Full Press Release Details
INDIANAPOLIS , May 13, 2019 /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), as a single agent, 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. Concurrent with this FDA approval – the fifth for CYRAMZA – the FDA has also removed the boxed warning from the CYRAMZA labeling.
HCC is the most common form of liver cancer, which is the fourth-leading cause of cancer-related death worldwide. 1,2 In the U.S., liver cancer is one of the few major cancers with incidence rates that continue to rise every year 3 and is the fastest rising cause of cancer death. 4
AFP is a prognostic biomarker that can be assessed through a simple blood test, now allowing physicians to select patients who may benefit from treatment and to monitor disease progression in advanced HCC. 5-8
"This approval of CYRAMZA is an important step forward in the treatment of advanced hepatocellular carcinoma," said Andrew X. Zhu , M.D., director of Liver Cancer Research at Massachusetts General Hospital Cancer Center, professor of medicine at Harvard Medical School and principal investigator of the REACH-2 trial. "While there have been some recent advances, there are still limited treatment options for people with this type of cancer and – until now – there was no treatment option specifically indicated for patients with increased alpha-fetoprotein concentrations. These patients can have more aggressive disease and a poorer prognosis with increased angiogenesis."
This approval is based on the results from the REACH-2 study, the first positive Phase 3 HCC trial in a biomarker-selected patient population. REACH-2 is a global, randomized, double-blind, placebo-controlled Phase 3 study of CYRAMZA compared to placebo in patients with HCC who have been treated with sorafenib and are AFP-High (AFP ≥400 ng/mL).
"There is an urgent need for new liver cancer treatments that take into account the things that make each patient unique, particularly for those with advanced stages of the disease," said Donna Cryer , president and CEO of the Global Liver Institute . "We welcome this approval and the hope it may bring to people living with this devastating disease."
The labeling for CYRAMZA contains warnings and precautions for hemorrhage and GI hemorrhage, including severe and sometimes fatal events; gastrointestinal (GI) perforations, a potentially fatal event; impaired wound healing; arterial thromboembolic events (ATEs), including serious and sometimes fatal events; hypertension; infusion-related reactions; worsening of pre-existing hepatic impairment, reversible posterior leukoencephalopathy syndrome (RPLS); 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, RPLS, or nephrotic syndrome. CYRAMZA should be withheld prior to surgery and discontinued if a patient develops wound healing complications.
The most common adverse reactions (all Grades) observed in single agent CYRAMZA-treated HCC patients at a rate of ≥15 percent and ≥2 percent higher than placebo were fatigue (36% vs 20%), peripheral edema (25% vs 14%), hypertension (25% vs 13%), abdominal pain (25% vs 16%), decreased appetite (23% vs 20%), proteinuria (20% vs 4%), nausea (19% vs 12%), ascites (18% vs 7%). Please see Important Safety Information below.
REACH-2 Trial Results Supporting the Approval In the REACH-2 trial, CYRAMZA showed a statistically significant benefit in the primary endpoint of overall survival (OS) and in the secondary endpoint of progression-free survival (PFS).
| Endpoint | CYRAMZA + BSC N=197 | Placebo + BSC N=95 | ||||||||
| OS | ||||||||||
| Number of deaths (%) | 147 (75%) | 74 (78%) | ||||||||
| Median in months (95% CI) | 8.5 (7.0–10.6) | 7.3 (5.4–9.1) | ||||||||
| Hazard ratio (95% CI) | 0.71 (0.53–0.95) | |||||||||
| p-Value | 0.020 | |||||||||
| PFS | ||||||||||
| Number of deaths (%)* | 172 (87%) | 86 (91%) | ||||||||
| Median in months (95% CI) | 2.8 (2.8–4.1) | 1.6 (1.5–2.7) | ||||||||
| Hazard ratio (95% CI) | 0.45 (0.34–0.60) | |||||||||
| p-Value | <0.0001 | |||||||||
| ORR †‡ | ||||||||||
| Overall response rate (95% CI) | 4.6% (1.7–7.5) | 1.1% (0.0–3.1) |
Abbreviations: BSC = best supportive care; CI = confidence interval * 26 of 172 events in CYRAMZA-treated patients and 9 of 86 events in placebo-treated patients were deaths. † Does not include stable disease; all responses were partial. ‡ Disease progression and tumor response were assessed by investigators in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
The REACH-2 study design was informed by findings from the REACH study, which uncovered AFP as a potential predictive biomarker in HCC.
CYRAMZA was discontinued due to adverse reactions in 18 percent of CYRAMZA-treated patients, with proteinuria being the most frequent (2%). The most common adverse reactions of any grade observed in single agent CYRAMZA-treated HCC patients at a rate of ≥15 percent and ≥2 percent higher than placebo were fatigue (36%), peripheral edema (25%), hypertension (25%), abdominal pain (25%), decreased appetite (23%), proteinuria (20%), nausea (19%), and ascites (18%). The most common serious adverse reactions with CYRAMZA were ascites (3%) and pneumonia (3%). The most common laboratory abnormalities occurring in >30 percent of patients and ≥2 percent higher than placebo were thrombocytopenia (46%), hypoalbuminemia (33%), and hyponatremia (32%).
Lilly has also submitted applications for marketing authorization in the European Union and Japan based on the REACH-2 results and regulatory action in these geographies is expected in mid-2019.
The National Comprehensive Cancer Network ® (NCCN ® ) Guidelines recognize ramucirumab (CYRAMZA ® ) as a Category 1 recommendation treatment option for second-line HCC patients who have AFP ≥400 ng/mL and have been treated with sorafenib. 9
With this approval, Lilly has now received five FDA approvals for CYRAMZA to treat four of the world's most deadly cancers. These approvals are based on a demonstrated survival benefit in Phase 3 studies of advanced forms of gastric and gastroesophageal junction adenocarcinoma, metastatic non-small cell lung cancer, metastatic colorectal cancer, and AFP-High HCC. Two of these studies have shown the proven benefit of CYRAMZA as a single agent in treating advanced gastric cancer and AFP-High HCC.
Additionally, Lilly recently announced top-line results from its Phase 3 study of CYRAMZA in EGFR-mutated metastatic non-small cell lung cancer. These results will be presented at the American Society of Clinical Oncology 2019 Annual Meeting and are the basis for global regulatory submissions planned in mid-2019.
Notes to Editors
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. 10 It is estimated that approximately forty percent of all people with advanced HCC are AFP-High (AFP ≥400 ng/mL) and these patients are known to have a poorer prognosis relative to the general HCC patient population. 11 Specifically, these patients can have more aggressive disease and a poorer prognosis with increased angiogenesis, tumor activity, and tumor burden. Tumor burden is the amount of cancer in a person's body.
About Hepatocellular Carcinoma Hepatocellular carcinoma (HCC) is the most common form of liver cancer – accounting for up to ninety percent of all cases. 12 Liver cancer is the sixth most common cancer worldwide and the fourth-leading cause of cancer-related death. Each year approximately 841,000 new cases of liver cancer are diagnosed worldwide, and more than 781,000 will die of the disease. In Europe and Japan, an estimated 82,000 and 36,000 people are diagnosed with liver cancer, and 62,000 and 33,000 will die, respectively. In the U.S., approximately 38,000 people are diagnosed with liver cancer, and 30,000 will die from the disease each year. 1 Liver cancer is one of the few major cancers with incidence rates that continue to rise every year in the U.S. 3 and is the fastest rising cause of cancer death. 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. 11
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; lack of access to viral hepatitis disease therapy; and the persistent risk of cancer even after viral hepatitis cure. 13
About CYRAMZA ® (ramucirumab) In the U.S., CYRAMZA (ramucirumab) has five 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 110 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 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 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.
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.
IMPORTANT SAFETY INFORMATION FOR CYRAMZA ® (ramucirumab)
Warnings and Precautions Hemorrhage
Gastrointestinal Perforations
Impaired Wound Healing
Arterial Thromboembolic Events
Infusion-Related Reactions
Worsening of Pre-existing Hepatic Impairment
Reversible Posterior Leukoencephalopathy Syndrome
Proteinuria Including Nephrotic Syndrome
Thyroid Dysfunction
Embryo-Fetal Toxicity
Most Common Adverse Reactions— CYRAMZA Administered as a Single Agent (REGARD)
Most Common Adverse Reactions— CYRAMZA Administered in Combination with Paclitaxel (RAINBOW)
Most Common Adverse Reactions— CYRAMZA Administered in Combination with Docetaxel (REVEL)
Most Common Adverse Reactions— CYRAMZA Administered in Combination with FOLFIRI (RAISE)
Most Common Adverse Reactions— CYRAMZA Administered as a Single Agent (REACH-2)
Please see full Prescribing Information for CYRAMZA. RB-P HCP ISI 10MAY2019
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
CYRAMZA ® is a trademark owned by or licensed to Eli Lilly and Company, its subsidiaries, or affiliates.
National Comprehensive Cancer Network ® and NCCN ® are trademarks owned by the National Comprehensive Cancer Network, Inc.
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 treatment for patients with hepatocellular carcinoma, 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.
Refer to: Tracy Henrikson ; [email protected] ; 609-454-7116 (media) Kevin Hern ; [email protected] ; 317-277-1838 (investors)
SOURCE Eli Lilly and Company