CHICAGO — Patients with stage III melanoma may soon have access to yet another immunotherapeutic agent after they undergo surgery. New data from a pivotal phase 3 trial show that patients who received adijuvant pembrolizumab (Keytruda, Merck) were at a 43% reduced risk for recurrence compared to patients who received placebo. These data are expected to lead to approval for this new indication.
The data come from the KEYNOTE 054/EORTC 1325-MG trial, presented here at the American Association for Cancer Research (AACR) 2018 Annual Meeting and simultaneously published online in the New England Journal of Medicine.
Currently, ipilimumab (Yervoy, Bristol-Myers Squibb) and nivolumab (Opdivo, Bristol-Myers Squibb) are approved for the adjuvant treatment of patients with stage III melanoma.
“The dose of ipilimumab approved for adjuvant therapy is associated with significant toxicity,” said Alexander M. M. Eggermont, MD, PhD, director general of Gustave Roussy Cancer Campus Grand Paris in Villejuif, France, in an AACR news release. Although nivolumab and pembrolizumab have not been compared in a head-to-head study, he noted that when pembrolizumab becomes available, clinicians will have to decide when pembrolizumab may be preferred.
KEYNOTE-054 Study Details
The global study enrolled 1019 patients with stage III melanoma who were at high risk for recurrence after surgical resection.
“Patients with stage III melanoma have metastatic disease in one or more regional lymph nodes,” presenter Eggermont explained at a press conference. “A patient’s risk of recurrence depends on the number of lymph nodes affected and the tumor load. Those classified as having a high risk of recurrence have one or more regional lymph nodes with melanoma metastasis. In the case of a single lymph node, the diameter must be greater than 1 mm,” he said.
Patients were randomly assigned to receive pembrolizumab (n = 514) or placebo (n = 505). Pembrolizumab was administered at a flat dose of 200 mg every 3 weeks after surgery for up to a year — a total of 18 doses. Median follow-up was 1.25 years.
Eggermont noted that the trial had a crossover design — patients who received placebo and who experienced recurrence were offered treatment with pembrolizumab.
“This crossover design is unique in the world of adjuvant trials in melanoma and will permit us to analyze if adjuvant therapy with pembrolizumab right after surgery is better or not than treating only those who relapse and start treatment at relapse,” he said.
A primary endpoint was 12-month recurrence-free survival (RFS), which was significantly improved by pembrolizumab. For the intent-to-treat population, the 12-month RFS rate was 75.4%, vs 61.0% for patients who received placebo. With a hazard ratio (HR) of 0.57, patients who received pembrolizumab were at a 43% reduced risk for disease recurrence (P < .0001). The 2-year RFS rates were 71.4% and 53.2%, respectively.
The significant improvement was seen with pembrolizumab regardless of programmed cell death ligand–1 (PD-L1) status. Patients with PD-L1-positive tumors (n = 853) had a 46% reduced risk for recurrence (P < .0001), and patients with PD-L1-negative tumors (n = 116) had a 53% reduced risk for recurrence (P = .01).
The KEYNOTE-054 results also showed that the cumulative incidence of distant metastasis as the first RFS event was significantly higher for patients in the placebo arm: 29.7% vs 16.7% for pembrolizumab (HR, 0.53; 95% confidence interval, 0.37 – 0.76).
Eggermont reported that 14.7% of patients who received pembrolizumab had drug-related grade 3 or 4 adverse events, compared with 3.4% for patients who received placebo. One patient who received pembrolizumab died of myositis. Immune-related adverse events typically seen with immunotherapies were also seen with pembrolizumab. Endocrine disorders of grade 1 or 2 were reported in 23.4% of patients taking pembrolizumab and in 5% of patients taking placebo. Pembrolizumab (vs placebo) was also associated with grade 3 or 4 colitis (7.1% vs 0.6%), pneumonitis (0.8% vs 0%), and hepatitis (1.4% vs 0.2%).
“We were pleased to see that adjuvant pembrolizumab, given as a flat dose of 200 mg every 3 weeks after surgery for up to a year, which is 18 doses, significantly reduced the risk of recurrence for patients with high-risk stage III melanoma that has been completely resected,” Eggermont said. “We hope that these data will lead to regulators in the United States and Europe approving pembrolizumab as a new treatment option for these patients,” he added.
Implications for Clinical Practice
Approached for comment about the new data, Michael A. Postow, MD, medical oncologist at the Memorial Sloan Kettering Cancer Center in New York City, noted that the pembrolizumab study is the first to include patients with stage IIIA disease.
“Stage IIIA patients were included in the adjuvant pembrolizumab study and not in the adjuvant nivolumab vs adjuvant ipilimumab study,” he said.
“Generally, since PD-1 inhibition with either nivolumab or pembrolizumab is better tolerated than adjuvant ipilimumab, and the fact that nivolumab has demonstrated superiority over adjuvant ipilimumab in terms of RFS, I think PD-1 therapy is the preferred option in the adjuvant space after resection of high-risk melanoma,” Postow told Medscape Medical News.
“Outside of a clinical trial, ipilimumab would only be considered for patients with metastatic disease,” he added.
He explained that the only difference between pembrolizumab and nivolumab as adjuvant therapies is the difference in the intervals of administration.
“Efficacy appears roughly similar between the two,” he said, but he pointed out that the two drugs have not been compared in head-to-head studies.
He also pointed out the one difference between the two drugs evaluated in the adjuvant setting. “Stage IIIA patients were included in the adjuvant pembrolizumab study and not in the adjuvant nivolumab vs adjuvant ipilimumab study,” he said. “There are more data for adjuvant pembrolizumab for patients with stage IIIA disease,” he added.
This study was conducted by the European Organisation for Research and Treatment of Cancer and was sponsored by Merck. Dr Eggermont has received honoraria for scientific advisory board and data monitoring board functions from Actelion, Agenus, Bayer, Bristol-Myers Squibb, GlaxoSmithKline, HalioDx, Incyte, ISA Pharmaceuticals, Merck, Merck Serono, Nektar, Novartis, Pfizer, and Sanofi.
American Association for Cancer Research (AACR) 2018 Annual Meeting. Abstract CT001, presented April 15, 2018.
N Engl J Med. Published online April 15, 2018. Full text
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