FROM THE AACR ANNUAL MEETING
Pembrolizumab was superior to ipilimumab, the standard of care, as first-line therapy for advanced melanoma in the phase III KEYSTONE-006 trial.
Pembrolizumab (Keytruda) hit all of its primary survival end points and nearly tripled response rates from 12% with ipilimumab (Yervoy) to 33% in the first frontline head-to-head comparison of the two immune checkpoint inhibitors.
Pembrolizumab reduced the risk of progression by 42% and the risk of death by 31% to 37%, compared with ipilimumab, study author Dr. Antoni Ribas reported at the annual meeting of the American Association for Cancer Research.
“We think that this data should change the paradigm of treatment for these patients, and the standard of care should quickly shift to giving PD-1 antibodies,” he said at a press briefing.
Pembrolizumab, a monoclonal antibody that inhibits programmed death receptor-1 (PD-1), is approved as second-line therapy for unresectable or metastatic melanoma after failing iplimumab or a BRAF inhibitor, if a BRAF V600 mutation is present.
Ipilimumab has been the gold standard against which everything else was measured, but “this is now expected to change the treatment landscape for melanoma. This is a very high impact trial,” Dr. Suzanne Topalian , director of the melanoma program at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, said during the briefing.
The 2011 approval of ipilimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, as first-line therapy for advanced melanoma was a landmark moment, she said, not only for melanoma because it was the first drug ever to show a survival advantage in a randomized trial, but also for immunotherapy because it was the first checkpoint blocker to show such a benefit.
Results of the KEYSTONE-006 trial, simultaneously published on line ( N. Engl. J. Med. 2015. DOI: 10.1056/NEJMoa1503093 ), prompted the safety monitoring committee to recommend stopping the trial early and allowing ipilimumab patients to receive pembrolizumab.
Lead investigator Dr. Caroline Robert , head of dermatology at Institut Gustave-Roussy in Paris, said in a statement that she hoped the results would accelerate regulatory approval of pembrolizumab in Europe, where the drug is still not on the market.
KEYNOTE-006 included 834 patients with unresectable, ipilimumab-naive, stage III or IV melanoma treated with no more than one previous systemic therapy who were randomly assigned to 10 mg/kg pembrolizumab either every 2 weeks or every 3 weeks or four cycles of 3 mg/kg ipilimumab every 3 weeks, until disease progression or unacceptable toxicity. Treatment response was assessed 12 weeks after randomization and every 6 weeks thereafter per RECIST guideline v1.1 by central review and per immune-related response criteria by investigator review.
Two-thirds of patients were treatment naive, 79% had PD-ligand 1(PD-L1)-positive tumors, and 36% had BRAF V600-mutant tumors.
At the first interim analysis after a median follow-up of 8 months, 6-month progression-free survival rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (Hazard ratio, 0.58; P < .001), Dr. Antoni Ribas of the University of California Los Angeles Jonsson Comprehensive Cancer Center, reported.
The benefit was seen across all prespecified subgroups, including PD-L1-positive and PD-L1-negative tumors.
At the time of the analysis, responses by RECIST were ongoing in 89.4% of patients treated with pembrolizumab every 2 weeks, 96.7% on pembrolizumab every 3 weeks, and 88% given ipilumumab.
The median duration of response was 251 days in the pembrolizumab every 2 weeks-arm, but had not been reached in the other two arms.
There has been no evidence of resistance, and only a small minority, perhaps 5-10% of patients, have escape lesions or progress after response, he said.
At the second interim analysis after a median follow-up of 13.8 months, 1-year overall survival rates were 74% for pembrolizumab every 2 weeks (HR, 0.63; P = .0005), 68.4% for pembrolizumab every 3 weeks (HR, 0.69; P = .0036), and 58.2% for ipilimumab. The survival benefit extended to all subgroups, except the 18% of patients with PD-L1-negative tumors, although sample sizes were small and confidence intervals wide.
Efficacy and tolerability was similar for both pembrolizumab dosing schedules, Dr. Ribas said. Treatment-related grade 3-4 adverse events were lower in the pembrolizumab every 2 and 3 weeks arms than with ipilimumab (13.3% vs. 10.1% vs. 20%), despite exposure to pembrolizumab being nearly 3 times as long (164 days vs. 151.5 days vs. 50 days).
When asked how the findings would change his practice tomorrow, Dr. Ribas said pembrolizumab should be used first line but that he will continue to use ipilimumab, either alone or in combination with a PD-1 inhibitor, because it can give durable responses. The critical unanswered question of what the most effective sequence or combination of checkpoint inhibitors is will take years to answer.
“This is just the start,” he said. “This is amazing that single-agent checkpoint blockade gives these responses in melanoma and as you will see in lung cancer, but the reality is that there’s two-thirds of patients who do not respond and we have to do something about that.”
The study was funded by Merck Sharp & Dohme. Dr. Ribas is a consultant to Merck, with the honoraria paid to his institution. Dr. Robert is a consultant with honoraria for MSD, Bristol Myers Squibb, Roche, Novartis, GlaxoSmithKline, and Amgen.
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