Pembrolizumab (Keytruda) Approved by European Commission for Advanced Melanoma

Roger M. Perlmutter, MD, PhD

The PD-1 inhibitor pembrolizumab (Keytruda) was recently approved by the European Commission for the treatment of adult patients who have unresectable or metastatic melanoma in the first-line and previously treated settings, based on data from three clinical trials that evaluated the medication in over 1500 patients.

The European Commission decision follows a recommendation from the 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.

&ldquo;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,&rdquo; Deepak Khanna, senior vice president and regional president, Europe, MSD Oncology, said in a statement. &ldquo;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.&rdquo;

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, ifBRAF V600mutation 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.&nbsp;