IZABRIGHT-Bladder01: A randomized, open-label, phase 2/3 trial of izalontamab brengitecan (iza-bren; BL-B01D1), an EGFR x HER3 bispecific antibody-drug conjugate (ADC), vs platinum-based chemotherapy (PBC) for patients (pts) with advanced urothelial cancer (aUC) and disease progression on or after immunotherapy.

TPS883 Background: While ADC + immunotherapy has been transformative as first-line therapy for aUC, treatment options are limited for pts who progress on or after standard of care immunotherapy-based therapies. Iza-bren is a potentially first-in-class ADC composed of an EGFR x HER3 bispecific antibody, conjugated to a novel topo I inhibitor payload (Ed-04) via a stable tetrapeptide-based cleavable linker. Iza-bren induces tumor cell death via the cytotoxic Ed-04 payload, antibody-dependent cellular cytotoxicity, and inhibition of EGFR and HER3 signaling (both highly expressed in UC). Early-phase study data showed promising antitumor activity and a manageable safety profile in heavily pretreated locally advanced/metastatic tumors, including UC (Ye et al, ESMO 2024). This global, randomized, open-label, phase 2/3 trial evaluates the efficacy and safety of iza-bren vs PBC (gemcitabine + cisplatin or carboplatin) in pts with aUC who progressed on or after anti–PD-(L)1-based therapy. Methods: Key inclusion criteria: adults with histologically/cytologically confirmed advanced transitional cell carcinoma (renal pelvis, ureter, bladder, or urethra), ECOG performance status 0–1, measurable disease per RECIST v1.1, progression or recurrence on or after anti–PD-(L)1-based therapy, and a tumor biopsy collected within 5 years. Pts must be eligible for a PBC regimen with cisplatin or carboplatin and have a ≥ 12-month platinum-free interval. Key exclusions: prior treatment with EGFR and/or HER3-targeted ADCs; topo I inhibitors and/or > 2 prior systemic regimens in any setting. The study comprises 2 parts: phase 2 (dose optimization) and phase 3 (efficacy and safety at recommended phase 3 dose [RP3D]). In phase 2, ~90 pts will be randomized 1:1:1 to iza-bren dose 1 or 2 IV on days 1 and 8 every 3 weeks (D1D8 Q3W) in 21-day cycles, or PBC (cisplatin 70 mg/m 2 IV D1 Q3W or carboplatin AUC 4.5 or 5.0 IV D1 Q3W, + gemcitabine 1000 mg/m 2 D1D8 Q3W for up to 6 cycles). The phase 2 primary endpoint is to determine RP3D (based on safety, efficacy, and PK/PD). Secondary endpoints include objective response rate (ORR), duration of response (DOR), and progression-free survival (PFS) (each per RECIST v1.1 by investigator), overall survival (OS), and PK. In phase 3, ~380 pts will be randomized 1:1 to iza-bren at RP3D or PBC. Treatment continues until progression / unacceptable toxicity (PBC limited to 6 cycles). Phase 3 dual primary endpoints are OS and PFS per RECIST v1.1 by blinded independent central review (BICR). Secondary endpoints include ORR, DOR (each per RECIST v1.1 by BICR), and time to definitive deterioration (per EORTC QLQ-C30). Further HRQoL is exploratory. Enrollment is ongoing (ClinicalTrials.gov: NCT07106762). Clinical trial information: NCT07106762 .