Early Assessment Of Treatment Effect In Advanced Lung Adenocarcinoma Via Longitudinal Ctdna Analysis

12088 Background: Despite routine use of chemotherapy in advanced non-small-cell lung cancer (NSCLC) patients, the knowledge of optimal prognostic methods is still limited to imaging-based methods. We hypothesized that an early response assessed by mutant molecules count in plasma could predict the treatment effect. Methods: We employed AVENIO ctDNA Surveillance Kit, a 197-gene NGS assay, which allowed us to perform longitudinal ctDNA analysis and measure the mutant molecules per milliliter-of-plasma (MMPM), which quantifies ctDNA at the variant level. The association between changes in ctDNA levels and survival was evaluated in advanced lung adenocarcinoma subjects. Post-treatment MMPM values were compared with the MMPM value at baseline and/or the previous treatment timepoint. Results: At baseline (b0), we identified variants in all (93/93) subjects to enable ctDNA monitoring. From the training cohort (50 subjects), we were able to set the cutoff of 40 for the mean MMPM at post-first treatment cycle (p1). Applying the MMPM cutoff of p1 to the validation cohort (43 subjects with stage IV lung adenocarcinoma, from a prospective, observational study) low levels of ctDNA toward the end of first treatment cycle was associated with better progression-free survival (PFS) (P = 0.0088 HR 0.4; 95% CI 0.20 - 0.83) and overall survival (OS) (P = 0.0026 HR 0.32; 95% CI 0.15 - 0.71). The prognostic value is increased by applying the Continuous Responder algorithm, defined by a continuous drop in ctDNA levels represented by mean MMPM reduction over time (p2 < p1 < b0), to a mean MMPM below 8 at p2. As a result, continuous responders 13/43 (30%) were associated with a better therapy response indicated by PFS (P = 0.028 HR 0.45; 95% CI 0.23 - 0.90) and OS (P = 0.0074 HR 0.3; 95% CI 0.12 - 0.77). The continuous responders demonstrated a median overall survival benefit of 11.25 months over the poor responders. Conclusions: A decrease in post-treatment ctDNA level measured by NGS was associated with better prognosis in advanced lung adenocarcinoma. An early assessment of treatment effect can be measured by mutant molecule counts in the plasma within 1 or 2 treatment cycles.