FG-M108 plus capecitabine and oxaliplatin (CAPOX) for first-line treatment of CLDN18.2+/HER2- advanced gastric/gastroesophageal junction adenocarcinoma (GC): Update results of a phase I/II trial to determine RP2D.

431 Background: There exists unmet need for previously untreated pts with CLDN18.2+/HER2- advanced GC. FG-M108, an mAb specifically targeting CLDN18.2 and exhibiting enhanced ADCC activity, has the potential to benefit these pts. Methods: This phase I/II trial evaluated safety, pharmacokinetics and preliminary antitumor activity of FG-M108 plus CAPOX in previously untreated pts with CLDN18.2+/HER2- advanced GC, where FG-M108 was administered intravenously at 300 mg/m 2 or 600 mg/m 2 Q3W. Here we compare results of FG-M108 at 300mg/m 2 (Cohort A) with 600mg/m 2 (Cohort B) to establish RP2D. Results: As of August 28, 2024, 63 pts with CLDN18.2+ (IHC 1/2/3+≥10%) GC were treated, 70% of whom had CLDN18.2 Medium-High expression (CMH, IHC 2/3+≥40%). Baseline characteristics were comparable between Cohorts A & B. Increasing the FG-M108 dosage did not result in a higher incidence or severity of treatment-related adverse events (TRAE) overall. However, nausea and vomiting, identified as CLDN18.2 on-target toxicities, were significantly more frequent and severe in Cohort B compared to Cohort A.When 300 or 600 mg/m² of FG-M108 was administered intravenously Q3W, serum trough concentration exceeded the target drug concentration predicted by in vitro ADCC activity. The 300 mg/m² dose is expected to provide sufficient drug exposure as the effective dose.Moreover, in Cohort A, pts with CMH expression had a confirmed ORR of 78% (unconfirmed ORR=81%) and a median PFS of 11.0 months（95%CI 6.9-12.7）, significantly better than those in Cohort B. Based on safety, PK and efficacy trends, the RP2D was determined to be FG-M108 at 300mg/m 2 plus CAPOX. Conclusions: FG-M108 plus CAPOX had a manageable safety profile and promising antitumor activity in GC, with RP2D at 300mg/m 2 . A phase III trial is ongoing to confirm the efficacy of FG-M108 at 300mg/m 2 plus CAPOX as first-line treatment (NCT06177041). Clinical trial information: NCT04894825 . Cohort A n=52 Cohort B n=11 CMH % 71 64 Primary lesion-Stomach % 92 100 Metastatic organs ≥3 % 27 9 ORR/DCR with CMH % 81/97 57/86 PFS/DOR with CMH months 11.0/9.9 5.5/4.2 ≥G3 TRAE % 37 18 TRAE-Nausea % / ≥G3 Nausea % 38/2 64/9 TRAE-Vomiting % / ≥G3 Vomiting % 23/2 73/9