Lilly’s Cyramza (ramucirumab) Becomes First FDA-Approved Biomarker-Driven Therapy in Patients with Hepatocellular Carcinoma

By | May 14, 2019

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 year3 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).

“This new indication for Cyramza further reinforces Lilly’s ongoing commitment to delivering meaningful medicines that are tailored for people with advanced cancers and the physicians that work in partnership with them,” said Anne White, president of Lilly Oncology. “Our work is focused on helping people who are living with cancer and Lilly is making strides in its efforts to develop precision medicine-based therapies for patients, to give them a fighting chance against their disease.”

“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.”

This approval adds to the body of evidence demonstrating the safety of Cyramza. The FDA has removed the boxed warning from the Cyramza labeling which highlighted warnings pertaining to hemorrhage, gastrointestinal perforation and impaired wound healing. The updated Cyramza labeling continues to provide important information on these specific risks, as well as other adverse events, to physicians and the patients that work in partnership with them so that they can make informed decisions regarding cancer care.

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).

REACH-2 Trial

 

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.

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.

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

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.

  1. 1 Ferlay J, Shin HR, Bray F et al. GLOBOCAN 2018 Fact Sheet, Estimated Cancer Incidence, Mortality and Prevalence Worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer; 2018. Available at http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Accessed on May 10, 2019.
  2. 2 Ghouri YA, Mian I, Rowe JH. Review of hepatocellular carcinoma: Epidemiology, etiology, and carcinogenesis. J Carcinog. 2017;16:1.
  3. 3 Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7-30.
  4. 4 Islami F, Miller KD, Siegel RL, et al. Disparities in liver cancer occurrence in the United States by race/ethnicity and state. CA Cancer J Clin. 2017;67:273–289.
  5. 5 Mitsuhashi N, Kobayashi S, Doki T, et al. Clinical significance of α-fetoprotein: involvement in proliferation, angiogenesis, and apoptosis of hepatocellular carcinoma. J Gastroenterol Hepatol. 2008;23(7, pt 2):e189-e197.
  6. 6 Gopal P, Yopp AC, Waljee AK, et al. Factors that affect accuracy of α-fetoprotein test in detection of hepatocellular carcinoma in patients with cirrhosis. Clin Gastroenterol Hepatol. 2014;12(5):870-877.
  7. 7 Chan SL, Chan ATC, Yeo W. Role of alpha-fetoprotein in hepatocellular carcinoma: prognostication, treatment monitoring or both? Future Oncol. 2009;5(6):889-899.
  8. 8 Mizejewski GJ. Does alpha-fetoprotein contribute to the mortality and morbidity of human hepatocellular carcinoma? A commentary. J Hepatocell Carcinoma. 2016;3:37-40
  9. 9 Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Hepatobiliary Cancers V.2.2019. © National Comprehensive Cancer Network, Inc. 2019. All rights reserved. Accessed May 10, 2019. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content use or application and disclaims any responsibility for their application or use in any way. Category 1 recommendations are made based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
  10. 10 University of Rochester Medical Center. Health Encyclopedia: Alpha-Fetoprotein Tumor Marker (Blood). Available at https://www.urmc.rochester.edu/encyclopedia/content.aspx?contenttypeid=167&contentid=alpha_fetoprotein_tumor_marker. Accessed May 10, 2018.
  11. 11 Zhu AX, Park JO, Ryoo BY et al. Ramucirumab Versus Placebo as Second-Line Treatment in Patients with Advanced Hepatocellular Carcinoma Following First-Line Therapy with Sorafenib (REACH): A Randomised, Double-Blind, Multicentre, Phase 3 Trial. Lancet Oncol. 2015;16(7): 859-870
  12. 12 National Organization for Rare Disorders. Hepatocellular Carcinoma. Available at: https://rarediseases.org/rare-diseases/hepatocellular-carcinoma. Accessed May 10, 2019.
  13. 13 Venook, AP, Papandreou, C, Furuse, J et al. The Incidence and Epidemiology of Hepatocellular Carcinoma: A Global and Regional Perspective. The Oncologist. 2010;15(suppl 4): 5-13.

SOURCE Eli Lilly and Company

Posted: May 2019

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