Risk Stratification for Treatment Intensification in EGFR-Mutated Non-Small Cell Lung Cancer: TP53, ctDNA, and the TOP Trial

Dr. Leal discusses the clinical and molecular features most useful for identifying patients likely to benefit from frontline treatment intensification in EGFR-mutated NSCLC. Across FLAURA2 and MARIPOSA, patients with TP53 co-mutations, positive baseline circulating tumor DNA (ctDNA), baseline brain metastases, and EGFR L858R mutation status, which are all associated with worse prognosis on monotherapy, consistently derived benefit from combination strategies, reinforcing the relevance of these markers for treatment selection.

She highlights the TOP trial presented at ELCC 2026, a Chinese phase 3 study specifically designed to evaluate osimertinib plus chemotherapy versus osimertinib monotherapy in patients with TP53 co-mutations. The trial demonstrated median PFS of 34 months with the combination versus 15.6 months with monotherapy, a trend toward improved OS, and meaningfully prolonged duration of response (32.7 versus 15 months). No new safety signals emerged, and as in FLAURA2, patients experienced an extended chemotherapy-free interval after completing induction therapy and transitioning to pemetrexed maintenance, then osimertinib alone.

Dr. Leal considers these data, spanning FLAURA2, MARIPOSA, and now TOP, as collectively supportive of identifying TP53 co-mutations upfront to guide patients with this feature toward combination therapy. She notes that uncertainty remains regarding which specific patient subgroups may benefit preferentially from the FLAURA2 (osimertinib-chemotherapy) versus MARIPOSA (amivantamab-lazertinib) approach, an area still requiring further clarification.