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Mechanism of Action
Regorafenib is a small molecule inhibitor of multiple membrane-bound and intracellular kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment. In in vitro biochemical or cellular assays, regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl at concentrations of regorafenib that have been achieved clinically. In in vivo models, regorafenib demonstrated anti-angiogenic activity in a rat tumor model, and inhibition of tumor growth as well as anti-metastatic activity in several mouse xenograft models including some for human colorectal carcinoma.
Following a single 160 mg dose of Stivarga in patients with advanced solid tumors, regorafenib reaches a geometric mean peak plasma level (Cmax) of 2.5 μg/mL at a median time of 4 hours and a geometric mean area under the plasma concentration vs. time curve (AUC) of 70.4 μg*h/mL. The AUC of regorafenib at steady-state increases less than dose proportionally at doses greater than 60 mg. At steady-state, regorafenib reaches a geometric mean Cmax of 3.9 μg/mL and a geometric mean AUC of 58.3 μg*h/mL. The coefficient of variation of AUC and Cmax is between 35% and 44%.
The mean relative bioavailability of tablets compared to an oral solution is 69% to 83%.
In a food-effect study, 24 healthy men received a single 160 mg dose of Stivarga on three separate occasions: under a fasted state, with a high-fat meal and with a low-fat meal. A high-fat meal (945 calories and 54.6 g fat) increased the mean AUC of regorafenib by 48% and decreased the mean AUC of the M-2 and M-5 metabolites by 20% and 51%, respectively, as compared to the fasted state. A low-fat meal (319 calories and 8.2 g fat) increased the mean AUC of regorafenib, M-2 and M-5 by 36%, 40% and 23%, respectively as compared to fasted conditions. Stivarga was administered with a low-fat meal in Studies 1 and 2 [see DOSAGE AND ADMINISTRATION, Clinical Studies].
Regorafenib undergoes enterohepatic circulation with multiple plasma concentration peaks observed across the 24-hour dosing interval. Regorafenib is highly bound (99.5%) to human plasma proteins.
Regorafenib is metabolized by CYP3A4 and UGT1A9. The main circulating metabolites of regorafenib measured at steady-state in human plasma are M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl), both of them having similar in vitro pharmacological activity and steady-state concentrations as regorafenib. M-2 and M-5 are highly protein bound (99.8% and 99.95%, respectively).
Following a single 160 mg oral dose of Stivarga, the geometric mean (range) elimination half-lives for regorafenib and the M-2 metabolite in plasma are 28 hours (14 to 58 hours) and 25 hours (14 to 32 hours), respectively. M-5 has a longer mean (range) elimination half-life of 51 hours (32 to 70 hours).
Approximately 71% of a radiolabeled dose was excreted in feces (47% as parent compound, 24% as metabolites) and 19% of the dose was excreted in urine (17% as glucuronides) within 12 days after administration of a radiolabeled oral solution at a dose of 120 mg.
Patients with hepatic impairment
The pharmacokinetics of regorafenib, M-2, and M-5 were evaluated in 14 patients with hepatocellular carcinoma (HCC) and mild hepatic impairment (Child-Pugh A); 4 patients with HCC and moderate hepatic impairment (Child-Pugh B); and 10 patients with solid tumors and normal hepatic function after the administration of a single 100 mg dose of Stivarga. No clinically important differences in the mean exposure of regorafenib, M-2, or M-5 were observed in patients with mild or moderate hepatic impairment compared to the patients with normal hepatic function. The pharmacokinetics of regorafenib has not been studied in patients with severe hepatic impairment (Child-Pugh C).
Patients with renal impairment
The pharmacokinetics of regorafenib, M-2, and M-5 were evaluated in 10 patients with mild renal impairment (CLcr 6089 mL/min) and 18 patients with normal renal function following the administration of Stivarga at a dose of 160 mg daily for 21 days. No differences in the mean steady-state exposure of regorafenib, M-2, or M-5 were observed in patients with mild renal impairment compared to patients with normal renal function. Limited pharmacokinetic data are available from patients with moderate renal impairment (CLcr 30-59 mL/min). The pharmacokinetics of regorafenib has not been studied in patients with severe renal impairment or end-stage renal disease.
In vitro screening on cytochrome P450 enzymes: In vitro studies with human hepatic microsomes or recombinant enzymes showed that regorafenib competitively inhibits CYP2C8, CYP2C9, CYP2B6, CYP3A4, and CYP2C19 with R1 values > 1.1; M-2 inhibits CYP2C9, CYP2C8, CYP3A4, and CYP2D6 with R1 values > 1.1 and M-5 inhibits CYP2C8 with a R1 value > 1.1. In vitro studies with primary human hepatocytes showed that regorafenib is not expected to induce CYP1A2, CYP2B6, CYP2C19, and CYP3A4 enzyme activity.
In vitro screening on uridine diphosphate glucuronosyltransferases: In vitro studies with human hepatic microsomes showed that regorafenib, M-2, and M-5 competitively inhibits UGT1A9 and UGT1A1 at therapeutically relevant concentrations.
Effect of CYP3A4 Strong Inducers on Regorafenib: Twenty-two healthy men received a single 160 mg dose of Stivarga alone and then 7 days after starting rifampin. Rifampin, a strong CYP3A4 inducer, was administered at a dose of 600 mg daily for 9 days. The mean AUC of regorafenib decreased by 50% and mean AUC of M-5 increased by 264%. No change in the mean AUC of M-2 was observed [see DRUG INTERACTIONS].
Effect of CYP3A4 Strong Inhibitors on Regorafenib: Eighteen healthy men received a single 160 mg dose of Stivarga alone and then 5 days after starting ketoconazole. Ketoconazole, a strong CYP3A4 inhibitor, was administered at a dose of 400 mg daily for 18 days. The mean AUC of regorafenib increased by 33% and the mean AUC of M-2 and M-5 both decreased by 93%.
Effect of regorafenib on a substrate of UGT1A1 substrates: Eleven patients received irinotecan-containing combination chemotherapy with Stivarga at a dose of 160 mg. The mean AUC of irinotecan increased 28% and the mean AUC of SN38 increased by 44% when irinotecan was administered 5 days after the last of 7 daily doses of Stivarga.
Animal Toxicology and/or Pharmacology
In a chronic 26 week repeat dose study in rats there was a dose-dependent increase in the finding of thickening of the atrioventricular valve. At a dose that resulted in an exposure of approximately 12% of the human exposure at the recommended dose, this finding was present in half of the examined animals.
The clinical efficacy and safety of Stivarga were evaluated in an international, multi-center, randomized (2:1), double-blind, placebo-controlled trial (Study 1) in 760 patients with previously treated metastatic colorectal cancer. The major efficacy outcome measure was overall survival (OS); supportive efficacy outcome measures included progression-free survival (PFS) and objective tumor response rate.
Patients were randomized to receive 160 mg regorafenib orally once daily (N=505) plus Best Supportive Care (BSC) or placebo (N=255) plus BSC for the first 21 days of each 28-day cycle. Stivarga was administered with a low-fat breakfast that contains less than 30% fat [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY]. Treatment continued until disease progression or unacceptable toxicity.
In the all-randomized population, median age was 61 years, 61% were men, 78% were White, and all patients had baseline ECOG performance status of 0 or 1. The primary site of disease was colon (65%), rectum (29%), or both (6%). History of KRAS evaluation was reported for 729 (96%) patients; 430 (59%) of these patients were reported to have KRAS mutation. The median number of prior lines of therapy for metastatic disease was 3. All patients received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, and with bevacizumab. All but one patient with KRAS mutation-negative tumors received panitumumab or cetuximab.
The addition of Stivarga to BSC resulted in a statistically significant improvement in survival compared to placebo plus BSC (see Table 5 and Figure 1).
Table 5 : Efficacy Results from Study 1
|Number of deaths, N (%)||275 (55%)||157 (62%)|
|Median Overall Survival (months)||6.4||5|
|95% CI||(5.8, 7.3)||(4.4, 5.8)|
|HR (95% CI)||0.77 (0.64, 0.94)|
|Stratified Log-Rank Test P-valuea,b||0.0102|
|Number of Death or Progression, N (%)||417 (83%)||231 (91%)|
|Median Progression-free Survival (months)||2||1.7|
|95% CI||(1.9, 2.3)||(1.7, 1.8)|
|HR (95% CI)||0.49 (0.42, 0.58)|
|Stratified Log-Rank Test P-valuea||< 0.0001|
|Overall Response Rate|
|Overall response, N (%)||5 (1%)||1 (0.4%)|
|95% CI||0.3%, 2.3%||0%, 2.2%|
|aStratified by geographic region and time from diagnosis of
bCrossed the O'Brien-Fleming boundary (two-sided p-value < 0.018) at second interim analysis.
Figure 1 : Kaplan-Meier Curves of Overall Survival
Gastrointestinal Stromal Tumors
The efficacy and safety of Stivarga were evaluated in an international, multi-center, randomized (2:1), double-blind, placebo-controlled trial (Study 2) in 199 patients with unresectable, locally advanced or metastatic gastrointestinal stromal tumor (GIST), who had been previously treated with imatinib mesylate and sunitinib malate. Randomization was stratified by line of therapy (third vs. four or more) and geographic region (Asia vs. rest of the world).
The major efficacy outcome measure of Study 2 was progression-free survival (PFS) based on disease assessment by independent radiological review using modified RECIST 1.1 criteria, in which lymph nodes and bone lesions were not target lesions and progressively growing new tumor nodule within a pre-existing tumor mass was progression. The key secondary outcome measure was overall survival.
Patients were randomized to receive 160 mg regorafenib orally once daily (N=133) plus best supportive care (BSC) or placebo (N=66) plus BSC for the first 21 days of each 28-day cycle. Treatment continued until disease progression or unacceptable toxicity. In Study 2, the median age of patients was 60 years, 64% were men, 68% were White, and all patients had baseline ECOG performance status of 0 (55%) or 1 (45%). At the time of disease progression as assessed by central review, the study blind was broken and all patients were offered the opportunity to take Stivarga at the investigator's discretion. Fifty-six (85%) patients randomized to placebo and 41 (31%) patients randomized to Stivarga received open-label Stivarga.
A statistically significant improvement in PFS was demonstrated among patients treated with Stivarga compared to placebo (see Table 6 and Figure 2). There was no statistically significant difference in overall survival at the time of the planned interim analysis based on 29% of the total events for the final analysis.
Table 6 : Efficacy Results for Study 2
|Number of Death or Progression, N (%)||82 (62%)||63 (96%)|
|Median Progression-free Survival (months)||4.8||0.9|
|95% CI||(3.9, 5.7)||(0.9, 1.1)|
|HR (95% CI)||0.27 (0.19, 0.39)|
|Stratified Log-Rank Test P-value a||<0.0001|
|Number of Deaths, N (%)||29 (22%)||17 (26%)|
|Median Overall Survival (months)||NRb||NRb|
|HR (95% CI)||0.77 (0.42, 1.41)|
|Stratified Log-Rank Test P-value a, b||0.2|
|aStratified by line of treatment and geographical region.
bNR: Not Reached.
Figure 2 : Kaplan-Meier Curves of Progression-free Survival for Study
Last reviewed on RxList: 3/7/2013
This monograph has been modified to include the generic and brand name in many instances.
Additional Stivarga Information
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