Standard of care of EGFR mutated metastatic NSCLC in first treatment and beyond progression

Among the oncogenic alterations of non-small cell lung cancer (NSCLC), the EGFR gene mutation is observed in 15% of patients in France, particularly among non-smokers and women. Treatment mainly relies on tyrosine kinase inhibitors (TKIs) targeting EGFR. In first-line metastatic treatment, osimertinib, a third-generation TKI, has become the standard, improving progression-free survival (PFS) and overall survival (OS) compared to first- or second-generation TKIs. The combination of TKI/chemotherapy (osimertinib/carboplatine-pemetrexed) and TKI/bispecific antibodies (e.g., amivantamab/lazertinib) are alternatives under evaluation, with benefits in PFS but increased toxicity. In case of progression under first- or second-generation TKIs, the most common resistance is the T790M mutation, which can be targeted by osimertinib. For other resistances, platinum-based chemotherapy remains an option. Amivantamab combined with chemotherapy has shown an improvement in PFS in the second line and has early access in France. Other emerging approaches include conjugated antibodies (patritumab deruxtecan, datopotamab deruxtecan) and next-generation TKIs. In the future, personalized treatment based on the molecular profile and early response to TKIs could optimize management, particularly by integrating predictive markers such as EGFR clearance under treatment.