Capmatinib – Uses, Dosage, Side Effects, Interaction

Capmatinib Hydrochloride is the hydrochloride salt form of capmatinib, an orally bioavailable inhibitor of the proto-oncogene c-Met (also known as hepatocyte growth factor receptor (HGFR)) with potential antineoplastic activity. Capmatinib selectively binds to c-Met, thereby inhibiting c-Met phosphorylation and disrupting c-Met signal transduction pathways. This may induce cell death in tumor cells by overexpressing the c-Met protein or expressing the constitutively activated c-Met protein. c-Met, a receptor tyrosine kinase overexpressed or mutated in many tumor cell types, plays key roles in tumor cell proliferation, survival, invasion, metastasis, and tumor angiogenesis.

Capmatinib inhibits the overactivity of c-Met, a receptor tyrosine kinase encoded by the _MET_ proto-oncogene. Mutations in _MET_ are involved in the proliferation of many cancers, including non-small cell lung cancer (NSCLC). Capmatinib may cause photosensitivity reactions in patients following ultraviolet (UV) exposure – patients undergoing therapy with capmatinib should be advised to use sunscreen and protective clothing to limit exposure to UV radiation. Instances of interstitial lung disease/pneumonitis, which can be fatal, occurred in patients being treated with capmatinib. Patients presenting with signs or symptoms of lung disease (e.g. cough, dyspnea, fever) should have capmatinib immediately withheld, and capmatinib should be permanently discontinued if no other feasible causes of the lung-related symptoms are identified.

Use in Cancer

Capmatinib hydrochloride is approved to treat:

• Non-small cell lung cancer has a certain mutation in the MET gene. It is used in adults whose cancer has spread to other parts of the body.

Capmatinib hydrochloride is also being studied in the treatment of other types of cancer.

Contraindication

• abnormal liver function tests
• pregnancy
• a patient who is producing milk and breastfeeding
• lung tissue problem
• pancreatitis

Dosage

Strengths: 150 mg; 200 mg

Non-Small Cell Lung Cancer

• 400 mg orally 2 times daily
• For the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have a mutation that leads to mesenchymal-epithelial transition (MET) exon 14 skipping as detected by an approved test

Dose Adjustments

DOSE MODIFICATION RECOMMENDATIONS:

• First dose reduction: 300 mg orally 2 times daily
• Second dose reduction: 300 mg orally 2 times daily
• Permanently discontinue this drug in patients who are unable to tolerate 200 mg orally 2 times daily.

DOSE MODIFICATION FOR ADVERSE REACTIONS:
INTERSTITIAL LUNG DISEASE (ILD)/PNEUMONITIS:

• Any Grade: Permanently discontinue this drug.

Increased ALT and/or AST without increased total bilirubin:

• Grade 3: Withhold therapy until recovery to baseline ALT/AST; if recovered to baseline within 7 days, resume this drug at the same dose; otherwise resume at a reduced dose.
• Grade 4: Permanently discontinue this drug.

INCREASED ALT AND/OR AST WITH INCREASED TOTAL BILIRUBIN IN THE ABSENCE OF CHOLESTASIS OR HEMOLYSIS:

• ALT and/or AST greater than 3 times the upper limit of normal (ULN) with total bilirubin greater than 2 x ULN: Permanently discontinue this drug.

INCREASED TOTAL BILIRUBIN WITHOUT CONCURRENT INCREASED ALT AND/OR AST:

• Grade 2: Withhold therapy until recovery to baseline bilirubin; if recovered to baseline within 7 days, resume this drug at the same dose; otherwise resume at a reduced dose.
• Grade 3: Withhold therapy until recovery to baseline bilirubin; if recovered to baseline within 7 days, resume this drug at a reduced dose; otherwise permanently discontinue this drug.
• Grade 4: Permanently discontinue this drug.

OTHER ADVERSE REACTIONS:

• Grade 2: Maintain dose level; if intolerable, consider withholding this drug until resolved, then resume at a reduced dose.
• Grade 3: Withhold this drug until resolved then resume at a reduced dose.
• Grade 4: Permanently discontinue this drug.

Side Effects

The Most Common

• vomiting
• nausea
• diarrhea
• constipation
• muscle, bone, or back pain
• loss of appetite
• tiredness and weakness
• dizziness
• swelling in hands, feet, ankles, or lower legs
• rash
• shortness of breath or trouble breathing, cough, fever, or other signs of infection
• chest pain
• pain in right upper part of the stomach; swelling in your stomach area; unusual bruising or bleeding; dark urine; yellowing of the skin and eyes; nausea, vomiting; light-colored stools; loss of appetite
• ongoing pain that begins in the stomach area, but may spread to the back; nausea; vomiting; weight loss

More Common

• our skin or the white part of your eyes turns yellow
  (jaundice)
• loss of appetite for several days or longer
• dark or “tea-colored” urine o nausea and vomiting
• light-colored stools (bowel movements)
• confusion
• pain, aching, or tenderness on the right side of your
• stomach area (abdomen)
• tiredness o weakness
• swelling in your stomach-area

Rare

• new or worsening cough, chest pain, trouble breathing;
• fever, cough with mucus;
• severe ongoing nausea and vomiting; or
• signs of liver or pancreas problems–loss of appetite, upper stomach pain (that may spread to your back), nausea or vomiting, fast heart rate, dark urine, jaundice (yellowing of the skin or eyes).
• trouble breathing;
• vomiting decreased appetite;
• feeling weak or tired
• abnormal liver function tests;
• swelling in your hands or feet.

Drug Interaction

Pregnancy and Lactation

US FDA pregnancy category: Not assigned.

Pregnancy

Based on findings from animal studies and its mechanism of action, TABRECTA can cause fetal harm when administered to a pregnant woman. There are no available data on TABRECTA use in pregnant women. Oral administration of capmatinib to pregnant rats and rabbits during the period of organogenesis resulted in malformations at maternal exposures less than the human exposure based on AUC at the 400 mg twice daily clinical dose. Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Lactation

There are no data on the presence of capmatinib or its metabolites in either human or animal milk or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with TABRECTA and for 1 week after the last dose.

References