IMPORTANT SAFETY INFORMATION:

WARNING: HEPATOTOXICITY - Severe and sometimes fatal hepatotoxicity has occurred in clinical trials. Monitor hepatic function prior to and during treatment...
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STIVARGA in HCC

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The RESORCE trial evaluated the efficacy and safety of STIVARGA® (regorafenib)1,2

REgorafenib after SORafenib in patients with hepatoCEllular carcinoma (RESORCE) was an international, multicenter, randomized (2:1), double-blind, placebo-controlled phase 3 trial that evaluated the efficacy and safety of STIVARGA in HCC patients with progression following NEXAVAR (N=573).

  • Patients who permanently discontinued NEXAVAR due to toxicity or who were unable to tolerate NEXAVAR doses of 400 mg once daily were ineligible for the trial

*The mean daily STIVARGA dose was 144 mg.1

Patients were followed up for radiological tumor assessments every 6 weeks up to 8 cycles, after which assessments were conducted every 12 weeks with scans that documented radiological progression.1

Primary endpoint1:
  • Overall survival (OS), analyzed by intention to treat
Secondary endpoints1,2:
  • Progression-free survival (PFS), time to progression, overall response rate (ORR; patients with complete response [CR] or partial response [PR]), disease control rate (DCR; patients with CR, PR, or stable disease [SD] for ≥6 weeks)
    • Analyzed by intention to treat; assessed using modified Response Evaluation Criteria In Solid Tumors (mRECIST) and RECIST 1.1
Tertiary endpoint1,2:
  • Duration of response

Patients in the RESORCE trial had good performance status and preserved liver function1,2

Baseline patient characteristics were similar between each arm1,2

Includes patients from China, Japan, South Korea, Singapore, and Taiwan.1

§The Child-Pugh system describes liver disease severity: Patients are divided into classes from A to C, with class C representing the worst prognosis. Child-Pugh class was missing in 1 patient in the STIVARGA group. Those patients who progressed to Child-Pugh B after screening and before randomization were included.1

||Patients could have more than 1 etiology of HCC.1

IMPORTANT SAFETY INFORMATION (continued)

Hepatotoxicity: Severe drug-induced liver injury with fatal outcome occurred in STIVARGA-treated patients across all 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 metastatic colorectal cancer (mCRC), fatal hepatic failure occurred in 1.6% of patients in the STIVARGA arm and in 0.4% of patients in the placebo arm. In gastrointestinal stromal tumor (GIST), fatal hepatic failure occurred in 0.8% of patients in the STIVARGA arm. In hepatocellular carcinoma (HCC), there was no increase in the incidence of fatal hepatic failure as compared to placebo.

Liver Function Monitoring: Obtain liver function tests (ALT, AST, and bilirubin) before initiation of STIVARGA and monitor at least every 2 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 upper limit of normal (ULN) or baseline values. 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.

Please see full Important Safety Information below.

Results from RESORCE represent a significant advance in treatment for HCC patients previously treated with NEXAVAR1

10.6-month median OS achieved with STIVARGA vs 7.8 months with placebo1,2

STIVARGA (regorafenib) results in a clinical trial. Visit hcp.stivarga-us.com to see full Safety and Prescribing Information, Including Boxed Warning.

CI, confidence interval; HR, hazard ratio.

STIVARGA OS based on exploratory, preplanned patient subgroup analyses1

STIVARGA (regorafenib) analysis. Visit hcp.stivarga-us.com to see full Safety and Prescribing Information, Including Boxed Warning.

STIVARGA more than doubled PFS vs placebo1,2

3.1-month median PFS achieved with STIVARGA vs 1.5 months with placebo

Review data on STIVARGA (regorafenib). Visit hcp.stivarga-us.com to see full Safety and Prescribing Information, Including Boxed Warning.
Reduction in risk of progression or death with STIVARGA was consistent when assessed by RECIST 1.12
  • 3.4-month (95% CI, 2.9-4.2) median PFS achieved with STIVARGA vs 1.5 months (95% CI, 1.4-1.5 with placebo (HR: 0.43; 95% CI, 0.35-0.52) (RECIST 1.1)
    • Number of progressions or deaths: 288 of 379 (76%) in the STIVARGA arm; 184 of 194 (95%) in the placebo arm

Break through response barriers with STIVARGA1-3

Information about STIVARGA (regorafenib). Visit hcp.stivarga-us.com to see full Safety and Prescribing Information, Including Boxed Warning.

DCR, CR + PR + SD; ORR, CR + PR.

Duration of disease response, assessed using mRECIST3

  • Median duration of response in patients with a complete or partial response was 3.5 months in the STIVARGA arm vs 2.7 months in the placebo arm3
  • Median duration of stable disease was 5.5 months in the STIVARGA arm vs 3.1 months in the placebo arm3

STIVARGA® (regorafenib) safety profile1

Adverse events (AEs) reported in ≥10% of patients and at a higher rate in the STIVARGA arm vs placebo in RESORCE*

*AEs graded according to National Cancer Institute Common Terminology Criteria for Adverse Events v4.0.

Fatal outcomes observed.

  • The median duration of therapy was 3.5 months (range: 1 day to 29.4 months) for patients receiving STIVARGA
  • 58.3% of patients receiving STIVARGA required dose interruptions for AEs
    • 48% of patients receiving STIVARGA had their doses reduced due to AEs
  • 10.4% of STIVARGA-treated patients reported AEs that resulted in discontinuation vs 3.6% of patients who received placebo

Selected common TEAEs occurred during the first cycle of treatment with STIVARGA1,2

  • The most frequently observed adverse drug reactions (≥30%) in STIVARGA-treated patients vs placebo treated patients in HCC, respectively, were pain (55% vs 44%), HFSR/PPES (51% vs 7%), asthenia/fatigue (42% vs 33%), diarrhea (41% vs 15%), hypertension (31% vs 6%), infection (31% vs 18%), and decreased appetite and food intake (31% vs 15%)1‡

IQR, interquartile range; TEAE, treatment-emergent adverse event.

n=195 for worst grade.2

§n=148 for worst grade.2

Indications

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.

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.

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


Important Safety Information

Warning: Hepatotoxicity

  • Severe and sometimes fatal hepatotoxicity has occurred in clinical trials.
  • Monitor hepatic function prior to and during treatment.
  • Interrupt and then reduce or discontinue STIVARGA for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence.

Hepatotoxicity: Severe drug-induced liver injury with fatal outcome occurred in STIVARGA-treated patients across all 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 metastatic colorectal cancer (mCRC), fatal hepatic failure occurred in 1.6% of patients in the STIVARGA arm and in 0.4% of patients in the placebo arm. In gastrointestinal stromal tumor (GIST), fatal hepatic failure occurred in 0.8% of patients in the STIVARGA arm. In hepatocellular carcinoma (HCC), there was no increase in the incidence of fatal hepatic failure as compared to placebo.

Liver Function Monitoring: Obtain liver function tests (ALT, AST, and bilirubin) before initiation of STIVARGA and monitor at least every 2 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 upper limit of normal (ULN) or baseline values. 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.

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% vs 0.2%). Withhold STIVARGA for Grade 3 or 4 infections, or worsening infection of any grade. Resume STIVARGA at the same dose following resolution of infection.

Hemorrhage: STIVARGA caused an increased incidence of hemorrhage. The overall incidence (Grades 1-5) was 18.2% in 1142 patients treated with STIVARGA vs 9.5% with 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 and monitor INR levels more frequently in patients receiving warfarin.

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 in 0.2% of patients in the placebo arm across randomized, placebo-controlled trials. Permanently discontinue STIVARGA in patients who develop gastrointestinal perforation or fistula.

Dermatological Toxicity: In randomized, placebo-controlled trials, adverse skin reactions occurred in 71.9% of patients with STIVARGA arm and 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% vs 8%) than in the placebo-treated patients. Most cases of HFSR in STIVARGA-treated patients appeared during the first cycle of treatment. The incidences of Grade 3 HFSR (16% vs <1%), Grade 3 rash (3% vs <1%), serious adverse reactions of erythema multiforme (<0.1% vs 0%), and Stevens-Johnson syndrome (<0.1% vs 0%) were higher in STIVARGA-treated patients. Across all trials, a higher incidence of HFSR was observed in Asian patients treated with STIVARGA (all grades: 72%; Grade 3: 18%). 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 depending on the severity and persistence of dermatologic toxicity.

Hypertension: Hypertensive crisis occurred in 0.2% in STIVARGA-treated patients and in none of the patients in placebo arm across all randomized, placebo-controlled trials. STIVARGA caused an increased incidence of hypertension (30% vs 8% in mCRC, 59% vs 27% in GIST, and 31% vs 6% in HCC). 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 until 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.

Cardiac Ischemia and Infarction: STIVARGA increased the incidence of myocardial ischemia and infarction (0.9% with STIVARGA vs 0.2% with placebo) in randomized placebo-controlled trials. Withhold STIVARGA in patients who develop new or acute cardiac ischemia or infarction, and resume only after resolution of acute cardiac ischemic events if the potential benefits outweigh the risks of further cardiac ischemia.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Reversible posterior leukoencephalopathy syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristics 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.

Wound Healing Complications: 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.

Embryo-Fetal Toxicity: STIVARGA can cause fetal harm when administered to a pregnant woman. There are no available data on STIVARGA use in pregnant women. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with STIVARGA and for 2 months after the final dose.

Nursing Mothers: 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.

Most Frequently Observed Adverse Drug Reactions in mCRC (30%): The most frequently observed adverse drug reactions (≥30%) in STIVARGA-treated patients vs placebo-treated patients in mCRC, respectively, were: asthenia/fatigue (64% vs 46%), pain (59% vs 48%), decreased appetite and food intake (47% vs 28%), HFSR/PPE (45% vs 7%), diarrhea (43% vs 17%), mucositis (33% vs 5%), weight loss (32% vs 10%), infection (31% vs 17%), hypertension (30% vs 8%), and dysphonia (30% vs 6%).

Most Frequently Observed Adverse Drug Reactions in GIST (30%): The most frequently observed adverse drug reactions (≥30%) in STIVARGA-treated patients vs placebo-treated patients in GIST, respectively, were: HFSR/PPE (67% vs 12%), pain (60% vs 55%), hypertension (59% vs 27%), asthenia/fatigue (52% vs 39%), diarrhea (47% vs 9%), mucositis (40% vs 8%), dysphonia (39% vs 9%), infection (32% vs 5%), decreased appetite and food intake (31% vs 21%), and rash (30% vs 3%).

Most Frequently Observed Adverse Drug Reactions in HCC (30%): The most frequently observed adverse drug reactions (≥30%) in STIVARGA-treated patients vs placebo-treated patients in HCC, respectively, were: pain (55% vs 44%), HFSR/PPE (51% vs 7%), asthenia/fatigue (42% vs 33%), diarrhea (41% vs 15%), hypertension (31% vs 6%), infection (31% vs 18%), decreased appetite and food intake (31% vs 15%).

For important risk and use information, please see the full Prescribing Information including the Boxed Warning.

You are encouraged to report side effects or quality complaints of products to the FDA by visiting www.fda.gov/medwatch or calling 1-800-FDA-1088. For Bayer products, you can report these directly to Bayer by clicking here.

REFERENCES:

1. STIVARGA Prescribing Information. Whippany, NJ: Bayer HealthCare Pharmaceuticals, Inc; February 2020. 2. Data on file. Bayer HealthCare Pharmaceuticals Inc., Whippany, NJ.