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XL647-A 多靶点酪氨酸激酶抑制剂：一项在吉非替尼或厄洛替尼治疗缓解后发生进展的非小细胞肺癌受试者中进行的II期研究结果

本文研究了XL647（EGFR、VEGFR2、HER2和EphB4等多种受体酪氨酸激酶的小分子抑制剂）治疗已知或怀疑T790M突变的NSCLC患者。符合条件的患者包括在厄洛替尼或吉非替尼治疗达到疾病稳定或缓解≥12周后发生疾病进展的复发性晚期NSCLC患者和/或证实有EGFR T790M突变的患者。给予了XL647 300 mg，每日一次。主要终点为客观缓解率。

入选了41名患者；33名可评价疗效。观察到一例部分缓解（缓解率3%，90%置信区间：0% 至14%）。肿瘤含T790M的患者中，67% (8/12)的最佳反应为疾病进展，而无该突变的患者中为14% (3/21)。40例患者的血浆样本可用于突变检测，发现其中14例(35%)有EGFR突变。

摘要
INTRODUCTION:Although patients with non-small cell lung cancer (NSCLC) whose tumors harbor epidermal growth factor receptor (EGFR) activating mutations commonly experience significant regressions when treated with erlotinib or gefitinib, they uniformly develop resistance to these agents. The secondary EGFR T790M mutation is found in 50% of patients with acquired resistance. Herein, we studied XL647, an oral small molecule inhibitor of multiple receptor tyrosine kinases, including EGFR, VEGFR2, HER2, and EphB4, in NSCLC patients known or suspected of having tumors harboring T790M.

METHODS:Eligible patients included those with relapsed or recurrent advanced NSCLC who progressed after ≥12 weeks of stable disease or response to erlotinib or gefitinib and/or those patients with a documented EGFR T790M. XL647 300 mg was administered once daily. The primary end point was objective response rate. Pretreatment plasma samples were collected for mutation testing of circulating tumor DNA.

RESULTS:Forty-one patients were enrolled; 33 were evaluable for efficacy. One partial response was observed (response rate 3% and 90% confidence interval, 0% to 14%). Of patients whose tumors harbored T790M, 67% (8/12) had progression of disease as best response compared with 14% (3/21) of those without this mutation. Plasma samples from 40 patients were available for mutation testing, 14 (35%) of which were found to have EGFR mutations.

CONCLUSIONS:The 3% response rate observed did not meet the prespecified threshold to recommend further study of XL647 in patients who develop acquired resistance to erlotinib or gefitinib. Patients with T790M had a significantly worse progression-free survival.