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

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 (P0.030). In a subset of 40 patients that received 4 weeks of lapatinib or placebo, objective response rate (ORR) was 17% (n4/24) vs 0% (n0/16). 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.