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Lilly’s Cyramza (ramucirumab) Receives FDA Approval as First-Line Treatment for Metastatic EGFR-Mutated Non-Small Cell Lung Cancer

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INDIANAPOLIS, May 29, 2020 /PRNewswire/ — Eli Lilly and Company (NYSE: LLY) today announced that the U.S. Food and Drug Administration (FDA) has approved Cyramza® (ramucirumab injection, 10 mg/mL solution), in combination with erlotinib, for the first-line treatment of people with metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) mutations. With this approval, Cyramza has now received six FDA approvals to treat certain types of lung, liver, stomach and colorectal cancers.

Cyramza plus erlotinib is the first and only FDA-approved anti-VEGFR/EGFR TKI combination therapy for metastatic EGFR-mutated NSCLC. This approval is based on the efficacy and safety from the global, randomized, placebo-controlled Phase 3 RELAY trial. In the RELAY study, Cyramza, a VEGF receptor 2 antagonist, in combination with erlotinib, a globally approved EGFR-targeting tyrosine kinase inhibitor (TKI), demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) – the time patients lived without their cancer growing or spreading after starting treatment – compared to placebo in combination with erlotinib [19.4 months in the Cyramza-containing arm compared to 12.4 months in the placebo-containing arm (HR=0.59; 95% CI, 0.46, 0.76; p<0.0001)]. The PFS treatment effect was consistent across exon 19 and exon 21 subgroups. The overall safety profile observed in the RELAY study was consistent with that of its individual components. RELAY is the second positive Phase 3 trial of Cyramza in metastatic NSCLC. The first was REVEL, which supported the approval of Cyramza plus docetaxel as a treatment for people with metastatic NSCLC whose cancer has progressed after prior platinum-based chemotherapy.

“The approval of this new first-line metastatic EGFR-mutated non-small cell lung cancer regimen, which inhibits the VEGFR and EGFR pathways together, is an important milestone in the treatment of this disease. It is wonderful that patients now have multiple options for initial therapy capable of delaying disease progression for considerably longer than erlotinib, which has been our traditional standard approach,” said Edward Garon, M.D., David Geffen School of Medicine, University of California, and North America lead investigator of the RELAY trial. “Ramucirumab, in combination with erlotinib, is a welcomed first-line option to offer our patients with metastatic EGFR-mutated non-small cell lung cancer.”

“This Cyramza combination regimen represents a new and meaningful treatment option for people with metastatic EGFR-mutated non-small cell lung cancer, and we are proud that it has been approved by the FDA for patients with this disease and the doctors who treat them,” said Anne White, president of Lilly Oncology. “Today’s approval underscores Lilly’s continued commitment to people living with lung cancer and to delivering meaningful medicines that are tailored for those with advanced or metastatic cancers. It also further reinforces the value that Cyramza can provide in treating certain advanced or metastatic cancers.”

Fifty percent of people with NSCLC present with advanced or metastatic disease at diagnosis.1 The five-year survival rate for metastatic NSCLC patients is six percent.2 In the U.S., it is estimated that approximately 15 percent of people diagnosed with NSCLC have an EGFR mutation.3

“We’re encouraged by Cyramza’s latest approval, which represents one step towards our goal of making EGFR-mutated non-small cell lung cancer into a manageable chronic disease,” said Ivy Elkins, cofounder of EGFR Resisters. “Each new treatment option gives hope to those living with this disease and provides oncologists with more options that may help slow the spread of this deadly cancer, which is an important goal for many patients.”

The labeling for Cyramza contains warnings and precautions for hemorrhage and gastrointestinal (GI) hemorrhage, including severe and sometimes fatal events; GI perforations, a potentially fatal event; impaired wound healing; arterial thromboembolic events (ATEs), including serious and sometimes fatal events; hypertension; infusion-related reactions (IRR) including severe and life-threatening reactions; worsening of pre-existing hepatic impairment; Posterior Reversible Encephalopathy Syndrome (PRES); proteinuria including nephrotic syndrome; thyroid dysfunction; and embryo-fetal toxicity. Cyramza should be permanently discontinued in patients who experience severe bleeding, a GI perforation, an ATE, uncontrolled hypertension, Grade 3 or 4 IRR, PRES, or nephrotic syndrome. Withhold CYRAMZA for 28 days prior to elective surgery. Do not administer Cyramza for at least two weeks following a major surgical procedure and until adequate wound healing.

The most common adverse reactions (all grades) observed in Cyramza with erlotinib-treated patients at a rate of ≥30% of patients and ≥2% higher than placebo with erlotinib-treated patients were infections, hypertension, stomatitis, proteinuria, alopecia, and epistaxis. The most common laboratory abnormalities ≥30% and ≥2% higher than the placebo were increased alanine aminotransferase, increased aspartate aminotransferase, anemia, thrombocytopenia, and neutropenia. Please see Important Safety Information below.

In addition to a recent approval for Cyramza in the European Union based on the RELAY results, Lilly has made a submission in Japan with regulatory action expected by the end of 2020. 

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 exon 19 deletions or exon 21 (L858R) substitution mutations. EGFR-targeting TKIs are the current standard treatment options for EGFR-mutated NSCLC. Erlotinib, the TKI included in the RELAY trial regimen, is a globally approved treatment option for this type of lung cancer.

Initiated in 2015, the study randomized 449 patients across North America, Europe and Asia. The primary endpoint of the RELAY trial is PFS; key secondary endpoints include safety, overall response rate (ORR), duration of response (DoR), and overall survival (OS). On the primary endpoint of investigator-assessed PFS, Cyramza plus erlotinib (N=224) demonstrated statistically significant and clinically meaningful improvement in median PFS – the time patients lived without their cancer growing or spreading after starting treatment – by seven months compared to placebo plus erlotinib (N=225) [19.4 months in the Cyramza-containing arm compared to 12.4 months in the placebo-containing arm (HR=0.59; 95% CI, 0.46, 0.76; p<0.0001)]. The PFS treatment effect was consistent across exon 19 and exon 21 subgroups. At the time of the final analysis of PFS, OS data were not mature as only 26 percent of planned events for the final analysis had occurred (HR=0.83, 95% CI: 0.53, 1.30). A final OS analysis is planned when at least 300 events have occurred.

RELAY Trial Efficacy Results Supporting Approval















Endpoint

CYRAMZA + erlotinib

N=224

Placebo + erlotinib

N=225

Progression-Free Survival (primary outcome measure)

Number of events (%)a

122 (55%)

158 (70%)

Median – months (95% CI)

19.4 (15.4, 21.6)

12.4 (11.0, 13.5)

Hazard Ratio (95% CI)

0.59 (0.46, 0.76)

Stratified Log-rank p-value

<0.0001

Overall Response Rate (Complete Response + Partial Response) (secondary outcome measure)

Rate – percent (95% CI)

76% (71, 82)

75% (69, 80)

Duration of Response (DoR) (secondary outcome measure)

 

N=171

N=168

Median – months (95% CI)

18.0 (13.9, 19.8)

11.1 (9.7, 12.3)

Abbreviations: CI = confidence interval

a 4 of 122 events in CYRAMZA-treated patients and 1 of 158 events in placebo-treated patients were deaths.

Treatment discontinuation of all study drugs due to adverse reactions occurred in 13 percent of Cyramza with erlotinib-treated patients, with increased alanine aminotransferase (1.4%) and paronychia (1.4%) being the most common. The most common adverse reactions leading to treatment discontinuation of Cyramza were proteinuria (8.6%) and hyperbilirubinemia (6%).

Detailed RELAY efficacy and safety results were published in The Lancet Oncology.

About Lung Cancer and EGFR Mutations

Globally, lung cancer is the leading cause of cancer death, killing nearly 1.8 million people worldwide each year.4 In the U.S., lung cancer is the second most common cancer (not counting skin cancer) and the leading cause of cancer death, responsible for almost 25 percent of all cancer deaths – more than those from colorectal, breast and prostate cancers combined.5 It is estimated that there will be 228,820 new cases of lung cancer and 135,720 deaths from lung cancer in the U.S. in 2020.4 Non-small cell lung cancer (NSCLC) is much more common than other types of lung cancer and accounts for about 85 percent of all lung cancers.6 Stage IV NSCLC is a very difficult-to-treat cancer and the prognosis is poor for metastatic NSCLC.7 Fifty percent of NSCLC patients present with advanced or metastatic disease at diagnosis.1 The five-year survival rate for metastatic NSCLC is six percent.2

EGFR is a protein that helps cells grow and divide. When the EGFR gene is mutated it can cause the protein to be overactive, causing cells to grow and divide more quickly. EGFR mutations may occur in 10 to 35 percent of NSCLC tumors globally.8 In the U.S., it is estimated that approximately 15 percent of people diagnosed with NSCLC have an EGFR mutation.3 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.9,10,11 Regardless of ethnicity, these mutations are commonly found in females, non-smokers and those with adenocarcinoma histology.12,13 The most common activating mutations in EGFR are deletions within exon 19 and a substitution in exon 21 (L858R). These mutations are present in 90 percent of EGFR-mutated NSCLC tumors. The presence of these activating EGFR mutations in advanced NSCLC is associated with sensitivity to small-molecule EGFR TKIs.10,11

About Cyramza (ramucirumab)

In the U.S., Cyramza (ramucirumab) has six FDA approvals to treat four different types of cancers. Cyramza is being investigated in a broad global development program that has enrolled more than 15,000 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. To date, more than 150,000 patients have been treated with Cyramza.

Cyramza is an antiangiogenic therapy. It is a vascular endothelial growth factor (VEGF) Receptor 2 antagonist that binds specifically to VEGFR-2, thereby blocking the binding of the receptor ligands (VEGF-A, VEGF-C, and VEGF-D) – which may slow tumor growth. Cyramza 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 binding to the receptors located on the surface of 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 FOR CYRAMZA

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 erlotinib, for first-line treatment of metastatic non-small cell lung cancer with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) mutations.

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 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.

Hepatocellular Carcinoma
Cyramza, as a single agent, is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have an alpha-fetoprotein (AFP) of ≥400 ng/mL and have been treated with sorafenib.

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 lilly.com/newsroom. P-LLY

© Lilly USA, LLC 2020. ALL RIGHTS RESERVED.

CYRAMZA® is a registered 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 Lilly’s CYRAMZA (ramucirumab), in combination with erlotinib, for the first-line treatment of people with metastatic non-small cell lung cancer with EGFR exon 19 deletions or exon 21 (L858R) mutations 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 continue to 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.

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1 Riess, J. Shifting Paradigms in Non-Small Cell Lung Cancer: An Evolving Therapeutic Landscape Supplement. Am J Manag Care. 2013;19:S390-S397.
2 Cancer.Net. Lung Cancer – Non Small Cell: Statistics. Available at: https://www.cancer.net/cancer-types/lung-cancer-non-small-cell/statistics. Accessed May 13, 2020.
3 Li Y, Appius A, Pattipaka T, Feyereislova A, Cassidy A, Ganti AK. Real-world management of patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer in the USA [published correction appears in PLoS One. 2019 Feb 20;14(2):e0212831]. PLoS One. 2019;14(1):e0209709. Published 2019 Jan 4. doi:10.1371/journal.pone.0209709.
4 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 May 13, 2020. 
5 American Cancer Society. Key Statistics for Lung Cancer. Available at: https://www.cancer.org/cancer/lung-cancer/about/key-statistics.html.  Accessed May 13, 2020.
6 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 May 13, 2020. 
7 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 May 13, 2020.
8 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.
9 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.
10 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.
11 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  May 13, 2020.
12 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.
13 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 and Company

Posted: May 2020

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