Pembrolizumab Outperforms Ipilimumab in Patients With Advanced Melanoma

Results of the long-awaited Keynote 006 study prove the superiority of pembrolizumab to ipilimumab on criteria of both progression-free survival and overall survival.

Treatment guidelines for melanoma may soon be changing.

Official results of Keynote 006 were published June 25, 2015 in the New England Journal of Medicine. Positive results were previously mentioned, but little else had been announced at a meeting of the American Association of Cancer Research (AACR) Annual Meeting in Philadelphia in April 2015. The study compared pembrolizumab with ipilimumab in patients with advanced melanoma.

Both drugs are immune checkpoint inhibitors, but with different targets. Ipilimumab inhibits the programmed cell death 1 (PD-1) receptor, while pembrolizumab inhibits the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Cancer cells use these receptors to evade attack by human immune cells and blocking these receptors with drugs stimulates immune-mediated cancer killing. The relative efficacy of the 2 approaches has been unclear, however, and ipilimumab has been the immunotherapy of choice for patients with advanced melanoma.

With the results of Keynote 006, pembrolizumab will be the new standard immunotherapy for patients with advanced melanomas.

The phase 3 study involved 843 patients randomized equally to receive 1) more intensive pembrolizumab (10 mg/kg every 2 weeks), 2) less intensive pembrolizumab (10 mg/kg every 3 weeks), or 3) ipilimumab 3 mg/kg every 3 weeks for 4 administrations. Investigators assessed progression-free survival (PFS) and overall survival (OS).

After 6 months, approximately half of patients receiving pembrolizumab achieved PFS after 6 months of treatment (47.3% of patients receiving more intensive pembrolizumab, 46.4% of patients receiving less intensive pembrolizumab). Results with ipilimumab were significantly worse, with just over one-fourth of patients (26.3%) attaining the PFS end point. This translates to a 42% lower likelihood of PFS with ipilimumab than with pembrolizumab regimens (hazard ratio: 0.58; P <.001).

OS rates and response rates after 12 months were also significantly improved in patients receiving pembrolizumab (either dose) versus ipilimumab. While 74.1% of patients receiving more intensive pembrolizumab and 68.4% of patients receiving less intensive pembrolizumab survived through 12 months, just 58.2% of patients receiving ipilimumab were alive at this time point. This translates to a 37% lower risk of death (P = .0005) with more intensive pembrolizumab than with ipilimumab, and a 31% lower risk of death (P = .0036) with less intensive pembrolizumab than with ipilimumab.

Not only was pembrolizumab superior to ipilimumab in efficacy, but pembrolizumab was also associated with a lower risk of grade 3 through 5 adverse events than pembrolizumab. A total of 13.3% of patients receiving more intensive pembrolizumab experienced grade 3 to 5 adverse events, and 10.3% of patients receiving less intensive pembrolizumab experienced grade 3 to 5 adverse events--nearly half the 19.9% rate of such adverse events occurring in patients assigned to ipilimumab.

Common adverse events with pembrolizumab and ipilimumab included fatigue, diarrhea, rash, and pruritus. Of these adverse events, events of grade 3 through 5 severity occurred in fewer than 1% of patients receiving either therapy with the exception of diarrhea (2.5% with more intensive and 1.1% with less intensive pembrolizumab), diarrhea (3.1%), and fatigue (1.2%) with ipilimumab.

Immune-related adverse events observed in the study included hypothyroidism, hyperthyroidism, colitis, hepatitis, and hypophysitis (an inflamed pituitary gland). Of these adverse events, hypothyroidism, and hyperthyroidism occurred more often with pembrolizumab than with ipiliumab, but colitis and hypophysitis occurred more frequently with ipiliumab than with pembrolizumab.

In their conclusion, investigators stated, “pembrolizumab, as compared with ipilimumab, significantly prolonged progression-free and overall survival with fewer high-grade toxic events in patients with advanced melanoma.”

These practice-changing results will likely raise the priority of pembrolizumab in treatment of patients with advanced melanoma in the very near future.

Reference

Robert C, Schachter J, Long GV, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015;372(26):2521-2532.