Martin Gutierrez

Comprehensive Target Engagement by the EZH2 Inhibitor Tulmimetostat Allows for Targeting of ARID1A Mutant Cancers

Abstract Recurrent somatic mutations in the BRG1/BRM-associated factor (BAF) chromatin remodeling complex subunit ARID1A occur frequently in advanced urothelial, endometrial, and ovarian clear cell carcinomas, creating an alternative chromatin state that may be exploited therapeutically. The histone methyltransferase EZH2 has been previously identified as targetable vulnerability in the context of ARID1A mutations. In this study, we describe the discovery of tulmimetostat, an orally available, clinical stage EZH2 inhibitor, and it elucidates the aspects of its application potential in ARID1A mutant tumors. Tulmimetostat administration achieved efficacy in multiple ARID1A mutant bladder, ovarian, and endometrial tumor models and improved cisplatin response in chemotherapy-resistant models. Consistent with its comprehensive and durable level of target coverage, tulmimetostat demonstrated greater efficacy than other PRC2-targeted inhibitors at comparable or lower exposures in a bladder cancer xenograft mouse model. Tulmimetostat mediated extensive changes in gene expression, in addition to a profound reduction in global H3K27me3 levels in tumors. Phase I clinical pharmacokinetic and pharmacodynamic data indicated that tulmimetostat exhibits durable exposure and profound target engagement. Importantly, a tulmimetostat controlled gene expression signature identified in whole blood from a cohort of 32 patients with cancer correlated with tulmimetostat exposure, representing a pharmacodynamic marker for the assessment of target coverage for PRC2-targeted agents in the clinic. Collectively, these data suggest that tulmimetostat has the potential to achieve clinical benefit in solid tumors as a monotherapy but also in combination with chemotherapeutic agents, and may be beneficial in various indications with recurrent ARID1A mutations. Significance: The EZH2 inhibitor tulmimetostat achieves comprehensive target inhibition in ARID1A mutant solid tumor models and cancer patients that can be assessed with a pharmacodynamic gene signature in peripheral blood.

Phase 2 Study of Zilovertamab Vedotin in Participants with Metastatic Solid Tumors

Abstract Purpose: Zilovertamab vedotin, an antibody–drug conjugate targeting receptor tyrosine kinase–like orphan receptor 1 (ROR1), had manageable safety and promising antitumor activity in participants with relapsed or refractory non–Hodgkin lymphomas. We evaluated zilovertamab vedotin in participants with previously treated metastatic solid tumors. Patients and Methods: This phase 2, open-label, nonrandomized study (NCT04504916) enrolled participants with metastatic triple-negative breast cancer, hormone receptor–positive breast cancer, nonsquamous non–small-cell lung cancer, platinum-resistant ovarian cancer, or pancreatic cancer. Participants received zilovertamab vedotin ≤2.5 mg/kg once every 3 weeks (Q1/3W) or <1.75 mg/kg twice every 3 weeks (Q2/3W). The primary endpoint was objective response rate per RECIST version 1.1 by blinded independent central review. ROR1 protein expression was correlated with clinical outcomes. Results: A total of 102 participants were enrolled (Q1/3W, n = 70; Q2/3W, n = 32). The objective response rate was 1% [95% confidence interval (CI), 0%–8%] with Q1/3W dosing (one partial response, hormone receptor–positive/HER2-negative breast cancer cohort) and 0% with Q2/3W dosing. The median progression-free survival (95% CI) was 2.3 (2.0–4.1) and 1.9 (1.7–2.1) months, respectively; the median overall survival (95% CI) was 8.3 (5.2–10.3) and 5.5 (4.4–11.0) months, respectively. Across dosing regimens, treatment-related adverse events were reported in 85 participants (83%), most commonly fatigue (29%) and nausea (28%). Treatment-related peripheral neuropathy occurred in 8%. Treatment-related adverse events led to dose interruption/reduction in 32 participants (31%) and permanent treatment discontinuation in 7 (7%). Tissue for ROR1 IHC was available on 17 participants, with only 3 (all nonresponders) showing ROR1 expression. Conclusions: Zilovertamab vedotin had minimal antitumor activity, with only a single responder, and manageable safety in participants with previously treated metastatic solid tumors. Significance: Zilovertamab vedotin had minimal antitumor activity and manageable safety in participants with previously treated metastatic solid tumors of various histologic subtypes. The results suggest that further development of zilovertamab vedotin in these solid tumors is not warranted.