PURPOSE In patients with resectable gastric/gastroesophageal junction (GEJ) adenocarcinoma, surgery plus perioperative platinum-based chemotherapy is the standard of care. Perioperative chemotherapy remains debatable for gastric/GEJ adenocarcinoma with deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H). PATIENTS AND METHODS NEONIPIGA (ClinicalTrials.gov identifier: NCT04006262 ) phase II study evaluated neoadjuvant nivolumab 240 mg once every two weeks ×6 and ipilimumab 1 mg/kg once every six weeks ×2, followed by surgery and adjuvant nivolumab 480 mg once every four weeks (nine injections) in patients with locally advanced resectable dMMR/MSI-H, clinical (c) tumor (T)2-T4 node (N)x metastasis (M)0 gastric/GEJ adenocarcinoma. The primary end point was a pathological complete response (pCR) rate. RESULTS Between October 2019 and June 2021, 32 patients with dMMR/MSI-H gastric/GEJ adenocarcinoma were enrolled. The median age was 65.5 years (range, 40-80). Clinical stages were cT2-T3N0 (n = 9), cT2-T3N1 (n = 22), and cT3N1M1 (n = 1, wrongly included). With a median follow-up of 14.9 months (95% CI, 10.6 to 17.6), 32 patients received neoadjuvant immunotherapy (27 patients completed all cycles). Neoadjuvant therapy-related grade 3/4 adverse events occurred in six patients (19%). Twenty-nine patients underwent surgery; three did not have surgery and had complete endoscopic response with tumor-free biopsies and a normal computed tomography scan (two refused surgery and one had metastasis at inclusion). The rate of surgical morbidity (Clavien-Dindo classification) was 55% (one postoperative death occurred). All 29 patients had an R0 resection, and 17 (58.6%; 90% CI, 41.8 to 74.1) had pCR (pathological T0N0). Becker tumor regression grades 1a, 1b, 2, and 3 were observed in 17 patients, three (including two pathological T0N1), two, and seven patients, respectively. Of the 29 patients with surgery, 23 received adjuvant nivolumab. At database lock, no patient had relapse and one died without relapse. CONCLUSION Nivolumab and ipilimumab-based neoadjuvant therapy is feasible and associated with no unexpected toxicity and a high pCR rate in patients with dMMR/MSI-H resectable gastric/GEJ adenocarcinoma.

244 Background: In pts with resectable gastric adenocarcinoma or OGA, radical surgery is the only curative option and perioperative chemotherapy seems worthless for those with MSI/dMMR tumors. Methods: We conducted phase II study evaluating the efficacy of neo-adjuvant nivolumab and ipilimumab followed by adjuvant nivolumab in pts with resectable MSI/dMMR, T2-T4 NxM0 tumors. Treatment consisted of nivolumab 240 mg every 2 weeks (6 infusions) and ipilimumab 1 mg/kg every 6 weeks (2 infusions), followed by radical surgery 5 weeks (±1 week) after last injection of nivolumab. Pts with Becker tumor regression grade (TRG) < 3 were treated with adjuvant nivolumab 480 mg every 4 weeks (9 infusions). The primary objective was pathological complete response (pCR) rate. Results: From 10/2019 to 06/2021, a total of 32 pts were enrolled (all had dMMR±MSI-H status; 16 with gastric cancer and 16 with OGA). The median age was 65.5 years (range, 40-80). Initial stage was: usT3Nx = 22, usT2Nx = 4, and usTxNx = 6 (not evaluable by ultrasound endoscopy). At data lock, 32 pts had terminated neo-adjuvant period and 27 (84%) completed all 6 neo-adjuvant cycles. 8 pts (32%) experienced G3/4 adverse events (AEs) during neo-adjuvant treatment. 29 pts underwent surgery; 2 refused surgery and had complete endoscopic response with tumor-free biopsies, 1 had surgery not performed in relation with a metastatic progression. The median delay between last injection and surgery was 35 days (extreme, 25-170). Overall surgical morbidity (54%, n = 14) was related to: anastomotic leakage = 4, pancreatitis = 2, pneumonia = 2, and other = 6. The incidence of post-operative mortality was 3.8% (n = 1) due to cardiovascular AE at post-operative day 3. All the 29 pts who underwent surgery had R0 resection: 17 (59%) had pCR (i.e., TRG 1a as per Becker grade, ypT0N0) and 4 (14%) had TRG 1b as per Beker grade (< 10% residual tumor per tumor bed). 1 pt had TRG 2 (10-50% of residual tumor) and 7 pts had TRG 3 (˃50% of residual tumor) as per Becker grade, per local pathological assessment (central pathological review is awaited). With a median follow-up of 10.9 months, 1 pt had metastatic relapse, 1 pt died without relapse and 30 pts were recurrence/progression-free. Conclusions: Neo-adjuvant therapy with nivolumab and ipilimumab is feasible and is associated with a high pCR rate in pts with MSI/dMMR resectable OGA. Data will be updated for the congress. Clinical trial information: NCT04006262.