Next-Generation Sequencing-Based MSI Scoring Predicts Benefit in Mismatch Repair-Deficient Tumors Treated with Nivolumab: Follow-up on NCI-MATCH Arm Z1D

Authors

Jonathan D Schoenfeld
Nilofer S Azad
Jacob Gross
Li Chen
Michael J Overman
Katrina Kao
Latifa Jackson
Donna Brunnquell
Xiangning Bu
Christina Coppola
Ping Guan
Jennifer Lee
David Sims
Rebecca Fuchs
Jason L Weirather
Kathleen L Pfaff
Lauren Gunasti
Srin Ranasinghe
Stanley R Hamilton
Victoria Wang
Peter J O'Dwyer
Catherine J Wu
Scott J Rodig
David R Patton
Lyndsay Harris

Publication Date

2-17-2025

Journal

Clinical Cancer Research

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.

Patients and methods: We undertook integrated evaluation performed on samples collected from 28 of 42 patients enrolled on the NCI-Molecular Analysis for Therapy Choice arm Z1D trial that evaluated PD-1 inhibition treatment with nivolumab in patients with noncolorectal 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 were 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 IFN signaling, antigen processing, and PI3K-AKT-mTOR signaling, whereas 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 microsatellite instability could serve as biomarkers of immunotherapy response.

Keywords

Humans, Nivolumab, Microsatellite Instability, High-Throughput Nucleotide Sequencing, DNA Mismatch Repair, Female, Male, Follow-Up Studies, Immune Checkpoint Inhibitors, Middle Aged, Biomarkers, Tumor, Aged, Neoplasms, Adult, Treatment Outcome

DOI

10.1158/1078-0432.CCR-24-0427

PMID

39670863

PMCID

PMC11831103

PubMedCentral® Posted Date

12-13-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes