Neoadjuvant Nivolumab Plus Ipilimumab and Adjuvant Nivolumab in Localized Deficient Mismatch Repair/Microsatellite Instability–High Gastric or Esophagogastric Junction Adenocarcinoma: The GERCOR NEONIPIGA Phase II Study

Abstract

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.

Clinical Significance and Immune Infiltration Analyses of the Cuproptosis-Related Human Copper Proteome in Gastric Cancer

“…Recently, immunotherapy based on inhibitors to immune checkpoints has been well-developed and greatly improved the prognosis of patients with GC. Recent studies revealed that tumor mutation burden (TMB) and microsatellite instability (MSI) are important factors related to response to immunotherapy in cancer [ 25 , 26 ]. Then, we investigated the association between CBPscores, TMB and MSI in TCGA and ACRG cohorts.…”

Dual immune checkpoint blockade in gastroesophageal tumors: never say never

“…There is high clinical rationale for treating this subgroup with immunotherapy in resectable stages [21,22]. In this regard, neoadjuvant treatment of patients with resectable MSI-H/dMMR gastroesophageal tumors with nivolumab+ipilimumab proved feasible and was associated with a high pCR rate [23]. Therefore, it might be worth further developing immunotherapy approaches for MSI-H tumors in resectable settings as part of a tissue-agnostic treatment strategy, as has been successfully implemented for advanced tumors [27].…”

“…The NEONIPIGA was an investigator-initiated single arm phase II study evaluating the efficacy of neoadjuvant nivolumab+ipilimumab followed by adjuvant nivolumab in patients with resectable MSI-H/ mismatch repair deficient (dMMR) gastroesophageal tumors [23]. A total of 32 patients were enrolled.…”

Immunotherapy in Localized Microsatellite Instability–High/Mismatch Repair Deficient Solid Tumors: Are We Ready for a New Standard of Care?

“…In the noncolorectal area, the phase II GERCOR NEONIPIGA trial is investigating the use of neoadjuvant nivolumab and ipilimumab and adjuvant nivolumab in patients with localized dMMR/MSI-H gastric or gastroesophageal junction adenocarcinoma. 19 In 29 patients with cT2-4NxM0 disease who underwent surgery after a total 12-week course of neoadjuvant dual immunotherapy combination, an encouraging 59% pathologic CR rate was observed. Given the promising initial results of these studies, there has been substantial interest in the potential adoption of neoadjuvant immunotherapy as definitive treatment for patients with dMMR/MSI-H solid tumors.…”