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The clinical development of the mesothelin-directed T-cell engager ZW171 for the treatment of patients with gynecological, thoracic, and gastrointestinal (GI) cancers is being discontinued, according to an announcement from Zymeworks.1
The decision stemmed from data from planned cohorts of a phase 1 trial (NCT06523803), which was evaluating the agent in patients with ovarian cancer and non–small cell lung cancer (NSCLC). Based on results of the study, Zymeworks determined that further evaluation of the agent in dose expansion would be unlikely to support an acceptable risk:benefit profile for ZW171 given as monotherapy.
Patients currently receiving ZW171 as a part of the study will be allowed to continue treatment at investigator discretion. Those who have discontinued therapy will still be monitored as a part of the study’s safety follow-up.
“While this is a disappointing outcome given the promising preclinical activity observed with ZW171, we are deeply grateful to the patients, providers, and caregivers for their support and participation in the ZW171 phase 1 study,” Kenneth Galbraith, chair and chief executive officer of Zymeworks. “As part of Zymeworks’ disciplined approach to the management of our broad product portfolio, we are committed to careful and consistent evaluation of clinical progress for each product candidate to ensure our resources are directed towards those product candidates with the greatest potential impact for patients. We continue to advance our broader product pipeline, including the ongoing phase 1 trial of ZW191 and the initiation of a phase 1 study for ZW251 expected in 2025. We are also preparing an investigational new drug filing for ZW209, our DLL3-directed trispecific T-cell engager, planned in the first half of 2026.”
ZW171 Background and Phase 1 Trial Overview
Mesothelin is overexpressed in a variety of tumor types, and researchers have aimed at improving on early signs of efficacy and safety for agents targeting this glycoprotein.2 In preclinical studies, ZW171 had displayed the ability to induce potent preferential killing of mesothelin-overexpressing target cells and stimulate mesothelin-dependent T-cell activation.
The open-label, multicenter study was enrolling patients at least 18 years of age with pathologically confirmed, locally advanced unresectable and/or metastatic mesothelin-expressing cancers.3 Patients needed to have malignancies that were refractory to all available standard-of-care (SOC) treatment or cancers without SOC treatment available. Patients who were unable tolerate or refused SOC therapy were allowed to participate. Other key inclusion criteria comprised an ECOG performance status of 0 or 1, adequate organ function, and adequate cardiac left ventricular function, defined by a left ventricular ejection fraction of at least 50%.
The study excluded patients who received a prior allogenic tissue or solid organ transplantation within 5 years of enrollment; those with ongoing, clinically significant toxicity of grade 2 or higher from prior treatments; patients with advanced or metastatic, symptomatic visceral spread that could create short-term life-threatening complications; those with acute or chronic uncontrolled renal disease, pancreatitis, or liver disease; and patients with active or recurrent, clinically significant autoimmune disease requiring systemic high-dose corticosteroids or immunosuppressive drugs.
All patients received ZW171 in a dose-escalation manner.
Safety, including the incidence of dose-limiting toxicities, cytokine release syndrome, immune effector cell–associated neurotoxicity syndrome, and clinical abnormalities, served as a primary end point in parts 1 and 2 of the study; objective response rate (ORR) was a primary for part 2.
ORR was a secondary end point in part 1. In part 2, other secondary end points included duration of response, progression-free survival, disease control rate, overall survival, and pharmacokinetics.
References
- Zymeworks announces decision to discontinue clinical development of ZW171, a mesothelin-directed T cell engager. News release. Zymeworks. September 2, 2025. Accessed September 2, 2025. https://ir.zymeworks.com/news-releases/news-release-details/zymeworks-announces-decision-discontinue-clinical-development
- Afacan N, Piscitelli C, Zwierzchowski P, et al. ZW171, a T cell-engaging, bispecific antibody for the treatment of mesothelin-expressing solid tumors. Presented at: 2023 AACR Annual Meeting; April 14-19, 2023; Orlando, FL. Abstract 2942.
- A study of ZW171 in participants with advanced or metastatic mesothelin-expressing cancers. ClinicalTrials.gov. Updated July 22, 2025. Accessed September 2, 2025. https://clinicaltrials.gov/study/NCT06523803