What is the optimal duration of pembrolizumab (pembrolizumab) therapy for a patient with metastatic microsatellite instability-high (MSI-H) colorectal adenocarcinoma who has achieved a sustained complete response?

Discontinuing Pembrolizumab After Sustained Complete Response in MSI-H Metastatic Colorectal Cancer

Discontinuing pembrolizumab immediately is the most appropriate approach for this patient with MSI-H metastatic colorectal cancer who has achieved a sustained complete response for 18 months after 35 cycles (24 months) of therapy.

Rationale for Discontinuation

Evidence Supporting Discontinuation

• Long-term follow-up data from multiple studies demonstrates that complete responses to immune checkpoint inhibitors like pembrolizumab are highly durable, even after treatment discontinuation.
• A pooled analysis of KEYNOTE-001 cohorts showed that complete responses to pembrolizumab were highly durable (88% of CRs persisting after median follow-up of 30 months from first CR declaration; 91% disease-free survival at 24 months after CR), even among patients who discontinued pembrolizumab 1.
• The patient has already completed 24 months (35 cycles) of pembrolizumab therapy, which is considered an adequate treatment duration based on clinical trial protocols.

Risk-Benefit Assessment

• The patient has maintained a complete response for 18 months with normalized CEA levels and no metabolically active disease on PET scan.
• She has tolerated pembrolizumab well with only grade 1 fatigue and occasional arthralgias, but continuing therapy unnecessarily exposes her to potential immune-related adverse events.
• Discontinuing therapy after complete response allows the patient to avoid cumulative toxicity while maintaining the clinical benefit.

Optimal Duration of Immunotherapy

Clinical Trial Evidence

• In the KEYNOTE-006 melanoma trial, pembrolizumab was administered for a maximum of 2 years, with durable responses maintained even after discontinuation 1.
• Although the KEYNOTE-177 trial (which studied pembrolizumab in MSI-H metastatic colorectal cancer) did not specifically address optimal treatment duration, it showed significant improvements in progression-free survival compared to chemotherapy 1.
• The final analysis of KEYNOTE-177 showed that median overall survival was not reached with pembrolizumab compared with 36.7 months with chemotherapy, supporting the durability of response 1.

Considerations for MSI-H Colorectal Cancer

• MSI-H/dMMR tumors are particularly responsive to immune checkpoint inhibition due to their high mutational burden and immunogenicity.
• The patient's tumor characteristics (MSI-H status with dMMR, high tumor mutational burden of 89 mutations per megabase) are strong predictors of durable response to immunotherapy.

Management Algorithm After Discontinuation

1. Discontinue pembrolizumab immediately

   • The patient has completed 24 months (35 cycles) of therapy
   • Has maintained complete response for 18 months
   • Has excellent performance status and quality of life

2. Implement surveillance protocol

   • CT chest/abdomen/pelvis every 3-4 months for the first year after discontinuation
   • CEA monitoring every 3 months
   • Annual colonoscopy to monitor anastomotic site

3. Monitor for late immune-related adverse events

   • Continue thyroid function, liver enzymes, and renal function monitoring every 3 months for 6-12 months

4. Consider retreatment options if recurrence occurs

   • Rechallenge with pembrolizumab would be reasonable if recurrence happens after a significant treatment-free interval
   • Case series in other tumor types show that rechallenge with pembrolizumab after relapse can result in renewed responses 2, 3

Potential Pitfalls and Caveats

• Pseudoprogression: Rarely, patients may experience apparent progression followed by response. This is less likely after a sustained complete response.
• Late recurrence: While responses are typically durable, monitoring should continue as late recurrences can occur.
• Patient anxiety: Discontinuing effective therapy may cause anxiety; thorough discussion about the durability of complete responses even after discontinuation is important.
• Lack of MSI-H CRC-specific data: Most evidence for discontinuation comes from melanoma trials, though immunologic principles are likely similar across MSI-H tumors.

By discontinuing pembrolizumab now, the patient can maintain her excellent quality of life and avoid unnecessary treatment-related toxicity while preserving the clinical benefit of her complete response.