VT3989 Shows Activity, Tolerability in Mesothelioma and Other NF2-Mutated Solid Tumors

Timothy A. Yap, MD, PhD

VT3989, a first-in-class yes-associated protein (YAP)/transcriptional enhancer activator domain (TEAD) inhibitor, showcased durable antitumor activity and tolerability in patients with malignant mesothelioma and other solid tumors harboring NF2 mutations, according to data from a phase 1 trial (NCT04665206) presented at the 2023 AACR Annual Meeting.^1,2

Findings showed that 7 of 69 patients with measurable disease experienced a reduction in tumor size and experienced partial responses (PRs) by RECIST v1.1 criteria; 6 of the patients had a confirmed PR, and 1 had an unconfirmed PR. Additionally, 34 patients with measurable disease had stable disease as their best response to treatment.

VT3989 was also found to be well tolerated, with no dose-limiting toxicities reported. No grade 5 adverse effects (AEs) occurred.

“These are encouraging results that provide the first clinical proof-of-concept for drugging the Hippo-YAP-TEAD pathway,” lead study author Timothy A. Yap, MD, PhD, stated in a press release.² “Preclinical data suggested that blocking the YAP-TEAD interaction could shrink tumors, and these clinical data validate that approach. These are early clinical trial data, but we look forward to future results from this trial and continuing to investigate the benefits to patients.”

Yap is an associate professor in the Department for Investigational Cancer Therapeutics (Phase I Program) and the Department of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston, Texas.

The transcription factors YAP and transcriptional coactivator with PDZ-binding motif (TAZ) are regulated by Hippo signaling. When YAP/TAZ are translocated to the nucleus, they interact with DNA-binding TEAD proteins to initiate the transcription of target genes. The dysfunction of the Hippo pathway, which can occur with NF2 mutations, leads to uncontrolled proliferation and impaired differentiation.

VT3989 is designed to inhibit the transcription function of TEAD/YAP by occupying the palmitate pocket and inhibiting palmitoylation. Preclinical studies showed that mesothelioma cell lines treated with VT3989 had selectivity for NF2 deficiency, and activity was observed in merlin-negative mesothelioma lines with and without NF2 mutations. Xenografts of NF2-deficient mesothelioma produced activity for the agent at an oral 3 mg/kg dose per day.

The ongoing first-in-human phase 1 study of VT3989 is enrolling patients with advanced refractory solid tumors, with enrichment for malignant pleural mesothelioma and other tumors with NF2 mutations. Patients are required to have an ECOG performance status between 0 and 2.

The dose-escalation portion of the study utilized a 3+3 design where patients received 1 of 5 doses of VT3989. Treatment cycles lasted for 3 or 4 weeks, and tumor response assessments were conducted approximately every 8 to 9 weeks.

In the original 5 dose-escalation cohorts, patients received continuous VT3989 at daily doses of 25 mg (n = 5), 50 mg (n = 6), 100 mg (n = 6), 150 mg (n = 6), and 200 mg (n = 4). Various intermittent dosing schedules of VT3989 were subsequently evaluated, including 50 mg continuously for 15 days, then weekly (n = 6); 100 mg continuously for 15 days, then weekly (n = 6); 150 mg on a 1-week-on/3-weeks-off schedule (n = 6); 100 mg on a 2-weeks-on/2-weeks-off schedule (n = 7); 200 mg on a 2-weeks-on/2-weeks-off schedule (n = 5); 200 mg on a 1-week-on/2-weeks-off schedule (n = 6); and 200 mg on a 2-weeks-on/1-week-off schedule (n = 6).

The dose-expansion portion of the trial will feature 3 cohorts, including one that is to be determined. In cohort 1 (n = 10 to 27), patients with mesothelioma with or without NF2 mutations will be given 100 mg of VT3989 per day on a 2-weeks-on/2-weeks-off schedule, given every 4 weeks. For cohort 2 (n = 10 to 27), investigators will examine 50 mg of VT3989 per day for 15 days, followed by 100 mg per week thereafter, in patients with mesothelioma with or without NF2 mutations.

The primary end points of the study are safety/tolerability, as well as determining the maximum tolerated dose and the recommended phase 2 dose of the agent. Secondary end points include preliminary antitumor activity in patients with NF2-mutant solid tumors, pharmacokinetics, time to response, and duration of response. Exploratory end points consist of Hippo/YAP signaling in sequential tumor biopsies, circulating tumor DNA changes, and YAP and Merlin by immunohistochemistry.

Among patients treated in the dose-escalation portion of the trial (n = 69), the median age was 63.5 years (range, 21-83), 51% of patients were male, 87% of patients were White, and 84% of patients had an ECOG performance status of 1.

Tumor types included pleural mesothelioma (48%), peritoneal mesothelioma (12%), dual pleural and peritoneal mesothelioma (1%), pericardial mesothelioma (1%), meningioma (13%), and other solid tumors (23%).

Thirty-seven patients had NF2 mutations, which included 31 somatic mutations and 6 germline mutations. Thirteen patients had NF2 wild-type disease, and NF2 status was unknown in 19 patients. The median number of prior lines of therapy received was 3 (range, 0-8). Seventy-eight percent of patients had prior chemotherapy, 57% had prior checkpoint inhibition, and 30% received a prior anti-VEGF inhibitor.

Among the 7 responders, 4 patients had peritoneal mesothelioma, 1 had pericardial mesothelioma, 1 had sarcoma, and 1 had dual pleural/peritoneal mesothelioma (TABLE).

Forty-eight percent of all patients received treatment for more than 16 weeks, and 32% received it for more than 24 weeks. Among those with mesothelioma, 46% and 28% continued treatment for more than 16 weeks and more than 24 weeks, respectively. In those with other solid tumors, 50% continued treatment for longer than 16 weeks and 38% continued for longer than 24 weeks.

Regarding safety, most AEs were grade 1/2. Grade 3 AEs included albuminuria (4.3%), peripheral edema (1.4%), fatigue (1.4%), increased alanine transaminase (1.4%), and increased aspartate transaminase (1.4%).

An 82-year-old male with advanced pleural mesothelioma experienced grade 4 cardiomyopathy that was possibly related to VT3989. The patient had known coronary artery disease, hypertension, aortic regurgitation, and mild renal dysfunction and was treated with 150 mg of VT3989 daily for 7 months (11 cycles). A symptom-driven cardiac evaluation led to a diagnosis of grade 4 dilated cardiomyopathy with no clear etiology.

Notably, albuminuria was observed to be less frequent and less severe when VT3989 was given at dose levels of 100 mg or less on intermittent schedules. All instances of albuminuria and proteinuria were reversible in patients treated at all doses and schedules.

“It is gratifying to see the extensive preclinical data that we have generated for VT3989 translate so well into humans in both the antitumor activity and tolerability profile demonstrated in this clinical study,” Sofie Qiao, PhD, chief executive officer of Vivace Therapeutics, stated in a news release. “We view this as a significant milestone as these data position VT3989 as the very first cancer treatment targeting the Hippo pathway to show clinical relevance.”

Different doses and schedules of VT3989 are currently being examined in dose-optimization expansion cohorts utilizing 2-stage designs.

References

1. Yap TA, Kwiatkowski DJ, Desai, et al. First-in-class, first-in-human phase 1 trial of VT3989, an inhibitor of Yes-Associated Protein (YAP)/transcriptional enhancer activator domain (TEAD), in patients (pts) with advanced solid tumors enriched for malignant mesothelioma and other tumors with neurofibromatosis 2 (NF2) mutations. Presented at: 2023 AACR Annual Meeting; April 14-19, 2023; Orlando, FL. Abstract CT006.
2. Researchers report clinical proof-of-concept data for Vivace Therapeutics’ VT3989, a first for a cancer drug targeting the Hippo pathway, in oral presentation at AACR 2023. News release. Vivace Therapeutics. April 16, 2023. Accessed April 26, 2023. https://www.prnewswire.com/news-releases/