INDIANAPOLIS, May 29, 2020 /PRNewswire/ -- Eli Lilly and
Company (NYSE: LLY) today announced that the U.S. Food and Drug
Administration (FDA) has approved CYRAMZA® (ramucirumab
injection, 10 mg/mL solution), in combination with erlotinib, for
the first-line treatment of people with metastatic non-small cell
lung cancer (NSCLC) with epidermal growth factor receptor (EGFR)
exon 19 deletions or exon 21 (L858R) mutations. With this approval,
CYRAMZA has now received six FDA approvals to treat certain types
of lung, liver, stomach and colorectal cancers.
CYRAMZA plus erlotinib is the first and only FDA-approved
anti-VEGFR/EGFR TKI combination therapy for metastatic EGFR-mutated
NSCLC. This approval is based on the efficacy and safety from the
global, randomized, placebo-controlled Phase 3 RELAY trial. In the
RELAY study, CYRAMZA, a VEGF receptor 2 antagonist, in combination
with erlotinib, a globally approved EGFR-targeting tyrosine kinase
inhibitor (TKI), demonstrated a statistically significant and
clinically meaningful improvement in progression-free survival
(PFS) – the time patients lived without their cancer growing or
spreading after starting treatment – compared to placebo in
combination with erlotinib [19.4 months in the CYRAMZA-containing
arm compared to 12.4 months in the placebo-containing arm (HR=0.59;
95% CI, 0.46, 0.76; p<0.0001)]. The PFS treatment effect was
consistent across exon 19 and exon 21 subgroups. The overall safety
profile observed in the RELAY study was consistent with that of its
individual components. RELAY is the second positive Phase 3 trial
of CYRAMZA in metastatic NSCLC. The first was REVEL, which
supported the approval of CYRAMZA plus docetaxel as a treatment for
people with metastatic NSCLC whose cancer has progressed after
prior platinum-based chemotherapy.
"The approval of this new first-line metastatic EGFR-mutated
non-small cell lung cancer regimen, which inhibits the VEGFR and
EGFR pathways together, is an important milestone in the treatment
of this disease. It is wonderful that patients now have multiple
options for initial therapy capable of delaying disease progression
for considerably longer than erlotinib, which has been our
traditional standard approach," said Edward
Garon, M.D., David Geffen
School of Medicine, University of
California, and North
America lead investigator of the RELAY
trial. "Ramucirumab, in combination with erlotinib, is a
welcomed first-line option to offer our patients with metastatic
EGFR-mutated non-small cell lung cancer."
"This CYRAMZA combination regimen represents a new and
meaningful treatment option for people with metastatic EGFR-mutated
non-small cell lung cancer, and we are proud that it has been
approved by the FDA for patients with this disease and the doctors
who treat them," said Anne White,
president of Lilly Oncology. "Today's approval underscores Lilly's
continued commitment to people living with lung cancer and to
delivering meaningful medicines that are tailored for those with
advanced or metastatic cancers. It also further reinforces the
value that CYRAMZA can provide in treating certain advanced or
metastatic cancers."
Fifty percent of people with NSCLC present with advanced or
metastatic disease at diagnosis.1 The five-year survival
rate for metastatic NSCLC patients is six percent.2 In
the U.S., it is estimated that approximately 15 percent of people
diagnosed with NSCLC have an EGFR mutation.3
"We're encouraged by CYRAMZA's latest approval, which represents
one step towards our goal of making EGFR-mutated non-small cell
lung cancer into a manageable chronic disease," said
Ivy Elkins, cofounder of EGFR
Resisters. "Each new treatment option gives hope to those living
with this disease and provides oncologists with more options that
may help slow the spread of this deadly cancer, which is an
important goal for many patients."
The labeling for CYRAMZA contains warnings and precautions for
hemorrhage and gastrointestinal (GI) hemorrhage, including severe
and sometimes fatal events; GI perforations, a potentially fatal
event; impaired wound healing; arterial thromboembolic events
(ATEs), including serious and sometimes fatal events; hypertension;
infusion-related reactions (IRR) including severe and
life-threatening reactions; worsening of pre-existing hepatic
impairment; Posterior Reversible Encephalopathy Syndrome (PRES);
proteinuria including nephrotic syndrome; thyroid dysfunction; and
embryo-fetal toxicity. CYRAMZA should be permanently discontinued
in patients who experience severe bleeding, a GI perforation, an
ATE, uncontrolled hypertension, Grade 3 or 4
IRR, PRES, or nephrotic syndrome. Withhold CYRAMZA for 28
days prior to elective surgery. Do not administer CYRAMZA for at
least two weeks following a major surgical procedure and until
adequate wound healing.
The most common adverse reactions (all grades) observed in
CYRAMZA with erlotinib-treated patients at a rate of ≥30% of
patients and ≥2% higher than placebo with erlotinib-treated
patients were infections, hypertension, stomatitis, proteinuria,
alopecia, and epistaxis. The most common laboratory abnormalities
≥30% and ≥2% higher than the placebo were increased alanine
aminotransferase, increased aspartate aminotransferase, anemia,
thrombocytopenia, and neutropenia. Please see Important Safety
Information below.
In addition to a recent approval for CYRAMZA in the European
Union based on the RELAY results, Lilly has made a submission in
Japan with regulatory action
expected by the end of 2020.
Click here to view the EGFR-mutated NSCLC fact sheet.
Click here to view the CYRAMZA product photo.
Click here to view the CYRAMZA logo.
About the RELAY Trial
RELAY is a global randomized, double-blind, placebo-controlled
Phase 3 study of CYRAMZA in combination with erlotinib, compared to
placebo in combination with erlotinib, as a first-line
treatment in previously untreated patients with metastatic NSCLC
whose tumors have EGFR exon 19 deletions or exon 21 (L858R)
substitution mutations. EGFR-targeting TKIs are the current
standard treatment options for EGFR-mutated NSCLC. Erlotinib, the
TKI included in the RELAY trial regimen, is a globally approved
treatment option for this type of lung cancer.
Initiated in 2015, the study randomized 449 patients
across North America, Europe and Asia. The
primary endpoint of the RELAY trial is PFS; key secondary endpoints
include safety, overall response rate (ORR), duration of response
(DoR), and overall survival (OS). On the primary endpoint of
investigator-assessed PFS, CYRAMZA plus erlotinib (N=224)
demonstrated statistically significant and clinically meaningful
improvement in median PFS – the time patients lived without their
cancer growing or spreading after starting treatment – by seven
months compared to placebo plus erlotinib (N=225) [19.4 months in
the CYRAMZA-containing arm compared to 12.4 months in the
placebo-containing arm (HR=0.59; 95% CI, 0.46, 0.76; p<0.0001)].
The PFS treatment effect was consistent across exon 19 and exon 21
subgroups. At the time of the final analysis of PFS, OS data were
not mature as only 26 percent of planned events for the final
analysis had occurred (HR=0.83, 95% CI: 0.53, 1.30). A final OS
analysis is planned when at least 300 events have occurred.
RELAY Trial Efficacy Results Supporting Approval
Endpoint
|
CYRAMZA +
erlotinib
N=224
|
Placebo +
erlotinib
N=225
|
Progression-Free
Survival (primary outcome measure)
|
Number of events
(%)a
|
122 (55%)
|
158 (70%)
|
Median – months (95%
CI)
|
19.4 (15.4,
21.6)
|
12.4 (11.0,
13.5)
|
Hazard Ratio (95%
CI)
|
0.59 (0.46,
0.76)
|
Stratified Log-rank
p-value
|
<0.0001
|
Overall Response
Rate (Complete Response + Partial Response) (secondary outcome
measure)
|
Rate – percent (95%
CI)
|
76% (71,
82)
|
75% (69,
80)
|
Duration of
Response (DoR) (secondary outcome measure)
|
|
N=171
|
N=168
|
Median – months (95%
CI)
|
18.0 (13.9,
19.8)
|
11.1 (9.7,
12.3)
|
Abbreviations: CI =
confidence interval
a 4
of 122 events in CYRAMZA-treated patients and 1 of 158 events in
placebo-treated patients were deaths.
|
Treatment discontinuation of all study drugs due to adverse
reactions occurred in 13 percent of CYRAMZA with erlotinib-treated
patients, with increased alanine aminotransferase (1.4%) and
paronychia (1.4%) being the most common. The most common adverse
reactions leading to treatment discontinuation of CYRAMZA were
proteinuria (8.6%) and hyperbilirubinemia (6%).
Detailed RELAY efficacy and safety results were published in
The Lancet Oncology.
Notes to Editors
About Lung Cancer and EGFR Mutations
Globally, lung
cancer is the leading cause of cancer death, killing nearly 1.8
million people worldwide each year.4 In the U.S.,
lung cancer is the second most common cancer (not counting skin
cancer) and the leading cause of cancer death, responsible for
almost 25 percent of all cancer deaths – more than those from
colorectal, breast and prostate cancers combined.5 It is
estimated that there will be 228,820 new cases of lung cancer and
135,720 deaths from lung cancer in the U.S. in 2020.4
Non-small cell lung cancer (NSCLC) is much more common than other
types of lung cancer and accounts for about 85 percent of all lung
cancers.6 Stage IV NSCLC is a very
difficult-to-treat cancer and the prognosis is poor for metastatic
NSCLC.7 Fifty percent of NSCLC patients present
with advanced or metastatic disease at diagnosis.1 The
five-year survival rate for metastatic NSCLC is six
percent.2
EGFR is a protein that helps cells grow and divide. When the
EGFR gene is mutated it can cause the protein to be overactive,
causing cells to grow and divide more quickly. EGFR mutations may
occur in 10 to 35 percent of NSCLC tumors globally.8 In
the U.S., it is estimated that approximately 15 percent of people
diagnosed with NSCLC have an EGFR mutation.3 Activating
EGFR mutations are found in about 10 to 20 percent of Caucasian
patients with lung adenocarcinomas and in up to 40 to 60 percent of
Asian patients.9,10,11 Regardless of ethnicity, these
mutations are commonly found in females, non-smokers and those with
adenocarcinoma histology.12,13 The most common
activating mutations in EGFR are deletions within exon 19 and a
substitution in exon 21 (L858R). These mutations are present in 90
percent of EGFR-mutated NSCLC tumors. The presence of these
activating EGFR mutations in advanced NSCLC is associated with
sensitivity to small-molecule EGFR TKIs.10,11
About CYRAMZA® (ramucirumab)
In the
U.S., CYRAMZA (ramucirumab) has six FDA approvals to treat
four different types of cancers. CYRAMZA is being investigated in a
broad global development program that has enrolled more than 15,000
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. To
date, more than 150,000 patients have been treated with
CYRAMZA.
CYRAMZA is an antiangiogenic therapy. It is a vascular
endothelial growth factor (VEGF) Receptor 2 antagonist that binds
specifically to VEGFR-2, thereby blocking the binding of the
receptor ligands (VEGF-A, VEGF-C, and VEGF-D) – which may slow
tumor growth. CYRAMZA inhibited angiogenesis in an in vivo animal
model.
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 binding to the receptors located on the surface
of 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.
INDICATIONS FOR CYRAMZA
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 erlotinib, for first-line treatment of metastatic non-small
cell lung cancer with epidermal growth factor receptor (EGFR) exon
19 deletions or exon 21 (L858R) mutations.
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 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.
Hepatocellular Carcinoma
CYRAMZA, as a single agent,
is indicated for the treatment of patients with hepatocellular
carcinoma (HCC) who have an alpha-fetoprotein (AFP) of ≥400 ng/mL
and have been treated with sorafenib.
IMPORTANT SAFETY INFORMATION FOR CYRAMZA®
(ramucirumab)
Warnings and Precautions
Hemorrhage
- CYRAMZA increased the risk of hemorrhage and gastrointestinal
hemorrhage, including Grade ≥3 hemorrhagic events. In 2137 patients
with various cancers treated with CYRAMZA, the incidence of all
Grade hemorrhage ranged from 13-55%. Grade 3-5 hemorrhage incidence
ranged from 2-5%.
- Patients with gastric cancer receiving nonsteroidal
anti-inflammatory drugs (NSAIDs) were excluded from enrollment in
REGARD and RAINBOW; therefore, the risk of gastric hemorrhage in
CYRAMZA-treated patients with gastric tumors receiving NSAIDs is
unknown.
- Patients with NSCLC receiving therapeutic anticoagulation or
with evidence of major airway invasion by cancer were excluded from
REVEL. In addition, patients with NSCLC with a recent history of
gross hemoptysis, those receiving chronic therapy with NSAIDs or
other anti-platelet therapy other than once daily aspirin or with
radiographic evidence of major blood vessel invasion or intratumor
cavitation were excluded from REVEL and RELAY; therefore the risk
of pulmonary hemorrhage in these groups of patients is
unknown.
- Permanently discontinue CYRAMZA in patients who experience
severe (Grade 3 or 4) bleeding.
Gastrointestinal Perforations
- CYRAMZA can increase the risk of gastrointestinal perforation,
a potentially fatal event. In 2137 patients with various cancers
treated with CYRAMZA, the incidence of all Grade and Grade 3-5
gastrointestinal perforations ranged from <1-2%.
- Permanently discontinue CYRAMZA in patients who experience a
gastrointestinal perforation.
Impaired Wound Healing
- CYRAMZA has the potential to adversely affect wound healing.
CYRAMZA has not been studied in patients with serious or
non-healing wounds.
- Withhold CYRAMZA for 28 days prior to elective surgery. Do not
administer CYRAMZA for at least 2 weeks following a major surgical
procedure and until adequate wound healing. The safety of
resumption of CYRAMZA after resolution of wound healing
complications has not been established.
Arterial Thromboembolic Events (ATEs)
- Serious, sometimes fatal, ATEs, including myocardial
infarction, cardiac arrest, cerebrovascular accident, and cerebral
ischemia, occurred across clinical trials. In 2137 patients with
various cancers treated with CYRAMZA, the incidence of all Grade
ATE was 1-3%. Grade 3-5 ATE incidence was <1-2%.
- Permanently discontinue CYRAMZA in patients who experience an
ATE.
Hypertension
- An increased incidence of severe hypertension occurred in
patients receiving CYRAMZA. Across five clinical studies, excluding
RELAY, in 1916 patients with various cancers treated with CYRAMZA,
the incidence of all Grade hypertension ranged from 11-26%. Grade
3-5 hypertension incidence ranged from 6-15%. In 221 patients with
NSCLC receiving CYRAMZA in combination with erlotinib in the RELAY
study, the incidence of new or worsening hypertension was higher
(45%), as was the incidence of Grade 3-5 hypertension (24%). Of the
patients experiencing new or worsening hypertension in RELAY (N=100
CYRAMZA and erlotinib; N=27 placebo and erlotinib), 13% of those
treated with CYRAMZA and erlotinib required initiation of 3 or more
antihypertensive medications compared to 4% of patients treated
with placebo and erlotinib.
- Control hypertension prior to initiating treatment with
CYRAMZA. Monitor blood pressure every two weeks or more frequently
as indicated during treatment. Withhold CYRAMZA for severe
hypertension until medically controlled. Permanently discontinue
CYRAMZA for medically significant hypertension that cannot be
controlled with antihypertensive therapy or in patients with
hypertensive crisis or hypertensive encephalopathy.
Infusion-Related Reactions (IRR)
- IRR, including severe and life-threatening IRR, occurred in
CYRAMZA clinical trials. Symptoms of IRR included rigors/tremors,
back pain/spasms, chest pain and/or tightness, chills, flushing,
dyspnea, wheezing, hypoxia, and paresthesia. In severe cases,
symptoms included bronchospasm, supraventricular tachycardia, and
hypotension. In 2137 patients with various cancers treated with
CYRAMZA in which premedication was recommended or required, the
incidence of all Grade IRR ranged from <1- 9%. Grade
3-5 IRR incidence was <1%.
- Premedicate prior to each CYRAMZA infusion. Monitor patients
during the infusion for signs and symptoms of IRR in a setting with
available resuscitation equipment. Reduce the infusion rate by 50%
for Grade 1-2 IRR. Permanently
discontinue CYRAMZA for Grade 3- 4
IRR.
Worsening of Pre-existing Hepatic Impairment
- 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. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis
only if the potential benefits of treatment are judged to outweigh
the risks of clinical deterioration.
- Based on safety data from REACH-2, in patients with Child-Pugh
A liver cirrhosis, the pooled incidence of hepatic encephalopathy
and hepatorenal syndrome was higher for patients who received
CYRAMZA (6%) compared to patients who received placebo (0%).
Posterior Reversible Encephalopathy Syndrome (PRES)
- PRES (also known as Reversible Posterior Leukoencephalopathy
Syndrome [RPLS]) has been reported in <0.1% of 2137 patients
with various cancers treated with CYRAMZA. Symptoms of PRES include
seizure, headache, nausea/vomiting, blindness, or altered
consciousness, with or without associated hypertension.
- Permanently discontinue CYRAMZA in patients who develop PRES.
Symptoms may resolve or improve within days, although some patients
with PRES can experience ongoing neurologic sequelae or death.
Proteinuria Including Nephrotic Syndrome
- In 2137 patients with various cancers treated with CYRAMZA, the
incidence of all Grade proteinuria ranged from 3-34%. Grade ≥3
proteinuria (including 4 patients with nephrotic syndrome)
incidence ranged from <1-3%.
- Monitor for proteinuria. Withhold CYRAMZA for urine protein
levels that are 2 or more grams over 24 hours. Reinitiate CYRAMZA
at a reduced dose once the urine protein level returns to less than
2 grams over 24 hours. Permanently discontinue CYRAMZA for urine
protein levels greater than 3 grams over 24 hours or in the setting
of nephrotic syndrome.
Thyroid Dysfunction
- In 2137 patients with various cancers treated with CYRAMZA, the
incidence of Grade 1-2 hypothyroidism ranged from <1-3%; there
were no reports of Grade 3-5 hypothyroidism. Monitor thyroid
function during treatment with CYRAMZA.
Embryo-Fetal Toxicity
- CYRAMZA can cause fetal harm when administered to pregnant
women. 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 3 months after
the last dose.
Lactation
- Because of the potential risk for serious adverse reactions in
breastfed children from ramucirumab, advise women not to breastfeed
during treatment with CYRAMZA and for 2 months after the last
dose.
Adverse Reactions
REGARD:
- The most common adverse reactions (all Grades) observed in
single agent CYRAMZA-treated gastric cancer patients at a rate of
≥5% and ≥2% higher than placebo were hypertension (16% vs 8%),
diarrhea (14% vs 9%), headache (9% vs 3%), and hyponatremia (6% vs
2%).
- The most common serious adverse reactions with CYRAMZA 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 in REGARD were neutropenia
(4.7%), epistaxis (4.7%), rash (4.2%), intestinal obstruction
(2.1%), and arterial thromboembolic events (1.7%).
- 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 IRR. In REGARD, 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 REGARD was 0.8% and the rate of IRR
was 0.4%.
RAINBOW:
- The most common adverse reactions (all Grades) observed in
patients treated with CYRAMZA with paclitaxel at a rate of ≥5% and
≥2% higher than placebo with paclitaxel were fatigue/asthenia (57%
vs 44%), neutropenia (54% vs 31%), diarrhea (32% vs 23%), epistaxis
(31% vs 7%), hypertension (25% vs 6%), peripheral edema (25% vs
14%), stomatitis (20% vs 7%), proteinuria (17% vs 6%),
thrombocytopenia (13% vs 6%), hypoalbuminemia (11% vs 5%), and
gastrointestinal hemorrhage events (10% vs 6%).
- The most common serious adverse reactions with CYRAMZA with
paclitaxel were neutropenia (3.7%) and febrile neutropenia (2.4%);
19% of patients who received CYRAMZA with paclitaxel received
granulocyte colony-stimulating factors.
- Adverse reactions resulting in discontinuation of any component
of the CYRAMZA with paclitaxel combination in ≥2% of patients in
RAINBOW were neutropenia (4%) and thrombocytopenia (3%).
- Clinically relevant adverse reactions reported in ≥1% and
<5% of patients receiving CYRAMZA with paclitaxel were sepsis
(3.1%), including 5 fatal events, and gastrointestinal perforations
(1.2%), including 1 fatal event.
REVEL:
- The most common adverse reactions (all Grades) observed in
patients treated with CYRAMZA with docetaxel at a rate of ≥5% and
≥2% higher than placebo with docetaxel were neutropenia (55% vs
46%), fatigue/asthenia (55% vs 50%), stomatitis/mucosal
inflammation (37% vs 19%), epistaxis (19% vs 7%), febrile
neutropenia (16% vs 10%), peripheral edema (16% vs 9%),
thrombocytopenia (13% vs 5%), lacrimation increased (13% vs 5%),
and hypertension (11% vs 5%).
- The most common serious adverse reactions with CYRAMZA with
docetaxel were febrile neutropenia (14%), pneumonia (6%), and
neutropenia (5%). The use of granulocyte colony-stimulating factors
was 42% in CYRAMZA with docetaxel- treated patients versus 37% in
patients who received placebo with docetaxel.
- Treatment discontinuation due to adverse reactions occurred
more frequently in CYRAMZA with docetaxel-treated patients (9%)
than in placebo with docetaxel-treated patients (5%). The most
common adverse reactions leading to treatment discontinuation of
CYRAMZA were IRR (0.5%) and epistaxis (0.3%).
- For patients with non-squamous histology, the overall incidence
of pulmonary hemorrhage was 7% and the incidence of Grade ≥3
pulmonary hemorrhage was 1% for CYRAMZA with docetaxel compared to
6% overall incidence and 1% for Grade ≥3 pulmonary hemorrhage for
placebo with 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 with docetaxel
compared to 12% overall incidence and 2% for Grade ≥3 pulmonary
hemorrhage for placebo with docetaxel.
- Clinically relevant adverse reactions reported in ≥1% and
<5% of CYRAMZA with docetaxel-treated patients in REVEL were
hyponatremia (4.8%) and proteinuria (3.3%).
RELAY:
- The most common adverse reactions (all Grades) observed in
patients treated with CYRAMZA with erlotinib at a rate of ≥ 5% and
≥2% higher than placebo with erlotinib were infections (81% vs
76%), diarrhea (70% vs 71%), hypertension (45% vs 12%), stomatitis
(42% vs 36%), alopecia (34% vs 20%), epistaxis (34% vs 12%),
proteinuria (34% vs 8%), peripheral edema (23% vs 4%), headache
(15% vs 7%), gastrointestinal hemorrhage (10% vs 3%), gingival
bleeding (9% vs 1%), and pulmonary hemorrhage (7% vs 2%).
- The most common serious adverse reactions with CYRAMZA with
erlotinib were pneumonia (3.2%), cellulitis (1.8%), and
pneumothorax (1.8%). Red blood cell transfusions were given to 3.2%
of CYRAMZA-treated patients versus 0 patients who received
placebo.
- Treatment discontinuation of all study drugs due to adverse
reactions occurred in 13% of CYRAMZA with erlotinib-treated
patients, with increased alanine aminotransferase (1.4%) and
paronychia (1.4%) being the most common. The most common adverse
reactions leading to treatment discontinuation of CYRAMZA were
proteinuria (8.6%) and hyperbilirubinemia (6%).
- Of the 221 patients who received CYRAMZA with erlotinib, 119
(54%) were 65 and over, while 29 (13%) were 75 and over. Adverse
reactions occurring at a 10% or higher incidence in patients
receiving CYRAMZA with erlotinib and with a 10% or greater
difference between patients aged 65 or older compared to patients
aged less than 65 years were: diarrhea (75% versus 65%),
hypertension (50% versus 40%), increased ALT (49% versus 35%),
increased AST (49% versus 33%), stomatitis (46% versus 36%),
decreased appetite (32% versus 19%), dysgeusia (23% versus 12%),
and weight loss (19% versus 6%).
RAISE:
- The most common adverse reactions (all Grades) observed in
patients treated with CYRAMZA with FOLFIRI at a rate of ≥5% and ≥2%
higher than placebo with FOLFIRI were diarrhea (60% vs 51%),
neutropenia (59% vs 46%), decreased appetite (37% vs 27%),
epistaxis (33% vs 15%), stomatitis (31% vs 21%), thrombocytopenia
(28% vs 14%), hypertension (26% vs 9%), peripheral edema (20% vs
9%), proteinuria (17% vs 5%), palmar-plantar erythrodysesthesia
syndrome (13% vs 5%), gastrointestinal hemorrhage events (12% vs
7%), and hypoalbuminemia (6% vs 2%). Twenty percent of patients
treated with CYRAMZA with FOLFIRI received granulocyte colony-
stimulating factors.
- The most common serious adverse reactions with CYRAMZA with
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 with FOLFIRI-treated
patients (29%) than in placebo with FOLFIRI-treated patients (13%).
The most common adverse reactions leading to discontinuation of any
component of CYRAMZA with FOLFIRI as compared to placebo with
FOLFIRI were neutropenia (12.5% vs 5.3%) and thrombocytopenia (4.2%
vs 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 reaction reported in ≥1% and <5%
of patients receiving CYRAMZA with FOLFIRI was gastrointestinal
perforation (1.7%), including 4 fatal events.
- Thyroid-stimulating hormone (TSH) levels were evaluated in 224
patients (115 CYRAMZA with FOLFIRI-treated patients and 109 placebo
with FOLFIRI-treated patients) with normal baseline TSH levels.
Increased TSH levels were observed in 53 (46%) patients treated
with CYRAMZA with FOLFIRI compared with 4 (4%) patients treated
with placebo with FOLFIRI.
REACH-2:
- The most common adverse reactions (all Grades) observed in
single agent CYRAMZA-treated HCC patients at a rate of ≥10% and ≥2%
higher than placebo were fatigue (36% vs 20%), peripheral edema
(25% vs 14%), hypertension (25% vs 13%), abdominal pain (25% vs
16%), decreased appetite (23% vs 20%), proteinuria (20% vs 4%),
nausea (19% vs 12%), ascites (18% vs 7%), headache (14% vs 5%),
epistaxis (14% vs 3%), insomnia (11% vs 6%), pyrexia (10% vs 3%),
vomiting (10% vs 7%), and back pain (10% vs 7%).
- The most common serious adverse reactions with CYRAMZA were
ascites (3%) and pneumonia (3%).
- Treatment discontinuations due to adverse reactions occurred in
18% of CYRAMZA-treated patients, with proteinuria being the most
frequent (2%).
- Clinically relevant adverse reactions reported in ≥1% and
<10% of CYRAMZA-treated patients in REACH-2 were IRR (9%),
hepatic encephalopathy (5%) including 1 fatal event, and
hepatorenal syndrome (2%) including 1 fatal event.
RB-P HCP ISI 29MAY2020
Please see full U.S. Prescribing Information for
CYRAMZA.
About Lilly Oncology
For more than 50 years, Lilly has
been dedicated to delivering life-changing medicines and support to
people living with cancer and those who care for them. Lilly is
determined to build on this heritage and continue making life
better for all those affected by cancer around the world. To learn
more about Lilly's commitment to people with cancer, please visit
www.LillyOncology.com.
About Eli Lilly and Company
Lilly is a global
healthcare leader that unites caring with discovery to create
medicines that make life better for people around the world. We
were founded more than a century ago by a man committed to creating
high-quality medicines that meet real needs, and today we remain
true to that mission in all our work. Across the globe, Lilly
employees work to discover and bring life-changing medicines to
those who need them, improve the understanding and management of
disease, and give back to communities through philanthropy and
volunteerism. To learn more about Lilly, please visit us at
www.lilly.com and lilly.com/newsroom. P-LLY
© Lilly USA, LLC 2020. ALL
RIGHTS RESERVED.
CYRAMZA® is a registered 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 Lilly's
CYRAMZA (ramucirumab), in combination with erlotinib, for the
first-line treatment of people with metastatic non-small cell lung
cancer with EGFR exon 19 deletions or exon 21 (L858R)
mutations 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 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 Riess, J. Shifting Paradigms in Non-Small
Cell Lung Cancer: An Evolving Therapeutic Landscape
Supplement. Am J Manag Care.
2013;19:S390-S397.
2 Cancer.Net. Lung Cancer
– Non Small Cell: Statistics. Available at:
https://www.cancer.net/cancer-types/lung-cancer-non-small-cell/statistics.
Accessed May 13, 2020.
3 Li Y, Appius A, Pattipaka T, Feyereislova A, Cassidy
A, Ganti AK. Real-world management of patients with epidermal
growth factor receptor (EGFR) mutation-positive non-small-cell lung
cancer in the USA [published
correction appears in PLoS One. 2019 Feb
20;14(2):e0212831]. PLoS One. 2019;14(1):e0209709.
Published 2019 Jan 4.
doi:10.1371/journal.pone.0209709.
4 International Agency for Research on Cancer. 2018
Lung Cancer Fact Sheet. Available
at: http://gco.iarc.fr/today/data/factsheets/cancers/15-Lung-fact-sheet.pdf. Accessed May
13, 2020.
5 American Cancer Society. Key Statistics for Lung
Cancer. Available at:
https://www.cancer.org/cancer/lung-cancer/about/key-statistics.html.
Accessed May 13, 2020.
6 American Cancer Society. What is non-small cell
lung cancer? Available at:
http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-what-is-non-small-cell-lung-cancer.
Accessed May 13, 2020.
7 American Cancer Society. Non-Small Cell Lung
Cancer Survival Rates, by Stage. Available at:
http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-survival-rates.
Accessed May 13, 2020.
8 Dong L, Lei D, Zhang H. Clinical strategies for
acquired epidermal growth factor receptor tyrosine kinase inhibitor
resistance in non-small-cell lung cancer patients.
Oncotarget. 2017 Sep 8; 8(38):
64600–64606.
9 Girard N. Optimizing outcomes in EGFR
mutation-positive NSCLC: which tyrosine kinase inhibitor and when?
Future Oncol. 2018 May;14(11):1117-1132. doi:
10.2217/fon-2017-0636.
10 Hirsh V. Turning EGFR mutation-positive
non-small-cell lung cancer into a chronic disease: optimal
sequential therapy with EGFR tyrosine kinase inhibitors. Ther
Adv Med Oncol. 2018 Jan 22;10:1758834017753338. doi:
10.1177/1758834017753338.
11 National Comprehensive Cancer Network. NCCN
Clinical Practice Guidelines in Oncology 2019: Non-Small Cell Lung
Cancer (Version 3).
https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf.
Accessed May 13, 2020.
12 Midha A, Dearden S, McCormack R. EGFR mutation
incidence in non-small-cell lung cancer of adenocarcinoma
histology: a systematic review and global map by ethnicity
(mutMapII). Am J Cancer Res. 2015 Aug 15;5(9):2892-911.
13 Ladanyi M, Pao W.
Lung adenocarcinoma: guiding EGFR-targeted therapy and
beyond. Mod Pathol. 2008 May;21 Suppl 2:S16-22. doi:
10.1038/modpathol.3801018.
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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