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FDA Approves Pembrolizumab (Keytruda) for Advanced Melanoma

First anti-PD-1 therapy to get agency nod

The FDA has approved pembrolizumab (Keytruda, Merck) at a dosage of 2 mg/kg every 3 weeks for the treatment of patients with unresectable or metastatic melanoma and disease progression after treatment with ipilimumab (Yervoy, Bristol-Myers Squibb) and, if BRAF V600 mutation-positive, a BRAF inhibitor.

This indication received accelerated approval based on the tumor response rate and the durability of response. An improvement in survival or disease-related symptoms has not yet been established.

Melanoma, which accounts for approximately 5% of all new cancers in the U.S., occurs when cancer cells form in skin cells that make the pigment responsible for color in the skin. According to the National Cancer Institute, an estimated 76,100 Americans will be diagnosed with melanoma and 9,710 will die from the disease in 2014.

Pembrolizumab is the first anti-programmed death receptor-1 (PD-1) therapy approved in the U.S. and received the FDA’s “breakthrough therapy” designation for the treatment of advanced melanoma. It is the sixth new melanoma treatment passed by the agency since 2011. The five prior FDA approvals for melanoma include ipilimumab (2011), peginterferon alfa-2b (2011), vemurafenib (2011), dabrafenib (2013), and trametinib (2013).

For the recommended 2-mg/kg dose of pembrolizumab based on data in 89 patients, the overall response rate was 24%, with one complete response and 20 partial responses (21/89). At the time of the analysis, 86% (18/21) of the patients with objective responses had ongoing responses, with durations ranging from 1.4+ to 8.5+ months, including eight patients with ongoing responses of 6 months or longer. Fourteen percent (3/21) of the patients had disease progression 2.8, 2.9, and 8.2 months after the initial response.

Pembrolizumab is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to fight advanced melanoma. The drug blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, and may affect both tumor cells and healthy cells. Immune-mediated adverse reactions have included pneumonitis, colitis, hepatitis, hypophysitis, nephritis, hyperthyroidism, and hypothyroidism. Pembrolizumab may cause fetal harm when administered to a pregnant woman.

The approval of pembrolizumab was based on data from an open-label, randomized, dose-comparative cohort in the ongoing KEYNOTE-001 phase Ib trial in patients with unresectable or metastatic melanoma and disease progression. Key eligibility criteria included prior treatment with ipilimumab (two or more doses at 3 mg/kg or higher) and a BRAF or MEK inhibitor, if BRAF V600 mutation-positive; and disease progression within 24 weeks after the last dose of ipilimumab.

The patients were randomly assigned to receive 2 mg/kg (n = 89) or 10 mg/kg (n = 84) of pembrolizumab every 3 weeks until unacceptable toxicity or disease progression occurred. The major efficacy outcome measures were the confirmed overall response rate and the duration of response. The tumor response was assessed every 12 weeks.

Phase II and Phase III clinical studies in advanced melanoma are being conducted to provide further confirmatory evidence for pembrolizumab in this indication.

Pembrolizumab is expected to be available within 1 week from the FDA’s September 4 approval.

Sources: FDA; September 4, 2014; and Merck; September 4, 2014.

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