Clinical Scenario 2: Frontline Treatment Selection for Metastatic EGFR-Mutated NSCLC with CNS Metastases

Dr. Kareff presents clinical scenario 2: a 68-year-old man, former light smoker (10 pack-years, quit 20 years prior), with a 2-month history of headaches and word-finding difficulty. Brain MRI demonstrates 3 small asymptomatic supratentorial lesions (largest 8 mm) consistent with metastases. Staging CT shows a 2.8 cm left upper lobe mass with ipsilateral mediastinal lymphadenopathy and a 1.2 cm adrenal nodule suspicious for metastasis. Tissue NGS confirmed on plasma ctDNA shows no T790M or other resistance alterations; PD-L1 TPS is 1%; EGFR testing was not performed at this time. Hemoglobin is 11.2 g/dL; renal and hepatic function are normal; LDH is 260 U/L. He is staged IVB (T2aN2M1c) adenocarcinoma, ECOG performance status 1, neurologically intact except for mild word-finding hesitancy, and is concerned about preserving cognition and independence.

Dr. Kareff identifies 3 NCCN-recommended frontline options for patients with confirmed sensitizing EGFR mutations: osimertinib monotherapy (increasingly reserved for patients with reduced performance status or contraindications to more intensive regimens), osimertinib plus platinum-pemetrexed (FLAURA2), and amivantamab plus lazertinib (MARIPOSA). He describes the presence of CNS metastases as making frontline selection more complex, noting that both FLAURA2 and MARIPOSA demonstrated CNS PFS benefit over osimertinib monotherapy, but with different brain MRI surveillance cadences that complicate direct comparison. He adds that molecular co-alterations identified on liquid biopsy, visceral metastasis sites including liver involvement, and other co-mutations further refine this decision.

Dr. Herbst suggests he would likely choose FLAURA2 for this patient, favoring osimertinib's established CNS penetrance combined with chemotherapy for more advanced disease. He agrees with Dr. Kareff that osimertinib monotherapy is no longer the preferred approach for fit, treatment-naive patients given the OS benefit from treatment intensification.