Herceptin - Drug Monograph

Introduction

Herceptin (trastuzumab) is a monoclonal antibody therapy that represents a landmark advancement in targeted cancer treatment. Developed by Genentech, it was first approved by the FDA in 1998 for HER2-positive breast cancer. Herceptin specifically targets the human epidermal growth factor receptor 2 (HER2), a protein overexpressed in approximately 15-20% of breast cancers and other malignancies. This targeted approach has significantly improved outcomes for patients with HER2-positive cancers.

Mechanism of Action

Herceptin exerts its antitumor effects through multiple mechanisms:

• Receptor binding: Binds with high affinity to the extracellular domain IV of HER2 receptors
• Signal inhibition: Disrupts HER2-mediated signaling pathways (PI3K/AKT and RAS/MAPK) that promote cell proliferation and survival
• Antibody-dependent cellular cytotoxicity (ADCC): Recruits immune cells (natural killer cells) to mediate tumor cell destruction
• Receptor internalization: Promotes downregulation of HER2 receptors from the cell surface
• Anti-angiogenic effects: Inhibits formation of new blood vessels that supply tumors

Indications

• HER2-positive breast cancer (adjuvant treatment, neoadjuvant treatment, and metastatic disease)
• HER2-positive gastric or gastroesophageal junction adenocarcinoma

• Early-stage HER2-positive breast cancer following surgery
• Metastatic HER2-positive breast cancer (as monotherapy or combination therapy)
• HER2-positive breast cancer in combination with pertuzumab and chemotherapy
• HER2-overexpressing metastatic gastric or GEJ adenocarcinoma

Dosage and Administration

• Initial dose: 8 mg/kg IV infusion over 90 minutes
• Maintenance dose: 6 mg/kg IV infusion over 30-90 minutes every 3 weeks

• Weekly regimen: 4 mg/kg initial dose, then 2 mg/kg weekly

• Administer as IV infusion only
• Do not administer as IV push or bolus
• Observe patients for infusion-related reactions during and after administration
• Premedication with acetaminophen and diphenhydramine may be considered

• Renal impairment: No dosage adjustment required
• Hepatic impairment: No formal recommendations; use with caution
• Elderly: No dosage adjustment required
• Pediatric: Safety and effectiveness not established

Pharmacokinetics

• Absorption: Administered intravenously; complete bioavailability
• Distribution: Volume of distribution approximates plasma volume (44 mL/kg)
• Metabolism: Cleared via proteolytic degradation; no cytochrome P450 involvement
• Elimination: Biphasic elimination with half-life approximately 28-38 days
• Steady-state: Reached approximately by week 24 with q3week dosing

Contraindications

• Hypersensitivity to trastuzumab or any component of the formulation
• Known hypersensitivity to Chinese hamster ovary cell proteins

Warnings and Precautions

• May cause left ventricular dysfunction, heart failure, and decreased left ventricular ejection fraction (LVEF)
• Risk increased with concurrent anthracycline therapy
• Assess LVEF at baseline and regularly during treatment

• Can include fever, chills, and rarely severe reactions including anaphylaxis
• Monitor during and for several hours after first infusion

• May cause interstitial lung disease (ILD), including pneumonitis
• Can be fatal; monitor for pulmonary symptoms

• Can cause fetal harm when administered to pregnant women
• Verify pregnancy status prior to initiation
• Advise effective contraception during and for 7 months after treatment

• May increase risk of neutropenia and febrile neutropenia

Drug Interactions

• Anthracyclines: Increased risk of cardiotoxicity (avoid concurrent use)
• Other cardiotoxic agents: Additive cardiac risk
• Myelosuppressive chemotherapy: Increased risk of neutropenia

Adverse Effects

• Fever
• Chills
• Headache
• Infection
• Insomnia
• Cough
• Rash
• Fatigue
• Nausea
• Diarrhea
• Cardiotoxicity
• Neutropenia

• Cardiomyopathy (up to 11% in metastatic setting)
• Heart failure (NYHA Class III-IV: 2-5%)
• Severe infusion reactions
• Pulmonary events (including ARDS)
• Febrile neutropenia
• Severe neutropenia

Monitoring Parameters

• HER2 status confirmation (IHC 3+ or FISH-positive)
• Cardiac function: LVEF measurement (ECHO or MUGA scan)
• Complete blood count
• Comprehensive metabolic panel
• Pregnancy test

• LVEF every 3 months during treatment and upon completion
• Signs/symptoms of congestive heart failure
• Infusion reactions during and after administration
• Pulmonary symptoms (cough, dyspnea)
• Hematologic parameters
• Hepatic and renal function

• Cardiac function monitoring for several years after completion
• Surveillance for disease recurrence

Patient Education

• Importance of HER2 testing before treatment
• Potential cardiac side effects and need for regular heart monitoring
• Signs of heart problems: shortness of breath, swelling, weight gain
• Infusion reaction symptoms and management
• Need for effective contraception during and after treatment
• Importance of keeping all scheduled appointments and tests
• Not to stop treatment without consulting healthcare provider
• Management of common side effects (fever, fatigue, nausea)
• Importance of informing all healthcare providers about Herceptin treatment

• Maintain regular physical activity as tolerated
• Follow a heart-healthy diet
• Stay hydrated
• Report any new or worsening symptoms promptly

References

1. Slamon DJ, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783-792. 2. Piccart-Gebhart MJ, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353(16):1659-1672. 3. Herceptin® (trastuzumab) prescribing information. Genentech, Inc. 2023. 4. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Version 3.2023. 5. Romond EH, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353(16):1673-1684. 6. Bang YJ, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687-697. 7. Seidman A, et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol. 2002;20(5):1215-1221.