Reductions in ctDNA Associated With Improved Clinical Outcomes in NSCLC Treated With an Immune Checkpoint Inhibitor

Findings from a pooled analysis indicated that reductions in ctDNA were associated with improved clinical benefit across multiple end points in patients with non–small cell lung cancer treated with immune checkpoint inhibitors.

Patients with non–small cell lung cancer (NSCLC) who were treated with immune checkpoint inhibitors who experienced a reduction in circulating tumor DNA (ctDNA) had promising outcomes across multiple end points, according to results from a pooled analysis of 5 independent clinical trials published in the Journal of Clinical Oncology Precision Medicine.

Improved overall survival (OS) was found to be strongly associated with a reduction in ctDNA levels from on-treatment liquid biopsies (HR, 2.28; 95% CI, 1.62-3.20; P <.001). A similar association was observed for progression-free survival (PFS; HR, 1.76; 95% CI, 1.31-2.36; P <.001).

“Among patients with NSCLC treated with [immune checkpoint inhibitor] whose data were analyzed in aggregate, consistent and robust associations between reductions in ctDNA and clinical benefit were found across multiple end points. Although the results presented in this manuscript are consistent with recent reports, these individual studies have limited sample sizes, and were constrained in their generalizability, given that each study used a particular treatment and a specific ctDNA assay on a carefully selected group of patients,” the investigators wrote.

Of 254 potential patients, 200 were included in the study. Patient characteristics varied widely, including differences in age, sex, stage at enrollment, histology, PD-L1 expression, and previous lines of therapy. Investigators found that smoking history was univariately associated with ctDNA value changes.

Variation was observed between cohorts in terms of ctDNA timing and frequency due to the different protocols used in each study. Investigators also noted that that variability across cohorts in terms of detected variants, including the magnitude of the variant allele frequencies (VAF) and the range of baseline VAF values. Investigators reported that 32% of patients had a decrease, 51% had intermediate change, and 17% had an increase in ctDNA levels from baseline while on treatment within a 3-level Max VAF Percent Change Group.

Unadjusted and adjusted Cox models identified a relationship between reduction in ctDNA levels and OS outcomes. A strong separation in different ctDNA categories was observed with statistically significant pairwise comparisons. The 1 year survival rates were 75%, 58%, and 32% for those who experienced a decrease, intermediate change, or increase in Max VAF. PFS was not associated with changes in ctDNA level.

Smoking history was associated with improved outcomes for both PFS and OS, according to the adjusted Cox models. Investigators noted these findings were similar to previous studies that identified that cancers resulting from accumulation of tobacco-related mutations may have increased tumor burden and be more potentially more responsive to immunotherapies. Investigators observed a lack of association with PD-L1 positivity because of variation in how it was measured and defined in each trial.


Vega DM, Nishimura KK, Zariffa N, et al. Changes in circulating tumor DNA reflect clinical benefit across multiple studies of patients with non-small-cell lung cancer treated with immune checkpoint inhibitors. JCO Precis Oncol. Published online August 11, 2022. doi:10.1200/PO.21.00372