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Inhibition of MET Signaling with Ficlatuzumab in Combination with Chemotherapy in Refractory AML: Clinical Outcomes and High-Dimensional Analysis.
- Wang, Victoria E;
- Blaser, Bradley W;
- Patel, Ravi K;
- Behbehani, Gregory K;
- Rao, Arjun A;
- Durbin-Johnson, Blythe;
- Jiang, Tommy;
- Logan, Aaron C;
- Settles, Matthew;
- Mannis, Gabriel N;
- Olin, Rebecca;
- Damon, Lloyd E;
- Martin, Thomas G;
- Sayre, Peter H;
- Gaensler, Karin M;
- McMahon, Emma;
- Flanders, Michael;
- Weinberg, Vivian;
- Ye, Chun J;
- Carbone, David P;
- Munster, Pamela N;
- Fragiadakis, Gabriela K;
- McCormick, Frank;
- Andreadis, Charalambos
- et al.
Published Web Location
https://doi.org/10.1158/2643-3230.bcd-21-0055Abstract
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.
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