Genomic Profiling Identifies Outcome-Relevant Mechanisms of Innate and Acquired Resistance to Third-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy in Lung Cancer.

Abstract

PURPOSE:

Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective in acquired resistance (AR) to early-generation EGFR TKIs in EGFR-mutant lung cancer. However, efficacy is marked by interindividual heterogeneity. We present the molecular profiles of pretreatment and post-treatment samples from patients treated with third-generation EGFR TKIs and their impact on treatment outcomes.

METHODS:

Using the databases of two lung cancer networks and two lung cancer centers, we molecularly characterized 124 patients with EGFR p.T790M-positive AR to early-generation EGFR TKIs. In 56 patients, correlative analyses of third-generation EGFR TKI treatment outcomes and molecular characteristics were feasible. In addition, matched post-treatment biopsy samples were collected for 29 patients with progression to third-generation EGFR TKIs.

RESULTS:

Co-occurring genetic aberrations were found in 74.4% of EGFR p.T790-positive samples (n = 124). Mutations in TP53 were the most frequent aberrations detected (44.5%; n = 53) and had no significant impact on third-generation EGFR TKI treatment. Mesenchymal-epithelial transition factor (MET) amplifications were found in 5% of samples (n = 6) and reduced efficacy of third-generation EGFR TKIs significantly (eg, median progression-free survival, 1.0 months; 95% CI, 0.37 to 1.72 v 8.2 months; 95% CI, 1.69 to 14.77 months; P ≤ .001). Genetic changes in the 29 samples with AR to third-generation EGFR TKIs were found in EGFR (eg, p.T790M loss, acquisition of p.C797S or p.G724S) or in other genes (eg, MET amplification, KRAS mutations).

CONCLUSION:

Additional genetic aberrations are frequent in EGFR-mutant lung cancer and may mediate innate and AR to third-generation EGFR TKIs. MET amplification was strongly associated with primary treatment failure and was a common mechanism of AR to third-generation EGFR TKIs. Thus, combining EGFR inhibitors with TKIs targeting common mechanisms of resistance may delay AR.

• Authors: Sebastian Michels, Carina Heydt, Bianca van Veggel, Barbara Deschler-Baier, Nuria Pardo, Kim Monkhorst, Vanessa Rüsseler, Jan Stratmann, Frank Griesinger, Susanne Steinhauser, Anna Kostenko, Joachim Diebold, Jana Fassunke, Rieke Fischer, Walburga Engel-Riedel, Oliver Gautschi, Eva Geissinger, Stefan Haneder, Michaela A Ihle, Hans-Georg Kopp, Adrianus J de Langen, Alex Martinez-Marti, Lucia Nogova, Thorsten Persigehl, Dennis Plenker, Michael Puesken, Ernst Rodermann, Andreas Rosenwald, Andreas H Scheel, Matthias Scheffler, Werner Spengler, Ruth Seggewiss-Bernhardt, Johannes Brägelmann, Martin Sebastian, Bart Vrugt, Martin Hellmich, Martin L Sos, Lukas C Heukamp, Enriqueta Felip, Sabine Merkelbach-Bruse, Egbert F Smit, Reinhard Büttner, Jürgen Wolf
• Journal: JCO precision oncology (JCO Precis Oncol) Vol. 3 ( 2019) ISSN: 2473-4284 [Electronic] United States
• PMID: 32914023 (Publication Type: Journal Article)
• Copyright: © 2019 by American Society of Clinical Oncology.