New Study Findings Confirm Pembrolizumab's Durable Responses in Metastatic Melanoma

Antoni Ribas, MD, PhD

The anti-PD 1 checkpoint inhibitor, pembrolizumab, continues to deliver impressive results in patients with advanced melanoma—producing long-lasting responses and improved overall survival, regardless of whether patients have been previously treated with ipilimumab. The new findings are based on a phase I study presented at the 2014 ASCO Annual Meeting.

With 411 participants, the study represents “the largest phase I clinical trial ever done in this disease,” noted lead author Antoni Ribas, MD, PhD, professor of Medicine at the David Geffen School of Medicine at UCLA. “Together with the lung cancer cohort, this phase I trial involves close to 1000 patients and thus is the largest phase I trial ever done in oncology.”

Early data based on 135 patients enrolled in this study were reported last year. Pembrolizumab produced an overall response rate of 41% and was well-tolerated, said Ribas.

Before presenting the new findings, and to clarify any possible confusion, Ribas explained that pembrolizumab is now the approved generic name for the anti-PD 1 checkpoint inhibitor (formerly MK-3475); the name lambrolizumab had previously been designated for the drug, but based only on approval in the United States and not by international counterparts.

Of the 411 patients in the study reported here, 221 had prior treatment with ipilimumab, and 190 patients were ipilimumab-naïve. All trial participants had advanced melanoma that had spread to the skin, lungs, or other major organs.

Three dose schedules of single-agent pembrolizumab were investigated: 162 patients were treated with 2 mg/kg every 3 weeks, 192 patients received 10 mg/kg every 3 weeks, and 57 patients received the 10 mg/kg dose every 2 weeks. Responses were evaluated every 3 months.

Overall, 34% of patients experienced tumor response with pembrolizumab, which Ribas said, is “a remarkably high response rate for an antibody that hits the immune system and not the tumor.” In patients whose disease had progressed on prior ipilimumab, the overall response rate (ORR) was 28%, and for patients with no prior ipilimumab therapy, the ORR was 40%.

The estimated 1-year survival rate was 69% (74% in ipilimumab-naïve patients and 65% in those who had received it previously); median overall survival was not reached. Median progression-free survival was 5.5 months.

However, the finding that has really generated excitement from this larger cohort of patients, said Ribas, is the durability of responses: 88% of patients had sustained responses at the time of analysis in October 2013 after a median follow-up of 12 months. This response applied across all dose levels, and regardless of prior ipilimumab therapy, tumor stage, BRAF mutation status, and the number/type of previous treatments.

Notably, pembrolizumab demonstrated a manageable safety profile across all doses, schedules, and ipilimumab-status subgroups. “This is one of the most benign therapies I have used in my clinic,” said Ribas. Overall, just 12% of patients experienced grade 3/4 toxicities. The most common all-grade adverse events were fatigue (36%), pruritis (24%), and rash (20%).

“This [agent] is just blocking one checkpoint; yet, in melanoma, about two-thirds of patients are getting some clinical benefit, meaning stable disease or shrinkage,” said Steven J. O’Day, MD, a medical oncologist with the Beverly Hills Cancer Center in California who moderated the ASCO panel on progress in immunotherapy. “In this study, prior exposure to ipilimumab doesn’t seem to have any dramatic effect,” a finding which O’Day said is critical to understanding the merits of combining or sequencing these drugs.

International, randomized, controlled studies are ongoing to confirm trial results. On May 6, the FDA assigned a priority review designation to pembrolizumab as a treatment for patients with unresectable or metastatic melanoma following progression on ipilimumab. 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.

Ribas A, Hodi FS, Kefford R, et al. Efficacy and safety of the anti-PD-1 monocolonal antibody MK-3475 in 411 patients with melanoma. J Clin Oncol. 2014;32:5s (suppl; abstr LBA9000).

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