Frontline Pembrolizumab Trumps Ipilimumab in Head-to-Head Melanoma Trial

Antoni Ribas, MD, PhD

Pembrolizumab (Keytruda) elicited significantly better outcomes compared with ipilimumab (Yervoy) in a randomized phase III trial of patients with advanced melanoma. Results from the study, the first head-to-head comparison of the two FDA-approved checkpoint inhibitors, were presented April 19 at the 2015 AACR Annual Meeting.

In the trial, named KEYNOTE-006, two separate dosing regimens of pembrolizumab demonstrated superiority over ipilimumab for all primary (overall survival [OS] and progression-free survival [PFS]) and secondary endpoints (overall response rate [ORR] and toxicity).

"This is the first clinical trial to compare head-to-head two immune checkpoint inhibitors, which unleash an immune response against the cancer," Antoni Ribas, MD, PhD, who presented the results, said in a statement. "We are delighted that we found that pembrolizumab is superior to ipilimumab as first-line therapy by improving responses and survival."

Ribas is a professor of hematology and oncology and director of the Tumor Immunology Program Area at UCLA Jonsson Comprehensive Cancer Center.

Patients enrolled on the trial had unresectable stage III or IV advanced melanoma and received no more than one prior systemic therapy. In total, 834 patients were randomized to receive four cycles of ipilimumab 3 mg/kg every 3 weeks (the approved dosage), 10 mg/kg of pembrolizumab every 3 weeks (Q3W), or 10 mg/kg of pembrolizumab every 2 weeks (Q2W). Both dosing regimens of pembrolizumab are higher than the FDA-approved regimen of 2 mg/kg every 3 weeks. Response was assessed at week 12 and every 6 weeks thereafter by RECIST 1.1. Median follow-up was 8 months.

PFS rates after 6 months of treatment were 47.3% for pembrolizumab Q3W, 46.4% for pembrolizumab Q2W, and 26.5% for ipilimumab, according to the second interim analysis. Six-month OS rates were 84.8%, 87.6%, and 74.6%, respectively. Both PFS and OS benefits were seen across all subgroups.

Further, ORR was also improved among patients treated with pembrolizumab. ORR was 33.7% for pembrolizumab Q2W (P = .00013), 32.9% for pembrolizumab Q3W (P = .00002), and 11.9% for ipilimumab. The toxicity profiles of the agents were consistent with what has been previously observed, the study authors noted. Though pembrolizumab was administered for a longer duration, rates of grade 3-5 adverse events were numerically lower than in the ipilimumab arm (11.7% versus 19.9%).

The most common side effects associated with pembrolizumab (occurring in ≥20% of patients) are fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea, according to results from KEYNOTE-001, the trial that led to the agent’s approval in 2014.

Currently, ipilimumab and pembrolizumab are approved for the treatment of metastatic melanoma in the first and second lines, respectively. Ribas said he hopes this will change. Ribas said results from KEYNOTE-006 could lead to a frontline indication for pembrolizumab.

“Our thinking about how to use the immune system to treat cancer began to change dramatically two decades ago, when the focus shifted from turning on the immune system to releasing the brakes that limit immune responses to cancer,” Ribas said in a statement. “This led to the development of both ipilimumab and pembrolizumab, and now we have clear evidence that this approach helps improve the lives of people with advanced melanoma.”

Investigator Caroline Robert, MD, PhD, anticipates that these results will help pembrolizumab gain regulatory approval in Europe.

“As of today, pembrolizumab is still not on the market in Europe, except in the context of an expanded access program after failure of ipilimumab,” Robert, head of the Dermatology Unit at the Institut Gustave-Roussy in Paris, said in a statement. “We also look forward to having pembrolizumab in Europe as a frontline therapy for metastatic melanoma, and we hope that these results are going to accelerate the process.”

Both ipilimumab and pembrolizumab continue to progress. Ipilimumab is demonstrating long-term benefit and is now moving into later lines of therapy. According to ClinicalTrials.gov, there are more than 75 open studies looking at the agent in melanoma.

Pembrolizumab is being examined in nearly 20 open melanoma studies and is expanding into other tumor types, including metastatic triple-negative breast cancer and classical Hodgkin lymphoma.

Ribas A, Schachter J, Long GV, et al. KEYNOTE-006: Phase III study of pembrolizumab (MK-3475) versus ipilimumab in patients with IPI-naive advanced melanoma. AACR Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. Abstract CT101.

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