Rapidly Progressing Advanced Non-Small Cell Lung Cancer Patients Shown to Benefit in New CYRAMZA® (ramucirumab) Phase 3 Subgroup Analysis
INDIANAPOLIS, Oct. 16, 2017 /PRNewswire/ -- New subgroup analysis from Eli Lilly and Company's (NYSE: LLY) Phase 3 REVEL trial of CYRAMZA(®) (ramucirumab) in advanced non-small cell lung cancer (NSCLC) was presented today at the 18(th) World Conference on Lung Cancer (WCLC), hosted by the International Association for the Study of Lung Cancer in Yokohama, Japan. Specifically, these new data are an exploratory, post-hoc analysis focused on patients whose cancer rapidly progressed on first-line therapy. Time-to-progression (TTP) is defined as the time from start of first-line therapy until progressive disease - when the person's cancer grows, spreads or gets worse. In this analysis, aggressive disease was defined based on rapid TTP on first-line therapy.
"Despite recent advancements, patients with aggressive, rapidly progressing advanced non-small cell lung cancer who progress before or at the time of their first scan - which is typically done between nine and 12 weeks - often have a less favorable response to their second-line therapy. This is a population that has poor prognosis and immediate unmet needs with limited treatment options," said Martin Reck, M.D., Ph.D., Department of Thoracic Oncology, Lung Clinic Grosshansdorf.
Dr. Reck continued, "This REVEL exploratory analysis demonstrated that efficacy, safety, and quality-of-life outcomes among patients receiving ramucirumab plus docetaxel who have aggressive disease with rapid progression on first-line therapy are consistent with the outcomes of the intent-to-treat population. These results suggest that such patients may derive meaningful benefit from ramucirumab plus docetaxel in the second-line setting."
The global, randomized, double-blind, placebo-controlled REVEL Phase 3 study evaluated ramucirumab, in combination with docetaxel, in patients with metastatic NSCLC whose cancer had progressed on or after prior platinum-based chemotherapy for locally advanced or metastatic disease. REVEL, which included patients with nonsquamous and squamous forms of NSCLC, demonstrated improved overall survival ?OS?, progression?free survival ?PFS?, and objective response rate ?ORR) - independent of histology.(1) Please see the 'About REVEL' section below for more detailed efficacy and safety results in the trial's intent-to-treat (ITT) patient population. The REVEL ITT trial results, presented at the American Society of Clinical Oncology Annual Meeting in 2014, supported the U.S. Food and Drug Administration approval of ramucirumab in NSCLC in December 2014.
This new subgroup analysis focused on outcomes from patients according to their TTP on first-line treatment. Of the 1,253 patients enrolled in REVEL, on first-line therapy, 11 percent (n=133) had TTP <=9 weeks, 17 percent (n=209) had TTP <=12 weeks, and 28 percent (n=354) had TTP <=18 weeks. Baseline characteristics of each subgroup were balanced between treatment arms.
The results show that the trend for OS and PFS outcomes favored the ramucirumab-plus-docetaxel treatment arm, with hazard ratios similar to those of the ITT population. In all three subpopulations, ORR also favored the ramucirumab-plus-docetaxel treatment arm.
<=9 Weeks <=12 Weeks <=18 Weeks REVEL ITT Population
--------- ---------- ---------- --------------------
Ramucirumab + Placebo + Ramucirumab + Placebo + Ramucirumab + Placebo + Ramucirumab + Placebo +
Docetaxel Docetaxel Docetaxel Docetaxel Docetaxel Docetaxel Docetaxel Docetaxel
n=71 n=62 n=111 n=98 n=182 n=172 n=628 n=625
---- ---- ----- ---- ----- ----- ----- -----
Median OS, months 8.28 4.83 9.10 5.78 8.51 5.95 10.51 9.13
(95% CI) (9.53-11.24)
(5.19-10.84) (3.09-6.90) (6.70-10.84) (4.30-7.49) (6.97-9.95) (4.44-6.97) (8.44-10.02)
--- ----------- ---------- ----------- ---------- ---------- ---------- -----------
Unstratified HR 0.69 0.74 0.80 0.86
(95% CI)
(0.47-1.01) (0.54-1.00) (0.63-1.01) (0.75-0.98)
--- ---------- ---------- ---------- ----------
Median PFS, months 3.01 1.48 3.61 1.61 3.22 1.61 4.50 3.02
(95% CI)
(2.66-4.07) (1.41-1.87) (2.76-4.21) (1.45-2.60) (2.79-4.14) (1.48-2.60) (4.21-5.36) (2.79-3.94)
--- ---------- ---------- ---------- ---------- ---------- ---------- ---------- ----------
Unstratified HR 0.69 0.73 0.72 0.78
(95% CI)
(0.48-0.98) (0.55-0.97) (0.58-0.89) (0.69-0.87)
--- ---------- ---------- ---------- ----------
ORR, % 18.3 3.2 18.9 9.2 19.2 10.5 22.9 13.6
(95% CI)
(10.1-29.3) (0.4-11.2) (12.1-27.5) (4.3-16.7) (13.8-25.7) (6.3-16.0) (19.7-26.4) (11.0-16.5)
--- ---------- --------- ---------- --------- ---------- --------- ---------- ----------
Safety overview outcomes from patients with TTP on first-line therapy <=18 weeks are similar to what was observed from patients with TTP on first-line therapy <=9 weeks and <=12 weeks, as well as in the ITT population. There were no new safety signals observed in these subpopulations.
"We are encouraged by this REVEL subgroup analysis, as patients with this aggressive type of cancer who experience rapid disease progression on first-line therapy urgently need additional treatment options that can help stop or slow the cancer from growing and spreading," said Levi Garraway, M.D., Ph.D., senior vice president, global development and medical affairs, Lilly Oncology. "The results of this REVEL analysis add to the growing body of knowledge we have about aggressive lung cancer and demonstrates Lilly's longstanding commitment to advancing the science in lung cancer treatment and to improving the care of patients with this disease."
Notes to Editor
About REVEL
REVEL was a global, double-blind, randomized Phase 3 study of CYRAMZA (ramucirumab) plus docetaxel compared to placebo plus docetaxel in people with metastatic non-small cell lung cancer (NSCLC) whose cancer had progressed on or after prior platinum-based chemotherapy for locally advanced or metastatic disease. In total, 1,253 patients - including people with nonsquamous (73%) and squamous (26%) forms of NSCLC - were randomized in 26 countries over six continents.(1)
In the trial, CYRAMZA plus docetaxel achieved a statistically significant improvement in overall survival (the primary endpoint), progression-free survival and objective response rate (secondary endpoints). CYRAMZA plus docetaxel significantly extended median overall survival compared to placebo plus docetaxel (10.5 months [95% confidence interval (CI): 9.5, 11.2] vs. 9.1 months [95% CI: 8.4, 10.0], respectively; hazard ratio 0.86 [95% CI: 0.75, 0.98]; P=0.024). Furthermore, CYRAMZA plus docetaxel significantly delayed disease progression (progression-free survival of 4.5 months for CYRAMZA plus docetaxel [95% CI: 4.2, 5.4] vs. 3.0 months for placebo plus docetaxel [95% CI: 2.8, 3.9]; hazard ratio 0.76 [95% CI: 0.68, 0.86]; P<0.001). The percentage of deaths at the time of analysis was 68% (428 patients) and 73% (456 patients) in the CYRAMZA-plus-docetaxel and placebo-plus-docetaxel arms, respectively. The progression-free survival number of events was 558 (89%) and 583 (93%) for CYRAMZA-plus-docetaxel and placebo-plus-docetaxel treatment arms, respectively. Significantly more patients responded to CYRAMZA combined with docetaxel than with placebo plus docetaxel (23% [95% CI: 20, 26] for CYRAMZA plus docetaxel vs. 14% [95% CI: 11, 17] for placebo plus docetaxel; P<0.001).
The labeling for CYRAMZA contains a Boxed Warning for hemorrhage and additional Warnings and Precautions for arterial thromboembolic events, hypertension, infusion-related reactions, gastrointestinal perforations, impaired wound healing, clinical deterioration in patients with Child-Pugh B or C cirrhosis, and reversible posterior leukoencephalopathy syndrome. In the REVEL trial, the most common adverse reactions (all grades) observed in patients treated with CYRAMZA plus docetaxel at a rate of >=30% and >=2% higher than placebo were neutropenia (low white blood cell count) (55% vs. 46%), fatigue/asthenia (weakness) (55% vs. 50%) and stomatitis/mucosal inflammation (37% vs. 19%). The most common serious adverse events with CYRAMZA were febrile neutropenia (fever and potentially other infection signs along with low white blood cell count) (14%), pneumonia (6%), and neutropenia (5%); 42% of patients treated with CYRAMZA plus docetaxel received granulocyte colony-stimulating factors (treatment for low white blood cells) vs. 37% of patients who received placebo plus docetaxel. See the Important Safety Information at the end of this press release and the Prescribing Information.
About Lung Cancer
Lung cancer is the leading cause of cancer death in the U.S. and most other countries, killing nearly 1.6 million people worldwide each year.(2) In the U.S., lung cancer is responsible for approximately 27 percent of all cancer deaths, more than those from breast, colon and prostate cancers combined.(3) Stage IV non-small cell lung cancer (NSCLC) is a very difficult-to-treat cancer and the prognosis is poor for metastatic NSCLC.(4) NSCLC is much more common than other types of lung cancer, and accounts for about 85 percent of all lung cancer cases.(5) For those people affected by NSCLC, about 70 percent have nonsquamous cell carcinoma, while about 30 percent have squamous cell carcinoma.(5) Approximately half of patients with metastatic NSCLC who begin first-line therapy will move on to second-line treatment.(6) Despite currently available therapies, there continues to be a need for new second-line treatment options for patients with NSCLC.(1)
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.
Ramucirumab is being investigated in a broad global development program that has enrolled more than 10,000 patients across more than 70 trials worldwide. There are several studies underway or planned to investigate ramucirumab as a single agent and in combination with other anti-cancer therapies for the treatment of multiple tumor types. Previously completed Phase 3 studies of ramucirumab have demonstrated benefit in advanced forms of gastric, non-small cell lung and colorectal cancer ¾ three of the world's leading causes of cancer-related deaths.
Ramucirumab 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. Ramucirumab 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 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.
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
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 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 newsroom.lilly.com/social-channels. P-LLY
© Lilly USA, LLC 2017. 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 Cyramza as a potential treatment for patients with advanced non-small cell lung cancer, gastric cancer, and colorectal cancer, 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 additional regulatory approvals or 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 Garon EB, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384:665-73.
2 International Agency for Research on Cancer. GLOBOCAN 2012. Lung Cancer Estimated Incidence, Mortality and Prevalence Worldwide in 2012. http://globocan.iarc.fr. Accessed October 12, 2017.
3 American Cancer Society. What are the key statistics about lung cancer? http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-key-statistics. Updated January 5, 2017. Accessed October 12, 2017.(
)4 American Cancer Society. Learn about cancer: Non-small cell lung cancer survival rates by stage http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-survival-rates. Updated May 16, 2016. Accessed October 12, 2017.
5 American Cancer Society. What is non-small cell lung cancer? http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-what-is-non-small-cell-lung-cancer. Updated May 16, 2016. Accessed October 12, 2017.
6 Stinchcombe TE, Socinski MA. Considerations for Second-Line Therapy of Non-Small Cell Lung Cancer. Oncologist. 2008;13:28-36.
Refer to: Tracy Henrikson; tracy.henrikson@lilly.com; 609-240-3902 (media)
Phil Johnson; johnson_philip_l@lilly.com; 317-655-6874 (investors)
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