Disitamab vedotin (DV, RC48-ADC) combined with cadonilimab (anti-PD-1/CTLA-4 bispecific antibody) in patients with locally advanced or metastatic urothelial carcinoma (la/mUC): An open-label, single-arm, phase II study.

Wasilijiang Wahafu Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, General Internal Medicine, Beijing, China info_outline Wasilijiang Wahafu, Shuqing Wei, Xiaoyuan Qiao, Xi Zhang, Mingshuai Wang, Sujun Han, Yu Cui, Xuebing Han, Dongzi Pang, Hongsong Bai, Linjun Hu, Zhibin Li, Xin Wang, Yuzhu Fan, Nianzeng Xing

Authors Wasilijiang Wahafu Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, General Internal Medicine, Beijing, China info_outline Wasilijiang Wahafu, Shuqing Wei, Xiaoyuan Qiao, Xi Zhang, Mingshuai Wang, Sujun Han, Yu Cui, Xuebing Han, Dongzi Pang, Hongsong Bai, Linjun Hu, Zhibin Li, Xin Wang, Yuzhu Fan, Nianzeng Xing Organizations Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, General Internal Medicine, Beijing, China, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, General Internal Medicine, Taiyuan, China, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, general internal medicine, Taiyuan, China, Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China, Cancer Hospital of HuanXing ChaoYang District Beijing, Beijing, China, Oncology, Shanxi Cancer Hospital, Taiyuan, China Abstract Disclosures Research Funding RemeGen Akesobio Background: The first-line regimens for locally advanced or metastatic urothelial carcinoma(la/mUC)remain an unmet need. RC48-ADC has been approved in China for platinum-refractory la/mUC with HER2 overexpression (IHC 2+ or 3+). Cadonilimab (AK104, PD-1/CTLA-4 bsAb) showed encouraging antitumor activity in gynecologic cancer, urological tumors, etc. The aim of this study is to evaluate the efficacy and safety characteristics of RC-48 ADC combined with cadonilimab in the treatment of la/mUC with HER2 expression. Methods: This is an open-label, multicenter, prospective, phase 2 trial to evaluate RC48-ADC combined with cadonilimab in mUC. The study set a safe introduction period, 6 patients were included and received the initial dose of RC48-ADC at 2 mg/kg combined with cadonilimab at 6 mg/kg every two weeks. If no DLT event occurred in the 6 patients, then continued to expand 30 patients, with an expected sample size of 36 cases; If DLT safety event occurred in 6 cases, the RC48-ADC dose reduced to 1.5 mg/kg and cadonilimab dose reduced to 4 mg/kg for Q2W; Treatment continued until disease progression, intolerable toxicity, death, etc. Primary endpoint was ORR and safety, Secondary endpoints included DOR, PFS, OS, and exploration of tumor biomarkers. Results: By the cutoff date of 4 February 2024, Thirteen la/mUC patients were enrolled who have not received systematic treatment or intolerant to cisplatin or refuse chemotherapy {8 males; median age 72 y [61-83]; 77%(10/13) of patients had distant metastasis. HER2 expression IHC 2+ or 3+ was in 85% patients (11/13), and PD-L1 low expression was 100% (6/6)}. Dose-limiting toxicity was observed (Bullous rash, ALT/AST elevated) among first 6 patients, therefore reduced cadonilimab from 6mg/kg to 4mg/kg Q2W, RC48-ADC remained. 8 patients have efficacy evaluation, ORR was 75.0% (6/8), including 12.5% CR (1/8). DCR was 100%. Median progression-free survival (PFS) and overall survival (OS) were not reached. 69.2% (9/13) Pts experienced treatment-related adverse events (TRAEs). The most common TRAEs were AST/ALT increase (30.8%), fever (23.1%), anemia (23.1%), rash (15.4%), and pruritus (15.4%), etc. TRAEs ≥G3 were occurred in 15.4%(2/13) patients, one patient died due to a cerebrovascular event. 30.8% had immune-related AEs(≥G3 irAE 15.4%), including immune-related skin reactions, hepatitis, and colitis. Conclusions: This was the first study to evaluate RC48-ADC in combination with cadonilimab (anti-PD-1/CTLA-4 bispecific antibody) in urothelial carcinoma. Preliminary results showed that the combination have promising efficacy in first-line treatment of la/mUC and a manageable safety profile, it may potentially provide a new option for la/mUC treatment, especially for those who cannot tolerate cisplatin-based chemotherapy. Clinical trial information: NCT06178601.

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