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Tepotinib authorised for advanced non-small cell lung cancer with METex14 skipping

5th October 2021

Tepotinib has received a marketing authorisation from the MHRA for the treatment of advanced, non-small cell lung cancer with METex14 skipping.

In the UK, lung cancer is the third most common cancer with approximately 47,800 new cases every year or 130 every day. There are two main forms of lung cancer: small cell and non-small cell with non-small cell lung cancer (NSCLC) being the most common form, responsible for between 80 to 85% of cases. Survival depends to some extent, on the stage at diagnosis and in women, for example, five-year net survival drops from 62% when diagnosed at Stage 1, to 3% when diagnosed at Stage 4. Mesenchymal epithelial transition (MET) dysfunction, involving a loss of transcription of exon 14 (i.e., MET exon 14 skipping) and occurs an approximately 5% of NSCLC cases. MET codes for a receptor tyrosine kinase and overactive MET-mediated signalling leads to cell proliferation and tumour growth. Tepotinib is the first oral MET inhibitor to be approved and it received approval from the FDA in February 2021, for the treatment of adult patients with metastatic NSCLC harbouring mesenchymal-epithelial transition (MET) exon 14 skipping alterations. It is also under regulatory review by the European Medicines Agency (EMA).

Clinical efficacy

In the Phase II VISION study tepotinib was given once daily at a dose of 500mg to patients with advanced or metastatic NSCLC with a confirmed MET exon 14 skipping mutation. The primary endpoint was an objective response by independent review among patients who had undergone at least 9 months of follow-up. The study found that a partial response occurred in approximately half the patients given tepotinib. In an updated analysis of 146 patients who had at least 9 months of follow-up and were assessed for efficacy, the overall objective response (OOR), by an independent review was 46.2% (95% CI 37.0 – 53.6), with a median duration of follow-up of 11.1 months.

Tepotinib was approved via the FDA project ORBIS, which reviews and approves any promising cancer treatments concurrently with regulatory authorities in six other countries, including the UK’s MHRA. It aims to deliver faster patient access to innovative cancer treatments with potential benefits over existing therapies across the globe.

Tepotinib was originally approved at a dose 450mg tepotinib (2 tablets) once daily via the MRHA’s Early Access to Medicines Scheme in July 2021.

Use of tepotinib in advanced NSCLC granted via EAMS

16th July 2021

Through its early access to medicines scheme, the UK MHRA has permitted the use of tepotinib for advanced non-small-cell lung cancer.

According to Cancer Research UK, lung cancer is the 3rd most common cancer in the UK with approximately 47,800 new cases every year or 130 every day. There are two different types of primary lung cancer: small cell and non-small cell, with the latter accounting for around 80–85% of all cases. While early detection of non-small cell lung cancer has an excellent prognosis with 5-year survival rates of 70–90%, around three-quarters (75%) of patients have advanced disease (i.e., stages III/IV) at the time of diagnosis. In fact, the one-year survival for patients with stage IV disease is only 19%, dropping to 2.9% at 5 years.

In recent years, it has become apparent that there are molecular abnormalities associated with lung cancer and this has led to the search for treatments specifically directed at these abnormalities. One such abnormality relates to Mesenchymal-epithelial transition (MET) factor gene, which, under normal circumstances, plays a crucial role in various cellular functions. The MET gene encodes for a receptor tyrosine kinase that activates signalling pathways involved in cell proliferation, survival and growth and it is mutations in this gene that drives oncogenic activation. One particular aberration identified in non-small-cell lung cancer is skipping of METex14 whereby substitutions or deletions at intron 13, result in skipping intron 14. MET skipping occurs in approximately 5% of non-small-cell lung cancer cases and the resultant loss of exon 14, increases the concentration of MET protein and which drives activation of downstream signalling that promote tumour development via phosphoinositide 3-kinase pathways.

Tepotinib is an oral MET kinase inhibitor which works by inhibiting MET-dependent downstream signalling pathways. The effectiveness of tepotinib as mono-therapy for patients with metastatic non-small-cell lung cancer with MET exon 14 skipping alterations was examined in the phase II VISION study which was published in May 2020. In this open-label phase 2 study, tepotinib was given as a daily dose of 500mg to patients, 18 years and older, with advanced or metastatic non-small-cell lung cancer, confirmed by either liquid or tissue biopsy, with a MET exon 14 skipping mutation. The primary endpoint was the response rate based on the RECIST 1.1 criteria, which represents a standard way to measure a patient’s response to cancer treatment.

A total of 152 patients received tepotinib, of whom, 99 had 9 months of follow-up. The response rate was 46% (95% CL 36 – 57%). Moreover, this response rate was consistent for both liquid and tissue-biopsy (48% and 50% respectively) and the response was similar regardless of baseline characteristics or the number of prior treatments. Adverse reactions of grade 3 severity or higher occurred in 28% of patients, including, most commonly, peripheral oedema (7%) although adverse effects led to treatment discontinuation in only 11% of patients. The authors of the VISION study concluded that tepotinib was associated with a partial response in at least half of all patients.

Based on these findings, the MHRA has permitted the use of tepotinib, via the Early Access to Medicines Scheme (EAMS), for patients with advanced non-small-cell lung cancer. While this does not mean that tepotinib is actually licensed for use, the EAMS recognises the potential value of a treatment where there is a high unmet clinical need.