Clinical Scenario: CNS-Only Progression on Osimertinib in EGFR-Mutated NSCLC

Dr. Nagpal presents a 58-year-old female non-smoker with stage IVB lung adenocarcinoma, EGFR L858R mutation, and TP53 co-mutation who maintained partial systemic response on first-line osimertinib for approximately 3.5 years. Routine brain MRI identifies four new CNS lesions: right temporal lobe 17 mm, left frontal lobe 13 mm, left parietal lobe 11 mm, and one non-target left cerebellar lesion under 10 mm. There are no new systemic lesions. Liquid biopsy confirms persistent EGFR L858R with no additional actionable mutations, performance status is ECOG 1, the patient is asymptomatic from her CNS lesions, and she has no prior brain radiation.

Dr. Alder highlights several key case features: the detection of small, asymptomatic lesions through routine surveillance, which expands the range of better-tolerated treatment options, and the importance of repeated genomic testing given the frequency of acquired resistance mutations on targeted therapy. She rules out small cell transformation (which would require tissue biopsy) given the non-rapid progression pattern. For this patient with multiple small lesions, good performance status, and no prior brain radiation, she favors stereotactic radiosurgery (SRS), emphasizing to patients that SRS is radiation, not surgery, that is highly precise and well-tolerated. She advocates strongly against whole brain radiation and notes SRS is now supported by evidence for up to approximately 20 lesions. Following focal CNS treatment, she would continue osimertinib monotherapy, reserving systemic escalation for the next progression event.

Dr. Nagpal agrees with this approach and raises the FLAURA2 data as supporting consideration of adding chemotherapy at this juncture. Dr. Alder emphasizes multidisciplinary discussion involving neurosurgery, neuro-oncology, radiation oncology, and medical oncology, and encourages second opinions regarding access to optimal radiation technology. Clinical trial enrollment at any treatment transition is highlighted as a priority.