How should immune checkpoint inhibitors be incorporated into the treatment plan for a patient with cT3 N3 M0 gastric cancer who is MSI-H, PDL1 1%, and HER2 negative, considering the standard FLOT protocol?

Incorporate Nivolumab Plus Chemotherapy as First-Line Treatment for This MSI-H Gastric Cancer

For your 67-year-old patient with cT3 N3 M0 MSI-H gastric cancer, you should replace FLOT with nivolumab plus fluoropyrimidine and oxaliplatin-based chemotherapy as first-line treatment, independent of the low PD-L1 expression. 1

Why MSI-H Status Overrides PD-L1 Expression

Your instinct about the N3 status is correct, but the MSI-H status is even more compelling for immunotherapy incorporation:

• MSI-H tumors demonstrate exceptional responses to checkpoint inhibitors regardless of PD-L1 status. 1 The NCCN 2025 guidelines explicitly state that for MSI-H/dMMR tumors, nivolumab plus chemotherapy is recommended "independent of PD-L1 status" as a Category 2A preferred option. 1

• The survival benefit in MSI-H patients is dramatic. In the CheckMate-649 trial subset analysis, MSI-H patients treated with nivolumab plus chemotherapy achieved a median OS of 38.7 months versus 12.3 months with chemotherapy alone (HR 0.34). 1 For MSI-H patients with PD-L1 CPS ≥5, the benefit was even more pronounced: 44.8 months versus 8.8 months (HR 0.29). 1

• Your patient's PD-L1 of 1% should not deter you. While this falls below typical thresholds, MSI-H tumors are inherently immunogenic due to their high mutational burden, making them responsive to checkpoint inhibition independent of PD-L1 expression. 1, 2

Specific Treatment Recommendations

Preferred First-Line Regimen:

Nivolumab 360 mg IV every 3 weeks (or 240 mg every 2 weeks) plus FOLFOX or CAPOX 1

• This combination is a Category 2A preferred option for MSI-H tumors regardless of PD-L1 status. 1
• Continue nivolumab for up to 24 months or until disease progression or unacceptable toxicity. 1
• The fluoropyrimidine-oxaliplatin backbone is preferred over cisplatin due to lower toxicity. 1

Alternative First-Line Options for MSI-H:

1. Pembrolizumab monotherapy 1

   • This is a Category 2A preferred option for MSI-H tumors. 1
   • The KEYNOTE-158 trial showed 45.8% ORR with median PFS of 11 months in previously treated MSI-H gastric cancer. 1
   • Can be considered if chemotherapy tolerance is a concern, though combination therapy generally shows superior outcomes. 1

2. Nivolumab plus ipilimumab 1

   • Category 2A preferred option for first-line MSI-H disease. 1
   • CheckMate-649 showed median OS not reached versus 10 months with chemotherapy (HR 0.28) in MSI-H patients. 1
   • ORR was 70% versus 57% with chemotherapy. 1
   • Consider this if you want to avoid chemotherapy entirely, though toxicity may be higher. 1

Why Not Standard FLOT?

• FLOT alone would be suboptimal for MSI-H disease. While FLOT is effective for microsatellite stable (MSS) gastric cancer, you would be missing the opportunity to leverage the exceptional immunotherapy responsiveness of MSI-H tumors. 1

• The evidence for immunotherapy in MSI-H is stronger than for standard chemotherapy alone. The hazard ratios for survival with checkpoint inhibitors in MSI-H disease (HR 0.28-0.34) are among the most impressive in solid tumor oncology. 1

Safety Considerations

• Grade 3-4 treatment-related adverse events occurred in 59% with nivolumab plus chemotherapy versus 44% with chemotherapy alone in CheckMate-649. 1
• Sixteen treatment-related deaths occurred in the nivolumab plus chemotherapy group versus 4 in chemotherapy alone. 1
• Most common adverse events were nausea, diarrhea, and peripheral neuropathy. 1
• Monitor closely for immune-related adverse events including colitis, hepatitis, pneumonitis, and endocrinopathies. 1

Common Pitfalls to Avoid

1. Don't be deterred by the low PD-L1 of 1%. MSI-H status is the dominant predictive biomarker here, not PD-L1. 1

2. Don't default to FLOT just because it's familiar. The evidence for immunotherapy in MSI-H gastric cancer is compelling and guideline-supported. 1

3. Don't delay treatment to retest MSI-H status unless there's genuine concern about the accuracy of the initial test. MSI-H occurs in only 3-8% of gastric cancers, so confirmation is reasonable if not already done with robust methodology. 1

4. Don't forget HER2 and CLDN18.2 testing if not already completed, though these are less relevant given the MSI-H status and HER2-negative result you've already documented. 1

Reassessment Strategy

• Restage after 2-3 cycles with CT imaging to assess response. 1
• Consider surgical resection if downstaging occurs and the patient becomes resectable with clear margins achievable. 1
• Continue immunotherapy for up to 24 months if good response and tolerability. 1