INSIGHT 2: a Phase II Study of Tepotinib Plus Osimertinib in MET -Amplified NSCLC and First-Line Osimertinib Resistance

Abstract

MET amplification (METamp), a mechanism of acquired resistance to EGFR tyrosine kinase inhibitors, occurs in up to 30% of patients with non-small-cell lung cancer (NSCLC) progressing on first-line osimertinib. Combining osimertinib with a MET inhibitor, such as tepotinib, an oral, highly selective, potent MET tyrosine kinase inhibitor, may overcome METamp-driven resistance. INSIGHT 2 (NCT03940703), an international, open-label, multicenter Phase II trial, assesses tepotinib plus osimertinib in patients with advanced/metastatic EGFR-mutant NSCLC and acquired resistance to first-line osimertinib and METamp, determined centrally by fluorescence in situ hybridization (gene copy number ≥5 and/or MET/CEP7 ≥2) at time of progression. Patients will receive tepotinib 500 mg (450 mg active moiety) plus osimertinib 80 mg once-a-day. The primary end point is objective response, and secondary end points include duration of response, progression-free survival, overall survival and safety. Trial registration number: NCT03940703 (clinicaltrials.gov)

Osimertinib + Savolitinib to Overcome Acquired MET-Mediated Resistance in Epidermal Growth Factor Receptor–Mutated, MET-Amplified Non–Small Cell Lung Cancer: TATTON

“…For patients with MET-mediated resistance to osimertinib, savolitinib plus osimertinib is currently being assessed prospectively in the ongoing SAVANNAH ( 31 ), ORCHARD ( 43 ), and SAFFRON (NCT05261399) studies, and tepotinib plus osimertinib is being assessed in the INSIGHT2 study (NCT03940703; ref. 46 ).…”

Treatment strategies and outcomes for patients with EGFR-mutant non-small cell lung cancer resistant to EGFR tyrosine kinase inhibitors: Focus on novel therapies

“…Another phase 1b/2 study (NCT02468661) investigating the safety and efficacy of capmatinib alone or in combination with erlotinib vs chemotherapy in patients with advanced EGFRm NSCLC with MET amplification was terminated due to enrollment issues. An identical effort is ongoing with the phase 2 INSIGHT-2 trial (NCT03940703) investigating tepotinib, a highly selective MET inhibitor, in combination with osimertinib for patients with advanced EGFRm NSCLC and MET amplification [93].…”

From targeted therapy to a novel way: Immunogenic cell death in lung cancer

“…A study fully illustrated the role of Hh signaling in EGFR mutant lung cancer, their result showed that, through the induction of mesenchymal properties, Hh could mediate the resistance of EGFR inhibitors (110). Several clinical studies reported acquired resistance to targeted drugs, such as Osimertinib, a MET tyrosine kinase inhibitor (111). The advance in K-RAS targeted medicine faced huge challenge (112).…”