FDA Grants Priority Review to PD-1 Inhibitor Pembrolizumab in Advanced Melanoma

Roger M. Perlmutter, MD, PhD

The FDA has assigned a priority review designation to the PD-1 inhibitor pembrolizumab (MK-3475) as a treatment for patients with unresectable or metastatic melanoma following progression on ipilimumab (Yervoy). As part of this program, the agency plans to take action on the drug's application within 6 months instead of the standard 10 months under regular review, placing a decision date in late October 2014.

The priority review follows a Breakthrough Therapy designation from the FDA for pembrolizumab (formerly lambrolizumab) in April 2013. This designation and the priority review are based on results from a single-arm study that examined intravenous pembrolizumab at various doses in patients refractory or naive to treatment with ipilimumab. The overall response rate (ORR) for all patients was 41% by RECIST criteria with a 1-year overall survival (OS) rate of 81%, according to an update of the study presented at the 10th International Congress of the Society for Melanoma Research (SMR).

“Patients with advanced melanoma have few therapeutic options and often fail to respond to all available treatments,” Roger M. Perlmutter, MD, PhD, the president of Merck Research Laboratories, said in a release. “We are hopeful that the FDA, through their priority review of our application, will agree to make MK-3475 available to patients with advanced melanoma who have no other therapeutic options.”

In the phase Ib study (PN 001), 135 patients were enrolled to receive intravenous pembrolizumab at a dose of 10 mg/kg every 2 weeks (n = 57). In an expansion cohort, additional patients were enrolled in concurrent cohorts that received pembrolizumab at 10 mg/kg (n = 56) or 2 mg/kg (n = 22) every 3 weeks. The maximum tolerated dose was determined to be 10 mg/kg every 2 weeks. Tumor responses were assessed every 12 weeks. The primary objective of the study was safety with a secondary focus on efficacy.

The study included 48 patients who received prior treatment with the CTLA-4 inhibitor ipilimumab. Patients with poor prognostic factors were included, such as those with visceral metastases (>50%), elevated lactate dehydrogenase levels (25%), and brain metastases (9%).

In an initial analysis that was published in the New England Journal of Medicine in July 2013, the confirmed ORR by RECIST criteria across all doses was 38%. For patients receiving the 2-mg/kg dose every 3 weeks, the ORR was 25% compared with 52% in the 10 mg/kg every 2-week cohort.

Updated findings were presented at the SMR meeting, which included the first analysis of OS data. At this point, the ORR across all doses had increased to 41% by RECIST with many responses occurring 48 to 70 weeks following the initiation of therapy. The median duration of response and median OS had not yet been reached at the time of this analysis.

All grade side effects included fatigue, asthenia, fever, chills, myalgias, and headaches. In total, 23% of patients in the 10 mg/kg every 2 weeks—dose experienced grade 3/4 adverse events, compared with 4% receiving 10 mg/kg of the drug every 3 weeks and 9% receiving a 2 mg/kg dose every 3 weeks. Additionally, across all doses, 9% of patients reported experiencing vitiligo.

“Our priority is advancing breakthrough immunomodulatory molecules that reveal the ability of the immune system to eliminate cancer cells," Perlmutter noted in the release. "While MK-3475 provides a firm foundation for Merck’s research and development strategy in oncology, we are also advancing a broad pipeline of immune checkpoint agonists and antagonists.”

Pembrolizumab continues to be explored as a monotherapy and in combinations across a variety of tumor types, including non-small cell lung cancer (NSCLC). Merck announced that it plans to present data from 15 company-sponsored studies at the 2014 ASCO Annual Meeting, six of which will be presented in oral presentations.

In February 2014, Merck announced that it had formed several collaborations to explore pembrolizumab across a variety of tumor types. As part of the collaboration, phase I/II studies will examine the drug in combination with axitinib in renal cell carcinoma, talimogene laherparepvec (T-VEC) in previously untreated advanced melanoma, the immunotherapy INCB24360 in previously treated metastatic recurrent NSCLC, and PF-2566 in multiple cancer types.