MO01.48 INSIGHT 2: Tepotinib + Osimertinib in EGFR-Mutant NSCLC with Resistance to 1st-Line Osimertinib due to MET Amplification

Background: MET amplification is a mechanism of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), occurring in ∼15% of patients who progress on 1st-line osimertinib therapy. Combination of osimertinib 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 patients with EGFR-mutant MET-amplified non-small cell lung cancer (NSCLC) and EGFR TKI resistance compared to chemotherapy (INSIGHT: NCT01982955); progression-free survival was 16.6 vs 4.2 months (hazard ratio [HR]=0.13; 90% CI: 0.04, 0.43) and overall survival was 37.3 vs 13.1 months (HR=0.08; 90% CI: 0.01, 0.51). Methods: INSIGHT 2 is a global, open-label, Phase II trial of tepotinib + osimertinib in patients with advanced EGFR-mutant NSCLC. Following a protocol amendment in April 2020, the study is enrolling patients with acquired resistance to 1st-line osimertinib due to MET amplification. Enrollment is allowed based on local fluorescence in situ hybridization (FISH) testing while awaiting central confirmation of MET amplification. Patients must be ≥18 years old, have ECOG PS of 0/1 and normal organ function. Patients 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 patients is ongoing (endpoint: dose-limiting toxicities). The study is anticipated to enroll 120 patients. Twelve patients will initially receive tepotinib monotherapy followed by combination of tepotinib + osimertinib upon disease progression. The primary endpoint is objective response rate by independent review committee (RECIST v1.1) in patients with MET amplification determined centrally by FISH. Secondary endpoints are objective response rate by investigator assessment, duration of response, disease control, progression-free survival, overall survival, 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. Results and conclusions: As this is a trial in progress, results and conclusions cannot be shared yet. Previously presented at ESMO Congress 2020, “FNP:1415TiP”, “Egbert F. Smit et al.” - Reused with permission