In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
On November 5, 2014, ramucirumab (Cyramza) was approved for use in combination with paclitaxel in the treatment of advanced gastric or gastroesophageal junction adenocarcinoma.1,2 Ramucirumab was approved in April 2014 as a single-agent treatment for advanced gastric or gastroesophageal junction adenocarcinoma refractory to or progressing after first-line platinum or fluoropyrimidine chemotherapy.
Supporting Trial
The current approval was based on demonstration of improved overall survival in a phase III double-blind trial in which 665 patients with advanced or metastatic gastric or gastroesophageal junction adenocarcinoma previously treated with platinum or fluoropyrimidine therapy were randomly assigned to receive ramucirumab at 8 mg/kg intravenously every 2 weeks plus paclitaxel at 80 mg/m2 once a week for 3 weeks every 28 days (n = 330) or paclitaxel plus placebo (n = 335). Patients were required to have adequate hematopoietic and hepatic function prior to each dose of paclitaxel. The paclitaxel dose was permanently reduced in increments of 10 mg/m2 for a maximum of two dose reductions for grade 4 hematologic toxicity or grade 3 paclitaxel-related nonhematologic toxicity
Patients had to have disease progression during or within 4 months after the last dose of first-line therapy, Eastern Cooperative Oncology Group performance status of 0 or 1, and bilirubin ≤ 1.5 times the upper limit of normal. Patients had a median age of 61 years, 71% were men, 61% were white and 35% were Asian, 39% had performance status of 0, 78% had measurable disease, 79% had gastric cancer, 67% had recurrence while on first-line therapy, and 25% received an anthracycline in combination with platinum/fluoropyrimidine therapy.
The ramucirumab group had significantly longer median overall survival (9.6 vs 7.4 months, hazard ratio [HR] = 0.81, P = .017), median progression-free survival (4.4 vs 2.9 months, P < .001), and objective response rate (28% vs 16%, P < .001).
How It Works
Ramucirumab is a recombinant human IgG1 monoclonal antibody that acts as a vascular endothelial growth factor receptor 2 (VEGFR2) antagonist. It specifically binds to VEGFR2 and blocks binding of the VEGFR ligands VEGF-A, VEGF-C, and VEGF-D. As a result of receptor blockade, ramucirumab inhibits ligand-stimulated activation of VEGFR2, thus inhibiting ligand-induced proliferation and migration of endothelial cells. Ramucirumab inhibits angiogenesis in animal models.
How It Is Given
The recommended dose of ramucirumab in combination with weekly paclitaxel is 8 mg/kg via intravenous infusion over 60 minutes every 2 weeks, with treatment continuing until disease progression or unacceptable toxicity. Ramucirumab should be given before paclitaxel. All patients should be premedicated with an intravenous histamine H1 antagonist (eg, diphenhydramine hydrochloride) prior to each infusion, and patients who have a grade 1 or 2 infusion reaction should also be premedicated with dexamethasone (or equivalent) and acetaminophen.
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. Treatment should be interrupted in patients with severe hypertension, urine protein levels ≥ 2 g/24 hours, prior to surgery until wounds are fully healed and permanently discontinued in those with severe hypertension that cannot be managed with antihypertensive therapy, proteinuria of > 3 g/24 hours or nephrotic syndrome, arterial thromboembolic events, gastrointestinal perforation, grade 3 or 4 bleeding, or reversible posterior leukoencephalopathy syndrome.
No dose adjustment is recommended for patients with renal impairment. No dose adjustment is recommended for patients with mild hepatic impairment; clinical deterioration has been observed in patients with Child-Pugh B or C cirrhosis who received single-agent ramucirumab.
Safety Profile
In the phase III trial, ramucirumab patients received a median of nine doses, median duration of exposure was 18 weeks, and 28% received ramucirumab for ≥ 6 months. The most common adverse events of any grade in the ramucirumab/paclitaxel group were fatigue/asthenia (57% vs 44% in the paclitaxel group), neutropenia (54% vs 31%), diarrhea (32% vs 23%), epistaxis (31% vs 7%), peripheral edema (25% vs 14%), and hypertension (25% vs 6%). The most common grade ≥ 3 adverse events were neutropenia (41% vs 19%), hypertension (15% vs 3%), fatigue/asthenia (12% vs 6%), diarrhea (4% vs 2%), and gastrointestinal hemorrhage (4% vs 2%).
The most common serious adverse events with the combination were neutropenia (4%) and febrile neutropenia (2.4%); 19% of patients received granulocyte colony-stimulating factors. The most common adverse events resulting in discontinuation of either component of ramucirumab/paclitaxel treatment were neutropenia (4%) and thrombocytopenia (3%). Other clinically relevant adverse events in the combination group were sepsis (3.1% vs 1.8%) and gastrointestinal perforation (1.2% vs 0.3%).
Ramucirumab carries a boxed warning for hemorrhage, including fatal bleeding. It also has warnings/precautions for arterial thromboembolic events (sometimes fatal), hypertension, infusion-related reactions, gastrointestinal perforation, impaired wound healing, clinical deterioration in patients with cirrhosis (including new onset or worsening encephalopathy, ascites, or hepatorenal syndrome), and reversible posterior leukoencephalopathy syndrome. Ramucirumab may cause fetal harm, and nursing mothers should discontinue nursing or discontinue ramucirumab. ■
References
1. U.S. Food and Drug Administration: Ramucirumab in combination with paclitaxel. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm421930.htm.
2. CYRAMZATM (ramucirumab) injection prescribing information, Eli Lilly and Co, November 2014. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2014/125477s002lbl.pdf.
Report Adverse Events
Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at www.fda.gov/medwatch/report.htm, by faxing (800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (800-FDA-1088).
