Brain metastases and mortality in patients with ALK + metastatic non-small cell lung cancer treated with second-generation ALK tyrosine kinase inhibitors as first-line targeted therapies: An observational cohort study

BACKGROUND: Brain metastases (BM) are common in patients with ALK + metastatic non-small cell lung cancer (mNSCLC). Limited contemporary real-world evidence exists on the burden of BM in these patients. This study estimated the cumulative incidence of BM in patients with ALK + mNSCLC treated with second-generation ALK tyrosine kinase inhibitors (TKI) as first-line (1L) targeted therapies and assessed the association between BM and mortality. MATERIALS AND METHODS: Using a 100 % sample of Medicare fee-for-service and Advantage beneficiaries from 2017 to 2022, patients > 65 years with ALK + mNSCLC (index date = 1L alectinib/brigatinib following lung cancer diagnosis) were identified. The cumulative incidence of BM was calculated, accounting for competing risk of death, overall and by age and race/ethnicity. To assess the association between BM and death, a time-varying Cox proportional hazards model compared the risk of death in those with incident, and baseline BM, separately, to those without BM, adjusting for confounders. RESULTS: In 1040 patients, 289 (28 %) had baseline BM. In 751 patients without baseline BM, the cumulative incidence of BM was 20 % after 5 years. After 4 years, the cumulative incidence of BM was highest in patients ≥ 85 years (25 %) and in non-White patients (23 %). Patients with incident BM had 2.6 times the risk of mortality compared to patients without BM (hazard ratio (HR): 2.59, 95 % confidence interval (CI): 1.98-3.38), while patients with baseline BM had 1.5 times the risk of mortality compared to patients without BM (HR: 1.46, 95 % CI: 1.20-1.77). CONCLUSIONS: Patients with ALK + mNSCLC treated with second-generation ALK TKIs as 1L targeted therapies faced a high burden of BM. Incident BM were associated with increased mortality risk to a greater extent than baseline BM. Efforts are needed to provide safe and efficacious approaches to prevention and treatment of BM, including additional monitoring as required, in patients with ALK + mNSCLC.