Sugemalimab

Sugemalimab is a fully human immunoglobulin G4 (IgG4) monoclonal antibody against programmed death-ligand 1 (PD-L1), produced in Chinese hamster ovary cells by recombinant DNA technology. It is an immune checkpoint inhibitor: it lifts the PD-L1 brake that tumours use to suppress T cells.

Mechanism of Action

• PD-L1 blockade: sugemalimab binds PD-L1 and stops it from engaging PD-1. PD-L1 on tumour cells and tumour-infiltrating immune cells can contribute to inhibition of the anti-tumour immune response.
• CD80 interaction: PD-L1 binding to PD-1 and CD80 (B7.1) on T cells and antigen-presenting cells suppresses cytotoxic T-cell activity, T-cell proliferation and cytokine production. Blocking both interactions releases this inhibition.
• No ADCC: the SmPC states that this happens without inducing antibody-dependent cell-mediated cytotoxicity. DrugBank additionally describes antibody-dependent cellular phagocytosis of PD-L1-expressing tumour cells by tumour-associated macrophages.
• Immune-related effects: by releasing immune restraint, sugemalimab can cause immune-related adverse reactions in many organs (see Special Instructions).

Pharmacokinetics

• Absorption: given by intravenous infusion, so it is immediately and completely bioavailable. Exposure (AUC and Cmax) rises about in proportion to dose from 3 to 40 mg/kg, including the fixed 1,200 mg dose every 3 weeks. With repeated 1,200 mg doses every 3 weeks, exposure accumulates about 2-fold.
• Distribution: the volume of distribution at steady state is small, as expected for a monoclonal antibody: a geometric mean of 5.56 L in stage IV NSCLC and 4.74 L in stage III NSCLC.
• Metabolism: like other antibodies, it is broken down through non-specific catabolic pathways; metabolism does not contribute to its clearance.
• Elimination: geometric mean total clearance after a single dose is 0.235 L/day in stage IV and 0.214 L/day in stage III NSCLC; at steady state elimination is slightly lower because of target-mediated drug disposition. DrugBank gives a geometric mean elimination half-life of about 17.9 days (population analysis in NSCLC); the SmPC remains the reference.

• Metastatic NSCLC, first line: in combination with platinum-based chemotherapy, for adults with metastatic non-small-cell lung cancer with no sensitising EGFR mutations, or ALK, ROS1 or RET genomic tumour aberrations.
• Unresectable stage III NSCLC (monotherapy): for adults with unresectable stage III NSCLC with no sensitising EGFR mutations, or ALK or ROS1 genomic tumour aberrations, whose tumours express PD-L1 on at least 1% of tumour cells and whose disease has not progressed after platinum-based chemoradiotherapy.

• Hypersensitivity to sugemalimab or to any of the excipients.

Safety was assessed in 1,003 patients given 1,200 mg every 3 weeks in clinical studies across tumour types (435 with chemotherapy, 568 as monotherapy). Adverse reactions occurred in 95.6% of patients on the combination (grade 3 or higher in 33.1%) and in 81.5% of those on monotherapy (grade 3 or higher in 16.7%). Anaemia was the most common grade 3 or higher reaction in both settings (17.5% with chemotherapy, 3.2% as monotherapy). The reactions below are listed by frequency and treatment setting.

Very common (≥1/10): with chemotherapy, anaemia, hypothyroidism, hyperthyroidism, hyperlipidaemia, hyperglycaemia, hyponatraemia, hypokalaemia, hypocalcaemia, hypoaesthesia, abdominal pain, increased hepatic enzymes, rash, arthralgia, proteinuria, fatigue. As monotherapy, anaemia, hypothyroidism, hyperthyroidism, hyperlipidaemia, hyperglycaemia, increased hepatic enzymes, increased blood bilirubin, rash, proteinuria, pyrexia.

Common (≥1/100 to <1/10): with chemotherapy, hyperuricaemia, hypochloraemia, hypomagnesaemia, diabetes mellitus, peripheral neuropathy, conjunctivitis, dry eye, tachycardia, hypertension, pneumonitis, stomatitis, dry mouth, abnormal liver function, increased blood bilirubin, hepatitis, skin hypopigmentation, myalgia, bone pain, increased blood creatinine, nephritis, increased creatine phosphokinase, amylase and lipase, infusion-related reaction. As monotherapy, hypocalcaemia, hyponatraemia, tachycardia, hypertension, pneumonitis, diarrhoea, stomatitis, abnormal liver function, arthralgia, myalgia, increased blood creatinine, nephritis, fatigue, increased creatine phosphokinase and amylase.

Uncommon (≥1/1,000 to <1/100): with chemotherapy, immune-related pancytopenia or bicytopenia, anaphylactic reaction, immune-related hypophysitis, adrenal insufficiency, immune-mediated thyroiditis, dyslipidaemia, immune-mediated encephalitis, Guillain-Barré syndrome or immune-related demyelination, immune-mediated myocarditis, pancreatitis, proctitis, immune-mediated arthritis, increased troponin T, decreased cortisol. As monotherapy, haemolytic anaemia, hypersensitivity, vasculitis associated with antineutrophil cytoplasmic antibodies, immune-related hypophysitis, diabetes mellitus, conjunctivitis, myocarditis, colitis, hepatitis, myositis, immune-mediated arthritis, increased troponin T, infusion-related reaction.

Immune-related reactions (pneumonitis, colitis, hepatitis, nephritis, endocrine disorders, myocarditis and others) can be serious or fatal and can occur after treatment has been stopped. Infusion-related reactions, including anaphylaxis, have been reported.

• Pharmacokinetic interactions: no formal interaction studies have been done. Because sugemalimab is cleared by catabolism, metabolic interactions with other medicines are not expected.
• Systemic corticosteroids and immunosuppressants: avoid them before starting sugemalimab, because they may interfere with its pharmacodynamic activity and efficacy. After treatment has started, they can be used to treat immune-related adverse reactions.
• Chemotherapy partners: for interactions with carboplatin, paclitaxel or pemetrexed, see the SmPCs of those medicines.

Therapy should be started and supervised by a physician experienced in anticancer medicines. Cejemly is for intravenous use only. After dilution it is infused over 60 minutes and never given as an intravenous push or bolus. When it is combined with chemotherapy, the diluted sugemalimab is given first and chemotherapy may start 30 minutes after the infusion ends.

PD-L1 Testing for Stage III Disease

To decide eligibility for unresectable stage III NSCLC, PD-L1 expression on tumour cells should be assessed with a CE-marked in vitro diagnostic test intended for this purpose. If none is available, an alternative validated test should be used.

Recommended Dose

The dose depends on body weight: 1,200 mg for people weighing 115 kg or less and 1,500 mg for people weighing more than 115 kg. It is given every 3 weeks as a 60-minute infusion. Treatment continues until disease progression or unacceptable toxicity.

• Unresectable stage III NSCLC (monotherapy, consolidation): 1,200 mg or 1,500 mg every 3 weeks.
• First-line metastatic squamous NSCLC: sugemalimab followed by carboplatin and paclitaxel on day 1 for up to 4 cycles every 3 weeks. After the platinum-based chemotherapy, sugemalimab alone every 3 weeks for the duration of therapy.
• First-line metastatic non-squamous NSCLC: sugemalimab followed by carboplatin and pemetrexed on day 1 for up to 4 cycles every 3 weeks. After the platinum-based chemotherapy, sugemalimab and pemetrexed every 3 weeks for the duration of therapy.

Treatment Modification

The dose is never increased or reduced. Treatment is withheld or stopped according to individual safety and tolerability. The main rules in the SmPC (Table 2) are:

• Immune-related pneumonitis: grade 2, withhold until grade 0 to 1; grade 3 or 4, or recurrent grade 2, permanently discontinue.
• Immune-related colitis: grade 2 or 3, withhold; grade 4 or recurrent grade 3, permanently discontinue.
• Immune-related nephritis: grade 2 creatinine rise, withhold; grade 3 or 4, permanently discontinue.
• Immune-related hepatitis: grade 2 (AST or ALT above 3 to 5 times the upper limit of normal, or bilirubin above 1.5 to 3 times), withhold; grade 3 or 4 (AST or ALT above 5 times, or bilirubin above 3 times), permanently discontinue.
• Immune-related skin reactions: grade 3 or suspected Stevens-Johnson syndrome or toxic epidermal necrolysis, withhold; grade 4 or confirmed Stevens-Johnson syndrome or toxic epidermal necrolysis, permanently discontinue.
• Myocarditis (grade 2, 3 or 4), grade 3 or 4 encephalitis and grade 4 myositis: permanently discontinue.
• Infusion-related reactions: grade 2, interrupt and resume at 50% of the previous rate once resolved or grade 1 or lower; grade 3 or 4, permanently discontinue.
• Non-immune-mediated reactions: grade 2 and 3, withhold until grade 0 to 1; grade 4, permanently discontinue.

The SmPC table also covers pancreatitis, ocular toxicities, endocrine disorders and other immune-related reactions, including recurrent grade 3 or 4 reactions.

Special Populations

• Elderly (65 years and over): no treatment modification.
• Renal impairment: no modification in mild or moderate impairment; not studied in severe impairment, where it must be used with caution.
• Hepatic impairment: no modification recommended in mild impairment; not studied in moderate or severe impairment, where it must be used with caution.
• Children and adolescents: safety and efficacy below 18 years have not been established; no data are available.

Traceability

To improve traceability of biological medicines, the name and batch number of the administered product must be clearly recorded.

Immune-Related Adverse Reactions

Serious and fatal immune-related adverse reactions have occurred, and they can appear after treatment has stopped. Most were reversible and were managed by withholding sugemalimab, corticosteroids and supportive care. Several body systems can be affected at the same time. Suspected reactions should be evaluated to confirm the cause or exclude others; depending on severity, sugemalimab is withheld or permanently discontinued and corticosteroids are considered. After improvement to grade 1 or 0, corticosteroids are tapered over at least 1 month, and sugemalimab can be restarted if the reaction stays at grade 1 or 0. If another severe episode occurs, it is permanently discontinued. The reactions described in the SmPC are:

• Pneumonitis: monitor for signs and symptoms and confirm with imaging. Radiation pneumonitis looks very similar; pneumonitis or radiation pneumonitis was reported in patients who had recently completed chemoradiation.
• Skin reactions: severe immune-related skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, which have been reported with PD-1/PD-L1 inhibitors. In suspected cases withhold sugemalimab and refer the patient to a specialised unit. Use caution in patients who had a severe or life-threatening skin reaction on other immune-stimulating anticancer agents.
• Colitis: reported with monotherapy; monitor for signs and symptoms and exclude other causes.
• Hepatitis and nephritis: check liver tests and kidney function before and during treatment.
• Endocrine disorders: thyroid disorders (hyperthyroidism, hypothyroidism, thyroiditis), type-1 diabetes mellitus, adrenal insufficiency and hypophysitis. Monitor thyroid function at the start and periodically, watch for hyperglycaemia, and monitor pituitary function and hormone levels. Replacement therapy is given as clinically indicated.
• Myositis, myocarditis, pancreatitis and ocular toxicities: monitor for signs; refer suspected myositis to a specialist without delay; suspected myocarditis needs prompt corticosteroids and cardiology review; monitor amylase and lipase for pancreatitis.
• Other reactions: upper gastrointestinal disorders, arthritis, pancytopenia or bicytopenia, meningoencephalitis or encephalitis, Guillain-Barré syndrome or demyelination, rhabdomyolysis or myopathy, haemolytic anaemia and vasculitis.

Infusion-Related Reactions

Infusion-related reactions, including anaphylactic reaction, excessive sweating, fever, chills, erythema and rash, have been reported. Patients should be monitored closely during the infusion and managed as described under Treatment Modification.

Patients Not Studied

Patients with the following were excluded from the clinical studies: active autoimmune disease, immunosuppressive treatment, a live-virus vaccine within 28 days before starting, HIV, hepatitis B or hepatitis C infection, and a history of interstitial lung disease or idiopathic pulmonary fibrosis.

Patient Card

All physicians administering sugemalimab must be familiar with the Physician Information and Management Guidelines. The physician must discuss the risks of treatment with the patient, who receives a patient card to carry at all times.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential must be advised to avoid pregnancy and use reliable contraception during treatment and for at least 4 months after the last dose.
• Pregnancy: there are no data in pregnant women and no animal reproduction studies. In mouse models, PD-L1 blockade disrupted tolerance to the foetus and increased foetal loss. Sugemalimab is not recommended in pregnancy or in women of childbearing potential not using contraception.
• Breastfeeding: it is unknown whether sugemalimab passes into human milk. Antibodies can, so a risk to the infant cannot be excluded; a decision is made whether to stop breastfeeding or stop treatment.
• Fertility: no clinical data. Animal data showed no notable effects on the male and female reproductive organs.

Sodium and Polysorbate 80

Each vial contains 25.8 mg of sodium; a 1,200 mg dose contains 51.6 mg and a 1,500 mg dose 64.5 mg (2.58% and 3.23% of the WHO recommended maximum daily intake of 2 g for an adult). Dilution in sodium chloride 9 mg/mL (0.9%) solution adds to this. Each vial contains 2.04 mg of polysorbate 80 (4.08 mg per 1,200 mg dose and 5.10 mg per 1,500 mg dose); polysorbates may cause allergic reactions.

Effect on Driving

Sugemalimab has a minor influence on the ability to drive and use machines. Fatigue has been reported; patients with fatigue should not drive or use machines until it has resolved.

Store unopened vials in a refrigerator at 2–8 °C. Do not freeze. Keep the vial in the outer carton to protect it from light. Cejemly is a refrigerated product and needs an unbroken cold chain at 2–8 °C until it is prepared for infusion at the hospital.

After dilution, chemical and physical in-use stability has been shown for up to 24 hours at 2–8 °C and up to 4 hours at room temperature (up to 25 °C) from preparation. From a microbiological point of view the diluted product should be used immediately. If it is not, in-use times and conditions are the responsibility of the user and would normally not exceed 24 hours at 2–8 °C, unless dilution took place under controlled and validated aseptic conditions.

It is supplied as 20 mL of concentrate in a type 1 glass vial with an elastomeric stopper and a blue flip-off aluminium seal, in packs of 2 vials.

36 months for the unopened vial. For the diluted solution see Storage Conditions.

Prescription only (Rx), subject to restricted medical prescription (Annex II B); therapy is started and supervised by physicians experienced in anticancer medicines. Sugemalimab is a hospital infusion, so it is supplied to the hospital or clinic that administers it, as a cold-chain delivery at 2–8 °C.