First Line and Treatment Sequencing in EGFR-Mutated Metastatic NSCLC: What is Right for Which Patient?

The therapeutic landscape for non-small-cell lung cancer (NSCLC) harbouring epidermal growth factor (EGFR) gene mutations is undergoing significant transformation. For classical EGFR mutations such as exon 19 deletion and exon 21 L858R mutation, combination strategies in the first-line setting, based on the results of the MARIPOSA (lazertinib and amivantamab) and FLAURA 2 (platinum-based doublet chemotherapy and osimertinib) trials, provide promising outcomes. Compared to osimertinib monotherapy, they potentially delay both the onset of molecular resistance to treatment and the intracranial progression of the disease. Selecting the best first-line option should take into consideration patient and genome-related factors as well as the burden of the disease including the presence of central nervous system metastases. Beyond first-line therapy, novel agents-including antibody-drug conjugates, bispecific antibodies, and T-cell engagers-have emerged as innovative options for pretreated patients with EGFR-mutated disease. Optimising the treatment sequence in advanced EGFR-mutated NSCLC is crucial to ensure the best survival outcomes along with the best treatment tolerance and quality of life. Predictive biomarkers are strongly needed as well as biomarker-based escalation and de-escalation clinical trials.