Twenty-year survival outcomes after multipeptide vaccination for resected high-risk melanoma: A post-hoc analysis of a randomized clinical trial

In this post-hoc analysis, we report long-term clinical outcomes of a randomized phase II clinical trial (Mel39, NCT00938223) that tested the immunogenicity of two multipeptide vaccines designed to stimulate CD8+ T cells in patients with high-risk melanoma. Fifty-one participants with resected stage IIB-IV melanoma randomized to vaccination with 4 or 12 melanoma peptides were followed for clinical outcomes. Overall survival (OS) and recurrence-free survival (RFS) by vaccine arm, immune response, age, sex, and stage were evaluated. Median follow-up was 16.1 years for all participants and 21.2 years for living participants. OS rates (95% CI) for both vaccine arms were 65% (51-78%) and 49% (35-63%) at 10 and 20 years, respectively, favoring vaccination with 12 melanoma peptides (HR 0.64, 95% CI: 0.29-1.40; p = .26) with a promising difference given the study sample size. Females had significantly improved RFS compared to males after either vaccine regimen, independent of peripheral immune response to the vaccine (HR 0.42, 95% CI: 0.19-0.91; p = .03). Overall, clinical efficacy was not significantly improved with more class I major histocompatibility complex (MHC)-restricted peptides to the vaccine despite more favorable peripheral immune response rates on treatment. Females had durable RFS after vaccination that was not explained by sex-associated differences in peripheral CD8+ T cell response rates during treatment. Further work to identify clinically meaningful vaccine-induced T cell responses and how to optimize vaccines to elicit these responses is needed, including investigation into the influence of host factors on the response to immunotherapy.