In the past decade, immunotherapy has been incorporated into the standard of care for many malignancies. Agents have shown efficacy in malignant melanoma, kidney cancer, and non–small cell lung cancer, and investigators are examining the efficacy of checkpoint inhibitors in less immunogenic tumors such as colon cancer, particularly in tumors with high microsatellite instability (MSI-H) and deficient mismatch repair (dMMR) genes.

The DNA MMR genes MLH1, MSH2, MSH6, and PMS2 are involved in correcting errors that occur in DNA replication. If these genes are deficient, the cells are unable to correct errors and they accumulate mutations that ultimately lead to malignant potential. Deficiency in these MMR genes is MSI or dMMR, and tumors with heavily mutated MMR genes are identified as MSI-H. Testing for MSI can be done by immunohistochemistry that stains for tumor expression, or polymerase chain reaction alone or within a next-generation sequencing panel.

MSI/dMMR mutations can be somatic or germline mutations and testing for them has been part of the standard of care for patients with colon cancer since around 2013.

The genes with germline mutations are present in familial colon cancer syndromes such as hereditary nonpolyposis colorectal cancer, or Lynch syndrome, which makes up approximately 2% to 4 % of all colon cancer diagnoses. Therefore, if MSI/dMMR is detected, it has implications for the patient’s treatment and prognosis as well as for the patient’s family members, who may have the same mutations.

Patients with MSI-H/dMMR colon cancer typically present with lower-stage disease and have a better prognosis. The availability of mutational status at diagnosis helps to determine if adjuvant therapy would benefit patients with stage II colon cancer. If a patient presents with stage II MSI-H colon cancer, the prognosis is better and clinicians typically do not recommend adjuvant therapy. Alternatively, patients with stage II microsatellite stable colon cancer have a less favorable prognosis and, in certain cases, clinicians recommend adjuvant treatment with a f luorouracil (5-FU)–based therapy.

Until recently, MSI-H/dMMR metastatic colon cancer was treated with standard cytotoxic 5-FU–based chemotherapy plus VEGF or EGFR inhibitors depending on the tumor mutational status. In 2017, data from the CheckMate 142 trial (NCT02060188) showed that the anti–PD-1 agent nivolumab (Opdivo) alone or nivolumab plus the anti–CTLA-4 agent ipilimumab (Yervoy) could be used as a second-line therapy in patients with metastatic colon cancer not believed to be candidates for intensive chemotherapy and who had not received prior immunotherapy agents, and whose cancer was MSI-H.

Results from the phase 2 study demonstrated an objective response rate (ORR) of 60%, a 12-month progression-free survival (PFS) rate of 77%, and an overall survival (OS) rate of 83% with the combination of nivolumab and ipilimumab.

 In addition, results from KEYNOTE-164 (NCT02460198) showed the anti–PD-1 agent pembrolizumab (Keytruda) to be an effective subsequent therapy in metastatic MSI-H/dMMR colon cancer. The ORR was 33%, and the 12-month OS rate was 76% for patients who had received more than 1 prior line of therapy.

Neither of these studies compared immunotherapy with standard of care. Immunotherapy did not show efficacy in patients with metastatic colon cancer that was MSI-low or with proficient MMR genes.

Until this year, there were minimal data to support immune checkpoint inhibitors as first-line therapy for patients with MSI-H/dMMR metastatic colon cancer. KEYNOTE-177 (NCT02563002) was a multicenter, open label, randomized control trial that evaluated pembrolizumab versus standard of care with 5-FU–based therapy plus bevacizumab (Avastin) or cetuximab (Erbitux) for metastatic MSI-H/dMMR colon cancer. The study findings showed a PFS of 55% with pembrolizumab versus 37% with chemotherapy at 12 months, and 48% versus 19%, respectively, at 24 months.

Investigators did not report OS as the study is ongoing; however, 83% of patients who received pembrolizumab continued to show response to therapy at 24 months. Patients tolerated pembrolizumab better than chemotherapy, in addition to its being more efficacious.

 On June 29, 2020, the FDA approved pembrolizumab for first-line therapy for patients with metastatic MSI-H/dMMR colon cancer.

The MSI-H/dMMR subset of patients with colon cancer is a special population that requires a nuanced approach to determine therapy. Immunotherapy with checkpoint inhibitors has a role in the treatment of these patients, specifically in those with metastatic disease. However, given that MSI-H/dMMR colon cancer has a unique tumor biology, immunotherapy may have a role in local disease as well. Studies are evaluating the efficacy of immunotherapy in both the adjuvant and neoadjuvant settings, as well as the efficacy of immunotherapy plus chemotherapy in this patient population. As investigators gather more data, it is likely that the role of immunotherapy will continue to extend into the other stages of colon cancer.

NCCN. Clinical Practice Guidelines in Oncology. Colon cancer: NCCN evidence blocks, version 4.2020. Accessed November 6, 2020. https://www.nccn.org/professionals/physician_gls/pdf/colon_blocks.pdf

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Ganesh K, Stadler ZK, Cercek A, et al. Immunotherapy in colorectal cancer: rationale, challenges and potential. 

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Lonardi S, Andre T, Wong KYM, et al. Combination of nivolumab (nivo) + ipilimumab (ipi) in the treatment of patients (pts) with deficient DNA mismatch repair (dMMR)/high microsatellite instability (MSI-H) metastatic colorectal cancer (mCRC): CheckMate 142 study. 

. 2017;28(suppl 6):VI3. doi:10.1093/annonc/mdx422.001

Lenz HJ, Lonardi S, Zagonel V, et al. Nivolumab plus low-dose ipilimumab as first-line therapy in microsatellite instability-high/DNA mismatch repair deficient metastatic colorectal cancer: clinical update. 

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Lenz HJJ, Van Cutsem E, Limon ML, et al. Durable clinical benefit with nivolumab (NIVO) plus low-dose ipilimumab (IPI) as first-line therapy in microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). 

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Le DT, Kim TW, Van Cutsem E, et al. Phase II open-label study of pembrolizumab in treatment-refractory, microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: KEYNOTE-164. 

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Andre T, Shiu KK, Kim TW, et al. Pembrolizumab vs chemotherapy for microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: the phase 3 KEYNOTE-177 study. 

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FDA approves pembrolizumab for first-line treatment of MSI-H/dMMR colorectal cancer. FDA. Updated June 30, 2020. Accessed November 6, 2020. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-first-line-treatment-msi-hdmmr-colorectal-cancer

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December 14, 2020 - Immunotherapy agents have shown efficacy in malignant melanoma, kidney cancer, and non–small cell lung cancer, and investigators are examining the efficacy of checkpoint inhibitors in less immunogenic tumors such as colon cancer, particularly in tumors with high microsatellite instability and deficient mismatch repair genes.

Candice Schwartz, MD

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