Central Nervous System–Specific Outcomes of Phase 3 Randomized Clinical Trials in Patients With Advanced Breast Cancer, Lung Cancer, and Melanoma

Abstract

Brain metastases (BrM) are among the most common neurologic complications of cancer. In fact, up to 40% of patients with a metastatic malignant tumor will develop BrM during their lifetime. 1 Historically, patients with BrM have been excluded from clinical trials due to concerns about poor prognosis and increased risk of neurologic toxic effects. 2 This has resulted in a scarcity of evidence for the efficacy of systemic therapies in the central nervous system (CNS). Our objective was to determine the proportion of phase 3 clinical trials investigating a systemic therapy intervention for patients with metastatic breast cancer, lung cancer, and melanoma that included patients with BrM and/or evaluated CNS-specific end points.Methods | A search was conducted on January 19, 2020, using the online, publicly accessible ClinicalTrials.gov database to identify eligible studies. Details regarding search terms, inclusion/exclusion criteria, and statistical methods are outlined in the Supplement. Patient consent was waived due to the deidentified nature of the data analyzed. The Sunnybrook Health Sciences Centre Research Ethics Board determined that ethical review was not required for the use of publicly available data.

Brain Metastases in HER2-Positive Breast Cancer: Current and Novel Treatment Strategies

“…Even more difficult is the evaluation of patients with a leptomeningeal disease, since the nature of the condition and the variety of symptoms hamper objective radiological size measures and reproducibility [75]. As evidence informing the intracranial activity of the new TKIs and ADC grows, clinical trials no longer exclude patients with BM by default, although enrollment of patients with progressive BM is still uncommon [76]. In the same spirit, the FDA issued a guidance for the industry last year, encouraging the inclusion of patients with BM, with some reservations for investigational drugs expected to have CNS toxicity (Guidance document, cancer clinical trial eligibility criteria: brain metastases, July 2020.…”

Efficacy of tyrosine kinase inhibitors for the treatment of patients with HER2-positive breast cancer with brain metastases: a systematic review and meta-analysis

“…Of note, brain-specific outcomes are rarely reported in clinical trials and, often, their collection is not specified in study protocols, highlighting challenges in assessing brain-specific response to systemic therapies. 39 It would be of paramount importance to unify the definitions of brain-specific endpoints across clinical trials, particularly in the modern era of target therapies. 39 By contrast, our study has the strength of being a large meta-analysis including a homogeneous population of 2437 patients with HER2-positive MBC from five RCTs that assessed the relevant topic of evaluating the efficacy of a class of agents (TKIs) in patients with BM, who have a dismal prognosis and represent a huge challenge of modern oncology.…”

“…These and other studies may drive changes in treatment paradigms and expand the role of systemic therapies in CNS disease control with the goal of achieving more effective and better tolerated treatment options for patients with a condition still associated with high morbidity and mortality. Finally, limited CNS activity of systemic therapies is not only determined by impaired drug delivery to the brain, 39 but also by differences in underlying tumor biology and tumor microenvironment. 40-42 Initiatives that aim to better understand the risk factors, clinical behavior, and biology of BM as proposed by some prospective trials and clinical research platforms (NCT04109131, NCT04030507, NCT03617341) will provide key elements for the development of new treatment strategies for patients with BM.…”

Subsequent treatments beyond progression on osimertinib in EGFR-mutated NSCLC and leptomeningeal metastases

“…Leptomeningeal metastasis (LM) is a complication of deeper concerns due to its increasing incidence rate, limited treatment options, and dismal survival outcomes in patients with EGFR -mutated non-small cell lung cancer (NSCLC) [ 1 ]. One major obstacle is the exclusion of patients with LM in most clinical trials [ 2 ]. Even though osimertinib has been proved to be effective for patients with EGFR -mutated LM, treatment after progression on osimertinib is still limited [ 3 – 5 ].…”