Optimizing the sequencing of tyrosine kinase inhibitors (TKIs) in epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC)

Tumor resistance to EGFR tyrosine kinase inhibitors (TKIs) occurs invariably, and receptor tyrosine kinase (RTK) fusions have emerged as rare but actionable resistance mechanisms. In 2015, the detection of RTK fusions as acquired resistance (AR) in two cases was first reported. Subsequently, a survey of FGFR3-TACC3 fusion and other RTK fusions from a large commercial genomic sequencing company database was published, followed by large-scale clinical trials of EGFR TKIs demonstrating the emergence of RTK fusions in AR. However, detailed examination of the AR RTK fusion landscape in non-small-cell lung cancer is lacking. Hence, we conducted a comprehensive review to categorize these fusion events by the generation of EGFR TKIs, the specific RTK fusions and their fusion partners, the founder EGFR mutations, and their methods of detection. To support the actionability and clinical significance of AR RTK fusions we present all available data demonstrating clinical benefit of concurrent dual blockade of the AR RTK fusion and the original EGFR mutation.

Receptor Tyrosine Kinase Fusions as an Actionable Resistance Mechanism to EGFR TKIs in EGFR-Mutant Non-Small-Cell Lung Cancer.

Background Abivertinib is a novel oral, third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that overcomes T790M-induced resistance in non-small cell lung cancer (NSCLC) patients. Here, we report the results of a complete and detailed clinical data of patients treated with abivertinib at our hospital in a phase I dose escalation/expansion study of abivertinib. Methods NSCLC patients with the EGFR T790M mutation were orally administered abivertinib (150-300 mg) twice daily for cycles of 28 continuous days and tumor response was assessed. Further data regarding subsequent treatment protocols and survival were collected. Results A total of 28 NSCLC patients were included. Of the 24 assessable patients, 12 (50%) achieved a partial response (PR), and six (25%) achieved stable disease (SD). Median progression-free survival (PFS) was 5.9 months (95% confidence interval (CI): 3.259-8.541) and median overall survival (OS) was 17.9 months (95% CI: 11.36-24.5). For salvage therapy in 15 (53.6%) patients after abivertinib, the median PFS following osimertinib treatment was 12 months. The median total treatment duration for the two third-generation EGFR TKIs was 15.9 months (95% CI: 12.5-19.3). The most frequent abivertinib-associated adverse effects were elevated hepatic transaminases (10/28, 35.7%) and diarrhea (10/28, 35.7%). Conclusions Abivertinib is a unique novel third-generation EGFR TKI with good tolerance and efficacy in EGFR T790M(+) NSCLC patients. For patients with progressive disease after treatment with abivertinib, osimertinib could be an option for subsequent therapy but further studies are required. Key points Abivertinib is a novel third-generation EGFR TKI targeting the EGFR T790M mutation Abivertinib is well tolerated and efficacious in T790M-positive patients Abivertinib has a unique structure, efficacy, and resistance mechanism compared with osimertinib Osimertinib treatment after AC0010 showed a good response.

Abivertinib in patients with T790M-positive advanced NSCLC and its subsequent treatment with osimertinib.

https://doi.org/10.1016/j.jtocrr.2022.100343

Response to Pralsetinib Observed in Meningeal-Metastatic EGFR-Mutant NSCLC With Acquired RET Fusion: A Brief Report

Clinical management of third-generation EGFR inhibitor-resistant patients with advanced non-small cell lung cancer: Current status and future perspectives

OA10.07 Resistance Mechanisms of Osimertinib in Chinese Non-Small Cell Lung Cancer patients: Analysis from AURA17 Trial

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OA10.07 Resistance Mechanisms of Osimertinib in Chinese Non-Small Cell Lung Cancer patients: Analysis from AURA17 Trial