This information is intended for use by health professionals

 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. Name of the medicinal product

LIBTAYO 350 mg concentrate for solution for infusion.

2. Qualitative and quantitative composition

One ml of concentrate contains 50 mg of cemiplimab.

Each vial contains 350 mg of cemiplimab in 7 ml of solution.

Cemiplimab is produced by recombinant DNA technology in Chinese hamster ovary (CHO) cell suspension culture.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Concentrate for solution for infusion (sterile concentrate).

Clear to slightly opalescent, colourless to pale yellow solution with a pH of 6.0 and osmolality between 300 and 360 mmol/kg. The solution may contain trace amounts of translucent to white particles in a single-use vial.

4. Clinical particulars
4.1 Therapeutic indications

LIBTAYO as monotherapy is indicated for the treatment of adult patients with metastatic or locally advanced cutaneous squamous cell carcinoma who are not candidates for curative surgery or curative radiation.

4.2 Posology and method of administration

Treatment must be initiated and supervised by physicians experienced in the treatment of cancer.

Posology

Recommended dose

The recommended dose is 350 mg cemiplimab, every 3 weeks, administered as an intravenous infusion over 30 minutes.

Treatment may be continued until disease progression or unacceptable toxicity.

Dose modifications

No dose reductions are recommended. Dosing delay or discontinuation may be required based on individual safety and tolerability. Recommended modifications to manage adverse reactions are provided in Table 1.

Detailed guidelines for the management of immune-related adverse reactions are described in Table 1.

Table 1: Recommended treatment modifications

Adverse reaction

Severitya

Dose modification

Additional intervention

Pneumonitis

Grade 2

Withhold LIBTAYO

Initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a taper

Resume LIBTAYO if pneumonitis improves and remains at Grade 0 to 1 after corticosteroid taper to ≤10 mg/day prednisone or equivalent

Grade 3 or 4

or

recurrent Grade 2

Permanently discontinue

Initial dose of 2 to 4 mg/kg/day prednisone or equivalent followed by a taper

Colitis

Grade 2 or 3

Withhold LIBTAYO

Initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a taper

Resume LIBTAYO if colitis or diarrhoea improves and remains at Grade 0 to 1 after corticosteroid taper to ≤10 mg/day prednisone or equivalent

Grade 4

or

recurrent Grade 3

Permanently discontinue

Initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a taper

Hepatitis

Grade 2 with AST or ALT >3 and ≤5×ULN

or

total bilirubin >1.5 and ≤3×ULN

Withhold LIBTAYO

Initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a taper

Resume LIBTAYO if hepatitis improves and remains at Grade 0 to 1 after corticosteroid taper to ≤10 mg/day prednisone or equivalent or returns to baseline AST or ALT after completion of corticosteroid taper

Grade ≥3 with AST or ALT >5×ULN

or

total bilirubin >3×ULN

Permanently discontinue

Initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a taper

Hypothyroidism

Grade 3 or 4

Withhold LIBTAYO

Initiate thyroid hormone replacement as clinically indicated

Resume LIBTAYO when hypothyroidism returns to Grade 0 to 1 or is otherwise clinically stable

Hyperthyroidism

Grade 3 or 4

Withhold LIBTAYO

Initiate symptomatic management

Resume LIBTAYO when hyperthyroidism returns to Grade 0 to 1 or is otherwise clinically stable

Hypophysitis

Grade 2 to 4

Withhold LIBTAYO

Initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a taper and hormone replacement as clinically indicated

Resume LIBTAYO if hypophysitis improves and remains at Grade 0 to 1 after corticosteroid taper to ≤10 mg/day prednisone or equivalent or is otherwise clinically stable

Adrenal insufficiency

Grade 2 to 4

Withhold LIBTAYO

Initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a taper

Resume LIBTAYO if adrenal insufficiency improves and remains at Grade 0 to 1 after corticosteroid taper to ≤10 mg/day prednisone or equivalent or is otherwise clinically stable

Type 1 diabetes mellitus

Grade 3 or 4 (hyperglycaemia)

Withhold LIBTAYO

Initiate treatment with anti-hyperglycaemics as clinically indicated

Resume LIBTAYO when diabetes mellitus returns to Grade 0 to 1 or is otherwise clinically stable

Skin adverse reactions

Grade 2 lasting longer than 1 week,

Grade 3

or

suspected Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN)

Withhold LIBTAYO

Initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a taper

Resume LIBTAYO if skin reaction improves and remains at Grade 0 to 1 after corticosteroid taper to ≤10 mg/day prednisone or equivalent

Grade 4 or confirmed SJS or TEN

Permanently discontinue

Initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a taper

Immune-related skin reaction or other immune-related adverse reactions in patients with prior treatment with idelalisib

Grade 2

Withhold LIBTAYO

Initiate symptomatic management immediately, including initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a taper

Resume LIBTAYO if skin reaction or other immune-related adverse reaction improves and remains at Grade 0 to 1 after corticosteroid taper to ≤10 mg/day prednisone or equivalent

Grade 3 or 4 (excluding endocrinopathies)

or recurrent Grade 2

Permanently discontinue

Initiate symptomatic management immediately, including initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a taper

Nephritis

Grade 2

Withhold LIBTAYO

Initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a taper

Resume LIBTAYO if nephritis improves and remains at Grade 0 to 1 after corticosteroid taper to ≤10 mg/day prednisone or equivalent

Grade 3 or 4

Permanently discontinue

Initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a taper

Other immune-related adverse reactions

(including but not limited to meningitis, paraneoplastic encephalomyelitis, arthritis, Guillain-Barre syndrome, encephalitis, chronic inflammatory demyelinating polyradiculoneuropathy, central nervous system inflammation, autoimmune myocarditis, and immune thrombocytopenic purpura, myalgia, Sjogren's syndrome, vasculitis, myasthenia gravis)b

Grade 3 clinical signs or symptoms of an immune-related adverse reaction not described above

Withhold LIBTAYO

Initiate symptomatic management

Resume LIBTAYO if other immune-related adverse reaction improves and remains at Grade 0 to 1 after corticosteroid taper to ≤10 mg/day prednisone or equivalent

– Grade 4 adverse reaction (excluding endocrinopathies)

– Recurrent severe Grade 3 immune-related adverse reaction

– Persistent Grade 2 or 3 immune-related adverse reactions lasting 12 weeks or longer (excluding endocrinopathies)

– Inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks

Permanently discontinue

Initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a taper

Infusion-related reaction

Grade 1 or 2

Interrupt or slow rate of infusion

Initiate symptomatic management

Grade 3 or 4

Permanently discontinue

ALT: alanine aminotransferase; AST: aspartate aminotransferase; ULN: upper limit of normal.

a Toxicity should be graded with the current version of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE).

b Observed with LIBTAYO or with other anti-PD-1/PD-L1 monoclonal antibodies

Patient Alert Card

All prescribers of LIBTAYO should be familiar with the educational materials and inform the patients about the Patient Alert Card explaining what to do should they experience any symptom of immune-related adverse reactions and infusion-related reactions. The physician will provide the Patient Alert Card to each patient.

Special populations

Paediatric population

The safety and efficacy of LIBTAYO in children and adolescents below the age of 18 years have not been established. No data are available.

Elderly

No dose adjustment is recommended for elderly patients. Cemiplimab exposure is similar across all age groups (see sections 5.1 and 5.2).

Renal impairment

No dose adjustment of LIBTAYO is recommended for patients with renal impairment. There are limited data for LIBTAYO in patients with severe renal impairment CLcr <30 ml/min (see section 5.2).

Hepatic impairment

No dose adjustment is recommended for patients with mild hepatic impairment. LIBTAYO has not been studied in patients with moderate or severe hepatic impairment. There are insufficient data in patients with moderate or severe hepatic impairment for dosing recommendations (see section 5.2).

Method of administration

LIBTAYO is for intravenous use. It must be administered by intravenous infusion over 30 minutes through an intravenous line containing a sterile, non-pyrogenic, low-protein binding, in-line or add-on filter (0.2 micron to 5 micron pore size).

Other medicinal products should not be co-administered through the same infusion line.

For instructions on dilution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Immune-related adverse reactions

Severe and fatal immune-related adverse reactions have been observed with cemiplimab (see section 4.8). These immune-related reactions may involve any organ system. Most immune-related reactions initially manifest during treatment with cemiplimab; however, immune-related adverse reactions can occur after discontinuation of cemiplimab.

Immune-related adverse reactions should be managed with cemiplimab treatment modifications, hormone replacement therapy (if clinically indicated), and corticosteroids. For suspected immune-related adverse reactions, patients should be evaluated to confirm an immune-related adverse reaction and to exclude other possible causes. Depending upon the severity of the adverse reaction, cemiplimab should be withheld or permanently discontinued (see section 4.2).

Immune-related pneumonitis

Immune-related pneumonitis, defined as requiring use of corticosteroids with no clear alternate aetiology, including fatal cases, has been observed in patients receiving cemiplimab (see section 4.8). Patients should be monitored for signs and symptoms of pneumonitis. Patients with suspected pneumonitis should be evaluated with radiographic imaging as indicated based on clinical evaluation and managed with cemiplimab treatment modifications and corticosteroids. (see section 4.2).

Immune-related colitis

Immune-related diarrhoea or colitis, defined as requiring use of corticosteroids with no clear alternate aetiology, has been observed in patients receiving cemiplimab (see section 4.8). Patients should be monitored for signs and symptoms of diarrhoea or colitis and managed with cemiplimab treatment modifications, anti-diarrhoeal agents, and corticosteroids (see section 4.2).

Immune-related hepatitis

Immune-related hepatitis, defined as requiring use of corticosteroids with no clear alternate aetiology, including fatal cases, has been observed in patients receiving cemiplimab (see section 4.8). Patients should be monitored for abnormal liver tests prior to and periodically during treatment as indicated based on clinical evaluation and managed with cemiplimab treatment modifications and corticosteroids (see section 4.2).

Immune-related endocrinopathies

Immune-related endocrinopathies, defined as treatment-emergent endocrinopathies with no clear alternate aetiology, have been observed in patients receiving cemiplimab (see section 4.8).

Thyroid disorders (Hypothyroidism/Hyperthyroidism)

Immune-related thyroid disorders have been observed in patients receiving cemiplimab. Thyroid disorders can occur at any time during the treatment. Patients should be monitored for changes in thyroid function at the start of treatment and periodically during the treatment as indicated based on clinical evaluation (see section 4.8). Patients should be managed with hormone replacement therapy (if indicated) and cemiplimab treatment modifications. Hyperthyroidism should be managed according to standard medical practice (see section 4.2).

Hypophysitis

Immune-related hypophysitis has been observed in patients receiving cemiplimab (see section 4.8). Patients should be monitored for signs and symptoms of hypophysitis and managed with cemiplimab treatment modifications and corticosteroids (see section 4.2).

Adrenal insufficiency

Adrenal insufficiency has been observed in patients receiving cemiplimab (see section 4.8). Patients should be monitored for signs and symptoms of adrenal insufficiency during and after treatment and managed with cemiplimab treatment modifications and corticosteroids (see section 4.2).

Type 1 Diabetes mellitus

Immune-related type 1 diabetes mellitus, including diabetic ketoacidosis, has been observed in patients receiving cemiplimab (see section 4.8). Patients should be monitored for hyperglycaemia and signs and symptoms of diabetes as indicated based on clinical evaluation and managed with oral anti-hyperglycaemics or insulin and cemiplimab treatment modifications (see section 4.2). Cemiplimab should be withheld and anti-hyperglycaemics or insulin should be administered in patients with severe or life-threatening (Grade ≥ 3) hyperglycaemia. Cemiplimab should be resumed when metabolic control is achieved on insulin replacement or anti-hyperglycaemics (see section 4.2).

Immune-related skin adverse reactions

Immune-related skin adverse reactions, defined as requiring use of systemic corticosteroids with no clear alternate aetiology, including severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) (some cases with fatal outcome), and other skin reactions such as rash, erythema multiforme, pemphigoid, have been reported in association with cemiplimab treatment (see section 4.8).

Patients should be monitored for evidence of suspected severe skin reactions and exclude other causes. Patients should be managed with cemiplimab treatment modifications and corticosteroids (see section 4.2).

Cases of SJS, fatal TEN and stomatitis occurred following 1 dose of cemiplimab in patients with prior exposure to idelalisib, who were participating in a clinical trial evaluating cemiplimab in Non-Hodgkin Lymphoma (NHL), and who had recent exposure to sulfa containing antibiotics (see section 4.8). Patients should be managed with cemiplimab treatment modifications and corticosteroids as described above (see section 4.2).

Immune-related nephritis

Immune-related nephritis, defined as requiring use of corticosteroids with no clear alternate aetiology, has been observed in patients receiving cemiplimab (see section 4.8). Patients should be managed with cemiplimab treatment modifications and corticosteroids (see section 4.2).

Other immune-related adverse reactions

Other fatal and life-threatening immune-related adverse reactions have been observed in patients receiving cemiplimab including paraneoplastic encephalomyelitis and meningitis (see section 4.8 for other immune-related adverse reactions).

Patients should be monitored for signs and symptoms of immune-related adverse reactions and managed with cemiplimab treatment modifications and corticosteroids (see section 4.2).

Infusion-related reactions

Cemiplimab can cause severe or life-threatening infusion-related reactions (see section 4.8). Patients should be monitored for signs and symptoms of infusion-related reactions and managed with cemiplimab treatment modifications and corticosteroids. Cemiplimab should be interrupted or the rate of infusion slowed for mild or moderate infusion-related reactions. The infusion should be stopped and cemiplimab should be permanently discontinued for severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions (see section 4.2).

Patients excluded from clinical studies

Patients that had active infections or that were immunocompromised were not included in the main study. For a full list of patients excluded from clinical trials, see section 5.1.

In the absence of data, cemiplimab should be used with caution in these populations after careful evaluation of the balance of benefits and risks for the patient.

4.5 Interaction with other medicinal products and other forms of interaction

No pharmacokinetic drug-drug interaction studies have been conducted with cemiplimab.

The use of systemic corticosteroids or immunosuppressants before starting cemiplimab, except for physiological doses of systemic corticosteroid (≤10 mg/day prednisone or equivalent), should be avoided because of their potential interference with the pharmacodynamic activity and efficacy of cemiplimab. However, systemic corticosteroids or other immunosuppressants can be used after starting cemiplimab to treat immune-related adverse reactions (see sections 4.2).

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential should use effective contraception during treatment with cemiplimab and for at least 4 months after the last dose of cemiplimab.

Pregnancy

Animal reproduction studies have not been conducted with cemiplimab. There are no available data on the use of cemiplimab in pregnant women. Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing foetus resulting in foetal death (see section 5.3).

Human IgG4 is known to cross the placental barrier and cemiplimab is an IgG4; therefore, cemiplimab has the potential to be transmitted from the mother to the developing foetus. Cemiplimab is not recommended during pregnancy and in women of childbearing potential not using effective contraception unless the clinical benefit outweighs the potential risk.

Breast-feeding

It is unknown whether cemiplimab is secreted in human milk. It is known that antibodies (including IgG4) are secreted in human milk; a risk to the breast-feeding newborns/infants cannot be excluded.

If a woman chooses to be treated with cemiplimab, she should be instructed not to breast-feed while being treated with cemiplimab and for at least 4 months after the last dose.

Fertility

No clinical data are available on the possible effects of cemiplimab on fertility. No effects on fertility assessment parameters or in the male and female reproductive organs were observed in a 3-month repeat dose fertility assessment study with sexually mature cynomolgus monkeys.

4.7 Effects on ability to drive and use machines

Cemiplimab has no or negligible influence on the ability to drive and use machines. Fatigue has been reported following treatment with cemiplimab (see section 4.8).

4.8 Undesirable effects

Summary of the safety profile

Immune-related adverse reactions can occur with cemiplimab. Most of these, including severe reactions, resolved following initiation of appropriate medical therapy or withdrawal of cemiplimab (see “Description of selected adverse reactions” below).

The safety of cemiplimab has been evaluated in 591 patients with advanced solid malignancies including 219 advanced CSCC patients who received cemiplimab monotherapy in 2 clinical studies (R2810-ONC-1423 and R2810-ONC-1540). Immune-related adverse reactions occurred in 20.1% of patients treated with cemiplimab in clinical trials including Grade 5 (0.7%), Grade 4 (1.2%) and Grade 3 (6.1%). Immune-related adverse reactions led to permanent discontinuation of cemiplimab in 4.4% of patients. The most common immune-related adverse reactions were hypothyroidism (7.1%), pneumonitis (3.7%), immune-related skin adverse reactions (2.0%), hyperthyroidism (1.9%) and hepatitis (1.9%) (see “Description of selected adverse reactions” below, Special warnings and precautions for use in section 4.4 and Recommended treatment modifications in section 4.2). Adverse reactions were serious in 8.6% patients and led to permanent discontinuation of cemiplimab in 5.8% of patients.

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in association with cemiplimab treatment (see section 4.4).

Tabulated list of adverse reactions

Listed in Table 2 are adverse reactions by system organ class and by frequency. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to <1/1,000); very rare (< 1/10,000); not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 2: Tabulated list of adverse reactions in patients treated with cemiplimab

System organ class

preferred term

Grade 1-5

(Frequency category)

Grade 1-5

(%)

Grade 3-5

(%)

Immune system disorders

Infusion-related reaction

Common

4.1

0

Sjogren's syndrome

Uncommon

0.5

0

Immune thrombocytopenic purpura

Uncommon

0.2

0

Vasculitis

Uncommon

0.2

0

Endocrine disorders

Hypothyroidism

Common

9.6

0

Hyperthyroidism

Common

2.7

0

Type 1 diabetes mellitusa

Uncommon

0.7

0.7

Adrenal insufficiency

Uncommon

0.5

0.5

Hypophysitis

Uncommon

0.5

0.5

Thyroiditis

Uncommon

0.2

0

Nervous system disorders

Paraneoplastic encephalomyelitis

Uncommon

0.2

0.2

Chronic inflammatory demyelinating polyradiculoneuropathy

Uncommon

0.5

0

Encephalitis

Uncommon

0.5

0.5

Meningitisb

Uncommon

0.5

0.5

Guillain-Barre syndrome

Uncommon

0.2

0.2

Central nervous system inflammation

Uncommon

0.2

0

Neuropathy peripheralc

Uncommon

0.5

0

Myasthenia gravis

Uncommon

0.2

0

Eye disorders

Keratitis

Uncommon

0.5

0

Cardiac disorders

Myocarditisd

Uncommon

0.5

0.5

Pericarditis

Uncommon

0.5

0.5

Respiratory, thoracic and mediastinal disorders

Pneumonitis

Common

5.9

2.3

Gastrointestinal disorders

Diarrhoeae

Very common

13.2

0.5

Stomatitis

Common

2.4

0

Hepatobiliary disorders

Hepatitisf

Common

1.4

1.4

Skin and subcutaneous skin disorders

Rashg

Very common

23.3

1.4

Pruritush

Very common

12.3

0

Musculoskeletal and connective tissue disorders

Arthralgia

Common

5.0

0

Musculoskeletal paini

Common

4.1

0.5

Arthritisj

Common

1.4

0.5

Muscular weakness

Uncommon

0.9

0

Renal and urinary disorders

Nephritis

Uncommon

0.5

0

General disorders and administration site conditions

Fatiguek

Very common

21.5

0.9

Investigations

Alanine aminotransferase increased

Common

5.5

0.5

Aspartate aminotransferase increased

Common

5.0

0.9

Blood alkaline phosphatase increased

Common

2.7

0

Blood creatinine increased

Common

1.8

0

Version v.4.03 of NCI CTCAE was used to grade toxicity.

a. Type 1 diabetes mellitus is a composite term that includes diabetes mellitus, diabetic ketoacidosis and type 1 diabetes mellitus.

b. Meningitis is a composite term that includes meningitis and meningitis aseptic.

c. Neuropathy peripheral is a composite term that includes neuropathy peripheral and neuritis.

d. Myocarditis is a composite term that includes autoimmune myocarditis and myocarditis.

e. Diarrhoea is a composite term that includes diarrhoea and colitis.

f. Hepatitis is a composite term that includes hepatitis and autoimmune hepatitis.

g. Rash is a composite term that includes rash maculo-papular, rash, dermatitis, rash generalised, dermatitis bullous, drug eruption, erythema, pemphigoid, psoriasis, rash erythematous, rash macular, rash pruritic and skin reaction.

h. Pruritus is a composite term that includes pruritus and pruritus allergic.

i. Musculoskeletal pain is a composite term that includes back pain, musculoskeletal pain, myalgia, neck pain and pain in extremity.

j. Arthritis is a composite term that includes arthritis and polyarthritis.

k. Fatigue is a composite term that includes fatigue and asthenia.

Description of selected adverse reactions

The selected adverse reactions described below are based on safety of cemiplimab in 591 patients in uncontrolled clinical studies.

Immune-related adverse reactions (see section 4.4)

Immune-related pneumonitis

Immune-related pneumonitis occurred in 22 (3.7%) of 591 patients receiving cemiplimab, including 2 (0.3%) patients with Grade 5, 2 (0.3%) patients with Grade 4, and 6 (1.0%) patients with Grade 3 pneumonitis. Immune-related pneumonitis led to permanent discontinuation of cemiplimab in 11 (1.9%) of 591 patients. Among the 22 patients with immune-related pneumonitis, the median time to onset was 3.8 months (range: 7 days to 18 months) and the median duration of pneumonitis was 21.5 days (range: 5 days to 6.5 months). Eighteen patients (3.0%) received high-dose corticosteroids for a median of 8.5 days (range: 1 day to 5.9 months). Resolution of pneumonitis had occurred in 14 (63.6%) of the 22 patients at the time of data cut-off.

Immune-related colitis

Immune-related diarrhoea or colitis occurred in 7 (1.2%) of 591 patients receiving cemiplimab including 2 (0.3%) with Grade 3 immune-related diarrhoea or colitis. Immune-related diarrhoea or colitis led to permanent discontinuation of cemiplimab in 1 (0.2%) of 591 patients. Among the 7 patients with immune-related diarrhoea or colitis, the median time to onset was 3.8 months (range: 15 days to 6.0 months) and the median duration of immune-related diarrhoea or colitis was 30 days (range: 4 days to 8.6 months). Four patients (0.7%) with immune-related diarrhoea or colitis received high-dose corticosteroids for a median of 29 days (range: 19 days to 2.0 months). Resolution of immune-related diarrhoea or colitis had occurred in 4 (57.1%) of the 7 patients at the time of data cut-off.

Immune-related hepatitis

Immune-related hepatitis occurred in 11 (1.9%) of 591 patients receiving cemiplimab including 1 (0.2%) patient with Grade 5, 1 (0.2%) patient with Grade 4, and 9 (1.5%) patients with Grade 3 immune-related hepatitis. Immune-related hepatitis led to permanent discontinuation of cemiplimab in 5 (0.8%) of 591 patients. Among the 11 patients with immune-related hepatitis, the median time to onset was 1.0 month (range: 7 days to 4.2 months) and the median duration of hepatitis was 15 days (range: 8 days to 2.7 months). Ten (1.7%) patients with immune-related hepatitis received high-dose corticosteroids for a median of 10.5 days (range: 2 days to 1.9 months). Resolution of hepatitis had occurred in 8 (72.7%) of the 11 patients at the time of data cut-off.

Immune-related endocrinopathies

Hypothyroidism occurred in 42 (7.1%) of 591 patients receiving cemiplimab including 1 (0.2%) patient with Grade 3 hypothyroidism. No patient discontinued cemiplimab due to hypothyroidism. Among the 42 patients with hypothyroidism, the median time to onset was 4.2 months (range: 15 days to 18.9 months).

Hyperthyroidism occurred in 11 (1.9%) of 591 patients receiving cemiplimab including 1 (0.2%) patient with Grade 3 hyperthyroidism. No patient discontinued cemiplimab due to hyperthyroidism. Among the 11 patients with hyperthyroidism, the median time to onset was 1.9 months (range: 28 days to 14.8 months).

Adrenal insufficiency occurred in 3 (0.5%) of 591 patients receiving cemiplimab including 1 (0.2%) patient with Grade 3 adrenal insufficiency. No patient discontinued cemiplimab due to adrenal insufficiency. Among the 3 patients with adrenal insufficiency, the median time to onset was 11.5 months (range: 10.4 months to 12.3 months). One of the 3 patients was treated with systemic corticosteroids.

Immune-related hypophysitis occurred in 1 (0.2%) of 591 patients receiving cemiplimab. The event was Grade 3 hypophysitis.

Type 1 diabetes mellitus without an alternative aetiology occurred in 4 (0.7%) of 591 patients including 3 (0.5%) patients with Grade 4 and 1 (0.2%) patient with Grade 3 type 1 diabetes mellitus. Type 1 diabetes mellitus led to permanent discontinuation of cemiplimab in 1 (0.2%) of 591 patients. Among the 4 patients with type 1 diabetes mellitus, the median time to onset was 2.3 months (range: 28 days to 6.2 months).

Immune-related skin adverse reactions

Immune-related skin adverse reactions occurred in 12 (2.0%) of 591 patients receiving cemiplimab including 6 (1.0%) patients with Grade 3 immune-related skin adverse reactions. Immune-related skin adverse reactions led to permanent discontinuation of cemiplimab in 2 (0.3%) of 591 patients. Among the 12 patients with immune-related skin adverse reactions, the median time to onset was 1.5 months (range: 2 days to 10.9 months) and the median duration was 4.4 months (range: 14 days to 9.6 months). Nine patients (1.5%) with immune-related skin adverse reactions received high-dose corticosteroids for a median of 16 days (range: 7 days to 2.6 months). Resolution had occurred in 6 (50%) of 12 patients at the time of data cut-off.

Immune-related nephritis

Immune-related nephritis occurred in 3 (0.5%) of 591 patients receiving cemiplimab including 2 (0.3%) patients with Grade 3 immune-related nephritis. Immune-related nephritis led to permanent discontinuation of cemiplimab in 1 (0.2%) of 591 patients. Among the 3 patients with immune-related nephritis, the median time to onset was 1.8 months (range: 29 days to 4.1 months) and the median duration of nephritis was 18 days (range: 9 days to 29 days). Two (0.3%) patients with immune-related nephritis received high-dose corticosteroids for a median of 1.5 months (range: 16 days to 2.6 months). Resolution of nephritis had occurred in all patients at the time of data cut-off.

Other immune-related adverse reactions

The following clinically significant, immune-related adverse reactions occurred at an incidence of less than 1% of 591 patients treated with cemiplimab. The events were Grade 3 or less unless stated otherwise:

Nervous system disorders: Meningitisa (Grade 4), Paraneoplastic encephalomyelitis (Grade 5), Guillain-Barre syndrome, central nervous system inflammation, Chronic inflammatory demyelinating polyradiculoneuropathy, Encephalitisb, Myasthenia gravis, Neuropathy peripheral.

Cardiac Disorders: Myocarditisc, Pericarditis

Immune system disorders: Immune thrombocytopenic purpura

Vascular disorders: Vasculitis

Musculoskeletal and connective tissue disorders: Myalgia, Arthritisd, Sjogren's syndrome

Eye disorders: Keratitis

Gastrointestinal disorders: Stomatitis

a includes meningitis and meningitis aseptic

b includes encephalitis and noninfective encephalitis

c includes autoimmune myocarditis and myocarditis

d includes arthritis and polyarthritis

Infusion-related reactions

Infusion-related reactions occurred in 54 (9.1%) of 591 patients treated with cemiplimab including 1 (0.2%) patient with Grade 3 infusion-related reaction. Infusion-related reaction led to permanent discontinuation of cemiplimab in 2 (0.3%) patients. The most common symptoms of infusion-related reaction were nausea, pyrexia, vomiting, abdominal pain, chills and flushing. All patients recovered from the infusion-related reaction.

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity with cemiplimab. Five out of 398 patients (1.3%) administered cemiplimab developed treatment-emergent antibodies, with 1 out of 398 patients (0.3%) exhibiting persistent antibody responses. No neutralizing antibodies have been observed. There was no evidence of an altered pharmacokinetic or safety profile with anti-cemiplimab antibody development.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9 Overdose

In case of overdose, patients must be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment instituted.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies. ATC code: not yet assigned

Mechanism of action

Cemiplimab is a fully human immunoglobulin G4 (IgG4) monoclonal antibody that binds to the programmed cell death-1 (PD-1) receptor and blocks its interaction with its ligands PD-L1 and PD-L2. Engagement of PD-1 with its ligands PD-L1 and PD-L2, which are expressed by antigen presenting cells and may be expressed by tumour cells and/or other cells in the tumour microenvironment, results in inhibition of T cell function such as proliferation, cytokine secretion, and cytotoxic activity. Cemiplimab potentiates T cell responses, including anti-tumour responses, through blockade of PD-1 binding to PD-L1 and PD-L2 ligands.

Clinical efficacy and safety

The efficacy and safety of cemiplimab in patients with metastatic (nodal or distant) CSCC (mCSCC) or locally advanced CSCC (laCSCC) who were not candidates for curative surgery or curative radiation were studied in clinical trial R2810-ONC-1540 (Study 1540). Study 1540 was a phase 2, open-label, multi-centre study that had enrolled 193 patients with mCSCC or laCSCC with a combined median follow-up time of 9.4 months total. Median follow-up was 16.5 months for the mCSCC 3 mg/kg every 2 weeks group, 9.3 months for the laCSCC 3 mg/kg every 2 weeks group and 8.1 months for the mCSCC 350 mg every 3 weeks group.

Patients with any of the following were excluded: autoimmune disease that required systemic therapy with immunosuppressant agents within 5 years; history of solid organ transplant; history of pneumonitis within the last 5 years; prior treatment with anti-PD-1/PD-L1 or other immune checkpoint inhibitor therapy; active infection requiring therapy, including known infection with human immunodeficiency virus, or active infection with hepatitis B or hepatitis C virus; chronic lymphocytic leukaemia (CLL); brain metastases or Eastern Cooperative Oncology Group (ECOG) performance score ≥ 2.

In Study 1540, patients received cemiplimab until progression of disease, unacceptable toxicity or completion of planned treatment [3 mg/kg every 2 weeks for 96 weeks or 350 mg every 3 weeks for 54 weeks]. If patients with locally advanced disease showed sufficient response to treatment, surgery with curative intent was permitted. Tumour response assessments were performed every 8 or 9 weeks (for patients receiving 3 mg/kg every 2 weeks or 350 mg every 3 weeks, respectively). The primary endpoint of Study 1540 was confirmed objective response rate (ORR), as assessed by independent central review (ICR). For patients with metastatic CSCC without externally visible target lesions, ORR was determined by Response Evaluation Criteria in Solid Tumours (RECIST 1.1). For patients with externally visible target lesions (locally advanced CSCC and metastatic CSCC), ORR was determined by a composite endpoint that integrated ICR assessments of radiologic data (RECIST 1.1) and digital medical photography (WHO criteria). Secondary endpoints were duration of response (DOR) by ICR and by investigator assessment (IA), ORR by IA, progression free survival (PFS) by ICR and IA, overall survival (OS), complete response rate (CRR) by ICR, and change in scores in patient reported outcomes on the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (EORTC QLQ-C30).

Results are presented from 193 patients in Study 1540. Of these 193 patients, 115 had mCSCC and 78 had laCSCC. The median age was 72 years (range: 38 to 96): Seventy-eight (40.4%) patients were 75 years or older, 66 patients (34.2%) were 65 to less than 75 years, and 49 patients (25.4%) were less than 65 years. A total of 161 (83.4 %) patients were male, and 187 (96.9%) patients were White; the ECOG performance score was 0 (44.6%) or 1 (55.4%). Thirty-three and 7/10 per cent (33.7%) of patients had received at least 1 prior anti-cancer systemic therapy, 90.2% of patients had received prior cancer related surgery, and 67.9% of patients had received prior radiotherapy. Among patients with mCSCC, 76.5% had distant metastases, and 22.6% had only nodal metastases.

Efficacy results for Study 1540 are presented in Table 3.

Table 3: Efficacy results – Study 1540 - metastatic CSCC by dosing group, locally advanced CSCC

mCSCC

cemiplimab:

3 mg/kg Q2W

(Group 1)

(N = 59)

laCSCC

cemiplimab:

3 mg/kg Q2W

(Group 2)

(N = 78)

mCSCC

cemiplimab:

350 mg Q3W

(Group 3)

(N = 56)

ICR

ICR

ICR

Confirmed objective response rate (ORR) a

ORR

49.2%

43.6%

39.3%

95% CI for ORR

(35.9, 62.5)

(32.4, 55.3)

(26.5, 53.2)

Complete response (CR)b

16.9%

12.8%

3.6%

Partial response (PR)

32.2%

30.8%

35.7%

Stable disease (SD)

15.3%

35.9%

14.3%

Progressive disease (PD)

16.9%

11.5%

26.8%

Duration of response (DOR)a

Median (range) (months)

NR

(2.8-21.6+)

NR

(1.9 – 24.2+)

NR

(2.1-11.1+)

Patients with DOR ≥ 6 months, %

93.1%

67.6%

63.6%

Time to response

Median (months) range (min:max)

1.9

(1.7: 9.1)

1.9

(1.8: 8.8)

2.1

(2.0: 8.3)

Progression free survival (PFS)a, c

6 months

66.0%

(52.0, 76.8)

71.5%

(58.9, 80.9)

59.3%

(45.0, 71.0)

12 months

53.1%

(39.1, 65.2)

58.1%

(43.7, 70.0)

44.6%

(26.5, 61.3)

Overall survivala, c, d

12 months

81.3%

(68.7, 89.2)

93.2%

(84.4, 97.1)

76.1%

(56.9, 87.6)

Data cut-off was Sep 20, 2018 for Groups 1 and 3 patients, and Oct 10, 2018 for Group 2 patients.

CI: confidence interval; ICR: Independent Central Review; NR: Not Reached; +: Denotes ongoing at last assessment

a. In Groups 1, 2, and 3, median durations of follow-up were 16.5, 9.3, and 8.1 months, respectively.

b. Only includes patients with complete healing of prior cutaneous involvement; locally advanced CSCC patients in Study 1540 required biopsy to confirm complete response.

c. Based on Kaplan Meier estimates

d. Overall survival does not require central review.

Efficacy and PD-L1 status

Clinical activity was observed regardless of tumour PD-L1 expression status. The relationship between PD-L1 status and efficacy was analysed post-hoc in patients with available tissue samples. Overall in Studies 1423 and 1540, PD-L1 IHC results were available for 75 advanced CSCC patients. Among 22 advanced CSCC patients with PD-L1 < 1%, ORR per independent central review was 40.9% (9/22). Among 53 advanced CSCC patients with PD-L1 ≥ 1%, ORR was 54.7% (29/53). Among 21 mCSCC patients, ORR was 60% (3/5) in patients with PD-L1 < 1% and 56.3% (9/16) among patients with PD-L1 ≥ 1%. Among 54 patients with laCSCC, ORR was 35.3% (6/17) in patients with PD-L1 < 1% and 54.1% (20/37) among patients with PD-L1 ≥ 1%.

Elderly population

Of the 219 patients with mCSCC and laCSCC treated with cemiplimab, 25.1% (55/219) were less than 65 years, 34.2% (75/219) were 65 to less than 75 years, and 40.6% (89/219) were 75 years or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

In the 193 patients in the efficacy analysis, the objective response rate by ICR (95% CI) was 40.8% (27.0%, 55.8%) in patients less than 65 years, 48.5% (36.0%, 61.1%) in patients 65 to less than 75 years, and 42.3% (31.2%, 54.0%) in patients 75 years or older.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with cemiplimab in all subsets of the paediatric population in the treatment of all conditions included in the category of malignant neoplasms, except haematopoietic and lymphoid tissue (see section 4.2 for information on paediatric use).

Conditional approval

This medicinal product has been authorised under a so-called 'conditional approval' scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.

5.2 Pharmacokinetic properties

Concentration data were collected in 548 patients with various solid tumours, including 178 patients with CSCC, who received cemiplimab. At dosing regimens of 1 mg/kg to 10 mg/kg every 2 weeks and 350 mg every 3 weeks, kinetics of cemiplimab were observed to be linear and dose proportional, suggesting saturation of the target-mediated pathway over the dosing interval. Similar exposures to cemiplimab are achieved with the doses of 350 mg every 3 weeks and 3 mg/kg every 2 weeks. With 350 mg every 3 weeks, the mean steady-state concentration of cemiplimab ranged between Cmax of 168 mg/l and a Ctrough of 61 mg/l. Steady-state exposure is achieved after approximately 4 months of treatment.

Absorption

Cemiplimab is administered via the intravenous route and hence is completely bioavailable.

Distribution

Cemiplimab is primarily distributed in the vascular system with a volume of distribution at steady-state (Vss) is 5.2 l.

Biotransformation

Specific metabolism studies were not conducted because cemiplimab is a protein. Cemiplimab is expected to degrade to small peptides and individual amino acids.

Elimination

Clearance of cemiplimab is linear at doses of 1 mg/kg to 10 mg/kg every two weeks. Cemiplimab clearance after the first dose is approximately 0.33 l/day. The total clearance appears to decrease by approximately 35% over time, resulting in a steady state clearance (CLss) of 0.21 l/day; the decrease in CL is not considered clinically relevant. The within dosing interval half-life at steady state is 19.4 days.

Linearity/non-linearity

At the dosing regimens of 1 mg/kg to 10 mg/kg every two weeks, kinetics of cemiplimab were observed to be linear and dose proportional, suggesting saturation of the target-mediated pathway.

Special populations

A population PK analysis suggests that the following factors have no clinically significant effect on the exposure of cemiplimab: age, gender, body weight, race, cancer type, albumin level, mild hepatic impairment and renal impairment.

Renal impairment

The effect of renal impairment on the exposure of cemiplimab was evaluated by a population PK analysis in patients with mild (CLcr 60 to < 89 ml/min; n= 197), moderate (CLcr 30 to < 60 ml/min; n= 90), or severe (CLcr <30 ml/min; n= 4) renal impairment. No clinically important differences in the exposure of cemiplimab were found between patients with renal impairment and patients with normal renal function. Cemiplimab has not been studied in patients with CLcr <25 ml/min (see section 4.2).

Hepatic impairment

The effect of hepatic impairment on the exposure of cemiplimab was evaluated by population PK analysis. In patients with mild hepatic impairment (n= 5) (total bilirubin [TB] greater than 1.0 to 1.5 times the upper limit of normal [ULN] and any aspartate aminotransferase [AST]); no clinically important differences in the exposure of cemiplimab were found compared to patients with normal hepatic function. Cemiplimab has not been studied in patients with moderate or severe hepatic impairment. There are insufficient data in patients with moderate or severe hepatic impairment for dosing recommendations (see section 4.2).

5.3 Preclinical safety data

No studies have been performed to test the potential of cemiplimab for carcinogenicity or genotoxicity.

Animal reproduction studies have not been conducted with cemiplimab (see section 4.6). As reported in the literature, PD-1 / PD-L1 signalling pathway plays a role in sustaining pregnancy by maintaining immunological tolerance and studies have shown that PD-1 receptor blockade results in early termination of pregnancy. The increase of spontaneous abortion and/or resorption in animals with restricted PD-L1 expression (knock-out or anti-PD1 / PD-L1 monoclonal antibodies) has been shown in both mice and monkeys. These animal species have similar maternal-foetal interface to that in humans.

6. Pharmaceutical particulars
6.1 List of excipients

L-histidine

L-histidine monohydrochloride monohydrate

Sucrose

L-proline

Polysorbate 80

Water for injections

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

Unopened vial

30 months

After opening

Once opened, the medicinal product should be diluted and infused immediately.

After preparation of infusion

Once prepared, administer the diluted solution immediately. If diluted solution is not administered immediately, it may be stored temporarily either:

• at room temperature up to 25°C for no more than 8 hours from the time of preparation. This includes room temperature storage of the infusion solution in the intravenous container and time for administration of the infusion.

Or

• under refrigeration at 2°C to 8°C for no more than 24 hours from the time of infusion preparation. Do not freeze. Allow the diluted solution to come to room temperature prior to administration.

6.4 Special precautions for storage

Unopened vial

Store in a refrigerator (2°C to 8°C).

Do not freeze.

Store in the original carton in order to protect from light.

For storage conditions after first opening or dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

LIBTAYO is provided in a 10 ml clear Type 1 glass vial, with a grey chlorobutyl stopper with FluroTec coating and seal cap with a flip-off button.

Each carton contains 1 vial.

6.6 Special precautions for disposal and other handling

Preparation and administration

• Visually inspect medicinal product for particulate matter and discoloration prior to administration. LIBTAYO is a clear to slightly opalescent, colourless to pale yellow solution that may contain trace amounts of translucent to white particles

• Discard the vial if the solution is cloudy, discoloured or contains extraneous particulate matter other than a few translucent-to-white particles.

• Do not shake the vial.

• Withdraw 7 ml (350 mg) from the vial of LIBTAYO and transfer into an intravenous infusion bag containing sodium chloride 9 mg/ml (0.9%) solution for injection or glucose 50 mg/ml (5%) solution for injection. Mix the diluted solution by gentle inversion. Do not shake the solution. The final concentration of the diluted solution should be between 1 mg/ml to 20 mg/ml.

• LIBTAYO must be administered by intravenous infusion over 30 minutes through an intravenous line containing a sterile, non-pyrogenic, low-protein binding, in-line or add-on filter (0.2 micron to 5 micron pore size).

• Do not co-administer other medicinal products through the same infusion line.

LIBTAYO is for single use only. Dispose of any unused medicinal product or waste material in accordance with local requirements.

7. Marketing authorisation holder

Regeneron Ireland Designated Activity Company (DAC).

Europa House

Harcourt Centre

Harcourt Street

Dublin 2

Ireland

8. Marketing authorisation number(s)

EU/1/19/1376/001

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 28 June 2019

10. Date of revision of the text

6th September 2019

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.