What Is Cabozantinib (Cabometyx)? FDA Approval, Licensing in Turkey, and Reimbursement
| Active ingredient | Cabozantinib (cabozantinib-s-malate) |
| Brand names | Cabometyx (film-coated tablet) · Cometriq (capsule) — the same active ingredient, but different products and indications |
| Class | Multitargeted tyrosine kinase inhibitor (TKI) — signaling inhibitor |
| Category | Targeted agent (small-molecule kinase inhibitor) |
| Route of administration | Oral, once daily — Cabometyx tablets or Cometriq capsules (not interchangeable) |
| Main targets | VEGFR-1/2/3, MET, AXL, RET, KIT, FLT-3, TIE-2 |
| FDA-approved cancers for Cabometyx | Renal cell carcinoma (RCC) · hepatocellular carcinoma (HCC) · differentiated thyroid carcinoma (DTC) · neuroendocrine tumors (NET) — new · RCC combined with nivolumab |
| Approved cancer for Cometriq | Medullary thyroid carcinoma (MTC) — capsules only |
| FDA-approved | Yes — initial Cabometyx approval: April 25, 2016; NET approval: March 26, 2025 |
| Manufacturer | Exelixis |
| Distribution in Turkey | Gen İlaç ve Sağlık Ürünleri San. ve Tic. A.Ş. |
| Half-life | Approximately 80–90 hours |
| Metabolism | In the liver, primarily CYP3A4 mediated |
Cabozantinibis an oral targeted medicine that binds to several kinases simultaneously , rather than a single target. This versatility underlies its activity in very different cancers: Kidney, liver, thyroid, and, most recently, neuroendocrine tumors.
This monograph examines its mechanism, expanding FDA approvals (including the neuroendocrine tumor approval added in 2025), access in Turkey, dosing, and adverse effects. It also clarifies the two often-confused products, Cabometyx tablets and Cometriq capsules, because they contain the same active ingredient but are used for different cancers at different doses.
Cabozantinib is available as two separate products, and they are not interchangeable:
· Cometriq (capsules) is only for medullary thyroid cancer (MTC) at a dose of 140 mg daily.
· Cabometyx (tablets) is for kidney cancer (RCC), liver cancer (HCC), differentiated thyroid cancer (DTC) and neuroendocrine tumors (NET) at a usual dose of 60 mg daily (40 mg when combined with nivolumab). Cabometyx is not approved for medullary thyroid cancer — however, it is used off-label in MTC in practice based on exposure similarity (see dosing section).
Tyrosine kinases are enzymes that transmit signals telling cells to "proliferate, spread, and form blood vessels." They are often overactive in cancer cells. Tyrosine kinase inhibitors (TKIs) block these enzymes, suppressing proliferation, metastasis, and new blood vessel formation (angiogenesis).
Cabozantinib is a multitargeted member of this family: It inhibits several kinases simultaneously rather than a single pathway, explaining its activity across different tumor types.
On March 26, 2025, the FDA approved Cabometyx for previously treated, unresectable, locally advanced or metastatic, well-differentiated pancreatic (pNET) and extrapancreatic (epNET) neuroendocrine tumors. Approval covers adults and children over 12 .
The supporting study was the National Cancer Institute-sponsored phase 3 CABINET trial (Alliance A021602) : 298 patients were randomized to cabozantinib (60 mg) or placebo, and the trial demonstrated a statistically significant and clinically meaningful improvement in progression-free survival versus placebo . Results were presented at ESMO 2024 and published in the New England Journal of Medicine. Neuroendocrine tumors have long had limited systemic treatment options, so this approval addresses an important practical gap.
| Product / Form | Indication | Dose (Oral, Once Daily) |
|---|---|---|
| Cometriq (capsule) | Medullary thyroid carcinoma (MTC) | 140 mg |
| Cabometyx (tablet) | Renal cell carcinoma (RCC) — monotherapy | 60 mg |
| Cabometyx (tablet) | Hepatocellular carcinoma (HCC) | 60 mg |
| Cabometyx (tablet) | Differentiated thyroid carcinoma (DTC) | 60 mg |
| Cabometyx (tablet) | Neuroendocrine tumors (pNET / epNET) — new | 60 mg |
| Cabometyx (tablet) | RCC + nivolumab (combination) | 40 mg Cabometyx + nivolumab (IV) |
The discussion so far describes the licensed indications : Medullary thyroid cancer is not an approved Cabometyx indication. The licensed medicine for MTC is Cometriq 140 mg capsules. However, real-world clinical practice includes an important nuance.
Pharmacological Rationale: Nguyen et al. (Anti-Cancer Drugs, 2016) compared the pharmacokinetics of Cabometyx tablets and Cometriq capsules in healthy volunteers and found higher relative bioavailability with the tablet than the capsule . In other words, the same milligram dose yields higher exposure with tablets. This is one reason a 60 mg tablet provides exposure comparable to a 140 mg capsule and the products are approved at different milligram doses.
Conclusion: Based on this exposure similarity, particularly where Cometriq is unavailable or not marketed in many countries , many patients with medullary thyroid cancer are treated in practice with Cabometyx 60 mg off-label. Nevertheless, it must be emphasized that this is off-label use , the products are not equivalent milligram for milligram , and they are not officially interchangeable. The decision rests with the treating oncologist, who considers both access and clinical circumstances; this use does not change the medicine's licensed status.
The medicine should be taken on an empty stomach, with no food for at least 2 hours before and 1 hour after the dose , and swallowed whole. Tablets and capsules are not interchangeable.
Hepatic impairment: No change is needed with mild impairment; reduce to 40 mg with moderate impairment (Child-Pugh B). Data are insufficient in severe impairment (Child-Pugh C). Renal impairment: No adjustment is needed with mild-to-moderate impairment; severe or end-stage impairment has not been studied. Doses are reduced stepwise according to adverse effects. Dose decisions belong exclusively to the treating oncology team; this monograph does not provide prescriptive dosing instructions.
Renal cell carcinoma: As monotherapy for metastatic clear-cell RCC in intermediate/high-risk patients in the first line , and after previous VEGF-targeted therapy in the second line , or as anti-VEGF treatment after anti-PD-1/PD-L1. It is also indicated in combination with nivolumabfor first-line advanced clear-cell RCC with Karnofsky ≥70 and no active brain metastases.
Hepatocellular carcinoma: Monotherapy in Child-Pugh A patients previously treated with sorafenib.
Differentiated thyroid carcinoma: Monotherapy for locally advanced or metastatic DTC unsuitable for local treatment, progressing during or after prior VEGF-targeted therapy and refractory to radioactive iodine .
- Covered: For intermediate/high-risk metastatic clear-cell RCC as first-line monotherapy until progression.
- Covered: For metastatic clear-cell RCC progressing after at least one VEGF-targeted regimen and/or one line of anti-PD-1 treatment, until progression.
- Not covered: Sequential or combined temsirolimus, sunitinib, sorafenib, or pazopanib after progression on cabozantinib.
- Without Additional TİTCK Approval: Use is appropriate in non-clear-cell histology, including papillary, chromophobe, translocation-associated, and unclassified types, as first-line treatment and after progression on a VEGF-targeted TKI.
As of August 2025, reported pharmacy retail prices in Turkey were: Cabometyx 40 mg, 30 tablets ≈ 157,985 TL, Cabometyx 60 mg, 30 tablets ≈ 157,985 TL. Medicine prices change frequently with exchange rates and regulations. These figures apply only to that period and are not current. Consult official sources, such as TİTCK or medicine price lists, for updated prices.
- The neuroendocrine tumor (NET) indication, approved by the FDA in 2025 and in Europe in mid-2025, is very new , and its licensing and reimbursement status in Turkey must be confirmed separately using current information.
- The SGK reimbursement provisions above mainly concern RCC . For HCC, DTC, and NET, coverage should be checked with the treating center and current SUT/reimbursement lists.
- FDA or European approval does not mean that a medicine is licensed, accessible, or reimbursed for that indication in Turkey.
Rates vary between studies; the list below runs from more to less common.
- Very common: Diarrhea (~63%) · fatigue (~56%) · mouth sores/mucositis (~44%) · hand-foot syndrome (~42%) · hypertension (~37%) · decreased appetite (~34%) · nausea (~31%) · vomiting (~23%) · constipation (~20%) · weight loss (~19%)
- Common: Taste disturbance (~15%) · protein in urine/proteinuria (~15%) · anemia (~10%) · hypothyroidism (~8%) · rash/itching (~7%) · hoarseness (~5%) · hypokalemia/hypomagnesemia (~4–6%)
- Less common but serious: Bleeding, such as nosebleeds (~3%) · thrombocytopenia (~2–4%)
- Rare but severe (<1%): Gastrointestinal perforation and fistula · arterial thromboembolism (heart attack, stroke) · reversible posterior leukoencephalopathy syndrome (RPLS) · osteonecrosis of the jaw
- Bleeding: Do not use in patients with a recent history of serious bleeding or coughing up blood (hemoptysis).
- Gastrointestinal Perforation/Fistula: Monitor new abdominal symptoms carefully.
- Blood Pressure: Monitor regularly and keep controlled.
- Arterial Thromboembolism: If a heart attack or stroke occurs, treatment must be stopped immediately.
- Proteinuria: Check urine protein regularly; discontinue the medicine if nephrotic syndrome develops.
- Osteonecrosis of the Jaw: Perform an oral examination before treatment and maintain good oral hygiene. Stop the medicine at least 3 weeks before planned dental procedures.
- Hand-foot syndrome or RPLS requires dose adjustment or discontinuation.
- Pregnancy/Breastfeeding: Do not use because of embryo-fetal toxicity risk; breastfeeding is not recommended.
Absorption: Peak plasma levels occur in 2–6 hours; fatty food increases absorption, hence fasting administration. Distribution: Plasma protein binding >99.7%; steady state reached in ~15 days. Metabolism/Elimination: Hepatic, via CYP3A4; ~54% of the dose is excreted in feces and ~27% in urine. Half-life ~80–90 hours (long, which also means adverse effects may resolve slowly).
Strong CYP3A4 Inducers (phenytoin, carbamazepine, rifampin, phenobarbital, St. John's wort/Hypericum) lower cabozantinib levels and effectiveness. Strong CYP3A4 Inhibitors (ketoconazole, itraconazole, clarithromycin, erythromycin) raise levels and toxicity. Dose adjustment may be needed with these medicines. Tell your doctor about all medicines and herbal products you use.
- Activation of Alternative Signaling Pathways: The tumor may bypass blocked MET/VEGFR pathways and activate EGFR, FGFR, PI3K/AKT, MAPK, or other pathways.
- Secondary MET or RET Mutations: These may prevent drug binding to the kinase.
- Target Overproduction: Overexpression of MET, AXL, or VEGFR may make inhibition insufficient.
- Drug Efflux From Cells: Increased pumps such as P-gp and BCRP lower intracellular drug levels.
- Microenvironmental Changes (hypoxia) and Epithelial–Mesenchymal Transition (EMT): These may make cells more invasive and resistant.
Cabozantinib is a leading example of a "multitargeted TKI," targeting VEGFR-mediated vascular activity and MET/AXL-mediated resistance to vascular therapy simultaneously. This design has taken it from kidney, liver, and thyroid cancers to neuroendocrine tumors in 2025 . With limited systemic options in these rare tumors, the approval is clinically meaningful.
FDA approvals: RCC (second-line in 2016, first-line in 2017; nivolumab combination in 2021), HCC (2019, after sorafenib), DTC (2021, COSMIC-311, RAI-refractory) and NET (2025, CABINET; pNET+epNET, 60 mg, significant PFS improvement in phase 3). Medullary thyroid cancer is treated with Cometriq capsules at 140 mg . Cabometyx tablets have no MTC indication; tablet doses are 60 mg, or 40 mg in combination. The half-life is long (~80–90 hours), and metabolism occurs through CYP3A4.
The burden of adverse effects is substantial: Diarrhea, fatigue, hand-foot syndrome, mucositis, and hypertension are very common, and dose adjustment is frequently needed. Rare but serious risks, including gastrointestinal perforation/fistula, arterial thromboembolism, bleeding, jaw osteonecrosis, and RPLS , require close monitoring. Tablets and capsules are not interchangeable , and dosing requires a clear understanding of this distinction. Reimbursement in Turkey primarily concerns RCC; access for HCC, DTC, and particularly the new NET indication requires separate confirmation.
Matching the Correct Product and Dose Is Critical: MTC → Cometriq 140 mg (capsules); RCC/HCC/DTC/NET → Cabometyx 60 mg (tablets); RCC+nivolumab → 40 mg. Take the medicine fasting, review CYP3A4 interactions, including "natural" products such as St. John's wort, monitor blood pressure and urine protein, and interrupt treatment before invasive dental procedures. Adverse effects are often manageable through dose adjustment. Patient education, particularly about hand-foot syndrome and diarrhea, influences treatment continuation.
In NET, what should be cabozantinib's position relative to other options such as everolimus, sunitinib, PRRT, and somatostatin analogues , and how should treatments be sequenced? Which tumors benefit from combinations with immunotherapy? What comes after resistance? For Turkey, the most practical question is: When will licensing and reimbursement be clarified for DTC and the new NET indication?
- Cabometyx tablets and Cometriq capsules are separate products with different indications and doses; they are not interchangeable.
- Medullary thyroid cancer is treated with Cometriq (140 mg); Cabometyx has no MTC indication.
- Doses given here are for general information; the actual dose is determined exclusively by the treating physician.
- FDA/European approval does not establish licensing, access, or reimbursement in Turkey; the NET indication is very new and requires separate confirmation.
- Prices are period-specific and change rapidly; the figures in this article relate to August 2025.
- Treatment and monitoring decisions belong exclusively to the oncology team familiar with the patient.
- FDA / Exelixis approval announcements: Cometriq (medullary thyroid cancer, November 29, 2012); Cabometyx (RCC 2016 and 2017; HCC 2019; RCC+nivolumab and DTC 2021).
- Exelixis. FDA approval of CABOMETYX (cabozantinib) for previously treated advanced neuroendocrine tumors. Press release, March 26, 2025.
- CABINET (Alliance A021602) — cabozantinib in pancreatic and extra-pancreatic neuroendocrine tumors. N Engl J Med. 2024; presented at ESMO 2024.
- COSMIC-311 — cabozantinib in radioiodine-refractory differentiated thyroid cancer. Lancet Oncol. 2021. (Basis for the 2021 DTC approval.)
- Cabometyx (cabozantinib) US Prescribing Information (USPI) and Cometriq USPI — differences in indications and doses; tablets and capsules are not interchangeable.
- Nguyen L, Holland J, Miles D, et al. Pharmacokinetics of cabozantinib tablet and capsule formulations in healthy adults. Anti-Cancer Drugs. 2016;27(7):669–678. (Relative bioavailability is higher with tablets than capsules; 60 mg tablets ≈ 140 mg capsule exposure—the pharmacological rationale for off-label Cabometyx in MTC.)
- Turkish Ministry of Health / SGK SUT reimbursement conditions and the TİTCK list of off-label medicines usable without additional approval. (Consult official sources for the current version.)
- Related Reading (drozdogan.com): Prof. Dr. Mustafa Özdoğan — oncology articles and drug monographs.
Editor's note: This monograph is for general information only. It does not constitute medical advice, diagnosis, or treatment recommendations, and does not promote any product. The information was checked against primary sources and presented without direct quotations. Cabozantinib is available as two separate products: Cabometyx film-coated tablets and Cometriq capsules. They are not interchangeable; indications and doses differ. Medullary thyroid carcinoma is treated with Cometriq capsules (140 mg daily) ; Cabometyx tablets have no medullary thyroid indication , and doses for all tablet indications are 60 mg (40 mg with nivolumab). The earlier statement "Cabometyx 140 mg for medullary thyroid cancer" was therefore corrected. However, this licensed status does not fully describe real-world practice: In the pharmacokinetic comparison of tablets and capsules by Nguyen et al. (Anti-Cancer Drugs, 2016), relative bioavailability was higher with tablets; consequently, Cabometyx 60 mg tablets were shown to provide exposure comparable to Cometriq 140 mg capsules . On this pharmacological basis, particularly where Cometriq is unavailable in many countries, many patients with medullary thyroid cancer are treated off-label with Cabometyx 60 mg in practice. This is off-label use. The products are not equivalent milligram for milligram or officially interchangeable, and the decision rests solely with the treating oncologist. Similarly, the September 17, 2021 approval concerns differentiated thyroid carcinoma (COSMIC-311, radioactive iodine-refractory), rather than "RET-mutated/fusion-positive thyroid cancer." RET-specific medicines include selpercatinib and pralsetinib. The March 26, 2025 approval for neuroendocrine tumors (NET) adds a new indication. Dosing information in this monograph provides a general framework only; actual dosing, adjustments, and monitoring are entirely the treating physician's responsibility. Adverse-effect rates may vary by study and population. FDA or European approval does not establish licensing, access, or reimbursement in Turkey; particularly because NET is a very new indication, its Turkish licensing and reimbursement status require separate, up-to-date confirmation. Prices fluctuate with exchange rates and regulations; those quoted relate to August 2025 and may no longer be current. Do not start, stop, or change any medicine without consulting your doctor. Consult the physician familiar with your circumstances for all health decisions.
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