Phase 1 dose-escalation study of S-222611, an oral reversible dual tyrosine kinase inhibitor of EGFR and HER2, in patients with solid tumours. Issue 2 (January 2015)

• Record Type: Journal Article
• Authors: Spicer, J.; Baird, R.; Suder, A.; Cresti, N.; Corbacho, J. Garcia; Hogarth, L.; Frenkel, E.; Matsumoto, S.; Kawabata, I.; Donaldson, K.; Posner, J.; Sarker, D.; Jodrell, D.; Plummer, R.
• Is Part Of: European journal of cancer. Volume 51:Issue 2(2015:Jan.)
• Page Start: 137
• Page End: 145
• Publication Date: 2015-01
• Subjects: Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Cancer; Tumors; Electronic journals; Periodicals; Electronic journals; 616.994
• DOI: 10.1016/j.ejca.2014.11.003
• Languages: English
• ISSNs: 0959-8049

Abstract

<abstract xml:lang="en" abstract-type="author" id="ab005"> <title id="st075">Abstract</title> <sec> <title id="st080">Background</title> <p id="sp0005">S-222611 is a reversible inhibitor of EGFR, HER2 and HER4 with preclinical activity in models expressing these proteins. We have performed a Phase 1 study to determine safety, maximum tolerated dose (MTD), pharmacokinetic profile (PK) and efficacy in patients with solid tumours expressing EGFR or HER2.</p> </sec> <sec> <title id="st085">Patients and methods</title> <p id="sp0010">Subjects had advanced tumours not suitable for standard treatment, expressing EGFR or HER2, and/or with amplified <italic>HER2</italic>. Daily oral doses of S-222611 were escalated from 100 mg to 1600 mg. Full plasma concentration profiles for drug and metabolites were obtained.</p> </sec> <sec> <title id="st090">Results</title> <p id="sp0015">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. MTD was not reached. Plasma exposure increased with dose up to 800 mg, 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 in oesophageal, breast and renal tumours, including a complete clinical response in a patient with HER2-positive breast carcinoma previously treated with lapatinib and trastuzumab. Four patients have remained on treatment for more than 12 months. Downregulation of pHER3 was seen in paired tumour biopsies from a responding patient.</p> </sec> <sec> <title id="st095">Conclusions</title> <p id="sp0020">Continuous daily oral S-222611 is well tolerated, modulates oncogenic signalling, and has significant antitumour activity. The recommended Phase 2 dose, based on PK and efficacy, is 800 mg/day.</p> </sec> </abstract>