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Randomized Trial of Tepotinib Plus Gefitinib versus Chemotherapy in EGFR-Mutant NSCLC with EGFR Inhibitor Resistance Due to MET Amplification: INSIGHT Final Analysis

Liam CK 1 , Ahmad AR 2 , Hsia TC 3 , Zhou J 4 , Kim DW 5 , Soo RA 6 Show all authors , Cheng Y 7 , Lu S 8 , Shin SW 9 , Yang JC 10 , Zhang Y 11 , Zhao J 12 , Berghoff K 13 , Bruns R 14 , Johne A 15 , Wu YL 16

Affiliations 

  • 1 Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 2 Beacon International Specialist Centre Sdn Bhd, Selangor, Malaysia
  • 3 China Medical University Hospital, Taichung City, Taiwan
  • 4 The First Affiliated Hospital, Zhejiang University, Hangzhou, China
  • 5 Seoul National University Hospital, Seoul, South Korea
  • 6 National University Cancer Institute, Singapore
  • 7 Jilin Province Cancer Hospital, Changchun, China
  • 8 Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
  • 9 Korea University Anam Hospital, Seoul, South Korea
  • 10 National Taiwan University Hospital, Taipei, Taiwan
  • 11 Zhejiang Cancer Hospital, Hangzhou, China
  • 12 Department of Thoracic Oncology, Peking University Cancer Hospital and Institute, Beijing, China
  • 13 Global Patient Safety, the healthcare business of Merck KGaA, Darmstadt, Germany
  • 14 Department of Biostatistics, the healthcare business of Merck KGaA, Darmstadt, Germany
  • 15 Global Clinical Development, the healthcare business of Merck KGaA, Darmstadt, Germany
  • 16 Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China
Clin Cancer Res, 2023 May 15;29(10):1879-1886.
PMID: 36971777 DOI: 10.1158/1078-0432.CCR-22-3318

Abstract

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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