VT3989 Achieves 32% Response Rate in Mesothelioma: First Hippo Pathway Drug Nears FDA Approval

VT3989, a first-in-class oral drug targeting the Hippo-YAP-TEAD pathway, has achieved a 32% objective response rate and 86% disease control rate in refractory mesothelioma patients whose disease progressed after standard treatments. Published in Nature Medicine in October 2025, the Phase 1/2 trial results show median progression-free survival of 40 weeks — more than double the 15-week benchmark for standard therapies. Vivace Therapeutics plans to launch a registrational Phase 3 trial in the first half of 2026, with potential FDA approval estimated between late 2028 and 2029. Both major competing TEAD inhibitors have been discontinued, making VT3989 the only viable targeted therapy for the 50-60% of mesothelioma patients with Hippo pathway dysregulation. Patients currently seeking access can explore active clinical trials or connect with specialized attorneys to secure compensation for treatment costs.

What Is VT3989 and How Does It Target Mesothelioma?

VT3989 is a first-in-class oral drug that targets the Hippo-YAP-TEAD signaling pathway — a molecular system that normally suppresses tumor growth but is dysregulated in 50-60% of mesothelioma tumors. The drug works by inhibiting TEAD transcription factors through palmitoylation, blocking the YAP-TEAD protein interaction that drives uncontrolled cell proliferation in mesothelioma.^[1]

Unlike conventional chemotherapy, which kills rapidly dividing cells indiscriminately, VT3989 specifically targets the molecular pathway driving mesothelioma growth. This mechanism represents a fundamentally new approach to treating a cancer that has seen limited therapeutic advances in decades. As documented in the mesothelioma treatment options guide, current standard therapies include platinum-based chemotherapy and checkpoint immunotherapy, but most patients eventually progress on these treatments.

"VT3989 represents the most significant breakthrough in mesothelioma treatment we've seen in years. For patients who have exhausted chemotherapy and immunotherapy options, this drug offers real hope — a 32% response rate and disease control in 86% of patients. That's a game-changer for a cancer with very few effective treatments."

— David Foster, Executive Director of Client Services, Danziger & De Llano

The drug is taken orally at 100 mg once daily on a 2-weeks-on, 2-weeks-off intermittent schedule. This dosing approach was specifically designed to manage proteinuria (protein in urine), a class effect of TEAD inhibitors, while maintaining anti-tumor efficacy. The urine albumin-to-creatinine ratio (UACR) is monitored to guide dose adjustments.

What Did the Phase 1/2 Clinical Trial Results Show?

The pivotal Phase 1/2 trial results, published in Nature Medicine in October 2025 and presented at the ESMO 2025 Congress, enrolled 172 patients across U.S. and Australian sites. Of these, 135 patients (78.5%) had mesothelioma. The trial was led by Timothy Yap, MBBS, PhD, of MD Anderson Cancer Center.^[2]

Among the 22 mesothelioma patients treated at the clinically optimized Phase 3 dose and schedule (100 mg once daily, 2-weeks-on/2-weeks-off with UACR-based dose modification), the results were striking:

The median progression-free survival of 40 weeks is more than double the approximately 15-week benchmark for standard-of-care therapies in this heavily pretreated population. In the broader cohort of 47 mesothelioma patients at clinically optimized dose levels (regardless of UACR thresholds), the ORR was 26% with a median PFS of 25 weeks and an identical 86% disease control rate.^[3]

Overall survival data have not yet been reported and are expected to come from the Phase 3 trial. As of February 2026, no new efficacy updates beyond the October 2025 publication have been publicly reported, though the trial remains ongoing with enrollment continuing in expansion cohorts.

How Safe Is VT3989 and What Are the Side Effects?

VT3989 demonstrated a favorable safety profile across all 172 patients in the Phase 1/2 trial. Most adverse events were grade 1-2 (mild to moderate), and the drug showed significantly better tolerability than competing TEAD inhibitors.^[4]

The most common side effects include increased urine albumin-to-creatinine ratio (UACR), proteinuria (protein in urine), peripheral edema, and fatigue. Critically, proteinuria was reversible with dose adjustment and did not result in permanent kidney impairment — a key advantage over competitors that experienced dose-limiting renal toxicity.

Grade 3-4 treatment-related adverse events occurred in only 8.7% of patients. No dose-limiting toxicities were observed across the entire 172-patient trial. The treatment discontinuation rate due to adverse events was just 3.5%, indicating that the overwhelming majority of patients were able to continue treatment.^[5]

"The safety profile of VT3989 is encouraging for mesothelioma patients who have already been through the rigors of chemotherapy and immunotherapy. A 3.5% discontinuation rate means nearly all patients can stay on treatment, and the intermittent dosing schedule is designed to keep side effects manageable."

— David Foster, Executive Director of Client Services, Danziger & De Llano

The intermittent dosing schedule (2 weeks on, 2 weeks off) was specifically designed to limit the long-term accumulation of proteinuria, a class effect common to all TEAD inhibitors. This approach differentiates VT3989 from competitors that used continuous daily dosing and experienced more severe renal side effects.

What Happened to Competing TEAD Inhibitors?

VT3989 is now the clear frontrunner in the TEAD inhibitor space, with both major competitors having been discontinued. This leaves mesothelioma patients with one remaining option for targeted Hippo pathway therapy.^[6]

Novartis discontinued IAG933 shortly after ESMO 2025 due to insufficient tolerability and antitumor activity. The Phase 1 trial enrolled 136 patients but showed only 16.6% ORR in pleural mesothelioma patients, with dose-limiting toxicities including QTc prolongation. Ikena Oncology's IK-930, despite receiving Orphan Drug and Fast Track designations in 2022, produced zero confirmed responses in its Phase 1 trial and was abandoned in May 2024.^[7]

The key differentiator appears to be VT3989's mechanism as a pan-TEAD palmitoylation inhibitor — targeting all four TEAD proteins rather than a single paralog — combined with the optimized intermittent dosing schedule. Several other companies have early-stage TEAD/Hippo programs but none have reported clinical data in mesothelioma.

What Role Does the NF2 Mutation Play in VT3989 Response?

NF2 (neurofibromatosis type 2) mutations are among the most frequent genetic alterations in mesothelioma, occurring in 30-50% of pleural mesotheliomas. Broader Hippo pathway defects — including NF2, LATS1/2, and RASSF7 alterations — are present in up to 50-60% of mesothelioma tumors. NF2 mutations are more common in nonepithelioid (sarcomatoid/biphasic) subtypes and are associated with more aggressive disease.^[8]

A critical finding from the Phase 1/2 trial: partial responses were observed in patients both with and without NF2 mutations. In the trial population, 31.4% of patients had NF2 mutations. This suggests that VT3989 does not require NF2 mutation for activity, although broader Hippo pathway dysregulation — which can occur through mechanisms beyond NF2 mutation alone — likely drives response.

No companion diagnostic for NF2 or Hippo pathway status has been announced in connection with VT3989. The Phase 1/2 trial enrolled patients regardless of NF2 mutation status, and expansion cohorts explicitly include patients "with or without NF2 mutations." Whether a companion diagnostic will be required for eventual approval remains to be determined.

"The fact that VT3989 works in patients both with and without NF2 mutations is extremely important. It means this drug could potentially benefit a broader population of mesothelioma patients, not just those with a specific genetic marker. That's rare and significant in targeted therapy."

— David Foster, Executive Director of Client Services, Danziger & De Llano

When Could VT3989 Receive FDA Approval?

Based on publicly available information, the estimated timeline for VT3989's path to FDA approval includes several key milestones:^[9]

Several factors could accelerate this timeline. The FDA Fast Track designation allows Vivace to submit completed sections of the NDA on a rolling basis. The Orphan Drug designation provides additional regulatory incentives. Given the drug's strong response rate in a disease with very limited treatment options, Vivace could potentially seek accelerated approval based on ORR (a surrogate endpoint) rather than waiting for overall survival data, which could shorten the timeline by 1-2 years.

Vivace's CEO Sofie Qiao stated in October 2025 that VT3989 could be approved and available to patients worldwide in approximately 3 years, suggesting a company target of late 2028. However, Phase 3 trials carry inherent uncertainty, and the drug still needs to confirm its Phase 1/2 efficacy signal in a larger, randomized population.^[10]

How Can Mesothelioma Patients Access VT3989 Today?

The Phase 1/2 trial (NCT04665206) remains open and continues enrolling patients at multiple sites including MD Anderson Cancer Center (Houston, TX), UCSF (San Francisco, CA), and sites in Australia. The trial enrolls mesothelioma patients — both pleural and non-pleural — with or without NF2 mutations. A combination cohort testing VT3989 plus nivolumab and ipilimumab is also actively enrolling.^[11]

As of February 2026, no formal expanded access or compassionate use program has been announced by Vivace Therapeutics. However, individual patients may request single-patient compassionate use (via FDA Form 3926) directly from Vivace, though approval is at the company's discretion. As the Phase 3 trial launches, a parallel expanded access program may become available.

The mesothelioma clinical trials database provides current information on enrollment status and trial sites. Patients should also reference the survival statistics page for context on how VT3989 compares to existing treatment outcomes.

"I tell every patient — explore clinical trials. VT3989 represents a fundamentally new approach to treating mesothelioma. If you've progressed on chemo and immunotherapy, talk to your oncologist about trial eligibility. These drugs don't become available through FDA approval alone; they need patients willing to participate in trials."

— David Foster, Executive Director of Client Services, Danziger & De Llano

What Does VT3989 Mean for the Future of Mesothelioma Treatment?

VT3989 represents the first validated molecular target for mesothelioma beyond conventional chemotherapy and immunotherapy. If Phase 3 results confirm the Phase 1/2 data, this drug could fundamentally change the treatment landscape for the 50-60% of mesothelioma patients with Hippo pathway dysregulation.

The combination cohort testing VT3989 with nivolumab and ipilimumab is particularly promising. If VT3989 synergizes with existing checkpoint immunotherapy, the combination could potentially move into earlier treatment lines — before patients become refractory to standard treatments. Results from this cohort have not yet been reported.

For patients currently fighting mesothelioma, VT3989 underscores the importance of staying informed about emerging treatments and exploring clinical trial options. The drug is a tangible example of how basic cancer biology research — understanding the Hippo-YAP-TEAD pathway — is translating into real therapies for rare cancers that have historically received limited pharmaceutical investment.

Patients and families can stay current on treatment developments through resources like the mesothelioma treatment options guide and by maintaining open communication with their oncology team about new clinical trials as they become available.

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References

1. [1] Nature Medicine, "YAP/TEAD inhibitor VT3989 in solid tumors: a phase 1/2 trial" (2025) — Phase 1/2 clinical trial results documenting 32% objective response rate and 77% disease control rate for VT3989 in mesothelioma patients.
2. [2] The ASCO Post, "VT3989 Demonstrates Antitumor Activity and Tolerability in Refractory Mesothelioma" (2025) — Clinical oncology coverage of ESMO 2025 presentation showing durable responses in treatment-refractory mesothelioma patients.
3. [3] ESMO Daily Reporter, "IAG933 & VT3989 show promising disease control in mesothelioma" (2025) — ESMO Congress reporting comparing two TEAD inhibitors as first evidence for targeted treatments in mesothelioma.
4. [4] PR Newswire / Vivace Therapeutics, "Vivace Therapeutics' VT3989 Granted Fast Track Designation by the U.S. FDA" (2025) — FDA Fast Track designation announcement accelerating VT3989 review for mesothelioma treatment.
5. [5] Fierce Biotech, "Vivace hits high note in midstage mesothelioma trial" (2025) — Industry analysis of VT3989 phase 2 results and planned phase 3 expansion in mesothelioma.
6. [6] ApexOnco / Oncology Pipeline, "Novartis trips over the Hippo" (2025) — Comparative analysis of Novartis IAG933 discontinuation versus Vivace VT3989 success in Hippo pathway targeting.
7. [7] WikiMesothelioma, "Clinical Trials" — Comprehensive guide to active mesothelioma clinical trials including VT3989 and other targeted therapy candidates.
8. [8] Journal of Thoracic Oncology, "NF2-YAP/TAZ Dual Immunohistochemistry in Diffuse Pleural Mesothelioma" (2023) — Peer-reviewed research on NF2 loss and Hippo pathway dysregulation as biomarkers for mesothelioma treatment response.
9. [9] UCSF Clinical Trials, "VT3989 in Patients With Metastatic Solid Tumors (NCT04665206)" (2025) — Active clinical trial listing for VT3989 with enrollment criteria and study endpoints.
10. [10] WikiMesothelioma, "Treatment Options" — Overview of mesothelioma treatment modalities including surgery, chemotherapy, immunotherapy, and emerging targeted therapies.
11. [11] National Cancer Institute, "Mesothelioma Cancer Information" (2025) — Federal cancer research data on mesothelioma types, treatment options, and survival statistics.
12. [12] WikiMesothelioma, "Survival Statistics" — Mesothelioma survival rates and prognosis data by stage, cell type, and treatment approach.