Brain metastases in patients with EGFR -mutated or ALK -rearranged non-small-cell lung cancers

Abstract

Introduction Brain metastases (BM) are common in non-small-cell lung cancer (NSCLC). However, the baseline incidence and evolution of BM over time in oncogene-driven NSCLCs are seldom reported. In this study, we evaluated the frequency of BM in patients with epidermal growth factor receptor (EGFR)-mutated or anaplastic lymphoma kinase (ALK)-rearranged NSCLC. Methods The presence of BM, clinicopathologic data, and tumor genotype were retrospectively compiled and analyzed from a cohort of 381 patients. Results We identified 86 EGFR-mutated (90.7% with metastatic disease; 85.9% received an EGFR inhibitor) and 23 ALK-rearranged (91.3% with metastatic disease; 85.7% received an ALK inhibitor) NSCLCs. BM were present in 24.4% of EGFR-mutated and 23.8% of ALK-rearranged NSCLCs at the time of diagnosis of advanced disease. This study did not demonstrate a difference in the cumulative incidence of BM over time between the two cohorts (EGFR/ALK cohort competing risk regression [CRR] coefficient of 0.78 [95% CI 0.44–1.39], p=0.41). In still living patients with advanced EGFR-mutated NSCLC, 34.2% had BM at 1 year, 38.4% at 2 years, 46.7% at 3 years, 48.7% at 4 years, and 52.9% at 5 years. In still living patients with advanced ALK-rearranged NSCLC, 23.8% had BM at 1 year, 45.5% at 2 years, and 58.4% at 3 years. Conclusions BM are frequent in advanced EGFR-mutated or ALK-rearranged NSCLCs, with an estimated >45% of patients with CNS involvement by three years of survival with the use of targeted therapies. These data point toward the CNS as an important unmet clinical need in the evolving schema for personalized care in NSCLC.

Emerging findings into molecular mechanism of brain metastasis

“…The incidence of BM in patients with ALK + NSCLC ranges from 20% to 30%, which could be compared with those observed in EGFR‐mutated NSCLC patients 69, 70. Furthermore, ALK‐rearranged NSCLC patients who have not treated with ALK therapy, exhibited a high incidence of CNS metastasis from approximately 45%‐70%, implying that BM is the most common pattern in ALK + NSCLC with therapy failure 71, 72.…”

Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity

“…However, penetration may be increased in patients with more advanced brain metastases where BBB disruption has already occurred (20)(21)(22). In addition, there is a cumulative increase in brain metastases incidence in patients with EGFRm NSCLC over time (23). Although many patients die of systemic progression, rather than brain lesion progression, quality of life is significantly worsened, both directly and as a result of whole brain radiotherapy (WBRT), which degrades cognitive function (24).…”

Cell-Cycle and DNA-Damage Response Pathway Is Involved in Leptomeningeal Metastasis of Non–Small Cell Lung Cancer

“…EGFR tyrosine kinase inhibitors (TKIs) have opened up an era of target therapy in NSCLC and markedly extended progression-free survival (PFS) of patients with EGFR-activating mutations (1-6). However, there have been reports of cumulative incidence of central nervous system (CNS) metastases over time (7,8). Diagnosis and treatment of leptomeningeal metastases (LM), a form of CNS metastases, remain particularly challenging.…”