Researchers from New Jersey, California, Canada, Israel, Australia, and several European countries joined forces to determine what the optimal course of anti-PD-1 is for patients with advanced melanoma. After 5 years of follow-up on patients from the KEYNOTE-006 study, the authors published their findings in The Lancet Oncology.
Compared with ipilimumab, pembrolizumab improves progression-free survival (PFS) and overall survival (OS) in patients with advanced melanoma. Once this became the first-line standard of care, researchers began to explore and hone details of the therapeutic protocol.
KEYNOTE-006 was a multicenter, open-label, randomized, controlled, phase 3 study carried out across 87 academic institutions, hospitals, and cancer centers in 16 different nations. Advanced melanoma patients aged 18 years and older with Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were recruited. None had been treated with ipilimumab, but had had up to one previous systemic therapy. All had known BRAFV600 status. They were randomly assigned (1:1:1) to 10 mg/kg intravenous pembrolizumab every 2 weeks or every 3 weeks, or to four doses of 3 mg/kg intravenous ipilimumab every 3 weeks. Treatments choices were randomly assigned through a centralized computer system. Data used to perform analyses of the two different pembrolizumab dosing regimen were not protocol specific. Treatment with pembrolizumab was continued for up to 2 years (24 months). Patients who stabilized and discontinued pembrolizumab after 24 months or discontinued after a complete response following at least 6 months, but then progressed, were eligible for an additional 17 cycles.
The researchers used coprimary endpoints of OS and PFS. They analyzed efficacy in all randomly assigned patients, and analyzed safety in all randomly assigned patients who had been assigned at least one dose.
In 2013 and 2014, 834 patients enrolled in a randomized study to receive treatment with either pembrolizumab (every 2 weeks, n=279; every 3 weeks, n=277), or ipilimumab (n=278). After a median follow-up at 57·7 months (IQR 56·7–59·2), median OS was 32·7 months (95% CI 24·5–41·6) in the combined pembrolizumab groups and 15·9 months (13·3–22·0) in the ipilimumab group (hazard ratio [HR] 0·73, 95% CI 0·61–0·88, p=0·00049). Median PFS came in at 8·4 months (95% CI 6·6–11·3) in the combined pembrolizumab groups vs 3·4 months (2·9–4·2) in the ipilimumab group (HR 0·57, 95% CI 0·48–0·67, p<0·0001). Grade 3–4 adverse events from treatment occurred in 96 (17%) of 555 patients in the combined pembrolizumab groups and in 50 (20%) out of 256 patients in the ipilimumab group. Among all events, the most often reported were colitis (11 [2%] vs 16 [6%]), diarrhea (ten [2%] vs seven [3%]), and fatigue (four [<1%] vs three [1%]). Significant adverse events stemming from treatment were reported by 75 (14%of) patients in the combined pembrolizumab groups and by 45 (18% of) patients in the ipilimumab group. One patient taking pembrolizumab died as a result of sepsis caused by treatment.
The authors concluded that pembrolizumab treatment offered superior outcomes compared with ipilimumab after almost 5 years of patient follow-up. These results support the protocol of pembrolizumab in advanced melanoma patients.