Pharmacology Update: Regorafenib Tablets (Stivarga®)
Pharmacology Update
Regorafenib Tablets (Stivarga®)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD, Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationships relevant to this field of study.
An oral multikinase inhibitor has been approved by the FDA for treatment of metastatic colorectal cancer as well as advanced gastrointestinal stromal tumors (GIST). Regorafenib is marketed by Bayer HealthCare Pharmaceuticals as Stivarga.
Indications
Regorafenib is indicated for the treatment of metastatic colorectal cancer in patients who have been treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and anti-EGFR therapy (KRAS wild type).1 It is also indicated for the treatment of locally advanced, unresectable, or metastatic gastrointestinal stromal tumor in patients who have been treated with imatinib and sunitinib.
Dosage
The recommended dose is 160 mg (four tablets) taken once daily with a low-fat breakfast.1 It is taken for the first 21 days of each 28-day cycle. Regorafenib is available as 40 mg tablets.
Potential Advantages
Regorafenib provides a modest extension of overall survival in patients previously treated for metastatic colorectal cancer and extended progression-free survival in patients with locally advanced unresectable or metastatic GIST who were previously treated with imatinib and sunitinib.1-3
Potential Disadvantages
Severe, even fatal, hepatoxicity has been associated with regorafenib.1 The frequency of fatal outcome was 1.6% in one study and 0.8% in the second. Liver function tests should be done before starting therapy, every 2 weeks during the first 2 months and monthly thereafter or as clinically appropriate. Regorafenib also increases the risk of hemorrhage, hypertension, myocardial ischemia/infarction, gastrointestinal perforation/fistula, and reversible posterior leukoencephalopathy syndrome. Regorafenib is metabolized by CYP3A4 and concomitant use with a strong 3A4 inducer or inhibitor should be avoided.
Comments
Protein tyrosine kinases have been implicated in the signal pathway for cancer growth and proliferation. Regorafenib and its active metabolites have been shown to inhibit multiple membrane-bound and intracellular kinases.1 Its efficacy was assessed in colorectal cancer in patients with progressing disease after all approved standard therapies.1,2 Patients were randomized in a 2:1 ratio to regorafenib (160 mg; n = 505) or placebo (n = 255). All patients received best supportive care (no other pharmacologic therapy). The primary endpoint was overall survival. The secondary endpoint was progression-free survival. Response rates were based on RECIST criteria or the investigator’s clinical assessment. The median survival was 6.4 months for regorafenib and 5.0 months for placebo (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.64, 0.94). The median time to disease progression was 2.0 months compared to 1.7 months for placebo (HR, 0.49; 95% CI, 0.42, 0.58). No patients had complete response, while five on regorafenib and one on placebo had partial response. For GIST, patients with locally advanced, unresectable, or metastatic GIST who had failed at least imatinib and sunitinib were randomized in a 2:1 ratio to regorafenib 160 mg (n = 133) and best supportive care or placebo (n = 66) and best supportive care.1,3 Median progression-free survival was 4.8 months for regorafenib compared to 0.9 months for placebo (HR, 0.27; 95% CI, 0.19, 0.39). The median overall survival has not been determined due to low event rates (22% vs 26%). The most common (> 30%) adverse events (vs placebo) in colorectal cancer patients were asthenia/fatigue (64% vs 46%), decreased appetite (47% vs 28%), hand-foot skin reaction (45% vs 7%), diarrhea (43% vs 17%), mucositis (33% vs 5%), infection (31% vs 17%), and weight loss (32% vs 10%). The adverse reaction profile in patients treated for GIST was similar with higher frequencies of hypertension, hand-foot skin reactions, and dysphonia. Laboratory abnormalities included anemia, thrombocytopenia, lymphopenia, hypocalcemia, hypophosphatemia, hyperbilirubinemia, increased ALT/AST, proteinuria, and increased lipase.
Clinical Implications
Regorafenib provides an alternative for patients who had a second or third progression with advanced or metastatic colorectal cancer.4 It appears to offer a modest benefit in terms of survival. It is also an option for patients with advanced GIST after progression following treatment with imatinib and sunitinib. The wholesale cost for one cycle (21 days) of treatment with regorafenib is $9350.
References
1. Stivarga Prescribing Information. Wayne, NJ: Bayer HealthCare Pharmaceuticals; February 2013.
2. Grothey A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): An international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013;381:303-312.
3. Demetri GD, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): An international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013;381:295-302.
4. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#colon. Accessed march 27, 2013.
An oral multikinase inhibitor has been approved by the FDA for treatment of metastatic colorectal cancer as well as advanced gastrointestinal stromal tumors (GIST). Regorafenib is marketed by Bayer HealthCare Pharmaceuticals as Stivarga.Subscribe Now for Access
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