4.5 Article

Phase I results of S49076 plus gefitinib in patients with EGFR TKI-resistant non-small cell lung cancer harbouring MET/AXL dysregulation

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LUNG CANCER
卷 155, 期 -, 页码 127-135

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ELSEVIER IRELAND LTD
DOI: 10.1016/j.lungcan.2021.03.012

关键词

Tyrosine kinase inhibitors; Epidermal growth factor receptor; Non-small cell lung cancer; Gefitinib; MET; AXL

资金

  1. I.R.I.S., France
  2. Laboratorios Servier in Spain
  3. Servier, France

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The combination of gefitinib with S49076 showed limited anti-tumour activity with good tolerability in EGFR TKI-resistant NSCLC patients. The study did not reveal a clear trend in activity within specific molecular subsets due to the small number of eligible patients.
Background: MET and AXL dysregulation is reported as a bypass mechanism driving tumour progression in nonsmall cell lung cancer (NSCLC) with acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). This non-comparative phase I study investigated the combination of gefitinib with S49076, a MET/AXL inhibitor, in advanced EGFR TKI-resistant NSCLC patients with MET and/or AXL dysregulation. Methods: Patients received S49076 at escalating doses of 500 or 600 mg with a fixed dose of 250 mg gefitinib orally once daily in continuous 28day cycles. MET and AXL dysregulation and EGFR/T790M mutation status were centrally assessed in tumour biopsies at screening. Tumour response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST). EGFR TKI resistance mechanisms were analysed by next-generation sequencing. The clonal evolution of tumours was monitored with the analysis of circulating tumour DNA. Results: Of 92 pre-screened patients, 22 met the molecular inclusion criteria and 14 were included. The recommended dose was 600 mg daily S49076. Best overall responses were 2 partial responses (1 patient with MET dysregulation only, 1 MET and AXL co-dysregulation) and 8 patients with stable disease. Other potential concomitant mechanisms of resistance to EGFR TKI were identified in more than half of the included patients. Conclusions: S49076 plus gefitinib demonstrated a good tolerability with limited anti-tumour activity. Due to the low number of eligible patients, no tendency in term of activity appeared in any specific molecular subset and the data did not allow for identification of AXL overexpression as an oncogenic driver.

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