Discussion
AtezoTRIBE, tumor, death, CRC, RAS-mutated, MSS, tumors
TUMOR, INFILTRATION, LIVER METASTASES, INFILTRATE, MUTANT, TUMORS
This study reports clinical and biological response with first-line chemo-immunotherapy for RAS-mutated metastatic CRC. This study reached its primary objective, with 3-month PFS of 90.7%, 6-month PFS of 60% and median PFS of 8.2 months, whereas the expected median PFS for such a population is 5–6 months with FOLFOX alone. This protocol yielded similar results to those observed with a chemotherapy doublet with bevacizumab, which gave around 8 months of PFSIn terms of response rate, our study reports an objective response rate of 63%, comparing favorably with the reported 36% in mutant RAS tumors treated with FOLFOX monotherapy (BECOME study). Our trial yielded one of the best objective response rates in the literature to date for bi-chemotherapy treatmentsMSS CRCs represent 95% of all metastatic CRC and are characterized by low TMB and low immune infiltration compared to MSI CRCTwo clinical trials (REGOMUNE and REGONIVO) suggest that immune checkpoint inhibitors may harbor some features of efficacy in patients with MSS tumors, especially in the absence of liver metastases, which are an immune resistance factorOur study underlines that CTLA-4 expression at the tumor site is associated with better response. Previous reports testing botensilimab plus balstilimab or durvalumab plus tremelimumab or radiotherapy plus nivolumab and ipilimumab in third-line CRCHigh immune infiltrate on transcriptomic analysis, plus a combination of high CD8 and high PD-L1, were associated with outcome in our study. These findings mirror those of the GONO group, which observed in AtezoTRIBE that patients with high Immunoscore yielded a benefit from atezolizumab plus FOLFOXIRINY-ESO1 and telomerase immune response has previously been reported in CRC, with spontaneous response detected in 24% of patients for telomeraseThis study is limited by its small sample size and the absence of a FOLFOX monotherapy control arm. However, the clinical data compared favorably to previous trials of doublet chemotherapy alone. Because of the lack of control group and small sample size, genomic and transcriptomic data must be taken as exploratory, and the predictive versus prognostic nature of our results warrants confirmation in larger randomized trials. Due to the absence of a control group without oxaliplatin, the role of immunogenic cell death has not been directly proven.In summary, we report favorable clinical efficacy with first-line chemo-immunotherapy for unresectable MSS metastatic CRC, with in-depth molecular and immune analyses, providing clues for better selection of patients with MSS metastatic CRC for chemo-immunotherapy, with potentially broad clinical implications.