Tepotinib

Tepotinib is a highly selective, reversible type I ATP-competitive small-molecule inhibitor of MET. MET is a receptor tyrosine kinase that supports tumour cell proliferation, survival, invasion and migration; alterations leading to METex14 skipping are one cause of its oncogenic activation.

Mechanism of Action

• MET inhibition: tepotinib blocks MET phosphorylation and MET-dependent downstream signalling, including the PI3K/Akt and MAPK/ERK pathways, in a dose-dependent manner. In laboratory studies it inhibited proliferation, anchorage-independent growth and migration of MET-dependent tumour cells, with an average IC50 of about 1.7 nmol/L.
• Anti-tumour activity: pronounced in tumours with oncogenic MET activation such as METex14 skipping alterations.
• Cardiac electrophysiology: a concentration-dependent increase in the QTc interval was seen. At the recommended dose no large mean increase (more than 20 ms) was detected in patients with solid tumours; the effect at higher exposures has not been evaluated.

Pharmacokinetics

• Absorption: mean absolute bioavailability is 71.6% (single 450 mg dose, fed state), with a median time to peak of 8 hours (range 6–12 hours). A high-fat, high-calorie meal raised AUC about 1.6-fold and Cmax 2-fold, which is why tablets are taken with food. Exposure is roughly dose-proportional up to 450 mg and unchanged over time; with daily dosing, accumulation is about 2.5-fold for Cmax and 3.3-fold for AUC0–24h.
• Distribution: 98% bound to plasma proteins, mainly albumin and alpha-1-acid glycoprotein. The volume of distribution after an intravenous tracer dose was 574 L.
• Metabolism: metabolism is a major route of elimination, but no single pathway accounts for more than 25% of it. One major circulating metabolite (MSC2571109A) has been identified and contributes only minimally to efficacy.
• Elimination: after a radiolabelled oral dose about 78% was recovered in faeces, and urinary excretion is minor. Biliary excretion is a major pathway; unchanged tepotinib accounted for 45% (faeces) and 7% (urine) of the radioactivity. Total clearance after intravenous dosing was 12.8 L/h and the effective half-life is about 32 hours.
• Special populations: age (18–89 years), race, sex and body weight had no clinically meaningful effect. Exposure did not change meaningfully in mild or moderate renal impairment; severe renal impairment was not studied. In mild hepatic impairment (Child-Pugh A) exposure was similar to healthy subjects; in moderate impairment (Child-Pugh B) total AUC was 13% lower and Cmax 29% lower, while unbound AUC was 13% (mild) and 24% (moderate) higher. Severe hepatic impairment (Child-Pugh C) was not studied.
• Transporters in vitro: tepotinib or its main metabolite inhibits P-gp, BCRP, OCT1 and 2 and MATE1 and 2 at clinically relevant concentrations, which underlies the interaction advice below.

• Advanced non-small cell lung cancer (NSCLC): as monotherapy for adult patients with advanced NSCLC harbouring alterations leading to mesenchymal-epithelial transition factor gene exon 14 (METex14) skipping, who require systemic therapy following prior treatment with immunotherapy and/or platinum-based chemotherapy.

• Hypersensitivity to the active substance or to any of the excipients.

The most common reactions (20% or more of 313 patients treated in the target indication) are oedema (81.5%, mainly peripheral oedema at 72.5%), hypoalbuminaemia (32.9%), nausea (31.0%), increased creatinine (29.1%) and diarrhoea (28.8%). The most common serious reactions are peripheral oedema (3.2%), generalised oedema (1.9%) and interstitial lung disease (1.0%). Reactions led to permanent discontinuation in 14.7% of patients, temporary discontinuation in 43.1% and dose reduction in 33.5%. Frequencies for laboratory parameters are based on worsening by at least one grade from baseline.

Very common (≥1/10): oedema (peripheral oedema, generalised oedema, genital and facial oedema among them; grade 3 or higher in 15.7%); decreased albumin (78.6%, laboratory finding); increased creatinine (58.8%); increased alkaline phosphatase (50.8%), alanine aminotransferase (48.9%) and aspartate aminotransferase (39.3%); nausea (31.0%), diarrhoea (28.8%), vomiting (14.4%); increased amylase (24.0%) and lipase (20.4%), asymptomatic and not linked to pancreatitis.

Common (≥1/100 to <1/10): QT prolongation (2.6%); interstitial lung disease-like reactions, including interstitial lung disease, pneumonitis and acute respiratory failure (2.6%).

The SmPC table places no other reactions in the uncommon, rare or not-known categories.

Interstitial lung disease or ILD-like reactions occurred in 8 patients, serious in 4 and fatal in 1, with a median onset of 9.4 weeks. Oedema appeared after a median of 9.1 weeks and often persisted; it led to permanent discontinuation in 8% of patients, temporary discontinuation in 28.4% and dose reduction in 21.7%. The rise in creatinine is thought to come mainly from inhibition of renal tubular secretion. Liver enzyme increases were mostly reversible, and alkaline phosphatase rises were not associated with cholestasis. Serious treatment-related events were more frequent in patients aged 75 years or over than in those under 65.

• Strong CYP and P-gp inducers: carbamazepine lowered tepotinib AUC by 35% and Cmax by 11%; this is not clinically relevant.
• Strong CYP3A and P-gp inhibitors: itraconazole raised tepotinib AUC by 22% with no change in Cmax, a weak interaction that is not clinically relevant. CYP3A and P-gp inhibitors are not expected to influence tepotinib exposure.
• Acid-reducing agents: omeprazole (given with food) had no clinically relevant effect on tepotinib or its metabolites.
• P-gp substrates: tepotinib inhibits P-gp. It raised the AUC of dabigatran etexilate by about 50% and Cmax by about 40%, so the dabigatran etexilate dose may need adjusting. Take care and monitor for adverse reactions with other P-gp substrates of narrow therapeutic index, such as digoxin, aliskiren, everolimus and sirolimus.
• BCRP substrates: tepotinib can inhibit BCRP in vitro. Monitor for adverse reactions of sensitive substrates such as rosuvastatin, methotrexate and topotecan.
• OCT and MATE substrates: tepotinib or its metabolite may change exposure to substrates of OCT1/2 and MATE1/2. The clinically most relevant example is metformin, whose clinical effects should be monitored.
• CYP3A4 substrates: repeated tepotinib dosing had no clinically relevant effect on a sensitive CYP3A4 substrate.
• Hormonal contraceptives: it is unknown whether tepotinib reduces the effectiveness of systemically acting hormonal contraceptives, so a barrier method should be added during treatment and for at least 1 week after the last dose.
• QT-prolonging medicines: monitoring is recommended in patients taking medicines known to prolong the QTc interval.
• Food: take with food, which improves absorption.

Treatment must be started and supervised by a physician experienced in the use of anticancer therapies. Before it begins, the presence of METex14 skipping alterations must be confirmed by a validated test method. The tablets are taken with food and swallowed whole so that the full dose is given.

Recommended Dose

• 450 mg (2 tablets of 225 mg) once daily, for as long as clinical benefit is observed.

Dose Modification for Adverse Reactions

The recommended reduced dose is 225 mg (1 tablet) daily.

• Interstitial lung disease (any grade): withhold if suspected; permanently discontinue if confirmed.
• ALT and/or AST more than 5 and up to 20 times the upper limit of normal (ULN), without raised bilirubin: withhold until recovery to baseline. If this takes 7 days or less, resume at the same dose; otherwise resume at the reduced dose.
• ALT and/or AST more than 20 times ULN: permanently discontinue.
• ALT and/or AST more than 3 times ULN with total bilirubin more than 2 times ULN (no cholestasis or haemolysis): permanently discontinue.
• Other adverse reactions of grade 3 or higher: reduce to 225 mg until the reaction recovers to grade 2 or lower. A temporary interruption of no more than 21 days can also be considered.

Special Populations

• Renal impairment: no adjustment in mild or moderate impairment (creatinine clearance 30 to 89 mL/min). Severe impairment (below 30 mL/min) has not been studied, and use is not recommended. Creatinine-based estimates of renal function should be read with caution.
• Hepatic impairment: no adjustment in mild (Child-Pugh A) or moderate (Child-Pugh B) impairment. Severe impairment (Child-Pugh C) has not been studied, and use is not recommended.
• Elderly: no adjustment at 65 years and above.
• Children and adolescents: safety and efficacy under 18 years have not been established.

Patients Who Cannot Swallow Tablets

Disperse the tablets without crushing them in 30 mL of non-carbonated water (no other liquid), stir for a few minutes until they break into small pieces (they do not dissolve completely), and swallow within 1 hour. Rinse the glass with another 30 mL and drink it at once. For a naso-gastric tube of at least 8 French gauge, disperse the same way, give the 30 mL within 1 hour following the tube maker’s instructions, and rinse twice with 30 mL each.

Missed Dose

A missed daily dose can be taken as soon as remembered on the same day, unless the next dose is due within 8 hours.

METex14 Skipping Status Must Be Confirmed

Tepotinib is used only after the presence of METex14 skipping alterations has been confirmed by a validated test method. Tissue-based or plasma-based specimens may be used, and a well-validated, robust test must be chosen to avoid false negative or false positive results. In the clinical studies, alterations were identified by next-generation sequencing of RNA or DNA from tumour tissue or of circulating cell-free DNA from plasma, and in Japan also by an RNA-based reverse transcriptase PCR method on fresh frozen tissue.

Interstitial Lung Disease and Pneumonitis

ILD or ILD-like reactions, including pneumonitis, have occurred at the recommended dose and may be fatal. Patients should be monitored for pulmonary symptoms. If ILD is suspected, tepotinib is withheld and the patient investigated promptly for another diagnosis; it must be permanently discontinued if ILD is confirmed, and the patient treated appropriately.

Liver Enzymes

ALT, AST and bilirubin should be measured before starting and then as clinically indicated. Grade 3 or higher increases (ALT and/or AST above 5 times ULN) call for dose adjustment or discontinuation as set out above.

QTc Prolongation

QTc prolongation was reported in a limited number of patients. In patients at risk, including those with known electrolyte disturbances or taking medicines that prolong the QTc interval, monitoring (for example ECG and electrolytes) is recommended as clinically indicated.

Interpretation of Laboratory Tests

Tepotinib or its main metabolite inhibits the renal tubular transporters OCT2, MATE1 and MATE2. Because creatinine is a substrate of these transporters, a rise in creatinine may reflect reduced tubular secretion rather than kidney injury. If creatinine rises, further assessment of kidney function is recommended to exclude renal impairment.

Pregnancy, Breastfeeding and Fertility

• Embryo-foetal toxicity: tepotinib can cause foetal harm. A pregnancy test is recommended in women of childbearing potential before starting treatment. There are no clinical data in pregnant women, and animal studies showed teratogenicity; it should not be used in pregnancy unless the woman’s clinical condition requires treatment, and the potential risk to the foetus should be explained.
• Contraception: women of childbearing potential should use effective contraception during treatment and for at least 1 week after the last dose, and those using systemically acting hormonal contraceptives should add a barrier method. Male patients with female partners of childbearing potential should use barrier contraception during treatment and for at least 1 week after the last dose.
• Breastfeeding: there are no data on secretion into human milk. Breast-feeding should be stopped during treatment and for at least 1 week after the last dose.
• Fertility: no human data on the effect of tepotinib on fertility are available. In repeat-dose studies in rats and dogs no morphological changes were seen in the male or female reproductive organs, except reduced secretion in the seminal vesicles of male rats at exposures comparable to human clinical exposure.

Effect on Driving

Tepmetko has no influence on the ability to drive and use machines.

Tepmetko tablets do not require any special storage conditions. They are supplied in aluminium/PVC-PE-PVDC-PE-PVC blisters, in packs of 60 film-coated tablets.

3 years. Do not use after the expiry date on the pack.

Prescription only (Rx), on the prescription of a physician experienced in the use of anticancer therapies, once METex14 skipping alterations have been confirmed by a validated test. The tablets are taken at home, so Tepmetko is supplied to the patient or to the treating clinic on prescription.