Pembrolizumab Increases Progression-Free Survival vs Chemotherapy in Ipilimumab-Refractory Advanced Melanoma
In the randomized phase II KEYNOTE-002 trial reported in The Lancet Oncology, Ribas et al found that treatment with the anti–PD-1 antibody pembrolizumab (Keytruda) prolonged progression-free survival vs investigator-choice chemotherapy in patients with advanced melanoma progressing on ipilimumab (Yervoy) and, if BRAF V600 mutant–positive, a BRAF or MEK inhibitor.
Study Details
The open-label trial included 540 patients from 12 countries with progressive disease within 24 weeks after two or more ipilimumab doses and, if BRAF V600 mutant–positive, previous treatment with a BRAF or MEK inhibitor or both. Patients were randomly assigned 1:1:1 between November 2012 and November 2013 to receive pembrolizumab 2 mg/kg (n = 180) or 10 mg/kg (n = 181) every 3 weeks or investigator-choice chemotherapy (n = 179, including 42 to paclitaxel plus carboplatin, 28 to paclitaxel, 13 to carboplatin, 45 to dacarbazine, and 43 to temozolomide).
Patients had to have resolution of all ipilimumab-related adverse events to grade 0 or 1 and prednisone ≤ 10 mg/d for ≥ 2 weeks. Randomization was stratified by Eastern Cooperative Oncology Group performance status, lactate dehydrogenase (LDH) concentration, and BRAF V600–mutation status. Patients were masked to the dose of pembrolizumab. The primary endpoint was progression-free survival in the intent-to-treat population.
Patients had a median age of 60 to 63 years, 96% to 99% were white, 54% to 55% had a performance status of 0, 76% to 78% had wild-type BRAF, 55% to 60% had normal LDH levels, 30% to 33% had at least three lines of prior therapy, and 24% to 26% had received a BRAF or MEK inhibitor.
Progression-Free Survival
At the prespecified second interim analysis, at a median follow-up of 10 months, progression-free survival was significantly prolonged in the pembrolizumab 2 mg/kg group (hazard ratio [HR] = 0.57, P < .0001) and in the pembrolizumab 10 mg/kg group (HR = 0.50, P < .0001) compared with the chemotherapy group. Six-month progression-free survival was 34% (95% confidence interval [CI] = 27%–41%) and 38% (95% CI = 31%–45%) in the 2-mg/kg and 10-mg/kg groups vs 16% (95% CI = 10%–22%) in the chemotherapy group.
Benefit of both pembrolizumab doses was observed in all prespecified subgroups, including BRAF and LDH status subgroups.
On independent central review, response was observed in 21% of patients in the pembrolizumab 2-mg/kg group and 25% of the 10-mg/kg group vs 4% of the chemotherapy group (P < .0001 for both comparisons).
Adverse Events
Treatment-related grade 3 or 4 adverse events occurred in 11% of patients in the pembrolizumab 2-mg/kg group, 14% of the pembrolizumab 10-mg/kg group, and 26% of the chemotherapy group, with the most common in pembrolizumab patients being fatigue (1%, < 1%, and 5%). Treatment-related adverse events led to treatment discontinuation in 2.2%, 6.7%, and 5.8%.
The investigators concluded: “These findings establish pembrolizumab as a new standard of care for the treatment of ipilimumab-refractory melanoma.”
Antoni Ribas, MD, of Jonsson Comprehensive Cancer Center, University of California, Los Angeles, is the corresponding author of the The Lancet Oncology article.
The study was funded by Merck Sharp & Dohme. For full disclosures of the study authors, visit www.thelancet.com.
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