Efficacy and safety of cadonilimab in combination with pulocimab and paclitaxel as second-line therapy in patients with advanced gastric or gastroesophageal junction (G/GEJ) cancer who failed immunochemotherapy: A multicenter, double-blind, randomized trial.
Authors: Xiaotian Zhang, Yakun Wang, Xiaojun Xiang, Hongming Pan, Jingdong Zhang, Xiaobing Chen, Yi Ba, Ying Jieer, Yifu He, Xianli Yin, Huiting Xu, Li Xiao, Lian Liu, Juan Chen, Jiachi Ma, Lin Shen, Ting Liu, Wei Liu, Baiyong Li, Yu Xia
Journal: Journal of Clinical Oncology (2024)

4012 Background: Anti-PD-1 monoclonal antibody (mAbs) plus chemotherapy has become standard first-line therapy for patients (pts) with advanced/metastatic G/GEJ cancer. In this phase Ib/II study (NCT04982276), we assessed the safety and efficacy of cadonilimab, a PD-1/CTLA-4 bispecific antibody, in combination with pulocimab, an anti-VEGFR-2 mAb, and paclitaxel in G/GEJ cancer pts who failed immunochemotherapy. Methods: This study consisted of two parts: safety run-in (arms A, B and C, n = 6 each) and expansion (a randomized, double-blind phase II study). In safety part, pts received intravenous pulocimab 10mg/kg, every 2 weeks (Q2W) + paclitaxel 80 mg/m 2 , days 1, 8, 15 (arm A), or cadonilimab 10mg/kg + pulocimab 10mg/kg, Q2W (arm B), or cadonilimab 10mg/kg + pulocimab 10mg/kg + paclitaxel 150 mg/m 2 , Q3W (arm C). In expansion part, pts were randomly assigned at 1:1 ratio to receive cadonilimab 10mg/kg + pulocimab 10mg/kg + paclitaxel 150 mg/m 2 , Q3W (arm 1) or placebo + pulocimab + paclitaxel (arm 2). The primary endpoint was safety and objective response rate (ORR), secondary endpoints included progression-free survival (PFS) and overall survival (OS). Results: As of 30 Oct. 2023, a total of 77 pts were enrolled. In safety part (n = 18), dose-limiting toxicity (DLT) was observed in 1/6 pts in arm B, whereas no DLT was observed in either arm A or C. In expansion part, 59 pts were randomly assigned to arm 1 (n = 29) and arm 2 (n = 30). 6 pts were excluded due to treatment interruptions caused by Covid-19 epidemic between September and December, 2022. Baseline characteristics were generally balanced between treatment arms. With median follow-up of 7.3 months (mo, range: 1.4-16.1), 53 pts had at least one post-baseline tumor evaluation. ORR was 48.0% (12/25) for arm 1 vs 35.7% (10/28) for arm 2, disease control rate (DCR) was 96.0% (24/25) vs 92.9% (26/28), mPFS was 6.8 mo (95% CI 4.1, 11.2) vs 4.9 mo (95% CI 3.2, 7.1) , median duration of response (mDoR) was not reached vs 4.0 mo (95%CI 1.58, NE), the median OS was not reached for the two arms, 9-mo OS rate was 65.5% (95% CI 33.2, 85.0) vs 34.0% (95% CI 9.5, 60.9). Grade 3-4 treatment-related adverse events (TRAEs) occurred in ≥10% pts were neutrophil count decreased (27.6% vs 33.3%), white blood cell count decreased (10.3% vs 26.7%) and blood pressure increased (13.8% vs 10.0%). No new safety signals were identified. Conclusions: The combination of cadonilimab with pulocimab and paclitaxel demonstrated manageable safety profile and encouraging efficacy as second-line therapy in pts with G/GEJ cancer progressed after immunochemotherapy. Incorporation of dual immunotherapy to VEGFR-2 targeting therapy could be a potential strategy to overcome immunotherapy resistance. Additional phase III study is warranted to confirm it. Clinical trial information: NCT04982276 .