Broadening clinical trial inclusivity of patients with lung cancer and brain metastases utilizing the Graded Prognostic Assessment (GPA): A call to action.

Brain metastases (BM) occur in 30-50% of non-small cell lung cancer (NSCLC) and up to 80% of small cell lung cancer (SCLC) patients, yet historically over 80% of clinical trials excluded this population. Current eligibility requirements often mandate completion of radiation therapy with prolonged washout periods, delaying systemic therapy initiation and limiting trial generalizability. Despite recommendations from ASCO-Friends of Cancer Research and FDA guidance, only 11.4% of lung cancer trials include patients with active, untreated BM. We propose incorporating the Graded Prognostic Assessment (GPA) to standardize and broaden clinical trial enrollment. The 2022 Lung GPA, validated in 4,183 patients, incorporates age, Karnofsky Performance Status, extracranial metastases, number of BM, and molecular markers (EGFR, ALK, PD-L1 for NSCLC). The GPA-based Eligibility Quotient (EQ) uses conditional probability to determine trial eligibility for patients with previously treated BM. We recommend including patients with GPA-predicted median survival ≥ 12 months or EQ ≥ 0.50. For asymptomatic, untreated BM, enrollment should be permitted with protocol-specified CNS imaging at 4-6-week intervals, reserving radiation for progression or inadequate response. Trials should stratify by GPA category, specify RANO-BM or modified RECIST criteria prospectively, and report both full analysis sets and evaluable CNS disease subsets. This evidence-based framework ensures patients with BM gain timely access to potentially life-extending therapies while maintaining trial integrity.