Lilly Announces CYRAMZA® (ramucirumab) Phase 3 REACH-2 Study in Second-Line Hepatocellular Carcinoma Patients Met Overall Survival Endpoint

REACH-2 is the first positive Phase 3 hepatocellular carcinoma (HCC) trial in a biomarker-selected population; Approximately half of all advanced HCC patients have a high alpha-fetoprotein (AFP-High), a marker of poor prognosis

INDIANAPOLIS, IN, USA I April 4, 2018 I Eli Lilly and Company (NYSE: LLY) today announced top-line results from its Phase 3 REACH-2 study of CYRAMZA® (ramucirumab) as a single agent in the second-line treatment of people with hepatocellular carcinoma (HCC), also known as liver cancer. The trial met its primary endpoint of overall survival (OS) as well as the secondary endpoint of progression-free survival (PFS). CYRAMZA has now demonstrated a survival benefit in four aggressive, difficult-to-treat tumor types in Phase 3 studies, including as a single agent in both gastric cancer and HCC.

The safety profile observed in the REACH-2 study was consistent with what has been previously observed for single-agent CYRAMZA. The only Grade ≥3 adverse events occurring at a rate of five percent or greater in the CYRAMZA arm were hypertension and hyponatremia (low sodium). The efficacy and safety results will be submitted for presentation at a future medical meeting.

REACH-2 is the first positive Phase 3 HCC trial in a biomarker-selected patient population. The REACH-2 study evaluated the benefit of CYRAMZA treatment in HCC patients who were intolerant to, or had disease progression while on or following treatment with, sorafenib and had a high alpha-fetoprotein (AFP-High), defined as an AFP of ≥400 ng/mL. Approximately half of all advanced HCC patients are AFP-High and these patients are among those with the poorest prognosis relative to the general HCC patient population. While there have been some recent advances in treating HCC, there remains a very high unmet need for patients in this treatment setting.

"Advanced liver cancer is an aggressive disease that has a poor prognosis – and for those that have elevated AFP levels, the prognosis is even more dismal. The expected survival of these patients is only a few months following first-line treatment if they don't go onto second-line therapy. For this reason, Lilly is encouraged by the results of REACH-2 and the potential for CYRAMZA to benefit patients in this setting," said Levi Garraway, M.D., Ph.D., senior vice president, global development and medical affairs, Lilly Oncology.

With this positive outcome, the REACH-2 study has confirmed the hypothesis generated by the REACH trial results,1 which showed that a pre-specified subgroup of advanced HCC patients who were AFP-High derived a survival benefit from treatment with CYRAMZA following first-line treatment with sorafenib. This REACH-2 outcome also builds upon Lilly's efforts and commitment to providing treatment options for people living with HCC and gastrointestinal cancers. In addition to the Phase 3 REACH and REACH-2 trials, Lilly is evaluating CYRAMZA with an immuno-oncology agent in HCC in a Phase 1b study cohort, and is conducting various studies of CYRAMZA in other gastrointestinal cancers, including gastric, colorectal and biliary tract. 

Dr. Garraway added, "We thank the patients, their caregivers and investigators for their support of and participation in the REACH-2 study. Without their contributions, we could not have achieved today's milestone – which represents important progress in our efforts to help people living with liver cancer and, more broadly, gastrointestinal cancers."

Lilly intends to initiate regulatory submissions in mid-2018.

Previously completed Phase 3 studies of CYRAMZA have demonstrated benefit in advanced forms of gastric, non-small cell lung and colorectal cancer – three of the world's leading causes of cancer-related death. An ongoing Phase 3 trial in advanced urothelial carcinoma has met its primary endpoint of PFS, and OS data are expected in the first half of 2018. Another ongoing Phase 3 study of CYRAMZA – in EGFR-positive non-small cell lung cancer – is ongoing, with an expected PFS data readout in late 2018.

Notes to Editors

About REACH-2
REACH-2 is a global, randomized, double-blind, placebo-controlled Phase 3 study of CYRAMZA and best supportive care (BSC) compared to placebo and BSC in hepatocellular carcinoma (HCC) patients who were intolerant to, or that had disease progression while on or following treatment with, sorafenib and had a high alpha-fetoprotein (AFP-High), defined as an AFP of ≥400 ng/mL.

Initiated in 2015, the study has enrolled 292 patients across 20 countries in North America, Asia, Europe and Latin America. The primary endpoint of the REACH-2 trial is overall survival and key secondary endpoints include progression-free survival, objective response rate, quality of life, and safety. 

The design of the REACH-2 trial was based on the findings of the Phase 3 REACH study,1 which also evaluated single-agent CYRAMZA in the second-line treatment of HCC following first-line treatment with sorafenib. While the REACH trial's primary endpoint of OS favored the CYRAMZA arm, it was not statistically significant. However, in a pre-specified subgroup of patients who were AFP-High, a greater survival benefit was observed along with meaningful improvements in key secondary endpoints and a safety profile consistent with what has been previously observed for single-agent CYRAMZA.

About Alpha-Fetoprotein
Alpha-fetoprotein (AFP) is a glycoprotein that is produced in early fetal life by the liver and by a variety of tumors including HCC, hepatoblastoma, and nonseminomatous germ cell tumors of the ovary and testis. A person's AFP, measured in nanograms per milliliter (ng/mL), is assessed through a blood test. An AFP level of less than 10 ng/mL is generally considered normal for adults.2,3 It is estimated that approximately half of all people with advanced HCC are AFP-High (≥400 ng/mL) and these patients are known to have a poorer prognosis relative to the general HCC patient population.1 

About Hepatocellular Carcinoma 
Liver cancer is the sixth most common cancer worldwide and the second-leading cause of cancer-related death. Each year approximately 780,000 new cases of liver cancer are diagnosed worldwide, and more than 740,000 will die of the disease. According to the World Health Organization, approximately 30,000 people are diagnosed with liver cancer, and 24,000 will die from the disease each year in the United States. In Europe and Japan, an estimated 63,000 and 36,000 people are diagnosed with liver cancer, and 62,000 and 33,000 will die, respectively.4 

The prognosis for advanced HCC patients is typically very poor. Surgery is not an option for the majority of advanced HCC patients, as the tumor has often grown or metastasized to the extent that resection is not feasible. Advanced HCC is a disease with few approved systemic treatments, and most patients have significant liver damage which can further limit therapy options. Once patients who are AFP-High enter the second-line treatment setting, the expected survival is three to five months if untreated.1

Despite recent advances in the treatment of chronic liver disease, the incidence of HCC is still expected to rise in the coming decades due to several factors: under-diagnosis of chronic liver disease; increasing prevalence of diabetes, obesity and fatty liver disease; and, lack of access to viral hepatitis disease therapy and the persistent risk of cancer even after viral hepatitis cure.5

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.

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 12,000 patients across more than 70 trials worldwide. These include several studies investigating CYRAMZA in combination with other anti-cancer therapies for the treatment of multiple tumor types.

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.

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 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    

SOURCE: Eli Lilly

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