Pembrolizumab Promised Fast FDA Action on Frontline Melanoma Indication

In a separate action, the FDA delayed its decision date on an application for pembrolizumab in ipilimumab-refractory advanced melanoma to December 24, 2015, based on the need to review additional data submitted by Merck.

“Through our clinical program for KEYTRUDA we have accumulated substantial data on the role of our anti—PD-1 therapy in advanced melanoma. We look forward to the FDA's review of each of these applications, and to delivering on our goal of helping patients with advanced melanoma to achieve long-term disease control and survival,” said Roger M. Perlmutter, MD, PhD, president, Merck Research Laboratories.

The news from Merck on frontline pembrolizumab follows a recent announcement from Bristol-Myers Squibb that the FDA extended the review period for frontline nivolumab (Opdivo) in advanced melanoma to November 27, 2015, to review additional data. This sets up an end-of-the-year clash between the rival anti—PD-1 agents.

The priority review for frontline pembrolizumab is based on the phase III KEYNOTE-006 trial, which included 834 patients with unresectable stage III or IV advanced melanoma who had received no more than one prior systemic therapy. Patients were randomized to receive 4 cycles of ipilimumab at 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 dosing regimens of pembrolizumab were higher than the FDA-approved regimen of 2 mg/kg every 3 weeks. However, the priority review of frontline pembrolizumab is based on the FDA-approved dosage.

Patient response in KEYNOTE-006 was assessed at week 12 and every 6 weeks thereafter by RECIST 1.1. Median follow-up was 8 months. 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%.

The toxicity profiles of the agents were consistent with other reported studies of the two checkpoint agents. Though pembrolizumab was administered for a longer duration, rates of grade 3 to 5 adverse events were numerically lower than in the ipilimumab arm (11.7% vs 19.9%).

The most common side effects associated with pembrolizumab (occurring in ≥20% of patients) are fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea, according to results from KEYNOTE-001, the trial that led to the agent’s initial approval in 2014.

The FDA’s review of pembrolizumab in the ipilimumab-refractory setting is based on the phase II KEYNOTE-002 study, which included 540 patients with ipilimumab-refractory advanced melanoma who received pembrolizumab at 2 mg/kg (n = 180), 10 mg/kg (n = 181), or chemotherapy (n = 179). Chemotherapy was selected by investigators and consisted primarily 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 PFS of 34% at 6 months and 24% at 9 months. In the chemotherapy arm, the PFS 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%, and the median response duration was 37 weeks. At the analysis, 63% of responses were ongoing.

The FDA&rsquo;s decision to extend its review of pembrolizumab in this setting was based on Merck&rsquo;s submission of additional supporting information from KEYNOTE-002.

Pembrolizumab is currently approved by the FDA for patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, ifBRAF V600-mutation positive, a BRAF inhibitor.