Going beneath the tip of the iceberg. Identifying and understanding EML4-ALK variants and TP53 mutations to optimize treatment of ALK fusion positive (ALK+) NSCLC

Zhang, Shannon; Nagasaka, Misako; Zhu, Viola W.; Ou, Sai‐Hong Ignatius

doi:10.1016/j.lungcan.2021.06.012

Cited by 58 publications

(46 citation statements)

References 67 publications

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“…Prior studies indicated a differential response of EML4-ALK v1 versus v3 to ALK TKIs 18 , 19 as well as TP53 mutations as a poor prognostic factor for progression-free survival (PFS) and overall survival. 20 Further studies also showed that EML4-ALK v3/ TP53mt patients had even shorter median PFS.…”

Section: Resultsmentioning

confidence: 99%

Real-world circulating tumor DNA analysis depicts resistance mechanism and clonal evolution in ALK inhibitor-treated lung adenocarcinoma patients

Hua

Zhang

et al. 2022

ESMO Open

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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 realworld 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 ¼ 0.03) and v3þ/ 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 resistancerelated genetic alterations, including PTPRD and CNKN2A/B loss, MYC, MYCN and KRAS amplification, and EGFR 19del . 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.

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Section: Resultsmentioning

confidence: 99%

Real-world circulating tumor DNA analysis depicts resistance mechanism and clonal evolution in ALK inhibitor-treated lung adenocarcinoma patients

Hua

Zhang

et al. 2022

ESMO Open

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“…Among>15 EML4-ALK variants have been identified to date, the five most common variants are variant 1 (v1; E13, A20), variant 2 (v2; E20, A20), variant 3 (v3; E6, A20), variant 4 (v4; E15, A20), and variant 5 (v5; E2, A20). The two EML4-ALK variants that together account for up to 70-80% of all EML4-ALK variants are v1 and EML4-ALK v3a/b (108). The ALTA-1L analysis by variants was the first validation of the significance of EML4-ALK variants in the context of a prospective randomized phase 3 study (109).…”

Section: Discussionmentioning

confidence: 99%

The Resistance Mechanisms and Treatment Strategies for ALK-Rearranged Non-Small Cell Lung Cancer

et al. 2021

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Anaplastic lymphoma kinase (ALK) is a validated molecular target for non-small-cell lung cancer (NSCLC). The use of tyrosine kinase inhibitors (TKIs) has led to significantly improved survival benefits. However, the clinical benefits of targeting ALK using TKIs are limited due to the emergence of drug resistance. The landscape of resistance mechanisms and treatment decisions has become increasingly complex. Therefore, continued research into new drugs and combinatorial therapies is required to improve outcomes in NSCLC. In this review, we explore the resistance mechanisms of ALK TKIs in advanced NSCLC in order to provide a theoretical basis and research ideas for solving the problem of ALK drug resistance.

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“…), of the targeted therapy or the immuno/chemotherapy responsiveness and the follow‐up of the disease is a major challenge for the better understanding of NSCLC. Notably, it is essential to look for the different concurrent genomic alterations, notably TP53 mutations, in NSCLC showing a gene fusion 31,171–174 . This may lead to the development of new therapeutic strategies in the future.…”

Section: Technical Aspects Of Gene Fusion Detection In Lung Cancer: T...mentioning

confidence: 99%

“…Notably, it is essential to look for the different concurrent genomic alterations, notably TP53 mutations, in NSCLC showing a gene fusion. 31,[171][172][173][174] This may lead to the development of new therapeutic strategies in the future. So, a longterm vision of integration of NSCLC associated with a gene fusion is of strong interest.…”

Section: Management Of a Global Complex Genomic Signaturementioning

confidence: 99%

Fusion‐positive non‐small cell lung carcinoma: Biological principles, clinical practice, and diagnostic implications

Kazdal

Hofman

Christopoulos

et al. 2022

Genes Chromosomes & Cancer

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Based on superior efficacy and tolerability, targeted therapy is currently preferred over chemotherapy and/or immunotherapy for actionable gene fusions that occur in late‐stage non‐small cell lung carcinoma (NSCLC). Consequently, current clinical practice guidelines mandate testing for ALK, ROS1, NTRK, and RET gene fusions in all patients with newly diagnosed advanced non‐squamous NSCLC (NS‐NSCLC). Gene fusions can be detected using different approaches, but today RNA next‐generation sequencing (NGS) or combined DNA/RNA NGS is the method of choice. The discovery of other gene fusions (involving, eg, NRG1, NUT, FGFR1, FGFR2, MET, BRAF, EGFR, SMARC fusions) and their partners has increased progressively in recent years, leading to the development of new and promising therapies and mandating the development and implementation of comprehensive detection methods. The purpose of this review is to focus on recent data concerning the main gene fusions identified in NSCLC, followed by the discussion of major challenges in this domain.

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Going beneath the tip of the iceberg. Identifying and understanding EML4-ALK variants and TP53 mutations to optimize treatment of ALK fusion positive (ALK+) NSCLC

Cited by 58 publications

References 67 publications

Real-world circulating tumor DNA analysis depicts resistance mechanism and clonal evolution in ALK inhibitor-treated lung adenocarcinoma patients

Real-world circulating tumor DNA analysis depicts resistance mechanism and clonal evolution in ALK inhibitor-treated lung adenocarcinoma patients

The Resistance Mechanisms and Treatment Strategies for ALK-Rearranged Non-Small Cell Lung Cancer

Fusion‐positive non‐small cell lung carcinoma: Biological principles, clinical practice, and diagnostic implications

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