What is the optimal first‑line systemic treatment for a 61‑year‑old patient with treatment‑naïve stage IV caecal adenocarcinoma, oligometastatic to a single para‑aortic lymph node, deficient mismatch repair/microsatellite instability‑high, and Eastern Cooperative Oncology Group performance status 0‑1?

First-Line Treatment for Stage IV Caecal Cancer with dMMR/MSI-H and Oligometastatic Disease

For this 61-year-old patient with treatment-naïve stage IV caecal adenocarcinoma that is dMMR/MSI-H with oligometastatic disease (single para-aortic node), pembrolizumab monotherapy is the preferred first-line treatment based on the KEYNOTE-177 trial results and current guideline recommendations. 1

Rationale for Immunotherapy-First Approach

Superior Efficacy in dMMR/MSI-H Disease

• Pembrolizumab monotherapy is the standard first-line treatment for dMMR/MSI-H metastatic colorectal cancer, demonstrating superior progression-free survival and overall response rates compared to chemotherapy with or without targeted agents. 1

• The KEYNOTE-177 phase III trial established pembrolizumab as first-line therapy for dMMR/MSI-H mCRC, showing improved PFS and higher response rates versus chemotherapy, with the control arm (chemotherapy ± targeted therapy) achieving only 33.1% response rate and 8.2 months PFS—substantially lower than expected for standard mCRC patients. 1

• dMMR/MSI-H tumors accumulate high mutation loads and generate neoantigens that stimulate robust anti-tumor immune responses, making them particularly sensitive to immune checkpoint inhibition. 2, 3

Evidence Against Chemotherapy in dMMR/MSI-H Disease

• dMMR mCRC patients demonstrate significantly lower response rates to first-line chemotherapy with or without monoclonal antibodies (5% versus 44% in pMMR patients) and worse overall survival (16.0 months versus 23.6 months in pMMR). 1

• Multiple trials including CAIRO and FOCUS demonstrate that dMMR patients receiving irinotecan-containing doublet therapy had similar PFS to 5-FU monotherapy (4.0 vs 4.2 months), while pMMR patients showed clear benefit from doublet therapy (8.3 vs 5.8 months), suggesting chemotherapy intensification provides minimal benefit in dMMR disease. 1

• The CALGB bevacizumab trial showed that dMMR patients treated with cetuximab had significantly worse OS (11.9 months) compared to pMMR patients (30.7 months; p=0.0014), indicating poor response to anti-EGFR therapy in this population. 1

Specific Treatment Recommendation

First-Line Therapy

• Pembrolizumab 200 mg IV every 3 weeks or 400 mg IV every 6 weeks should be initiated as monotherapy. 1

• Alternative immune checkpoint inhibitors include nivolumab monotherapy or nivolumab plus ipilimumab, though pembrolizumab has the strongest evidence base from the KEYNOTE-177 trial. 1, 3

• The CheckMate-649 trial demonstrated that patients with MSI-H tumors treated with nivolumab plus ipilimumab had improved median OS versus chemotherapy (not reached vs 10 months; HR 0.28), supporting dual immunotherapy as an alternative option. 1

Oligometastatic Disease Considerations

• After achieving response or stable disease with pembrolizumab, consider local ablative therapy (surgical resection or stereotactic radiotherapy) to the para-aortic node if technically feasible, as oligometastatic disease may benefit from combined systemic and local treatment approaches. 1

• Restaging imaging should be performed every 6-9 weeks initially to assess response and determine optimal timing for local therapy consideration. 1

Critical Caveats and Pitfalls

Confirm dMMR/MSI-H Status

• Ensure dMMR/MSI-H testing was performed using validated methods (immunohistochemistry for MMR proteins or PCR-based MSI testing) with concordance between techniques (90-97% agreement expected). 3, 4

• If only one testing method was used, consider confirmatory testing with the alternative method before committing to immunotherapy, as misclassification would lead to treatment failure. 3, 5

Monitor for Pseudoprogression

• Approximately 30-50% of dMMR/MSI-H mCRC patients experience early or secondary progression on immune checkpoint inhibitors, requiring careful distinction between true progression and pseudoprogression. 4

• If radiographic progression occurs within the first 12 weeks, continue pembrolizumab for at least one additional cycle with repeat imaging before declaring treatment failure, as pseudoprogression can occur. 4

Avoid Unnecessary Chemotherapy

• Do not initiate chemotherapy with or without bevacizumab or anti-EGFR antibodies as first-line treatment in confirmed dMMR/MSI-H disease, as this exposes the patient to unnecessary toxicity without survival benefit and delays effective immunotherapy. 1

• Chemotherapy should be reserved for patients who progress on immunotherapy or for the rare scenario where immunotherapy is contraindicated. 1, 4

Second-Line Options if Immunotherapy Fails

After Pembrolizumab Progression

• FOLFOX (leucovorin, 5-fluorouracil, oxaliplatin) or FOLFIRI (leucovorin, 5-fluorouracil, irinotecan) chemotherapy doublets are recommended second-line options after immunotherapy failure in dMMR/MSI-H disease. 1

• Consider dual immunotherapy with nivolumab plus ipilimumab if not previously used, as this combination showed HR 0.28 for OS versus chemotherapy in MSI-H patients in CheckMate-649. 1

• Bevacizumab can be added to chemotherapy doublets in the second-line setting, though evidence of benefit specifically in dMMR disease is limited. 1

Expected Outcomes

• Response rates to first-line pembrolizumab in dMMR/MSI-H mCRC range from 40-50%, with at least two-thirds of responding patients achieving durable responses lasting beyond 12 months. 2, 3, 4

• Median progression-free survival with pembrolizumab exceeds 16 months in most trials, substantially longer than the 8.2 months observed with chemotherapy in the KEYNOTE-177 control arm. 1, 3