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.

Conflict of interest statement

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.

Figures

Fig. 1. Plasma concentration profiles for WNT974 and LHA333.

Mean plasma concentration profiles are shown for WNT974 (a) and LHA333 (b), on cycle 1 day 1 and cycle 1 day 15 following once-daily oral administration of WNT974. Dose-escalation phase; data cut-off: 2 March 2015. C cycle; D day.

Fig. 2. Best percentage change from baseline in the sum of longest diameters of target lesions (investigator assessed).

Best percentage change is shown for n = 63 evaluable patients. The best overall response is shown above/below bars. *Patient had alteration of RNF43 as determined by local or central (next-generation sequencing) testing; #Percentage changes from baseline >100% are set to 100%. Data cut-off: 2 March 2017. 4/7 QD drug administered 4 days on, 3 days off, BID twice-daily, UNK unknown.

Fig. 3. Percentage change in AXIN2 mRNA expression from baseline, by treatment group.

Upper panel, skin samples (frozen; n = 52); and lower panel, tumour tissue samples (frozen; n = 35). The indication is shown for each patient. Data cut-off: 2 March 2017. 4/7 QD drug administered 4 days on, 3 days off, BID twice-daily.

Fig. 4. Association between AXIN2 change and immune signature change in tumours.

aAXIN2 change vs. change in chemokine signature associated with T-cell recruitment, and bAXIN2 change vs. change in activated dendritic cell signature. Data cut-off: 2 March 2017.