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FDA Approves Cyramza (Ramucirumab) for Use with FOLFIRI in Second-Line Treatment of Metastatic Colorectal Cancer

INDIANAPOLIS, April 24, 2015 /PRNewswire/ -- Eli Lilly and Company (NYSE: LLY) has received its fourth U.S. Food and Drug Administration (FDA) approval for Cyramza (ramucirumab). Cyramza (ramucirumab injection 10 mg/mL solution) is now also indicated in combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil) chemotherapy for the treatment of patients with metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.

"Cyramza now has approvals in advanced or metastatic forms of three of the world's most common and deadly cancers – gastric, non-small cell lung, and colorectal – with four FDA approvals received in just over a year," said Sue Mahony, Ph.D., senior vice president and president, Lilly Oncology. "This progress is encouraging and supports our ongoing development program for Cyramza. Achieving today's milestone is another example of Lilly's commitment to people living with gastrointestinal cancers."

Dr. Mahony added, "We are also pleased with the efficient and collaborative reviews we had with the FDA on these submissions." While granted a standard review, this application for Cyramza in mCRC was reviewed and approved in approximately nine weeks following its submission to the FDA. All three supplemental applications for Cyramza received FDA approval within six months from the time of submission.

The approval is based on the Phase III trial known as RAISE, which compared Cyramza plus FOLFIRI to placebo plus FOLFIRI in people with mCRC who had disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. Efficacy endpoints in the trial included the major efficacy outcome measure of overall survival (OS) and the supportive efficacy outcome measure of progression-free survival (PFS). The labeling for Cyramza contains Boxed Warnings for: hemorrhage, including severe and sometimes fatal events; gastrointestinal (GI) perforation, a potentially fatal event; and impaired wound healing. Cyramza should be permanently discontinued in patients who experience severe bleeding or a GI perforation. Cyramza should be withheld prior to surgery and discontinued if a patient develops wound healing complications. See the Important Safety Information and the Prescribing Information for Cyramza.

For patients receiving Cyramza treatment, Lilly is committed to offering patient assistance programs. Patients, physicians, pharmacists, or other healthcare professionals with additional questions about CYRAMZA should contact The Lilly Answers Center at 1-800-LillyRx (1-800-545-5979) or visit www.lilly.com.

About Cyramza (ramucirumab)

In the U.S., Cyramza (ramucirumab) is approved for use as a single agent or in combination with paclitaxel (a type of chemotherapy) 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 (a type of chemotherapy) 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 (a type of chemotherapy) as a therapy for people with metastatic colorectal cancer (mCRC) whose cancer has progressed on or after therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.

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.

About Angiogenesis and VEGF

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 and 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 the RAISE Trial

RAISE was a global, double-blind Phase III study of Cyramza plus FOLFIRI compared to placebo plus FOLFIRI as a second-line treatment for mCRC in patients who had disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. Patients were randomized in a 1:1 ratio to receive Cyramza plus FOLFIRI (n=536) or placebo plus FOLFIRI (n=536) every two weeks.

In the RAISE trial, patients treated with the Cyramza-FOLFIRI combination achieved a median OS, the study's primary endpoint, of 13.3 months as compared to those treated with placebo-FOLFIRI who achieved 11.7 months, a statistically significant improvement that reduced the risk of patient death by 15 percent (HR 0.85; 95% CI: 0.73-0.98; p=0.023). The percentage of deaths at the time of analysis was 69 percent (372 patients) and 74 percent (397 patients) in the Cyramza-plus-FOLFIRI and placebo-plus-FOLFIRI treatment arms, respectively. The Cyramza combination also demonstrated a statistically significant improvement in the secondary endpoint of PFS over the placebo-FOLFIRI regimen, with a median PFS of 5.7 months vs. 4.5 months, respectively (HR 0.79; 95% CI: 0.70-0.90; p<0.001). The percentage of events at the time of analysis was 89 percent (476 patients) and 92 percent (494 patients) in the Cyramza-plus-FOLFIRI and placebo-plus-FOLFIRI treatment arms, respectively. In the RAISE trial, randomization was stratified by geographic region, tumor KRAS status, and time to disease progression after beginning first-line treatment (<6 months vs. ≥6 months). The treatment effect was consistent across the pre-specified stratification factors.

The labeling for Cyramza contains Boxed Warnings for hemorrhage, GI perforation, and impaired wound healing and additional Warnings and Precautions for arterial thromboembolic events, hypertension, infusion-related reactions, clinical deterioration in patients with Child-Pugh B or C cirrhosis, reversible posterior leukoencephalopathy syndrome, proteinuria including nephrotic syndrome, thyroid dysfunction, and embryofetal toxicity. The most common adverse reactions (all grades) observed in Cyramza-plus-FOLFIRI-treated patients at a rate of ≥30 percent and ≥2 percent higher than placebo plus FOLFIRI were diarrhea (60% vs. 51%), neutropenia (59% vs. 46%), decreased appetite (37% vs. 27%), epistaxis (33% vs. 15%), and stomatitis (31% vs. 21%). The most common serious adverse events with Cyramza plus FOLFIRI were diarrhea (3.6%), intestinal obstruction (3.0%), and febrile neutropenia (2.8%).

About Colorectal Cancer

Colorectal cancer (CRC) is a cancer that develops in the colon or the rectum, which are both parts of the gastrointestinal system. Metastatic CRC (mCRC) occurs when the disease has spread to at least one distant organ, such as the liver, lungs, or lining of the abdomen.

Despite advances in treating CRC in recent years, the mortality rate remains significant. CRC is the second leading cause of cancer death in the U.S. and fourth leading cause of cancer death worldwide, killing nearly 700,000 people in 2012.i,ii,iii The global incidence of CRC is estimated to be over 1.3 million.i Approximately one out of five CRC patients is diagnosed with metastatic disease, and the five-year survival rate for these patients is 12.9 percent.iii

Lilly PatientOne

The Lilly PatientOne program addresses financial and coverage issues for qualified uninsured, underinsured, and insured patients who are prescribed a Lilly Oncology product. Lilly PatientOne provides reimbursement assistance for eligible patients who are prescribed a Lilly Oncology product, such as information about coding and billing, prior authorization, benefits investigation, and denied claim appeals, as well as operating a patient assistance program. To learn more, visit www.LillyPatientOne.com or call 1-866-4PatOne (1-866-472-8663).

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 newsroom.lilly.com/social-channels. (P-LLY)

RB96717 04/2015 © Lilly USA, LLC 2015. ALL RIGHTS RESERVED.

Cyramza is a trademark owned by or licensed to Eli Lilly and Company, its subsidiaries, or affiliates.

This press release contains forward-looking statements about the potential of Cyramza (ramucirumab) as a treatment of metastatic 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. There can be no guarantee that future study results and patient experience will be consistent with the study findings to date. There can also be no guarantee that Cyramza will receive regulatory approval for any future indications or that it will prove to be commercially successful. For further discussion of these and other risks and uncertainties that could cause actual results to differ from Lilly's expectations, please see the company's latest Forms 10-K and 10-Q filed with the U.S. Securities and Exchange Commission. Except as required by law, Lilly undertakes no duty to update forward-looking statements.

i Globocan: Estimated Cancer Incidence, Mortality and Prevalence Worldwide, 2012. http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx (Accessed: April 22, 2015).
ii American Cancer Society, Cancer Facts & Figures 2015. Atlanta: American Cancer Society; 2015. http://www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf (Accessed: March 5, 2015).
iii National Cancer Institute, SEER 18 2004-2010, All Races, Both Sexes by SEER Summary Stage 2000. http://seer.cancer.gov/statfacts/html/colorect.html (Accessed: April 22, 2015).

SOURCE Eli Lilly and Company

Posted: April 2015

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