Multicenter, double-blind, placebo-controlled trial of seviprotimut-L polyvalent melanoma vaccine in patients with post-resection melanoma at high risk of recurrence

Abstract

Background: Most patients with advanced melanomas relapse after checkpoint blockade therapy. Thus, immunotherapies are needed that can be applied safely early, in the adjuvant setting. Seviprotimut-L is a vaccine containing human melanoma antigens, plus alum. To assess the efficacy of seviprotimut-L, the Melanoma Antigen Vaccine Immunotherapy Study (MAVIS) was initiated as a three-part multicenter, double-blind, placebo-controlled phase III trial. Results from part B1 are reported here.

Methods: Patients with AJCC V.7 stage IIB-III cutaneous melanoma after resection were randomized 2:1, with stage stratification (IIB/C, IIIA, IIIB/C), to seviprotimut-L 40 mcg or placebo. Recurrence-free survival (RFS) was the primary endpoint. For an hypothesized HR of 0.625, one-sided alpha of 0.10, and power 80%, target enrollment was 325 patients.

Results: For randomized patients (n=347), arms were well-balanced, and treatment-emergent adverse events were similar for seviprotimut-L and placebo. For the primary intent-to-treat endpoint of RFS, the estimated HR was 0.881 (95% CI: 0.629 to 1.233), with stratified logrank p=0.46. However, estimated HRs were not uniform over the stage randomized strata, with HRs (95% CIs) for stages IIB/IIC, IIIA, IIIB/IIIC of 0.67 (95% CI: 0.37 to 1.19), 0.72 (95% CI: 0.35 to 1.50), and 1.19 (95% CI: 0.72 to 1.97), respectively. In the stage IIB/IIC stratum, the effect on RFS was greatest for patients <60 years old (HR=0.324 (95% CI: 0.121 to 0.864)) and those with ulcerated primary melanomas (HR=0.493 (95% CI: 0.255 to 0.952)).

Conclusions: Seviprotimut-L is very well tolerated. Exploratory efficacy model estimation supports further study in stage IIB/IIC patients, especially younger patients and those with ulcerated melanomas.

Trial registration number: NCT01546571.

Keywords: active; immunotherapy; melanoma; vaccination.

Conflict of interest statement

Competing interests: CLS discloses research funding to his University from Merck, Celldex, and GlaxoSmithKline; research support in kind to his University from Theraclion, 3M, Merck, and Celldex; Scientific Advisory Board role with Immatics (prior), and Curevac; principal investigator role for Polynoma with compensation to his university, related to this manuscript; and patent royalties as co-inventor of peptides for use in cancer vaccines (patents held by the UVA Licensing and Ventures Group). KDL received research funding from Polynoma. JH served on an advisory board for Nektar and BMS in 2020. SNM has received research grants from BMS and from Sorrento Pharma. TB is receiving time and effort support from Genentech for a melanoma prevention study and is the principal investigator for melanoma clinical studies sponsored by Genentech, Amgen, and Replimune. JC serves as consultant/speaker for Amgen, BMS, Merck, Novartis, Pfizer, Roche. SGH serves as an advisor to Incyte. BC has received honoraria from Merck (DSMB member), Clinigen (Ad board), Nektar (Ad Board), research support from Galectin Therapeutics, Clinigen. BMS (to Institution) and AstraZeneca (to Institution). MOB discloses roles on Advisory boards (Merck, BMS, Novartis, EMD Serono, Sanofi, Pfizer, Immunocore, GSK); safety Review Committees (GSK, Adaptimmune), and research funding from Merck and Takara Bio. JL has received research funding to his institution from BMS, Immunocore, Polynoma, Iovance and has participated in advisory boards from Regeneron and Array. DM directly is on speaker’s bureaus for Pfizer, Merck, Astellas, and SeaGen. TS serves on Advisory boards for Immunocore and Castle Biosciences. EH is on the speakers’ bureaus for Amgen and Castle Biosciences. SK is on the speakers’ bureau for Janssen, Pfizer, Roche/Genentech, AstraZeneca. RW is on a Speaker’s bureau for AstraZeneca. ABe has served as an advisor to Cardinal Health and Castle Biosciences. ABa is a consultant/speaker for Regeneron, Castle Biosciences, and receives research funding to her institution from Polynoma, Castle Biosciences, Pellepharm. CM has received grants, ad board and speaker fees from Novartis, BMS, Merck and Pfizer. VG is an investor in Medocity. DB: Research support- Natera; served on advisory boards for Merck, AstraZeneca, Novartis, Eli Lilly, Janssen, Oncocyte; speaker’s bureau-Janssen, Guardant. JJP is a paid consultant for Polynoma.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Recurrence-free survival (RFS) by arm, stage, and age. Kaplan-Meier estimates of RFS are plotted, with analysis results in the legend and risk set and censoring accumulation below the time axis. The designation ‘(cut-off)’ indicates possible data truncation based on designated cut-off date. (A) RFS by arm, stratified by stage, for the intent-to-treat (ITT) data set, (B) RFS by arm and stage for the ITT data set, (C) RFS by arm and age for the ITT data set, (D) RFS by arm and age for Stage IIB/C stratum. P values by logrank test. P value, HR and 95% CI are based on a univariate Cox regression model assuming proportional hazards with treatment, age, and treatment×age as factors, stratified for the randomisation stratification variable of disease stage.

Figure 2

Recurrence-free survival (RFS) by arm, age, and ulceration for stage IIB/IIC stratum. Kaplan-Meier estimates of RFS are plotted for stage IIB/IIC patients (A) by arm and ulceration, and (B) by arm, age and ulceration. Shown in (C) is a forest plot for stage IIB/IIC patients as a function of age, ulceration, and both. In (D) is the Kaplan-Meier estimate for RFS for stage IIB/IIC patients under age 60, by arm and ulceration. P values by logrank test.

Figure 3

Survival effect modification by arm, age, and stage. Kaplan-Meier estimates of overall survival (OS) are plotted (A) for all intent-to-treat (ITT) patients stratified by stage, by arm, (B) for all ITT patients by arm and stage, and (C) for all ITT patients by arm and age. Shown in (D) is a forest plot for all ITT patients by stage and by age. In (E) is the Kaplan-Meier estimate for OS for stage IIB/IIC patients by arm and age. P values by logrank test.