Zolbetuximab, Durvalumab, and FLOT Combination Neoadjuvant Chemotherapy for CLDN18.2-Positive Gastric Cancer or Gastroesophageal Junction Adenocarcinoma

<Background and Rationale> Locally advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma are commonly treated with perioperative chemotherapy. In Japan, FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) plus durvalumab is expected to be established as a standard perioperative treatment for cT2-4 and/or cN+ gastric/GEJ cancer in 2026, with a reported pathological complete response (Grade 3, per the Japanese Classification of Gastric Carcinoma) rate of 19.2%. Zolbetuximab, a chimeric monoclonal antibody against Claudin 18.2 (CLDN18.2), has demonstrated clinically meaningful benefit in combination with chemotherapy for CLDN18.2-positive unresectable advanced or recurrent gastric/GEJ adenocarcinoma, both as first-line therapy in combination with oxaliplatin/fluoropyrimidine-based chemotherapy and, with monotherapy, in later lines. Identified risks of zolbetuximab include nausea, vomiting, and hypersensitivity reactions (including infusion-related reactions); potential risks include neutropenia and anemia. Based on this efficacy and safety profile, this trial investigates whether adding zolbetuximab to FLOT plus durvalumab further improves the pathological response of neoadjuvant chemotherapy for CLDN18.2-positive, locally advanced, resectable gastric or GEJ adenocarcinoma, anticipating an improvement in the Grade 3 histological response rate, a reduction in recurrence, and prolonged survival.

<Study Objectives> The primary objective is to evaluate the efficacy of neoadjuvant chemotherapy with FLOT plus durvalumab plus zolbetuximab, using the histological complete response rate (Grade 3, per central pathological review) as the primary endpoint. The secondary objective is to evaluate the safety, tolerability, and efficacy of this combination therapy.

<Study Design> This is a single-arm, open-label, multicenter, investigator-initiated phase II trial conducted at 4 sites in Japan (National Cancer Center Hospital [coordinating site], The Cancer Institute Hospital of JFCR, Saitama Cancer Center, and Kanagawa Cancer Center). The tolerability and safety of zolbetuximab combined with FLOT plus durvalumab are evaluated during a dose-limiting toxicity (DLT) evaluation period covering the first 2 weeks after the first dose of zolbetuximab (Cycle 1). If the 800 mg/m^2 loading dose of zolbetuximab is not tolerated based on this DLT evaluation, a reduced loading dose of 600 mg/m^2 is evaluated in an additional cohort of 3-6 participants before proceeding to the efficacy evaluation cohort.

<Study Treatment>

Participants receive 4 cycles (2-week cycles) of neoadjuvant chemotherapy:

• Zolbetuximab: 800 mg/m^2 (loading dose) on Cycle 1 Day 1, then 400 mg/m^2 on Day 1 of Cycles 2-4 (reduced to 600 mg/m^2 in the dose-reduction cohort if the loading dose is not tolerated).
• Durvalumab: 1500 mg (or 20 mg/kg for participants weighing 30 kg or less) on Cycle 1 Day 2 and Cycle 3 Day 1-2, administered in Cycles 1 and 3 only (2 administrations in total).
• FLOT (docetaxel, oxaliplatin, leucovorin, and fluorouracil): administered on Cycle 1 Day 2, and on Day 1-2 of Cycles 2-4.

Zolbetuximab and FLOT plus durvalumab may be administered on the same day (zolbetuximab first) or, per investigator judgment, split across 2 consecutive days. After completion of the 4 cycles of neoadjuvant chemotherapy, surgery is performed within 4-8 weeks.

<Efficacy Assessments> The primary efficacy endpoint, histological response, is evaluated on the surgical specimen by a central pathological review committee according to the Japanese Classification of Gastric Carcinoma, 15th edition (Grade 3 for the primary endpoint; Grade 2 or higher for a key secondary endpoint).

<Endpoints> Primary Endpoint: Histological complete response rate (Grade 3), per central pathological review.

Secondary Endpoints: Incidence of adverse events; treatment completion rate through surgery; dose intensity of neoadjuvant chemotherapy; R0 resection rate; histological response rate (Grade 2 or higher), per central pathological review.

<Statistical Considerations> The historical Grade 3 histological response rate with FLOT plus durvalumab alone is reported as 19.2%; this trial sets a threshold response rate of 19% and an expected response rate of 37% for the combination with zolbetuximab. With a one-sided alpha of 5% and 80% power, simulation-based sample size calculation (evaluated using the two-sided 90% Wilson score confidence interval for the response rate) indicates that 29 evaluable participants are required; the planned enrollment is approximately 30 participants (target annual enrollment: 15 participants; planned enrollment period: 2 years).

<Study Oversight and Funding> National Cancer Center Hospital, Japan, is the coordinating site, responsible for overall trial coordination (Coordinating Investigator: Hirokazu Shoji). Astellas Pharma Inc. supplies zolbetuximab and provides funding for the trial under a contract with National Cancer Center Hospital.