Results of KEYNOTE-716 trial may ‘level the playing field against melanoma’
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Patients with resected stage IIB or stage IIC melanoma who received adjuvant pembrolizumab demonstrated a 35% reduction in risk for disease recurrence or death, according to results of the randomized phase 3 KEYNOTE-716 study.
Pembrolizumab (Keytruda, Merck) also significantly extended RFS compared with placebo and had a favorable risk-benefit profile, researchers noted.
The results, presented during the virtual ESMO Congress 2021, will substantially change the population of patients with melanoma who undergo treatment in the adjuvant setting, according to Jason J. Luke, MD, FACP, director of the Cancer Immunotherapeutics Center and associate professor of medicine at UPMC Hillman Cancer Center and University of Pittsburgh School of Medicine.
“Patients with stage IIB/C melanoma have similar rates of recurrence and melanoma specific survival to those with stage IIIA/B disease. Despite this, adjuvant anti-PD-1 immunotherapy has only been available in standard practice for stage III disease,” Luke told Healio. “The results of KEYNOTE-716 will facilitate access to anti-PD-1 for stage IIB/C patients and, in a sense, level the playing field against melanoma.”
The study included 976 patients aged 12 years or older who underwent complete resection of cutaneous stage IIB or stage IIC melanoma and had no lymph node involvement. Researchers randomly assigned 487 patients to 200 mg pembrolizumab (2 mg/kg for children) and 489 patients to placebo every 3 weeks for 17 cycles up to 1 year, until disease recurrence or unacceptable toxicity. They stratified randomization according to T category, with a separate stratum for children.
RFS per investigator assessment served as the primary endpoint. Researchers also evaluated safety.
Median follow-up was 14.4 months for the pembrolizumab group and 14.3 months for the placebo group.
Results of the interim analysis, which had a data cutoff date of Dec. 4, 2020, showed pembrolizumab significantly extended RFS compared with placebo (HR = 0.65; 95% CI, 0.46-0.92). Fewer patients in the pembrolizumab group experienced recurrence (11.1% vs. 16.8%), and slightly more than half as many distant recurrence events occurred with pembrolizumab (23 vs. 38). RFS rates at 12 months were 90.5% with pembrolizumab and 83.1% with placebo.
“The benefit of pembrolizumab was completely unsurprising and the results of this study were, in fact, better than what was initially predicted in the statistical design,” Luke told Healio. “We expect that the magnitude of the RFS benefit will substantially increase as the trial data become more mature.”
The pembrolizumab group had higher rates of grade 3 or higher adverse events of any cause (25.9% vs. 17.1%) and drug-related adverse events that led to discontinuation (15.3% vs. 2.5%). However, no deaths due to any of these events occurred in the pembrolizumab group, whereas four deaths due to any-cause adverse events occurred in the placebo group. Immune-mediated adverse events — mostly grade 1 or grade 2 — occurred at a higher rate with pembrolizumab (36.2% vs. 8.4%) and included hypothyroidism (13.9% vs. 3.5%) and hyperthyroidism (10.4% vs. 0.6%). About 20% of patients in the pembrolizumab group received long-term hormonal therapy to manage endocrine toxicities.
Quality of life was maintained with adjuvant pembrolizumab compared with placebo, Luke said during the presentation.
“There is a misplaced bias in the field for patients with stage IIB/C melanoma. In fact, they have high-risk disease as suggested by the rapid rate of recurrences and the distant metastatic recurrences observed in the trial,” Luke told Healio. “The clinical implications here are that all patients with stage IIB/C melanoma deserve to be offered pembrolizumab for adjuvant management of melanoma following surgery. The number of patients who can potentially benefit from pembrolizumab in the adjuvant setting should double based on KEYNOTE-716.”
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Luke JJ, et al. Abstract LBA3_PR. Presented at: European Society for Medical Oncology Congress (virtual meeting); Sept. 17-21, 2021.
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