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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

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.

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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

Affiliations

Authors

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 (2021). https://doi.org/10.1038/s41416-021-01389-8

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