Cyramza (ramucirumab) - 5 indications

Scroll down for information on each indication:

• Advanced or metastatic gastric cancer; approved 04/01/2014
• Metastatic non-small cell lung cancer; approved 12/01/2014
• Hepatocellular carcinoma with elevated alpha-fetoprotein (AFP); approved 05/01/2019
• In combination with erlotinib for the first-line treatment of metastatic non-small cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 (L858R) mutatioMetastatic colorectal cancer; approved 04/01/2015ns; approved 05/01/2020

General Information

Cyramza (ramucirumab) is a human VEGFR2 antagonist. It is a recombinant human IgG1 monoclonal antibody.

Cyramza is specifically indicated for the following conditions:

• as a single agent or in combination with paclitaxel for the treatment of patients with advanced or metastatic, gastric or gastro-esophageal junction (GEJ) adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.
• in combination with docetaxel for the treatment of metastatic non-small cell lung cancer with disease progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving Cyramza.
• in combination with erlotinib for the first-line treatment of patients with metastatic non-small cell lung cancer with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) mutations.
• in combination with FOLFIRI (irinotecan, folinic acid, and fluorouracil) for the treatment of patients with metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.
• 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.

Cyramza is supplied as an injection for intravenous administration. Prior to each Cyramza infusion, pre-medicate all patients with an intravenous histamine-1 receptor antagonist (e.g., diphenhydramine hydrochloride). For patients who have experienced a Grade 1 or 2 IRR, pre-medicate with a histamine-1 receptor antagonist, dexamethasone (or equivalent), and acetaminophen prior to each Cyramza infusion. 

Scroll down for specific dosing recommendations for each indication.

Mechanism of Action

Cyramza (ramucirumab) is a human VEGFR2 antagonist and it is a recombinant human IgG1 monoclonal antibody. Cyramza specifically binds VEGFR2 and blocks binding of 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.

Side Effects

Scroll down to see the most frequent adverse effects associated with each condition and treatment combination.

Indication 1 - Advanced or metastatic gastric cancer

approved 04/01/2014

Dosing and Administration

The recommended dosage of Cyramza, either as a single agent or in combination with weekly paclitaxel, is 8 mg/kg every 2 weeks administered by intravenous infusion over 60 minutes. If the first infusion is tolerated, all subsequent Cyramza infusions may be administered over 30 minutes. Continue until disease progression or unacceptable toxicity. 

• When given in combination with paclitaxel, administer Cyramza prior to administration of paclitaxel. 
• Refer to the prescribing information for paclitaxel for dosage information

Side Effects

Adverse effects associated with the use of single agent Cyramza may include, but are not limited to, the following:

• hypertension
• diarrhea

Adverse effects associated with the use of Cyramza and paclitaxel may include, but are not limited to, the following:

• fatigue/asthenia
• neutropenia
• diarrhea
• epistaxis

Clinical Trial Results

The FDA approval of Cyramza for gastric cancer was based on a multinational, randomized, double-blind study evaluating Cyramza plus best supportive care (BSC) versus placebo plus BSC in 355 subjects with locally advanced or metastatic gastric cancer (including adenocarcinoma of the gastro-esophageal junction) who previously received platinum- or fluoropyrimidine-containing chemotherapy. The major efficacy outcome measure was overall survival and the supportive efficacy outcome measure was progression-free survival. The subjects treated with Cyramza experienced a median overall survival of 5.2 months compared to 3.8 months in psubjects receiving placebo. Additionally, subjects who took Cyramza experienced a delay in tumor growth (progression-free survival) compared to subjects who were given placebo.

Indication 2 - Metastatic non-small cell lung cancer

approved 12/01/2014

Dosing/Administration

The recommended dosage of Cyramza is 10 mg/kg administered by intravenous infusion over 60 minutes on Day 1 of a 21-day cycle prior to docetaxel infusion. If the first infusion is tolerated, all subsequent Cyramza infusions may be administered over 30 minutes. Continue Cyramza until disease progression or unacceptable toxicity.

• Refer to the prescribing information for docetaxel for dosage information.

Side Effects

Adverse effects associated with the use of Cyramza plus docetaxel may include, but are not limited to, the following:

• neutropenia
• fatigue/asthenia
• stomatitis/mucosal inflammation

Clinical Trial Results

The FDA approval of Cyramza for non-small cell lung cancer was based on the phase 3 REVEL trial. The trial enrolled 1253 patients with mostly non-squamous stage 4 disease, but did include about a quarter of patients with squamous carcinoma. Patients were given either docetaxel in combination with placebo or 10 mg/kg of Cyramza  on day 1 of a three-week cycle. Patients were treated until disease progression or unacceptable toxicity. Data which showed a 1.4-month improvement in overall survival (OS) when comparing the combination with docetaxel alone. Median OS was 10.5 months in the combination arm compared with 9.1 months in the docetaxel-alone arm. Progression-free survival (PFS) was also improved with the combination: Median PFS was 4.5 months with the combination and 3 months with docetaxel alone.

Indication 3 - Metastatic colorectal cancer

approved 04/01/2015

Dosing/Administration

The recommended dosage of Cyramza is 8 mg/kg every 2 weeks administered by intravenous infusion over 60 minutes prior to FOLFIRI administration. If the first infusion is tolerated, all subsequent Cyramza infusions may be administered over 30 minutes. Continue Cyramza until disease progression or unacceptable toxicity.

• Refer to the prescribing information for fluorouracil, leucovorin, and irinotecan for dosage information.

Side Effects

Adverse effects associated with the use of Cyramza plus FOLFIRI may include, but are not limited to, the following:

• diarrhea
• neutropenia
• decreased appetite
• epistaxis
• stomatitis

Clinical Trial Results

The FDA approval of Cyramza for colorectal cancer was based on the phase 3 global, double-blind RAISE study of Cyramza plus FOLFIRI compared to placebo plus FOLFIRI as a second-line treatment for mCRC in patients who had disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. Patients were randomized in a 1:1 ratio to receive Cyramza plus FOLFIRI (n=536) or placebo plus FOLFIRI (n=536) every two weeks. In the RAISE trial, patients treated with the Cyramza-FOLFIRI combination achieved a median OS, the study's primary endpoint, of 13.3 months as compared to those treated with placebo-FOLFIRI who achieved 11.7 months, a statistically significant improvement that reduced the risk of patient death by 15 percent. The percentage of deaths at the time of analysis was 69 percent (372 patients) and 74 percent (397 patients) in the Cyramza-plus-FOLFIRI and placebo-plus-FOLFIRI treatment arms, respectively.

Indication 4 - Hepatocellular carcinoma with elevated alpha-fetoprotein (AFP)

approved 05/01/2019

Dosing/Administration

The recommended dosage of Cyramza is 8mg/kg every 2 weeks administered by intravenous infusion over 60 minutes. Continue Cyramza until disease progression or unacceptable toxicity.

Side Effects

Adverse effects associated with the use of Cyramza for hepatocellular carcinoma may include, but are not limited to, the following:

• fatigue
• peripheral edema
• hypertension
• abdominal pain
• decreased appetite
• proteinuria
• nausea
• ascites
• Laboratory abnormalities, including thrombocytopenia, hypoalbuminemia, and hyponatremia

Clinical Trial Results

The FDA approval of Cyramza for hepatocellular carcinoma was based on results from the REACH-2 study, a Phase 3 HCC trial in a biomarker-selected patient population. REACH-2 was a global, randomized, double-blind, placebo-controlled study evaluating Cyramza versus placebo in patients with HCC who have been treated with sorafenib and are AFP-High (AFP ≥400 ng/mL). Cyramza showed a statistically significant benefit in the primary endpoint of overall survival (OS) and in the secondary endpoint of progression-free survival (PFS). Results showed that treatment with Cyramza significantly improved the OS of patients compared to placebo. Median OS was 8.5 months with Cyramza compared to 7.3 months with placebo. For the secondary endpoints, median PFS was improved with Cyramza to 2.8 months compared to 1.6 months for placebo. Objective response rate was numerically higher with Cyramza compared to placebo, 4.6 percent vs. 1.1 percent. In addition, disease control was higher with Cyramza than placebo, 59.9 percent compared to 38.9 percent.

Indication 5 - In combination with erlotinib for the first-line treatment of metastatic non-small cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 (L858R) mutations

approved 05/01/2020

Dosing/Administration

The recommended dose of Cyramza in combination with Erlotinib for EGFR Exon 19 deletions or Exon 21 (L858R) substitution mutations is Cyramza 10 mg/kg every 2 weeks administered by intravenous infusion over 60 minutes. If the first infusion is tolerated, all subsequent Cyramza infusions may be administered over 30 minutes. Continue Cyramza until disease progression or unacceptable toxicity.

• Refer to the prescribing information for erlotinib for dosage information.

Side Effects

Adverse effects associated with the use of Cyramza plus erlotinib may include, but are not limited to, the following:

• infections
• hypertension
• stomatitis
• proteinuria
• alopecia
• epistaxis
• laboratory abnormalities: increased alanine aminotransferase, increased aspartate aminotransferase, anemia, thrombocytopenia, and neutropenia.

Clinical Trial Results

The FDA approval of Cyramza for use in combination with erlotinib, for the first-line treatment of  patients with metastatic non-small cell lung cancer with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) mutations was based on the global, randomized, placebo-controlled Phase 3 RELAY trial. In the RELAY study, Cyramza in combination with erlotinib, a globally approved EGFR-targeting tyrosine kinase inhibitor (TKI), demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) – the time patients lived without their cancer growing or spreading after starting treatment – compared to placebo in combination with erlotinib [19.4 months in the Cyramza-containing arm compared to 12.4 months in the placebo-containing arm. The PFS treatment effect was consistent across exon 19 and exon 21 subgroups.