YAP/TEAD inhibitor VT3989 in solid tumors: a phase 1/2 trial.

Constitutive YAP activation resulting from dysregulated Hippo signaling drives tumor progression in mesothelioma and other cancers. VT3989, a first-in-class potent oral TEAD palmitoylation inhibitor, disrupts YAP transcriptional activity. Here we report the first-in-human phase 1/2 trial findings evaluating VT3989 in refractory solid tumors with a focus on mesothelioma. This study is ongoing, and we report results from the dose escalation and non-prespecified interim efficacy results of the expansion cohorts for which recruitment is ongoing. Dose escalation (n = 85) and expansion (n = 87) cohorts included 172 patients (135 mesothelioma). VT3989 exhibited a favorable safety profile with mostly grade 1-2 toxicities, including increased urine albumin:creatinine ratio (UACR), proteinuria, peripheral edema and fatigue. Proteinuria was reversible with dose adjustment and did not result in renal impairment. The overall response rate (ORR) was 26% in 47 patients with mesothelioma treated at clinically optimized doses, whereas the ORR was 32% (disease control rate 86%; median progression-free survival 10 months) in 22 patients with mesothelioma when clinically optimized doses and UACR thresholds were incorporated. These data provide the first early clinical proof of concept for effectively drugging the Hippo-YAP-TEAD pathway. VT3989 was recently awarded orphan drug designation and fast-track designation for the treatment of mesothelioma by the US Food and Drug Administration (FDA). ClinicalTrials.gov Identifier: NCT04665206 .