VT3989

P1, N=188, Recruiting, Vivace Therapeutics, Inc | Trial completion date: Feb 2024 --> Dec 2024 | Trial primary completion date: Feb 2024 --> Nov 2024

The 44 mesothelioma patients had a median age of 65 (range 21-83), ECOG PS of 0 (n=7) or 1 (n=37), median of 3 prior regimens (range 1-8); all had received prior platinum and pemetrexed, 43/44 (98%) had prior immune checkpoint inhibitors and 16/44 (36%) had VEGF antibodies; 33 had epithelioid, 7 biphasic and 4 sarcomatoid histology. VT3989 is well tolerated with durable responses in patients with refractory mesothelioma. This study provides the first clinical proof-of-concept for drugging the Hippo-YAP-TEAD pathway. RP2D optimization including further schedule evaluation and expansion are ongoing in mesothelioma patients evaluating different intermittent schedules.

Therefore, small molecules that target palmitoylation of TEAD have been explored and VT3989 (NCT04665206) and IK-930 (NCT05228015) have success to enter the clinical trials...In line with the results of the in-vitro experiments, another YAP/TEAD inhibitor TY-0536 in combination with TY-9591 significantly delay the tumor regrowth in the PC9 CDX mouse model...[Shengli Dong and Apeng Liang contributed equally to this work. Jun Li, Shengli Dong, and Apeng Liang are the corresponding authors.]

In vivo, we observed strong VT3989 and osimertinib combination effect in NCI-H1975 and HCC827 cell line-derived xenograft models. We also tested the combination in several EGFR mutant NSCLC patient-derived xenograft models and demonstrated that the addition of VT3989 enhanced the efficacy of osimertinib and delayed tumor regrowth compared to osimertinib alone.