Figure 4.

Dynamic changes in cfTL during therapy. Longitudinal changes in cfTL across plasma time points analyzed for each patient were used to assign a combined molecular response classification. Representative examples are shown of patients who were assigned to each of the 3 classifications. A, Patient 10 was classified as a molecular responder based on the complete elimination of cfTL, assessed using tumor-derived sequence alterations, between baseline and week 5 sampling during cisplatin/etoposide chemotherapy treatment (indicated by the green shaded area). A reduction in PA scores to undetectable levels from baseline was also observed in this patient. B and C, Patients 26 and 21 were assigned a classification of molecular response followed by recrudescence based on the elimination of cfTL between baseline and intermediate time points [during atezolizumab/etoposide/carboplatin (purple) and carboplatin/etoposide (green) treatment, respectively], after which an increase in cfTL was observed at the final time points analyzed. C, In patient 21, a shift in mutation profiles defined by the presence of tumor-derived RET (p.Y314F) and TP53 (p.V173E) mutations at recrudescence, which were not present at the baseline timepoint, was observed. D, Patient 1 was classified as a molecular progressor based on the persistence of cfTL, defined by a tumor-derived TP53 (p.C135S) sequence alteration, across all time points analyzed during treatment with nivolumab (blue). E, Combined molecular responses were significantly associated with clinical evaluations of best radiographic response (P = 0.003, Fisher exact test). F, A broader comparison between the elimination of cfTL at any timepoint analyzed for the study and radiographic assessments further revealed concordance (P = 0.001, Fisher exact test) between each variable. G, Molecular responses were determined on average 4 weeks prior to best radiographic response assessments in 28 patients with comparable ctDNA and imaging assessments in this cohort (mean 5.61 weeks vs. 10.21 weeks; P = 0.01 Mann–Whitney U test). Patients without baseline plasma samples available (n = 2) and cases with discordant molecular and radiographic responses (n = 3) were excluded from analyses. Mean times to response assessment are shown alongside standard error for each modality.