Neoadjuvant nivolumab plus ipilimumab and adjuvant nivolumab in patients with localized microsatellite instability-high (MSI)/mismatch repair deficient (dMMR) oeso-gastric adenocarcinoma: Long-term follow-up of the GERCOR NEONIPIGA phase II study.

4099 Background: Neoadjuvant nivolumab and ipilimumab in localized MSI/dMMR gastric cancer were evaluated in the NEONIPIGA study (NCT04006262). The primary endpoint was pathological complete response (pCR) and has been previously reported. Here, we report on the long-term follow-up analysis and the secondary objectives of event-free survival (EFS) and overall survival (OS). Methods: This phase II, single-arm study evaluated neoadjuvant nivolumab 240 mg q2w x 6 and ipilimumab 1 mg/kg q6w x 2, followed by surgery 5 weeks (±1 week) after the last injection of nivolumab and adjuvant nivolumab 480 mg q4w x 9 in patients with resectable MSI/dMMR, T2-T4 NxM0 oeso-gastric adenocarcinoma. EFS and OS were evaluated through Kaplan-Meier curves. Results: 32 patients were included: 16 (50%) with gastric location and 16 (50%) with gastro-esophageal junction; 28 (88%) were initially classified as usT3 and four (12%) as usT2; 23 (72%) were lymph node positive. Three patients did not undergo surgery (one metastatic progression, two refusals). 27 (84%) patients completed the planned 6 cycles of neoadjuvant therapy, and 14 (44%) received the full neoadjuvant and adjuvant treatment. Median follow-up was 48.3 months (44.8-52.0). In the ITT population, 4-year OS was 84.1% (65.8-93). In the population eligible for surgery, 4-year EFS was 83.5% (64.8-92.8). Only one patient (classified as ypT0N1 and TRG1b at surgery) relapsed with cerebral metastases 29 months after initiation of neoadjuvant treatment. Six deaths were reported, including two related to gastric cancer (one post-operative due to surgery complications, one from cerebral metastases). The four remaining deaths were unrelated to gastric cancer or treatment toxicity and were due to pulmonary infections (n = 2; 33 and 60 months after initiation of neoadjuvant treatment), perforation of a strangulated hernia (13 months), and metastatic tongue cancer (30 months). All three patients without surgery achieved a clinical complete response after immunotherapy (including one deceased patient reported above). Combined with the 17 (59%) patients in pCR previously reported, 20 of 32 (62.5%) patients achieved complete response. No new safety signals were reported during extended follow-up. Conclusions: Neoadjuvant nivolumab and ipilimumab before surgery and adjuvant nivolumab in localized MSI/dMMR oeso-gastric adenocarcinoma achieved a high curative rate. These findings strongly support further investigation of a watch-and-wait approach in case of clinical complete response after immune checkpoint inhibitors, which is currently being evaluated in the DEWI GERCOR phase II study (NCT06059495). Clinical trial information: NCT04006262 .