Lilly Builds Upon Body of Clinical Evidence for CYRAMZA® (ramucirumab) with Phase 3 RANGE Data Demonstrating Superior Progression-Free Survival in Advanced or Metastatic Urothelial Cancer

Randomized, placebo-controlled study confirms ramucirumab, in combination with docetaxel, significantly extended progression-free survival (PFS) in patients with platinum-refractory advanced urothelial carcinoma, also shows objective response rate of 24.5 percent at this PFS data readout
RANGE data presented at ESMO 2017 Congress Presidential Symposium and to be published in The Lancet

INDIANAPOLIS, IN, USA I September 10, 2017 I At the European Society for Medical Oncology (ESMO) 2017 Congress today, Phase 3 RANGE data from Eli Lilly and Company (NYSE: LLY) were presented in the Presidential Symposium (abstract#: LBA4_PR). These are the first detailed results from the global, randomized, double-blinded, placebo-controlled RANGE study of CYRAMZA® (ramucirumab), in combination with docetaxel, in patients with advanced or metastatic urothelial carcinoma whose disease progressed on or after platinum-based chemotherapy. The data showed a statistically significant improvement in progression-free survival (PFS) in patients treated with ramucirumab plus docetaxel when compared to those who received placebo plus docetaxel, with a 46 percent prolongation in median PFS. These RANGE data will be published online in The Lancet on Tuesday, September 12, 2017 at 6:30 p.m. EDT.

RANGE is the first and only Phase 3 study of any therapy to show superior PFS over chemotherapy in a post-platinum setting in urothelial cancer. Also, ramucirumab is the first anti-angiogenic agent to extend PFS in a Phase 3 trial in urothelial cancer. Patients previously treated with a checkpoint inhibitor were allowed to enroll in the RANGE study. PFS is the trial's primary endpoint, and secondary endpoints include overall survival (OS), objective response rate (ORR), disease control rate (DCR) and patient-reported outcomes (PRO).

"It's been an exciting and eventful time in urothelial carcinoma medicine research and development over the last several years, going from very few approved therapies to many new treatment options now available this year. However, many patients treated with these new therapies have progressive disease as best response--meaning that their cancer is still growing, spreading or getting worse. This is what is driving the clinical community to continue to investigate additional targets for treatments that can help quickly control disease progression," said Daniel Petrylak, M.D., professor of medical oncology and urology at Yale Cancer Center and principal investigator of the RANGE study. "We are looking at ramucirumab in this way, as RANGE is the first Phase 3 study to show the benefit of targeting angiogenesis in urothelial cancer and the first therapy to show superior progression-free survival over chemotherapy in a post-platinum setting. This benefit also confirms the efficacy seen in the Phase 2 study."

Patients treated on the ramucirumab-plus-docetaxel arm (n=263) achieved a median PFS of 4.1 months compared to 2.8 months for patients on the placebo-plus-docetaxel arm (n=267). The PFS hazard ratio (HR) was 0.757 (95% CI, 0.607-0.943, p=0.0118), which corresponds to a 24 percent reduction in the rate of disease progression or death. These investigator-assessed PFS results were confirmed by a blinded central radiographic review (HR, 0.672; 95% CI, 0.536-0.842; p=0.0005). In addition, PFS results were consistent across pre-specified subgroups.

Importantly, the PFS HR was consistent across three subgroups defined by poor prognostic factors (HR, 0.694-0.764)--patients with ECOG 1 performance status, liver metastases or a short interval of < 3 months since prior therapy. The majority of patients (415 of 530) had at least one risk factor--44 percent had two or more.

An analysis of the PFS data in the first 437 patients of the intent-to-treat (ITT) population showed that the ramucirumab-plus-docetaxel arm had an ORR of 24.5 percent (95% CI, 18.8-30.3) compared to 14.0 percent in the placebo-plus-docetaxel arm (95% CI, 9.4-18.6). Given the gated statistical design of the protocol, statistical analysis for significance of ORR will be assessed following the OS endpoint (at the time of the primary PFS analysis, OS data were immature). Although the number of enrolled patients that had received a prior immune checkpoint inhibitor was relatively small--as this trial was initiated in 2015 when several other such trials were ongoing and no approved agents were available--the ORR at this PFS readout in those patients was consistent with the ITT population. Disease control in the ITT population occurred in 63.4 percent (95% CI, 57.0-69.8) of patients in the ramucirumab-plus-docetaxel arm and 56.1 percent (95% CI, 49.6-62.7) in the placebo-plus-docetaxel arm.

The PFS and ORR demonstrated at this RANGE data readout confirm previously reported results from a Phase 2 study evaluating the combination of ramucirumab and docetaxel in the same patient population.1

The safety profile observed in the RANGE study at this data readout was consistent with what has previously been observed for ramucirumab. Grade ≥3 adverse events were reported at a similar frequency in both arms. The grade ≥3 adverse events occurring at a rate of five percent or greater, and that were higher on the ramucirumab-plus-docetaxel arm compared to the placebo-plus-docetaxel arm, were neutropenia (15.1% vs. 13.6%), febrile neutropenia (9.7% vs. 6.4%), and hypertension (5.8% vs. 1.9%). Grade ≥3 cardiovascular events, including arterial or venous thromboembolism and congestive heart failure, were rare in both arms, affecting ≤ 2% of patients.

"We are encouraged by these results from the RANGE study, as patients with this aggressive type of cancer who experience disease progression 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. "These RANGE data provide additional evidence in favor of combining CYRAMZA with other therapeutic backbones, which has now demonstrated an efficacy improvement in treating several types of aggressive metastatic cancers."

RANGE OS data are immature and final OS results are currently expected in mid-2018. Investigators, patients and Lilly study personnel involved in patient-level decision-making will remain blinded to patient-treatment assignments until that time.

Overall, RANGE is the sixth positive Phase 3 trial of ramucirumab to date. Previously completed Phase 3 studies of ramucirumab 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 deaths.

Notes to Editor

About the RANGE Study
The RANGE trial, which enrolled 530 patients globally, is a randomized, double-blind study designed to evaluate the safety and efficacy of ramucirumab and docetaxel versus placebo and docetaxel in patients with locally advanced or unresectable or metastatic urothelial carcinoma whose disease progressed on or after platinum-based chemotherapy. The trial includes: 1) patients who progressed following adjuvant and/or neoadjuvant therapy; 2) patients who progressed following first-line metastatic therapy; and 3) patients who had received prior platinum-based and immune checkpoint inhibitor regimens. The trial's primary endpoint is progression-free survival, and other secondary endpoints include overall survival, objective response rate, disease control rate and patient-reported outcomes.

About Urothelial Cancer 
Urothelial cancer includes carcinomas that arise in the urothelial or transitional cells that line the urinary collecting system, including the bladder, which is the most common site for this type of tumor. Other potential primary sites of this cancer include the renal pelvis, ureter and urethra. Bladder cancer accounts for the majority of all urothelial carcinoma.

Worldwide, bladder cancer ranks ninth in the topmost common cancers overall,2 and the ninth leading cause of cancer-related deaths, afflicting approximately 430,000 people per year and resulting in more than 165,000 deaths.3 The global incidence of bladder cancer increased 11 percent from 2008 to 2012.  In the U.S., bladder cancer is the sixth most common and deadly cancer,4 with an estimated 79,000 new cases and nearly 17,000 deaths expected in 2017.5

Generally, this is an aggressive disease and, unfortunately, despite recently approved therapies, the majority of patients who have disease progression will eventually succumb to their cancer.

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.

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 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    

1 Petrylak DP, Tagawa ST, Kohli M,, et al. Docetaxel as Monotherapy or Combined With Ramucirumab or Icrucumab in Second-Line Treatment for Locally Advanced or Metastatic Urothelial Carcinoma: An Open-Label, Three-Arm, Randomized Controlled Phase II Trial. J Clin Oncol. 2016; 34(13):1500-9.
2 World Cancer Research Fund International. "Bladder cancer statistics." Accessed September 7, 2017. Available at: http://www.wcrf.org/int/cancer-facts-figures/data-specific-cancers/bladder-cancer-statistics
3 World Health Organization. "GLOBOCAN 2012: Estimated Cancer Incidence, Mortality and Prevalence Worldwide 2012." Accessed September 7, 2017. Available at: http://globocan.iarc.fr/Pages/fact_sheets_population.aspx.
4 National Institute of Health National Cancer Institute Surveillance, Epidemiology, and End Results Program. "Cancer Stat Facts: Bladder Cancer." Accessed September 7, 2017. Available at: https://seer.cancer.gov/statfacts/html/urinb.html.
5 American Cancer Society. "Key Statistics for Bladder Cancer." Accessed September 7, 2017. Available at: http://www.cancer.org/cancer/bladdercancer/detailedguide/bladder-cancer-key-statistics.

SOURCE: Eli Lilly

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