Phase I Trial of the Irreversible EGFR and HER2 Kinase Inhibitor BIBW 2992 in Patients With Advanced Solid Tumors
Phase I Trial of the Irreversible EGFR and HER2 Kinase Inhibitor BIBW 2992 in Patients With Advanced Solid Tumors
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DOI：
10.1200/jco.2009.26.7278
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发表时间：
2010-09-01
影响因子：
45.3
通讯作者：
Plummer, Ruth
中科院分区：
文献类型：
--
作者：
Yap, Timothy A.;Vidal, Laura;Plummer, Ruth
目的临床前数据表明，BIBW 2992是ErbB 1（EGFR/HER 1）和突变ErbB 1受体（包括T790 M变体）以及ErbB 2（HER 2）的强效不可逆抑制剂。进行了一项连续每日一次口服BIBW 2992的I期研究，以确定安全性、最大耐受剂量、药代动力学（PK）、食物效应和初步抗肿瘤疗效。患者和方法治疗晚期实体瘤患者。PK评价后进行的第一次剂量和稳态。Results 53例患者接受BIBW 2992在10至50 mg/d。BIBW 2992通常耐受性良好。最常见的副作用包括腹泻、恶心、呕吐、皮疹和疲劳。剂量限制性毒性包括3级皮疹（n = 2）和继发于肺炎的可逆性呼吸困难（n = 1）。推荐的II期剂量为50 mg/d。PK与剂量成比例，第1天终末消除半衰期范围为21.3 - 27.7小时，第27天为22.3 - 67.0小时;进食后BIBW 2992暴露量降低。3例非小细胞肺癌（NSCLC; 2例具有框内外显子19突变缺失）患者分别经历了持续24、18和34个月的确认部分缓解（PR）。另外2例患者（食管癌和NSCLC）有未经证实的PR。10 mg/d剂量下PR的患者发生进展并出现症状性脑转移，随后在BIBW 2992剂量增加至40 mg/d后消退。另外7例患者病情稳定持续>= 6 months.ConclusionContinuous，每日，口服BIBW 2992是安全的，具有持久的抗肿瘤活性。目前正在进行III期临床试验。
PurposePreclinical data have demonstrated that BIBW 2992 is a potent irreversible inhibitor of ErbB1 (EGFR/HER1) and mutated ErbB1 receptors including the T790M variant, as well as ErbB2 (HER2). A phase I study of continuous once-daily oral BIBW 2992 was conducted to determine safety, maximum-tolerated dose, pharmacokinetics (PK), food effect, and preliminary antitumor efficacy.Patients and MethodsPatients with advanced solid tumors were treated. PK evaluation was performed after the first dose and at steady-state.ResultsFifty-three patients received BIBW 2992 at 10 to 50 mg/d. BIBW 2992 was generally well-tolerated. The most common adverse effects included diarrhea, nausea, vomiting, rash, and fatigue. Dose-limiting toxicities included grade 3 rash (n = 2) and reversible dyspnea secondary to pneumonitis (n = 1). The recommended phase II dose was 50 mg/d. PK was dose proportional with a terminal elimination half-life ranging between 21.3 and 27.7 hours on day 1 and between 22.3 and 67.0 hours on day 27; BIBW 2992 exposure decreased after food intake. Three patients with non-small-cell lung carcinoma (NSCLC; two with in-frame exon 19 mutation deletions) experienced confirmed partial responses (PR) sustained for 24, 18, and 34 months, respectively. Two other patients (esophageal carcinoma and NSCLC) had nonconfirmed PRs. A patient with a PR at 10 mg/d progressed and developed symptomatic brain metastases, which subsequently regressed with an increased dose of 40 mg/d of BIBW 2992. A further seven patients had disease stabilization lasting >= 6 months.ConclusionContinuous, daily, oral BIBW 2992 is safe and has durable antitumor activity. It is currently being evaluated in phase III trials.