Phase II study evaluating ivonescimab in combination with chemotherapy as first- and second-line treatment of advanced or metastatic gastric and gastroesophageal adenocarcinoma patients (UCGI 52 – GRACIE).

TPS4239 Background: The prognosis of advanced/metastatic gastroesophageal adenocarcinomas (GEA) has recently improved with new targeted therapies, including immune checkpoint inhibitors, mostly developed in the first-line setting. However, for patients (pts) without actionable biomarkers or for those who become refractory to first-line therapy, a significant unmet need remains for effective therapeutic options. Ivonescimab, a bispecific antibody targeting both VEGF-A and PD-1, appears to be a promising strategy in this setting. Methods: This phase 2 multicenter two-cohort, non-randomized study (NCT06846346) is designed to evaluate the efficacy and safety of ivonescimab + chemotherapy in pts with advanced or metastatic GEA, with and without actionable biomarker. Main eligibility criteria are age ≥ 18 years, histologically proven GEA, stage 4 disease, no prior treatment for pts without actionable biomarker (cohort 1) or only one prior line for pts with actionable biomarker (cohort 2), ECOG-PS 0-1, and adequate organs functions. The tumor has to be measurable (RECIST 1.1). Treatment regimens are ivonescimab 20mg/kg IV on D1 Q2W combined with: cohort 1: FOLFOX (oxaliplatin 85mg/m² IV, folinic acid 400 mg/m² IV or L-folinic acid 200 mg/m², 5-FU bolus 400 mg/m² then 5-FU 2400 mg/m² as a 46-hours continuous IV infusion on D1 Q2W; oxaliplatin will be stopped after 8 cycles); cohort 2: at investigator discretion, paclitaxel (80 mg/m2 IV at D1, D8 and D15, Q4W for at least 4 cycles) or irinotecan (180 mg/ m2 IV on D1 Q2W). Treatment will be administered until disease progression or unacceptable toxicity. The primary endpoint is ORR by central review. Secondary endpoints include ORR assessed by investigator, duration of response, PFS, OS, safety, time to PS deterioration >2, and quality of life. According to a single stage phase II A’Hern’s design, a sample of 33 evaluable pts in cohort 1 and 47 evaluable pts in cohort 2 is required to distinguish between a maximum futility proportion of 0.5 (cohort 1)|0.2 (cohort 2) and a minimum efficacy proportion of 0.75 (cohort 1)|0.4 (cohort 2) with a one-sided significance level of 0.04 and 90% power. 88 patients have to be enrolled to observe a minimum of 80 evaluable patients. Planned accrual duration is 1 year, 12 patients have already been enrolled. Clinical trial information: NCT06846346 .