Simple Summary Since the recent approval of osimertinib, a third generation tyrosine
kinase inhibitor (TKI) targeting EGFR in non-small cell lung cancer (NSCLC), tracing
the resistance mechanisms that yield to failure of osimertinib has become of interest.
As the spectrum of osimertinib-resistance related genomic alterations appears significantly
more diverse compared to first and second generation TKI, comprehensive, and preferably
non-invasive molecular diagnostic methods are required for the detection of resistance
mechanisms. In this study, we present molecular results of 56 NSCLC patients during
disease progression on first and second line osimertinib treatment using a hybrid
capture (HC) next generation sequencing (NGS) based liquid biopsy approach. We show
examples of polyclonal resistance development which leads to the presence of multiple
resistance mechanisms in the same patient, and highlight the clinical utility of HC
NGS over single gene testing. Since 2009, several first, second, and third generation
EGFR tyrosine kinase inhibitors (TKI) have been approved for targeted treatment of
EGFR mutated metastatic non-small lung cancer (NSCLC). A vast majority of patients
is improving quickly on treatment; however, resistance is inevitable and typically
occurs after one year for TKI of the first and second generation. Osimertinib, a third
generation TKI, has recently been approved for first line treatment in the palliative
setting and is expected to become approved for the adjuvant setting as well. Progression-free
survival (PFS) under osimertinib is superior to its predecessors but its spectrum
of resistance alterations appears significantly more diverse compared to first and
second generation EGFR TKI. As resistance mechanisms to osimertinib are therapeutically
targetable in some cases, it is important to comprehensively test for molecular alterations
in the relapse scenario. Liquid biopsy may be advantageous over tissue analysis as
it has the potential to represent tumor heterogeneity and clonal diversification.
We have previously shown high concordance of hybrid capture (HC) based next generation
sequencing (NGS) in liquid biopsy versus solid tumor biopsies. In this study, we now
present real-word data from 56 patients with metastatic NSCLC that were tested by
liquid biopsy at the time of disease progression on mostly second line treated osimertinib
treatment. We present examples of single and multiple TKI resistance mechanisms, including
mutations in multiple pathways, copy number changes and rare fusions of RET, ALK,
FGFR3 and BRAF. In addition, we present the added value of HC based NGS to reveal
polyclonal resistance development at the DNA level encoding multiple EGFR C797S and
PIK3CA mutations.
