Disitamab Vedotin Plus Tislelizumab in Transurethrally Unresectable, ERBB2-Positive, Non-Muscle-Invasive Bladder Cancer: A Nonrandomized Clinical Trial.

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.