Abstract 1415TiP
Background
METamp is a mechanism of acquired resistance to EGFR TKIs, occurring in ∼15% of pts who progress on 1st-line osimertinib therapy. Combination with a MET TKI may overcome MET-related osimertinib resistance. Tepotinib is an oral, once-daily (QD), highly selective, potent MET TKI. Tepotinib + gefitinib is associated with improved outcomes in pts with EGFR-mutant METamp NSCLC and EGFR TKI resistance compared to chemotherapy (INSIGHT: NCT01982955); progression-free survival (PFS) was 16.6 vs 4.2 months (HR=0.13; 90% CI: 0.04, 0.43) and overall survival (OS) was 37.3 vs 13.1 months (HR=0.08; 90% CI: 0.01, 0.51).
Trial design
INSIGHT 2 is a global, open-label, phase II trial of tepotinib + osimertinib in pts with advanced EGFR-mutant NSCLC. Following a protocol amendment in Apr 2020, the study is enrolling pts with acquired resistance to 1st-line osimertinib due to METamp. Enrollment is allowed based on local FISH testing while awaiting central confirmation of METamp. Pts must be ≥18 years old, have ECOG PS of 0/1 and normal organ function. Pts will receive tepotinib (500 mg QD) + osimertinib (80 mg QD) until disease progression, unacceptable toxicity, or consent withdrawal. A safety run-in confirming the dose and regimen comprising ≥6 pts is ongoing (endpoint: dose-limiting toxicities). The study is anticipated to enroll 120 pts. Twelve pts will initially receive tepotinib monotherapy followed by combination of tepotinib + osimertinib upon disease progression. Primary endpoint: objective response rate (ORR) by independent review committee (RECIST v1.1) in pts with METamp determined centrally by FISH. Secondary endpoints: ORR by investigator assessment, duration of response, disease control, PFS, OS, pharmacokinetics, health-related quality of life, tolerability, and safety (NCI-CTCAE v5.0). Recruitment is ongoing, with >300 patients prescreened. Approximately 100 sites in 15 countries in Europe, Asia, and North America are expected to participate.
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
E.F. Smit: Advisory/Consultancy: Lilly; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution): Boehringer Ingelheim; Advisory/Consultancy, Research grant/Funding (institution): Roche/Genentech; Advisory/Consultancy, Research grant/Funding (institution): BMS; Advisory/Consultancy: Merck KGaA; Advisory/Consultancy: MSD Oncology; Advisory/Consultancy: Takeda; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy: Regeneron; Advisory/Consultancy: Novartis; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: Seattle Genetics. E. Felip: Advisory/Consultancy, Speaker Bureau/Expert testimony: Pfizer; Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy, Speaker Bureau/Expert testimony: AstraZeneca; Advisory/Consultancy, Speaker Bureau/Expert testimony: BMS; Advisory/Consultancy: Guardant Health; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony: Takeda; Advisory/Consultancy: AbbVie; Advisory/Consultancy: Blueprint Medicines; Advisory/Consultancy, Speaker Bureau/Expert testimony: Lilly; Advisory/Consultancy: Merck KGaA; Advisory/Consultancy, Speaker Bureau/Expert testimony: MSD; Advisory/Consultancy: Janssen; Advisory/Consultancy: Samsung; Speaker Bureau/Expert testimony: Medscape; Speaker Bureau/Expert testimony: prIME Oncology; Speaker Bureau/Expert testimony: Touchtime; Research grant/Funding (self): Fundación Merck Salud; Research grant/Funding (self): Grant for Oncology Innovation (GOI); Officer/Board of Directors: Grifols (Independent Member). N. Karachaliou, B. Ellers-Lenz: Full/Part-time employment: Merck KGaA, Darmstadt, Germany. Y-L. Wu: Research grant/Funding (institution), Institute grants and personal fees: AstraZeneca; Research grant/Funding (institution), Institute grants and personal fees: Roche; Research grant/Funding (institution), Institute grants and personal fees: Boehringer Ingelheim; Speaker Bureau/Expert testimony: BMS; Speaker Bureau/Expert testimony: MSD; Speaker Bureau/Expert testimony: Eli Lilly; Speaker Bureau/Expert testimony: Pfizer.