Tepotinib: First Approval

Abstract

Tepotinib (Tepmetko™, Merck) is a MET tyrosine kinase inhibitor being developed for the treatment of solid tumours. In quarter three of 2019 tepotinib was granted breakthrough therapy status by the US FDA and orphan drug designation by the Japanese Ministry of Health, Labour and Welfare for the treatment of non-small cell lung cancer harbouring MET alterations, and in March 2020 was approved for use in Japan in this indication. This article summarizes the milestones in the develop- ment of tepotinib leading to this first approval.

1 Introduction

Tepotinib (Tepmetko™) is a selective mesenchymal-epithe- lial transition factor (MET) tyrosine kinase inhibitor being developed by Merck KGaA (Merck) for the treatment of solid tumours. MET is a receptor tyrosine kinase overex- pressed or mutated in many tumour cell types that has a role in tumour cell proliferation, survival, invasion, and mobilisation [1]. Tepotinib selectively binds to MET and inhibits MET phosphorylation disrupting the oncogenic MET receptor signalling caused by MET gene alterations, including both MET exon 14 (METex14) skipping alterations and MET protein overexpression. This results in cell death in tumour cells overexpressing MET protein or expressing constitutively activated MET protein [2, 3]. Tepotinib was recently approved for use in Japan as treatment for unre- sectable, advanced or recurrent non-small cell lung cancer (NSCLC) harbouring METex14 skipping alterations [4]. The recommended dose of tepotinib in Japan is 500 mg [500 mg tepotinib hydrochloride hydrate [active ingredient] contains 450 mg tepotinib free base (active moiety)] orally once daily after food [5].

1.1 Company Agreements

In August 2009 EMD Serono, the biopharmaceutical busi- ness of Merck in the US and Canada, entered into a three year research and development agreement with the Univer- sity of Texas M. D. Anderson Cancer Center, to provide M. D. Anderson with early insight into potential cancer treat- ments and to accelerate EMD Serono′s preclinical and early clinical research. Both parties elected not to disclose financial details [6]. This collaboration was renewed in August Enhanced material for this AdisInsight Report can be found at https://doi.org/10.6084/m9.figshare.12170448.

2 Scientific Summary
2.1 Pharmacodynamics

Tepotinib inhibited MET kinase activity with an average IC50 of 1.7 nmol/L and screening against > 400 kinases showed high selectivity of tepotinib for MET [1]. Among a Key milestones in the development of tepotinib for the treatment of non-small cell lung cancer harbouring MET alterations panel of 242 human protein kinases only IRAK4, TrkA, Axl, IRAK1 and Mer were inhibited by ≥ 50% in the presence of tepotinib 10 mmol/L. Formal IC50 determinations revealed values ranging between 615 and 2272 nmol/L indicating the drug is unlikely to have pharmacologically relevant inhibi- tory activity against these off-target kinases [2]. In vivo, tepotinib was associated with tumour regression in murine xenograft models of human cancers, regardless of whether or not MET activation was dependent on hepatocyte growth factor [2].A phase I trial in patients with solid tumours (n = 149) with the primary endpoints of dose-limiting toxicity and treatment emergent adverse events established the phase II recom- mended dose (RP2D) of tepotinib as 500 mg once daily [1].

2.2 Pharmacokinetics

The pharmacokinetic profile of various oral formulations, dosages and regimens of tepotinib has been investigated in a phase I trial NCT01014936 in patients with solid tumours (n = 149). In fed patients receiving the optimised capsule formulation of the drug the median tmax of tepotinib was 8 to 10 h after the first dose. Cmax and AUC0–24 h increased with increasing dose after administration of single and mul- tiple doses either once daily or 3 times per week. A dose proportional increase in Cmax and AUC0–24 h was observed for once-daily doses ≤ 300 mg, with less than dose propor- tional increases observed at higher doses with the capsule formulation [1]. Apparent clearance at steady state (Clss/f) was 11.35–24.50 L/h for tepotinib doses ≤ 315 mg and 35.24 to 40.92 L/h at doses ≥ 700 mg. Estimated Clss/f for the 500 mg tablet formulation was 26.43 L/h. Accumulation was observed upon multiple dosing with all tested regimens. The 500 mg tablet formulation had an estimated average effective t½ of ≈ 46 h based on a median 3.3 accumulation ratio. Peak-to-trough fluctuations were 32.1% around the geometric mean average plasma concentration at steady state (1097.9 ng/ml) [1]. In the phase I study NCT01832506 in Japanese patients with solid tumours (n = 12) [7], the phar- macokinetic profile of tepotinib (e.g. exposure, apparent clearance) was similar to that seen the phase I study in West- ern patients (NCT01014936) [1] across the tepotinib dosage range studied (215–500 mg once daily).

In healthy volunteers (n = 12) administration of a single 500 mg dose of tepotinib in the fasted state and after a high- fat, high-calorie breakfast, produced fasted:fed AUC0-∞ and Cmax ratios of 1.87 and 2.37, respectively [8].After administration of a single oral dose of radiola- belled tepotinib (comprising tepotinib 498 mg spiked with 2.67 MBq [14C]-tepotinib) to volunteers (n = 6) 78.7% (median) of radioactivity was recovered from faeces and 14.4% (median) from urine, mainly as the parent compound (45 and 7%, respectively) [9].

Administration of multiple doses of tepotinib 500 mg once daily to volunteers had no appreciable effect on the AUC or Cmax of the sensitive cytochrome P450 3A4 substrate mida- zolam but increased mean exposure of the sensitive P-glyco- protein substrate dabigatran etexilate [10]. On this basis patients receiving concomitant therapy with tepotinib and P-glycopro- tein substrates should be carefully monitored for the emergence of potential tepotinib-related adverse events [5].Coadministration with omeprazole had a negligible effect on the bioavailability of a single 500 mg dose of tepotinib under fed conditions in volunteers (n = 12) [8].

2.3 Therapeutic Trials

2.3.1 NSCLC

2.3.1.1 Phase Ib/II Tepotinib had promising clinical effi- cacy in patients with NSCLC with METex14 skipping in an interim analysis of the multinational phase II VISION study (NCT02864992). In cohort A, patients with advanced epidermal growth factor receptor (EGFR)/ALK wild-type NSCLC harbouring METex14 skipping identified by liquid or tumour biopsies were treated with tepotinib 500 mg once daily until progression, intolerable toxicity or withdrawal. At data cut-off (18 February 2019), 87 patients had been treated with tepotinib, with 47 continuing to receive the drug. The overall response rate ranged between 45 and 55% according to biopsy method (liquid or tumour) and inde- pendent or investigator assessment. The median duration of response was 12.4–17.1 months, with 55–70% of patients event free at 12 months. Median progression-free survival was 9.5–12.2 months [11].
Tepotinib in combination with gefitinib had durable anti- tumour activity in the phase Ib/II INSIGHT trial in patients with EGFR-positive, T790M-negative, MET overexpression and/or MET amplification NSCLC with resistance to prior EGFR tyrosine kinase inhibitor therapy (NCT01982955) [12]. Patients were randomized to treatment with oral tepotinib 500 mg/day plus gefitinib 250 mg/day (n = 31) or chemother- apy (pemetrexed plus cisplatin/carboplatin for up to 6 × 21-day cycles or 4 cycles plus pemetrexed maintenance; n= 24), until progression, unacceptable toxicity, or withdrawal. At data cut- off (12 December 2018), the median duration of treatment with tepotinib plus gefitinib was 21.4 weeks, with 3 patients remaining on treatment as of January 2020, versus an 18 week median duration of treatment in the chemotherapy group. The overall response rate was 45.2 and 33.3% in the tepotinib plus gefitinib and chemotherapy groups, respectively (hazard ratio/ odds ratio 1.99). Median investigator-assessed progression- free survival was 4.9 and 4.4 months respectively and median overall survival was 17.3 and 18.7 months, respectively. Sub- group analyses revealed overall response rates of 68.4 and 33.3%, respectively, in MET IHC3-positive patients (haz- ard ratio/odds ratio 4.33) and 66.7 and 42.9%, respectively in patients with MET amplification (hazard ratio/odds ratio 2.67). In addition, subgroup analyses in MET IHC3-positive patients showed median PFS in tepotinib/gefitinib recipients was 8.3 months versus 4.4 months in chemotherapy recipi- ents and in patients with MET amplification was 16.6 versus 4.2 months respectively. OS outcomes were also better with tepotinib/gefitinib compared with chemotherapy in MET IHC3-positive patients (median OS 37.3 vs 17.9 months) and in patients with MET amplification (median OS 37.3 vs 13.1 months) [12].

2.3.2 Hepatocellular Carcinoma

2.3.2.1 Phase Ib/II Tepotinib was associated with a sig- nificantly longer time to progression and progression-free survival than sorafenib in Asian patients with MET-posi- tive advanced hepatocellular carcinoma in a phase II study (NCT01988493) [13]. Patients received treatment with tepo- tinib 500 mg once daily (n = 38) or sorafenib 400 mg twice daily (n = 37) in 21-day cycles. The time to progression by independent review was 2.8 months in the tepotinib group compared to 1.4 months in the sorafenib group (p = 0.0043). Median progression-free survival was 2.8 and 1.4 months in tepotinib and sorafenib recipients, respectively (p = 0.0229), and median overall survival was 9.3 and 8.6 months, respec- tively (not significant) [13].

The efficacy of tepotinib was also evaluated in an open- label, multicentre phase Ib/II study NCT02115373 in patients with MET-positive HCC who had previously failed treatment with sorafenib [14]. The primary endpoint in phase II was 12-week investigator-assessed PFS. The 12-week PFS rate was 63.3% (90% CI 50.5, 74.7), which showed consist- ency between predefined subgroups.some cases [5]. Tepotinib should be discontinued if symp- toms of interstitial lung disease are observed and appropriate measures such as administration of corticosteroids should be instituted [5].

2.4 Adverse Events

In an analysis of pooled adverse event data from five phase I and II studies evaluating the anti-tumour efficacy of tepotinib 500 mg/day (NCT01014936, NCT01832506, NCT01988493, NCT02115373 and NCT02864992), 172 (75.4%) and 52 (22.8%) of 228 patients experienced any grade or grade ≥ 3 treatment-related adverse events, respec- tively, including peripheral oedema (33.8 and 3.5%), diar- rhoea (19.7 and 1.8%), fatigue (14.9 and 1.3%), nausea (12.7
and 0%), decreased appetite (11.8 and 0%), increased blood creatinine levels (7.9 and 0.4%), hypoalbuminaemia (7.0 and 0.4%) and increased amylase levels (5.7 and 1.8%). Thirty three (14.5%) patients had dosage reductions because of adverse events and 49 (21.5%) discontinued treatment. Two fatal adverse events were considered by the investigator to be potentially treatment-related, one case each of upper gas- trointestinal haemorrhage and hypoglycaemic coma [15].Interstitial lung disease has been reported in 3.8% of patients treated with tepotinib and has resulted in death.

2.5 Companion Diagnostic

Merck KGaA has entered into a strategic partnership with genomic analysis company ArcherDX to develop a compan- ion diagnostic to identify METex14 skipping alterations in patients with NSCLC [4].

2.6 Ongoing Clinical Trials

The open-label phase II INSIGHT 2 trial (NCT03940703) is currently enrolling patients with stage IIIB/IV NSCLC resistant to first to third generation EGFR tyrosine kinase inhibitors driven by METamp. Participants will receive tepotinib in combination with osimertinib until disease progression, unacceptable toxicity, or withdrawal of con- sent. Recruitment of an anticipated total of 90 patients is ongoing at ≈ 80 study sites in 17 countries in Europe, Asia, and North America [16]. The open-label phase II VISION study NCT02864992 is also ongoing (Cohort C) to confirm the findings from Cohort A and is enrolling patients with METex14 skipping (regardless of METamp status) using the ArcherDX diagnostic assay at > 100 sites in Austria, Bel- gium, France, Germany, Israel, Italy, Japan, the Netherlands, Poland, Spain, South Korea, Taiwan and the USA.

3 Current Status

Tepotinib received its first approval on 25 March 2020 in Japan for the treatment of patients with unresectable, advanced or recurrent NSCLC with METex14 skipping alterations [4]. In September 2019 the US Food and Drug Administration also granted Breakthrough Therapy Designa- tion to tepotinib in patients with metastatic NSCLC harbour- ing METex14 skipping alterations who progressed following platinum-based cancer therapy [17].

Compliance with Ethical Standards

Funding The preparation of this review was not supported by any external funding.

Conflict of interest During the peer review process the manufacturer of the agent under review was offered an opportunity to comment on the article. Changes resulting from any comments received were made by the authors on the basis of scientific completeness and accuracy. A. Markham, a contracted employee of Adis International Ltd/Springer Nature, is responsible for the article content and declares no relevant conflicts of interest.

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