Immune-Checkpoint Inhibitors (ICIs) in Metastatic Colorectal Cancer (mCRC) Patients beyond Microsatellite Instability

SIMPLE SUMMARY: The manuscript reports the most recent literature regarding treatment with ICIs in mCRC, focusing on dMMR/MSI-H and POLE-mutated tumors, discussing current knowledge and potential hypotheses about molecular and/or clinical features related to intrinsic and secondary resistance to ICIs. Starting from the results of pivotal clinical trials and based on remarkable findings of CheckMate-142 and Keynote-177 trials, our manuscript provides a complete overview of the treatment with ICIs in dMMR/MSI-H metastatic colorectal cancer (mCRC), also putting an emphasis on current challenges as the optimal duration of ICIs therapy, the role of curative surgery on metastases, and we discuss mechanisms of resistance to anti-PD1 therapy in more detail. Interesting data investigating possible predictive biomarkers (e.g., TMB, PD-L1 expression, and TILs) of ICIs benefit in dMMR/MSI-H mCRC and promising ICI-based combinations able to enlarge their therapeutic efficacy are discussed. ABSTRACT: Immune-checkpoint inhibitors (ICIs) showed impressive results in terms of activity and efficacy in metastatic colorectal cancer (mCRC) patients bearing tumors with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H). Despite that microsatellite status is the major predictive biomarker for the efficacy of ICIs, a proportion of dMMR/MSI-H mCRC tumors do not achieve benefit from immunotherapy due to the primary resistance. Deeper knowledge of biological mechanisms regulating dMMR/MSI-H CRC tumors and immune response may be useful to find new predictive biomarkers of ICIs benefit and tailor the use of immunotherapy even in dMMR/MSI-H mCRC patients. Moreover, several issues are still open, such as the secondary resection of metastases and the optimal duration of ICIs therapy in dMMR/MSI-H mCRC patients. Looking beyond microsatellite status, in a future perspective, several tools (i.e., Tumor Mutational Burden and PD-L1 expression) have been investigated to clarify their possible role as predictive biomarkers. Furthermore, a small subgroup of pMMR/MSS CRC tumors with a POLE mutation of the proofreading domain is characterized by hypermutated phenotype and might derive benefit from immune checkpoint inhibition. In the present work, we aim to review the most recent literature regarding treatment with ICIs in mCRC, focusing on dMMR/MSI-H and special subgroups of CRC patients. Hence, we summarize possible future targets and the most promising predictive biomarkers.