In a protocol-specified fourth interim and final distant metastasis-free survival (DMFS) analysis of KEYNOTE-716 study, adjuvant treatment with pembrolizumab continued to demonstrate a DMFS and a recurrence-free survival (RFS) benefit compared with placebo in patients with resected stage IIB or IIC melanoma. After an additional 12 months of follow-up, the DMFS benefit previously reported at the third interim analysis was sustained, with pembrolizumab providing a reduction in the risk of distant metastasis compared with placebo. The DMFS benefit was also consistent across prespecified subgroups, including stage IIB and IIC melanoma.
The RFS benefit previously observed with pembrolizumab was also sustained, with pembrolizumab reducing the risk of recurrence or death in the intention-to-treat population, in patients with stage IIB or stage IIC melanoma, and in most subgroups. The findings are reported by Dr. Jason J. Luke of the UPMC Hillman Cancer Center and University of Pittsburgh in Pittsburgh, PA, US and colleagues on 7 March 2024 in the JCO.
In the randomised, double-blind, phase III KEYNOTE-716 study conducted in patients with resected stage IIB or IIC melanoma, pembrolizumab as adjuvant treatment significantly improved RFS at the first interim analysis (hazard ratio [HR] 0.65, 95% confidence interval [CI] 0.46 to 0.92; p = 0.0066) and DMFS at the third interim analysis (HR 0.64, 95% CI 0.47 to 0.88]; p = 0.0029) compared with placebo. These results led to the approval of pembrolizumab as adjuvant treatment in adult and paediatric patients with stage IIB or IIC melanoma by numerous regulatory authorities.
In the latest article, published in the JCO, the study team reports findings from the protocol-specified fourth interim analysis of KEYNOTE-716, including final DMFS and updated RFS results. Overall, 487 patients were randomly allocated to pembrolizumab and 489 to placebo. As of 4 January 2023, median follow-up was 39.4 months (range, 26.0-51.4 months).
The median DMFS was not reached in either treatment arm, and the estimated 36-month DMFS was 84.4% for pembrolizumab and 74.7% for placebo (HR 0.59, 95% CI 0.44 to 0.79). The median RFS was not reached in either treatment arm, and the estimated 36-month RFS was 76.2% for pembrolizumab and 63.4% for placebo (HR 0.62, 95% CI 0.49 to 0.79). DMFS and RFS results were consistent across most prespecified subgroups, including stage IIB and stage IIC melanoma.
For both DMFS and RFS, a continued separation of the Kaplan-Meier curves was observed over time and appeared to be widening for DMFS. Overall survival results will be reported at the fifth interim analysis.
The safety profile of pembrolizumab was manageable and consistent with previous reports. Treatment-related adverse events (TRAEs) occurred in 82.6% of patients in the pembrolizumab arm (with grade 3 and 4 in 17.2% of patients) and 63.6% in the placebo arm (with grade 3 and 4 in 5.1%). TRAEs led to treatment discontinuation in 15.9% and 2.5% of patients in the pembrolizumab and placebo arms. No patients died because of TRAEs. Immune-mediated AEs and infusion reactions occurred in 37.9% of patients in the pembrolizumab arm (with grade 3 and 4 occurring in 11.0%) and 9.5% in the placebo arm (with grade 3 and 4 reported in 1.2%).
The authors commented that KEYNOTE-716 is the only study with long-term follow-up data available. Other studies investigating adjuvant treatments include the phase III CheckMate-76K study. In a prespecified interim analysis of patients with resected stage IIB or IIC melanoma enrolled in CheckMate-76K, adjuvant nivolumab improved RFS (HR 0.42, 95% CI 0.30 to 0.59; p < 0.0001) and DMFS (HR 0.47, 95% CI 0.30 to 0.72) compared with placebo.
Additional studies underway include the phase III COLOMBUS-AD study, which is being conducted to investigate adjuvant encorafenib plus binimetinib versus placebo in resected stage IIB or IIC BRAFV600-mutated melanoma. Adjuvant pembrolizumab treatment for patients with resected high-risk stage IIB-IV melanoma is also being investigated as coformulation with vibostolimab in the phase III KEYVIBE-010 study and in combination with the individualised neoantigen therapy V940 in the phase III V940-001 study.
The findings were previously presented at the ASCO 2023 Annual Meeting.
The study is supported by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, US.
Reference
Luke JJ, Ascierto PA, Khattak MA, et al. Pembrolizumab Versus Placebo as Adjuvant Therapy in Resected Stage IIB or IIC Melanoma: Final Analysis of Distant Metastasis-Free Survival in the Phase III KEYNOTE-716 Study. JCO; Published online 7 March 2024. DOI: https://doi.org/10.1200/JCO.23.02355