Data from Inhibition of MET Signaling with Ficlatuzumab in Combination with Chemotherapy in Refractory AML: Clinical Outcomes and High-Dimensional Analysis
Year: 2023
Type: other
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. Significance: This study demonstrates a favorable safety profile and promising clinical activity of ficlatuzumab and cytarabine in high-risk AML, thus supporting further investigation of this combination in a randomized trial. It also shows the utility of a novel application using multiplexed single-cell analyses to detect on-target activity and identify biomarkers of response. This article is highlighted in the In This Issue feature, p. 403
Authors: Victoria E. Wang, Bradley W. Blaser, Ravi K. Patel, Gregory K. Behbehani, Arjun A. Rao, Blythe Durbin-Johnson, Tommy Jiang, Aaron C. Logan, Matthew Settles, Gabriel N. Mannis, Rebecca Olin, Lloyd E. Damon, Thomas G. Martin, Peter H. Sayre, Karin M. Gaensler, Emma McMahon, Michael Flanders, Vivian Weinberg, Chun J. Ye, David P. Carbone, Pamela N. Munster, Gabriela K. Fragiadakis, Frank McCormick, Charalambos Andreadis
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W4362546921