Changes in Circulating Tumor DNA Reflect Clinical Benefit Across Multiple Studies of Patients With Non-Small-Cell Lung Cancer Treated With Immune Checkpoint Inhibitors

Abstract

Purpose: As immune checkpoint inhibitors (ICI) become increasingly used in frontline settings, identifying early indicators of response is needed. Recent studies suggest a role for circulating tumor DNA (ctDNA) in monitoring response to ICI, but uncertainty exists in the generalizability of these studies. Here, the role of ctDNA for monitoring response to ICI is assessed through a standardized approach by assessing clinical trial data from five independent studies.

Patients and methods: Patient-level clinical and ctDNA data were pooled and harmonized from 200 patients across five independent clinical trials investigating the treatment of patients with non-small-cell lung cancer with programmed cell death-1 (PD-1)/programmed death ligand-1 (PD-L1)-directed monotherapy or in combination with chemotherapy. CtDNA levels were measured using different ctDNA assays across the studies. Maximum variant allele frequencies were calculated using all somatic tumor-derived variants in each unique patient sample to correlate ctDNA changes with overall survival (OS) and progression-free survival (PFS).

Results: We observed strong associations between reductions in ctDNA levels from on-treatment liquid biopsies with improved OS (OS; hazard ratio, 2.28; 95% CI, 1.62 to 3.20; P < .001) and PFS (PFS; hazard ratio 1.76; 95% CI, 1.31 to 2.36; P < .001). Changes in the maximum variant allele frequencies ctDNA values showed strong association across different outcomes.

Conclusion: In this pooled analysis of five independent clinical trials, consistent and robust associations between reductions in ctDNA and outcomes were found across multiple end points assessed in patients with non-small-cell lung cancer treated with an ICI. Additional tumor types, stages, and drug classes should be included in future analyses to further validate this. CtDNA may serve as an important tool in clinical development and an early indicator of treatment benefit.

FIG 1.

Flow diagram. ctDNA, circulating tumor DNA.

FIG 2.

Timing of plasma collection and tumor response per patient by study in the analysis data set (N = 200). Unique patients are represented as horizontal lines, with markers denoting the timing of RECIST evaluations and ctDNA samples. The x-axis is truncated at 200 days, with some patients having longer follow-up. ctDNA, circulating tumor DNA.

FIG 3.

(A) Forest plot with Cox regression results for OS and the three-level max VAF percent change group variable, adjusted by baseline clinical covariates. Red means the HR is > 1.0 (increased risk of death) and blue means the HR is < 1.0 (decreased risk of death); unfilled box = nonsignificant P value, filled box = significant P < .05. (B) Kaplan-Meier plot for OS and the three-level max VAF percent change groups, landmarked at 70 days from treatment initiation (the sampling window for the first on-treatment ctDNA sample); patients with an event during the 70-day landmark were excluded from the analysis. ^aDenotes a time-dependent variable. ctDNA, circulating tumor DNA; HR, hazard ratio; LL, lower limit; OS, overall survival; PD-L1, programmed death ligand-1; UL, upper limit; VAF, variant allele frequency.

FIG 4.

(A) Forest plot with Cox regression results for PFS and the three-level max VAF percent change group variable, adjusted by baseline clinical covariates. Red means the HR is > 1.0 (increased risk of death/progression) and blue means the HR is < 1.0 (decreased risk of death/progression); unfilled box = nonsignificant P value, filled box = significant P < .05. (B) Kaplan-Meier plot for PFS and the three-level max VAF percent change groups, landmarked at 70 days from treatment initiation (the sampling window for the first on-treatment ctDNA sample); patients with an event during the 70-day landmark were excluded from the analysis. ^aDenotes a time-dependent variable. ctDNA, circulating tumor DNA; HR, hazard ratio; LL, lower limit; PD-L1, programmed death ligand-1; PFS, progression-free survival; UL, upper limit; VAF, variant allele frequency.