Ramucirumab

Introduction to Ramucirumab

Ramucirumab (brand name: Cyramza) is a fully human monoclonal antibody that targets the vascular endothelial growth factor receptor 2 (VEGFR-2). It was developed by ImClone Systems (now part of Eli Lilly and Company) and received FDA approval in 2014.

Ramucirumab is primarily used in the treatment of various advanced cancers, including gastric cancer, non-small cell lung cancer (NSCLC), and colorectal cancer. Its mechanism of action, targeting angiogenesis, makes it a valuable tool in oncology, with potential applications in pediatric cancers as well.

Mechanism of Action

Ramucirumab's mechanism of action centers on its ability to inhibit angiogenesis:

  • Specifically binds to VEGFR-2 with high affinity
  • Blocks the binding of VEGF ligands (VEGF-A, VEGF-C, and VEGF-D) to VEGFR-2
  • Prevents VEGF-stimulated endothelial cell proliferation and migration
  • Inhibits new blood vessel formation in tumors

By inhibiting angiogenesis, ramucirumab aims to:

  • Reduce tumor blood supply
  • Slow tumor growth and progression
  • Potentially enhance the effects of chemotherapy by improving drug delivery to tumors

Pharmacokinetics

Understanding the pharmacokinetics of ramucirumab is crucial for its effective use:

  • Distribution:
    • Mean volume of distribution at steady state: 5.4 L (coefficient of variation [CV] 15%)
    • Suggests limited extravascular distribution
  • Metabolism:
    • As a protein, ramucirumab is expected to be degraded into small peptides and amino acids via catabolic pathways
    • Not metabolized by cytochrome P450 enzymes
  • Elimination:
    • Mean clearance: 0.015 L/hour (CV 30%)
    • Elimination half-life: approximately 14 days (range 9-21 days)
  • Dose linearity: Exhibits approximately dose-proportional pharmacokinetics
  • Special populations:
    • Age, sex, and race do not significantly affect pharmacokinetics
    • Mild to moderate renal impairment or mild hepatic impairment does not significantly impact pharmacokinetics
    • Limited data in severe renal impairment or moderate to severe hepatic impairment

Indications and Clinical Use

Ramucirumab is FDA-approved for the following indications:

  1. Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma:
    • As a single agent or in combination with paclitaxel after prior fluoropyrimidine- or platinum-containing chemotherapy
  2. Non-Small Cell Lung Cancer (NSCLC):
    • In combination with docetaxel after platinum-based chemotherapy
    • In combination with erlotinib for first-line treatment of metastatic NSCLC with EGFR exon 19 deletions or exon 21 (L858R) mutations
  3. Colorectal Cancer:
    • In combination with FOLFIRI for metastatic disease that has progressed on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine
  4. Hepatocellular Carcinoma (HCC):
    • As a single agent in patients who have an alpha-fetoprotein (AFP) ≥ 400 ng/mL and have been treated with sorafenib

Clinical use considerations:

  • Ramucirumab is generally used in advanced or metastatic cancers
  • Often employed as a second-line or later therapy after progression on standard first-line treatments
  • Can be used as monotherapy or in combination with chemotherapy, depending on the indication
  • Selection of patients based on biomarkers (e.g., AFP in HCC) may improve response rates

Dosage and Administration

The recommended dosing of ramucirumab varies by indication:

  1. Gastric or GEJ Adenocarcinoma:
    • 8 mg/kg every 2 weeks as a single agent
    • 8 mg/kg every 2 weeks with paclitaxel
  2. NSCLC:
    • 10 mg/kg every 3 weeks with docetaxel
    • 10 mg/kg every 2 weeks with erlotinib
  3. Colorectal Cancer:
    • 8 mg/kg every 2 weeks prior to FOLFIRI
  4. Hepatocellular Carcinoma:
    • 8 mg/kg every 2 weeks as a single agent

Administration guidelines:

  • Administer as an intravenous infusion over 60 minutes
  • Do not administer as an intravenous push or bolus
  • Reduce the infusion rate by 50% for Grade 1 or 2 infusion-related reactions
  • Use a 0.22 micron in-line filter during administration

Ramucirumab is available as:

  • 100 mg/10 mL (10 mg/mL) solution in a single-dose vial
  • 500 mg/50 mL (10 mg/mL) solution in a single-dose vial

Clinical Efficacy

The efficacy of ramucirumab has been demonstrated in several large, randomized clinical trials across multiple cancer types:

  1. Gastric/GEJ Cancer:
    • REGARD trial (monotherapy): Improved overall survival (OS) vs. placebo (5.2 vs. 3.8 months, HR 0.78)
    • RAINBOW trial (with paclitaxel): Improved OS vs. paclitaxel alone (9.6 vs. 7.4 months, HR 0.81)
  2. NSCLC:
    • REVEL trial (with docetaxel): Improved OS vs. docetaxel alone (10.5 vs. 9.1 months, HR 0.86)
    • RELAY trial (with erlotinib): Improved progression-free survival (PFS) vs. erlotinib alone in EGFR-mutated NSCLC (19.4 vs. 12.4 months, HR 0.59)
  3. Colorectal Cancer:
    • RAISE trial (with FOLFIRI): Improved OS vs. FOLFIRI alone (13.3 vs. 11.7 months, HR 0.84)
  4. Hepatocellular Carcinoma:
    • REACH-2 trial (monotherapy): Improved OS vs. placebo in patients with AFP ≥400 ng/mL (8.5 vs. 7.3 months, HR 0.71)

Key efficacy outcomes:

  • Consistently demonstrates improvements in overall survival and/or progression-free survival across multiple cancer types
  • Generally provides modest but clinically meaningful benefits in the second-line or later setting
  • Efficacy may be enhanced when combined with chemotherapy or targeted therapies
  • Biomarker selection (e.g., AFP in HCC) may identify patients more likely to benefit

Adverse Effects

Common adverse reactions (incidence ≥10%) include:

  • Fatigue
  • Peripheral edema
  • Hypertension
  • Diarrhea
  • Decreased appetite
  • Abdominal pain
  • Stomatitis
  • Proteinuria
  • Thrombocytopenia
  • Neutropenia (when combined with chemotherapy)

Serious adverse effects include:

  • Hemorrhage: Including severe and sometimes fatal events
  • Gastrointestinal perforations: Rare but potentially fatal
  • Impaired wound healing: Can delay or impair proper healing
  • Arterial thromboembolic events: Including myocardial infarction and stroke
  • Hypertension: Can be severe and require management
  • Infusion-related reactions: Generally mild to moderate
  • Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Rare but serious neurological condition

Management of adverse effects often involves dose modifications, supportive care, and in some cases, discontinuation of ramucirumab. The overall safety profile is generally consistent with other anti-angiogenic agents.

Precautions and Contraindications

Contraindications:

  • None specifically listed in the prescribing information

Precautions:

  • Hemorrhage:
    • Avoid use in patients with severe bleeding
    • Discontinue in patients who experience severe bleeding
  • Gastrointestinal Perforations:
    • Discontinue in patients who experience perforations
  • Impaired Wound Healing:
    • Withhold for 28 days prior to elective surgery
    • Do not administer for at least 2 weeks following major surgery
  • Arterial Thromboembolic Events:
    • Discontinue in patients who experience severe arterial thromboembolic events
  • Hypertension:
    • Monitor blood pressure and treat hypertension
    • Temporarily suspend for severe hypertension
  • Infusion-Related Reactions:
    • Monitor for signs and symptoms during infusion
    • Reduce infusion rate for mild to moderate reactions
  • Worsening of Pre-existing Hepatic Impairment:
    • Use with caution in patients with Child-Pugh B or C cirrhosis
  • Reversible Posterior Leukoencephalopathy Syndrome (RPLS):
    • Discontinue in patients who develop RPLS
  • Proteinuria:
    • Monitor for proteinuria
    • Withhold for severe proteinuria; discontinue for nephrotic syndrome
  • Thyroid Dysfunction:
    • Monitor thyroid function during treatment


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