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YAP/TEAD inhibitor VT3989 in solid tumors: a phase 1/2 trial

Nature Medicine volume 31, pages 4281–4290 (2025)Cite this article

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Abstract

Constitutive YAP activation resulting from dysregulated Hippo signaling drives tumor progression in mesothelioma and other cancers. VT3989, a first-in-class potent oral TEAD palmitoylation inhibitor, disrupts YAP transcriptional activity. Here we report the first-in-human phase 1/2 trial findings evaluating VT3989 in refractory solid tumors with a focus on mesothelioma. This study is ongoing, and we report results from the dose escalation and non-prespecified interim efficacy results of the expansion cohorts for which recruitment is ongoing. Dose escalation (n = 85) and expansion (n = 87) cohorts included 172 patients (135 mesothelioma). VT3989 exhibited a favorable safety profile with mostly grade 1–2 toxicities, including increased urine albumin:creatinine ratio (UACR), proteinuria, peripheral edema and fatigue. Proteinuria was reversible with dose adjustment and did not result in renal impairment. The overall response rate (ORR) was 26% in 47 patients with mesothelioma treated at clinically optimized doses, whereas the ORR was 32% (disease control rate 86%; median progression-free survival 10 months) in 22 patients with mesothelioma when clinically optimized doses and UACR thresholds were incorporated. These data provide the first early clinical proof of concept for effectively drugging the Hippo−YAP−TEAD pathway. VT3989 was recently awarded orphan drug designation and fast-track designation for the treatment of mesothelioma by the US Food and Drug Administration (FDA). ClinicalTrials.gov Identifier: NCT04665206.

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Fig. 1: VT3989 clinical response.
Fig. 2: VT3989 pharmacokinetics and modulation of the Hippo−YAP/TEAD pathway after oral administration.
Fig. 3: Mesotheliomas responding to VT3989 without detected NF2 mutations are Merlin negative by IHC.

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Data availability

All data used in the interim analyses supporting the findings of the present study are available within the paper and its Supplementary Information files. All requests for further data sharing will be reviewed by Vivace Therapeutics to verify whether the request is subject to any intellectual property or confidentiality obligations. Further requests for access to the individual participant-level data from this study can be submitted via email to the corresponding author with detailed proposals. The corresponding author will provide a response after evaluating the proposal, within 90 days. Each participant’s rights and privacy must be carefully protected when sharing information. A signed data access agreement with the collaborator is required before accessing shared data.

References

  1. Harvey, K. F. & Tang, T. T. Targeting the Hippo pathway in cancer. Nat. Rev. Drug Discov. https://doi.org/10.1038/s41573-025-01234-0 (2025).

  2. Cerami, E. et al. The cBio Cancer Genomics Portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2, 401–404 (2012).

    PubMed  Google Scholar 

  3. Gao, J. et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1 (2013).

    PubMed  PubMed Central  Google Scholar 

  4. Sanchez-Vega, F. et al. Oncogenic signaling pathways in The Cancer Genome Atlas. Cell 173, 321–337 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Wang, Y. et al. Comprehensive molecular characterization of the Hippo signaling pathway in cancer. Cell Rep. 25, 1304–1317 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Murakami, H. et al. LATS2 is a tumor suppressor gene of malignant mesothelioma. Cancer Res. 71, 873–883 (2011).

    CAS  PubMed  Google Scholar 

  7. Ruttledge, M. H. et al. Evidence for the complete inactivation of the NF2 gene in the majority of sporadic meningiomas. Nat. Genet. 6, 180–184 (1994).

    CAS  PubMed  Google Scholar 

  8. Dwianingsih, E. K., Krisnugraha, Y. P., Bawono, R. G. & Malueka, R. G. Molecular biomarkers in meningioma (Review). Biomed. Rep. 22, 56 (2025).

    PubMed  PubMed Central  Google Scholar 

  9. Sekido, Y. & Sato, T. NF2 alteration in mesothelioma. Front. Toxicol. 5, 1161995 (2023).

    PubMed  PubMed Central  Google Scholar 

  10. Bueno, R. et al. Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations. Nat. Genet. 48, 407–416 (2016).

    CAS  PubMed  Google Scholar 

  11. Hiltbrunner, S. et al. Genomic landscape of pleural and peritoneal mesothelioma tumours. Br. J. Cancer 127, 1997–2005 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Hmeljak, J. et al. Integrative molecular characterization of malignant pleural mesothelioma. Cancer Discov. 8, 1548–1565 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Sekido, Y. Inactivation of Merlin in malignant mesothelioma cells and the Hippo signaling cascade dysregulation. Pathol. Int. 61, 331–344 (2011).

    CAS  PubMed  Google Scholar 

  14. Miyanaga, A. et al. Hippo pathway gene mutations in malignant mesothelioma: revealed by RNA and targeted exon sequencing. J. Thorac. Oncol. 10, 844–851 (2015).

    CAS  PubMed  Google Scholar 

  15. Tang, T. et al. PB195: Evaluating the use of Merlin-YAP dual-label immunohistochemistry for predicting response to TEAD inhibitor VT3989. Eur. J. Cancer 211, 114725 (2024).

    Google Scholar 

  16. Szulzewsky, F., Holland, E. C. & Vasioukhin, V. YAP1 and its fusion proteins in cancer initiation, progression and therapeutic resistance. Dev. Biol. 475, 205–221 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Guo, S. et al. VGLL2 and TEAD1 fusion proteins identified in human sarcoma drive YAP/TAZ-independent tumorigenesis by engaging EP300. Elife https://doi.org/10.7554/eLife.98386 (2025).

  18. Stacchiotti, S. et al. Epithelioid hemangioendothelioma, an ultra-rare cancer: a consensus paper from the community of experts. ESMO Open 6, 100170 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Cunningham, R. & Hansen, C. G. The Hippo pathway in cancer: YAP/TAZ and TEAD as therapeutic targets in cancer. Clin. Sci. (Lond.) 136, 197–222 (2022).

    CAS  PubMed  Google Scholar 

  20. Dey, A., Varelas, X. & Guan, K.-L. Targeting the Hippo pathway in cancer, fibrosis, wound healing and regenerative medicine. Nat. Rev. Drug Discov. 19, 480–494 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Noland, C. L. et al. Palmitoylation of TEAD transcription factors is required for their stability and function in Hippo pathway signaling. Structure 24, 179–186 (2016).

    CAS  PubMed  Google Scholar 

  22. Pobbati, A. V. et al. Targeting the central pocket in human transcription factor TEAD as a potential cancer therapeutic strategy. Structure 23, 2076–2086 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Chan, P. et al. Autopalmitoylation of TEAD proteins regulates transcriptional output of the Hippo pathway. Nat. Chem. Biol. 12, 282–289 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Tang, T. T. et al. Small molecule inhibitors of TEAD auto-palmitoylation selectively inhibit proliferation and tumor growth of NF2-deficient mesothelioma. Mol. Cancer Ther. 20, 986–998 (2021).

    CAS  PubMed  Google Scholar 

  25. Carbone, M. et al. Mesothelioma: scientific clues for prevention, diagnosis, and therapy. CA Cancer J. Clin. 69, 402–429 (2019).

    PubMed  PubMed Central  Google Scholar 

  26. Kindler, H. L. et al. Treatment of pleural mesothelioma: ASCO guideline update. J. Clin. Oncol. 43, 1006–1038 (2025).

    CAS  PubMed  Google Scholar 

  27. Zauderer, M. G. et al. Vinorelbine and gemcitabine as second- or third-line therapy for malignant pleural mesothelioma. Lung Cancer 84, 271–274 (2014).

    PubMed  Google Scholar 

  28. Kindler, H. L. et al. Anetumab ravtansine versus vinorelbine in patients with relapsed, mesothelin-positive malignant pleural mesothelioma (ARCS-M): a randomised, open-label phase 2 trial. Lancet Oncol. 23, 540–552 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Fennell, D. A. et al. Active symptom control with or without oral vinorelbine in patients with relapsed malignant pleural mesothelioma (VIM): a randomised, phase 2 trial. EClinicalMedicine 48, 101432 (2022).

    PubMed  PubMed Central  Google Scholar 

  30. Armato, S. G. 3rd& Nowak, A. K. Revised modified Response Evaluation Criteria in Solid Tumors for assessment of response in malignant pleural mesothelioma (version 1.1). J. Thorac. Oncol. 13, 1012–1021 (2018).

    PubMed  Google Scholar 

  31. Tang, T. T. & Post, L. Abstract 7282: Comparing TEAD palmitoylation inhibitors with differential TEAD selectivity in combination efficacy with targeted therapies and in renal safety. Cancer Res. 84, 7282 (2024).

    Google Scholar 

  32. Otsuki, H. et al. Reversible and monitorable nephrotoxicity in rats by the novel potent transcriptional enhanced associate domain (TEAD) inhibitor, K-975. J. Toxicol. Sci. 49, 175–191 (2024).

    CAS  PubMed  Google Scholar 

  33. Schwartzman, M. et al. Podocyte-specific deletion of Yes-associated protein causes FSGS and progressive renal failure. J. Am. Soc. Nephrol. 27, 216–226 (2016).

    CAS  PubMed  Google Scholar 

  34. Chung, J. J. et al. Single-cell transcriptome profiling of the kidney glomerulus identifies key cell types and reactions to injury. J. Am. Soc. Nephrol. 31, 2341–2354 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Chen, J., Wang, X., He, Q. & Harris, R. C. TAZ is important for maintenance of the integrity of podocytes. Am. J. Physiol. Ren. Physiol. 322, F419–F428 (2022).

    CAS  Google Scholar 

  36. Rinschen, M. M. et al. YAP-mediated mechanotransduction determines the podocyte’s response to damage. Sci. Signal. 10, eaaf8165 (2017).

    PubMed  Google Scholar 

  37. Huh, H. D., Kim, D. H., Jeong, H. S. & Park, H. W. Regulation of TEAD transcription factors in cancer biology. Cells 8, 600 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Muller, F., Kunnimalaiyaan, S., Mangrolia, P. & Olson, J. Abstract 5913: TEAD1/4 inhibitors exhibit deeper biological impact and broader activity compared to TEAD1-only inhibitors in both monotherapy and combination without additional kidney toxicity. Cancer Res. 84, 5913 (2024).

    Google Scholar 

  39. Lin, L. et al. The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies. Nat. Genet. 47, 250–256 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Tsuji, T. et al. YAP1 mediates survival of ALK-rearranged lung cancer cells treated with alectinib via pro-apoptotic protein regulation. Nat. Commun. 11, 74 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Kurppa, K. J. et al. Treatment-induced tumor dormancy through YAP-mediated transcriptional reprogramming of the apoptotic pathway. Cancer Cell 37, 104–122 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Nilsson, M. B. et al. A YAP/FOXM1 axis mediates EMT-associated EGFR inhibitor resistance and increased expression of spindle assembly checkpoint components. Sci. Transl. Med. 12, eaaz4589 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Haderk, F. et al. Focal adhesion kinase-YAP signaling axis drives drug-tolerant persister cells and residual disease in lung cancer. Nat. Commun. 15, 3741 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Tang, T. T. & Post, L. Abstract 5364: The TEAD autopalmitoylation inhibitor VT3989 improves efficacy and increases durability of efficacy of osimertinib in preclinical EGFR mutant tumor models. Cancer Res. 82, 5364 (2022).

    Google Scholar 

  45. Tang, T. T. & Post, L. Abstract B088: VT3989, the first-in-class and first-in-human TEAD auto-palmitoylation inhibitor, enhances the efficacy and durability of multiple targeted therapies of the MAPK and P13K/AKT/mTOR pathways. Mol. Cancer Ther. 22, B088 (2023).

    Google Scholar 

  46. Edwards, A. C. et al. TEAD inhibition overcomes YAP1/TAZ-driven primary and acquired resistance to KRASG12C inhibitors. Cancer Res. 83, 4112–4129 (2023).

    PubMed  PubMed Central  Google Scholar 

  47. Mukhopadhyay, S. et al. Genome-wide CRISPR screens identify multiple synthetic lethal targets that enhance KRASG12C inhibitor efficacy. Cancer Res. 83, 4095–4111 (2023).

    PubMed  PubMed Central  Google Scholar 

  48. Ogimoto, T. et al. Combination therapy with EGFR tyrosine kinase inhibitors and TEAD inhibitor increases tumor suppression effects in EGFR mutation–positive lung cancer. Mol. Cancer Ther. 23, 564–576 (2024).

    CAS  PubMed  Google Scholar 

  49. Eisenhauer, E. A. et al. New response evaluation criteria in solid tumors. Revised RECIST guideline (version 1.1). Eur. J. Cancer 45, 228–247 (2009).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank K. J. Gordon at Boudicca DX LLC and J. L. Sauter at Memorial Sloan Kettering Cancer Center for scientific advice, J. Lewis, T. Cloherty and N. McBrearty at Discovery Life Sciences for their services in Merlin−YAP IHC assay development, and K. Watson at Certara for PK modeling. We also thank D. Vallner, J. Abbey and InClin, Inc. for program management and clinical operations support. T.A.Y. holds the Ransom Horne, Jr. Endowed Professorship for Cancer Research at The University of Texas MD Anderson Cancer Center and is supported by National Cancer Center Cancer Center Support Grant CA016672, awarded to The University of Texas MD Anderson Cancer Center. Vivace Therapeutics funded the conduct of the clinical study and contributed to study conceptualization, design, data collection, analysis and manuscript preparation. Apart from participation as investigators in this study, the authors received no additional funding or financial support from Vivace Therapeutics for the research or preparation of this manuscript.

Author information

Authors and Affiliations

  1. The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Timothy A. Yap & Kanwal P. S. Raghav

  2. Brigham and Women’s Hospital, Dana Farber Cancer Institute, Boston, MA, USA

    David J. Kwiatkowski

  3. Massachusetts General Hospital Cancer Center, Boston, MA, USA

    Ibiayi Dagogo-Jack

  4. Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Michael Offin

  5. Westchester Medical Center, New York, NY, USA

    Marjorie G. Zauderer

  6. University of Minnesota Medical School, Minneapolis, MN, USA

    Robert Kratzke

  7. Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    Jayesh Desai

  8. Monash Medical Centre, Clayton, Victoria, Australia

    Amy Body

  9. School of Medicine, University of Western Australia & Linear Clinical Research Perth, Perth, Western Australia, Australia

    Michael Millward

  10. NEXT Oncology, San Antonio, TX, USA

    Anthony W. Tolcher

  11. Toxicology Solutions, Marana, AZ, USA

    Archie Thurston

  12. Vivace Therapeutics, San Mateo, CA, USA

    Len Post, F. Andrew Dorr, Tracy T. Tang, Yufeng Li & Neelesh Sharma

  13. University of Chicago, Chicago, IL, USA

    Hedy L. Kindler

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Contributions

All authors were substantial contributors to the study, including design, data acquisition and analysis and interpretation of the data. All have critically reviewed the manuscript, agreed with the content and approved the final version.

Corresponding authors

Correspondence to Timothy A. Yap or Neelesh Sharma.

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Competing interests

T.A.Y. is an employee of The University of Texas MD Anderson Cancer Center, where he is Vice President, Head of Clinical Development, in the Therapeutics Discovery Division, which has a commercial interest in DDR and other inhibitors (IACS30380/ART0380 was licensed to Artios); has received funding paid to his institution from Acrivon, Artios, AstraZeneca, Bayer, BeiGene, BioNTech, Blueprint, Bristol Myers Squibb, Boundless Bio, Clovis, Constellation, Cyteir, Eli Lilly, EMD Serono, Forbius, F-Star, GlaxoSmithKline, Genentech, Haihe, Ideaya ImmuneSensor, Insilico Medicine, Ionis, Ipsen, Jounce, Karyopharm, KSQ, Kyowa, Merck, Mirati, Novartis, Pfizer, Ribon Therapeutics, Regeneron, Repare, Rubius, Sanofi, Scholar Rock, Seattle Genetics, Tango, Tesaro, Vivace Therapeutics and Zenith; has received consultancy funding from AbbVie, Acrivon, Adagene, Almac, Aduro, Amphista, Artios, Astex, AstraZeneca, Athena, Atrin, Avenzo, Avoro, Axiom, Baptist Health Systems, Bayer, BeiGene, BioCity Pharma, Blueprint, Boxer, Bristol Myers Squibb, C4 Therapeutics, Calithera, Cancer Research UK, Carrick Therapeutics, Circle Pharma, Clovis, Cybrexa, Daiichi-Sankyo, Dark Blue Therapeutics, Diffusion, Duke Street Bio, 858 Therapeutics, EcoR1 Capital, Ellipses Pharma, EMD Serono, Entos, F-Star, Genesis Therapeutics, Genmab, Glenmark, GLG, Globe Life Sciences, GlaxoSmithKline, Guidepoint, Ideaya Biosciences, Idience, Ignyta, I-Mab, ImmuneSensor, Impact Therapeutics, Institut Gustave Roussy, Intellisphere, Jansen, Kyn, MEI Pharma, Mereo, Merck, Merit, Monte Rosa Therapeutics, Natera, Nested Therapeutics, Nexys, Nimbus, Novocure, Odyssey, OHSU, OncoSec, Ono Pharma, Onxeo, PanAngium Therapeutics, Pegascy, Physiciansʼ Education Resource, Pfizer, Piper-Sandler, Pliant Therapeutics, Prolynx, Radiopharma Theranostics, Repare, resTORbio, Roche, Ryvu Therapeutics, SAKK, Sanofi, Schrodinger, Servier, Synnovation, Synthis Therapeutics, Tango, TCG Crossover, TD2, Terremoto Biosciences, Tessellate Bio, Theragnostics, Terns Pharmaceuticals, Tolremo, Tome, Thryv Therapeutics, Trevarx Biomedical, Varian, Veeva, Versant, Vibliome, Voronoi, Xinthera, Zai Labs and ZielBio; and is a stockholder in Seagen. He was supported by National Cancer Institute Cancer Center Support Grant CA016672 to The University of Texas MD Anderson Cancer Center; US Department of Defense grants W81XWH2210504_BC211174 and W81XWH-21-1-0282_OC200482; V Foundation Scholar Grant VC2020-001; and National Institutes of Health R01 grant 1R01CA255074. D.J.K. has research contracts with Genentech, AADI and Revolution Medicines and is a consultant to Genentech, AADI, Expertconnect, Guidepoint, Bridgebio, Slingshot Insights, William Blair, MEDACorp and Radyus Research. I.D.-J. has advisory roles with AstraZeneca, Bayer, BostonGene, Bristol Myers Squibb, Catalyst, Eli Lilly, Genentech, Janssen, Merus, Novocure, Pfizer, Sanofi/Genzyme and Thermo Fisher Scientific and has received research funding from Array, BostonGene, Genentech, Novartis and Pfizer. M.O. has consulting roles with/honoraria from Novartis, Jazz Pharmaceuticals, Pfizer, Targeted Oncology, OncLive, the American Society for Radiation Oncology, Servier and Vivace Therapeutics and grant support from the Druckenmiller Foundation, the US Department of Defense and the LUNGevity Foundation. M.O. is also an uncompensated scientific advisory board member for the Mesothelioma Applied Research Foundation. M.G.Z. has received consulting fees from Vivace Therapeutics, MedImmune, Orion and Roche Diagnostics; honoraria for continuing medical education content from Physiciansʼ Education Resource and HMP Global; and research funding to employer from MedImmune, Bristol Myers Squibb, Merck, Sapience, Werewolf, Vivace Therapeutics, GlaxoSmithKline, Epizyme, Polaris and Sellas Life Sciences. M.G.Z. is also Chair, Board of Directors, for the Mesothelioma Applied Research Foundation (uncompensated). R.K. has no disclosures. J.D. has consulting or advisory roles with BeiGene, Pierre Fabre, Bayer, GlaxoSmithKline, Merck KGaA, Boehringer Ingelheim, Roche/Genentech, Daiichi-Sankyo Europe GmbH, Novartis, Pfizer, Ellipses Pharma, Axelia Oncology, Incyte and Amgen and has received institutional research funding from Roche, GlaxoSmithKline, Novartis, BeiGene, Bristol Myers Squibb, AstraZeneca, Amgen and Genentech. A.B. has research contracts (payment to institution) with Vivace Therapeutics, PMV Pharmaceuticals, Prelude Therapeutics, BeiGene, Hanmi Pharmaceuticals and Stingray Therapeutics and is an uncompensated advisory board member with Hanmi Pharmaceuticals. M.M. has consulting roles/advisory board for AstraZeneca Australia Pty Ltd., Bayer Australia Pty Ltd., BeiGene Australia Pty Ltd., Bristol Myers Squibb Australia Pty Ltd., Eli Lilly Australia Pty Ltd., IQVIA Australia Pty Ltd. and The Limbic. A.W.T. has consulting roles with AbbVie, Aclaris Therapeutics, Affinia Therapeutics, Agenus, Asana Biosciences, Ascentage, Astex Pharmaceuticals, Axlmmune, Bayer, Bluprint Oncology, Compugen Ltd., Coretag Therapeutics, Daiichi-Sankyo, Day One Biopharmaceuticals, Exelixis, FibroGen, Gilde Healthcare Partners, HBM Partners, Horizon CME, IDEA Pharma, Ikena Oncology, Immuneering, Immunomet Therapeutics, Impact Therapeutics US, Indupro, Karma Oncology B.V., Kirilys Therapeutics, Lengo Therapeutics, Link Immunotherapeutics, Medicxi, Merck KGA, Mekanistic Therapeutics, Menarini Ricerche, Mersana, Mythic Therapeutics (Cytel), Nanobiotix, Nerviano Medical Sciences, Novo Nordisk, Novo Ventures, Nurix Therapeutics, Ocellaris Pharma & Eli Lilly, Partner Therapeutics, Pfizer, Pierre Fabre, Praxia Precision Medicines, Prelude Therapeutics, Pyramid Biosciences, Qualigen Therapeutics, Roche, RYVU Therapeutics, Seattle Genetics, Singzyme Pte Ltd., SK Life Science, SOTIO Biotechnology, Senti Biosciences, Sun Pharma Advanced Research Company (SPARC), Tensegrity Pharma, TheraTechnologies, Transcenta Therapeutics, Transgene, Trillium Therapeutics, Tubulis, Venus Oncology, Verastem Oncology, Vida Ventures Advisors and Voyant Bio (Ask Mendel AI, Inc.). A.W.T. also serves on advisory boards for Adagene, BioInvent, Boeringer Ingelheim International GmbH, Bright Peak Therapeutics, Cullinan Oncology, Curadev Pharma, Elucida Oncology, EMD Serono/Merck KGaA, Hexagon Bio, Immunome, Jazz Pharmaceuticals, Kivu, Leerink, Mirati, NBE Therapeutics, Nested Therapeutics, Pheon Therapeutics, PYXIS Oncology, Roche, SPARC, Spirea Limited, Tagworks Pharmaceuticals, Vincerx, VRISE Therapeutics, Zentalis Pharmaceuticals and ZielBio. K.P.S.R. has consulting roles with AbbVie, AstraZeneca, Bayer, Daiichi-Sankyo, Eisai, Jazz Pharmaceuticals and Seagen and has received research funding or contracted research from AbbVie, AstraZeneca, Bayer, Daiichi-Sankyo, D3-Bio, Eisai, Genentech, Grail, Guardant Health, Hibercell, Innovent, Janssen, Merck, Seattle Genetics, UCB BioSciences and Xencor. A.T. is a consultant for Vivace Therapeutics. L.P. is the former Chief Scientific Officer for Vivace Therapeutics; has equity in Vivace Therapeutics; and is an advisor for Canaan Partners. F.A.D. is a consultant for Vivace Therapeutics. T.T.T. reports employment and stock incentives with Vivace Therapeutics. Y.L. reports employment and stock incentives with Vivace Therapeutics. N.S. reports employment and stock incentives with Vivace Therapeutics. H.L.K. has consultant/advisory roles with AstraZeneca, Amgen, Enlaza and Vivace Therapeutics.

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Yap, T.A., Kwiatkowski, D.J., Dagogo-Jack, I. et al. YAP/TEAD inhibitor VT3989 in solid tumors: a phase 1/2 trial. Nat Med 31, 4281–4290 (2025). https://doi.org/10.1038/s41591-025-04029-3

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