Tepmetko Mechanism of Action

Pharmacotherapeutic group: Antineoplastic agents, other protein kinase inhibitors. ATC code: L01EX21.
Pharmacology: Pharmacodynamics: Mechanism of action: Tepotinib is a kinase inhibitor that targets MET, including variants with exon 14 skipping alterations. Tepotinib inhibits hepatocyte growth factor (HGF)-dependent and -independent MET phosphorylation and MET-dependent downstream signaling pathways. Tepotinib also inhibited melatonin 2 and imidazoline 1 receptors at clinically achievable concentrations.
In vitro, tepotinib inhibited tumor cell proliferation, anchorage-independent growth, and migration of MET-dependent tumor cells. In mice implanted with tumor cell lines with oncogenic activation of MET, including METex14 skipping alterations, tepotinib inhibited tumor growth, led to sustained inhibition of MET phosphorylation, and, in one model, decreased the formation of metastases.
Pharmacodynamic effects: Exposure-Response: Tepotinib exposure-response relationships and the time course of pharmacodynamic response have not been fully characterized.
Cardiac electrophysiology: At the recommended dosage, no large mean increases in QTc (i.e. >20 ms) were detected in patients with various solid tumors. A concentration-dependent increase in QTc interval was observed. The QTc effect of tepotinib at high clinical exposures has not been evaluated.
Clinical efficacy and safety: The efficacy of tepotinib was evaluated in a single-arm, open-label, multicentre study (VISION) in adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harbouring METex14 skipping alterations (n=313).
Patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1 and were either treatment-naïve or had progressed on up to 2 lines prior systemic therapies.
Neurologically stable patients with central nervous system metastases were permitted. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) activating alterations were excluded.
Patients had a median age of 72 years (range 41 to 94), 51% were female and 49% male. The majority of patients were white (62%), followed by Asian patients (34%) and were never (49%) or former smokers (45%). Most patients were ≥65 years of age (79%) and 41% of patients were ≥75 years of age.
The majority of patients (94%) had stage IV disease, 81% had adenocarcinoma histology. Thirteen percent of the patients had stable brain metastases. Patients received tepotinib as first-line (52%) or second- or later line (48%) therapy.
METex14 skipping was prospectively tested by next-generation sequencing in tumour (RNA-based) and/or plasma (ctDNA-based).
Patients received 450 mg tepotinib once daily until disease progression or unacceptable toxicity. Median treatment duration was 7.5 months (range 0.03 to 72 months).
The primary efficacy outcome measure was confirmed objective response (complete response or partial response) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as evaluated by an Independent Review Committee (IRC). Additional efficacy outcome measures included duration of response and progression-free survival assessed by IRC as well as overall survival. Efficacy results are presented in Table 1. (See Table 1).

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Efficacy outcome was independent of the testing modality (liquid biopsy or tumour biopsy) used to establish the METex14 skipping status. Consistent efficacy results in subgroups by prior therapy, presence of brain metastasis or age were observed.
Pharmacokinetics: Absorption: A mean absolute bioavailability of 71.6% was observed for a single 450 mg dose of tepotinib administered in the fed state; the median time to C_max was 8 hours (range from 6 to 12 hours).
The presence of food (standard high-fat, high-calorie breakfast) increased the AUC of tepotinib by about 1.6-fold and C_max by 2-fold.
Distribution: In human plasma, tepotinib is highly protein bound (98%). The mean volume of distribution (Vz) of tepotinib after an intravenous tracer dose (geometric mean and geoCV%) was 574 L (14.4%).
In vitro studies indicate that tepotinib is a substrate for P-glycoprotein (P-gp). While P-gp inhibitors are not expected to alter tepotinib exposure to a clinically relevant extent, strong P-gp inducers may have the potential to decrease tepotinib exposure.
Biotransformation: Metabolism is not the major route of elimination. No metabolic pathway accounted for more than 25% of tepotinib elimination. Tepotinib is primarily metabolized by CYP3A4 and CYP2C8. Only one major circulating plasma metabolite has been identified. There is only a minor contribution of the major circulating metabolite to the overall efficacy of tepotinib in humans.
Elimination: After intravenous administration of single doses, a total systemic clearance (geometric mean and geoCV%) of 12.8 L/h was observed.
Tepotinib is mainly excreted via the faeces (approximately 85% total recovery of radioactivity), with urinary excretion being a minor excretion pathway. After a single oral administration of a radiolabelled dose of 450 mg tepotinib, the unchanged tepotinib represented 45% and 7% of the total radioactivity in faeces and urine, respectively. The major circulating metabolite accounted for only about 3% of the total radioactivity in the faeces.
The effective half-life for tepotinib is approximately 32 h. After multiple daily administrations of 450 mg tepotinib, median accumulation was 2.5-fold for C_max and 3.3-fold for AUC_0-24h.
Dose and time dependence: Tepotinib exposure increases dose-proportionally over the clinically relevant dose range up to 450 mg. The pharmacokinetics of tepotinib did not change with respect to time.
Special populations: A population kinetic analysis did not show any effect of age (range 18 to 89 years), race, gender or body weight, on the pharmacokinetics of tepotinib.
Renal impairment: There was no clinically meaningful change in exposure in patients with mild and moderate renal impairment. Patients with severe renal impairment (creatinine clearance less than 30 mL/min) were not included in clinical trials.
Hepatic impairment: Following a single oral dose of 450 mg, tepotinib exposure was similar in healthy subjects and patients with mild hepatic impairment (Child-Pugh Class A), and was slightly lower (-13% AUC and -29% C_max) in patients with moderate hepatic impairment (Child-Pugh Class B) compared to healthy subjects. However, the free plasma concentrations of tepotinib were in a similar range in the healthy subjects, patients with mild hepatic impairment and in patients with moderate hepatic impairment. The pharmacokinetics of tepotinib have not been studied in patients with severe (Child Pugh Class C) hepatic impairment.
Pharmacokinetic interaction studies: Clinical studies: CYP2C9 Substrates: Physiologically based pharmacokinetic modeling suggested CYP2C9 inhibition is not clinically significant.
Effect of CYP3A/P-gp inducers on tepotinib: In healthy participants, co-administration of a single 450 mg tepotinib dose with the strong CYP3A inducer carbamazepine (300 mg twice daily for 14 days) decreased tepotinib AUC_inf by 35% and C_max by 11% compared to administration of tepotinib alone.
Effect of CYP3A/P-gp inhibitors on tepotinib: In healthy participants, co-administration of a single 450 mg tepotinib dose with the strong CYP3A inhibitor itraconazole (200 mg once daily for 11 days) increased tepotinib AUC_inf by 22% with no change in tepotinib C_max compared to administration of tepotinib alone.
Effect of tepotinib on CYP3A4 substrates: Multiple administrations of 450 mg tepotinib orally once daily had no clinically relevant effect on the pharmacokinetics of the sensitive CYP3A4 substrate midazolam.
Effect of tepotinib on P-gp substrates: Tepotinib is an inhibitor of P-gp. Multiple administrations of tepotinib 450 mg orally once daily had a mild effect on the pharmacokinetics of the sensitive P-gp substrate dabigatran etexilate, increasing its AUC_t by approximately 50% and C_max by approximately 40%.
Effect of acid-reducing agents on tepotinib: Co-administration of omeprazole under fed conditions had no marked effect on the pharmacokinetic profile of tepotinib and its metabolites.
In-vitro studies: Effects of tepotinib on other transporters: Tepotinib or its major circulating metabolite inhibit BCRP, OCT1 and 2, organic-anion-transporting polypeptide (OATP) 1B1 and MATE1 and 2 at clinically relevant concentrations. At clinically relevant concentrations tepotinib represents a remote risk for bile salt export pump (BSEP) whilst it presents no risk for OATP1B3, organic anion transporter (OAT) 1 and 3.
Effects of tepotinib on UDP-glucuronosyltransferase (UGT): The perpetrator risk of tepotinib or its major circulating metabolite on UGT1A1, 1A9 and 2B17 is considered unlikely, whilst it is excluded for the other isoforms (UGT1A3/4/6, and 2B7/15.
Effect of tepotinib on CYP 450 enzymes: At clinically relevant concentrations neither tepotinib nor the major circulating metabolite represent a risk of inhibition of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP2E1. Tepotinib or its major circulating metabolite do not induce CYP1A2, and 2B6.
Toxicology: Preclinical safety data: Oral repeat-dose toxicity studies have been conducted in rats up to 26 weeks and dogs up to 39 weeks.
Increased hepato-biliary parameters concomitant with pronounced cholangitis and pericholangitis were seen in dogs starting at doses of 30 mg tepotinib hydrochloride hydrate per kg per day (approximately 18% the human exposure at the recommended dose of TEPMETKO 450 mg once daily based on AUC). Slightly increased liver enzymes were seen in rats starting at doses 15 mg tepotinib hydrochloride hydrate per kg per day (approximately 3% of the human exposure at the recommended dose of TEPMETKO 450 mg once daily based on AUC). In dogs vomiting and diarrhoea were seen starting at 2.5 mg tepotinib hydrochloride hydrate per kg per day and at exposures approximately 0.3% of the human exposure at the recommended dose of 450 mg TEPMETKO based on AUC. All changes proved to be reversible or showed indications of reversibility or improvements.
A no-observed-adverse-effect-level (NOAEL) was established at 45 mg tepotinib hydrochloride hydrate per kg per day in the 26-week study in rats and at 10 mg tepotinib hydrochloride hydrate per kg per day in the 39-week study in dogs (both equivalent to approximately 4% of the human exposure at the recommended dose of 450 mg TEPMETKO based on AUC).
Genotoxicity: No mutagenic or genotoxic effects of tepotinib were observed in in vitro and in vivo studies. The major circulating metabolite was also shown to be non-mutagenic.
Carcinogenicity: No studies have been performed to evaluate the carcinogenic potential of tepotinib.
Reproduction toxicity: In a first oral embryo-foetal development study, pregnant rabbits received doses of 50, 150, and 450 mg tepotinib hydrochloride hydrate per kg per day during organogenesis. The dose of 450 mg/kg was discontinued due to severe maternal toxic effects. In the 150 mg per kg group, two animals aborted and one animal died prematurely. Mean foetal body weight was decreased at doses of ≥150 mg per kg per day. A dose-dependent increase of skeletal malformations, including malrotations of fore and/or hind paws with concomitant misshapen scapula and/or malpositioned clavicle and/or calcaneous and/or talus, were observed at 50 and 150 mg per kg per day.
In the second embryo-foetal development study, pregnant rabbits received oral doses of 0.5, 5, and 25 mg tepotinib hydrochloride hydrate per kg per day during organogenesis. Two malformed foetuses with malrotated hind limbs were observed (one in the 5 mg/kg group (approximately 0.21% of the human exposure at the recommended dose of TEPMETKO 450 mg once daily based on AUC) and one in the 25 mg/kg group), together with a generally increased incidence of foetuses with hind limb hyperextension.
Fertility studies of tepotinib to evaluate the possible impairment of fertility have not been performed. No morphological changes in male or female reproductive organs were seen in the repeat-dose toxicity studies in rats and dogs.