Clinical impact of subclonal EGFR T790M mutations in advanced-stage EGFR-mutant non-small-cell lung cancers

Tereza Vaclova, Ursula Grazini, Lewis Ward, Daniel O’Neill, Aleksandra Markovets, Xiangning Huang, Juliann Chmielecki, Ryan Hartmaier, Kenneth S. Thress, Paul D. Smith, J. Carl Barrett, Julian Downward and Elza C. de Bruin ()
Additional contact information
Tereza Vaclova: Oncology R&D, AstraZeneca
Ursula Grazini: Oncology R&D, AstraZeneca
Lewis Ward: BioPharmaceutical R&D, AstraZeneca
Daniel O’Neill: BioPharmaceutical R&D, AstraZeneca
Aleksandra Markovets: Oncology R&D, AstraZeneca
Xiangning Huang: Oncology R&D, AstraZeneca
Juliann Chmielecki: Oncology R&D, AstraZeneca
Ryan Hartmaier: Oncology R&D, AstraZeneca
Kenneth S. Thress: Oncology R&D, AstraZeneca
Paul D. Smith: Oncology R&D, AstraZeneca
J. Carl Barrett: Oncology R&D, AstraZeneca
Julian Downward: Francis Crick Institute
Elza C. de Bruin: Oncology R&D, AstraZeneca

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-22057-8

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