Colorectal cancer is cancer that develops in the colon or the rectum, which are part of the body’s digestive or gastrointestinal system. Colorectal cancer is the third most common form of cancer, with a worldwide incidence of 1.4 million cases, and is the fourth most common cause of cancer deaths. In the U.S., CRC is the second leading cause of cancer-related deaths among men and women combined, with more than 135,000 individuals expected to be diagnosed annually.
Microsatellite instability (MSI) is the condition of genetic hypermutability or a predisposition to mutations in cells that results from the bodies impaired DNA mismatch repair (MMR) mechanism. DNA MMR is an essential function and the way the body naturally corrects errors that spontaneously occur during cell division associated DNA replication.
DNA mismatch repair deficiency (dMMR) occurs when the proteins that repair mismatch errors in DNA replication are missing or non-functional, which leads to MSI-H tumors in certain types of cancer, including CRC. Approximately 15% of CRC patients and 5% of metastatic CRC patients have dMMR or MSI-H biomarkers. Patients with dMMR or MSI-H CRC are less likely to benefit from conventional chemotherapy but respond to treatment with immunotherapy. Routine testing to determine dMMR or MSI-H status should be conducted for all CRC patients.
Immunotherapy Treatment of Metastatic MSI-H Colon Cancer
Checkpoint inhibitors are a type of precision cancer immunotherapy that helps to restore the body’s immune system to fight the cancer by releasing checkpoints that cancer uses to shut down the immune system. PD-1 and PD-L1 are proteins that inhibit certain types of immune responses, allowing cancer cells to evade detection and attack by certain immune cells in the body. A checkpoint inhibitor can block the PD-1 and PD-L1 pathway and enhance the ability of the immune system to fight cancer. By blocking the binding of the PD-L1 ligand these drugs restore an immune cells’ ability to recognize and fight colon cancer cells.
Single Agent Immunotherapy
Results from the Keynote-177 clinical trial demonstrated that initial therapy with the immune checkpoint inhibitor Keytruda doubles progression-free survival compared to chemotherapy in patients with advanced colorectal cancer and microsatellite instability high/mismatch repair deficient (MSI-H/dMMR). The results of the Keynote-177 clinical trial led to Food and Drug Administration approval of Keytruda as initial therapy for MSI-H colon cancer in June of 2020.
Keynote-177 evaluated first-line treatment with Keytruda for patients with MSI-H or dMMR in 307 patients with unresectable or metastatic colorectal cancer. Patients were randomly assigned to receive first-line Keytruda for up to 2 years or the doctors choice of six different standard chemotherapy regimens: mFOLFOX6 (5-fluorouracil, leucovorin, and oxaliplatin); mFOLFOX6+bevacizumab; mFOLFOX6+cetuximab; FOLFIRI (leucovorin, 5-fluorouracil, and irinotecan); FOLFIRI+bevacizumab; or FOLFIRI+cetuximab and directly compared.
Keytruda treated patients survived on average 16 months without cancer progression compared to 8.2 months for those treated with standard chemotherapy. At 24-months follow up, progression-free survival was 55.3% with Keytruda compared to 18.6% with chemotherapy. All patients with colon cancer should undergo genomic biomarker testing to determine whether they have MSI-high or either markers that can help determine optimal treatment.
Dual Immunotherapy Treatment
The combination of Opdivo (nivolumab) and Yervoy (ipilimumab) has also been approved by the US FDA for the treatment of metastatic MSI-H or dMMR metastatic colorectal cancer.3,4 Dual immunotherapy with Opdivo plus Yervoy was shown to significantly reduce the risk of colon cancer disease progression in patients with MSI-H/dMMR mCRC when directly compared to chemotherapy, as shown in the CheckMate-8HW trial.The trial demonstrated that treatment with the combination led to a 79% reduction in the risk of disease progression or death when compared to chemotherapy. The combination also reduced the risk of disease progression or death compared to treatment with Opdivo alone.6,7
How long should ICI Therapy be Administered?
The initial trials demonstrating the effectiveness of ICI’s in the management of MSI-H colon cancer administered the drug for up to 2 years or until disease progression. Many patients however respond immediately and the correct duration of therapy is unknown. ICI’s are not without side effects so determining the optimal duration of therapy is important. Regular testing with ctDNA may be the best way to determine optimal treatment duration.
Should ICI Therapy be Used for Early Stage Colon Cancer?
Current guidelines suggest ICI therapy should be used for treatment of stage IV colon cancer or in individuals that have a recurrence following treatment for stage II-III disease. Given the effectiveness of ICI’s in treating MSI-H disease a legitimate question is why not use the treatment initially for earlier stage disease? Research is emerging to support earlier use and patients should discuss this option with their oncologist.
Initial results from the NICHE-2 clinical trial have demonstrated that short-term (1-3 doses) of neoadjuvant ICI therapy led to pathologic responses (PRs) in nearly all patients with non-metastatic mismatch repair (MMR)-deficient colon cancer. The findings, presented at the European Society for Medical Oncology (ESMO) Congress 2022 in Paris.
None of the patients had experienced a disease recurrence at a median follow-up of 13 months and the three-year disease-free survival data is expected to be reported in 2023.5
Learn about other cancer driving mutations that can be targeted: Precision Cancer Medicines and Colon Cancer
Connect With Others for Support and information
CancerConnect was the first social network created for people with lung cance. Founded by oncologists to support cancer patients and their caregivers, over 40 million individuals have accessed CancerConnect programs since 1997. CancerConnect is used by leading cancer centers like Dana Farber, Roswell Park and The James at Ohio State to support their patients. Join the conversation, ask questions, share your experience, and learn how the best cancer centers are treating lung cancer from others. Share your experience, ask a question, or start a conversation by posting on CancerConnect.
References
- Merck Announces KEYTRUDA® (pembrolizumab) Significantly Improved Progression-Free Survival as First-Line Treatment for Advanced Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Colorectal Cancer
- FDA approves pembrolizumab for first-line treatment of MSI-H/dMMR colorectal cancer
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FDA Approves Combination Therapy for Metastatic Colorectal Cancer.
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Bristol Myers Squibb receives positive CHMP opinion for Opdivo (nivolumab) plus Yervoy (ipilimumab) for the first-line treatment of adult patients with microsatellite instability–high or mismatch repair deficient metastatic colorectal cancer. News release. Bristol Myers Squibb. November 15, 2024. Accessed November 15, 2024. https://news.bms.com/news/corporate-financial/2024/Bristol-Myers-Squibb-Receives-Positive-CHMP-Opinion-for-Opdivo-nivolumab-plus-Yervoy-ipilimumab-for-the-First-Line-Treatment-of-Adult-Patients-with-Microsatellite-InstabilityHigh-or-Mismatch-Repair-Deficient-Metastatic-Colorectal-Cancer/default.aspx
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FDA grants accelerated approval to ipilimumab for MSI-H or dMMR metastatic colorectal cancer. FDA. July 11, 2018. Accessed November 15, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-ipilimumab-msi-h-or-dmmr-metastatic-colorectal-cancer
