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Updated: Aug 31, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
EGFR-mutant NSCLC: monitoring the molecular evolution of tumors in 2022
Nicolas Girard1, Clémence Basse1
1Thoracic Oncology Service, Institut Curie, Institut du Thorax Curie Montsouris, Paris, France.
Introduction:
Epidermal growth factor receptor (EGFR) activating mutations define a subset of advanced, metastatic non-small cell lung cancers (NSCLCs), which was historically identified along with the clinical development of specific EGFR tyrosine kinase inhibitors (TKIs), opening the era of precision medicine in thoracic oncology.
Areas Covered:
Progression after EGFR TKIs is a major challenge for patients, as it occurs ineluctably along with disease evolution. Osimertinib is the current standard-of-care for the first-line treatment of EGFR-mutant NSCLC. Mechanisms of resistance to osimertinib are challenging to identify, and are dominated by MET pathway activation, and acquired EGFR mutations.
Expert Opinion:
The current vision for clinical practice in patients with EGFR-mutant NSCLC developing disease progression after osimertinib includes the following 5 steps:- continuation of osimertinib beyond progression, and local treatment of oligoprogressive disease, - comprehensive genomic profiling based on tissue rebiopsy of progressing sites, - access to new treatment agents through clinical trials, - molecular tumor board to discuss the off-label use of targeted agents, depending on the availability of drugs and/or expanded access programs - chemotherapy may be the best choice, based on combination of platinum-based regimen and antiangiogenic agents and possibly immune checkpoint inhibitors.
Insights
Treating advanced non-small cell lung cancer (NSCLC) with EGFR mutations requires managing resistance to osimertinib. Strategies include continuing treatment, genomic profiling, clinical trials, and chemotherapy.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Epidermal growth factor receptor (EGFR) activating mutations are key in advanced NSCLC, driving precision medicine.
- EGFR tyrosine kinase inhibitors (TKIs) revolutionized treatment, but acquired resistance remains a challenge.
- Osimertinib is the standard first-line therapy for EGFR-mutant NSCLC, yet resistance mechanisms necessitate further research.
Purpose of the Study:
- To outline current clinical practice for managing EGFR-mutant NSCLC progression after osimertinib.
- To identify key steps and therapeutic options for patients who develop resistance.
- To provide a framework for clinical decision-making in advanced NSCLC.
Main Methods:
- Review of current treatment paradigms and resistance mechanisms.
- Description of a 5-step clinical management strategy.
- Discussion of diagnostic and therapeutic interventions.
Main Results:
- Resistance to osimertinib is common, often involving MET pathway activation or acquired EGFR mutations.
- A structured approach including continued osimertinib, genomic profiling, clinical trials, and chemotherapy is recommended.
- Personalized treatment decisions are guided by molecular profiling and multidisciplinary tumor boards.
Conclusions:
- Managing osimertinib resistance in EGFR-mutant NSCLC requires a multifaceted strategy.
- Genomic profiling and access to novel therapies are crucial for optimizing patient outcomes.
- Chemotherapy, potentially combined with antiangiogenic agents or immunotherapy, remains a viable option.
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