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.
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.
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DOI：
10.1038/bjc.2011.237
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发表时间：
2011-08-23
影响因子：
8.8
通讯作者：
Harrington, K. J.
中科院分区：
文献类型：
--
作者：
del Campo, J. M.;Hitt, R.;Sebastian, P.;Carracedo, C.;Lokanatha, D.;Bourhis, J.;Temam, S.;Cupissol, D.;De Raucourt, D.;Maroudias, N.;Nutting, C. M.;Compton, N.;Midwinter, D.;Downie, L.;Biswas-Baldwin, N.;El-Hariry, I.;Harrington, K. J.
拉帕替尼是一种表皮生长因子受体(EGFR)和人EGFR-2(HER-2)酪氨酸激酶的双重抑制剂。本研究探讨了拉帕替尼治疗局部晚期头颈鳞状细胞癌(SCCHN)的药效学和临床疗效。总共有107名未接受治疗的局部晚期SCCHN患者被随机(2 ： 1)在化疗前接受2-6周的拉帕替尼或安慰剂治疗。终点包括细胞凋亡率和增殖率、临床反应和毒性。与安慰剂相比，拉帕替尼单一治疗并没有显著增加末端脱氧核苷酸转移酶介导的脱氧尿苷-生物素缺口末端标记或caspase-3检测到的细胞凋亡。Ki67检测显示细胞增殖显著降低(P=0.030)。在接受⩾治疗4周的拉帕替尼或安慰剂的40名患者中，客观有效率为17%(n=4/24)vs0%(n=16)。在拉帕替尼单药应答组中，免疫组织化学显示ALL有EGFR过表达，50%有EGFR扩增，50%有HER2表达(包括1例HER2扩增患者)。然而，这些患者在药物治疗中表现出不同程度的细胞凋亡、增殖和磷酸化EGFR的调节。CRT后，拉帕替尼组(70%)和安慰剂组(53%)的ORR差异无统计学意义。细胞凋亡或增殖的变化与放化疗的反应之间没有明显的相关性。粘膜炎症、虚弱、吞咽疼痛和吞咽困难是拉帕替尼最常见的不良反应。短期的拉帕替尼单一治疗没有显示细胞凋亡的变化，但提供了局部晚期SCCHN临床活动的证据，并值得在这种疾病中进行进一步的研究。
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.
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影响因子：
3.5
作者：
Bonner, JA;De los Santos, J;Raisch, KP
通讯作者：
Raisch, KP
DOI：
10.1016/j.ijrobp.2003.09.043
发表时间：
2004-02-01
影响因子：
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作者：
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作者：
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影响因子：
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作者：
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通讯作者：
Distel, L
影响因子：
11.5
作者：
Goulart, Bernardo H. L.;Clark, Jeffrey W.;Chabner, Bruce A.
通讯作者：
Chabner, Bruce A.