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Brain metastases are a common problem in patients with EGFR-mutated non-small cell lung cancer (NSCLC), . Many brain metastases will be asymptomatic at diagnosis.

"Brain metastases are very often detected on screening MRI, which is part of the standard work-up for patients with suspected metastatic NSCLC of any type, and particularly EGFR-mutated NSCLC," said Liza Villaruz, MD, of the UPMC Hillman Cancer Center in Pittsburgh.

Historically, management of brain metastases might incorporate local resection, stereotactic radiosurgery, or whole-brain radiotherapy. However, in the last decade treatment has moved away from some of these modalities, particularly whole-brain radiotherapy, thanks to the efficacy of EGFR tyrosine kinase inhibitors (TKIs).

"The silver lining, so to speak, is that disease within the brain responds very well to oral TKIs like osimertinib [Tagrisso] or lazertinib [Lazcluze], which is reflective of their penetrance across the blood-brain barrier," said Villaruz.

If a patient with EGFR-mutated disease presents with asymptomatic brain metastases, they will most likely be started immediately on an oral EGFR-TKI, explained Vamsidhar Velcheti, MD, of NYU Langone's Perlmutter Cancer Center in New York City.

CNS Penetration

Early clinical evidence showed the activity of osimertinib for central nervous system (CNS) metastases. The phase II AURA trial compared osimertinib with chemotherapy in patients with T790M-positive NSCLC who had progressed on first-line EGFR-TKIs. Patients assigned to osimertinib had significantly improved progression-free survival (PFS) compared with chemotherapy and those PFS benefits extended to patients with CNS metastases (median PFS 8.5 vs 4.2 months). showed that patients with CNS disease had a response rate of 54% and a 92% disease control rate.

The phase III AURA 3 trial further confirmed the with 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 showed a decreased CNS progression among patients assigned osimertinib (6% vs 15%). FLAURA2 showed that osimertinib plus chemotherapy compared with osimertinib alone, regardless of baseline CNS status.

Finally, included a subset analysis looking at CNS outcomes with lazertinib compared with gefitinib in treatment-naive advanced EGFR-mutated disease. Among these 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

Despite these excellent results, questions still remain whether the use of oral EGFR-TKI therapy alone is sufficient, or if certain patients may still require upfront radiation in combination with oral therapy.

compared outcomes in 147 patients with EGFR- or ALK-positive disease who received a CNS-penetrant TKI alone versus in combination with radiation. The researchers identified no significant differences for time to progression, time to intracranial progression, or time to treatment failure between patients who did or did not receive radiation.

"Patients can be started on an oral TKI much sooner than they can start radiation," Villaruz said. "I do tend to reserve radiation as a sort of salvage therapy rather than upfront therapy."

Many patients with asymptomatic brain metastases are able to live a long time with newer therapies. That means a clinician's ability to sequence therapies is important.

"The neurological morbidity associated with radiation can be delayed for later in the course of treatment," Villaruz said.

Interestingly, showed that recommendations related to first-line management of asymptomatic brain metastases in EGFR-mutant disease varied according to specialty. Researchers surveyed medical oncologists, clinical oncologists, radiation oncologists, and neurosurgeons on treatment recommendations in this patient group. Medical and clinical oncologists were more likely to recommend first-line TKI therapy alone. For patients with four or more metastases, respondents from all specialties preferred radiation plus TKI.

"Appropriate treatment requires a lot of education," Velcheti said. "Unfortunately there are times, even in large academic centers, where a patient presents with brain metastases and genomic testing may not be back. If they see a radiation oncologist first, there may be situations where they get whole-brain radiation without realizing that they have an EGFR mutation."

Because testing can take up to 2 weeks, Velcheti said it is important that patients see a medical oncologist as soon as possible.

Patients with brain metastases started on an EGFR-TKI alone will be monitored closely with MRIs, with additional follow-up prompted by the patient's symptomology.

"We make sure that the patient is mindful of any progressive neurological symptoms -- headache, blurry vision, focal weakness, confusion," Villaruz said. "These are all warning signs to call a physician and go to the ED immediately."

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