VT3989 TEAD Inhibitor Trial Opens to Mesothelioma Patients
VT3989, a first-in-class YAP/TEAD inhibitor from Vivace Therapeutics, is being tested in a Phase I/II mesothelioma trial (NCT04665206).
A Phase I/II trial is testing VT3989, an experimental drug that works through a mechanism never before targeted in approved cancer therapy, in people with mesothelioma and other advanced solid tumors.
The trial (NCT04665206) is sponsored by Vivace Therapeutics and evaluates VT3989, a first-in-class YAP/TEAD inhibitor, given alone or in combination with other cancer drugs. It is currently recruiting and aims to enroll up to 434 participants across sites in the United States and Australia.
What the Trial Is Testing
VT3989 belongs to a new class of drugs called YAP/TEAD inhibitors. They target the Hippo signaling pathway, which controls how cells grow and divide. When this pathway breaks down, a protein called YAP can drive uncontrolled tumor growth. VT3989 blocks the TEAD protein that YAP depends on, which is meant to shut off that growth signal. Mesothelioma is one of the cancers most often linked to a damaged Hippo pathway, which is why the disease is a focus of this study.
The trial is an open-label study with three parts:
- Dose escalation: the first phase used a standard 3+3 design to find a safe, tolerable dose of VT3989 given on its own. This part is no longer recruiting.
- Dose expansion: additional groups received VT3989 alone to study mesothelioma and tumors with alterations in the NF2, YAP, or TAZ genes. This part is no longer recruiting.
- Combination: the currently recruiting part pairs VT3989 with other cancer drugs across three cohorts.
According to the trial record, the combination cohorts are:
- Cohort A: VT3989 plus nivolumab and ipilimumab, two immune checkpoint inhibitors, for mesothelioma
- Cohort B: VT3989 plus osimertinib, a targeted therapy, for non-small cell lung cancer
- Cohort C: VT3989 plus pemetrexed and carboplatin, standard chemotherapy, for pleural mesothelioma
Who Can Participate
The trial is open to adults aged 18 and older with confirmed metastatic or unresectable mesothelioma, or with locally advanced or metastatic non-small cell lung cancer carrying specific mutations. Based on the trial record, key requirements include:
- Measurable disease by RECIST version 1.1 criteria
- An ECOG performance status of 0 or 1, meaning the person is fully active or restricted only in strenuous activity
- Adequate organ function
People are not eligible if they have active brain or central nervous system tumors, untreated infections including HIV or active hepatitis B or C, significant cardiovascular disease, or a heart-rhythm measurement (QTcF) above 470 milliseconds. Anyone who has previously received a TEAD inhibitor cannot enroll.
The trial is listed on ClinicalTrials.gov as NCT04665206. People interested in screening should review the full eligibility criteria there and discuss the study with their oncologist. The listed study director is Neelesh Sharma, MD, of Vivace Therapeutics.
What the Drug Does
VT3989 is taken as a capsule. The trial record lists dose levels of 25, 50, 100, 150, and 200 milligrams, given in 21-day or 28-day cycles depending on the part of the study. The drug is the first of its kind to reach patients by blocking TEAD, a step the YAP protein needs to switch on tumor-growth genes.
The trial’s main goals are to measure safety. The two primary outcomes are how often dose-limiting toxicity occurs in the first 21 days and how often general side effects occur over the course of treatment. Secondary goals include tumor response by RECIST criteria, how the body processes the drug, progression-free survival, and overall survival measured at 6, 12, 18, and 24 months.
Early Results Reported Elsewhere
While this trial record describes how the study is designed and does not report outcomes, the research team has presented early findings in other settings.
At the 2025 European Society for Medical Oncology (ESMO) Congress, investigators presented Phase I/II data on VT3989 and published them at the same time in Nature Medicine. Timothy Yap, MBBS, PhD, of The University of Texas MD Anderson Cancer Center, presented the work. According to MD Anderson and a report in The ASCO Post, the trial had enrolled 172 patients in total, including 135 with refractory mesothelioma, meaning their cancer had stopped responding to prior treatment.
Among 22 mesothelioma patients treated on a recommended intermittent dosing schedule, 7 had partial responses, for an objective response rate of 32%, and 12 had stable disease, for a disease control rate of 86%. The reported median progression-free survival in that group was 40 weeks. All 22 had previously received immunotherapy, and most had received chemotherapy. Reported side effects were mainly low grade.
These figures come from the ESMO 2025 presentation and a 22-patient subgroup, not from the trial record itself. Early-phase results in small groups can change as more patients are studied.
Why This Trial Matters
Most approved mesothelioma treatments fall into a few categories: surgery, chemotherapy, and immune checkpoint inhibitors. VT3989 takes a different route by going after the Hippo pathway, a growth-control system that is frequently disrupted in mesothelioma. Investigators have described it as the first clinical proof-of-concept for blocking this part of the pathway.
The drug has drawn regulatory attention. According to The ASCO Post and CancerNetwork, the FDA has granted VT3989 both Orphan Drug designation and Fast Track designation for the treatment of mesothelioma. Orphan Drug status is reserved for treatments aimed at rare diseases, and Fast Track is meant to speed the review of drugs that address a serious condition with unmet need.
Limitations to Consider
This is an early-phase study. Its primary purpose is to assess safety and find the right dose, not to prove that VT3989 works better than existing options. The reported response numbers come from a small subgroup and from outside sources, not from the trial record, and they have not been confirmed in a large, randomized study.
The trial enrolls at a limited number of academic centers in the United States and Australia, so location may be a barrier for some people. As with any early trial, meaningful long-term survival data will take years to mature. The estimated primary completion date listed in the trial record is November 2029.
References
ClinicalTrials.gov. Study to Evaluate VT3989 in Patients With Metastatic Solid Tumors (NCT04665206).
https://clinicaltrials.gov/study/NCT04665206
UT MD Anderson Cancer Center. ESMO 2025: VT3989 continues to show promising early results in patients with advanced mesothelioma.
https://www.mdanderson.org/newsroom/research-newsroom/esmo-2025--vt3989-continues-to-show-promising-early-results-in-p.h00-159780390.html
The ASCO Post. VT3989 Demonstrates Antitumor Activity and Tolerability in Refractory Mesothelioma.
https://ascopost.com/news/october-2025/vt3989-demonstrates-antitumor-activity-and-tolerability-in-refractory-mesothelioma/
CancerNetwork. VT3989 Receives Orphan Drug Designation for the Treatment of Mesothelioma.
https://www.cancernetwork.com/view/vt3989-receives-orphan-drug-designation-for-the-treatment-of-mesothelioma
Reader Q&A
Frequently Asked Questions
What drug is being tested in trial NCT04665206?
The lead drug is VT3989, a first-in-class YAP/TEAD inhibitor developed by Vivace Therapeutics. It is taken as a capsule. In the combination part of the study, it is paired with other drugs depending on the cohort: nivolumab and ipilimumab for mesothelioma, osimertinib for non-small cell lung cancer, or pemetrexed and carboplatin for pleural mesothelioma.
How does a YAP/TEAD inhibitor work?
A YAP/TEAD inhibitor targets the Hippo signaling pathway, which normally keeps cell growth in check. When the pathway is disrupted, a protein called YAP can drive tumor growth by activating genes through a partner protein called TEAD. VT3989 blocks TEAD so that YAP can no longer switch those genes on. Mesothelioma is one of the cancers most commonly associated with a damaged Hippo pathway.
Who is eligible for the VT3989 mesothelioma trial?
The trial is open to adults aged 18 and older with confirmed metastatic or unresectable mesothelioma, or with certain forms of non-small cell lung cancer. Participants need measurable disease, an ECOG performance status of 0 or 1, and adequate organ function. People with active brain tumors, untreated infections, significant heart disease, or prior treatment with a TEAD inhibitor are not eligible.
Is VT3989 approved by the FDA?
No. VT3989 is investigational and is being studied in this trial. According to The ASCO Post and CancerNetwork, the FDA has granted it Orphan Drug designation and Fast Track designation for mesothelioma, which are steps that support development of a drug for a rare and serious disease, but they are not the same as approval.
Where is the VT3989 trial being conducted?
According to the trial record, sites are located in the United States, including San Francisco, Chicago, Boston, Minneapolis, New York, Houston, San Antonio, and Arlington, Virginia, as well as in Australia near Melbourne and Perth. The most current site list and contact information are on ClinicalTrials.gov under NCT04665206.