Background
Acquired epidermal growth factor receptor
(EGFR)
T790M mutation is the primary resistance mechanism to first-generation EGFR tyrosine kinase inhibitors (TKIs) used in advanced,
EGFR
mutation-positive non-small-cell lung cancer (NSCLC). Available data, predominantly in Asian patients, suggest that this mutation is also the major cause of resistance to the irreversible ErbB family blocker, afatinib. For
EGFR
T790M-positive patients who progress on EGFR TKI therapy, osimertinib is an effective treatment option. However, data on osimertinib use after afatinib are, to date, scarce.
Objective
To identify the prevalence of
EGFR
T790M mutations in predominantly Caucasian patients with stage IV
EGFR
mutation-positive NSCLC who progressed on afatinib, and to investigate the subsequent response to osimertinib.
Patients and Methods
In this single-center, retrospective analysis,
EGFR
T790M mutation status after afatinib failure was assessed using liquid biopsy and tissue rebiopsy.
EGFR
T790M-positive patients subsequently received osimertinib.
Results
Sixty-seven patients received afatinib in the first-, second-, or third-line (80.6%, 14.9%, and 4.5%, respectively). After afatinib failure, the T790M mutation was identified in 49 patients (73.1%). Liquid biopsy and tissue rebiopsy were concordant in 79.4% of cases. All patients with T790M-positive tumors received osimertinib (73.5% after first-line afatinib); 37 (75.5%) of these had an objective response (complete response: 22.4%; partial response: 53.1%). Response rate was independent of T790M copy number.
Conclusion
EGFR
T790M mutation is a major mechanism of acquired resistance to afatinib. Osimertinib confers high response rates after afatinib failure in
EGFR
T790M-positive patients and its use in sequence potentially allows extended chemotherapy-free treatment.
Plasma genotyping using digital polymerase chain reaction is clinically useful for the selection of patients who had progressed during first-line EGFR-TKI therapy for treatment with osimertinib.
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