P1.01-34 Early Assessment of Therapy Response in Non-Small Cell Lung Cancer (NSCLC) via Longitudinal ctDNA Analysis

Quantifying circulating tumor DNA (ctDNA) is an emerging method to non-invasively assess treatment effect for solid tumors. Despite disease heterogeneity in NSCLC, we set out to identify a broadly applicable ctDNA-based method for disease monitoring. By employing plasma taken during early treatment cycles, we tested whether early response assessed by ctDNA level could predict treatment effect. Using a 197-gene NGS assay, the AVENIO ctDNA Surveillance Kit (For Research Use Only, not for use in diagnostic procedures), we measured ctDNA levels in post-treatment plasma samples based on variants identified at baseline. We used samples from an observational German Lung Cancer Multi-Marker Study. In a cohort of 83 stage IV lung adenocarcinoma treated with first-line chemo or chemoradiation therapies, we evaluated the association between survival and ctDNA levels in the first available post-treatment plasma sample (median number of days after start of treatment = 23). We used a ctDNA-based monitoring algorithm and applied it to an independent set of 22 late stage lung squamous cell carcinoma that also underwent chemo or chemoradiation therapies to further evaluate the algorithm in different histology subtypes. We divided the 83 adenocarcinoma cohort into training (n=53) and test (n=30) sets. We found that subjects with longer progression free survival (PFS) had mean allele fraction (AF) <1% in the training set. We applied the classifier to our adenocarcinoma test set and found that subjects with mean AF <1% had longer PFS (HR 0.35; 95% CI 0.12 - 0.93; log-rank P = 0.028) and overall survival (OS) (HR 0.29; 95% CI 0.09 - 0.89; log-rank P= 0.021). Using cutoffs identified in adenocarcinoma, we applied the same algorithms to the squamous cell carcinoma cohort. Subjects with mean AF < 1% had longer PFS (HR 0.26; 95% CI 0.10 - 0.71; log-rank P = 0.005) and OS (HR 0.12; 95% CI 0.05 - 0.51; log-rank P= 0.001). Even in heterogeneous diseases such as NSCLC, changes in ctDNA levels in response to treatment may prove to be a valuable way of identifying subjects who may not benefit, before current standard of care methods like computed tomography (CT) scan. Future prospective studies to confirm these results are warranted.