Role of immune checkpoint inhibitors in the treatment of colorectal cancer: focus on nivolumab

ABSTRACT

Introduction: Metastatic colorectal cancer (mCRC) is a challenging disease, whose systemic therapy has traditionally been based on a generalized population of patients, with unsatisfactory clinical outcomes. Immunotherapy has been shown to be efficacious in hypermutated tumors, such as those with microsatellite-instability (MSI-H). Nivolumab, and other immune checkpoint inhibitors (ICI), have recently been evaluated in MSI-H mCRC, with remarkable results.

Areas covered: Focused on nivolumab, we aim to present the rationale for the applicability of ICI in MSI-H CRC, and the results of completed phase I/II studies. Ongoing studies, including randomized clinical trials, and perspectives of immunotherapy in clinical scenarios in CRC will be discussed.

Expert opinion: Phase I and II clinical trials provide strong evidence for the use of nivolumab and other ICI in the systemic therapy of MSI-H mCRC. Regulatory approvals are restricted to subsequent lines of therapy, but preliminary results in treatment-naïve patients are encouraging. The findings for advanced disease and in the pilot phase II study in early-stage colon cancer open a new avenue for the applicability of immunotherapy in neoadjuvant and adjuvant settings, which are currently under investigation. With the exception of POLE-mutated patients, there is little evidence for the use of immunotherapy in MSS patients.

KEYWORDS:

• Anti-PD-1
• anti-PD-L1
• anti-CTLA-4
• colorectal cancer
• immune checkpoint inhibitors
• immunotherapy
• microsatellite instability
• nivolumab
• tumor mutational burden

Article highlights

• Comprehensive molecular characterization of CRC has demonstrated the presence of two main groups of patients, with distinct genomic, epigenomic, and transcriptomic profiles: chromosomal instability (CIN) and microsatellite instability (MSI-H).

• Nivolumab, the most extensively studied immune checkpoint inhibitor (ICI) in metastatic CRC, as well as other ICI, has shown to be efficacious in the MSI-H population, who typically present with high tumor mutational burden (TMB).

• PD-L1 expression and TMB are emerging predictive biomarkers for immunotherapy, but MSI-H is the only biomarker used to select patients for ICI in mCRC.

• Intensive research is currently underway with the intent to identify non-MSI-H patients who may derive benefit from ICI, such as, POLE-mutated patients.

• Promising ongoing clinical trials may extend the use of immunotherapy to adjuvant setting of stage III MSI-H and/or POLE-mutated CRC patients.

• Adoptive T-cell therapies, and strategies to overcome resistance to immunotherapy may benefit a larger population of CRC patients than expected.

Declaration of interest

C Eng has received research grants from Advaxis, Roche, and Forty Seven and has had Speaker’s Bureau Appointments with Roche, Bayer, Sirtex, and Merck. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.