What Is Subcutaneous Trastuzumab Plus Pertuzumab (Phesgo)? FDA Approval, Licensing in Turkey, and Reimbursement

• FDA Approval: Yes (Initial approval date: June 29, 2020)
• Brand Name: Phesgo
• Active Ingredients: Pertuzumab + Trastuzumab + Hyaluronidase-zzxf
• Route of Administration: Subcutaneous (fixed-dose injection under the skin)
• Class: Monoclonal antibody combination + enzyme (hyaluronidase)
• Category: HER2 (Human Epidermal Growth Factor Receptor 2)-targeted treatment
• Manufacturer: Genentech, Inc. (Roche Group)
• Availability in Turkey: Licensed in Turkey.
• Approved Cancer Indications: HER2-positive early-stage, locally advanced, and metastatic breast cancer

What Is Phesgo? How Does It Work?

Phesgo is a fixed-dose subcutaneous (under-the-skin) formulation of pertuzumab and trastuzumab, two different monoclonal antibodies used to treat HER2-positive breast cancer. It also contains the enzyme hyaluronidase to assist these antibodies.

Hyaluronidase increases the absorption of medicines administered into subcutaneous tissue, making it possible to deliver large molecules in a single injection.

How Does It Work?

Trastuzumab (Herceptin)

• Binds to subdomain IV of the HER2 receptor.
• This binding prevents the cancer cell from receiving growth signals.
• Enables the immune system to destroy the cell through antibody-dependent cellular cytotoxicity (ADCC).

Pertuzumab (Perjeta)

• Binds to a different region of the HER2 receptor (subdomain II).
• Prevents HER2 from dimerizing with other HER receptors, such as HER3.
• This interrupts intracellular growth signals and stops cancer cells from growing.

Hyaluronidase-zzxf

• Breaks down hyaluronic acid between tissues, allowing the antibodies to spread more quickly and effectively from the subcutaneous injection site.
• Facilitates absorption of the injection and allows administration without intravenous access.

FDA (US Food and Drug Administration) Approval History

• June 3, 2023: A clinical trial demonstrating the potential for chemotherapy-free treatment of early-stage HER2-positive breast cancer was announced.
• June 29, 2020: The FDA approved Phesgo (pertuzumab, trastuzumab, and hyaluronidase-zzxf) for HER2-positive breast cancer.
• February 24, 2020: The FDA accepted Genentech's Biologics License Application for the fixed-dose subcutaneous combination of Perjeta and Herceptin for treating HER2-positive breast cancer.

Licensing in Turkey

It was licensed in Turkey on 22.08.2024 by Roche Müstahzarları Sanayi Anonim Şirketi.

Therapeutic Indications

• Neoadjuvant Treatment of Early-Stage Breast Cancer: Phesgoro, in combination with chemotherapy, is indicated as neoadjuvant treatment for patients with HER2-positive, locally advanced, inflammatory, or locally advanced-stage breast cancer (T3-4 and/or node-positive). Neoadjuvant Phesgoro treatment is limited to 4 cycles.
• Metastatic Breast Cancer: Phesgoro is indicated in combination with docetaxel chemotherapy as first-line treatment until progression for HER-2/neu-positive metastatic breast cancer in patients with an ECOG performance status of 0-1 who have not previously received systemic chemotherapy or trastuzumab for their metastatic disease. In patients whose disease progresses during Phesgoro treatment, it must not be continued, either as monotherapy or as part of combination treatment.

SGK Reimbursement

It is not reimbursed because it is not included in the EK-4A List of Reimbursable Medicines.

Price in June 2026:

Phesgoro solution for sc injection, 1200 mg+600 mg/15 ml, 1 vial 143,651.73 Turkish lira.

Phesgoro solution for sc injection, 600 mg+600 mg/15 ml, 1 vial 82,715.40 Turkish lira.

Mechanisms of Resistance

• Structural Changes in the HER2 Receptor (Truncation/Mutation): The extracellular portion of the HER2 receptor may be truncated (for example, the p95HER2 form). In this situation, the site to which trastuzumab binds disappears or changes, preventing the drug from binding to the receptor.
• Reduced HER2 Expression: Tumor cells eliminate the target by reducing HER2 protein levels. This leaves the drugs unable to find their target.
• Activation of Alternative Signaling Pathways: Intracellular growth pathways such as PI3K/AKT/mTOR or MAPK can be activated independently of HER2. PIK3CA mutations and PTEN loss, in particular, cause excessive activation of these pathways. Even when HER2 is blocked, the cell continues to grow, resulting in functional resistance.
• Dimerization With Other Receptors Such as HER3 and IGF-1R: Tumor cells bypass the pathways blocked by trastuzumab and pertuzumab by making greater use of receptors such as HER3 and IGF-1R. Even when pertuzumab prevents HER3 from dimerizing with HER2, the tumor cell may continue signaling through other alternative dimers.
• Reduced Internalization of the Antibody: Trastuzumab must remain on the cell surface for its antibody-directed cell-killing mechanism (ADCC) to work. Cells can evade this effect by rapidly internalizing or recycling the antibody.
• Reduction in Immune System-Mediated Resistance: One effect of trastuzumab is ADCC, in which immune cells recognize and kill the tumor cell. If immunosuppressive cells increase in the tumor microenvironment, ADCC becomes less effective and immunological resistance develops.

Absorption

• Route of administration: Subcutaneous injection, usually into the thigh
• Hyaluronidase-zzxf allows large volumes of antibodies injected under the skin to spread easily between tissues.
• Trastuzumab and pertuzumab gradually enter the systemic circulation after subcutaneous administration.
• Maximum plasma concentration (Cmax) is usually reached within 3-7 days.

Distribution

• Volume of distribution (Vd): Pertuzumab: Approximately 3.1 L; Trastuzumab: Approximately 3.1–5.6 L
• As large molecules, monoclonal antibodies generally remain confined to extracellular fluid.
• Plasma protein binding is low.

Metabolism

• Unlike conventional medicines, trastuzumab and pertuzumab are not metabolized in the liver.
• They are broken down through the reticuloendothelial system (RES) and intracellular lysosomal pathways.
• Enzymatic breakdown converts them into amino acids; they do not form active metabolites.

Elimination

• Half-life (t½): Pertuzumab: Approximately 18 days; Trastuzumab: Approximately 28 days
• Elimination occurs primarily through the reticuloendothelial system.
• There is no significant renal or hepatic elimination, so dose adjustment is not required in patients with mild-to-moderate renal or hepatic impairment.

Dosing Schedule

For neoadjuvant treatment, early-stage breast cancer, and metastatic breast cancer: 

Loading dose 1200 mg pertuzumab/600 mg trastuzumab, administered as a subcutaneous injection over 8 minutes,

Maintenance dose 600 mg pertuzumab/600 mg trastuzumab, administered as a subcutaneous injection over 8 minutes every 3 weeks.

• Phesgo does not require dose adjustment based on body weight or the concomitant chemotherapy regimen.
• Patients receiving intravenous (IV) pertuzumab and trastuzumab can switch to Phesgo. If less than 6 weeks have elapsed since the last IV dose, start with the maintenance dose of 600 mg pertuzumab/600 mg trastuzumab, administered every 3 weeks.
• If 6 weeks or more have elapsed since the last IV dose, administer the initial dose of 1200 mg pertuzumab/600 mg trastuzumab, then switch to maintenance dosing every 3 weeks.
• In the neoadjuvant (preoperative) setting, it is administered every 3 weeks for 3 to 6 cycles.
• After surgery, Phesgo is continued for a total of 1 year (up to 18 cycles).
• Treatment continues until disease recurrence or the development of intolerable toxicity.
• In the adjuvant setting, Phesgo is administered every 3 weeks for 1 year (up to 18 cycles) with standard chemotherapy based on an anthracycline and/or a taxane. Phesgo is started on day 1 of the first taxane-containing cycle.
• In metastatic breast cancer, it is administered with docetaxel. The initial docetaxel dose is 75 mg/m² by IV infusion and may be increased to 100 mg/m² if well tolerated. Phesgo is administered until disease progression or intolerable toxicity develops.

Drug Interactions

• It does not affect liver enzymes (CYP450), so direct metabolic interactions with conventional medicines are not expected.
• When used with chemotherapy medicines, particularly docetaxel, shared adverse effects such as diarrhea, neutropenia, and weakness may become more severe.
• When used with medicines that can affect cardiac function, such as anthracyclines, the risk of cardiotoxicity increases; cardiac function should be monitored regularly.
• When used with immunosuppressive medicines, the risk of infection may increase; patients should be monitored clinically.
• Concomitant use with live-virus vaccines is not recommended. Suppression of the immune response may reduce vaccine effectiveness or create a risk of infection.
• Using other biological agents with Phesgo may alter the immune response; such combinations should be planned carefully.

Precautions

• Cardiac Function Must Be Monitored: Phesgo may cause cardiotoxicity, particularly because it contains trastuzumab and pertuzumab. Left ventricular ejection fraction (LVEF) should be checked before treatment and regularly during treatment. Greater caution is needed in patients with a history of heart failure.
• Risk of Hypersensitivity and Anaphylaxis: Allergic reactions, including redness, shortness of breath, and hypotension, may develop during or immediately after administration. The patient should be observed for at least 15-30 minutes after the first dose.
• Risks During Pregnancy: It may have embryotoxic and fetotoxic effects. It should not be used during pregnancy, and effective contraception should be recommended for patients of childbearing potential. A risk-benefit assessment should be performed for patients planning a pregnancy.
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• Diarrhea May Occur: The combination of trastuzumab and pertuzumab can cause severe diarrhea, particularly when given with chemotherapy. Monitoring for dehydration and electrolyte loss is necessary.
• Immune Suppression and Infection Risk: Although it does not directly suppress the immune system, some patients may have an increased risk of infection. Fever, weakness, or respiratory symptoms should prompt assessment.
• Local Reactions May Occur With Subcutaneous Administration: Pain, edema, redness, and discoloration may occur at the injection site. Extravasation, described as the medicine escaping outside a blood vessel while spreading under the skin, may rarely create a risk of skin necrosis.
• It Must Not Be Used Concurrently With Live Vaccines: Because the immune response may be suppressed, live vaccines, such as measles and chickenpox vaccines, should not be given during Phesgo treatment.
• Subcutaneous Administration: Must Be Performed by Trained Healthcare Personnel. The injection should be given into the thigh, alternating between legs. Attention should be paid to needle depth and injection speed.

Adverse Effects

• Diarrhea 72%
• Fatigue 41%
• Nausea 33%
• Hair loss 30%
• Vomiting 26%
• Headache 25%
• Peripheral neuropathy 23%
• Rash 21%
• Musculoskeletal pain 20%
• Anemia 19%
• Fever 18%
• Decreased appetite 17%
• Injection-site reaction 16%
• Leukopenia 15%
• Joint pain 14%
• Cough 13%
• Mouth sores 13%
• Neutropenia 12%
• Insomnia 10%
• Cardiotoxicity (decreased LVEF) 1–4%
• Anaphylactic reaction <1%
• Hypophosphatemia <5%
• Hypokalemia <5%