Antibody-drug conjugates (ADCs) have transformed the landscape of targeted cancer therapy by combining the specificity of monoclonal antibodies with the potency of cytotoxic agents. ZW191*, a novel FRα-targeted ADC developed by Zymeworks, is at the forefront of this therapeutic evolution, offering potential benefits for patients with advanced ovarian, endometrial, and non-small cell lung cancer (NSCLC). Here, we summarize the latest clinical and preclinical data supporting ZW191’s differentiated profile, efficacy, and safety, as presented at the annual meeting of the American Association for Cancer Research (AACR), held April 17-22, 2026, in San Diego, CA.
Background and Rationale
Folate receptor alpha (FRα), a glycosylphosphatidylinositol-anchored glycoprotein encoded by the FOLR1 gene, is highly expressed in approximately 75% of high-grade non-mucinous (serous) ovarian carcinomas, more than 50% of endometrial cancers, and up to 70% of lung adenocarcinomas, making it an attractive therapeutic target. [1][2] While the US Food and Drug Administration (FDA)-approved FRα-targeted ADC, mirvetuximab soravtansine (Elahere®, AbbVie), has provided clinical benefit, limitations remain, particularly regarding efficacy in tumors with low FRα expression and tolerability at higher dosing levels.
ZW191 builds on this foundation with two key innovations: a highly effective, proprietary FRα-targeted antibody and a novel topoisomerase I inhibitor payload (ZD06519; TOPO1i). The payload’s moderate potency is intentionally designed to optimize therapeutic index, enabling higher dosing in the clinic and facilitating combination with other drug modalities.
Preclinical Efficacy and Mechanistic Insights
ZW191 exhibits robust antitumor activity in patient-derived xenograft (PDX) models of ovarian cancer, outperforming mirvetuximab soravtansine in both high- and low-FRα expression settings. In nonclinical studies, ZW191 demonstrates strong efficacy when combined with platinum-based agents (e.g., carboplatin), microtubule inhibitors (e.g., paclitaxel), and anti-angiogenic antibodies (e.g., bevacizumab). Furthermore, in 3D spheroid models, ZW191 shows synergistic or additive effects with PARP inhibitors and platinum agents, as assessed by the Bliss independence model.
Mechanistically, ZW191’s TOPO1i payload and platinum drugs both induce DNA strand breaks, thereby enhancing cytotoxicity when administered in combination. This is evidenced by increased levels of the DNA damage marker gamma H2AX (γH2AX) in treated tumor cells, indicating greater DNA damage and tumor cell kill.[3]
The nonclinical tolerability profile of ZW191 is best-in-class, with the highest non-severely toxic dose (HNSTD) of 60 mg/kg in non-human primates (NHPs). This broad therapeutic window offers significant flexibility for combination strategies in clinical settings.
Clinical Study Design and Patient Population
ZW191 is currently under investigation in a global, two-part, first-in-human (FIH) Phase 1 study (ZWI-ZW191-101; NCT06555744). Part 1 (dose-escalation) focused on evaluating safety, tolerability, and preliminary antitumor activity in patients with advanced, recurrent platinum-resistant ovarian cancer (PROC), endometrial cancer (EC), and NSCLC, regardless of FRα expression.[4]
A total of 51 patients (49 female; median age: 60 years, range 35–79) were enrolled and treated with ZW191 intravenously every 3 weeks at doses ranging from 1.6 to 11.2 mg/kg. Patients had received a median of 3 prior lines of systemic therapy (range 1–9) and had exhausted available treatment options. 67% remained on study treatment as of the data cut-off (December 1, 2025).[4]
Safety and Tolerability
ZW191 was generally well tolerated up to the highest tested dose. The most common Grade ≥3 treatment-related adverse events (TRAEs) included neutropenia (18%), anemia (10%), and thrombocytopenia (6%). Across all patients, severe (Grade ≥3) treatment-emergent adverse events (TEAEs) occurred in 55%, with most being Grade 3. Serious TEAEs occurred in 35%, and 20% discontinued due to adverse events. Grade 4 events were rare, and a single Grade 5 event—reported at the top dose—was not treatment-related. Importantly, the safety profile was manageable, with no unexpected toxicities observed.
The moderate potency of ZW191’s payload is believed to contribute to its broad therapeutic window and favorable tolerability, supporting further clinical development and enabling combination regimens with other anti-cancer agents.
Efficacy Outcomes
Among 48 response-evaluable patients, the unconfirmed objective response rate (ORR) was 52%. Notably, responses were observed across all levels of FRα expression—including low/negative, intermediate, and high—emphasizing the potential utility of ZW191 in a broader patient population than previously achievable with FRα-targeted ADCs.[4]
In the 6.4–9.6 mg/kg dose cohorts, patients with ovarian and endometrial cancer had unconfirmed ORRs of 61% and 57%, respectively. In platinum-resistant ovarian cancer, ZW191 achieved a confirmed ORR (cORR) of 61% in the 6.4–9.6 mg/kg range, with a median time to response of 6 weeks. Tumor regressions were observed in 68% of patients, and disease control was achieved in 94%. Median progression-free survival (PFS) was 7.6 months, and median duration of response was not reached at the time of data cut-off, indicating durable benefit.
In endometrial cancer, ZW191’s cORR was 40% across all doses and 57% in the 6.4–9.6 mg/kg cohort, with disease control rates of 80% and 86%, respectively. These results support the efficacy of ZW191 in heavily pretreated, difficult-to-treat patient populations.
Implications for Combination Therapy
ZW191’s design and tolerability profile make it an ideal candidate for combination strategies. Preclinical data demonstrate enhanced cytotoxic effects when ZW191 is combined with platinum agents, PARP inhibitors, and other standard-of-care drugs, supporting ongoing and future clinical studies exploring these regimens. The ability to safely administer ZW191 at higher doses than conventional ADCs may further improve outcomes by maximizing the therapeutic index.
Future Directions
Part 2a of the ongoing Phase 1 trial has completed enrollment and is evaluating dose optimization in ovarian cancer at 6.4 and 9.6 mg/kg. The results from this cohort will inform recommended dosing for future registration studies. The encouraging efficacy and safety data support continued development of ZW191 in ovarian, endometrial, and potentially other FRα-expressing malignancies.
ZW191 is a differentiated, next-generation FRα-targeted ADC demonstrating strong antitumor activity and a favorable safety profile in heavily pretreated patients with ovarian and endometrial cancers, regardless of FRα expression level. Its moderate-potency, novel TOPO1i payload, and high drug-to-antibody ratio provide a broad therapeutic window, enabling combination with other anticancer agents. These attributes position ZW191 as a promising candidate to address unmet medical needs and expand the reach of ADC therapy in solid tumors.
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Note: * ZW191 is a novel bystander active ADC comprised of a humanized IgG1 antibody conjugated to a novel camptothecin-based topoisomerase 1 inhibitor (TOPO1i) payload, ZD06519, via a maleimidocaproyl (MC) anchor and a glycyl glycyl phenylalanyl glycyl (GGFG)-aminomethyl (AM) cleavable linker at a drug-to-antibody ratio (DAR) of 8. [3]
Clinical trials
A Study of ZW191 in Participants With Solid Tumors – ClinicalTrials.gov ID NCT06555744
Highlights of prescribing information
Mirvetuximab soravtansine (Elahere®, AbbVie) [Prescribing Information]
References
[1] Zannoni GF, Santoro A, d’Amati A, D’Alessandris N, Scaglione G, Padial Urtueta B, Valente M, Narducci N, Addante F, Spadola S, Bragantini E, Angelico G. Folate Receptor Alpha in Advanced Epithelial Ovarian Cancer: Diagnostic Role and Therapeutic Implications of a Clinically Validated Biomarker. Int J Mol Sci. 2025 May 29;26(11):5222. doi: 10.3390/ijms26115222. PMID: 40508029; PMCID: PMC12154392.
[2] O’Shannessy DJ, Yu G, Smale R, Fu YS, Singhal S, Thiel RP, Somers EB, Vachani A. Folate receptor alpha expression in lung cancer: diagnostic and prognostic significance. Oncotarget. 2012 Apr;3(4):414-425. doi: 10.18632/oncotarget.519. PMID: 22547449; PMCID: PMC3380576.
[3] Lawn S, Rojas AH, Colombo R, Wong J, Wu K, Fung V, Lasalle M, Petersen ME, Degefie L, Sagoe-Wagner A, Urosev D, Yang L, Wu A, Kim C, Chua A, Stahl K, Winters GC, Fann JC, Rich J, Barnscher S. ZW191 – a FRα-targeting antibody drug conjugate with strong preclinical activity across multiple FRα-expressing indications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1862.
[4] LoRusso P, Sommerhalder D, Hasegawa K, Harano K, Tan DS, Yamamoto N, O’Malley DM, Moore KN, Church SE, Lu L, Mekan S, Chauha P, Lee JY. Phase 1 first-in-human multicenter open-label study of ZW191, a folate receptor α (FRα)-targeting antibody-drug conjugate (ADC), in patients with advanced solid tumors: Part 1 dose-escalation results [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT306.
Featured image San Diego, CA – The AACR 2026 Annual Meeting – Photo courtesy 2026 © AACR/Luke Franke. Used with permission.
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