Assessing response to immunotherapy in patients with non-small cell lung cancer using circulating tumor DNA

Abstract

Background: Evaluation of response to immune checkpoint inhibitors by serial imaging can be complicated by the possibility of pseudo-progression or delayed response, sometimes resulting in discontinuation of an effective therapy or delay of alternate treatment. Monitoring tumor cell death by measuring changes in circulating tumor DNA (ctDNA) levels in blood may permit early assessment of immunotherapy efficacy. Methods: We examined ctDNA levels in plasma samples from patients with metastatic non-small cell lung cancer (NSCLC) undergoing treatment with a PD-1 or PD-L1 inhibitor. CtDNA was quantified in plasma by determining the allele fraction of cancerassociated somatic mutations using a multi-gene next-generation sequencing assay. A ctDNA response was defined as more than 50% decrease in mutant allele fraction from baseline, with a second confirmatory measurement. Radiographic response assessment was performed using RECIST 1.1. Changes in ctDNA levels over time were correlated with imaging findings and with clinical outcomes. Results: Twenty-eight patients with metastatic NSCLC had ctDNA quantified in serial blood samples collected before and during treatment with a PD-1 axis inhibitor. Strong agreement was observed between ctDNA response and radiographic response (Cohen's Kappa = 0.753, P<0.001). The median time to response was 24.5 days by ctDNA versus 72.5 days by imaging. Patients who had a ctDNA response remained on immunotherapy for a median of 205.5 days compared to a median of 69 days for those who did not have a ctDNA response (p<0.001). Progression-free survival (PFS) and overall survival (OS) were significantly better for patients with a ctDNA response versus those without (hazard ratio [HR] for PFS, 0.29; 95% confidence interval [CI], 0.09-0.89; P=0.03 and HR for OS 0.17; 95% CI, 0.05-0.62; P=0.007). Conclusions: An early drop in ctDNA level enables assessment of response to immune checkpoint inhibitor therapies at a time when radiographic response may be uncertain for patients with metastatic NSCLC. Achievement of such a ctDNA response is predictive of a longer duration of therapeutic benefit as well as superior PFS and OS.