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

Autor:	Tabernero J; Vall d'Hebron Hospital Campus, Vall d'Hebron Institute of Oncology (VHIO), UVic-UCC, IOB-Quiron, Barcelona, Spain., Van Cutsem E; University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium., Garralda E; START Madrid, Hospital Universitario HM Sanchinarro, Madrid, Spain., Tai D; Division of Medical Oncology, National Cancer Centre Singapore, Singapore., De Braud F; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Geva R; Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel., van Bussel MTJ; Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Fiorella Dotti K; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Elez E; Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain., de Miguel MJ; START Madrid, Hospital Universitario HM Sanchinarro, Madrid, Spain., Litwiler K; Pfizer, Boulder, CO, USA., Murphy D; Pfizer, La Jolla, CA, USA., Edwards M; Pfizer, New York, NY, USA., Morris VK; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Jazyk:	angličtina
Zdroj:	The oncologist [Oncologist] 2023 Mar 17; Vol. 28 (3), pp. 230-238.
DOI:	10.1093/oncolo/oyad007
Abstrakt:	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. (© The Author(s) 2023. Published by Oxford University Press.)
Databáze:	MEDLINE
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