1 Name of Medicine
Tepotinib (as hydrochloride monohydrate).
2 Qualitative and Quantitative Composition
Tepmetko is supplied as film coated tablets containing 225 mg tepotinib (equivalent to 250 mg tepotinib hydrochloride monohydrate).
For the full list of excipients, see Section 6.1 List of Excipients.
3 Pharmaceutical Form
White-pink, oval, biconvex film-coated tablet with embossment "M" on one side and plain on the other side.
4.1 Therapeutic Indications
Tepmetko is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harbouring mesenchymal-epithelial transition (MET) exon 14 skipping alterations.
4.2 Dose and Method of Administration
Treatment should be initiated and supervised by a physician experienced in the treatment of cancer.
METex14 skipping alterations testing.
When considering the use of Tepmetko as a treatment for advanced NSCLC harbouring METex14 skipping alterations, the METex14 skipping status should be established prior to initiation of Tepmetko therapy. METex14 skipping status in tumour or plasma specimens should be determined using a validated or approved test. Only robust, reliable and sensitive tests for the determination of METex4 skipping status should be used.
Dosage and method of administration.
Recommended dose. The recommended dose of Tepmetko is 450 mg (two 225 mg tablets) orally once daily with food. Treatment should continue as long as clinical benefit is observed.
Missed dose. 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 adjustment. Dose adjustment may be required based on individual safety and tolerability. If dose adjustment is necessary, then the recommended dose reduction of Tepmetko is 225 mg (one tablet) orally once daily with food.
Treatment modification guidelines for the management of adverse reactions are provided hereafter (see Table 1):
Renal impairment.
No dose adjustment is recommended in patients with mild or moderate renal impairment (creatinine clearance 30 to 89 mL/min). The pharmacokinetics and safety of Tepmetko in patients with severe renal impairment (creatinine clearance below 30 mL/min) have not been studied (see Section 5.2 Pharmacokinetic Properties).
Hepatic impairment.
No dose adjustment is recommended in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment. The pharmacokinetics and safety of Tepmetko in patients with severe hepatic impairment (Child Pugh C) have not been studied (see Section 5.2 Pharmacokinetic Properties).
Elderly (> 65 years of age).
No dose adjustment is necessary in patients aged 65 years and above (see Section 5.2 Pharmacokinetic Properties).
Administration.
Tepmetko is for oral use. The tablet(s) should be taken with food and should be swallowed whole. Do not break, crush or chew the tablets.4.3 Contraindications
Tepmetko is contraindicated in patients with known hypersensitivity to tepotinib or to any of the excipients (see Section 6.1 List of Excipients).
4.4 Special Warnings and Precautions for Use
Assessment of METex14 skipping alterations status.
Patients treated with Tepmetko must have a confirmed METex14 skipping status based on a validated or approved test.
Interstitial lung disease.
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 Tepmetko 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 of 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 accordingly.
Monitoring of liver function.
Increases in ALT and/or AST have been reported in the VISION study in patients with advanced NSCLC harbouring METex14 skipping alterations (see Section 4.8 Adverse Effects (Undesirable Effects)), which were mostly non-serious and of low grade. ALT and/or AST increase did not lead to permanent drug discontinuation and infrequently led to temporary discontinuation or dose reduction.
Based on laboratories values, a worsening from baseline to grade 1 or higher was observed for 49.5% of patients for ALT and 39.9% for AST. A worsening to grade 3 or higher occurred in 4.9% of patients for ALT and 3.6% of patients for AST.
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. If grade 3 or higher increases occur, dose adjustment is recommended (see Section 4.2 Dose and Method of Administration, Dose adjustment).
Embryo-fetal toxicity.
Tepmetko can cause fetal harm when administered to pregnant women. There are no available data on the use of Tepmetko in pregnant women. However, studies in animals showed malformations (teratogenicity) (see Section 4.6 Fertility, Pregnancy and Lactation).
Women of childbearing potential or male patients with female partners of childbearing potential should be advised of the potential risk to a fetus.
Women of childbearing potential must use effective contraception during Tepmetko treatment and for at least 1 week after the last dose. Pregnancy testing is recommended in women of childbearing potential prior to initiating treatment with Tepmetko.
Male patients with female partners of childbearing potential must use barrier contraception during Tepmetko treatment and for at least 1 week after the last dose.
Use in hepatic impairment.
See Section 4.2 Dose and Method of Administration.
Use in renal impairment.
See Section 4.2 Dose and Method of Administration.
Use in the elderly.
Of 313 patients with METex14 skipping alterations in the VISION study who received 450 mg Tepmetko once daily, 21.4%, 37.4%, 33.5% and 7.7% were < 65 years, 65 to < 75 years, 75 to < 85 years and 85 years or older, respectively. No clinically important differences in safety or efficacy were observed between patients aged 65 or older and younger patients in VISION study.
Paediatric use.
The safety and efficacy of Tepmetko in paediatric patients below the age of 18 years have not been studied.
Effects on laboratory tests.
Nonclinical studies suggest that tepotinib or its main metabolite inhibit the renal tubular transporter proteins organic cation transporter (OCT) 2, multidrug and toxin extrusion transporters (MATE) 2K (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Creatinine is a substrate of these transporters, and the observed increases in creatinine (see Section 4.8 Adverse Effects (Undesirable Effects)) may be the result of inhibition of active tubular secretion rather than actual 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.4.5 Interactions with Other Medicines and Other Forms of Interactions
Effects of other medicines on tepotinib.
Strong CYP3A and/or P-gp inducers.
Tepotinib is a substrate for P-glycoprotein (P-gp). In healthy participants, co-administration of a single 450 mg tepotinib dose with the strong inducer carbamazepine (300 mg twice daily for 14 days) decreased tepotinib AUCinf by 35% and Cmax by 11% compared to administration of tepotinib alone. The decreased exposure is not clinically relevant.
Dual strong CYP3A inhibitors and P-gp inhibitors.
In healthy participants, co-administration of a single 450 mg tepotinib dose with the strong CYP3A inhibitor and P-gp inhibitor itraconazole (200 mg once daily for 11 days) increased tepotinib AUCinf by 22% with no change in tepotinib Cmax compared to administration of tepotinib alone. This is classified as a weak interaction, and the observed changes in systemic exposure to tepotinib are not considered clinically relevant. Therefore, CYP3A and P-gp inhibitors are not expected to influence tepotinib exposure.
Acid-reducing agents.
Co-administration of omeprazole had no marked effect on the pharmacokinetic profile of tepotinib and its metabolites when administered under fed conditions.
Effects of tepotinib on other medicines.
P-gp substrates.
Tepotinib is an inhibitor of P-gp in vitro. Tepotinib can inhibit the transport of sensitive substrates of P-gp. Multiple administrations of Tepmetko 450 mg orally once daily had a mild effect on the pharmacokinetics of the sensitive P-gp substrate dabigatran etexilate, increasing its AUCt by approximately 50% and Cmax by approximately 40%. Monitoring of the clinical effects of P-gp-dependent substances with a narrow therapeutic index (e.g. digoxin) is recommended during co-administration with Tepmetko.
BCRP substrates.
Tepotinib is an inhibitor of BCRP in vitro. Tepotinib can inhibit the transport of sensitive substrates of the breast cancer resistance protein (BCRP). Monitoring of the clinical effects of sensitive BCRP substrates is recommended during co-administration with Tepmetko.
Other transporters.
Tepotinib or its major circulating metabolite inhibited OCT2 and MATE2K in vitro at clinically relevant concentrations.
Based on in vitro data, tepotinib or its metabolite may have the potential to increase the AUC of co-administered metformin in humans through inhibition of metformin's renal excretion mediated via OCT2 and MATE2K. Monitoring of the clinical effects of metformin is recommended during co-administration with Tepmetko.
CYP 450 substrates.
Multiple administrations of Tepmetko 450 mg orally once daily had no clinically relevant effect on the PK of the sensitive CYP3A substrate midazolam. Based on in vitro data, neither tepotinib nor its major circulating metabolite present a perpetrator for other cytochrome P450 enzymes.
UGT substrates.
In vitro data do not predict clinically relevant effects on UGT substrates.4.6 Fertility, Pregnancy and Lactation
Effects on fertility.
No human data on the effect of Tepmetko on fertility are available. No specific studies with tepotinib have been conducted in animals to evaluate the effect on fertility. No morphological changes in male or female reproductive organs were seen in the repeat-dose toxicity studies in rats and dogs, except for reduced secretion in seminal vesicles of male rats in a 4-week repeat dose toxicity study at 450 mg/kg/day (comparable to human clinical exposure based on AUC).
(Category D)
There are no clinical data on the use of Tepmetko in pregnant women. Studies in animals have shown teratogenicity (including malformations). Based on the mechanism of action and findings in animals Tepmetko can cause fetal harm when administered to pregnant women. Tepmetko must not be used during pregnancy. Women of childbearing potential or male patients with female partners of childbearing potential should be advised of the potential risk to a fetus (see Section 4.4 Special Warnings and Precautions for Use).
A dose-dependent increase in malformed fetuses (hyperextension of limbs and malrotation of limbs along with concomitant misshapen scapula and/or malpositioned clavicle and/or calcaneous and/or talus) was observed after oral administration of tepotinib to pregnant rabbits at ≥ 5 mg/kg/day (approximately 0.003 times the human exposure based on AUC).
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.4.7 Effects on Ability to Drive and Use Machines
Tepmetko may have minor influence on the ability to drive and use machines, as during treatment with tepotinib, fatigue and asthenia have been reported.
4.8 Adverse Effects (Undesirable Effects)
Clinical trial experience.
The safety profile of Tepmetko reflects exposure to tepotinib in 506 patients with various solid tumours enrolled in five open-label, single-arm studies, in which patients received tepotinib as a single agent at a dose of 450 mg once daily. This includes 313 patients with advanced NSCLC harbouring METex14 skipping alterations included in the main clinical study (VISION). The median duration of exposure in this study was 7.5 months (range 0 to 72 months).
Serious treatment emergent adverse events (TEAEs) occurred in 50.8% of patients who received Tepmetko. Serious TEAEs in ≥ 2% of patients included pleural effusion (6.1%), pneumonia (5.4%), general health deterioration (3.8%), dyspnoea (3.5%), peripheral oedema (3.2%), and pulmonary embolism (2.2%).
Permanent discontinuation due to TEAEs occurred in 24.9% of patients who received Tepmetko. Common TEAEs (> 1.0%) leading to permanent discontinuation of Tepmetko were peripheral oedema (5.4%), pleural effusion (1.6%), general health deterioration (1.6%), and oedema (1.3%).
Dosage interruptions due to TEAEs occurred in 52.7% of patients who received Tepmetko. TEAEs which required dosage interruption in > 2% of patients who received Tepmetko included peripheral oedema (19.8%), increased blood creatinine (5.8%), generalised oedema (4.8%), oedema (3.8%), pleural effusion (3.5%), nausea (3.2%), increased ALT (2.9%), pneumonia (2.6%), localised oedema (2.2%), decreased appetite (2.2%) and dyspnoea (2.2%).
TEAEs leading to treatment dose reduction occurred in 36.1% of patients who received Tepmetko. The most frequent TEAEs (> 2.0%) leading to treatment dose reduction included peripheral oedema (15.7%), generalised oedema (3.2%), increased blood creatinine (2.9%), oedema (2.6%), pleural effusion (2.2%).
Table 2 summarises the incidence of adverse reactions that occurred in patients with NSCLC harbouring METex14 skipping alterations in VISION study.
The adverse drug reactions are listed by System Organ Class (SOC) and frequency categories, defined using the following conventions: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), and very rare (< 1/10,000).
Reporting suspected adverse effects.
Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.4.9 Overdose
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
5 Pharmacological Properties
5.1 Pharmacodynamic Properties
Mechanism of action.
Tepotinib is a Type I adenosine triphosphate (ATP)-competitive small molecule inhibitor of MET. Tepotinib inhibits HGF-dependent and independent MET phosphorylation and MET-dependent downstream signalling including the phosphatidylinositol 3-kinase/protein kinase B and mitogen-activated protein kinase/extracellular-signal regulated kinase pathways in a dose-dependent manner.
Clinical trials.
The efficacy of Tepmetko was evaluated in a single-arm, open-label, multicenter study (VISION) in adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harbouring METex14 skipping alterations (MS200095-0022).
The study included patients with measurable disease according to response evaluation criteria in solid tumours (RECIST 1.1) and an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. Patients were to have histologically or cytologically confirmed advanced NSCLC (all types including squamous and sarcomatoid) 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. Before entering the study, eligible patients were required to have confirmed METex14 skipping alterations status by next-generation sequencing assay using tissue and/or liquid biopsy samples.
A total of 313 patients in VISION Cohorts A and C had received treatment with tepotinib. Patients had a median age of 72 years (range 41 to 94), 49% were female and 51% male. The majority of patients were Caucasians (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 had stage IV disease (94%) and 81% had adenocarcinoma histology. Thirteen percent of the patients had stable brain metastases. Patients received Tepmetko as first-line (52%) or second- or later line (48%) therapy.
Patients received 450 mg Tepmetko once daily until disease progression or unacceptable toxicity.
The primary efficacy outcome measure was confirmed objective response (complete response or partial response) according to Response Evaluation Criteria in Solid Tumours (RECIST v1.1) as evaluated by an Independent Review Committee (IRC). Additional efficacy outcome measures included duration of response, objective disease control, progression-free survival, overall survival as well as patient-reported outcomes of quality of life.
The Kaplan-Meier curves for Progression-free Survival (PFS) and Overall Survival (OS) are shown in Figures 1 and 2, respectively.
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.
5.2 Pharmacokinetic Properties
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 Cmax 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 Cmax 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%).
Metabolism.
Metabolism is not the major route of elimination. No metabolic pathway accounted for more than 25% of tepotinib elimination in humans. Only one major circulating plasma metabolite (MSC2571109A) has been identified. There is only a minor contribution of the major circulating metabolite to the overall efficacy of tepotinib in humans.
Excretion.
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 hours. After multiple daily administrations of 450 mg tepotinib, median accumulation was 2.5 fold for Cmax and 3.3 fold for AUC0-24h.
Special populations and conditions.
A population kinetic analysis did not show any effect of age (range 18 to 89 years), race, sex, body weight, or mild to moderate renal impairment (CLcr 30 to 89 mL/min) on the pharmacokinetics of tepotinib.
Patients with hepatic impairment.
Following a single oral dose of 450 mg Tepmetko, the exposure was similar in healthy subjects and patients with mild hepatic impairment (Child-Pugh Class A) and was slightly lower (-13% AUC and -29% Cmax) 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 Tepmetko have not been studied in patients with severe (Child Pugh Class C) hepatic impairment.
Patients with 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.
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.
Cardiac electrophysiology.
In the VISION study (patients with METex14 skipping alterations; n = 181), 4 patients (2.2%) experienced a QTcF prolonged to > 500 ms and 10 patients (5.5%) had a QTcF prolonged by at least 60 ms from baseline.
In an exposure-QTc analysis, the QTcF interval prolongation potential of Tepmetko was assessed in 392 patients with various solid tumours following single or multiple daily doses of Tepmetko ranging from 27 mg to 1,261 mg. At the recommended dose, no large mean increases in QTc (i.e. > 20 ms) were detected. A concentration-dependent increase in QTc interval was observed. The QTc effect of tepotinib at high clinical exposures has not been evaluated.
5.3 Preclinical Safety Data
Genotoxicity.
No mutagenic or genotoxic effects of tepotinib were observed in the bacterial reverse mutation assay and mouse lymphoma assay in vitro and a rat micronucleus test in vivo.
The major circulating metabolite was also shown to be non-mutagenic in the bacterial reverse mutation assay and mouse lymphoma assay in vitro.
Carcinogenicity.
No studies have been performed to evaluate the carcinogenic potential of tepotinib.6 Pharmaceutical Particulars
6.1 List of Excipients
Tablet core.
Mannitol, colloidal anhydrous silica, crospovidone, magnesium stearate, microcrystalline cellulose.
Film coating.
Hypromellose, lactose monohydrate, macrogol 3350, triacetin, iron oxide red, titanium dioxide.
6.2 Incompatibilities
Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
6.3 Shelf Life
In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
6.4 Special Precautions for Storage
Store below 30°C in the original package in order to protect from moisture.
6.5 Nature and Contents of Container
Blister foil.
Multilayer composite, consisting of polyvinylchloride-polyethylene-polyvinylidenechloride-polyethylene-polyvinylchloride.
Lidding foil (child-resistant).
Aluminum-polyethylene terephthalate.
Each pack contains 6 blister foils, each containing 10 Tepmetko tablets.
6.6 Special Precautions for Disposal
In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.
6.7 Physicochemical Properties
Chemical structure.
Chemical name: 3-(1-(3-(5-(1-Methylpiperidin-4-ylmethoxy)-pyrimidin-2-yl-benzyl)-1,6-dihydro-6-oxo-pyridazin-3-yl)-benzonitrile hydrochloride hydrate.
CAS number.
1100598-30-8.7 Medicine Schedule (Poisons Standard)
S4 (Prescription Only Medicine).
Summary Table of Changes
