1081MO - Phase I study of WNT974 in combination with spartalizumab in patients with cutaneous melanoma

Background

Wnt/β-catenin signaling has been linked to T-cell exclusion in melanoma, a feature that is associated with primary resistance to immunotherapy. WNT974, a porcupine inhibitor, has shown evidence of Wnt pathway inhibition in patients (pts) and is well tolerated when combined with spartalizumab, an anti-PD-1 mAb. We therefore hypothesized that WNT974 + spartalizumab may lead to clinical benefit in pts with advanced melanoma resistant to anti-PD-1-based therapy.

Methods

In the combination dose expansion (CDE) part of the Phase I study (NCT01351103), pts with advanced cutaneous melanoma received the recommended dose for expansion (RDE) of WNT974 (10 mg orally QD, d1-8 Q4W) for the first 4 cycles + spartalizumab IV Q4W. Eligible pts had disease that was either 1) primary refractory (PrR) to prior anti-PD-1-based therapy (best response of progressive disease [PD] or stable disease [SD] for ≤ 4 months (mo), or disease recurrence within the first 6 mo of adjuvant anti-PD-1 therapy) or 2) developed acquired resistance (AR) to prior anti-PD-1 based therapy (PD following response or SD for > 4 mo). Here, we present secondary objectives examined during the dose expansion part which include safety, pharmacokinetics, pharmacodynamics, and antitumor activity. We report on pts treated in the CDE, plus 4 pts with PrR cutaneous melanoma treated at RDE in the dose escalation part.

Results

Among 42 treated pts, 28 had PrR disease and 14 had AR. As of Jan 1, 2024, 39 pts had discontinued (81%; 34 due to PD) and 3 were ongoing. Treatment-related adverse events (TRAEs) were reported in 31 pts. The 2 most common TRAEs of any grade were nausea (23.8%) and alopecia (19%); 6 pts had Grade 3/4 TRAEs (increased lipase, n=4, increased amylase, n = 2, increased blood bilirubin, n = 1 and immune-mediated gastritis, n = 1); no TRAE was fatal. In the PrR group, the overall response rate per RECIST v1.1 was 17.9% (4 partial responses, 1 complete response); 80% of responses were ongoing at 9 mo. Five pts (17.9%) had a best response of SD. Best response observed in the AR group was SD (n = 6, 42.9%). Biomarker analyses are ongoing.

Conclusions

WNT974 + spartalizumab was well-tolerated and demonstrated preliminary antitumor activity in pts with advanced melanoma who progressed on prior anti-PD-1-based therapy.

Clinical trial identification

NCT01351103.

Editorial acknowledgement

Anupama Tamta of Novartis Healthcare Pvt. Ltd, has provided medical writing support.

Legal entity responsible for the study

Novartis Pharmaceuticals Corporation.

Funding

Novartis Pharmaceuticals Corporation.

Disclosure

P.A. Ascierto: Financial Interests, Personal, Other, Consultant and Advisory Role: BMS, Roche Genentech, Novartis, Merck Serono, Sun Pharma, Sanofi, Sandoz, Immunocore, Boehringer Ingelheim Ingelheim, Regeneron; Financial Interests, Personal, Other, Consultant, Advisory Role and Travel support: MSD, Pierre Fabre; Financial Interests, Personal, Other, Consultant and Advisory Role.Travel support: Pfizer/Array; Financial Interests, Personal, Other, Consultant Role: Italfarmaco; Financial Interests, Personal, Other, Consultant Role: Pfizer, Nouscom, Lunaphore; Financial Interests, Personal, Other, Consultant role: Medicenna; Financial Interests, Personal, Other, Consultant role and travel support: Bio-AI Health; Financial Interests, Personal, Advisory Board, Consultant and Advisory role: ValoTx; Financial Interests, Personal, Advisory Board, Consultant and Advisor role.Travel support: Replimmune; Financial Interests, Personal, Advisory Board, Advisor role: Bayer; Financial Interests, Personal, Other, Consultant and Advisory: Erasca; Financial Interests, Personal, Other, Consultant: Philogen; Financial Interests, Personal, Advisory Board: BionTech, Anaveon; Financial Interests, Institutional, Funding, Clinical trial and translational research: BMS; Financial Interests, Institutional, Funding, Clinical Trial: Roche Genentech, Pfizer/Array, Sanofi; Non-Financial Interests, Leadership Role, President since 2010: Fondazione Melanoma Onlus Italy; Non-Financial Interests, Leadership Role, President since 2014: Campania Society of ImmunoTherapy of Cancer (SCITO) Italy; Non-Financial Interests, Other, Member of Steering Committee since 2016: Society for Melanoma Research (SMR); Non-Financial Interests, Member of Board of Directors, November 2017 - December 2021: Society for Immunotherapy of Cancer (SITC); Non-Financial Interests, Member: ASCO, SITC, EORTC Melanoma Cooperative Group, AIOM, SMR. J. Rodon: Financial Interests, Personal, Advisory Board: Ellipses Pharma, IONCTURA SA, Aadi Bioscience, Envision Pharma, Molecular Partners, Mekanistic, Amgen; Financial Interests, Personal, Other, Consultancy: Clarion Healthcare, Debiopharm, Cullgen, Pfizer, Macrogenics, Oncology One, Columbus Venture Partners, Sardona Therapeutics, Avoro Capital Advisors, Vall d'Hebron Institute of Oncology/Ministero De Empleo Y Seguridad, Chinese University of Hong Kong, Boxer Capital, LLC, Tang Advisors, LLC, Alnylam Pharmaceuticals, Bridgebio Pharma; Financial Interests, Personal, Other, Consultancy/Advisory Board: Monte Rosa Therapeutics, Merus N.V, Incyte; Financial Interests, Institutional, Other, Clinical Research: Novartis, Spectrum Pharmaceuticals, Symphogen, BioAtla, Pfizer, GenMab, CytomX, Kelun-Biotech, Takeda-Millenium, GSK; Financial Interests, Institutional, Other, Research Funding: Blueprint Medicines, Black Diamond, Merck Sharp & Dohme; Financial Interests, Institutional, Research Grant, Research Funding/Clinical Research: Hummingbird, Yingli; Financial Interests, Institutional, Research Grant, Research Funding: Vall d'Hebron Institute of Oncology/Cancer Core Europe; Financial Interests, Institutional, Research Grant, Clinical Research: Bicycle Therapeutics, Taiho, Roche Pharmaceuticals, Merus, Curis, AadiBioscience, Nuvation, ForeBio, BioMed Valley Discoveries, Loxo Oncology, Cellestia, Deciphera, Ideaya, Amgen, Tango Therapeutics, Mirati, Linnaeus Therapeutics, Bayer, Hutchinson MediPharma; Other, Other, Other: VHIO/Ministero De Empleo Y Seguridad Social; Other, Other, Travel: European Society for Medical Oncology, Loxo Oncology. F.Y.F.L. De Vos: Financial Interests, Institutional, Advisory Board: BMS; Financial Interests, Institutional, Local PI: Novartis, GSK, Bristol Myers Squibb, Servier; Non-Financial Interests, Member of Board of Directors, dutch society of medical experts treating rare cancers: Dutch Rare Cancer Platform; Non-Financial Interests, Leadership Role, chair Quality of Care Committee: Dutch Society of Medical Oncology; Non-Financial Interests, Leadership Role, board member of Quality Assurance in Brain Tumor Group: European Organisation for Research and Treatment of Cancer; Non-Financial Interests, Member of Board of Directors, national databank on care in brain tumor patients: Dutch Brain Tumor Registry; Non-Financial Interests, Leadership Role, board member of Education Committee: European Association for Neuro-Oncology; Other, Other, grant for research project given bij non-profit patient advocacy group: Foundation STOPBraintumors.org. V. Gambardella: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Institutional, Other, Research: Research Funding: Bayer, Boehringer Ingelheim, Roche; Financial Interests, Institutional, Other, Institutional: Institutional Funding: Genentech, Merck, Roche, Bayer, Lilly, Novartis, Takeda, AstraZeneca, BM. M. De Miguel: Financial Interests, Institutional, Invited Speaker: Janssen, MSD; Non-Financial Interests, Principal Investigator: Janssen, MSD, Roche, Pharmamar, Replimune, Novartis, AbbVie, Achilles, Amunix, Arcus, Furmo, Biontech, Catalym, Dizal, Genentech, Loxo, Numab, Seagen. I. Marquez-Rodas: Financial Interests, Personal, Advisory Board: BMS, MSD, Novartis, Pierre Fabre, Roche, GSK, AstraZeneca, Celgene, Regeneron, Sanofi, Merck Serono, Highligth Therapeutics, Bioline Rx, Sun Pharma, Immunocore; Financial Interests, Personal and Institutional, Coordinating PI, GEM1802 clinical trial: Pierre Fabre; Financial Interests, Institutional, Coordinating PI, GEM1801 clinical study: Novartis, BMS, Roche, Pierre Fabre, Incyte, MSD; Financial Interests, Institutional, Coordinating PI, National coordinator of Spotlight 203 clinical trial: Highlight Therapeutics; Non-Financial Interests, Member of Board of Directors: Spanish Melanoma Group. M. Gil Martín: Financial Interests, Personal, Invited Speaker: MSD, GSK, Clovis; Financial Interests, Personal, Advisory Board: AstraZeneca. C. Robert: Financial Interests, Personal, Advisory Board, Consultancy fees: BMS, Roche, Pierre Fabre, Novartis, Sanofi, Msd, Pfizer, Sun Pharma, Merck, Ultimovacs, Regeneron, EGLE, Philogen, MAAT Pharma; Financial Interests, Personal, Other, Steering Committee: Novartis, Regeneron, Pfizer, IO Biotech; Financial Interests, Personal, Other, IDMC: ULTIMOVACS; Financial Interests, Personal, Invited Speaker: Pierre Fabre, Sanofi, BMS, MSD, Novartis. M. Del Vecchio: Financial Interests, Personal, Advisory Board, Advisor and Consultant and Invited Speaker: Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Immunocore; Non-Financial Interests, Principal Investigator, Clinical Trials: Bristol Myers Squibb, Merck Sharp & Dohme, Immunocore. V. Moreno Garcia: Financial Interests, Personal, Advisory Board: BMS, Janssen, Roche, Basilea, Bayer, astra zeneca; Financial Interests, Personal, Full or part-time Employment: START; Financial Interests, Institutional, Local PI, AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca Bayer Beigene BioInvent International AB, BMS, Boehringer Ingelheim, Boheringer, Boston, Celgene, Daichii Sankyo, DEBIOPHARM,Eisai, e-Terapeutics, Exelisis, Forma Therapeutics, Genmab, GSK, Harpoon, Hutchison, Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa Kirin, Lilly, Loxo, MedSir, Menarini, Merck, Merus, Millennium, MSD, Nanobiotix, Nektar, Novartis, Odonate Therapeutics, Pfizer, Pharma Mar, PharmaMar, Principia, PsiOxus, Puma, Regeneron, Rigontec, Roche, Sanofi, Sierra Oncology, Synthon, Taiho, Takeda, Tesaro, Transgene, Turning Point Therapeutics, Upshersmith: Multiple. D. Schadendorf: Financial Interests, Personal, Invited Speaker: BMS, MSD, Merck Serono, Sanofi, Neracare, SunPharma; Financial Interests, Personal, Advisory Board: BMS, Novartis, MSD, Immunocore, Pierre Fabre, Sanofi/Regeneron, Pfizer, Philogen, Neracare, InFlarX, BioAlta, Daiichi Sanyko, NoviGenix, Anaveon, AstraZeneca, PamGene, BioNTech, Immatics, CureVac, Erasca, Formycon, Replimune, Seagen, SunPharma, Ultimovacs; Financial Interests, Personal, Steering Committee Member: Novartis, BMS, MSD; Financial Interests, Institutional, Coordinating PI: Novartis, BMS, MSD, Pierre Fabre; Financial Interests, Institutional, Research Grant: BMS, MSD; Financial Interests, Institutional, Local PI: Sanofi, Philogen; Non-Financial Interests, Member of Board of Directors: EORTC-MG; Non-Financial Interests, Leadership Role, Founding member and SC chair: European Melanoma Registry (EuMelaReg). R. Jamal: Financial Interests, Personal, Research Grant: Iovance Therapeutics; Financial Interests, Personal, Other, Honoraria: BMS, Pfizer, Medison Pharm. S. Sloan, M. Mclaughlin, E. Hsiue, S. Moody: Financial Interests, Personal, Full or part-time Employment: Novartis. S. Murray: Financial Interests, Personal, Full or part-time Employment, Employee of and a stockholder in Novartis: Novartis. B. Gomez-Carrillo Ruiz: Financial Interests, Personal, Stocks or ownership, Full time employment: Novartis. A.M. Arance: Financial Interests, Personal, Other, Advisory, Speaker, Travel Expenses: Pierre Fabre; Financial Interests, Personal and Institutional, Other, Advisory, Speaker, Travel Expenses, Research Funding (Institution): Novartis, Roche, BMS, MSD; Financial Interests, Personal and Institutional, Other, Advisory Role, Research Funding (Institution): Biontech; Financial Interests, Personal, Advisory Role: Almirall; Financial Interests, Institutional, Research Funding: Replimune.