CHICAGO – The investigational targeted agent pembrolizumab induced durable treatment responses in a high percentage of patients with advanced metastatic melanoma, in a phase I study.
Of 411 patients, 1-year overall survival was 69%, and 88% of patients who had a treatment response continued to have a response at 1 year, reported Dr. Antoni Ribas, professor of medicine at the University of California, Los Angeles, at a media briefing and in an oral abstract session at the annual meeting of the American Society for Clinical Oncology.
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Dr. Antoni Ribas
"We used to say that melanoma had a median survival of 6-9 months – that wasn’t that long ago. Then we said well, maybe it’s getting closer to 12 months. Here, we have not reached the median overall survival," Dr. Ribas said.
At 18 months of follow-up, overall survival is 62%, and seems to be plateauing, but longer follow-up will be required to see how long the survival benefit can be maintained, he said.
"The remarkable thing is that almost 90% of these patients are having durable responses with a toxicity profile that is almost unheard of in metastatic cancer," commented Dr. Steven O’Day of the Beverly Hills (Calif.) Cancer Center, who moderated the briefing but was not involved in the study.
Grade 3 or 4 toxicities occurred in 12% of patients, making pembrolizumab "one of the most benign therapies that I have ever used in my clinic," he said.
New name, same PD-1 antibody
Pembrolizumab, formerly known as lambrolizumab or MK-3475, is a humanized monoclonal antibody targeted against the PD-1 immune system checkpoint. By binding to and inhibiting what Dr. Ribas called the "do not kill me" signal, the antibody allows the immune system to recognize and mount a more potent T-cell–mediated defense against melanoma.
The Food and Drug Administration previously granted permbrolizumab a breakthrough therapy designation, and in May 2014 gave it a priority review designation under the agency’s accelerated approval program.
At the 2013 ASCO annual meeting, Dr. Ribas and colleagues reported a 41% overall response rate (ORR) in the first 135 patients with metastatic melanoma treated with the antibody in the phase I study KEYNOTE 001.
The data he presented at this year’s ASCO meeting on the melanoma expansion cohort from that trial support the earlier findings from the study, showing an overall ORR of 34%, with responses seen in 44% of treatment-naive patients, 28% of those who had previously been treated with a different checkpoint inhibitor, ipilimumab (Yervoy), and 40% in patients who had received prior therapies other than ipilimumab.
The current study is an analysis of pooled data on 411 patients, 221 of whom had disease progression on ipilimumab and 190 of whom had never received ipilimumab. All patients had melanoma metastatic to the lungs or other organs.
Neil Osterweil/ Frontline Medical News
Dr. Steven O'Day
The patients received pembrolizumab in one of three dosing schedules: 10 mg/kg every 2 weeks (57 patients) or every 3 weeks (192), or 2 mg/kg every 3 weeks (162).
As noted, the overall survival rate at 1 year was 69% (74% for ipilimumab-naive patients and 65% for ipilimumab-treated patients), with the median overall survival not yet reached.
Dr. O’Day said it was encouraging that prior exposure to ipilimumab did not appear to dramatically decrease the benefit from pembrolizumab.
"This is critical to us understanding whether to combine or sequence these drugs, because there does not seem to be a lot of cross-resistance between ipilimumab and PD-1 [inhibition]," he said.
The most common adverse event of any grade was fatigue, occurring in 36% of patients, but only 2% of patients had grade 3 or 4 fatigue. Other common events were pruritus (24%), rash (20%), diarrhea (16%), arthralgia (16%), nausea (12%), and vitiligo (11%). The overall rate of any adverse events was 83%, but as noted before, only 12% of patients had a grade 3 or 4 adverse event. These events were manageable across all doses and in both ipilmumab-naive and experienced patients.
Pembrolizumab is currently being investigated in international, randomized controlled clinical trials, Dr. Ribas noted.
The study was supported by Merck. Dr. Ribas disclosed serving as a consultant/adviser to the company. Dr. O’Day reported having no relevant disclosures.