Clinical risk factors for developing brain metastases during first-line (chemo-)immunotherapy in patients with non-small cell lung cancer without known baseline brain metastases.

Background: Brain metastases (BM) are common in non-small cell lung cancer (NSCLC). Although guidelines recommend baseline BM screening in asymptomatic patients, its benefit remains unproven. Routine imaging burdens healthcare systems and patients. Immune checkpoint inhibitors (ICI) show similar intra-and extracranial response percentages, supporting deferral of local BM treatment and possibly screening. However, dissociated responses occur. Therefore, patients newly diagnosed with BM during first-line ICI probably would have benefited most from baseline (and follow-up) screening. Identifying high-risk patients for BM progression or development during first-line ICI-based therapy is crucial to optimize screening.

Methods: Retrospective multicenter cohort study of patients with stage IV NSCLC without known baseline BM, treated with first-line (chemo-)ICI between 2018-2021. Incidence, timing, and symptom burden of newly diagnosed BM were analyzed. Cox regression identified predictive factors, and a nomogram was developed.

Results: Among 589 patients, BM were diagnosed during therapy in 9.0 %, 88.7 % occurred within the first year. Most cases (90.6 %) were symptomatic. Four factors predicted higher BM risk: age < 65 years (HR 2.66; 95 % CI: 1.49-4.74), T4 stage (HR 2.08; 95 % CI: 1.18-3.65), M1c stage (HR 2.19; 95 % CI: 1.22-3.94) and PD-L1 < 50 % (HR 2.03; 95 % CI: 1.16-3.54). The nomogram showed good performance (C-index 0.70). Twelve-month cumulative incidence was 11.7 % (95 % CI: 8.5-14.9 %).

Conclusion: BM detection during first-line (chemo-)ICI is relatively low in patients with stage IV NSCLC without known baseline BM, but the burden (symptoms) is high. Upon validation, the identified risk factors may support selective brain imaging in high-risk patients, avoiding routine screening in low-risk patients.