What question did this study set out to answer?

The aim is to evaluate the efficacy and tolerability of ZW191, a novel FRα-targeted ADC, in advanced cancers versus existing treatments.

April 5, 2026

Abstract 1707: ZW191 - a differentiated FRα-targeted topoisomerase I antibody drug conjugate active in combination with standard of care drugs

Key Points

The aim is to evaluate the efficacy and tolerability of ZW191, a novel FRα-targeted ADC, in advanced cancers versus existing treatments.
Investigated ZW191 in combinations with carboplatin, paclitaxel, and bevacizumab in xenograft models.
Evaluated combination effects using 3D spheroid tumor cell models and the Bliss independence model.
Conducted a clinical landscape analysis comparing moderate potency ADC payloads with existing therapies.
ZW191 exhibited strong antitumor effects in combination with platinum-based drugs in ovarian cancer models.
The drug demonstrated improved cytotoxic activity correlated with higher levels of γH2AX, indicating effective DNA damage.
Clinical data suggests ZW191’s favorable tolerability allows for higher dosing than prior ADCs.

Abstract

Abstract ZW191 is a clinical stage differentiated FRα-targeted ADC under ongoing investigation for tolerability and efficacy in patients with advanced cancers, including ovarian, endometrial, and NSCLC (NCT06555744). ZW191 markedly improves on the FDA-approved FRα-targeted ADC mirvetuximab soravtansine in its efficacy in patient-derived xenograft tumors with both high and low level of FRα by virtue of its novel and highly effective FRα-targeted antibody and its novel ZD06519 TOPO1i payload. The by-design moderate potency of ZW191’s payload confers a best-in-class nonclinical tolerability profile, with an HNSTD of 60 mg/kg in NHP, potentially enabling its clinical application in combination with multiple other clinically relevant drug modalities and in various lines of treatment. Here, we demonstrate ZW191’s strong antitumor activity in a xenograft model of ovarian cancer when dosed in combination with each of the platinum-based drug carboplatin, the microtubule inhibitor paclitaxel, and the anti-angiogenic antibody bevacizumab. In multiple 3D spheroid tumor cell models in vitro, ZW191 demonstrates combination effects with poly (ADP-ribose) polymerase (PARP) inhibitor and platinum-based drugs as determined by the Bliss independence model of drug interactions. Mechanistically, ZW191’s TOPO1i payload and platins both drive DNA strand breaks in tumor cells, and we show the enhanced target-dependent cytotoxic activity of these drugs in combination is associated with greater levels of the DNA damage marker gamma H2AX (γH2AX). A clinical landscape analysis demonstrates that moderate potency ADC payloads facilitate higher dosing levels in the clinic. Together with encouraging early clinical data that highlight ZW191’s single agent activity and differentiated safety profile, these data reinforce its potential to achieve meaningful efficacy gains through combination with other agents. Citation Format: Sam Lawn, Andrea Hernández Rojas, Jodi Wong, Araba Sagoe-Wagner, Vincent Fung, Kurt Stahl, Ambroise Wu, Lemlem T. Degefie, Steve Seredick, Pranshul Chauhan, Raffaele Colombo, Jamie R. Rich, Stuart D. Barnscher, Paul A. Moore. ZW191 - a differentiated FRα-targeted topoisomerase I antibody drug conjugate active in combination with standard of care drugs abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1707.

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