A phase 1/2, first-in-human study of AVZO-103, a bispecific Nectin4/Trop2 antibody-drug conjugate (ADC), as monotherapy and in combination therapy in patients with locally advanced or metastatic urothelial cancer (UC) or other solid tumors.

Abstract

TPS908 Background: Nectin4 and TROP2 are transmembrane proteins frequently overexpressed in UC and other solid tumors, but with limited co-expression in normal tissue. Current single-target ADCs such as enfortumab vedotin (EV) have demonstrated clinical benefit, yet are limited by resistance mechanisms and safety concerns. AVZO-103 is a novel bispecific ADC designed to selectively target tumor cells expressing Nectin4 and TROP2. In preclinical xenograft studies including EV refractory models, AVZO-103 demonstrated robust tumor growth inhibition. By targeting both Nectin4 and TROP2, AVZO-103 potentially increases tumor cell coverage by addressing tumor heterogeneity of target expression while also delivering a potent topoisomerase I inhibitor, exatecan, to help overcome resistance to prior therapies. Methods: The Phase 1 part of AVZO-103-1001 study will assess the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary antitumor activity of AVZO-103 as monotherapy (Part A) and in combination with an immunotherapy (Part B). Part A will enroll ~80 patients in a Q3W escalating schedule using a BOIN design to determine the maximum tolerated dose and preliminary recommended Phase 2 dose. Eligible patients are ≥18 years of age, ECOG PS ≤1, life expectancy of > 3 months, ≤3 lines of cytotoxic chemotherapy in the metastatic setting (including non-topoisomerase inhibitor payload ADCs), with other prior therapies permitted including immunotherapy. Patients in Part A dose escalation have locally advanced or metastatic solid tumors known to express Nectin4 (UC, cervical cancer, triple-negative breast cancer, squamous cell carcinoma of the head and neck, non-squamous EGFR m NSCLC, and non-squamous NSCLC with no actionable genomic alterations) for whom standard therapies are no longer effective, appropriate, or declined by the patient. Backfill in Part A will enroll patients with locally advanced or metastatic UC. Part B will enroll ~35 patients, with doses to be guided by the outcomes of Part A. Primary objectives are safety/tolerability and secondary objectives include preliminary anti-tumor activity. Phase 2 will enroll ~240 patients. The trial is active and plans to enroll patients at centers across North America, Europe, and APAC. Clinical trial information: NCT07193511 .