Phase 2 trial of zolbetuximab in combination with mFOLFOX6 and nivolumab in patients with advanced or metastatic claudin 18.2-positive, HER2-negative gastric or gastroesophageal junction adenocarcinomas.

Kohei Shitara Department of gastroenterology and gastrointestinal oncology, National Cancer Center Hospital East, Kashiwa, Japan info_outline Kohei Shitara, Kensei Yamaguchi, Hirokazu Shoji, Maria Matsangou, Pranob P. Bhattacharya, Jung Wook Park, Samuel J Klempner

Authors Kohei Shitara Department of gastroenterology and gastrointestinal oncology, National Cancer Center Hospital East, Kashiwa, Japan info_outline Kohei Shitara, Kensei Yamaguchi, Hirokazu Shoji, Maria Matsangou, Pranob P. Bhattacharya, Jung Wook Park, Samuel J Klempner Organizations Department of gastroenterology and gastrointestinal oncology, National Cancer Center Hospital East, Kashiwa, Japan, The Cancer Institute Hospital of JFCR, Tokyo, Japan, Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Chuo City, Tokyo, Japan, Astellas Pharma Global Development, Inc., Northbrook, IL, Mass General Cancer Center, Boston, MA Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Astellas Pharma, Inc Background: Zolbetuximab, a chimeric immunoglobulin G1 monoclonal antibody, binds to claudin 18.2 (CLDN18.2) and mediates tumor cell death through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. In the pivotal phase 3 SPOTLIGHT study, zolbetuximab with modified FOLFOX6 (mFOLFOX6; leucovorin [folinic acid], fluorouracil [5-FU], and oxaliplatin) significantly prolonged progression-free survival (PFS) and overall survival (OS) in patients with CLDN18.2-positive, HER2-negative gastric and gastroesophageal junction (G/GEJ) adenocarcinomas. The phase 2 ILUSTRO trial is investigating the efficacy and safety of zolbetuximab, alone and in multiple combinations, in patients with CLDN18.2-positive, HER2-negative advanced/metastatic G/GEJ adenocarcinomas. Methods: The ILUSTRO trial is enrolling two new cohorts, 4A (safety cohort) and 4B, with approximately 12 and 50 patients planned, respectively, to assess safety and efficacy of the first-line combination of zolbetuximab, mFOLFOX6, and nivolumab in G/GEJ adenocarcinomas. Both cohorts are enrolling patients whose tumors are HER2-negative with high or intermediate CLDN18.2 positivity (moderate to strong immunohistochemistry staining intensity in ≥75% of tumor cells [high] or ≥50% but <75% of tumor cells [intermediate]). In Cohort 4A, patients will receive a loading dose of 800 mg/m 2 of zolbetuximab with 240 mg of nivolumab and mFOLFOX6 on cycle 1 day 1, followed by 400 mg/m 2 of zolbetuximab with 240 mg of nivolumab and mFOLFOX6 every 2 weeks (on days 15 and 29 of each 42-day cycle). Up to 12 mFOLFOX6 treatments (4 cycles) will be administered; patients may continue to receive folinic acid and 5-FU alongside zolbetuximab and nivolumab. Tolerability and safety of the combination of zolbetuximab, mFOLFOX6, and nivolumab will be evaluated during a 2-week dose-limiting toxicity assessment period. If the 800 mg/m 2 loading dose of zolbetuximab was assessed as not tolerable, patients were to be de-escalated to 600 mg/m 2 as their loading dose but received the same subsequent 400 mg/m 2 doses of zolbetuximab every 2 weeks. Cohort 4B will receive this combination at the dose level determined in Cohort 4A. Efficacy endpoints include objective response rate, disease control rate, duration of response, PFS, and OS. Safety and tolerability, pharmacokinetics, immunogenicity, and health-related quality of life will also be evaluated. Currently, 20+ sites are recruiting in 6 countries (France, Italy, Japan, Korea, Taiwan, United States); more US sites are planned. Clinical trial information: NCT03505320.

Clinical