INDIANAPOLIS, Jan. 18, 2019 /PRNewswire/ -- Eli Lilly and
Company (NYSE: LLY) announced that results from the global Phase 3
REACH-2 study of CYRAMZA® (ramucirumab) as a single
agent in the second-line treatment of people with AFP-High
(alpha-fetoprotein ≥400 ng/mL) hepatocellular carcinoma (HCC) were
published online today in The Lancet Oncology. Data from
REACH-2 are also being presented today at the 2019 Gastrointestinal
Cancers Symposium in San
Francisco. HCC is also known as liver cancer, which is a
leading cause of cancer-related death worldwide.1 In the
U.S., liver cancer is one of the few major cancers with incidence
rates that continue to rise every year2 and is the
fastest rising cause of cancer death.3
REACH-2 showed a statistically significant improvement in the
primary endpoint of overall survival (OS) as well as in the
secondary endpoint of progression-free survival (PFS). The safety
profile observed in the REACH-2 study was consistent with what has
been previously observed for single-agent CYRAMZA in patients
with HCC. Additionally, in a pooled analysis comprised of all
AFP-High HCC patients across both the REACH-2 and REACH studies,
CYRAMZA treatment also resulted in an improvement in median OS.
"AFP has been used as a prognostic factor for hepatocellular
carcinoma for decades. Some studies have suggested that
AFP-producing tumors have an aggressive phenotype and increased
angiogenesis," said Andrew X. Zhu,
M.D., Director of Liver Cancer Research at Massachusetts General
Hospital Cancer Center, Professor of Medicine at Harvard Medical School, and principal investigator
of the REACH-2 and REACH trials. "These results not only further
add to the body of evidence that poor prognosis tumors with
elevated AFP may have a distinct biology, but also show a tailored
treatment approach is feasible."
REACH-2, the first positive Phase 3 HCC trial in a
biomarker-selected patient population, evaluated the benefit of
CYRAMZA treatment in AFP-High HCC patients who were intolerant to,
or had disease progression while on or following treatment with,
sorafenib. Approximately half of all advanced HCC patients are
AFP-High, and these patients are among those with the poorest
prognosis relative to the general HCC patient population.
On the primary endpoint of OS, treatment with CYRAMZA
significantly improved the OS of patients compared to placebo (HR
0.71; 95% CI, 0.53-0.95; P=0.02). The median OS was 8.5 months with
CYRAMZA (95% CI, 7.0-10.6), compared to 7.3 months with placebo
(95% CI, 5.4-9.1). On the secondary endpoint of PFS, median PFS was
significantly improved with CYRAMZA (2.8 months [95% CI, 2.8-4.1]
vs. 1.6 months for placebo [95% CI, 1.5-2.7]) (HR 0.45; 95% CI,
0.34-0.60; P<0.0001). Objective response rate (ORR) was
numerically higher with CYRAMZA compared to placebo (4.6% vs. 1.1%;
P=0.1697). Disease control rate (ORR + stable disease) was higher
with CYRAMZA than with placebo (59.9% vs. 38.9%).
In a pooled analysis of AFP-High patients (n=542) from REACH-2
and REACH, which provided a larger data set to assess outcomes in
this particular patient population, CYRAMZA improved OS compared to
placebo (HR 0.69; 95% CI, 0.57-0.84; P=0.0002), and an improvement
of 3.1 months in median OS was observed (8.1 and 5.0 months with
CYRAMZA and placebo, respectively). The HR for OS across all
pre-specified pooled subgroup analyses favored the CYRAMZA
treatment arm. PFS, ORR and disease control rate were consistent
with those in REACH and REACH-2, and supported the pooled OS
result.
"Demonstrating a significant improvement in survival for this
group of patients with advanced liver cancer and elevated AFP is
particularly exciting as these patients have the poorest prognosis
– with an expected survival of only a few months following
first-line treatment if they don't go onto a second-line therapy.
Treatment options are still limited in second-line liver cancer,
and CYRAMZA is the first treatment specifically evaluated in this
biomarker-selected population of liver cancer patients," said
Maura Dickler, M.D., vice president,
late phase development, Lilly Oncology. "The published results of
REACH-2 demonstrate the potential for CYRAMZA to make an impact on
the treatment of people with this aggressive cancer, which is
encouraging for healthcare providers and the patient
community."
The safety profile observed in the REACH-2 study was consistent
with what has been previously observed for single-agent
CYRAMZA in patients with HCC. The Grade ≥3 adverse events
occurring at a rate of five percent or greater in the CYRAMZA arm
were hypertension and hyponatremia (low sodium).
These data were first presented at the 2018 Annual Meeting of
the American Society of Clinical Oncology (ASCO) and 2018 World
Congress on Gastrointestinal Cancer.
Lilly has made regulatory submissions in the U.S., European
Union and Japan based on the
REACH-2 results. CYRAMZA is not yet approved for the HCC
indication.
Notes to Editors
About REACH-2
REACH-2 is a global, randomized, double-blind,
placebo-controlled Phase 3 study of CYRAMZA and best
supportive care (BSC) compared to placebo and BSC in
hepatocellular carcinoma (HCC) patients who were intolerant to, or
who had disease progression while on or following treatment with,
sorafenib and had a high alpha-fetoprotein (AFP-High), defined
as an AFP of ≥400 ng/mL.
Initiated in 2015, the study has enrolled 292 patients across 20
countries in North America,
Asia, Europe and Latin
America. Patients were assigned to 8 mg/kg of intravenous
CYRAMZA (n=197) or placebo (n=95) at every two weeks until disease
progression, unacceptable toxicity, or withdrawal of consent, with
all patients receiving BSC. The primary endpoint of the REACH-2
trial is overall survival (OS) and key secondary endpoints include
progression-free survival, objective response rate, quality of life
and safety.
The design of the REACH-2 trial was based on the findings of the
Phase 3 REACH study,4 which also evaluated single-agent
CYRAMZA in the second-line treatment of HCC following first-line
treatment with sorafenib. The REACH trial's primary endpoint of OS
favored the CYRAMZA arm but was not statistically significant.
However, in the prespecified subgroup of patients with baseline
AFP-High treatment with CYRAMZA led to an improvement in OS (7.8
months versus 4.2 months in placebo; HR=0.674 (95% CI: 0.508,
0.895)). No OS benefit was observed in patients with baseline AFP
<400 ng/mL (OS HR=1.093; 95% CI: 0.836, 1.428). The OS result in
the subgroup with AFP-High was supported by improvements in key
secondary endpoints and a safety profile consistent with what has
been previously observed for single-agent CYRAMZA.
About REACH
REACH is a global, randomized,
double-blind Phase 3 study of CYRAMZA plus best supportive care
compared to placebo plus best supportive care as a second-line
treatment in patients with hepatocellular carcinoma who have been
previously treated with sorafenib in the first-line setting.
Initiated in 2010, the study enrolled 565 patients across 27
countries; as defined in the trial protocol, the primary analyses
are focused on patients with a Child-Pugh score of <7
(Child-Pugh Class A only). The primary endpoint of the REACH trial
was overall survival and key secondary endpoints include:
progression-free survival; objective response rate; time to
progression; and safety.
About Alpha-Fetoprotein
Alpha-fetoprotein (AFP) is a
glycoprotein that is produced in early fetal life by the liver and
by a variety of tumors including HCC, hepatoblastoma, and
nonseminomatous germ cell tumors of the ovary and testis. A
person's AFP, measured in nanograms per milliliter (ng/mL), is
assessed through a blood test. An AFP level of less than 10
ng/mL is generally considered normal for
adults.5,6 It is estimated
that approximately half of all people with advanced HCC are
AFP-High (≥400 ng/mL) and these patients are known to have a poorer
prognosis relative to the general HCC patient
population.4
About Liver Cancer
Liver cancer is the sixth most common cancer worldwide and the
fourth-leading cause of cancer-related death. Each year an
estimated 841,080 new cases of liver cancer are diagnosed
worldwide, and an estimated 781,631 will die due to the
disease. According to the World Health Organization,
approximately 38,000 people are diagnosed with liver cancer, and
30,000 will die from the disease each year in the United States.1 Liver
cancer is one of the only major cancers with incidence rates that
continue to rise every year in the United
States2 and is the fastest rising cause of cancer
death.3 In Europe and
Japan, an estimated 82,000 and
36,000 people are diagnosed with liver cancer, and 77,000 and
29,000 will die, respectively.1
The prognosis for advanced HCC patients is typically very poor.
Surgery is not an option for the majority of advanced HCC patients,
as the tumor has often grown or metastasized to the extent that
resection is not feasible. Advanced HCC is a disease with few
approved systemic treatments, and most patients have significant
liver damage which can further limit therapy options. Once patients
who are AFP-High enter the second-line treatment setting, the
expected survival is three to five months if
untreated.4
Despite recent advances in the treatment of chronic liver
disease, the incidence of HCC is still expected to rise in the
coming decades due to several factors: under-diagnosis of chronic
liver disease; increasing prevalence of diabetes, obesity and fatty
liver disease; and, lack of access to viral hepatitis disease
therapy and the persistent risk of cancer even after viral
hepatitis cure.7
About Angiogenesis and VEGF Protein
Angiogenesis is
the process of making new blood vessels. In a person with cancer,
angiogenesis creates new blood vessels that give a tumor its own
blood supply, allowing it to grow and spread.
Some tumors create proteins called VEGF. These proteins attach
to the VEGF receptors of blood vessel cells causing new blood
vessels to form around the tumors, enabling growth. Blocking the
VEGF protein from linking to the blood vessels helps to inhibit
tumor growth by slowing angiogenesis and the blood supply that
feeds tumors. Of the three known VEGF receptors, VEGF Receptor 2 is
linked most closely to VEGF-induced tumor angiogenesis.
About CYRAMZA® (ramucirumab)
In the U.S.,
CYRAMZA (ramucirumab) is approved for use as a single agent or in
combination with paclitaxel as a treatment for people with advanced
or metastatic gastric (stomach) or gastroesophageal junction (GEJ)
adenocarcinoma whose cancer has progressed on or after prior
fluoropyrimidine- or platinum-containing chemotherapy. It is also
approved in combination with docetaxel as a treatment for people
with metastatic non-small cell lung cancer (NSCLC) whose cancer has
progressed on or after platinum-based chemotherapy. Additionally,
it is approved with FOLFIRI as a treatment for people with
metastatic colorectal cancer (mCRC) whose cancer has progressed on
or after therapy with bevacizumab, oxaliplatin, and a
fluoropyrimidine.
CYRAMZA is being investigated in a broad global development
program that has enrolled more than 14,000 patients across more
than 100 trials worldwide. These include several studies
investigating CYRAMZA in combination with other anti-cancer
therapies for the treatment of multiple tumor types.
CYRAMZA is an antiangiogenic therapy. It is a vascular
endothelial growth factor (VEGF) Receptor 2 antagonist that
specifically binds and blocks activation of VEGF Receptor 2 by
blocking the binding of VEGF receptor ligands VEGF-A, VEGF-C, and
VEGF-D. CYRAMZA inhibited angiogenesis in an in vivo animal
model.
INDICATIONS
Gastric Cancer
CYRAMZA, as a
single agent or in combination with paclitaxel, is indicated for
the treatment of patients with advanced or metastatic, gastric or
gastroesophageal junction (GEJ) adenocarcinoma with disease
progression on or after prior fluoropyrimidine- or
platinum-containing chemotherapy.
Non-Small Cell Lung Cancer
CYRAMZA, in combination
with docetaxel, is indicated for the treatment of patients with
metastatic non-small cell lung cancer (NSCLC) with disease
progression on or after platinum-based chemotherapy. Patients with
epidermal growth factor receptor (EGFR) or anaplastic lymphoma
kinase (ALK) genomic tumor aberrations should have disease
progression on FDA-approved therapy for these aberrations prior to
receiving CYRAMZA.
Colorectal Cancer
CYRAMZA, in combination with
FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil), is
indicated for the treatment of patients with metastatic colorectal
cancer (mCRC) with disease progression on or after prior therapy
with bevacizumab, oxaliplatin, and a fluoropyrimidine.
IMPORTANT SAFETY INFORMATION FOR CYRAMZA
WARNING:
HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND
IMPAIRED WOUND HEALING
Hemorrhage:
CYRAMZA increased the risk of hemorrhage and
gastrointestinal hemorrhage,
including severe and sometimes fatal hemorrhagic
events. Permanently discontinue CYRAMZA in
patients who experience severe bleeding.
Gastrointestinal
Perforation: CYRAMZA can increase the risk of gastrointestinal
perforation, a potentially fatal event. Permanently discontinue
CYRAMZA in patients who experience a gastrointestinal
perforation.
Impaired Wound
Healing: Impaired wound healing can occur with antibodies
inhibiting the VEGF pathway. Discontinue CYRAMZA therapy in
patients with impaired wound healing. Withhold CYRAMZA prior to
surgery and discontinue CYRAMZA if a patient develops wound healing
complications.
|
Warnings and Precautions
Hemorrhage
- In study 1, which evaluated CYRAMZA as a single agent in
advanced gastric cancer, the incidence of severe bleeding was 3.4%
for CYRAMZA and 2.6% for placebo. In study 2, which evaluated
CYRAMZA plus paclitaxel in advanced gastric cancer, the incidence
of severe bleeding was 4.3% for CYRAMZA plus paclitaxel and 2.4%
for placebo plus paclitaxel. Patients with gastric cancer receiving
nonsteroidal anti-inflammatory drugs (NSAIDs) were excluded from
enrollment in studies 1 and 2. In study 3, which evaluated CYRAMZA
plus docetaxel in metastatic non-small cell lung cancer (NSCLC),
the incidence of severe bleeding was 2.4% for CYRAMZA plus
docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC
receiving therapeutic anticoagulation or chronic therapy with
NSAIDs or other antiplatelet therapy other than once-daily aspirin
or with radiographic evidence of major airway or blood vessel
invasion or intratumor cavitation were excluded from study
3. In study 4, which evaluated CYRAMZA plus FOLFIRI in
metastatic colorectal cancer, the incidence of severe bleeding was
2.5% for CYRAMZA plus FOLFIRI and 1.7% for placebo plus FOLFIRI.
Permanently discontinue CYRAMZA in patients who experience severe
bleeding.
Arterial Thromboembolic Events (ATEs)
- Serious, sometimes fatal, ATEs including myocardial infarction,
cardiac arrest, cerebrovascular accident, and cerebral ischemia
occurred in clinical trials. Permanently discontinue CYRAMZA in
patients who experience a severe ATE.
Hypertension
- An increased incidence of severe hypertension occurred in
patients receiving CYRAMZA as a single agent (8%) as compared to
placebo (3%), in patients receiving CYRAMZA plus paclitaxel (15%)
as compared to placebo plus paclitaxel (3%), and in patients
receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus
docetaxel (2%), and in patients receiving CYRAMZA plus FOLFIRI
(11%) as compared to placebo plus FOLFIRI (3%). Monitor blood
pressure every 2 weeks or more frequently as indicated during
treatment. Temporarily suspend CYRAMZA for severe hypertension
until medically controlled. Permanently discontinue CYRAMZA if
medically significant hypertension cannot be controlled with
antihypertensive therapy or in patients with hypertensive crisis or
hypertensive encephalopathy.
Infusion-Related Reactions (IRRs)
- Prior to the institution of premedication recommendations
across clinical trials of CYRAMZA, IRRs occurred in 6 out of 37
patients (16%), including 2 severe events. The majority of IRRs
across trials occurred during or following a first or second
CYRAMZA infusion. Monitor patients during the infusion for signs
and symptoms of IRRs in a setting with available resuscitation
equipment. Immediately and permanently discontinue CYRAMZA for
grade 3 or 4 IRRs.
Gastrointestinal Perforations
- Four of 570 patients (0.7%) who received CYRAMZA as a single
agent in advanced gastric cancer clinical trials experienced
gastrointestinal perforation. In study 2, the incidence of
gastrointestinal perforation was 1.2% for CYRAMZA plus paclitaxel
as compared to 0.3% for placebo plus paclitaxel. In study 3, the
incidence of gastrointestinal perforation was 1% for CYRAMZA plus
docetaxel as compared to 0.3% for placebo plus docetaxel. In
study 4, the incidence of gastrointestinal perforation was 1.7% for
CYRAMZA plus FOLFIRI and 0.6% for placebo plus FOLFIRI. Permanently
discontinue CYRAMZA in patients who experience a gastrointestinal
perforation.
Impaired Wound Healing
- CYRAMZA has not been studied in patients with serious or
nonhealing wounds. CYRAMZA has the potential to adversely affect
wound healing. Discontinue CYRAMZA therapy in patients with
impaired wound healing. Withhold CYRAMZA prior to surgery. Resume
CYRAMZA following the surgical intervention based on clinical
judgment of adequate wound healing. If a patient develops wound
healing complications during therapy, discontinue CYRAMZA until the
wound is fully healed.
Clinical Deterioration in Child-Pugh B or C Cirrhosis
- Clinical deterioration, manifested by new onset or worsening
encephalopathy, ascites, or hepatorenal syndrome, was reported in
patients with Child-Pugh B or C cirrhosis who received single-agent
CYRAMZA.
Reversible Posterior Leukoencephalopathy Syndrome
(RPLS)
- RPLS has been reported at a rate of <0.1% in clinical
studies with CYRAMZA. Discontinue CYRAMZA in patients who develop
RPLS. Symptoms may resolve or improve within days, although some
patients with RPLS can experience ongoing neurologic sequelae or
death.
Proteinuria Including Nephrotic Syndrome
- In study 4, severe proteinuria occurred more frequently in
patients treated with CYRAMZA plus FOLFIRI compared to patients
receiving placebo plus FOLFIRI. Severe proteinuria was reported in
3% of patients treated with CYRAMZA plus FOLFIRI (including 3 cases
[0.6%] of nephrotic syndrome) compared to 0.2% of patients treated
with placebo plus FOLFIRI. Monitor proteinuria by urine dipstick
and/or urinary protein creatinine ratio for the development of
worsening of proteinuria during CYRAMZA therapy. Withhold CYRAMZA
for urine protein levels that are ≥2 g over 24 hours. Reinitiate
CYRAMZA at a reduced dose once the urine protein level returns to
<2 g over 24 hours. Permanently discontinue CYRAMZA for urine
protein levels >3 g over 24 hours or in the setting of nephrotic
syndrome.
Thyroid Dysfunction
- Monitor thyroid function during treatment with CYRAMZA. In
study 4, the incidence of hypothyroidism reported as an adverse
event was 2.6% in the CYRAMZA plus FOLFIRI-treated patients and
0.9% in the placebo plus FOLFIRI-treated patients.
Embryofetal Toxicity
- Based on its mechanism of action, CYRAMZA can cause fetal harm
when administered to pregnant women. Animal models link
angiogenesis, VEGF, and VEGF Receptor 2 (VEGFR2) to critical
aspects of female reproduction, embryofetal development, and
postnatal development. Advise pregnant women of the potential risk
to a fetus. Advise females of reproductive potential to use
effective contraception during treatment with CYRAMZA and for at
least 3 months after the last dose of CYRAMZA.
Most Common Adverse Reactions—Single Agent
- The most commonly reported adverse reactions (all grades; grade
3/4) occurring in ≥5% of patients receiving CYRAMZA and ≥2% higher
than placebo in study 1 were hypertension (16% vs 8%; 8% vs 3%),
diarrhea (14% vs 9%; 1% vs 2%), headache (9% vs 3%; 0% vs 0%), and
hyponatremia (6% vs 2%; 3% vs 1%).
- The most common serious adverse events with CYRAMZA in study 1
were anemia (3.8%) and intestinal obstruction (2.1%). Red blood
cell transfusions were given to 11% of CYRAMZA-treated patients vs
8.7% of patients who received placebo.
- Clinically relevant adverse reactions reported in ≥1% and
<5% of CYRAMZA-treated patients vs placebo in study 1 were:
neutropenia (4.7% vs 0.9%), epistaxis (4.7% vs 0.9%), rash (4.2% vs
1.7%), intestinal obstruction (2.1% vs 0%), and arterial
thromboembolic events (1.7% vs 0%).
- Across clinical trials of CYRAMZA administered as a single
agent, clinically relevant adverse reactions (including grade ≥3)
reported in CYRAMZA-treated patients included proteinuria,
gastrointestinal perforation, and infusion-related reactions. In
study 1, according to laboratory assessment, 8% of CYRAMZA-treated
patients developed proteinuria vs 3% of placebo-treated patients.
Two patients discontinued CYRAMZA due to proteinuria. The rate of
gastrointestinal perforation in study 1 was 0.8% and the rate of
infusion-related reactions was 0.4%.
Most Common Adverse Reactions—Combination With
Paclitaxel
- The most commonly reported adverse reactions (all grades; grade
3/4) occurring in ≥5% of patients receiving CYRAMZA plus paclitaxel
and ≥2% higher than placebo plus paclitaxel in study 2 were
fatigue/asthenia (57% vs 44%; 12% vs 6%), neutropenia (54% vs 31%;
41% vs 19%), diarrhea (32% vs 23%; 4% vs 2%), epistaxis (31% vs 7%;
0% vs 0%), hypertension (25% vs 6%; 15% vs 3%), peripheral edema
(25% vs 14%; 2% vs 1%), stomatitis (20% vs 7%; 1% vs 1%),
proteinuria (17% vs 6%; 1% vs 0%), thrombocytopenia (13% vs 6%; 2%
vs 2%), hypoalbuminemia (11% vs 5%; 1% vs 1%), and gastrointestinal
hemorrhage events (10% vs 6%; 4% vs 2%).
- The most common serious adverse events with CYRAMZA plus
paclitaxel in study 2 were neutropenia (3.7%) and febrile
neutropenia (2.4%); 19% of patients treated with CYRAMZA plus
paclitaxel received granulocyte colony-stimulating factors.
- Adverse reactions resulting in discontinuation of any component
of the CYRAMZA plus paclitaxel combination in 2% or more patients
in study 2 were neutropenia (4%) and thrombocytopenia (3%).
- Clinically relevant adverse reactions reported in ≥1% and
<5% of the CYRAMZA plus paclitaxel-treated patients in study 2
were sepsis (3.1% for CYRAMZA plus paclitaxel vs 1.8% for placebo
plus paclitaxel) and gastrointestinal perforations (1.2% for
CYRAMZA plus paclitaxel vs 0.3% for placebo plus paclitaxel).
Most Common Adverse Reactions—Combination With
Docetaxel
- The most commonly reported adverse reactions (all grades; grade
3/4) occurring in ≥5% of patients receiving CYRAMZA plus docetaxel
and ≥2% higher than placebo plus docetaxel in study 3 were
neutropenia (55% vs 46%; 49% vs 40%), fatigue/asthenia (55% vs 50%;
14% vs 11%), stomatitis/mucosal inflammation (37% vs 19%; 7% vs
2%), epistaxis (19% vs 7%; <1% vs <1%), febrile neutropenia
(16% vs 10%; 16% vs 10%), peripheral edema (16% vs 9%; 0% vs
<1%), thrombocytopenia (13% vs 5%; 3% vs <1%), lacrimation
increased (13% vs 5%; <1% vs 0%), and hypertension (11% vs 5%;
6% vs 2%).
- The most common serious adverse events with CYRAMZA plus
docetaxel in study 3 were febrile neutropenia (14%), pneumonia
(6%), and neutropenia (5%). The use of granulocyte
colony-stimulating factors was 42% in CYRAMZA plus
docetaxel-treated patients versus 37% in patients who received
placebo plus docetaxel.
- In patients ≥65 years of age, there were 18 (8%) deaths on
treatment or within 30 days of discontinuation for CYRAMZA plus
docetaxel and 9 (4%) deaths for placebo plus docetaxel. In patients
<65 years of age, there were 13 (3%) deaths on treatment or
within 30 days of discontinuation for CYRAMZA plus docetaxel and 26
(6%) deaths for placebo plus docetaxel.
- Treatment discontinuation due to adverse reactions occurred
more frequently in CYRAMZA plus docetaxel-treated patients (9%)
than in placebo plus docetaxel-treated patients (5%). The most
common adverse events leading to treatment discontinuation of
CYRAMZA in study 3 were infusion-related reaction (0.5%) and
epistaxis (0.3%).
- For patients with nonsquamous histology, the overall incidence
of pulmonary hemorrhage was 7% and the incidence of grade ≥3
pulmonary hemorrhage was 1% for CYRAMZA plus docetaxel compared to
6% overall incidence and 1% for grade ≥3 pulmonary hemorrhage for
placebo plus docetaxel. For patients with squamous histology, the
overall incidence of pulmonary hemorrhage was 10% and the incidence
of grade ≥3 pulmonary hemorrhage was 2% for CYRAMZA plus docetaxel
compared to 12% overall incidence and 2% for grade ≥3 pulmonary
hemorrhage for placebo plus docetaxel.
- Clinically relevant adverse reactions reported in ≥1% and
<5% of CYRAMZA plus docetaxel-treated patients in study 3 were
hyponatremia (4.8% CYRAMZA plus docetaxel versus 2.4% for placebo
plus docetaxel) and proteinuria (3.3% CYRAMZA plus docetaxel versus
0.8% placebo plus docetaxel).
Most Common Adverse Reactions—Combination With
FOLFIRI
- The most commonly reported adverse reactions (all grades; grade
3/4) occurring in ≥5% of patients receiving CYRAMZA plus FOLFIRI
and ≥2% higher than placebo plus FOLFIRI in study 4 were diarrhea
(60% vs 51%; 11% vs 10%), neutropenia (59% vs 46%; 38% vs 23%),
decreased appetite (37% vs 27%; 2% vs 2%), epistaxis (33% vs 15%;
0% vs 0%), stomatitis (31% vs 21%; 4% vs 2%), thrombocytopenia (28%
vs 14%; 3% vs <1%), hypertension (26% vs 9%; 11% vs 3%),
peripheral edema (20% vs 9%; <1% vs 0%), proteinuria (17% vs 5%;
3% vs <1%), palmar-plantar erythrodysesthesia syndrome (13% vs
5%; 1% vs <1%), gastrointestinal hemorrhage events (12% vs 7%;
2% vs 1%), hypoalbuminemia (6% vs 2%; 1% vs 0%). Twenty
percent of patients treated with CYRAMZA plus FOLFIRI received
granulocyte colony-stimulating factors.
- The most common serious adverse events with CYRAMZA plus
FOLFIRI were diarrhea (3.6%), intestinal obstruction (3.0%), and
febrile neutropenia (2.8%).
- Treatment discontinuation of any study drug due to adverse
reactions occurred more frequently in CYRAMZA plus FOLFIRI-treated
patients (29%) than in placebo plus FOLFIRI-treated patients (13%).
The most common adverse reactions leading to discontinuation of any
component of CYRAMZA plus FOLFIRI as compared to placebo plus
FOLFIRI were neutropenia (12.5% versus 5.3%) and thrombocytopenia
(4.2% versus 0.8%). The most common adverse reactions leading to
treatment discontinuation of CYRAMZA were proteinuria (1.5%) and
gastrointestinal perforation (1.7%).
- Clinically relevant adverse reactions reported in ≥1% and
<5% of CYRAMZA plus FOLFIRI-treated patients in study 4
consisted of gastrointestinal perforation (1.7% CYRAMZA plus
FOLFIRI versus 0.6% for placebo plus FOLFIRI).
- Thyroid-stimulating hormone (TSH) was evaluated in 224 patients
(115 CYRAMZA plus FOLFIRI-treated patients and 109 placebo plus
FOLFIRI-treated patients) with normal baseline TSH levels.
Increased TSH was observed in 53 (46%) patients treated with
CYRAMZA plus FOLFIRI compared with 4 (4%) patients treated with
placebo plus FOLFIRI.
Drug Interactions
- No pharmacokinetic interactions were observed between
ramucirumab and paclitaxel, between ramucirumab and docetaxel, or
between ramucirumab and irinotecan or its active metabolite,
SN-38.
Use in Specific Populations
- Pregnancy: Based on its mechanism of action, CYRAMZA can cause
fetal harm. Animal models link angiogenesis, VEGF, and VEGF
Receptor 2 (VEGFR2) to critical aspects of female reproduction,
embryofetal development, and postnatal development. There are no
available data on CYRAMZA use in pregnant women to inform any
drug-associated risks. No animal studies have been conducted to
evaluate the effect of ramucirumab on reproduction and fetal
development. Advise females of reproductive potential of the
potential risk for maintaining pregnancy, risk to the fetus, and
risk to newborn and pediatric development, and to use effective
contraception during CYRAMZA therapy and for at least 3 months
following the last dose of CYRAMZA.
- Lactation: Because of the potential risk for serious adverse
reactions in nursing infants from ramucirumab, advise women that
breastfeeding is not recommended during treatment with
CYRAMZA.
- Females of Reproductive Potential: Advise females of
reproductive potential that based on animal data CYRAMZA may impair
fertility.
Please see full Prescribing Information for CYRAMZA,
including Boxed Warning for hemorrhage, gastrointestinal
perforation, and impaired wound healing.
RB-P-HCP ISI 16FEB2017
About Lilly Oncology
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Lilly has been dedicated to delivering life-changing medicines and
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visit www.LillyOncology.com.
About Eli Lilly and Company
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and today we remain true to that mission in all our work. Across
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medicines to those who need them, improve the understanding and
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© Lilly USA, LLC 2019. ALL
RIGHTS RESERVED.
CYRAMZA is a trademark owned by or licensed to Eli Lilly and
Company, its subsidiaries, or affiliates.
Lilly Forward-Looking Statement
This press release
contains forward-looking statements (as that term is defined in the
Private Securities Litigation Reform Act of 1995) about the REACH-2
trial and CYRAMZA as a potential treatment for patients
with hepatocellular carcinoma and reflects Lilly's current
beliefs. However, as with any pharmaceutical product, there are
substantial risks and uncertainties in the process of development
and commercialization. Among other things, there can be no
guarantee that CYRAMZA will receive regulatory approval
for hepatocellular carcinoma or continue to be commercially
successful. For further discussion of these and other risks and
uncertainties, see Lilly's most recent Form 10-K and Form 10-Q
filings with the United States Securities and Exchange Commission.
Except as required by law, Lilly undertakes no duty to update
forward- looking statements to reflect events after the date of
this release.
1 Ferlay J, Shin HR, Bray F et al. GLOBOCAN 2018 Fact
Sheet, Estimated Cancer Incidence, Mortality and Prevalence
Worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for
Research on Cancer; 2018. Available at
http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Accessed on
January 18, 2019.
2 Siegel RL, Miller KD, Jemal A.
Cancer statistics, 2018. CA Cancer J Clin 2018;68:7-30.
3 Islami F, Miller KD, Siegel RL, et al. Disparities in
liver cancer occurrence in the United
States by race/ethnicity and state. CA Cancer J Clin
2017;67:273–289.
4 Zhu, AP, Park, JO, Ryoo, BK et al. Ramucirumab Versus
Placebo as Second-Line Treatment in Patients with Advanced
Hepatocellular Carcinoma Following First-Line Therapy with
Sorafenib (REACH): A Randomised, Double-Blind, Multicentre, Phase 3
Trial. Lancet Oncol. 2015;16(7): 859-870.
5 Mayo Medical Laboratories. Test ID: AFP Clinical
and Interpretive. Available at
http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+interpretive/8162.
Accessed on January 18, 2019.
6 University of Rochester Medical Center. Health
Encyclopedia: Alpha-Fetoprotein Tumor Marker (Blood). Available at
https://www.urmc.rochester.edu/encyclopedia/content.aspx?contenttypeid=167&contentid=alpha_fetoprotein_tumor_marker.
Accessed on January 18, 2019.
7 Venook, AP, Papandreou, C, Furuse, J et al. The
Incidence and Epidemiology of Hepatocellular Carcinoma: A Global
and Regional Perspective. The Oncologist 2010;15(suppl 4):
5-13.
Refer to:
|
Tracy Henrikson;
tracy.henrikson@lilly.com; 609-454-7116 (media)
|
|
Kevin Hern;
hern_kevin_r@lilly.com; 317-277-1838
(investors)
|
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