History of Drug Development and US Food and Drug Administration Approval
Stivarga® is the brand name for regorafenib, a generic, oral, chemotherapeutic multikinase inhibitor developed by Bayer HealthCare Pharmaceuticals Inc. Bayer originally applied to the US Food and Drug Administration (FDA) in May 2012 to seek FDA approval for the use of regorafenib to treat metastatic colorectal cancer. In August 2012, Bayer submitted another new drug application for regorafenib to treat gastrointestinal stromal tumors (GISTs). The FDA approved regorafenib for advanced colorectal cancer on September 27, 2012, and again for advanced GIST on February 25, 2013. The FDA later expanded approval for the use of regorafenib to treat hepatocellular carcinoma in April 2017.1
Mechanism of Action and Pharmacokinetics
The vast majority of GISTs result from gene mutations in either the KIT proto-oncogene (80% of GISTs) or the platelet-derived growth factor receptor alpha (PDGFRA) gene (5% to 10% of GISTs). These mutated genes encode for abnormal tyrosine kinase proteins, the KIT protein and the PDGFRA protein. Under normal circumstances, these proteins require ligand binding to activate the signal transduction pathways that encourage cell proliferation and survival. Stem cell factor is the ligand for the KIT protein, and platelet-derived growth factor is the ligand for the PDGFRA protein. These mutated proteins are continuously activated without requiring the binding of a ligand; therefore, cell growth and survival are unregulated, resulting in GIST formation.2
Regorafenib is a targeted tyrosine kinase inhibitor (TKI) chemotherapy that binds to tyrosine kinase protein receptor sites. Regorafenib is especially effective in inhibiting endothelial growth factor receptors (EGFR) and vascular endothelial growth factor (VEGF) receptors. This, in turn, blocks specific pathways required for cell proliferation and angiogenesis. Therefore, regorafenib is an antiangiogenesis inhibitor, preventing oxygenated blood supply to the tumors and causing them to shrink without nutrients.3
Get detailed prescribing information on the Stivarga monograph page at MPR.
In vitro biochemical and cellular assays have demonstrated regorafenib’s ability to inhibit the activities of RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, Abl, and CSF1R after achieving clinically therapeutic concentrations.4
Regorafenib is a stronger inhibitor of c-KIT than sorafenib. Unlike sorafenib, regorafenib also partially blocks TIE2, a molecule that plays a key role in angiogenesis.5
Efficacy and Safety of Stivarga
A phase III randomized, double-blind, controlled trial, GRID (GIST–Regorafenib In Progressive Disease), analyzed the efficacy of regorafenib in patients with metastatic or unresectable GISTs who had previously been treated with imatinib and sunitinib. Regorafenib demonstrated a 73% reduction in risk of GIST progression with a median progression-free survival (PFS) of 4.8 months compared to 0.9 months in the placebo group. In the regorafenib patients, 82 of 133 (62%) experienced disease progression or died compared to 63 of 66 (96%) patients in the placebo group.6
The most frequently recorded adverse drug reactions to regorafenib for the treatment of GIST included hand-foot skin reaction/palmar plantar erythrodysesthesia (HFSR/PPE) (67%), pain (60%), hypertension (59%), asthenia/fatigue (52%), diarrhea (47%), mucositis (40%), dysphonia (39%), infection (32%), decreased appetite and food intake (31%), and rash (30%).6
The most severe side effect of taking regorafenib was severe and occasionally fatal hepatotoxicity, which occurred across all clinical trials. Within 2 months of initiating regorafenib treatment, a characteristic hepatocellular pattern of injury causing liver dysfunction occurred in most of these cases. In the GIST arm of the drug’s clinical trial, fatal hepatotoxicity occurred in 0.8% of patients.6
Due to the potential for liver failure, it is recommended to monitor liver function by testing alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin prior to administration of the first dose of regorafenib and every two weeks throughout the first 2 months of treatment. Following this 2-month trial period, monitoring liver function may decrease to once a month or weekly if elevated liver parameters are present until improvement is observed. If necessary, treatment may be discontinued depending on the severity and persistence of hepatotoxicity as evidenced by elevated liver parameters or the presence of hepatocellular necrosis.6
Regorafenib increased the risk of infections, with an overall incidence of 32% in 1142 patients in the treatment arm of the clinical trial. Grade 3 or higher infections occurred in 9% of patients treated with regorafenib. The most common types of infections included urinary tract infections (UTIs) (5.7%), nasopharyngitis (4%), mucocutaneous and systemic fungal infections (3.3%), and pneumonia (2.6%). The most common fatal infections were respiratory infections (0.6%). Cessation of therapy during grade 3 or 4 infections is recommended, with resumption of the TKI treatment following resolution of the infection.6
Regorafenib increased the likelihood of hemorrhage, with an overall incidence of 18.2% in 1142 patients. The incidence of grade 3 or higher hemorrhage was 3%, while the incidence of fatal hemorrhagic events was 0.7%. International normalized ratio (INR) levels should be monitored frequently, especially in patients receiving warfarin treatment. It is recommended to discontinue regorafenib in cases of life-threatening or severe hemorrhage.6
Gastrointestinal perforation or fistula rarely occurred, with incidences of 0.6% and 0.8%, respectively, in 4518 patients across all clinical trials. Eight fatal events occurred that were related to this side effect.6
Adverse skin reactions, including HFSR/PPE and rash, occurred in 71.9% of patients treated with regorafenib, with an overall incidence of 53% in 1142 patients. Grade 3 HFSR (16%), grade 3 rash (3%), serious erythema multiforme (<0.1%), and Stevens-Johnson syndrome (<0.1%) occurred more frequently in the regorafenib group than in the control group. HFSR occurred more frequently in Asian patients. Toxic epidermal necrolysis had an incidence of 0.02% in 4518 patients treated with regorafenib.6
Regorafenib increased the likelihood of myocardial ischemia and infarction, with an incidence of 0.9%. In only 1 patient, regorafenib was associated with the development of reversible posterior leukoencephalopathy syndrome (RPLS), which should be suspected and assessed via magnetic resonance imaging in any patient that develops seizures, severe headaches, visual disturbances, confusion, or an altered mental status while taking regorafenib.6
Due to the nature of regorafenib’s mechanism of action in inhibiting angiogenesis via the VEGF signaling pathway, patients taking this TKI may experience wound healing complications. Elective surgeries are not recommended while on regorafenib. Discontinuation of regorafenib for at least 2 weeks prior to and 2 weeks following any surgical procedure is recommended to allow for adequate wound healing.6
Regorafenib is not recommended for pregnant women, as this chemotherapeutic agent can cause fetal harm. Doctors should advise pregnant women about the risk of harm to the fetus, as well as recommend the use of effective contraception for women of childbearing age and their partners during treatment with regorafenib and for at least 2 months following the last administered dose. For breastfeeding women, it is recommended not to breastfeed during treatment with regorafenib and for at least 2 weeks following the last administered dose.6
Recommended Dosage of Stivarga
The recommended starting dose of regorafenib is 160 mg (four 40-mg oral tablets) once daily for the first 3 weeks followed by a 1-week treatment break. This cycle of treatment is repeated every month. It is recommended that regorafenib is swallowed whole with water after a low-fat meal containing <600 calories and <30% fat around the same time each day.7
Adjuvant Therapy with Stivarga
The Phase 3 VOYAGER clinical trial showed that regorafenib improved PFS in individuals with third- or fourth-line advanced GIST compared to treatment with avapritinib. Avapritinib demonstrated a median PFS of 4.2 months compared to the 5.6-month median PFS of patients taking regorafenib.8 Therefore, physicians should attempt regorafenib as the third- or fourth-line TKI adjuvant therapy in patients with GIST prior to avapritinib, unless the GIST is caused by a PDGFRA D842V gene mutation that would be treated more effectively with avapritinib as a first-line TKI.8
- Stivarga FDA approval history. Drugs.com. Accessed August 11, 2021.
- Gastrointestinal stromal tumors (GISTs), c-KIT mutation analysis with reflex to PDGFRA mutation analysis. Labcorp. Accessed August 11, 2021.
- Stivarga®. Chemocare.com. Accessed August 11, 2021.
- Mechanism of action. Bayer. Updated June 2021. Accessed August 11, 2021.
- Frenette CT. The role of regorafenib in hepatocellular carcinoma. Gastroenterol Hepatol (N Y). 2017;13(2):122-124.
- GIST: efficacy. Bayer. Updated June 2021. Accessed August 11, 2021.
- Dosing and modifications: dosage and administration. Bayer. Updated June 2021. Accessed August 10, 2021.
- Blueprint Medicines announces top-line results from phase 3 VOYAGER trial of avapritinib versus regorafenib in patients with advanced gastrointestinal stromal tumor. Blueprint Medicines Corp. April 28, 2020. Accessed August 11, 2021.
Reviewed by Debjyoti Talukdar, MD, on 8/16/2021.