A YAP/TEAD inhibitor is showing promising results for people with mesothelioma and other cancers. The inhibitor, known as VT3989, was well tolerated and had good anti-tumor effects in cancer patients with mesothelioma and NF2 mutations. Results were recently published from the first human study. Seven of 69 patients had radiological partial responses, which includes tumor shrinkage, for at least 21 months. Thirty-four patients had stable disease. Researchers measured the benefits for mesothelioma and other cancers with and without NF2 mutations. This treatment is the first proof of concept for drugging the Hippo-YAP-TEAD pathway. Yap has been known to increase the growth of tumors, so in theory, blocking it can shrink tumors. This study is the first time seeing the benefits of targeting YAP in a clinical setting.
YAP (yes-associated protein) works with TEAD (transcriptional enhancer activator domain) in the HIPPO signaling pathway. This pathway is crucial for normal cell growth and controlling the immune response. For certain types of cancer, YAP is over-expressed or over activated, which then helps with cancer growth. This makes it an important target for treating certain cancers. VT3989 inhibits TEAD palmitoylation, which then blocks YAP function. Researchers chose NF2-mutant cancers because they depend on YAP to grow.
The trial was completed to determine the safety, tolerability, and recommended Phase II dose of VT3989. There is data on 43 patients with mesothelioma and 26 patients with other solid tumors, for a total of 69 patients. Patients in the study had extensive pretreatment with three prior lines of therapy. There were 37 patients with NF2 mutations. Fifty-one percent of patients were male, 49 percent were female, 87 percent were white, 10 percent were Hispanic, and three percent were black. The median age of patients was 63.5.
Researchers found that the drug was well tolerated and there were no dose limiting toxicities, so doctors have a wider variety of dosages to use. The most common adverse effects for patients included albuminuria (increase in protein albumin in the urine which is reversible), swelling in extremities, fatigue, and nausea. Only seven grade three adverse events occurred that could have happened due to treatment including albuminuria, swelling, fatigue, and an increase in liver enzymes alanine transaminase and aspartate aminotransferase. There was one possible grade four event, which was cardiomyopathy.
The results from this study are very early but are still seen as promising. It shows that the undruggable target and anti-cancer strategy can be useful in a clinical setting. The study needs to continue to see what results are possible in a wider range of patients. More clinical trials are being done to find the best possible dosage and schedule for treating patients.
Source:
“YAP/TEAD inhibitor VT3989 is well tolerated, shows antitumor activity in advanced mesothelioma and NF2-mutant cancers” University of Texas M.D. Anderson Cancer center (April 17, 2023). [Link]
