Cemiplimab

Cemiplimab is a fully human immunoglobulin G4 (IgG4) monoclonal antibody, produced by recombinant DNA technology in Chinese hamster ovary cells. It binds to the programmed cell death-1 (PD-1) receptor and blocks its interaction with the ligands PD-L1 and PD-L2, which restores T-cell activity against tumours.

Mechanism of Action

• The PD-1 checkpoint: PD-1 is an inhibitory receptor found mainly on T cells. Its ligands PD-L1 and PD-L2 are expressed by antigen-presenting cells and may also be expressed by tumour cells and other cells in the tumour microenvironment. When they engage PD-1, T-cell proliferation, cytokine secretion and cytotoxic activity are inhibited.
• Blockade: cemiplimab binds PD-1 with high affinity and prevents its binding to PD-L1 and PD-L2. This potentiates T-cell responses, including anti-tumour responses.
• Preclinical effect: in mouse tumour models, blocking PD-1 with cemiplimab reduced tumour growth.
• Immune-mediated effects: because the brake on the immune system is lifted broadly, the immune system can also attack normal tissue, which explains the immune-mediated adverse reactions described below.

Pharmacokinetics

• Absorption: given intravenously, cemiplimab is completely bioavailable. In a population analysis of 1,063 patients, mean steady-state concentrations at 350 mg every 3 weeks ranged from a trough of 59 mg/L to an end-of-infusion peak of 171 mg/L. Steady-state exposure is reached after about 4 months and is similar at 350 mg every 3 weeks and 3 mg/kg every 2 weeks. In simulations for high-risk cutaneous squamous cell carcinoma, 350 mg every 3 weeks for 12 weeks followed by 700 mg every 6 weeks gave concentrations between 52.5 mg/L (trough) and 233 mg/L (peak), and 350 mg every 3 weeks for 48 weeks gave 66.3 to 154 mg/L.
• Distribution: mainly in the vascular system, with a steady-state volume of distribution of 5.9 L. The median time to peak concentration is the end of the 30-minute infusion.
• Metabolism: specific metabolism studies were not done because cemiplimab is a protein; it is expected to break down into small peptides and amino acids.
• Elimination: clearance is linear at 1–10 mg/kg every 2 weeks. Clearance after the first dose is about 0.25 L/day and falls by about 11% over time to a steady-state clearance of 0.22 L/day, which is not clinically relevant. The half-life within the dosing interval at steady state is about 22 days.
• Special populations: age, sex, body weight, race, cancer type, albumin level, renal impairment and mild to moderate hepatic impairment have no clinically significant effect on exposure.

Cemiplimab is indicated in adults for:

• Cutaneous squamous cell carcinoma (CSCC): as monotherapy for metastatic or locally advanced CSCC in patients who are not candidates for curative surgery or curative radiation; and as monotherapy for the adjuvant treatment of CSCC at high risk of recurrence after surgery and radiation.
• Basal cell carcinoma (BCC): as monotherapy for locally advanced or metastatic BCC in patients who have progressed on, or are intolerant to, a hedgehog pathway inhibitor.
• Non-small cell lung cancer (NSCLC), first-line, with no EGFR, ALK or ROS1 aberrations, in locally advanced disease not suitable for definitive chemoradiation, or in metastatic disease: as monotherapy when the tumour expresses PD-L1 in at least 50% of tumour cells; or in combination with platinum-based chemotherapy when the tumour expresses PD-L1 in at least 1% of tumour cells.
• Cervical cancer: as monotherapy for recurrent or metastatic cervical cancer with disease progression on or after platinum-based chemotherapy.

• Hypersensitivity to cemiplimab or to any of the excipients.

Immune-mediated adverse reactions can occur; most of them, including severe ones, resolved after appropriate medical treatment or withdrawal of cemiplimab. The monotherapy safety data come from 1,281 patients with advanced solid tumours (median exposure 28 weeks). The most frequent reactions were fatigue (29.9%), musculoskeletal pain (28.3%) and rash (21.4%).

• Monotherapy: immune-mediated reactions occurred in 21% of patients (grade 5 in 0.3%, grade 4 in 0.6%, grade 3 in 5.7%, grade 2 in 11.2%) and led to permanent discontinuation in 4.6%. The most common were hypothyroidism (6.8%), hyperthyroidism (3.0%), immune-mediated pneumonitis (2.6%), hepatitis (2.4%), colitis (2.0%) and skin reactions (1.9%). Adverse events were serious in 32.4% and led to permanent discontinuation in 9.4%.
• Adjuvant CSCC (205 patients, median exposure 47.9 weeks): the profile was consistent with monotherapy in advanced cancer. Immune-mediated reactions occurred in 22.9%; adverse events were serious in 17.6% and led to discontinuation in 9.8%.
• With platinum-based chemotherapy (465 patients with NSCLC): immune-mediated reactions occurred in 18.9% (grade 5 in 0.3%). Adverse events were serious in 25.3% and led to discontinuation in 5.1%.
• Severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported.

Very common (≥1/10): upper respiratory tract infection, anaemia, decreased appetite, cough, nausea, diarrhoea, constipation, abdominal pain, rash, pruritus, musculoskeletal pain, fatigue. With platinum-based chemotherapy, also neutropenia, thrombocytopenia, peripheral neuropathy, hyperglycaemia, hypoalbuminaemia, dyspnoea, vomiting, insomnia, alopecia, weight loss and raised ALT and AST.

Common (≥1/100 to <1/10): urinary tract infection, infusion-related reaction, hypothyroidism, hyperthyroidism, headache, peripheral neuropathy, hypertension, dyspnoea, pneumonitis, vomiting, colitis, stomatitis, hepatitis, actinic keratosis, nephritis, pyrexia, oedema, raised ALT, AST, alkaline phosphatase and blood creatinine.

Uncommon (≥1/1,000 to <1/100): immune thrombocytopenia, Sjögren’s syndrome, thyroiditis, hypophysitis, adrenal insufficiency, myocarditis, pericarditis, gastritis, pancreatitis, arthritis, myositis, muscular weakness, polymyalgia rheumatica, raised thyroid-stimulating hormone, raised transaminases, raised bilirubin. With chemotherapy, type 1 diabetes mellitus and raised gamma-glutamyltransferase.

Rare (≥1/10,000 to <1/1,000): type 1 diabetes mellitus (uncommon with chemotherapy), meningitis, encephalitis, myasthenia gravis, paraneoplastic encephalomyelitis, chronic inflammatory demyelinating polyradiculoneuropathy, keratitis, uveitis, decreased thyroid-stimulating hormone. With chemotherapy, vasculitis, Guillain-Barré syndrome, central nervous system inflammation and meningitis (grade 4) were also rare.

Not known: haemophagocytic lymphohistiocytosis and solid organ transplant rejection (both post-marketing events), non-infective cystitis.

Infusion-related reactions occurred in 7.3% of monotherapy patients (94 of 1,281); 0.2% were grade 3 or 4, and nausea, pyrexia and vomiting were the common symptoms. In clinical studies, 2.1% of patients developed antibodies to cemiplimab, about 0.3% persistently, with no neutralising antibodies and no change in pharmacokinetics or safety.

No pharmacokinetic drug interaction studies have been done with cemiplimab.

• Systemic corticosteroids and immunosuppressants before starting: avoid them, except physiological doses of systemic corticosteroid (10 mg/day prednisone or equivalent, or less), because they may interfere with the activity and efficacy of cemiplimab.
• After starting: systemic corticosteroids and other immunosuppressants can be used to treat immune-mediated adverse reactions.

Treatment must be started and supervised by physicians experienced in the treatment of cancer. Patients with NSCLC are evaluated for treatment based on tumour PD-L1 expression confirmed by a validated test. Cemiplimab is given intravenously over 30 minutes through a line with a sterile, non-pyrogenic, low-protein-binding in-line or add-on filter (0.2 to 5 micron pore size). No other medicinal product should be given through the same infusion line. The concentrate is diluted before use according to the instructions in the SmPC.

Recommended Dose

• Locally advanced or metastatic CSCC, NSCLC, BCC, and recurrent or metastatic cervical cancer: 350 mg every 3 weeks as a 30-minute infusion, until disease progression or unacceptable toxicity. For the combination with platinum-based chemotherapy, see the SmPC for the chemotherapy schedule.
• Adjuvant treatment of high-risk CSCC: 350 mg every 3 weeks for 12 weeks followed by 700 mg every 6 weeks, or 350 mg every 3 weeks. Treatment continues until disease recurrence, unacceptable toxicity, or up to 48 weeks in total.

Dose Modifications

No dose reductions are recommended. Dosing may be delayed or stopped depending on safety and tolerability. The SmPC lists the actions by reaction and severity; examples are:

• Pneumonitis: grade 2, withhold and give prednisone 1–2 mg/kg/day or equivalent with a taper; resume if it improves and stays at grade 0–1 after the taper to 10 mg/day or less. Grade 3 or 4, or recurrent grade 2: permanently discontinue (prednisone 2–4 mg/kg/day or equivalent with a taper).
• Colitis: grade 2 or 3, withhold and give prednisone 1–2 mg/kg/day or equivalent with a taper; resume if colitis or diarrhoea improves and stays at grade 0–1 after the taper to 10 mg/day or less. Grade 4 or recurrent grade 3: permanently discontinue.
• Hepatitis: grade 2 with AST or ALT above 3 and up to 5 times the upper limit of normal, or total bilirubin above 1.5 and up to 3 times, withhold and give prednisone 1–2 mg/kg/day or equivalent with a taper. See the SmPC for the other grades and for the remaining reactions.
• Infusion-related reactions: interrupt or slow the infusion for mild or moderate reactions. Stop the infusion and permanently discontinue for severe (grade 3) or life-threatening (grade 4) reactions.
• Haemophagocytic lymphohistiocytosis: discontinue if confirmed and start treatment for it.

Special Populations

• Elderly: no dose adjustment. Exposure is similar across age groups; data are limited in patients aged 75 or over on monotherapy.
• Renal impairment: no dose adjustment. Data are limited in severe impairment (creatinine clearance 15 to 29 mL/min).
• Hepatic impairment: no dose adjustment for mild or moderate impairment. Cemiplimab has not been studied in severe impairment, and there are not enough data for dosing recommendations.
• Children and adolescents: safety and efficacy below 18 years have not been established.

Traceability

To improve traceability of this biological medicine, the name and batch number of the administered product should be clearly recorded.

Immune-Mediated Reactions

Severe and fatal immune-mediated adverse reactions have been seen. They can involve any organ system, can appear at any time during treatment, and can occur even after cemiplimab has been stopped. More than one body system can be affected at once, for example myositis with myocarditis or myasthenia gravis. The same guidance applies alone or with chemotherapy.

Patients are monitored for signs and symptoms. Suspected reactions are evaluated to confirm them and to exclude other causes, including infection. Management consists of withholding or permanently stopping cemiplimab depending on severity, hormone replacement where clinically indicated, and corticosteroids.

Observational data suggest that the risk of immune-mediated reactions with immune checkpoint inhibitors may be higher in patients with pre-existing autoimmune disease; flares of the underlying disease were frequent, but mostly mild and manageable.

Lung, Bowel and Liver

• Pneumonitis: immune-mediated pneumonitis, including fatal cases, has occurred. Monitor for signs and symptoms, rule out other causes, and image as indicated.
• Colitis: immune-mediated diarrhoea or colitis is managed with treatment modifications, anti-diarrhoeal medicines and corticosteroids.
• Hepatitis: immune-mediated hepatitis, including fatal cases, has occurred. Liver tests are checked before and periodically during treatment.

Endocrine Disorders

• Thyroid disorders (hypothyroidism, hyperthyroidism, thyroiditis) can occur at any time. Thyroiditis can present with or without changes in thyroid function tests, and hypothyroidism can follow hyperthyroidism. Thyroid function is monitored at the start and periodically, with hormone replacement if indicated.
• Hypophysitis and adrenal insufficiency: monitor for signs and symptoms, during and after treatment for adrenal insufficiency, and manage with treatment modifications, corticosteroids and hormone replacement as clinically indicated.
• Type 1 diabetes mellitus, including diabetic ketoacidosis, has occurred. Monitor for hyperglycaemia and signs of diabetes; manage with oral anti-hyperglycaemic medicines or insulin and treatment modifications.

Skin Reactions

Immune-mediated skin reactions requiring systemic corticosteroids have been reported, including severe cutaneous adverse reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis (some fatal), and rash, erythema multiforme and pemphigoid. Patients are monitored for suspected severe skin reactions; for signs of Stevens-Johnson syndrome or toxic epidermal necrolysis, they are referred for specialised care. Cases of Stevens-Johnson syndrome, fatal toxic epidermal necrolysis and stomatitis occurred after a single dose in patients who had earlier taken idelalisib and had recently taken sulfa-containing antibiotics, in a clinical trial in non-Hodgkin lymphoma.

Kidney and Other Immune-Mediated Reactions

• Nephritis: immune-mediated nephritis, including a fatal case, has occurred. Kidney function is monitored.
• Other fatal and life-threatening reactions include paraneoplastic encephalomyelitis, meningitis, myositis, myocarditis and pancreatitis. Non-infective cystitis has been reported with other PD-1/PD-L1 inhibitors, and coeliac disease and pancreatic exocrine insufficiency with other immune checkpoint inhibitors; they might also occur with cemiplimab.
• Haemophagocytic lymphohistiocytosis has been reported. Patients are monitored for its signs and symptoms.

Infusion-Related Reactions

Cemiplimab can cause severe or life-threatening infusion-related reactions. Patients are monitored and managed with treatment modifications and corticosteroids (see Administration and Dosage).

Transplant Recipients

Solid organ transplant rejection has been reported after marketing in patients treated with PD-1 inhibitors. Cemiplimab may increase the risk of rejection in transplant recipients, so the benefit must be weighed against that risk. Graft-versus-host disease has been reported with other PD-1/PD-L1 inhibitors in patients who had an allogeneic haematopoietic stem cell transplant.

Patients Not Studied

Patients with active infections, with immunocompromise, with a history of autoimmune disease, with ECOG performance status of 2 or more, or with a history of interstitial lung disease were not included in the studies. In the absence of data, cemiplimab should be used with caution in these patients after careful evaluation of the balance of benefits and risks.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential should use effective contraception during treatment and for at least 4 months after the last dose.
• Pregnancy: there are no data in pregnant women, and animal reproduction studies have not been done. Animal studies show that inhibiting the PD-1/PD-L1 pathway can lead to immune-mediated rejection of the developing foetus and foetal death. Cemiplimab is an IgG4 antibody and may cross the placenta. It is not recommended in pregnancy, or in women of childbearing potential not using effective contraception, unless the clinical benefit outweighs the potential risk.
• Breastfeeding: it is unknown whether cemiplimab is secreted in human milk, but antibodies are, and a risk to the breastfed infant cannot be excluded. Women should not breastfeed during treatment and for at least 4 months after the last dose.
• Fertility: no clinical data are available. A 3-month study in sexually mature monkeys found no effects on fertility parameters or on the male and female reproductive organs.

Excipients

Each 7 mL vial contains 105 mg of L-proline, which may be harmful for patients with hyperprolinaemia type I or II, and 14 mg of polysorbate 80, which may cause allergic reactions.

Effect on Driving

Cemiplimab has no or negligible influence on the ability to drive and use machines. Fatigue has been reported.

Store unopened vials in a refrigerator at 2–8 °C, in the original carton to protect from light. Do not freeze. Vials are shipped and held under cold-chain conditions until the hospital pharmacy prepares the infusion.

4 years for the unopened vial. Once the vial is opened, the medicine should be diluted and infused immediately. The prepared infusion solution should be used immediately; if it is not, in-use storage times and conditions are the responsibility of the user. Chemical and physical in-use stability has been shown for up to 8 hours at room temperature (up to 25 °C), or for up to 10 days at 2–8 °C, in each case from preparation of the infusion to the end of the infusion.

Prescription only (Rx), under restricted medical prescription (Annex II B). Treatment must be started and supervised by physicians experienced in the treatment of cancer. Cemiplimab is given by intravenous infusion in hospital, so it is supplied to the hospital or clinic that administers it, with cold-chain delivery at 2–8 °C.