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Clinical Study

Phase 1 study of single-agent WNT974, a first-in-class Porcupine inhibitor, in patients with advanced solid tumours

British Journal of Cancer volume 125, pages 28–37 (2021)Cite this article

Subjects

Abstract

Background

This Phase 1 study assessed the safety and efficacy of the Porcupine inhibitor, WNT974, in patients with advanced solid tumours.

Methods

Patients (n = 94) received oral WNT974 at doses of 5–30 mg once-daily, plus additional dosing schedules.

Results

The maximum tolerated dose was not established; the recommended dose for expansion was 10 mg once-daily. Dysgeusia was the most common adverse event (50% of patients), likely resulting from on-target Wnt pathway inhibition. No responses were seen by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1; 16% of patients had stable disease (median duration 19.9 weeks). AXIN2 expression by RT-PCR was reduced in 94% of paired skin biopsies (n = 52) and 74% of paired tumour biopsies (n = 35), confirming inhibition of the Wnt pathway. In an exploratory analysis, an inverse association was observed between AXIN2 change and immune signature change in paired tumour samples (n = 8).

Conclusions

Single-agent WNT974 treatment was generally well tolerated. Biomarker analyses suggest that WNT974 may influence immune cell recruitment to tumours, and may enhance checkpoint inhibitor activity.

Clinical trial registration

NCT01351103.

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Fig. 1: Plasma concentration profiles for WNT974 and LHA333.
Fig. 2: Best percentage change from baseline in the sum of longest diameters of target lesions (investigator assessed).
Fig. 3: Percentage change in AXIN2 mRNA expression from baseline, by treatment group.
Fig. 4: Association between AXIN2 change and immune signature change in tumours.

References

  1. Zhan, T., Rindtorff, N. & Boutros, M. Wnt signaling in cancer. Oncogene 36, 1461–1473 (2017).

    Article  CAS  Google Scholar 

  2. Polakis, P. Wnt signaling in cancer. Cold Spring Harb. Perspect. Biol. 4, a008052 (2012).

    Article  Google Scholar 

  3. Segditsas, S. & Tomlinson, I. Colorectal cancer and genetic alterations in the Wnt pathway. Oncogene 25, 7531–7537 (2006).

    Article  CAS  Google Scholar 

  4. Takada, R., Satomi, Y., Kurata, T., Ueno, N., Norioka, S., Kondoh, H. et al. Monounsaturated fatty acid modification of Wnt protein: its role in Wnt secretion. Dev. Cell 11, 791–801 (2006).

    Article  CAS  Google Scholar 

  5. Rey, J.-P. & Ellies, D. L. Wnt modulators in the biotech pipeline. Dev. Dyn. 239, 102–114 (2010).

    Article  CAS  Google Scholar 

  6. Seshagiri, S., Stawiski, E. W., Durinck, S., Modrusan, Z., Storm, E. E., Conboy, C. B. et al. Recurrent R-spondin fusions in colon cancer. Nature 488, 660–664 (2012).

    Article  CAS  Google Scholar 

  7. Jiang, X., Hao, H.-X., Growney, J. D., Woolfenden, S., Bottiglio, C., Ng, N. et al. Inactivating mutations of RNF43 confer Wnt dependency in pancreatic ductal adenocarcinoma. Proc. Natl Acad. Sci. USA 110, 12649–12654 (2013).

    Article  CAS  Google Scholar 

  8. Waddell, N., Pajic, M., Patch, A.-M., Chang, D. K., Kassahn, K. S., Bailey, P. et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 518, 495–501 (2015).

    Article  CAS  Google Scholar 

  9. Cancer Genome Atlas Research Network. Integrated genomic characterization of pancreatic ductal adenocarcinoma. Cancer Cell 32, 185–203 (2017).

    Article  Google Scholar 

  10. Giannakis, M., Hodis, E., Mu, X. J., Yamauchi, M., Rosenbluh, J., Cibulskis, K. et al. RNF43 is frequently mutated in colorectal and endometrial cancers. Nat. Genet. 46, 1264–1266 (2014).

    Article  CAS  Google Scholar 

  11. Bond, C. E., McKeone, D. M., Kalimutho, M., Bettington, M. L., Pearson, S.-A., Dumenil, T. D. et al. RNF43 and ZNRF3 are commonly altered in serrated pathway colorectal tumorigenesis. Oncotarget 7, 70589–70600 (2016).

    Article  Google Scholar 

  12. Liu, J., Pan, S., Hsieh, M. H., Ng, N., Sun, F., Wang, T. et al. Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. Proc. Natl Acad. Sci. USA 110, 20224–20229 (2013).

    Article  CAS  Google Scholar 

  13. Spranger, S., Bao, R. & Gajewski, T. F. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 523, 231–235 (2015).

    Article  CAS  Google Scholar 

  14. Spranger, S. & Gajewski, T. F. A new paradigm for tumor immune escape: β-catenin-driven immune exclusion. J. Immunother. Cancer 3, 43 (2015).

    Article  Google Scholar 

  15. Holtzhausen, A., Zhao, F., Evans, K. S., Tsutsui, M., Orabona, C., Tyler, D. S. et al. Melanoma-derived Wnt5a promotes local dendritic-cell expression of IDO and immunotolerance: opportunities for pharmacologic enhancement of immunotherapy. Cancer Immunol. Res. 3, 1082–1095 (2015).

    Article  CAS  Google Scholar 

  16. Grasso, C. S., Giannakis, M., Wells, D. K., Hamada, T., Mu, X. J., Quist, M. et al. Genetic mechanisms of immune evasion in colorectal cancer. Cancer Discov. 8, 730–749 (2018).

    Article  CAS  Google Scholar 

  17. Eisenhauer, E. A., Therasse, P., Bogaerts, J., Schwartz, L. H., Sargent, D., Ford, R. et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer 45, 228–247 (2009).

    Article  CAS  Google Scholar 

  18. Neuenschwander, B., Branson, M. & Gsponer, T. Critical aspects of the Bayesian approach to phase I cancer trials. Stat. Med. 27, 2420–2439 (2008).

    Article  Google Scholar 

  19. Babb, J., Rogatko, A. & Zacks, S. Cancer phase I clinical trials: efficient dose escalation with overdose control. Stat. Med. 17, 1103–1120 (1998).

    Article  CAS  Google Scholar 

  20. Harlin, H., Meng, Y., Peterson, A. C., Zha, Y., Tretiakova, M., Slingluff, C. et al. Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment. Cancer Res. 69, 3077–3085 (2009).

    Article  CAS  Google Scholar 

  21. Ng, M., Tan, D. S. P., Subbiah, V., Weekes, C. D., Teneggi, V., Diermayr, V. et al. First-in-human phase 1 study of ETC-159 an oral PORCN inhibitor in patients with advanced solid tumours. J. Clin. Oncol. 35(Suppl 15), abstract 2584 (2017).

  22. Smith, D. C., Rosen, L. S., Chugh, R., Goldman, J. W., Xu, L., Kapoun, A. et al. First-in-human evaluation of the human monoclonal antibody vantictumab (OMP-18R5; anti-Frizzled) targeting the WNT pathway in a phase I study for patients with advanced solid tumors. J. Clin. Oncol. 31(Suppl 15), abstract 2540 (2013).

  23. Jimeno, A., Gordon, M., Chugh, R., Messersmith, W., Mendelson, D., Dupont, J. et al. A first-in-human phase 1 study of anticancer stem cell agent ipafricept (OMP-54F28), a decoy receptor for WNT ligands, in patients with advanced solid tumors. Clin. Cancer Res. 23, 7490–7497 (2017).

    Article  CAS  Google Scholar 

  24. Bendell, J., Eckhardt, G. S., Hochster, H. S., Morris, V. K., Strickler, J., Kapoun, A. M. et al. Initial results from a phase 1a/b study of OMP-131R10, a first-in-class anti-RSPO3 antibody, in advanced solid tumors and previously treated metastatic colorectal cancer (CRC). Eur. J. Cancer 69(Suppl 1), S29–S30 (abstract P039) (2016).

  25. Gaillard, D., Bowles, S. G., Salcedo, E., Xu, M., Millar, S. E. & Barlow, L. A. β-catenin is required for taste bud cell renewal and behavioral taste perception in adult mice. PLoS Genet. 13, e1006990 (2017).

    Article  Google Scholar 

  26. Hayashi, M., Nakashima, T., Taniguchi, M., Kodama, T., Kumanogoh, A. & Takayanagi, H. Osteoprotection by semaphorin 3A. Nature 485, 69–74 (2012).

    Article  CAS  Google Scholar 

  27. Lee, H., Macpherson, L. J., Parada, C. A., Zuker, C. S. & Ryba, N. J. P. Rewiring the taste system. Nature 548, 330–333 (2017).

    Article  CAS  Google Scholar 

  28. Ji, Y., Morawiak, J., Mignault, A., Dolan, S., Huang, P.-H., Mahajan, C., et al. Population PK/PD modeling of a first-in-class Porcupine inhibitor WNT974 in advanced cancer patients to support dose selection for phase I expansion. Clin. Pharmacol. Ther. 99(Suppl 1), abstract LB-001 (2016).

  29. El-Khoueiry, A. B., Ning, Y., Yang, D., Cole, S., Kahn, M., Zoghbi, M. et al. A phase I first-in-human study of PRI-724 in patients (pts) with advanced solid tumors. J. Clin. Oncol. 31(Suppl 15), abstract 2501 (2013).

  30. Voloshanenko, O., Erdmann, G., Dubash, T. D., Augustin, I., Metzig, M., Moffa, G. et al. Wnt secretion is required to maintain high levels of Wnt activity in colon cancer cells. Nat. Commun. 4, 2610 (2013).

    Article  Google Scholar 

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Acknowledgements

We would like to thank the participating patients and their families, all study co-investigators, and research coordinators. We would also like to thank Sinead Dolan, Jun Liu, Steve Woolfenden, and Ramu Thiruvamoor for contributions to biomarker assay development and analyses, and Jie Zhang for contributions to pharmacokinetic assay development and sample analyses. Medical editorial assistance was provided by Laura Hilditch, PhD, and was funded by Novartis Pharmaceuticals Corporation.

Author information

Author notes

  1. Jordi Rodon

    Present address: The University of Texas MD Anderson Cancer Center, Houston, TX, USA

  2. Roisin M. Connolly

    Present address: CancerResearch@UCC, College of Medicine and Health, University College Cork, Cork, Ireland

Authors and Affiliations

  1. Vall d’Hebron University Hospital and Universitat Autònoma de Barcelona, Barcelona, Spain

    Jordi Rodon & Guillem Argilés

  2. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Roisin M. Connolly

  3. Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA

    Ulka Vaishampayan

  4. Department of Medical Oncology, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands

    Maja de Jonge

  5. START Madrid, Hospital Universitario Madrid Sanchinarro, Madrid, Spain

    Elena Garralda

  6. Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    Marios Giannakis

  7. University of Michigan, Ann Arbor, MI, USA

    David C. Smith

  8. Novartis Institutes for BioMedical Research, Cambridge, MA, USA

    Jason R. Dobson, Margaret E. McLaughlin, Jennifer Morawiak & Susan E. Moody

  9. Novartis Pharma AG, Basel, Switzerland

    Abdelkader Seroutou

  10. Novartis Institutes for BioMedical Research, East Hanover, NJ, USA

    Yan Ji

  11. Department of Investigational Cancer Therapeutics (Phase 1 Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Filip Janku

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Contributions

R.M.C, M.E.M., and Y.J. were involved in the conception and design of the study. J.R., G.A., R.M.C., U.V., M.d.J., E.G., M.G., D.C.S., and F.J. were involved in the acquisition of the data. J.R., G.A., R.M.C., U.V., M.d.J., E.G., M.G., J.R.D., M.E.M., A.S., Y.J., J.M., and S.E.M. contributed to the analysis and interpretation of the data. J.R., G.A., R.M.C., U.V., M.d.J., E.G., M.G., D.C.S., J.R.D., M.E.M., A.S., Y.J., J.M., S.E.M., and F.J. were involved in the writing, review, and/or revision of the manuscript. J.R., G.A., R.M.C., U.V., M.deJ., E.G., M.G., D.C.S., J.R.D., M.E.M., A.S., Y.J., J.M., S.E.M., and F.J. approved the final manuscript and are accountable for all aspects of the work.

Corresponding author

Correspondence to Jordi Rodon.

Ethics declarations

Ethics approval and consent to participate

The study protocol was approved by an independent ethics committee or institutional review board (IRB) for each centre: Medisch Ethische Toetsings Commissie, Erasmus MC; Vall d’Hebron Clinical Research Ethics Committee; University of Texas MD Anderson Cancer Center IRB; Wayne State University IRB; John Hopkins Medicine IRB; University of Michigan Medical School IRB; Dana Farber Cancer Institute IRB. The study was conducted according to the principles of the Declaration of Helsinki and was performed in compliance with Good Clinical Practice guidelines. Written informed consent was obtained from each patient.

Consent to publish

NA.

Data availability

The datasets generated and/or analysed for this publication are available from the corresponding author on reasonable request.

Competing interests

J.R. reports non-financial support and reasonable reimbursement for travel from European Journal of Cancer, Vall d’Hebron Institut of Oncology, Chinese University of Hong Kong, SOLTI, Elsevier, and GlaxoSmithKline; consulting and travel fees from Novartis, Eli Lilly, Orion Pharmaceuticals, Servier Pharmaceuticals, Peptomyc, Merck Sharp & Dohme, Kelun Pharmaceutical/Klus Pharma, Spectrum Pharmaceuticals Inc, Pfizer, Roche Pharmaceuticals, Ellipses Pharma, NovellusDx, Ionctura, and Molecular Partners (including scientific advisory boards, 2015 to present); research funding from Blueprint Pharmaceuticals, Bayer, and Novartis; serving as an investigator in clinical trials with Spectrum Pharmaceuticals, Tocagen, Symphogen, BioAtla, Pfizer, GenMab, CytomX, Kelun-Biotech, Takeda-Millennium, GlaxoSmithKline, Ipsen; and travel fees from ESMO, US Department of Defense, Louisiana State University, Hunstman Cancer Institute, Cancer Core Europe, Karolinska Cancer Institute and King Abdullah International Medical Research Center (KAIMRC), and Molecular Partners. G.A. received honoraria, travel grants, and research grants from Hoffman La Roche, Bristol-Myers Squibb, Bayer, Servier, Amgen, Merck Serono, and Menarini, and has a non-financial interest as an advisor of TREOS-Bio Ltd. R.M.C. received research grants (institution) for clinical trials from Novartis, Puma Biotechnology, Merck, Genentech, and Macrogenics, and received travel support from Genentech. U.V. received research support from BMS and Exelixis Inc, consulting and honoraria from BMS, Exelixis, OncLive, Bayer, Sanofi, Eisai, Pfizer and Merck Inc. E.G. received research support from Novartis, Roche, and ThermoFisher; consultant honoraria from Roche/Genentech, F. Hoffmann-La Roche, Ellipses Pharma, Neomed Therapeutics Inc, Boehringer Ingelheim, Janssen Global Services, SeaGen, TFS, Alkermes, ThermoFisher, and Bristol-Myers Squibb; travel grants from Bristol-Myers Squibb, Merck Sharp & Dohme, Menarini, and Glycotope; and attended speaker’s bureaus for Merck Sharp & Dohme, Roche, and ThermoFisher. E.G. reports financial disclosures of the institution for Agios Pharmaceuticals, Amgen, Bayer, Beigene USA, Blueprint Medicines, BMS, Cellestia Biotech, Debiopharm, F. Hoffmann-La Roche Ltd, Forma Therapeutics, Genentech Inc, Genmab B.V., GlaxoSmithKline, Glycotope GmbH, Incyte Biosciences, Incyte Corporation, ICO, Kura Oncology Inc, Lilly S.A., Loxo Oncology Inc, Macrogenics Inc, Menarini Ricerche Spa, Merck, Sharp & Dohme de España S.A., Nanobiotix S.A., Novartis Farmacéutica S.A., Pfizer SLU, Pharma Mar S.A.U., Pierre Fabre Medicament, Principia Biopharma Inc, Psioxus Therapeutics Ltd, Sanofi, Sierra Oncology Inc, Sotio A.S., and Symphogen A/S. M.G. received research funding from Bristol-Myers Squibb, Servier, and Merck and an honorarium from AstraZeneca. D.C.S. received research support from Novartis. J.R.D. is employed by and owns stock with Bristol Myers-Squibb. M.E.M. and A.S. are employed by Novartis. J.M. was recently employed by Novartis. S.E.M. and Y.J. are employed by and own stock with Novartis. F.J. received institutional grant and research funding from Novartis, Genentech, BioMed Valley Discoveries, Plexxikon, Deciphera, Piqur, Symphogen, Bayer, FujiFilm Corporation and Upsher-Smith Laboratories, Astex, Asana, Astellas, Agios, Proximagen, and Bristol-Myers Squibb; has served on scientific advisory boards for Deciphera, IFM Therapeutics, Synlogic, Guardant Health, ldeaya, and PureTech Health; is a paid consultant for Trovagene, lmmunomet, Jazz Pharmaceuticals, and Sotio; and has ownership interests in Travogene. M.d.J. declared no competing interests.

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This study was supported by Novartis Pharmaceuticals Corporation.

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Rodon, J., Argilés, G., Connolly, R.M. et al. Phase 1 study of single-agent WNT974, a first-in-class Porcupine inhibitor, in patients with advanced solid tumours. Br J Cancer 125, 28–37 (2021). https://doi.org/10.1038/s41416-021-01389-8

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