Mature Data Sustain Frontline OS Benefit of Pembrolizumab in Melanoma

Jacob Schachter, MD

A final analysis of the overall survival (OS) data from the KEYNOTE-006 trial showed that frontline pembrolizumab (Keytruda) was superior to ipilimumab (Yervoy) in the treatment of patients with advanced melanoma.

At 2 years’ follow-up, patients receiving either of 2 pembrolizumab doses administered in the trial had a 32% reduced risk of death compared with patients who received ipilimumab (HR, 0.68; P = .0008). “Approximately 30% of pembrolizumab-treated patients were alive and progression-free at 24 months,” lead author Jacob Schachter, MD, deputy director of the Oncology Division, Ella Institute for Treatment and Research of Melanoma and Skin Cancer, said when presenting the data earlier this year at the 2016 ASCO Annual Meeting.

“Responses to pembrolizumab, including complete responses, continued to accrue and were as durable as responses to ipilimumab,” added Schachter.

The KEYNOTE-006 trial randomized 834 patients with unresectable stage III or IV advanced melanoma in a 1:1:1 ratio to receive 4 cycles of ipilimumab at 3 mg/kg every 3 weeks (n = 278), 10 mg/kg of pembrolizumab every 3 weeks (n = 277), or 10 mg/kg of pembrolizumab every 2 weeks (n = 279).

Patients had received ≤1 prior therapy, excluding immunotherapy with anti¬—CTLA-4, –PD-1, or –PD-L1 agents. BRAF-positive patients may or may not have received prior BRAF inhibitors. Among the overall patient population, 65.8% had not previously received systemic treatment for advanced melanoma.

Baseline characteristics were well balanced among the 3 treatment arms. Approximately one-third of patients had a BRAF mutation, and 80% of patients in all 3 arms had positive PD-L1 staining. Patients had an ECOG performance status of 0 or 1. The primary endpoints were OS and progression-free survival (PFS), with secondary outcome measures including overall response rate (ORR), duration of response, and safety.

Responses were assessed starting at week 12 of treatment, then every 6 weeks until week 48, and finally every 12 weeks for the duration of the trial. Primary assessment was conducted by independent central review per RECIST 1.1. Survival was assessed every 12 weeks, and the final OS analysis was conducted after all patients had been followed for ≥21 months.

Poststudy antineoplastic therapy was administered to 40% of patients receiving pembrolizumab and 52% of patients receiving ipilimumab. Twenty-seven percent and 24% of patients receiving pembrolizumab every 2 weeks and every 3 weeks, respectively, received some form of poststudy immunotherapy, compared with 36% of patients in the ipilimumab arm.

The 12-month OS rate was 74% for patients receiving pembrolizumab every 2 weeks and 68% for those receiving the therapy every 3 weeks. For patients receiving ipilimumab, the 12-month OS rate was 59%. At 24 months, OS was 55% for both pembrolizumab arms and 43% for the ipilimumab arm. The median OS at 2 years was not reached for either treatment group receiving pembrolizumab. In the ipilimumab treatment arm, the 2-year median OS was 16 months.

Schachter noted that, “Ipilimumab outperformed expectations in this study based on historical data, making the survival advantage of pembrolizumab less dramatic.”

PFS data assessed at 12 months showed no significant difference between rates for the every-2-week and every-3-week pembrolizumab regimens (39% and 38%, respectively), and a 19% rate for patients receiving ipilimumab. The 2-year PFS rates were 31%, 28%, and 14%, respectively, with a 24-month median PFS of 5.6, 4.1, and 2.8 months, respectively.

The ORR was 37% for patients receiving pembrolizumab every 2 weeks, 36% for the every-3-week regimen, and 13% with ipilimumab (P <.001). The complete response rates were 12%, 13%, and 5%, respectively.

In terms of adverse events, a greater exposure to pembrolizumab was not found to be associated with higher toxicity. However, thyroid abnormalities, pneumonitis, and nephritis were generally more common in patients receiving pembrolizumab, while colitis was more common for patients receiving ipilimumab. Grade 3/4 toxicities occurred in 17% of patients receiving pembrolizumab versus 20% of patients receiving ipilimumab.

Based on the primary findings from KEYNOTE-006, the FDA approved pembrolizumab in December 2015 for the frontline treatment of patients with advanced melanoma regardless of BRAF status.

Reference

1. Schachter J, Ribas A, Long GV, et al. Pembrolizumab versus ipilimumab for advanced melanoma: Final overall survival analysis of KEYNOTE-006. J Clin Oncol 34, 2016 (suppl; abstr 9504).