Disitamab Vedotin Plus Tislelizumab in Transurethrally Unresectable, ERBB2 -Positive, Non–Muscle-Invasive Bladder Cancer

Importance Very high-risk non–muscle-invasive bladder cancer (VHR NMIBC) includes extensive high-grade T1 (T1HG) disease, T1HG with carcinoma in situ, variant histology, lymphovascular invasion, or bacille Calmette-Guérin (BCG)–unresponsive disease. Transurethrally unresectable disease warrants radical cystectomy, but patients ineligible for or declining cystectomy lack established nonsurgical therapy. Objective To evaluate the efficacy and safety of disitamab vedotin (DV, an anti- ERBB2 [formerly HER2 ] antibody-drug conjugate) plus tislelizumab (an anti–programmed cell death 1 protein immune checkpoint inhibitor) in transurethrally unresectable ERBB2 -positive VHR NMIBC. Design, Setting, and Participants This was an open-label, single-arm, phase 2, nonrandomized clinical trial with a Simon 2-stage design, conducted in an academic hospital from August 2022 to May 2024 with a median follow-up of 29.4 months. The analysis included adults with transurethrally unresectable ERBB2 -positive NMIBC who met the 2019 European Association of Urology VHR criteria and who were ineligible for or declined cystectomy. Intervention Patients received an intravenous injection of DV (120 mg, day 1) plus tislelizumab (200 mg, day 2) every 3 weeks for 3 cycles; patients who responded received up to 8 DV cycles and 17 tislelizumab cycles. Main Outcomes and Measures The primary outcome was complete response (CR) of high-risk disease, defined as no high-grade tumor, T1 disease, carcinoma in situ, or progression. Secondary outcomes were response duration, progression-free survival, overall survival, and safety. Results Among 137 screened patients, 28 participants (median [IQR] age, 72 [67-74] years; 25 male [89%]) were included. Two preassessment withdrawals were counted as nonresponders in the all-treated analysis, which left 26 efficacy-evaluable patients. CR of high-risk disease was achieved in 19 of 26 (73.1%; 95% CI, 54.8%-91.3%), meeting the prespecified 70% alternative-rate goal. Among all 28, 19 responded (67.9%; 95% CI, 49.4%-86.3%), exceeding the 17-response exact binomial threshold. Both analyses met the primary criterion. Among responders, the 24-month sustained response was 83.5% (95% CI, 68.0%-100.0%), and no muscle invasive or metastatic progression occurred. Treatment-related adverse events occurred in 25 patients (89.3%), most commonly paresthesia (12 [42.9%]), alopecia (11 [39.3%]), and pruritus (10 [35.7%]); 4 (14.3%) had grade 3 to 4 events; 2 (7.1%) discontinued treatment; and none had grade 5 events. Conclusions and Relevance Findings of this nonrandomized clinical trial suggest that DV plus tislelizumab may show a high CR rate and durable disease control in patients with transurethrally unresectable ERBB2 -positive VHR NMIBC, supporting randomized clinical trials. Trial Registration ClinicalTrials.gov Identifier: NCT05495724