INDIANAPOLIS, Sept. 18, 2014 /PRNewswire/ -- Eli Lilly and Company (NYSE: LLY) today announced that results of the global Phase III trial of ramucirumab (CYRAMZA™) in combination with paclitaxel in patients with advanced gastric (stomach) cancer or gastroesophageal junction (GEJ) adenocarcinoma were published in the online version of The Lancet Oncology.

In the trial, known as RAINBOW, the addition of ramucirumab to paclitaxel showed a statistically significant improvement in median overall survival, meeting its primary endpoint; it also met secondary endpoints of progression-free survival and objective response rate. RAINBOW is the largest trial in second-line gastric cancer to date and the first Phase III study to demonstrate a survival benefit with a biologic used in combination with chemotherapy in this setting.  Data from the RAINBOW trial were first presented at the Gastrointestinal Cancers Symposium (ASCO GI) in January 2014.

Ramucirumab has now been the focus of two positive Phase III gastric cancer trials that have demonstrated statistically significant improvements in both overall survival and progression-free survival. The first trial, REGARD, examined ramucirumab as a single-agent treatment for patients with advanced or metastatic gastric or GEJ adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy. These study results were published in 2013. 

"As the third leading cause of cancer death worldwide, stomach cancer is a major global health issue," said Richard Gaynor, M.D., senior vice president, product development and medical affairs for Lilly Oncology. "We are encouraged by the RAINBOW study results and are pleased that we now have a second Phase III trial of ramucirumab which has demonstrated improved survival in advanced gastric cancer patients."

RAINBOW was a global, randomized, double-blinded Phase III study of ramucirumab and paclitaxel compared to placebo and paclitaxel as treatment in patients with advanced (locally advanced, unresectable or metastatic) gastric cancer or GEJ adenocarcinoma that was refractory to or progressive after initial platinum- and fluoropyrimidine-containing chemotherapy.

"I am very pleased that this trial demonstrated a significant and clinically meaningful benefit for patients with advanced stomach cancer," said Hansjochen Wilke, M.D., department of medical oncology, hematology with the Center for Palliative Care at Kliniken Essen-Mitte in Germany, and principal investigator of the RAINBOW trial. "Currently, there is a significant need for effective therapies to help combat this deadly disease and ramucirumab in this combination could provide a valuable second-line treatment option."

Patients randomized to the ramucirumab-plus-paclitaxel arm had a median survival benefit of 9.6 months, compared to 7.4 months for patients on the placebo-plus-paclitaxel arm (stratified hazard ratio 0.807 [95% confidence interval (CI), 0.678-0.962; p=0.0169]). Treatment with ramucirumab plus paclitaxel significantly reduced the risk of disease progression or death (by 37 percent), with a 52 percent increase in median progression-free survival compared with placebo plus paclitaxel (4.4 months vs. 2.9 months; stratified hazard ratio 0.635 [95% CI, 0.536-0.752; p < 0.0001]).  There was a statistically significant increase in objective response rate, from 16 to 28 percent, with the addition of ramucirumab (p=0.0001).

The following adverse events (grade 3 or higher) occurred at a higher rate and for more than 10 percent of patients on the ramucirumab-plus-paclitaxel arm: neutropenia, or a decrease in a specific type of white blood cell (neutrophils) (41% vs. 19%); leukopenia, or decreased white blood cell count (all white blood cells) (17% vs. 7%); hypertension, or high blood pressure (15% vs. 3%); and fatigue/asthenia (12% vs. 5%). The incidence of febrile neutropenia, or a fever combined with decreased neutrophils, was low in both trial arms (3% vs. 2%, respectively).

Data from the RAINBOW trial are the basis for regulatory submissions in the U.S. and EU; plans for a submission to Japanese regulatory authorities in the second half of 2014 are on track.

Notes to Editor                              
About the RAINBOW Trial             
RAINBOW was a global, randomized, double-blinded, placebo-controlled Phase III study of ramucirumab and paclitaxel compared to placebo and paclitaxel in patients with advanced (locally advanced, unresectable or metastatic) gastric cancer (including adenocarcinomas of the gastroesophageal junction) refractory to or progressive after initial platinum- and fluoropyrimidine-containing chemotherapy. Initiated in 2010, the global study randomized a total of 665 patients across 27 countries in North America, South America, Europe, Australia and Asia. 

About Gastric Cancer                    
Gastric (stomach) cancer is a major health problem. It is the fifth most common cancer in the world and is the third-leading cause of cancer death. There were nearly one million new cases worldwide in 2012 (631,000 men, 320,000 women) with approximately 723,000 deaths (469,000 men, 254,000 women).ⁱ Stomach cancer is more prevalent in countries outside the U.S. and EU.ⁱⁱ In the U.S., it is estimated that approximately 22,000 people will be diagnosed with gastric cancer in 2014.ⁱⁱⁱ

Gastric cancer is a disease in which cancer cells form in the stomach. It develops slowly, usually over many years, and often goes undetected.^iv As stomach cancer advances, it can travel through the bloodstream and spread to organs such as the liver, lungs and bones.^v

The most common type of stomach cancer is called adenocarcinoma, which starts from one of the common cell types found in the lining of the stomach.^vi

About Angiogenesis               
Angiogenesis is the process of making new blood vessels. This process involves the migration, growth, and differentiation of endothelial cells, which line the inside wall of blood vessels. Chemical signals in the body stimulate the repair of damaged blood vessels and formation of new blood vessels during this process.

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.^vii

About Ramucirumab (CYRAMZA™)
Ramucirumab, marketed as CYRAMZA, is approved for use as a single agent in the U.S. for patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma who have progressed after prior fluoropyrimidine- or platinum-containing chemotherapy. CYRAMZA inhibited angiogenesis in an in vivo animal model. CYRAMZA is a VEGF Receptor 2 antagonist that specifically binds and blocks activation of VEGF Receptor 2 and blocks binding of VEGF receptor ligands VEGF-A, VEGF-C, and VEGF-D.

There are several studies underway or planned to investigate CYRAMZA as a single agent and in combination with other anti-cancer therapies for the treatment of multiple tumor types.

Indication for CYRAMZA           
CYRAMZA as a single agent is indicated for the treatment of patients with advanced or metastatic gastric or gastroesophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.

IMPORTANT SAFETY INFORMATION FOR CYRAMZA

Warnings and Precautions            
Hemorrhage

• CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. 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. Patients with gastric cancer receiving nonsteroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Study 1; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Arterial Thromboembolic Events

• Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. 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%). Control hypertension prior to initiating treatment with CYRAMZA. 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

• Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion-related reactions (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. Symptoms of IRRs 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. 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

• CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation. 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 is an antiangiogenic therapy with the potential to adversely affect 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. 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. 

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

• RPLS has been reported at a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and 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.

Most Common Adverse Reactions

• 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 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%.
• As with all therapeutic proteins, there is the potential for immunogenicity. In clinical trials, 33/443 (7.4%) CYRAMZA-treated patients with post-baseline serum samples tested positive for anti-ramucirumab antibodies using an enzyme-linked immunosorbent assay (ELISA). However, this assay has limitations in detecting anti-ramucirumab antibodies in the presence of ramucirumab; therefore, the incidence of antibody development may not have been reliably determined. Neutralizing antibodies were detected in 1 of the 33 patients who tested positive for anti-ramucirumab antibodies.

Drug Interactions

• No formal drug interaction studies have been conducted.

Use in Specific Populations

• Pregnancy Category C: Based on its mechanism of action, CYRAMZA may cause fetal harm. Advise females of reproductive potential to avoid getting pregnant, including use of adequate contraception, while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. Animal models link angiogenesis, VEGF and VEGF Receptor 2 to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no adequate or well-controlled studies of ramucirumab in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.
• Nursing Mothers: It is recommended to discontinue nursing or discontinue CYRAMZA due to the potential risks to the nursing infant.
• Females of Reproductive Potential: Advise females of reproductive potential that CYRAMZA may impair fertility.

Please see full Prescribing Information for CYRAMZA, including Boxed Warning for hemorrhage.

RB HCP ISI 21 JUL2014

About Lilly Oncology             
For more than fifty 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 http://newsroom.lilly.com/social-channels.

P-LLY

This press release contains forward-looking statements about the potential of Cyramza (ramucirumab) as a treatment of various cancers 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. There is no guarantee that future studies will be positive or that ramucirumab will receive additional regulatory approvals or prove to be commercially successful. For further discussion of these and other risks and uncertainties, see Lilly's filings with the United States Securities and Exchange Commission. Lilly undertakes no duty to update forward-looking statements.

ⁱ Globocan 2012 Cancer Fact Sheet. Stomach cancer estimated incidence, mortality and prevalence worldwide in 2012. http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Accessed September 17, 2014.

ⁱⁱ Globocan 2012 Cancer Fact Sheet. Stomach cancer estimated incidence, mortality and prevalence worldwide in 2012. http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Accessed September 17, 2014.

ⁱⁱⁱ American Cancer Society. What are the key statistics about stomach cancer? http://www.cancer.org/Cancer/StomachCancer/DetailedGuide/stomach-cancer-key-statistics. Updated May 27, 2014. Accessed September 17, 2014.

^iv American Cancer Society. What is stomach cancer? http://www.cancer.org/cancer/stomachcancer/detailedguide/stomach-cancer-what-is-stomach-cancer. Updated May 27, 2014. Accessed September 17, 2014.

^v American Cancer Society. What is stomach cancer? http://www.cancer.org/cancer/stomachcancer/detailedguide/stomach-cancer-what-is-stomach-cancer. Updated May 27, 2014. Accessed September 17, 2014.

^vi National Center for Biotechnology Information. Gastric cancer. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001270/. Updated October 30, 2013. Accessed September 17, 2014.

^vii Spratlin J. Ramucirumab (IMC-1121B): monoclonal antibody inhibition of vascular endothelial growth factor receptor-2. Curr Oncol Rep. 2011;13(2):97-102.

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