What are the checkpoint inhibitors for rectal cancer with deficient mismatch repair (dMMR)?

From the Guidelines

Checkpoint inhibitors, such as pembrolizumab or dostarlimab, are recommended as a treatment option for patients with rectal cancer and deficient mismatch repair (dMMR) due to their remarkable efficacy in achieving complete clinical responses and improving patient outcomes. For patients with dMMR rectal cancer, PD-1 inhibitors such as pembrolizumab (200mg IV every 3 weeks) or dostarlimab (500mg IV every 3 weeks for 6 months, then 1000mg every 6 weeks) are recommended treatment options 1. These immunotherapy regimens typically continue for up to 2 years or until disease progression or unacceptable toxicity occurs.

Key Considerations

• Before initiating treatment, patients should undergo testing to confirm dMMR status through immunohistochemistry or PCR testing 1.
• Patients should be monitored for immune-related adverse events including colitis, pneumonitis, hepatitis, endocrinopathies, and skin reactions, which may require prompt intervention with corticosteroids 1.
• Checkpoint inhibitors work by blocking the PD-1/PD-L1 pathway, allowing T cells to recognize and attack cancer cells, making them particularly effective in dMMR tumors due to their high mutational burden and neoantigen expression 1.
• Some patients with dMMR rectal cancer have achieved complete clinical responses with checkpoint inhibitor monotherapy, potentially avoiding the need for surgery, radiation, or conventional chemotherapy in select cases 1.

Surveillance and Follow-up

• The NCCN panel stresses the critical importance of careful surveillance for those considering a nonoperative management (NOM) approach to detect and treat tumor regrowth in a timely manner 1.
• A surveillance protocol for watch-and-wait may include digital rectal examination, flexible sigmoidoscopy, and CEA every 4 months for the first 2 years, then every 6 months for years 3 to 5; MRI every 6 months for the first 2 years, then every 12 months for years 3 to 5 1.

From the FDA Drug Label

The FDA drug label does not answer the question.

From the Research

Checkpoint Inhibitors for Rectal Cancer with dMMR

• The use of checkpoint inhibitors, such as pembrolizumab, has shown promise in treating patients with mismatch repair-deficient (dMMR) rectal cancer 2, 3, 4, 5, 6.
• A study published in 2023 found that neoadjuvant pembrolizumab was effective in treating patients with locally advanced dMMR rectal cancer, with no recurrences reported after a median follow-up of 26 months 2.
• Another study published in 2022 discussed the role of immunotherapy in treating dMMR colorectal cancer, including the use of checkpoint inhibitors such as pembrolizumab 3.
• The KEYNOTE-177 study, published in 2022 and 2025, compared pembrolizumab to chemotherapy in patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer, and found that pembrolizumab was associated with improved progression-free survival and overall survival 4, 5.
• A phase 2 study published in 2025 found that neoadjuvant dostarlimab, a PD-1 blocking agent, eliminated the need for surgery in a high proportion of patients with dMMR locally advanced rectal cancer 6.

Efficacy and Safety

• The studies suggest that checkpoint inhibitors, such as pembrolizumab and dostarlimab, are effective in treating patients with dMMR rectal cancer, with high response rates and durable responses 2, 3, 4, 5, 6.
• The safety profiles of these treatments were generally favorable, with few grade 3 or higher adverse events reported 2, 3, 4, 5, 6.

Future Directions

• Further studies are needed to confirm the efficacy and safety of checkpoint inhibitors in treating patients with dMMR rectal cancer, and to explore their use in combination with other treatments 2, 3, 4, 5, 6.