Christine Lovly
Faculty Member
Last active: 9/10/2020

Monitoring Therapeutic Response and Resistance: Analysis of Circulating Tumor DNA in Patients With ALK+ Lung Cancer.

Horn L, Whisenant JG, Wakelee H, Reckamp KL, Qiao H, Leal TA, Du L, Hernandez J, Huang V, Blumenschein GR, Waqar SN, Patel SP, Nieva J, Oxnard GR, Sanborn RE, Shaffer T, Garg K, Holzhausen A, Harrow K, Liang C, Lim LP, Li M, Lovly CM
J Thorac Oncol. 2019 14 (11): 1901-1911

PMID: 31446141 · PMCID: PMC6823161 · DOI:10.1016/j.jtho.2019.08.003

INTRODUCTION - Despite initial effectiveness of ALK receptor tyrosine kinase inhibitors (TKIs) in patients with ALK+ NSCLC, therapeutic resistance will ultimately develop. Serial tracking of genetic alterations detected in circulating tumor DNA (ctDNA) can be an informative strategy to identify response and resistance. This study evaluated the utility of analyzing ctDNA as a function of response to ensartinib, a potent second-generation ALK TKI.

METHODS - Pre-treatment plasma was collected from 76 patients with ALK+ NSCLC who were ALK TKI-naive or had received prior ALK TKI, and analyzed for specific genetic alterations. Longitudinal plasma samples were analyzed from a subset (n = 11) of patients. Analysis of pre-treatment tumor biopsy specimens from 22 patients was compared with plasma.

RESULTS - Disease-associated genetic alterations were detected in 74% (56 of 76) of patients, the most common being EML4-ALK. Concordance of ALK fusion between plasma and tissue was 91% (20 of 22 blood and tissue samples). Twenty-four ALK kinase domain mutations were detected in 15 patients, all had previously received an ALK TKI; G1269A was the most prevalent (4 of 24). Patients with a detectable EML4-ALK variant 1 (V1) fusion had improved response (9 of 17 patients; 53%) to ensartinib compared to patients with EML4-ALK V3 fusion (one of seven patients; 14%). Serial changes in ALK alterations were observed during therapy.

CONCLUSIONS - Clinical utility of ctDNA was shown, both at pre-treatment by identifying a potential subgroup of ALK+ NSCLC patients who may derive more benefit from ensartinib and longitudinally by tracking resistance. Prospective application of this technology may translate to improved outcomes for NSCLC patients treated with ALK TKIs.

Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

MeSH Terms (18)

Adult Aged Aged, 80 and over Anaplastic Lymphoma Kinase Carcinoma, Non-Small-Cell Lung Circulating Tumor DNA Drug Resistance, Neoplasm Female Humans Lung Neoplasms Male Middle Aged Mutation Oncogene Proteins, Fusion Piperazines Prognosis Protein Kinase Inhibitors Pyridazines

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