First Approval of PD-1 Inhibitor: Pembrolizumab in Unresectable or Metastatic Melanoma

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Pembrolizumab in Melanoma

In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.


On September 4, 2014, pembrolizumab (Keytruda) was granted accelerated approval for the treatment of patients with unresectable or metastatic melanoma with disease progression following treatment with ipilimumab (Yervoy) and, in BRAF V600 mutation–positive patients after treatment with a BRAF inhibitor.1 Pembrolizumab is the first programmed death receptor-1 (PD-1) inhibitor to be approved for use in the United States.

As a condition of accelerated approval, Merck is required to conduct a multicenter, randomized trial establishing the superiority of pembrolizumab over standard therapy. Two ongoing confirmatory trials are assessing pembrolizumab in either ipilimumab-refractory (Trial P002) or ipilimumab-naive (Trial P006) patients with unresectable or metastatic melanoma, both with the coprimary endpoints of progression-free survival and overall survival.

Supporting Study

Approval was based on overall response rate and duration of response in a multicenter phase I study in 173 patients with unresectable or metastatic melanoma with disease progression within 24 weeks of the last dose of ipilimumab and with prior BRAF inhibitor treatment in those with BRAF V600–mutant disease.2,3 Patients were randomly assigned to receive intravenous pembrolizumab at 2 mg/kg (n = 89) or 10 mg/kg (n = 84) every 3 weeks until disease progression or unacceptable toxicity.

To be enrolled in the study, patients could not have autoimmune disease, any medical condition that required immunosuppression, or a history of severe immune-mediated adverse reactions to ipilimumab. Patients had a median age of 61 years (64% < 65 years), 60% were male, 97% were white, 66% and 34% had Eastern Cooperative Oncology Group performance status of 0 and 1, 17% had BRAF V600–mutant disease, 39% had elevated lactate dehydrogenase, 82% had M1c disease, 9% had brain metastases, and 73% had received at least two prior therapies for advanced or metastatic disease.

The objective response rate was 24% (95% confidence interval = 15%–34%) in patients receiving 2 mg/kg (the approved dose), with 1 complete response and 20 partial responses being observed. Among the 21 patients with a response, 3 (14%) had disease progression at 2.8, 2.9, and 8.2 months after initial response. The remaining 18 patients (86%) had ongoing responses with durations of 1.4+ to 8.5+ months, including 8 with ongoing responses of ≥ 6 months.

One additional patient developed two new asymptomatic lesions at the first tumor assessment while exhibiting a 75% decrease in overall tumor burden. With continuation of treatment, this reduction in tumor burden was durable for more than 5 months.

Responses were observed in patients with and without BRAF V600–mutant disease. A similar response rate was observed in the 10-mg/kg group.

How It Works

Pembrolizumab is an anti–PD-1 monoclonal antibody. It binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2 ligands, thereby releasing PD-1 pathway–mediated inhibition of the immune response, including antitumor immune response. Binding of PD-L1 and PD-L2 to the PD-1 receptor found on T cells inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands is observed in some tumors, and signaling through this pathway can contribute to inhibition of active T-cell tumor immune surveillance. In syngeneic mouse models, inhibition of PD-1 activity resulted in decreased tumor growth.

How It Is Given

The recommended dose of pembrolizumab is 2 mg/kg via intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity.

Treatment should be withheld for grade 2 pneumonitis, grade 2 or 3 colitis, symptomatic hypophysitis, grade 2 nephritis, grade 3 hyperthyroidism, AST or ALT > 3 to 5 times or total bilirubin > 1.5 to 3 times upper limit of normal, and any other severe or grade 3 treatment-related adverse reaction. Treatment can be resumed when adverse reactions recover to grade 0 or 1.

Pembrolizumab should be permanently discontinued for any life-threatening adverse reaction, grade 3 or 4 pneumonitis, grade 3 or 4 nephritis, AST or ALT > 5 times or total bilirubin > 3 times upper limit of normal, AST or ALT increases of ≥ 50% in patients with liver metastasis who began treatment with grade 2 increased AST or ALT, grade 3 or 4 infusion-related reactions, inability to reduce corticosteroid dose to ≤ 10 mg/d prednisone or equivalent within 12 weeks, persistent grade 2 or 3 adverse reactions that do not recover to grade 0 or 1 within 12 weeks of last dose, and any recurrent severe or grade 3 treatment-related adverse reaction.

No dose adjustment is needed for patients with renal impairment. No dose adjustment is needed for patients with mild hepatic impairment; the drug has not been studied in patients with moderate or severe hepatic impairment

Safety Profile

The most common clinical adverse events of any grade in patients receiving pembrolizumab 2 mg/kg were fatigue (47%), cough (30%), nausea (30%), pruritus (30%), rash (29%), and decreased appetite (26%). The most common grade 3 events were fatigue (7%), anemia (5%), and dyspnea (2%).

The most common laboratory abnormalities of any grade were anemia (55%), hyperglycemia (40%), hyponatremia (35%), and hypoalbuminuria (34%), and the most common grade 3 or 4 events were hyponatremia (9%), anemia (8%), hyperglycemia (2%), and increased AST (2%).

The most frequent (≥ 2%) serious adverse events were renal failure, dyspnea, pneumonia, and cellulitis. Additional clinically significant immune-mediated adverse reactions included pneumonitis, colitis, hypophysitis, hyperthyroidism, hypothyroidism, nephritis, and hepatitis. Treatment was discontinued due to adverse events in 6% of patients.

Pembrolizumab carries warnings/precautions for immune-mediated adverse reactions, including immune-mediated pneumonitis, colitis, hepatitis, hypophysitis, nephritis, and hyperthyroidism and hypothyroidism, and embryofetal toxicity. Corticosteroid treatment of immune-mediated reactions should be based on severity. Hepatic, renal, and thyroid function should be routinely monitored.   ■


1. U.S. Food and Drug Administration: Pembrolizumab. Available at

2. Robert C, Ribas A, Wolchok JD, et al: Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: A randomised dose-comparison cohort of a phase 1 trial. Lancet. July 14, 2014 (early release online).

3. KEYTRUDA® (pembrolizumab) for injection prescribing information, Merck Sharp & Dohme Corp., September 2014. Available at