ctDNA analysis reveals different molecular patterns upon disease progression in patients treated with osimertinib

Abstract

Background: Several clinical trials have demonstrated the efficacy and safety of osimertinib in advanced nonsmall-cell lung cancer (NSCLC). However, there is significant unexplained variability in treatment outcome.Methods: Observational prospective cohort of 22 pre-treated patients with stage IV NSCLC harboring the epidermal growth factor receptor (EGFR) p.T790M resistance mutation and who were treated with osimertinib. Three hundred and twenty-six serial plasma samples were collected and analyzed by digital PCR (dPCR) and next-generation sequencing (NGS). Results:The median progression-free survival (PFS), since the start of osimertinib, was 8.9 [interquartile range (IQR): 4.6-18.0] months. The median treatment durations of sequential gefitinib + osimertinib, afatinib + osimertinib and erlotinib + osimertinib treatments were 30.1, 24.6 and 21.1 months, respectively. The p.T790M mutation was detected in 19 (86%) pre-treatment blood samples. Undetectable levels of the original EGFR-sensitizing mutation after 3 months of treatment were associated with superior PFS (HR: 0.2, 95% CI: 0.05-0.7). Likewise, re-emergence of the original EGFR mutation, alone or together with the p.T790M mutation was significantly associated with shorter PFS (HR: 8.8, 95% CI: 1.1-70.7 and HR: 5.9, 95% CI: 1.2-27.9, respectively). Blood-based monitoring revealed three molecular patterns upon progression to osimertinib: sensitizing+/T790M+/C797S+, sensitizing+/T790M+/C797S-, and sensitizing+/T790M-/ C797S-. Median time to progression in patients showing the triplet pattern (sensitizing+/T790M+/C797S+) was 12.27 months compared with 4.87 months in patients in whom only the original EGFR sensitizing was detected, and 2.17 months in patients showing the duplet pattern (sensitizing+/T790M+). Finally, we found that mutations in exon 545 of the PIK3CA gene were the most frequent alteration detected upon disease progression in patients without acquired EGFR-resistance mutations.Conclusions: Different molecular patterns identified by plasma genotyping may be of prognostic significance, suggesting that the use of liquid biopsy is a valuable approach for tumor monitoring.

Plasma Predictive Features in Treating EGFR-Mutated Non-Small Cell Lung Cancer

“…These results therefore do not only support the finding that disappearance of the primary EGFR mutation in plasma is associated with a better outcome in first line [24,25], but also confirm its predictive value in the second line for osimertinib-treated patients with EGFR p.T790M [26]. The concept of losing detectable EGFR mutations in plasma in association with better outcome was recently also demonstrated at other centers [26], but often with less sensitive techniques (e.g., Cobas ® ) than our NGS panel [25,27], or cross-sectional at a single time point rather than sequentially analyzed as a change in time [28,29]. In our second line cohort, isolated EGFR p.T790M loss in plasma at week 6 was associated with decreased PFS (5.1 vs. 18.8 months).…”

NGS‐based liquid biopsy profiling identifies mechanisms of resistance to ALK inhibitors: a step toward personalized NSCLC treatment

“…Consistent with our results, mutations in TP53, FGFR2, PIK3CA, and MET have been identified in the tumor biopsy of patients progressing on ceritinib [11]. The E545K and E545A mutations in PIK3CA have not only been detected upon progression in advanced ALK-positive NSCLC patients, but also in EGFR-positive NSCLC patients [28,29]. The IDH2 R140Q detected in our cohort is known to transform cells in vitro and induces myeloid and lymphoid neoplasms in mice [30,31].…”

Identification of Mechanisms of Resistance to ALK Inhibitors. Next-generation sequencing-based liquid biopsy profiling: A step towards personalized treatment.

“…Similarly, mutations in TP53, FGFR2, PIK3CA, MET have been identi ed in the tumor biopsy of patients progressing on ceritinib (11). The E545K and E545A mutations, which are two of the most common oncogenic mutations in PIK3CA, have also been detected upon progression in advanced EGFR-positive NSCLC patients (24). On the other hand, the IDH2 R140Q detected in our cohort is known to transform cells in vitro and induces myeloid and lymphoid neoplasms in mice (25,26).…”