ORLANDO – In a first-in-human study, Vivace Therapeutics' YAP-TEAD inhibitor VT3989 showed efficacy in patients with NF2-mutant mesothelioma and other solid tumors.
But since a few patients without NF2 mutations also responded to VT3989 in this early study, researchers are conducting additional biomarker analysis to better understand the efficacy of the drug.
Timothy Yap, associate professor of investigational cancer therapeutics at MD Anderson Cancer Center and an investigator on this study, presented the results at the American Association for Cancer Research's annual meeting on Sunday. The study is the latest in several early-stage trials to show that TEAD inhibitors have promising activity in NF2-mutant tumors.
Yap and colleagues enrolled nearly 70 patients into the Phase I trial of VT3989. Across all tumor types, 10 percent (seven patients) responded to the treatment, and one patient had an unconfirmed response. The clinical benefit rate, which includes patients who responded and those who had stable disease, was 57 percent.
"These data provide the first early clinical proof of concept for effectively dragging the Hippo-YAP-TEAD pathway," Yap said. "The dysfunction of the Hippo signaling pathway promotes activation of YAP and TAZ, resulting in uncontrolled proliferation and impaired differentiation. NF2 mutations are one mechanism by which Hippo control of YAP and TAZ is inactivated in tumors."
Most responders to VT3989 had NF2-mutant mesothelioma, including those with pleural, non-pleural, peritoneal, and pericardial subtypes. However, there were two NF2-wild-type mesothelioma patients who also responded along with one NF2-mutant spindle cell sarcoma patient.
Dean Fennell, director of the University of Leicester Mesothelioma Research Institute in the UK, pointed out that since there were responders without NF2 mutations, it raises questions about what other mutations might play a role in the regulation of the Hippo-YAP signaling pathway. Fennell, who was not involved in the study presented at AACR, noted that according to data from The Cancer Genome Atlas, other Hippo pathway alterations in LATS1, LATS2, SAV1, WWTR1, and TEAD4 occur in 36 percent of mesotheliomas, while NF2 mutations alone occur in 34 percent of patients.
"These additional mutations could theoretically phenocopy the NF2 mutation," Fennell said, adding that the latest data suggest that "NF2 can perhaps capture some of the activity of this drug, but clearly not everyone [responding]."
Fennell also suggested that further analysis of NF2-mutant non-responders and non-NF2-mutant responders could provide clues about how to overcome genomic resistance to TEAD inhibition. Previous studies, for instance, have suggested that TEAD inhibitor resistance is driven by the AKT pathway.
"If you inhibit AKT, you can actually re-sensitize the TEAD inhibitor," he explained. "We don't know what this pathway is doing in these patients [in the trial], but that may be something worthy of exploration. The possibility may exist that these patients who harbor the NF2 mutation could be re-sensitized [to TEAD inhibition] using combination strategies."
Yap's team is analyzing genomic data from patients in the study, including NF2-mutant patients who did not respond to Vivace's VT3989, to explore if they have other mutations related to this pathway. The researchers are analyzing the molecular characteristics of both pre- and on-treatment tissue from patients.
Other firms developing drugs for NF2-mutant cancers include Novartis, which is studying the TEAD inhibitor IAG933 in a Phase I study involving patients with mesothelioma; NF2-, LATS1-, and LATS2-mutated tumors; and tumors with functional YAP/TAZ fusions. Ikena Oncology is also studying the TEAD inhibitor IK-930 in unresectable NF2-deficient malignant pleural mesothelioma.
Vivace, meanwhile, is continuing to study VT3989 in this Phase I trial. Researchers have begun the dose-expansion portion of the study, and according to Yap, both NF2-mutant and NF2-wild-type patients will enroll in this portion of the trial.