Tumor-Naïve Circulating Tumor DNA as an Early Response Biomarker for Patients Treated With Immunotherapy in Early Phase Clinical Trials.

Purpose: To evaluate early circulating tumor DNA (ctDNA) kinetics using a tumor-naïve assay and correlate it with clinical outcomes in early phase immunotherapy (IO) trials.

Methods: Plasma samples were analyzed using a 425-gene next-generation sequencing panel at baseline and before cycle 2 (3-4 weeks) in patients with advanced solid tumors treated with investigational IO agents. Variant allele frequency (VAF) for mutations in each gene, mean VAF (mVAF) from all mutations, and change in mVAF between both time points were calculated. Hyperprogression (HyperPD) was measured using Matos and Caramella criteria.

Results: A total of 162 plasma samples were collected from 81 patients with 27 different tumor types. Patients were treated in 37 different IO phase I/II trials, 72% of which involved a PD-1/PD-L1 inhibitor. ctDNA was detected in 122 plasma samples (75.3%). A decrease in mVAF from baseline to precycle 2 was observed in 24 patients (37.5%) and was associated with longer progression-free survival (hazard ratio [HR], 0.43; 95% CI, 0.24 to 0.77; < .01) and overall survival (HR, 0.54; 95% CI, 0.3 to 0.96; = .03) compared with an increase. These differences were more marked if there was a >50% decrease in mVAF for both progression-free survival (HR, 0.29; 95% CI, 0.13 to 0.62; < .001) and overall survival (HR, 0.23; 95% CI, 0.09 to 0.6; = .001). No differences in mVAF changes were observed between the HyperPD and progressive disease patients.

Conclusion: A decrease in ctDNA within 4 weeks of treatment was associated with treatment outcomes in patients in early phase IO trials. Tumor-naïve ctDNA assays may be useful for identifying early treatment benefits in phase I/II IO trials.