MO19-2 INSIGHT2: Tepotinib + osimertinib in pts with EGFR-mutant NSCLC and acquired resistance to 1L osimertinib due to METamp

MET amplification (METamp) is a mechanism of acquired resistance to EGFR TKIs, occurring in ∼15% of patients (pts) who progress on 1st-line (1L) 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). 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 1L 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 an 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 will confirm the dose and regimen in at least 6 pts (endpoint: dose-limiting toxicities). The study is anticipated to enroll 120 pts. Twelve pts will initially receive tepotinib monotherapy followed by a combination of tepotinib + osimertinib upon disease progression. Primary endpoint: objective response rate (ORR) by independent review (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 pts prescreened. Approximately 103 sites in 15 countries in Europe, Asia, and North America are expected to participate.