Second-Line Sequencing After Osimertinib Progression in EGFR-Mutated NSCLC: COMPEL, TROPION-Lung, and MARIPOSA-2

Dr. Nagpal asks how Dr. Alder synthesizes the growing CNS evidence base for second-line therapy after osimertinib progression, referencing COMPEL, TROPION-Lung01 and TROPION-Lung05, MARIPOSA-2, and real-world sequencing data from ASCO 2026.

Dr. Alder frames the discussion with a marathon-versus-sprint analogy: selecting the next best treatment while preserving downstream options. Clinical trial enrollment remains the preferred first consideration.

COMPEL enrolled patients with non-CNS progression on osimertinib and added platinum-pemetrexed chemotherapy while continuing osimertinib, demonstrating a PFS benefit of 8.4 versus 4.4 months over first-line osimertinib alone, with signals of CNS protection even in patients without baseline brain metastases. MARIPOSA-2 provides the relevant option for patients who did not receive FLAURA2-based frontline therapy: amivantamab added to platinum-pemetrexed chemotherapy showed intracranial PFS of 12.5 versus 8.3 months versus chemotherapy alone, supporting meaningful blood-brain barrier penetration for amivantamab. Datopotamab deruxtecan from TROPION-Lung01 and TROPION-Lung05 is now FDA-approved for EGFR-directed and platinum-pretreated NSCLC, with an overall objective response rate of 45%, median PFS of 5.8 months, and intracranial objective response rate of approximately 22%. These results are promising but show room for improvement, particularly given the small CNS patient numbers.

Both panelists discuss the rationale for continuing osimertinib beyond CNS progression when systemic disease remains controlled, given its intracranial penetration advantage. Dr. Alder considers discontinuing osimertinib if progression has been rapid or recurrent in the CNS, or if the EGFR mutation is no longer detectable.