Phase I ficlatuzumab monotherapy or with erlotinib for refractory advanced solid tumours and multiple myeloma

Abstract

Background:Ficlatuzumab, a humanised hepatocyte growth factor (HGF) IgG1κ inhibitory monoclonal antibody, was evaluated for recommended phase II dose (RP2D), safety, pharmacokinetics (PKs), antidrug antibody (ADA), pharmacodynamics (PDs) and antitumour activity as monotherapy or combined with erlotinib.Methods:Patients with solid tumours received ficlatuzumab 2, 5, 10 or 20 mg kg–1 intravenously every 2 weeks (q2w). Additional patients were treated at the RP2D erlotinib.Results:Forty-one patients enrolled at doses ⩽20 mg kg–1. Common adverse events (AEs) included peripheral oedema, fatigue and nausea. Three patients experienced grade ⩾3 treatment-related hyperkalaemia/hypokalaemia, diarrhoea or fatigue. Best overall response (44%) was stable disease (SD); median duration was 5.5 months (0.4–18.7 months). One patient has been on therapy with SD for >4 years. Pharmacokinetics of ficlatuzumab showed low clearance (0.17–0.26 ml h–1 kg–1), a half-life of 6.8–9.4 days and dose-proportional exposure. Ficlatuzumab/erlotinib had no impact on the PK of either agent. No ADAs were detected. Ficlatuzumab increased serum HGF levels.Conclusions:Recommended phase II dose is 20 mg kg–1 q2w for ficlatuzumab monotherapy or with erlotinib. Preliminary antitumour activity and manageable AEs were observed. Pharmacokinetics were dose-proportional and consistent with other IgG therapeutics. Ficlatuzumab was not immunogenic, and serum HGF was a potential PD marker.

The Therapeutic Potential of Targeting the HGF/cMET Axis in Ovarian Cancer

“…However, transcriptional upregulation has been observed resulting from Stat-3 and c-Src expression [60], and the co-expression of HGF and cMET in tumour cells can drive autocrine activation, as well as increased transcription for both genes. A number of studies have identified that HGF expression and autocrine cMET activation decreases sensitivity to cMET inhibitors, and stromal HGF levels have been linked to clinical responses in patients treated with the anti-HGF agent, ficlatuzumab [61][62][63], demonstrating the importance of the use of biomarkers in predicting clinical responses.…”

“…Both onartuzumab and ficlatuzumab, therapeutic antibodies directed against HGF, stabilise the protein, and cause increases in the serum with treatment [87,61,88]. This enables circulating HGF to be used as a pharmacodynamic marker for these agents, but perhaps not as a catch-all predictive biomarker for selecting patients for HGF/cMET therapies.…”

“…Interestingly, a number of phase I trials of HGF/cMET targeting agents have included patients with ovarian cancer, [82,97,88,54,98,61] …”

MET/HGF pathway activation as a paradigm of resistance to targeted therapies

“…Ficlatuzumab (AV-299) is a potent, high affinity and selective HGF-inhibitory antibody developed to inhibit HGF/MET-driven biological activities (79). A phase II study of ficlatuzumab and erlotinib versus placebo and erlotinib (FOCAL study, NCT02318368) is ongoing to assess the value of combined inhibition in patients with EGFR-mutated, EGFR TKI-naïve advanced NSCLC.…”

MET/HGF pathway in multiple myeloma: from diagnosis to targeted therapy?

“…The recommended dose for a Phase II trial was identified as 20 mg/Kg every 14 days. [64] Cabozantinib (XL184) It is an inhibitor of several tyrosine kinases including MET, VEGFR2, RET, TYROL3 and AXL. It has been tested in a syngeneic 5TGM1 mouse model of MM with the primary aim of investigating its activity on bone lesions.…”