Phase II study of erlotinib in patients with malignant pleural mesothelioma: A Southwest Oncology Group study
Phase II study of erlotinib in patients with malignant pleural mesothelioma: A Southwest Oncology Group study
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DOI：
10.1200/jco.2006.09.7634
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发表时间：
2007-06-10
影响因子：
45.3
通讯作者：
Borden, Ernest C.
中科院分区：
文献类型：
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作者：
Garland, Linda L.;Rankin, Cathryn;Borden, Ernest C.
目的恶性胸膜间皮瘤（MPM）表达高水平的表皮生长因子受体（EGFR），临床前研究发现EGFR酪氨酸激酶抑制剂（TKIs）在MPM中具有抗肿瘤活性。我们在先前未经治疗的MPM患者中进行了EGFR TKI厄洛替尼的II期试验。患者和方法可测量和不可测量疾病患者在每28天给药周期的第1天至第28天使用厄洛替尼150 mg/d。对存档的患者肿瘤进行EGFR、磷酸化EGFR、人表皮生长因子受体2 （HER2）、磷酸化细胞外信号调节激酶（ERK）、磷酸酶和紧张素同源物（PTEN）的免疫组化表达和磷脂酰肌醇3-激酶/Akt信号通路成员的磷酸化分析。结果共治疗63例患者。EGFR在75%的患者肿瘤中高表达，phospho-ERK（82%）、phospho-Akt（84%）、phospho-哺乳动物雷帕霉素靶蛋白（74%）和phospho-forkhead（74%）也是如此。HER2很少表达，PTEN的缺失也很少见。对于33例可测量疾病的患者，没有客观反应；14名患者（42%）病情稳定，15名患者（45%）病情进展，4名患者评估不充分，无法确定疗效。毒性主要是体质（51%）、皮肤（82%）和胃肠道（52%）；审判中有一人死亡，与呼吸困难有关。中位总生存时间为10个月- 1年生存率为43%；中位无进展生存期为2个月。结论单药厄洛替尼治疗MPM无效，尽管EGFR高表达。激活ERK和磷脂酰肌醇3-激酶/Akt下游通路可能是EGFR TKI的耐药机制。活化的磷脂酰肌醇3-激酶/Akt通路是MPM的潜在治疗靶点。
Purpose Malignant pleural mesothelioma (MPM) expresses high levels of epidermal growth factor receptor (EGFR), and preclinical studies have identified antitumor activity of EGFR tyrosine kinase inhibitors (TKIs) in MPM. We conducted a phase II trial of the EGFR TKI erlotinib in previously untreated patients with MPM.Patients and Methods Patients with measurable and nonmeasurable disease were treated with erlotinib 150 mg/d on days 1 through 28 of each 28-day dosing cycle. Archived patient tumors were analyzed for immunohistochemical expression of EGFR, phospho-EGFR, human epidermal growth factor receptor 2 (HER2), phospho-extracellular signal-regulated kinase (ERK), and phosphatase and tensin homolog (PTEN) and phosphorylation of members of the phosphatidylinositol 3-kinase/Akt signaling pathway.Results Sixty-three patients were treated on the study. EGFR was highly expressed in 75% of patient tumors, as was phospho-ERK (82%), phospho-Akt (84%), phospho-mammalian target of rapamycin (74%), and phospho-forkhead (74%). HER2 was rarely expressed, and loss of PTEN was rare. For 33 patients with measurable disease, there were no objective responses; 14 patients (42%) had stable disease, 15 patients (45%) had disease progression, and four patients had inadequate assessments to determine response. Toxicities were mainly constitutional (51%), dermatologic (82%), and GI (52%); there was one death on trial, which was related to dyspnea. Median overall survival time was 10 months-, 1-year survival rate was 43%; and median progression-free survival time was 2 months.Conclusion Single-agent erlotinib was not effective in MPM, despite high expression of EGFR. Activation of the ERK and phosphatidylinositol 3-kinase/Akt downstream pathways are possible resistance mechanisms to EGFR TKI. The activated phosphatidylinositol 3-kinase/Akt pathway is a potential therapeutic target for MPM.