Thierry André1, David Tougeron2, Guillaume Piessen3, Christelle de la Fouchardière4, Christophe Louvet5, Antoine Adenis6, Marine Jary7, Christophe Tournigand8, Thomas Aparicio9, Jérôme Desrame10, Astrid Lièvre11, Marie-Line Garcia-Larnicol12, Thomas Pudlarz1, Romain Cohen1, Salomé Memmi13, Dewi Vernerey14,15, Julie Henriques14,15, Jérémie H Lefevre16, Magali Svrcek13. 1. Sorbonne University, Department of Medical Oncology, Saint-Antoine Hospital, AP-HP, INSERM 938, SIRIC CURAMUS, Paris, France. 2. Department of Hepatology and Gastroenterology, Poitiers University Hospital, Poitiers, France. 3. University of Lille, CNRS, INSERM, CHU Lille, Department of Digestive and Oncological Surgery, UMR9020-U1277-CANTHER-Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France. 4. Department of Medical Oncology, Leon Berard Cancer Centre, Lyon, France. 5. Department of Medical Oncology, Institut Mutualiste Montsouris, Paris, France. 6. Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM, University of Montpellier, Montpellier Cancer Institute (ICM), Montpellier, France. 7. University Hospital of Besançon, Clinical Investigational Center, CIC-1431, Besançon, France. 8. Department of Medical Oncology, Henri Mondor Hospital, AP-HP, Paris-East Créteil University, INSERM, IMRB, Creteil, France. 9. Paris Cité University, Department of Gastroenterology, Saint Louis Hospital, Paris, France. 10. Cancerology Institute, Jean Mermoz Hospital, Lyon, France. 11. Department of Gastroenterology, CHU Pontchaillou, INSERM U1242, "Chemistry, Oncogenesis Stress Signaling", Rennes 1 University, Rennes, France. 12. Oncology Multidisciplinary Group (GERCOR), Paris, France. 13. Sorbonne University, Department of Pathology, Saint-Antoine Hospital, AP-HP, Paris, France. 14. Methodology and Quality of Life Unit in Oncology, University of Besançon, Besançon, France. 15. Bourgogne Franche-Comté University, INSERM, Etablissement Français du Sang Bourgogne Franche-Comté, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France. 16. Sorbonne University, Department of Digestive Surgery, Saint-Antoine Hospital, AP-HP, Paris, France.
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.
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.