Targeting lung cancer brain metastases: a narrative review of emerging insights for anaplastic lymphoma kinase (ALK)-positive disease

Abstract

Background and Objective: Lung cancer is commonly associated with brain metastasis formation, and certain subtypes, such as anaplastic lymphoma kinase (ALK) rearranged disease, have an especially high propensity for early and frequent central nervous system (CNS) involvement for which treatment can be challenging. Historical management has centered on surgery and radiation therapy (RT), which persist as mainstays of treatment for large, symptomatic lesions and widespread CNS disease. To date, sustained disease control remains elusive, and the role for effective systemic adjunctive therapies is clear. Here we discuss the epidemiology, genomics, pathophysiology, identification, and management of lung cancer brain metastases with a particular emphasis on systemic treatment of ALK-positive disease according to the best available evidence.Methods: Review of PubMed and Google Scholar databases as well as ClinicalTrials.gov provided background and seminal trials for the local and systemic management of ALK rearranged lung cancer brain metastases.

Current opportunities and challenges in ALK-positive lung cancer

“…Through the lens of ALK-positive lung cancer, we also take a deep dive into topics broadly relevant to oncogene-addicted tumors, including: (I) the biology and targeting of brain metastases ( 24 ); (II) lineage plasticity (e.g., epithelial mesenchymal transition and histologic transformation) ( 25 ); and (III) the barriers in harnessing immune responses [i.e., lack of benefit from anti-PD(L)1 immune checkpoint inhibition] and future directions for leveraging immunotherapy (e.g., ALK-directed vaccine approaches, adoptive cell therapy, oncolytic viruses) ( 26 ). Each of these topics currently represents a major scientific and therapeutic bottleneck, relevant across oncogene-addicted lung cancers, and we anticipate that breakthroughs therein will move the needle on patient outcomes.…”