FDA Approval for Ramucirumab

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Brand name(s): Cyramza®

Full prescribing information is available, including clinical trial information, safety, dosing, drug–drug interactions, and contraindications.  

Approved in combination with FOLFIRI for metastatic colorectal cancer

On April 24, 2015, the Food and Drug Administration approved ramucirumab (Cyramza® Injection, made by Eli Lilly and Company) for use in combination with FOLFIRI for the treatment of patients with metastatic colorectal cancer (mCRC) whose disease has progressed on a first-line regimen containing bevacizumab, oxaliplatin, and a fluoropyrimidine.  

This approval was based on the results of a randomized double-blind multinational trial enrolling patients with mCRC that progressed during, or within 6 months after stopping, bevacizumab-, oxaliplatin-, and fluoropyrimidine-based combination chemotherapy.

The trial enrolled 1072 patients: 536 were assigned to receive FOLFIRI plus ramucirumab and 536 were assigned to receive FOLFIRI plus placebo. Treatment cycles in both groups were repeated every 2 weeks, and ramucirumab was administered at a dose of 8 mg/kg body weight by intravenous infusion. Treatment was continued until disease progression or unacceptable toxicity.  

The primary endpoint was overall survival, and secondary endpoints included progression-free survival and safety. Treatment assignment was stratified by geographic region (North America versus Europe versus other regions), tumor KRAS status (wild-type versus mutant), and time to disease progression after the beginning of first-line treatment (less than 6 months versus 6 months or longer).  

The median age of the study population was 62 years, 57 percent were men, and 99 percent had an ECOG performance status of 0 or 1. A statistically significant improvement in overall survival was observed in patients who received FOLFIRI plus ramucirumab compared with those who received FOLFIRI plus placebo [median overall survival: 13.3 versus 11.7 months; HR 0.85 (95 percent CI: 0.73, 0.98), p=0.023, stratified log-rank test].  Progression-free survival was also significantly improved in patients who received ramucirumab in combination with FOLFIRI [median progression-free survival: 5.7 versus 4.5 months; HR 0.79 (95 percent CI: 0.70, 0.90), p<0.001].

In general, the safety data were consistent with the known safety profile established in previously approved indications. However, thyroid dysfunction (hypothyroidism) was reported in 2.6 percent of patients based on thyroid monitoring in patients with mCRC.

The recommended dose and schedule in patients receiving ramucirumab in combination with FOLFIRI after progression on a first-line bevacizumab-containing regimen is 8 mg/kg administered every 2 weeks as a 60-minute IV infusion.  

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Approved in combination with docetaxel for platinum-resistant metastatic non-small cell lung cancer

On December 12, 2014, the Food and Drug Administration (FDA) approved ramucirumab (Cyramza® Injection, made by Eli Lilly and Company) for use in combination with docetaxel to treat patients with metastatic non-small cell lung cancer (NSCLC) whose cancer continues to grow during or after treatment with platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor mutations should have disease progression while being treated with FDA-approved drugs for these indications prior to receiving ramucirumab.  

The approval of ramucirumab in combination with docetaxel for NSCLC patients was based on the demonstration of improved overall survival in a multicenter double-blinded placebo-controlled clinical trial (I4T-MC-JVBA) that enrolled 1,253 patients with previously treated metastatic NSCLC. Patients were randomly assigned to receive ramucirumab in combination with docetaxel or a matching placebo plus docetaxel once every 3 weeks.

A statistically significant increase in overall survival was demonstrated [HR 0.86; (95 percent CI: 0.75, 0.98); p=0.024]; median overall survival was 10.5 months in the ramucirumab plus docetaxel arm and 9.1 months in the placebo plus docetaxel arm. Progression-free survival was also significantly longer for patients receiving ramucirumab plus docetaxel [HR=0.76 (95 percent CI: 0.68, 0.86); p<0.001)].  

Safety data was evaluated in 1,245 patients who received at least one dose of the study drug. The most frequently reported adverse reactions with ramucirumab plus docetaxel (seen in 30 percent or more of patients) were neutropenia, fatigue/asthenia, and stomatitis/mucosal inflammation. The most common serious adverse reactions with ramucirumab plus docetaxel were febrile neutropenia (14 percent), pneumonia (6 percent), and neutropenia (5 percent).

The recommended dose and schedule for ramucirumab in combination with docetaxel for NSCLC is ramucirumab 10 mg/kg intravenously and docetaxel 75 mg/m2 intravenously administered on the first day of a 21-day cycle.

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Approved in combination with paclitaxel for advanced gastric or gastroesophageal junction adenocarcinoma

On November 5, 2014, the Food and Drug Administration (FDA) approved ramucirumab (Cyramza®, made by Eli Lilly and Company) for use in combination with paclitaxel to treat patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. Ramucirumab was approved in April 2014 for use as a single agent to treat patients with advanced gastric or GEJ adenocarcinoma that did not respond to, or had progressed following, first-line therapy with platinum- or fluoropyrimidine-containing chemotherapy.

The approval of ramucirumab in combination with paclitaxel was based on the demonstration of improved overall survival in a multicenter randomized double-blind placebo-controlled phase III trial (I4T-IE-JVBE), which compared ramucirumab plus paclitaxel with placebo plus paclitaxel. The main outcome of the trial was overall survival. Secondary outcome measures included progression-free survival and safety.

The trial enrolled 665 patients with previously treated advanced or metastatic gastric or GEJ adenocarcinoma: 330 patients were assigned to receive ramucirumab in combination with paclitaxel and 335 patients were assigned to receive a placebo in combination with paclitaxel.

Overall survival was statistically significantly longer for patients who received ramucirumab plus paclitaxel compared with patients who received placebo plus paclitaxel [HR 0.81; (95 percent CI: 0.68, 0.96); p=0.017 (stratified log-rank test)]; median overall survival was 9.6 months in the ramucirumab plus paclitaxel group and 7.4 months in the placebo plus paclitaxel group. Progression-free survival was also statistically significantly longer for patients who received ramucirumab plus paclitaxel [HR=0.64 (95 percent CI: 0.54, 0.75); p<0.001 (stratified log-rank test)]; median progression-free survival was 4.4 months in the ramucirumab plus paclitaxel group and 2.9 months in the placebo plus paclitaxel group.

Safety data were evaluated in 656 patients who received at least one dose of study drug. The most frequently reported adverse reactions with ramucirumab plus paclitaxel (at least 30 percent of patients) were fatigue/weakness, neutropenia, diarrhea, and nosebleeds. The most common serious adverse reactions with ramucirumab plus paclitaxel were neutropenia (3.7 percent of patients) and febrile neutropenia 2.4 percent of patients).

The recommended dose and schedule for ramucirumab in combination with paclitaxel for advanced gastric or GEJ adenocarcinoma is ramucirumab 8 mg/kg administered intravenously every 2 weeks and paclitaxel 80 mg/m2 administered intravenously once a week for 3 weeks of every 28-day cycle. Treatment should continue until disease progression or unacceptable toxicity.

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Approved for gastric or gastroesophageal junction adenocarcinoma

On April 21, 2014, the Food and Drug Administration (FDA) approved ramucirumab (Cyramza™, made by Eli Lilly and Company) for use as a single agent for the treatment of patients with advanced or metastatic gastric or gastroesophageal junction adenocarcinoma whose disease has progressed during or after prior treatment with fluoropyrimidine- or platinum-containing chemotherapy. Ramucirumab is a recombinant monoclonal antibody of the IgG1 class that binds to vascular endothelial growth factor receptor-2 (VEGFR-2) and blocks activation of the receptor.    

This approval was based on the demonstration of improved overall survival in a multinational randomized double-blind study (I4T-IE-JVBD) that enrolled 355 patients with previously treated advanced or metastatic gastric or gastroesophageal junction adenocarcinoma. Patients enrolled in Study I4T-IE-JVBD were randomly assigned (2:1) to receive ramucirumab plus best supportive care (BSC) or placebo plus BSC.  

In that study, median overall survival was 5.2 months in the ramucirumab group and 3.8 months in the placebo group [HR 0.78 (95 percent CI: 0.60, 0.998), p =0.047]. Median progression-free survival was also longer in the ramucirumab group compared with the placebo group [HR 0.48 (95 percent CI: 0.38, 0.62), p <0.001, stratified log rank test].  

The safety of ramucirumab as a single agent was evaluated in 570 patients, including 236 patients with locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma, with an ECOG performance status of 1 or less, who received ramucirumab in Study I4T-IE-JVBD. The most common adverse reactions (all grades) observed in ramucirumab-treated patients at a rate of 10 percent, and at least 2 percent higher than placebo-treated patients, were high blood pressure and diarrhea. The grade 3-4 adverse reactions reported at a higher incidence in the ramucirumab arm (at least 2 percent difference between arms) included high blood pressure and hyponatremia (low blood sodium). The most common serious adverse events in patients who received ramucirumab were intestinal obstruction (2.1 percent) and anemia (3.8 percent). Other important risks described in product labeling include hemorrhage, arterial thromboembolic events, infusion-related reactions, gastrointestinal perforation, impaired wound healing, clinical deterioration in patients with cirrhosis, and reversible posterior leukoencephalopathy.  

The sponsor recently reported the findings of Study I4T-IE-JVBE, a multinational randomized placebo-controlled study that enrolled 665 patients with previously treated advanced or metastatic gastric or gastroesophageal junction adenocarcinoma in which patients received either paclitaxel plus placebo or paclitaxel plus ramucirumab. This trial was reported to demonstrate a survival advantage for the ramucirumab combination.

The recommended ramucirumab dose and schedule is 8 mg/kg administered as a 60-minute intravenous infusion every 2 weeks.

  • Updated: April 30, 2015