Highlight
– VT3989, a first-in-class oral TEAD palmitoylation inhibitor, was evaluated in a first-in-human phase 1/2 study in refractory solid tumors with a prespecified focus on mesothelioma.
– In 135 patients with mesothelioma across dose-escalation and expansion cohorts, clinically optimized dosing yielded objective response rates (ORR) of 26–32% (with a disease control rate of 86% and median progression-free survival 10 months in an interim subgroup).
– The safety profile was predominantly grade 1–2; notable class-relevant events included increased urine albumin:creatinine ratio (UACR), reversible proteinuria, peripheral edema and fatigue without evidence of renal impairment when managed by dose modification.
Background: clinical need and biological rationale
Malignant pleural mesothelioma is an aggressive neoplasm with limited effective systemic therapies and a poor prognosis. Frequent alterations in Hippo pathway components (for example NF2, LATS1/2) or upstream regulators result in constitutive activation of YAP/TAZ transcriptional coactivators, which partner with TEAD family transcription factors to drive oncogenic programs including proliferation, survival and stromal remodeling. Because YAP/TEAD-driven transcription lacks conventional enzymatic pockets, it has been historically difficult to target directly. TEAD palmitoylation inhibitors are an emerging strategy to block YAP–TEAD transcriptional activity by disrupting TEAD function and its interaction with YAP, thereby inhibiting the transcriptional output of the dysregulated Hippo pathway. Demonstrating meaningful antitumor activity in humans would provide a key translational proof of concept for this approach and create a new therapeutic avenue for tumors dependent on Hippo–YAP signaling, notably mesothelioma.
Study design
This is a first-in-human, phase 1/2, open-label study evaluating VT3989 — an oral TEAD palmitoylation inhibitor — in patients with refractory solid tumors, with an emphasis on mesothelioma. The report covers dose-escalation and interim expansion cohort results from the ongoing program. Overall, 172 patients were treated across dose-escalation (n = 85) and expansion (n = 87) cohorts; 135 of these patients had mesothelioma.
Key elements reported include safety and tolerability, pharmacodynamic rationale of TEAD palmitoylation inhibition, and antitumor activity (overall response rate, disease control rate, progression-free survival) in mesothelioma cohorts at clinically optimized doses. The trial identifier is ClinicalTrials.gov NCT04665206.
Key findings: efficacy
VT3989 produced clinically meaningful antitumor activity in mesothelioma patients treated at clinically optimized doses.
– Overall response rate (ORR): In 47 patients with mesothelioma treated at clinically optimized doses, the ORR was 26%.
– When the analysis incorporated both clinically optimized dosing and prespecified urine albumin:creatinine ratio (UACR) thresholds to guide dose modifications, an interim subgroup of 22 mesothelioma patients showed an ORR of 32%, a disease control rate (DCR) of 86%, and a median progression-free survival (PFS) of 10 months.
These response rates are notable in a refractory mesothelioma population and represent the first reported clinical proof of concept that pharmacologic TEAD inhibition can yield objective tumor responses in humans.
Key findings: safety and tolerability
VT3989 was generally well tolerated. The adverse events observed were mainly grade 1–2 and included increased urine albumin:creatinine ratio (UACR), proteinuria, peripheral edema and fatigue. Importantly, episodes of proteinuria were reversible with dose adjustment and did not result in clinically meaningful renal impairment in the reported cohort.
The investigators reported that monitoring of UACR and protocol-defined thresholds for dose modification were effective risk management strategies. No unusual off-target toxicities were described in the report; full safety tables and longer follow-up will be required to characterize less frequent or late-onset events.
Interpretation and clinical significance
These results represent a milestone: VT3989 provides the first human evidence that the Hippo–YAP–TEAD axis can be pharmacologically targeted with an acceptable safety profile and yield antitumor activity in a disease where YAP activation is a known driver. An ORR in the 26–32% range and a median PFS of about 10 months in an interim cohort are encouraging in the context of refractory mesothelioma, where treatment options and response rates are limited.
The reversible proteinuria and UACR signal appear to be class-related and manageable with proactive monitoring and dose modifications. The absence of renal function decline in this early dataset is reassuring but requires confirmation in larger and longer studies.
Expert commentary: strengths, limitations and practical considerations
Strengths:
- Biology-driven drug development: VT3989 directly targets a central and mechanistically validated transcriptional axis in mesothelioma and other cancers.
- Meaningful single-agent activity: objective responses and disease control in a refractory population are notable for a first-in-human targeted agent against a previously intractable protein–protein interaction.
- Manageable safety profile with a clear monitoring parameter (UACR) and reversible toxicity.
Limitations and open questions:
- Interim and non-prespecified analyses: the most favorable response data were reported from a non-prespecified interim expansion subgroup and thus require validation in prespecified cohorts or randomized comparisons.
- Patient selection and biomarkers: the report does not provide granular data correlating genomic alterations (for example NF2, LATS1/2, or other Hippo pathway aberrations) or YAP/TEAD transcriptional signatures with response. Prospective biomarker development is critical to identify patients most likely to benefit and to understand mechanisms of sensitivity and resistance.
- Long-term safety and rare toxicities: first-in-human data give only an early window into safety. Renal-related signals need prolonged surveillance and mechanistic study.
- Generalizability beyond mesothelioma: although Hippo pathway activation occurs in multiple tumor types, clinical activity across other histologies will need confirmation in adequately powered cohorts.
Practical considerations for clinicians and trialists:
- UACR monitoring should be implemented early in trials and clinical use, with clear thresholds for dose interruption/reduction and re-challenge strategies.
- Integration of comprehensive genomic profiling and transcriptomic signatures into future VT3989 studies will help define predictive biomarkers and rational combination partners.
- Combination strategies: biologic rationale exists to combine TEAD inhibition with chemotherapy, antiangiogenic agents or immunotherapy — for example, YAP-driven programs can influence tumor microenvironment and immune evasion — but safety and sequence must be established in early-phase combination trials.
Implications for future research
Key next steps include prespecified expansion cohorts with biomarker-enriched designs, randomized studies comparing VT3989 to standard therapies or incorporating it into combination regimens, and translational studies to map on-target pharmacodynamics and mechanisms of acquired resistance. Longitudinal monitoring of renal biomarkers and standardized UACR management algorithms should be embedded in further development.
Conclusion
The phase 1/2 data for VT3989 represent a pivotal early advance: for the first time, direct pharmacologic inhibition of TEAD palmitoylation yields objective responses in human cancers driven by Hippo–YAP signaling, particularly mesothelioma. The safety profile — dominated by reversible proteinuria and modest systemic toxicities — is manageable with protocolized monitoring. Confirmation of efficacy in larger, prespecified cohorts, development of predictive biomarkers, and exploration of rational combinations will determine the long-term clinical impact of TEAD-targeted therapy.
Regulatory and trial information
VT3989 has received orphan drug designation and fast-track designation for the treatment of mesothelioma by the US Food and Drug Administration. ClinicalTrials.gov Identifier: NCT04665206.
References
1. Yap TA, Kwiatkowski DJ, Dagogo-Jack I, Offin M, Zauderer MG, Kratzke R, Desai J, Body A, Millward M, Tolcher AW, Raghav KPS, Thurston A, Post L, Dorr FA, Tang TT, Li Y, Sharma N, Kindler HL. YAP/TEAD inhibitor VT3989 in solid tumors: a phase 1/2 trial. Nat Med. 2025 Oct 19. doi: 10.1038/s41591-025-04029-3. Epub ahead of print. PMID: 41111090.
2. ClinicalTrials.gov. NCT04665206. https://clinicaltrials.gov/ct2/show/NCT04665206 (accessed 2025).
Funding
Funding sources and sponsor information are detailed in the primary manuscript (Yap et al., Nat Med 2025).
