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The clinical efficacy of combinatorial therapy of EGFR-TKI and crizotinib in overcoming MET amplification-mediated resistance from prior EGFR-TKI therapy.

EGFR-TKI 和 crizotinib 组合治疗克服既往 EGFR-TKI 治疗中 MET 扩增介导的耐药的临床疗效。

  • 影响因子:4.52
  • DOI:10.1016/j.lungcan.2020.06.003
  • 作者列表:"Wang Y","Tian P","Xia L","Li L","Han R","Zhu M","Lizaso A","Qin T","Li M","Yu B","Mao X","Han-Zhang H","He Y
  • 发表时间:2020-06-06
Abstract

BACKGROUND:MET amplification is one of the EGFR-independent mechanisms of EGFR tyrosine kinase inhibitor (TKI) resistance. Combinatorial therapy of EGFR-TKI and crizotinib has been explored as a strategy to overcome resistance by simultaneously targeting both EGFR and MET pathways; however, no consensus still exists on the optimal combination regimen with the most benefit. METHODS:Retrospective analysis was performed on the clinical and sequencing data obtained from eleven patients with lung adenocarcinoma who acquired MET amplification at progression from prior EGFR-TKI therapy and received a combination of EGFR-TKI and crizotinib. RESULTS:Acquired MET amplification was detected in four and seven patients who progressed from first-line gefitinib and second-line osimertinib, respectively. Six and five patients received a combination of either first-generation (gefitinib, erlotinib, or icotinib) or third-generation (osimertinib) EGFR-TKI and crizotinib, respectively. Nine patients achieved partial response, resulting in an overall response rate of 81.8 %. The median progression-free survival of the cohort was 5.8 months. Moreover, analysis of acquired resistance mechanisms from nine patients identified EGFR T790 M from three patients who progressed from first-generation EGFR-TKI and crizotinib, while EGFR T790 M/trans-C797S and L718Q, EGFR G724S, and CCDC6-RET fusion were detected from one patient each who progressed from osimertinib and crizotinib regimen. Loss of MET amplification was also observed in a majority of the patients at progression from the combination therapy. CONCLUSIONS:Our study provides clinical evidence of the efficacy of combinatorial regimen with either first- or third-generation EGFR-TKI and crizotinib after the emergence of MET amplification-mediated EGFR-TKI resistance in patients with EGFR-mutant NSCLC.

摘要

背景: MET 扩增是 EGFR 酪氨酸激酶抑制剂 (TKI) 耐药的 EGFR 非依赖性机制之一。EGFR-TKI 和 crizotinib 的组合治疗已经被探索为通过同时靶向 EGFR 和 MET 通路来克服耐药的策略; 然而,对获益最大的最佳组合方案仍然没有共识。 方法: 对 11 例肺腺癌患者的临床和测序数据进行回顾性分析,这些患者在既往 EGFR-TKI 治疗进展时获得 MET 扩增,并接受了 EGFR-TKI 和 crizotinib 联合治疗。 结果: 分别在 4 例和 7 例从一线吉非替尼和二线奥希替尼进展的患者中检测到获得性 MET 扩增。6 例和 5 例患者分别接受了第一代 (吉非替尼、厄洛替尼或埃克替尼) 或第三代 (奥希替尼) EGFR-TKI 和克唑替尼的联合治疗。9 例患者获得部分缓解,总反应率为 81.8%。队列的中位无进展生存期为 5.8 个月。此外,对 9 例患者获得性耐药机制的分析发现 EGFR T790 m 来自 3 例第一代 EGFR-TKI 和 crizotinib 进展的患者,而 EGFR T790 m/trans-C797S 和 L718Q,从 osimertinib 和 crizotinib 方案进展的每个患者中检测到 EGFR G724S 和 CCDC6-RET 融合。在大多数从联合治疗进展的患者中也观察到 MET 扩增的丢失。 结论: 在 EGFR 患者出现 MET 扩增介导的 EGFR-TKI 耐药后,我们的研究提供了第一代或第三代 EGFR-TKI 和 crizotinib 组合方案疗效的临床证据-突变型 NSCLC。

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影响因子:1.84
发表时间:2020-01-01
来源期刊:Oncology letters
DOI:10.3892/ol.2019.11149
作者列表:["Das SK","Huang YY","Li B","Yu XX","Xiao RH","Yang HF"]

METHODS::The aim of the present study was to compare the safety and efficacy of cryoablation (CA) and microwave ablation (MWA) as treatments for non-small cell lung cancer (NSCLC). Patients with stage IIIB or IV NSCLC treated with CA (n=45) or MWA (n=56) were enrolled in the present study. The primary endpoint was progression-free survival (PFS); the secondary endpoints included overall survival (OS) time and adverse events (AEs). The median PFS times between the two groups were not significantly different (P=0.36): CA, 10 months [95% confidence interval (CI), 7.5-12.4] vs. MWA, 11 months (95% CI, 9.5-12.4). The OS times between the two groups were also not significantly different (P=0.07): CA, 27.5 months (95% CI, 22.8-31.2 months) vs. MWA, 18 months (95% CI, 12.5-23.5). For larger tumors (>3 cm), patients treated with MWA had significantly longer median PFS (P=0.04; MWA, 10.5 months vs. CA, 7.0 months) and OS times (P=0.04; MWA, 24.5 months vs. CA, 14.5 months) compared patients treated with CA. However, for smaller tumors (≤3 cm), median PFS (P=0.79; MWA, 11.0 months vs. CA, 13.0 months) and OS times (P=0.39; MWA, 30.0 months vs. CA, 26.5 months) between the two groups did not differ significantly. The incidence rates of AEs were similar in the two groups (P>0.05). The number of applicators, tumor size and length of the lung traversed by applicators were associated with a higher risk of pneumothorax and intra-pulmonary hemorrhage in the two groups. Treatment with CA resulted in significantly less intraprocedural pain compared with treatment with MWA (P=0.001). Overall, the present study demonstrated that CA and MWA were comparably safe and effective procedures for the treatment of small tumors. However, treatment with MWA was superior compared with CA for the treatment of large tumors.

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影响因子:8.44
发表时间:2020-02-01
DOI:10.1016/j.annonc.2019.10.022
作者列表:["Mazieres J","Cropet C","Montané L","Barlesi F","Souquet PJ","Quantin X","Dubos-Arvis C","Otto J","Favier L","Avrillon V","Cadranel J","Moro-Sibilot D","Monnet I","Westeel V","Le Treut J","Brain E","Trédaniel J","Jaffro M","Collot S","Ferretti GR","Tiffon C","Mahier-Ait Oukhatar C","Blay JY"]

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