title: Phase 1 dose-escalation study of S-222611, an oral reversible dual tyrosine kinase inhibitor of EGFR and HER2, in patients with solid tumours.
abstract: 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 1 study to determine safety, maximum tolerated dose (MTD), pharmacokinetic profile (PK) and efficacy in patients with solid tumours expressing EGFR or HER2.
  
  
  METHODS
  Subjects had advanced tumours not suitable for standard treatment, expressing EGFR or HER2, and/or with amplified HER2. Daily oral doses of S-222611 were escalated from 100mg to 1600 mg. Full plasma concentration profiles for drug and metabolites were obtained.
  
  
  RESULTS
  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 24h, 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: King's College London, Guy's Hospital, London, UK. Electronic address: james.spicer@kcl.ac.uk.
authors.forename: J
authors.initials: J
authors.lastname: Spicer
authors.affiliation: University of Cambridge, Department of Oncology, Cambridge, UK.
authors.forename: R
authors.initials: R
authors.lastname: Baird
authors.affiliation: King's College London, Guy's Hospital, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Suder
authors.affiliation: Northern Centre for Cancer Care, Newcastle upon Tyne, UK.
authors.forename: N
authors.initials: N
authors.lastname: Cresti
authors.affiliation: University of Cambridge, Department of Oncology, Cambridge, UK.
authors.forename: J Garcia
authors.initials: JG
authors.lastname: Corbacho
authors.affiliation: Northern Centre for Cancer Care, Newcastle upon Tyne, UK.
authors.forename: L
authors.initials: L
authors.lastname: Hogarth
authors.affiliation: University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: E
authors.initials: E
authors.lastname: Frenkel
authors.affiliation: Shionogi & Co. Ltd., Osaka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Matsumoto
authors.affiliation: Shionogi & Co. Ltd., Osaka, Japan.
authors.forename: I
authors.initials: I
authors.lastname: Kawabata
authors.affiliation: Shionogi & Co. Ltd., Osaka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Donaldson
authors.affiliation: Shionogi & Co. Ltd., Osaka, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Posner
authors.affiliation: King's College London, Guy's Hospital, London, UK.
authors.forename: D
authors.initials: D
authors.lastname: Sarker
authors.affiliation: University of Cambridge, Department of Oncology, Cambridge, UK.
authors.forename: D
authors.initials: D
authors.lastname: Jodrell
authors.affiliation: Northern Centre for Cancer Care, Newcastle upon Tyne, UK.
authors.forename: R
authors.initials: R
authors.lastname: Plummer
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005076:Exanthema / Q000139:chemically induced; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D011799:Quinazolines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D066246:ErbB Receptors; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C000592810:S-222611; C512478:EGFR protein, human
keywords: EGFR; HER2; HER4; Phase 1 clinical trial; Protein kinase inhibitor