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ESMO Open
2022 Feb 01;71:100337. doi: 10.1016/j.esmoop.2021.100337.
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Real-world circulating tumor DNA analysis depicts resistance mechanism and clonal evolution in ALK inhibitor-treated lung adenocarcinoma patients.
Hua G
,
Zhang X
,
Zhang M
,
Wang Q
,
Chen X
,
Yu R
,
Bao H
,
Liu J
,
Wu X
,
Shao Y
,
Liang B
,
Lu K
.
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BACKGROUND: Sequential treatment with different generations of anaplastic lymphoma kinase (ALK) inhibitors have been widely applied to ALK-positive lung cancer; however, resistance mutations inevitably developed. Further characterization of ALK resistance mutations may provide key guidance to subsequent therapies. Here we explored the emergence of secondary ALK mutations during sequential ALK tyrosine kinase inhibitor (TKI) treatment in a real-world study of Chinese lung adenocarcinoma (ADC) patients.
METHODS: A clinical-genomic database was queried for lung ADC patients with at least one ALK inhibitor treatment and at least one plasma sample collected following ALK inhibitor treatment. Targeted genome profiling was performed with a 139-gene panel in baseline tumor tissue and serial plasma samples of patients.
RESULTS: A total of 116 patients met inclusion criteria. ALK G1202R was more common in patients with echinoderm microtubule-associated protein-like 4 (EML4)-ALK v3 fusion, whereas ALK L1196M was more common in v1. TP53 mutant patients were significantly associated with harboring multiple ALK resistance mutations (P = 0.03) and v3+/TP53 mutant patients had the highest rate of multiple ALK resistance mutations. The sequential use of ALK TKI led to an increased incidence of concurrent ALK mutations along the lines of therapies. Alectinib had a lower rate (9%) harboring ALK resistance mutation as first-line ALK TKI compared with crizotinib (36%). ALK compound mutations identified included ALK D1203N/L1196M, ALK G1202R/L1196M, and ALK G1202R/F1174C, which may be lorlatinib resistant. Using paired pretreatment and post-treatment samples, we identified several ALK-independent resistance-related genetic alterations, including PTPRD and CNKN2A/B loss, MYC, MYCN and KRAS amplification, and EGFR19del.
CONCLUSIONS: Sequential postprogression plasma profiling revealed that increased lines of ALK inhibitors can accelerate the accumulation of ALK resistance mutations and may lead to treatment-refractory compound ALK mutations. The selection for optimal first-line TKI is very important to achieve a more efficacious long-term strategy and prevent the emergence of on-target resistance, which may provide guidance for clinical decision making.
Figure 1. (A) Number of ALK resistance mutation identified in samples from patients progressing on different ALK TKIs (B) Number of ALK resistance mutation identified in samples from patients progressing on different ALK TKIs.ALK, anaplastic lymphoma kinase; TKI, tyrosine kinase inhibitor; WT, wild type.
Figure 2. (A) ALK resistance mutations in plasma samples after progression on an ALK TKI according to EML4-ALK variant. (B) Multiple frequencies of ALK resistance mutations in plasma samples after progression on an ALK TKI according to EML4-ALK variants and TP53 status. (C) Kaplan–Meier curve of RFS in patients stratified by EML4-ALK variants. (D) Kaplan–Meier curve of RFS in patients stratified by TP53 status.ALK, anaplastic lymphoma kinase; EML4, echinoderm microtubule-associated protein-like 4; RFS, recurrence-free survival; TKI, tyrosine kinase inhibitor.
Figure 3. (A) ALK resistance mutations of serial plasma samples during sequential treatment with crizotinib, one second-generation ALK TKI, and lorlatinib. ALK-activating mutations detected along the disease course of (B) Patient P050 and (C) Patient P068.ALK, anaplastic lymphoma kinase; MUT, mutation; TKI, tyrosine kinase inhibitor.
Figure 4. Non-ALK acquired mutations detected using paired pretreatment and post-treatment plasma samples.ALK, anaplastic lymphoma kinase.
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