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REACH-2 trial: Ramucirumab for treatment of hepatocellular carcinoma


In the REACH-2 trial, Ramucirumab ( Cyramza ) has shown a statistically significant benefit in the primary endpoint of overall survival ( OS ) and in the secondary endpoint of progression-free survival ( PFS ) in hepatocellular carcinoma ( HCC ).

Ramucirumab 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.

The REACH-2 study design was informed by findings from the REACH study, which uncovered AFP ( Alpha-FetoProtein ) as a potential predictive biomarker in hepatocellular carcinoma.

Ramucirumab was discontinued due to adverse reactions in 18% of Ramucirumab-treated patients, with proteinuria being the most frequent ( 2% ).

The most common adverse reactions of any grade observed in single agent Ramucirumab-treated HCC patients at a rate of greater than or equal to 15% and greater than or equal to 2% 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 Ramucirumab were ascites ( 3% ) and pneumonia ( 3% ).

The most common laboratory abnormalities occurring in more than 30% of patients and greater than or equal 2% higher than placebo were thrombocytopenia ( 46% ), hypoalbuminemia ( 33% ), and hyponatremia ( 32% ).

The National Comprehensive Cancer Network ( NCCN ) Guidelines recognize Ramucirumab as a Category 1 recommendation treatment option for second-line HCC patients who have AFP greater than or equal to 400 ng/mL and have been treated with Sorafenib ( Nexavar ).

Alpha-fetoprotein ( AFP ) is a glycoprotein that is produced in early fetal life by the liver and by a variety of tumors including hepatocellular carcinoma, hepatoblastoma, and nonseminomatous germ cell tumors of the ovary and testis.
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.

It is estimated that approximately 40% of all people with advanced hepatocellular carcinoma are AFP-High ( AFP greater than otr equal to 400 ng/mL ) and these patients are known to have a poorer prognosis relative to the general HCC patient population.
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.

Hepatocellular carcinoma is the most common form of liver cancer – accounting for up to 90% of all cases.
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.

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.

Despite recent advances in the treatment of chronic liver disease, the incidence of hepatocellular carcinoma 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. ( Xagena )

Source: Lilly, 2019

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