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

Area of Science:

• Oncology
• Molecular Biology
• Drug Development

Background:

• Dysregulated Hippo signaling and constitutive YAP activation drive mesothelioma progression.
• Targeting the YAP-TEAD pathway presents a therapeutic strategy for cancers, including mesothelioma.
• VT3989 is a first-in-class oral TEAD palmitoylation inhibitor designed to disrupt YAP transcriptional activity.

Purpose of the Study:

• To evaluate the safety and efficacy of VT3989 in a first-in-human phase 1/2 trial for patients with refractory solid tumors, with a focus on mesothelioma.
• To report interim efficacy results from dose escalation and expansion cohorts.
• To provide early clinical proof of concept for targeting the Hippo-YAP-TEAD pathway.

Main Methods:

• Phase 1/2 clinical trial including dose escalation (n=85) and expansion (n=87) cohorts.
• 172 patients enrolled, with 135 diagnosed with mesothelioma.
• Interim efficacy and safety data were analyzed from ongoing recruitment.

Main Results:

• VT3989 demonstrated a favorable safety profile with manageable toxicities, primarily grade 1-2.
• Increased urine albumin:creatinine ratio (UACR) and proteinuria were observed but reversible without renal impairment.
• An overall response rate (ORR) of 32% and a disease control rate of 86% were observed in mesothelioma patients at optimized doses and UACR thresholds, with a median progression-free survival of 10 months.

Conclusions:

• VT3989 exhibits a promising safety and efficacy profile for mesothelioma treatment.
• These findings represent the first clinical validation of targeting the Hippo-YAP-TEAD pathway.
• VT3989 has received orphan drug and fast-track designations from the FDA for mesothelioma treatment.