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Multicenter Study
. 2025 Oct:208:108745.
doi: 10.1016/j.lungcan.2025.108745. Epub 2025 Sep 2.

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

Jarno W J Huijs  1 , Anna M Sadowska  2 , Juliette H R J Degens  3 , Christi M J Steendam  4 , Frederike Bensch  5 , Lucie B M Hijmering-Kappelle  5 , Tom M T de Schrevel  2 , Wouter H van Geffen  6 , Magdolen Youssef-El Soud  7 , Michelle M H Steens  8 , Cordula Pitz  9 , Dirk K M De Ruysscher  10 , Lizza E L Hendriks  11
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Free article
Multicenter Study

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

Jarno W J Huijs et al. Lung Cancer. 2025 Oct.
Free article

Abstract

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.

Keywords: Brain metastases; Immune checkpoint inhibitors; Non-small cell lung cancer; Risk factors; Screening.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jarno W.J. Huijs: Declares no competing interests. Anna M. Sadowska: Declares no competing interests. Juliette H.R.J. Degens: Declares no competing interests. Christi M.J. Steendam: Outside of this manuscript research funding: AstraZeneca, NVALT studies, ICON Clinical Research/Arcus Biosciences, VitroScan Leiden. Advisory: BMS, Johnson & Johnson Speaker educationals: MSD. Other: Lilly. Frederike Bensch: Declares no competing interests. Lucie B.M. Hijmering-Kappelle: Declares no competing interests. Tom M.T. de Schrevel: Declares no competing interests. Wouter H. van Geffen: Outside of this manuscript: Leadership: Fiduciary Officer for the NVALT (Dutch Society of Respiratory Physicians), IKNL medical adviser. Other interests: Site investigator for trials run by his department funded by Roche, Pfizer, Novartis, Novocure, and MSD. Magdolen Youssef-El Soud: Declares no competing interests. Michelle M.H. Steens: Declares no competing interests. Cordula Pitz: Declares no competing interests. Dirk K.M. De Ruysscher: Outside of the manuscript research grant/support/Advisory Board: Institutional financial interests (no personal financial interests) from AstraZeneca, BMS, BeiGene, Philips, Olink, Eli-Lilly. Lizza E.L. Hendriks: Research funding from Pfizer (paid to institution). Outside of this manuscript, research funding from: Roche Genentech, AstraZeneca, Boehringer Ingelheim, Takeda, Merck, Pfizer, Novartis, Gilead. Summit under negotiation, Amgen under negotiation (All payments were paid to the institution). Speaker educationals/webinars: AstraZeneca, Bayer, Lilly, MSD, high5oncology, Takeda, Janssen, GSK, Sanofi, Pfizer (Institution), Medtalks, Benecke, VJOncology, Medimix (self). Advisory boards: AbbVie, Amgen, Anhearth, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Daiichi, Gilead, GSK, Janssen, Lilly, Merck, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi, Summit Therapeutics, Takeda (All payments were paid to the institution). Member guideline committees: Dutch guidelines on NSCLC, brain metastases, and leptomeningeal metastases (payment to self), ESMO guidelines on metastatic NSCLC, non-metastatic NSCLC, and SCLC (non-financial). Other (non-financial): former secretary and current chair NVALT studies foundation, secretary EORTC metastatic NSCLC systemic therapy, vice-chair scientific committee Dutch Thoracic Group. local PI of clinical trials: AstraZeneca, GSK, Novartis, Merck, Roche, Takeda, Blueprint, Mirati, Abbvie(also steering committee), Gilead, MSD, Merck, Amgen, Boehringer Ingelheim, Pfizer, Daiichi, Amgen, BMS (All payments to institution).

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