Anti–PD-1 Antibody Pembrolizumab Improves Progression-Free and Overall Survival vs Ipilimumab in Advanced Melanoma
In the phase III KEYNOTE-006 trial reported in The New England Journal of Medicine, Robert et al found that the anti–PD-1 antibody pembrolizumab (Keytruda) increased progression-free and overall survival compared with ipilimumab in patients with advanced melanoma.
Study Details
In this open-label trial, 834 patients from 16 countries were randomly assigned 1:1:1 between September 2013 and March 2014 to receive pembrolizumab at 10 mg/kg every 2 weeks (n = 279) or 3 weeks (n = 277) or four doses of ipilimumab (Yervoy) at 3 mg/kg every 3 weeks (n = 278). Randomization was stratified by Eastern Cooperative Oncology Group (ECOG) performance status, line of therapy, and PD-L1 expression. The primary endpoints were progression-free and overall survival.
The three groups were generally balanced for age (median, 61-63 years), sex (58%–63% male), ECOG performance status (0 for 68%–70%, 1 for 30%–32%), elevated lactate dehydrogenase (29%–35%), metastasis stage (M0 in 3%–5%, M1–not otherwise specified in 1%–2%, M1a in 8%–12%, M1b in 15%–23%, M1c in 64%–68%), PD-L1–positive status (80%–81%), BRAF V600E–mutant status (35%–38%), brain metastases (8%–10%), previous lines of systemic therapy (0 in 65%–67%, 1 in 33%-35%), and type of previous systemic therapy (chemotherapy in 10%–15%, immunotherapy in 3%–4%, BRAF or MEK inhibitor or both in 16%–20%).
Median duration of follow-up at the time of data cutoff was 7.9 months (range = 6.1–11.5 months). The mean duration of exposure was 164 days for pembrolizumab every 2 weeks, 151 days for pembrolizumab every 3 weeks, and 50 days for ipilimumab.
Progression-Free Survival
On first interim analysis for progression-free survival, estimated 6-month progression-free-survival rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (hazard ratio [HR] = 0.58, P < .001 for both pembrolizumab vs ipilimumab comparisons). Median progression-free survival was 5.5 months (95% confidence interval [CI] = 3.4–6.9 months), 4.1 months (95% CI = 2.9–6.9 months), and 2.8 months (95% CI = 2.8–2.9 months).
Benefit of both pembrolizumab regimens vs ipilimumab was evident in all examined subgroups. For the every-2-week and every-3-week pembrolizumab groups vs ipilimumab, hazard ratios were 0.53 (95% CI = 0.41–0.67) and 0.52 (95% CI = 0.40–0.66) among PD-L1–positive patients and 0.67 (95% CI = 0.41–1.11) and 0.76 (95% CI = 0.47–1.24) among PD-L1–negative patients.
Hazard ratios were significant in favor of the pembrolizumab groups among patients with wild-type BRAF (0.58 and 0.57) and among patients with BRAF mutation who had received no BRAF inhibitor (0.54 and 0.44); among patients with BRAF mutation who had received BRAF inhibitor therapy, the hazard ratio was significant for the every-2-week group (0.58) but not for the every-3-week group (0.87, 95% CI = 0.53–1.40).
Overall Survival
At the second interim analysis for overall survival, estimated 12-month overall survival rates were 74.1% (HR = 0.63, P = .0005 vs ipilimumab), 68.4% (HR = 0.69, P = .0036 vs ipilimumab), and 58.2%. Due to the superiority of pembrolizumab, the independent data and safety monitoring committee recommended stopping the study early to permit patients in the ipilimumab group to receive pembrolizumab. Median overall survival was not reached in any group.
Hazard ratios favored pembrolizumab for all subgroups, except in the comparison of every-3-week pembrolizumab vs ipilimumab in patients with PD-L1–negative tumors; among these patients, hazard ratios were 0.91 (95% CI = 0.49–1.69) for every-2-week pembrolizumab and 1.02 (95% CI = 0.56–1.85) for every-3-week pembrolizumab. Among patients with PD-L1–positive tumors, hazard ratios were 0.55 (95% CI = 0.40–0.76) and 0.58 (95% CI = 0.42–0.79). Hazard ratios were significant in favor of the two pembrolizumab groups among patients with wild-type BRAF and nonsignificantly in favor of pembrolizumab among patients with BRAF mutation irrespective of whether they had received BRAF inhibitor treatment.
Response rates were 33.7% for pembrolizumab every 2 weeks, 32.9% for pembrolizumab every 3 weeks, and 11.9% for ipilimumab (P < .001 for both comparisons), with compete response rates of 5.0%, 6.1%, and 1.4%. Median times to response were 86, 85, and 87 days. Median duration of response was not reached in any group, with 89.4%, 96.7%, and 87.9% of responses ongoing at the time of analysis.
Adverse Events
The most common treatment-related adverse events of any grade in the pembrolizumab groups were fatigue (20.9% in the every-2-week group and 19.1% in the every-3-week group), diarrhea (16.9% and 14.4%), rash (14.7% and 13.4%), and pruritus (14.4% and 14.1%). The most common in the ipilimumab group were pruritus (25.4%), diarrhea (22.7%), and fatigue (15.2%).
Treatment-related grade ≥ 3 adverse events occurred in 13.3%, 10.1%, and 19.9% of patients; the most common in pembrolizumab patients were diarrhea (2.5% and 1.1%), colitis (1.4% and 2.5%), and hepatitis (1.1% and 1.8%) and the most common in ipilimumab patients were colitis (7.0%), diarrhea (3.1%), hypophysitis (1.6%), and fatigue (1.2%). The most common autoimmune or immune-related adverse events of special interest in the pembrolizumab groups were hypothyroidism (10.1% and 8.7%) and hyperthyroidism (6.5% and 3.2%).
Treatment-related adverse events led to discontinuation of study drug in 4.0%, 6.9%, and 9.4% of patients. One treatment-related death occurred in an ipilimumab patient (cardiac arrest from diarrhea-related metabolic imbalances in a patient with diabetes).
The investigators concluded: “The anti–PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma.”
Caroline Robert, MD, PhD, of Gustave Roussy and Université Paris-Sud, is the corresponding author for The New England Journal of Medicine article.
The study was funded by Merck Sharp & Dohme. For full disclosures of the study authors, visit www.nejm.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
