What chemotherapy is recommended for rectal adenocarcinoma with deficient mismatch repair (dMMR) who progressed on Keytruda (pembrolizumab) immunotherapy?

Chemotherapy Options for dMMR Rectal Adenocarcinoma After Progression on Pembrolizumab

For rectal adenocarcinoma with deficient mismatch repair (dMMR) that has progressed on Keytruda (pembrolizumab), FOLFOX (fluorouracil, leucovorin, and oxaliplatin) is the recommended chemotherapy regimen. 1

Understanding dMMR Rectal Cancer

Deficient mismatch repair (dMMR) occurs in approximately 5-10% of rectal cancers 1. These tumors have distinct characteristics compared to proficient mismatch repair (pMMR) tumors:

• Higher tumor mutational burden
• Typically more responsive to immunotherapy
• Lower response rates to traditional fluoropyrimidine-based chemotherapy
• Often associated with Lynch syndrome

Treatment Algorithm for dMMR Rectal Cancer After Immunotherapy Failure

First-line option after immunotherapy failure:

• FOLFOX regimen: Oxaliplatin 85 mg/m², leucovorin 200 mg/m², fluorouracil bolus 400 mg/m² on day 1, followed by fluorouracil infusion 2,400 mg/m² over 46 hours 2, 3

Key considerations:

1. Response monitoring: Close monitoring is essential as dMMR tumors may show resistance to chemotherapy

   • Up to 29% of dMMR rectal cancers may progress on neoadjuvant chemotherapy 4
   • Monitor response after 2-3 cycles with imaging and clinical assessment

2. Radiation therapy consideration:

   • dMMR tumors have shown sensitivity to chemoradiation therapy (93% tumor downstaging) 4
   • Consider adding radiation if not previously administered

3. Alternative regimens if FOLFOX fails:

   • FOLFIRI (fluorouracil, leucovorin, and irinotecan)
   • FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) for selected patients with good performance status

Evidence for Treatment Recommendations

The 2024 ASCO guidelines for locally advanced rectal cancer state that while immunotherapy is recommended for MSI-H/dMMR tumors, the standard treatment options (including chemotherapy regimens) are recommended for patients with dMMR tumors who have contraindications to immunotherapy or who have progressed on immunotherapy 1.

Clinical evidence shows that:

• dMMR tumors have been shown to be sensitive to chemoradiation therapy 1
• Historically, fluorouracil-based chemotherapy has been less effective in patients with dMMR 1
• Oxaliplatin-containing regimens may provide better outcomes than fluoropyrimidine monotherapy in rectal cancer 3

Important Caveats and Considerations

1. Resistance patterns: Be aware that dMMR rectal cancers show higher rates of resistance to traditional chemotherapy compared to pMMR tumors 1, 4

2. Clinical trial options: Consider clinical trials combining chemotherapy with other immunotherapy agents, as several trials are investigating combination approaches 1

3. Genetic testing: Ensure comprehensive genetic testing has been performed, as 84% of dMMR rectal cancer patients may have Lynch syndrome 4

4. Monitoring for other malignancies: Up to 45.5% of deaths in dMMR rectal cancer patients may be due to extracolorectal malignancies 5

5. Emerging data: Limited case reports suggest that combination approaches (such as pembrolizumab + FOLFOX) may be effective in some patients with dMMR rectal cancer 6

By following this approach, you can optimize treatment for patients with dMMR rectal adenocarcinoma who have progressed on pembrolizumab immunotherapy, recognizing the unique challenges this molecular subtype presents.