克唑替尼联合或不联合 EGFR-TKI 治疗 EGFR 突变型 NSCLC 患者 EGFR-TKI 治疗失败后获得性 MET 扩增：一项多中心回顾性研究。
Crizotinib with or without an EGFR-TKI in treating EGFR-mutant NSCLC patients with acquired MET amplification after failure of EGFR-TKI therapy: a multicenter retrospective study.
机构信息
Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, 310022, China.
Department of Lung Cancer, The Fifth Medical Center, General of PLA, Beijing, 100071, China.
出版信息
J Transl Med. 2019 Feb 21;17(1):52. doi: 10.1186/s12967-019-1803-9.
BACKGROUND
MET amplification is associated with acquired resistance to first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in treating non-small-cell lung cancer (NSCLC); however, the therapeutic strategy in these patients is undefined. Herein we report the clinical outcomes of patients with c-MET amplification resistance to EGFR-TKIs treated with crizotinib.
METHODS
We retrospectively analyzed advanced NSCLC patients from five sites who were diagnosed with EGFR-mutant NSCLC and received EGFR-TKI treatment. After disease progression, these patients were confirmed to have a MET-to-centromere ratio (MET:CEN) ≥ 1.8 based on fluorescence in situ hybridization (FISH) examination and without a T790M mutation. We assessed the efficacy and safety of crizotinib to overcome EGFR-TKI resistance in EGFR-activating mutations NSCLC with acquired MET amplification.
RESULTS
Amplification of the acquired MET gene was identified in 18 patients with EGFR-mutant NSCLC. Fourteen patients received crizotinib treatment after acquired resistance to EGFR-TKIs. Among the 14 patients, 6 (42.9%) received crizotinib plus EGFR-TKI and 8 (57.1%) received crizotinib monotherapy. The overall objective response rate (ORR) and disease control rate (DCR) were 50.0% (7/14) and 85.7% (12/14), respectively. The median PFS (mPFS) of patients receiving crizotinib monotherapy and crizotinib plus EGFR-TKI was 6.0 and 12.6 months, respectively (P = 0.315). Notably, treatment efficacy was more pronounced in patients with crizotinib than patients with chemotherapy (24.0 months vs. 12.0 months, P = 0.046). The mOS for 8 of 14 patients receiving crizotinib monotherapy and 6 of 14 patients receiving crizotinib plus EGFR-TKI was 17.2 and 24.0 months, respectively (P = 0.862). Among the 14 patients, 1 who received crizotinib monotherapy (grade 3 nausea) and 2 who received crizotinib plus EGFR-TKI (grade 3 elevated liver aminotransferase levels) received reduced doses of crizotinib (200 mg twice daily) to better tolerate the dose.
CONCLUSIONS
We observed the clinical evidence of efficacy generated by combination of crizotinib and previous EGFR-TKIs after the resistance to first-generation EGFR-TKIs. These results might increase evidence of more effective therapeutic strategies for NSCLC treatment. Combination therapy did not increase the frequency of adverse reactions.
背景
MET 扩增与第一代表皮生长因子受体（EGFR）-酪氨酸激酶抑制剂（TKI）治疗非小细胞肺癌（NSCLC）获得性耐药相关；然而，这些患者的治疗策略尚未确定。在此，我们报告了接受克唑替尼治疗的 EGFR-TKI 耐药的 c-MET 扩增患者的临床结果。
方法
我们回顾性分析了来自五个地点的被诊断为 EGFR 突变型 NSCLC 并接受 EGFR-TKI 治疗的晚期 NSCLC 患者。疾病进展后，这些患者通过荧光原位杂交（FISH）检查证实 MET 与着丝粒的比值（MET：CEN）≥1.8，且无 T790M 突变。我们评估了克唑替尼克服 EGFR 激活突变 NSCLC 获得性 MET 扩增对 EGFR-TKI 耐药的疗效和安全性。
结果
在 18 例 EGFR 突变型 NSCLC 患者中发现了获得性 MET 基因扩增。14 例患者在 EGFR-TKI 获得性耐药后接受了克唑替尼治疗。在这 14 例患者中，6 例（42.9%）接受了克唑替尼联合 EGFR-TKI 治疗，8 例（57.1%）接受了克唑替尼单药治疗。总的客观缓解率（ORR）和疾病控制率（DCR）分别为 50.0%（7/14）和 85.7%（12/14）。接受克唑替尼单药和克唑替尼联合 EGFR-TKI 治疗的患者的中位无进展生存期（mPFS）分别为 6.0 个月和 12.6 个月（P=0.315）。值得注意的是，与接受化疗的患者相比，接受克唑替尼治疗的患者的治疗效果更为显著（24.0 个月 vs. 12.0 个月，P=0.046）。接受克唑替尼单药治疗的 8 例患者和接受克唑替尼联合 EGFR-TKI 治疗的 6 例患者的中位总生存期（mOS）分别为 17.2 个月和 24.0 个月（P=0.862）。在这 14 例患者中，1 例接受克唑替尼单药治疗（3 级恶心）和 2 例接受克唑替尼联合 EGFR-TKI 治疗（3 级肝转氨酶升高）减少了克唑替尼的剂量（200mg，每日两次）以更好地耐受剂量。
结论
我们观察到第一代 EGFR-TKI 耐药后克唑替尼联合先前 EGFR-TKI 的疗效产生的临床证据。这些结果可能为 NSCLC 的治疗提供更有效的治疗策略的证据。联合治疗并未增加不良反应的发生频率。
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