The first-in-class YAP-TEAD inhibitor VT3989 has demonstrated promising antitumor activity and tolerability in patients with refractory mesothelioma, according to findings from a phase I/II trial presented at the European Society for Medical Oncology (ESMO) Congress 2025 (Abstract 920O) and published in Nature Medicine.
“This study has multiple important takeaways, including the demonstration of significant disease control even in this heavily pretreated population,” said presenting author Timothy Yap, MBBS, PhD, Professor of Investigational Cancer Therapeutics, and Vice President and Head of Clinical Development, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center. “The safety profile was also encouraging, with mainly low-grade adverse effects. These data were strong enough to support the continued clinical development of VT3989 in mesothelioma, and we look forward to the next clinical study of the compound.”
Timothy Yap, MBBS, PhD
Rationale and Study Methods
In mesothelioma, tumor progression is often driven by dysregulated Hippo pathway signaling that leads to YAP activation.
VT3989 is a first-in-class potent oral TEAD palmitoylation inhibitor that can disrupt YAP transcriptional activity. The novel agent is being explored in phase I/II trials for patients with advanced solid tumors.
This study explored dose escalation for VT3989 at continuous and intermittent dosing schedules for patients with advanced cancer. Dose adjustments were guided using urine albumin creatinine ratios. Expansion cohorts focused on patients with refractory mesothelioma treated with intermittent dosing schedules.
Key Study Findings
Of 172 patients enrolled, the study included 135 patients with mesothelioma. The study found that doses of VT3839 at 50 or 100 mg administered in a 2-weeks-on and 2-weeks-off schedule were clinically active; 100 mg was chosen as the recommended dose for expansion. The researchers noted that intermittent scheduling can limit the long-term accumulation of the drug while still maintaining therapeutic levels during off periods due to the drug's long half-life.
Twenty-two patients with mesothelioma were treated with this schedule and optimal urine albumin creatinine ratio thresholds for modifications of dosing were used. Among this subgroup, 7 patients achieved partial responses, for an objective response rate of 32%; another 12 patients had stable disease, for a disease control rate of 86%. The median progression-free survival was 40 weeks (95% confidence interval [CI] = 23 weeks to not evaluable).
Across different doses, patients with mesothelioma achieved durable partial responses, even after prior immunotherapy receipt and whether or not their tumor had NF2 mutations.
Treatment with VT3989 was considered safe and the agent was well tolerated. Mostly low-grade toxicities were reported, including treatment-related increased urine albumin creatinine ratios in 31%, proteinuria in 28%, peripheral edema in 23%, and fatigue in 20%.
The FDA has granted an Orphan Drug Designation and Fast Track Designation to VT3989 for the treatment of mesothelioma. Additionally, based on the results of this study, a phase III trial is planned to further explore the use of VT3989 in mesothelioma.
Disclosure: The trial was funded by Vivace Therapeutics. For full disclosures of the study authors, visit nature.com.
