Tumor mutational burden (TMB), BRAF status, and C-reactive protein (CRP) predict response to first-line alternating oxaliplatin-based chemotherapy and nivolumab in metastatic microsatellite-stable (MSS) colorectal cancer (CRC)

BackgroundThe randomized METIMMOX trial evaluated short-course oxaliplatin-based chemotherapy (FLOX) alternating with nivolumab for previously untreated, unresectable abdominal metastases from MSS-CRC. A subgroup of patients assigned to this experimental treatment had remarkably extended progression-free survival (PFS) compared to the control-group patients given standard FLOX chemotherapy with median PFS 9.3 months. We explored if tumor mutations or patients’ systemic inflammation might provide insights into responsiveness to the METIMMOX regimen.MethodsPatients were randomly assigned to the control group of FLOX (oxaliplatin, 5-fluorouracil, folinic acid) Q2W or the experimental group of alternating 2 cycles each of FLOX Q2W and nivolumab Q2W, with prespecified break periods. Radiologic response assessment was done every 8 weeks with PFS as the primary endpoint. Tumor biopsies were sequenced with the TruSight Oncology 500 assay to identify driver mutations and calculate TMB (in mutations/megabase). CRP (in mg/L) was analyzed at every study visit.ResultsSequencing data were acquired from 34 experimental-group patients with median PFS 9.9 months (min 1.9, max 41.6). Median TMB was 8.0 (min 0.8, max 12.2). Four cases were BRAF-V600E. The median TMB value or BRAF status distinguished between patient groups (p = 0.0003, log-rank test) with median PFS 19.8 months (95% CI 11.3-28.3; TMB>8.0/BRAF-V600E, n = 17) and median PFS 5.8 months (95% CI 1.4-10.2; TMB<or=8.0/BRAF-nonV600E, n = 17). The initial 2 FLOX cycles lowered patients’ CRP (p = 0.032, Mann-Whitney U-test) from baseline median 13 (min 0.7, max 78) to median 5.1 (min 0.6, max 46). The TMB>8.0/BRAF-V600E cases with CRP<5.0 when starting nivolumab (n = 11) attained median PFS 34.9 months (95% CI 6.8-63.0).ConclusionsTMB>8.0 or BRAF-V600E, with the additional inhibitory effect of the initial chemotherapy on systemic inflammation, was associated with extended PFS for patients with abdominal metastases from MSS-CRC given first-line alternating oxaliplatin-based chemotherapy and nivolumab.Clinical trial identificationNCT03388190.Legal entity responsible for the studyAkershus University Hospital.FundingNorwegian Cancer Society.DisclosureA.H. Ree: Financial Interests, Institutional, Research Funding: Bristol-Myers Squibb; Financial Interests, Personal, Expert Testimony: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Board: Takeda. H.M. Hamre: Financial Interests, Personal, Expert Testimony: Bayer, Roche; Financial Interests, Personal, Advisory Board: AstraZeneca, Eisai, InCyte. C. Kersten: Financial Interests, Personal, Advisory Board: AstraZeneca, Roche. H. Sorbye: Financial Interests, Personal, Expert Testimony: Ipsen, Pierre Fabre, Daiichi Sankyo, SAM Nordic; Financial Interests, Personal, Advisory Board: AAA Pharma. S. Meltzer: Financial Interests, Personal, Advisory Board: GSK. All other authors have declared no conflicts of interest.