First-in-class YAP/TEAD inhibitor VT3989 shows promising responses in refractory mesothelioma
A phase 1/2 trial of oral VT3989, which blocks the Hippo-YAP-TEAD pathway, reported a 26% response rate in mesothelioma and manageable, mostly mild side effects.
Summary
Many cancers, including mesothelioma, depend on a growth pathway called Hippo-YAP-TEAD that is stuck in the 'on' position. VT3989 is a first-in-class oral drug that blocks TEAD palmitoylation, which shuts down YAP-driven gene activity. This first-in-human phase 1/2 trial enrolled 172 patients with refractory solid tumors, 135 of them with mesothelioma. Side effects were mostly grade 1-2 and included proteinuria, higher urine albumin:creatinine ratio, peripheral edema and fatigue. Proteinuria was reversible with dose adjustment and did not cause renal impairment. Among 47 mesothelioma patients at clinically optimized doses, 26% responded. In a 22-patient subgroup that also applied urine-protein thresholds, the response rate was 32%, disease control was 86% and median progression-free survival was 10 months. These are early, non-prespecified interim results, but they offer the first clinical proof of concept that this pathway can be drugged.
Detailed Summary
Mesothelioma is an aggressive cancer with few effective options once first-line therapy fails. In many mesotheliomas, loss of Hippo pathway control leaves the transcriptional co-activator YAP constitutively active. YAP partners with TEAD transcription factors to drive tumor growth. Despite years of effort, no drug targeting this pathway had shown clear clinical benefit.
This open-label, first-in-human phase 1/2 trial tested VT3989, an oral inhibitor of TEAD palmitoylation that disrupts YAP transcriptional activity. The dose-escalation phase (n=85) and expansion cohorts (n=87) included 172 patients with refractory solid tumors, 135 of whom had mesothelioma. The study is ongoing, and the efficacy data from the expansion cohorts are non-prespecified interim results.
VT3989 had a favorable safety profile, with mostly grade 1-2 toxicities. The most common were increased urine albumin:creatinine ratio, proteinuria, peripheral edema and fatigue. Proteinuria was reversible with dose adjustment and did not lead to renal impairment. Among 47 mesothelioma patients treated at clinically optimized doses, the overall response rate was 26%. In 22 patients treated at optimized doses with UACR thresholds incorporated, the response rate was 32%, disease control was 86% and median progression-free survival was 10 months.
The results are the first early clinical proof of concept that the Hippo-YAP-TEAD pathway can be drugged. The FDA has granted VT3989 orphan drug and fast-track designations for mesothelioma, which may speed further development.
Several caveats apply. The trial is single-arm with no control group, the efficacy analyses are interim and not prespecified, and the best-performing subgroup is small. Selecting patients and doses using UACR thresholds may overstate benefit. Several authors are employed by or hold equity in the sponsor. Randomized trials with longer follow-up are needed to confirm durability and benefit over standard care.
Key Findings
- The trial enrolled 172 patients with refractory solid tumors, including 135 with mesothelioma, across dose-escalation and expansion cohorts.
- Overall response rate was 26% in 47 mesothelioma patients treated at clinically optimized doses.
- With optimized doses and UACR thresholds, 22 mesothelioma patients had a 32% response rate, 86% disease control and 10-month median PFS.
- Toxicities were mostly grade 1-2: elevated UACR, proteinuria, peripheral edema and fatigue.
- Proteinuria was reversible with dose adjustment and did not cause renal impairment; FDA granted orphan and fast-track designations.
Methodology
This is an ongoing multicenter, first-in-human phase 1/2 trial with dose escalation (n=85) and expansion cohorts (n=87) of oral VT3989 in refractory solid tumors, focusing on mesothelioma (ClinicalTrials.gov NCT04665206). Reported outcomes include safety, ORR, disease control rate and PFS. The expansion efficacy results are non-prespecified interim analyses.
Study Limitations
The study is single-arm and uncontrolled, and the efficacy analyses are interim, non-prespecified and based on small subgroups, especially the 22-patient UACR-threshold group. Only the abstract was available, so detailed toxicity, duration of response and non-mesothelioma tumor results could not be assessed. Substantial sponsor involvement and author financial ties to Vivace Therapeutics may introduce bias.
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