Inhibition of MET Signaling with Ficlatuzumab in Combination with Chemotherapy in Refractory AML: Clinical Outcomes and High-Dimensional Analysis
Abstract
Acute myeloid leukemia (AML) patients refractory to induction therapy or relapsed within 1 year have poor outcomes. Autocrine production of hepatocyte growth factor by myeloid blasts drives leukemogenesis in preclinical models. A phase Ib trial evaluated ficlatuzumab, a first-in-class anti-HGF antibody, in combination with cytarabine in this high-risk population. Dose-limiting toxicities were not observed, and 20 mg/kg was established as the recommended phase II dose. The most frequent treatment-related adverse event was febrile neutropenia. Among 17 evaluable patients, the overall response rate was 53%, all complete remissions. Phospho-proteomic mass cytometry showed potent on-target suppression of p-MET after ficlatuzumab treatment and that attenuation of p-S6 was associated with clinical response. Multiplexed single-cell RNA sequencing using prospectively acquired patient specimens identified IFN response genes as adverse predictive factors. The ficlatuzumab and cytarabine combination is well tolerated, with favorable efficacy. High-dimensional analyses at single-cell resolution represent promising approaches for identifying biomarkers of response and mechanisms of resistance in prospective clinical studies.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 16, 2021
- Source ID
- 10.1158/2643-3230.bcd-21-0055
Entities
People
- Aaron C Logan
- Arjun A. Rao
- Blythe Durbin-johnson
- Bradley W. Blaser
- Charalambos Andreadis
- Chun J. Ye
- David Carbone
- Emma Mcmahon
- Frank McCormick
- Gabriel N. Mannis
- Gabriela K Fragiadakis
- Gregory K. Behbehani
- Karin M. Gaensler
- Lloyd E Damon
- Matthew Settles
- Michael Flanders
- Pamela N. Munster
- Peter H. Sayre
- Ravi K Patel
- Rebecca Olin
- Thomas G. Martin
- Tommy Jiang
- Victoria E. Wang
- Vivian Weinberg
Organizations
- Damon Runyon Cancer Research Foundation
- Gateway for Cancer Research
- Lung Cancer Research Foundation
- National Cancer Institute
- National Institute of Diabetes and Digestive and Kidney Diseases
- United States Department of Defense
- University of California
- University of California, San Francisco