Combination of ZG005 with etoposide and cisplatin (EP) vs. EP as the first-line therapy for advanced neuroendocrine carcinoma: A randomized, multicenter, phase I/II trial.

e16344 Background: Treatment options for patients (pts) with advanced neuroendocrine carcinoma (NEC) are very limited, of which etoposide and cisplatin (EP) is the first-line standard treatment. Combination of immune checkpoint inhibitors with chemotherapy is a potential therapeutic strategy in NEC. This study is designed to evaluate ZG005 (a recombinant humanized anti-PD-1/TIGIT bispecific antibody with dual-targeted blocking effects on PD-1 and TIGIT) plus EP as the first-line therapy in pts with NEC. Methods: This phase 1/2, multiple-centers, dose escalation (Part 1) and expansion (Part 2) study was conducted to evaluate the safety and efficacy of ZG005 in combination with EP as a first-line treatment in the pts with NEC (excluding small cell lung cancer [SCLC]). In Part 1, pts received escalating doses of ZG005 (10 mg/kg or 20 mg/kg) with a fixed dose of EP every three weeks (Q3W). In Part 2, pts were administered ZG005 10 mg/kg + EP, ZG005 20 mg/kg + EP, and placebo + EP, respectively. The primary objective of Part 1 was to evaluate the safety and determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ZG005 + EP. The primary efficacy endpoint of Part 2 was investigator-assessed ORR by RECIST V1.1, while key secondary endpoints included PFS, DOR, DCR, etc. Results: As of Jan 10, 2025, a total of 21 pts were enrolled. The median age was 61 (range 48-70), with 81% male, 100% Ki-67 ≥ 55%, and 66.7% liver metastasis. The most common primary site of the tumor was gastrointestinal (38.1%), and median treatment cycles were 4 (range 2-4). No dose-limiting toxicities (DLT) were observed in Part 1. The most common treatment-related adverse events (TRAEs) were anaemia (23.8%), white blood cell count decreased (14.3%), neutrophil count decreased (14.3%), and alanine aminotransferase increased (14.3%). Three (14.3%) pts experienced Grade ≥3 TRAEs. Serious adverse events (SAEs) occurred in 4 (19.0%) pts, with only immune-mediated enterocolitis (immune-related) being related to the ZG005. Of the 12 efficacy-evaluable pts, 6 (2 on ZG005 10 mg/kg + EP and 4 on ZG005 20 mg/kg + EP) achieved partial responses (PR, 4 confirmed PRs) and 5 pts were stable disease (SDs), with an ORR of 50% and DCR of 91.7%; DOR and mPFS were not reached yet. Conclusions: Combination of ZG005 with chemotherapy was well tolerated and showed encouraging ORR in patients with NEC. This clinical trial is still going on, and updated safety and efficacy will be presented in the future. Clinical trial information: NCT06372626 . Research Sponsor: Suzhou Zelgen Biopharmaceuticals Co., Ltd.