Targeting MET and FGFR in Relapsed or Refractory Acute Myeloid Leukemia: Preclinical and Clinical Findings, and Signal Transduction Correlates

by Selleckchem | May 19 2023

Purpose: Patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) have poor outcomes and require new therapies. In AML, autocrine production of hepatocyte growth factor (HGF) drives MET signaling that promotes myeloblast growth and survival, making MET an attractive therapeutic target. MET inhibition exhibits activity in AML preclinical studies, but HGF upregulation by the FGFR pathway is a common mechanism of resistance.

Patients and methods: We performed preclinical studies followed by a Phase I trial to investigate the safety and biological activity of the MET inhibitor merestinib in combination with the FGFR inhibitor LY2874455 for patients with R/R AML. Study Cohort 1 underwent a safety lead-in to determine a tolerable dose of single-agent merestinib. In Cohort 2, dose-escalation of merestinib and LY2874455 was performed following a 3+3 design. Correlative studies were conducted.

Results: The primary dose-limiting toxicity (DLT) observed for merestinib alone or with LY2874455 was reversible grade 3 transaminase elevation, occurring in 2 of 16 patients. Eight patients had stable disease and one achieved complete remission (CR) without measurable residual disease. Although the MTD of combination therapy could not be determined due to drug supply discontinuation, single-agent merestinib administered at 80 mg daily was safe and biologically active. Correlative studies showed therapeutic plasma levels of merestinib, on-target attenuation of MET signaling in leukemic blood, and increased HGF expression in bone marrow aspirate samples of refractory disease.

Conclusions: We provide prospective, preliminary evidence that MET and FGFR are biologically active and safely targetable pathways in AML.

Comments：

The study investigated the safety and biological activity of the MET inhibitor merestinib in combination with the FGFR inhibitor LY2874455 for patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). In AML, autocrine production of hepatocyte growth factor (HGF) drives MET signaling that promotes myeloblast growth and survival, making MET an attractive therapeutic target. However, HGF upregulation by the FGFR pathway is a common mechanism of resistance to MET inhibition.

The study was conducted in two cohorts. Cohort 1 underwent a safety lead-in to determine a tolerable dose of single-agent merestinib, while Cohort 2 underwent dose-escalation of merestinib and LY2874455 following a 3+3 design. Correlative studies were conducted to assess the therapeutic plasma levels of merestinib, on-target attenuation of MET signaling in leukemic blood, and increased HGF expression in bone marrow aspirate samples of refractory disease.

The primary dose-limiting toxicity observed for merestinib alone or with LY2874455 was reversible grade 3 transaminase elevation, occurring in 2 of 16 patients. Eight patients had stable disease and one achieved complete remission (CR) without measurable residual disease. Although the maximum tolerated dose (MTD) of combination therapy could not be determined due to drug supply discontinuation, single-agent merestinib administered at 80 mg daily was safe and biologically active.

The study provides prospective, preliminary evidence that MET and FGFR are biologically active and safely targetable pathways in AML. The findings suggest that combination therapy with MET and FGFR inhibitors could be a potential treatment option for patients with R/R AML. However, further studies are needed to confirm the efficacy and safety of this combination therapy.