Minimal residual disease by circulating tumor DNA as a biomarker of recurrence free survival in resected high-risk melanoma patients treated with mRNA-4157/V940, a personalized cancer vaccine, and pembrolizumab

Document Type

Abstract

Publication Date

6-2-2023

Keywords

oregon; chiles; genomics

Abstract

Background:The combination of mRNA-4157/V940 and pembrolizumab improved recurrence free survival (RFS) compared to pembrolizumab monotherapy in patients with resected high-risk stage III/IV cutaneous melanoma in the randomized Phase 2 mRNA-4157-P201/KEYNOTE-942 trial (RFS event rate of 22.4% (24/107) versus 40% (20/50); HR = 0.561; 95% CI: 0.309, 1.017). Across multiple cancer types and disease settings, detection of minimal residual disease (MRD) by circulating tumor DNA (ctDNA) assays in plasma identifies patients at higher risk of relapse and progression, and can monitor presence of disease throughout treatment. Herein, we report ctDNA analyses to explore the association between minimal residual disease and the probability of recurrence.Methods:In mRNA-4157-201, baseline tumor core biopsies and matched whole blood were subjected to whole exome sequencing (WES). The personalized amplicon-based NGS assay by Inivata (RaDaR) was used to identify and prioritize up to 48 patient-specific somatic variants to analyze ctDNA in longitudinal plasma samples for MRD detection. This method for ctDNA analysis is distinct from most prior studies in melanoma that report use of ddPCR for single mutations or fixed-gene panels. The association of MRD with RFS was evaluated with Kaplan Meier analyses and assessed with hazard ratio (95% CI) in ctDNApos and ctDNAneg subgroups and across study arms.Results:Of patients enrolled in this study with evaluable ctDNA, 88% (110/125) were ctDNAneg at start of treatment. Significantly longer RFS was observed in patients who were ctDNAneg compared to those with ctDNApos at baseline across study arms (RFS event rate of 20.9% (23/110) versus 80.0% (12/15); HR = 0.150; 95% CI: 0.073, 0.306). Within the mRNA-4157/V940 and pembrolizumab combination arm, significantly longer RFS was observed in patients with ctDNAneg compared to ctDNApos samples (RFS event rate of 10.4% (8/77) versus 76.9% (10/13); HR = 0.087; 95% CI: 0.034, 0.222). This trend was also observed in the pembrolizumab arm (RFS event rate of 45.5% (15/33) versus 100% (2/2); HR = 0.008; 95% CI: 0.001, 0.088) study arm, although the small sample size in pembrolizumab arm (n = 2) limits interpretation.Conclusions:MRD detection by plasma ctDNA assay at the start of adjuvant melanoma treatment is uncommon in mRNA4157-p201 but is associated with shorter RFS. Treatment with the combination of mRNA-4157/V940 and pembrolizumab was associated with prolonged RFS compared to pembrolizumab monotherapy in patients with high-risk resectable melanoma, irrespective of MRD status Additional analyses including assessment of longitudinal ctDNA patterns are ongoing. The association between MRD and mRNA-4157/V940 treatment effect will be further explored in upcoming planned studies. Clinical trial information: NCT03897881.

Clinical Institute

Cancer

Department

Oncology

Comments

Carlino MS, Khattak A, Weber JS, Meniawy T, Sullivan RJ, Taylor MH, Kim KB, McKean M, Faries MB, Cowey CL, Gibney GT, Luke JJ, Thomas SS, Sehgal V, Feldman I, Aanur P, Brown M, Meehan RS, Robert-Tissot C, Long GV. ASCO Annual Meeting; June 2-6; Chicago, IL. 2023: LBA9515.

This document is currently not available here.

PSJH Full Text

Share

COinS