From the Guidelines
Immunotherapy with pembrolizumab, nivolumab, or nivolumab plus ipilimumab is the recommended treatment option for patients with metastatic mismatch repair deficient (dMMR) colorectal cancer, as it has shown significant improvements in overall response rate, progression-free survival, and overall survival compared to traditional chemotherapy. The use of checkpoint inhibitors, such as pembrolizumab and nivolumab, has revolutionized the treatment of colorectal cancer, particularly for patients with dMMR tumors 1. These medications work by blocking the PD-1 receptor, allowing the immune system to recognize and attack cancer cells. The recommended dosing for pembrolizumab is 200-240mg intravenously every 2-3 weeks, while nivolumab is administered at a dose of 240-480mg intravenously every 2-3 weeks 1. It is essential to test for biomarkers such as MSI-H/dMMR status and BRAF mutations before starting treatment, as these markers can predict the effectiveness of immunotherapy 1. Common side effects of immunotherapy include fatigue, skin rash, diarrhea, and potential immune-related adverse events affecting various organ systems, which require prompt management 1. Overall, immunotherapy has shown significant promise in improving the outcomes of patients with metastatic dMMR colorectal cancer, and its use is expected to continue to grow in the coming years. Key considerations for the use of immunotherapy in colorectal cancer include:
- Patient selection: Immunotherapy is most effective in patients with dMMR tumors, and testing for MSI-H/dMMR status and BRAF mutations is essential before starting treatment.
- Dosing and administration: Pembrolizumab and nivolumab are typically administered intravenously every 2-3 weeks, with treatment continuing for up to 2 years or until disease progression or unacceptable toxicity.
- Management of side effects: Immunotherapy can cause significant side effects, including immune-related adverse events, which require prompt management to minimize their impact on patient outcomes.
From the FDA Drug Label
OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg: Immune-mediated rash occurred in 16% (108/666) of patients with RCC or CRC who received OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, including Grade 3 (3.5%) and Grade 2 (4.2%) adverse reactions.
- Immunotherapy for colorectal cancer: The FDA drug label for nivolumab (OPDIVO) mentions that it can be used in combination with ipilimumab for the treatment of colorectal cancer (CRC).
- Key points:
- OPDIVO 3 mg/kg with ipilimumab 1 mg/kg can cause immune-mediated adverse reactions, including rash.
- The incidence of immune-mediated rash in patients with CRC who received OPDIVO 3 mg/kg with ipilimumab 1 mg/kg was 16%.
- Systemic corticosteroids were required in 100% of patients with immune-mediated rash.
- Rash resolved in 75% of patients.
- Clinical decision: Nivolumab (OPDIVO) in combination with ipilimumab can be considered as an immunotherapy option for colorectal cancer, but it is essential to monitor patients for potential immune-mediated adverse reactions, including rash 2.
From the Research
Immunotherapy for Colorectal Cancer
- Immunotherapy, especially immune checkpoint inhibitors, has revolutionized the standard-of-care for multiple types of tumors, including colorectal cancer 3.
- The clinical development of immune checkpoint inhibitors for colorectal cancer is mainly separated according to the status of microsatellite instability or mismatch repair in a tumor 3.
- High-level microsatellite instability/deficient mismatch repair metastatic colorectal cancer generally has a tumor microenvironment with infiltration of T cells, associated with a favorable response to immune checkpoint inhibitors 3, 4.
Types of Immunotherapy
- Immune checkpoint inhibitors, including pembrolizumab (anti-PD-1 inhibitor) and nivolumab (anti-PD-1 inhibitor) with or without ipilimumab (anti-CTLA-4 inhibitor), have been integrated into the standard-of-care for high-level microsatellite instability/deficient mismatch repair metastatic colorectal cancer 3, 4.
- PD-1/PD-L1 immune checkpoint blockade-based combinational treatment is being explored as an immunotherapeutic amplification strategy against colorectal cancer 5.
- Combination therapy (e.g., nivolumab with low-dose ipilimumab) has demonstrated numerically higher response rates and improved long-term clinical benefit relative to anti-programmed death-1 monotherapy 4.
Challenges and Future Directions
- Limited T-cell infiltration in the tumor microenvironment of microsatellite stable/proficient mismatch repair metastatic colorectal cancer is a major resistant mechanism to immune checkpoint inhibitors 3.
- Clinical trials to improve the clinical activity of immune checkpoint inhibitors by immunomodulation are ongoing for metastatic colorectal cancer 3.
- Understanding the biology and mechanisms underlying dMMR-associated immunogenicity is urgently needed for improving the therapeutic efficacy of immunotherapy on CRC 6.
- Advances in the understanding of immunotherapy resistance mechanisms hold promise for both biomarker identification and development of novel strategies to circumvent treatment resistance 7.