Histomolecular Resistance Mechanisms to First-Line Osimertinib in EGFR-Mutated Advanced Non-Small Cell Lung Cancer: A Multicentric Retrospective French Study.

Abstract

Osimertinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) used in first line for the treatment of advanced EGFR-mutated non-small cell lung cancer (NSCLC). The identification of related histomolecular resistance mechanisms to first-line osimertinib is a critical step to define the optimal treatment strategy beyond progression. All consecutive patients treated in the first line with osimertinib for advanced EGFR-mutated NSCLC at 10 hospitals in the Greater Paris area between April 2015 and January 2021 were included. Histomolecular data from plasma and tissue samples taken at progression under osimertinib were collected, and all samples were analyzed using DNA next-generation sequencing. Data on objective response rate (ORR), overall survival (OS), progression-free survival (PFS), and time to treatment discontinuation (TTD) were also collected. Overall, 104 patients were included. Most patients had adenocarcinoma (n=102, 98%) with an exon 19 EGFR deletion (n=54, 52%). Forty-two patients (50%) had central nervous system (CNS) metastasis at the time of osimertinib initiation. ORR was 76%, median PFS and OS were 12.6 months and 52 months, respectively, and TTD was 33 months. At the time of analysis, 44 patients (42%) had tumor progression, and among these patients, 27 (61%) contributive samples were available. The most frequent molecular alterations at progression were mesenchymal epithelial transition factor (MET) amplification (15%; n=4) and EGFR C797S mutation (11%; n=3). Histological transformation was found in one patient (4%). RNA next-generation sequencing was performed in eight patients and showed a CCDC6-RET fusion in one patient (12%). We confirmed the efficacy of osimertinib in patients with advanced EGFR mutation-positive NSCLC. At progression, the most frequent histomolecular alterations were MET amplification and EGFR C797S mutation.