What Is Tepotinib (Tepmetko)? FDA Approval, Licensing and Reimbursement in Turkey

• FDA Approval: Yes (First approval: February 3, 2021)
• Brand Name: Tepmetko
• Active Ingredient: Tepotinib
• Administration: Oral tablet taken 1 time daily
• Class: MET tyrosine kinase inhibitor (MET inhibitor)
• Category: Antineoplastic / Targeted Therapy
• Manufacturer: Merck KGaA (EMD Serono – US market)
• Availability in Turkey: Not yet licensed in Turkey.
• Approved Cancers: MET exon 14 skipping (METex14) mutation-positive metastatic NSCLC

What Is Tepotinib? How Does It Work?

Tepotinib is an oral targeted MET tyrosine kinase inhibitor (TKI), particularly for metastatic NSCLC positive for MET exon 14 skipping mutations (METex14). These drugs bind specific molecular targets controlling tumor growth.

Mechanism of Action

MET, also known as hepatocyte growth factor receptor, is a receptor tyrosine kinase involved in growth, survival, invasion and metastasis. It normally regulates signaling, but MET exon 14 skipping prevents protein degradation, leaving MET signaling continuously active.

Tepotinib binds the mutant receptor's tyrosine kinase region, preventing autophosphorylation. It blocks intracellular signaling, stopping or reducing cancer cell growth and spread.

Consequently, tepotinib:

• Suppresses MET signaling,
• Inhibits tumor cell proliferation,
• Promotes apoptosis (programmed cell death),
• May reduce metastatic spread.

FDA (US Food and Drug Administration) Approval History

February 15, 2024: The FDA granted traditional approval to Tepmetko (tepotinib) for metastatic NSCLC.

February 3, 2021: The FDA approved Tepmetko (tepotinib) as the first and only once-daily oral MET inhibitor for metastatic NSCLC with METex14 skipping alterations.

August 25, 2020: The FDA accepted the tepotinib New Drug Application for metastatic NSCLC with METex14 skipping alterations.

Licensing in Turkey

Not yet licensed in Turkey. Not included on TİCK's overseas medicines list.

Resistance Mechanisms

Tepotinib blocks MET tyrosine kinase activity. Some cancer cells develop acquired mechanisms to bypass this blockade, principally through target-site changes or activation of alternative signaling pathways:

• Secondary MET Mutations: Cancer cells acquire additional MET mutations during treatment, structurally changing the binding region. Tepotinib then binds less easily or becomes ineffective despite binding.
• MET Amplification: Increased MET copies produce excess protein, creating signaling too strong for complete blockade.
• Alternative Signaling Activation: Activating EGFR, HER2, KRAS or PI3K/AKT/mTOR allows growth and proliferation despite MET inhibition.
• Phenotypic Change:  Changes such as epithelial-mesenchymal transition may reduce MET dependence, enabling proliferation independent of MET blockade.

Absorption

• Tepotinib is well absorbed orally.
• Single-dose bioavailability is high (~72%).
• Food may improve absorption; fatty meals may particularly increase plasma concentrations.
• Peak plasma levels (Tmax) generally occur within 6-8 hours.

Distribution

• Highly bound to plasma proteins (>90%).
• Large distribution volume (Vd), indicating good tissue penetration.
• Accumulates particularly in tumor regions with high MET expression.

Metabolism

• Mainly metabolized in the liver.
• Predominantly through CYP3A4.
• Also a P-gp substrate; transport proteins contribute to movement into and out of cells.

Elimination

• Mainly through bile and feces.
• Approximately 45-50% is excreted unchanged in feces; urinary excretion is very low (<10%).
• Elimination half-life (t½) is approximately 32-40 hours, supporting dosing 1 time daily.

Dosing Interval

• Recommended dose: 450 mg (2 tablets) once daily.
• Taken orally 1 time daily, preferably with food (fatty meals may increase bioavailability).
• Taken regularly at the same time every day without breaks.
• Stop for progression, intolerable toxicity or a physician's decision.

Drug Interactions

CYP3A4 Inhibitors

• Tepotinib is metabolized by hepatic CYP3A4.
• Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, grapefruit juice) may increase levels and adverse effect risk.
• Monitor closely if combination is necessary.

CYP3A4 Inducers

• Strong CYP3A4 inducers (e.g., rifampicin, phenytoin, carbamazepine, St. John's Wort) lower levels and may reduce efficacy.
• Avoid potent inducers if possible or select alternatives.

P-Glycoprotein (P-gp) Inhibitors / Inducers

• Tepotinib is a P-gp substrate.
• P-gp inhibitors (e.g., verapamil, cyclosporine) may raise levels.
• P-gp inducers (e.g., rifampicin) may lower levels.

Acid Suppressants

There is no significant gastric pH interaction; no major issue with PPIs or antacids has been reported, unlike gefitinib.

Other Targeted Treatments

Combining with other MET inhibitors, EGFR inhibitors or potent chemotherapy may accumulate toxicity rather than cause pharmacokinetic interactions; careful planning is needed.

Precautions

Confirm the MET Mutation: Efficacy is established only for MET exon 14 skipping (METex14). Do not start before confirmation by an accredited laboratory.

Interstitial Lung Disease Risk: ILD may rarely develop. New/worsening cough, dyspnea or fever require immediate assessment and discontinuation if necessary.

Edema (Fluid Retention): Peripheral edema was common in trials. Leg swelling or weight gain may require withholding doses or edema treatment.

Liver Dysfunction: Because of hepatic metabolism, monitor ALT and AST regularly. Significant elevations may require temporary interruption or discontinuation.

Drug Interactions: Strong CYP3A4 inhibitors or inducers alter tepotinib levels. Manage under medical supervision; avoid natural CYP3A4 inhibitors such as grapefruit.

Pregnancy and Breastfeeding: Fetotoxicity risk means it should not be used during pregnancy. Effective contraception is recommended. Stop breastfeeding during use.

QT Prolongation Risk: QT prolongation may rarely occur. ECG monitoring may be needed, particularly with pre-existing arrhythmias.

Adverse Effects

• Peripheral edema (foot-leg swelling): 63%
• Hypoalbuminemia: 26%
• Nausea: 21%
• Diarrhea: 20%
• Fatigue: 14%
• Elevated creatinine: 13%
• Vomiting: 12%
• Elevated ALT (liver enzyme): 11%
• Elevated AST (liver enzyme): 10%
• Anemia: 9%
• Itching: 8%
• Rash: 7%
• Interstitial lung disease (ILD): 4%
• QT prolongation (rare; frequency varies by study)