Neoadjuvant anti-PD-1 monotherapy in MSI-H locally advanced gastric cancer: 3-Year survival without surgery.

106

Background: Neoadjuvant immunotherapy (IO) with anti–PD-1 inhibitors has shown promise in microsatellite instability–high (MSI-H) locally advanced gastric cancer (LAGC), with potential to improve treatment radicality. We evaluated 3-year overall survival in patients with MSI-H LAGC treated with neoadjuvant anti–PD-1 monotherapy without planned surgery. Methods: Among 405 patients with LAGC screened between 2019 and 2025, 27 (6.7%) had MSI-H tumors and received neoadjuvant anti–PD-1 IO. Of these, 9 (33.3%) were not operated and were included in this analysis. Treatment consisted of nivolumab 240 mg IV q2w (n = 4) or pembrolizumab 200 mg IV q3w (n = 5). The median number of cycles was 13 (range, 2–50). Reasons for omitting surgery were patient refusal (n = 7), medical contraindications (n = 1), or disease progression on therapy (n = 1). Tumor response was assessed radiologically and endoscopically with biopsy. Survival was estimated using Kaplan–Meier methodology. Results: Median age was 78 years (range, 56–86); 6 patients were >75 years, and 7/9 were female. Stage was IIB in 4 and IIIB in 5 patients. The objective response rate (ORR) was 7/9, including 6 complete responses (CR) and 1 partial response (PR). Median time to best response was 68 days (range, 33–512). One patient had stable disease (SD), and 1 had progressive disease (PD) after 2 cycles of IO. At data cut-off, 5/9 patients had discontinued IO due to confirmed CR by PET–CT and endoscopic biopsy (n = 2), refusal to continue therapy (n = 1), tumor progression–related death (n = 1), or comorbid pathology (diabetes mellitus with ketoacidosis; n = 1). The median number of treatment cycles was 30 (range, 2–50). Four patients remained on therapy (median, 13 cycles; range, 12–46). Median progression-free survival and overall survival were not reached. Estimated 3-year overall survival was 77.8%. Two patients have been followed for 71.5 and 60 months, respectively, without evidence of disease progression. No grade ≥3 immune-related adverse events or clinically significant treatment-related toxicities were observed. Conclusions: In this highly selected cohort of patients with MSI-H LAGC, non-operative management after neoadjuvant anti–PD-1 IO was associated with high CR rates and durable survival. A 3-year OS of 77.8% suggests that omission of surgery may be feasible for selected MSI-H responders.