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

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.

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.

Of 223 included trials, 52 (23%) excluded all patients with preexisting BrM while 124 (56%) permitted enrollment of patients with BrM under certain conditions, the most common being stable/nonprogressing BrM (n = 83, 67%), prior treatment for BrM (n = 62, 50%) and lack of neurologic symptoms (n = 49, 40%). Exclusion of patients with BrM decreased over 5-year increments from 2000 to 2019 (P = .006); for example, 8 of 16 studies (50%) in 2000 through 2004 excluded patients with BrM, compared with 3 of 27 studies (11%) in 2015 through 2019. Factors associated with exclusion of patients with BrM are outlined in Table 1. There was no association between inclusion of patients with brain metastases in trials and reporting of CNS-specific end points.

Of 223 trials, CNS-specific outcomes were evaluated in 13 (6%; 95% CI, 3.1-9.5) studies. The most commonly reported CNS-specific outcomes included the presence vs absence of CNS progression (7 of 13, 54%), time to CNS progression (7 of 13, 54%), CNS-specific response (4 of 13, 31%), and duration of CNS response (3 of 13, 23%). Among studies that included CNS-specific outcomes, there was considerable heterogeneity in the selection and definition of these end points. Only 2 studies (15%) addressed the effect of systemic therapy on neurologic quality of life and only 1 study assessed neuro-cognition.

The majority of phase 3 clinical trials for patients with advanced breast cancer, lung cancer, and melanoma excluded or restricted enrollment of patients with BrM. Furthermore, collection of CNS-specific outcomes is rarely specified in trial protocols, highlighting challenges (Table 2) in assessing CNS response to systemic therapies.

Because this study involved a search of the ClinicalTrials.gov website, it does not capture reporting of CNS-specific outcomes as part of exploratory analyses in future publications. Whether trials appropriately excluded patients with brain metastases (eg, based on the clinical study purpose) also is not captured. Nevertheless, in accordance with recommendations from the American Society of Clinical Oncology and Friends of Cancer Research, patients with treated and/or stable BrM should be routinely included in clinical trials of all phases, while patients with active BrM should be evaluated for inclusion based on specified criteria.^3,4 Unfortunately, several potential barriers to including patients with BrM in clinical trials exist; examples derived from the experience of individual experts and the Response Assessment in Neuro-Oncology (RANO) group^5,6 are provided in Table 2.

It is notable that varying definitions of CNS-specific end points were used across included trials. For example, 3 different criteria were used to evaluate CNS-specific response (Response Evaluation Criteria in Solid Tumors 1.1, World Health Organization, and RANO-BM criteria), which differ with respect to the definition of target lesions, the maximum number of target lesions in the brain, and the definition of progression vs response. It is important to unify the definitions of CNS-specific end points across trials, particularly in the modern era of stereotactic radiosurgery and immunotherapy. Finally, since CNS-penetrating systemic therapies may impact neurologic-specific quality of life and neurocognition, efforts must be made to measure these patient-reported outcomes using validated tools.

Accepted for Publication: March 29, 2021.

Published Online: May 20, 2021. doi:10.1001/jamaoncol.2021.1359

Corresponding Author: Katarzyna J. Jerzak, MD, MSc, Department of Medicine, University of Toronto, 2075 Bayview Ave, Room T2 045, Toronto, ON M4N 3M5, Canada (katarzyna.jerzak@sunnybrook.ca).

Author Contributions: Dr Jerzak had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Corbett, Sharma, Sahgal, Jerzak.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Corbett, Sharma, Pond, Sahgal, Jerzak.

Critical revision of the manuscript for important intellectual content: Pond, Brastianos, Das, Sahgal, Jerzak.

Statistical analysis: Corbett, Pond, Sahgal, Jerzak.

Obtained funding: Sahgal.

Administrative, technical, or material support: Sharma, Brastianos, Sahgal, Jerzak.

Supervision: Brastianos, Das, Sahgal, Jerzak.

Conflict of Interest Disclosures: Dr Pond reported personal fees from Takeda, AstraZeneca, Merck, and Profound Medical outside the submitted work, as well as Independent Data Monitoring Committee (IDMC) membership for Takeda; and a family member who is an employee of Roche Canada Ltd, and who owns stock in Roche. Dr Brastianos reported personal fees from Angiochem, Genentech-Roche, Eli Lilly, Tesaro, Voyager Therapeutics, ElevateBio, Pfizer, Array, SK Life Sciences, Dantari, and Merck, and grants from Merck, Eli Lilly, and Mirati outside the submitted work. Dr Das reported serving as CNS Tumour Lead for Cancer Care Ontario, speaker fees from Society for NeuroOncology, American Association of Neurological Surgery, Congress of Neurological Surgeons, personal fees from Subcortical Surgery Group Advisory Board, nonfinancial support from Xpan Medical Advisory Board, and grants from Medicenna and Alkermes outside the submitted work. Dr Sahgal reported advisory and consulting fees from Varian, Elekta (Gamma Knife Icon), and BrainLAB; grants from Elekta AB and Varian, personal fees from Elekta, Varian, and BrainLAB; honoraria from AstraZeneca, Elekta AB, Varian, BrainLAB, and Medtronic Kyphon; board membership for the International Stereotactic Radiosurgery Society and AO Spine Knowledge Forum Tumor; and membership to the Elekta MR Linac Research Consortium, Elekta Spine, Oligometastases and Linac Based SRS Consortia. Dr Jerzak reported personal fees from Amgen, AstraZeneca, Apo Biologix, Eli Lilly, Esai, Genomic Health, Knight Therapeutics, Merck, Myriad Genetics Inc, Pfizer, Roche, Novartis, and Purdue Pharma, and grants from AstraZeneca and Eli Lilly outside the submitted work. No other disclosures were reported.

Additional Contributions: We would like to thank Hany Soliman, MD, and Danilo Giffoni, MD, for their feedback on the manuscript. Neither was compensated for their work on this manuscript.