Treatment of dMMR Metastatic Colorectal Cancer in 2025

Authors

  • Renata D’Alpino Peixoto, MD, PhD B.C. Cancer Agency, Vancouver, B.C.
  • Thiago Miranda do Amaral, MD B.C. Cancer Agency, Vancouver, B.C.

DOI:

https://doi.org/10.58931/cot.2025.2340

Abstract

Deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC), accounting for approximately 4–5% of cases, represents a distinct molecular subgroup with unique therapeutic implications. These malignancies are characterized by a high mutational burden and increased immune cell infiltration, making them particularly responsive to immune checkpoint inhibitors (ICI). Conversely, this subgroup tends to be less sensitive to traditional chemotherapy.

Author Biographies

Renata D’Alpino Peixoto, MD, PhD, B.C. Cancer Agency, Vancouver, B.C.

Dr. Peixoto is a Clinical Assistant Professor at the University of British Columbia and a medical oncologist at BC Cancer, Vancouver Centre, specializing in gastrointestinal cancers. She completed her PhD in Oncology Universidade Nove de Julho, focusing on pancreatic cancer. She received her medical degree at Faculdade de Ciencias Medicas da Santa Casa de Sao Paulo in 2006, completed her Internal Medicine at Faculdade de Medicina da Universidade de Sao Paulo and Medical Oncology Residency at Hospital Sirio Libanes, Sao Paulo, Brazil. She subsequently undertook a Gastrointestinal Oncology fellowship at BC Cancer‑Vancouver from 2012 to 2014. Her research interests include molecular studies, outcomes-based research, and clinical trials in gastrointestinal cancers.

Thiago Miranda do Amaral, MD, B.C. Cancer Agency, Vancouver, B.C.

Dr. Thiago Miranda do Amaral completed his residency in Medical Oncology at the Superior School of Health Sciences of Brasília and holds a master’s degree from the Instituto Sírio-Libanês de Ensino e Pesquisa. He is currently a clinical-research Fellow in Gastrointestinal Oncology at BC Cancer, Vancouver.

References

Venderbosch S, Nagtegaal ID, Maughan TS, Smith CG, Cheadle JP, Fisher D, et al. Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: A Pooled Analysis of the CAIRO, CAIRO2, COIN, and FOCUS studies. Clin Cancer Res. 2014;20(20):5322–30.

Llosa NJ, Cruise M, Tam A, Wicks EC, Hechenbleikner EM, Taube JM, et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov. 2015;5(1):43–51.

Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. 2003;349(3):247–57.

Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, et al. Phase I study of single-agent anti–programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28(19):3167–75.

Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–20.

André T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, et al. Pembrolizumab in microsatellite-instability–high advanced colorectal cancer. N Engl J Med. 2020;383(23):2207–18.

Lenz HJ, Van Cutsem E, Luisa Limon M, Wong KYM, Hendlisz A, Aglietta M, et al. First-line nivolumab plus low-dose ipilimumab for microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: the Phase II CheckMate 142 study. J Clin Oncol. 2022;40(2):161–70.

Le DT, Kim TW, Van Cutsem E, Geva R, Jäger D, Hara H, et al. Phase II open-label study of pembrolizumab in treatment-refractory, microsatellite instability–high/mismatch repair–deficient metastatic colorectal cancer: KEYNOTE-164. J Clin Oncol. 2020;38(1):11–9.

André T, Elez E, Lenz HJ, Jensen LH, Touchefeu Y, Van Cutsem E, et al. Nivolumab plus ipilimumab versus nivolumab in microsatellite instability-high metastatic colorectal cancer (CheckMate 8HW): a randomised, open-label, phase 3 trial. Lancet. 2025;405(10476):383–95.

Overman MJ, McDermott R, Leach JL, Lonardi S, Lenz HJ, Morse MA, 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(9):1182–91.

Overman MJ, Lonardi S, Wong KYM, Lenz HJ, Gelsomino F, Aglietta M, 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(8):773–9.

Diaz LA, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, et al. Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study. Lancet Oncol. 2022;23(5):659–70.

Overman MJ, Yothers G, Jacobs SA, Sanoff HK, Cohen DJ, Guthrie KA, et al. Colorectal cancer metastatic dMMR immuno-therapy (COMMIT) study: A randomized phase III study of atezolizumab (atezo) monotherapy versus mFOLFOX6/bevacizumab/atezo in the first-line treatment of patients (pts) with deficient DNA mismatch repair (dMMR) or . J Clin Oncol. 2024;42(3_suppl):TPS231–TPS231.

André T, Elez E, Van Cutsem E, Jensen LH, Bennouna J, Mendez G, et al. Nivolumab plus ipilimumab in microsatellite-instability–high metastatic colorectal cancer. N Engl J Med. 2024;391(21):2014–26.

André T, Elez E, Lenz HJ, Jensen LH, Touchefeu Y, Van Cutsem E, et al. Nivolumab plus ipilimumab versus nivolumab in microsatellite instability-high metastatic colorectal cancer (CheckMate 8HW): a randomised, open-label, phase 3 trial. Lancet. 2025;405(10476):383–95.

Margalit O, Stemmer A, Chapin WJ, Shacham-Shmueli E, Kopetz S, Andre T, et al. Duration of immunotherapy in dMMR/MSI-H metastatic colorectal cancer patients. Eur J Cancer. 2024;212:114336.

Kopetz S, Yoshino T, Van Cutsem E, Eng C, Kim TW, Wasan HS, et al. Encorafenib, cetuximab and chemotherapy in BRAF-mutant colorectal cancer: a randomized phase 3 trial. Nat Med. 2025;31(3):901–8.

Tabernero J, Grothey A, Van Cutsem E, Yaeger R, Wasan H, Yoshino T, et al. Encorafenib plus cetuximab as a new standard of care for previously treated BRAF V600E–mutant metastatic colorectal cancer: updated survival results and subgroup analyses from the BEACON study. J Clin Oncol. 2021;39(4):273–84.

Hamre TR, Stougaard JK, Havelund BM, Jensen LH, Hansen TF. Re‐exposure to immunotherapy in metastatic colon cancer: A case report. Clin Case Reports. 2021;9(6):e04349.

Das S, Allen A, Berlin J. Immunotherapy after immunotherapy: response rescue in a patient with microsatellite instability-high colorectal cancer post-pembrolizumab. Clin Colorectal Cancer. 2020;19(2):137–40.

Cohen R, Hain E, Buhard O, Guilloux A, Bardier A, Kaci R, et al. Association of primary resistance to immune checkpoint inhibitors in metastatic colorectal cancer with misdiagnosis of microsatellite instability or mismatch repair deficiency status. JAMA Oncol. 2019;5(4):551.

Bever KM, Durham JN, Qi H, Azad NS, Laheru D, Fisher GA, et al. 10-year follow up of a phase 2 clinical trial of pembrolizumab (pembro) in microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) advanced solid tumors. J Clin Oncol. 2025;43(16_suppl):4019–4019.

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Published

2025-11-05

How to Cite

Peixoto, R. D., & Miranda do Amaral, T. (2025). Treatment of dMMR Metastatic Colorectal Cancer in 2025. Canadian Oncology Today, 2(3), 6–11. https://doi.org/10.58931/cot.2025.2340

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Volume 2, Issue 3, Fall 2025

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Articles

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