDA® at a dose of 200 mg every three weeks until unacceptable toxicity or disease progression occurred (clinically or radiographically).

The median duration of KEYTRUDA® treatment was 2.8 months (range: 1 day to 15.8 months).

KEYTRUDA® was discontinued due to adverse reactions in 11% of patients. Eighteen patients (5%) died from causes unrelated to disease progression. Sepsis leading to death occurred in five patients (1.4%) treated with KEYTRUDA®; pneumonia leading to death occurred in three patients (0.8%). Adverse reactions that led to interruption of KEYTRUDA® occurred in 22% of patients; the most frequent (≥1%) were: increased liver enzymes, diarrhea, urinary tract infection, acute kidney injury, fatigue, arthralgia, and pneumonia. Serious adverse reactions were observed in 42% of patients. The most frequent serious adverse reactions (≥2%) were: urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis.

Immune-mediated adverse reactions requiring systemic glucocorticoids occurred in 8% of patients; 8% of patients received hormonal therapy due to immune-mediated adverse reactions, and 5% required at least one dose of ≥40 mg of a corticosteroid (prednisone equivalent).

Table 28 summarizes adverse reactions observed in patients treated with KEYTRUDA® in KEYNOTE-052.

Table 28. Adverse reactions occurring in ≥10% of patients treated with KEYTRUDA® in KEYNOTE-052

* Grades according to NCI CTCAE v4.0

† Includes fatigue, asthenia

‡ Includes back pain, bone pain, chest musculoskeletal pain, musculoskeletal pain, myalgia, neck pain, limb pain, spinal pain

§ Includes diarrhea, colitis, enterocolitis, gastroenteritis, frequent bowel movements

¶ Includes abdominal pain, pelvic pain, flank pain, lower abdominal pain, tumor pain, bladder pain, liver pain, suprapubic pain, abdominal discomfort, upper abdominal pain

Includes autoimmune hepatitis, hepatitis, toxic hepatitis, hepatic injury, increased transaminase levels, hyperbilirubinemia, increased plasma bilirubin, increased ALT, increased AST, increased liver enzyme levels, increased liver function test results

Þ Includes dermatitis, bullous dermatitis, eczema, erythema, rash, macular rash, maculopapular rash, pruritic rash, pustular rash, skin reaction, acneiform dermatitis, seborrheic dermatitis, hand-foot erythrodysesthesia syndrome, generalized rash

β Includes peripheral edema, peripheral swelling

Urothelial carcinoma previously treated

The safety of KEYTRUDA® was evaluated in KEYNOTE-045 in patients with locally advanced or metastatic urothelial carcinoma who had received prior platinum-containing chemotherapy. KEYNOTE-045 was a multicenter, open-label, randomized (1:1), active-controlled trial involving 266 patients who received KEYTRUDA® at a dose of 200 mg every 3 weeks or investigator’s choice chemotherapy (n = 255), which included paclitaxel (n = 84), docetaxel (n = 84), or vinflunine (n = 87). Patients with autoimmune disease or conditions requiring systemic corticosteroids or other immunosuppressants were excluded from the study. The median duration of exposure was 3.5 months (range: 1 day to 20 months) in patients receiving KEYTRUDA® and 1.5 months (range: 1 day to 14 months) in patients receiving chemotherapy.

KEYTRUDA® was discontinued in 8% of patients due to adverse reactions. The most frequent adverse reaction leading to complete discontinuation of KEYTRUDA® was pneumonitis (1.9%). Adverse reactions leading to interruption of KEYTRUDA® occurred in 20% of patients; the most frequent (≥1%) adverse reactions were urinary tract infection (1.5%), diarrhea (1.5%), and colitis (1.1%).

Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA®. The most frequent serious adverse reactions (≥2%) in patients treated with KEYTRUDA® were urinary tract infection, pneumonia, anemia, and pneumonitis.

Tables 29 and 30 summarize adverse reactions and laboratory abnormalities, respectively, that occurred in patients receiving KEYTRUDA® in KEYNOTE-045.

Table 29. Adverse reactions occurring in ≥10% of patients receiving KEYTRUDA® in KEYNOTE-045

* Chemotherapy: paclitaxel, docetaxel, or vinflunine

† Grades according to NCI CTCAE v4.0

‡ Includes asthenia, fatigue, malaise, lethargy

§ Includes back pain, myalgia, bone pain, musculoskeletal pain, limb pain, chest musculoskeletal pain, musculoskeletal discomfort, neck pain

¶ Includes maculopapular rash, genital rash, erythematous rash, papular rash, pustular rash, erythema, drug rash, eczema, asteatotic eczema, contact dermatitis, acneiform dermatitis, dermatitis, seborrheic keratosis, lichenoid keratosis

Includes diarrhea, gastroenteritis, colitis, enterocolitis

Þ Includes cough, productive cough

ß Includes dyspnea, dyspnea on exertion, wheezing

à Includes blood in urine, hematuria, chromaturia

Table 30. Laboratory abnormalities compared to baseline occurring in ≥ 20% of patients with urothelial carcinoma treated with KEYTRUDA® in KEYNOTE-045

* Frequency is based on the number of patients with baseline test results and at least 1 post-baseline assessment during the study: Keytruda® (range: 240 to 248 patients) and chemotherapy (range: 238 to 244 patients); decreased phosphate levels: Keytruda® n = 232 and chemotherapy n = 222.

† Grading according to NCI CTCAE v4.0

High-risk non-muscle-invasive bladder cancer unresponsive to BCG therapy

The safety of Keytruda® was evaluated in a multicenter, open-label, single-arm trial, KEYNOTE-057, which included 148 patients with high-risk non-muscle-invasive bladder cancer, including 96 patients with carcinoma in situ with or without papillary tumors who had not responded to BCG therapy. Patients received Keytruda® at a dose of 200 mg every three weeks until unacceptable toxicity, persistent or recurrent high-risk non-muscle-invasive bladder cancer, disease progression, or for up to 24 months in the absence of disease progression.

The median duration of exposure to Keytruda® was 4.3 months (range: 1 day to 25.6 months).

Treatment with Keytruda® was discontinued due to adverse reactions in 11% of patients. The most common adverse reaction (>1%) leading to permanent discontinuation of Keytruda® was pneumonitis (1.4%). Adverse reactions leading to temporary interruption of Keytruda® occurred in 22% of patients; the most frequent (≥2%) were diarrhea (4%) and urinary tract infection (2%). Serious adverse reactions occurred in 28% of patients receiving Keytruda®. The most common serious adverse reactions (≥2%) in patients treated with Keytruda® were pneumonia (3%), ischemic heart disease (2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and urinary tract infection (2%).

Tables 31 and 32 summarize adverse reactions and laboratory abnormalities, respectively, in patients who received Keytruda® in the KEYNOTE-057 trial.

Table 31. Adverse reactions occurring in ≥10% of patients receiving Keytruda® in KEYNOTE-057

* NCI CTCAE v4.03 grades

† Includes asthenia, fatigue, malaise

‡ Includes peripheral edema, peripheral swelling

§ Includes diarrhea, gastroenteritis, colitis

¶ Includes maculopapular rash, rash, erythematous rash, pruritic rash, pustular rash, erythema, eczema, asteatotic eczema, lichenoid keratosis, urticaria, dermatitis

Includes back pain, myalgia, musculoskeletal pain, limb pain, chest musculoskeletal pain, neck pain

Þ Includes cough, productive cough

Table 32. Laboratory abnormalities compared to baseline occurring in ≥ 20% of patients with high-risk non–muscle-invasive bladder cancer who did not respond to BCG therapy and received Kētra® in KEYNOTE-057

* Frequency of each test was based on the number of patients who had baseline laboratory testing and at least one on-study test: KEYTRUDA® (range: 124 to 147 patients).

† Grading according to NCI CTCAE v4.03

Cancer with high microsatellite instability or deficient mismatch repair

The safety of KEYTRUDA® was evaluated in 504 patients with MSI-H or dMMR cancers enrolled in KEYNOTE-158, KEYNOTE-164, and KEYNOTE-051. The median duration of exposure to KEYTRUDA® was 6.2 months (range: 1 day to 53.5 months). Adverse reactions observed in patients with MSI-H or dMMR cancers were similar to those observed in patients with other solid tumors receiving KEYTRUDA® as monotherapy.

High microsatellite instability or deficient mismatch repair in patients with colorectal cancer

In 153 patients with MSI-H or dMMR CRC enrolled in the KEYNOTE-177 study who received KEYTRUDA®, the median duration of treatment was 11.1 months (range: 1 day to 30.6 months). Patients with autoimmune disease or medical conditions requiring immunosuppression were not allowed in the study. Adverse reactions observed in patients with MSI-H or dMMR CRC were similar to those in 2799 patients with melanoma or NSCLC who received KEYTRUDA® as monotherapy.

Gastric cancer

First-line therapy of locally advanced unresectable or metastatic HER2-positive gastric adenocarcinoma or gastroesophageal junction (GEJ) adenocarcinoma

The safety of KEYTRUDA® was evaluated in 433 patients with HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma enrolled in KEYNOTE-811, including 217 patients who received KEYTRUDA® 200 mg, trastuzumab, and either CAPOX (n = 189) or FP (n = 28) every 3 weeks, compared to 216 patients who received placebo, trastuzumab, and either CAPOX (n = 187) or FP (n = 29) every 3 weeks. The median duration of exposure to KEYTRUDA® was 5.8 months (range: 1 day to 17.7 months). Characteristics of the study population: median age 63 years (range: 19 to 84 years), 43% of patients were aged 65 years or older; 81% were male; 58% were White, 35% Asian, and 0.9% Black; 44% had ECOG performance status 0 and 56% had ECOG performance status 1. Treatment with KEYTRUDA® or placebo was discontinued due to adverse reactions in 6% of patients in each group. The most common adverse reaction leading to permanent discontinuation of KEYTRUDA® was pneumonitis (1.4%). Adverse reactions leading to interruption of KEYTRUDA® occurred in 58% of patients; the most common adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA® (≥2%) were neutropenia (18%), thrombocytopenia (12%), diarrhea (6%), anemia (3.7%), hypokalemia (3.7%), fatigue/asthenia (3.2%), decreased appetite (3.2%), increased AST (2.8%), increased blood bilirubin (2.8%), pneumonia (2.8%), increased ALT (2.3%), and vomiting (2.3%). In the KEYTRUDA® group compared to placebo, there was a ≥5% difference in the incidence of diarrhea (53% vs. 44%) and nausea (49% vs. 44%) between patients receiving KEYTRUDA® compared to those receiving standard therapy alone. There were no clinically meaningful differences between groups in the incidence of grade 3–4 toxicity. A ≥5% difference in incidence was observed for increased ALT levels (34% vs. 29%) and increased creatinine levels (20% vs. 10%) between patients receiving KEYTRUDA® and those receiving standard therapy. There were no clinically significant differences between groups in the incidence of grade 3–4 toxicity.

First-line therapy of locally advanced unresectable or metastatic HER2-negative gastric adenocarcinoma or gastroesophageal junction (GEJ) adenocarcinoma

The safety of KEYTRUDA® was evaluated in 1572 patients with HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma enrolled in KEYNOTE-859, including 785 patients who received KEYTRUDA® 200 mg and either FP (n = 106) or CAPOX (n = 674) every 3 weeks, compared to 787 patients who received placebo and either FP (n = 107) or CAPOX (n = 679) every 3 weeks.

The median duration of exposure to KEYTRUDA® was 6.2 months (range: 1 day to 33.7 months).

Serious adverse reactions occurred in 45% of patients receiving KEYTRUDA®. Serious adverse reactions occurring in >2% of patients included pneumonia (4.1%), diarrhea (3.9%), hemorrhage (3.9%), and vomiting (2.4%). Fatal adverse reactions occurred in 8% of patients receiving KEYTRUDA®, including infection (2.3%) and thromboembolism (1.3%).

Treatment with KEYTRUDA® was permanently discontinued due to adverse reactions in 15% of patients. Adverse reactions leading to permanent discontinuation of KEYTRUDA® in ≥1% of patients were infections (1.8%) and diarrhea (1.0%).

Treatment with KEYTRUDA® was interrupted due to an adverse reaction in 65% of patients. Adverse reactions or laboratory abnormalities leading to interruption of KEYTRUDA® (≥2%) included neutropenia (21%), thrombocytopenia (13%), diarrhea (5.5%), fatigue (4.8%), infection (4.8%), anemia (4.5%), increased AST (4.3%), increased ALT (3.8%), increased blood bilirubin (3.3%), decreased white blood cell count (2.2%), nausea (2%), palmar-plantar erythrodysesthesia syndrome (2%), and vomiting (2%).

Tables 33 and 34 summarize adverse reactions and laboratory abnormalities, respectively, observed in patients receiving KEYTRUDA® in KEYNOTE-859.

Table 33. Adverse reactions occurring in ≥20% of patients receiving KEYTRUDA® in KEYNOTE-859

Table 34. Changes in laboratory parameters from baseline occurring in ≥ 20% of patients treated with KEYTRUDA® in KEYNOTE-859

Esophageal Cancer

First-line therapy for the treatment of locally advanced unresectable or metastatic esophageal/gastroesophageal junction cancer

The safety of KEYTRUDA® in combination with cisplatin and fluorouracil (FU) chemotherapy was evaluated in KEYNOTE-590. This was a multicenter, double-blind, randomized (1:1), placebo-controlled first-line trial in patients with metastatic or locally advanced carcinoma of the esophagus or gastroesophageal junction (tumor center located 1–5 cm above the gastroesophageal junction) who were not candidates for surgical resection or definitive chemoradiotherapy. A total of 740 patients received KEYTRUDA® at a dose of 200 mg (n = 370) or placebo (n = 370) every 3 weeks for up to 35 cycles, in combination with cisplatin for up to 6 cycles and with FU for up to 35 cycles.

The median duration of exposure to KEYTRUDA® was 5.7 months (range: 1 day to 26 months) in the KEYTRUDA® combination group and 5.1 months (range: 3 days to 27 months) in the chemotherapy group.

Permanent discontinuation of KEYTRUDA® due to adverse reactions occurred in 15% of patients. The most frequent adverse reactions leading to permanent discontinuation of KEYTRUDA® (≥1%) were pneumonitis (1.6%), acute kidney injury (1.1%), and pneumonia (1.1%). Adverse reactions leading to interruption of KEYTRUDA® occurred in 67% of patients. The most frequent adverse reactions leading to discontinuation of KEYTRUDA® (≥2%) were neutropenia (19%), fatigue/asthenia (8%), decreased white blood cell count (5%), pneumonia (5%), decreased appetite (4.3%), anemia (3.2%), increased blood creatinine (3.2%), stomatitis (3.2%), malaise (3.0%), thrombocytopenia (3%), pneumonitis (2.7%), diarrhea (2.4%), dysphagia (2.2%), and nausea (2.2%).

Tables 35 and 36 summarize adverse reactions and laboratory abnormalities, respectively, observed in patients treated with KEYTRUDA® in the KEYNOTE-590 study.

Table 35. Adverse Reactions Occurring in ≥20% of Patients Receiving KEYTRUDA® in KEYNOTE-590

* Grades according to NCI CTCAE v4.03

† One case of diarrhea with fatal outcome was reported in each group.

‡ Includes asthenia, fatigue

Table 36. Laboratory abnormalities occurring in ≥ 20% of patients with esophageal cancer who received KEYTRUDA® in KEYNOTE-590, compared to baseline values

* Frequency is based on the number of patients with baseline laboratory results and at least 1 result during the study: Keytruda®/cisplatin/5-FU (range: 345 to 365 patients) and placebo/cisplatin/5-FU (range: 330 to 358 patients).

† Grades according to NCI CTCAE v4.03

Previously treated recurrent locally advanced or metastatic esophageal cancer

In 314 patients with esophageal cancer included in KEYNOTE-181 and treated with Keytruda®, the median duration of exposure to Keytruda® was 2.1 months (range: 1 day to 24.4 months). Patients with autoimmune disease or medical conditions requiring immunosuppression were not included in the study. Adverse reactions observed in patients with esophageal cancer were similar to those in 2799 patients with melanoma or NSCLC who received Keytruda® as monotherapy.

Cervical cancer

Cervical cancer FIGO 2014 stage III–IVA with chemoradiotherapy

The safety of Keytruda® in combination with chemoradiotherapy (cisplatin plus external beam radiotherapy [EBRT] followed by brachytherapy [BT]) was evaluated in KEYNOTE-A18, a placebo-controlled, randomized (1:1), multicenter, double-blind study involving 594 women with cervical cancer FIGO 2014 stage III–IVA. Two hundred ninety-two women received Keytruda® in combination with chemoradiotherapy, and 302 women received placebo in combination with chemoradiotherapy.

The median duration of exposure to Keytruda® was 12.1 months (range: 1 day to 27 months).

Fatal adverse reactions occurred in 1.4% of women who received Keytruda® in combination with chemoradiotherapy, including one case (0.3%) each of colonic perforation, urosepsis, sepsis, and vaginal bleeding.

Serious adverse reactions occurred in 30% of women receiving Keytruda® in combination with chemoradiotherapy. Serious adverse reactions occurring in ≥1% of women included urinary tract infection (2.7%), urosepsis (1.4%), and sepsis (1%).

Keytruda® was discontinued due to adverse reactions in 7% of women. The most frequent adverse reaction (≥1%) leading to complete discontinuation of Keytruda® was diarrhea (1%).

Adverse reactions that led to interruption of Keytruda® occurred in 43% of women; the most common adverse reactions leading to interruption of Keytruda® (≥2%) included anemia (8%), COVID-19 (6%), positive SARS-CoV-2 test (3.1%), neutropenia (2.7%), diarrhea (2.7%), urinary tract infection (2.7%), and increased ALT (2.4%).

Tables 37 and 38 summarize adverse reactions and laboratory abnormalities observed in women treated with Keytruda® in KEYNOTE-A18.

Table 37. Adverse reactions occurring in ≥10% of women with cervical cancer FIGO 2014 stage III–IVA treated with Keytruda® in KEYNOTE-A18

* Grades according to NCI CTCAE v5.0

† Includes urinary tract infection, Pseudomonas urinary tract infection, acute pyelonephritis, cystitis, Escherichia urinary tract infection

‡ Includes fatigue, asthenia

§ Includes hypothyroidism, autoimmune hypothyroidism

¶ Includes erythema multiforme, dermatitis, drug eruption, eczema, rash, skin desquamation, bullous dermatitis, maculopapular rash, lichen planus, dyshidrotic eczema, acneiform dermatitis

Table 38. Laboratory abnormalities worsening from baseline in ≥ 20% of patients with FIGO 2014 stage III–IVA cervical cancer who received KTRUDA® in KEYNOTE-A18

* The frequency of laboratory parameter changes is based on the number of patients who had both baseline and at least one post-baseline laboratory measurement for each parameter: Keytruda® + chemoradiotherapy (range: 286 to 291 patients) and placebo + chemoradiotherapy (range: 298 to 300 patients).

† Grades according to NCI CTCAE v5.0

Persistent, recurrent, or metastatic cervical cancer

The safety of Keytruda® in combination with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab, was evaluated in KEYNOTE-826. This was a multicenter, double-blind, randomized (1:1), placebo-controlled first-line therapy study involving patients with persistent, recurrent, or metastatic cervical cancer who had not received prior chemotherapy, except when used concurrently as a radiosensitizer. A total of 616 patients, regardless of tumor PD-L1 expression, received Keytruda® 200 mg plus chemotherapy with or without bevacizumab (n = 307) every 3 weeks or placebo plus chemotherapy with or without bevacizumab (n = 309) every 3 weeks. The median duration of exposure to Keytruda® was 9.9 months (range: 1 day to 26 months). Fatal adverse reactions occurred in 4.6% of patients receiving Keytruda® in combination with chemotherapy with or without bevacizumab, including 3 cases of hemorrhage, 2 cases of sepsis, 2 cases of unknown cause, and 1 case each of acute myocardial infarction, autoimmune encephalitis, cardiac arrest, cerebrovascular accident, femoral fracture with perioperative pulmonary embolism, intestinal perforation, and pelvic infection. Serious adverse reactions were observed in 50% of patients receiving Keytruda® and chemotherapy with or without bevacizumab. Serious adverse reactions occurring in ≥ 3% of patients included febrile neutropenia (6.8%), urinary tract infection (5.2%), anemia (4.6%), acute kidney injury (3.3%), and sepsis (3.3%). Keytruda® was discontinued due to adverse reactions in 15% of patients. The most frequent adverse reaction leading to complete discontinuation of Keytruda® (≥ 1%) was colitis (1%). Adverse reactions leading to interruption of Keytruda® administration occurred in 66% of patients; the most frequent adverse reactions or laboratory abnormalities leading to interruption of Keytruda® (≥ 2%) were thrombocytopenia (15%), neutropenia (14%), anemia (11%), increased ALT (6%), leukopenia (5%), fatigue/asthenia (4.2%), urinary tract infection (3.6%), increased AST (3.3%), pyrexia (3.3%), diarrhea (2.6%), acute kidney injury (2.6%), increased blood creatinine (2.6%), colitis (2.3%), decreased appetite (2.0%), and cough (2.0%). Among patients who received treatment with Keytruda®, chemotherapy, and bevacizumab (n = 196), the most common (≥ 20%) adverse reactions were peripheral neuropathy (62%), alopecia (58%), anemia (55%), fatigue/asthenia (53%), nausea (41%), neutropenia (41%), diarrhea (39%), hypertension (35%), thrombocytopenia (35%), constipation (31%), arthralgia (31%), vomiting (30%), urinary tract infection (27%), rash (26%), leukopenia (24%), hypothyroidism (22%), and decreased appetite (21%).

Tables 39 and 40 summarize the adverse reactions and laboratory parameter changes, respectively, observed in patients treated with Keytruda® in the KEYNOTE-826 study.

Table 39. Adverse reactions occurring in ≥ 20% of patients treated with Keytruda® in KEYNOTE-826

* Chemotherapy (paclitaxel and cisplatin or paclitaxel and carboplatin)

† Grades according to NCI CTCAE v4.0

‡ Includes peripheral neuropathy, peripheral sensory neuropathy, peripheral motor neuropathy, peripheral sensorimotor neuropathy, paresthesia

§ Includes rash, maculopapular rash, erythematous rash, macular rash, papular rash, pruritic rash, pustular rash

¶ Includes fatigue, asthenia

Table 40. Laboratory abnormalities occurring in ≥ 20% of patients who received KEYTRUDA® in KEYNOTE-826, compared to baseline

* Frequency is based on the number of patients with baseline laboratory test results and at least 1 result during the study: KEYTRUDA® plus chemotherapy (range: 297 to 301 patients) and placebo plus chemotherapy (range: 299 to 302 patients).

† Chemotherapy (paclitaxel and cisplatin or paclitaxel and carboplatin)

‡ Grades according to NCI CTCAE v4.0

Previously treated recurrent or metastatic cervical cancer

In 98 patients with cervical cancer included in cohort E of the KEYNOTE-158 study, the median duration of treatment with KEYTRUDA® was 2.9 months (range: 1 day to 22.1 months). Patients with autoimmune disease or medical conditions requiring immunosuppression were not included in the study.

Treatment with KEYTRUDA® was discontinued due to adverse reactions in 8% of patients. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA®. The most frequently reported serious adverse reactions were anemia (7%), fistula (4.1%), hemorrhage (4.1%), and infections [excluding urinary tract infections (UTIs)] (4.1%).

Tables 41 and 42 summarize adverse reactions and laboratory abnormalities, respectively, observed in patients receiving KEYTRUDA® in KEYNOTE-158.

Table 41. Adverse reactions occurring in ≥10% of patients with cervical cancer in KEYNOTE-158

* NCI CTCAE v4.0 grading

† Includes asthenia, fatigue, somnolence, malaise

‡ Includes chest pain, tumor pain, dysesthesia, dysuria, ear pain, gum pain, groin pain, lymph node pain, oropharyngeal pain, pain general, skin pain, pelvic pain, radicular pain, stoma site pain, toothache

§ Includes peripheral edema, peripheral swelling

¶ Includes arthralgia, back pain, musculoskeletal pain, musculoskeletal discomfort, myalgia, myositis, neck pain, non-cardiac chest pain, limb pain

Includes colitis, diarrhea, gastroenteritis

Þ Includes abdominal discomfort, abdominal distension, abdominal pain, lower abdominal pain, upper abdominal pain

ß Includes epistaxis, hematuria, hemoptysis, metrorrhagia, rectal bleeding, uterine hemorrhage, vaginal hemorrhage

à Includes bacterial pyelonephritis, acute pyelonephritis, urinary tract infection, bacterial urinary tract infection, Pseudomonas urinary tract infection, urosepsis

è Includes cellulitis, Clostridium difficile infection, device-related infection, empyema, gas gangrene, herpes virus infection, neoplasm-related infection, infection, influenza, lower respiratory tract infection, lung infection, oral candidiasis, oral fungal infection, osteomyelitis, Pseudomonas infection, respiratory tract infection, dental abscess, upper respiratory tract infection, uterine abscess, vulvovaginal candidiasis

ð Includes dermatitis, drug eruption, eczema, erythema, hand-foot syndrome, rash, generalized rash, maculopapular rash

Table 42. Laboratory abnormalities occurring at ≥ 20% of patients with cervical cancer in KEYNOTE-158 compared to baseline values

* The frequency of abnormalities for each parameter was calculated based on the number of patients who had the corresponding laboratory test performed both at baseline and at least once during the study: the pembrolizumab treatment group (range: 76 to 79 patients).

† Grading according to NCI CTCAE v4.0

Other laboratory abnormalities occurring in ≥ 10% of patients treated with pembrolizumab included hypophosphatemia (19% all grades; 6% grades 3–4), increased international normalized ratio (INR) (19% all grades; 0% grades 3–4), hypercalcemia (14% all grades; 2.6% grades 3–4), decreased platelet count (14% all grades; 1.3% grades 3–4), increased activated partial thromboplastin time (aPTT) (14% all grades; 0% grades 3–4), hypoglycemia (13% all grades; 1.3% grades 3–4), decreased white blood cell count (13% all grades; 2.6% grades 3–4), and hyperkalemia (13% all grades; 1.3% grades 3–4).

Hepatocellular Carcinoma (HCC)

Previously Treated HCC

The safety of pembrolizumab was evaluated in the multicenter, double-blind, randomized, placebo-controlled KEYNOTE-394 trial involving patients with previously treated HCC. Patients were randomized (2:1) to receive pembrolizumab 200 mg (n = 299) or placebo (n = 153) intravenously every 3 weeks for up to 35 cycles.

The median duration of exposure was 3.3 months (range: 1 day to 27.3 months) in the pembrolizumab group and 2.2 months (range: 1 day to 15.5 months) in the placebo group. Treatment with pembrolizumab was permanently discontinued due to adverse reactions in 13% of patients. The most frequent adverse reaction leading to permanent discontinuation of pembrolizumab was ascites (2.3%). Adverse reactions leading to interruption of pembrolizumab treatment occurred in 26% of patients; the most frequent adverse reactions or laboratory abnormalities leading to interruption of pembrolizumab (≥ 2%) were increased blood bilirubin levels (9%), increased AST (5%), and increased ALT (2%).

Tables 43 and 44 summarize adverse reactions and laboratory abnormalities observed in patients receiving pembrolizumab in KEYNOTE-394.

Table 43. Adverse Reactions Occurring in ≥ 10% of Patients with HCC Receiving Pembrolizumab in KEYNOTE-394

* Grades according to NCI CTCAE v4.03

† Includes dermatitis, allergic dermatitis, bullous dermatitis, rash, erythematous rash, maculopapular rash, pustular rash, and blisters.

Table 44. Laboratory test abnormalities from baseline occurring in ≥ 20% of patients with HCC treated with KTRUDA® in KEYNOTE-394

* The frequency of changes in each parameter is based on the number of patients for whom both baseline values and at least one laboratory measurement during the study of KEYTRUDA® were available (range: 223 to 297 patients) and placebo (range: 144 to 151 patients).

† Grades according to NCI CTCAE v4.03

Biliary tract cancer (BTC)

The safety of KEYTRUDA® in combination with gemcitabine and cisplatin was evaluated in a multicenter, double-blind, randomized, placebo-controlled trial, KEYNOTE-966, in patients with locally advanced unresectable or metastatic BTC who had not received prior systemic therapy for advanced disease. Overall, 1063 patients received KEYTRUDA® at a dose of 200 mg plus gemcitabine and cisplatin chemotherapy (n = 529) or placebo plus gemcitabine and cisplatin chemotherapy (n = 534) every 3 weeks.

The median duration of exposure to KEYTRUDA® was 6 months (range: 1 day to 28 months).

In 15% of patients, KEYTRUDA® was discontinued due to adverse reactions. The most frequent adverse reaction leading to complete discontinuation of KEYTRUDA® (≥ 1%) was pneumonitis (1.3%).

Adverse reactions leading to interruption of KEYTRUDA® administration occurred in 55% of patients. The most common adverse reactions or laboratory parameter changes leading to interruption of KEYTRUDA® (≥ 2%) were neutropenia (18%), thrombocytopenia (10%), anemia (6%), leukopenia (4%), pyrexia (3.8%), fatigue (3.0%), cholangitis (2.8%), increased ALT (2.6%), increased AST (2.5%), and biliary tract obstruction (2.3%).

In the KEYTRUDA® plus chemotherapy group compared to the placebo plus chemotherapy group, a difference ≥ 5% in the incidence of adverse reactions was observed between patients receiving KEYTRUDA® and those receiving placebo for the following adverse reactions: pyrexia (26% vs 20%), rash (21% vs 13%), pruritus (15% vs 10%), and hypothyroidism (9% vs 2.6%). No clinically significant differences in the incidence of grade 3–4 toxicity were observed between the groups.

A difference ≥ 5% in the frequency of laboratory parameter changes was observed between patients receiving KEYTRUDA® plus chemotherapy and those receiving placebo plus chemotherapy for lymphopenia (69% vs 61%). No clinically significant differences in the incidence of grade 3–4 toxicity were observed between the groups.

Merkel cell carcinoma (MCC)

In 150 patients with MCC enrolled in KEYNOTE-017 and KEYNOTE-913, the median duration of treatment with KEYTRUDA® was 6.3 months (range: 1 day to 28 months).

Patients with autoimmune disease or medical conditions requiring immunosuppression were not included in the studies. Adverse reactions observed in patients with Merkel cell carcinoma were similar to those in 2799 patients with melanoma or NSCLC who received KEYTRUDA® as monotherapy. Laboratory abnormalities (grade 3–4 severity) observed at higher frequency included elevated lipase (17%).

Renal cell carcinoma (RCC)

The safety of KEYTRUDA® in combination with axitinib was evaluated in KEYNOTE-426. Patients with conditions requiring systemic corticosteroids or other immunosuppressants, or with a history of severe autoimmune diseases, except for type 1 diabetes, vitiligo, Sjögren’s syndrome, and hypothyroidism stable on hormone replacement therapy, were not included in the study. Patients received KEYTRUDA® 200 mg intravenously every 3 weeks and axitinib 5 mg orally twice daily or sunitinib 50 mg once daily for 4 weeks, followed by 2 weeks off treatment. The median duration of combination therapy with KEYTRUDA® and axitinib was 10.4 months (range: 1 day to 21.2 months).

Study participants had the following characteristics: median age 62 years (range: 30 to 89); 40% were aged 65 years or older; 71% were male; 80% were White; 80% had a Karnofsky Performance Status (KPS) of 90–100 and 20% had a KPS of 70–80.

Fatal adverse reactions occurred in 3.3% of patients receiving KEYTRUDA® in combination with axitinib. These included 3 cases of cardiac arrest, 2 cases of pulmonary embolism, and 1 case each of heart failure, death from unknown cause, myasthenia gravis, myocarditis, Fournier’s gangrene, multiple myeloma, pleural effusion, pneumonitis, and respiratory failure.

Serious adverse reactions occurred in 40% of patients receiving KEYTRUDA® in combination with axitinib. Serious adverse reactions in ≥ 1% of patients receiving KEYTRUDA® plus axitinib included hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), pneumonitis (1%).

Treatment was permanently discontinued due to adverse reactions in 31% of patients: 13% of patients discontinued only KEYTRUDA®, 13% discontinued only axitinib, and 8% discontinued both drugs. The most common serious adverse reactions (> 1%) leading to permanent discontinuation of KEYTRUDA®, axitinib, or the combination included hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and stroke (1.2%).

Adverse reactions leading to temporary interruption or dose reduction, excluding temporary interruption of KEYTRUDA® due to infusion-related reactions, occurred in 76% of patients receiving KEYTRUDA® in combination with axitinib, including discontinuation of KEYTRUDA® in 50% of patients. Axitinib was discontinued in 64% of patients and dose reduced in 22% of patients. The most common adverse reactions (> 10%) leading to discontinuation of KEYTRUDA® were hepatotoxicity (14%) and diarrhea (11%), and the most common adverse reactions (> 10%) leading to discontinuation or dose reduction of axitinib were hepatotoxicity (21%), diarrhea (19%), and hypertension (18%).

The most common adverse reactions (≥ 20%) in patients receiving KEYTRUDA® and axitinib included diarrhea, fatigue/asthenia, hypertension, hypothyroidism, decreased appetite, hepatotoxicity, palmar-plantar erythrodysesthesia, nausea, stomatitis/mucosal inflammation, dysphonia, rash, cough, and constipation.

Twenty-seven percent (27%) of patients receiving KEYTRUDA® in combination with axitinib received daily doses of oral prednisone equivalent to ≥ 40 mg for the treatment of immune-mediated adverse reactions.

Tables 45 and 46 summarize adverse reactions and laboratory abnormalities, respectively, occurring in at least 20% of patients who received KEYTRUDA® and axitinib in KEYNOTE-426.

Table 45. Adverse reactions occurring in ≥ 20% of patients receiving KEYTRUDA® and axitinib in KEYNOTE-426

* Grading according to NCI CTCAE v4.03

† Includes diarrhea, colitis, enterocolitis, gastroenteritis, enteritis, hemorrhagic enterocolitis

‡ Includes hypertension, increased blood pressure, hypertensive crisis, labile hypertension

§ Includes increased ALT, increased AST, autoimmune hepatitis, increased blood bilirubin, drug-induced liver injury, increased liver enzyme levels, liver function disorder, hepatitis, fulminant hepatitis, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, immune-mediated hepatitis, increased liver function tests, liver injury, transaminase elevation

¶ Includes rash, butterfly rash, dermatitis, acneiform dermatitis, atopic dermatitis, bullous dermatitis, contact dermatitis, exfoliative rash, genital rash, erythematous rash, generalized rash, macular rash, maculopapular rash, papular rash, pruritic rash, seborrheic dermatitis, skin discoloration, skin desquamation, perineal rash

Table 46. Laboratory abnormalities occurring at ≥ 20% of patients compared to baseline values with KEYTRUDA® and axitinib in KEYNOTE-426

* Frequency is based on the number of patients with baseline and at least one post-baseline test result in the study: KEYTRUDA®/axitinib (range: 342 to 425 patients) or sunitinib (range: 345 to 422 patients).

† Grades according to NCI CTCAE v4.03

‡ Adjusted for albumin

§ Two patients with Grade 3 prolonged activated partial thromboplastin time (aPTT) also had adverse reactions of hepatotoxicity reported.

Adjuvant Treatment of RCC

The safety of KEYTRUDA® as monotherapy was evaluated in KEYNOTE-564. This was a randomized (1:1), double-blind, placebo-controlled trial involving 984 patients who underwent nephrectomy for RCC and received either 200 mg of KEYTRUDA® administered as an intravenous infusion every three weeks (n = 488) or placebo (n = 496) for up to one year. The median duration of exposure to KEYTRUDA® was 11.1 months (range: 1 day to 14.3 months). Patients with active autoimmune disease or a medical condition requiring immunosuppression were excluded from the study. Serious adverse reactions occurred in 20% of patients receiving KEYTRUDA®. Serious adverse reactions (≥1%) included acute kidney injury, adrenal insufficiency, pneumonia, colitis, and diabetic ketoacidosis (each 1%). Fatal adverse reactions occurred in 0.2% of patients receiving KEYTRUDA®, including one case of pneumonia. Discontinuation of KEYTRUDA® due to adverse reactions occurred in 21% of patients; the most frequent (≥1%) were increased ALT (1.6%), colitis (1%), and adrenal insufficiency (1%). Interruption of KEYTRUDA® due to adverse reactions occurred in 26% of patients; the most frequent (≥1%) were increased AST (2.3%), arthralgia (1.6%), hypothyroidism (1.6%), diarrhea (1.4%), increased ALT (1.4%), fatigue (1.4%), rash, decreased appetite, and vomiting (each 1%).

Tables 47 and 48 list adverse reactions and laboratory abnormalities, respectively, observed in patients treated with KEYTRUDA® in the KEYNOTE-564 study.

Table 47. Individual* adverse reactions occurring in ≥10% of patients treated with KEYTRUDA® in the KEYNOTE-564 study

* Adverse reactions that occurred with equal or higher frequency compared to the placebo group

† Grades according to NCI CTCAE v4.0

‡ Includes arthralgia, back pain, myalgia, arthritis, limb pain, neck pain, musculoskeletal pain, musculoskeletal stiffness, spinal pain, musculoskeletal chest pain, bone pain, musculoskeletal discomfort

§ Includes asthenia, fatigue

¶ Includes rash, maculopapular rash, papular rash, exfoliative skin conditions, lichen planus, erythematous rash, eczema, macular rash, acneiform dermatitis, dermatitis, pruritic rash, Stevens-Johnson syndrome, asteatotic eczema, hand-foot syndrome (hand-foot erythrodysesthesia)

Includes diarrhea, colitis, enterocolitis, frequent defecation, enteritis

Þ Includes abdominal pain, lower abdominal pain, upper abdominal pain, abdominal discomfort, gastrointestinal pain

ß Includes upper respiratory tract infection with cough, productive cough, cough

à Includes tension headache, headache, sinus headache, migraine with aura

è Includes increased alanine aminotransferase levels, increased aspartate aminotransferase levels, increased blood bilirubin levels, drug-induced liver injury, elevated liver enzymes, liver function abnormalities, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, immune-mediated hepatitis, increased liver function test results, increased transaminase levels, increased gamma-glutamyltransferase levels, increased conjugated bilirubin levels

ð Includes acute kidney injury, increased blood creatinine levels, renal failure, kidney function impairment, oliguria, decreased glomerular filtration rate, toxic nephropathy

Table 48. Individual* laboratory abnormalities from baseline occurring in ≥ 20% of melanoma patients treated with KEYTRUDA® in KEYNOTE-564

* Laboratory abnormalities occurring at an equal or higher frequency compared to the placebo group

† Frequency based on the number of patients with baseline laboratory test results and at least one on-study result: KEYTRUDA® (range: 440 to 449 patients) and placebo (range: 461 to 469 patients); elevated INR: KEYTRUDA® n = 228 and placebo n = 254.

‡ Grades according to NCI CTCAE v4.03

Endometrial carcinoma

Advanced or recurrent endometrial carcinoma

The safety of KEYTRUDA® in combination with chemotherapy (paclitaxel and carboplatin) was evaluated in KEYNOTE-868, a randomized (1:1), multicenter, double-blind, placebo-controlled trial in patients with advanced or recurrent endometrial carcinoma. Overall, 759 patients received KEYTRUDA® 200 mg every 3 weeks in combination with chemotherapy for 6 cycles, followed by KEYTRUDA® 400 mg every 6 weeks for 14 cycles (n = 382), or placebo with chemotherapy for 6 cycles followed by placebo for 14 cycles (n = 377). The median duration of exposure to KEYTRUDA® was 5.6 months (range: 1 day to 24.0 months).

Serious adverse reactions occurred in 35% of patients who received KEYTRUDA® in combination with chemotherapy, compared to 19% of patients who received placebo with chemotherapy.

Fatal adverse reactions occurred in 1.6% of patients who received KEYTRUDA® in combination with chemotherapy, including COVID-19 (0.5%) and cardiac arrest (0.3%).

In 14% of patients, KEYTRUDA® treatment was discontinued due to adverse reactions. Chemotherapy dose reductions were required in 29% of patients who received KEYTRUDA® in combination with chemotherapy, compared to 23% of patients who received placebo with chemotherapy. There were no clinically meaningful differences in the discontinuation or interruption of chemotherapy between the study groups.

Adverse reactions observed in patients who received KEYTRUDA® and chemotherapy were generally similar to those observed with monotherapy with KEYTRUDA® or chemotherapy alone, except for rash (33% all grades; 2.9% grade 3–4).

As a single agent for the treatment of advanced endometrial carcinoma with MSI-H or dMMR

In 90 patients with MSI-H or dMMR endometrial carcinoma included in the KEYNOTE-158 trial who received KEYTRUDA® as monotherapy, the median duration of treatment was 8.3 months (range: 1 day to 26.9 months). Adverse reactions observed in patients with endometrial carcinoma were similar to those observed in 2799 patients with melanoma or NSCLC who received KEYTRUDA® as monotherapy.

Cancer with high tumor mutational burden (TMB-H)

The safety of KEYTRUDA® was evaluated in 105 patients with TMB-H cancer included in the KEYNOTE-158 trial. The median duration of treatment with KEYTRUDA® was 4.9 months (range: 0.03 to 35.2 months). Adverse reactions observed in patients with TMB-H cancer were similar to those in patients with other solid tumors who received KEYTRUDA® as monotherapy.

Cutaneous squamous cell carcinoma (cSCC)

In 159 patients with advanced cSCC (recurrent, metastatic, or locally advanced disease) included in the KEYNOTE-629 trial who received KEYTRUDA®, the median duration of treatment was 6.9 months (range: 1 day to 28.9 months). Patients with autoimmune disease or medical conditions requiring systemic corticosteroids or other immunosuppressive therapy were not included in the trial. Adverse reactions observed in patients with recurrent or metastatic cSCC or locally advanced cSCC were similar to those in 2799 patients with melanoma or NSCLC who received KEYTRUDA® as monotherapy. Pathological laboratory abnormalities (grade 3–4) observed at high frequency included lymphopenia (10%) and decreased sodium levels (10%).

Triple-negative breast cancer (TNBC)

Neoadjuvant and adjuvant treatment of high-risk early-stage TNBC

The safety of KEYTRUDA® in combination with neoadjuvant chemotherapy (carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide), followed by surgery and continued adjuvant treatment with KEYTRUDA® as monotherapy, was evaluated in KEYNOTE-522, a multicenter, randomized (2:1), double-blind, placebo-controlled trial in patients with newly diagnosed, previously untreated, high-risk early-stage TNBC.

A total of 778 patients in the KEYTRUDA® group received at least one dose of KEYTRUDA® in combination with neoadjuvant chemotherapy, followed by adjuvant treatment with KEYTRUDA® after surgery, compared to 389 patients who received at least one dose of placebo in combination with neoadjuvant chemotherapy followed by adjuvant placebo after surgery.

The median duration of exposure to KEYTRUDA® 200 mg every 3 weeks was 13.3 months (range: 1 day to 21.9 months).

Fatal adverse reactions occurred in 0.9% of patients who received KEYTRUDA®, including one case each of acute adrenal insufficiency, autoimmune encephalitis, hepatitis, pneumonia, pneumonitis, pulmonary embolism, sepsis with multi-organ dysfunction syndrome, and myocardial infarction. Serious adverse reactions were observed in 44% of patients who received KEYTRUDA®.

Serious adverse reactions in ≥ 2% of patients who received KEYTRUDA® included febrile neutropenia (15%), pyrexia (3.7%), anemia (2.6%), and neutropenia (2.2%).

KEYTRUDA® was discontinued due to adverse reactions in 20% of patients. The most frequent adverse reactions (≥ 1%) leading to permanent discontinuation of KEYTRUDA® were increased ALT (2.7%), increased AST (1.5%), and rash (1%). Adverse reactions leading to interruption of KEYTRUDA® occurred in 57% of patients. The most frequent adverse reactions leading to interruption of KEYTRUDA® (≥ 2%) were neutropenia (26%), thrombocytopenia (6%), increased ALT (6%), increased AST (3.7%), anemia (3.5%), rash (3.2%), febrile neutropenia (2.8%), leukopenia (2.8%), upper respiratory tract infection (2.6%), pyrexia (2.2%), and fatigue (2.1%).

Tables 49 and 50 summarize adverse reactions and laboratory abnormalities, respectively, observed in patients treated with KEYTRUDA® in the KEYNOTE-522 trial.

Table 49. Adverse reactions occurring in ≥ 20% of patients treated with KEYTRUDA® in KEYNOTE-522

* Chemotherapy: carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide

† Grades according to NCI CTCAE v4.0

‡ Includes asthenia, fatigue

§ Includes aphthous ulcer, cheilitis, lip pain, lip ulcer, mouth ulcer, mucosal inflammation, oral mucosal erythema, oral pain, stomatitis, tongue blister, tongue ulcer

¶ Includes abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, abdominal tenderness

Includes dermatitis, acneiform dermatitis, allergic dermatitis, bullous dermatitis, exfoliative dermatitis generalized, drug-related rash, eczema, incision site rash, injection site rash, rash, erythematous rash, follicular rash, macular rash, maculopapular rash, morbilliform rash, papular rash, pruritic rash, pustular rash, rubelliform rash, exfoliative dermatitis, skin toxicity, toxic skin eruption, urticaria, vasculitic rash, viral rash

Þ Includes peripheral neuropathy, peripheral motor neuropathy, peripheral sensory-motor neuropathy, peripheral sensory neuropathy

ß Includes cough, productive cough, upper respiratory tract cough syndrome

Table 50. Laboratory abnormalities occurring in ≥ 20% of patients treated with KEYTRUDA® in KEYNOTE-522 compared to baseline values

* Frequency is based on the number of patients with baseline test results and at least 1 result during the study: Keytruda® in combination with chemotherapy followed by Keytruda® monotherapy (range: 759 to 777 patients) and placebo in combination with chemotherapy followed by placebo (range: 378 to 389 patients).

† Chemotherapy: carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide

† Grades according to NCI CTCAE v4.0

Locally recurrent unresectable or metastatic TNBC

The safety of Keytruda® in combination with paclitaxel, protein-bound paclitaxel, or gemcitabine and carboplatin was evaluated in a multicenter, double-blind, randomized (2:1), placebo-controlled trial, KEYNOTE-355, in patients with locally recurrent unresectable or metastatic TNBC who had not received prior chemotherapy for metastatic disease. Overall, 596 patients (including 34 patients from the initial safety run-in phase) received Keytruda® 200 mg every 3 weeks in combination with paclitaxel, protein-bound paclitaxel, or gemcitabine and carboplatin.

The median duration of treatment with Keytruda® was 5.7 months (range: 1 day to 33.0 months).

Fatal adverse reactions occurred in 2.5% of patients receiving Keytruda® in combination with chemotherapy, including cardiac arrest and respiratory arrest (0.7%) and septic shock (0.3%).

Serious adverse reactions occurred in 30% of patients receiving Keytruda® in combination with paclitaxel, protein-bound paclitaxel, or gemcitabine and carboplatin. Serious adverse reactions in ≥ 2% of patients included pneumonia (2.9%), anemia (2.2%), and thrombocytopenia (2%).

Treatment with Keytruda® was discontinued due to adverse reactions in 11% of patients. The most common adverse reactions leading to permanent discontinuation of Keytruda® (≥ 1%) included increased ALT (2.2%), increased AST (1.5%), and pneumonitis (1.2%). Adverse reactions leading to interruption of Keytruda® therapy occurred in 50% of patients. The most common adverse reactions leading to interruption of Keytruda® therapy (≥ 2%) were neutropenia (22%), thrombocytopenia (14%), anemia (7%), increased ALT (6%), leukopenia (5%), increased AST (5%), decreased white blood cell count (3.9%), and diarrhea (2%).

Tables 51 and 52 summarize adverse reactions and laboratory abnormalities in patients who received Keytruda® in KEYNOTE-355.

Table 51. Adverse reactions occurring in ≥ 20% of patients receiving Keytruda® with chemotherapy in KEYNOTE-355

* NCI CTCAE v4.03 grades

† Includes fatigue and asthenia

‡ Includes rash, maculopapular rash, pruritic rash, pustular rash, macular rash, papular rash, butterfly rash, erythematous rash, eyelid rash

§ Includes cough, productive cough, upper respiratory tract cough syndrome

¶ Includes headache, migraine, tension headache

Table 52. Laboratory abnormalities compared to baseline occurring in ≥ 20% of patients receiving KEYTRUDA® in combination with chemotherapy in KEYNOTE-355

* The frequency of each test is based on the number of patients with baseline test results and at least 1 test result during the study of Keytruda® + chemotherapy (range: 566 to 592 patients) and placebo + chemotherapy (range: 269 to 280 patients).

† Grading according to NCI CTCAE v4.03

Adverse reactions observed in clinical studies or reported during post-marketing experience

The following adverse reactions have been reported in clinical studies or during the post-marketing period: eosinophilia, immune thrombocytopenic purpura, hypophysitis, adrenal insufficiency, thyroiditis, diabetes mellitus, epilepsy, lethargy, Guillain-Barré syndrome, myasthenic syndrome, meningitis (aseptic), dry eye sensation, hypertension, dry mouth, pancreatitis, small intestine perforation, hair color changes, dry skin, Stevens-Johnson syndrome, toxic epidermal necrolysis, arthritis, Vogt-Koyanagi-Harada syndrome, hemophagocytic lymphohistiocytosis, tenosynovitis, influenza-like illness, chills, increased amylase levels, gastrointestinal ulcer, glomerulonephritis, vasculitis, sclerosing cholangitis, non-infectious cystitis, gastritis, optic neuritis, and celiac disease.

Reporting of adverse reactions

Reporting of adverse reactions after drug registration is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Incompatibilities

As compatibility studies with other medicinal products have not been conducted, Keytruda® must not be mixed with other medicinal products, except as specified in the section "Dosage and administration".

Shelf life

Unopened vial

2 years.

Storage of diluted solution

The diluted product should be used immediately. The diluted solution must not be frozen.

If not used immediately, diluted solutions of Keytruda® may be stored at room temperature for a total of up to 6 hours.

Diluted solutions of Keytruda® may also be stored in a refrigerator at 2 to 8°C; however, the total time from dilution of Keytruda® to completion of infusion must not exceed 96 hours.

When stored in the refrigerator, vials and/or intravenous infusion bags should be allowed to reach room temperature before administration.

Do not use the product after the expiry date stated on the packaging.

Storage conditions

Store in a refrigerator at 2 to 8°C. Do not freeze. Store in the original packaging, protected from light and out of reach of children.

Packaging

4 mL of concentrate for infusion solution in a 10 mL clear glass type I vial containing 100 mg of pembrolizumab.

1 vial per carton.

Prescription category

Prescription only.

Manufacturer

Organon Heist bv, Belgium

Manufacturer's address and location of operations

Industriepark 30, 2220 Heist-op-den-Berg, Belgium / Industriepark 30, 2220 Heist-op-den-Berg, Belgium.