WHIPPANY, N.J., May 4, 2016 /PRNewswire/ -- Bayer today
announced that a Phase III trial evaluating its oncology compound
Stivarga® (regorafenib) tablets for the treatment of
patients with unresectable hepatocellular carcinoma (HCC) has met
its primary endpoint of a statistically significant improvement in
overall survival. The study, called RESORCE, evaluated the efficacy
and safety of regorafenib in patients with HCC whose disease has
progressed after treatment with sorafenib. The safety and
tolerability were generally consistent with the known profile of
regorafenib. Detailed efficacy and safety analyses from this
study are expected to be presented at an upcoming scientific
congress.
"Effective treatment options are urgently needed for patients
with unresectable liver cancer," said Dr. Joerg Moeller, member of the Executive Committee
of Bayer AG's Pharmaceutical Division and Head of Development.
"With sorafenib having been the only systemic option for the
treatment of unresectable HCC since 2007, regorafenib could now
become the second proven systemic option. We would like to thank
the patients and the study investigators for their contributions
and participation in this study."
Bayer plans to submit data from the RESORCE study as the basis
for marketing authorization of regorafenib in the treatment of
unresectable HCC in 2016.
About the Phase III Study
The RESORCE [REgorafenib
after SORafenib in patients with hepatoCEllular carcinoma] clinical
trial is a randomized, double blind, placebo controlled,
multicenter Phase III study of regorafenib in patients with
hepatocellular carcinoma (HCC) whose disease has progressed after
treatment with sorafenib. The trial enrolled approximately 573
patients who were randomized in a 2:1 ratio to receive either
regorafenib plus best supportive care (BSC) or placebo plus
BSC.
Patients received 160 mg regorafenib once daily, for 3 weeks
on/1week off, or placebo with 28 days constituting one full
treatment cycle. The primary endpoint of the study was overall
survival, and secondary efficacy endpoints were time to
progression, progression-free survival, objective tumor response
rate and disease control rate. Safety and tolerability of patients
were continuously monitored.
About Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC) is the most common form of liver
cancer and represents 70-85 percent of liver cancer
worldwide.1 Liver cancer is the sixth most common cancer
in the world and the second leading cause of cancer-related deaths
globally.2 More than 780,000 cases of liver cancer are
diagnosed worldwide each year (more than 395,000 in China, 52,000 in the European Union, and
30,000 in the United States) and
the incidence rate is increasing.2,3 In 2012,
approximately 746,000 people died of liver cancer including
approximately 383,000 in China,
48,000 in the European Union, and 24,000 in the United States.2
About Stivarga (regorafenib)
In the United States, 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 KRAS 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.4
Stivarga is a compound developed by Bayer. In 2011, Bayer
entered into an agreement with Onyx Pharmaceuticals, Inc., now an
Amgen subsidiary (NASDAQ: AMGN), under which Onyx receives a
royalty on all global net sales of Stivarga in oncology.
Important Safety Information for Stivarga®
(regorafenib) tablets:
WARNING: HEPATOTOXICITY
- Severe and sometimes fatal hepatotoxicity has been observed
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 0.3% of 1200 Stivarga-treated
patients across all clinical trials. 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; all
the patients with hepatic failure had metastatic disease in the
liver. In gastrointestinal stromal tumor (GIST), fatal hepatic
failure occurred in 0.8% of patients in the Stivarga arm.
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.
Hemorrhage: Stivarga caused an increased incidence of
hemorrhage. The overall incidence (Grades 1-5) was 21% and 11% with
Stivarga vs 8% and 3% with placebo in mCRC and GIST patients,
respectively. Fatal hemorrhage occurred in 4 of 632 (0.6%)
Stivarga-treated patients and involved 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.
Dermatological Toxicity: Stivarga caused an increased
incidence of hand-foot skin reaction (HFSR) (also known as
palmar-plantar erythrodysesthesia [PPE]) and severe rash,
frequently requiring dose modification. The overall incidence was
45% and 67% with Stivarga vs 7% and 12% with placebo in mCRC and
GIST patients, respectively. Incidence of Grade 3 HFSR (17% vs 0%
in mCRC and 22% vs 0% in GIST), Grade 3 rash (6% vs <1% in mCRC
and 7% vs 0% in GIST), serious adverse reactions of erythema
multiforme (0.2% vs 0% in mCRC), and Stevens-Johnson syndrome (0.2%
vs 0% in mCRC) was higher in Stivarga-treated patients. Toxic
epidermal necrolysis occurred in 0.17% of 1200 Stivarga-treated
patients across all clinical trials. Withhold Stivarga, reduce the
dose, or permanently discontinue depending on the severity and
persistence of dermatologic toxicity.
Hypertension: Stivarga caused an increased incidence of
hypertension (30% vs 8% in mCRC and 59% vs 27% in GIST with
Stivarga vs placebo, respectively). Hypertensive crisis occurred in
0.25% of 1200 Stivarga-treated patients across all clinical 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 in mCRC (1.2% with
Stivarga vs 0.4% with placebo). 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 Laukoencephalopathy Syndrome (RPLS):
Reversible Posterior Leukoencephalopathy Syndrome (RPLS) occurred
in 1 of 1200 Stivarga-treated patients across all clinical trials.
Perform an evaluation for RPLS in any patient presenting with
seizures, headache, visual disturbances, confusion, or altered
mental function. Confirm the diagnosis of RPLS with MRI and
discontinue Stivarga in patients who develop RPLS.
Gastrointestinal Perforation or Fistula: Gastrointestinal
perforation or fistula occurred in 0.6% of 1200 patients treated
with Stivarga across clinical trials. In GIST, 2.1% (4/188) of
Stivarga-treated patients developed gastrointestinal fistula or
perforation: of these, 2 cases of gastrointestinal perforation were
fatal. Permanently discontinue Stivarga in patients who develop
gastrointestinal perforation or fistula.
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. Use effective contraception
during treatment and up to 2 months after completion of therapy. If
this drug is used during pregnancy, or if the patient becomes
pregnant while taking this drug, the patient should be apprised of
the potential hazard to the fetus.
Nursing Mothers: Because many drugs are excreted in human
milk and because of the potential for serious adverse reactions in
nursing infants from Stivarga, a decision should be made whether to
discontinue nursing or discontinue the drug, taking into account
the importance of the drug to the mother.
Most Frequently Observed Adverse Drug Reactions in mCRC:
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%), 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:
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%), 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%).
For full prescribing information, including the Boxed
Warning, visit
http://labeling.bayerhealthcare.com/html/products/pi/Stivarga_PI.pdf.
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 that is refractory to
radioactive iodine treatment.
Important Safety Considerations For NEXAVAR®
(sorafenib) Tablets
- NEXAVAR is contraindicated in patients with known severe
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%).There was no Grade 4 bleeding reported and there was one
fatal hemorrhage in a placebo-treated patient. If bleeding
necessitates medical intervention, consider permanent
discontinuation of NEXAVAR. Due to the potential risk of bleeding,
tracheal, bronchial, and esophageal infiltration should be treated
with local therapy prior to administering NEXAVAR in patients with
DTC
- 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 and 12.4% 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
- In a subset analysis of two randomized controlled trials in
chemo-naïve patients with Stage IIIB-IV non-small cell lung cancer,
patients with squamous cell carcinoma experienced higher mortality
with the addition of NEXAVAR compared to those treated with
carboplatin/paclitaxel alone (HR 1.81, 95% CI 1.19–2.74) and
gemcitabine/cisplatin alone (HR 1.22, 95% CI 0.82-1.80). 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 a
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. For patients with
impaired TSH suppression while receiving NEXAVAR, the median
maximal TSH was 1.6 mU/L and 25% had TSH levels greater than 4.4
mU/L. 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%), and
hypocalcemia (36% vs. 11%).The relative increase for the following
laboratory abnormalities observed in NEXAVAR-treated DTC patients
as compared to placebo-treated patients is similar to that observed
in the RCC and HCC studies: lipase, amylase, hypokalemia,
hypophosphatemia, neutropenia, lymphopenia, anemia, and
thrombocytopenia
- 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%
For full prescribing information, visit
http://labeling.bayerhealthcare.com/html/products/pi/Nexavar_PI.pdf.
About Oncology at Bayer
Bayer is committed to
delivering science for a better life by advancing a portfolio of
innovative treatments. The oncology franchise at Bayer now 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 2015, the Group
employed around 117,000 people and had sales of EUR 46.3 billion. Capital expenditures amounted
to EUR 2.6 billion, R&D expenses
to EUR 4.3 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.
Bayer® and the Bayer Cross® are registered
trademarks of Bayer.
Intended for U.S. Media Only
Forward-Looking Statements
This release may contain forward-looking statements based on
current assumptions and forecasts made by Bayer 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.
____________________________________________________
- Jemal A, Bray F, Center M, et. al. Global Cancer Statistics. CA
Cancer J Clin. 2011;61:69–90.
- GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and
Prevalence Worldwide in 2012.
http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Accessed on
April 25, 2016
- American Cancer Society. Liver Cancer. 2016.
http://www.cancer.org/acs/groups/cid/documents/webcontent/003114-pdf.pdf.
Accessed April 25, 2016.
- STIVARGA® (regorafenib) [Prescribing Information]. Whippany, NJ: Bayer HealthCare
Pharmaceuticals, April 2015.
- NEXAVAR® (sorafenib) [Prescribing Information]. Whippany, NJ: Bayer HealthCare
Pharmaceuticals, November 2013.
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