VT3989 continues to show promising early results in patients with advanced mesothelioma

The first-in-class YAP-TEAD inhibitor VT3989 continued to be well tolerated and demonstrated notable initial antitumor activity, particularly in patients with refractory mesothelioma, according to results from a trial led by researchers from The University of Texas MD Anderson Cancer Center.

Data from the Phase I/II trial were presented today by Timothy Yap, M.B.B.S., Ph.D., professor of Investigational Cancer Therapeutics and vice president and head of clinical development of MD Anderson’s Therapeutics Discovery division, at the 2025 European Society for Medical Oncology (ESMO) Congress and published simultaneously in Nature Medicine.

What are the notable results of this study evaluating VT3989?

The trial enrolled 172 patients, including 135 with refractory mesothelioma. Of the 22 mesothelioma patients treated with the optimized dose levels, seven had partial responses and 12 had stable disease—a disease control rate of 86%. All 22 mesothelioma patients had previously received immunotherapy, and 82% had previously received chemotherapy.

“This study has multiple important takeaways, including the demonstration of significant disease control even in this heavily pretreated population,” Yap said. “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.”

How does VT3989 work?

This trial of VT3989 represents the first clinical proof-of-concept for inhibiting part of an important signaling pathway that regulates cell growth and immune response. This pathway is known as the Hippo signaling pathway and, within this pathway, the yes-associated proteins (YAP) work with transcriptional enhancer activator domain (TEAD) proteins.

In several cancer types, YAP is overexpressed or overactivated due to dysfunction in the pathway, which fuels cancer growth. VT3989 inhibits a specific modification on the TEAD protein, which blocks YAP function. Hence, VT3989 is known as a YAP-TEAD inhibitor.

Why is this being studied in mesothelioma patients?

Cancers with NF2 gene mutations are particularly dependent on the YAP-TEAD pathway. The NF2 gene encodes a protein called Merlin, and NF2 gene mutations/Merlin protein loss are common in mesothelioma patients.

Additionally, mesothelioma is a cancer that is very difficult to treat, and there are currently limited options for patients who do not respond to first-line treatments, making this a major unmet clinical need.

Initial data from this trial were presented at the American Association for Cancer Research (AACR) Annual Meeting 2023, demonstrating encouraging Phase I results.