Inlyta
Inlyta
Generic Name
Inlyta
Mechanism
- Cabozantinib irreversibly inhibits multiple receptor tyrosine kinases (RTKs) that are essential for tumor proliferation, angiogenesis, and metastatic spread.
- Key targets:
- MET (hepatocyte growth factor receptor) – drives tumor invasion and resistance to VEGF blockade.
- VEGFR‑2, VEGFR‑3 – suppress tumor vascular growth.
- AXL, RET, KIT, FLR‑3, TIE‑2, and others – contribute to angiogenesis, survival, and metastasis.
- By blocking these RTKs simultaneously, cabozantinib disrupts the signaling circuitry that tumors use to evade anti‑angiogenic therapies and metastasize.
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Pharmacokinetics
| Parameter | Typical value (average) |
| Absorption | ~5 h T_max; food increases AUC by ~30 % |
| Bioavailability | 20–25 % (high inter‑patient variability) |
| Distribution | Protein‑bound > 80 %; volume of distribution ~5.5 L/kg |
| Metabolism | Primarily hepatic via CYP3A4; minor CYP2C19 contribution |
| Elimination | Metabolites excreted via liver (≈60 %) and feces (≈25 %); renal excretion minimal |
| Half‑life | ~45–65 h (steady‑state) |
Clinical implications
• Co‑administration with strong CYP3A4 inhibitors (ketoconazole, itraconazole) should be avoided or dose reduced.
• Strong CYP3A4 inducers (rifampin, carbamazepine) lower exposure and may diminish efficacy.
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Indications
| Indication | Disease Stage & Prior Therapy | Approved Setting |
| Metastatic RCC | After one prior systemic therapy (e.g., anti‑VEGF or immune checkpoint inhibitor) | First‑line beyond VEGF therapy |
| RCC – progressive disease after VEGF/anti‑PD‑L1 therapy | Previously treated with VEGF‑targeted agents or PD‑1/PD‑L1 inhibitors | Second/third line |
| Hepatocellular carcinoma | Prior treatment with sorafenib | First‑line following sorafenib failure |
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Contraindications
Contraindicated
• Known hypersensitivity to cabozantinib or its components.
• Severe hepatic impairment (Child‑Pugh B‑C).
• Pregnancy (teratogenic risk).
Warnings
• Bleeding, including GI and intracranial – due to anti‑angiogenic effect.
• Weight loss, anorexia – may affect nutrition and overall outcomes.
• Hypertension – requires careful blood‑pressure monitoring.
• Cytopenias – hematologic toxicity can be significant.
• QTc prolongation – particularly with concomitant QT‑prolonging agents.
• Drug interactions – especially with strong CYP3A4 inhibitors/inducers.
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Dosing
| Population | Dose | Route | Frequency | Notes |
| Adults (≥ 60 kg) | 60 mg | Oral | QD | Take with water, food increases absorption. |
| Adults (≤ 60 kg) | 30 mg | Oral | QD | Dose reduction for smaller body size. |
| Pediatric (≥ 8 yo, < 12 kg) | 60 µg/kg (max 30 mg) | Oral | QD | Limited data; dose adjustment may be needed. |
Administration tips
• Discontinue abruptly if signs of bleeding or severe adverse effects appear.
• Counsel patients to avoid alcohol and NSAIDs with ingestion.
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Adverse Effects
| Class | Common (≥ 10 %) | Serious (≤ 5 %) |
| Gastrointestinal | Diarrhea (up to 40 %), nausea, vomiting, oral mucositis | GI hemorrhage, perforation |
| Dermatologic | Hand‑foot syndrome (erythrodysesthesia), rash, alopecia | Severe skin necrosis |
| Hematologic | Fatigue, anemia | Cytopenias (neutropenia, thrombocytopenia) |
| Cardiovascular | Hypertension, palpitations | QTc prolongation, ventricular arrhythmias |
| Laboratory | Elevated ALT/AST (30 % transient) | Severe hepatotoxicity (ALT > 5× ULN) |
| Pulmonary | Dyspnea | Pneumonitis, interstitial lung disease |
Management
• Use loperamide for diarrhea; dose hold if grade ≥ 3.
• Hydrate, monitor electrolytes for hypertension.
• Regular labs (CBC, CMP, LFTs) every 2–4 weeks.
• Discontinue if grade > 3 toxicity or liver injury.
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Monitoring
| Monitor | Target | Frequency (Typical) | Rationale |
| Blood pressure | ≤ 140/90 mmHg | ≥ weekly (first 4 weeks), then every 2 weeks | CV risk |
| CBC | Hemoglobin, neutrophils, platelets | Every 2 weeks (first 3 months) | Detect cytopenias |
| CMP (LFTs, electrolytes) | ALT/AST, bilirubin, BUN/Cr | Every 2 weeks | Hepatic/renal safety |
| Tumor response | Radiographic | Every 8–12 weeks | Efficacy assessment |
| ECG (QTc) | ≤ 450 ms | At baseline, 30 days, and if clinically indicated | Cardiac safety |
| Weight & BMI | Maintain > 80 % of baseline | Every visit | Nutritional status |
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Clinical Pearls
- Food interaction: A high‑fat meal should be avoided because it can significantly increase cabozantinib exposure; schedule dosing on an empty stomach for consistency.
- Blood‑pressure clusters: Hypertension generally begins in the first week; pre‑emptive ACE‑I or ARB use can mitigate event rates.
- Drug–drug notices: When co‑administered with CYP3A4 inhibitors, reduce initial dose to 30 mg until toxicity is assessed.
- Abrupt discontinuation: Severe neuropathy or myopathy may arise if therapy stops suddenly; consider taper or dose hold rather than a full stop.
- Second‑line care in RCC: Cabozantinib sets a high bar for progression‑free survival after VEGF therapy; hence a rapid evaluation for disease progression can inform next‑line options sooner.
- Patient education focus: Label “dizziness, blurred vision, or sudden weakness” as red flags signaling acute bleeding or cardiovascular events.
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• References
1. Rini BI, et al. *Cabozantinib for renal cell carcinoma:* Clinical trials and practice. *Ann Surg Oncol.* 2021.
2. Mansour R, et al. *Cabozantinib Pharmacokinetics & Drug Interactions.* *Clin Pharmacok.* 2022.
3. FDA prescribing information for Inlyta® (cabozantinib). Updated 2023.