I presented the first in class, first in human, phase I trial of VT3989 which is an inhibitor of yes-associated protein /transcriptional enhancer activator domain in patients with advanced solid tumours, enriched for patients with malignant mesothelioma and other cancer types with NF2 mutations.
Prior to this study, the YAP/TEAD pathway has long been considered undruggable and this is the first in class agent that targets that pathway. This is a really important pathway because Hippo signalling regulates transcription factors, both YAP and TAZ, in response to diverse upstream signals. When translocated to the nucleus, YAP and TAZ interact with DNA binding T proteins, activating the transcription of target genes. Dysfunction of the Hippo pathway in tumours promotes the activation of YAP and TAZ, resulting in uncontrolled cellular proliferation and impaired differentiation. NF2 mutations are one mechanism by which Hippo control of YAP and TAZ is inactivated in tumours and are common in mesothelioma.
Importantly, palmitoylation of a conserved cysteine is required for TEAD interaction with YAP and the palmitate is actually buried in a central pocket in the YAP binding domain of TEAD. So VT3989 occupies the palmitate pocket, inhibiting palmitoylation and therefore inhibiting the transcription function of TEAD and YAP.
Preclinically, mesothelioma cell lines, when treated with VT3989, showed selectivity for NF2 deficiency and activity was observed in Merlin negative mesothelioma cell lines with and without detected NF2 mutations. VT3989, importantly, was also found to be active in NF2 deficient mesothelioma xenografts.
With these promising preclinical data and good rationale, we then proceeded to the clinic to test VT3989 in this first in human, first in class phase I trial. What we found was that VT3989 was safe and well tolerated in all patients. Importantly, we observed at this very early stage already durable anti-tumour activity in patients with advanced mesothelioma with or without NF2 mutations as well as other solid tumours and NF2 mutations. We saw multiple patients with RECIST partial responses. We also saw very prolonged and durable responses to this treatment with multiple patients still remaining on trial today.
What we observed in terms of side effects was reversible albuminuria, but this was easily managed with dose interruption or reductions if needed and avoidable with doses on intermittent schedules whilst maintaining the anti-tumour activity.
Overall, VT3989 demonstrated dose proportional pharmacokinetic exposures and a long half-life. But overall, importantly, these data provide the first early proof of concept for effectively drugging the Hippo YAP/TEAD pathway in oncology. Dose optimisation expansion cohorts are currently evaluating different doses and schedules using two-stage designs.
