A phase I study of erlotinib and hydroxychloroquine in advanced non-small-cell lung cancer.
A phase I study of erlotinib and hydroxychloroquine in advanced non-small-cell lung cancer.
复制标题
DOI：
10.1097/jto.0b013e318262de4a
复制
发表时间：
2012-10
期刊：
影响因子：
--
通讯作者：
Sequist LV
中科院分区：
文献类型：
--
作者：
Goldberg SB;Supko JG;Neal JW;Muzikansky A;Digumarthy S;Fidias P;Temel JS;Heist RS;Shaw AT;McCarthy PO;Lynch TJ;Sharma S;Settleman JE;Sequist LV
本研究探讨了羟氯喹（HCQ）联合或不联合厄洛替尼治疗晚期非小细胞肺癌（NSCLC）患者的安全性、最大耐受剂量（MTD）、临床反应和药代动力学（PK）。既往从表皮生长因子受体（EGFR）酪氨酸激酶抑制剂中获得临床获益的患者被随机分配至HCQ组或HCQ+厄洛替尼组（3+3剂量递增方案）。27例患者接受治疗，8例接受HCQ（A组），19例接受HCQ+厄洛替尼（B组）。74%的患者检测到EGFR突变，85%的患者接受过≥2种既往治疗。A组无剂量限制性毒性（DLT），但未达到MTD，因为该组提前关闭以增加总体研究入组。在组B中，各有1名患者出现3级皮疹、指甲变化、皮肤变化、恶心、脱水和中性粒细胞减少症，1名患者出现4级贫血，1名患者出现致命性肺炎，所有这些均被认为与HCQ无关。无DLT，因此厄洛替尼150 mg的HCQ最高试验剂量为每日1000 mg。1例患者对厄洛替尼/HCQ有部分缓解（PR），总体缓解率为5%（95% CI，1-25）。该患者有EGFR突变，并持续治疗20个月。HCQ给药不会改变厄洛替尼的PK。HCQ联合或不联合厄洛替尼均安全且耐受性良好。HCQ与厄洛替尼150 mg联合给药时，推荐的II期剂量为1000 mg。
This investigator-initiated study explores the safety, maximum tolerated dose (MTD), clinical response, and pharmacokinetics (PK) of hydroxychloroquine (HCQ) with and without erlotinib in patients with advanced non-small cell lung cancer (NSCLC). Patients with prior clinical benefit from an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor were randomized to HCQ or HCQ plus erlotinib in a 3+3 dose escalation schema. Twenty-seven patients were treated, 8 with HCQ (arm A) and 19 with HCQ plus erlotinib (arm B). EGFR mutations were detected in 74% of patients and 85% had received ≥2 prior therapies. Arm A had no dose-limiting toxicities (DLTs), but the MTD was not reached as this arm closed early to increase overall study accrual. In arm B, 1 patient each experienced grade 3 rash, nail changes, skin changes, nausea, dehydration, and neutropenia, 1 had grade 4 anemia, and 1 developed fatal pneumonitis, all considered unrelated to HCQ. There were no DLTs, therefore the highest tested dose for HCQ with erlotinib 150mg was 1000mg daily. One patient had a partial response (PR) to erlotinib/HCQ, for an overall response rate of 5% (95% CI, 1–25). This patient had an EGFR mutation and remained on therapy for 20 months. Administration of HCQ did not alter the PK of erlotinib. HCQ with or without erlotinib was safe and well-tolerated. The recommended phase 2 dose of HCQ was 1000mg when given in combination with erlotinib 150mg.