September 2014, Part 3
First Anti–PD-1 Immunotherapy, Pembrolizumab, Receives Accelerated FDA Approval for Advanced Melanoma
On September 4, 2014, the FDA has approved pembrolizumab (Keytruda; Merck), the first anti–programmed death-1 (PD-1) therapy for the treatment of patients with advanced (ie, unresectable or metastatic) melanoma and disease progression after therapy with ipilimumab, or, for a patient with a BRAF V600 mutation, after ipilimumab plus BRAF inhibitor therapy. The approved dosing schedule for pembrolizumab is 2 mg/kg every 3 weeks, based on early results from the study leading to the approval.
The FDA applied its accelerated process for this approval based on early clinical data showing tumor response rate and durability of response rather than on actual improvements in survival or in disease progression. Ongoing phase 2 and 3 clinical trials are expected to provide confirmatory information to demonstrate clinically meaningful benefits, 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-1 ligand 1 and PD-1 ligand 2. It is the first- ever anti–PD-1therapy to receive FDA approval. The FDA granted pembrolizumab a breakthrough therapy designation for advanced melanoma based on the positive early results from a phase 1b trial in 89 patients with unresectable or metastatic melanoma and progression of disease, in light of the 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 an ongoing multicenter, open-label, randomized, dose-comparative study cohort of the KEYNOTE-001 phase 1b trial. All patients received a 2-mg/kg dose every 3 weeks. Early results showed an overall response rate of 24% (95% confidence interval, 15 – 34), including 1 complete response and 20 partial responses. At the time of the analysis, 86% (N = 18) of patients with objective responses had ongoing responses, with 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. After the initial response, 14% of the patients had disease progression at 2.8, 2.9, and 8.2 months.
All patients had previous treatment with ipilimumab and a BRAF or a MEK inhibitor if the patient had a BRAF V600 mutation; patients had disease progression within 24 weeks after the last dose of ipilimumab. 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 disease progression. The major efficacy outcome measures were confirmed overall response rate and duration of response.
Pembrolizumab was discontinued because of adverse events in 6% of 89 patients receiving the recommended dose and in 9% of 411 patients across all doses studied. Serious adverse reactions occurred in 36% of patients receiving pembrolizumab.
The most common serious adverse events with pembrolizumab reported in ?2% of patients included renal failure, dyspnea, pneumonia, and cellulitis. The most common adverse events (reported in ?20% of patients) were fatigue (47%), cough (30%), nausea (30%), pruritus (30%), rash (29%), decreased appetite (26%), constipation (21%), arthralgia (20%), and diarrhea (20%).
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