Second-generation <italic style="font-style: italic">ALK-TKIs</italic> have different molecular profiles of drug resistance-associated genetic alterations after failure of second-line treatment for <italic style="font-style: italic">ALK</italic> fusion positive advanced NSCLC

Ning DING; Xiaobo XU; Jiebai ZHOU; Yong ZHANG; Zilong LIU; Jie LIU; Donghui ZHANG; Jiamin LI; Jie HU

doi:10.16016/j.2097-0927.202209192

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Second-generation ALK-TKIs have different molecular profiles of drug resistance-associated genetic alterations after failure of second-line treatment for ALK fusion positive advanced NSCLC

Monographic Reports: Targeted therapy of lung cancer | 更新时间：2026-02-13

- Second-generation ALK-TKIs have different molecular profiles of drug resistance-associated genetic alterations after failure of second-line treatment for ALK fusion positive advanced NSCLC
- Journal of Army Medical University Vol. 44, Issue 24, Pages: 2493-2499(2022)
- 作者机构：
  
  1.200032 上海，复旦大学附属中山医院呼吸与危重症医学科
  2.201104 上海，上海市老年医学中心呼吸与危重症医学科
- 作者简介：
- 基金信息：
  
  the Project of Clinical Key Specialty Construction of Shanghai(shslczdzk02201)
- DOI：10.16016/j.2097-0927.202209192
  CLC： R734.2;R969.4;R979.19
- Received：21 September 2022，
  
  Revised：2022-10-08，
  
  Published：30 December 2022
- 稿件说明：
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Ning DING, Xiaobo XU, Jiebai ZHOU, et al. Second-generation ALK-TKIs have different molecular profiles of drug resistance-associated genetic alterations after failure of second-line treatment for ALK fusion positive advanced NSCLC[J]. Journal of Army Medical University, 2022, 44(24): 2493-2499.
DOI：

Ning DING, Xiaobo XU, Jiebai ZHOU, et al. Second-generation ALK-TKIs have different molecular profiles of drug resistance-associated genetic alterations after failure of second-line treatment for ALK fusion positive advanced NSCLC[J]. Journal of Army Medical University, 2022, 44(24): 2493-2499. DOI： 10.16016/j.2097-0927.202209192.

摘要

目的

比较和探索不同二代间变性淋巴瘤激酶-酪氨酸激酶抑制剂(anaplastic lymphoma kinase-tyrosine kinase inhibitors，

ALK-TKIs

)获得性耐药基因变异图谱差异，为

ALK

阳性晚期非小细胞肺癌(non-small cell lung cancer，NSCLC)的全程管理提供依据。

方法

本研究为观察性研究，纳入2014年至2020年共计103例

ALK

阳性晚期NSCLC患者，在一线克唑替尼治疗和二线二代

ALK-TKIs

治疗发生耐药后，通过组织样本或液体样本行下一代测序(next generation sequencing，NGS)检测，分析不同的二代靶向药物发生获得性耐药的基因变异分子图谱的异同。

结果

二代TKIs获得性耐药以

ALK

激酶结构域突变为主(66.7%)，发生率

3型显著高于

1型(85.7%

. 55.6%，

=0.003 9)；最常见

1202

R/K

和

1196

，前者多见于

3型(57.1%

.4.4%，

0.000 1)，后者在

1型相对多见(31.1%

. 14.3%，

=0.079 4)。阿来替尼耐药以

ALK

继发突变发生率最高，常见

1202

(31.6%)和

1269

(12.3%)；色瑞替尼

1202

、

1196

、

1174

和

1156

发生率较高；而布加替尼

1174

、

1203

、

1210

发生率较高。

1203

. 6.7%

. 20%，

=0.000 2)和

1210

(1.8%

. 0

.15%，

=0.003 5)主要发生在布加替尼耐药后。

ALK-TKIs

的序贯应用可引起

ALK

基因的复合突变。

结论

二代

ALK-TKIs

二线治疗耐药后基因变异图谱复杂多样，不同药物、不同

ALK

变体之间差异较大，且存在复合突变，增加后线治疗难度，因此

ALK

阳性晚期NSCLC的临床治疗决策需充分考虑耐药分子机制后进行全局化管理。

Abstract

Objective

To compare and investigate the molecular profiles in acquired resistance-associated genetic alterations of second-generation anaplastic lymphoma kinase-tyrosine kinase inhibitors (

ALK-TKIs

) in order to provide evidence for the management of

ALK

fusion positive advanced non-small cell lung cancer (NSCLC).

Methods

An observational study was conducted on 103 patients with

ALK

-fusion positive advanced NSCLC who received first-line treatment of crizotinib and then second-line treatment of second-generation

ALK-TKIs

in Zhongshan Hospital from 2014 to 2020. Genetic alteration profiles were analyzed by next generation sequencing (NGS) on tissue or liquid samples after relapse of second-generation ALK-TKIs.

Results

The acquired

ALK-TKIs

-resistant genetic alterations were dominated by

ALK

kinase domain mutations (66.7%)

which had a significant higher incidence in

3 variant compared with

1 variant (85.7%

55.6%

=0.003 9). The most common

ALK

mutations were

1202

R/K

and

1196

and the former was more common in

3 subtype (57.1%

4.4%

0.000 1) while the latter in

1 subtype (31.1%

14.3%

=0.079 4). The patients who were resistant to alectinib had the highest incidence of secondary mutations

with

1202

(31.6%) and

1269

(12.3%) were the top 2 mutations.

1202

1196

1174

and

1156

were more common in the patients resistant to ceritinib.

1174

1203

and

1210

were the top 3 mutations among the patients who progressed after brigatinib therapy.

1203

6.7%

20%

=0.000 2) and

1210

(1.8%

15.0%

=0.003 5) mainly occurred in the brigatinib group. The sequential application of

ALK TKIs

may cause co-mutations of

ALK

gene.

Conclusion

The profile of genetic alteration failed from second-line second-generation

ALK-TKIs

treatment are complex and diverse. There are differences between different drugs and different

ALK

variants

as well as compound mutations

which increase the difficulty in later line therapy. Therefore

the clinical treatment decisions of advanced NSCLCs with

ALK

positive should be established on the fully consideration of the drug resistance m

echanism.

关键词

Keywords

references

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Second-generation ALK-TKIs have different molecular profiles of drug resistance-associated genetic alterations after failure of second-line treatment for ALK fusion positive advanced NSCLC

DOI：10.16016/j.2097-0927.202209192

摘要

Abstract

关键词

Keywords

references