Clinical Case 2 Continued: Second-Line Therapy Selection and CNS Management in ROS1-Positive Advanced Non-Small Cell Lung Cancer After Solvent-Front Resistance

For the patient with a G2032R resistance mutation and intracranial progression, the panel unanimously favors lorlatinib-based therapy in second line based on its known activity against solvent-front mutations and documented CNS penetrance, with median duration of response of approximately 7 to 8 months in this setting. Repotrectinib also has activity against G2032R and is considered; however, its dosing titration requirement and neurological adverse effects (dizziness, cognitive symptoms) cause particular hesitation when CNS disease is already present and symptomatic overlap could confuse clinical assessment.

For 3 small, asymptomatic intracranial lesions with available CNS-active systemic therapy, the panel agrees to defer radiation and initiate second-line systemic therapy first, with repeat brain MRI within 6 weeks of starting the new agent to assess CNS response. If intracranial disease is stable or responding, radiation may be deferred further. If disease is progressing despite systemic therapy, focal SRS is preferred over whole brain radiation, consistent with the panel's general approach to minimize neurocognitive toxicity. For patients with brain metastases at baseline, the panel follows MRI every 3 months; for those without baseline CNS disease, every 6 months is minimum, without waiting for symptoms given that small lesions at 3 mm are not clinically detectable but may be imaged and treated meaningfully with modern SRS technology.

Dr. Rodriguez references a randomized trial from India comparing early versus delayed radiation in patients receiving systemic therapy, noting the difference between EGFR-mutated NSCLC (where the data were primarily generated) and ROS1-positive NSCLC may be meaningful, and that in settings with access to MRI surveillance and modern SRS, the panel favors systemic therapy first with selective, delayed radiation.