Real-world circulating tumor DNA analysis depicts resistance mechanism and clonal evolution in ALK inhibitor-treated lung adenocarcinoma patients
1Department of Cardiothoracic Surgery, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, China; Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, China.
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.
Insights
Sequential anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) treatments in lung cancer can accelerate resistance mutations. Understanding these ALK mutations guides future therapies for better long-term strategies.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Anaplastic lymphoma kinase (ALK) inhibitors are standard for ALK-positive lung cancer.
- Resistance mutations inevitably develop, necessitating further study for improved treatment strategies.
- This study investigates secondary ALK mutations in Chinese lung adenocarcinoma (ADC) patients undergoing sequential TKI treatment.
Purpose of the Study:
- To explore the emergence and characteristics of secondary ALK mutations during sequential TKI therapy.
- To identify ALK-independent resistance mechanisms.
- To provide guidance for clinical decision-making in ALK-positive lung cancer treatment.
Main Methods:
- Utilized a clinical-genomic database of lung ADC patients with prior ALK inhibitor treatment and post-treatment plasma samples.
- Performed targeted genome profiling on tumor tissue and serial plasma samples using a 139-gene panel.
- Analyzed 116 patients meeting inclusion criteria for ALK mutations and other genetic alterations.
Main Results:
- ALK G1202R mutations correlated with EML4-ALK v3, while L1196M correlated with v1.
- TP53 mutations were linked to multiple ALK resistance mutations, especially in v3+/TP53 patients.
- Alectinib showed a lower rate of resistance mutations (9%) compared to crizotinib (36%) as first-line therapy. Compound mutations like G1202R/L1196M may confer resistance to lorlatinib. ALK-independent alterations included PTPRD/CDKN2A/B loss and MYC/KRAS amplification.
Conclusions:
- Increased lines of ALK inhibitors accelerate ALK resistance mutation accumulation, potentially leading to refractory compound mutations.
- Optimal first-line TKI selection is crucial for long-term efficacy and preventing on-target resistance.
- Findings offer guidance for clinical strategies in managing ALK-positive lung cancer progression.
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