Checkpoint Inhibitors: Changing Colorectal Cancer Treatment

Immune checkpoint inhibitors (ICIs) have altered the management of several cancers, including a subset of colorectal cancers (CRCs) characterized by deficient mismatch repair (dMMR) and microsatellite instability (MSI).

In a presentation at the Hematology/Oncology Pharmacy Association 2025 Annual Conference in Portland, OR, Darla Quevedo, PharmD, BCOP, who is a Clinical Pharmacy Specialist in medical oncology and hematology at the outpatient setting of the Orlando Health Cancer Institute in Orlando, FL, and Charlotte Martin, PharmD, BCOP, who is also a Clinical Pharmacy Specialist at the Orlando Health Cancer Institute, discussed how checkpoint inhibitors have changed CRC treatment, and offered practical insights on use.¹

CRC remains the third most common cancer in men and women in the United States, excluding skin cancer, accounting for an estimated 53,000 deaths annually, according to the presenters. Five-year survival hovers approximately 74% for regional disease but drops to 15% for metastatic disease.² Department of Veterans Affairs officials note that they diagnose approximately 4000 new CRC cases annually, accounting for approximately 9% of all cancer cases among veterans.^3,4

Approximately 12% to 15% of CRC cases are associated with dMMR/MSI-high (MSI-H) status.⁵ These tumors exhibit an impaired ability to repair DNA replication errors, leading to genomic instability. dMMR tumors invariably present with MSI, although MSI status can also arise from other mechanisms, such as epigenetic silencing of mismatch repair genes.

Chemotherapy in dMMR CRC

dMMR/MSI-high(H) CRCs typically do not respond well to conventional chemotherapy. The FOxTROT trial demonstrated that a subgroup of those patients who were randomly assigned to neoadjuvant FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) had minimal tumor regression and did not reduce recurrence at 2 years in dMMR.⁶ Similarly, in rectal cancer, a separate trial noted disease progression in 29% of dMMR patients receiving neoadjuvant FOLFOX, compared with no progression in mismatch repair–proficient tumors.⁷

These findings underscore the need for alternate strategies, according to the speakers.

Checkpoint Inhibitors in Early-Stage CRC

In early-stage CRC, neoadjuvant checkpoint inhibitor immunotherapy options include single-agent pembrolizumab or combination regimens like nivolumab ± ipilimumab, although adjuvant use of ICIs is not yet standard.

A phase 2 trial of neoadjuvant dostarlimab in stage II/III dMMR rectal cancer showed a 100% complete clinical response rate among 12 patients, allowing all to avoid chemoradiation and surgery.^8,9 Responses were rapid, and the study researchers noted that the adverse events were manageable, primarily limited to rash and fatigue.

In the multicenter basket GARNET trial, researchers demonstrated use of a 500-mg intravenous dose of dostarlimab in 3 weeks for 4 cycles, then 1000 mg intravenously every 6 weeks in patients with dMMR/MSI-high tumors, showing a 44% response rate in patients with CRC and a durable disease control rate at 28 months.¹⁰

In another study that looked at neoadjuvant pembrolizumab across various dMMR/MSI-high solid tumors, including CRC, 82% of patients achieved a significant response, and many avoided surgery altogether.¹¹

Immunotherapy Use for Metastatic dMMR/MSI-High CRC

Checkpoint inhibitors are the cornerstone of treatment for metastatic dMMR/MSI-High CRC. In the CheckMate 142 trial, nivolumab monotherapy yielded a 31% objective response rate (ORR), with 69% disease control at 12 weeks. At a median follow-up of 12 months, overall survival was 73%.¹²

Combination therapy with nivolumab and ipilimumab improved response rates further, according to the speakers. In a cohort where 40% had received ≥3 prior lines of therapy, the ORR was 55%, with 85% 12-month overall survival. Grade 3/4 toxicity occurred in 32% of patients, which is consistent with expectations for combination immunotherapy.¹³

An extension of this data from CheckMate 8HW compared nivolumab/ipilimumab to nivolumab alone. Early data showed an ORR of >70% in the combination arm versus approximately 50% in the monotherapy group. Median progression-free survival (PFS) had not yet been reached for the combination, whereas it was 39 months for nivolumab alone.¹⁴

The KEYNOTE-177 trial demonstrated the superiority of pembrolizumab over chemotherapy in the first-line metastatic setting. Among 304 patients, pembrolizumab achieved an ORR of 43.8% versus 33.1% with chemotherapy. Median PFS was 16.5 months versus 8.2 months, and grade 3/4 toxicities were lower with pembrolizumab (22% vs 66%).¹⁵

Clinical Application

Checkpoint inhibitors offer strong response rates and improved tolerability in dMMR/MSI-high CRC.

Key considerations for oncology healthcare professionals include:

• Testing and Biomarker Evaluation: Ensure that MSI and mismatch repair status are routinely evaluated for all CRC diagnoses
• Therapy Selection: Tailor ICI regimens to disease stage and patient comorbidities. For patients with extensive metastatic disease and high tumor burden, combination therapy may offer faster and deeper responses
• Toxicity Management: Monitor for immune-related adverse events, including dermatitis, colitis, endocrinopathies, and pneumonitis. Early recognition and steroid management are critical*

References

1. Martin C, Quevedo D. New updates integrating checkpoint inhibitors into the management of colorectal cancer. Presented at: Hematology/Oncology Pharmacy Association (HOPA) 2025 Annual Conference. April 9-12, 2025; Portland, OR.
2. National Cancer Institute Surveillance, Epidemiology, and End Results Program. Cancer stat facts: colorectal cancer. Accessed May 19, 2025. https://seer.cancer.gov/statfacts/html/colorect.html
3. Department of Veterans Affairs. VHA 2024 Annual Report: VA Health Care: A Strong Foundation. A Healthy Future. Accessed May 19, 2025. www.va.gov/health/docs/vha-annual-report-2024.pdf
4. Adenusi AO, Obaitan I, Monteiro JFG, et al. Endoscopic and stool-based colorectal cancer screening coverage among US veterans: a survey analysis using 2021 Behavioral Risk Factor Surveillance System (BRFSS) data. Gastrointest Endosc. 2024;2:181-185.
5. Zhang X, Wu T, Cai X, et al. Neoadjuvant immunotherapy for MSI-H/dMMR locally advanced colorectal cancer: new strategies and unveiled opportunities. Front Immunol. 2022;13:795972.
6. Bonneville R, Krook MA, Kautto EA, et al. Landscape of microsatellite instability across 39 cancer types. JCO Precis Oncol. 2017;1:1-15.
7. Morton D, Seymour M, Magill L, et al; for the FOxTROT Collaborative Group. Preoperative chemotherapy for operable colon cancer: mature results of an international randomized controlled trial. J Clin Oncol. 2023;41:1541-1552.
8. Cercek A, Dos Santos Fernandes G, Roxburgh CS, et al. Mismatch repair-deficient rectal cancer and resistance to neoadjuvant chemotherapy. Clin Cancer Res. 2020;26:3271-3279.
9. Cercek A, Lumish M, Sinopoli J, et al. PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer. N Engl J Med. 2022;386:2363-2376.
10. André T, Berton D, Curigliano G, et al. Antitumor activity and safety of dostarlimab monotherapy in patients with mismatch repair deficient solid tumors: a nonrandomized controlled trial. JAMA Netw Open. 2023;6:e2341165.
11. Ludford K, Ho WJ, Thomas JV, et al. Neoadjuvant pembrolizumab in localized microsatellite instability high/deficient mismatch repair solid tumors. J Clin Oncol. 2023;41:2181-2190.
12. Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017;18:1182-1191.
13. Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol. 2018;36:773-779.
14. Andre T, Elez E, Lenz HJ, et al. First results of nivolumab (NIVO) plus ipilimumab (IPI) vs NIVO monotherapy for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) from CheckMate 8HW. J Clin Oncol. 2025;43(4 suppl):Abstract LBA143.
15. André T, Shiu KK, Kim TW, et al; for the KEYNOTE-177 Investigators. Pembrolizumab in microsatellite-instability–high advanced colorectal cancer. N Engl J Med. 2020;383:2207-2218.

*This article was written with assistance from artificial intelligence.