4.1. Therapeutic indications

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

4.2. Posology and method of administration

Treatment must be initiated and supervised by a physician experienced in the use of anticancer therapies.

Assessment of METex14 skipping alterations status

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 either tumour or plasma specimens. Testing for the presence of METex14 skipping alterations in tissue specimens is recommended because of higher sensitivity. However, plasma specimens may be used in patients for whom a tumour biopsy cannot be obtained. If an alteration is not detected in a plasma specimen, the feasibility of biopsy for tumour tissue testing should be evaluated.

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

Dose interruption, dose reduction or discontinuation of treatment with TEPMETKO may be required based on adverse reactions. The recommended dose reduction level for the management of adverse reactions is 225 mg (1 tablet) daily. TEPMETKO should be permanently discontinued if patients are unable to tolerate 225 mg (1 tablet) daily. Detailed recommendations for dose modification are provided in the table below.

Recommended dose modifications for TEPMETKO for adverse reactions

Adverse reaction

Severity

Dose modification

Interstitial Lung Disease (ILD) (see section 4.4)

Any grade

Withhold tepotinib if ILD is suspected.

Permanently discontinue tepotinib if ILD is confirmed.

Increased ALT and/or AST without increased total bilirubin (see section 4.4)

Grade 3

Withhold tepotinib until recovery to baseline ALT/AST.

If recovered to baseline within 7 days, then resume tepotinib at the same dose; otherwise resume tepotinib at a reduced dose.

Grade 4

Permanently discontinue tepotinib.

Increased ALT and/or AST with increased total bilirubin in the absence of cholestasis or hemolysis (see section 4.4)

ALT and/or AST greater than 3 times ULN with total bilirubin greater than 2 times ULN

Permanently discontinue tepotinib.

Increased total bilirubin without concurrent increased ALT and/or AST (see section 4.4)

Grade 3

Withhold tepotinib until recovery to baseline bilirubin.

If recovered to baseline within 7 days, then resume tepotinib at a reduced dose; otherwise permanently discontinue.

Grade 4

Permanently discontinue tepotinib.

Other adverse reactions (see section 4.8)

Grade 2

Maintain dose level. If intolerable, consider withholding tepotinib until resolved, then resume tepotinib at a reduced dose.

Grade 3

Withhold tepotinib until resolved, then resume tepotinib at a reduced dose.

Grade 4

Permanently discontinue tepotinib.

Renal impairment

No dose adjustment is recommended in patients with mild or moderate renal impairment (creatinine clearance 30 to 89 mL/min) (see section 5.2). 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 (Child Pugh Class B) hepatic impairment (see section 5.2). 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 section 5.2).

Paediatric population

Safety and efficacy 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 (patients should not crush or chew the tablet before swallowing).

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. The tablets should be dropped in a glass with water without crushing and stirred until the tablets are dispersed into small pieces (the tablet will not completely dissolve). The dispersion should be thoroughly stirred and should be swallowed immediately or within 1 hour. The pieces of the tablet should not be chewed. If the dispersion is taken within 1 hour, it should be thoroughly stirred again to ensure the whole dose is administered. In both cases, the glass should be rinsed with an additional 30 mL to ensure that no residue remains and should be swallowed immediately.

If an administration via a naso-gastric tube (with at least 8 French gauge) is required, the tablets should be dispersed in 30 mL of non-carbonated water as described above. The 30 mL of liquid should be thoroughly stirred, then drawn up by syringe and administered immediately or within 1 hour as per naso-gastric tube manufacturer's instructions. If the drawn-up suspension in the syringe is administered within 1 hour, it should first be shaken thoroughly to disperse the contents again. In both cases, immediately rinse twice with 30 mL each to ensure that no residue remains in the syringe.

4.3. Contraindications

Hypersensitivity to tepotinib or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Interstitial lung disease/Pneumonitis

Interstitial lung disease (ILD) or ILD-like adverse reactions (e.g. pneumonitis) have been reported, including a fatal case (see section 4.8).

Patients should be monitored for new or worsening pulmonary symptoms indicative for ILD-like reactions (e.g. dyspnoea, cough, fever). TEPMETKO should be withheld immediately 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 according to local clinical practice.

Hepatotoxicity

Increases in ALT and/or AST have been reported (see section 4.8).

Liver enzymes (ALT and AST) and bilirubin should be monitored prior to the start of TEPMETKO, every 2 weeks during the first 3 months of treatment, then once a month. If grade 3 or higher increases occur, dose adjustment is recommended (see section 4.2).

Embryo-foetal toxicity

TEPMETKO can cause foetal harm when administered to pregnant women (see section 4.6).

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 section 5.2). Creatinine is a substrate of these transporters, and the observed increases in creatinine (see section 4.8) 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. In case of blood creatinine increase while on treatment, it is recommended that further assessment of the renal function be performed to exclude renal impairment.

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.

4.5. Interaction with other medicinal products and other forms of interaction

Pharmacokinetic interactions

P-gp substrates

Tepotinib can inhibit the transport of sensitive substrates of P‑gp (see section 5.2). 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 can inhibit the transport of sensitive substrates of the Breast Cancer Resistance Protein (BCRP) (see section 5.2). 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 section 5.2). Monitoring of the clinical effects of metformin is recommended during co-administration with TEPMETKO.

4.6. Fertility, pregnancy and lactation

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 section 5.3). 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 at least 1 week after the last 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 section 5.3).

4.7. Effects on ability to drive and use machines

TEPMETKO may have minor influence on the ability to drive and use machines. During treatment with tepotinib, fatigue and asthenia have been reported.

4.8. Undesirable effects

Summary of the safety profile

The safety data described reflect exposure to tepotinib 450 mg once daily in 313 patients with advanced NSCLC harbouring METex14 skipping alterations included in the main clinical study (VISION). Median duration of treatment was 32.4 weeks (range: 0 to 312 weeks).

The most common adverse reactions in ≥ 20% of patients exposed to tepotinib at the recommended dose in the target indication (N = 313) are oedema (81.5%), mainly peripheral oedema (72.5%), hypoalbuminaemia (32.9%), nausea (31.0%), fatigue/asthenia (29.7%), increase in creatinine (29.1%) and diarrhoea (28.8%).

The most common serious adverse reactions in ≥ 1% of patients are peripheral oedema (3.2%), generalised oedema (1.9%), asthenia (1.0%) and ILD (1.0%).

The percentage of patients who had adverse events leading to permanent treatment discontinuation is 24.9%. The most common adverse reactions leading to permanent discontinuation in ≥ 1% of patients are peripheral oedema (5.4%), oedema (1.3%), genital oedema (1.0%), pneumonitis (1.0%) and ILD (1.0%).

The percentage of patients who had adverse events leading to temporary treatment discontinuation is 52.7%. The most common adverse reactions leading to temporary discontinuation in ≥ 2% of patients are peripheral oedema (19.8%), increase in creatinine (5.8%), generalised oedema (4.8%), oedema (3.8%), nausea (3.2%), increase in ALT (2.9%) and localised oedema (2.2%).

The percentage of patients who had adverse events leading to dose reduction is 36.1%. The most common adverse reactions leading to dose reduction in ≥ 2% of patients are peripheral oedema (15.7%), increase in creatinine (2.9%), generalised oedema (3.2%) and oedema (2.6%).

List of adverse reactions

An asterisk (*) indicates that additional information on the respective adverse reaction is provided below the table.

The following definitions apply to the frequency terminology used hereafter:

Very common (≥ 1/10)

Common (≥ 1/100 to < 1/10)

Uncommon (≥ 1/1,000 to < 1/100)

Rare (≥ 1/10,000 to < 1/1,000)

Very rare (< 1/10,000)

Frequency not known (cannot be estimated from the available data)

Adverse reactions in patients with NSCLC harbouring METex14 skipping alterations who received TEPMETKO in VISION

System organ class/Adverse reaction

TEPMETKO

N=313

(cut-off date: Nov 2022)

Frequency category

All grades

n (%)

Grade ≥ 3

n (%)

Metabolism and nutrition disorders

Hypoalbuminaemia*,a

Decreased appetite

Very common

Very common

246 (78.6)

67 (21.4)

28 (8.9)

6 (1.9)

Respiratory, thoracic and mediastinal disorders

ILD-like reactions*,†

Common

8 (2.6)

1 (0.3)

Gastrointestinal disorders

Nausea

Diarrhoea

Abdominal painb

Constipation

Vomiting

Very common

Very common

Very common

Very common

Very common

97 (31.0)

90 (28.8)

58 (18.5)

60 (19.2)

45 (14.4)

4 (1.3)

2 (0.6)

2 (0.6)

1 (0.3)

3 (1.0)

Hepatobiliary disorders

Increase in alanine aminotransferase (ALT)*

Increase in alkaline phosphatase (ALP)*

Increase in aspartate aminotransferase (AST)*

Increase in gamma-glutamyltransferase (GGT)

Very common

Very common

Very common

Common

57 (18.2)

35 (11.2)

43 (13.7)

29 (9.3)

10 (3.2)

1 (0.3)

6 (1.9)

7 (2.2)

General disorders and administration site conditions

Oedema*,c

Fatigue/Asthenia

Very common

Very common

255 (81.5)

93 (29.7)

49 (15.7)

6 (1.9)

Investigations

Increase in creatinine*,d

Increase in amylase*,e

Increase in lipase*

Very common

Very common

Very common

184 (58.8)

75 (24.0)

64 (20.4)

3 (1.0)

16 (5.1)

16 (5.1)

Musculoskeletal and connective tissue disorders

Musculoskeletal painf

Very common

95 (30.4)

10 (3.2)

Skin and subcutaneous tissue disorders

Rashg

Very common

47 (15.0)

3 (1.0)

* Additional information on the respective adverse reaction is provided below

† ILD as per Integrated Assessment. Includes terms interstitial lung disease, pneumonitis, and acute respiratory failure.

a includes terms hypoalbuminaemia and blood albumin decreased

b includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, gastrointestinal pain and hepatic pain

c includes terms oedema peripheral, oedema, generalised oedema, oedema genital, face oedema, localised oedema, periorbital oedema, peripheral swelling, and scrotal oedema

d includes terms blood creatinine increased, and hypercreatinaemia

e includes terms amylase increased and hyperamylasaemia

f includes terms arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, non-cardiac chest pain, pain in extremity, and spinal pain

g includes terms rash, rash maculo-papular, rash erythematous, and rash pruritic

Description of selected adverse reactions

Interstitial lung disease

8 out of 313 patients (2.6%) in the VISION study developed interstitial lung disease (ILD) or ILD-like reactions, including 1 case (0.3%) of Grade 3 or higher; serious cases occurred in 4 patients (1.3%). The median time to onset was 9.43 weeks (range: 3.0 to 42.1 weeks). Treatment was permanently discontinued in 5 patients (1.6%) and temporarily discontinued in 3 patients (1.0%). One fatal case (0.3%) of acute respiratory failure secondary to ILD was reported. For clinical recommendations, see sections 4.2 and 4.4.

Hepatotoxicity

In the VISION study, based on laboratory assessment, ALT and AST a worsening from baseline to Grade 1 or higher was reported in 153 (49.5%) and 123 (39.9%) patients, respectively. A worsening to Grade 3 or higher ALT and AST were reported in 15 (4.9%) and 11 (3.6%) of patients, respectively. The median time to first onset was 9.07 weeks (range: 0.1 to 151.1 weeks) for any grade of ALT and/or AST increase. 10 patients (3.2%) temporarily discontinued treatment, and 2 patients (0.6%) required a dose reduction of tepotinib. The median time to resolution was 3.57 weeks (range: 0.1+ to 77.9 weeks). For clinical recommendations, see sections 4.2 and 4.4.

Based on laboratory assessment, a worsening from baseline to Grade 1 or higher ALP increase was reported in 159 patients (51.6%). A worsening to Grade 3 or 4 occurred in 5 patients (1.6%). The median time to first onset for ALP increase of any grade was 9.14 weeks (range: 0.7 to 54.0 weeks) and the median time to resolution was 9.14 weeks (range: 0.9+* to 81.1 weeks). The observed ALP increase was not associated with cholestasis and did not lead to dose modification.

*'+' indicates censored observation

Oedema

Oedema was observed in 255 patients (81.5%). It includes peripheral oedema, which was the most frequent in 227 patients (72.5%), generalised oedema and localised oedema (e.g. oedema of the face, periorbital oedema, genital oedema). The median time to onset of any-grade oedema was 9.14 weeks (range: 0.1 to 96.6 weeks) and the median time to resolution was approximately 71.43 weeks (range: 0.1 to 286.6+ weeks). 25 patients (8.0%) had oedema events leading to permanent treatment discontinuation, of whom 17 (5.4%) had peripheral oedema. 89 patients (28.4%) temporarily discontinued treatment and 68 patients (21.7%) had dose reduction due to oedema. Most frequently peripheral oedema led to temporary treatment discontinuation and dose reductions (62 patients (19.8%) and 49 patients (15.7%), respectively). Generalised oedema events led to a dose reduction in 10 patients (3.2%) and to temporary treatment discontinuation in 15 patients (4.8%), and permanent discontinuation in 2 patients (0.6%).

Increase in creatinine

Based on laboratory assessment, a worsening from baseline to Grade 1 or higher creatinine increase was reported in 184 patients (59.9%). A worsening to Grade 3 or 4 occurred in 3 patients (1.0%). The observed increases in creatinine are thought to occur due to competition of renal tubular secretion (see section 4.4). The median time to onset of increased creatinine was 3.43 weeks (range: 0.1 to 78.4 weeks) and the median time to resolution was 9.14 weeks (range: 0.3 to 223.9+ weeks). Two patients (0.6%) permanently discontinued treatment due to increase in creatinine, 18 patients (5.8%) temporarily discontinued treatment and 9 patients (2.9%) required a dose reduction.

Hypoalbuminaemia

Based on laboratory assessment, a worsening from baseline to Grade 1 or higher decrease in albumin was reported in 246 patients (80.9%). A worsening to Grade 3 or 4 occurred in 28 patients (9.2%) . The median time to onset of any-grade hypoalbuminaemia was 9.43 weeks (range: 0.1 to 154.6 weeks) and the median time to resolution was 28.9 weeks (range 0.6 - 249.4+ weeks). Hypoalbuminaemia appeared to be long-lasting but did not lead to permanent treatment discontinuation. Dose reduction (5 patients (1.6%)) and temporary discontinuation (6 patients (1.9%)) were infrequent.

Increase in amylase or lipase

Based on laboratory assessment, increases in amylase and lipase from baseline were reported in 75 patients (24.9%) and 64 patients (21.2%), respectively. Grade 3 or 4 worsening in amylase and lipase were reported in 16 patients (5.3%) and 16 patients (5.3%), respectively. No pancreatitis was observed in the VISION study. The median time to onset of any grade in lipase/amylase increase was 15.0 weeks (range: 0.9 to 198 weeks). Median time to resolution was 6.14 weeks (range: 0.4 to 311.0+ weeks). 10 patients (3.2%) temporarily discontinued treatment. No patient required dose reduction or permanent treatment discontinuation.

Additional information on special populations

Elderly

Of 313 patients with METex14 skipping alterations in the VISION study who received 450 mg tepotinib once daily, 79% were 65 years or older, and 8% were 85 years or older. No clinically important differences in safety were observed between patients aged 65 years or older and younger patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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.