Preliminary data from the INSIGHT 2 study shows that combining osimertinib and tepotinib may be effective in overcoming METamp-induced resistance in EGFRm NSCLC patients

MET amplification (METamp) is a resistance mechanism to EGFR tyrosine kinase inhibitors (TKIs) occurring via the over-activation of downstream signaling pathways such as PI3K and MAPK. About 15–30% of patients with EGFRm NSCLC treated with osimertinib develop resistance through METamp. 

Tepotinib (TEPMETKO) was the first oral MET inhibitor to be approved for the treatment of advanced NSCLC with MET gene mutations anywhere in the world (first approval in Japan in March 2020). Tepotinib was granted accelerated approval by the US FDA in February 2021, making it the first oral MET inhibitor approved in the US for patients with metastatic NSCLC with METex14 skipping mutations. It is also approved by the European Commission (EC). The FDA has also approved another MET inhibitor, i.e., Capmatinib (TABRECTA). It is important to note that not only MET alterations are a main oncogenic driver in NSCLC, but it is also highly linked to resistance to targeted treatments, most notably those treated with EGFR inhibitors. Therefore, combining EGFR inhibitor and MET inhibitor may be effective in overcoming METamp-induced resistance.

INSIGHT 2  (NCT03940703) was a global single-arm, open-label, Phase II trial of tepotinib in patients with advanced or metastatic NSCLC harboring activating EGFR mutations that has progressed following first-line treatment with osimertinib. EMD Serono, the healthcare business of Merck KGaA, Darmstadt, Germany has sponsored the trial. 

According to the initial findings from this trial, confirmed ORR was 54.5% in 22 FISH METamp Tepotinib + Osimertinib treated patients with ≥ 9 months follow-up, with 6/12 responders still on treatment. ORR was 45.8% in 48 FISH METamp patients with ≥ 3 months follow-up. Median DoR was not reached. Responses in the tepotinib plus osimertinib arm were generally seen within 6 weeks, with half of the responders receiving therapy for ≥ 6 months. The median duration of response had not been attained at the time of analysis.

Of 88 Tepotinib plus Osimertinib treated patients, 73.9%/23.9% had any grade/Grade≥3 treatment-related adverse events (AEs). The primary reason for discontinuation was AEs in 6 patients (6.8%).

According to this study, Tepotinib and Osimertinib showed better responses than Tepotinib alone. The ORR at ≥ 6 months of follow-up in 12 patients who received tepotinib monotherapy was 8.3%.

The development of acquired resistance to osimertinib has reduced the remarkable efficacy of osimertinib in the treatment of patients with advanced EGFR-mutated NSCLC. A better molecular characterization of treatment-naive patients who progressed on osimertinib is eagerly anticipated due to the limited information currently available concerning resistance mechanisms to front-line osimertinib. To address MET-related osimertinib resistance, combination therapy with a MET TKI such as tepotinib may emerge as a treatment option. In conclusion, the initial analysis of INSIGHT 2, Tepotinib + Osimertinib was highly active and well tolerated in patients with EGFRm NSCLC with METamp after progression on 1L osimertinib. 

Expert Opinion: “Tepotinib plus Osimertinib is an active oral regimen, providing a potential chemotherapy-sparing targeted therapy option for patients with EGFRm NSCLC with METamp after progression on IL Osimertinib, who have a high unmet need”

For more insights: Non-small Cell Lung Cancer (NSCLC) Market, Small Cell Lung Cancer (SCLC) Market, BRAF-Non-small cell lung cancer (NSCLC) Market, EGFR-Non-small cell lung cancer (NSCLC) Market, c-MET-Non-small cell lung cancer (NSCLC) Market, ALK-Non-small cell lung cancer (NSCLC) Market