Role of ctDNA Tumor Fraction in Selecting Immunotherapy-Based Regimens in Advanced Non–Small Cell Lung Cancer

作者：Filippo Gustavo Dall’Olio, Wael Zrafi, Damien Vasseur, Camilo Garcia, Kristi Beshiri, Arianna Marinello, Marco Tagliamento, David Planchard, Nathalie Lassau, Damien Drubay, Aaron Mamann, Lama Dawi, Littisha Lawrance, Ludovic Lacroix, Fabrice Barlési, Daniel Gautheret, Étienne Rouleau, Désirèe Deandreis, Amaya Gascó Hernández, Lincoln W. Pasquina, Antoîne Italiano, Geoffrey R. Oxnard, Russell W. Madison, Benjamin Besse · 发表于：Clinical Cancer Research · 年份：2026 · DOI：10.1158/1078-0432.ccr-25-3917 · 研究领域：Cancer Immunotherapy and Biomarkers、Lung Cancer Treatments and Mutations、Lung Cancer Research Studies

BACKGROUND: Immune checkpoint blockers (ICBs) have transformed advanced non-small cell lung cancer (aNSCLC) treatment, but identifying patients who benefit from adding chemotherapy remains challenging, especially in PD-L1 ≥ 50%. PD-L1 is an imperfect biomarker, highlighting the need for better selection tools. METHODS: Liquid biopsy (LBx) assessment was performed using hybrid capture-based next-generation sequencing of plasma cell-free DNA. LBx data, molecular profile, and clinico-pathological data were collected. The predictive and prognostic values of tumor fraction (TF) were assessed using a de-identified nationwide (US-based) NSCLC clinicogenomic database (CGDB). An independent cohort with aNSCLC from Gustave Roussy was used to validate the findings and to study the correlation of ctDNA tumor fraction and total metabolic tumor volume (tMTV) and its molecular correlates. RESULTS: In the CGDB Database (n=965), elevated ctDNA TF was prognostic for worse outcomes on ICBs and, when ≥5%, predictive of benefit from ICB+chemotherapy (HR for real-world progression-free survival 0.58 [0.41-0.82], p=0.002). The 5% cutoff for TF was validated in an independent cohort from Gustave Roussy. In 283 patients with paired PET scans, ctDNA TF correlated with metabolic tumor volume (rho=0.46, p<0.001) and was influenced by TP53/RB1 mutations. CONCLUSIONS: ctDNA TF integrates disease burden and biology. Patients with high ctDNA TF derive greater benefit from chemo-immunotherapy, supporting its...