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Resistance mechanisms to osimertinib in EGFR-mutated advanced non-small-cell lung cancer: A multicentric retrospective French study

Camille Mehlman 1, 2 Jacques Cadranel 3 Gaelle Rousseau-Bussac 4 Roger Lacave 5 Anaïs Pujals 6 Nicolas Girard 7, 8 Céline Callens 7 Valérie Gounant 9 Nathalie Théou-Anton 9 Sylvie Friard 10 Jean Trédaniel 11 Hélène Blons 12, 13 Cécile Dujon 14 Boris Duchemann 15, 16, 17 Pierre Olivier Schischmanoff 18, 15 Thierry Chinet 1, 2 Etienne Giroux Leprieur 1, 2, * 
Abstract : Objectives: The understanding of histo-molecular mechanisms associated with resistance to osimertinib is a critical step to define the optimal treatment strategy in advanced EGFR-mutated Non-Small-Cell-Lung-Cancer (NSCLC). Materials and methods: We performed a multicentric retrospective analysis on a cohort of consecutive patients treated with osimertinib for an advanced EGFR-mutated NSCLC and collected histo-molecular data from plasma and tumor samples at the time of progression. Next-generation sequencing (NGS) was performed for all samples. Best Overall Response Rate (ORR), Progression Free Survival (PFS), Overall Survival (OS) and data on treatment post-progression efficacy were also collected. Results: Two-hundred and twenty-six patients were included from 9 Academic French Hospitals between April 2015-October 2018. Osimertinib was given in second-line or more in 219 patients (97%). Best ORR was 52% and best central nervous system ORR was 56%. Median PFS and OS were 9.5 months (IQR 4.0-17.2) and 24 months (IQR 12.4-NR) respectively. At the time of analysis, 150 patients (66%) had tumor progression. Among them, 73 contributive samples (56 tumor biopsies) were available. The most frequent molecular alterations were C797S mutation (n = 9 (13%)) and MET amplification (n = 8 (11%)). Histologic transformation occurred in 5 patients (9% of tumor biopsies). In T790M + NSCLC, loss of T790 M occurred in 68% of cases. Median PFS and OS with treatment beyond progression were 6.0 months (IQR 2.0-10.4) and 15.1 months (IQR 6.7-NR) respectively and longer in case of osimertinib continuation beyond progression. Conclusion: We confirmed the efficacy of osimertinib in patients with advanced EGFR mutation positive NSCLC. At progression, the most frequent molecular alterations were MET amplification and C797S mutation.
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Camille Mehlman, Jacques Cadranel, Gaelle Rousseau-Bussac, Roger Lacave, Anaïs Pujals, et al.. Resistance mechanisms to osimertinib in EGFR-mutated advanced non-small-cell lung cancer: A multicentric retrospective French study. Lung Cancer, Elsevier, 2019, 137, pp.149 - 156. ⟨10.1016/j.lungcan.2019.09.019⟩. ⟨hal-03488638⟩



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