Ningetinib plus gefitinib in EGFR-mutant non-small-cell lung cancer with MET and AXL dysregulations: A phase 1b clinical trial and biomarker analysis
Ningetinib plus gefitinib in EGFR-mutant non-small-cell lung cancer with MET and AXL dysregulations: A phase 1b clinical trial and biomarker analysis
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DOI：
10.1016/j.lungcan.2024.107468
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发表时间：
2024-01-04
期刊：
影响因子：
5.3
通讯作者：
Zhao，Hongyun
中科院分区：
文献类型：
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作者：
Zhao，Shen;Ma，Yuxiang;Zhao，Hongyun
背景MET 和 AXL 失调与 NSCLC 中 EGFR-TKI 的获得性耐药有关。但对于 EGFR 突变 NSCLC 中 MET/AXL 失调的最佳定义尚缺乏共识。在这里，我们研究了宁格替尼（一种 MET/AXL 抑制剂）加吉非替尼在 EGFR 突变 NSCLC 中的疗效和耐受性，并通过不同的定义评估了 MET/AXL 失调的临床相关性。 方法 1b 期剂量递增/剂量扩展试验中的患者接受宁格替尼 30 mg/40 mg/60 mg 加吉非替尼 250 mg 每日一次。主要终点是耐受性（剂量递增）和客观缓解率（剂量扩展）。使用 FISH 和 IHC 分析 MET/AXL 状态。结果 2017 年 3 月至 2021 年 1 月期间，入组了 108 名患者。 MET焦点扩增、MET多体性、MET过表达、AXL扩增和AXL过表达的比例分别为18.1%、5.6%、55.8%、8.1%和45.3%。 6.8% 的患者同时存在 MET 扩增和 AXL 过度表达。对于 MET 扩增的肿瘤，ORR 为 30.8%；对于 MET 多体性，ORR 为 0%；对于 MET 过表达，ORR 为 24.1%；对于 AXL 扩增，ORR 为 20%；对于 AXL 过表达，ORR 为 27.6%。对于同时发生 MET 扩增和 AXL 过表达的患者，宁格替尼加吉非替尼的 ORR 为 80%，DCR 为 100%，中位 PFS 为 4.7 个月。 MET 拷贝数和 AXL 表达较高的肿瘤往往具有较高的缓解可能性。生物标志物分析表明，MET 局灶性扩增和过表达在预测 MET 抑制的临床获益方面是互补的，而任意水平定义的 AXL 异常调节可能会削弱 AXL 阻断的疗效。结论本研究表明，联合阻断 MET、AXL 和 EGFR 对于 EGFR 突变 NSCLC 的子集是可行的策略。试验注册中国药品试验网，CTR20160875。
BackgroundMET and AXL dysregulations are implicated in acquired resistance to EGFR-TKIs in NSCLC. But consensus on the optimal definition for MET/AXL dysregulations inEGFR-mutant NSCLC is lacking. Here, we investigated the efficacy and tolerability of ningetinib (a MET/AXL inhibitor) plus gefitinib inEGFR-mutant NSCLC, and evaluated the clinical relevance of MET/AXL dysregulations by different definitions.MethodsPatients in this phase 1b dose-escalation/dose-expansion trial received ningetinib 30 mg/40 mg/60 mg plus gefitinib 250 mg once daily. Primary endpoints were tolerability (dose-escalation) and objective response rate (dose-expansion). MET/AXL status were analyzed using FISH and IHC.ResultsBetween March 2017 and January 2021, 108 patients were enrolled. The proportion ofMETfocal amplification,METpolysomy, MET overexpression,AXLamplification and AXL overexpression is 18.1 %, 5.6 %, 55.8 %, 8.1 % and 45.3 %, respectively. 6.8 % patients have concurrentMETamplification and AXL overexpression. ORR is 30.8 % for tumors withMETamplification, 0 % forMETpolysomy, 24.1 % for MET overexpression, 20 % forAXLamplification and 27.6 % for AXL overexpression. For patients with concurrentMETamplification and AXL overexpression, ningetinib plus gefitinib provides an ORR of 80 %, DCR of 100 % and median PFS of 4.7 months. Tumors with higherMETcopy number and AXL expression tend to have higher likelihood of response. Biomarker analyses show thatMETfocal amplification and overexpression are complementary in predicting clinical benefit from MET inhibition, whileAXLdysregulations defined by an arbitrary level may dilute the efficacy of AXL blockade.ConclusionsThis study demonstrates that combined blockade of MET, AXL and EGFR is a feasible strategy for a subset ofEGFR-mutant NSCLC.Trial registrationChinadrugtrials.org.cn, CTR20160875.