3.9 Article

Inhibition of MET Signaling with Ficlatuzumab in Combination with Chemotherapy in Refractory AML: Clinical Outcomes and High-Dimensional Analysis

期刊

BLOOD CANCER DISCOVERY
卷 2, 期 5, 页码 434-449

出版社

AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2643-3230.BCD-21-0055

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资金

  1. NCI [CA249744-01]
  2. Damon Runyon Postdoctoral Award [121570]
  3. ASCO Young Investigator Award [P0511381]
  4. Lung Cancer Research Foundation Fellowship [LC170486]
  5. U.S. Department of Defense [W81XWH-17-1-0365, W81XWH-18-1-0551]
  6. National Institute of Diabetes and Digestive and Kidney Diseases [DK111920]
  7. NCI R03 [5R03CA188236-02]
  8. Gateway for Cancer Research grant

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This study demonstrates the favorable safety profile and promising clinical activity of ficlatuzumab and cytarabine in high-risk AML, 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.
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 lb 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.

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