Earlier this year, ramucirumab was approved as a single agent for hepatocellular carcinoma in patients who have an alpha-fetoprotein (AFP) level ≥ 400 ng/mL and have been previously treated with sorafenib.1,2
Supporting Efficacy Data
Approval was based on findings in the double-blind phase III REACH‑2 trial (ClinicalTrials.gov identifier NCT02435433).2,3 In the trial, 292 patients with advanced hepatocellular carcinoma and AFP ≥ 400 ng/mL who had disease progression on or after sorafenib therapy or were intolerant of sorafenib were randomly assigned 2:1 to receive ramucirumab at 8 mg/kg plus best supportive care (n = 197) or placebo plus best supportive care (n = 95) every 2 weeks until disease progression or unacceptable toxicity.
Ramucirumab labeling includes warnings/precautions for hemorrhage, gastrointestinal perforations, impaired wound healing, arterial thromboembolic events, infusion-related reactions, worsening of preexisting hepatic impairment, reversible posterior leukoencephalopathy syndrome, proteinuria including nephrotic syndrome, thyroid dysfunction, and embryofetal harm.
Patients had a median age of 64 years (range = 26–88 years), 80% were male, 50% were Asian, 35% had macrovascular invasion, 72% had extrahepatic spread, 17% were sorafenib intolerant, 37% had hepatitis B, 26% had hepatitis C, 24% had significant prior alcohol use, and 64% had prior locoregional therapy.
Median overall survival was 8.5 months (95% confidence interval [CI] = 7.0–10.6 months) in the ramucirumab group vs 7.3 months (95% CI = 5.4–9.1 months) in the placebo group (hazard ratio [HR] = 0.71, 95% CI = 0.53–0.95; P = .020). Median progression-free survival was 2.8 vs 1.6 months (HR = 0.45, P < .0001). Objective response rates were 4.6% vs 1.1%.
How It Works
Ramucirumab is a vascular endothelial growth factor receptor 2 (VEGFR2) antagonist that specifically binds VEGFR2 and blocks binding of the VEGFR ligands VEGF-A, VEGF-C, and VEGF-D. As a result, ramucirumab inhibits ligand-stimulated activation of VEGFR2, thereby inhibiting ligand-induced proliferation and migration of human endothelial cells. Ramucirumab inhibits angiogenesis in animal models.
How It Is Used
The recommended dosage of ramucirumab in hepatocellular carcinoma is 8 mg/kg every 2 weeks via intravenous (IV) infusion over 60 minutes, with treatment continuing until disease progression or unacceptable toxicity.
All patients should be premedicated with an IV histamine-1 receptor antagonist (eg, diphenhydramine hydrochloride) prior to each infusion. Patients who have a grade 1 or 2 infusion-related reaction should also be premedicated with a histamine-1 antagonist, dexamethasone (or an equivalent), and acetaminophen prior to each infusion.
The infusion rate should be reduced by 50% for grade 1 or 2 infusion-related reactions, and treatment should be permanently discontinued for grade 3 or 4 infusion-related reactions. To avoid wound-healing complications, treatment should be withheld for 28 days prior to elective surgery and resumed no sooner than 28 days after surgery and the wound is fully healed. Treatment should be discontinued for wound-healing complications that require medical intervention.
Treatment should be withheld for severe hypertension until controlled with medical management and permanently discontinued for severe hypertension that cannot be controlled with therapy. Treatment should be permanently discontinued for grade 3 or 4 hemorrhage, any grade gastrointestinal perforation, any grade arterial thromboembolic events, and reversible posterior leukoencephalopathy syndrome.
For proteinuria, treatment should be interrupted in patients with urine protein levels ≥ 2 g per 24 hours and can be restarted after improvement to < 2 g per 24 hours at a reduced dose (eg, from 8 mg/kg to 6 mg/kg). For recurrence after initial dose reduction, treatment can be resumed with a reduced dose (eg, from 6 mg/kg to 5 mg/kg) after improvement to < 2 g per 24 hours. Treatment should be permanently discontinued for proteinuria > 3 g per 24 hours or for nephrotic syndrome.
REACH-2 excluded patients with clinically meaningful ascites, a history of or current hepatic encephalopathy, uncontrolled hypertension, major surgery within 28 days, bilirubin level > 1.5 times the upper limit of normal, severe variceal bleeding in the 3 months prior to treatment or with varices at high risk of bleeding, and patients receiving therapeutic anticoagulation or chronic antiplatelet therapy other than once-daily aspirin.
In REACH-2, the most common adverse events of any grade reported in ≥ 15% of patients and at a ≥ 2% higher incidence vs 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%), and ascites (18% vs 7%). The most common grade ≥ 3 adverse events included hypertension (13% vs 5%), fatigue (5% vs 3%), and ascites (4% vs 1%). The most common grade ≥ 3 laboratory abnormalities were hyponatremia (16% vs 5%), thrombocytopenia (8% vs 1%), and neutropenia (8% vs 3%).
The most common serious adverse events with ramucirumab were ascites (3%) and pneumonia (3%). Treatment discontinuations due to adverse events occurred in 18% of ramucirumab patients, with the most common cause being proteinuria (2%).
Boxed warnings for hemorrhage and gastrointestinal hemorrhage, gastrointestinal perforation, and impaired wound healing were removed from product labeling in May 2019. Nevertheless, ramucirumab has warnings/precautions for hemorrhage, including severe and fatal events; gastrointestinal perforations, which can be fatal; impaired wound healing; arterial thromboembolic events, including serious and fatal events; hypertension; infusion-related reactions; worsening of preexisting hepatic impairment (new onset or worsening encephalopathy, ascites or hepatorenal syndrome can occur in patients with Child-Pugh B or C cirrhosis); reversible posterior leukoencephalopathy syndrome; proteinuria including nephrotic syndrome; thyroid dysfunction; and embryofetal harm. Patients should be monitored for hypertension, proteinuria, and thyroid function during treatment and for infusion-related reactions. Patients should be advised not to breastfeed during ramucirumab therapy. ■
1. U.S. Food and Drug Administration: FDA approves ramucirumab for hepatocellular carcinoma. Available at www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ramucirumab-hepatocellular-carcinoma. Accessed September 6, 2019.
2. Cyramza (ramucirumab) injection prescribing information, Eli Lilly and Company, May 2019. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2019/125477s029lbl.pdf. Accessed September 6, 2019.
3. Zhu AX, Kang YK, Yen CJ, et al: Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 20:282-296, 2019.