Figure 1:Mutation profile of the cohort prior to osimertinib therapy (A), and at disease progression with osimertinib (B). The mutation profiles from the two time-points were also compared and depicted in (C). A-C. The patients were grouped according to baseline EGFR mutations 19del (green) or L858R (red) as indicated by the bar located at the bottom of the oncoprint. B–C. An annotation depicting the EGFR T790M status of each patient at progression, whether lost (blue) or retained (yellow) was also added at the bottom of the oncoprint. Each column represents a patient and each row represents a gene. Table on the left represents the mutation rate of each gene. Top plot represents the overall number of mutations a patient carried. Different colors denote different types of mutation.

Figure 2: Distribution of the osimertinib-treated patients according to the major acquired mutations. Shaded slices refer to those with T790M loss.

Figure 3: Distinct acquired mutations between EGFR 19del and L858R-mutant patients. Summarized spectra of the mutations acquired by the cohort at PD. The first three rows reflect the baseline EGFR sensitizing mutations 19del and L858R and T790M and is the basis of the grouping of the patients. Each column represents a patient and each row represents a gene mutation indicated on the right. Percentage on the left and the histogram on the right represents the mutation rate of each gene.

Figure 4: EGFR 19del-mutant patients acquired significantly more mutations in the MAPK/PI3K pathway (P=0.007) and TP53 (P=0.021), while ERBB2 amplifications were only detected from L858-mutant patients (P=0.045). Histograms illustrating the acquired mutations detected among 19del and L858R-mutant patients in A. MAPK/PI3K pathway; B. TP53 and C. ERBB2 amplification. Reported includes only specific mutations already established in the development of osimertinib or EGFR-TKI resistance, Others refers to mutations that have not been associated with the EGFR-TKI resistance mechanism.

Figure 5: The loss of EGFR T790M at PD was associated with marginally shorter PFS (P=0.05) and significantly shorter OS (P=0.04). Kaplan-Meier analysis of the PFS and OS of the advanced NSCLC patients treated with osimertinib who retained (n=36) or lost (n=60) EGFR T790M at PD, indicated by red and blue lines, respectively. The risk table below illustrates the number of patients included per time point.

Figure 6:The acquisition of tertiary EGFR mutations, particularly C797X, at PD was associated with significantly longer PFS (P=0.006; C797 P=0.021) and a trend of longer OS (P=0.06). Kaplan-Meier analysis of the PFS and OS of the advanced NSCLC patients treated with osimertinib who acquired tertiary EGFR mutations (n=31) or other mutations (n=65) at PD, indicated by blue and red lines, respectively. The risk table below illustrates the number of patients included per time point.

Figure 7:The acquisition of MET amplification at PD was associated with significantly shorter PFS (P=0.0321). Kaplan-Meier analysis of the PFS and OS of the advanced NSCLC patients treated with osimertinib who acquired MET amplification (n=17) or other mutations (n=79) at PD, indicated by blue and red lines, respectively. The risk table below illustrates the number of patients included per time point.