Immunotherapy in colorectal cancer: an unmet need deserving of change

The efficacy of immunotherapy in colorectal cancer is currently restricted to patients with metastatic colorectal cancer presenting deficient mismatch repair (dMMR) or microsatellite instability (MSI). So far, neither immunotherapy agents as monotherapy nor immunotherapy-based combinations have shown benefit for metastatic colorectal cancer with proficient mismatch repair (pMMR) or microsatellite stability (MSS), which are mostly immunologically cold. 1 Ganesh K Stadler ZK Cercek A et al. Immunotherapy in colorectal cancer: rationale, challenges and potential. Nat Rev Gastroenterol Hepatol. 2019; 16: 361-375 Crossref PubMed Scopus (480) Google Scholar However, the immune landscape of colorectal cancer is complex and heterogenous, and the development of these treatment strategies must consider, not only the histological context, but also its potential distinctive features. 2 Guinney J Dienstmann R Wang X et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015; 21: 1350-1356 Crossref PubMed Scopus (2403) Google Scholar In The Lancet Oncology, Carlotta Antoniotti and colleagues 3 Antoniotti C Rossini D Pietrantonio F et al. Upfront FOLFOXIRI plus bevacizumab with or without atezolizumab in the treatment of patients with metastatic colorectal cancer (AtezoTRIBE): a multicentre, open-label, randomised, controlled, phase 2 trial. Lancet Oncol. 2022; (published online May 27.)https://doi.org/10.1016/S1470-2045(22)00274-1 Summary Full Text Full Text PDF PubMed Google Scholar report the results of the addition of atezolizumab to front-line FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab (the atezolizumab group) compared with FOLFOXIRI plus bevacizumab (the control group) in patients with metastatic colorectal cancer from the phase 2 AtezoTRIBE trial, irrespective of tumour microsatellite status. The superiority of FOLFOXIRI plus bevacizumab over FOLFIRI (leucovorin, fluorouracil, and irinotecan) plus bevacizumab as front-line treatment of metastatic colorectal cancer was previously demonstrated in the phase 3 TRIBE trial. Drawing from this rationale, in this multicentre, academic study, the investigators raised the question of whether the restoration of the anticancer immunity through inhibition of the PD-1–PD-L1 axis enhances efficacy of an upfront intensified chemotherapy regimen. The underlying hypothesis was that chemotherapy can induce tumour cells to release more neoantigens, leading to immunogenic cell death and activation of CD8 T lymphocytes, while bevacizumab-mediated vasculature normalisation upon VEGF or VEGFR blockade promotes increased tumour-infiltrating lymphocytes and activation of effector immune cells. 4 Kanterman J Sade-Feldman M Biton M et al. Adverse immunoregulatory effects of 5FU and CPT11 chemotherapy on myeloid-derived suppressor cells and colorectal cancer outcomes. Cancer Res. 2014; 74: 6022-6035 Crossref PubMed Scopus (113) Google Scholar , 5 Terme M Pernot S Marcheteau E et al. VEGFA–VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. Cancer Res. 2013; 73: 539-549 Crossref PubMed Scopus (413) Google Scholar Given that no significant benefit has been derived from the combination of immunotherapy with non-intensified regimens, 6 Grothey A Tabernero J Arnold D et al. Fluoropyrimidine (FP) + bevacizumab (BEV) + atezolizumab vs FP/BEV in BRAFwt metastatic colorectal cancer (mCRC): findings from Cohort 2 of MODUL—a multicentre, randomized trial of biomarker-driven maintenance treatment following first-line induction therapy. Ann Oncol. 2018; 29: viii714-viii715 Google Scholar , 7 Lenz HJ Parikh AR Spigel DR et al. Nivolumab (NIVO) + 5-fluorouracil/leucovorin/oxaliplatin (mFOLFOX6)/bevacizumab (BEV) versus mFOLFOX6/BEV for first-line (1L) treatment of metastatic colorectal cancer (mCRC): phase 2 results from CheckMate 9X8. Proc Am Soc Clin Oncol. 2022; 40 (abstr).: 8 Crossref PubMed Google Scholar the use of FOLFOXIRI is a rational partner in an untreated RAS-mutated enriched metastatic colorectal cancer population. Upfront FOLFOXIRI plus bevacizumab with or without atezolizumab in the treatment of patients with metastatic colorectal cancer (AtezoTRIBE): a multicentre, open-label, randomised, controlled, phase 2 trialThe addition of atezolizumab to first-line FOLFOXIRI plus bevacizumab is safe and improved progression-free survival in patients with previously untreated metastatic colorectal cancer. Full-Text PDF