Zymeworks Halt Cancer Drug Development After Trial Setback

Zymeworks has halted development of its cancer drug after a trial setback. The biotechnology company is focused on discovering, developing, and commercializing multifunctional biotherapeutics to treat cancer and other serious diseases. Its lead product candidate, zanidatamab, targets HER2, while its second product candidate, zanidatamab zovodotin, combines a biparatopic antibody design with ZymeLink auristatin technology. The company has four preclinical candidates in its pipeline.

Vancouver, British Columbia, September 02, 2025 – Zymeworks Inc. (Nasdaq: ZYME), a clinical-stage biotechnology company, has announced the discontinuation of clinical development for ZW171, a T cell engager targeting mesothelin-driven cancers. The decision follows the completion of Phase 1 trial dose escalation cohorts in ovarian cancer and non-small cell lung cancer patients. While cytokine release syndrome was manageable, the trial revealed dose-limiting toxicities related to mesothelin-targeted effects. The company determined that further dose evaluation would not support a favorable benefit-risk profile [1].

Zymeworks' decision to discontinue ZW171 represents a significant setback in their oncology pipeline. The mesothelin-targeting T cell engager was being evaluated for gynecological, thoracic, and digestive system cancers - all areas with substantial unmet needs. The termination came after completing the planned dose escalation portion of the Phase 1 trial and establishing a maximum tolerated dose. The critical issue identified was an unfavorable benefit-risk profile due to dose-limiting toxicities consistent with mesothelin-related on-target off-tumor effects. This highlights a common challenge with mesothelin as a target - it's expressed not only on tumor cells but also on normal mesothelial cells lining the pleura, peritoneum, and pericardium [1].

The company continues to advance other pipeline candidates, including the ongoing Phase 1 trial of ZW191, planned Phase 1 study for ZW251 in 2025, and an IND filing for ZW209 in early 2026. Zymeworks' portfolio management approach, while disappointing for the mesothelin program, represents prudent resource allocation for a clinical-stage company with multiple candidates. The disconnect between promising preclinical activity and clinical reality with ZW171 also reinforces the limitations of preclinical models in predicting human toxicity profiles, particularly for novel modalities like T cell engagers that have complex safety considerations [1].

Zymeworks remains committed to its mission of improving the standard of care for difficult-to-treat diseases. The company's lead product candidate, zanidatamab, targets HER2, and its second product candidate, zanidatamab zovodotin, combines a biparatopic antibody design with ZymeLink auristatin technology. Zymeworks has four preclinical candidates in its pipeline [1].

References:
[1] https://www.stocktitan.net/news/ZYME/zymeworks-announces-decision-to-discontinue-clinical-development-of-qezs3habk5i6.html