Exploratory biomarkers for oxaliplatin-induced nivolumab responsiveness in metastatic microsatellite-stable colorectal cancer

TL;DR

The study explores how tumor mutations and inflammation levels may predict response to a treatment combining chemotherapy and immunotherapy in a specific type of colorectal cancer.

Contribution

The study identifies TMB ≥9, BRAF-V600E mutation, and low C-reactive protein as potential biomarkers for better treatment outcomes in metastatic colorectal cancer.

Findings

Patients with TMB ≥9 or BRAF-V600E mutation had significantly longer progression-free survival.

Those with TMB ≥9, BRAF-V600E, and normal C-reactive protein levels had even longer survival.

TMB, BRAF status, and systemic inflammation are proposed as practical biomarkers for treatment prediction.

Abstract

The randomised METIMMOX trial evaluated short-course oxaliplatin-based chemotherapy alternating with nivolumab for metastatic microsatellite-stable/mismatch repair-proficient colorectal cancer. In a post hoc analysis, we investigated whether tumour mutations or patients’ systemic inflammation might provide insights into responsiveness to the METIMMOX regimen.

Patients received either oxaliplatin-based chemotherapy (control group) or alternating two cycles each of chemotherapy and nivolumab (experimental group), with progression-free survival (PFS) as the primary endpoint. Tumour biopsies were sequenced with the TruSight Oncology 500 assay.

The median tumour mutational burden (TMB; in mutations/megabase) was 8 (range, 1–13). The experimental-arm patients with TMB ≥9 or BRAF-V600E mutation (n = 17) achieved median PFS of 19.8 months (95% confidence interval, 11.3–28.3), longer (p = 0.0090) than experimental-arm patients with TMB < 9 not BRAF-V600E (n = 19) and control-arm patients with either TMB and BRAF status combination (n = 31). With TMB ≥9 or BRAF-V600E and normal, non-inflammatory level of C-reactive protein when starting nivolumab (n = 11), median PFS was 35.0 months (95% confidence interval, 6.8–63.0; p < 0.0001).

TMB, somatic BRAF status and systemic inflammation should be prospectively investigated as practical biomarkers for predicting potential responsiveness to immune checkpoint inhibitors in metastatic microsatellite-stable/mismatch repair-proficient colorectal cancer.

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