Who Truly Benefits From First-Line Intensification in EGFR-Mutant NSCLC?

The treatment landscape for advanced non-small cell lung cancer (NSCLC) with common EGFR mutations has evolved significantly, with osimertinib established as the first-line standard. Two recent phase III trials, FLAURA2 and MARIPOSA, demonstrated that first-line intensification-through osimertinib plus chemotherapy or amivantamab-lazertinib-significantly prolongs overall survival compared to osimertinib alone. The aim of this review was to critically assess whether treatment intensification should be adopted as a new standard and, if so, in which patients.

We identified high-risk subgroups more likely to benefit from upfront combination strategies, such as those with brain or liver metastases, L858R mutations, TP53 co-mutations, or detectable ctDNA. However, the improved efficacy comes with increased rates of grade ≥ 3 adverse events and treatment discontinuation, raising concerns about tolerability and quality of life (QoL), particularly in real-world settings with frailer patients. Post-progression strategies are also evolving and may impact the long-term value of upfront intensification. Emerging approaches, including targeted and untargeted therapies, and novel antibody-drug conjugates (ADCs), offer promising alternatives that may change future treatment options. Careful patient selection, improved toxicity management, and integration of QoL measures will be critical to ensure that the survival advantage demonstrated in trials can translate into true benefit in routine clinical practice. Future research should focus on identifying robust clinical and molecular markers to guide personalized treatment decisions.