Abstract CT006: 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
Authors: Yap Timothy A. , Kwiatkowski David J. , Desai Jayesh , Dagogo-Jack Ibiayi , Millward Michael , Kindler Hedy L. , Tolcher Anthony W. , Frentzas Sophia , Thurston Archie W. , Post Len , Dorr F Andrew 
Published: April 2023

Background: Inactivation of the Hippo pathway is a common finding in MM and other cancers, leading to constitutive YAP activation, but has thus far been undruggable. NF2 encodes Merlin that activates Hippo kinase resulting in inactivation of YAP, which is the major effector of Hippo signaling. NF2-deficient tumors, often due to inactivating NF2 mutations (NF2m), are dependent on YAP for growth. VT3989 is an oral, highly potent and selective inhibitor of TEAD palmitoylation, which blocks YAP function and has shown promising preclinical activity.

Materials and Methods: This FIH trial used a 3 + 3 dose escalation design and evaluated VT3989 from 25 to 200 mg QD continuously and 50 to 200 mg intermittently. Pts with refractory solid tumors, ECOG PS 0-1, serum albumin &gt; 2.5, urinary protein creatinine ratio ≤ 0.5 mg/mg and albumin creatinine ratio ≤ 100 mg/g were enrolled. Objectives were to determine the safety, tolerability and recommended Phase 2 dose (RP2D) of VT3989; to evaluate antitumor activity, pharmacokinetics (PK) and correlate NF2m and other alterations in tumor and ctDNA with response.

Results: 67 pts have been enrolled. Median age 63.5y (21-83y), ECOG PS 0:1 13:54 pts. Median prior therapies 3 (range 0-8). Tumor types: 42 MM (29 pleural and 13 non-pleural) and 25 solid tumors including 9 meningioma and 4 sarcoma pts. 34 pts had NF2m (29 somatic and 5 germline). All MM pts had progressed on prior platinum/pemetrexed; all but 2 had prior immune checkpoint inhibitors.

VT3989 is safe and well tolerated with no dose limiting toxicities. No MTD was defined up to 200 mg QD. The most common AEs are proteinuria, albuminuria and peripheral edema, mainly observed with the continuous schedule. There were 7 possibly related G3 AEs (fatigue, ALT, AST, dehydration, dyspnea, hypotension and peripheral edema) and 1 G4 cardiomyopathy. No pt developed decreased renal function or nephrotic syndrome. VT3989 has a 12-15 day half-life, dose proportional PK and reaches steady state within 2 weeks.

Seven pts (6 refractory MM and 1 NF2m sarcoma) achieved RECIST v1.1 partial responses (PRs) with 4 confirmed, 3 unconfirmed (1 pending). 3 PRs in MM pts are ongoing up to 18+ months. The clinical benefit response rate (PR + SD &gt; 8 weeks, per protocol) in MM pts is 57%.

Of the 6 MM pts (1 pericardial, 1 pleural/peritoneal and 4 peritoneal) with PR, 2 have NF2m, 3 are wildtype, and 1 is unknown.

Conclusions: VT3989 is safe and well tolerated with durable RECIST v1.1 antitumor responses in pts with advanced MM and NF2m cancers, providing the first early clinical proof-of-concept for effectively drugging the Hippo-YAP-TEAD pathway. RP2D optimization including further schedule evaluation and expansion are ongoing in pts with MM and NF2m tumors.

Citation Format: Timothy A. Yap, David J. Kwiatkowski, Jayesh Desai, Ibiayi Dagogo-Jack, Michael Millward, Hedy L. Kindler, Anthony W. Tolcher, Sophia Frentzas, Archie W. Thurston, Len Post, F Andrew Dorr. 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 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT006.