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First-in-human phase I study of oral S49076, a unique MET/AXL/FGFR inhibitor, in advanced solid tumours
Jordi Rodon1, Sophie Postel-Vinay2, Antoine Hollebecque2
1Medical Oncology, Vall D'Hebron University Hospital and Vall D'Hebron Institut D'Oncologia, Barcelona, Spain.
Background And Objectives:
S49076 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 Methods:
Patients 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.
Results:
A 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.
Conclusion:
S49076 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 Number:
ISRCTN00759419.
Insights
S49076, a novel tyrosine kinase inhibitor, showed a tolerable safety profile in a Phase I study. Further investigation in combination therapies is recommended due to encouraging pharmacodynamic results.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- S49076 is a novel ATP-competitive tyrosine kinase inhibitor targeting MET, AXL, and FGFR.
- A Phase I open-label study was conducted to assess tolerability, recommended dose (RD), and administration schedule.
Purpose of the Study:
- Determine the safety and tolerability profile of S49076.
- Establish the recommended dose (RD) and administration schedule for S49076.
- Evaluate preliminary anti-tumour activity and pharmacodynamics.
Main Methods:
- 103 patients with advanced solid tumors received escalating oral doses of S49076 (15-900 mg) once-daily or twice-daily.
- Dose-escalation followed a 3+3 design, with an expansion phase at the RD.
- Pharmacokinetic (PK) and pharmacodynamic (PD) parameters were assessed, along with anti-tumour activity using RECIST 1.1.
Main Results:
- The recommended dose (RD) was determined to be 600 mg once-daily.
- 81.4% of patients experienced drug-related adverse events (AEs), mostly Grade I-II, with only 3% leading to discontinuation.
- Intratumoural PK analysis at the RD indicated target engagement of MET, AXL, and FGFR.
Conclusions:
- S49076 demonstrated a tolerable safety profile in this Phase I study.
- Limited single-agent anti-tumour activity was observed.
- Encouraging PK/PD results support further investigation of S49076 in combination therapies.
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