Bayer Receives FDA Approval for Stivarga® (regorafenib) for the Second-Line Systemic Treatment of Liver Cancer

WHIPPANY, N.J., April 27, 2017 /PRNewswire/ -- Bayer announced today that the U.S. Food and Drug Administration (FDA) approved Stivarga^® (regorafenib) tablets for the second-line treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with Nexavar^® (sorafenib).² Stivarga is the first and only treatment to demonstrate significant improvement in overall survival in second-line HCC patients.² In the RESORCE trial, Stivarga was shown to provide a statistically significant and clinically meaningful improvement in overall survival (OS) versus placebo; the median OS was 10.6 [(n=379) (CI 9.1, 12.1)] vs 7.8 [(n=194) (CI 6.3, 8.8)] months, respectively (HR 0.63, 95% CI 0.50-0.79; p<0.0001).² This translates to a 37% reduction in the risk of death. The number of deaths in each arm included 233 of 379 (62%) with Stivarga and 140 of 194 (72%) with placebo.²  Today's FDA approval expands Bayer's leadership in liver cancer with a treatment plan in HCC involving use of Stivarga directly after progression on Nexavar.²

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Stivarga is an oral inhibitor of multiple kinases involved in normal cellular functioning and in pathological processes such as oncogenesis, tumor angiogenesis, metastasis and tumor immunity.² The FDA's approval is based on data from the international, multicenter, placebo-controlled Phase III RESORCE [REgorafenib after SORafenib in patients with hepatoCEllular carcinoma; NCT 01774344] trial, which investigated patients with HCC whose disease had progressed during treatment with Nexavar.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/PPE (51% vs 7%), pain (55% vs 44%), 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%).²

"Bayer is proud to have played a significant role in the treatment of hepatocellular carcinoma," said Robert LaCaze, executive vice president and head of the Oncology Strategic Business Unit at Bayer. "We first embarked on our scientific research in this area 20 years ago and we have remained steadfast in our mission to deliver new treatment options to these patients. We could not have done it alone: we would like to thank the patients, caregivers and investigators for their participation and engagement in the study."

Thomas F. Nealon III, national board chair and chief executive officer of the American Liver Foundation, commented, "Given that the incidence of liver cancer continues to rise,³ we applaud the efforts of Bayer and the RESORCE study investigators for ushering in this much-needed treatment option for patients with liver cancer."

The approval of Stivarga in liver cancer marks the third time that this therapy has been granted FDA approval on a priority basis. The FDA granted Fast Track designation to Stivarga in this indication, which is an expedited program designed to facilitate development and review of drugs to address unmet medical need in the treatment of a serious or life-threatening condition. The FDA also granted Orphan Drug Designation (ODD) to Stivarga in HCC. The ODD program provides orphan status to drugs and biologics which are defined as those intended for the safe and effective treatment, diagnosis or prevention of rare diseases and disorders.

Additional regulatory filings for Stivarga in HCC are under review in countries around the world, including the EU, Japan and China. Decisions in the EU and Japan are expected later in this year.

About Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC) is the most common form of liver cancer and represents approximately three quarters of liver cancers in the United States.⁴ It is estimated that more than 40,000 people in the U.S. will be diagnosed with liver cancer in 2017.⁴ Liver cancer is still on the rise and death rates are increasing faster than any other type of cancer.³ In the United States, the incidence of liver cancer has more than tripled since 1980 and nearly 29,000 deaths from liver cancer are expected in 2017.⁴ In 2012, 782,000 men and women were diagnosed with liver cancer and approximately 746,000 people died of liver cancer worldwide.⁵ Globally, it is the second leading cause of cancer-related deaths.⁵

About Stivarga^® (regorafenib)
In April 2017, Stivarga was approved for use in patients with hepatocellular carcinoma who have been previously treated with Nexavar.² In the United States, Stivarga is also 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. It is also 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.²

Regorafenib is a compound developed by Bayer. In 2011, Bayer entered into an agreement with Onyx, now an Amgen subsidiary, under which Onyx receives a royalty on all global net sales of regorafenib in oncology.

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 subcortial 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.

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 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%).

Please see full Prescribing Information, including Boxed Warning.

About Oncology at Bayer
Bayer is committed to delivering science for a better life by advancing a portfolio of innovative treatments. Bayer is a global leader in the management and treatment of hepatocellular carcinoma. The oncology franchise at Bayer includes three oncology products and several other compounds in various stages of clinical development. Together, these products reflect the company's approach to research, which prioritizes targets and pathways with the potential to impact the way that cancer is treated.

Bayer: Science For A Better Life
Bayer is a global enterprise with core competencies in the Life Science fields of health care and agriculture. Its products and services are designed to benefit people and improve their quality of life. At the same time, the Group aims to create value through innovation, growth and high earning power. Bayer is committed to the principles of sustainable development and to its social and ethical responsibilities as a corporate citizen. In fiscal 2016, the Group employed around 115,200 people and had sales of EUR 46.8 billion. Capital expenditures amounted to EUR 2.6 billion, R&D expenses to EUR 4.7 billion. These figures include those for the high-tech polymers business, which was floated on the stock market as an independent company named Covestro on October 6, 2015. For more information, go to www.bayer.us.

© 2017 Bayer
BAYER, the Bayer Cross, Stivarga and Nexavar are registered trademarks of Bayer.

Media Contact:
Rose Talarico, Tel. +1 862.404.5302
E-Mail: [email protected]

Forward-Looking Statement
This news release may contain forward-looking statements based on current assumptions and forecasts made by Bayer Group or subgroup management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performance of the company and the estimates given here. These factors include those discussed in Bayer's public reports which are available on the Bayer website at  www.bayer.com. The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments.

1. U.S. Food and Drug Administration website. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm555608.htm. Accessed April 2017.
2. STIVARGA^® (regorafenib) [Prescribing Information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, April 2017.
3. Ryerson, A. B., et al (2016), Annual Report to the Nation on the Status of Cancer, 1975-2012, featuring the increasing incidence of liver cancer. Cancer, 122: 1312–1337. doi:10.1002/cncr.29936. https://seer.cancer.gov/report_to_nation/. Accessed April 2017.
4. American Cancer Society. Liver Cancer. 2017. https://www.cancer.org/cancer/liver-cancer.html. Accessed April 2017.
5. GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012. http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Accessed April 2017.

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