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Clinical Trial
. 2011 Aug 23;105(5):618-27.
doi: 10.1038/bjc.2011.237. Epub 2011 Aug 9.

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

J M Del Campo  1 , R Hitt, P Sebastian, C Carracedo, D Lokanatha, J Bourhis, S Temam, D Cupissol, D De Raucourt, N Maroudias, C M Nutting, N Compton, D Midwinter, L Downie, N Biswas-Baldwin, I El-Hariry, K J Harrington
Affiliations
Clinical Trial

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

J M Del Campo et al. Br J Cancer. .

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.

Conclusion: 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.

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Figures

Figure 1
Figure 1
Study design and patient disposition. (A) Study design and allocated therapies are shown. (B) CONSORT diagram showing patient accountability. Abbreviations: CT=computed tomography; CTx=chemotherapy; ECOG=Eastern Cooperative Oncology Group; F/U=follow-up; ITT=intent-to-treat; LVEF=left ventricular ejection fraction; mITT=modified ITT; NPC=nasopharyngeal carcinoma; PS=performance status; RT=radiotherapy; SCCHN=squamous cell carcinoma of the head and neck.
Figure 2
Figure 2
AI by TUNEL assay. Representative IHC TUNEL staining pretreatment (A) and posttreatment (B) with lapatinib, and pretreatment (C) and posttreatment (D) with placebo.
Figure 3
Figure 3
Effect of lapatinib on proliferation determined by Ki-67; box whisker plot of pretreatment and posttreatment proliferative index with lapatinib and placebo. The median values are presented to the left of each box. The mean values were: lapatinib pretreatment −62.7%, posttreatment −56.7% placebo pretreatment −66.1%, posttreatment −64.4%.
Figure 4
Figure 4
(A) Waterfall plot of independently assessed ORR following lapatinib/placebo phase; (B) Bar chart of ORR following CRT versus tumour site; (C) Waterfall plot of the change from baseline in independently read SUVmax measurements. Abbreviations: R=responders (complete and partial response); NR=nonresponders (stable and progressive disease); HP=hypopharynx; L=larynx; OC=oral cavity; OP=oropharynx. *Percent within levels of tumour site.
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