Zymeworks Inc. announced the voluntary discontinuation of clinical development for ZW171, a mesothelin-directed T cell engager designed to treat gynecological, thoracic, and digestive system cancers. The decision follows completion of planned dose escalation cohorts in the Phase 1 trial, which established a maximum tolerated dose but revealed safety concerns that would preclude further development.
Phase 1 Trial Results Drive Discontinuation Decision
The Phase 1 study evaluated ZW171 in patients with ovarian cancer and non-small cell lung cancer. After completing the planned dose escalation cohorts and establishing a maximum tolerated dose, Zymeworks determined that further dose evaluation would be unlikely to support a benefit-risk profile consistent with the desired monotherapy target product profile.
While cytokine release syndrome was well-managed during the Phase 1 study, dose-limiting toxicities were consistent with mesothelin-related on-target off-tumor toxicity. This finding represents a significant challenge for mesothelin-targeted therapeutics, as the target is well-recognized but historically challenging to address safely.
Mesothelin as a Therapeutic Target
ZW171 was designed to address cancers driven by mesothelin, which the company describes as "a well-recognized but historically challenging target." The on-target off-tumor toxicity observed in the trial highlights the difficulties associated with targeting mesothelin, as the protein is expressed in normal tissues as well as tumor cells.
Ongoing participants in the Phase 1 trial will continue treatment at the discretion of their investigator, and participants who have discontinued treatment will continue safety follow-up according to the study protocol.
Company Response and Strategic Focus
"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," said Kenneth Galbraith, Chair and Chief Executive Officer of Zymeworks.
Galbraith emphasized the company's disciplined approach to portfolio management, stating that Zymeworks is "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."
Pipeline Advancement Continues
Despite the ZW171 setback, Zymeworks continues to advance its broader product pipeline. The company is currently conducting a Phase 1 trial of ZW191 and expects to initiate a Phase 1 study for ZW251 in 2025. Additionally, Zymeworks is preparing an IND filing for ZW209, a DLL3-directed trispecific T cell engager, planned for the first half of 2026.
The company's approved product zanidatamab, a HER2-targeted bispecific antibody, has received accelerated approval from the U.S. FDA, conditional approval from the NMPA in China, and conditional marketing authorization from the European Commission for treating adults with previously treated, unresectable or metastatic HER2-positive biliary tract cancer. It represents the first and only dual HER2-targeted bispecific antibody approved for this indication in the U.S., Europe, and China.
