Assya Akli1, Nicolas Girard2, Vincent Fallet3, Gaelle Rousseau-Bussac4, Valérie Gounant5, Sylvie Friard6, Jean Trédaniel7, Cécile Dujon8, Marie Wislez9, Boris Duchemann10, Etienne Giroux-Leprieur11. 1. Department of Respiratory Diseases and Thoracic Oncology, APHP-Hopital Ambroise Pare, Paris-Saclay University, UVSQ, 9 avenue Charles de Gaulle, 92100, Boulogne-Billancourt, France. 2. Institute Curie, Thorax Institute, Paris-Saclay University, UVSQ, Paris, France. 3. Department of Pneumology and Thoracic Oncology, APHP-Hopital Tenon, Sorbonne University, Paris, France. 4. Chest Department, Creteil Intercommunal Hospital, Créteil, France. 5. Thoracic Oncology Department, Paris-Cité University, APHP-Hopital Bichat, Paris, France. 6. Pneumology Department, Foch Hospital, Suresnes, France. 7. Pneumology Department, Saint-Joseph Hospital, Paris, France. 8. Pneumology Department, André Mignot Hospital, Le Chesnay, France. 9. Department of Pulmonology, Thoracic Oncology Unit, APHP-Hopital Cochin, Paris-Cité University, Paris, France. 10. Department of Medical Oncology, APHP-Hopital Avicenne, Sorbonne Paris Nord University, Bobigny, France. 11. Department of Respiratory Diseases and Thoracic Oncology, APHP-Hopital Ambroise Pare, Paris-Saclay University, UVSQ, 9 avenue Charles de Gaulle, 92100, Boulogne-Billancourt, France. etienne.giroux-leprieur@aphp.fr.
Abstract
BACKGROUND: 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). OBJECTIVE: The identification of related histomolecular resistance mechanisms to first-line osimertinib is a critical step to define the optimal treatment strategy beyond progression. PATIENTS AND METHODS: 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. RESULTS: 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%). CONCLUSIONS: 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.
BACKGROUND: 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). OBJECTIVE: The identification of related histomolecular resistance mechanisms to first-line osimertinib is a critical step to define the optimal treatment strategy beyond progression. PATIENTS AND METHODS: 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. RESULTS: 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%). CONCLUSIONS: 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.