Abstract PS5-02-17: Assessment of phase iii/iv randomized clinical trials including patients with symptomatic brain metastases: a systematic review

Abstract Background: Brain metastases (BrM) are a common neurologic complication of advanced malignancy. However, clinical trials often exclude patients with symptomatic disease, limiting enrollment opportunities for this population. Therefore, we sought to determine the proportion of phase III/IV breast cancer, lung cancer, and melanoma clinical trials that excluded patients with “symptomatic” BrM and evaluate which trials clearly defined the “symptomatic” phenotype. Methods: A search was conducted in June 2024 and updated in May 2025 using the publicly accessible Clinicaltrials.gov website. Results were screened to include phase III/IV systemic therapy trials for patients with advanced breast cancer, lung cancer, and melanoma. Trial characteristics were abstracted by two independent reviewers. Enrollment criteria were analyzed for the exclusion of patients with “symptomatic” brain or central nervous system metastases. Various employed definitions of the “symptomatic” phenotype were collected. Results: A total of 356 lung cancer, breast cancer, and melanoma trials were analyzed. 58.4%(n=208) of trials allowed conditional enrollment of patients with BrM, with symptom status comprising the conditional criteria for 46.2% (n=96) of these trials. Trial protocols were available and reviewed for 89 studies to better characterize requirements related to symptom status. Ultimately, 83.3% (n=80/96) of trials failed to mention specific neurological manifestations, and only stated that patients must not be “symptomatic”. Of the remaining trials that provided criteria above and beyond “symptomatic”, 87.5% (n=14/16) required patients to be “neurologically stable” without further clarification and 12.5% (n=2/16) mandated a lack of cerebral edema and/or shift. Furthermore, of the 96 trials allowing enrollment of patients with symptomatic BrM, 12.5% (n=12/96) excluded patients requiring anti-convulsant medications and 14.6% (n=14/96) excluded patients taking steroids; an additional 40.6% (n=39/96) of trials had stipulations regarding steroid use, with 87.2% (n=34/39) mandating time restrictions on steroid administration prior to trial commencement and 38.5% (n=15/39) requiring specific steroid dosing to meet eligibility. Conclusion: Most randomized phase III/IV clinical trials with enrollment stipulations surrounding symptom status associated with BrM failed to define the symptomatic phenotype, and no trials provided explicit disease manifestations that would warrant trial exclusion. This broad terminology threatens the eligibility of a high proportion of patients with BrM for clinical trials. Clinical trials should incorporate clear, standardized definitions of symptom status to prevent the unwarranted exclusion of patients with mild and/or improving symptoms related to BrM, thereby increasing consistency across trials and enabling better cross-comparison of results. Citation Format: C. M. Zatzman, I. Kojundzic, J. Han, A. Van Swearingen, H. Tawbi, K. J. Jerzak. Assessment of phase iii/iv randomized clinical trials including patients with symptomatic brain metastases: a systematic review [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-02-17.