Tepmetko

White-pink, oval, biconvex film-coated tablet with embossment 'M' on one side and plain on the other side. The film-coated tablets have a length of approximately 18 mm, a width of approximately 9 mm, and a thickness of approximately 7 mm.
Each film-coated tablet contains 225 mg tepotinib (equivalent to 250 mg tepotinib hydrochloride hydrate).
Excipient with known effect: Each film-coated tablet contains 4.37 mg lactose monohydrate.
Excipients/Inactive Ingredients: Tablet core: Mannitol, Colloidal anhydrous silica, Crospovidone, Magnesium stearate, Microcrystalline cellulose.
Film-coating: Hypromellose, Lactose monohydrate, Macrogol, Triacetin, Red iron oxides (E172), Titanium dioxide.

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.

TEPMETKO is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) harbouring mesenchymal-epithelial transition factor gene (MET) exon 14 (METex14) skipping alterations.

Treatment must be initiated and supervised by a physician experienced in the use of anticancer therapies.
Prior to initiation of treatment with TEPMETKO the presence of METex14 skipping alterations should be confirmed by a validated test method using nucleic acids isolated from plasma or tumour specimens.
Posology: The recommended dose is 450 mg tepotinib (2 tablets) taken once daily. Treatment should continue until disease progression or unacceptable toxicity.
If a daily dose is missed, it can be taken as soon as remembered on the same day, unless the next dose is due within 8 hours.
Dose modification for adverse reactions: If pulmonary symptoms indicative of interstitial lung disease (ILD)-like reactions occur, TEPMETKO should be withheld and patients should be promptly investigated for alternative diagnosis or specific aetiology of interstitial lung disease. TEPMETKO must be permanently discontinued if interstitial lung disease is confirmed and the patient treated appropriately (see Precautions).
The recommended dose reduction of TEPMETKO for the management of adverse reactions is 225 mg orally once daily. Permanently discontinue TEPMETKO in patients who are unable to tolerate 225 mg orally once daily.
The recommended dosage modifications of TEPMETKO for adverse reactions are provided in Table 2. (See Table 2.)

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Renal impairment: No dose adjustment is recommended in patients with mild or moderate renal impairment (creatinine clearance 30 to 89 mL/min) (see Pharmacology: Pharmacokinetics under Actions). The pharmacokinetics and safety of tepotinib in patients with severe renal impairment (creatinine clearance below 30 mL/min) have not been studied.
Hepatic impairment: No dose adjustment is recommended in patients with mild (Child Pugh Class A) or moderate (ChildPugh Class B) hepatic impairment (see Pharmacology: Pharmacokinetics under Actions). The pharmacokinetics and safety of tepotinib in patients with severe hepatic impairment (Child Pugh Class C) have not been studied.
Elderly: No dose adjustment is necessary in patients aged 65 years and above (see Pharmacology: Pharmacokinetics under Actions).
Paediatric population: Safety and effectiveness of TEPMETKO in paediatric patients below 18 years of age have not been established.
Method of administration: TEPMETKO is for oral use. The tablet(s) should be taken with food and should be swallowed whole.
Administration to patients who have difficulty swallowing solids: If the patient is unable to swallow, the tablets can be dispersed in 30 mL of non-carbonated water. No other liquids should be used or added. Drop the tablets in a glass with water without crushing, stir until the tablets dispersed into small pieces (the tablet will not completely dissolve) and swallow the dispersion immediately or within 1 hour. Do not chew pieces of the tablet. Rinse with additional 30 mL and drink immediately to ensure that no residues remain in the glass and the full dose is administered.
If an administration via a naso-gastric tube (with at least 8 French gauge) is required, disperse the tablets in 30 mL of non-carbonated water as described above. Administer the 30 mL of liquid immediately or within 1 hour as per naso-gastric tube manufacturer's instructions. Immediately rinse twice with 30 mL each to ensure that no residues remain in the glass or syringe and the full dose is administered.

Tepotinib has been investigated at doses up to 1,261 mg. Symptoms of overdose have not been identified. There is no specific treatment in the event of tepotinib overdose. In case of overdose, TEPMETKO should be withheld and symptomatic treatment initiated.

Hypersensitivity to the active substance or to any of the excipients listed in Description.

Interstitial lung disease/Pneumonitis: Interstitial lung disease (ILD) or ILD-like adverse reactions have been reported in 8 patients (2.6%) with advanced NSCLC with METex14 skipping alterations who received tepotinib monotherapy at the recommended dosage regimen (n=313), including 1 case of Grade 3 or higher; serious cases occurred in 4 patients (1.3%), 1 case was fatal.
Patients should be monitored for pulmonary symptoms indicative for ILD-like reactions. TEPMETKO should be withheld and patients should be promptly investigated for alternative diagnosis or specific aetiology of interstitial lung disease. TEPMETKO must be permanently discontinued if interstitial lung disease is confirmed and the patient be treated appropriately.
Hepatotoxicity: Hepatotoxicity occurred in patients treated with TEPMETKO (see Adverse Reactions). Increased alanine aminotransferase (ALT)/increased aspartate aminotransferase (AST) occurred in 18% of patients treated with TEPMETKO. Grade 3 or 4 increased ALT/AST occurred in 4.7% of patients. Four patients (0.8%) discontinued TEPMETKO due to increased ALT/AST. The median time-to-onset of Grade 3 or higher increased ALT/AST was 47 days (range 1 to 262).
Monitor liver function tests (including ALT, AST, and total bilirubin) prior to the start of TEPMETKO, every 2 weeks during the first 3 months of treatment, then once a month or as clinically indicated, with more frequent testing in patients who develop increased transaminases or bilirubin. Based on the severity of the adverse reaction, withhold, dose reduce, or permanently discontinue TEPMETKO (see Dosage & Administration).
Embryo-foetal toxicity: TEPMETKO can cause foetal harm when administered to pregnant women (see Use in Pregnancy & Lactation).
Women of childbearing potential or male patients with female partners of childbearing potential should be advised of the potential risk to a foetus.
Women of childbearing potential should use effective contraception during TEPMETKO treatment and for at least 1 week after the last dose.
Male patients with female partners of childbearing potential should use barrier contraception during TEPMETKO treatment and for at least 1 week after the last dose.
Interpretation of laboratory tests: Nonclinical studies suggest that tepotinib or its main metabolite inhibit the renal tubular transporter proteins organic cation transporter (OCT) 2 and multidrug and toxin extrusion transporters (MATE) 1 and 2 (see Pharmacology: Pharmacokinetics under Actions). Creatinine is a substrate of these transporters, and the observed increases in creatinine (see Adverse Reactions) may be the result of inhibition of active tubular secretion rather than renal injury. Renal function estimates that rely on serum creatinine (creatinine clearance or estimated glomerular filtration rate) should be interpreted with caution considering this effect.
Lactose content: TEPMETKO contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Effects on ability to drive and use machines: TEPMETKO has no influence on the ability to drive and use machines.

Contraception in males and females: Pregnancy testing is recommended in women of childbearing potential prior to initiating treatment with TEPMETKO.
Women of childbearing potential should use effective contraception during TEPMETKO treatment and for at least 1 week after the last dose.
Male patients with female partners of childbearing potential should use barrier contraception during TEPMETKO treatment and for at least 1 week after the last dose.
Pregnancy: There are no clinical data on the use of TEPMETKO in pregnant women. Studies in animals have shown teratogenicity (see Pharmacology: Toxicology: Preclinical safety data under Actions). Based on the mechanism of action and findings in animals TEPMETKO can cause foetal harm when administered to pregnant women.
TEPMETKO should not be used during pregnancy, unless the clinical condition of the woman requires treatment with tepotinib. Women of childbearing potential or male patients with female partners of childbearing potential should be advised of the potential risk to a foetus.
Breast-feeding: There are no data regarding the secretion of tepotinib or its metabolites in human milk or its effects on the breast-fed infant or milk production. Breast-feeding should be discontinued during treatment with TEPMETKO and for one week after final dose.
Fertility: No human data on the effect of TEPMETKO on fertility are available. No morphological changes in male or female reproductive organs were seen in the repeat-dose toxicity studies in rats and dogs (see Pharmacology: Toxicology: Preclinical safety data under Actions).

The following adverse reactions are described in greater detail elsewhere in the labeling: Interstitial Lung Disease (see Precautions); Hepatotoxicity (see Precautions).
Clinical trials experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The pooled safety population described in Precautions reflect exposure to TEPMETKO in 506 patients with solid tumors enrolled in five open-label, single-arm studies receiving TEPMETKO as single agent at a dose of 450 mg once daily. This included 313 patients with NSCLC positive for METex14 skipping alterations, who received TEPMETKO in VISION. Among 506 patients who received TEPMETKO, 44% were exposed for 6 months or longer, and 22% were exposed for greater than one year.
The data described as follows reflect exposure to TEPMETKO 450 mg once daily in 313 patients with metastatic non-small cell lung cancer (NSCLC) with METex14 skipping alterations in VISION (see Pharmacology: Pharmacodynamics under Actions).
Serious treatment-emergent adverse events occurred in 51% of patients who received TEPMETKO. Serious treatment-emergent adverse events in >2% of patients included pleural effusion (6.1%), pneumonia (5.4%), edema (5.1%), general health deterioration (3.8%), dyspnea (3.5%), musculoskeletal pain (2.9%), and pulmonary embolism (2.2%). Fatal adverse events occurred in one patient (0.3%) due to pneumonitis, and in one patient (0.3%) due to dyspnea from fluid overload.
Permanent discontinuation due to a treatment-emergent adverse event occurred in 24.9% of patients who received TEPMETKO. The most frequent treatment-emergent adverse events (>1%) leading to permanent discontinuations of TEPMETKO were edema (8%), pleural effusion (1.6%), and general health deterioration (1.6%).
Dosage interruptions due to a treatment-emergent adverse event occurred in 52.7% of patients who received TEPMETKO. Treatment-emergent adverse events which required dosage interruption in >2% of patients who received TEPMETKO included edema (28.4%), increased blood creatinine (5.8%), pleural effusion (3.5%), nausea (3.2%), increased ALT (2.9%), pneumonia (2.4%), decreased appetite (2.2%), and dyspnea (2.2%).
Dose reductions due to a treatment-emergent adverse event occurred in 36.1% of patients who received TEPMETKO. Treatment-emergent adverse events which required dose reductions in >2% of patients who received TEPMETKO included edema (21.7%), increased blood creatinine (2.6%), and pleural effusion (2.2%).
The most common adverse reactions (≥20%) in patients who received TEPMETKO were edema, nausea, fatigue, musculoskeletal pain, diarrhea, dyspnea, and decreased appetite. The most common Grade 3 to 4 laboratory abnormalities (≥2%) were decreased lymphocytes, decreased albumin, decreased sodium, increased gamma-glutamyltransferase, increased amylase, increased ALT, increased AST, and decreased hemoglobin.
Table 3 summarizes the adverse reactions in VISION. (See Table 3.)

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Clinically relevant adverse reactions in <10% of patients who received TEPMETKO included ILD/pneumonitis, rash, fever, dizziness, pruritus, and headache.
Table 4 summarizes the laboratory abnormalities observed in VISION. (See Table 4.)

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Increased creatinine: A median increase in serum creatinine of 30% was observed 21 days after initiation of treatment with TEPMETKO. The serum creatinine increases persisted throughout treatment and were reversible upon treatment completion.

P-gp substrates: Tepotinib can inhibit the transport of sensitive substrates of P-gp (see Pharmacology: Pharmacokinetics under Actions). Concomitant use of TEPMETKO increases the concentration of P-gp substrates, which may increase the incidence and severity of adverse reactions of these substrates. Avoid concomitant use of TEPMETKO with certain P-gp substrates where minimal concentration changes may lead to serious or life-threatening toxicities. If concomitant use is unavoidable, reduce the P-gp substrate dosage if recommended in its approved product labeling.
BCRP substrates: Tepotinib can inhibit the transport of sensitive substrates of the breast cancer resistance protein (BCRP) (see Pharmacology: Pharmacokinetics under Actions). Monitoring of the clinical effects of sensitive BCRP substrates is recommended during co-administration with TEPMETKO.
Metformin: Based on in vitro data, tepotinib or its metabolite may have the potential to alter the exposure to co-administered metformin in humans through inhibition of metformin's renal excretion or hepatic uptake mediated via OCT1 and 2 and MATE1 and 2 (see Pharmacology: Pharmacokinetics under Actions). Monitoring of the clinical effects of metformin is recommended during co-administration with TEPMETKO.

Special precautions for disposal: No special requirements.

Store below 30°C. Store in the original package in order to protect from moisture.

Targeted Cancer Therapy

L01EX21 - tepotinib ; Belongs to the class of other protein kinase inhibitors. Used in the treatment of cancer.

POM