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Randomized Trial of Tepotinib Plus Gefitinib versus Chemotherapy in EGFR-Mutant NSCLC with EGFR Inhibitor Resistance
Chong Kin Liam1, Azura Rozila Ahmad2, Te-Chun Hsia3
1Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
Purpose:
The final analyses of the INSIGHT phase II study evaluating tepotinib (a selective MET inhibitor) plus gefitinib versus chemotherapy in patients with MET-altered EGFR-mutant NSCLC (data cut-off: September 3, 2021).
Patients And Methods:
Adults with advanced/metastatic EGFR-mutant NSCLC, acquired resistance to first-/second-generation EGFR inhibitors, and MET gene copy number (GCN) ≥5, MET:CEP7 ≥2, or MET IHC 2+/3+ were randomized to tepotinib 500 mg (450 mg active moiety) plus gefitinib 250 mg once daily, or chemotherapy. Primary endpoint was investigator-assessed progression-free survival (PFS). MET-amplified subgroup analysis was preplanned.
Results:
Overall (N = 55), median PFS was 4.9 months versus 4.4 months [stratified HR, 0.67; 90% CI, 0.35-1.28] with tepotinib plus gefitinib versus chemotherapy. In 19 patients with MET amplification (median age 60.4 years; 68.4% never-smokers; median GCN 8.8; median MET/CEP7 2.8; 89.5% with MET IHC 3+), tepotinib plus gefitinib improved PFS (HR, 0.13; 90% CI, 0.04-0.43) and overall survival (OS; HR, 0.10; 90% CI, 0.02-0.36) versus chemotherapy. Objective response rate was 66.7% with tepotinib plus gefitinib versus 42.9% with chemotherapy; median duration of response was 19.9 months versus 2.8 months. Median duration of tepotinib plus gefitinib was 11.3 months (range, 1.1-56.5), with treatment >1 year in six (50.0%) and >4 years in three patients (25.0%). Seven patients (58.3%) had treatment-related grade ≥3 adverse events with tepotinib plus gefitinib and five (71.4%) had chemotherapy.
Conclusions:
Final analysis of INSIGHT suggests improved PFS and OS with tepotinib plus gefitinib versus chemotherapy in a subgroup of patients with MET-amplified EGFR-mutant NSCLC, after progression on EGFR inhibitors.
Insights
Tepotinib plus gefitinib improved progression-free survival and overall survival in patients with MET-amplified EGFR-mutant NSCLC who progressed on EGFR inhibitors. This combination therapy shows promise for a specific subset of non-small cell lung cancer patients.
Area of Science:
- Oncology
- Pharmacology
Background:
- Non-small cell lung cancer (NSCLC) with EGFR mutations is often treated with EGFR inhibitors.
- Acquired resistance to EGFR inhibitors, particularly through MET amplification, is a significant clinical challenge.
- Tepotinib is a selective MET inhibitor investigated for overcoming resistance mechanisms.
Purpose of the Study:
- To evaluate the efficacy of tepotinib plus gefitinib versus chemotherapy in patients with MET-altered, EGFR-mutant NSCLC.
- To analyze progression-free survival (PFS) as the primary endpoint in a phase II study.
- To conduct a preplanned subgroup analysis for patients with MET amplification.
Main Methods:
- Randomized phase II trial (INSIGHT study) comparing tepotinib plus gefitinib against chemotherapy.
- Inclusion criteria: advanced/metastatic EGFR-mutant NSCLC, resistance to prior EGFR inhibitors, and specific MET alterations (GCN ≥5, MET:CEP7 ≥2, or MET IHC 2+/3+).
- Primary endpoint: investigator-assessed PFS. Secondary endpoints included overall survival (OS) and objective response rate (ORR).
Main Results:
- In the overall population (N=55), median PFS was 4.9 months for tepotinib plus gefitinib versus 4.4 months for chemotherapy (HR, 0.67).
- In the MET-amplified subgroup (N=19), tepotinib plus gefitinib significantly improved PFS (HR, 0.13) and OS (HR, 0.10) compared to chemotherapy.
- The objective response rate was 66.7% with tepotinib plus gefitinib versus 42.9% with chemotherapy in the MET-amplified subgroup, with a longer median duration of response (19.9 vs 2.8 months).
Conclusions:
- Tepotinib plus gefitinib demonstrates improved PFS and OS in patients with MET-amplified EGFR-mutant NSCLC post-EGFR inhibitor progression.
- The combination therapy offers a potential treatment option for this specific resistant NSCLC subgroup.
- Final INSIGHT study analyses support the efficacy of targeting MET in combination with EGFR inhibition in selected NSCLC patients.
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