Brain metastases are a common complication in patients with EGFR-mutated non-small cell lung cancer (NSCLC), occurring in approximately one-fifth to one-quarter of patients. Many of these brain metastases are asymptomatic at diagnosis, often detected during routine screening MRIs. The management of brain metastases has evolved, with a shift away from modalities like whole-brain radiotherapy towards targeted therapies, particularly EGFR tyrosine kinase inhibitors (TKIs).
Efficacy of TKIs in CNS Metastases
Oral TKIs, such as osimertinib (Tagrisso) and lazertinib (Lazcluze), have shown significant efficacy due to their ability to penetrate the blood-brain barrier. Liza Villaruz, MD, of the UPMC Hillman Cancer Center in Pittsburgh, noted that disease within the brain responds very well to these oral TKIs.
Early clinical evidence supporting the use of osimertinib in central nervous system (CNS) metastases comes from the phase II AURA trial. This trial compared osimertinib with chemotherapy in patients with T790M-positive NSCLC who had progressed on first-line EGFR-TKIs. Patients treated with osimertinib experienced significantly improved progression-free survival (PFS) compared to those treated with chemotherapy (median PFS 8.5 vs 4.2 months). Pooled results from the AURA and AURA2 trials demonstrated a 54% response rate and a 92% disease control rate in patients with CNS disease.
The phase III AURA 3 trial further validated the utility of osimertinib for CNS metastases, reporting a CNS overall response rate of 70% among patients treated with osimertinib. More recently, the phase III FLAURA trial compared osimertinib with gefitinib (Iressa) or erlotinib (Tarceva) in patients with previously untreated advanced EGFR-mutated NSCLC. Results indicated a decreased CNS progression among patients assigned to osimertinib (6% vs 15%). The FLAURA2 trial showed that osimertinib plus chemotherapy delayed CNS progression compared with osimertinib alone, regardless of baseline CNS status.
The LASER301 study included a subset analysis examining CNS outcomes with lazertinib compared with gefitinib in treatment-naive advanced EGFR-mutated disease. Among patients with baseline CNS metastases, lazertinib significantly improved intracranial PFS (28.2 vs 8.4 months) and intracranial objective response rate (94% vs 73%).
Role of Radiotherapy and Treatment Sequencing
Despite the success of oral EGFR-TKI therapy, questions remain regarding whether it is sufficient as a standalone treatment or if certain patients may still benefit from upfront radiation in combination with oral therapy. A retrospective study involving 147 patients with EGFR- or ALK-positive disease compared outcomes in those who received a CNS-penetrant TKI alone versus in combination with radiation. The study found no significant differences in time to progression, time to intracranial progression, or time to treatment failure between the two groups.
Villaruz suggests reserving radiation as a salvage therapy rather than an upfront therapy, noting that patients can start on an oral TKI much sooner than they can start radiation. The ability to sequence therapies is crucial, as many patients with asymptomatic brain metastases can live longer with newer treatments. Delaying neurological morbidity associated with radiation can be beneficial later in the course of treatment.
A 2023 study revealed that recommendations for first-line management of asymptomatic brain metastases in EGFR-mutant disease varied among medical oncologists, clinical oncologists, radiation oncologists, and neurosurgeons. Medical and clinical oncologists were more likely to recommend first-line TKI therapy alone, while respondents from all specialties preferred radiation plus TKI for patients with four or more metastases.
Vamsidhar Velcheti, MD, of NYU Langone's Perlmutter Cancer Center, emphasized the importance of education for appropriate treatment. He noted that delays in genomic testing can lead to situations where patients receive whole-brain radiation without realizing they have an EGFR mutation. Velcheti recommends that patients see a medical oncologist as soon as possible, given that testing can take up to 2 weeks.
Patients with brain metastases who start on an EGFR-TKI alone should be closely monitored with MRIs, with additional follow-up based on the patient's symptoms. Villaruz advises patients to be mindful of any progressive neurological symptoms, such as headache, blurry vision, focal weakness, or confusion, and to seek immediate medical attention if these symptoms arise.
