The role of immune checkpoint inhibitors for patients with advanced stage microsatellite stable colorectal cancer and high tumor mutation burden: quantity or quality?

ABSTRACT

Introduction

The US Food and Drug Administration (FDA) approved pembrolizumab for patients with unresectable or metastatic solid tumors with tumor mutational burden (TMB) of ≥ 10 mutations/megabase. However, the clinical implications of this universal cutoff of TMB ≥ 10 for patients with microsatellite stable (MSS) metastatic colorectal cancer (CRC) remain debatable.

Areas covered

In this review, we discuss the tissue agnostic approval of pembrolizumab, its efficacy, and clinical relevance in the management of patients with MSS CRC patients with high TMB (defined as TMB ≥ 10). We also elaborate on molecular subgroups of MSS CRC that influence the immune checkpoint inhibitor (ICI) response for patients with MSS CRC, including pathogenic POLE and POLD1 mutations associated with ultramutated tumors.

Expert opinion

Patients with microsatellite stable CRC with TMB ≥ 10 without POLE and POLD1 mutations may not significantly benefit from immune checkpoint inhibitors therapy. Predetermined cutoff TMB ≥ 10 mutation per MB does not seem to define a universal cutoff for the benefit of disease-agnostic ICI therapy, particularly for patients with MSS CRC. Patients with POLE/POLD1 mutations with MSS CRC represent a unique biological subgroup of MSS CRC with favorable responses to ICI therapy.

KEYWORDS:

• Colorectal cancer
• high tumor mutation burden
• immune checkpoint inhibitors
• microsatellite stable
• immunotherapy

Article highlights

• US Food and Drug Administration approved pembrolizumab for unresectable or metastatic solid tumors with tumor mutational burden-high (TMB-H) with ≥ 10 mutations/megabase (mut/Mb) irrespective of tumor histology.

• Microsatellite instability-high (MSI-H) colorectal cancer (CRC) represents hypermutable biology which is characterized by increased neoantigens and significant response to immune check inhibitors (ICIs).

• Monotherapy with PD-1 ICIs is highly effective in MSI-H CRC. However, their role in patients with microsatellite stable (MMS) CRC remains unclear.

• Molecular characteristics and tumor microenvironments vary with each cancer type, and evidence to date does not support the use of ICIs solely based on TMB of ≥ 10 mut/Mb. In addition, the universal cutoff may underestimate disease biology, defined by molecular characteristics and the tumor microenvironment of each disease.

• POLE/POLD1 mutant CRC represents an ultramutated, highly immunogenic subgroup of MSS CRC that may derive benefit from ICI therapy.

Declaration of Interest

IH Sahin received Advisory Board fees in Seattle Genetics, GSK and Lumanity. A Saeed reports research grants (to their institution) from AstraZeneca, Bristol Myers Squibb, Merck, Clovis, Exelixis, Actuate Therapeutics, Incyte Corporation, Daiichi Sankyo, Five Prime Therapeutics, Amgen, Innovent Biologics, Dragonfly Therapeutics, KAHR Medical, Biontech, and advisory board fees from AstraZeneca, Bristol Myers Squibb, Exelixis, Pfizer, and Daiichi Sankyo. 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 or other relationships to disclose.

Additional information

Funding

This paper was not funded.