Investigational treatment strategies in glioblastoma: progress made and barriers to success.

INTRODUCTION: Glioblastoma, isocitrate dehydrogenase wildtype (IDHwt), remains an incurable disease despite considerable research effort. The current standard of care since 2005 comprises maximal safe resection followed by radiation with concurrent and adjuvant temozolomide; more recently, the addition of tumor treating fields was approved in the newly diagnosed and recurrent disease settings. AREAS COVERED: Searches of PubMed, Cochrane Library, and ClinicalTrials.gov provided a foundation for this review. We first describe early research including carmustine wafers, brachytherapy, anti-angiogenesis, and immune checkpoint inhibition for glioblastoma. Next, we discuss challenges precluding the translation of preclinical successes. This is followed by a description of promising treatments such as chimeric antigen receptor T-cell therapy as well as the recent qualified successes of cancer vaccinations. Non-immunotherapy trials are also highlighted, and ongoing or pending phase 2 and 3 clinical trials are codified in study tables. EXPERT OPINION: Unfortunately, hundreds of trials, including of agents effective in systemic malignancy, have not drastically changed management of glioblastoma. This may reflect unique resistance mechanisms and highlights a need for multimodality treatments beyond surgery, radiation, and conventional chemotherapy. Novel techniques, such as those in the emerging field of cancer neuroscience, may help uncover tolerable and effective regimens for this lethal malignancy.

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

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. Key Content and Findings: The development of effective, CNS-penetrant systemic agents-including alectinib, brigatinib, ceritinib, and lorlatinib-has dramatically changed the management and prevention of ALK rearranged brain metastases. Most notably, there is a burgeoning role for upfront systemic therapy for both symptomatic and incidentally discovered lesions. Conclusions: Novel targeted therapies offer patients a pathway to delay, obviate, or supplement traditional local therapies while minimizing neurologic sequelae of treatment and may reduce the risk of brain metastasis formation. However, the selection of patients to whom local and targeted treatments is offered is not trivial, and the risks and benefits of both must be weighed carefully. More work is needed to establish treatment regimens that yield durable intra- and extracranial disease control.