As reported in The Lancet by Luke et al, the phase III KEYNOTE-716 trial has shown significantly prolonged recurrence-free survival with adjuvant pembrolizumab vs placebo in patients with high-risk completely resected stage IIB/IIC melanoma at both first and second interim analyses.
The first interim analysis of the trial supported the December 2021 approval of pembrolizumab as adjuvant treatment of adult and pediatric (≥ 12 years of age) patients with stage IIB or IIC melanoma following complete resection.
Study Details
In the double-blind trial, 976 patients aged ≥ 12 years with newly diagnosed, completely resected stage IIB or IIC melanoma (TNM stage T3b or T4 with a negative sentinel lymph node biopsy) were randomly assigned between September 2018 and November 2020 to receive pembrolizumab (n = 487) at 200 mg in adult patients or 2 mg/kg in pediatric patients or placebo (n = 489) every 3 weeks for 17 cycles or until disease recurrence or unacceptable toxicity. The primary endpoint was investigator-assessed recurrence-free survival in the intention-to-treat population. First interim analysis was performed after approximately 128 patients had recurrence-free survival events, and second interim analysis was performed after 179 patients had events.
Recurrence-Free Survival
KEY POINTS
- Pembrolizumab significantly improved recurrence-free survival vs placebo.
- Recurrence-free survival events occurred in 11% vs 17% of patients at first interim analysis and in 15% vs 24% at second interim analysis.
At first interim analysis (data cutoff in December 2020), median follow-up was 14.4 months (interquartile range [IQR] = 10.2–18.7 months) in the pembrolizumab group and 14.3 months (IQR = 10.1–18.7 months) in the placebo group. Recurrence-free survival events occurred in 54 (11%) of 487 patients in the pembrolizumab group vs 82 (17%) of 489 in the placebo group (hazard ratio [HR] = 0.65, 95% confidence interval [CI] = 0.46–0.92, P = .0066). Estimated 12-month rates were 90% (95% CI = 87%–93%) vs 83% (95% CI = 79%–86%).
At second interim analysis (data cutoff in June 2021), median follow-up was 20.9 months (IQR = 16.7–25.3 months) in the pembrolizumab group and 20.9 months (IQR = 16.6–25.3 months) in the placebo group. Recurrence-free survival events occurred in 72 patients (15%) in the pembrolizumab group vs 115 (24%) in the placebo group (HR = 0.61, 95% CI = 0.45–0.82). At second interim analysis, first recurrence-free survival events consisted of local, regional, or locoregional recurrence in 8% vs 10% of patients, distant recurrence in 6% vs 12%, and death in 1% vs 1%.
Adverse Events
At first interim analysis, the most common treatment-related adverse events of any grade in the pembrolizumab group were pruritus (23%), diarrhea (18%), and rash (16%); hypothyroidism and hyperthyroidism occurred in 14% and 10%, respectively. Grade 3–4 treatment-related adverse events occurred in 16% of the pembrolizumab group vs 4% of the placebo group, with the most common in the pembrolizumab group being skin reactions (3%), hepatitis (2%), and colitis (2%). No treatment-related deaths were reported.
The investigators concluded: “Pembrolizumab as adjuvant therapy for up to approximately 1 year for stage IIB or IIC melanoma resulted in a significant reduction in the risk of disease recurrence or death versus placebo, with a manageable safety profile.”
Jason J. Luke, MD, of UPMC Hillman Cancer Center, Pittsburgh, is the corresponding author for The Lancet article.
Disclosure: The study was funded by Merck Sharp & Dohme, a subsidiary of Merck & Co. For full disclosures of the study authors, visit www.thelancet.com.
