Sequencing Approaches for EGFR mutant NSCLC

When patients who started on frontline osimertinib require a systemic therapy change without evidence of histologic transformation or a secondary driver mutation, there are several treatment options to consider. One approach is switching from osimertinib to chemotherapy combined with targeted agents like an anti-MET antibody, which has shown superior efficacy in randomized studies compared to chemotherapy alone. However, these regimens come with increased toxicity, so careful patient monitoring and proactive management of side effects are essential. Another option includes quadruple-drug combinations that have demonstrated improved outcomes but also carry significant toxicity risks. For patients unable to tolerate these aggressive regimens, adding carboplatin and pemetrexed chemotherapy to ongoing targeted therapy may be a more manageable alternative.

Sequencing treatment becomes more nuanced when patients progress after receiving newer combinations such as the FLORE2 regimen. Regulatory approval and prior exposure to chemotherapy impact available options, sometimes making the use of docetaxel or immunotherapy the default but less appealing choices. Molecular testing remains critical in guiding treatment decisions, especially when MET amplification is detected. Recent phase three trial data show that adding MET inhibitors to treatment improves progression-free survival in patients with MET amplification, which encourages the use of oral targeted therapies in this subset. Despite their toxicity, these targeted agents can be modulated to reduce hospital visits and intravenous therapy burdens, improving patient quality of life.

In cases where patients start with frontline combinations like MARIPOSA, the strategy after progression involves repeating biopsy to rule out actionable resistance mechanisms. If no such mechanisms are identified, chemotherapy with carboplatin and pemetrexed remains a mainstay, with the added consideration of protecting the brain to prevent metastases. Newer EGFR TKIs with blood-brain barrier penetration play a vital role in this setting. Overall, personalized sequencing based on prior therapies, molecular profiling, and patient tolerance guides optimal treatment strategies while emphasizing vigilant toxicity management and supportive care.