Rapidly Progressing Advanced Non-Small Cell Lung Cancer Patients Shown to Benefit in New CYRAMZA® (ramucirumab) Phase 3 Subgroup Analysis

Data presented at 18th World Conference on Lung Cancer

INDIANAPOLIS, Oct. 16, 2017 /PRNewswire/ -- New subgroup analysis from Eli Lilly and Company's (NYSE: LLY) Phase 3 REVEL trial of CYRAMZA® (ramucirumab) in advanced non-small cell lung cancer (NSCLC) was presented today at the 18th World Conference on Lung Cancer (WCLC), hosted by the International Association for the Study of Lung Cancer in Yokohama, Japan. Specifically, these new data are an exploratory, post-hoc analysis focused on patients whose cancer rapidly progressed on first-line therapy. Time-to-progression (TTP) is defined as the time from start of first-line therapy until progressive disease - when the person's cancer grows, spreads or gets worse. In this analysis, aggressive disease was defined based on rapid TTP on first-line therapy.

"Despite recent advancements, patients with aggressive, rapidly progressing advanced non-small cell lung cancer who progress before or at the time of their first scan - which is typically done between nine and 12 weeks - often have a less favorable response to their second-line therapy. This is a population that has poor prognosis and immediate unmet needs with limited treatment options," said Martin Reck, M.D., Ph.D., Department of Thoracic Oncology, Lung Clinic Grosshansdorf.

Dr. Reck continued, "This REVEL exploratory analysis demonstrated that efficacy, safety, and quality-of-life outcomes among patients receiving ramucirumab plus docetaxel who have aggressive disease with rapid progression on first-line therapy are consistent with the outcomes of the intent-to-treat population. These results suggest that such patients may derive meaningful benefit from ramucirumab plus docetaxel in the second-line setting."

The global, randomized, double-blind, placebo-controlled REVEL Phase 3 study evaluated ramucirumab, in combination with docetaxel, in patients with metastatic NSCLC whose cancer had progressed on or after prior platinum-based chemotherapy for locally advanced or metastatic disease. REVEL, which included patients with nonsquamous and squamous forms of NSCLC, demonstrated improved overall survival ﴾OS﴿, progression‐free survival ﴾PFS﴿, and objective response rate ﴾ORR) - independent of histology.1 Please see the 'About REVEL' section below for more detailed efficacy and safety results in the trial's intent-to-treat (ITT) patient population. The REVEL ITT trial results, presented at the American Society of Clinical Oncology Annual Meeting in 2014, supported the U.S. Food and Drug Administration approval of ramucirumab in NSCLC in December 2014.

This new subgroup analysis focused on outcomes from patients according to their TTP on first-line treatment. Of the 1,253 patients enrolled in REVEL, on first-line therapy, 11 percent (n=133) had TTP ≤9 weeks, 17 percent (n=209) had TTP ≤12 weeks, and 28 percent (n=354) had TTP ≤18 weeks. Baseline characteristics of each subgroup were balanced between treatment arms.

The results show that the trend for OS and PFS outcomes favored the ramucirumab-plus-docetaxel treatment arm, with hazard ratios similar to those of the ITT population. In all three subpopulations, ORR also favored the ramucirumab-plus-docetaxel treatment arm.

 


≤9 Weeks

≤12 Weeks

≤18 Weeks

REVEL ITT Population


Ramucirumab +
Docetaxel

n=71

Placebo +
Docetaxel

n=62

Ramucirumab +
Docetaxel

n=111

Placebo +
Docetaxel

n=98

Ramucirumab +
Docetaxel

n=182

Placebo +
Docetaxel

n=172

Ramucirumab +
Docetaxel

n=628

Placebo +
Docetaxel

n=625

Median OS, months
(95% CI)

8.28

(5.19-10.84)

4.83

(3.09-6.90)

9.10

(6.70-10.84)

5.78

(4.30-7.49)

8.51

(6.97-9.95)

5.95

(4.44-6.97)

10.51
(9.53-11.24)

9.13

(8.44-10.02)

Unstratified HR
(95% CI)

0.69

(0.47-1.01)

0.74

(0.54-1.00)

0.80

(0.63-1.01)

0.86

(0.75-0.98)

Median PFS, months
(95% CI)

3.01

(2.66-4.07)

1.48

(1.41-1.87)

3.61

(2.76-4.21)

1.61

(1.45-2.60)

3.22

(2.79-4.14)

1.61

(1.48-2.60)

4.50

(4.21-5.36)

3.02

(2.79-3.94)

Unstratified HR
(95% CI)

0.69

(0.48-0.98)

0.73

(0.55-0.97)

0.72

(0.58-0.89)

0.78

(0.69-0.87)

ORR, %
(95% CI)

18.3

(10.1-29.3)

3.2

(0.4-11.2)

18.9

(12.1-27.5)

9.2

(4.3-16.7)

19.2

(13.8-25.7)

10.5

(6.3-16.0)

22.9

(19.7-26.4)

13.6

(11.0-16.5)

 

Safety overview outcomes from patients with TTP on first-line therapy ≤18 weeks are similar to what was observed from patients with TTP on first-line therapy ≤9 weeks and ≤12 weeks, as well as in the ITT population. There were no new safety signals observed in these subpopulations.

"We are encouraged by this REVEL subgroup analysis, as patients with this aggressive type of cancer who experience rapid disease progression on first-line therapy 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. "The results of this REVEL analysis add to the growing body of knowledge we have about aggressive lung cancer and demonstrates Lilly's longstanding commitment to advancing the science in lung cancer treatment and to improving the care of patients with this disease."

Notes to Editor

About REVEL 
REVEL was a global, double-blind, randomized Phase 3 study of CYRAMZA (ramucirumab) plus docetaxel compared to placebo plus docetaxel in people with metastatic non-small cell lung cancer (NSCLC) whose cancer had progressed on or after prior platinum-based chemotherapy for locally advanced or metastatic disease. In total, 1,253 patients - including people with nonsquamous (73%) and squamous (26%) forms of NSCLC - were randomized in 26 countries over six continents.1

In the trial, CYRAMZA plus docetaxel achieved a statistically significant improvement in overall survival (the primary endpoint), progression-free survival and objective response rate (secondary endpoints). CYRAMZA plus docetaxel significantly extended median overall survival compared to placebo plus docetaxel (10.5 months [95% confidence interval (CI): 9.5, 11.2] vs. 9.1 months [95% CI: 8.4, 10.0], respectively; hazard ratio 0.86 [95% CI: 0.75, 0.98]; P=0.024). Furthermore, CYRAMZA plus docetaxel significantly delayed disease progression (progression-free survival of 4.5 months for CYRAMZA plus docetaxel [95% CI: 4.2, 5.4] vs. 3.0 months for placebo plus docetaxel [95% CI: 2.8, 3.9]; hazard ratio 0.76 [95% CI: 0.68, 0.86]; P < 0.001). The percentage of deaths at the time of analysis was 68% (428 patients) and 73% (456 patients) in the CYRAMZA-plus-docetaxel and placebo-plus-docetaxel arms, respectively. The progression-free survival number of events was 558 (89%) and 583 (93%) for CYRAMZA-plus-docetaxel and placebo-plus-docetaxel treatment arms, respectively. Significantly more patients responded to CYRAMZA combined with docetaxel than with placebo plus docetaxel (23% [95% CI: 20, 26] for CYRAMZA plus docetaxel vs. 14% [95% CI: 11, 17] for placebo plus docetaxel; P < 0.001).

The labeling for CYRAMZA contains a Boxed Warning for hemorrhage and additional Warnings and Precautions for arterial thromboembolic events, hypertension, infusion-related reactions, gastrointestinal perforations, impaired wound healing, clinical deterioration in patients with Child-Pugh B or C cirrhosis, and reversible posterior leukoencephalopathy syndrome. In the REVEL trial, the most common adverse reactions (all grades) observed in patients treated with CYRAMZA plus docetaxel at a rate of  ≥30% and ≥2% higher than placebo were neutropenia (low white blood cell count) (55% vs. 46%), fatigue/asthenia (weakness) (55% vs. 50%) and stomatitis/mucosal inflammation (37% vs. 19%). The most common serious adverse events with CYRAMZA were febrile neutropenia (fever and potentially other infection signs along with low white blood cell count) (14%), pneumonia (6%), and neutropenia (5%); 42% of patients treated with CYRAMZA plus docetaxel received granulocyte colony-stimulating factors (treatment for low white blood cells) vs. 37% of patients who received placebo plus docetaxel. See the Important Safety Information at the end of this press release and the Prescribing Information.

About Lung Cancer 
Lung cancer is the leading cause of cancer death in the U.S. and most other countries, killing nearly 1.6 million people worldwide each year.2 In the U.S., lung cancer is responsible for approximately 27 percent of all cancer deaths, more than those from breast, colon and prostate cancers combined.3 Stage IV non-small cell lung cancer (NSCLC) is a very difficult-to-treat cancer and the prognosis is poor for metastatic NSCLC.4 NSCLC is much more common than other types of lung cancer, and accounts for about 85 percent of all lung cancer cases.5 For those people affected by NSCLC, about 70 percent have nonsquamous cell carcinoma, while about 30 percent have squamous cell carcinoma.5 Approximately half of patients with metastatic NSCLC who begin first-line therapy will move on to second-line treatment.6 Despite currently available therapies, there continues to be a need for new second-line treatment options for patients with NSCLC.1

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. Previously completed Phase 3 studies of ramucirumab have demonstrated benefit in advanced forms of gastric, non-small cell lung and colorectal cancer ¾ three of the world's leading causes of cancer-related deaths.

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.

IMPORTANT SAFETY INFORMATION FOR CYRAMZA

 

WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, AND IMPAIRED WOUND HEALING




Hemorrhage: CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding.




Gastrointestinal Perforation: CYRAMZA can increase the risk of gastrointestinal perforation, a potentially fatal event. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.




Impaired Wound Healing: Impaired wound healing can occur with antibodies inhibiting the VEGF pathway. Discontinue CYRAMZA therapy in patients with impaired wound healing. Withhold CYRAMZA prior to surgery and discontinue CYRAMZA if a patient develops wound healing complications.


 

Warnings and Precautions

Hemorrhage

Arterial Thromboembolic Events (ATEs)

Hypertension

Infusion-Related Reactions (IRRs)

Gastrointestinal Perforations

Impaired Wound Healing

Clinical Deterioration in Child-Pugh B or C Cirrhosis

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

Proteinuria Including Nephrotic Syndrome

Thyroid Dysfunction

Embryofetal Toxicity

Most Common Adverse Reactions—Single Agent

Most Common Adverse Reactions—Combination With Paclitaxel

Most Common Adverse Reactions—Combination With Docetaxel

Most Common Adverse Reactions—Combination With FOLFIRI

Drug Interactions

Use in Specific Populations

Please see full Prescribing Information for CYRAMZA, including Boxed Warning for hemorrhage, gastrointestinal perforation, and impaired wound healing.  
RB-P-HCP ISI 16FEB2017

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    

© Lilly USA, LLC 2017. ALL RIGHTS RESERVED.

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

Lilly Forward-Looking Statement 
This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about Cyramza as a potential treatment for patients with advanced non-small cell lung cancer, gastric cancer, and 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. Among other things, there can be no guarantee that Cyramza will receive additional regulatory approvals or be commercially successful. For further discussion of these and other risks and uncertainties, see Lilly's most recent Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission. Except as required by law, Lilly undertakes no duty to update forward- looking statements to reflect events after the date of this release.

1 Garon EB, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384:665-73.  
2 International Agency for Research on Cancer. GLOBOCAN 2012. Lung Cancer Estimated Incidence, Mortality and Prevalence Worldwide in 2012. http://globocan.iarc.fr. Accessed October 12, 2017
3 American Cancer Society. What are the key statistics about lung cancer? http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-key-statistics. Updated January 5, 2017. Accessed October 12, 2017.   
4 American Cancer Society. Learn about cancer: Non-small cell lung cancer survival rates by stage http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-survival-rates. Updated May 16, 2016. Accessed October 12, 2017
5 American Cancer Society. What is non-small cell lung cancer? http://www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-what-is-non-small-cell-lung-cancer. Updated May 16, 2016. Accessed October 12, 2017.   
6 Stinchcombe TE, Socinski MA. Considerations for Second-Line Therapy of Non-Small Cell Lung Cancer. Oncologist. 2008;13:28-36. 

Refer to:                    Tracy Henrikson; tracy.henrikson@lilly.com; 609-240-3902 (media)  
                                  Phil Johnson; johnson_philip_l@lilly.com; 317-655-6874 (investors)

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