What Is Regorafenib (Stivarga)? FDA Approval, Turkish Authorization and Reimbursement

• FDA-Approved: Yes (first approval: September 27, 2012)
• Brand Name: Stivarga
• Active Ingredient: Regorafenib
• Administration: Tablet
• Class: Signal transduction inhibitor, tyrosine kinase inhibitor (TKI)
• Category: Targeted therapy
• Manufacturer: Bayer
• Approved Cancers: Colorectal cancer, gastrointestinal stromal tumor (GIST), hepatocellular (liver) cancer

What Is Stivarga and How Does It Work?

Stivarga contains regorafenib, a multikinase inhibitor that blocks protein kinases in intracellular signaling pathways. It particularly targets kinases involved in tumor-cell proliferation, angiogenesis (new blood vessel formation) and interactions with stromal cells in the tumor microenvironment, inhibiting cancer growth, vascular development and metastasis.

Carcinogenesis, tumor angiogenesis and maintenance of the tumor microenvironment involve multiple membrane-bound and intracellular kinases inhibited by this small molecule.

It inhibits tyrosine kinases associated with vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, VEGFR-3), platelet-derived growth factor receptors (PDGFR-α, PDGFR-β) and Tie-2. It also inhibits oncogenic kinases c-Kit, RET, RAF-1 and BRAF, and kinases associated with fibroblast growth factor receptors (FGFR-1, FGFR-2), DDR2, Trk2A, Eph2A, SAPK2, PTK5 and Abl.

FDA Approval Timeline for Stivarga

• April 27, 2017: FDA Expands Stivarga (Regorafenib) Approval to Hepatocellular Carcinoma
• February 25, 2013: FDA Approves Stivarga for Advanced Gastrointestinal Stromal Tumors
• September 27, 2012: FDA Approves Stivarga for Advanced Colorectal Cancer

Turkish Marketing Authorization for Stivarga

Stivarga first received authorization from Turkey's Ministry of Health on 18.05.2015.

Its authorized therapeutic indications in Turkey are stated as follows:

“- STIVARGA is indicated for unresectable metastatic colorectal cancer (mCRC) progressing after fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, anti-VEGF therapy and, for RAS wild-type disease, anti-EGFR therapy. Patients must have an ECOG performance score of 0-1, adequate organ function and life expectancy exceeding three months.

- STIVARGA is indicated for unresectable metastatic gastrointestinal stromal tumors (GIST) progressing after imatinib mesylate and sunitinib malate.

- STIVARGA is indicated until progression in locally advanced, metastatic or recurrent hepatocellular carcinoma (HCC) progressing after sorafenib, in patients with Child-Pugh A liver function.”

Is Stivarga Reimbursed?

For the 3 cancers authorized by the Ministry of Health, Turkey's Social Security Institution (SGK) provides reimbursement.

Price: As of August 2025, the pharmacy retail price of Stivarga 40 mg film-coated tablets, pack of 84, is 55.250.21 Turkish lira.

Resistance Mechanisms

AKT signaling activation; Notch-1 signaling activation; increased expression and activity of multidrug resistance-associated protein 2 (MRP2); KRAS mutations; defects in PUMA-mediated apoptosis.

Absorption

Rapidly absorbed orally, reaching peak plasma levels at a median 4 hours. Mean relative tablet bioavailability versus oral solution is 69-83%. High-fat food increases oral bioavailability by 48%.

Distribution

Highly bound to human plasma proteins (99.5%).

Metabolism

Metabolized mainly by hepatic CYP3A4 and UGT1A9. Main circulating metabolites M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl) have activity similar to the parent drug. Approximately 71% of a dose is excreted in feces, 47% as parent drug and 24% as metabolites, with 19% in urine. Regorafenib's terminal half-life is 28 hours; M-2 and M-5 half-lives are approximately 25 and 51 hours, respectively.

Dose

Start at 80 mg/day and, if no significant drug-related adverse effect occurs, increase weekly by 40 mg to 160 mg/day.

The standard recommended dose is 160 mg orally once daily after a low-fat meal for the first 21 days of each 28-day cycle.

Drug Interactions

Strong CYP3A4 inhibitors such as ketoconazole, itraconazole, clarithromycin, nefazodone, telithromycin and voriconazole reduce regorafenib metabolism, increasing drug levels and potentially toxicity.

Precautions

• Take at the same time daily with a low-fat breakfast containing fewer than 600 calories and 30% fat.
• No initial adjustment is required with mild or moderate preexisting liver disease. Severe liver disease has not been studied, and use is not recommended. No adjustment is needed for impaired kidney function; dialysis patients have not been studied.
• Interrupt treatment for hand-foot skin reaction>grade 2/3, symptomatic grade 2 hypertension or any NCI CTCAE v3.0 grade 3/4 toxicity.
• Warn patients about hepatotoxicity and monitor liver function tests (LFTs) closely during treatment.
• Permanently discontinue if the reduced 80 mg dose is intolerable, with any grade 4 adverse effect, or with dose reduction to 120 mg and AST/ALT>20 times normal, AST/ALT>3 times normal and serum bilirubin>2 times normal.
• Dose may be reduced to 120 mg and then 80 mg according to the specific conditions in the product information.
• The escalation strategy starts at 80 mg/day, then increases weekly by 40 mg to 160 mg/day if no significant adverse effects occur. This has been shown to reduce adverse-effect frequency while preserving clinical activity.
• Because regorafenib inhibits UGT1A1, use caution with agents metabolized and/or eliminated through UGT1A1, such as irinotecan.
• Monitor PT and INR frequently in patients receiving oral warfarin, because increased INR and bleeding have been observed.
• Monitor blood pressure closely, especially during the first 6 weeks, and treat with standard oral antihypertensives as needed.
• Check LFTs at least every 2 weeks for the first 2 months, then monthly.
• Manage rash and hand-foot skin reactions early with topical measures for symptom relief, temporary interruption, dose reduction and/or discontinuation. Use 0.05% topical corticosteroids for grade 2 and 3 skin toxicity. Avoid sun exposure; periodic dermatological assessment is recommended.
• Stop regorafenib for major surgical procedures.
• Avoid blood oranges, pomelo and grapefruit juice during treatment.
• Pregnancy category D. Avoid breastfeeding.

Adverse Effects

1. Hypertension occurs in approximately 30%, usually within 6 weeks of starting therapy, and is generally controlled with oral antihypertensives. Hypertensive crisis is rare.
2. Hand-Foot Syndrome and rash occur at rates up to 45% and 26%, respectively, generally within the first treatment cycle.
3. Bleeding complications occur in approximately 20%.
4. Diarrhea and Nausea are the commonest gastrointestinal adverse effects.
5. Fatigue and asthenia.
6. Hepatotoxicity with elevated AST/ALT and bilirubin. Severe drug-induced liver injury, rarely fatal, has been reported.
7. Gastrointestinal perforation and fistula occur rarely.
8. Myocardial ischemia and/or infarction occur in approximately 1%.
9. Reversible posterior leukoencephalopathy syndrome (RPLS) is a central nervous system adverse effect.