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

Dmitrii Shek, Liia Akhuba, Matteo S Carlino, Adnan Nagrial, Tania Moujaber, Scott A Read, Bo Gao, Golo Ahlenstiel, Dmitrii Shek, Liia Akhuba, Matteo S Carlino, Adnan Nagrial, Tania Moujaber, Scott A Read, Bo Gao, Golo Ahlenstiel

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.

Keywords: atezolizumab; colorectal cancer; immune-checkpoint inhibitors; ipilimumab; nivolumab; pembrolizumab; targeted therapy.

Conflict of interest statement

All authors declare that there are no competing interests that could have inappropriately influenced results of this study.

Figures

Figure 1
Figure 1
Colorectal cancer stages according to the American Joint Committee on Cancer (AJCC), 8th edition [8]. TNM staging is based on the size of the tumor, growth into lymph nodes and distant metastases to organs and/or tissues. Relative survival rate is an epidemiological characteristic comparing people with the specific histological type and stage of cancer to the overall population in a specific area/region of our country. 1-, 3- and 5-year relative survival rates reduce drastically as CRC progresses from stage 0 to 4.
Figure 2
Figure 2
Molecular mechanisms of targeted drugs approved by the Food and Drug Administration for the treatment of metastatic colorectal cancer. (1) Anti-EGFR (epidermal growth factor receptor) monoclonal antibodies (mAbs) cetuximab and panitumumab; (2) encorafenib, an inhibitor of the Raf protein as part of the MAPK/ERK signaling pathway; (3) VEGF-A (vascular endothelial growth factor-A) inhibitors aflibercept and bevacizumab; (4) VEGF receptor inhibitors regorafenib and ramucirumab; (5) anti-PD-1 (programmed cell death-1) mAbs nivolumab and pembrolizumab and anti-PD-L1 (programmed cell death ligand 1) mAbs atezolizumab, durvalumab and avelumab; (6) anti-CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) mAb ipilimumab. Current targeted therapies inhibit three major processes crucial for cancer growth: unrestricted proliferation, neo-angiogenesis and suppression of T cell immune responses.
Figure 3
Figure 3
PRISMA flow chart of the systematic review.
Figure 4
Figure 4
Forest plot visualizing the objective response rate across selected studies. The cumulative response rate is estimated to be 21.46% with non-significant differences in weight distribution across selected studies and study heterogeneity of 48.38% (deemed as moderate).

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