Journal Article

Early plasma circulating tumor DNA (ctDNA) changes predict response to first-line pembrolizumab-based therapy in non-small cell lung cancer (NSCLC)

Jones, Greg, Lydon, Christine, Nishino, Mizuki, Recondo, Gonzalo, Alessi, Joao V, Awad, Mark, Lawrence, Marissa, Ricciuti, Biagio, Severgnini, Mariano, Cheng, Michael, Forshew, Tim

2021

Overview

BackgroundCurrently available biomarkers are imperfect in their ability to predict responses to the multiple first-line treatment options available for patients with advanced non-small cell lung cancer (NSCLC). Having an early pharmacodynamic marker of treatment resistance may help redirect patients onto more effective alternative therapies. We sought to determine if changes in circulating tumor DNA (ctDNA) levels after initiation of first-line pembrolizumab±chemotherapy in NSCLC would enable early prediction of response prior to radiological assessment.MethodsPlasma collected from patients with advanced NSCLC prior to and serially after starting first-line pembrolizumab±platinum doublet chemotherapy was analyzed by next-generation sequencing using enhanced tagged-amplicon sequencing of hotspots and coding regions from 36 genes. Early change in ctDNA allele fraction (AF) was correlated with radiographic responses and long-term clinical outcomes.ResultsAmong 62 patients who received first-line pembrolizumab±platinum/pemetrexed and underwent ctDNA assessment, 45 had detectable ctDNA alterations at baseline. The median change in AF at the first follow-up (at a median of 21 days after treatment initiation) was −90.1% (range −100% to +65%) among patients who subsequently had a radiologic response (n=18), –19.9% (range: −100% to +1884%) among stable disease cases (n=15), and +28.8% (range: −100% to +410%) among progressive disease cases (n=12); p=0.003. In addition, there was a significant correlation between the percent change in ctDNA at the first follow-up and the percent change in tumor target lesions from baseline (R=0.66, p<0.001). AF decrease between the pretreatment and first on-treatment blood draw was associated with significantly higher response rate (60.7% vs 5.8%, p=0.0003), and significantly longer median progression-free survival (8.3 vs 3.4 months, HR: 0.29 (95% CI: 0.14 to 0.60), p=0.0007) and median overall survival (26.2 vs 13.2 months, HR: 0.34 (95% CI: 0.15 to 0.75), p=0.008) compared with cases with an AF increase.ConclusionIn patients with advanced NSCLC, rapid decreases in ctDNA prior to radiological assessment correlated with clinical benefit. These results suggest a potential role for ctDNA as an early pharmacodynamic biomarker of response or resistance to immunotherapies.

• Publisher: BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Adult / Aged / Aged, 80 and over / Antibodies, Monoclonal, Humanized - adverse effects / Antibodies, Monoclonal, Humanized - therapeutic use / Antineoplastic Combined Chemotherapy Protocols - adverse effects / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Apoptosis / Biomarkers / Biomarkers, Tumor - blood / Biomarkers, Tumor - genetics / Cancer / Cancer therapies / Carcinoma, Non-Small-Cell Lung - blood / Carcinoma, Non-Small-Cell Lung - diagnostic imaging / Carcinoma, Non-Small-Cell Lung - drug therapy / Carcinoma, Non-Small-Cell Lung - genetics / Chemotherapy / Circulating Tumor DNA - blood / Circulating Tumor DNA - genetics / Clinical outcomes / Disease Progression / Early Diagnosis / Female / Genes / Genomes / Humans / Immune Checkpoint Inhibitors - adverse effects / Immune Checkpoint Inhibitors - therapeutic use / Immunotherapy / Immunotherapy Biomarkers / Laboratories / Lung cancer / Lung Neoplasms - blood / Lung Neoplasms - diagnostic imaging / Lung Neoplasms - drug therapy / Lung Neoplasms - genetics / Male / Middle Aged / Monoclonal antibodies / Mutation / Patients / Plasma / Predictive Value of Tests / Progression-Free Survival / Retrospective Studies / Targeted cancer therapy / Time Factors / Treatment resistance