Philadelphia, PA—As new immunotherapies become available for the treatment of melanoma and other cancers, head-to-head trials of these agents shed more light on how best to use them. In the phase 3 KEYNOTE-006 trial, pembrolizumab (Keytruda) outperformed ipilimumab (Yervoy)—a current standard of care—as upfront treatment for patients with unresectable advanced melanoma. The data were presented at the 2015 American Association for Cancer Research annual meeting.
Pembrolizumab significantly improved overall survival (OS), progression-free survival (PFS), and overall response rate compared with ipilimumab, and was associated with fewer adverse events, including high-grade adverse events.
The study was just published in the New England Journal of Medicine (Robert C, et al. 2015 April 19. Epub ahead of print) to coincide with the presentation at the meeting.
“This is a paradigm shift. In the past we would be able to cure maybe 1 in 10 patients with melanoma, and with the newer therapies we can cure 1 in 3. The data from KEYNOTE-006 should change the standard of care for advanced melanoma,” stated senior investigator of the study, Antoni Ribas, MD, PhD, Director, Tumor Immunology Program Area, Jonsson Comprehensive Cancer Center, University of California, Los Angeles.
Ipilimumab is an anti–CTLA-4 therapy, and pembrolizumab is an anti–PD-1 antibody. These drugs take the “brakes” off of the immune system by different mechanisms of action, enabling the immune system to attack the cancer. Both immune checkpoint inhibitors are approved by the FDA.
Ipilimumab is approved as first-line therapy for advanced melanoma. Pembrolizumab and nivolumab, another anti–PD-1 antibody, are FDA-approved for disease progression after ipilimumab therapy, and if BRAF V600 mutation–positive, a BRAF inhibitor.
The global KEYNOTE-006 trial enrolled 834 patients from 83 sites. All the patients had unresectable stage III or IV advanced melanoma, and no more than 1 previous systemic therapy was allowed. Previous therapy with CTLA-4, PD-1, or PD-1 ligand 1 inhibitors was not allowed.
Patients were randomized in a 1:1:1 manner to pembrolizumab 10 mg/kg every 2 weeks (N = 279), to pembrolizumab 10 mg/kg every 3 weeks (N = 277), or to 4 cycles of ipilimumab 3 mg/kg every 3 weeks (N = 278).
At a median follow-up of 7.9 months, the median PFS was 5.5 months for the 2-week pembrolizumab dose, 4.1 months for the 3-week group, and 2.8 months for ipilimumab, showing a 42% relative reduction in risk for disease progression favoring pembrolizumab (P <.001). The estimated 6-month PFS rates for the 3 treatment arms were 47.3%, 46.4%, and 26.5%, respectively.
The median follow-up was 13.8 months. The 1-year OS rates were 74.1% and 68.4% for the 2-week and 3-week pembrolizumab groups, respectively, compared with 58.2% for ipilimumab.
The 37% improvement in survival with pembrolizumab was statistically significant compared with ipilimumab (P = .005 and P = .003, respectively).
The objective response rates were 33% in the pembrolizumab arms versus 11.9% in the ipilimumab arm. The complete response rates were 5%, 6.1%, and 1.4%, respectively. Responses were ongoing in 89.4% of the 2-week pembrolizumab group, 96.7% of the 3-week pembrolizumab group, and 87.9% of the ipilimumab group.
No difference in safety and efficacy was observed between the 2 dose levels of pembrolizumab studied in the trial.
Toxicity results favored pembrolizumab as well. Grade 3 or 4 adverse events occurred in 19% of the patients who received ipilimumab and in 10% to 13% of the patients in the pembrolizumab arm.
Pembrolizumab-related autoimmune- or immune-related adverse events included hypothyroidism (10.1% for the 2-week group, 8.7% for the 3-week group) and hyperthyroidism (6.5% and 2.5%, respectively). Colitis was reported in 8.2% of the patients who received ipilimumab.
Dr Ribas anticipates that upfront treatment with pembrolizumab will be added to its labeling, but noted that ipilimumab will still continue to be used for the treatment of melanoma, because it achieves durable responses.
Studies of combinations of anti–PD-1 agents with ipilimumab are ongoing, and these combinations are expected to be superior to either drug alone.
