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

PURPOSE: Immune checkpoint blockers (ICB) 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. EXPERIMENTAL DESIGN: Liquid biopsy (LBx) assessment was performed using hybrid capture-based next-generation sequencing of plasma cell-free DNA. LBx data, molecular profile, and clinicopathologic data were collected. The predictive and prognostic values of tumor fraction (TF) were assessed using a deidentified nationwide (US-based) NSCLC clinicogenomic database [Clinico-Genomic Database (CGDB)]. An independent cohort with aNSCLC from Gustave Roussy was used to validate the findings and to study the correlation of circulating tumor DNA (ctDNA) TF and total metabolic tumor volume 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 chemoimmunotherapy, supporting its use as a biomarker to guide treatment intensification.