On April 27, 2017, the indications for regorafenib (Stivarga) were expanded to include treatment of patients with hepatocellular carcinoma who have been previously treated with sorafenib (Nexavar).1,2
Supporting Efficacy Data
The new approval was based on the finding of improved overall survival with regorafenib in the phase III double-blind RESORCE trial, in which 573 patients with Child-Pugh A and Barcelona Clinic Liver Cancer (BCLC) stage B or C hepatocellular carcinoma were randomized 2:1 to receive oral regorafenib at 160 mg once daily plus best supportive care (n = 379) or placebo plus best supportive care (n = 194) for the first 21 days of 28-day cycles.2,3 Treatment continued until disease progression or unacceptable toxicity.
OF NOTE
Regorafenib carries a boxed warning for hepatotoxicity.
Patients had a median age of 63 years, 88% were male, 41% were Asian and 36% were white, all had Eastern Cooperative Oncology Group performance status of 0 or 1, 98% had Child-Pugh A and 2% had Child-Pugh B disease, 81% had macroscopic vascular invasion or extrahepatic tumor spread, Barcelona Clinic Liver Cancer stage was C in 87% and B in 13% of patients, and 61% had received locoregional transarterial embolization or chemoinfusion procedures. Risk factors for underlying cirrhosis included hepatitis B (38%), alcohol use (25%), hepatitis C (21%), and nonalcoholic steatohepatitis (7%).
Median overall survival was 10.6 vs 7.8 months (hazard ratio [HR] = 0.63, P < .0001). Median progression-free survival was 3.1 vs 1.5 months (HR = 0.46, P < .0001). The overall response rate was 11% vs 4%.
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, metastasis, and tumor immunity. During in vitro testing, regorafenib or its major active metabolites (M-2, M-5) inhibited the activity of RET, vascular endothelial growth factor receptor (VEGFR)1, VEGFR2, VEGFR3, KIT, PDGFR-α, PDGFR-β, FGFR1, FGFR2, TIE2, DDR2, Trk2A, Eph2A, RAF-1, BRAF, BRAF V600E, SAPK2, PTK5, Abl, and CSF1R at clinically achievable concentrations.
How It Is Used
The recommended dosage of regorafenib in hepatocellular carcinoma 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. Dose reductions should be made in 40-mg increments; the lowest recommended daily dose is 80 mg.
Treatment should be interrupted for grade 2 hand-foot skin reaction (palmar-plantar erythrodysesthesia) that is recurrent or does not improve within 7 days despite dose reduction or grade 3 hand-foot skin reaction, with interruption for a minimum of 7 days for grade 3 hand-foot skin reaction; symptomatic grade 2 hypertension; any grade 3 or 4 adverse event; and worsening infection of any grade.
BCLC STAGING SYSTEM
The Barcelona Clinic Liver Cancer (BCLC) staging system takes into account the number and size of tumors, the patient’s performance status (PS), and liver function (based on the Child-Pugh score).
- Stage 0: tumor < 2 cm; PS 0; Child-Pugh A
- Stage A: 1 tumor < 5 cm or ≤ 3 tumors, all less than 3 cm; PS 0; Child-Pugh A or B
- Stage B: many tumors in the liver; PS 0; Child-Pugh A or B
- Stage C: cancer has spread into the blood vessels, lymph nodes, or other body organs; PS 1 or 2; Child-Pugh A or B
- Stage D: PS 3 or 4 or Child-Pugh C
The dose should be reduced to 120 mg for the first occurrence of grade 2 hand-foot skin reaction of any duration, after recovery from any grade 3 or 4 adverse event (except infection), and for grade 3 aspartate transaminase (AST) or alanine transaminase (ALT) elevations (with resumption of treatment only if potential benefit outweighs the risk of hepatotoxicity). The dose should be reduced to 80 mg for reoccurrence of grade 2 hand-foot skin reaction at the 120-mg dose and after recovery of any grade 3 or 4 adverse event at the 120-mg dose (except hepatotoxicity or infection).
Treatment should be discontinued for failure to tolerate the 80-mg dose, any occurrence of AST or ALT > 20 times the upper limit of normal, any occurrence of AST or ALT more than 3 times upper limit of normal with concurrent bilirubin > 2 times upper limit of normal, reoccurrence of AST or ALT > 5 times upper limit of normal despite dose reduction to 120 mg, and any grade 4 adverse event reaction. Treatment should be resumed only if potential benefit outweighs risks.
Concomitant use of regorafenib with strong CYP3A4 inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital, and St. John’s Wort) and strong CYP3A4 inhibitors (eg, clarithromycin, grapefruit juice, itraconazole, ketoconazole, nefazodone, posaconazole, telithromycin, and voriconazole) should be avoided.
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.
Safety Profile
In the phase III trial, the most common adverse events of any grade in the regorafenib group were pain (55% vs 44% with placebo) and hand-foot skin reaction (51% vs 7%). The most common grade ≥ 3 adverse events were hypertension (15% vs 5%), hand-foot skin reaction (12% vs < 1%), asthenia/fatigue (10% vs 5%), and infection (8% vs 6%). The most common grade ≥ 3 laboratory abnormalities were hypophosphatemia (34% vs 7%), increased AST (18% vs 20%), lymphopenia (18% vs 11%), and proteinuria (17% vs 3%).
NEW INDICATION FOR REGORAFENIB
The approved indications for regorafenib (Stivarga) have been expanded to include the treatment of patients with hepatocellular carcinoma who have been previously treated with sorafenib.
The recommended dosage of regorafenib in hepatocellular carcinoma 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.
Adverse events led to dose interruption in 58% of regorafenib patients and to dose reduction in 48%, with the most common causes of dose modification being hand-foot skin reaction (21%), blood bilirubin increase (5.9%), fatigue (5.1%), and diarrhea (5.3%). Adverse events led to treatment discontinuation in 10.4% of regorafenib patients (vs 3.6% of placebo patients), with the most common causes being hand-foot skin reaction (1.9%) and increased AST (1.6%).
Regorafenib carries a boxed warning for hepatotoxicity. Severe and sometimes fatal hepatotoxicity have been observed in clinical trials. Regorafenib also carries warnings/precautions for hepatotoxicity, infections, hemorrhage, gastrointestinal perforation or fistulae, dermatologic toxicity, hypertension, cardiac ischemia or infarction, reversible posterior leukoencephalopathy syndrome, wound healing complications, and embryofetal toxicity. ■
CHILD-PUGH SCORE
The Child-Pugh score, a prognostic measure used in patients with chronic liver disease, is determined by five clinical measures, including total bilirubin level; serum albumin level; prothrombin time expressed by international normalized ratio, presence of ascites (none, mild, severe); and presence of hepatic encephalopathy (none; grade I–II; grade III–IV). Each clinical measure is assigned 1 to 3 points ranging from least severe (1 point) to most severe (3 points). A total score based on the five clinical measures is used to determine Child-Pugh class of disease (A, B, or C).
REFERENCES
1. U.S. Food and Drug Administration: Regorafenib. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm555548.htm. Accessed August 28, 2017.
2. Stivarga (regorafenib) tablets prescribing information. Bayer HealthCare Pharmaceuticals Inc, April 2017. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2017/203085s007lbl.pdf. Accessed August 28, 2017.
3. Bruix J, Qin S, Merle P, et al: Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 389:56-66, 2017.
