4.1. Therapeutic indications

Cutaneous Squamous Cell Carcinoma

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

LIBTAYO as monotherapy is indicated for the adjuvant treatment of adult patients with CSCC at high risk of recurrence after surgery and radiation (see section 5.1 for selection criteria).

Basal Cell Carcinoma

LIBTAYO as monotherapy is indicated for the treatment of adult patients with locally advanced or metastatic basal cell carcinoma (laBCC or mBCC) who have progressed on or are intolerant to a hedgehog pathway inhibitor (HHI).

Non‑Small Cell Lung Cancer

LIBTAYO as monotherapy is indicated for the first‑line treatment of adult patients with non‑small cell lung cancer (NSCLC) expressing PD‑L1 (in ≥ 50% tumour cells), with no EGFR, ALK or ROS1 aberrations, who have:

• locally advanced NSCLC who are not candidates for definitive chemoradiation, or

• metastatic NSCLC.

LIBTAYO in combination with platinum‑based chemotherapy is indicated for the first‐line treatment of adult patients with NSCLC expressing PD‑L1 (in ≥ 1% of tumour cells), with no EGFR, ALK or ROS1 aberrations, who have:

• locally advanced NSCLC who are not candidates for definitive chemoradiation, or

• metastatic NSCLC.

Cervical Cancer

LIBTAYO as monotherapy is indicated for the treatment of adult patients with recurrent or metastatic cervical cancer and disease progression on or after platinum‑based chemotherapy.

4.2. Posology and method of administration

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

PD‑L1 testing for patients with NSCLC

Patients with NSCLC should be evaluated for treatment based on the tumour expression of PD‑L1 confirmed by a validated test (see section 5.1).

Posology

Recommended dose

Locally advanced or metastatic CSCC, NSCLC, BCC and recurrent or metastatic cervical cancer

The recommended dose is 350 mg cemiplimab every 3 weeks (Q3W) administered as an intravenous infusion over 30 minutes.

Treatment may be continued until disease progression or unacceptable toxicity.

Adjuvant treatment of high-risk CSCC

The recommended dose of cemiplimab administered as an intravenous infusion over 30 minutes is:

• 350 mg every 3 weeks for 12 weeks followed by 700 mg every 6 weeks, or

• 350 mg every 3 weeks.

Treatment may be continued until disease recurrence, unacceptable toxicity, or up to 48 weeks of total therapy.

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‑mediated adverse reactions are described in Table 1 (see also sections 4.4 and 4.8).

Table 1: Recommended treatment modifications

Adverse reactiona

Severityb

Dose modification

Additional intervention

Immune‑mediated adverse reactions

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

Thyroiditis

Grade 3 to 4

Withhold LIBTAYO

Initiate symptomatic management

Resume LIBTAYO when thyroiditis 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 and hormone replacement as clinically indicated

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‑mediated skin reaction or other immune‑mediated adverse reactions in patients with prior treatment with idelalisib

Grade 2

Withhold LIBTAYO

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

Nephritis with renal dysfunction

Grade 2 creatinine increased

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 creatinine increased

Permanently discontinue

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

Other immune‑mediated adverse reactions (including but not limited to paraneoplastic encephalomyelitis, meningitis, myositis, solid organ transplant rejection, graft‑vs‑host disease, Guillain‑Barre syndrome, central nervous system inflammation, chronic inflammatory demyelinating polyradiculoneuropathy, encephalitis, myasthenia gravis, neuropathy peripheral, myocarditis, pericarditis, immune thrombocytopaenia, vasculitis, arthralgia, arthritis, muscular weakness, myalgia, polymyalgia rheumatica, Sjogren's syndrome, pruritus, keratitis, immune‑mediated gastritis, stomatitis and haemophagocytic lymphohistiocytosis)

Grade 2 or 3 based on type of reaction

Withhold LIBTAYO

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

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

– Grade 3 based on type of reaction or Grade 4 (excluding endocrinopathies)

– Grade 3 or 4 neurologic toxicity

– Grade 3 or 4 myocarditis or pericarditis

– Confirmed haemophagocytic lymphohistiocytosis

– Recurrent Grade 3 immune‑mediated adverse reaction

– Persistent Grade 2 or 3 immune‑mediated 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 as clinically indicated followed by a taper

Infusion‑related reactionsa

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. See also sections 4.4 and 4.8

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

Patient Card

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

Currently available data are described in sections 5.1 and 5.2 but no recommendation on posology can be made.

Elderly

No dose adjustment is recommended for elderly patients. Cemiplimab exposure is similar across all age groups (see sections 5.1 and 5.2). Data are limited in patients ≥ 75 years on cemiplimab monotherapy.

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 15 to 29 ml/min (see section 5.2).

Hepatic impairment

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

Method of administration

LIBTAYO is for intravenous use. It is 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‑mediated adverse reactions

Severe and fatal immune‑mediated adverse reactions have been observed with cemiplimab (see section 4.2 and section 4.8). These immune‑mediated reactions may involve any organ system. Immune‑mediated reactions can manifest at any time during treatment with cemiplimab; however, immune‑mediated adverse reactions can occur after discontinuation of cemiplimab.

The guidance for immune‑mediated adverse reactions applies to cemiplimab whether administered as monotherapy or in combination with chemotherapy.

Immune‑mediated adverse reactions affecting more than one body system can occur simultaneously, such as myositis and myocarditis or myasthenia gravis, in patients treated with cemiplimab or other PD‑1/PD‑L1 inhibitors.

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

In patients with pre-existing autoimmune disease (AID), data from observational studies suggest that the risk of immune-mediated adverse reactions following immune checkpoint inhibitor therapy may be increased as compared with the risk in patients without pre-existing AID. In addition, flares of the underlying AID were frequent, but the majority were mild and manageable.

Immune‑mediated pneumonitis

Immune‑mediated 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 and causes other than immune‑mediated pneumonitis should be ruled out. 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‑mediated colitis

Immune‑mediated 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‑mediated hepatitis

Immune-mediated 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‑mediated endocrinopathies

Immune‑mediated 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/Thyroiditis)

Immune‑mediated thyroid disorders have been observed in patients receiving cemiplimab. Thyroiditis can present with or without an alteration in thyroid function tests. Hypothyroidism can follow hyperthyroidism. 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‑mediated 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, corticosteroids and hormone replacement, as clinically indicated (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, corticosteroids and hormone replacement, as clinically indicated (see section 4.2).

Type 1 Diabetes mellitus

Immune‑mediated 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).

Immune‑mediated skin adverse reactions

Immune‑mediated 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). For symptoms or signs of SJS or TEN, refer the patient for specialised care for assessment and treatment and manage patient with treatment modifications (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‑mediated nephritis

Immune‑mediated nephritis, defined as requiring use of corticosteroids with no clear alternate aetiology, including a fatal case, has been observed in patients receiving cemiplimab (see section 4.8). Monitor patients for changes in renal function. Patients should be managed with cemiplimab treatment modifications and corticosteroids (see section 4.2).

Other immune‑mediated adverse reactions

Other fatal and life‑threatening immune‑mediated adverse reactions have been observed in patients receiving cemiplimab including paraneoplastic encephalomyelitis, meningitis, myositis, myocarditis, and pancreatitis (see section 4.8 for other immune‑mediated adverse reactions).

Noninfective cystitis has been reported with other PD‑1/PD‑L1 inhibitors.

Evaluate suspected immune‑mediated adverse reactions to exclude other causes. Patients should be monitored for signs and symptoms of immune‑mediated adverse reactions and managed with cemiplimab treatment modifications and corticosteroids as clinically indicated (see section 4.2 and section 4.8).

Solid organ transplant rejection has been reported in the post‑marketing setting in patients treated with PD‑1 inhibitors. Treatment with cemiplimab may increase the risk of rejection in solid organ transplant recipients. The benefit of treatment with cemiplimab versus the risk of possible organ rejection should be considered in these patients. Cases of graft‑versus‑host disease have been reported in the post‑marketing setting in patients treated with other PD‑1/PD‑L1 inhibitors in association with allogeneic haematopoietic stem cell transplant.

Haemophagocytic lymphohistiocytosis (HLH) has been reported in patients receiving cemiplimab (see section 4.8). Patients should be monitored for clinical signs and symptoms of HLH. If HLH is confirmed, administration of cemiplimab should be discontinued and treatment for HLH initiated (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, were immunocompromised, had a history of autoimmune diseases, ECOG PS ≥ 2 or a history of interstitial lung disease were not included. For a full list of patients excluded from clinical studies, 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.

Excipients

Each 7 ml vial contains 105 mg of L-proline and 14 mg of polysorbate 80.

L-proline may be harmful for patients with hyperprolinaemia type I or type II.

This medicinal product contains polysorbate 80, which may cause allergic reactions.

4.5. Interaction with other medicinal products and other forms of interaction

No pharmacokinetic (PK) 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‑mediated adverse reactions (see section 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 newborn/infant 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‑mediated 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).

Cemiplimab as monotherapy

The safety of cemiplimab as monotherapy has been evaluated in 1281 patients with advanced solid malignancies who received cemiplimab monotherapy in 5 clinical studies. The median duration of exposure to cemiplimab was 28 weeks (range: 2 days to 144 weeks).

Immune‑mediated adverse reactions occurred in 21% of patients treated with cemiplimab in clinical trials including Grade 5 (0.3%), Grade 4 (0.6%), Grade 3 (5.7%), and Grade 2 (11.2%). Immune‑mediated adverse reactions led to permanent discontinuation of cemiplimab in 4.6% of patients. The most common immune‑mediated adverse reactions were hypothyroidism (6.8%), hyperthyroidism (3.0%), immune‑mediated pneumonitis (2.6%), immune‑mediated hepatitis (2.4%), immune‑mediated colitis (2.0%), and immune‑mediated skin adverse reactions (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 events were serious in 32.4% of patients.

Adverse events led to permanent discontinuation of cemiplimab in 9.4% 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).

Cemiplimab in the adjuvant CSCC setting

The safety of cemiplimab as monotherapy in the adjuvant treatment of patients with CSCC at high risk of recurrence was evaluated in 205 patients in the C-POST study. The median duration of exposure was 47.9 weeks (range: 3 weeks to 52 weeks) in the cemiplimab group.

The safety profile of cemiplimab in the adjuvant setting in the C-POST study is consistent with the known safety profile for cemiplimab monotherapy in advanced cancers. The incidence of immune‑mediated adverse reactions of cemiplimab as monotherapy in the C-POST study was 22.9% compared to 20.8% in the monotherapy population with advanced solid malignancies.

Adverse events were serious in 17.6% of patients.

Adverse events led to permanent discontinuation of cemiplimab in 9.8% of patients.

Cemiplimab in combination with platinum‐based chemotherapy

The safety of cemiplimab in combination with platinum‐based chemotherapy has been evaluated in a clinical study of 465 patients with locally advanced or metastatic NSCLC. The median duration of exposure was 38.5 weeks (10 days to 102.6 weeks) in the cemiplimab and chemotherapy group, and 21.3 weeks (4 days to 95 weeks) in the chemotherapy group.

Immune‑mediated adverse reactions occurred in 18.9% of patients including Grade 5 (0.3%), Grade 3 (2.6%), and Grade 2 (7.4%). Immune‑mediated adverse reactions led to permanent discontinuation of cemiplimab in 1.0% of patients. The most common immune‑mediated adverse reactions were hypothyroidism (7.7%), hyperthyroidism (5.1%), increased blood thyroid stimulating hormone (4.2%), immune‑mediated skin reaction (1.9%), immune‑mediated pneumonitis (1.9%), and decreased blood thyroid stimulating hormone (1.6%) (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 events were serious in 25.3% of patients.

Adverse events led to permanent discontinuation of cemiplimab in 5.1% of patients.

Tabulated list of adverse reactions

Table 2 lists the incidence of adverse reactions in the monotherapy safety dataset and in patients treated with cemiplimab in combination with chemotherapy. Adverse reactions are presented 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).

Adverse reactions known to occur with cemiplimab or combination therapy components given alone may occur during treatment with these medicinal products in combination.

Table 2: Tabulated list of adverse reactions in patients treated with cemiplimab monotherapy and cemiplimab in combination with chemotherapy

Cemiplimab Monotherapy

Cemiplimab in Combination with Chemotherapy

System organ class

Preferred term

Any Grade %

Grade 3‑5 (%)

Any Grade %

Grade 3‑5 (%)

Infections and infestations

Upper respiratory tract infectiona

Very common

10.9

0.4

Urinary tract infectionb

Common

8.4

2.3

Blood and lymphatic system disorders

Anaemia

Very common

15.0

5.2

Very common

43.6

9.9

Neutropaenia

Very common

15.4

5.8

Thrombocytopaenia

Very common

13.1

2.6

Haemophagocytic lymphohistiocytosisd

Not Known

--

--

Immune system disorders

Infusion‑related reaction

Common

3.3

< 0.1

Uncommon

0.3

0

Thrombocytopaeniac

Uncommon

0.9

0

Sjogren's syndrome

Uncommon

0.2

0

Solid organ transplant rejectiond

Not known

--

--

Endocrine disorders

Hypothyroidisme

Common

6.8

< 0.1

Common

7.7

0.3

Hyperthyroidism

Common

3.0

< 0.1

Common

5.1

0

Thyroiditisf

Uncommon

0.6

0

Uncommon

0.6

0

Hypophysitisg

Uncommon

0.5

0.2

Adrenal insufficiency

Uncommon

0.5

0.5

Type 1 diabetes mellitush

Rare

< 0.1

< 0.1

Uncommon

0.3

0

Nervous system disorders

Headache

Common

8.0

0.3

Peripheral neuropathyi

Common

1.3

< 0.1

Very common

21.2

0

Meningitisj

Rare

< 0.1

< 0.1

Encephalitis

Rare

< 0.1

< 0.1

Myasthenia Gravis

Rare

< 0.1

0

Paraneoplastic encephalomyelitis

Rare

< 0.1

< 0.1

Chronic inflammatory demyelinating polyradiculoneuropathy

Rare

< 0.1

0

Eye disorders

Keratitis

Rare

< 0.1

0

Uveitis

Rare

< 0.1

< 0.1

Cardiac disorders

Myocarditisk

Uncommon

0.5

0.3

Pericarditisl

Uncommon

0.3

0.2

Vascular disorders

Hypertensionm

Common

5.7

2.6

Metabolism and nutrition disorders

Decreased appetite

Very common

13.0

0.6

Very common

17.0

1.0

Hyperglycaemia

Very common

17.6

1.9

Hypoalbuminaemia

Very common

10.3

0.6

Respiratory, thoracic and mediastinal disorders

Coughn

Very common

10.8

0.2

Dyspnoeao

Common

9.7

1.2

Very common

12.8

2.2

Pneumonitisp

Common

3.3

1.1

Common

4.2

0.6

Gastrointestinal disorders

Nausea

Very common

14.7

0.2

Very common

25.0

0

Diarrhoea

Very common

16.3

0.7

Very common

10.6

1.3

Constipation

Very common

12.3

0.2

Very common

13.8

0.3

Abdominal painq

Very common

11.5

0.7

Vomiting

Common

9.9

0.2

Very common

12.2

0

Colitisr

Common

2.0

0.8

Common

1.0

0.3

Stomatitis

Common

1.8

< 0.1

Gastritiss

Uncommon

0.2

0

Pancreatitist

Uncommon

0.2

0.2

Hepatobiliary disorders

Hepatitisu

Common

2.7

1.8

Psychiatric Disorders

Insomnia

Very common

10.9

0

Skin and subcutaneous skin disorders

Rashv

Very common

21.4

1.6

Very common

12.5

1.3

Pruritusw

Very common

12.7

0.2

Common

3.5

0

Actinic keratosis

Common

3.7

0

Alopecia

Very common

36.9

0

Musculoskeletal and connective tissue disorders

Musculoskeletal painx

Very common

28.3

1.8

Very common

26.9

1.3

Arthritisy

Uncommon

0.9

0.2

Common

1.0

0

Myositisz

Uncommon

0.3

< 0.1

Muscular weakness

Uncommon

0.2

0

Polymyalgia rheumatica

Uncommon

0.2

0

Renal and urinary disorders

Nephritisaa

Common

1.2

0.2

Common

2.6

0

Noninfective cystitis

Not known

--

--

General disorders and administration site conditions

Fatiguebb

Very common

29.9

2.6

Very common

23.4

3.8

Pyrexiacc

Common

8.7

0.2

Oedemadd

Common

7.9

0.4

Investigations

Alanine aminotransferase increased

Common

4.6

0.5

Very common

16.3

2.2

Aspartate aminotransferase increased

Common

4.4

0.7

Very common

14.7

0.3

Blood alkaline phosphatase increased

Common

1.9

0.2

Common

4.5

0

Blood creatinine increased

Common

1.6

0

Common

8.7

0

Blood thyroid stimulating hormone increased

Uncommon

0.8

0

Common

4.2

0

Transaminases increased

Uncommon

0.4

< 0.1

Blood bilirubin increased

Uncommon

0.4

< 0.1

Common

1.6

0.3

Blood thyroid stimulating hormone decreased

Rare

< 0.1

0

Common

1.6

0

Weight decreased

Very common

11.2

1.3

Gamma‑glutamyltransferase increased

Uncommon

0.6

0.3

Version 4.03 of NCI CTCAE was used to grade toxicity.

a. Upper respiratory tract infection includes upper respiratory tract infection, nasopharyngitis, sinusitis, respiratory tract infection, rhinitis, viral upper respiratory tract infection, viral respiratory tract infection, pharyngitis, laryngitis, viral rhinitis, acute sinusitis, tonsillitis, and tracheitis.

b. Urinary tract infection includes urinary tract infection, cystitis, pyelonephritis, kidney infection, pyelonephritis acute, urosepsis, bacterial cystitis, escherichia urinary tract infection, pyelocystitis, bacterial urinary tract infection, and urinary tract infection pseudomonal.

c. Thrombocytopaenia includes thrombocytopaenia and immune thrombocytopaenia.

d. Post‑marketing event.

e. Hypothyroidism includes hypothyroidism and immune‑mediated hypothyroidism.

f. Thyroiditis includes thyroiditis, autoimmune thyroiditis, and immune‑mediated thyroiditis.

g. Hypophysitis includes hypophysitis and lymphocytic hypophysitis.

h. Type 1 diabetes mellitus includes diabetic ketoacidosis and Type 1 diabetes mellitus.

i. Peripheral neuropathy includes peripheral sensory neuropathy, peripheral neuropathy, paraesthesia, polyneuropathy, neuritis, and peripheral motor neuropathy.

j. Meningitis includes aseptic meningitis.

k. Myocarditis includes myocarditis, autoimmune myocarditis, and immune‑mediated myocarditis.

l. Pericarditis includes autoimmune pericarditis and pericarditis.

m. Hypertension includes hypertension and hypertensive crisis.

n. Cough includes cough, productive cough, and upper‑airway cough syndrome.

o. Dyspnea includes dyspnea and dyspnea exertional.

p. Pneumonitis includes pneumonitis, immune‑mediated lung disease, interstitial lung disease, and pulmonary fibrosis.

q. Abdominal pain includes abdominal pain, abdominal pain upper, abdominal distension, abdominal pain lower, abdominal discomfort, and gastrointestinal pain.

r. Colitis includes colitis, autoimmune colitis, enterocolitis, and immune‑mediated enterocolitis.

s. Gastritis includes gastritis and immune‑mediated gastritis.

t. Pancreatitis (acute pancreatitis and immune-mediated pancreatitis) was not observed in the studies included in the monotherapy pool (n=1281) and frequency is based on exposure in patients treated in relevant studies with cemiplimab monotherapy

u. Hepatitis includes autoimmune hepatitis, immune‑mediated hepatitis, hepatitis, hepatotoxicity, hyperbilirubinemia, hepatocellular injury, hepatic failure, and abnormal hepatic function.

v. Rash includes rash, rash maculo‑papular, dermatitis, erythema, rash pruritic, urticaria, rash erythematous, dermatitis bullous, dermatitis acneiform, rash macular, psoriasis, rash papular, dyshidrotic eczema, pemphigoid, autoimmune dermatitis, dermatitis allergic, atopic dermatitis, drug eruption, erythema nodosum, skin reaction, skin toxicity, dermatitis exfoliative, dermatitis exfoliative generalised, dermatitis psoriasiform, erythema multiforme, exfoliative rash, immune‑mediated dermatitis, lichen planus, and parapsoriasis.

w. Pruritus includes pruritus and allergic pruritus.

x. Musculoskeletal pain includes arthralgia, back pain, pain in extremity, myalgia, neck pain, musculoskeletal chest pain, bone pain, musculoskeletal pain, spinal pain, musculoskeletal stiffness, and musculoskeletal discomfort.

y. Arthritis includes arthritis, polyarthritis, autoimmune arthritis, and immune‑mediated arthritis.

z. Myositis includes myositis and dermatomyositis.

aa. Nephritis includes acute kidney injury, renal impairment, immune‑mediated nephritis, nephritis, renal failure, tubulointerstitial nephritis, and nephropathy toxic.

bb. Fatigue includes fatigue, asthenia, and malaise.

cc. Pyrexia includes pyrexia, hyperthermia, and hyperpyrexia.

dd. Oedema includes peripheral oedema, face oedema, peripheral swelling, face swelling, localised oedema, generalised oedema, and swelling.

Description of selected adverse reactions

The selected adverse reactions described below are based on safety of cemiplimab in 1281 patients in clinical studies in monotherapy.

These selected adverse reactions were consistent when cemiplimab was administered as monotherapy in patients with advanced solid malignancies, as monotherapy in the adjuvant setting, or in combination with chemotherapy.

Immune‑mediated adverse reactions (see section 4.2 and section 4.4)

Immune‑mediated pneumonitis

Immune‑mediated pneumonitis occurred in 33 (2.6%) of 1281 patients receiving cemiplimab, including 4 (0.3%) patients with Grade 4, and 8 (0.6%) patients with Grade 3 immune‑mediated pneumonitis. Immune‑mediated pneumonitis led to permanent discontinuation of cemiplimab in 17 (1.3%) of 1281 patients. Among the 33 patients with immune‑mediated pneumonitis, the median time to onset was 2.7 months (range: 7 days to 22.2 months) and the median duration of pneumonitis was 1.1 months (range: 5 days to 16.9 months). Twenty‑seven of the 33 patients (81.8%) received high‑dose corticosteroids for a median of 15 days (range: 1 day to 5.9 months). Resolution of pneumonitis had occurred in 20 (60.6%) of the 33 patients at the time of data cutoff.

Immune‑mediated colitis

Immune‑mediated diarrhoea or colitis occurred in 25 (2.0%) of 1281 patients receiving cemiplimab, including 10 (0.8%) with Grade 3 immune‑mediated diarrhoea or colitis. Immune‑mediated diarrhoea or colitis led to permanent discontinuation of cemiplimab in 5 (0.4%) of 1281 patients. Among the 25 patients with immune‑mediated diarrhoea or colitis, the median time to onset was 3.8 months (range: 1 day to 16.6 months) and the median duration of immune‑mediated diarrhoea or colitis was 2.1 months (range: 4 days to 26.8 months). Nineteen of the 25 patients (76.0%) with immune‑mediated diarrhoea or colitis received high‑dose corticosteroids for a median of 22 days (range: 2 days to 5.2 months). Resolution of immune‑mediated diarrhoea or colitis had occurred in 14 (56.0%) of the 25 patients at the time of data cutoff.

Immune‑mediated hepatitis

Immune‑mediated hepatitis occurred in 31 (2.4%) of 1281 patients receiving cemiplimab, including 1 (< 0.1%) patient with Grade 5, 4 (0.3%) patients with Grade 4, and 21 (1.6%) patients with Grade 3 immune‑mediated hepatitis. Immune‑mediated hepatitis led to permanent discontinuation of cemiplimab in 18 (1.4%) of 1281 patients. Among the 31 patients with immune‑mediated hepatitis, the median time to onset was 2.8 months (range: 7 days to 22.5 months) and the median duration of hepatitis was 2.3 months (range: 5 days to 8.7 months). Twenty‑seven of the 31 patients (87.1%) with immune‑mediated hepatitis received high‑dose corticosteroids for a median of 24 days (range: 2 days to 3.8 months). Resolution of hepatitis had occurred in 12 (38.7%) of the 31 patients at the time of data cutoff.

Immune‑mediated endocrinopathies

Hypothyroidism occurred in 87 (6.8%) of 1281 patients receiving cemiplimab, including 1 (< 0.1%) patient with Grade 3 hypothyroidism. Three (0.2%) of 1281 patients discontinued cemiplimab due to hypothyroidism. Among the 87 patients with hypothyroidism, the median time to onset was 4.0 months (range: 15 days to 18.9 months) with a median duration of 9.2 months (range: 1 day to 37.1 months). Resolution of hypothyroidism had occurred in 5 (5.7%) of the 87 patients at the time of data cutoff.

Hyperthyroidism occurred in 39 (3.0%) of 1281 patients receiving cemiplimab, including 1 (< 0.1%) patient with Grade 3 and 11 (0.9%) patients with Grade 2 hyperthyroidism. No patient discontinued cemiplimab due to hyperthyroidism. Among the 39 patients with hyperthyroidism, the median time to onset was 1.9 months (range: 20 days to 23.8 months) and the median duration was 1.9 months (range: 9 days to 32.7 months). Resolution of hyperthyroidism had occurred in 22 (56.4%) of the 39 patients at the time of data cutoff.

Thyroiditis occurred in 8 (0.6%) of 1281 patients receiving cemiplimab, including 4 (0.3%) patients with Grade 2 thyroiditis. No patient discontinued cemiplimab due to thyroiditis. Resolution of thyroiditis had occurred in 1 (12.5%) of the 8 patients at the time of data cutoff.

Adrenal insufficiency occurred in 6 (0.5%) of 1281 patients receiving cemiplimab, including 6 (0.5%) patients with Grade 3 adrenal insufficiency. One (< 0.1%) of 1281 patients discontinued cemiplimab due to adrenal insufficiency. Among the 6 patients with adrenal insufficiency, the median time to onset was 7.5 months (range: 4.2 months to 18.3 months) and the median duration was 2.9 months (range: 22 days to 6.1 months). Two of the 6 patients (33.3%) received high‑dose corticosteroids. Resolution of adrenal insufficiency had occurred in 1 (16.7%) of 6 patients at the time of data cutoff.

Immune‑mediated hypophysitis occurred in 7 (0.5%) of 1281 patients receiving cemiplimab, including 3 (0.2%) patients with Grade 3 immune‑mediated hypophysitis. One (< 0.1%) of 1281 patients discontinued cemiplimab due to hypophysitis. Among the 7 patients with hypophysitis, the median time to onset was 7.4 months (range: 2.5 months to 10.4 months) with a median duration of 2.7 months (range: 9 days to 34.9 months). Three of the 7 patients (42.9%) received high‑dose corticosteroids. Resolution of hypophysitis had occurred in 1 (14.3%) of 7 patients at the time of data cutoff.

Type 1 diabetes mellitus without an alternative aetiology occurred in 1 (< 0.1%) of 1281 patients (Grade 4).

Immune‑mediated skin adverse reactions

Immune‑mediated skin adverse reactions occurred in 24 (1.9%) of 1281 patients receiving cemiplimab, including 11 (0.9%) patients with Grade 3 immune‑mediated skin adverse reactions. Immune‑mediated skin adverse reactions led to permanent discontinuation of cemiplimab in 3 (0.2%) of 1281 patients. Among the 24 patients with immune‑mediated skin adverse reactions, the median time to onset was 2.0 months (range: 2 days to 17.0 months) and the median duration was 2.9 months (range: 8 days to 38.8 months). Seventeen of the 24 patients (70.8%) with immune‑mediated skin adverse reactions received high‑dose corticosteroids for a median of 10 days (range: 1 day to 2.9 months). Resolution of skin reaction had occurred in 17 (70.8%) of 24 patients at the time of data cutoff.

Immune‑mediated nephritis

Immune‑mediated nephritis occurred in 9 (0.7%) of 1281 patients receiving cemiplimab, including 1 (< 0.1%) patient with Grade 5, and 1 (< 0.1%) patient with Grade 3 immune‑mediated nephritis. Immune‑mediated nephritis led to permanent discontinuation of cemiplimab in 2 (0.2%) of 1281 patients. Among the 9 patients with immune‑mediated nephritis, the median time to onset was 2.1 months (range: 14 days to 12.5 months) and the median duration of nephritis was 1.5 months (range: 9 days to 5.5 months). Six of the 9 patients (66.7%) with immune‑mediated nephritis received high‑dose corticosteroids for a median of 18 days (range: 3 days to 1.3 months). Resolution of nephritis had occurred in 7 (77.8%) of the 9 patients at the time of data cutoff.

Other immune‑mediated adverse reactions

The following clinically significant, immune‑mediated adverse reactions occurred at an incidence of less than 1% (unless otherwise noted) of 1281 patients treated with cemiplimab monotherapy. The events were Grade 3 or less unless stated otherwise:

Nervous system disorders: Aseptic meningitis, paraneoplastic encephalomyelitis (Grade 5), chronic inflammatory demyelinating polyradiculoneuropathy, encephalitis, myasthenia gravis, peripheral neuropathya

Cardiac Disorders: Myocarditisb (Grade 5), pericarditisc

Immune system disorders: Immune thrombocytopaenia

Musculoskeletal and connective tissue disorders: Arthralgia (1.2%), arthritisd, muscular weakness, myalgia, myositise (Grade 4), polymyalgia rheumatica, Sjogren's syndrome

Skin and Subcutaneous Tissue Disorders: Pruritus

Eye disorders: Keratitis, Uveitisf (Grade 4)

Gastrointestinal disorders: Stomatitis, immune‑mediated gastritis, pancreatitis (Grade 4)

a. includes neuritis, peripheral neuropathy, peripheral sensory neuropathy, and polyneuropathy

b. includes autoimmune myocarditis, immune‑mediated myocarditis, and myocarditis

c. includes autoimmune pericarditis and pericarditis

d. includes arthritis, immune‑mediated arthritis, and polyarthritis

e includes myositis and dermatomyositis

f. reported in clinical studies outside the pooled dataset

The following additional immune‑mediated adverse reactions were observed in patients receiving combination therapy in clinical trials: vasculitis, Guillain‑Barre syndrome, central nervous system inflammation, and meningitis (Grade 4), each with the frequency of rare.

Immune checkpoint inhibitor class effects

There have been cases of the following adverse reactions reported during treatment with other immune checkpoint inhibitors, which might also occur during treatment with cemiplimab: coeliac disease, pancreatic exocrine insufficiency.

Infusion‑related reactions

Infusion‑related reactions occurred in 94 (7.3%) of 1281 patients treated with cemiplimab monotherapy including 2 (0.2%) patients with Grade 3 or 4 infusion‑related reactions. Infusion‑related reaction led to permanent discontinuation of cemiplimab in 1 (< 0.1%) patient. Common symptoms of infusion‑related reaction include nausea, pyrexia, and vomiting. Ninety‑three of 94 (98.9%) patients recovered from the infusion‑related reaction at the time of data cutoff.

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity with cemiplimab. In clinical studies with 1029 patients treated with cemiplimab, 2.1% of patients developed treatment‑emergent antibodies, with approximately 0.3% exhibiting persistent antibody responses. No neutralising 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 the 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 should be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment instituted.