Clonal architecture of EGFR mutation predicts the efficacy of EGFR-Tyrosine Kinase Inhibitors in advanced NSCLC: a prospective multicenter study (NCT03059641).

Purpose: Clonal architecture is fundamental for the understanding of cancer biology and therapy, however, multiregional sampling in advanced-stage cancers is not always applicable. This prospective clinical trial was to investigate whether paired tissue and circulating tumor DNA (ctDNA) could describe the clonal architecture of advanced non-small cell lung cancer (NSCLC) and its association with clinical outcome (NCT03059641). Experimental design: Paired tumor and plasma ctDNA samples were sequenced by target-capture deep sequencing of 1021 genes. Clonal dominance analysis was performed on the basis of PyClone. Results: Overall, 300 treatment naive patients with stage IIIB-IV NSCLC were recruited from 14 centers. Of the 94 patients with available ctDNA data for EGFR clonal architecture analysis, 72 (76.6%) showed EGFR as the dominant clone. The medium progress free survival (mPFS) was longer for these patients than for the 22 patients whose EGFR was non-dominant clone (11 vs 10 months, hazard ratio [HR] 0.46, 95% CI 0.24-0.88, p = 0.02). The difference was more significant if both tissue and ctDNA defined EGFR as dominant clone (n = 43) versus those not (n = 8) (11 vs 6 months, HR = 0.13, 95% CI 0.04-0.50, p = 0.003). Moreover, multivariate cox proportional hazard ratio analysis demonstrated EGFR clonal architecture as an independent prognostic indicator of the efficacy of EGFR-TKIs. Conclusions: Paired tissue and ctDNA could be analyzed for clonal architecture in advanced cancer. EGFR mutations do not always make up a dominant clone in advanced NSCLC, which was associated with the efficacy of EGFR-TKIs in NSCLC.