Next generation sequencing-based MSI scoring predict benefit in mismatch repair deficient tumors treated with nivolumab: follow-up on NCI-MATCH arm Z1D.

Abstract

Purpose: Mismatch repair deficient (dMMR) tumors have demonstrated favorable responses to immune checkpoint inhibition targeting PD-1. However, more in-depth identification of predictors of response could further refine patient selection for immunotherapy treatment.

Experimental design: We undertook integrated evaluation performed on samples collected from 28 of 42 patients enrolled on the NCI-MATCH arm Z1D trial that evaluated PD-1 inhibition treatment with nivolumab in patients with non-colorectal dMMR tumors. Genomic analyses were performed using next-generation sequencing (NGS), whole exome sequencing, and RNA sequencing and supplemented by multiplex immunofluorescence performed on tissue samples.

Results: In this dMMR population, more extensive alterations of microsatellites as assessed by measures of NGS was associated with clinical benefit and tumor mutational burden. RNA sequencing further revealed associations between clinical benefit and immune infiltration index. Gene sets enriched in patients with clinical benefit included interferon signaling, antigen processing and PI3K-AKT-mTOR signaling, while hedgehog signaling was found to be enriched in subjects lacking clinical benefit.

Conclusions: These genomic data highlight the importance of immune infiltration and antigen presentation in dMMR tumors that respond to immune checkpoint blockade. In addition, they suggest that, even within a dMMR population, NGS based measures of MSI could serve as biomarkers of immunotherapy response.