Tepotinib, a mesenchymal-epithelial transition (MET) tyrosine kinase inhibitor, is an antineoplastic agent.1, 3, 4, 5, 7
Tepotinib is used for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) harboring mesenchymal-epithelial transition ( MET ) exon 14 skipping alterations.1, 3 Tepotinib has been designated an orphan drug by FDA for use in this condition.2
Efficacy and safety of tepotinib for this indication were demonstrated in a nonrandomized, multicohort, multinational, open-label, phase 2 study (VISION) in adults with MET exon 14 skipping alteration-positive, wild-type epidermal growth factor receptor ( EGFR ), anaplastic lymphoma kinase ( ALK )-negative, locally advanced or metastatic NSCLC with at least one measurable lesion.1, 3 Identification of MET exon 14 skipping alterations were determined via polymerase chain reaction (PCR)-based or next-generation sequencing-based clinical trial assays using tissue (58%) and/or plasma (65%) samples.3 Patients with symptomatic CNS metastases, clinically significant uncontrolled cardiac disease, and those who received prior therapy with a MET or hepatocyte growth factor inhibitor were excluded.1 The efficacy population for the indication of NCSLC with a MET exon 14 skipping mutation included 69 previously untreated patients and 83 patients who had received at least one prior therapy for NSCLC.4 Patients received tepotinib 450 mg (equivalent to 500 mg tepotinib hydrochloride) orally once daily until disease progression or unacceptable toxicity occurred.1, 4 The primary measure of efficacy was overall response rate (complete plus partial responses) as assessed by a blinded independent review committee according to modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1); the key secondary end point was duration of response.1, 3 The median age of patients in the efficacy population was 73 years (range: 41-94 years); 71% of patients were Caucasian, 48% were female, 100% had an ECOG performance status of 0 or 1, 43% had never smoked, 86% had adenocarcinoma histology, 98% had metastatic disease, and 10% had brain metastases.4
At the time of initial analysis, overall response rate in previously untreated and previously treated patients was 43% for each group; no patients achieved complete response.3, 4 The median duration of response in previously untreated and previously treated patients was 10.8 and 11.1 months, respectively.4 In a long-term follow-up analysis of VISION, including 313 patients (164 treatment-naïve and 149 previously treated), the overall response rate was 57% in previously untreated and 45% in previously treated patients.1, 8 The median duration of response in previously untreated and previously treated patients was 46.4 and 12.6 months, respectively.8
A relatively small subset of patients with NSCLC have MET exon 14 skipping alterations (approximately 2-4%), which indicates potential responsiveness to MET inhibition therapy.3, 4, 5, 6, 7 Patients with NSCLC harboring MET exon 14 skipping alterations typically are female, are older in age, often have adenocarcinoma histology, and have poorer prognosis disease.5, 6, 7
The American Society of Clinical Oncology (ASCO) and Ontario Health (OH; formerly known as Cancer Care Ontario) 2021 joint guideline specifically addressed treatment of stage IV NSCLC harboring driver alterations, including MET exon 14 skipping mutation.9 The most recent update from ASCO on advanced NSCLC with driver alterations states that clinicians may offer capmatinib or tepotinib as a first-line treatment option in patients with MET exon 14 skipping mutation.10 If neither agent is available, clinicians may offer standard first-line therapy following the non-driver alteration guidelines.10 In the second-line setting, clinicians may offer capmatinib or tepotinib to patients who have not received MET -targeted therapy.10 For those who have received MET -targeted therapy prior, clinicians should offer standard therapy following the non-driver alteration guideline.10
Tepotinib is administered orally once daily at the same time each day with food.1 Tepotinib tablets should be swallowed whole; patients should not chew, crush, or split the tablets.1
If a dose of tepotinib is missed, the dose should be taken as soon as it is remembered, but not within 8 hours of the next scheduled dose.1 If a dose of tepotinib is vomited, patients should not take extra doses.1 The next dose should be taken at the regularly scheduled time.1
If a patient has difficulty swallowing solids, tepotinib tablet(s) may be placed in a glass containing 30 mL (1 ounce) of non-carbonated water and stirred, without crushing, until the tablet(s) is dispersed into small pieces.1 The patient should drink the tablet dispersion immediately or within 1 hour.1 Tablet pieces in the dispersion should not be chewed.1 The patient should rinse the glass with an additional 30 mL and drink immediately ensuring no residue remains in the glass and the full dose is administered.1
If nasogastric (NG; with at least 8 French gauge) administration is required, disperse tepotinib tablet(s) in 30 mL of non-carbonated water as noted above.1 Administer immediately or within 1 hour as per NG tube manufacturer's instructions.1 Immediately rinse twice with 30 mL each time to ensure that no residue remains and the full dose is administered.1
Dosage of tepotinib hydrochloride is expressed in terms of tepotinib.1
The recommended adult dosage of tepotinib for treating metastatic NSCLC harboring MET exon 14 skipping alterations is 450 mg orally once daily.1 Continue treatment until disease progression or unacceptable toxicity.1
Dosage Modification for Toxicity
If adverse reactions occur during tepotinib therapy, temporary interruption of therapy, dosage reduction, and/or discontinuation of therapy may be necessary.1
If dosage modification of tepotinib is necessary, an initial dosage reduction to 225 mg once daily is recommended.1
Dosage <225 mg once daily are not recommended; the drug should be permanently discontinued if the 225-mg daily dosage is not tolerated.1
If interstitial lung disease or pneumonitis of any grade is suspected, tepotinib therapy should be interrupted.1 If interstitial lung disease or pneumonitis is confirmed, tepotinib should be permanently discontinued.1
If grade 3 elevations in ALT or AST concentrations occur in the absence of elevated total bilirubin concentrations, tepotinib therapy should be interrupted until serum ALT and AST concentrations return to baseline values.1 If recovery occurs within 7 days, tepotinib may be resumed at the same dosage.1 If recovery is delayed beyond 7 days, therapy may be resumed at a reduced dosage.1
If grade 4 elevations in ALT or AST concentrations occur in the absence of elevated total bilirubin concentrations, tepotinib therapy should be permanently discontinued.1
If elevations in ALT or AST concentrations exceeding 3 times the upper limit of normal (ULN) occur concurrently with total bilirubin concentrations exceeding 2 times the ULN and in the absence of cholestasis or hemolysis, tepotinib therapy should be permanently discontinued.1
If grade 3 elevations in total bilirubin concentrations occur in the absence of elevated ALT and/or AST concentrations, tepotinib therapy should be withheld until total bilirubin concentrations return to baseline values.1 If recovery occurs within 7 days, tepotinib may be resumed at the recommended reduced dosage.1 If recovery is delayed beyond 7 days, tepotinib therapy should be permanently discontinued.1
If grade 4 elevations in total bilirubin concentrations occur in the absence of elevated ALT and/or AST concentrations, tepotinib therapy should be permanently discontinued.1
If grade 3 elevations in lipase or amylase occur, tepotinib therapy should be withheld until levels return to grade 2 or less or baseline.1 If recovery to baseline or grade 2 or less occurs within 14 days, resume tepotinib therapy at a reduced dose; otherwise, permanently discontinue tepotinib.1
If grade 4 elevations in lipase or amylase occur, tepotinib therapy should be permanently discontinued.1
If grade 3 or 4 pancreatitis occurs, tepotinib therapy should be permanently discontinued.1
If grade 2 adverse reactions occur, tepotinib therapy may be continued at the same dosage.1
If intolerable grade 2 adverse reactions occurs, interruption of tepotinib therapy should be considered.1 When the toxicity resolves, tepotinib may be resumed at the recommended reduced dosage.1
If grade 3 adverse reactions occur, tepotinib therapy should be interrupted.1 When the toxicity resolves, tepotinib may be resumed at the recommended reduced dosage.1
If grade 4 adverse reactions occur, tepotinib therapy should be permanently discontinued.1
No dosage adjustment is necessary in patients with mild to moderate hepatic impairment (Child-Pugh class A or B).1
Tepotinib has not been studied in patients with preexisting severe hepatic impairment (Child-Pugh class C); pharmacokinetics and safety of tepotinib in this population are unknown.1
No dosage adjustment is necessary in patients with mild to moderate renal impairment (creatinine clearance 30-89 mL/minute).1
The recommended dosage has not been established for patients with severe renal impairment (creatinine clearance <30 mL/minute).1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Interstitial Lung Disease/Pneumonitis
Tepotinib can cause potentially fatal interstitial lung disease or pneumonitis.1 Interstitial lung disease or pneumonitis occurred in 2% of patients administered tepotinib.1 One patient experienced a grade 3 or higher event that resulted in death.1 Discontinuance of tepotinib therapy was necessary because of interstitial lung disease or pneumonitis in 1% of patients receiving the drug.1
Monitor patients receiving tepotinib for new or worsening pulmonary symptoms such as dyspnea, cough, or fever.1 Tepotinib therapy should be withheld immediately in patients with suspected interstitial lung disease or pneumonitis.1 If no other etiology is identified, permanently discontinue tepotinib therapy.1
Drug-induced hepatotoxicity has been reported in patients receiving tepotinib.1 Elevations in ALT or AST concentrations occurred in 18% of patients receiving tepotinib; grade 3 or 4 elevations in ALT or AST concentrations occurred in 4.7% of patients, and permanent discontinuation of tepotinib was required in 0.8% of patients receiving the drug.1 Fatal hepatic failure occurred in 1 patient.1 The median time to onset of grade 3 or greater elevations in ALT or AST concentrations was 47 days (range: 1-262 days).1
Monitor liver function tests (i.e., ALT, AST, total bilirubin concentrations) prior to initiating tepotinib therapy, every 2 weeks during the first 3 months of therapy, monthly thereafter or as clinically indicated.1 More frequent testing is necessary in patients who develop aminotransferase or bilirubin elevations during therapy.1 If hepatotoxicity occurs, temporary interruption, dosage reduction, or discontinuation of tepotinib may be necessary.1
Elevations in amylase and lipase have been reported in patients receiving tepotinib.1 Increased amylase and/or lipase occurred in 13% of patients administered tepotinib; grade 3 or 4 elevations occurred in 5% and 1.2% of patients, respectively.1 Monitor amylase and lipase levels at baseline and periodically during treatment.1 Dependent upon severity, temporary interruption, dosage reduction, or discontinuation of tepotinib may be necessary.1
Fetal/Neonatal Morbidity and Mortality
Tepotinib can cause fetal harm if administered to pregnant females based on its mechanism of action and animal findings.1 Although there are no available data regarding the risk of tepotinib to pregnant females, embryofetal toxicity (i.e., decreased fetal body weight, abortion, premature fetal death) and teratogenic effects (i.e., skeletal malformations, neural tube defects) has been demonstrated in rabbits at exposure levels approximately 0.003-0.5 times the human exposure at the recommended dosage.1
Pregnancy should be avoided during tepotinib therapy.1 Verify pregnancy status in females of reproductive potential.1 Females of reproductive potential should use effective contraceptive methods while receiving the drug and for 1 week after the last dose; male partners of such females also should use effective contraceptive methods during therapy and for 1 week after the last dose.1 If tepotinib is used during pregnancy or if the patient or their partner becomes pregnant during therapy, the patient should be apprised of the potential fetal hazard.1
May cause fetal harm if administered to pregnant females based on its mechanism of action and animal findings.1
Verify pregnancy status in all females of reproductive potential prior to initiation of tepotinib therapy.1
It is not known whether tepotinib or its major metabolite (M506) are distributed into human milk.1 The effects of the drug on breast-fed infants or on milk production also are unknown.1
Because of the potential for serious adverse reactions to tepotinib in breast-fed infants, females should be advised not to breast-feed while receiving the drug and for 1 week after the last dose.1
Females and Males of Reproductive Potential
Verify pregnancy status in females of reproductive potential.1 Females of reproductive potential should use effective contraceptive methods while receiving the drug and for 1 week after the last dose; male partners of such females also should use effective contraceptive methods during therapy and for 1 week after the last dose.1
Safety and efficacy of tepotinib have not been established in pediatric patients.1
In the principal efficacy study (VISION), 79% of 313 patients with metastatic non-small cell lung cancer (NSCLC) receiving tepotinib were 65 years of age or older and 41% were 75 years of age or older.1 No overall differences in safety or efficacy were observed between geriatric patients and younger adults.1
In a population pharmacokinetic analysis, age (range of 18-89 years) did not have a substantial effect on the pharmacokinetics of tepotinib.1
Mild to moderate hepatic impairment (Child-Pugh class A and B) does not have a substantial effect on the pharmacokinetics of tepotinib.1
The effect of severe hepatic impairment (Child-Pugh class C) on the pharmacokinetics of tepotinib has not been evaluated.1
Mild to moderate renal impairment (creatinine clearance 30-89 mL/minute) does not have a substantial effect on the pharmacokinetics of tepotinib.1
The effect of severe renal impairment (creatinine clearance <30 mL/minute) on the pharmacokinetics of tepotinib has not been evaluated.1
The most common adverse reactions reported in 20% or more of patients receiving tepotinib for the treatment of advanced or metastatic NSCLC with MET exon 14 skipping alteration include edema, fatigue, nausea, diarrhea, musculoskeletal pain, decreased appetite, rash, and dyspnea.1
The most common grade 3 or 4 laboratory abnormalities reported in 2% or more of patients receiving tepotinib for the treatment of advanced or metastatic NSCLC with a MET exon 14 skipping alteration include decreased lymphocytes, decreased albumin, decreased sodium, increased gamma-glutamyltransferase, increased amylase, increased ALT, increased lipase, increased AST, and decreased hemoglobin.1
In the VISION study, a median increase in serum creatinine concentration of 30% occurred 21 days following initiation of tepotinib therapy.1 Serum creatinine remained elevated throughout tepotinib therapy but was reversible upon discontinuance of therapy.1
Tepotinib is metabolized principally by cytochrome P-450 (CYP) isoenzymes 3A4 and 2C8.1
In vitro, tepotinib and its major metabolite (M506) do not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6, or CYP2E1, and do not induce CYP1A2 or CYP2B6 at clinically relevant concentrations.1 Physiologically based pharmacokinetic modeling suggests tepotinib does not result in clinically important inhibition of CYP2C9.1
In vitro, tepotinib and M506 do not inhibit UDP-glucuronosyltransferase (UGT) 1A1, 1A9, 2B17, 1A3/4/6, or 2B7/15 at clinically relevant concentrations.1
In vitro, tepotinib is a substrate and inhibitor of P-glycoprotein (P-gp) and may inhibit intestinal breast cancer resistance protein (BCRP).1 Tepotinib does not inhibit bile salt export pump (BSEP), organic anion transporter polypeptide (OATP) 1B1 or 1B3, or organic anion transporter (OAT) 1 or 3.1
Drugs Affecting or Affected by Hepatic Microsomal Enzymes
Dual Strong CYP3A Inhibitors and P-gp Inhibitors
No clinically significant differences in the pharmacokinetics of tepotinib were observed when coadministered with itraconazole (a strong CYP3A and P-gp inhibitor).1
No clinically significant differences in the pharmacokinetics of tepotinib were observed when coadministered with carbamazepine (a strong CYP3A inducer).1
Concomitant administration of tepotinib and the CYP3A substrate midazolam did not result in clinically important changes in exposure to midazolam.1
Drugs Affecting or Affected by Transport Systems
Concomitant use of tepotinib and substrates of P-gp may result in increased plasma concentrations of the P-gp substrate and possible adverse events.1 Coadministration of tepotinib with dabigatran etexilate, a P-gp substrate, increased the peak plasma concentrations and area under the concentration-time curve (AUC) of dabigatran by approximately 40 and 50%, respectively.1
Avoid concomitant use of tepotinib with P-gp substrates that have a narrow therapeutic index.1 If coadministration cannot be avoided, clinicians should consult the manufacturer's labeling of the P-gp substrate for dosage adjustment recommendations.1
Concomitant administration of tepotinib and the MATE2 and OCT2 substrate metformin did not result in clinically important changes in plasma glucose concentrations.1
Drugs Affecting Gastric Acidity
Concomitant administration of tepotinib and repeated dosages (40 mg daily for 5 days) of omeprazole under fed conditions did not result in clinically important changes in tepotinib pharmacokinetics.1
Tepotinib, a highly selective type 1b mesenchymal-epithelial transition (MET) tyrosine kinase inhibitor, is an antineoplastic agent.1, 3, 5, 7 Activation of MET tyrosine kinase, occurring through overexpression, MET amplification, or exon 14 skipping mutation, is thought to initiate a cascade of intracellular signaling events leading to cell proliferation and processes critical to cell survival and tumor progression (e.g., angiogenesis, apoptosis, metastasis).1, 3, 5, 7 MET exon 14 skipping mutations are present in approximately 2-4% of patients with non-small cell lung cancer (NSCLC).3, 5, 6, 7 Tepotinib inhibits MET phosphorylation caused by the binding of hepatocyte growth factor or by MET amplification, resulting in downregulation of downstream MET signaling proteins and inhibition of proliferation and survival of MET-dependent tumor cells.1, 3, 4, 5, 7 Tepotinib also inhibits off-target receptors melatonin 2 and imidazoline 1.1, 4
Following oral administration, peak plasma concentrations of tepotinib are achieved in approximately 8 hours (range: 6-12 hours).1 The estimated extent of absorption of a single 450-mg oral dose is more than 70% in the fed state.1 The area under the plasma concentration-time curve (AUC) and peak plasma concentration of tepotinib increase in a dose-proportional manner over a dosage range of 27-450 mg daily.1 Following repeated daily dosing of tepotinib, median accumulation was 2.5-fold for peak plasma concentration and 3.3-fold for AUC.1 Administration of tepotinib with a high-fat, high-calorie meal increased the AUC and peak plasma concentration of the drug by 1.6- and 2-fold, respectively, compared with administration in the fasted state, and time to peak plasma concentration was decreased from 12 to 8 hours.1 Tepotinib is 98% bound to plasma proteins, and binding is independent of tepotinib concentration.1 Similar to capmatinib, tepotinib crosses the blood-brain barrier.4, 7 Tepotinib is metabolized mainly by cytochrome P-450 (CYP) isoenzymes 3A4 and 2C8 to the major circulating metabolite M506 (inactive metabolite).4 Following oral administration of a single radiolabeled dose of tepotinib, approximately 85% of the radioactivity was recovered in feces and 13.6% was recovered in urine; unchanged drug accounted for 45 or 7% of the dose recovered in feces or urine, respectively.1 The major metabolite M506 accounted for approximately 40% of the total radioactivity in plasma.1 The elimination half-life of tepotinib is 32 hours.1 The pharmacokinetics of tepotinib are not affected by age (18-89 years), sex, race (white, Black, Asian, Japanese, Hispanic), or body weight (35.5-136 kg).1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 225 mg (of tepotinib) | Tepmetko® | EMD Serono |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions November 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. EMD Serono. Tepmetko® (tepotinib hydrochloride) tablets prescribing information. Rockland, MA: 2024 Feb. [Web]
2. Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2024 Oct 1. [Web]
3. Paik PK, Felip E, Veillon R et al. Tepotinib in Non-Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations. N Engl J Med . 2020; 383:931-943. [PubMed 32469185]
4. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 214096Orig1s000: Multi-discipline review. From FDA website. [Web]
5. Bylicki O, Paleiron N, Assié JP et al. Targeting the MET-Signaling Pathway in Non-Small-Cell Lung Cancer: Evidence to Date. Onco Targets Ther . 2020; 13:5691-5706. [PubMed 32606781]
6. Awad MM, Oxnard GR, Jackman DM et al. MET Exon 14 Mutations in Non-Small-Cell Lung Cancer Are Associated With Advanced Age and Stage-Dependent MET Genomic Amplification and c-Met Overexpression. J Clin Oncol . 2016; 34:721-30. [PubMed 26729443]
7. Drusbosky LM, Dawar R, Rodriguez E et al. Therapeutic strategies in METex14 skipping mutated non-small cell lung cancer. J Hematol Oncol . 2021; 14:129. [PubMed 34425853]
8. Mazieres J, Paik PK, Garassino MC, et al. Tepotinib treatment in patients with MET exon 14-skipping non-small cell lung cancer. Long-term follow-up of the VISION phase 2 nonrandomized clinical trial. JAMA Oncol . 2023;9(9):1260-66.
9. Hanna N, Robinson A, Temin S, et al. Therapy for stage IV non-small-cell lung cancer with driver alterations: ASCO and OH (CCO) Joint Guideline update. J Clin Oncol . 2021;39:1040-1091.
10. Jaiyesimi IA, Leighl NB, Ismaila A, et al. Therapy for stage IV non-small-cell lung cancer with driver alterations: ASCO living guideline, Version 2023.3. J Clin Oncol . 2024;42:e1-e22.