PHILADELPHIA — Patients with advanced melanoma who received first-line pembrolizumab achieved significantly prolonged OS and PFS compared with patients who received ipilimumab, according to phase 3 study results presented at the American Association for Cancer Research Annual Meeting.
These results represent the first randomized comparison of two FDA-approved immune checkpoint inhibitors for the first-line treatment of advanced melanoma, according to the researchers.
“Not that long ago, when we were in front of our patients with melanoma and discussing treatments, one in 10 would benefit at most, and most of these were temporary effects,” Antoni Ribas, MD, PhD, professor of hematology and oncology and director of the Tumor Immunology Program Area at the UCLA Jonsson Comprehensive Cancer Center, said during a press conference. “But this has changed in the last few years with the development of new agents that turn on the immune system.”
Pembrolizumab (Keytruda, Merck) — an anti-programmed cell death-1 (PD-1) therapy — is currently FDA-approved as a second-line therapy for patients with metastatic melanoma whose disease progressed during treatment with ipilimumab (Yervoy, Bristol-Myers Squibb) or BRAF inhibitors. Ipilimumab — which blocks CTLA-4 — is the standard of care first-line therapy in this setting, and it was the first agent to improve survival in melanoma, Ribas said.
Ribas and colleagues sought to compare ipilimumab with two dosing regimens of pembrolizumab in 834 patients with metastatic melanoma who had not previously received ipilimumab. Sixty-six percent of the patients were treatment-naive and 69% had an ECOG performance status of 0. Eighty percent of patients were programmed death-ligand 1 (PD-L1) positive — defined as staining in 1% or more of tumor cells — and 36% harbored BRAF V600 mutations.
Researchers randomly assigned patients 1:1:1 to 10 mg/kg pembrolizumab every other week, 10 mg/kg pembrolizumab every 3 weeks or four doses of 3 mg/kg ipilimumab every 3 weeks.
PFS and OS served as the study’s primary endpoints. Secondary endpoints included objective response rate and safety.
Median follow-up for interim PFS analyses was 8 months.
After the occurrence of 502 PFS events, pembrolizumab at both doses was associated with a 42% lower risk for progression compared with ipilimumab (HR = 0.58; P ˂ .00001). The different dosing schedules of pembrolizumab were associated with comparable PFS (HR = 0.97; 95% CI, 0.77-1.21).
More patients assigned pembrolizumab arms achieved 6-month PFS (every 2 weeks, 47.3%; every 3 weeks, 46.4%) compared with patients in the ipilimumab arm (26.5%).
Median follow-up for OS analyses was 14 months.
After 202 deaths had occurred, pembrolizumab was associated with significantly improved OS compared with ipilimumab for the every 2-week schedule (HR = 0.6; 95% CI, 0.43-0.84) and every 3-week schedule (HR =0.56; 95% CI, 0.4-0.78).
Median survival had not yet been reached for either of the pembrolizumab cohorts. Median survival for the ipilimumab arm also had not yet been reached, but the lower bound of the 95% CI was 12.7 months.
“This study is out-performing all of our expectations,” Ribas said. “Even the ipilimumab arm is doing much better than expected.”
Six-month OS rates were 84.8% in the every 2-week cohort, 87.6% in the every 3-week cohort and 74.6% in the ipilimumab cohort. More patients assigned pembrolizumab also achieved 12-month OS in the every 2-week cohort (74%) and the every 3-week cohort (68%) compared with patients in the ipilimumab cohort (58%).
Researchers noted the PFS and OS benefits associated with pembrolizumab persisted in all patient subgroup analyses.
The ORR was 11.9% for patients assigned ipilimumab, whereas the ORR was 33.7% (P = .00013) for patients assigned pembrolizumab every 2 weeks and 32.9% (P = .00002) for patients assigned pembrolizumab every 3 weeks. Responses were ongoing in 89% of responders in the every 2-week cohort, 97% of responders in the every 3-week cohort, and 88% of the responders in the ipilimumab cohort.
The safety profiles were consistent with previously reported data for each agent. Although patients assigned pembrolizumab were exposed to the drug for a longer duration, more patients assigned ipilimumab experienced a grade 3 to grade 5 adverse event (19.9% vs. 11.7%).
“These results meet and exceed the baseline assumptions of the benefit of pembrolizumab over ipilimumab,” Ribas said in a press release. “I hope the drug regulatory agencies around the world act fast on approving pembrolizumab for the front-line therapy of metastatic melanoma. I think we made a remarkable advance in the treatment of patients with melanoma. We had the biggest change in our thinking about how to use the immune system to treat cancer 2 decades ago. And now we have clear evidence that this approach helps patients.” – by Alexandra Todak
Ribas A, et al. KEYNOTE-006. Phase III study of pembrolizumab (MK-3475) versus ipilimumab in patients with IPI-naive advanced melanoma. Presented at: American Association for Cancer Research Annual Meeting; April 18-22, 2015; Philadelphia.
Disclosure: The study was funded by Merck. Ribas reports a consultant role with and honoraria paid to his institution from Merck.