The YAP/TEAD inhibitor VT3989 was well tolerated and demonstrated to be antitumor

ABSTRACT: CT006

ORLANDO, Fla. ― The class one YAP/TEAD inhibitor VT3989 is well tolerated with a durable antitumor response in patients with advanced malignant mesothelioma and other tumors with NF2 mutation, according to results of a Phase I trial led by researchers at The University of Texas MD Anderson Cancer Center. The first human study was presented today at the 2023 American Association for Cancer Research (AACR) Annual Meeting.

Seven of the 69 patients had a partial radiological response lasting at least 21 months, indicating tumor shrinkage, while 34 had stable disease. Patient benefit was observed in patients with mesothelioma and other solid tumors, including those with and without tumors NF2 mutation.

“This is the first clinical proof of concept to anesthetize the Hippo-YAP-TEAD pathway,” said presenter and lead author Timothy A. Yap, MD, Ph.D., associate professor of Investigational Cancer Therapeutics. “We have long known that YAP is a major oncogenic cancer promoter, and preclinical studies show that blocking YAP can shrink tumors. However, this is the first data showing that targeting YAP can be successful in the clinical setting to actually benefit patients.”

YAP (yes-associated protein) is a transcriptional co-activator that works with TEAD (transcriptional enhancer activator domain) as part of the Hippo signaling pathway, which is important for normal cell growth and regulating immune responses. However, in some types of cancer, YAP is overexpressed or overactive due to a dysfunction in the pathway, triggering cancer cell growth. Therefore, YAP is an attractive therapeutic target.

VT3989 works by inhibiting TEAD palmitoylation, which in turn blocks YAP function. NF2-cancer mutants were selected for this experiment because of their dependence on YAP activity for growth.

The Phase I dose escalation trial was designed to evaluate the safety, tolerability, and recommended Phase II dose for VT3989. Today’s presentation includes data from 69 enrolled patients, including 43 with advanced malignant mesothelioma and 26 with other solid tumors. Patients were heavily pretreated and received a median of three previous lines of therapy. A total of 37 patients have NF2 mutation. Patients in the trial were 51% male and 49% female, 87% white, 10% Hispanic, and 3% black, with a mean age of 63.5 years.

The drug was well tolerated, with no dose-limiting toxicity observed. The most common side effects are albuminuria (reversible increase in albumin protein in the urine), swelling of the extremities, fatigue, and nausea. Only seven possible grade 3 adverse effects were associated with treatment, including albuminuria, swelling, fatigue, and increases in the liver enzymes alanine transaminase and aspartate aminotransferase, along with one possible degree 4-related cardiomyopathy.

“These are early but very promising results demonstrating that these previously ‘non-treatable’ anticancer targets and strategies can work in clinical settings,” said Yap. “We look forward to the results of this study in the future to evaluate whether this approach can lead to much-needed treatment options for these patients.”

The ongoing dose optimization cohort of this study is investigating different dosing and scheduling in a two-stage design.

This trial is supported by Vivace Therapeutics. A full list of collaborating authors and their disclosures can be found here.