tepotinib

Tepmetko (tepotinib) is an oral MET inhibitor designed to inhibit MET receptor signaling caused by MET gene mutations, including MET exon 14 skipping mutations, MET amplification, or MET protein overexpression.

Before Tepotinib, there were two multi-target inhibitors, crizotinib and cabozantinib, that could target MET.

On March 25, 2020, Merck announced that the Japanese Ministry of Health, Labor and Welfare approved the marketing of its Tepmetko (tepotinib) for the treatment of patients with unresectable, advanced or recurrent non-small cell lung cancer (NSCLC) with MET exon 14 skipping mutations.

Tepotinib is the world’s first approved oral single-target inhibitor of c-Met.

[Tepmetko (tepotinib, tepotinib) mechanism of action]

Tepotinib is a kinase inhibitor targeting MET, including exon 14 skipping variants. It inhibits MET phosphorylation and subsequent downstream signaling pathways to inhibit tumor cell proliferation, anchorage-independent growth and MET-dependent tumor cell migration.

Tepotinib can also down-regulate the expression of epithelial-mesenchymal transition (EMT) promoting genes (such as MMP 7, COX-2, WNT 1, MUC5B and c-MYC), and up-regulate EMT suppressing genes (such as MUC5AC, MUC 6, GSK) in c-met amplified gastric cancer cells 3β and E-cadherin), suggesting that the anti-tumor activity of Tepmetko is at least partly due to the negative regulation of c-met-induced EMT. It has also been shown to inhibit melatonin 1B and Nischarin at clinically relevant concentrations, although the mechanism of this activity with Tepmetko is unclear.

[Tepmetko (tepotinib, tepotinib) study data]

The regulatory approval of Tepmetko is based on data from the pivotal Phase II VISION study (NCT02864992). This is the largest clinical study to date in patients with metastatic NSCLC carrying METex14 skipping alterations. A total of 152 NSCLC patients carrying METex14 skipping alterations received Tepmetko treatment.

The results showed that the overall response rate (ORR) of Tepmetko in patients who had not received previous treatment (n=69, treatment-naïve group) and patients who had previously received treatment (n=83, treatment-experienced group) were 43% (99%CI: 32-56) and 43%, respectively. % (95% CI: 33-55), the median duration of response (DOR) in the two groups was 10.8 months and 11.1 months respectively, the proportions of patients in the two groups with response time ≥ 6 months were 67% and 75%, respectively, and the proportions of patients with response time ≥ 9 months were 30% and 50% respectively.