The yes-associated protein (YAP)/transcriptional enhancer activator domain (TEAD) inhibitor VT3989 may have been well tolerated with durable antitumor responses in patients with advanced malignant mesothelioma as well as other NF2-mutated solid tumors, according to new findings presented by Yap et al at the American Association for Cancer Research (AACR) Annual Meeting 2023 (Abstract CT006).
Background
YAP is a transcriptional coactivator that works with TEAD as a part of the Hippo signaling pathway—which is important for normal cell growth and immune response regulation. However, in several cancer types, YAP can become either overexpressed or overactivated as a result of dysfunction in the pathway, fueling cancer cell growth. Therefore, researchers suggested that YAP could represent a promising therapeutic target.
VT3989 works by inhibiting TEAD palmitoylation, which, in turn, blocks YAP function. NF2-mutant cancers were chosen for this trial because of their dependence on YAP activity for growth.
“This is the first clinical proof of concept for drugging the Hippo-YAP-TEAD pathway,” explained lead study author Timothy A. Yap, MD, MBBS, PhD, FRCP, Associate Professor of Investigational Cancer Therapeutics as well as Thoracic/Head and Neck Medical Oncology in the Division of Cancer Medicine, Medical Director of the Institute for Applied Cancer Science, and Associate Director of Translational Research at the Institute for Personalized Cancer Therapy at The University of Texas MD Anderson Cancer Center. “We’ve long known that YAP is a key oncogenic driver of cancer, and preclinical research suggested blocking YAP could shrink tumors. However, this is the first data demonstrating that targeting YAP can work in a clinical setting to actually benefit patients,” he added.
Study Methods and Results
In the new phase I dose-escalation trial, the researchers evaluated the safety, tolerability, and recommended phase II dose levels of VT3989 in 69 patients with a median age of 63.5 years—43 of whom had advanced malignant mesothelioma and 26 of whom had other solid tumors. The patients were heavily pretreated and received a median of three prior lines of therapy. Additionally, 37 of the patients had NF2 mutations. The researchers reported that 51% and 49% of the patients were male and female, respectively; and 87%, 10%, and 3% of them identified as White, Hispanic, and Black, respectively.
The researchers discovered that 10.1% (n = 7/69) of the patients had radiologic partial responses that persisted up to at least 21 months—indicating tumor shrinkage—while 49.3% (n = 34/69) of them demonstrated stable disease. Patient benefit was observed in those with both mesothelioma and other solid tumors with and without NF2 mutations.
Further, VT3989 was well tolerated, and the researchers observed no dose-limiting toxicities. The most common adverse events were albuminuria, swelling in the extremities, fatigue, and nausea. Only seven grade 3 adverse events were possibly treatment-related—including albuminuria, swelling, fatigue, and increases in the liver enzymes alanine transaminase and aspartate aminotransferase—along with one grade 4 adverse event: cardiomyopathy.
Conclusions
“These are early but very promising results showing that this previously ‘undruggable’ target and anticancer strategy can work in a clinical setting,” Dr. Yap highlighted. “We look forward to future results from this study in order to evaluate whether this approach may bring an urgently needed treatment option to these patients,” he concluded.
The researchers noted that ongoing dose-optimization cohorts of the study are currently investigating different dosing and scheduling in two-stage designs.
Disclosure: The research in this study was supported by Vivace Therapeutics. For full disclosures of the study authors, visit abstractsonline.com.
