626 Long-term outcomes of a randomized trial of two multipeptide melanoma vaccines (Mel39) suggests outcome differences based on participant sex

Background

Cancer vaccines containing peptides presented by Class I MHC can stimulate strong CD8+ T cell responses. Melanocyte differentiation proteins (MDP) and cancer-testis antigens (CTA) are shared antigens commonly expressed by melanoma cells, but effectiveness may be limited by immune evasion after vaccination with a limited number of antigens. The Mel39 vaccine trial tested safety and immunologic effects of vaccination with 12 Class I MHC-restricted melanoma peptides (12MP) derived from MDP and CTA compared to a four-peptide vaccine (4MP) derived from MDP. In our original report, 12MP vaccines produced a broader and more robust immune response than 4MP, despite competition for binding to MHC molecules.¹ Clinical outcome correlated with immune responses.¹ The objective of the present study was to assess long-term clinical outcomes. We hypothesized that vaccination with 12MP would improve overall survival (OS) and recurrence-free survival (RFS).

Methods

The Mel39 trial (NCT00938223) enrolled 51 eligible participants with resected stage IIB-IV melanoma randomized to vaccination with 12MP or 4MP; plus a tetanus helper peptide. Patients were followed long-term for survival and disease recurrence. To evaluate long-term clinical outcomes, differences in OS and RFS were evaluated using Kaplan-Meier survival estimates. Exploratory subgroup analyses based on patient sex were also performed. Hazard ratios (HR) are reported.

Results

With median followup of 11.1 years, OS was ~60% at 12 years for either vaccine, with a weak trend favoring vaccination with 12MP (HR 0.63, 95% CI 0.29 to 1.39; figure 1A), while RFS curves were similar (figure 1B). Exploratory analysis by patient sex revealed trends favoring 12MP for OS in males (HR 0.51, 95% CI 0.18 to 1.46, figure 2A) and for RFS in females (HR 0.43, 95% CI 0.15 to 1.22, figure 2B). Overall, females had significantly improved RFS compared to males regardless of vaccine regimen (HR 0.44, 95% CI: 0.21 to 0.90), with an approximately 30 percentage point difference in RFS at 5 and 10 years (figure 3).

Conclusions

After vaccination with multipeptide vaccines, most patients survive long-term. Adding more peptides did not significantly prolong OS or RFS, but this trial was not powered for clinical outcome. However, there were trends for favorable impact of the 12MP vaccine on OS for males and RFS for females. Also, females had significantly improved RFS compared to males, regardless of vaccine. These data support the need for analysis of the impact of patient sex on the clinical impact of cancer vaccines.