Introduction
Capmatinib (brand name Tabrecta) is an oral, highly selective small molecule inhibitor of mesenchymal-epithelial transition (MET) tyrosine kinase. It represents a significant advancement in precision oncology for patients with non-small cell lung cancer (NSCLC) harboring specific MET alterations. Approved by the FDA in May 2020, capmatinib is the first therapy specifically indicated for metastatic NSCLC with MET exon 14 skipping mutations.
Mechanism of Action
Capmatinib works by selectively targeting and inhibiting the MET receptor tyrosine kinase. The MET pathway plays a crucial role in normal cellular processes including proliferation, survival, and migration. In certain cancers, particularly NSCLC, MET exon 14 skipping mutations lead to constitutive activation of the MET signaling pathway, promoting tumor growth and metastasis. Capmatinib binds to the ATP-binding pocket of MET, inhibiting its phosphorylation and subsequent downstream signaling through the MAPK and PI3K/AKT pathways. This ultimately results in reduced tumor cell proliferation, increased apoptosis, and inhibition of angiogenesis.
Indications
Capmatinib is FDA-approved for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have a mutation that leads to MET exon 14 skipping, as detected by an FDA-approved test. This indication received accelerated approval based on overall response rate and duration of response, with continued approval contingent upon verification of clinical benefit in confirmatory trials.
Dosage and Administration
The recommended dosage is 400 mg orally twice daily with or without food. Tablets should be swallowed whole and not crushed, cut, or chewed.
Dose Modifications:- Hepatic Impairment: Reduce dose to 300 mg twice daily in patients with moderate hepatic impairment (Child-Pugh B). Not recommended in severe hepatic impairment (Child-Pugh C)
- Renal Impairment: No dose adjustment needed for mild to moderate impairment (eGFR ≥30 mL/min). Use with caution in severe impairment
- Adverse Reaction Management: Dose reductions to 300 mg twice daily or 200 mg twice daily may be required based on severity of specific adverse reactions
Treatment should continue until disease progression or unacceptable toxicity occurs.
Pharmacokinetics
Absorption: Capmatinib reaches peak plasma concentrations within 1-2 hours post-dose. The absolute bioavailability is approximately 42%. Food does not significantly affect exposure. Distribution: Mean apparent volume of distribution is 267 L. Protein binding is approximately 96%, primarily to albumin and alpha-1 acid glycoprotein. Metabolism: Primarily metabolized by CYP3A4 (∼70%) and aldehyde oxidase. The major circulating metabolite (M3) is pharmacologically inactive. Elimination: Mean elimination half-life is approximately 6.5 hours. Approximately 78% of the dose is excreted in feces (42% as unchanged drug) and 22% in urine (<1% as unchanged drug).Contraindications
There are no absolute contraindications listed in the prescribing information. However, capmatinib should not be used in patients who have demonstrated hypersensitivity to the drug or any of its components.
Warnings and Precautions
Interstitial Lung Disease (ILD)/Pneumonitis: ILD/pneumonitis, which can be fatal, occurred in patients treated with capmatinib. Monitor for pulmonary symptoms indicative of ILD/pneumonitis. Permanently discontinue capmatinib in patients diagnosed with ILD/pneumonitis. Hepatotoxicity: Drug-induced liver injury occurred in patients. Monitor liver function tests before starting capmatinib and periodically during treatment. Withhold, reduce dose, or permanently discontinue based on severity. Photosensitivity: Photosensitivity reactions have been reported. Advise patients to limit direct ultraviolet exposure during treatment and for at least 5 days after discontinuation. Embryo-Fetal Toxicity: Can cause fetal harm. Advise pregnant women of the potential risk to the fetus. Verify pregnancy status prior to initiation and use effective contraception during treatment and for 1 week after final dose.Drug Interactions
Strong CYP3A Inducers: Concomitant use with strong CYP3A inducers (e.g., rifampin, carbamazepine, St. John's wort) may decrease capmatinib exposure. Avoid concomitant use. Strong CYP3A Inhibitors: Concomitant use with strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, clarithromycin) may increase capmatinib exposure. Avoid concomitant use. If unavoidable, reduce capmatinib dose. Acid-Reducing Agents: Proton pump inhibitors may decrease capmatinib exposure. Consider alternatives to PPIs or use H2-receptor antagonists or antacids with appropriate dosing separation.Adverse Effects
Most Common Adverse Reactions (≥20%): Peripheral edema, nausea, fatigue, vomiting, dyspnea, decreased appetite, back pain, constipation, and fever. Serious Adverse Reactions: ILD/pneumonitis, hepatotoxicity, and photosensitivity reactions. Laboratory Abnormalities: Increased creatinine, increased gamma-glutamyl transferase, increased alanine aminotransferase, increased aspartate aminotransferase, increased alkaline phosphatase, increased amylase, decreased albumin, decreased hemoglobin, decreased lymphocytes, decreased platelets, decreased sodium, and decreased potassium.Monitoring Parameters
- Baseline: Complete metabolic panel (including liver function tests), complete blood count, pregnancy test in women of reproductive potential
- During Treatment: Liver function tests every 2 weeks during the first 3 months, then monthly thereafter; monitor for signs/symptoms of ILD/pneumonitis; assess for peripheral edema; monitor renal function
- Imaging: CT or PET scans every 6-12 weeks to assess treatment response
- Symptom Management: Regular assessment for nausea, vomiting, fatigue, and other treatment-related symptoms
Patient Education
- Take capmatinib exactly as prescribed, typically twice daily with or without food
- Swallow tablets whole; do not crush, chew, or break
- Report any new or worsening respiratory symptoms immediately
- Limit direct sun exposure and use protective measures (sunscreen, protective clothing)
- Report signs of liver problems (yellowing skin/eyes, dark urine, abdominal pain)
- Use effective contraception during treatment and for at least 1 week after final dose
- Inform all healthcare providers about capmatinib use before starting new medications
- Manage nausea with antiemetics as prescribed and small, frequent meals
- Report peripheral edema; elevation of legs may help manage swelling
- Keep all scheduled appointments for monitoring and laboratory tests
References
1. US Food and Drug Administration. (2020). TABRECTA (capmatinib) prescribing information. 2. Wolf J, Seto T, Han JY, et al. (2020). Capmatinib in MET Exon 14-Mutated or MET-Amplified Non-Small-Cell Lung Cancer. New England Journal of Medicine, 383(10), 944-957. 3. Paik PK, Felip E, Veillon R, et al. (2020). Tepotinib in Non-Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations. New England Journal of Medicine, 383(10), 931-943. 4. ClinicalTrials.gov. (2020). Study of Capmatinib in Patients With MET-Mutated Advanced Non-small Cell Lung Cancer (GEOMETRY mono-1). NCT02414139. 5. NCCN Guidelines Version 3.2022: Non-Small Cell Lung Cancer. 6. Salgia R, Sattler M, Scheele J, et al. (2020). The promise of selective MET inhibitors in non-small cell lung cancer with MET exon 14 skipping. Cancer Treatment Reviews, 87, 102022.
Note: This information is intended for educational purposes only and should not replace professional medical advice. Always consult with a qualified healthcare provider for personalized medical guidance.