European Commission Approves Pembrolizumab for Advanced Melanoma

Roger M. Perlmutter, MD, PhD

The European Commission has approved the PD-1 inhibitor pembrolizumab (Keytruda) as a treatment for adult patients with unresectable or metastatic melanoma in the first-line and previously treated settings, based on data from 3 clinical trials that assessed the medication in more than 1500 patients.

The European Commission decision follows a recommendation from Committee for Medicinal Products for Human Use, and allows for the medication to be marketed across 28 European Union member states. The medication is approved at a dose of 2 mg/kg every 3 weeks. In the 834-patient phase III KEYNOTE-006 study, pembrolizumab demonstrated an extension in overall survival (OS) and progression-free survival (PFS) compared with ipilimumab. Additionally, in the 540-patient phase II KEYNOTE-002 study, pembrolizumab improved PFS versus chemotherapy, with OS data pending maturity.

“Today’s European approval supports our goal of accelerating immuno-oncology research for the benefit of patients around the world,” Roger M. Perlmutter, MD, PhD, president, Merck Research Laboratories, said in a statement. “We believe that the broad data set supporting this approval helps illustrate the significant potential of Keytruda to treat advanced melanoma, a devastating disease.”

In the phase III KEYNOTE-006 trial, 834 patients were randomized to receive four cycles of ipilimumab 3 mg/kg every 3 weeks (n = 278), 10 mg/kg of pembrolizumab every 3 weeks (n = 277), or 10 mg/kg of pembrolizumab every 2 weeks (n = 279). Both doses of pembrolizumab were found to be superior to ipilimumab.

At a 6-month assessment, the PFS with pembrolizumab was 47% and 46% in the 2- and 3-week arms respectively. For ipilimumab, the PFS rate was 27%. At 9 months, PFS rates were 40% and 42% compared with 16%, in the 2-week, 3-week, and ipilimumab arms, respectively.

In the 3-week pembrolizumab arm, the 1-year OS rate was 68% compared with 58% for ipilimumab (HR = 0.69). In the 2-week arm, the 1-year OS rate was 74% (HR = 0.63). The objective response rates (ORR) were 33.7% and 32.9%, in the 2- and 3-week arms. In the ipilimumab arm, the ORR was 11.9%.

In the phase II KEYNOTE-002 study, 540 patients with ipilimumab-refractory advanced melanoma received pembrolizumab at 2 mg/kg (n = 180), 10 mg/kg (n = 181), or chemotherapy (n = 179). Chemotherapy was selected by investigators and consisted primary of paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine, or temozolomide. Pembrolizumab was administered every 3 weeks.

Both pembrolizumab arms were significantly superior to chemotherapy (P <.0001). At the recommended 2 mg/kg dose, pembrolizumab demonstrated an ORR of 34% at 6 months and 24% at 9 months. In the chemotherapy arm, the ORR was 16% and 8%, at the 6- and 9-month analyses, respectively.

At the 2 mg/kg dose, the ORR with pembrolizumab was 21% with a median duration of response that was not yet reached. The ORR in the chemotherapy arm was 4%, the median response duration was 37 weeks. At the analysis, 63% of responses were ongoing.

The phase I KEYNOTE-001 trial enrolled patients across a variety of tumor types. In the melanoma arm, 173 patients were treated with 2 mg/kg or 10 mg/kg. At the recommended 2 mg/kg dose (n = 140), the ORR was 33% in ipilimumab-naive patients (n = 51) and 25% in those who were previously treated with the CTLA-4 inhibitor (n = 89). The disease control rate was 50% with the every 2-week dose and the 24-week PFS rate was 47%.

The safety analysis was based on 1012 patients who received pembrolizumab at the lower doses utilized in the KEYNOTE-001 and 002 studies. At these doses, the most common all-grade adverse events with pembrolizumab (primarily grade 1/2) were diarrhea (15%), nausea (12%), pruritus (25%), rash (25%), arthralgia (13%), and fatigue (33%). The most serious adverse reactions were immune-related adverse reactions and severe infusion-related reactions.

“Merck has long-believed that innovation and access must go hand-in-hand, which is why we work to bring forward new innovations, and ensure access to those innovations,” Deepak Khanna, senior vice president and regional president, Europe, MSD Oncology, said in a statement. “Merck is committed to working collaboratively with governments and other stakeholders to ensure that Keytruda will be made available to advanced melanoma patients in Europe as rapidly as possible.”

Pembrolizumab is approved in the United States at a dose of 2 mg/kg every 3 weeks for patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. In June 2015, the FDA granted pembrolizumab a priority review for patients with non—small cell lung cancer across all histologies. The US regulatory agency will make a decision on this application by October 2, 2015.