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

Timothy A Yap1, David J Kwiatkowski2, Ibiayi Dagogo-Jack3

  • 1The University of Texas MD Anderson Cancer Center, Houston, TX, USA. tyap@mdanderson.org.

Nature Medicine
|October 19, 2025
PubMed

Insights

VT3989, a novel TEAD inhibitor, shows promise in treating mesothelioma by disrupting YAP signaling. Early trials indicate a favorable safety profile and promising efficacy, with an overall response rate of 32% in mesothelioma patients.

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.

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