HETRONIFLY (Serplulimab)

What Is HETRONIFLY and What Is It Used For?

HETRONIFLY (serplulimab) is a cancer immunotherapy medicine that helps the immune system fight cancer. It is a monoclonal antibody that blocks the PD-1 receptor on immune cells, preventing cancer cells from switching off the body's natural anti-tumour defences. It is used in combination with chemotherapy for previously untreated extensive-stage small cell lung cancer (ES-SCLC).

HETRONIFLY contains the active substance serplulimab, a humanised immunoglobulin G4 (IgG4) monoclonal antibody. It belongs to a class of cancer medicines known as immune checkpoint inhibitors, which represent one of the most significant advances in cancer treatment over the past decade. These medicines work by unleashing the body's own immune system to attack cancer cells, rather than directly killing the cancer cells with toxic chemicals.

The immune system normally uses a system of “checkpoints” to prevent it from attacking the body's own healthy cells. One of these checkpoints involves a protein called programmed death-1 (PD-1), which is found on the surface of T-cells (a type of white blood cell central to the immune response) and B-cells. When PD-1 binds to its partner proteins, PD-L1 and PD-L2, it sends a signal that essentially tells the T-cell to stand down and stop attacking. Many cancer cells have learned to exploit this mechanism by displaying high levels of PD-L1 on their surface, effectively “hiding” from the immune system.

Serplulimab works by binding to the PD-1 receptor on T-cells, blocking the interaction between PD-1 and its ligands (PD-L1 and PD-L2). This prevents cancer cells from sending the “stop” signal to the immune system. As a result, T-cells remain activated and are able to recognise and destroy cancer cells. This mechanism of action is referred to as immune checkpoint blockade.

Approved Indication

HETRONIFLY is approved for the treatment of adults with extensive-stage small cell lung cancer (ES-SCLC) in combination with platinum-based chemotherapy (carboplatin or cisplatin plus etoposide) as first-line therapy. “Extensive-stage” means the cancer has spread beyond one side of the chest, either within the lungs or to other parts of the body. “First-line” means this is the initial treatment the patient receives for this cancer – HETRONIFLY is not indicated for patients who have already received other treatments for ES-SCLC.

Small cell lung cancer (SCLC) accounts for approximately 13–15% of all lung cancers and is characterised by rapid growth and early metastatic spread. Unfortunately, the majority of patients (around 60–70%) are diagnosed at the extensive stage when the cancer has already spread widely. Historically, treatment for ES-SCLC was limited to platinum-based chemotherapy, which provided a high initial response rate but was followed by rapid disease progression in most patients. The addition of PD-1/PD-L1 checkpoint inhibitors to chemotherapy has represented a meaningful advance, improving both progression-free survival and overall survival.

What Should You Know Before Receiving HETRONIFLY?

Before starting HETRONIFLY, inform your oncologist about all your medical conditions, especially autoimmune diseases, organ transplant history, liver or kidney problems, and lung disease. HETRONIFLY is contraindicated if you are allergic to serplulimab or any of the excipients in the formulation.

Contraindications

You must not receive HETRONIFLY if you are allergic (hypersensitive) to serplulimab or to any of the other ingredients in this medicine (listed in the “What Does HETRONIFLY Contain?” section below). If you are uncertain whether you have an allergy, talk to your doctor or nurse before treatment begins.

Warnings and Precautions

Talk to your oncologist before receiving HETRONIFLY if you have or have had any of the following conditions:

• An autoimmune disease (a condition where the immune system attacks the body's own cells, such as rheumatoid arthritis, lupus, Crohn's disease, or ulcerative colitis) – HETRONIFLY can activate the immune system and may worsen autoimmune conditions
• Liver problems – pre-existing liver disease may increase the risk of immune-mediated hepatitis
• Kidney damage – kidney function should be monitored during treatment
• Lung problems or breathing difficulties – immune-mediated pneumonitis is a known serious side effect
• Previous organ transplant – HETRONIFLY may increase the risk of organ rejection by activating the immune system
• Previous severe reactions to other monoclonal antibody cancer treatments – including anti-PD-1, anti-PD-L1, or anti-CTLA-4 therapies

Your oncologist may prescribe other medicines (such as corticosteroids) to manage these immune-mediated reactions. In some cases, your doctor may need to delay the next dose of HETRONIFLY or stop treatment altogether. These decisions are based on the severity of the reaction and are made in your best interest.

Children and Adolescents

HETRONIFLY is not recommended for use in children and adolescents under 18 years of age. This is because there is no clinical data available on the safety and efficacy of serplulimab in this age group. Small cell lung cancer is extremely rare in children, and the benefit–risk profile of PD-1 inhibitors has not been established in paediatric patients.

Pregnancy and Breastfeeding

Pregnancy: You must not receive HETRONIFLY during pregnancy unless your doctor specifically recommends it after careful consideration of the potential benefits and risks. The PD-1/PD-L1 signalling pathway plays an essential role in maintaining immune tolerance during pregnancy. Blocking this pathway with serplulimab may lead to immune-mediated rejection of the foetus and could harm the unborn baby. Women of childbearing potential should use effective contraception during treatment with HETRONIFLY and for at least 5 months after the last dose.

Breastfeeding: It is not known whether serplulimab passes into breast milk. Because of the potential for serious adverse reactions in breastfed infants, you and your doctor will need to decide together whether you can breastfeed after receiving serplulimab. In general, breastfeeding is not recommended during treatment and for at least 5 months after the last dose.

Driving and Operating Machinery

HETRONIFLY may cause fatigue, dizziness, and other side effects that can impair your ability to drive or operate machinery safely. Do not drive or use machines after receiving HETRONIFLY unless you are certain that you feel well. If you experience any symptoms that affect your alertness or coordination, wait until these symptoms have resolved before driving.

Important Information About Excipients

Sodium: This medicine contains 22.5 mg sodium (the main component of table salt) per 10 mL vial. This is equivalent to approximately 1.1% of the recommended maximum daily dietary intake of sodium for an adult. This should be taken into consideration by patients on a controlled sodium diet.

Polysorbate 80: This medicine contains 2.0 mg polysorbate 80 per 10 mL vial. Polysorbates can cause allergic reactions. Tell your doctor if you have any known allergies to polysorbate 80.

How Does HETRONIFLY Interact with Other Drugs?

HETRONIFLY may interact with immunosuppressive medicines, particularly systemic corticosteroids, which can reduce its effectiveness. Tell your doctor about all medicines you are taking, including herbal remedies, supplements, and over-the-counter products.

Because HETRONIFLY works by stimulating the immune system, medicines that suppress the immune system may reduce its anti-cancer effectiveness. The most clinically important interaction involves systemic corticosteroids and other immunosuppressants, which should be avoided before starting HETRONIFLY. However, once treatment has begun, your doctor may prescribe corticosteroids to manage immune-mediated adverse reactions. Corticosteroids may also be given as pre-medication before chemotherapy to prevent nausea and vomiting.

As a monoclonal antibody, serplulimab is not metabolised by cytochrome P450 (CYP) liver enzymes, so traditional drug–drug interactions based on enzyme inhibition or induction are not expected. However, the combination with chemotherapy agents introduces additional interaction potential, as outlined below.

Clinically Important Interactions

Unlike many small-molecule drugs, monoclonal antibodies like serplulimab are cleared from the body through proteolytic degradation rather than liver metabolism. This means that food, grapefruit juice, and commonly used medications are unlikely to affect serplulimab blood levels directly. However, the overall treatment regimen involves concurrent chemotherapy agents that do have their own interaction profiles, so your oncology team will review your complete medication list before each treatment cycle.

What Is the Correct Dosage of HETRONIFLY?

The recommended dose of HETRONIFLY is 4.5 mg per kilogram of body weight, administered as an intravenous infusion every 3 weeks. It is given at a hospital or clinic under the supervision of an experienced oncologist.

HETRONIFLY is always administered by qualified healthcare professionals in a hospital or clinic setting. You will not need to prepare or administer this medicine yourself. Your oncologist will calculate the correct dose based on your body weight and will monitor you during and after each infusion.

Adults

Children and Adolescents

HETRONIFLY is not recommended for patients under 18 years of age. There are no clinical data to support its use in this population.

Dose Modifications

Dose reductions of HETRONIFLY are not recommended. Instead, treatment may be delayed or permanently discontinued depending on the type and severity of adverse reactions. Your oncologist will follow specific guidelines for managing immune-mediated side effects:

• Grade 2 immune-mediated reactions: Treatment may be withheld (paused) until the reaction improves to Grade 1 or less, with or without corticosteroid therapy
• Grade 3 immune-mediated reactions: Treatment is typically withheld and high-dose corticosteroids are initiated. HETRONIFLY may be resumed once the reaction improves to Grade 1 or less and corticosteroids have been tapered
• Grade 4 immune-mediated reactions: Treatment is permanently discontinued in most cases, with the exception of endocrinopathies that can be managed with hormone replacement therapy

Missed Dose

It is very important that you attend all scheduled appointments for your HETRONIFLY infusions. If you miss an appointment, contact your oncology team as soon as possible to reschedule. Consistent dosing every 3 weeks is important for maintaining the therapeutic effect of the medicine.

Overdose

Stopping Treatment

Do not stop treatment with HETRONIFLY without discussing it with your oncologist. If treatment is interrupted, the therapeutic effect of the medicine may be lost. Your doctor will carefully consider the benefits and risks of continuing or stopping treatment based on your individual circumstances, including treatment response, side effects, and overall health status.

What Are the Side Effects of HETRONIFLY?

HETRONIFLY can cause immune-mediated side effects affecting virtually any organ system, as well as side effects related to the concurrent chemotherapy. The most common side effects include decreased blood cell counts, infections, thyroid disorders, nausea, fatigue, rash, and hair loss. Some immune-mediated reactions can be severe or life-threatening and require immediate medical attention.

Like all medicines, HETRONIFLY can cause side effects, although not everybody gets them. Because HETRONIFLY works by activating the immune system, it can cause inflammation in various parts of the body. Some of these inflammatory conditions can be serious or life-threatening and require prompt treatment. Your oncology team will monitor you closely during treatment and may perform regular blood tests and imaging studies to detect problems early.

If you experience any side effects not listed above, or if any side effect becomes severe or persistent, tell your doctor or nurse. Reporting suspected side effects after a medicine has been authorised is important, as it helps to continuously monitor the medicine's benefit–risk balance. You can report side effects to your national medicines regulatory authority or through the European Medicines Agency (EMA) reporting system.

How Should HETRONIFLY Be Stored?

HETRONIFLY must be stored in a refrigerator (2°C to 8°C), protected from light, and must not be frozen. This medicine is handled and stored by hospital pharmacy staff – you will not need to store it at home.

Keep HETRONIFLY out of the sight and reach of children. Do not use this medicine after the expiry date printed on the outer carton and the vial label after “EXP”. The expiry date refers to the last day of the stated month.

Storage conditions:

• Store in a refrigerator at 2°C to 8°C
• Do not freeze
• Store in the original packaging to protect from light

After dilution: The diluted solution should be used immediately. If not used immediately, the diluted solution has been shown to be chemically and physically stable for up to 24 hours at 2°C to 8°C (refrigerated), which may include up to 6 hours at room temperature (at or below 25°C). The diluted solution must not be frozen.

Do not use this medicine if you observe visible particles or discolouration. Any unused medicinal product or waste material should be disposed of in accordance with local requirements for cytotoxic medicines.

What Does HETRONIFLY Contain?

Each 10 mL vial of HETRONIFLY contains 100 mg of serplulimab (10 mg/mL) as the active ingredient. The concentrate is a colourless to slightly yellow, clear to slightly opalescent liquid supplied in a glass vial.

Active Ingredient

The active substance is serplulimab. Each millilitre of concentrate contains 10 mg of serplulimab. One 10 mL vial contains 100 mg of serplulimab.

Inactive Ingredients (Excipients)

The other ingredients are:

• Citric acid monohydrate (buffering agent)
• Sodium citrate (buffering agent)
• Sodium chloride (tonicity agent) – see “Sodium” warning in Section 2
• Mannitol (stabiliser)
• Polysorbate 80 (surfactant) – see “Polysorbate 80” warning in Section 2
• Water for injections

Appearance and Packaging

HETRONIFLY is a concentrate for solution for intravenous infusion. The concentrate is a colourless to slightly yellow, clear to slightly opalescent liquid. It is supplied in a 10 mL Type I glass vial with a rubber stopper. Each carton contains 1 vial.

Marketing Authorisation Holder

Accord Healthcare S.L.U., World Trade Center, Moll de Barcelona, s/n, Edifici Est, 6a Planta, 08039 Barcelona, Spain.

How Does HETRONIFLY Work in the Body?

HETRONIFLY works by blocking the PD-1 immune checkpoint on T-cells, preventing cancer cells from evading the immune response. This restores the ability of the immune system to recognise and destroy tumour cells. Combined with chemotherapy, it provides a dual attack on cancer – direct cell killing plus immune-mediated tumour destruction.

The human immune system is equipped with powerful mechanisms to detect and eliminate abnormal cells, including cancer cells. However, tumours have evolved sophisticated strategies to evade immune surveillance. One of the most important of these strategies involves the PD-1/PD-L1 checkpoint pathway.

Under normal circumstances, the PD-1 receptor on T-cells acts as a “brake” to prevent excessive immune activation that could damage healthy tissues. When PD-1 binds to its ligands (PD-L1 and PD-L2), which are expressed on many normal cells throughout the body, it sends an inhibitory signal that dampens the T-cell response. This is an essential part of maintaining immune homeostasis and preventing autoimmunity.

Many cancers, including small cell lung cancer, exploit this natural immune checkpoint by overexpressing PD-L1 on their cell surfaces. When tumour-associated PD-L1 binds to PD-1 on T-cells that have infiltrated the tumour, it effectively sends a “do not attack” signal. The result is T-cell exhaustion – the immune cells become functionally impaired and unable to mount an effective anti-tumour response, even though they have already recognised the cancer as abnormal.

Serplulimab is a humanised IgG4 monoclonal antibody that binds with high affinity to the PD-1 receptor. By occupying the PD-1 binding site, serplulimab physically prevents PD-L1 and PD-L2 from engaging with PD-1. This removes the inhibitory brake on T-cells, allowing them to regain their anti-tumour activity. The reinvigorated T-cells can then proliferate, produce cytokines, and directly kill tumour cells through cytotoxic mechanisms.

Synergy with Chemotherapy

HETRONIFLY is used in combination with platinum-based chemotherapy (carboplatin/cisplatin plus etoposide) for good reason. Chemotherapy kills rapidly dividing cancer cells directly, but in doing so, it also causes the release of tumour-associated antigens – molecular fragments that can be recognised by the immune system. This phenomenon, sometimes called immunogenic cell death, can prime the immune system to recognise and attack remaining tumour cells. By combining chemotherapy with PD-1 blockade, the treatment creates a synergistic effect: chemotherapy exposes the tumour to the immune system, while serplulimab ensures that the immune response is not suppressed by the PD-1 checkpoint.

Pharmacokinetic Profile

Serplulimab is administered intravenously, so it achieves 100% bioavailability with immediate systemic distribution. Like other monoclonal antibodies, it is not metabolised by hepatic cytochrome P450 enzymes. Instead, it is cleared from the body through target-mediated drug disposition (binding to PD-1 on immune cells) and non-specific proteolytic degradation into amino acids. The pharmacokinetics of serplulimab are linear and predictable across the therapeutic dose range. Based on population pharmacokinetic analyses, the steady-state volume of distribution is consistent with that of other IgG4 monoclonal antibodies, and the terminal half-life supports the 3-weekly dosing regimen.

How Is HETRONIFLY Prepared and Administered?

HETRONIFLY is prepared and administered by trained healthcare professionals using aseptic technique. The concentrate is diluted in 0.9% sodium chloride solution and given as an intravenous infusion through an in-line filter. This section provides an overview – patients do not need to prepare the medicine themselves.

The following information provides a general overview of how HETRONIFLY is prepared and administered. Full preparation instructions are provided in the Summary of Product Characteristics (SmPC) and are followed by trained healthcare professionals.

• The vial is allowed to reach room temperature (at or below 25°C) before use
• The concentrate is visually inspected for particles and discolouration before administration – it should be colourless to slightly yellow, clear to slightly opalescent
• The required volume of HETRONIFLY is withdrawn from the vial and diluted in 0.9% sodium chloride solution for injection to achieve a final concentration of 1.0 to 8.0 mg/mL
• The diluted solution is mixed by gentle inversion (not shaking)
• The infusion is administered through a sterile, non-pyrogenic, low-protein-binding 0.2 to 5.0 μm in-line or add-on filter
• The initial infusion rate is set at 100 mL per hour (approximately 25 drops per minute) and may be adjusted if infusion-related reactions occur
• If no infusion-related reactions occur during the first infusion, subsequent infusions may be shortened to 30 minutes (± 10 minutes)
• The infusion line is flushed with 0.9% sodium chloride at the end of each infusion
• No other medicines should be administered through the same infusion line

Frequently Asked Questions About HETRONIFLY

References

Editorial Team