Identifying key circulating tumor DNA parameters for predicting clinical outcomes in metastatic non-squamous non-small cell lung cancer after first-line chemoimmunotherapy

Abstract

Circulating tumor DNA (ctDNA) provides valuable tumor-related information without invasive biopsies, yet consensus is lacking on optimal parameters for predicting clinical outcomes. Utilizing longitudinal ctDNA data from the large phase 3 IMpower150 study (NCT02366143) of atezolizumab in combination with chemotherapy with or without bevacizumab in patients with stage IV non-squamous Non-Small Cell Lung Cancer (NSCLC), here we report that post-treatment ctDNA response correlates significantly with radiographic response. However, only modest concordance is identified, revealing that ctDNA response is likely not a surrogate for radiographic response; both provide distinct information. Various ctDNA metrics, especially early ctDNA nadirs, emerge as primary predictors for progression-free survival and overall survival, potentially better assessing long-term benefits for chemoimmunotherapy in NSCLC. Integrating radiographic and ctDNA assessments enhances prediction of survival outcomes. We also identify optimal cutoff values for risk stratification and key assessment timepoints, notably Weeks 6–9, for insights into clinical outcomes. Overall, our identified optimal ctDNA parameters can enhance the prediction of clinical outcomes, refine trial designs, and inform therapeutic decisions for first-line NSCLC patients.

Circulating tumor DNA (ctDNA) is emerging as a minimally invasive biomarker for cancer diagnosis and prognosis assessment. Here, using longitudinal ctDNA data from the phase 3 IMpower150 trial, the authors analyse ctDNA parameters for predicting outcomes after first-line immunotherapy in patients with non-small cell lung cancer.