CNS Disease Considerations and Implications for Treatment Selection for BRAF V600E-Mutant Metastatic NSCLC

This segment addresses one of the most challenging areas of lung cancer management: patients with baseline brain metastases. Because BRAF-mutant lung cancer is not particularly CNS-tropic, the incidence of brain metastases is lower than in EGFR- or ALK-positive disease, yet the issue remains clinically relevant.

Dr. Rotow explains that PHAROS included ~10% of patients with CNS involvement, but the study lacked data on untreated, active CNS lesions, the gold standard for evaluating CNS penetration of targeted therapies. This creates uncertainty when deciding whether to start systemic therapy alone or prioritize upfront radiation.

Given the absence of dedicated CNS response data for encorafenib/binimetinib in lung cancer, she recommends a nuanced approach:

• For small, asymptomatic lesions: systemic therapy may be reasonable, with earlyinterval MRI (4–6 weeks) and parallel radiation-oncology consultation.
• For symptomatic or high-risk lesions (brainstem involvement, extensive edema): she favors early stereotactic radiation before systemic therapy.

Both clinicians note that while melanoma data show CNS activity of BRAF/MEK inhibitors, these findings cannot be assumed to apply directly to NSCLC.

Dr. Dagogo-Jack stresses the need for future prospective CNS-specific research, though she acknowledges that such studies may be difficult due to the rarity of the disease. Multi-institutional collaboration may be the most feasible path.

The segment concludes with a reminder that CNS management remains highly individualized and that clinicians must balance the theoretical benefits of systemic therapy with the known reliability of radiation. Until more robust data become available, cautious optimism and close monitoring are essential.