Promising clinical activity of tepotinib plus osimertinib in NSCLC with MET amplification after progression on first-line osimertinib

Tepotinib plus osimertinib improves overall objective response versus tepotinib alone in patients with EGFR-mutated non-small cell lung cancer (NSCLC) with MET amplification after progression on first-line osimertinib in the phase 2 INSIGHT-2 trial.

About 15–30% of patients with EGFR-mutated NSCLC treated with osimertinib develop resistance through MET amplification, which is associated with poor prognosis [1]. The previous phase 1/2 INSIGHT trial (NCT01982955) already showed clinical activity of the selective, oral MET-inhibitor tepotinib (plus gefitinib) in patients with MET amplification and acquired resistance to previous EGFR inhibitors [2]. Prof. Julien Mazières (CHU de Toulouse, France) presented the first findings from the current open-label phase 2 INSIGHT-2 trial (NCT03940703), which evaluated the clinical activity and safety of tepotinib plus osimertinib in this population [3].

The INSIGHT-2 trial enrolled 100 patients with locally advanced/metastatic EGFR-mutated NSCLC who acquired resistance to first-line osimertinib and had MET amplification. MET amplification was detected by in-situ hybridisation in tissue biopsies (MET GCN ≥5 and/or MET/CEP7 ≥2) and/or by next-generation sequencing in liquid biopsies (MET GCN ≥2.3). A total of 88 participants were treated with tepotinib (500 mg every day) plus osimertinib (80 mg every day) and 12 participants were treated with tepotinib alone. The primary endpoint was the overall response rate (ORR).

In participants treated with tepotinib plus osimertinib, ORR was 45.8% to 56.5% depending on the time of follow-up and/or MET amplification detection method. The ORR was only 8.3% in participants treated with tepotinib alone. The safety profile was consistent with the known safety profiles of tepotinib and osimertinib. Grade ≥3 adverse events were observed in 23.9% of patients treated with tepotinib plus osimertinib. Adverse events led to the discontinuation of one or both drugs in 18.2% of participants.

“Tepotinib plus osimertinib is an active oral regimen, providing a potential chemotherapy-sparing targeted therapy option for patients with EGFR-mutated NSCLC with MET amplification after progression on first-line osimertinib,” concluded Prof. Mazières.

1. Koulouris A, et al. Cancers (Basel) 2022; 13: 3337.
2. Wu Y-L, et al. Lancet Respir Med. 2020; 8: 1132-1143.
3. Mazieres J, et al. Tepotinib + osimertinib for EGFRm NSCLC with MET amplification (METamp) after progression on first-line (1L) osimertinib: Initial results from the INSIGHT 2 study. Abstract LBA52, ESMO Congress 2022, Paris, France, 09–13 September.

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Posted on 16 November 202229 February 2024