What is the recommended targeted therapy for non-small cell lung cancer (NSCLC) with brain metastasis, particularly for patients with EGFR (epidermal growth factor receptor), ALK (anaplastic lymphoma kinase), or ROS1 (c-ros oncogene 1) genetic mutations?

Targeted Therapy for NSCLC with Brain Metastasis

For patients with non-small cell lung cancer (NSCLC) with brain metastasis who have EGFR, ALK, or ROS1 genetic mutations, the recommended targeted therapy should be specific to the mutation type, with osimertinib being the preferred first-line treatment for EGFR-positive patients due to its superior CNS penetration and efficacy.

EGFR Mutation-Positive NSCLC with Brain Metastasis

• Osimertinib is the preferred first-line treatment for patients with EGFR-positive NSCLC with brain metastasis due to its superior blood-brain barrier penetration with CNS response rates >60% 1
• Osimertinib is FDA-approved for first-line treatment of metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations 2
• Other FDA-approved first-line options for EGFR-positive NSCLC include erlotinib, gefitinib, and afatinib (all category 1 recommendations), but osimertinib is preferred for patients with brain metastases 1
• For patients with T790M-positive disease who progress after first-line EGFR TKI therapy, osimertinib is indicated as subsequent therapy 2, 3
• In patients with ≥3 untreated brain metastases from EGFR-mutant NSCLC, the addition of EGFR TKIs to radiation therapy (WBRT or SRS) is suggested to improve OS, PFS, and intracranial PFS 3

ALK Rearrangement-Positive NSCLC with Brain Metastasis

• In patients with ALK mutation-positive NSCLC with untreated brain metastases, alectinib is recommended to delay the time to intracranial tumor progression (Level I evidence) 3
• Lorlatinib is recommended for patients with untreated brain metastases from ALK mutation-positive NSCLC to prolong intracranial tumor control and improve overall PFS (Level II evidence) 3
• For patients with ALK rearrangements whose disease progresses during or after first-line targeted therapy, recommended options include continuing crizotinib with local therapy, ceritinib, alectinib, or systemic chemotherapy regimens 3
• Crizotinib yields high response rates (>60%) in patients with ALK-positive NSCLC, including those with brain metastases 3

ROS1 Rearrangement-Positive NSCLC with Brain Metastasis

• Crizotinib is FDA-approved and recommended for patients with ROS1 rearrangements, with response rates of approximately 70%, including complete responses 3
• ROS1 rearrangements occur in approximately 1-2% of patients with NSCLC and are more common in younger women with adenocarcinoma who are never smokers 3
• For patients with ROS1 rearrangements whose disease becomes resistant to crizotinib, new agents are being studied, as alectinib and ceritinib are not effective in this population 3

Treatment Considerations and Sequencing

• Testing for EGFR mutations, ALK rearrangements, and ROS1 rearrangements is essential before initiating targeted therapy 3
• For patients with oligometastatic disease (1-3 brain metastases), consider definitive local therapy (stereotactic radiosurgery or surgery) in addition to targeted therapy 1
• Patients with multiple brain metastases, uncommon EGFR mutations, and liver metastases tend to have shorter overall survival 4
• Brain radiotherapy can delay intracranial disease progression but may not significantly impact overall survival when effective targeted therapies are available 4, 5
• Avoid PD-1/PD-L1 inhibitor monotherapy in EGFR-positive NSCLC as it shows inferior efficacy regardless of PD-L1 expression 1
• Data suggest that patients with EGFR mutations or ALK rearrangements have a low response rate to PD-1 or PD-L1 inhibitors compared with patients without these genetic alterations (response rate 3.6% vs 23%) 3

Common Pitfalls and Caveats

• Be cautious when using EGFR TKIs in combination with or following immune checkpoint inhibitors due to potential for increased adverse events, particularly pneumonitis 1
• For patients who progress on targeted therapy, rebiopsy is recommended to rule out transformation to small cell histology (occurs in ~5% of EGFR TKI-resistant tumors) 1
• Patients with KRAS mutations do not generally overlap with EGFR mutations, ALK rearrangements, or ROS1 rearrangements, and currently have limited targeted therapy options 3
• Genomic profiling has suggested genetic heterogeneity between brain metastases and primary tumor sites, which may affect treatment response 6
• Newer generation TKIs with improved CNS penetration have challenged the traditional approach of early radiotherapy in NSCLC patients with oncogenic driver mutations and brain metastases 7