Defining the current role of immune checkpoint inhibitors in the treatment of mismatch repair-deficient/microsatellite stability-high colorectal cancer and shedding light on future approaches

ABSTRACT

Introduction: Mismatch repair deficient (MMR-D)/microsatellite instability-high (MSI-H) colorectal cancer (CRC) carries unique biologic features including high tumor mutation burden, increased amount of mutation-associated neoantigen generation, and the presence of marked tumor-infiltrating lymphocytes. Immune checkpoint inhibitor (ICI) therapy has rapidly changed the treatment algorithm of MMR-D/MSI-H CRC.

Areas covered: In this review article, we discuss the recent data regarding the use of ICIs in metastatic MMR-D/MSI-H CRC patients. We also elaborated on potential biomarkers of ICI response and innovative therapeutic approaches that may prevail resistance mechanisms for the treatment of MMR-D/MSI-H colorectal cancer.

Expert opinion: Pembrolizumab was recently granted approval by the FDA as first-line therapy for metastatic MMR-D/MSI-H CRC based on the results of the Keynote 177 study. The combination of nivolumab and ipilimumab will also likely be a choice for the initial therapy of MMR-D/MSI-H CRC in the near future. More therapeutic modalities with novel immunomodulatory agents as well as targeted therapy directed to immune resistance pathways are needed. The novel approaches discussed in this review article will define potential treatment options for the management of MMR-D/MSI-H CRC patients who progress on first-line ICI therapy.

KEYWORDS:

• MSI-H
• MMR-D
• colorectal cancer
• immune checkpoint inhibitor
• biomarkers
• BRAF V600E
• MLH1/PMS2
• MSH2/MSH6
• immunotherapy

Article highlights

• MMR-D/MSI-H colorectal cancer is a heterogeneous disease with distinct molecular subgroups and clinical characteristics.

• Immune checkpoint inhibitor therapy has led to deep and durable responses in metastatic MMR-D/MSI-H colorectal cancer.

• Based on the KEYNOTE 177, pembrolizumab should be considered first-line therapy for metastatic MMR-D/MSI-H colorectal cancer patients.

• Preliminary results of nivolumab in combination with ipilimumab (The CheckMate 142 study) are highly promising as initial therapy, and this combination will also likely move to the first line in the near future.

• Second-line therapy and beyond for MMR-D/MSI-H colorectal cancer is evolving. The development of novel immune checkpoint inhibitors as well as targeting potential resistance mechanisms such as BRAF V600E mutation will define therapeutic choices of future for this subset of colorectal cancer.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

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

Additional information

Funding

The paper was not funded