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Clinical Trial
. 2023 Mar 17;28(3):230-238.
doi: 10.1093/oncolo/oyad007.

A Phase Ib/II Study of WNT974 + Encorafenib + Cetuximab in Patients With BRAF V600E-Mutant KRAS Wild-Type Metastatic Colorectal Cancer

Josep Tabernero  1 , Eric Van Cutsem  2 , Elena Garralda  3 , David Tai  4 , Filippo De Braud  5 , Ravit Geva  6 , Mark T J van Bussel  7 , Katia Fiorella Dotti  5 , Elena Elez  8 , María J de Miguel  3 , Kevin Litwiler  9 , Danielle Murphy  10 , Michelle Edwards  11 , Van Karlyle Morris  12
Affiliations
Clinical Trial

A Phase Ib/II Study of WNT974 + Encorafenib + Cetuximab in Patients With BRAF V600E-Mutant KRAS Wild-Type Metastatic Colorectal Cancer

Josep Tabernero et al. Oncologist. .

Abstract

Background: WNT974 is a small molecule inhibitor of Wnt signaling that specifically inhibits porcupine O-acyltransferase. This phase Ib dose--escalation study evaluated the maximum tolerated dose of WNT974 in combination with encorafenib and cetuximab in patients with BRAF V600E-mutant metastatic colorectal cancer with RNF43 mutations or RSPO fusions.

Patients and methods: Patients received once-daily encorafenib and weekly cetuximab, in addition to once-daily WNT974, in sequential dosing cohorts. In the first cohort, patients received 10-mg WNT974 (COMBO10), which was reduced in subsequent cohorts to 7.5-mg (COMBO7.5) or 5-mg (COMBO5) after dose-limiting toxicities (DLTs) were observed. Primary endpoints were incidence of DLTs and exposure to WNT974 and encorafenib. Secondary endpoints were anti-tumor activity and safety.

Results: Twenty patients were enrolled (COMBO10, n = 4; COMBO7.5, n = 6; COMBO5, n = 10). DLTs were observed in 4 patients, including grade 3 hypercalcemia (COMBO10, n = 1; COMBO7.5, n = 1), grade 2 dysgeusia (COMBO10, n = 1), and lipase increased (COMBO10, n = 1). A high incidence of bone toxicities (n = 9) was reported, including rib fracture, spinal compression fracture, pathological fracture, foot fracture, hip fracture, and lumbar vertebral fracture. Serious adverse events were reported in 15 patients, most frequently bone fracture, hypercalcemia, and pleural effusion. The overall response rate was 10% and disease control rate 85%; most patients achieved stable disease as their best response.

Conclusion: Concerns surrounding the safety and lack of preliminary evidence of improved anti-tumor activity of WNT974 + encorafenib + cetuximab, compared with previous encorafenib + cetuximab data, ultimately led to study discontinuation. Phase II was not initiated.

Trial registration: ClinicalTrials.gov, NCT02278133.

Keywords: WNT974; cetuximab; colorectal cancer; encorafenib; metastatic.

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Conflict of interest statement

Josep Tabernero Array Biopharma, AstraZeneca, Avvinity, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, NeoPhore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Scandion Oncology, Servier, Taiho, Tessa Therapeutics, and TheraMyc (consulting/advisory); Imedex, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education, and Physicians Education Resource (PER) (educational collaboration); Amgen Inc., Array Biopharma Inc., AstraZeneca Pharmaceuticals LP, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Hutchison MediPharma International, Janssen-Cilag SA, MedImmune, Menarini, Merck Health KGAA, Merck Sharp & Dohme, Merus NV, Mirati, Novartis Farmacéutica SA, Pfizer, Pharma Mar, Sanofi Aventis Recherche & Développement, Servier, Taiho Pharma USA Inc., Spanish Association Against Cancer Scientific Foundation, and Cancer Research UK (research funding). Eric Van Cutsem Array, AstraZeneca, Bayer, Biocartis, Bristol Myers Squibb, Celgene, Eli Lilly, Ipsen, MSD, Merck KGaA, Novartis, Pierre Fabre, Roche, Servier, Sirtex, and Taiho (consulting/advisory); Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Ipsen, Merck, Merck KGaA, Novartis, Roche, and Servier (research funding). Elena Garralda Alkermes, Anaveon, Boehringer, Bristol Myers Squibb, F. Hoffman/La Roche, Ingelheim, Janssen Global Services, MabDiscovery, Roche/Genentech, Seattle Genetics, TFS, and Thermo Fisher (consulting/advisory); AstraZeneca, BeiGene, Novartis, Roche, Taiho, and Thermo Fisher (research funding). David Tai F. Hoffman/La Roche. Filippo De Braud AstraZeneca, EMD Serono, Incyte, Menarini, MSD, NMS Nerviano Medical Science, Novartis, Roche, and Sanofi (consulting/advisory). Ravit Geva AstraZeneca, Bayer, Boehringer Ingelheim, BOL Pharma, EISAI, MSD, Novartis, and Roche (consulting/advisory); Bristol Myers Squibb, Janssen, Lilly, Medison, Merck, MSD, Novartis, Pfizer, Roche, and Takeda (honoraria); Novartis (research funding); Bayer, Bristol Myers Squibb, Medison, Merck, BOL Pharma, and Pyxis (travel, accommodations and/or expenses). Mark T.J. van Bussel reported no financial relationships. Katia Fiorella Dotti reported no financial relationships. Elena Elez Amgen, Array BioPharma, Bayer, Merck Serono, MSD, Pierre Fabre, Roche, Sanofi, and Servier (consulting/advisory). María J. de Miguel MSD, PharmaMar, Roche, Novartis, AbbVie, Array, Eisai, Faron, and Sanofi (research funding); MSD, Janssen, Roche (speakers’ bureau). Kevin Litwiler Volestra (consultant/advisory role); Pfizer (employee); OnKure Therapeutics (employee, leadership role, stockholder). Danielle Murphy Pfizer (employee, ownership interests). Michelle Edwards Pfizer (former employee and stockholder); Arvinia (employee and stockholder). Van Karlyle Morris Array, Axiom Healthcare Strategies, Bayer, Bicara Therapeutics, BioMedical Insights, Boehringer Ingelheim, Incyte, Pfizer, and Servier (consulting/advisory); BioNTech AG, Boehringer Ingelheim, Bristol Myers Squibb, EMD Serono, Immatics, Novartis, and Pfizer (research funding).

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