Pembrolizumab in unresectable or metastatic MSI-high colorectal cancer: safety and efficacy

ABSTRACT

Introduction

Microsatellite instability-high (MSI-H) colorectal cancer (CRC) represents a unique subset of CRC characterized by elevated neoantigen expression and a high degree of intraepithelial T-cell infiltrate. These characteristics make MSI-H tumors particularly susceptible to immune checkpoint inhibitors (ICIs) such as pembrolizumab which inhibit the negative regulation of cytotoxic T-cells and promote T-cell mediated anti-tumor activity.

Areas covered

We discuss the drug development of pembrolizumab including the seminal studies which enabled the drug to garner FDA approvals in the refractory and first-line settings for patients with MSI-H CRC, the pharmacokinetic & pharmacodynamic profile of the agent, and the adverse event profile of the ICI. We also discuss unmet needs in the arena of ICIs including strategies to overcome tumor resistance and to increase the applicability of the agents to a broader population of CRC patients.

Expert opinion

Despite the anti-tumor activity of pembrolizumab in patients with MSI-H CRC, 30–35% of patients fail to derive any benefit. Ongoing research efforts are seeking to identify ICI combinations, which can overcome CRC resistance to pembrolizumab, move ICIs into the treatment paradigm for patients with localized MSI-H CRC and enable ICIs to become meaningful treatment options for patients with microsatellite stable CRC.

KEYWORDS:

• Microsatellite instability-high colorectal cancer
• immune checkpoint inhibitor
• programmed death-ligand 1
• pembrolizumab
• tumor mutational burden

Article highlights

• Pembrolizumab was recently approved in the first-line setting for patients with MSI-H metastatic CRC, adding to its original approval for patients with refractory MSI-H metastatic CRC.

• Though pembrolizumab was initially trialed at different dosing schedules, the FDA approved dosing schedules for patients with MSI-H CRC are 200 mg every 3 weeks or 400 mg every 6 weeks.

• The half-life of the agent is between 14 and 27 days, with steady state reached after close to 5 months.

• Some of the main competitor compounds for pembrolizumab in patients with MSI-H CRC include nivolumab, nivolumab plus ipilimumab and atezolizumab.

• Even in patients with MSI-H colorectal cancer treated with pembrolizumab, 30–35% of patients develop progressive disease, creating a need to identify resistance mechanisms to the ICI.

• Though primary resistance to ICIs may be difficult to overcome, strategies to overcome acquired resistance include combining ICIs with other inhibitory checkpoint inhibitors (e.g. LAG3, CTLA-4), stimulatory checkpoint agonist molecules (e.g. OX40, 4-1BB) or other novel agents (e.g. DNA damage repair inhibiting drugs, antibody-drug conjugates).

• The adverse event profile of pembrolizumab is favorable compared with chemotherapy and similar with that of other checkpoint inhibitors such as nivolumab or atezolizumab.

• The most common TRAEs (all grades) experienced by patients with MSI-H CRC treated with pembrolizumab include rash, fatigue, diarrhea, thyroid abnormalities and arthritis.

• Patients with MSI-H CRC represent only 5% of all patients with metastatic CRC, leaving most patients ineligible to receive ICIs. One of the primary efforts to increase the number of patients who are exposed to the drugs is to move ICIs into the localized setting where 12–15% of patients with CRC demonstrate MSI-H disease.

Information resources

The most relevant articles pertaining to this topic arise from the following journals: The New England Journal of Medicine, Clinical Cancer Research, Science, Journal of Clinical Oncology, The Oncologist and the Journal for ImmunoTherapy of Cancer. The specific publications in each journal are starred as ** (of major importance) or * (or importance) in the references below. Other pertinent sources include the following websites:

https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-first-line-treatment-msi-hdmmr-colorectal-cancer, https://www.ema.europa.eu/en/medicines/human/EPAR/keytruda, https://ascopost.com/news/december-2019/pembrolizumab-in-previously-treated-metastatic-msi-hdmmr-colorectal-cancer/

https://ascopost.com/issues/june-10-2020/pembrolizumab-doubles-progression-free-survival-in-msi-hdmmr-metastatic-colorectal-cancer/#:~:text=Lung%20Cancer-,Pembrolizumab%20Doubles%20Progression%2DFree%20Survival%20in%20MSI,H%2FdMMR%20Metastatic%20Colorectal%20Cancer&text=For%20the%20first%20time%2C%20upfront,patients%20with%20metastatic%20colorectal%20cancer.

Diclosure statement

S Das has previously served on the Speakers’ Bureau for Ipsen, receives consulting fees from Cancer Expert Now and has received grant funding from Exelixis. 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 received no funding.