Clinical Case 2: Managing CNS Metastases in EGFR-Mutated NSCLC — Frontline Regimen Selection and Role of SRS

Dr. Riess presents a 55-year-old male former light smoker with stage IV EGFR L858R adenocarcinoma, ECOG performance status 1, three small asymptomatic brain metastases (largest 8 mm) on baseline brain MRI, no TP53 or other high-risk co-mutation, employed as a remote software engineer with concern about preserving cognitive function and work capacity.

Dr. Gumbleton confirms that the presence of small asymptomatic brain metastases does not substantially alter his frontline treatment approach, because he considers treatment-naïve patients with EGFR-mutated NSCLC uniformly at high risk for CNS disease progression over the course of their illness. He would not offer osimertinib monotherapy as a standard-of-care option for any treatment-naïve patient who is young and otherwise healthy in 2026, given the OS benefit from treatment intensification. He would discuss both amivantamab-lazertinib and osimertinib plus carboplatin-pemetrexed with this patient and select based on shared decision-making.

Regarding stereotactic radiosurgery (SRS) for the three asymptomatic brain metastases, Dr. Gumbleton favors initiating systemic therapy first given the high intracranial response rates with both intensified regimens (exceeding 80%), which are comparable to SRS local control rates for small lesions. He notes that SRS complicates subsequent interpretation of brain MRI by raising questions of radiation necrosis versus progression, whereas starting with highly active systemic therapy provides a cleaner readout. Radiation oncologists at his institution often prefer to hold systemic therapy during SRS, creating an unnecessary delay; initiating systemic therapy allows immediate treatment of both CNS and systemic disease. SRS would be reconsidered if the expected intracranial response is not achieved on systemic therapy. Dr. Riess agrees that small asymptomatic brain metastases warrant close MRI surveillance on systemic therapy rather than reflexive upfront radiation in this context.