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Showing papers by "Juliann Chmielecki published in 2021"

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

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Tereza Vaclova1, Ursula Grazini1, Lewis S. C. Ward1, Daniel O'Neill1, Aleksandra Markovets1, X. Huang1, Juliann Chmielecki1, Ryan J. Hartmaier1, Kenneth S. Thress1, Paul D. Smith1, J. Carl Barrett1, Julian Downward2, Elza C. de Bruin1 •
AstraZeneca1, Francis Crick Institute2
19 Mar 2021-Nature Communications
TL;DR: In this paper, the authors show that the size of the EGFR T790M-positive clone impacts response to osimertinib, which is associated with shorter progression-free survival (PFS).
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.

27 citations

Journal Article•DOI•
Biomarker-Directed Phase II Platform Study in Patients With EGFR Sensitizing Mutation-Positive Advanced/Metastatic Non-Small Cell Lung Cancer Whose Disease Has Progressed on First-Line Osimertinib Therapy (ORCHARD).

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Helena A. Yu1, Sarah B. Goldberg2, Xiuning Le3, Zofia Piotrowska4, Jonathan W. Goldman5, Adrianus J. de Langen6, Isamu Okamoto7, Byoung Chul Cho8, Paul D. Smith9, Ilhem Mensi9, Helen Ambrose9, Silvija Kraljevic9, Julie Maidment10, Juliann Chmielecki9, Xiaocheng Li-Sucholeiki9, Gail Doughton9, Gargi Patel9, Phil Jewsbury9, Phil Szekeres9, Jonathan W. Riess11 •
Memorial Sloan Kettering Cancer Center1, Yale University2, University of Texas MD Anderson Cancer Center3, Harvard University4, University of California, Los Angeles5, Netherlands Cancer Institute6, Kyushu University7, Yonsei University8, AstraZeneca9, National Patient Safety Foundation10, University of California, Davis11
25 Jun 2021-Clinical Lung Cancer
TL;DR: ORCHARD as discussed by the authors is a phase II study aiming to characterize first-line osimertinib resistance and identify post-progression treatments for non-small cell lung cancer (NSCLC) patients.

23 citations