1.1 Colorectal Cancer

STIVARGA is indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild- type, an anti-EGFR therapy.

1.2 Gastrointestinal Stromal Tumors

STIVARGA is indicated for the treatment of patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate and sunitinib malate.

1.3 Hepatocellular Carcinoma

STIVARGA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.

2.1 Recommended Dose

The recommended dose is 160 mg STIVARGA (four 40 mg tablets) taken orally once daily for the first 21 days of each 28-day cycle. Continue treatment until disease progression or unacceptable toxicity.

Take STIVARGA at the same time each day. Swallow tablet whole with water after a low-fat meal that contains less than 600 calories and less than 30% fat [see Clinical Pharmacology (12.3)]. Do not take two doses of STIVARGA on the same day to make up for a missed dose from the previous day.

2.2 Dose Modifications

If dose modifications are required, reduce the dose in 40 mg (one tablet) increments; the lowest recommended daily dose of STIVARGA is 80 mg daily.

Interrupt STIVARGA for the following:

•

Grade 2 hand-foot skin reaction (HFSR) [palmar-plantar erythrodysesthesia syndrome (PPES)] that is recurrent or does not improve within 7 days despite dose reduction; interrupt therapy for a minimum of 7 days for Grade 3 HFSR

•

Symptomatic Grade 2 hypertension

•

Any Grade 3 or 4 adverse reaction

•

Worsening infection of any grade

Reduce the dose of STIVARGA to 120 mg:

•

For the first occurrence of Grade 2 HFSR of any duration

•

After recovery of any Grade 3 or 4 adverse reaction except infection

•

For Grade 3 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation, only resume if the potential benefit outweighs the risk of hepatotoxicity

Reduce the dose of STIVARGA to 80 mg:

•

For re-occurrence of Grade 2 HFSR at the 120 mg dose

•

After recovery of any Grade 3 or 4 adverse reaction at the 120 mg dose (except hepatotoxicity or infection)

Discontinue STIVARGA permanently for the following:

•

Failure to tolerate 80 mg dose

•

Any occurrence of AST or ALT more than 20 times the upper limit of normal (ULN)

•

Any occurrence of AST or ALT more than 3 times ULN with concurrent bilirubin more than 2 times ULN

•

Re-occurrence of AST or ALT more than 5 times ULN despite dose reduction to 120 mg

•

For any Grade 4 adverse reaction; only resume if the potential benefit outweighs the risks

5.1 Hepatotoxicity

Severe drug-induced liver injury with fatal outcome occurred in STIVARGA-treated patients in clinical trials. In most cases, liver dysfunction occurred within the first 2 months of therapy and was characterized by a hepatocellular pattern of injury.

In the CORRECT study, fatal hepatic failure occurred in 1.6% of patients in the regorafenib arm and in 0.4% of patients in the placebo arm. In the GRID study, fatal hepatic failure occurred in 0.8% of patients in the regorafenib arm. In the RESORCE study, there was no increase in the incidence of fatal hepatic failure as compared to placebo [see Adverse Reactions (6.1)].

Obtain liver function tests (ALT, AST, and bilirubin) before initiation of STIVARGA and monitor at least every two weeks during the first 2 months of treatment. Thereafter, monitor monthly or more frequently as clinically indicated. Monitor liver function tests weekly in patients experiencing elevated liver function tests until improvement to less than 3 times the ULN or baseline.

Temporarily hold and then reduce or permanently discontinue STIVARGA depending on the severity and persistence of hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].

5.2 Infections

STIVARGA caused an increased risk of infections. The overall incidence of infection (Grades 1-5) was higher (32% vs. 17%) in 1142 STIVARGA-treated patients as compared to the control arm in randomized placebo‑controlled trials.The incidence of grade 3 or greater infections in STIVARGA treated patients was 9%. The most common infections were urinary tract infections (5.7%), nasopharyngitis (4.0%), mucocutaneous and systemic fungal infections (3.3%) and pneumonia (2.6%). Fatal outcomes caused by infection occurred more often in patients treated with STIVARGA (1.0%) as compared to patients receiving placebo (0.3%); the most common fatal infections were respiratory (0.6% in STIVARGA-treated patients vs 0.2% in patients receiving placebo).

Withhold STIVARGA for Grade 3 or 4 infections, or worsening infection of any grade. Resume STIVARGA at the same dose following resolution of infection [see Dosage and Administration (2.2)].

5.3 Hemorrhage

STIVARGA caused an increased incidence of hemorrhage. The overall incidence (Grades 1-5) was 18.2% in 1142 patients treated with STIVARGA and 9.5% in patients receiving placebo in randomized, placebo‑controlled trials. The incidence of grade 3 or greater hemorrhage in patients treated with STIVARGA was 3.0%. The incidence of fatal hemorrhagic events was 0.7%, involving the central nervous system or the respiratory, gastrointestinal, or genitourinary tracts.

Permanently discontinue STIVARGA in patients with severe or life-threatening hemorrhage. Monitor INR levels more frequently in patients receiving warfarin [see Clinical Pharmacology (12.3)].

5.4 Gastrointestinal Perforation or Fistula

Gastrointestinal perforation occurred in 0.6% of 4518 patients treated with STIVARGA across all clinical trials of STIVARGA administered as a single agent; this included eight fatal events.

Gastrointestinal fistula occurred in 0.8% of patients treated with STIVARGA and 0.2% of patients in placebo arm across randomized, placebo-controlled trials. Permanently discontinue STIVARGA in patients who develop gastrointestinal perforation or fistula.

5.5 Dermatologic Toxicity

In randomized, placebo-controlled trials, adverse skin reactions occurred in 71.9% of patients in the regorafenib arm and in 25.5% of patients in the placebo arm, including hand-foot skin reaction (HFSR) also known as palmar-plantar erythrodysesthesia syndrome (PPES), and severe rash requiring dose modification.

In the randomized, placebo-controlled trials, the overall incidence of HFSR was higher in 1142 STIVARGA-treated patients (53%) than in the placebo-treated patients (8%). Most cases of HFSR in STIVARGA-treated patients appeared during the first cycle of treatment. The incidences of Grade 3 HFSR (16% versus <1%), Grade 3 rash (3% versus <1%), serious adverse reactions of erythema multiforme (<0.1% vs. 0%) and Stevens-Johnson Syndrome (<0.1% vs. 0%) were also higher in STIVARGA-treated patients [see Adverse Reactions (6.1)].  Across all trials, a higher incidence of HFSR was observed in Asian patients treated with STIVARGA (all grades: 72%; Grade 3: 18%) [see Use in Specific Populations (8.8 )].

Toxic epidermal necrolysis occurred in 0.02% of 4518 STIVARGA-treated patients across all clinical trials of STIVARGA administered as a single agent.

Withhold STIVARGA, reduce the dose, or permanently discontinue STIVARGA depending on the severity and persistence of dermatologic toxicity [see Dosage and Administration (2.2)]. Institute supportive measures for symptomatic relief.

5.6 Hypertension

In randomized, placebo-controlled trials, hypertensive crisis occurred in 0.2% of patients in the regorafenib arms and in none of the patients in the placebo arms. STIVARGA caused an increased incidence of hypertension (30% versus 8% in CORRECT, 59% versus 27% in GRID, and 31% versus 6% in RESORCE) [see Adverse Reactions (6.1)]. The onset of hypertension occurred during the first cycle of treatment in most patients who developed hypertension (67% in randomized, placebo-controlled trials).

Do not initiate STIVARGA unless blood pressure is adequately controlled. Monitor blood pressure weekly for the first 6 weeks of treatment and then every cycle, or more frequently, as clinically indicated. Temporarily or permanently withhold STIVARGA for severe or uncontrolled hypertension [see Dosage and Administration (2.2)].

5.7 Cardiac Ischemia and Infarction

STIVARGA increased the incidence of myocardial ischemia and infarction (0.9% vs 0.2%) in randomized placebo-controlled trials [see Adverse Reactions (6.1)]. Withhold STIVARGA in patients who develop new or acute onset cardiac ischemia or infarction. Resume STIVARGA only after resolution of acute cardiac ischemic events, if the potential benefits outweigh the risks of further cardiac ischemia.

5.8 Reversible Posterior Leukoencephalopathy Syndrome

Reversible posterior leukoencephalopathy syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one of 4800 STIVARGA-treated patients across all clinical trials. Perform an evaluation for RPLS in any patient presenting with seizures, severe headache, visual disturbances, confusion or altered mental function. Discontinue STIVARGA in patients who develop RPLS.

5.9 Risk of Impaired Wound Healing

Impaired wound healing complications can occur in patients who receive drugs that inhibit the VEGF signaling pathway. Therefore, STIVARGA has the potential to adversely affect wound healing.

Withhold STIVARGA for at least 2 weeks prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of STIVARGA after resolution of wound healing complications has not been established.

5.10 Embryo-Fetal Toxicity

Based on animal studies and its mechanism of action, STIVARGA can cause fetal harm when administered to a pregnant woman. There are no available data on STIVARGA use in pregnant women. Regorafenib was embryolethal and teratogenic in rats and rabbits at exposures lower than human exposures at the recommended dose, with increased incidences of cardiovascular, genitourinary, and skeletal malformations. Advise pregnant women of the potential risk to a fetus.

Advise females of reproductive potential to use effective contraception during treatment with STIVARGA and for 2 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with STIVARGA and for 2 months after the final dose [see Use in Specific Populations (8.1), (8.3)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rate observed in practice.

The data described in the WARNINGS AND PRECAUTIONS section reflect exposure to STIVARGA in more than 4800 patients who were enrolled in four randomized, placebo-controlled trials (n=1142), an expanded access program (CONSIGN, n=2864), or single arm clinical trials (single agent or in combination with other agents). There were 4518 patients who received STIVARGA as a single agent; the distribution of underlying malignancies was 80% CRC, 4% GIST, 10% HCC, 6% other solid tumors; and 74% were White, 11% Asian, and 15% race not known. Among these 4518 patients, 83% received STIVARGA for at least 21 days and 20% received STIVARGA for 6 months or longer.

In randomized placebo-controlled trials (CORRECT, GRID, RESORCE and CONCUR), the most frequently observed adverse drug reactions (≥20%) in patients receiving STIVARGA are pain (including gastrointestinal and abdominal pain), HFSR, asthenia/fatigue, diarrhea, decreased appetite/food intake, hypertension, infection, dysphonia, hyperbilirubinemia, fever, mucositis, weight loss, rash, and nausea.

Colorectal Cancer

The safety data described below, except where noted, are derived from a randomized (2:1), double-blind, placebo-controlled trial (CORRECT) in which 500 patients (median age 61 years; 61% men) with previously-treated metastatic colorectal cancer (CRC) received STIVARGA as a single agent at the dose of 160 mg daily for the first 3 weeks of each 4 week treatment cycle and 253 patients (median age 61 years; 60% men) received placebo. The median duration of therapy was 1.7 months (range 2 days, 10.8 months) for patients receiving STIVARGA. Due to adverse reactions, 61% of the patients receiving STIVARGA required a dose interruption and 38% of the patients had their dose reduced. Adverse reactions that resulted in treatment discontinuation occurred in 8.2% of STIVARGA-treated patients compared to 1.2% of patients who received placebo. Hand-foot skin reaction (HFSR) and rash were the most common reasons for permanent discontinuation of STIVARGA.

Table 1 provides the incidence of adverse reactions (≥10%) in patients in CORRECT.

 

a Adverse reactions graded according to National Cancer Institute Common Toxicity for Adverse Events version 3.0 (NCI CTCAE v3.0).

 

bThe term rash represents reports of events of drug eruption, rash, erythematous rash, generalized rash, macular rash, maculo-papular rash, papular rash, and pruritic rash.

cFatal outcomes observed.

Table 2 provides laboratory abnormalities observed in CORRECT.

a % based on number of patients with post-baseline samples which may be less than 500 (regorafenib) or 253 (placebo).

b NCI CTCAE v3.0.

cBased on urine protein-creatinine ratio data.

dInternational normalized ratio: No Grade 4 denoted in NCI CTCAE, v3.0.

Gastrointestinal Stromal Tumors

The safety data described below are derived from a randomized (2:1), double-blind, placebo-controlled trial (GRID) in which 132 patients (median age 60 years; 64% men) with previously-treated GIST received STIVARGA as a single agent at a dose of 160 mg daily for the first 3 weeks of each 4 week treatment cycle and 66 patients (median age 61 years; 64% men) received placebo. The median duration of therapy was 5.7 months (range 1 day, 11.7 months) for patients receiving STIVARGA. Dose interruptions for adverse events were required in 58% of patients receiving STIVARGA and 50% of patients had their dose reduced. Adverse reactions that resulted in treatment discontinuation were reported in 2.3% of STIVARGA-treated patients compared to 1.5% of patients who received placebo.

Table 3 provides the incidence of adverse reactions (≥10%) in patients in GRID.

a Adverse reactions graded according to NCI CTCAE v4.0.

 

bThe term rash represents reports of events of rash, erythematous rash, macular rash, maculo-papular rash, papular rash and pruritic rash.

 

cFatal outcomes observed.

dHypothyroidism incidence based on subset of patients with normal TSH and no thyroid supplementation at baseline.

Table 4 provides laboratory abnormalities observed in GRID.

 

a Percent based on number of patients with post-baseline samples which may be less than 132 (regorafenib) or 66 (placebo).

b NCI CTCAE v4.0.

c Based on urine protein-creatinine ratio data.

d No Grade 4 denoted in NCI CTCAE v4.0.

Hepatocellular Carcinoma

The safety data described below are derived from a randomized (2:1), double-blind, placebo-controlled trial (RESORCE) in which patients with previously-treated HCC received either STIVARGA (n=374) 160 mg orally on days 1-21 of each 4 week treatment cycle or placebo (n=193). The median age was 63 years, 88% were men, 98% had Child-Pugh A cirrhosis, 66% had an ECOG performance status (PS) of 0 and 34% had PS of 1. The median duration of therapy was 3.5 months (range 1 day to 29.4 months) for patients receiving STIVARGA. Of the patients receiving STIVARGA, 33% were exposed to STIVARGA for greater than or equal to 6 months and 14% were exposed to STIVARGA for greater than or equal to 12 months. Dose interruptions for adverse events were required in 58.3% of patients receiving STIVARGA and 48% of patients had their dose reduced. The most common adverse reactions requiring dose modification (interruption or dose reduction) were HFSR/PPES (20.6%), blood bilirubin increase (5.9%), fatigue (5.1%) and diarrhea (5.3%). Adverse reactions that resulted in treatment discontinuation were reported in 10.4% of STIVARGA-treated patients compared to 3.6% of patients who received placebo; the most common adverse reactions requiring discontinuation of STIVARGA were HFSR/PPES (1.9%) and AST increased (1.6%).

Table 5 provides the incidence of adverse reactions (≥10%) in patients in RESORCE.

a Adverse reactions graded according to NCI CTCAE v4.0.

 

bFatal outcomes observed.

Other clinically significant adverse reactions observed in less than 10% of STIVARGA-treated patients were: alopecia (7%), hypothyroidism (6.4%), pancreatitis (1.6%), exfoliative rash (1.3%), tremor (1.3%), erythema multiforme (0.8%), myocardial ischemia (0.8%), gastrointestinal fistula (0.3%), and myocardial infarction (0.3%).

Table 6 provides laboratory abnormalities observed in RESORCE.

 

a Percent based on number of patients with post-baseline samples which may be less than 374 (regorafenib) or 193 (placebo).

b NCI CTCAE v4.0.

c Based on dipstick data.

d No Grade 4 denoted in NCI CTCAE v4.0.

6.2 Postmarketing Experience

The following adverse reaction has been identified during postapproval use of STIVARGA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:

•

hypersensitivity reaction

•

nephrotic syndrome

•

cardiac failure

•

arterial (including aortic) aneurysms, dissections, and rupture

7.1 Effect of Strong CYP3A4 Inducers on Regorafenib

Co-administration of a strong CYP3A4 inducer with STIVARGA decreased the plasma concentrations of regorafenib, increased the plasma concentrations of the active metabolite M-5, and resulted in no change in the plasma concentrations of the active metabolite M-2 [see Clinical Pharmacology (12.3)], and may lead to decreased efficacy. Avoid concomitant use of STIVARGA with strong CYP3A4 inducers (e.g. rifampin, phenytoin, carbamazepine, phenobarbital, and St. John’s Wort).

7.2 Effect of Strong CYP3A4 Inhibitors on Regorafenib

Co-administration of a strong CYP3A4 inhibitor with STIVARGA increased the plasma concentrations of regorafenib and decreased the plasma concentrations of the active metabolites M-2 and M-5 [see Clinical Pharmacology (12.3)], and may lead to increased toxicity. Avoid concomitant use of STIVARGA with strong CYP3A4 inhibitors (e.g. clarithromycin, grapefruit juice, itraconazole, ketoconazole, nefazodone, posaconazole, telithromycin, and voriconazole).

7.3 Effect of Regorafenib on Breast Cancer Resistance Protein (BCRP) Substrates

Co-administration of STIVARGA with a BCRP substrate increased the plasma concentrations of the BCRP substrate [see Clinical Pharmacology (12.3)]. Monitor patients closely for signs and symptoms of exposure related toxicity to the BCRP substrate (e.g. methotrexate, fluvastatin, atorvastatin). Consult the concomitant BCRP substrate product information when considering administration of such products together with STIVARGA.

8.1 Pregnancy

Risk Summary

Based on animal studies and its mechanism of action, STIVARGA can cause fetal harm when administered to a pregnant woman. There are no available data on STIVARGA use in pregnant women. Administration of regorafenib was embryolethal and teratogenic in rats and rabbits at exposures lower than human exposures at the recommended dose, with increased incidences of cardiovascular, genitourinary, and skeletal malformations [see Data]. Advise pregnant women of the potential hazard to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4 % and 15 to 20%, respectively.

Data

Animal Data

In embryo-fetal development studies, a total loss of pregnancy (100% resorption of litter) was observed in rats at doses as low as 1 mg/kg (approximately 6% of the recommended human dose, based on body surface area) and in rabbits at doses as low as 1.6 mg/kg (approximately 25% of the human exposure at the clinically recommended dose measured by AUC).

In a single dose distribution study in pregnant rats, there was increased penetration of regorafenib across the blood-brain barrier in fetuses compared to dams. Daily administration of regorafenib to pregnant rats during organogenesis resulted in fetal findings of delayed ossification at doses > 0.8 mg/kg (approximately 5% of the recommended human dose based on body surface area) and dose-dependent increases in skeletal malformations including cleft palate and enlarged fontanelle at doses ≥ 1 mg/kg (approximately 10% of the clinical exposure based on AUC). At doses ≥ 1.6 mg/kg (approximately 11% of the recommended human dose based on body surface area), there were dose-dependent increases in the incidence of cardiovascular malformations, external abnormalities, diaphragmatic hernia, and dilation of the renal pelvis.

In pregnant rabbits administered regorafenib daily during organogenesis, there were findings of ventricular septal defects evident at the lowest tested dose of 0.4 mg/kg (approximately 7% of the AUC in patients at the recommended dose). At doses of ≥ 0.8 mg/kg (approximately 15% of the human exposure at the recommended human dose based on AUC), administration of regorafenib resulted in dose-dependent increases in the incidence of additional cardiovascular malformations and skeletal anomalies, as well as significant adverse effects on the urinary system including missing kidney/ureter; small, deformed and malpositioned kidney; and hydronephrosis. The proportion of viable fetuses that were male decreased with increasing dose in two rabbit embryo-fetal toxicity studies.

8.2 Lactation

Risk Summary

There are no data on the presence of regorafenib or its metabolites in human milk, the effects of regorafenib on the breastfed infant, or on milk production. In rats, regorafenib and its metabolites are excreted in milk. Because of the potential for serious adverse reactions in breastfed infants from STIVARGA, do not breastfeed during treatment with STIVARGA and for 2 weeks after the final dose.

8.3 Females and Males of Reproductive Potential

Contraception

Females

Use effective contraception during treatment and for 2 months after completion of therapy.

Males

Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 2 months following the final dose of STIVARGA [see Nonclinical Toxicology (13.1)].

Infertility

There are no data on the effect of STIVARGA on human fertility. Results from animal studies indicate that regorafenib can impair male and female fertility [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and efficacy of STIVARGA in pediatric patients less than 18 years of age have not been established.

Animal Data

In 28-day repeat-dose studies in rats there were dose-dependent findings of dentin alteration and angiectasis. These findings occurred at regorafenib doses as low as 4 mg/kg (approximately 25% of the AUC in humans at the recommended dose). In 13-week repeat-dose studies in dogs there were similar findings of dentin alteration at doses as low as 20 mg/kg (approximately 43% of the AUC in humans at the recommended dose). Administration of regorafenib in these animals also led to persistent growth and thickening of the femoral epiphyseal growth plate.

8.5 Geriatric Use

Of the 1142 STIVARGA-treated patients enrolled in randomized, placebo-controlled trials, 40% were 65 years of age and over, while 10% were 75 and over. No overall differences in efficacy were observed between these patients and younger patients. There was an increased incidence of Grade 3 hypertension (18% versus 9%) in the placebo-controlled trials among STIVARGA-treated patients 65 years of age and older as compared to younger patients. In addition, one Grade 4 hypertension event has been reported in the 65 years and older age group and none in the younger age group.

8.6 Hepatic Impairment

No dose adjustment is recommended in patients with mild (total bilirubin ≤ULN and AST >ULN, or total bilirubin >ULN to ≤1.5 times ULN) or moderate (total bilirubin >1.5 to ≤3 times ULN and any AST) hepatic impairment, [see Clinical Pharmacology (12.3)]. Closely monitor patients with hepatic impairment for adverse reactions [see Warnings and Precautions (5.1)].

STIVARGA is not recommended for use in patients with severe hepatic impairment (total bilirubin >3x ULN) as STIVARGA has not been studied in this population.

8.7 Renal Impairment

No dose adjustment is recommended for patients with renal impairment. The pharmacokinetics of regorafenib have not been studied in patients who are on dialysis and there is no recommended dose for this patient population [see Clinical Pharmacology (12.3)].

8.8 Race

Based on pooled data from three placebo-controlled trials (CORRECT, GRID and CONCUR), a higher incidence of HFSR and liver function test abnormalities occurred in Asian patients treated with STIVARGA as compared with Whites [see Warnings and Precautions (5.1, 5.5)]. No starting dose adjustment is necessary based on race.

12.1 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, metastasis and tumor immunity. 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, BRAF V600E, SAPK2, PTK5, Abl and CSF1R 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 in several mouse xenograft models including some for human colorectal carcinoma, gastrointestinal stromal and hepatocellular carcinoma. Regorafenib also demonstrated anti-metastatic activity in a mouse xenograft model and two mouse orthotopic models of human colorectal carcinoma.

12.2 Pharmacodynamics

Cardiac Electrophysiology

The effect of multiple doses of STIVARGA (160 mg once daily for 21 days) on the QTc interval was evaluated in an open-label, single-arm study in 25 patients with advanced solid tumors. No large changes in the mean QTc interval (i.e., > 20 msec) were detected in the study.

12.3 Pharmacokinetics

Absorption

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 the CORRECT and GRID studies [see Dosage and Administration (2.1), Clinical Studies (14)].

Distribution

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.

Elimination

Following a single 160 mg oral dose of STIVARGA, the geometric mean (minimum to maximum) 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 (minimum to maximum) elimination half-life of 51 hours (32 to 70 hours).

Metabolism

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 metabolites have 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).

Excretion

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.

Specific Populations

Age, sex, race and weight had no clinically meaningful effect on the pharmacokinetics of regorafenib.

Hepatic Impairment

Based on a population pharmacokinetic analysis, no clinically important differences in the mean total exposure of regorafenib, including M-2 and M-5, were noted amongst patients with normal liver function (total bilirubin and AST ≤ ULN, n=744), mild hepatic impairment (total bilirubin ≤ ULN and AST >ULN or total bilirubin >ULN to ≤1.5x ULN, n=437), and moderate hepatic impairment (total bilirubin >1.5x to ≤3x ULN and any AST, n=36). The pooled analysis included 391 patients with HCC of whom 116, 249, and 26 were categorized as having normal liver function, mild, and moderate hepatic impairment, respectively. The pharmacokinetics of regorafenib were not evaluated in patients with severe hepatic impairment (total bilirubin >3x ULN).

Renal Impairment

The pharmacokinetics of regorafenib, M-2, and M-5 was evaluated in 6 patients with severe renal impairment (CLcr 15-29 mL/min) and 18 patients with normal/mild renal function (CLcr ≥60 mL/min) 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 severe renal impairment compared to patients with normal renal function. The pharmacokinetics of regorafenib has not been studied in patients with end-stage renal disease on dialysis.

Drug Interaction Studies

Effect of Regorafenib on Cytochrome P450 Substrates: In vitro studies suggested that regorafenib is an inhibitor of CYP2C8, CYP2C9, CYP2B6, CYP3A4 and CYP2C19; M-2 is an inhibitor of CYP2C9, CYP2C8, CYP3A4 and CYP2D6, and M-5 is an inhibitor of CYP2C8. In vitro studies suggested that regorafenib is not an inducer of CYP1A2, CYP2B6, CYP2C19, and CYP3A4 enzyme activity.

Patients with advanced solid tumors received single oral doses of CYP substrates, 2 mg of midazolam (CYP3A4), 40 mg of omeprazole (CYP2C19) and 10 mg of warfarin (CYP2C9) or 4 mg of rosiglitazone (CYP2C8) one week before and two weeks after STIVARGA at a dose of 160 mg once daily. No clinically meaningful effect was observed in the mean AUC of rosiglitazone (N=12) or the mean omeprazole (N=11) plasma concentrations measured 6 hours after dosing or the mean AUC of midazolam (N=15). The mean AUC of warfarin (N=8) increased by 25% [see Warnings and Precautions (5.2)].

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 (7.1)].

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% [see Drug Interactions (7.2)].

Effect of Neomycin on Regorafenib: Twenty-seven healthy men received a single 160 mg dose of STIVARGA and then 5 days after starting neomycin. Neomycin, a non-absorbable antibiotic, was administered at a dose of 1 gram three times daily for 5 days. No clinically meaningful effect on the mean AUC of regorafenib was observed; however, the mean AUC of M-2 decreased by 76% and the mean AUC of M-5 decreased by 86%. The decreased exposure of M-2 and M-5 may result in a decreased efficacy of STIVARGA. The effects of other antibiotics on the exposure of regorafenib and its active metabolites have not been studied.

Effect of Regorafenib on UGT1A1 Substrates: In vitro studies showed that regorafenib, M-2, and M-5 competitively inhibit UGT1A9 and UGT1A1 at therapeutically relevant concentrations. Eleven patients received irinotecan-containing combination chemotherapy with STIVARGA at a dose of 160 mg. The mean AUC of irinotecan increased by 28% and the mean AUC of SN-38 increased by 44% when irinotecan was administered 5 days after the last of 7 daily doses of STIVARGA.

Effect of Regorafenib on BCRP Substrates: Administration of regorafenib (160 mg for 14 days) prior to administration of a single dose of rosuvastatin (5 mg), a BCRP substrate, resulted in a 3.8-fold increase in mean exposure (AUC) of rosuvastatin and a 4.6-fold increase in Cmax [see Drug Interactions (7.3)].

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies examining the carcinogenic potential of regorafenib have not been conducted. Regorafenib itself did not demonstrate genotoxicity in in vitro or in vivo assays; however, a major human active metabolite of regorafenib, (M-2), was positive for clastogenicity, causing chromosome aberration in Chinese hamster V79 cells.

Dedicated studies to examine the effects of regorafenib on fertility have not been conducted; however, there were histological findings of tubular atrophy and degeneration in the testes, atrophy in the seminal vesicle, and cellular debris and oligospermia in the epididymides in male rats at doses similar to those in human at the clinical recommended dose based on AUC. In female rats, there were increased findings of necrotic corpora lutea in the ovaries at the same exposures. There were similar findings in dogs of both sexes in repeat dose studies at exposures approximately 83% of the human exposure at the recommended human dose based on AUC. These findings suggest that regorafenib may adversely affect fertility in humans.

13.2 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.

14.1 Colorectal Cancer

The clinical efficacy and safety of STIVARGA were evaluated in an international, multicenter, randomized (2:1), double-blind, placebo-controlled trial [Study “Patients with metastatic COloRectal cancer treated with REgorafenib or plaCebo after failure of standard Therapy” (CORRECT); NCT 01103323)] in 760 patients with previously-treated metastatic colorectal cancer. The major efficacy outcome measure was overall survival (OS); additional efficacy outcome measures included progression-free survival (PFS) and overall 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 (2.1), Clinical Pharmacology (12.3)]. Treatment continued until disease progression or unacceptable toxicity.

Baseline demographics were: median age 61 years, 61% men, 78% White, and all patients had an ECOG performance status of 0 or 1. The primary sites of disease were 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 7 and Figure 1).

 

a CI=confidence interval.

 

bStratified by geographic region and time from diagnosis of metastatic disease.

 

c Crossed the O’Brien-Fleming boundary (two-sided p-value < 0.018) at second interim analysis.

Figure 1: Kaplan-Meier Curves of Overall Survival

14.2 Gastrointestinal Stromal Tumors

The efficacy and safety of STIVARGA were evaluated in an international, multicenter, randomized (2:1), double-blind, placebo-controlled trial [Study “GIST Regorafenib In progressive Disease” (GRID); NCT 01271712] in 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 GRID 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 GRID, 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.

A statistically significant improvement in PFS was demonstrated among patients treated with STIVARGA compared to placebo (see Table 8 and Figure 2).

There was no statistically significant difference in overall survival at the final OS analysis, conducted at 162 OS events (Table 8). Cross-over to open label STIVARGA occurred in 58 (88%) placebo-treated patients after disease progression.

a 2-sided p-value by log-rank test stratified by line of treatment and geographical region.

Figure 2: Kaplan-Meier Curves of Progression-Free Survival for GRID

14.3 Hepatocellular Carcinoma (HCC)

The clinical efficacy and safety of STIVARGA were evaluated in an international, multicenter, randomized (2:1), double-blind, placebo-controlled trial [Study “REgorafenib after SORafenib in patients with hepatoCEllular carcinoma” (RESORCE); NCT 01774344]. The study enrolled adults with Child-Pugh A and Barcelona Clinic Liver Cancer Stage Category B or C hepatocellular carcinoma, with documented disease progression following sorafenib. The median duration of previous sorafenib treatment was 7.8 months; patients who permanently discontinued sorafenib due to toxicity or were unable to tolerate sorafenib doses of 400 mg once daily were ineligible.

Patients were randomized to receive 160 mg regorafenib orally once daily plus best supportive care (BSC) or matching placebo plus BSC for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity. Randomization was stratified by geographical region (Asia vs rest of world), ECOG performance status (0 vs 1), alpha-fetoprotein levels (<400 ng/mL vs ≥400 ng/mL), extrahepatic disease (presence vs absence), and macrovascular invasion (presence vs absence). The major efficacy outcome measure was overall survival (OS). Additional outcome measures were progression-free survival (PFS), overall tumor response rate (ORR) and duration of response as assessed by investigators using RECIST 1.1 and using modified RECIST (mRECIST) for HCC. Patients continued therapy with STIVARGA until clinical or radiological disease progression or unacceptable toxicity.

The characteristics of the study population were a median age of 63 years (range 19 to 85 years); 88% male; 41% Asian, 36% White, and 21% not reported; 66% had ECOG performance status (PS) of 0 and 34% had ECOG PS of 1; 98% had Child-Pugh A and 2% had Child-Pugh B. Risk factors for underlying cirrhosis included hepatitis B (38%), alcohol use (25%), hepatitis C (21%), and non-alcoholic steato hepatitis (7%). Macroscopic vascular invasion or extra-hepatic tumor spread was present in 81% of patients. Barcelona Clinic Liver Cancer (BCLC) was stage C in 87% and stage B in 13% of patients. All patients received prior sorafenib and 61% received prior loco-regional transarterial embolization or chemoinfusion procedures.

Efficacy results are summarized in Table 9 and Figure 3 below.

 

aCI=confidence interval.

 

bEstimated with Cox proportional hazard model stratified by geographic region, ECOG performance status, Alpha-fetoprotein level, presence versus absence of extrahepatic disease, and presence versus absence of macrovascular invasion.

 

cLog rank test stratified by geographic region, ECOG performance status, Alpha-fetoprotein level, presence versus absence of extrahepatic disease, and presence versus absence of macrovascular invasion.

Figure 3: Kaplan-Meier Curve of Overall Survival from Study RESORCE