In about 3–5% of all non-small cell lung cancers (NSCLCs), alterations of the MET signalling pathway are found. These correlate with particularly aggressive tumour behaviour and a poor clinical prognosis. Therefore, targeting the MET pathway could prove beneficial in these patients.
One such drug is being developed by Merck KGaA. Tepotinib is an oral small molecule MET inhibitor; it’s designed to inhibit the oncogenic MET receptor signalling that results from alterations in the MET gene.
These alterations include MET exon 14 skipping alterations, MET gene amplification and MET protein overexpression. The drug is being investigated for the treatment of unresectable, advanced or recurrent non-small cell lung cancer with MET exon 14 skipping alterations.
An open label Phase II study has been done in NSCLC patients with MET exon 14 skipping mutations.1 At the time of reporting, once daily 500 mg doses of tepotinib had been given to 152 patients with this form of cancer, 99 of whom had been followed for at least 9 months.
The response rate was 46% and the median duration of response was 11.1 months. Adverse events, including peripheral oedema, led to discontinuation in 11% of patients.
Its activity in combination with the epidermal growth factor receptor (EGFR) inhibitor, gefitinib, in EGFR-mutant NSCLC with MET overexpression or amplification in patients who have acquired resistance prior to EGFR inhibitor therapy has also been assessed.2
An open label, randomised Phase Ib/II study has been done. In the Phase Ib part, 18 adult patients with advanced or metastatic NSCLC were enrolled and given 300 or 500 mg of oral tepotinib plus 250 mg of gefitinib once a day. As no dose-limiting toxicities were observed, the Phase II dose was set at 500 mg.
In the Phase II part, 55 patients with EGFR-mutant, T790M-negative NSCLC MET overexpression or amplification were given the combination or standard platinum chemotherapy. Low recruitment numbers led to the Phase II part ending early, making the results exploratory.
Survival outcomes were similar between the groups: the median progression-free survival was 4.9 months for the tepotinib group and 4.4 with chemotherapy; the median overall survival was 17.3 months in the former and 18.7 months in the latter.
Both were longer with tepotinib plus gefitinib in those patients with high MET overexpression.
The most frequent treatment-related grade 3 or worse adverse events with the combination were increases in amylase and lipase.
It is also being investigated in combination with the tyrosine kinase inhibitor, osimertinib, in EGFR-mutant, MET gene amplified, locally advanced or metastatic NSCLC that has acquired resistance to prior treatment with EGFR tyrosine kinase inhibitors. The company is also assessing its potential in other combinations and in different tumours.
- P.K. Paik, et al., N. Engl. J. Med. (2020): doi: 10.1056/NEJMoa2004407.
- Y-L. Wu, et al., Lancet Respir. Med. 29, S2213 (2020).