Zymeworks Inc. has announced the dosing of the first patient in a Phase 1 clinical trial evaluating ZW171, a novel bispecific antibody, for the treatment of advanced or metastatic ovarian cancer, non-small cell lung cancer (NSCLC), and other mesothelin (MSLN)-expressing cancers. The trial, identified as NCT06523803, aims to assess the safety and tolerability of ZW171 in this patient population. This marks a significant step in Zymeworks' effort to develop new treatments for difficult-to-treat cancers.
ZW171: A Bispecific Antibody Targeting Mesothelin
ZW171 is designed to enable T cell-mediated tumor cell killing by simultaneously binding to the extracellular domain of MSLN on tumor cells and engaging CD3 on T cells. Mesothelin is highly expressed in various tumors, including ovarian cancer (~84%) and NSCLC (~36%), making it an attractive target for cancer therapy. The unique 2+1 format and incorporation of a novel low-affinity anti-CD3 binder aims to improve the therapeutic window in patients by limiting on-target, off-tumor effects and cytokine release syndrome (CRS) while maintaining potent anti-tumor activity against MSLN-expressing cancers.
Phase 1 Trial Design and Objectives
The Phase 1 study is a two-part, open-label, multi-center trial expected to enroll approximately 160 adult patients with advanced MSLN-expressing cancers. Part 1 will focus on dose escalation in patients with advanced ovarian and NSCLC to evaluate the safety and tolerability of ZW171. Secondary endpoints include assessing pharmacokinetics and confirmed objective response rate. Part 2 will involve dose expansion in three cohorts: ovarian cancer, NSCLC, and a basket cohort enrolling patients with any MSLN-expression. This part will evaluate the anti-tumor activity of ZW171, with primary endpoints focused on safety and tolerability and secondary endpoints assessing progression-free survival, duration of response rates, and overall survival. The study will be conducted at sites in the United States, Europe, and the Asia-Pacific region.
Preclinical Evidence
Preclinical studies have demonstrated that ZW171 exhibits potent preferential killing of MSLN-overexpressing target cells and stimulates MSLN-dependent T cell activation, mitigating the risk of on-target-off tumor toxicity and peripheral T cell activation and cytokine release syndrome. Data presented at the American Association for Cancer Research (AACR) Annual Meeting in 2023 showed that ZW171 has greater anti-tumor activity compared to benchmark in MSLN-expressing tumor models and is well tolerated in cynomolgus monkeys up to 30 mg/kg.
Expert Commentary
"We are very pleased to have initiated the clinical evaluation of ZW171 for the treatment of patients with ovarian cancer and NSCLC, where it has the potential to be a highly effective therapy with favorable tolerability based on our preclinical research results," said Jeff Smith, M.D., FRCP, Executive Vice President and Chief Medical Officer at Zymeworks. He added, "Initiation of this trial marks a significant step forward in our effort to bring a potential new treatment to people living with difficult to treat cancers and highlights our goal to advance two therapeutic candidates, ZW171 and ZW191, into clinical studies in 2024."
