ctDNA analysis reveals different molecular patterns upon disease progression in patients treated with osimertinib
Loading...
Identifiers
Publication date
2020
Start date of the public exhibition period
End date of the public exhibition period
Advisors
Journal Title
Journal ISSN
Volume Title
Publisher
Translational Lung Cancer Research
Share
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.
Doctoral program
Description
Keywords
Circulating tumor DNA (ctDNA), Epidermal growth factor receptor (EGFR), Non-small-cell lung cancer (NSCLC), Osimertinib