127 - Mid-Treatment ctDNA to Predict Outcomes in Stage IIB-IIIC NSCLC Treated with MRI-Adapted Chemoradiation
Presenter(s)
A. Hashmi1, P. S. Chauhan1, R. Ben-Shachkar2, K. Parikh3, N. P. Semenkovich4, A. S. Mansfield3, S. S. Park1, K. Olivier1, D. Owen1, D. Morgensztern5, R. Govindan5, C. G. Robinson6, S. Waqar5, P. Samson6, G. R. Vlacich7, and A. A. Chaudhuri1; 1Department of Radiation Oncology, Mayo Clinic, Rochester, MN, 2Tempus AI, Chicago, IL, 3Department of Medical Oncology, Mayo Clinic, Rochester, MN, 4Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, 5Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, 6Washington University School of Medicine in St. Louis, Department of Radiation Oncology, St. Louis, MO, 7Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO
Purpose/Objective(s):
Mid-chemoRT circulating tumor DNA (ctDNA) measurement could be a powerful tool for assessing early therapeutic response and informing treatment strategies in patients with inoperable stage IIB-IIIC non-small-cell lung cancer (NSCLC). We performed Tempus xF, a commercially available liquid biopsy assay that detects cancer-associated mutations across 105 genes in plasma cell-free DNA, to explore the potential for ctDNA levels to predict treatment outcomes, with the goal of integrating these biomarkers into radiation oncology clinical practice.Materials/Methods:
We conducted a prospective single-arm phase II clinical trial evaluating MRI-guided hypofractionated RT with intermittent adaptation combined with concurrent chemotherapy and consolidation durvalumab in 26 NSCLC patients. ctDNA analysis was performed across the full cohort with Tempus xF. Pre- and mid-chemoRT ctDNA levels were quantified by measuring the maximum variant allele frequency (max VAF) of nonsynonymous variants, and then further stratified into ctDNA high vs. low groups by median-splitting by max VAF levels. ctDNA-based stratification was then correlated with patient survival by Kaplan-Meier analysis, and separately by Cox regression models that incorporated ctDNA as a continuous variable. Results: Median follow-up time from study enrollment was 26 months. ctDNA max VAF levels ranged from 0.3% to 10.9% (median=1.4%) at baseline, and from 0.2% to 28.7% (median=1.5%) at the mid-chemoRT timepoint (median=14 days after XRT start). After median-splitting based on ctDNA levels, Kaplan-Meier survival analysis demonstrated that patients with elevated ctDNA max VAF had significantly worse overall survival (OS) at baseline (median=12 months vs. not reached; HR=4.3, p=0.04) and again when measured at the mid-chemoRT timepoint (median=13 vs. 38 months; HR=4.3, p=0.04). Additionally, patients with elevated ctDNA at baseline had worse time to progression (TTP) (median=7 vs. 39 months; HR=3.8, p=0.04) and disease-specific survival (DSS) (median=14 months vs. not reached; HR>10, p=0.03). Furthermore at the mid-chemoRT timepoint, patients with elevated ctDNA exhibited worse DSS (median=13 months vs. not reached; HR>10, p=0.005). Cox regression models with ctDNA included as a continuous variable again demonstrated the prognostic value of ctDNA max VAF at both the pre-treatment timepoint (p=0.02 for TTP, p=0.05 for OS, p=0.02 for DSS) and the mid-treatment timepoint (p=0.008 for TTP, p=0.04 for OS, p=0.01 for DSS).Conclusion:
Mid- and pre-chemoRT application of the Tempus xF assay to plasma cell-free DNA followed by max VAF analysis of nonsynonymous variants enables accurate risk stratification of inoperable stage IIB-IIIC NSCLC treated with MRI-guided chemoRT. Our prospective data suggest that early quantification of ctDNA using a commercially available ctDNA assay may help guide risk- and response-adapted radiotherapy and consolidation therapy personalization in future clinical practice.