Targeting MET and FGFR in Relapsed or Refractory Acute Myeloid Leukemia: Preclinical and Clinical Findings, and Signal Transduction Correlates

• Type of Material: Article
• Authors: Evan C. Chen, Dana-Farber Cancer Institute; Helen Gandler, University of Vermont; Isidora Tošić, Dana-Farber Cancer Institute; Geoffrey G. Fell, Dana-Farber Cancer Institute; Ashlee Fiore, CRISPR Therapeutics; Olga Pozdnyakova, Brigham and Women’s Hospital; Daniel J. DeAngelo, Dana-Farber Cancer Institute; Ilene Galinsky, Dana-Farber Cancer Institute; Marlise R. Luskin, Dana-Farber Cancer Institute; Martha S. Wadleigh, Dana-Farber Cancer Institute; Eric S. Winer, Dana-Farber Cancer Institute; Rebecca Leonard, Dana-Farber Cancer Institute; Kelsey O'Day, Bluebird Bio; Adrienne de Jonge, Karyopharm Therapeutics; Donna Neuberg, Dana-Farber Cancer Institute; A. Thomas Look, Dana-Farber Cancer Institute; Richard M. Stone, Dana-Farber Cancer Institute; David Alan Frank, Emory University; Jacqueline S. Garcia, Dana-Farber Cancer Institute
• Language: English
• Date: 2023-03-01
• Publisher: American Association for Cancer Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2023, American Association for Cancer Research
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): https://doi.org/10.1158%2F1078-0432.CCR-22-2540
• Title of Journal or Parent Work: Clinical Cancer Research
• Volume: 29
• Issue: 5
• Start Page: 878
• End Page: 887
• Grant/Funding Information: This study was funded and drug was supplied by Eli Lilly and Company. We thank the patients and their medical providers who participated in this study. We also thank Adrienne de Jong for her project management. J. Garcia is supported by the National Cancer Institute (NCI) of the National Institutes of Health (NIH) under award number K08CA245209. The laboratory studies were also supported by a generous gift from Stephen P. Koster, Esq. (DAF) and by the Ted and Eileen Pasquarello Tissue Bank in Hematologic Malignancies.
• Keywords: hepatocyte growth factor (HGF); prognosis; targeted therapies; relapsed/refractory (R/R); overall survival (OS); Mesenchymal Epithelial Transition (MET); acute myeloid leukemia (AML); oncogenic receptor tyrosine kinase; relapse
• Research Categories: Health Sciences, Oncology; Chemistry, Pharmaceutical

Abstract

Purpose: Patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) have poor outcomes and require new therapies. In AML, autocrine production of hepatocyte growth factor (HGF) drives MET signaling that promotes myeloblast growth and survival, making MET an attractive therapeutic target. MET inhibition exhibits activity in AML preclinical studies, but HGF upregulation by the fibroblast growth factor receptor (FGFR) pathway is a common mechanism of resistance. Patients and Methods: We performed preclinical studies followed by a phase 1 trial to investigate the safety and biological activity of the MET inhibitor merestinib in combination with the FGFR inhibitor LY2874455 for patients with R/R AML. Study Cohort 1 underwent a safety lead-in to determine a tolerable dose of single-agent merestinib. In Cohort 2, dose-escalation of merestinib and LY2874455 was performed following a 3+3 design. Correlative studies were conducted. Results: The primary DLT observed for merestinib alone or with LY2874455 was reversible grade 3 transaminase elevation, occurring in two of 16 patients. Eight patients had stable disease and one achieved complete remission (CR) without measurable residual disease. While the maximum tolerated dose of combination therapy could not be determined due to drug supply discontinuation, single-agent merestinib administered at 80mg daily was safe and biologically active. Correlative studies showed therapeutic plasma levels of merestinib, on-target attenuation of MET signaling in leukemic blood, and increased HGF expression in bone marrow aspirate samples of refractory disease. Conclusions: We provide prospective, preliminary evidence that MET and FGFR are biologically active and safely targetable pathways in AML.