Liquid-Biopsy-Based Identification of EGFR T790M Mutation-Mediated Resistance to Afatinib Treatment in Patients with Advanced EGFR Mutation-Positive NSCLC, and Subsequent Response to Osimertinib

Abstract

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.

Clinical Features and Progression Pattern of Acquired T790M-positive Compared With T790M-negative EGFR Mutant Non–small-cell Lung Cancer: Catching Tumor and Clinical Heterogeneity Over Time Through Liquid Biopsy

“…These findings are consistent with a recent analysis 51 but in conflict with other works. 33,52 European guidelines recommend a tissue or liquid biopsy in case of disease progression, 27 but the right time for cf-DNA analysis and subsequent liquid rebiopsies in case of a first negativity are not clearly defined.…”

Non-small cell lung cancer-small cell lung cancer transformation as mechanism of resistance to tyrosine kinase inhibitors in lung cancer

“…When TKI resistance develops, patients generally undergo either a second tissue or a first liquid biopsy to determine the molecular mechanisms of refractoriness in order to guide the next treatment step and to predict the response [13,15] . Resistance to EGFR inhibitors through histological transformation of lung EGFRmutant adenocarcinoma to SCLC has been reported in 3%-14% of cases in repeated biopsies series [11,[15][16][17] .…”

Clinical Utility of Liquid Biopsy for EGFR Driver, T790M Mutation and EGFR Amplification in Plasma in Patients with Aacquired Resistance to Afatinib

“…These results might be consistent with our data. Regarding the T790M status in plasma in patients treated with afatinib, Hochmair et al reported that the T790M mutation was detected using a liquid biopsy in 47 out of 67 patients who had been treated with afatinib (16). However, they did not use the cobas test, which is a companion diagnostic system test for T790M mutation, but rather the droplet digital PCR system, which is a more sensitive assay than the cobas test.…”