Zolbetuximab + CAPOX versus CAPOX in first-line treatment of claudin18.2+/HER2– advanced/metastatic gastric or gastroesophageal junction adenocarcinoma: GLOW phase 3 study.

TPS365 Background: Despite standard treatment options (eg, CAPOX, capecitabine + oxaliplatin), 5-year survival with advanced/metastatic gastric or gastroesophageal junction adenocarcinoma (G/GEJ) is poor and limited biomarkers exist to inform treatment selection. Claudin 18.2 (CLDN18.2), a targetable biomarker, is a tight junction protein that is normally confined to gastric mucosa of healthy tissue and is often retained in G/GEJ. Zolbetuximab, a chimeric IgG1 monoclonal antibody, binds to CLDN18.2 and mediates cell death through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Phase 2 (FAST; Sahin, Ann Oncol. 2021) results showed prolonged survival with zolbetuximab + EOX (epirubicin, oxaliplatin, capecitabine) vs EOX in CLDN18.2 + advanced G/GEJ. Preliminary phase 2 (NCT03505320, ILUSTRO Cohort 2; Klempner, J Clin Oncol. 2021) results showed promising antitumor activity with combination zolbetuximab + mFOLFOX6 (5-fluorouracil, folinic acid, oxaliplatin) in CLDN18.2 + advanced G/GEJ. Methods: GLOW (NCT03653507) is enrolling ̃500 adults from global sites. Patients are required to have radiologically evaluable (RECIST v1.1) CLDN18.2 + /HER2 – locally advanced unresectable or metastatic G/GEJ. Prior chemotherapy for advanced/metastatic G/GEJ is not permitted. Patients will be randomized 1:1 to zolbetuximab + CAPOX or placebo + CAPOX. Randomization will be stratified by region (Asia vs non-Asia), number of metastatic sites (0 to 2 vs ≥3), and prior gastrectomy (yes vs no). Zolbetuximab will be administered at 800 mg/m 2 IV on Cycle 1 Day 1 (loading dose), then at 600 mg/m 2 IV every 3 weeks; 8 cycles of CAPOX will be administered. Central testing of tumor tissue will determine CLDN18.2 status; tumors will be considered CLDN18.2 + if ≥75% of tumor cells show moderate to strong membranous immunohistochemical staining. Primary endpoint: progression-free survival per independent review. Secondary endpoints: overall survival; objective response rate; duration of response; safety/tolerability, pharmacokinetics, and immunogenicity of zolbetuximab. As of September 22, 2021, 135 sites were open for screening and enrollment. Clinical trial information: NCT03653507.