WHIPPANY, N.J. and SOUTH SAN FRANCISCO, Calif., July 25, 2014 /PRNewswire/ -- Bayer HealthCare and Onyx Pharmaceuticals Inc., an Amgen subsidiary (NASDAQ: AMGN), today announced that an investigational Phase 3 trial of NEXAVAR® (sorafenib) tablets in patients with advanced breast cancer did not meet its primary endpoint of improving progression-free survival (PFS).
The study, called RESILIENCE, evaluated the efficacy and safety of sorafenib in combination with capecitabine, an oral chemotherapeutic agent, compared to placebo plus capecitabine, in patients with HER2-negative breast cancer who are resistant to or have failed prior taxane therapy, and resistant to or failed anthracycline or for whom further anthracycline therapy is not indicated. Based on initial review of the data, the types of adverse events observed were generally comparable with those known for either sorafenib or capecitabine. Data from this study are expected to be presented at an upcoming scientific congress.
"We are disappointed that the trial did not show an improvement in progression-free survival in patients with advanced breast cancer," said Dr. Joerg Moeller, Member of the Bayer HealthCare Executive Committee and Head of Global Development. "While the primary endpoint of this trial was not met, the trial results do not affect the currently approved indications for NEXAVAR. We would like to thank the patients and the study investigators for their contributions and participation in this study."
Phase 3 Trial Design
The RESILIENCE (Phase 3 TRial Comparing CapecitabinE in Combination with SorafenIb or PLacebo for Treatment of Locally Advanced or MetastatIc HER2–Negative Breast CancEr) trial was a randomized, double-blind, placebo-controlled Phase III study which enrolled 537 patients in more than 20 countries, including the United States, Europe, Japan and Australia. The study evaluated sorafenib in combination with capecitabine in patients with locally advanced or metastatic HER2-negative breast cancer who are resistant to or failed prior taxane therapy, and resistant to or failed anthracycline or for whom further anthracycline is not indicated.
The primary endpoint of the study was progression-free survival. Secondary endpoints included overall survival, time to progression, overall response rate, disease control rate, duration of response, patient reported quality of life and safety. Patients were randomized to receive either 600 mg of oral sorafenib or matching placebo daily on a continuous schedule, in addition to 1,000 mg/m2 of capecitabine twice daily for 14 days of a 21 day cycle.
About NEXAVAR® (sorafenib) Tablets
NEXAVAR is approved in the U.S. for the treatment of patients with unresectable hepatocellular carcinoma, patients with advanced renal cell carcinoma and patients with locally recurrent or metastatic, progressive, differentiated thyroid carcinoma refractory to radioactive iodine treatment. NEXAVAR is thought to inhibit both the tumor cell and tumor vasculature. In in vitro studies, NEXAVAR has been shown to inhibit multiple kinases thought to be involved in both cell proliferation (growth) and angiogenesis (blood supply) – two important processes that enable cancer growth. These kinases include Raf kinase, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-B, KIT, FLT-3 and RET.
NEXAVAR is currently approved in more than 100 countries. NEXAVAR is also being evaluated by Bayer and Onyx, international study groups, government agencies and individual investigators in a range of cancers.
NEXAVAR is co-developed by Onyx and Bayer, except in Japan where Bayer manages all development. The companies co-promote NEXAVAR in the U.S. Outside of the U.S. Bayer has exclusive marketing rights, and Bayer and Onyx share profits globally, excluding Japan.
Important Safety Considerations For NEXAVAR® (sorafenib) Tablets
NEXAVAR is contraindicated in patients with known hypersensitivity to sorafenib or any other component of NEXAVAR.
NEXAVAR in combination with carboplatin and paclitaxel is contraindicated in patients with squamous cell lung cancer.
Cardiac ischemia and/or myocardial infarction may occur. The incidence of cardiac ischemia/infarction in NEXAVAR-treated vs placebo-treated patients was 2.7% vs 1.3%, 2.9% vs 0.4%, and 1.9% vs 0% in the HCC, RCC, and DTC studies, respectively. Temporary or permanent discontinuation of NEXAVAR should be considered in patients who develop cardiac ischemia and/or myocardial infarction.
An increased risk of bleeding may occur following NEXAVAR administration. The following bleeding adverse reactions were reported in the NEXAVAR-treated vs placebo-treated patients, respectively, in the HCC study: bleeding from esophageal varices (2.4% vs 4%) and bleeding with fatal outcome at any site (2.4% vs 4%); in the RCC study: bleeding regardless of causality (15.3% vs 8.2%), Grade 3 bleeding (2.0% vs 1.3%), Grade 4 bleeding (0% vs 0.2%), and one fatal hemorrhage in each treatment group; in the DTC study: bleeding (17.4% vs 9.6%) and Grade 3 bleeding (1% vs 1.4%). If bleeding necessitates medical intervention, consider permanent discontinuation of NEXAVAR.
Monitor blood pressure weekly during the first 6 weeks and periodically thereafter, and treat, if required. In the HCC study, hypertension was reported in approximately 9.4% of NEXAVAR treated patients and 4.3% of patients in the placebo-treated group. In the RCC study, hypertension was reported in approximately 16.9% of NEXAVAR treated patients and 1.8% of patients in the placebo treated group. In the DTC study, hypertension was reported in 40.6% of NEXAVAR-treated patients and12.4% of the placebo-treated patients. Hypertension was usually mild to moderate, occurred early in the course of treatment, and was managed with standard antihypertensive therapy. In cases of severe or persistent hypertension despite institution of antihypertensive therapy, consider temporary or permanent discontinuation of NEXAVAR.
Hand-foot skin reaction and rash are the most common adverse reactions attributed to NEXAVAR.Management may include topical therapies for symptomatic relief. In cases of any severe or persistent adverse reactions, temporary treatment interruption, dose modification, or permanent discontinuation of NEXAVAR should be considered. There have been reports of severe dermatologic toxicities, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). These cases may be life-threatening. Discontinue NEXAVAR if SJS or TEN are suspected.
Gastrointestinal perforation was an uncommon adverse reaction and has been reported in less than 1% of patients taking NEXAVAR. Discontinue NEXAVAR in the event of a gastrointestinal perforation.
Infrequent bleeding or elevations in the International Normalized Ratio (INR) have been reported in some patients taking warfarin while on NEXAVAR. Monitor patients taking concomitant warfarin regularly for changes in prothrombin time (PT), INR, or clinical bleeding episodes.
Temporary interruption of NEXAVAR therapy is recommended in patients undergoing major surgical procedures.
NEXAVAR, in combination with gemcitabine/cisplatin, is not recommended in patients with squamous cell lung cancer. The safety and effectiveness of NEXAVAR has not been established in patients with non-small cell lung cancer.
NEXAVAR can prolong the QT/QTc interval and increase the risk for ventricular arrhythmias. Avoid use in patients with congenital long QT syndrome and monitor electrolytes and electrocardiograms in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities. Correct electrolyte abnormalities (magnesium, potassium, calcium). Interrupt NEXAVAR if QTc interval is greater than 500 milliseconds or for an increase from baseline of 60 milliseconds or greater.
Sorafenib-induced hepatitis is characterized by hepatocellular pattern of liver damage with significant increases of transaminases which may result in hepatic failure and death. Increases in bilirubin and INR may also occur. Liver function tests should be monitored regularly and in cases of increased transaminases without alternative explanation NEXAVAR should be discontinued.
NEXAVAR may cause fetal harm when administered to a pregnant woman. Women of child-bearing potential should be advised to avoid becoming pregnant while on NEXAVAR.
Female patients should be advised against breastfeeding while receiving NEXAVAR.
In DTC, NEXAVAR impairs exogenous thyroid suppression. Elevation of thyroid stimulating hormone (TSH) level above 0.5 mU/L was observed in 41% of NEXAVAR-treated patients as compared with 16% of placebo-treated patients in the DTC study. Monitor TSH levels monthly and adjust thyroid replacement medication as needed in patients with DTC.
In the HCC study, the most common laboratory abnormalities observed in the NEXAVAR arm versus the placebo arm, respectively, were hypoalbuminemia (59% vs. 47%), lymphopenia (47% vs. 42%), thrombocytopenia (46% vs. 41%), elevation in INR (42% vs. 34%), elevated lipase (40% vs. 37%), hypophosphatemia (35% vs. 11%), elevated amylase (34% vs. 29%), hypocalcemia (27% vs. 15%), and hypokalemia (9.5% vs. 5.9%).
In the RCC study, the most common laboratory abnormalities observed in the NEXAVAR arm versus the placebo arm, respectively, were hypophosphatemia (45% vs. 11%), anemia (44% vs. 49%), elevated lipase (41% vs. 30%), elevated amylase (30% vs. 23%), lymphopenia (23% vs. 13%), neutropenia (18% vs. 10%), thrombocytopenia (12% vs. 5%), hypocalcemia (12% vs. 8%), and hypokalemia (5.4% vs. 0.7%).
In the DTC study, the most common laboratory abnormalities observed in the NEXAVAR arm versus the placebo arm, respectively, were elevated ALT (59% vs. 24%), elevated AST (54% vs. 15%), hypocalcemia (36% vs. 11%).
Avoid concomitant use of strong CYP3A4 inducers, when possible, because inducers can decrease the systemic exposure of sorafenib. NEXAVAR exposure decreases when co-administered with oral neomycin. Effects of other antibiotics on NEXAVAR pharmacokinetics have not been studied.
Most common adverse reactions reported for NEXAVAR-treated patients vs placebo-treated patients in unresectable HCC, respectively, were: diarrhea (55% vs. 25%), fatigue (46% vs. 45%), abdominal pain (31% vs. 26%), weight loss (30% vs. 10%), anorexia (29% vs. 18%), nausea (24% vs. 20%), and hand-foot skin reaction (21% vs. 3%). Grade 3/4 adverse reactions were 45% vs. 32%.
Most common adverse reactions reported for NEXAVAR-treated patients vs placebo-treated patients in advanced RCC, respectively, were: diarrhea (43% vs. 13%), rash/desquamation (40% vs. 16%), fatigue (37% vs. 28%), hand-foot skin reaction (30% vs. 7%), alopecia (27% vs. 3%),and nausea (23% vs. 19%). Grade 3/4 adverse reactions were 38% vs. 28%.
Most common adverse reactions reported for NEXAVAR-treated patients vs placebo-treated patients in DTC, respectively, were: Palmar-plantar erythrodysesthesia syndrome (PPES) (69% vs. 8%), diarrhea (68% vs. 15%), alopecia (67% vs. 8%), weight loss (49% vs. 14%), fatigue (41% vs. 20%), hypertension (41% vs. 12%), rash (35% vs. 7%), decreased appetite (30% vs. 5%), stomatitis (24% vs. 3%), nausea (21% vs. 12%), pruritus (20% vs. 11%), and abdominal pain (20% vs. 7%). Grade 3/4 adverse reactions were 65% vs. 30%.
About Bayer HealthCare Pharmaceuticals Inc.
Bayer HealthCare Pharmaceuticals Inc. is the U.S.-based pharmaceuticals business of Bayer HealthCare LLC, a subsidiary of Bayer AG. Bayer HealthCare is one of the world's leading, innovative companies in the healthcare and medical products industry, and combines the activities of the Animal Health, Consumer Care, Medical Care, and Pharmaceuticals divisions. As a specialty pharmaceutical company, Bayer HealthCare Pharmaceuticals Inc. provides products for General Medicine, Hematology, Neurology, Oncology and Women's Healthcare. The company's aim is to discover and manufacture products that will improve human health worldwide by diagnosing, preventing and treating diseases.
About Amgen
Amgen is committed to unlocking the potential of biology for patients suffering from serious illnesses by discovering, developing, manufacturing and delivering innovative human therapeutics. This approach begins by using tools like advanced human genetics to unravel the complexities of disease and understand the fundamentals of human biology.
Amgen focuses on areas of high unmet medical need and leverages its biologics manufacturing expertise to strive for solutions that improve health outcomes and dramatically improve people's lives. A biotechnology pioneer since 1980, Amgen has grown to be the world's largest independent biotechnology company, has reached millions of patients around the world and is developing a pipeline of medicines with breakaway potential.
For more information, visit www.amgen.com and follow us on www.twitter.com/amgen.
About Onyx Pharmaceuticals, Inc.
Based in South San Francisco, California, Onyx Pharmaceuticals, Inc., an Amgen subsidiary, is a biopharmaceutical company engaged in the development and commercialization of innovative therapies for improving the lives of people with cancer. The company is focused on developing novel medicines that target key molecular pathways. For more information about Onyx, visit the company's website at www.onyx.com. Onyx Pharmaceuticals is on Twitter. Sign up to follow our Twitter feed @OnyxPharm at http://twitter.com/OnyxPharm.
Forward Looking Statements
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The scientific information discussed in this news release relating to new indications for Amgen's products is preliminary and investigative and is not part of the labeling approved by the U.S. Food and Drug Administration (FDA) for the products. The products are not approved for the investigational use(s) discussed in this news release, and no conclusions can or should be drawn regarding the safety or effectiveness of the products for these uses.
NEXAVAR® is a registered trademark of Bayer.
SOURCE Bayer HealthCare; Onyx Pharmaceuticals, Inc.