Mayo Clinic, Scottsdale, Arizona 85259, USA.
Clin Cancer Res. 2010 Mar 15;16(6):1938-49. doi: 10.1158/1078-0432.CCR-08-3328. Epub 2010 Mar 9.
This randomized phase II study was initially designed to test the activity of two dose schedules of lapatinib (GW572016H), an oral, reversible, dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human EGFR-2 (HER2/neu; HER2), in chemotherapy-naive patients with non-small cell lung cancer (NSCLC); it was later amended to target patients with bronchioloalveolar carcinoma or no smoking history.
Patients with good performance status and recurrent or metastatic NSCLC were randomized to lapatinib (orally, 1,500 mg once daily or 500 mg twice daily) until progression or intolerance. Patients could have had a maximum of one prior systemic therapy (chemotherapy or biological therapy) for NSCLC. Safety and activity were assessed every 4 and 8 weeks, respectively. Tumors were analyzed for EGFR and HER2 mutations and/or amplifications.
Of 75 patients in the nontargeted population, 1 (1.3%) had partial response and 16 (21%) had stable disease of >or=24 weeks. No complete or partial responses were observed in 56 patients in the targeted population; 14 (25%) had stable disease of >or=24 weeks. No responses were seen in three patients with EGFR mutations and five with EGFR gene amplification. No mutations in HER2 were found. One of two patients with HER2 amplification had a 51% decrease in tumor size; however, this response was unconfirmed. The most common adverse events were grade 1 or 2 diarrhea, rash, fatigue, nausea, and anorexia. Adverse events were similar across dosing regimens.
Lapatinib was well tolerated, with no notable difference in toxicity between treatment groups. Lapatinib monotherapy did not induce a significant number of tumor regressions in NSCLC. Further studies may be warranted to determine whether lapatinib is active in combination with other agents in the treatment of NSCLC.
本随机二期研究最初旨在检测两种剂量方案的拉帕替尼（GW572016H）在初治非小细胞肺癌（NSCLC）患者中的活性，拉帕替尼是一种口服、可逆的表皮生长因子受体（EGFR）和人表皮生长因子受体-2（HER2/neu；HER2）双重酪氨酸激酶抑制剂；后修改方案，目标人群为细支气管肺泡癌或无吸烟史患者。
患者具有良好的表现状态，且患有复发性或转移性 NSCLC，随机分为拉帕替尼（口服，每日一次 1500mg 或每日两次 500mg）组，直至疾病进展或不能耐受。患者最多可以接受一次 NSCLC 的既往全身治疗（化疗或生物治疗）。分别每 4 周和 8 周评估安全性和活性。肿瘤分析 EGFR 和 HER2 突变和/或扩增。
在非目标人群的 75 例患者中，1 例（1.3%）患者有部分缓解，16 例（21%）患者有>或=24 周的稳定疾病。在靶向人群中 56 例患者中没有完全或部分缓解；14 例（25%）患者有>或=24 周的稳定疾病。在 3 例 EGFR 突变和 5 例 EGFR 基因扩增患者中没有观察到应答。HER2 无突变。2 例 HER2 扩增患者中，有 1 例肿瘤缩小 51%；然而，该缓解未经确认。最常见的不良反应是 1 级或 2 级腹泻、皮疹、乏力、恶心和厌食。两种剂量方案的不良反应相似。
拉帕替尼耐受良好，两组间毒性无显著差异。拉帕替尼单药治疗在 NSCLC 中未诱导大量肿瘤消退。可能需要进一步研究以确定拉帕替尼联合其他药物治疗 NSCLC 的活性。
