FDA Approves First Anti–PD-1: Pembrolizumab Indicated for Advanced Melanoma

September 2014, Vol 5, No 7

The FDA approved the first anti–programmed death receptor-1 (PD-1) therapy, pembrolizumab (Keytruda; Merck), for patients with unresectable or metastatic melanoma and disease progression after treatment with other melanoma therapy, such as ipilimumab, or, for a patient with BRAF V600 mutation, after BRAF inhibitor therapy.

The FDA accelerated its approval for pembrolizumab based on early clinical data from the KEYNOTE-001 phase 1b trial showing a high tumor response rate and long durability of response rather than on actual improvements in survival or in disease progression. Ongoing phase 2 and 3 clinical trials are being conducted to provide confirmatory information that is expected to demonstrate clinically meaningful improved outcomes, including potential improvement in survival and/or reduction in disease progression.

Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. It is the first-ever anti–PD-1 therapy to receive FDA approval. The FDA also granted pembrolizumab a breakthrough therapy designation for advanced melanoma based on the positive early results from the phase 1b trial in 173 patients with unresectable or metastatic melanoma whose disease progressed after previous therapy, reflecting an unmet medical need for this patient population.

“The accelerated FDA approval of Keytruda is a meaningful development for patients with advanced melanoma,” said Omid Hamid, MD, Director of the Melanoma Center at the Angeles Clinic and Research Institute, and a principal investigator for the pembrolizumab melanoma clinical program. “Our new ability to target the PD-1 pathway with Keytruda is a very exciting step in the immunotherapy field.”

The FDA approval was based on early results from the ongoing multicenter, open-label, randomized, dose-comparative KEYNOTE-001 phase 1b trial. A total of 89 patients received the 2-mg/kg dose every 3 weeks; other patients received different doses, including a 10-mg/kg dose, which was just as effective. Overall, 411 patients were included in this trial.

The overall response rate in the 89 patients receiving the 2-mg/kg dose was 24% (95% confidence interval, 15-34), including 1 complete response and 20 partial responses. At the time of the analysis, 86% of patients with objective responses had ongoing responses, with the duration of response ranging between 1.4 and 8.5 months. In addition, 8 of these patients are still showing ongoing responses of 6 months.

All patients had received previous treatment with ipilimumab or a BRAF inhibitor in patients with a BRAF V600 mutation; the patients had disease progression within 24 weeks after the last dose of previous therapy. Patients were randomized to receive 2 mg/kg (N = 89) or 10 mg/kg (N = 84) of pembrolizumab every 3 weeks until unacceptable toxicity or until disease progression. The major efficacy outcomes analyzed were confirmed overall response rate and duration of response.

The approved dosing schedule for pembrolizumab is 2 mg/kg every 3 weeks, based on these early results from the KEYNOTE-001 phase 1b trial. Severe immune-mediated adverse events were uncommon. Pembrolizumab was discontinued because of adverse events in 6% of 89 patients receiving the 2-mg/kg dose, and in 9% of the 411 patients across all doses investigated in the phase 1b trial. Serious adverse reactions occurred in 36% of all the patients receiving this new immunotherapy.

The most common serious adverse events reported in ?2% of patients who received pembrolizumab include renal failure, dyspnea, pneumonia, and cellulitis. The most common adverse events (reported in ?20% of patients) were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea. (September 4, 2014)

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