Dr Weber on the Background of the KEYNOTE-942 Trial in High-Risk Melanoma

Jeffrey S. Weber, MD, PhD, deputy director, codirector, Melanoma Research Program, New York University (NYU) Langone Perlmutter Cancer Center, Laura and Isaac Perlmutter Professor of Oncology, NYU Grossman School of Medicine, discusses the background for and rationale of the phase 2b mRNA-4157-P201/KEYNOTE-942 trial (NCT03897881), which was conducted in patients with resected high-risk cutaneous melanoma.

At the 2023 ESMO Congress, Weber presented data from the clinical investigation of the addition of a personalized mRNA neoantigen vaccine to standard-of-care (SOC) pembrolizumab (Keytruda) in patients with resected stage IIIB, IIIC, IIID, and IV cutaneous melanoma. Findings from the investigation indicated that this treatment strategy enhanced survival outcomes compared with pembrolizumab alone in this patient population. These data supported the inference that monitoring circulating tumor DNA can offer valuable insights into the extent of benefit patients may derive from receiving an mRNA vaccine plus pembrolizumab.

The rationale for this study stemmed from research conducted over the past 7 years, which demonstrated that neoantigen treatment approaches, including RNA vaccines, could effectively trigger neoantigen-specific T-cell responses, he explains. These treatment approaches also induced epitope spreading to other antigens and sustained responses, Weber notes.

Additionally, clinical responses were observed in a subset of patients with metastatic diseases, particularly melanoma and lung cancer, Weber continues. Based on this background information, a randomized phase 2 trial, which randomly assigned patients with high-risk melanoma 2:1 to receive the RNA vaccine with pembrolizumab vs pembrolizumab alone, was conducted to assess whether the combination could produce recurrence-free survival and distant metastasis–free survival benefits in this patient population, he states. Positive outcomes from this trial, which enrolled 157 patients, would provide the rationale for proceeding to investigating this combination in a larger, more costly, more extensive phase 3 study, with minimal risk associated with advancing to the larger trial, Weber concludes.