Clinical impact of subclonal EGFR T790M mutations in advanced-stage EGFR-mutant non-small-cell lung cancers.
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Embargo End Date
ICR Authors
Authors
Vaclova, T
Grazini, U
Ward, L
O'Neill, D
Markovets, A
Huang, X
Chmielecki, J
Hartmaier, R
Thress, KS
Smith, PD
Barrett, JC
Downward, J
de Bruin, EC
Grazini, U
Ward, L
O'Neill, D
Markovets, A
Huang, X
Chmielecki, J
Hartmaier, R
Thress, KS
Smith, PD
Barrett, JC
Downward, J
de Bruin, EC
Document Type
Journal Article
Date
2021-03-19
Date Accepted
2021-02-23
Abstract
Advanced non-small-cell lung cancer (NSCLC) patients with EGFR T790M-positive tumours benefit from osimertinib, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). Here we show that the size of the EGFR T790M-positive clone impacts response to osimertinib. T790M subclonality, as assessed by a retrospective NGS analysis of 289 baseline plasma ctDNA samples from T790M-positive advanced NSCLC patients from the AURA3 phase III trial, is associated with shorter progression-free survival (PFS), both in the osimertinib and the chemotherapy-treated patients. Both baseline and longitudinal ctDNA profiling indicate that the T790M subclonal tumours are enriched for PIK3CA alterations, which we demonstrate to confer resistance to osimertinib in vitro that can be partially reversed by PI3K pathway inhibitors. Overall, our results elucidate the impact of tumour heterogeneity on response to osimertinib in advanced stage NSCLC patients and could help define appropriate combination therapies in these patients.
Citation
Nature communications, 2021, 12 (1), pp. 1780 - ?
Source Title
Publisher
ISSN
2041-1723
eISSN
2041-1723
Collections
Research Team
Lung Cancer Group
Lung Cancer Group
Lung Cancer Group