What Is Trastuzumab (Herceptin)? FDA Approval, Licensing and Reimbursement in Türkiye

• FDA Approval: Yes. First Approval Date: September 25, 1998
• Brand Name: Herceptin
• Active Ingredient: Trastuzumab
• Route of Administration: Intravenous infusion; subcutaneous injection (Herceptin Hylecta)
• Drug Class: Monoclonal antibody (HER2 receptor antagonist)
• Category: Targeted biological cancer treatment
• Manufacturer: Genentech, Inc. (Roche Group)
• Distribution in Türkiye: Roche, Abdi İbrahim, Pfizer, Celtrion Heltcare 
• Approved Cancer Types: HER2-positive early-stage breast cancer, HER2-positive metastatic breast cancer, HER2-positive metastatic gastric and gastroesophageal junction adenocarcinoma

What Is Trastuzumab and How Does It Work?

Trastuzumab is a targeted monoclonal antibody used to treat cancers that overexpress a protein called HER2 (human epidermal growth factor receptor 2). It is widely used particularly in HER2-positive breast and gastric (gastroesophageal) cancers. It is commonly marketed as Herceptin and can be given intravenously (IV) or subcutaneously (under the skin).

How Does It Work?

Trastuzumab binds specifically to the HER2 receptor, stopping tumor-cell growth and proliferation through the following mechanisms:

• Inhibition of HER2 receptor activity: HER2 is present at limited levels in normal cells but is overexpressed in certain cancer cells, continuously sending growth signals. Trastuzumab binds to HER2 and blocks these signals, slowing or stopping cell proliferation.
• Antibody-dependent cellular cytotoxicity: Trastuzumab triggers an immune response by identifying the tumor cells it binds to for immune-system cells. Natural killer (NK) cells recognize and destroy these marked cells.
• Suppression of intracellular signaling pathways: Trastuzumab also promotes cancer-cell death by inhibiting intracellular growth and survival pathways such as PI3K/AKT and MAPK.

FDA (US Food and Drug Administration) Approval History

• September 25, 1998: Herceptin: A Biotechnology Breakthrough in Breast Cancer Receives FDA Approval.
• November 16, 2006: The FDA Approves Herceptin as Adjuvant Treatment for HER2-Positive, Node-Positive Breast Cancer.
• October 20, 2010: The FDA Approves Herceptin for HER2-Positive Metastatic Gastric Cancer.
• June 3, 2023: A Study Shows the Potential for Chemotherapy-Free Treatment in HER2-Positive Early-Stage Breast Cancer.
• August 1, 2023: Lunit Presents a Groundbreaking Study on Predicting Treatment Response Through HER2 Analysis in Colorectal Cancer.
• 2019: Approval of Herceptin Hylecta (subcutaneous formulation); A subcutaneous formulation containing trastuzumab + hyaluronidase was approved.

Licensing in Türkiye

Trastuzumab (Herceptin) is licensed by the Ministry of Health in Türkiye and imported and distributed by several companies.

SGK Reimbursement

The Social Security Institution (SGK) reimburses trastuzumab for specific indications and under certain conditions.

• Metastatic Breast Cancer: For patients with HER2 +3 on immunohistochemistry or positive FISH/CISH/SISH (+), medical oncologists may prescribe trastuzumab for metastatic breast cancer on the basis of a medical board report that includes a medical oncologist and documents this status. Treatment is discontinued if progression occurs during trastuzumab use.
• Early-Stage Breast Cancer: For patients with HER2 +3 on immunohistochemistry or positive FISH/CISH/SISH (+), treatment for early-stage breast cancer lasts 9 weeks. Where completing 52 weeks is considered under the Ministry of Health's drug regulations, prescribing after the initial 9 weeks requires a medical board report valid for 3 months, including at least one medical oncologist and an echocardiographic assessment.
• Metastatic Gastric and Gastroesophageal Junction Cancer: Trastuzumab is approved with chemotherapy in HER2-positive metastatic gastric and gastroesophageal junction adenocarcinoma.

In some situations it is also used with Ministry of Health off-label authorization.

Indications Permitted Without Additional TİCK Approval:

• Head and Neck: In metastatic HER2-positive (IHC +3 or FISH +) tumors with nonsecretory histology (mucoepidermoid, salivary gland carcinoma, adenocarcinoma NOS), use with chemotherapy or as monotherapy is appropriate after progression following one chemotherapy line.
• Stage IV Colorectal Cancer: The trastuzumab–lapatinib combination is appropriate from the 2nd line onward in HER2-positive (IHC 3+ or FISH+) and RAS wild-type disease.
• Stage IV Colorectal Cancer: The trastuzumab–pertuzumab combination is appropriate from the 2nd line onward in HER2-positive (IHC 3+ or FISH+) and RAS wild-type disease.
• Advanced Endometrial Cancer: In HER2-positive serous disease that is platinum-sensitive, use with carboplatin and paclitaxel is appropriate from the 2nd line onward. HER2 positivity must be demonstrated by both IHC and FISH.

Price: June 2026 Herceptin 150 mg vial: 12668.50 TL. 

Mechanisms of Resistance

• Structural Changes in the HER2 Receptor: Truncated HER2 forms such as p95HER2 may develop. These lack the trastuzumab-binding region but continue to transmit signals. Trastuzumab cannot bind to the altered receptor, resulting in resistance.
• Activation of Alternative Signaling Pathways Outside HER2: The PI3K/AKT/mTOR pathway may become overactive. PTEN loss or PIK3CA mutations in particular activate this pathway, allowing cells to escape Herceptin's effect.
• Increased HER2 Heterodimerization: HER2 can combine with other EGFR-family members such as HER3 to form active signaling pathways. These dimers may escape trastuzumab's effects.
• Suppression of the Immune Response: Trastuzumab works through antibody-dependent cellular cytotoxicity (ADCC). This mechanism may be disabled when immunity is weak or the tumor produces immunosuppressive molecules such as PD-L1.
• Physical Barriers: Trastuzumab may not adequately penetrate tumor tissue. Fibrous tissue around the tumor or poor vascular structure may create barriers.

Absorption

• As a large monoclonal antibody, trastuzumab is not absorbed orally.
• It is administered intravenously (IV) or subcutaneously (under the skin).
• Intravenous formulation: 100% bioavailability.
• Subcutaneous formulation (Herceptin Hylecta): absorption is completed in 2–6 days, with approximately 77% bioavailability.

Distribution

• Volume of distribution (Vd): approximately 3–7 L (close to plasma volume), with limited distribution in the systemic circulation.
• It does not bind to plasma proteins because it is itself a large protein.
• It can cross the placental barrier; caution is required during pregnancy.
• Tissue penetration is limited, although it can reach the area around the tumor.

Metabolism

• Unlike conventional drugs, trastuzumab is not metabolized by cytochrome P450 enzymes.
• It is slowly broken down through the reticuloendothelial system, particularly in the liver and spleen.
• Because of its antibody-protein structure, it is broken down into amino acids by peptidases and proteases.

Elimination

• Trastuzumab's mean half-life (t½) ranges from approximately 5–30 days.
• It exhibits dose-dependent, nonlinear pharmacokinetics: the half-life is shorter after the initial loading dose (~6 days) and becomes longer at steady state (~28 days).
• Elimination through the kidneys or liver is minimal. Dose adjustment in kidney or liver impairment is therefore generally unnecessary.

Dose Range

1. Early-Stage Breast Cancer (Adjuvant Treatment)

Intravenous (IV) Administration

• Loading dose: 8 mg/kg as an intravenous infusion in the first week
• Maintenance dose: 6 mg/kg every 3 weeks
• Treatment duration: Usually 52 weeks (1 year)

Subcutaneous (SC) Administration (Herceptin SC)

• Fixed dose: 600 mg + 10,000 units of hyaluronidase
• Administration frequency: Every 3 weeks
• Administration duration: A 5-minute subcutaneous injection
• Duration of use: 1 year (17 cycles)

2. Metastatic Breast Cancer

Intravenous (IV) Administration

When used as monotherapy or with chemotherapy:

• Loading dose: 4 mg/kg IV infusion (day 1)
• Maintenance dose: 2 mg/kg once weekly
• Alternative: 6 mg/kg every 3 weeks may also be given

Subcutaneous (SC) Administration

Fixed dose: 600 mg (every 3 weeks)

3. Metastatic Gastric and Gastroesophageal Junction Adenocarcinoma

Intravenous (IV) Administration

• Loading dose: 8 mg/kg IV infusion (day 1)
• Maintenance dose: 6 mg/kg every 3 weeks
• Combination: With cisplatin + capecitabine or 5-FU
• Note: Herceptin SC is not approved for this indication; only the IV formulation is used.

Administration Duration and Monitoring

• The first IV dose is administered slowly over 90 minutes
• Subsequent infusions may be shortened to 30 minutes if tolerated
• Cardiac function, particularly LVEF, should be monitored before each dose.
• Assessment by echocardiography or MUGA every 3 months is recommended.

Drug Interactions

• Interactions with Chemotherapy Drugs: Anthracyclines (doxorubicin, epirubicin): cardiotoxicity risk increases. Cardiac function may be more severely affected when these drugs are given concurrently or at short intervals. Herceptin is therefore generally started at least 4 weeks after anthracycline treatment ends. Paclitaxel and carboplatin: although used together in clinical practice, careful cardiac monitoring is recommended. Increased neurotoxicity or hematologic toxicity has not been demonstrated.
• Interactions with Cardiac Drugs: Beta-blockers and ACE inhibitors (such as enalapril) may be used for protection or treatment in patients who develop cardiotoxicity. However, cardiac function should be monitored closely during concurrent use.
• Vaccines (Particularly Live Vaccines): Although trastuzumab does not suppress the immune system, immunosuppression may occur when it is combined with chemotherapy. Live vaccines, such as yellow fever vaccine, are not recommended during this period.
• Other Monoclonal Antibodies / Immunotherapies: There is a theoretical interaction risk, but clinical data are limited. Monitoring of immune response and toxicity is important when they are used concurrently.

Points Requiring Attention

• Cardiac Dysfunction: This is among the most serious adverse reactions. Left ventricular ejection fraction (EF) may decrease, and congestive heart failure may develop. The risk increases with concurrent or sequential anthracycline use and in patients with pre-existing heart disease. Cardiac function should be monitored before, during, and after treatment (EF measured by echocardiography).
• Pregnancy and Breastfeeding: Pregnancy category D: there is a risk of fetal and embryonic toxicity, including reduced amniotic fluid and kidney damage. It is not fully known whether the drug passes into breast milk, but breastfeeding is not recommended. Pregnancy prevention is essential during treatment and for at least 7 months afterward.
• Allergic and Infusion Reactions: Fever, chills, shortness of breath, and angioedema may occur, more frequently with the first dose. Treatment may be stopped for severe reactions. Infusions should be given slowly, with readiness for emergency intervention.
• Pulmonary Complications: Interstitial lung disease, pulmonary infiltration, hypoxia, and pulmonary edema have rarely been reported. New cough or shortness of breath should be carefully evaluated.
• Older Patients: Cardiotoxicity risk may increase in patients older than 65 years. More frequent cardiac assessments and evaluation of overall tolerability are required.
• Liver and Kidney Impairment: There are no clear dose-adjustment recommendations because breakdown occurs through the reticuloendothelial system rather than hepatic metabolism. However, caution is required in advanced organ failure.

Adverse Reactions

• Fever: 40%
• Upper respiratory tract infection: 35%
• Diarrhea: 25%
• Nausea: 21%
• Chills: 19%
• Headache: 18%
• Vomiting: 15%
• Fatigue: 13%
• Rash (dermatologic reactions): 11%
• Cough: 11%
• Pain (musculoskeletal): 10%
• Heart failure (cumulative): 7%
• Mouth sores (stomatitis): 6%
• Shortness of breath (dyspnea): 6%
• Low blood pressure (hypotension): 4%
• Anemia: 3%
• Peripheral edema: 2%
• Elevated liver enzymes (AST/ALT): 2%
• Neutropenia: 1–2%
• Anaphylactoid reactions: <1%