First-in-Class YAP/TEAD Inhibitor Demonstrates Early Efficacy Targeting Hippo Pathway

Ibiayi Dagogo-Jack, MD

Investigators hope that first-in-class agents will combat dysfunction of the Hippo pathway, which promotes YAP and TAZ activation resulting in uncontrolled proliferation and impaired differentiation, by inhibiting the transcription function of TEAD-YAP.¹

“Perhaps the most recognizable component of the Hippo pathway is the gene NF2 that encodes the protein Merlin. When the pathway is on or intact, YAP and TAZ are sequestered or stuck in the cytoplasm where they’re degraded,” Ibiayi Dagogo-Jack, MD, explained in an interview with OncologyLive. “When the pathway is abnormal, YAP and TAZ are not phosphorylated— they’re free to go to the nucleus where they bind to TEAD transcription factors, and this leads to transcription of genes that promote survival [and] impaired differentiation.”

A first-in-human phase 1 clinical trial (NCT04665206) is evaluating the agent VT3989 in patients with advanced solid tumors and the trial is enriched for those with mesothelioma. It is also enriched for patients with NF2 mutations, which are common in mesothelioma and are one mechanism by which Hippo pathway control of YAP and TAZ is inactivated in tumors²—the inactivation of NF2 can contribute to dysregulation of the Hippo pathway.³

Dagogo-Jack, an assistant professor of medicine at Harvard Medical School and a thoracic oncologist at Massachusetts General Hospital, both in Boston, noted that “approximately 60% of mesotheliomas have some sort of dysregulation of the Hippo pathway.”

Additionally, investigators of the study explained that palmitoylation of a conserved cysteine is required for the binding of TEAD to YAP/TAZ; the palmitate is buried in a central pocket in the YAP-binding domain of TEAD.1 “VT3989 binds to a palmitoylation pocket that is used by TEAD transcription factors to bind to YAP and TAZ,” Dagogo-Jack said. “It inhibits that binding and then hopefully you subdue or suppress that transcription that is vital for cancer cell survival.”

Early Efficacy Signals When Targeting HIPPO-YAP-TEAD

Data presented at the 2023 International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer revealed that VT3989 demonstrated antitumor activity inhibiting the Hippo pathway and activity was durable in patients with advanced mesothelioma regardless of NF2 mutation status.²

“We always have to be careful when we’re looking at first-in-human studies because you get a variety of dose levels, and we’re trying to see a signal as far as the safety, but also we’re encouraged when we see some patients with partial responses [PRs],” Dagogo-Jack said.

As of July 31, 2023, among patients with mesothelioma from a total of 5 cohorts (n = 44), 3 patients achieved a PR and were continuing treatment, 1 patient achieved a PR and completed treatment, and 2 patients experienced a PR followed by disease progression. Additionally, 4 patients who achieved stable disease (SD) were continuing treatment and 7 patients who experienced SD had completed treatment.²

Data presented at the 2023 American Association for Cancer Research Annual Meeting from the study demonstrated that of 69 patients enrolled with advanced solid tumors primarily consisting of mesothelioma, 7 patients with measurable disease had a response per RECIST 1.1 criteria and 34 patients with measurable disease had a best response of SD. Responses were seen among patients with and without NF2 mutations.¹

“We’ve seen 7 PRs [and] most of these, all but 1, are in mesothelioma,” Dagogo-Jack noted. “I’ve been using mesothelioma as a broad term, but there [are patients with] pleural, peritoneal, and pericardial mesothelioma who are enrolled in this study. Interestingly, in those rare types of mesotheliomas we’ve been seeing the PRs.”

“The other key thing is that although we would love to have a response, response assessment is a bit more challenging to do in mesothelioma based on how the disease grows and so SD is also something that we’re happy with if the drug is not toxic. Some durable SD has been seen as well—approximately 30 of the 50-plus patients presented had SD. The final important point on the efficacy is we’ve seen some quite durable responses,” Dagogo-Jack said.

Examining VT3989 Dosing and Safety

VT3989 was administered in a 3 plus 3 dose escalation design with a dose expansion. The agent was given continuously at 25-, 50-, 100-, 150-, and 200-mg daily in cohorts 1 to 5 (n = 27). Intermittent dosing schedules were subsequently evaluated in cohorts 6 to 10 (n = 42) with patients receiving 200 mg for 2 weeks on/1 week off, 200 mg for 1 week on/2 weeks off, 200 mg for 2 weeks on/2 weeks off, 100 mg for 2 weeks on/2 weeks off, and 150 mg for 1 week on/3 weeks off. VT3989 was administered at 100 mg in cohort 11 and 50 mg in cohort 12, both for 15 days continuously, then weekly on days 1, 8, and 15. No dose-limiting toxicities were observed in any of the 12 cohorts.¹

“We have seen with this drug, because [investigators] monitor it very closely, that people do leak albumin in the urine and that has led to dose interruptions. It’s one of the reasons that they’re investigating and exploring a variety of dosing schedules, in particular interrupted dosing schedules, to try to maximize the efficacy while sparing any kind of nephrotoxicity,” Dagogo-Jack said.

Grade 1 to 3 albuminuria occurred in 53.5% of patients on the study, with 4.3% of patients experiencing the toxicity at grade 3. No grade 4 events were reported, and all albuminuria and proteinuria events recorded so far were reversible regardless of doses and schedules received.¹

Investigators noted that when VT3989 was administered at a dose of 100 mg or less intermittently, there were less frequent and less severe cases of albuminuria. The median urine albumin-creatinine ratio was 341.9 mg/gm (range, 17.0-2715.4) in patients who received VT3989 at 25 to 200 mg daily continuously or 150 to 200 mg on 4 intermittent dosing schedules (cohorts 1-8 and 10; n = 50) compared with 60.4 mg/gm (range, 7.55-431.2) in those who received the agent at 50 to 100 mg on 2 intermittent dosing schedules (cohorts 9, 11, and 12; n = 19).¹

"This drug is a little different; it’s an oral drug, so a bit of a departure from our traditional intravenous therapies that we use as far as our chemotherapies with mesothelioma. The integrity of the podocytes or the kidney filtration system is impacted by this drug and one of the key things that people are watching out for is whether it causes nephrotic syndrome,” Dagogo-Jack said.

The most common grade 1 to 3 adverse effects (AEs) aside from albuminuria included peripheral edema (36.2%), fatigue (24.6%), nausea (20.3%), increased alanine aminotransaminase (11.6%), increased aspartate aminotransaminase (11.6%), increased cholesterol (7.2%), anorexia (7.2%), hyperlipidemia (7.2%), and periorbital edema (7.2%). No grade 5 AEs occurred in the trial.¹

Moreover, VT3989 gives dose-proportional exposure following administration and the half-life of the agent is approximately 12 to 15 days—pharmacodynamic exposure on day 15 is approximately 7 times that on day 1. Due to the agent’s long half-life, Dagogo-Jack explained that “patients may need to hold the drug for quite a bit before their levels come to a level where you can resume dosing the drug.”

Future Directions With VT3989

“Preclinically when [investigators] looked at mesothelioma disease models and tried to predict who might benefit from treatment and were thinking about [whether the trial] should be restricted to patients with NF2 mutations, it did seem that having an NF2 mutation may have correlated with a greater antiproliferative effect of the drug,” Dagogo-Jack explained. “But that really hasn’t been the case clinically. We must have a bit of pause in terms of interpreting the clinical data because not everyone had NF2 mutation testing when they joined the study and there’s a large chunk of patients where NF2 [status] is unknown.”

Of the 69 patients enrolled in cohorts 1 through 12 of the trial, 37 had NF2 mutations including somatic (n = 31) and germline (n = 6). NF2 mutation status was unknown for 19 patients and 13 patients had NF2 wild-type disease.¹

“Perhaps the greatest area for this drug is in mesothelioma [as] this is a rare disease. There are only 2 approved therapies, their initial approvals are in the first-line setting, and we don’t have anything approved after these drugs,” Dagogo-Jack explained, as nivolumab (Opdivo) and ipilimumab (Yervoy) are currently approved for first-line treatment of adult patients with unresectable malignant pleural mesothelioma.⁵ “There are a couple of chemotherapies we turn to, and there is incredible need for more therapies and particularly more precise therapies for this patient population.”

Additionally, dose-optimization expansion cohorts are under way and are evaluating different schedules as well as doses of VT3989 in 2-stage designs. Investigators also revealed at IASLC that a multivariate analysis is under way and will explore potential predictors of nephropathy.²

“The hope is that a drug like VT3989, if with further study there’s good efficacy and a reasonable safety profile, [could] with future testing make its way into the therapeutic arsenal for mesothelioma,” Dagogo-Jack said. “But we still have work to do and future studies we need to do to learn more about this drug in larger cohorts and to figure out what is the right way to give the drug in terms of the dosing and the dosing schedule.”

References

1. Yap TA, Kwiatkowski DJ, Desai J, et al. First-in-class, first-inhuman phase 1 trial of VT3989, an inhibitor of yes-associated protein (YAP)/transcriptional enhancer activator domain (TEAD), in patients with advanced solid tumors enriched for malignant mesothelioma and other tumors with neurofibromatosis (NF2) mutations. Cancer Res. 2023;83(suppl 8):CT006. doi:10.1158/1538-7445.AM2023-CT006
2. Yap TA, Desai J, Dagogo-Jack I, et al. First-in-human phase 1 trial of VT3989, a first-in-class YAP/TEAD inhibitor in patients with advanced mesothelioma. Presented at: International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer; September 9-12, 2023; Singapore. P2.19-01.
3. Jablons D, Woodard G. Targeting the Hippo pathway. J Thorac Oncol. 2018;13(suppl 10):S306. doi:10.1016/j.jtho.2018.08.205
4. Luo J, Deng L, Zou H, et al. New insights into the ambivalent role of YAP/TAZ in human cancers. J Exp Clin Cancer Res. 2023;42(1):130.doi:10.1186/s13046-023-02704-2
5. FDA approves nivolumab and ipilimumab for unresectable malignant pleural mesothelioma. FDA. October 2, 2020. Accessed November 8, 2023. bit.ly/47q2EW6