FDA Grants Fast-Track Designation to FRα ADC in Advanced PROC

The FDA has granted fast track designation to ZW191, a novel folate receptor α (FRα)–targeting antibody-drug conjugate (ADC), for the treatment of patients with advanced or metastatic platinum-resistant ovarian cancer, according to a press release from the developer, Zymeworks Inc.¹ The designation applies to patients regardless of their FRα expression levels, potentially addressing a significant unmet need in the management of difficult-to-treat gynecologic malignancies.

ZW191 is designed as a differentiated ADC utilizing a humanized IgG1 antibody conjugated to a proprietary Top1 inhibitor payload, ZD06519. The agent’s mechanism of action involves target binding and receptor-mediated internalization, followed by the intracellular release of a bystander-active payload, which may enhance efficacy in tumors with heterogeneous FRα expression.

“Receiving fast track designation for ZW191 highlights the potential of this program to address significant unmet medical needs for patients with previously treated advanced ovarian cancer. Notably, the designation was granted irrespective of FRα expression highlighting ZW191’s potential of extending treatment benefits to a broad group of patients without need for biomarker selection,” stated Sabeen Mekan, MD, senior vice president and chief medical officer at Zymeworks, in the press release.¹ “This designation also further reinforces our expertise in ADC development, and we look forward to working closely with the FDA to advance this program for patients with difficult-to-treat cancers.”

How effective/safe is ZW191 in patients with cancer?

Preliminary efficacy findings from a phase 1 trial (NCT06555744) of ZW191 in patients with solid tumors were recently reported during a poster presentation at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.² In a cohort of 27 response-evaluable patients across various dose levels, the objective response rate (ORR) was 44%; among patients who received 6.4 mg/kg to 9.6 mg/kg, the ORR was 53%. Among the subset of patients with gynecological cancers (n = 24), the ORR was 50% across all dose levels; across doses from 6.4 mg/kg to 9.6 mg/kg, the ORR was 64%. Notably, investigators observed clinical responses starting at the 3.2 mg/kg dose level and in patients whose tumors exhibited low or negative FRα expression levels.

Safety data from the phase 1 trial indicated that ZW191 maintained a manageable toxicity profile with no reported treatment-related deaths or discontinuations due to adverse events (AEs) as of the primary data cutoff. The most frequent grade 3 or higher treatment-related AEs included anemia in 10% of patients, followed by neutropenia and thrombocytopenia, each occurring in 5% of the study population. Investigators noted that dose reductions and delays were infrequent, supporting the agent’s broad therapeutic window.

Further, the maximum tolerated dose was identified to be 11.2 mg/kg. Two doses were selected for dose optimization, being 6.4 and 9.6 mg/kg, with 30 patient cohorts planned for each.

How was the phase 1 trial evaluating ZW191 designed?

The ongoing phase 1 first-in-human multicenter open-label study is evaluating ZW191 in patients with advanced solid tumors, including ovarian, endometrial, and non–small cell lung cancers.³ The trial enrolled 41 patients to receive intravenous ZW191 from 1.6 to 11.2 mg/kg.

The primary end points of the trial were incidence of dose limiting toxicities, incidence of adverse events, incidence of clinical laboratory abnormalities, and confirmed objective response rate. Secondary end points included clinical benefit rate, duration of response, disease control rate, and progression-free survival.

Patient eligibility for the trial required a pathologically or cytologically confirmed diagnosis of locally advanced, recurrent, or metastatic solid tumors. Eligible participants must have measurable disease per RECIST v1.1 and an ECOG performance status of 0 or 1. Exclusion criteria include prior treatment with any topoisomerase 1 inhibitor–based ADC, known additional malignancy that is progressing or requires active treatment, and acute or chronic uncontrolled renal disease, pancreatitis, or liver disease.

References

1. Zymeworks receives U.S. FDA Fast Track designation for ZW191, an FRα-targeting antibody-drug conjugate. News release. Yahoo Finance. March 30, 2026. Accessed March 30, 2026. https://tinyurl.com/ahms5d92
2. A study of ZW191 in participants with solid tumors. ClinicalTrials.gov. Updated March 6, 2026. Accessed March 30, 2026. https://tinyurl.com/ym49586a
3. Zymeworks presents initial clinical data from the phase 1 trial of ZW191, an antibody-drug conjugate targeting folate receptor-α at AACR-NCI-EORTC conference. News release. Zymeworks Inc. October 23, 2025. Accessed March 30, 2026. https://tinyurl.com/5x5v4vyh