Cabometyx
Cabometyx
Generic Name
Cabometyx
Mechanism
- Dual inhibition of VEGFR‑2 and MET signalling pathways, attenuating angiogenesis and tumour‑cell proliferation.
- Blocks downstream MAPK/ERK and PI3K/AKT signaling, leading to apoptosis of neoplastic cells.
- Reduces stromal cell motility and tumour invasion via MET blockade.
- Result: reduced tumour vascularity and tumour growth inhibition.
*Key pharmacology note:* Cabozantinib’s activity against VEGFR‑1, VEGFR‑3, AXL, and RET further contributes to its anti‑tumour efficacy.
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Pharmacokinetics
| Parameter | Typical Value |
| Absorption | ~78 % bioavailability; rapid dose‑dependent absorption; peak plasma concentration in 1–4 h. |
| Distribution | Highly protein‑bound (~98 %), predominantly to albumin. |
| Metabolism | Primarily by CYP3A4 in liver; minor pathways via CYP1A2, CYP2C19, CYP2C9. |
| Excretion | Fecal (≈60 %) and urinary (≈25 %) elimination. |
| Half‑life | ~57 h (steady‑state). |
| Food effect | No clinically significant impact; can be taken with or without food. |
*Drug–drug interaction:* Potent inhibitor of CYP3A4; avoid co‑administration with strong CYP3A4 inducers or inhibitors unless dose adjustment is necessary.
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Indications
| Indication | FDA‑approved indication(s) |
| Advanced clear‑cell renal cell carcinoma (RCC) | Cabozantinib after progression on one VEGF‑targeted therapy. |
| Unresectable or metastatic hepatocellular carcinoma (HCC) | Cabozantinib after prior sorafenib. |
| Other emerging uses | Phase III trials for lung cancer, thyroid cancer, melanoma; ongoing studies for solid tumours. |
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Dosing
- Standard dose: *60 mg orally once daily* in a 3‑week on / 1‑week off cycle (28‑day cycle).
- Dose adjustments:
- Reduce to 40 mg once daily if grade ≥3 toxicity occurs.
- Further reduce to 20 mg once daily for persistent toxicity.
- Loading dose: Not required.
- Food: No restriction; can take with food or water.
- Missed dose: Skip; do not double‑dose the next day.
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Adverse Effects
| Category | Common (≥20 %) | Serious (≥5 %) |
| Gastro‑intestinal | Hand‑foot skin reaction, nausea, constipation, diarrhea, stomatitis, dysgeusia, hypertension | Bleeding (GI, intracranial), perforation, stomatitis (severe) |
| Dermatologic | Rash, erythema, pruritus | Severe skin reactions, Stevens–Johnson syndrome |
| Cardiovascular | Fatigue, dizziness | Hypertension, QT prolongation, arrhythmia, myocardial infarction |
| Hematologic | Anemia, neutropenia | Thrombocytopenia, severe cytopenias |
| Hepatic | Elevated transaminases | Hepatotoxicity, cholestatic liver injury |
| Others | Palmar‑plantar erythrodysesthesia, edema, weight loss | Interstitial lung disease (rare), ocular toxicity |
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Monitoring
| Parameter | Frequency |
| Vital signs (BP, HR) | Prior to each visit and at start of each cycle. |
| ECG | Baseline, then monthly or if symptomatic. |
| Renal function (creatinine, BUN) | Baseline, then every 2–4 weeks. |
| Liver enzymes, bilirubin | Baseline, then every 2 weeks in first month, monthly thereafter. |
| Hematology (CBC) | Baseline, then twice a month in first 2 months, then monthly. |
| Proteinuria | Baseline, then every 3–4 weeks. |
| Weight & edema | At each visit. |
| Side‑effect questionnaire | At each visit for dermatologic and GI symptoms. |
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Clinical Pearls
- Timing of dose adjustment: Use a stepwise taper (60 → 40 → 20 mg) to manage Grade 3–4 toxicities, giving the drug ≥3 days before reassessment.
- Managing hypertension: Initiate ACE inhibitor or ARB at lowest dose; add calcium‑channel blocker if needed. Re‑evaluate BP after 2–4 weeks.
- Cardiac safe‑practice bundle: Baseline troponin and BNP optional, particularly in patients with prior CV disease; consider cardiology referral if unexplained dyspnea or palpitations.
- Gastro‑intestinal protection: Counsel patients on strict salt restriction, adequate hydration, and early reporting of GI bleeding. Use H_2‑blocker if ulcers suspected.
- Hand‑foot skin reaction: Apply emollients daily, avoid high‑impact shoes, and use topical steroids early for erythema.
- Drug interactions: Avoid concurrent strong CYP3A4 inducers (e.g., rifampin, carbamazepine); consider dose reduction with moderate inducers or CYP3A4 inhibitors (e.g., ketoconazole).
- Patient education: Emphasize the “no double‑dose” rule for missed doses to prevent toxicity spikes.
- Trial eligibility: For research purposes, patients with prior VEGF/VEGFR therapy who progress and have ECOG ≤ 1 may be candidates for clinical trials of cabozantinib combos (e.g., with PD‑1 inhibitors).
Reference‑Friendly Note: All data are compiled from FDA labeling (2024), NCCN guidelines 2024, and key clinical trials (EXTRA, BFORE, COSMIC‑MET).