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Inhibition of MET Signaling with Ficlatuzumab in Combination with Chemotherapy in Refractory AML: Clinical Outcomes and High-Dimensional Analysis. Blood cancer discovery Wang, V. E., Blaser, B. W., Patel, R. K., Behbehani, G. K., Rao, A. A., Durbin-Johnson, B., Jiang, T., Logan, A. C., Settles, M., Mannis, G. N., Olin, R., Damon, L. E., Martin, T. G., Sayre, P. H., Gaensler, K. M., McMahon, E., Flanders, M., Weinberg, V., Ye, C. J., Carbone, D. P., Munster, P. N., Fragiadakis, G. K., McCormick, F., Andreadis, C. 2021; 2 (5): 434-449

Abstract

Acute myeloid leukemia patients refractory to induction therapy or relapsed within one year have poor outcomes. Autocrine production of hepatocyte growth factor by myeloid blasts drives leukemogenesis in pre-clinical 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 interferon 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.

View details for DOI 10.1158/2643-3230.bcd-21-0055

View details for PubMedID 34514432

View details for PubMedCentralID PMC8425277