Second-Line Treatment Decision-Making

Following osimertinib monotherapy progression without CNS involvement, clinicians choose between COMPEL (continuing osimertinib plus chemotherapy) and MARIPOSA-2 (amivantamab plus chemotherapy without osimertinib continuation).

Dr. Lopes analyzes the evidence hierarchy, noting stronger evidence for MARIPOSA-2 with over 600 patients in a fully-powered study versus COMPEL's under 100 patients in an early-stopped trial. MARIPOSA-2 was restricted to non-CNS progression patients, creating different population characteristics.

Despite stronger methodological evidence for MARIPOSA-2, Dr. Lopes pragmatically favors adding chemotherapy to continued osimertinib, acknowledging this represents their frontline bias confirmation. Most patients receive chemotherapy addition rather than the amivantamab-chemotherapy combination.

Dr. Devarakonda prioritizes continuing tyrosine kinase inhibition due to disease flare risks when discontinuing EGFR inhibitors, particularly CNS progression including leptomeningeal disease. He favors carboplatin-pemetrexed addition to osimertinib as the most convenient and familiar approach.

Dr. Rotow balances the stronger evidence for MARIPOSA-2 against real-world patient considerations including continued EGFR inhibitor benefits. For patients with extensive CNS involvement or leptomeningeal disease, she strongly favors COMPEL to maintain tyrosine kinase inhibitor coverage. For indolent progression with continued TKI benefit, chemotherapy addition may suffice, while aggressive progression warrants the full MARIPOSA-2 approach.

Dr. Levy notes improved tolerability with second-line amivantamab-chemotherapy combinations compared to frontline experiences, particularly with subcutaneous formulations, though acknowledging ongoing challenges requiring careful patient selection and monitoring.