Abstract 1366TiP
Background
METamp is a mechanism of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs), occurring in 7–15% of patients (pts) who progress on first-line osimertinib. Tepotinib is an oral, once daily (QD), highly selective, potent MET TKI. Tepotinib + gefitinib improved outcomes vs chemotherapy in pts with EGFR-mutant METamp NSCLC and EGFR TKI resistance (INSIGHT; NCT01982955). Median progression-free survival (PFS) was 16.6 vs 4.2 months (HR=0.13; 90% CI: 0.04, 0.43) and median overall survival (OS) was 37.3 vs 13.1 months (HR=0.08; 90% CI: 0.01, 0.51). The objective response (OR) rate was 67% vs 43% (odds ratio=2.67; 90% CI: 0.37, 19.56), and duration of response (DOR) was 19.9 (90% CI: 7.0, NE) vs 2.8 months (90% CI: 2.8, 9.7). Tepotinib + osimertinib may overcome MET-related osimertinib resistance.
Trial design
INSIGHT 2 (NCT03940703) is a global, open-label, phase II trial of tepotinib + osimertinib in pts with advanced EGFR-mutant NSCLC. Pts with acquired resistance to first-line osimertinib and METamp are enrolling (protocol amendment, April 2020). Pts must be ≥18 years old, ECOG PS 0/1 and have normal organ function. METamp in tissue and liquid biopsies, obtained at osimertinib progression, will be centrally confirmed by fluorescence in situ hybridization (FISH) and blood-based next generation sequencing, respectively. For pts with METamp detected by local FISH, central confirmation is not mandated prior to treatment initiation. Pts will receive tepotinib 500 mg (450 mg active moiety) QD + osimertinib 80 mg QD until progressive disease (PD) or withdrawal. The estimated enrollment is 120 pts. The primary endpoint is OR by independent review committee (IRC) (RECIST v1.1) in pts with METamp, centrally confirmed by FISH. Secondary endpoints: OR by investigator assessment, DOR, disease control, PFS, OS, pharmacokinetics, health-related quality of life, tolerability, and safety. An exploratory tepotinib monotherapy arm will enroll 12 pts. At PD (by IRC), pts can switch to combination treatment. These pts will be analyzed separately. Recruitment is ongoing; approximately 125 sites in 17 countries are expected to participate. As of April 2021, 95 sites are active.
Clinical trial identification
NCT03940703.
Editorial acknowledgement
Medical writing assistance (funded by Merck KGaA, Darmstadt, Germany) was provided by Syneos Health, London, UK.
Legal entity responsible for the study
Merck KGaA, Darmstadt, Germany.
Funding
Merck KGaA, Darmstadt, Germany.
Disclosure
Y. Wu: Financial Interests, Personal and Institutional, Other, Institute Grants and Personal fees: AstraZeneca; Financial Interests, Personal and Institutional, Other, Institute Grants and Personal fees: Roche; Financial Interests, Personal and Institutional, Other, Institute Grants and Personal fees: Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Eli Lilly; Financial Interests, Personal, Invited Speaker: Pfizer. E. Nadal: Financial Interests, Personal, Advisory Role: Merck Serono; Financial Interests, Personal, Research Grant: Merck Serono. J. Raskin: Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Lilly; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Other, Travel Expenses: Roche. I. Demedts: Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: Boehringer Ingelheim; Financial Interests, Personal, Advisory Role: GSK; Financial Interests, Personal, Advisory Role: Lilly; Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Takeda. J. Mazieres: Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Novartis. M. Wislez: Financial Interests, Personal, Other, Consulting fees: AstraZeneca; Financial Interests, Personal, Other, Consulting fees: Roche; Financial Interests, Personal, Other, Consulting fees: Novartis. L.M. Tho: Financial Interests, Personal, Other, Honoraria: Pfizer; Financial Interests, Personal, Other, Honoraria: Roche; Financial Interests, Personal, Other, Honoraria: AstraZeneca. S. Viteri: Financial Interests, Personal, Advisory Role: AbbVie; Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Speaker’s Bureau: BMS; Financial Interests, Personal, Speaker’s Bureau: MSD; Financial Interests, Personal, Speaker’s Bureau: Roche; Financial Interests, Personal, Other, Travel expenses: Roche; Financial Interests, Personal, Other, Travel expenses: OSE Pharma; Financial Interests, Personal, Other, Travel expenses: BMS; Financial Interests, Personal, Other, Travel expenses: Merck; Financial Interests, Personal, Other, Travel expenses: Merck Serono; Financial Interests, Personal, Other, Travel expenses: Puma Biotechnology; Financial Interests, Personal, Other, Travel expenses: Janssen Cilag. X. Le: Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Eli Lilly; Financial Interests, Personal, Advisory Role: EMD Serono; Financial Interests, Personal, Funding, for Research: Eli Lilly; Financial Interests, Personal, Funding, for Research: Boehringer Ingelheim. D. Tan: Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Research Grant: Bayer; Financial Interests, Personal, Research Grant: Novartis; Financial Interests, Personal, Research Grant: Pfizer; Financial Interests, Personal, Research Grant: AstraZeneca; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Advisory Role: Boehringer Ingelheim; Financial Interests, Personal, Advisory Role: Takeda; Financial Interests, Personal, Other, Honoraria: Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria: Takeda; Financial Interests, Personal, Other, Honoraria: Novartis; Financial Interests, Personal, Other, Honoraria: Roche; Financial Interests, Personal, Other, Honoraria: Pfizer; Financial Interests, Personal, Other, Honoraria: Merck; Financial Interests, Personal, Advisory Role: Eli Lilly; Financial Interests, Personal, Advisory Role: Merrimack; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Loxo Oncology; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: GlaxoSmithKline; Financial Interests, Institutional, Research Grant: AstraZeneca. M. Takeda: Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Speaker’s Bureau: MSD; Financial Interests, Personal, Speaker’s Bureau: BMS; Financial Interests, Personal, Speaker’s Bureau: Roche; Financial Interests, Personal, Funding, for Research: Roche; Financial Interests, Personal, Funding, for Research: Takeda; Financial Interests, Personal, Funding, for Research: AbbVie; Financial Interests, Personal, Funding, for Research: Merck; Financial Interests, Personal, Funding, for Research: BMS. R. Veillon: Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Speaker’s Bureau: MSD; Financial Interests, Personal, Speaker’s Bureau: BMS; Financial Interests, Personal, Speaker’s Bureau: Roche; Financial Interests, Personal, Funding, for Research: Roche; Financial Interests, Personal, Funding, for Research: Takeda; Financial Interests, Personal, Funding, for Research: AbbVie; Financial Interests, Personal, Funding, for Research: Merck; Financial Interests, Personal, Funding, for Research: BMS. N. Karachaliou: Financial Interests, Personal, Full or part-time Employment: Merck KGaA. B. Ellers-Lenz: Financial Interests, Personal, Full or part-time Employment: Merck KGaA. E.F.F. Smit: Financial Interests, Institutional, Advisory Role: Lilly; Financial Interests, Institutional, Advisory Role: AstraZeneca; Financial Interests, Institutional, Advisory Role: Boehringer Ingelheim; Financial Interests, Institutional, Advisory Role: Roche/Genentech; Financial Interests, Institutional, Advisory Role: Bristol Myers Squibb; Financial Interests, Institutional, Advisory Role: Merck KGaA; Financial Interests, Institutional, Advisory Role: MSD Oncology; Financial Interests, Institutional, Advisory Role: Takeda; Financial Interests, Institutional, Advisory Role: Bayer; Financial Interests, Institutional, Advisory Role: Regeneron; Financial Interests, Institutional, Advisory Role: Novartis; Financial Interests, Institutional, Advisory Role: Daiichi Sankyo; Financial Interests, Institutional, Advisory Role: Seattle Genetics; Financial Interests, Institutional, Funding, for Research: Boehringer Ingelheim; Financial Interests, Institutional, Funding, for Research: Bayer; Financial Interests, Institutional, Funding, for Research: Roche/Genentech; Financial Interests, Institutional, Funding, for Research: AstraZeneca; Financial Interests, Institutional, Funding, for Research: Bristol Myers Squibb. All other authors have declared no conflicts of interest.