Pembrolizumab

Previously treated patients. One study included 173 patients with unresectable or metastatic melanoma with disease progression within 24 weeks of the last dose of ipilimumab. If the patient had a BRAF V600 pathogenic variant, previous treatment with a BRAF inhibitor was also required. Patients were randomly assigned to one of two doses of pembrolizumab—2 mg/kg or 10 mg/kg—every 3 weeks. The trial excluded patients with an autoimmune disease, a condition requiring immunosuppression, or a history of severe immune-related adverse events (irAEs) from treatment with ipilimumab.Pembrolizumab was discontinued because of adverse events in 7% of the patients treated with 2 mg/kg, with 3% considered drug-related adverse events by the investigators. The most common adverse events were the following (2 mg/kg vs. 10 mg/kg arms):Other common adverse events included cough, nausea, decreased appetite, constipation, arthralgia, and diarrhea. The most frequent and serious adverse events that occurred in more than 2% of the 411 patients treated with pembrolizumab included renal failure, dyspnea, pneumonia, and cellulitis. Additional clinically significant irAEs included pneumonitis, colitis, hypophysitis, hyperthyroidism, hypothyroidism, nephritis, and hepatitis. The FDA label provides recommendations for suspected irAEs, including withholding the drug and administering corticosteroids.

Previously treated patients. One study included 173 patients with unresectable or metastatic melanoma with disease progression within 24 weeks of the last dose of ipilimumab. If the patient had a BRAF V600 pathogenic variant, previous treatment with a BRAF inhibitor was also required. Patients were randomly assigned to one of two doses of pembrolizumab—2 mg/kg or 10 mg/kg—every 3 weeks. The trial excluded patients with an autoimmune disease, a condition requiring immunosuppression, or a history of severe immune-related adverse events (irAEs) from treatment with ipilimumab.Pembrolizumab was discontinued because of adverse events in 7% of the patients treated with 2 mg/kg, with 3% considered drug-related adverse events by the investigators. The most common adverse events were the following (2 mg/kg vs. 10 mg/kg arms):Other common adverse events included cough, nausea, decreased appetite, constipation, arthralgia, and diarrhea. The most frequent and serious adverse events that occurred in more than 2% of the 411 patients treated with pembrolizumab included renal failure, dyspnea, pneumonia, and cellulitis. Additional clinically significant irAEs included pneumonitis, colitis, hypophysitis, hyperthyroidism, hypothyroidism, nephritis, and hepatitis. The FDA label provides recommendations for suspected irAEs, including withholding the drug and administering corticosteroids.

The median age was 61 years; 60% were male; 67% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0, and 33% had an ECOG PS of 1. Eighteen percent of patients had BRAF V600 pathogenic variants, 39% had an elevated lactate dehydrogenase (LDH) level, 64% had M1c disease, 9% had brain metastases, and 72% had undergone two or more therapies for advanced disease. The primary outcome measure was overall response rate according to Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1) criteria as assessed by blinded independent central review.[1][Level of evidence B3]

Previously treated patients. One study included 173 patients with unresectable or metastatic melanoma with disease progression within 24 weeks of the last dose of ipilimumab. If the patient had a BRAF V600 pathogenic variant, previous treatment with a BRAF inhibitor was also required. Patients were randomly assigned to one of two doses of pembrolizumab—2 mg/kg or 10 mg/kg—every 3 weeks. The trial excluded patients with an autoimmune disease, a condition requiring immunosuppression, or a history of severe immune-related adverse events (irAEs) from treatment with ipilimumab.Pembrolizumab was discontinued because of adverse events in 7% of the patients treated with 2 mg/kg, with 3% considered drug-related adverse events by the investigators. The most common adverse events were the following (2 mg/kg vs. 10 mg/kg arms):Other common adverse events included cough, nausea, decreased appetite, constipation, arthralgia, and diarrhea. The most frequent and serious adverse events that occurred in more than 2% of the 411 patients treated with pembrolizumab included renal failure, dyspnea, pneumonia, and cellulitis. Additional clinically significant irAEs included pneumonitis, colitis, hypophysitis, hyperthyroidism, hypothyroidism, nephritis, and hepatitis. The FDA label provides recommendations for suspected irAEs, including withholding the drug and administering corticosteroids.

The overall response rate was 26% (95% confidence interval [CI], -14 to 13; P = .96) for patients who received the 2 mg/kg dose, consisting of one complete response and 20 partial responses in 81 patients. Median follow-up was 8 months, and all patients had a minimum of 6 months of follow-up. Among the 21 patients with an objective response, 18 had ongoing responses, ranging from 1.4+ months to 8.5+ months.

Previously treated patients. One study included 173 patients with unresectable or metastatic melanoma with disease progression within 24 weeks of the last dose of ipilimumab. If the patient had a BRAF V600 pathogenic variant, previous treatment with a BRAF inhibitor was also required. Patients were randomly assigned to one of two doses of pembrolizumab—2 mg/kg or 10 mg/kg—every 3 weeks. The trial excluded patients with an autoimmune disease, a condition requiring immunosuppression, or a history of severe immune-related adverse events (irAEs) from treatment with ipilimumab.Pembrolizumab was discontinued because of adverse events in 7% of the patients treated with 2 mg/kg, with 3% considered drug-related adverse events by the investigators. The most common adverse events were the following (2 mg/kg vs. 10 mg/kg arms):Other common adverse events included cough, nausea, decreased appetite, constipation, arthralgia, and diarrhea. The most frequent and serious adverse events that occurred in more than 2% of the 411 patients treated with pembrolizumab included renal failure, dyspnea, pneumonia, and cellulitis. Additional clinically significant irAEs included pneumonitis, colitis, hypophysitis, hyperthyroidism, hypothyroidism, nephritis, and hepatitis. The FDA label provides recommendations for suspected irAEs, including withholding the drug and administering corticosteroids.

Patients who received the 10 mg/kg dose had a similar response rate (26%), consisting of 20 responses in 76 patients. Responses were seen in patients with and without BRAF V600 pathogenic variants.

Previously treated patients. One study included 173 patients with unresectable or metastatic melanoma with disease progression within 24 weeks of the last dose of ipilimumab. If the patient had a BRAF V600 pathogenic variant, previous treatment with a BRAF inhibitor was also required. Patients were randomly assigned to one of two doses of pembrolizumab—2 mg/kg or 10 mg/kg—every 3 weeks. The trial excluded patients with an autoimmune disease, a condition requiring immunosuppression, or a history of severe immune-related adverse events (irAEs) from treatment with ipilimumab.Pembrolizumab was discontinued because of adverse events in 7% of the patients treated with 2 mg/kg, with 3% considered drug-related adverse events by the investigators. The most common adverse events were the following (2 mg/kg vs. 10 mg/kg arms):Other common adverse events included cough, nausea, decreased appetite, constipation, arthralgia, and diarrhea. The most frequent and serious adverse events that occurred in more than 2% of the 411 patients treated with pembrolizumab included renal failure, dyspnea, pneumonia, and cellulitis. Additional clinically significant irAEs included pneumonitis, colitis, hypophysitis, hyperthyroidism, hypothyroidism, nephritis, and hepatitis. The FDA label provides recommendations for suspected irAEs, including withholding the drug and administering corticosteroids.

The approved dose was 2 mg/kg given as an intravenous (IV) infusion for 30 minutes every 3 weeks.

Previously treated patients. One study included 173 patients with unresectable or metastatic melanoma with disease progression within 24 weeks of the last dose of ipilimumab. If the patient had a BRAF V600 pathogenic variant, previous treatment with a BRAF inhibitor was also required. Patients were randomly assigned to one of two doses of pembrolizumab—2 mg/kg or 10 mg/kg—every 3 weeks. The trial excluded patients with an autoimmune disease, a condition requiring immunosuppression, or a history of severe immune-related adverse events (irAEs) from treatment with ipilimumab.Pembrolizumab was discontinued because of adverse events in 7% of the patients treated with 2 mg/kg, with 3% considered drug-related adverse events by the investigators. The most common adverse events were the following (2 mg/kg vs. 10 mg/kg arms):Other common adverse events included cough, nausea, decreased appetite, constipation, arthralgia, and diarrhea. The most frequent and serious adverse events that occurred in more than 2% of the 411 patients treated with pembrolizumab included renal failure, dyspnea, pneumonia, and cellulitis. Additional clinically significant irAEs included pneumonitis, colitis, hypophysitis, hyperthyroidism, hypothyroidism, nephritis, and hepatitis. The FDA label provides recommendations for suspected irAEs, including withholding the drug and administering corticosteroids.

Fatigue (33% vs. 37%).

Previously treated patients. One study included 173 patients with unresectable or metastatic melanoma with disease progression within 24 weeks of the last dose of ipilimumab. If the patient had a BRAF V600 pathogenic variant, previous treatment with a BRAF inhibitor was also required. Patients were randomly assigned to one of two doses of pembrolizumab—2 mg/kg or 10 mg/kg—every 3 weeks. The trial excluded patients with an autoimmune disease, a condition requiring immunosuppression, or a history of severe immune-related adverse events (irAEs) from treatment with ipilimumab.Pembrolizumab was discontinued because of adverse events in 7% of the patients treated with 2 mg/kg, with 3% considered drug-related adverse events by the investigators. The most common adverse events were the following (2 mg/kg vs. 10 mg/kg arms):Other common adverse events included cough, nausea, decreased appetite, constipation, arthralgia, and diarrhea. The most frequent and serious adverse events that occurred in more than 2% of the 411 patients treated with pembrolizumab included renal failure, dyspnea, pneumonia, and cellulitis. Additional clinically significant irAEs included pneumonitis, colitis, hypophysitis, hyperthyroidism, hypothyroidism, nephritis, and hepatitis. The FDA label provides recommendations for suspected irAEs, including withholding the drug and administering corticosteroids.

Pruritus (23% vs. 19%).

Previously treated patients. One study included 173 patients with unresectable or metastatic melanoma with disease progression within 24 weeks of the last dose of ipilimumab. If the patient had a BRAF V600 pathogenic variant, previous treatment with a BRAF inhibitor was also required. Patients were randomly assigned to one of two doses of pembrolizumab—2 mg/kg or 10 mg/kg—every 3 weeks. The trial excluded patients with an autoimmune disease, a condition requiring immunosuppression, or a history of severe immune-related adverse events (irAEs) from treatment with ipilimumab.Pembrolizumab was discontinued because of adverse events in 7% of the patients treated with 2 mg/kg, with 3% considered drug-related adverse events by the investigators. The most common adverse events were the following (2 mg/kg vs. 10 mg/kg arms):Other common adverse events included cough, nausea, decreased appetite, constipation, arthralgia, and diarrhea. The most frequent and serious adverse events that occurred in more than 2% of the 411 patients treated with pembrolizumab included renal failure, dyspnea, pneumonia, and cellulitis. Additional clinically significant irAEs included pneumonitis, colitis, hypophysitis, hyperthyroidism, hypothyroidism, nephritis, and hepatitis. The FDA label provides recommendations for suspected irAEs, including withholding the drug and administering corticosteroids.

Rash (18% vs. 18%).

Previously untreated and treated patients. A multicenter international trial (KEYNOTE 006 [NCT01866319]) randomly assigned 834 patients with metastatic melanoma in a 1:1:1 ratio to receive pembrolizumab (10 mg/kg IV every 2 weeks or every 3 weeks) or four cycles of ipilimumab (3 mg/kg every 3 weeks).[2] Patients were stratified by ECOG PS (0 vs. 1), line of therapy (first-line vs. second-line), and PD-L1 expression (positive vs. negative). The primary end points were PFS and OS.[2][Level of evidence A1]Approximately 66% of patients had received no previous systemic therapy for advanced melanoma. BRAF V600 pathogenic variants were present in 36% of patients and of these, approximately 50% had received previous BRAF inhibitor treatments. The study did not enroll patients with BRAF V600 pathogenic variants with high LDH levels and symptomatic or rapidly progressive disease who had not received anti-BRAF therapy, which could provide rapid clinical benefit. Approximately 80% of patients had PD-L1–positive tissue samples.

Previously untreated and treated patients. A multicenter international trial (KEYNOTE 006 [NCT01866319]) randomly assigned 834 patients with metastatic melanoma in a 1:1:1 ratio to receive pembrolizumab (10 mg/kg IV every 2 weeks or every 3 weeks) or four cycles of ipilimumab (3 mg/kg every 3 weeks).[2] Patients were stratified by ECOG PS (0 vs. 1), line of therapy (first-line vs. second-line), and PD-L1 expression (positive vs. negative). The primary end points were PFS and OS.[2][Level of evidence A1]Approximately 66% of patients had received no previous systemic therapy for advanced melanoma. BRAF V600 pathogenic variants were present in 36% of patients and of these, approximately 50% had received previous BRAF inhibitor treatments. The study did not enroll patients with BRAF V600 pathogenic variants with high LDH levels and symptomatic or rapidly progressive disease who had not received anti-BRAF therapy, which could provide rapid clinical benefit. Approximately 80% of patients had PD-L1–positive tissue samples.

The final protocol-specified analysis of OS was conducted at a median follow-up of 23 months. Median OS was not reached in either pembrolizumab group; however, OS was 16.0 months for the ipilimumab group (hazard ratio [HR], 0.68; 95% CI, 0.53−0.87 for pembrolizumab every 2 weeks vs. ipilimumab; P = .0009 and 0.68; 95% CI, 0.53−0.86 for pembrolizumab every 3 weeks vs. ipilimumab; P = .0008). The 24-month survival rate was 55% in the groups who received pembrolizumab every 2 weeks and every 3 weeks compared with 43% in the ipilimumab group.[3]

Previously untreated and treated patients. A multicenter international trial (KEYNOTE 006 [NCT01866319]) randomly assigned 834 patients with metastatic melanoma in a 1:1:1 ratio to receive pembrolizumab (10 mg/kg IV every 2 weeks or every 3 weeks) or four cycles of ipilimumab (3 mg/kg every 3 weeks).[2] Patients were stratified by ECOG PS (0 vs. 1), line of therapy (first-line vs. second-line), and PD-L1 expression (positive vs. negative). The primary end points were PFS and OS.[2][Level of evidence A1]Approximately 66% of patients had received no previous systemic therapy for advanced melanoma. BRAF V600 pathogenic variants were present in 36% of patients and of these, approximately 50% had received previous BRAF inhibitor treatments. The study did not enroll patients with BRAF V600 pathogenic variants with high LDH levels and symptomatic or rapidly progressive disease who had not received anti-BRAF therapy, which could provide rapid clinical benefit. Approximately 80% of patients had PD-L1–positive tissue samples.

Benefit was seen across all subgroups except for patients with PD-L1–negative tumors. However, since this subset was small (18% of patients) and the CI was wide, no definitive conclusions could be drawn from this study.