title: Effects of lapatinib monotherapy: results of a randomised phase II study in therapy-naive patients with locally advanced squamous cell carcinoma of the head and neck.
abstract: BACKGROUND
  Lapatinib is a dual inhibitor of epidermal growth factor receptor (EGFR) and human EGFR-2 (HER-2) tyrosine kinases. This study investigated the pharmacodynamic and clinical effects of lapatinib in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).
  
  
  METHODS
  In total, 107 therapy-naive patients with locally advanced SCCHN were randomised (2 : 1) to receive lapatinib or placebo for 2-6 weeks before chemoradiation therapy (CRT). Endpoints included apoptosis and proliferation rates, clinical response, and toxicity.
  
  
  RESULTS
  Versus placebo, lapatinib monotherapy did not significantly increase apoptosis detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labelling or caspase-3 assays. A statistically significant decrease in proliferation using Ki67 assay was observed (P=0.030). In a subset of 40 patients that received 4 weeks of lapatinib or placebo, objective response rate (ORR) was 17% (n=4/24) vs 0% (n=0/16). In the lapatinib single-agent responders, all had EGFR overexpression, 50% had EGFR amplification, and 50% had HER2 expression by immunohistochemistry (including one patient with HER2 amplification). However, these patients showed variable modulation of apoptosis, proliferation, and phosphorylated EGFR on drug treatment. Following CRT, there was a statistically non-significant difference in ORR between lapatinib (70%) and placebo (53%). There was no clear correlation between changes in apoptosis or proliferation and response to chemoradiation. Mucosal inflammation, asthenia, odynophagia, and dysphagia were the most commonly reported adverse events with lapatinib.
  
  
  CONCLUSIONS
  Short-term lapatinib monotherapy did not demonstrate apoptotic changes, but provided evidence of clinical activity in locally advanced SCCHN, and warrants further investigation in this disease.
authors.affiliation: Vall d'Hebron Hospital, Passeig Vall d'Hebron 119-12908035, Barcelona, Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: Del Campo
authors.forename: R
authors.initials: R
authors.lastname: Hitt
authors.forename: P
authors.initials: P
authors.lastname: Sebastian
authors.forename: C
authors.initials: C
authors.lastname: Carracedo
authors.forename: D
authors.initials: D
authors.lastname: Lokanatha
authors.forename: J
authors.initials: J
authors.lastname: Bourhis
authors.forename: S
authors.initials: S
authors.lastname: Temam
authors.forename: D
authors.initials: D
authors.lastname: Cupissol
authors.forename: D
authors.initials: D
authors.lastname: De Raucourt
authors.forename: N
authors.initials: N
authors.lastname: Maroudias
authors.forename: C M
authors.initials: CM
authors.lastname: Nutting
authors.forename: N
authors.initials: N
authors.lastname: Compton
authors.forename: D
authors.initials: D
authors.lastname: Midwinter
authors.forename: L
authors.initials: L
authors.lastname: Downie
authors.forename: N
authors.initials: N
authors.lastname: Biswas-Baldwin
authors.forename: I
authors.initials: I
authors.lastname: El-Hariry
authors.forename: K J
authors.initials: KJ
authors.lastname: Harrington
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology; D002294:Carcinoma, Squamous Cell; D018450:Disease Progression; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D000077341:Lapatinib; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D018307:Neoplasms, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D010919:Placebos; D011799:Quinazolines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016037:Single-Blind Method; D000077195:Squamous Cell Carcinoma of Head and Neck; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D010919:Placebos; D011799:Quinazolines; D000077341:Lapatinib