What is the role of pembrolizumab (pembrolizumab) in the treatment of stage III microsatellite instability-high (MSI-high) colon cancer?

Pembrolizumab in Stage III MSI-High Colon Cancer

Pembrolizumab is not currently established as standard treatment for stage III MSI-high colon cancer, but emerging evidence from neoadjuvant trials suggests it may offer organ-sparing potential in this population. The current evidence base and regulatory approvals focus on metastatic/unresectable disease, not stage III resectable disease.

Current Regulatory Status and Evidence Base

FDA-Approved Indications for MSI-H Colorectal Cancer

• Pembrolizumab received FDA approval in 2017 for unresectable or metastatic MSI-H/dMMR solid tumors that have progressed following prior treatment 1
• The approval was based on 149 patients with MSI-H/dMMR cancers across five multicenter trials, achieving an ORR of 39.6% with durable responses lasting ≥6 months in 78% of responders 1
• First-line pembrolizumab for metastatic MSI-H/dMMR colorectal cancer is strongly recommended based on the KEYNOTE-177 trial, which demonstrated superior PFS (16.5 vs 8.2 months; HR 0.60) and improved OS (77.5 vs 36.7 months; HR 0.73) compared to chemotherapy 1, 2, 3, 4

Stage III Disease: The Evidence Gap

There are no completed phase III trials specifically evaluating pembrolizumab in stage III MSI-high colon cancer. The guideline evidence focuses exclusively on metastatic or unresectable disease 1.

Emerging Neoadjuvant Data

KEYNOTE-164 Neoadjuvant Study

• A phase II trial evaluated neoadjuvant pembrolizumab in localized MSI-H/dMMR tumors (including 27 colorectal cancer patients), demonstrating a 65% pathologic complete response rate among 17 patients who underwent surgery 5
• The best overall response rate was 82% among 33 evaluable patients 5
• Ten patients (29%) elected organ-sparing surveillance after 1 year of pembrolizumab without surgical resection, though this approach remains investigational 5
• Six patients (17%) experienced progression events during follow-up, four requiring salvage surgery 5
• No new safety signals were observed compared to metastatic disease trials 5

Key Caveats for Neoadjuvant Approach

• This was a single-center, non-randomized phase II study without long-term follow-up data 5
• The 17% progression rate highlights that not all MSI-H tumors respond to pembrolizumab, even in the localized setting 5
• Patients who decline surgery after neoadjuvant pembrolizumab are accepting an unproven strategy with potential for disease progression 5

Clinical Decision-Making Algorithm for Stage III MSI-H Colon Cancer

Standard of Care Approach

1. Stage III MSI-high colon cancer should be treated with surgical resection followed by adjuvant chemotherapy (FOLFOX or CAPOX) as per standard guidelines - this remains the evidence-based standard despite the lack of specific guideline citations for this population

2. MSI-H status does NOT currently change the standard surgical approach for stage III disease - the neoadjuvant data is too preliminary 5

Investigational Considerations

If considering neoadjuvant pembrolizumab in stage III MSI-H colon cancer:

• This should only be done in the context of a clinical trial or with extensive informed consent about the investigational nature 5
• Patients must understand the 17% risk of progression and potential need for salvage surgery 5
• Close radiographic and clinical monitoring is essential (the median time to response is approximately 3 months) 2
• Initial progression may occur in up to 29% of MSI-H colorectal cancer patients before response (pseudoprogression), requiring careful assessment 2

When Pembrolizumab IS Appropriate

If stage III disease progresses to metastatic disease or becomes unresectable:

• Pembrolizumab becomes first-line standard of care for MSI-H/dMMR metastatic colorectal cancer 1, 2, 3
• Pembrolizumab monotherapy 200 mg IV every 3 weeks is preferred over chemotherapy 1, 2
• Expected PFS is 16.5 months with significantly fewer grade 3-5 adverse events (22% vs 66% with chemotherapy) 1, 3, 4

Safety Profile

• Grade 3-5 treatment-related adverse events occur in only 22% of patients receiving pembrolizumab, compared to 66-67% with chemotherapy 1, 3, 4
• Common adverse events include diarrhea, fatigue, pruritus, nausea, rash, arthralgia, and hypothyroidism 6
• Immune-mediated toxicities affecting skin, liver, kidneys, gastrointestinal tract, lungs, and endocrine systems require monitoring 7
• Pneumonitis occurs in approximately 3-7% of patients and represents one of the most serious complications 7

Critical Pitfalls to Avoid

• Do not assume MSI-H status alone justifies deviation from standard surgical management in stage III disease - the neoadjuvant data is phase II only 5
• Do not use pembrolizumab in MSI-H stage III colon cancer outside of clinical trials without extensive discussion of the investigational nature and risks 5
• Do not confuse the strong evidence for pembrolizumab in metastatic MSI-H disease with evidence for stage III disease - these are distinct clinical scenarios 1, 3, 5
• Testing for MSI/MMR status should be performed to guide future treatment decisions if disease progresses 7