Preliminary results of an open-label, single-arm, multi-center study on disitamab vedotin (DV) combined with torIpalimab and radiotherapy as bladder-preserving therapy in HER2 overexpression muscle-invasive bladder cancer (MIBC; DECIDING study-stage I).
Authors: Zhang Ruiyun , Jin Di , Qian Lei , Xia Jun , Wu Guangyu , Li Yi , Zang Jingyu , Zhuang Guanglei , Hou Yanli , Xue Wei , Huang Yiran , Chen Haige 
Published: August 2024

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Background: Cystectomy (RC) with or without (neo)adjuvant cisplatin-based chemotherapy [(N)AC] is standard in fit patients (pts) with MIBC. For those who decline or are ineligible for RC, trimodality bladder preservation therapy (TMT) is recommended. However, about 40% of MIBC pts are cisplatin-ineligible or refuse chemotherapy. A new bladder-preserving therapy is urgently needed. DV is an antibody-drug conjugate directed to HER2, which is highly expressed in urothelial cancer(UC). In a combined analysis of two phase II clinical trials, DV demonstrated a promising efficacy with a manageable safety profile in patients with HER2 overexpression (immunohistochemistry 3+ or 2+) locally advanced or metastatic UC who had progressed on at least one line of systemic chemotherapy (Xinan Sheng JCO 2023). Here, we introduce a prospective study on the safety and preliminary efficacy of Disitamab VEdotin Combined with torIpalimab and radiotherapy as blaDder-preservING therapy in HER2 overexpression muscle-invasive bladder cancer(DECIDING study-stage I). Methods: This was a two stage designed trial which planned to include 6 pts in stage I as safety introduction cohort and 45 pts in stage II as efficacy assessment expansion cohort. Major including criteria includes staging of cT2-T4aN0M0 MIBC, declining or ineligible for RC, HER2 overexpression, and ECOG PS 0/1. Pts receive DV 2.0 mg/kg and toripalimab 3.0 mg/kg in day1, every 14 days for 12 cycles. Radiotherapy performed simultaneously during drug treatment, with a total dose over 56 Gy/23 fx. CT/MRI, cystoscopy with biopsy and cytology were performed to evaluate response. Up to 6 pts were enrolled into stage I cohort. The primary endpoint were dose-limiting toxicity (DLT) in stage I. Secondary endpt were complete response (CR) rate at 3 months, (defined as negative urine cytology and no visible tumors on imaging and negative biopsies in the ITT population), CR rate at 12m and 24m, bladder-intact disease-free survival, cancer specific survival, and overall survival. Results: From 7/2023 to 8/2023, 6 pts of stage I cohort were enrolled. Median age 69 (60-79), 100% MIBC and declined RC, 3/6 and 3/6 of pts confirmed with HER2 IHC 2+ and 3+, respectively. All 6 pts completed first therapy. As of 28 days after first therapy, no DLTs in stage I. 1/6 of pts had grade 3 (Gr 3) TRAE (Hypertriglyceridemia), 2/6 of pts had Gr 2 TRAE (Hyperglycemia and Radiocystitis), and all 6 pts had Gr 1 TRAE(3/6 AST increased; 2/6 ALT increased, 2/6 rash, 1/6 GGT increased, 1/6 diarrhea, 1/6 pruritus, 1/6 nausea). Conclusions: DV combined with toripalimab instead of chemotherapy in TMT was well-tolerated in this early analysis. TRAE was consistent with prior trials and no DLTs in 28 days recived first drug therapy. Clinical trial information: NCT05979740 .