Phase I dose-escalation study of S-222611, an oral reversible dual tyrosine kinase inhibitor of EGFR and HER2, in patients with solid tumours
Corbacho, Javier Garcia
European Journal of Cancer
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Spicer, J., Baird, R., Suder, A., Cresti, N., Corbacho, J. G., Hogarth, L., Frenkel, E., et al. (2014). Phase I dose-escalation study of S-222611, an oral reversible dual tyrosine kinase inhibitor of EGFR and HER2, in patients with solid tumours. European Journal of Cancer, 51 137-145. https://doi.org/10.1016/j.ejca.2014.11.003
Background: S 222611 is a reversible inhibitor of EGFR, HER2 and HER4 with preclinical activity in models expressing these proteins. We have performed a Phase I study to determine safety, maximum tolerated dose (MTD), pharmacokinetic profile (PK) and preliminary efficacy in patients with solid tumours expressing EGFR or HER2. Methods: We conducted this first-in-patient study at 3 sites in the UK. Subjects had advanced tumours not suitable for standard treatment, expressing EGFR and/or overexpressing HER2 using immunohistochemistry, and/or with amplified HER2 using FISH. Daily oral doses of S 222611 were escalated from 100mg to 1600mg. Full plasma concentration profiles for drug and metabolites were obtained. Optional paired tumour biopsies were obtained for analysis of pharmacodynamic biomarkers. Findings: 33 patients received S 222611. It was well tolerated, and the most common toxicities, almost all mild (grade 1 or 2), were diarrhoea, fatigue, rash and nausea. Only two dose-limiting toxicities occurred (diarrhoea and rash), which resolved on interruption. Maximum tolerated dose was not reached. Plasma exposure increased with dose up to 800mg, exceeding levels eliciting pre-clinical responses. The plasma terminal half-life was more than 24 h, supporting once daily dosing. Responses were seen over a wide range of doses, including one complete clinical response in a patient with HER2-positive breast carcinoma previously treated with lapatinib and trastuzumab. Six partial responses were seen in EGFR- and/or HER2-positive oesophageal, breast and renal cancers, with prolonged stable disease in a further two patients (clinical benefit in 27%). Four patients have remained on treatment for more than 12 months. Interpretation: Continuous daily oral S-222611 is well tolerated, and has broad and significant antitumour activity. The recommended Phase 2 dose, based on PK and efficacy, is 800mg/day.
Protein kinase inhibitor, Phase 1 clinical trial, EGFR, HER2, HER4
The authors acknowledge financial support from the UK Department of Health via the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) award to Guy’s & St Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust (and NIHR Clinical Research Facility), and to The University of Cambridge and Cambridge University Hospital NHS Foundation Trust. Cambridge, King’s College London, and Newcastle are Experimental Cancer Medicine Centres.
External DOI: https://doi.org/10.1016/j.ejca.2014.11.003
This record's URL: https://www.repository.cam.ac.uk/handle/1810/247091