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Oral multikinase inhibitor

Cabozantinib

Source: COSMIC-311 / label · confirm locally
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Educational aid — verify against EANM/SNMMI/ATA/NCCN, the drug label and local protocol. Session-only.
1

Before planning therapy

2

Starting therapy & counselling

3

On-treatment monitoring

Background & evidence

Cabozantinib (Cabometyx tablets) is an oral multikinase inhibitor of VEGFR2, MET, RET and other kinases. MET signalling is one route of resistance to VEGFR inhibitors, which is the rationale for its use after lenvatinib or sorafenib. In COSMIC-311 it cut the risk of progression by about 78% in previously treated radioiodine-refractory DTC, and ATA 2025 recommends it as second-line therapy when no actionable driver is present.

Indications & contraindications

Indications

  • US label (revised 10/2025): adults and children aged 12 years or older with locally advanced or metastatic DTC that has progressed after prior VEGFR-targeted therapy and is radioactive iodine-refractory or ineligible.
  • EU SmPC: monotherapy for adults with locally advanced or metastatic DTC, refractory or not eligible for RAI, that has progressed during or after prior systemic therapy. Adolescents are outside the EU DTC licence.
  • ATA 2025 (strong, high certainty): offer cabozantinib as second-line therapy to patients without an actionable driver who progressed on, or could not tolerate, a prior MKI — usually first-line lenvatinib (SELECT) or sorafenib (DECISION) — and want further treatment.
  • Check for drivers first: BRAF V600E-directed therapy is recommended after progression on or intolerance of ≥1 MKI when the mutation is present; NTRK, RET or ALK fusion-targeted drugs take priority whenever present (ATA 2025). A new biopsy at progression can identify resistance mechanisms.

Contraindications

  • No contraindications in the US label.
  • Do not substitute Cabometyx tablets with cabozantinib capsules (Cometriq); the formulations differ, and COSMIC-311 used the tablets (US label; ATA 2025).
  • Relative: uncontrolled hypertension (do not start), recent or active bleeding, GI perforation or fistula risk, tumour invading the airway, oesophagus or great vessels, recent acute coronary syndrome or stroke, and non-healing wounds (US label; ATA 2025).
  • Surgery: stop at least 3 weeks before scheduled surgery, including dental surgery; do not restart for at least 2 weeks after major surgery and until the wound has healed (US label).
  • Pregnancy and breastfeeding (see below).
Activity, dosing & administration
SituationDose (US label)
Adults and children ≥12 years weighing ≥40 kg60 mg once daily until progression or unacceptable toxicity
Children ≥12 years weighing <40 kg40 mg once daily
Reductions from 60 mg40 mg daily, then 20 mg daily; if the lowest dose is not tolerated, stop
Reductions from 40 mg (<40 kg)20 mg daily, then 20 mg every other day
Strong CYP3A4 inhibitorReduce the daily dose by 20 mg; restore 2–3 days after the inhibitor stops
Strong or moderate CYP3A4 inducerIncrease the daily dose by 20 mg as tolerated, maximum 80 mg; restore 2–3 days after the inducer stops
Moderate hepatic impairmentStart at 40 mg (or 20 mg if the usual dose is 40 mg)
How to takeEmpty stomach: at least 1 h before or 2 h after food. Swallow whole. Do not take a missed dose within 12 h of the next one.
  • General rule: withhold for intolerable grade 2 or any grade 3–4 adverse reaction, and for osteonecrosis of the jaw. When it resolves to grade 1 or baseline, resume one level lower (US label).
  • Hypertension: grade 3 — withhold until controlled to ≤ grade 2, then resume at a lower dose; stop for hypertension that cannot be controlled, hypertensive crisis or grade 4 (US label).
  • Diarrhoea: grade 2–4 — withhold until ≤ grade 1, resume at a lower dose. Palmar-plantar erythrodysaesthesia: intolerable grade 2 or grade 3 — same approach (US label).
  • Proteinuria: grade 2–3 — withhold until ≤ grade 1, resume at a lower dose; stop for nephrotic syndrome (US label).
  • Stop permanently (US label): grade 3–4 haemorrhage; any GI perforation or grade 4 fistula; any myocardial infarction, grade ≥2 cerebral infarction, grade 3–4 arterial or grade 4 venous thromboembolism; RPLS.
  • Real-world dose: in COSMIC-311 the median average daily dose was 42 mg; 56% needed a reduction and 22% a second; 72% had an interruption; 5% stopped for toxicity (US label).
  • Review schedule: baseline, at least every 2 weeks for the first 2 months, then every 1–2 months (ATA 2025).
Key trials & evidence
Trial / studyPopulationResultReference
COSMIC-311 (phase 3), primary analysis187 patients aged ≥16 years with RAI-refractory DTC after lenvatinib and/or sorafenib (up to two VEGFR TKIs); 2:1 to cabozantinib 60 mg vs placebo; crossover on progression.Median PFS not reached vs 1.9 months, HR 0.22. Response 15% vs 0% in the first 100 patients — did not meet the prespecified significance level. Grade 3–4 events 57% vs 26%; no treatment-related deaths.Brose 2021
COSMIC-311, updated analysis258 randomised; median follow-up 10.1 months.Median PFS 11.0 vs 1.9 months, HR 0.22. Response 11.0% vs 0% (one complete response). Grade 3–4 hypertension 12%, palmar-plantar erythrodysaesthesia 10%, fatigue 9%.Brose 2022
ITOG phase 225 patients with RAI-refractory DTC progressing on prior VEGFR-targeted therapy; 60 mg, escalation to 80 mg allowed.Partial response 40%, stable disease 52%. Median PFS 12.7 months, OS 34.7 months. One drug-related death.Cabanillas 2017
Toxicity & its management
  • Commonest in COSMIC-311 (≥25%): diarrhoea, palmar-plantar erythrodysaesthesia, fatigue, hypertension and stomatitis. Grade 3–4 in ≥5%: PPE, hypertension, fatigue, diarrhoea and stomatitis. Serious adverse reactions 34% (US label).
  • Hypertension: 37% across single-agent studies (grade 3 16%). Monitor regularly; do not start if uncontrolled (US label).
  • Diarrhoea: 62% (grade 3 10%). Use antidiarrhoeals early (US label; ATA 2025).
  • PPE: 45% (grade 3 13%). Remove calluses, moisturise, use urea creams and cushioned footwear (ATA 2025).
  • Hypocalcaemia: 36% in COSMIC-311 (grade 3 6%, grade 4 3%) — check calcium (US label).
  • Bleeding: grade 3–5 haemorrhage 5% across RCC, HCC and DTC studies. Fatal reactions in COSMIC-311 (1.6%) included arterial haemorrhage and pulmonary embolism (US label).
  • Other serious effects: GI perforation and fistula, arterial and venous thrombosis, cardiac failure (0.5%), proteinuria, osteonecrosis of the jaw, impaired wound healing, hepatotoxicity and RPLS (US label).
  • Thyroid: MKIs alter TSH; monitor TSH and free T4 and adjust levothyroxine (ATA 2025).
Radiation protection & discharge
  • No radiation precautions apply.
  • Women of reproductive potential should use effective contraception during treatment and for 4 months after the last dose (US label).
  • Do not breastfeed during treatment and for 4 months after the last dose (US label).
  • Osteonecrosis of the jaw (<1%): examine the mouth before starting and periodically, advise good oral hygiene, and withhold for at least 3 weeks before invasive dental procedures where possible (US label).

References

  1. Ringel MD, Sosa JA, Baloch Z, et al. 2025 American Thyroid Association management guidelines for adult patients with differentiated thyroid cancer. Thyroid. 2025;35(8):841-985.
  2. Exelixis Inc. Cabometyx (cabozantinib) tablets: US prescribing information, revised 10/2025. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3850cce2-6137-42e5-a792-d318c4a4b3b5
  3. European Medicines Agency. Cabometyx: summary of product characteristics. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/cabometyx
  4. Brose MS, Robinson B, Sherman SI, et al. Cabozantinib for radioiodine-refractory differentiated thyroid cancer (COSMIC-311): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2021;22(8):1126-38.
  5. Brose MS, Robinson BG, Sherman SI, et al. Cabozantinib for previously treated radioiodine-refractory differentiated thyroid cancer: updated results from the phase 3 COSMIC-311 trial. Cancer. 2022;128(24):4203-12.
  6. Cabanillas ME, de Souza JA, Geyer S, et al. Cabozantinib as salvage therapy for patients with tyrosine kinase inhibitor-refractory differentiated thyroid cancer: results of a multicenter phase II International Thyroid Oncology Group trial. J Clin Oncol. 2017;35(29):3315-21.
  7. Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015;372(7):621-30.
  8. Brose MS, Nutting CM, Jarzab B, et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet. 2014;384(9940):319-28.
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