Regorafenib, Multikinase Inhibitor, for Previously Treated Metastatic Colorectal Cancer

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In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.


On September 27, 2012, regorafenib (Stivarga) was approved for the treatment of patients with metastatic colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, anti-VEGF therapy, and, if they had wild-type KRAS tumors, anti-EGFR therapy.1,2

Approval was based on results of an international, multicenter, double-blind trial (Study 14387) in which 760 patients with previously treated metastatic colorectal cancer were randomly assigned to receive regorafenib at 160 mg orally once daily (n = 505) plus best supportive care or placebo (n = 255) plus best supportive care for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity.2 Regorafenib was administered with a low-fat breakfast containing less than 30% fat.

All patients had received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and bevacizumab. Of the 96% of patients who had been evaluated for KRAS mutation status, 59% had mutant KRAS; all but one patient with wild-type KRAS had received panitumumab (Vectibix) or cetuximab (Erbitux). In the total population, patients had a median age of 61 years, 61% were men, 78% were white, and all had a baseline ECOG performance status of 0 or 1. The primary site of disease was the colon in 65% of patients, rectum in 29%, and both in 6%. Patients had a median of three prior lines of therapy for metastatic disease.

The mean duration of treatment was 12 weeks in regorafenib patients and 8 weeks in placebo patients. Median overall survival was 6.4 months in the regorafenib group vs 5.0 months in the placebo group, representing a significant 23% reduction in risk of death (hazard ratio [HR] = 0.77, 95% confidence interval [CI] = 0.64–0.94, P = .0102). Median progression-free survival was also significantly prolonged with regorafenib (2.0 vs 1.7 months, HR = 0.49, 95% CI = 0.42–0.58, P < .0001). Partial response was observed in 1% of regorafenib patients and in 0.4% of placebo patients.

How It Works

Regorafenib is an oral small-molecule inhibitor of multiple membrane-bound and intracellular kinases involved in normal cell function and in oncogenesis, tumor angiogenesis, and maintenance of tumor microenvironment.2,3 In in vitro testing, regorafenib or its two major active metabolites inhibited the activity of RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-α, PDGFR-β, FGFR1, FGFR2, TIE2, DDR2, Trk2A, Eph2A, RAF-1, BRAF, BRAFV600E , SAPK2, PTK5, and Abl kinases at clinically achievable concentrations. The drug has shown antiangiogenic activity in experimental models and inhibition of tumor growth and antimetastatic activity in xenograft models including colorectal cancer models.

How It Is Given

The recommended dose of regorafenib is 160 mg once daily for the first 21 days of each 28-day treatment cycle, with treatment continued until disease progression or unacceptable toxicity. It should be taken with a low-fat breakfast (< 30% fat). Dose reductions are recommended for grade 2 hand-foot skin reaction (palmar-plantar erythrodysesthesia), after recovery from any grade 3 or 4 adverse event, and for grade 3 AST or ALT elevations.

Interruption of treatment is recommended for grade 3 or recurrent grade 2 hand-foot skin reaction, symptomatic grade 2 hypertension, and any grade 3 or 4 adverse event. Regorafenib should be discontinued for failure to tolerate a dose of 80 mg/d after dose reductions, any occurrence of AST or ALT more than 20 times the upper limit of normal, and any occurrence of AST or ALT more than 3 times the upper limit of normal with bilirubin more than 2 times the upper limit of normal. Concomitant use of strong CYP3A4 inducers or inhibitors should be avoided (eg, carbamazepine, dexamethasone, phenobarbital).

Liver function tests must be performed before starting regorafenib, at least every 2 weeks during the first 2 months of treatment, and monthly or more frequently thereafter as clinically indicated. Tests should be performed weekly in patients experiencing elevated liver function tests.

Safety Profile

The most frequent adverse events of any grade in regorafenib patients (> 40%) that occurred more frequently than in placebo patients were asthenia/fatigue (64% vs 46%), decreased appetite and food intake (47% vs 28%), hand-foot skin reaction (45% vs 7%), and diarrhea (43% vs 17%).2 The most frequent grade ≥ 3 adverse events were hand-foot skin reaction (17% vs 0%), asthenia/fatigue (15% vs 9%), infection (9% vs 6%), diarrhea (8% vs 2%), hypertension (8% vs < 1%), and rash (6% vs < 1%).

The most common laboratory abnormalities of any grade in regorafenib patients (> 50%) were anemia (79% vs 66%), increased AST (65% vs 46%), proteinuria (60% vs 34%), hypocalcemia (59% vs 18%), hypophosphatemia (57% vs 11%), and lymphopenia (54% vs 34%). The most frequent (> 10%) grade 3 or 4 abnormalities were hypophosphatemia (32% vs 4%), hyperbilirubinemia (13% vs 8%), and increased lipase (11% vs 5%). Keratocanthoma/squamous cell carcinoma of the skin has been observed in 0.09% of 1,100 patients receiving regorafenib in clinical trials. ■


1. U.S. Food and Drug Administration: Regorafenib. Available at Accessed October 8, 2012.

2. STIVARGA® (regorafenib) tablets prescribing information. Bayer HealthCare Pharmaceuticals Inc, September 2012. Available at Accessed October 8, 2012.

3. Mross K, Frost A, Steinbild S, et al: A phase I dose-escalation study of regorafenib (BAY 73-4506), an inhibitor of oncogenic, angiogenic, and stromal kinases, in patients with advanced solid tumors. Clin Cancer Res 18:2658-2667, 2012.