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Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
Published on: August 11, 2017
Molecular characterization and clinical outcomes in EGFR-mutant de novo MET-overexpressed advanced non-small-cell
1Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China; Graduate School, University of South China, Hengyang, Hunan, China.
Background:
Approximately 2%-8% of non-small-cell lung cancer (NSCLC) harbors concurrent epidermal growth factor receptor (EGFR) sensitizing mutation and mesenchymal-epithelial transition factor (MET) amplification prior to EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapy. This study aimed to investigate the optimal first-line therapeutic options for patients with concurrent EGFR-mutant, MET-overexpressed/amplified advanced NSCLC.
Methods:
A total of 104 treatment-naïve patients with EGFR-mutant de novo MET-overexpressed advanced NSCLC were identified using immunohistochemistry and stratified to four groups according to treatment regimen: EGFR-TKI monotherapy (n = 48), EGFR-TKI combined with either crizotinib (n = 9) or chemotherapy (n = 12), and chemotherapy (n = 35). A subpopulation of 28 patients was also tested with next-generation sequencing (NGS). Objective response rate (ORR) and progression-free survival (PFS) outcomes were analyzed according to treatment strategies and molecular features.
Results:
All the patients (n = 104) achieved ORR of 36.5% and median PFS (mPFS) of 7.0 months. Baseline clinicopathologic characteristics were similar among the four treatment groups. Compared with chemotherapy, EGFR-TKI monotherapy or EGFR-TKI combination therapy achieved significantly higher ORR (P < 0.001) and longer mPFS (P = 0.003). No ORR or PFS difference was observed between EGFR-TKI monotherapy and combination therapy. In the NGS-identified population (n = 28), patients who received EGFR-TKI plus crizotinib (n = 9) achieved similar ORR (88.9% versus 57.9%, P = 0.195) and mPFS (9.0 versus 8.5 months, hazard ratio 1.10, 95% confidence interval 0.43-2.55, P = 0.45) than those who received EGFR-TKI monotherapy (n = 19), regardless of MET copy number status. Grade 3/4 rashes were significantly more among patients who received EGFR-TKI plus crizotinib (P = 0.026).
Conclusions:
Our findings provided clinical evidence that patients with concurrent EGFR sensitizing mutation and de novo MET amplification/overexpression could benefit from first-line EGFR-TKI monotherapy.
Insights
For non-small-cell lung cancer (NSCLC) with both EGFR mutations and MET amplification, first-line EGFR-tyrosine kinase inhibitor (EGFR-TKI) monotherapy is effective. This approach offers similar outcomes to combination therapies without increased toxicity.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Non-small-cell lung cancer (NSCLC) can present with concurrent epidermal growth factor receptor (EGFR) sensitizing mutations and mesenchymal-epithelial transition factor (MET) amplification.
- This specific molecular profile occurs in approximately 2%-8% of NSCLC cases prior to EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapy.
- Optimal first-line treatment strategies for advanced NSCLC with this co-mutation remain an area of investigation.
Purpose of the Study:
- To determine the optimal first-line therapeutic options for patients diagnosed with advanced NSCLC harboring both EGFR mutations and MET overexpression/amplification.
- To compare the efficacy and safety of different treatment regimens in this patient population.
Main Methods:
- A cohort of 104 treatment-naïve patients with EGFR-mutant, de novo MET-overexpressed advanced NSCLC were identified via immunohistochemistry.
- Patients were stratified into four groups: EGFR-TKI monotherapy, EGFR-TKI plus crizotinib, EGFR-TKI plus chemotherapy, and chemotherapy alone.
- Objective response rate (ORR) and progression-free survival (PFS) were analyzed, with a subset undergoing next-generation sequencing (NGS).
Main Results:
- EGFR-TKI monotherapy and combination therapies demonstrated significantly higher ORR and longer median PFS compared to chemotherapy.
- No significant difference in ORR or PFS was observed between EGFR-TKI monotherapy and combination therapies.
- Patients receiving EGFR-TKI plus crizotinib experienced a higher incidence of Grade 3/4 rashes compared to other groups.
Conclusions:
- First-line EGFR-TKI monotherapy is a clinically effective option for patients with concurrent EGFR mutations and MET amplification/overexpression in advanced NSCLC.
- EGFR-TKI monotherapy provides comparable efficacy to combination therapies in this setting.
- These findings support EGFR-TKI monotherapy as a beneficial first-line treatment strategy.
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