Original ResearchFirst-in-human phase I study of oral S49076, a unique MET/AXL/FGFR inhibitor, in advanced solid tumours

- In the first-in-human study, the recommended dose (RD) was defined at 600 mg once daily in continuous dosing.
- Most drug-related adverse events (93%) were grade I or II.
- The clinical benefit rate was 23%, and 9 patients had long-term stable disease (≥6 months).
- Intratumoural S49076 concentrations at RD exceeded IC50 values for c-Met, also called tyrosine-protein kinase Met (MET), AXL Receptor Tyrosine Kinase (AXL) and Fibroblast Growth Factor Receptor 1 (FGFR1).

Background and objectivesS49076 is a novel ATP-competitive tyrosine kinase inhibitor of MET, AXL and FGFR with a unique selectivity profile. A phase I open-label study was undertaken to establish the tolerability profile and determine the recommended dose (RD) and administration schedule.Materials and methodsPatients with advanced solid tumours received S49076 orally once-daily (qd) or twice-daily (bid) in continuous 21-day cycles at escalating doses guided by a 3 + 3 design and followed by an expansion phase at the RD. Pharmacokinetic (PK) parameters were assessed and pharmacodynamic end-points were evaluated in pre- and post-treatment tumour biopsies. Preliminary anti-tumour activity was evaluated as per the Response Evaluation Criteria In Solid Tumours 1.1 criteria.ResultsA total of 103 patients were treated: 79 in the dose-escalation and 24 in the expansion. Doses from 15 to 900 mg were evaluated. Dose-limiting toxicities were reported in 9 patients and occurred at 30, 760 and 900 mg in the qd arm and at 180, 225 and 285 mg in the bid arm. The RD was defined at 600 mg qd. Adverse events (AEs) occurred with similar frequency in both regimens at an equivalent total daily dose. Overall, 83 patients (81.4%) had drug-related AEs, the majority (93%) of which were grade I-II (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0) and only 3% led to drug discontinuation. Intratumoural PK analysis at the RD suggested hitting of MET, AXL and FGFR.ConclusionS49076 demonstrated a tolerable safety profile with limited single-agent activity. PK/pharmacodynamic readouts of S49076 are encouraging for further investigation of S49076 in combination therapies.Trial registration numberISRCTN00759419.