Lilly's CYRAMZA® (ramucirumab) Phase 3 RELAY Trial Met Primary Endpoint, Significantly Improving Progression-Free Survival in First-Line Treatment of Patients with Metastatic EGFR-Mutated Non-Small Cell Lung Cancer

Global, randomized, placebo-controlled study confirms CYRAMZA, in combination with erlotinib, significantly delayed disease progression in previously untreated patients with metastatic non-small cell lung cancer whose tumors have activating EGFR mutations

Global regulatory submissions to be initiated this year

Second positive Phase 3 study of CYRAMZA in metastatic non-small cell lung cancer

INDIANAPOLIS, IN, USA I March 12, 2019 I Eli Lilly and Company (NYSE: LLY) today announced that its Phase 3 RELAY study of CYRAMZA® (ramucirumab) met its primary endpoint of progression-free survival (PFS), demonstrating a statistically significant improvement in the time patients lived without their cancer growing or spreading after starting treatment. The Phase 3 global, randomized, double-blind trial is evaluating CYRAMZA in combination with erlotinib, compared to placebo in combination with erlotinib, as a first-line treatment in patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have activating EGFR mutations.

The safety profile observed in the RELAY study was consistent with what has been previously observed for CYRAMZA in Phase 3 clinical trials and the established safety profile of erlotinib. The most common (>5% incidence) Grade ≥3 adverse events occurring at a higher rate (≥5% difference) on the CYRAMZA-plus-erlotinib arm compared to the placebo-plus-erlotinib arm were hypertension, dermatitis acneiform (an acne-like rash), and diarrhea. Detailed efficacy and safety results will be submitted for presentation at a medical meeting in 2019.

"Despite recent treatment advances in metastatic EGFR-mutated non-small cell lung cancer, prognosis remains poor and there is an ongoing need for additional first-line treatment options to help patients with this deadly disease," said Maura Dickler, M.D., vice president of late phase development, Lilly Oncology.

There is no cure for people with metastatic lung cancer. The disease is associated with low survival rates and disease progression following acquired resistance remains a challenge. Most patients receive several lines of treatment and the therapeutic regimen prescribed for first-line treatment can impact a person's options for later lines of treatment. Tyrosine kinase inhibitors (TKIs) are the current standard treatment option for EGFR-mutated NSCLC. Erlotinib, the TKI included in the RELAY trial regimen, is a globally recognized standard of care for this type of lung cancer.

"We are excited about these results, which show CYRAMZA plus erlotinib significantly delayed disease progression in this patient population. The RELAY trial is another example of Lilly's deep commitment to providing new treatment options to patients with lung cancer," said Dr. Dickler. "We would like to thank the patients, investigators and clinical trial sites that are participating in the RELAY study, and we look forward to working with regulatory authorities globally on our submissions."

Lilly intends to initiate global regulatory submissions in mid-2019.

RELAY is the second positive Phase 3 study of CYRAMZA in metastatic NSCLC. In the positive Phase 3 REVEL study, CYRAMZA plus docetaxel was compared to placebo plus docetaxel in people with metastatic NSCLC whose cancer had progressed on or after prior platinum-based chemotherapy for locally advanced or metastatic disease. The primary endpoint of overall survival was met, as well as key secondary endpoints of PFS and response rate. The REVEL results supported CYRAMZA's current indication in second-line NSCLC.

Results of previously completed Phase 3 studies of CYRAMZA have also supported approvals in second-line gastric and colorectal cancer. Based on the REACH-2 results, Lilly has made regulatory submissions in the U.S., EU and Japan for the use of CYRAMZA in second-line treatment of patients with hepatocellular carcinoma.

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 (epidermal growth factor receptor) exon 19 deletions or exon 21 (L858R) substitution mutations. Initiated in 2015, the study randomized 449 patients across North America, Europe and Asia. The primary endpoint of the RELAY trial is progression-free survival; key secondary endpoints include safety, response rate, overall survival, and patient-reported outcomes. 

About Lung Cancer and EGFR Mutations
Lung cancer is the leading cause of cancer death in the U.S. and most other countries, killing nearly 1.7 million people worldwide each year.1 In the U.S., lung cancer is responsible for approximately 25 percent of all cancer deaths, more than those from breast, colon and prostate cancers combined.2 Non-small cell lung cancer (NSCLC) is much more common than other types of lung cancer and accounts for about 80 to 85 percent of all lung cancer cases.3 Stage IV NSCLC is a very difficult-to-treat cancer and the prognosis is poor for metastatic NSCLC.4 

EGFR is a protein that helps cells grow and divide. When the EGFR gene is mutated it can cause the protein to be overactive, resulting in the formation of cancer cells. EGFR mutations may occur in 10 to 35 percent of NSCLC tumors globally.5 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.6,7,8 Regardless of ethnicity, these mutations are commonly found in females, non-smokers and those with adenocarcinoma histology.9,10 The most common EGFR mutations are activating exon 19 deletion and exon 21 (L858R) substitution mutations, which are present in over 90 percent of EGFR-mutated tumors.7,8  

About CYRAMZA® (ramucirumab)
In the U.S., CYRAMZA (ramucirumab) is approved for use as a single agent or in combination with paclitaxel as a treatment for people with advanced or metastatic gastric (stomach) or gastroesophageal junction (GEJ) adenocarcinoma whose cancer has progressed on or after prior fluoropyrimidine- or platinum-containing chemotherapy. It is also approved in combination with docetaxel as a treatment for people with metastatic non-small cell lung cancer (NSCLC) whose cancer has progressed on or after platinum-based chemotherapy. Additionally, it is approved with FOLFIRI as a treatment for people with metastatic colorectal cancer (mCRC) whose cancer has progressed on or after therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.

CYRAMZA is being investigated in a broad global development program that has enrolled more than 14,000 patients across more than 100 trials worldwide. These include several studies investigating CYRAMZA in combination with other anti-cancer therapies for the treatment of multiple tumor types.

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.

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 http://newsroom.lilly.com/social-channels. P-LLY

1 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 March 11, 2019.  
2 American Cancer Society. Cancer Facts and Figures 2018. Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2018/cancer-facts-and-figures-2018.pdf. Accessed March 11, 2019.
3 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 March 11, 2019.  
4 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 March 11, 2019.
5 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.
6 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.
7 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.
8 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 March 11, 2019.
9 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.
10 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.

SOURCE: Eli Lilly

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