Cabozantinib

Approved Indications:

• Advanced Renal Cell Carcinoma (RCC):
• First-line treatment of advanced RCC in adults, alone or in combination with nivolumab.
• Monotherapy for patients previously treated with anti-angiogenic therapy.
• Hepatocellular Carcinoma (HCC):
• Treatment of HCC in adults who have been previously treated with sorafenib.
• Medullary Thyroid Carcinoma (MTC):
• Progressive, metastatic MTC in adults and pediatric patients ≥12 years of age (only cabozantinib capsules are indicated for this use).

Important Off-Label / Investigational Uses:

• Non-Small Cell Lung Cancer (NSCLC): Under study in combination with immunotherapy in advanced or metastatic cases.
• Prostate Cancer: Investigational use in metastatic castration-resistant prostate cancer (mCRPC).
• Other Tumor Types: Evaluated in trials for ovarian, breast, pancreatic, and colorectal cancers.

Formulations:

• Cabozantinib is available as tablets (Cabometyx) and capsules (Cometriq).
• Important: These two formulations are not interchangeable.

Recommended Dosages:

• RCC (Adults):
• Tablets (Cabometyx): 60 mg orally once daily without food.
• HCC (Adults):
• Tablets: 60 mg orally once daily (after sorafenib failure).
• MTC (Adults and Children ≥12 years):
• Capsules (Cometriq):
• ≤40 kg: 40 mg orally once daily
• >40 kg: 60 mg orally once daily

Special Populations:

• Hepatic Impairment:
• Moderate impairment (Child-Pugh B): Reduce dose to 40 mg (tablet) or 40 mg (capsule).
• Severe impairment (Child-Pugh C): Avoid use.
• Renal Impairment:
• Mild to moderate: No dose adjustment.
• Severe impairment: Use caution; limited data.
• Pediatric (≥12 years, MTC only):
• Dosing as above by weight (capsule form only).

Administration Notes:

• Take on an empty stomach: No food for at least 2 hours before and 1 hour after.
• Swallow whole; do not crush, chew, or open capsules/tablets.
• Continue treatment until disease progression or unacceptable toxicity.

Cabozantinib is a tyrosine kinase inhibitor (TKI) that targets multiple receptor tyrosine kinases implicated in tumor growth, angiogenesis, and metastatic progression. It inhibits VEGFR-1, -2, -3, MET, AXL, RET, KIT, FLT3, and others. By blocking these kinases, Cabozantinib suppresses tumor cell proliferation, disrupts angiogenesis, and inhibits metastatic potential. MET and AXL inhibition contributes to overcoming resistance to VEGFR-targeted therapies, making Cabozantinib particularly effective in previously treated cancers.

• Absorption:
• Time to peak: ~2–5 hours
• Bioavailability (oral): ~74% (tablet)
• Food increases exposure (hence taken without food)
• Distribution:
• Plasma protein binding: >99%
• Volume of distribution: ~349 L
• Metabolism:
• Predominantly hepatic via CYP3A4
• Minor contribution from CYP1A1 and CYP1A2
• Active Metabolites:
• Several, but less pharmacologically active than parent drug
• Elimination Half-Life:
• ~99 hours (capsule), ~55 hours (tablet)
• Excretion:
• Feces: ~54%
• Urine: ~27%

• Pregnancy:
• Classified as Category D (historical); based on mechanism and animal data, Cabozantinib may cause fetal harm.
• Avoid use in pregnancy; use effective contraception during and for 4 months after final dose.
• Lactation:
• Unknown if excreted in human milk.
• Due to potential serious adverse effects in infants, breastfeeding is not recommended during treatment and for 4 months after the last dose.

• Primary Class: Antineoplastic Agent
• Subclass: Tyrosine Kinase Inhibitor (Multikinase Inhibitor)
• Generation: Broad-spectrum VEGFR/MET/AXL inhibitor (second-generation TKI)

• Known hypersensitivity to Cabozantinib or any excipient
• Use in combination with strong CYP3A4 inhibitors or inducers (relative contraindication unless adjusted)
• Severe hepatic impairment (Child-Pugh C)
• Pregnancy and lactation
• Recent major bleeding or unhealed wounds

• Hemorrhage Risk: Serious and sometimes fatal bleeding; avoid in patients with high bleeding risk or brain metastases.
• GI Perforations and Fistulae: Monitor for symptoms; discontinue if confirmed.
• Thromboembolism: Increased risk of arterial and venous events; use with caution in patients with cardiovascular risk factors.
• Hypertension: Monitor and manage aggressively; may require dose reduction or interruption.
• Osteonecrosis of the Jaw (ONJ): Especially in patients on bisphosphonates; monitor dental health.
• Wound Healing: Delay surgery or hold treatment for at least 28 days before/after major procedures.
• Hepatotoxicity: Regular LFT monitoring advised.
• Palmar-Plantar Erythrodysesthesia (PPE): Dose modifications may be necessary.
• QT Prolongation: Use caution in patients with known cardiac arrhythmias.

Common (≥10%):

• GI: Diarrhea, nausea, vomiting, stomatitis, decreased appetite
• Dermatologic: Palmar-plantar erythrodysesthesia, rash, alopecia
• Musculoskeletal: Fatigue, weight loss
• CV: Hypertension

Less Common (1–10%):

• Proteinuria
• Voice changes (dysphonia)
• Elevated liver enzymes
• Hypothyroidism
• Mucosal inflammation

Serious/Rare:

• Gastrointestinal perforation
• Severe hemorrhage
• Arterial and venous thromboembolism (stroke, MI, DVT)
• Posterior reversible encephalopathy syndrome (PRES)
• Osteonecrosis of the jaw
• QT prolongation

Timing & Dose Dependency:

• Most adverse effects are dose-related and occur within the first 2–8 weeks.

• Strong CYP3A4 Inhibitors (e.g., ketoconazole, clarithromycin):
• Increase Cabozantinib levels → ↑ toxicity
• Reduce dose to 40 mg if coadministration is unavoidable
• Strong CYP3A4 Inducers (e.g., rifampin, phenytoin):
• Decrease efficacy by reducing plasma levels
• Avoid if possible
• Food Interaction:
• High-fat meals increase exposure; take on an empty stomach
• QT-Prolonging Agents:
• May potentiate cardiac risk; monitor ECG
• Anticoagulants and Antiplatelet Drugs:
• Increased risk of bleeding

• NCCN Guidelines: Recommend Cabozantinib + Nivolumab as first-line treatment for advanced RCC.
• FDA Updates:
• Approved expanded use in combination therapy for RCC (2021).
• Ongoing Clinical Trials:
• Studies evaluating combinations with checkpoint inhibitors in NSCLC, prostate cancer, and breast cancer.
• EMA Guidance: Emphasizes liver monitoring and surgical wound healing precautions.

• Temperature: Store at 20°C to 25°C (68°F to 77°F).
• Permitted Excursions: 15°C to 30°C (59°F to 86°F)
• Light Protection: Keep in original packaging to protect from light.
• Humidity: Store in a dry place.
• Handling Instructions:
• Do not crush, split, or chew tablets/capsules.
• Keep out of reach of children.
• No refrigeration or reconstitution needed.