Zymeworks Inc. has announced the dosing of the first patient in a Phase 1 clinical trial evaluating ZW191, an antibody-drug conjugate (ADC), for the treatment of advanced folate receptor-α (FRα)-expressing solid tumors. This global, multi-center study (NCT06555744) aims to assess the safety and tolerability of ZW191 in patients with advanced ovarian, endometrial, and non-small cell lung cancers (NSCLC).
ZW191 is designed to target FRα, a protein found on the surface of various tumors, including ovarian, endometrial, and lung cancers. The ADC is engineered to internalize into FRα-expressing cells and release ZD06519, a novel proprietary topoisomerase-1 inhibitor developed by Zymeworks, with the goal of killing tumor cells.
Trial Design and Objectives
The Phase 1 trial is a two-part study expected to enroll 145 adult patients with advanced FRα-expressing cancers across sites in North America, Europe, and the Asia-Pacific region. Part one will focus on dose escalation to evaluate the safety and tolerability of ZW191 in patients with advanced ovarian, endometrial, and NSCLC cancers. Secondary endpoints include assessing pharmacokinetics and confirmed objective response rate. Part two will further evaluate safety and explore the potential anti-tumor activity of ZW191.
Rationale for ZW191
FRα is highly expressed in several cancers, including approximately 75% of high-grade serous ovarian carcinomas and 70% of lung adenocarcinomas. This makes FRα a promising target for ADCs. Preclinical data presented at the American Association for Cancer Research (AACR) Annual Meeting in 2024 indicated that ZW191 demonstrated greater anti-tumor activity compared to benchmark in FRα-expressing tumor models and was well-tolerated in cynomolgus monkeys at doses up to 60 mg/kg.
Executive Commentary
"Our team is excited to initiate this important clinical trial to assess the safety and tolerability of ZW191...in patients with difficult-to-treat cancers," said Jeff Smith, M.D., FRCP, Executive Vice President and Chief Medical Officer at Zymeworks. "This global study represents a significant milestone in our mission to bring innovative and urgently needed therapies to patients in need."
Zymeworks' Pipeline
This trial initiation follows the recent commencement of a Phase 1 trial for ZW171, marking further progress in advancing Zymeworks' wholly-owned pipeline. Zymeworks is also developing zanidatamab, a HER2-targeted bispecific antibody, which has a Biologics License Application (BLA) under Priority Review with the U.S. FDA for biliary tract cancer (BTC).
