IMPORTANT SAFETY INFORMATION:
NEXAVAR is contraindicated in patients with known severe hypersensitivity to sorafenib or any other component of NEXAVAR. Continue reading below

NEXAVAR in unresectable HCC

A systemic treatment approach to unresectable HCC can start with NEXAVAR® (sorafenib), an established first-line standard of care1,2

Consider systemic treatment with NEXAVAR once LRT* is not a treatment option


Based on the results of the SHARP trial, 303 patients with unresectable HCC who were unsuitable for or who had progressed on locoregional therapy (LRT)* and were not given NEXAVAR (placebo arm) were shown to have a median survival of 7.9 months (95% CI, 6.8-9.1)


Potential treatment algorithm for patients with eligibility unresectable HCC1-3

NEXAVAR® (sorafenib) STIVARGA® (regorafenib) Treatment Algorithm

*Locoregional therapy (LRT) includes radiofrequency ablation, percutaneous ethanol injection, and transarterial chemoembolization (TACE).

NCCN guidelines list regorafenib if progression on or after sorafenib (Child-Pugh class A only).

  • Patients who permanently discontinued sorafenib therapy due to toxicity or who were unable to tolerate sorafenib doses of 400 mg once daily were ineligible for the RESORCE trial
    • RESORCE (REgorafenib after SORafenib in patients with hepatoCEllular carcinoma) was an international, multicenter, randomized (2:1), double-blind, placebo-controlled phase III trial that evaluated the efficacy and safety of STIVARGA in HCC patients with progression following NEXAVAR.2,4

INDICATION for STIVARGA® (regorafenib)

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

IMPORTANT SAFETY INFORMATION for STIVARGA (regorafenib)

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.

Selecting the appropriate patients for NEXAVAR

NEXAVAR® (sorafenib) Phase III Trial Patient Inclusion Criteria

ECOG, Eastern Cooperative Oncology Group.

Previous therapies for unresectable HCC that patients in the SHARP trial had received included (NEXAVAR and placebo, respectively): surgical resection (19.1% vs 20.5%), LRT* (38.8% vs 40.6%), radiotherapy (4.3% vs 5.0%), and systemic therapy (3.0% vs 5.0%)

Clinical guidelines can be used to identify appropriate patients for NEXAVAR® (sorafenib)

Selecting the appropriate patient with unresectable HCC for NEXAVAR

*LRT includes radiofrequency ablation, percutaneous ethanol injection, and TACE.

NEXAVAR® (sorafenib) Patient Types and Case Studies

Indications

NEXAVAR is indicated for the treatment of patients with unresectable hepatocellular carcinoma (HCC).

NEXAVAR is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

NEXAVAR is indicated for the treatment of patients with locally recurrent or metastatic, progressive, differentiated thyroid carcinoma (DTC) that is refractory to radioactive iodine treatment.

Important Safety Information

For important risk and use information about NEXAVAR, please see the full Prescribing Information.

INDICATION and IMPORTANT SAFETY INFORMATION for STIVARGA® (regorafenib)

INDICATION

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 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 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 (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% vs 0.2%) 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: Treatment with STIVARGA should be stopped at least 2 weeks prior to scheduled surgery. Resuming treatment after surgery should be based on clinical judgment of adequate wound healing. STIVARGA should be discontinued in patients with wound dehiscence.

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 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 about STIVARGA, please see the full Prescribing Information including the Boxed Warning.

You are encouraged to report negative side effects or quality complaints of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

REFERENCES:

1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines® ) for Hepatobiliary Cancers. V.3.2017. © National Comprehensive Cancer Network, Inc. 2017. All rights reserved. Accessed August 29, 2017. To view the most recent and complete version of the guideline, go online to NCCN.org. 2. Bruix J, Sherman M, for the American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53(3):1020-1022. 3. Llovet JM, Ricci S, Mazzaferro V, et al; for the SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378-390. 4. STIVARGA Prescribing Information. Whippany, NJ: Bayer HealthCare Pharmaceuticals, Inc. April 2017. 5. Data on file. Bayer HealthCare Pharmaceuticals, Inc. November 2007-May 2016.