Abstract
Simple SummaryImmune-checkpoint inhibitors (ICI) show modest activity and efficacy in microsatellite stable (MSS) metastatic colorectal cancer (mCRC) patients harbouring a proficient mismatch repair system (pMMR). Recently, two phase 2 trials -AtezoTRIBE and MAYA- have challenged this dogma through the administration of an intense first-line chemotherapy backbone consisting of FOLFOXIRI/bevacizumab in patients unselected for their microsatellite status, and immune priming with temozolomide in chemorefractory pMMR/MSS patients with silencing of O6-methylguanine-DNA methyltransferase (MGMT), respectively, reporting promising results. We here present the founding biological rationale of these two studies and their main findings. At the same time, we stress their strengths and drawbacks and open questions still to be address in future clinical investigations.In metastatic colorectal cancer (mCRC), remarkable advances have been achieved with immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 and CTLA-4, only in a small subset of tumours (4–5%), harbouring a deficient mismatch repair system (dMMR)/microsatellite instability–high (MSI-H) or mutations in the catalytic subunit of polymerase epsilon (POLE). Within this framework, several combination strategies have been investigated to sensitize proficient mismatch repair (pMMR)/microsatellite stable (MSS) mCRC to ICIs, with disappointing results so far. However, at the last ESMO meeting, two phase II trials AtezoTRIBE and MAYA provided promising results in this field. In the comparative AtezoTRIBE trial, the addition of atezolizumab to FOLFOXIRI (5-fluoruracil, oxaliplatin and irinotecan) and bevacizumab led to a significant advantage in terms of progression free survival (PFS) in a population of untreated mCRC patients, not selected according to MMR/MSI status. In the single-arm MAYA trial, immune priming with temozolomide in pMMR/MSS chemo-resistant mCRC patients with silencing of O6-methylguanine-DNA methyltransferase (MGMT) allowed reporting signals of sensitivity to the subsequent therapy with nivolumab and a low dose of ipilimumab in some patients. Here, we discuss the rationale, results, criticisms and research perspectives opened by these two studies.
Highlights
Immune checkpoint inhibitors (ICIs) targeting the programmed cell death 1 (PD1) and its ligand 1 (PD-L1) and the cytotoxic T-lymphocyte antigen-4 (CTLA-4) have revolutionized the treatment and prognosis of several solid and haematological malignancies, including lung, kidney, and urothelial cancers and melanoma and lymphoma [1,2]
The sensitivity to ICIs detected in deficient mismatch repair system (dMMR)/microsatellite instability–high (MSI-H) and polymerase epsilon (POLE) mutated tumours relies on a common hypermutated phenotype that causes the consequent development of neoantigens boosting an immune-inflamed microenvironment, where Cytotoxic T-lymphocytes (CTLs) activity against tumour cells is restrained by immune checkpoint, like PD1/PD-L1 and CTLA-4/B7 axes, and may be released by ICIs [17,18]
The majority of metastatic colorectal cancer (mCRC) patients, characterized by a proficient mismatch repair system/microsatellite stable and POLE integrity (95%), has an immune-desert or immune-excluded microenvironment, resulting in a blunted immune activation of tumour microenvironment that causes the futility of ICIs in these patients [19]
Summary
Immune checkpoint inhibitors (ICIs) targeting the programmed cell death 1 (PD1) and its ligand 1 (PD-L1) and the cytotoxic T-lymphocyte antigen-4 (CTLA-4) have revolutionized the treatment and prognosis of several solid and haematological malignancies, including lung, kidney, and urothelial cancers and melanoma and lymphoma [1,2]. The majority of mCRC patients, characterized by a proficient mismatch repair system/microsatellite stable (pMMR/MSS) and POLE integrity (95%), has an immune-desert or immune-excluded (or “cold”) microenvironment, resulting in a blunted immune activation of tumour microenvironment that causes the futility of ICIs in these patients [19] To this regard, in chemorefractory pMMR/MSS mCRC patients, Le et al and Chen et al showed a lack of efficacy of the anti-PD1 pembrolizumab and a modest clinical benefit of the anti-PD-L1 durvalumab plus the anti-CTLA-4 tremelimumab, reserved only to patients with a tumour mutational burden (TMB) more than 28 mut/Mb on circulating tumour DNA, respectively [4,20]. At the last ESMO meeting, two phase II studies named AtezoTRIBE and MAYA, assessing combinations of ICIs with chemotherapy, have rekindled hope for the use of immunotherapy in pMMR/MSS mCRC patients, representing a major breakthrough and a promising ground for future investigations in this setting [21,22]
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