Zimberelimab platform study: Safety and efficacy of zimberelimab in combination with futibatinib and chemotherapy in patients with first-line advanced or metastatic esophageal carcinoma.

409 Background: Zimberelimab: AB122 (Zim) platform study is a Phase 1 a/b study with multiple cohorts designed to evaluate the safety and efficacy of Zim, an anti-PD-1 antibody. Futibatinib (Futi) is an FGFR inhibitor that covalently binds FGFR1–4; FGFR inhibitors have been reported to modulate the tumor immune microenvironment, including reducing MDSCs and inhibiting CAFs. These immunomodulatory effects are expected to enhance the efficacy of the anti-PD-1 antibodies. The safety and efficacy of the combination of Zim, Futi, and chemotherapy were evaluated in patients (pts) with first-line advanced or metastatic esophageal cancer (EC) in Japan. Methods: Key eligibility criteria included age ≥ 18 years, histologically confirmed advanced or metastatic EC with measurable lesions by RECIST v1.1 regardless of FGFR and PD-L1 status, previously untreated, adenocarcinoma or squamous cell carcinoma, and ECOG PS 0 or 1. Patients received Zim 360 mg on day 1, Futi 20 mg QD, fluorouracil 800 mg/m2 on days 1–5, and cisplatin 80 mg/m2 on day-1 of a three-week cycle. The primary endpoint was dose-limiting toxicity (DLT). The secondary endpoints included adverse events, antitumor activity, pharmacokinetics, pharmacodynamics, and pharmacogenomics. Results: As of May 10, 2024, 43 pts were enrolled. At the data cutoff date for this analysis (July 15, 2024), treatment was ongoing in 23 pts. Safety and efficacy were evaluated in 43 and 41 pts, respectively. The median age of the pts was 61 years (53–70). An ECOG PS score of 0 was observed in 31 pts. DLTs were evaluated in the first three pts, and none were reported. Common treatment-emergent adverse events (TEAEs)were hyperphosphatemia (81.4%), diarrhea (67.4%), nausea (62.8%), decreased appetite (62.8%), constipation (55.8%), anemia (53.5%), stomatitis (51.2%), neutrophil count decreased (37.2%), alanine aminotransferase increased (34.9%), and palmar-plantar erythrodysaesthesia syndrome (30.2%). Grade ≥ 3 TEAEs occurred in 31 pts (72.1%), and common events (≥ 30%) were anaemia (30.2%) and neutrophil count decreased (30.2%). The objective response rate was 70.7% (95% CI: 54.5–83.9), and the confirmed overall response rate was 58.5% (95% CI: 42.1–73.7). The disease control rate was 92.7% (95% CI: 80.1–98.5). Median duration of response was 5.6 months (95% CI: 4.1–5.6), and median progression-free survival was 4.9 months (95% CI: 3.4–6.7). Conclusions: The combination of Zim, Futi, and chemotherapy has a manageable safety profile without new safety signals and shows promising antitumor activity in pts with advanced or metastatic EC. As more than half of the enrolled pts are still undergoing treatment, these are preliminary data; follow-up is needed to evaluate the viability of this combination appropriately. Clinical trial information: NCT04999761 .