Serplulimab

Serplulimab (HLX10) is a humanised IgG4 monoclonal antibody, produced in Chinese hamster ovary cells by recombinant DNA technology, that binds the programmed cell death-1 (PD-1) receptor. PD-1 is a negative regulator of T-cell activity; blocking it releases that brake and strengthens T-cell responses, including anti-tumour responses.

Mechanism of Action

• PD-1 blockade: serplulimab blocks the interaction of PD-1 with its ligands PD-L1 and PD-L2. These ligands are found on antigen-presenting cells and may also be expressed by tumours or other cells in the tumour microenvironment, and their binding to PD-1 inhibits T-cell proliferation and cytokine secretion.
• Immune effect: blocking the PD-1 pathway potentiates T-cell responses, including anti-tumour responses.
• Receptor occupancy: in a phase 1 trial of 29 Chinese patients with advanced solid tumours, PD-1 receptor occupation on peripheral T cells stayed saturated, with sustained functional blockade, at doses from 0.3 to 10 mg/kg every 2 weeks.

Pharmacokinetics

• Absorption: given by intravenous infusion, so it is immediately and completely bioavailable; other routes have not been investigated.
• Distribution: volume of distribution about 6.17–6.46 L (population analysis of 2,110 patients).
• Metabolism: the pathway has not been characterised; serplulimab is expected to be broken down into small peptides and amino acids by general protein degradation.
• Elimination: clearance after the first dose is 0.171–0.211 L/day and falls over time by up to 8.8%. The half-life at steady state is 25.0–31.2 days, and mean steady-state trough concentrations range from 44.2 to 60.7 µg/mL across tumour types. Pharmacokinetics are linear over 0.3–10 mg/kg every 2 weeks, including flat doses.
• Special populations: no dedicated studies. The population analysis found no difference in clearance by age (23–83 years), race (Asian and white patients) or ECOG performance status (0 or 1); clearance rises with body weight. Renal function (creatinine clearance, including mild and moderate impairment) had no effect on clearance.

Hetronifly is used in adults, always in combination with chemotherapy, for first-line treatment of:

• Small cell lung cancer (SCLC): with carboplatin and etoposide, extensive-stage SCLC (ES-SCLC).
• Non-small cell lung carcinoma (NSCLC), non-squamous: with carboplatin and pemetrexed, in patients with no EGFR, ALK or ROS1 positive mutations who have locally advanced NSCLC that is not suitable for surgery or radiotherapy, or metastatic NSCLC.
• NSCLC, squamous: with carboplatin and nab-paclitaxel, unresectable, locally advanced or metastatic squamous NSCLC.
• Oesophageal squamous cell carcinoma (OSCC): with fluoropyrimidine- and platinum-based chemotherapy, unresectable, locally advanced, recurrent or metastatic OSCC whose tumours express PD-L1 with a CPS of 5 or more.

• Hypersensitivity to serplulimab or to any of the excipients.

The safety data are pooled from 1,343 patients given serplulimab with chemotherapy. The most common reactions were anaemia (80.2%), neutropenia (74.5%), leukopenia (71.6%), thrombocytopenia (53.8%), nausea (44.4%), decreased appetite (36.0%), alopecia (33.6%), hypoproteinaemia (31.3%), asthenia (29.9%) and vomiting (28.2%). The most common grade 3 or higher reactions were neutropenia (46.2%), leukopenia (27.3%), anaemia (25.8%), thrombocytopenia (15.3%), hyponatraemia (6.9%) and pneumonia (5.6%). The most common immune-mediated reactions were hypothyroidism (11.5%), immune-mediated skin reactions (7.6%), hyperthyroidism (7.1%), immune-mediated lung disease (5.5%), abnormal liver function (3.2%), immune-mediated nephritis and renal insufficiency (3.1%) and immune-mediated colitis (1.6%). Serplulimab was stopped because of adverse reactions in 8.1% of patients, most often for pneumonitis (1.6%) and pneumonia (1.3%). The frequencies are all-cause rates in patients also receiving chemotherapy, so they are not all due to serplulimab alone.

Very common (≥1/10): pneumonia, neutropenia, leukopenia, anaemia, thrombocytopenia, lymphopenia, hypothyroidism, hyperthyroidism, hyperglycaemia or type 1 diabetes mellitus, hyperlipidaemia, decreased appetite, hypoproteinaemia, hyperuricaemia, electrolyte imbalance, decreased weight, insomnia, arrhythmia, cough, chest pain, nausea, constipation, diarrhoea, vomiting, raised ALT and AST, rash, alopecia, musculoskeletal pain, protein in urine, raised blood creatinine, pyrexia, asthenia.

Common (≥1/100 to <1/10): urinary tract infection, respiratory tract infection, skin infection, abnormal coagulation tests, granulocytopenia, febrile neutropenia, infusion-related reaction, thyroiditis, hypoglycaemia, paraesthesia, headache, dizziness, peripheral neuropathy, sinus tachycardia, conduction defects, sinus bradycardia, heart failure, raised troponin, myocardial injury, hypertension, vasculitis, hypotension, pneumonitis, dyspnoea, dysphonia, pulmonary embolism, dysphagia, abdominal pain, flatulence, gastrointestinal disorder, stomatitis, dyspepsia, dry mouth, gastritis, raised gamma-glutamyltransferase, hyperbilirubinaemia, liver injury, pruritus, dermatitis, arthritis, raised blood urea, haematuria, kidney injury, malaise, oedema, raised alkaline phosphatase, myoglobin, creatine phosphokinase and amylase.

Uncommon (≥1/1,000 to <1/100): septic shock, anaphylactic reaction, adrenal insufficiency, other thyroid disorders, hypophysitis, abnormal thyroid function tests, hypoparathyroidism, vertigo, immune-mediated encephalitis, neurotoxicity, cerebral infarction, taste disorder, memory impairment, blurred vision, keratitis, conjunctivitis, myocardial ischaemia, pericardial effusion, myocarditis, venous thrombosis, respiratory failure, enteritis, immune-mediated pancreatitis, gingival bleeding, oesophagitis, gastric ulcer, pigmentation disorder, psoriasis, dry skin, hyperhidrosis, dysuria, pollakiuria, chills.

Rare (≥1/10,000 to <1/1,000): gastrointestinal infection, herpetic meningoencephalitis, lymphadenitis, hyperadrenocorticism, abnormal lipoprotein, motor dysfunction, myasthenia gravis, myasthenic syndrome, cardiomyopathy, toxic epidermal necrolysis, myositis, raised lipase.

Immune-mediated pneumonitis, colitis, hepatitis, nephritis, endocrine disorders, skin reactions, pancreatitis and myocarditis can be serious and sometimes fatal, and infusion-related reactions occur (see Special Instructions).

No drug-drug interaction studies have been conducted.

• CYP enzymes: as a monoclonal antibody, serplulimab is not metabolised by cytochrome P450 or other drug-metabolising enzymes, so inhibition or induction of these enzymes by other medicines is not expected to change its pharmacokinetics.
• Systemic corticosteroids and immunosuppressants: avoid them before starting serplulimab because they may interfere with its pharmacodynamic activity and efficacy. After starting, they can be used to treat immune-mediated adverse reactions.
• Chemotherapy partners: for carboplatin, etoposide, pemetrexed, nab-paclitaxel, cisplatin and 5-fluorouracil, see the SmPC of each medicine.

Treatment must be initiated and supervised by a physician experienced in the treatment of cancer. Hetronifly is for intravenous use only, as an infusion given in hospital. Where the indication specifies it (oesophageal squamous cell carcinoma), PD-L1 expression is assessed with a CE-marked in vitro diagnostic for that purpose or, if none is available, an alternative validated test.

• Infusion: the initial infusion rate is up to 100 mL per hour. If the first infusion is well tolerated, later infusions may be shortened to 30 minutes (± 10 minutes).
• With chemotherapy: Hetronifly is given first, then the chemotherapy on the same day, using separate infusion bags.
• Not a push: it must not be given as an intravenous push or bolus injection. The total dose is diluted in sodium chloride 9 mg/mL (0.9%) solution for injection.

Recommended Doses

• SCLC: 4.5 mg/kg every 3 weeks in both the induction and maintenance phases, until disease progression or unacceptable toxicity. In the induction phase (4 cycles), carboplatin is given on day 1 and etoposide on days 1, 2 and 3 of each 3-week cycle.
• Non-squamous NSCLC: 4.5 mg/kg every 3 weeks. In the induction phase (4 cycles), carboplatin and pemetrexed are given on day 1 of each 3-week cycle; in maintenance, pemetrexed continues at the physician’s discretion.
• Squamous NSCLC: 4.5 mg/kg every 3 weeks. In the induction phase (4–6 cycles), carboplatin is given on day 1 and nab-paclitaxel on days 1, 8 and 15 of each 3-week cycle.
• OSCC: 3.0 mg/kg every 2 weeks. In the induction phase, cisplatin is given on day 1 of each 2-week cycle for up to 8 cycles, and 5-fluorouracil on day 1 of each 2-week cycle for up to 12 cycles.
• For the combination partners, see the SmPC of each medicine.

Dose Delay or Discontinuation

Dose escalation or reduction of Hetronifly is not recommended. Withholding or discontinuation may be needed according to individual safety and tolerability, and withholding for up to 12 weeks for tolerability is acceptable. The SmPC (Table 1) sets out how to manage immune-mediated adverse reactions by reaction and grade.

Special Populations

• Elderly: no dose adjustment for patients aged 65 years or older.
• Renal impairment: no adjustment in mild (creatinine clearance 60–89 mL/min) or moderate (30–59 mL/min) impairment; data are insufficient in severe impairment (15–29 mL/min) and no dose recommendation can be made.
• Hepatic impairment: no adjustment in mild impairment. Data are insufficient in moderate impairment and absent in severe impairment, so no dose recommendation can be made.
• Children and adolescents: there is no relevant use of serplulimab in the paediatric population.

Traceability

The name and batch number of the administered product should be clearly recorded.

PD-L1 Assessment

When PD-L1 status is assessed, a well validated method should be chosen to minimise false negative or false positive results.

Immune-Mediated Adverse Reactions

These have occurred, including severe and fatal cases, and can involve more than one body system at once. Most were reversible and managed by withholding treatment, corticosteroids and supportive care, but they have also occurred up to 3.6 months after the last dose. For a suspected reaction the cause is confirmed or other causes excluded, treatment is withheld according to severity and a corticosteroid is given. Serplulimab is withheld until recovery to grade 1 for most grade 2 and some grade 3 or 4 reactions, and permanently stopped for any grade 4 and some grade 3 reactions. For grade 3 and 4 reactions, and some grade 2 ones (for example pneumonitis or myocarditis), a corticosteroid (prednisone or equivalent 1–2 mg/kg/day) is given until improvement to grade 1, then tapered over at least 1 month, because rapid tapering may bring the reaction back. A non-corticosteroid immunosuppressant (for example infliximab) is added if there is no improvement.

• Lung disease: patients are monitored for pneumonitis (radiographic changes, dyspnoea, hypoxia); the diagnosis is confirmed by imaging and other causes excluded.
• Colitis: abdominal pain, diarrhoea, or mucus or blood in stool; the risk of gastrointestinal perforation should be considered.
• Hepatitis: liver function and bilirubin are monitored every month, more often if hepatitis occurs.
• Nephritis and renal insufficiency: renal function is monitored every month; most patients have an asymptomatic rise in creatinine.
• Endocrine disorders: thyroid disease (hypothyroidism, hyperthyroidism, thyroiditis), hypophysitis, adrenal insufficiency and hyperglycaemia or type 1 diabetes can occur. Serplulimab is withheld for symptomatic grade 2 or 3 disease and hormone or insulin replacement is started as needed; it is permanently stopped for life-threatening disease.
• Skin reactions: for grade 3 rash it is withheld; for grade 4 rash, Stevens-Johnson syndrome or toxic epidermal necrolysis it is permanently stopped.
• Pancreatitis: serum amylase and lipase are monitored; for grade 4 or recurrent pancreatitis it is permanently stopped.
• Myocarditis: confirmed by myocardial enzymes with other causes excluded; for grade 3 or 4 myocarditis it is permanently stopped, and restarting after grade 2 myocarditis needs a multidisciplinary discussion.
• Uveitis and other reactions: if uveitis occurs with other immune-mediated reactions such as Vogt-Koyanagi-Harada syndrome, systemic corticosteroids are given to prevent permanent blindness. Thrombocytopenia, acute coronary syndrome, myocardial infarction, immune-mediated encephalitis, myasthenia gravis and myasthenic syndrome have also been fatal or life-threatening in trials; patients should know the symptoms of myasthenia (muscle weakness, tiring easily).

Infusion-Related Reactions

Patients are monitored for signs. With grade 1 reactions the infusion may continue under close monitoring; with grade 2 the rate is reduced or the infusion interrupted, and an antipyretic and antihistamines may be considered. For grade 3 or higher the infusion is stopped at once and treatment permanently stopped.

Patients Excluded From Trials

Clinical trials excluded patients with active or previous autoimmune disease, active tuberculosis, hepatitis B or C or HIV infection, live attenuated vaccine within 28 days before the first dose, active infection needing systemic anti-infective treatment within 14 days, a history of pneumonitis or interstitial lung disease, active brain metastases, significant cardiovascular disease (for example myocardial infarction within half a year), hypersensitivity to another monoclonal antibody, or systemic immunosuppressive medicines within 2 weeks before the first dose.

Excipients With Known Effect

Each 10 mL vial contains 0.98 mmol (22.5 mg) sodium, equal to 1.1% of the WHO recommended maximum daily sodium intake of 2 g for an adult, and 2.0 mg of polysorbate 80, which may cause allergic reactions.

Patient Card

The prescriber must discuss the risks of serplulimab with the patient, who receives a patient card with each prescription.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential should use effective contraception during treatment and for at least 6 months after the last dose.
• Pregnancy: no data. Animal studies show that PD-1 pathway inhibition causes embryofoetal toxicity, and as an IgG4 antibody serplulimab can cross the placenta to the foetus. It is not recommended during pregnancy or in women of childbearing potential not using contraception.
• Breastfeeding: it is not known whether serplulimab passes into human milk. Human IgG is found in breast milk in the first few days after birth, falling to low levels soon afterwards, so a risk to the breast-fed infant cannot be excluded in that short period; afterwards serplulimab could be used during breastfeeding if clinically needed.
• Fertility: fertility studies have not been performed, so the effect on male and female fertility is unknown.

Effect on Driving

Serplulimab has a minor influence on the ability to drive and use machines. Because of possible reactions such as fatigue, patients should be careful when driving or operating machinery until they are sure it does not affect them.

Store in a refrigerator at 2–8 °C. Do not freeze. Keep the vial in the original package to protect it from light. Hetronifly is a refrigerated product, so it is kept in the cold chain from supply until the infusion is prepared. For storage after dilution, see Shelf Life. The medicine is supplied as 10 mL of concentrate (100 mg) in a Type I clear glass vial, one vial per pack.

• Unopened vial: 3 years.
• Diluted solution: from a microbiological point of view it should be used immediately and must not be frozen. If not used at once, in-use times and conditions are the responsibility of the user and should not exceed 24 hours at 2–8 °C, which may include up to 6 hours at room temperature (25 °C or below). If refrigerated, the vials and/or intravenous bags must come to room temperature before use.

Prescription only (Rx). Treatment is initiated and supervised by a physician experienced in the treatment of cancer. Hetronifly is a concentrate that is diluted and given as an intravenous infusion in hospital, so it is supplied to the hospital or clinic that administers it, in a cold chain at 2–8 °C.