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Axitinib: Indications, Adverse Effects, Contraindications and Dosage

Mechanism of Action of Axitinib

Axitinib is an oral, potent, and selective inhibitor of vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, and VEGFR-3). By blocking VEGFR signaling, axitinib suppresses pathologic angiogenesis and tumor vascular permeability, which contributes to antitumor activity and may lead to tumor cell death.

Urological Indications for Axitinib

• First-line therapy of metastatic renal cell carcinoma with Avelumab and axitinib: improved progression-free survival (14 vs. 7 months), response rate (complete response 4% vs. 2%, partial response 49% vs. 25%) compared to treatment with sunitinib independent of IMDC risk category. There is no data published for overall survival (Motzer et al., 2019).
• First-line therapy of metastatic renal cell carcinoma with pembrolizumab and axitinib: improved progression-free survival, response (complete response 6% vs. 2%, partial response 53% vs. 34%), and overall survival (HR 0.59; 1-year OS 90% vs. 79%) versus sunitinib, independent of IMDC risk category or PD-L1 expression (Rini et al., 2019).
• Second-line therapy of metastatic renal cell carcinoma: after progression with sunitinib. A randomized phase 3 trial (AXIS, Rini et al., 2011) demonstrated improved progression-free survival with axitinib versus sorafenib (6.7 vs. 4.7 months).

Pharmacokinetics of Axitinib

Patients take axitinib by mouth approximately every 12 hours, with or without food. Hepatic metabolism occurs primarily via CYP3A4/5. The terminal elimination half-life is approximately 2.5–6 hours.

Adverse Effects of Axitinib

The most common side effects include diarrhea, hypertension, fatigue, dysphonia, nausea, decreased appetite, and palmar–plantar erythrodysesthesia (hand–foot syndrome). Where available, grade ≥3 incidences appear in parentheses.

Gastrointestinal tract:

Diarrhea (10%), vomiting (1–2%), elevated liver enzymes.

Skin:

Impaired wound healing, hand-foot syndrome (5%), mucositis (1–2%).

Cardiovascular:

Hypertension (15%), arterial or venous thromboembolism (2–3%).

Other adverse effects:

Hypothyroidism, lack of appetite (3%), proteinuria, dehydration (2–3%), fatigue (10%).

Drug Interactions with Axitinib

Avoid concomitant use with strong CYP3A4/5 inhibitors (e.g., clarithromycin, ketoconazole, grapefruit) or strong inducers (e.g., rifampin), as they can significantly alter axitinib exposure.

Contraindications of Axitinib

• Severe hepatic impairment (Child-Pugh C)
• Pregnancy and lactation
• Discontinue axitinib for persistent or recurrent grade 3–4 toxicity despite dose modifications
• Pause perioperatively, until wound healing is complete.

Dosage of Axitinib

Monotherapie: Start at 5 mg by mouth twice daily with or without food. If tolerated and without hypertension, increase the dosage after two weeks to 7 mg twice daily and after another two weeks to 10 mg twice daily. For adverse reactions, reduce stepwise to 3 mg twice daily and then 2 mg twice daily, or interrupt therapy according to labeling.

Combination therapy with avelumab or pembrolizumab: Start at 5 mg by mouth twice daily with or without food. Consider dose escalation for patients without significant adverse effects after six weeks or longer.

Clinical Controls During Therapy:

Measure blood pressure at baseline and regularly thereafter. Periodically obtain a complete blood count, electrolytes, liver function tests, thyroid function, serum creatinine and blood glucose. Examine the skin and oral mucosa as clinically indicated.

Supportive Therapy:

Treat diarrhea with loperamide. Use gentle mouth rinses for mucositis. Manage hand–foot skin reaction by reducing friction and pressure, and consider keratolytics or low- to mid-potency topical corticosteroids. Treat hypertension with standard antihypertensive therapy. Replace thyroid hormone for hypothyroidism. If toxicity persists, reduce the dose or interrupt therapy.

References

R. J. Motzer et al., “Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma.,” NEJM, vol. 380, no. 12, pp. 1103–1115, 2019, doi: 10.1056/NEJMoa1816047.

Rini, B. I.; Escudier, B.; Tomczak, P.; Kaprin, A.; Szczylik, C.; Hutson, T. E.; Michaelson, M. D.; Gorbunova, V. A.; Gore, M. E.; Rusakov, I. G.; Negrier, S.; Ou, Y.; Castellano, D.; Lim, H. Y.; Uemura, H.; Tarazi, J.; Cella, D.; Chen, C.; Rosbrook, B.; Kim, S. & Motzer, R. J. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial.
Lancet, 2011, 378, 1931-1939.

Brian I. Rini and Elizabeth R. Plimack and Viktor Stus and Keynote 426 Investigators, “Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma.,” NEJM, vol. 380, no. 12, pp. 1116–1127, 2019, doi: 10.1056/NEJMoa1816714.

  Deutsche Version: Axitinib

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