Ramucirumab

Ramucirumab Instructions
Generic name: ramucirumab
Trade name: Cyramza
All names: Ramucirumab, Ramucirumab, Cyramza

Indications:
(1) As a single agent or in combination with paclitaxel (paclitaxel) for patients with advanced or metastatic gastric or gastroesophageal junction adenocarcinoma (GEJA) who have progressed during or after fluorouracil-containing or platinum-containing chemotherapy; (2) In combination with docetaxel for metastasis that has progressed during or after platinum-containing chemotherapy patients with non-small cell lung cancer (NSCLC); (3) combined with FOLFIRI regimen for patients with metastatic colorectal cancer (mCRC) whose disease has progressed during or after receiving bevacizumab, oxaliplatin, and fluorouracil; (4) as a monotherapy for the treatment of alpha-fetoprotein (AFP) ≥400ng/ mL of hepatocellular carcinoma (HCC).

Usage and dosage:
Non-small cell lung cancer
In combination with docetaxel for metastatic non-small cell lung cancer (NSCLC) with disease progression during or after platinum-based chemotherapy, patients with EGFR or ALK genomic tumor mutations should undergo genetic testing to detect whether EGFR or ALK gene mutations have occurred before receiving ramucirumab.
Infuse 10 mg/kg IV approximately 1 hour before docetaxel (75 mg/m²) IV on day 1 of a 21-day cycle
Continue until disease progression or unacceptable toxicity

Stomach Cancer
Single agent or in combination with paclitaxel: 8 mg/kg intravenously every two weeks; infused over 1 hour padding: 0px;">Paclitaxel dose (if given in combination): 80 mg/m once weekly every 28 days for 3 weeks
When given in combination, give ramucirumab before giving paclitaxel (Ramucirumab)
Continue until disease progression or unacceptable toxicity

Colorectal cancer
Investigated in combination with FOLFIRI for the treatment of patients with metastatic colorectal cancer (mCRC) whose disease has progressed on a first-line bevacizumab, oxaliplatin, and fluoropyrimidine-containing regimen
8 mg/kg intravenously every two weeks; administered by intravenous infusion 60 minutes before FOLFIRI administration
Continue until disease progression or unacceptable toxicity

Hepatocellular carcinoma
Studies have shown that sorafenib has been used to treat hepatocellular carcinoma (HCC) with alpha-fetoprotein (AFP) ≥400ng/mL as monotherapy
8 mg/kg IV every 2 weeks
Continue until disease progression or unacceptable toxicity

Adverse reactions:
> 10%
All grades unless otherwise stated
Gastrointestinal cancer (plus paclitaxel)
Fatigue/weakness (57%)
Neutropenia (54%)
Diarrhea (32%)
Nistaxis (31%)
Peripheral edema (25%)
Stomatitis (20%)
Proteinuria (17%)
Hypertension (25%)
Infusion-related reactions (16%)
Hypertension grade 3-4 (15%)
Thrombocytopenia (13%)
Hypoalbuminemia (11%)
NSCLC (plus docetaxel)
Neutropenia (55%)
Fatigue/asthenia (55%)
Stomatitis/mucosal inflammation (37%)
Estistaxis (19%)
Febrile neutropenia (16%)
Peripheral edema (16%)
Thrombocytopenia (13%)
Increased tear production (13%)
Hypertension (11%)

HCC
Thrombocytopenia (46%)
Fatigue (36%)
Hypoalbuminemia (33%)
Hyponatremia (32%)
Peripheral edema, hypertension, abdominal pain (25%)
Neutropenia (24%)
Decreased appetite (23%)
Proteinuria (20%)
Nausea (19%)
Ascites (18%)
Hypocalcemia (16%)
Headache (14%)
Nosebleeds (14%)
Insomnia (11%)

1-10%
Gastrointestinal bleeding events, gastric cancer (10%)

<1%
Gastrointestinal perforation (single dose) (0.7%)
Reversible posterior leukoencephalopathy syndrome (<0.1%)

Post-launch report

Thrombotic microangiopathy

Taboos:
None

Notes:
Increased risk of bleeding and gastrointestinal bleeding, including serious and sometimes fatal bleeding events; permanently discontinue treatment in patients who experience severe bleeding
Severe, sometimes fatal, arterial thromboembolic events, including myocardial infarction, cardiac arrest, cerebrovascular accidents, and cerebral ischemia, reported in clinical trials
Increased incidence of severe hypertension reported; Control hypertension before initiating treatment and monitor blood pressure q2 weeks or more frequently as directed; Temporarily discontinue treatment for severe hypertension
Infusion-related reactions observed include severe/tremor, back pain/cramping, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia; in severe cases, symptoms include bronchospasm, supraventricular tachycardia, and hypotension
Ramucirumab, an anti-angiogenic therapy that may increase the risk of gastrointestinal perforation and impair wound healing; withhold prior to surgery; permanently discontinue ramucirumab in patients who experience gastrointestinal perforation.
Impaired wound healing can occur with antibodies used to inhibit the VEGF pathway; withhold for 28 days before elective surgery; administer for at least 28 days after major surgical procedures until complete healing; discontinue if patient develops wound healing complications requiring medical intervention
Child-Pugh Clinical deterioration, manifested by new or worsening encephalopathy, ascites, or hepatorenal syndrome reported in patients with B or C cirrhosis; use only when benefits outweigh risks
Reversible posterior leukoencephalopathy syndrome (RPLS) has been reported (rare); Discontinuation of Ramucirumab
Severe proteinuria, including nephrotic syndrome, has been reported, especially when taken with FOLFIRI
Hypothyroidism may occur; monitor thyroid function during treatment
Based on its mechanism of action, Ramucirumab can cause fetal harm when given to pregnant women

Storage:
Unopened vial
Refrigerate at 2-8°C (36-46°F)
Place the sample vial in the outer carton to protect it from light

Dilute infusion
Administer within 24 hours after dilution
Refrigerate at 2-8°C (36-46°F) or refrigerate at room temperature (i.e. below 25°C [77°F]) for 4 hours
Do not freeze
Discard partially used vials

Mechanism of action:
ramucirumab is a human vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor. It can specifically bind to VEGF receptor 2 and block the coordination of VEGF ligands, VEGF-A, VEGF-C and VEGF-D. Thus, ramucirumab can inhibit ligand-induced activation of VEGF receptor 2, thereby inhibiting ligand-induced proliferation and migration of human endothelial cells.

Efficacy and safety:
Dr. Richard Pazdur, director of the Office of Hematology and Oncology Drugs in the FDA's Center for Drug Evaluation and Research, pointed out in a statement that ramucirumab has been proven to prolong patients' lives and slow down tumor growth, making it a new treatment option. The approval was based on a study of 355 patients with unresectable or metastatic gastric or gastroesophageal junction cancer. The median overall survival of patients in the ramucirumab group was 5.2 months compared with 3.8 months in the placebo group, with a hazard ratio (HR) of 0.78 (P=0.047). The progression-free survival of the Ramucirumab treatment group was also better than that of the placebo group, which was 2.1 months and 1.3 months respectively, with statistical significance (HR, 0.48). In another study comparing ramucirumab combined with paclitaxel and paclitaxel monotherapy, patients in the combination group also had an advantage in overall survival.
Cyramza has received FDA approval as a second-line therapy for the treatment of gastric cancer, NSCLC, colorectal cancer, and hepatocellular carcinoma (HCC).
449 patients with metastatic NSCLC carrying EGFR gene mutations (exon 19 deletion or exon 21 L858R substitution mutation) participated in the phase 3 RELAY trial. They were randomly assigned to receive a combination of Cyramza and erlotinib, or placebo and erlotinib. Compared with the PFS of 12.4 months in the erlotinib group, the PFS in the combination therapy group was 19.4 months, reaching the primary endpoint of significantly extending PFS. Improvements in secondary or exploratory endpoints such as duration of response, time to second progression or death (PFS2), and time on targeted therapy were seen in the combination therapy group.