Immune-Checkpoint Inhibitors for Metastatic Colorectal Cancer: A Systematic Review of Clinical Outcomes

SIMPLE SUMMARY: In 2018, colorectal cancer (CRC) was declared the fourth most deadly cancer worldwide. Unfortunately, a quarter of all patients are diagnosed at late stages, when curative surgery is not possible, rendering systemic therapy and/or best supportive care as the only options. To our knowledge, this is the first systematic review assessing response and survival rates in patients with mCRC treated with immune-checkpoint inhibitors (ICIs). Our study established that ICIs show potentially superior response rates in mCRC patients, though only in those with high microsatellite instability (MSI). Nivolumab + regorafenib was reported to provide encouraging response in low-MSI (MSI-L) patients; however, additional studies using cohort randomization are required. Further studies are required, particularly regarding the mechanism of resistance to ICIs in MSI-L patients. ABSTRACT: Background. Colorectal cancer (CRC) is the fourth most deadly cancer worldwide. Unfortunately, a quarter of the patients are diagnosed at late stages, when surgical options are limited. Targeted therapies, particularly immune-checkpoint inhibitors (ICIs), are the latest addition and have been studied herein regarding their efficacy outcomes. Methods. Clinical studies were identified through the PubMed, Scopus and Cochrane databases. Any trial that evaluated ICIs in patients with metastatic CRC (mCRC) and reported the objective response rate was deemed eligible. Data analysis was performed by employing the random-effects model in STATA v.17. Results. A total of 461 articles were identified; 13 clinical trials were included, encompassing a total cohort of 1209 patients. Our study determined that a single PD-1/PD-L1 checkpoint blockade provides durable clinical response in mCRC patients with high microsatellite instability (MSI-H). The combinatorial therapy of CTLA-4 + PD-1 inhibitors also showed high response rates in pre-treated MSI-H patients. The single-arm REGONIVO trial reported durable clinical response in patients with microsatellite stable (MSS) status. Conclusions. Our study surmises that PD-1/PD-L1 inhibitors as well as combination therapy with CTLA-4 and PD-1 inhibitors show encouraging response rates in mCRC patients, albeit exclusively in patients with cancer that are of MSI-H status. A single study suggests that nivolumab + regorafenib can reach a durable response rate in MSS patients; however, further studies in larger randomized settings are required.