Figure 1: Heterogeneity of resistance mechanisms and EGFR mutation dynamics in response to EGFR TKIs.

(a) Detection of EGFR-activating and T790M resistance mutations in pre-treatment and progression plasma samples from rociletinib-treated patients (n=43) using CAPP-Seq. (b) Summary of putative resistance mechanisms to first- and second-generation EGFR TKIs present in the pre-rociletinib plasma sample of patients with T790M mutations (n=41). (c) The percent change in the relative ratio of T790M to activating mutation alleles in progression plasma samples compared with pre-treatment samples from rociletinib-treated patients. Patients in whom the ratio decreased (n=28) are coloured blue and patients in whom the ratio increased (n=7) are coloured red. Only patients in whom both activating and T790M mutations were detectable pre-treatment, and activating mutations were detectable at progression are included. (d) Box and Whisker plots depicting the relative ratio of T790M and activating mutation alleles in pre-treatment and progression plasma samples from rociletinib-treated patients. The solid box represents the interquartile range of values and whiskers represent the 10th and 90th percentile values. All patients depicted in c are included. (n=35, ***P<0.0005, Wilcoxon signed-rank test). (e) Comparison of the ratio of T790M to EGFR-activating mutation in pre-treatment plasma samples and the best RECIST response to treatment with rociletinib. Patients with low baseline T790M (n=12, ratio ≤0.5) have significantly less reduction in tumour volume than patients with high baseline T790M (n=29, ratio > 0.5; * P<0.05, Wilcoxon rank-sum test). Only patients in whom both activating and T790M mutations were detectable pre-treatment are included.