【ASCO2014】中国研究：INC280联合吉非替尼治疗NSCLC患者的疗效
2014年美国临床肿瘤学会年会将于当地时间5月30日-6月3日在芝加哥召开，根据大会的会议日程，我国肿瘤专家吴一龙教授在6月3日上午有一项研究在“Poster Highlights Session”中展出，下面和大家提前分享这项精彩研究。医脉通小编们今年也将继续奔赴ASCO年会现场，及时将各项最新研究进展整理、发布，欢迎大家保持关注！
很多EGFR突变的NSCLC患者尽管对EGFR-TKI药物有比较高的应答率，但是最终会复发。MET通路的失调在耐药机制上起着一定的作用，这发生在15-20%的病例中。INC280是一种高选择性的口服MET抑制剂，研究发现其与EGFR-TKI药物联合在EGFR突变/MET活化的NSCLC中具有临床前活性。
研究方法
这是一项针对INC280联合吉非替尼的Ib/II期、开放标签、剂量逐步增加的研究，病人年龄≥18岁，ECOG PS≤2，EGFR突变的NSCLC患者，之前接受过EGFR-TKI药物治疗，后疾病出现进展，已经确认是MET失调（扩增[FISH≥5 CN]或者过表达[IHC 2/3+]）。
主要目的（Ib期）是确认MTD，推荐INC280联合吉非替尼的II期剂量；次要目的是安全性、疗效、药效学和药代学。通过过量控制指导下的剂量递增，使用一种自适应的贝叶斯logistic回归模型确定MTD。
研究结果
到2013年12月2日，41例病人进入Ib期研究（59%女性，平均年龄58岁）。INC280分为100-800mg QD和200-600mg BID的7个剂量队列，联合吉非替尼 250mg QD。剂量限制毒性（QLT）在两个病人中发生：头晕（800mg QD）和呼吸困难（600mg BID）。最常见的药物相关不良反应（任何等级）为恶心（27%），呕吐，腹泻和皮疹（所有为22%）。最常见的3/4级不良反应为脂肪酶增加（7%），淀粉酶增加（5%）。有一人死亡，未排除INC280的原因。
初步数据分析未发现INC280与吉非替尼有药代动力学相互作用。在6/41病人（15%）中出现局部缓解，包括3个在400mg BID组，其中有5个人在入组前EGFR-TKI药物是最后的治疗。所有的应答者都是高MET状态。
结论
口服INC280联合吉非替尼耐受性良好，II期推荐剂量还未定。初步临床活性支持对INC280联合吉非替尼在TKI耐药的MET阳性NSCLC患者中的进一步评估。临床试验信息：NCT01610336
英文摘要
Safety and efficacy of INC280 in combination with gefitinib (gef) in patients with EGFR-mutated (mut), MET-positive NSCLC: A single-arm phase lb/ll study.（Abstract 8017）
Authors: Yi-Long Wu, James Chih-Hsin Yang, Dong-Wan Kim, et al.
Session Type: Poster Highlights Session
Background: Despite high response rates to EGFR tyrosine kinase inhibitors (TKIs), most patients (pts) with EGFR-mut NSCLC ultimately relapse. Dysregulation of the MET pathway is implicated as a therapeutically tractable resistance mechanism, occurring in 15–20% of cases. INC280 is a highly selective, oral MET inhibitor with preclinical activity in EGFR-mut/MET-activated NSCLC when combined with EGFR TKIs.
Methods: This Ph Ib/II, open-label, dose-escalation study of INC280 plus gef was performed in pts (age ≥18 yrs, ECOG PS ≤2) with EGFR-mut NSCLC who progressed after prior EGFR TKI, and have confirmed MET dysregulation (amplification [FISH ≥5 CN] or overexpression [IHC 2/3+]). The primary objective (Ph Ib) was to determine the MTD/recommended Ph II dose (RP2D) of INC280 plus gef; secondary objectives were safety, efficacy, pharmacodynamics and PK. An adaptive Bayesian logistic regression model with overdose control guided dose escalation to establish the MTD.
Results: As of December 2, 2013, 41 pts were enrolled in the ongoing Ph Ib part of the study (59% female, median age 58 years). Pts were treated with INC280 at 7 dose cohorts of 100–800 mg QD and 200–600 mg BID, in combination with gef 250 mg QD. Dose-limiting toxicities (DLTs) occurred in 2 pts: dizziness (800 mg QD) and dyspnea (600 mg BID). The most frequent drug-related AEs (any grade [Gr]) were nausea (27 %), vomiting, diarrhea, and rash (all 22%). The most common drug-related Gr 3/4 AEs were increased lipase (7 %), and increased amylase (5%). For one death, causality to INC280 was not ruled out. INC280 exposure increased with dose from 100–800 mg QD and 200–400 mg BID; preliminary data show no PK interactions with gef. Partial responses were seen in 6/41 (15%) evaluable pts; 5 confirmed, 1 unconfirmed, including 3/7 pts (43%) on 400 mg BID; 5/6 responders had EGFR TKIs as a last treatment prior to study entry. All responders had high MET status.
Conclusions: Oral INC280 in combination with gef is well tolerated; the RP2D has not yet been defined. Preliminary clinical activity supports further evaluation of INC280 combined with gef in MET-positive NSCLC resistant to EGFR TKIs. Clinical trial identifier: NCT01610336. Clinical trial information: NCT01610336. |
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