In an analysis of the EORTC 1325/KEYNOTE-054 trial of adjuvant pembrolizumab vs placebo in stage III melanoma reported in JAMA Oncology, Alexander M.M. Eggermont, MD, PhD, and colleagues found that patients treated with pembrolizumab who experienced immune-related adverse events had improved recurrence-free survival vs those who did not.
“In this study, the occurrence of an immune-related adverse event was associated with a longer recurrence-free survival in the pembrolizumab arm.”— Alexander M.M. Eggermont, MD, PhD, and colleagues
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Study Details
In the trial, 1,019 adults with resected stage III melanoma (stage IIIA with at least one micrometastasis measuring > 1 mm in greatest diameter, IIIB, or IIIC without in-transit metastasis) were randomly assigned to receive 200 mg of pembrolizumab (n = 514) or placebo (n = 505) every 3 weeks for a total of 18 doses (approximately 1 year) or until disease recurrence or unacceptable toxicity. In the trial, pembrolizumab was associated with significantly prolonged recurrence-free survival.
In the current analysis among 1,011 patients who began treatment (509 in the pembrolizumab group and 502 in the placebo group), the association between immune-related adverse events and recurrence-free survival was estimated using a Cox model with adjustment for sex, age, and disease stage, with a time-varying covariate.
Key Findings
Consistent with findings in the primary intent-to-treat analysis, pembrolizumab was associated with significantly prolonged recurrence-free survival among the patients who actually began treatment (hazard ratio [HR] = 0.56, 98.4% confidence interval [CI] = 0.43–0.74).
Any-grade immune-related adverse events occurred in 190 patients in the pembrolizumab group (37.4%) vs 45 (9.0%) in the placebo group, with incidence in men and women being similar in each group.
Occurrence vs nonoccurrence of an immune-related adverse event was associated with improved recurrence-free survival among patients in the pembrolizumab group (HR = 0.61, P = .03). No such association was observed in the placebo group (HR = 1.37, P = .21).
Compared with the placebo group, reduction in the hazard for recurrence or death was greater (P = .03) after the onset of an immune-related adverse event (HR = 0.37, 95% CI =0.24–0.57) than in the absence of or before the onset of an immune-related adverse event (HR = 0.62, 95% CI = 0.49–0.78) in the pembrolizumab group.
Compared with the placebo group, for grade 3 or 4 immune-related adverse events, the hazard ratio for recurrence or death was 0.55 (95% CI = 0.44–0.68) without or before an event and 0.78 (95% CI = 0.32-0.91) after onset of an event in the pembrolizumab group (P = .43).
In men, the hazard ratio for recurrence or death was 0.36 (95% CI = 0.21–0.63) after the onset of an immune-related adverse event and 0.59 (95% CI = 0.44–0.79) without or before the onset of an immune-related adverse event compared with the placebo group. In women, the hazard ratio for recurrence or death was 0.42 (95% CI = 0.22–0.82) after the onset of an immune-related adverse event and 0.71 (95% CI = 0.48–1.04) without or before the onset of an immune-related adverse event compared with the placebo group.
The investigators concluded, “In this study, the occurrence of an immune-related adverse event was associated with a longer recurrence-free survival in the pembrolizumab arm.”
Stefan Suciu, PhD, of the European Organisation for Research and Treatment of Cancer Headquarters, Brussels, is the corresponding author for the JAMA Oncology article.
Disclosure: This study was supported by Merck & Co. For full disclosures of the study authors, visit jamanetwork.com.
