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 first-line treatment options for patients with rectal cancer and deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) due to their remarkable efficacy in improving overall survival and quality of life 1.

Key Considerations

• The high mutational burden in dMMR tumors creates numerous neoantigens that can be recognized by the immune system once PD-1/PD-L1 inhibition removes the tumor's immune evasion capability.
• Pembrolizumab (200mg IV every 3 weeks) or dostarlimab (500mg IV every 3 weeks for 6 months, then 1000mg every 6 weeks) are recommended options, with treatment typically continuing for up to 2 years or until disease progression or unacceptable toxicity.
• Patients should undergo testing to confirm dMMR status through immunohistochemistry for MMR proteins or PCR for microsatellite instability before initiating treatment.
• Patients should be monitored for immune-related adverse events, including colitis, pneumonitis, hepatitis, endocrinopathies, and skin reactions, which may require prompt intervention with corticosteroids and treatment interruption.

Evidence-Based Recommendations

• The phase III KEYNOTE-177 study demonstrated that pembrolizumab significantly improved median progression-free survival (PFS) compared to chemotherapy in patients with MSI-H/dMMR metastatic colorectal cancer (mCRC) 1.
• The CheckMate-142 trial showed that nivolumab in combination with ipilimumab achieved a high overall response rate (ORR) and disease control rate in patients with dMMR/MSI-H mCRC 1.
• A prospective phase II trial using dostarlimab in patients with dMMR, stage II or III rectal adenocarcinoma reported a complete clinical response (cCR) in all 12 patients, with no evidence of tumor on MRI, PET/CT, endoscopic evaluation, digital rectal examination, or biopsy 1.

Clinical Implications

• Checkpoint inhibitors offer a promising treatment option for patients with rectal cancer and dMMR or MSI-H, with the potential for improved overall survival and quality of life.
• The use of checkpoint inhibitors in non-metastatic locally advanced disease is increasingly being explored, with impressive complete response rates reported in clinical trials.
• A non-operative management (NOM) approach may be considered in centers with experienced multidisciplinary teams, after careful discussion with the patient about their risk tolerance and necessary surveillance schedule 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

• Checkpoint inhibitors have shown high response rates in patients with colorectal cancer (CRC) that have high microsatellite instability (MSI-H) or a deficient mismatch repair system (dMMR) 2
• The proportion of patients with MSI-H/dMMR cancers is 10-12% in colon cancers and 3% in rectal cancers 2
• In a small series of patients with MSI-H/dMMR rectal cancers, treatment with dostarlimab resulted in complete remission in all patients with no regrowth during an admittedly short follow-up 2

Neoadjuvant Immunotherapy-Based Systemic Treatment

• Neoadjuvant immunotherapy-based systemic treatment has been shown to be safe and effective in patients with dMMR locally advanced rectal cancer 3
• A case series reported three patients with dMMR locally advanced adenocarcinoma of the rectum who showed significant response with neoadjuvant immunotherapy-based systemic treatment 3
• Another study reported that therapy with pembrolizumab was feasible and effective in treatment-naïve patients with nonmetastatic, mismatch repair deficient colorectal cancer, including one patient with locally advanced rectum cancer 4

Pembrolizumab in MSI-H/dMMR Colorectal Cancer

• Pembrolizumab has been shown to be superior to chemotherapy in terms of progression-free survival and overall survival in patients with MSI-H/dMMR metastatic colorectal cancer 5, 6
• Pembrolizumab led to significantly longer progression-free survival than chemotherapy when received as first-line therapy for MSI-H/dMMR metastatic colorectal cancer, with fewer treatment-related adverse events 6
• With more than 5 years of follow-up, responses to pembrolizumab remained durable, and median overall survival was more than twice as long in patients treated with pembrolizumab versus chemotherapy in first line despite an effective crossover rate of 62% 5