Vall d'Hebron Hospital, Passeig Vall d'Hebron 119-12908035, Barcelona, Spain.
Br J Cancer. 2011 Aug 23;105(5):618-27. doi: 10.1038/bjc.2011.237. Epub 2011 Aug 9.
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).
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.
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.
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.
拉帕替尼是一种表皮生长因子受体（EGFR）和人表皮生长因子受体-2（HER-2）酪氨酸激酶的双重抑制剂。本研究探讨了拉帕替尼在局部晚期头颈部鳞状细胞癌（SCCHN）患者中的药效学和临床疗效。
共纳入 107 例局部晚期 SCCHN 初治患者，随机（2：1）接受拉帕替尼或安慰剂治疗 2-6 周，然后行放化疗（CRT）。主要终点包括细胞凋亡和增殖率、临床反应和毒性。
与安慰剂相比，拉帕替尼单药治疗并未显著增加末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸生物素切口末端标记或 caspase-3 检测到的细胞凋亡。Ki67 检测到增殖显著下降（P=0.030）。在接受 4 周拉帕替尼或安慰剂的 40 例患者亚组中，客观缓解率（ORR）分别为 17%（24 例中的 4 例）和 0%（16 例中的 0 例）。在拉帕替尼单药治疗的应答者中，所有患者均有 EGFR 过表达，50%患者有 EGFR 扩增，50%患者有免疫组化 HER2 表达（包括 1 例 HER2 扩增）。然而，这些患者在药物治疗时表现出凋亡、增殖和磷酸化 EGFR 的不同程度调节。在 CRT 后，拉帕替尼（70%）和安慰剂（53%）之间的 ORR 差异无统计学意义。细胞凋亡或增殖的变化与放化疗反应之间没有明显的相关性。粘膜炎症、乏力、吞咽疼痛和吞咽困难是拉帕替尼最常见的不良反应。
短期拉帕替尼单药治疗未显示出凋亡变化，但为局部晚期 SCCHN 提供了临床活性的证据，值得在该疾病中进一步研究。
