Neoadjuvant toripalimab plus CapeOX in patients with localized dMMR/MSI-H gastric or esophagogastric junction adenocarcinoma (GC/EGJC): Results from the cohort C of phase II NICE trial.
Authors: Zhao Liying , Liu Hao , Hu Yanfeng , Yu Jiang , Yuan Shu-Qiang , Wang Wei , Jiang Junliang , Chen Xinhua , Liang Li , Yu Lina , Huang Mengli , Li Fengping , Lin Tian , Zhao Mingli , Chen Yaoxu , Chen Tao , Chen Hao , Li Guoxin 
Published: January 2024

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Background: Surgery is the cornerstone of curative therapy for localized GC or EGJC and perioperative chemotherapy seems ineffective for those with dMMR/MSI-H tumors. Chemotherapy may booster antitumor immunity. There is a compelling need to investigate the efficacy of perioperative immunochemotherapy for those with dMMR/MSI-H tumors. Methods: NICE trial is a multicenter, multi-cohort phase II trial (NCT04744649) investigating the safety and efficacy of toripalimab combined with CapeOX regimen as perioperative treatment for localized GC or EGJC of PD-L1 CPS≥5 (IHC 22C3) (cohort A), EBV-positive (cohort B), and dMMR/MSI-H (cohort C). Among those cohorts, the cohort A was compared with the control group of perioperative CapeOX regimen in a randomized controlled trial manner, while the cohort B and C were single arm. In present study, we report the findings of Cohort C, and the patients (pts) received toripalimab 240 mg combined with standard dose CapeOX regimen q3 weeks for 4 cycles before and after surgery. The eligible tumor stages were cT3-4aNxM0 or cT2N+M0 diagnosed by chest and abdominal CT combined with staging laparoscopy as well as negative peritoneal cytology. The primary endpoint was major pathologic response (MPR, <10% viable cells) rate. Multiplex fluorescence immunohistochemistry (mIHC) was utilized to explore changes of immune microenvironment. Results: Between March 2021 and April 2023, 15 pts with dMMR/MSI-H localized GC/GEJC were recruited in Cohort C. Tumor stages were cT3N0(n=2), cT3N1-3 (n=2), cT4aN0 (n=1) and cT4aN1-3 (n=10). 14 pts completed all 4 cycles therapy preoperatively and one patient completed 2 cycles therapy because of AEs. None had disease progression, while one achieved a complete clinical response at radiology and endoscopy and refused surgery and the other 14 pts underwent resection. The R0 resection rate was 100% (14/14). The MPR rate was 92.9% (13/14) and the residual tumor percentage was 33.8% in the other one patient (cT4aN2). pCR rate was 78.6% (11/14). Therapy-related grade 3/4 AEs occurred in 5 pts of safety population (n=15). One patient occurred grade 3 immune-related liver toxicity after 2 cycles treatment and recovered after steroids therapy. No pts died during the perioperative treatment, and one patient died of COVID-19 238 days after surgery without relapse. No disease relapse was observed in all pts. The mIHC revealed a significant reduction in CD20+ B cells, CD3+ T cells, NK dim cells, and M1 macrophages within tumor area after treatment for patients who reached pCR. Conclusions: Neoadjuvant toripalimab and CapeOX regimen for the localized dMMR/MSI-H GC/GEJC is safety with high MPR rate. These data indicate that neoadjuvant immunochemotherapy may potentially become one of the treatment options for these patients. Clinical trial information: NCT04744649 .