Safety and efficacy results from the phase I/IIa study of FG-M108 plus CAPOX as first-line (1L) treatment for patients with CLDN18.2+/HER2- locally advanced unresectable or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma.
Authors: Liu Funan , Gong Jifang , Jin Zhaoyu , Zhang Miao , Zhang Shu , Zhang Yanqiao , Liang Xinjun , Li Yun , Yang Xiaochun , Yang Yaping , Shen Lin 
Published: August 2024

4049 Background: There is an unmet medical need for 1L treatment of patients with HER2- G/GEJ adenocarcinoma. CLDN18.2 is expressed in normal gastric mucosa cells and retained in G/GEJ tumor cells. FG-M108 is a monoclonal antibody specifically targeting CLDN18.2 with optimal affinity and enhanced antibody-dependent cellular cytotoxicity. FG-M108 has demonstrated potent anti-tumor activity and excellent safety profile in preclinical studies. Methods: This cohort of a phase I/IIa study evaluated the safety and preliminary efficacy of FG-M108 300 mg/m2 every 3 weeks plus CAPOX in patients with locally advanced unresectable or metastatic G/GEJ adenocarcinoma. Patients had measurable lesions and were HER2- and CLDN18.2+ (immunohistochemistry [IHC] 1+/2+/3+≥10%). At baseline, 22 patients (43.1%) had liver metastases and 15 (29.4%) had peritoneal metastases. Treatment-emergent adverse events (TEAEs) were categorized by CTCAE v5.0. Efficacy was evaluated every 6 weeks per RECIST1.1. Results: As of January 12, 2024, 52 patients were treated. Most TEAEs were grade 1-2; grade ≥3 TEAEs occurred in 55.8% of patients and serious TEAEs in 25.0%. The most common TEAEs were neutropenia (63.5%), thrombocytopenia (44.2%), and hypoalbuminemia (42.3%). FG-M108–related grade ≥3 TEAEs occurred in 36.5% of patients and FG-M108–related serious TEAEs in 11.5%. No FG-M108–related grade 4-5 TEAEs were reported. No patients withdrew due to severe nausea, vomiting or hypoalbuminemia during the treatment period. Confirmed objective response rate (ORR) and disease control rate (DCR) were 46.7% (7/15) and 100.0% (15/15), respectively, in 15 patients with low CLDN18.2 expressions (IHC 1+/2+/3+ ≥10% & 2+/3+ <40%). Median progression-free survival (mPFS) in patients with low CLDN18.2 expressions was 5.0 months, similar to treatment effect of CAPOX. For 36 patients with medium or high expressions of CLDN18.2 (IHC 2+/3+ ≥40%), confirmed ORR was 77.8% (28/36) and DCR was 97.2% (35/36). The median follow-up was 218 days, and mPFS and median duration of response (mDOR) have not been reached yet; However, FG-M108 plus CAPOX have shown a clear trend to prolong the PFS and DOR in this group as compared to patients with low CLDN18.2 expressions (estimated HR=0.33). Median overall survival has not been reached. Conclusions: FG-M108 plus CAPOX as 1L treatment for CLDN18.2+/HER2- advanced G/GEJ cancer showed good tolerability and improved efficacy compared to historical CAPOX control, with an apparent trend of better efficacy with higher CLDN18.2 expression. Based on these results, pivotal phase 3 study of FG-M108 plus CAPOX versus CAPOX as 1L treatment of locally advanced unresectable or metastatic G/GEJ adenocarcinoma expressing medium/high CLDN18.2 has been initiated and is ongoing. Clinical trial information: NCT06177041 .