LIBTAYO 350mg 50mg / ml perfusive solution concentrate medication leaflet

LIBTAYO 350 mg concentrate for solution for infusion.

One ml of concentrate contains 50 mg of cemiplimab.

Each vial contains 350 mg of cemiplimab in 7 ml.

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

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate).

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

Cutaneous Squamous Cell Carcinoma

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

Basal Cell Carcinoma

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

Non-Small Cell Lung Cancer

LIBTAYO as monotherapy is indicated for the first-line treatment of adult patients with non-small celllung cancer (NSCLC) expressing PD-L1 (in ≥ 50% tumour cells), with no EGFR, ALK or ROS1aberrations, 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 treatmentof 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 metastaticcervical cancer and disease progression on or after platinum-based chemotherapy.

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-L1confirmed by a validated test (see section 5.1).

Recommended dose

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

Treatment may be continued until disease progression or unacceptable toxicity.

No dose reductions are recommended. Dosing delay or discontinuation may be required based onindividual safety and tolerability. Recommended modifications to manage adverse reactions areprovided 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

Initial dose of

Withhold LIBTAYO 1 to 2 mg/kg/dayprednisone or equivalent

Grade 2 followed by a taper

Resume LIBTAYO if pneumonitis improves and

Pneumonitis remains at Grade 0 to 1 after corticosteroid taper to≤ 10 mg/day prednisone or equivalent

Grade 3 or 4 Initial dose ofor Permanently discontinue 2 to 4 mg/kg/dayrecurrent Grade 2 prednisone or equivalentfollowed by a taper

Initial dose of

Withhold LIBTAYO 1 to 2 mg/kg/dayprednisone or equivalent

Grade 2 or 3 followed by a taper

Resume LIBTAYO if colitis or diarrhoea improves

Colitis and remains at Grade 0 to 1 after corticosteroid taperto ≤ 10 mg/day prednisone or equivalent

Grade 4 Initial dose ofor Permanently discontinue 1 to 2 mg/kg/dayrecurrent Grade 3 prednisone or equivalentfollowed by a taper

Initial dose of 1 to

Withhold LIBTAYO 2 mg/kg/day prednisone

Grade 2 with AST or ALT or equivalent followed by> 3 and ≤ 5 × ULN a taperortotal bilirubin > 1.5 and Resume LIBTAYO if hepatitis improves and remains≤ 3 × ULN at Grade 0 to 1 after corticosteroid taper to

Hepatitis ≤ 10 mg/day prednisone or equivalent or returns tobaseline AST or ALT after completion ofcorticosteroid taper

Grade ≥ 3 with AST or

ALT > 5 × ULN Initial dose ofor Permanently discontinue 1 to 2 mg/kg/daytotal bilirubin > 3 × ULN prednisone or equivalentfollowed by a taper

Initiate thyroid hormone

Withhold LIBTAYO replacement as clinically

Hypothyroidism Grade 3 or 4 indicated

Resume LIBTAYO when hypothyroidism returns to

Grade 0 to 1 or is otherwise clinically stable

Withhold LIBTAYO Initiate symptomaticmanagement

Hyperthyroidism Grade 3 or 4

Resume LIBTAYO when hyperthyroidism returns to

Grade 0 to 1 or is otherwise clinically stable

Withhold LIBTAYO Initiate symptomaticmanagement

Thyroiditis Grade 3 to 4

Resume LIBTAYO when thyroiditis returns to Grade0 to 1 or is otherwise clinically stable

Initial dose of 1 to2 mg/kg/day prednisone

Withhold LIBTAYO or equivalent followed bya taper and hormonereplacement as clinically

Hypophysitis Grade 2 to 4 indicated

Resume LIBTAYO if hypophysitis improves andremains at Grade 0 to 1 after corticosteroid taper to≤ 10 mg/day prednisone or equivalent or is otherwiseclinically stable

Initial dose of1 to 2 mg/kg/day

Withhold LIBTAYO prednisone or equivalentfollowed by a taper andhormone replacement as

Adrenal insufficiency Grade 2 to 4 clinically indicated

Resume LIBTAYO if adrenal insufficiency improvesand remains at Grade 0 to 1 after corticosteroid taperto ≤10 mg/day prednisone or equivalent or isotherwise clinically stable

Initiate treatment with

Withhold LIBTAYO anti-hyperglycaemics as

Type 1 diabetes mellitus Grade 3 or 4 clinically indicated(hyperglycaemia) Resume LIBTAYO when diabetes mellitus returns to

Grade 0 to 1 or is otherwise clinically stable

Grade 2 lasting longer than Initial dose of 1 to1 week, Withhold LIBTAYO 2 mg/kg/day prednisone

Grade 3 or equivalent followed byor a tapersuspected Stevens-Johnson Resume LIBTAYO if skin reaction improves and

Skin adverse reactions syndrome (SJS) or toxic remains at Grade 0 to 1 after corticosteroid taper toepidermal necrolysis (TEN) ≤ 10 mg/day prednisone or equivalent

Initial dose of

Grade 4 or confirmed SJS 1 to 2 mg/kg/dayor TEN Permanently discontinue prednisone or equivalentfollowed by a taper

Initiate managementimmediately, including

Withhold LIBTAYO initial dose of1 to 2 mg/kg/dayprednisone or equivalent

Immune-mediated skin Grade 2 followed by a taperreaction or other Resume LIBTAYO if skin reaction or otherimmune-mediated adverse immune-mediated adverse reaction improves andreactions in patients with remains at Grade 0 to 1 after corticosteroid taper toprior treatment with ≤ 10 mg/day prednisone or equivalentidelalisib Initiate management

Grade 3 or 4 (excluding immediately, includingendocrinopathies) Permanently discontinue initial dose ofor recurrent Grade 2 1 to 2 mg/kg/dayprednisone or equivalentfollowed by a taper

Initial dose of

Withhold LIBTAYO 1 to 2 mg/kg/dayprednisone or equivalent

Grade 2 creatinine followed by a taperincreased

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

Initial dose of

Grade 3 or 4 creatinineincreased Permanently discontinue 1 to 2 mg/kg/dayprednisone or equivalentfollowed by a taper

Other immune-mediated Initiate symptomaticadverse reactions management includinginitial dose of(including but not limited to Withhold LIBTAYO 1 to 2 mg/kg/dayparaneoplastic prednisone or equivalentencephalomyelitis, Grade 2 or 3 based on type as clinically indicatedmeningitis, myositis, solid of reaction followed by a taperorgan transplant rejection, Resume LIBTAYO if other immune-mediated adversegraft-vs-host disease, reaction improves and remains at Grade 0 to 1 after

Guillain-Barre syndrome, corticosteroid taper to ≤ 10 mg/day prednisone orcentral nervous system equivalentinflammation, chronic - Grade 3 based on type ofinflammatory reaction or Grade 4demyelinating (excludingpolyradiculoneuropathy, endocrinopathies) Initial dose of 1 toencephalitis, myasthenia 2 mg/kg/day prednisonegravis, neuropathy - Grade 3 or 4 neurologic Permanently discontinue or equivalent as clinicallyperipheral, myocarditis, toxicity indicated followed by apericarditis, immune taperthrombocytopaenia, - Grade 3 or 4 myocarditisvasculitis, arthralgia, or pericarditisarthritis, muscularweakness, myalgia, - Confirmedpolymyalgia rheumatica, haemophagocytic

Sjogren’s syndrome, lymphohistiocytosispruritus, keratitis,immune-mediated gastritis, - Recurrent Grade 3stomatitis and immune-mediatedhaemophagocytic adverse reactionlymphohistiocytosis)- Persistent Grade 2 or 3immune-mediatedadverse reactions lasting12 weeks or longer(excludingendocrinopathies)- Inability to reducecorticosteroid dose to10 mg or less ofprednisone or equivalentper day within 12 weeks

Infusion-related reactionsa

Grade 1 or 2 Interrupt or slow rate of

Infusion-related reaction infusion Initiate symptomatic

Grade 3 or 4 Permanently discontinue management

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 Alert Card

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

Patient Alert Card to each patient.

The safety and efficacy of LIBTAYO in children and adolescents below the age of 18 years have notbeen established.

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

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

No dose adjustment of LIBTAYO is recommended for patients with renal impairment. There arelimited data for LIBTAYO in patients with severe renal impairment CLcr 15 to 29 ml/min (seesection 5.2).

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 datain patients with severe hepatic impairment for dosing recommendations (see section 5.2).

LIBTAYO is for intravenous use. It is administered by intravenous infusion over 30 minutes throughan 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.

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

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

Immune-mediated adverse reactions

Severe and fatal immune-mediated adverse reactions have been observed with cemiplimab (seesection 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 asmonotherapy 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-mediatedadverse reactions should be managed with cemiplimab treatment modifications, hormone replacementtherapy (if clinically indicated), and corticosteroids. For suspected immune-mediated adversereactions, patients should be evaluated to confirm an immune-mediated adverse reaction and toexclude other possible causes, including infection. Depending upon the severity of the adversereaction, cemiplimab should be withheld or permanently discontinued (see section 4.2).

Immune-mediated pneumonitis

Immune-mediated pneumonitis, defined as requiring use of corticosteroids with no clear alternateaetiology, 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 thanimmune-mediated pneumonitis should be ruled out. Patients with suspected pneumonitis should beevaluated with radiographic imaging as indicated based on clinical evaluation and managed withcemiplimab treatment modifications and corticosteroids (see section 4.2).

Immune-mediated colitis

Immune-mediated diarrhoea or colitis, defined as requiring use of corticosteroids with no clearalternate aetiology, has been observed in patients receiving cemiplimab (see section 4.8). Patientsshould be monitored for signs and symptoms of diarrhoea or colitis and managed with cemiplimabtreatment 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 alternateaetiology, 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 asindicated based on clinical evaluation and managed with cemiplimab treatment modifications andcorticosteroids (see section 4.2).

Immune-mediated endocrinopathies

Immune-mediated endocrinopathies, defined as treatment-emergent endocrinopathies with no clearalternate 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. Thyroiditiscan present with or without an alteration in thyroid function tests. Hypothyroidism can followhyperthyroidism. Thyroid disorders can occur at any time during the treatment. Patients should bemonitored for changes in thyroid function at the start of treatment and periodically during thetreatment as indicated based on clinical evaluation (see section 4.8). Patients should be managed withhormone replacement therapy (if indicated) and cemiplimab treatment modifications. Hyperthyroidismshould 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 cemiplimabtreatment modifications, corticosteroids and hormone replacement, as clinically indicated (seesection 4.2).

Adrenal insufficiency has been observed in patients receiving cemiplimab (see section 4.8). Patientsshould be monitored for signs and symptoms of adrenal insufficiency during and after treatment andmanaged with cemiplimab treatment modifications, corticosteroids and hormone replacement, asclinically indicated (see section 4.2).

Type 1 Diabetes mellitus

Immune-mediated type 1 diabetes mellitus, including diabetic ketoacidosis, has been observed inpatients receiving cemiplimab (see section 4.8). Patients should be monitored for hyperglycaemia andsigns and symptoms of diabetes as indicated based on clinical evaluation and managed with oralanti-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 noclear alternate aetiology, including severe cutaneous adverse reactions (SCARs), such as

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) (some cases with fataloutcome), and other skin reactions such as rash, erythema multiforme, pemphigoid, have beenreported 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 (seesection 4.2). For symptoms or signs of SJS or TEN, refer the patient for specialised care forassessment 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 priorexposure 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 (seesection 4.8). Patients should be managed with cemiplimab treatment modifications and corticosteroidsas described above (see section 4.2).

Immune-mediated nephritis

Immune-mediated nephritis, defined as requiring use of corticosteroids with no clear alternateaetiology, 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 treatmentmodifications and corticosteroids (see section 4.2).

Other immune-mediated adverse reactions

Other fatal and life-threatening immune-mediated adverse reactions have been observed in patientsreceiving cemiplimab including paraneoplastic encephalomyelitis, meningitis, myositis andmyocarditis (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 bemonitored for signs and symptoms of immune-mediated adverse reactions and managed withcemiplimab treatment modifications and corticosteroids as clinically indicated (see section 4.2 andsection 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 organtransplant recipients. The benefit of treatment with cemiplimab versus the risk of possible organrejection should be considered in these patients. Cases of graft-versus-host disease have been reportedin the post-marketing setting in patients treated with other PD-1/PD-L1 inhibitors in association withallogeneic haematopoietic stem cell transplant.

Haemophagocytic lymphohistiocytosis (HLH) has been reported in patients receiving cemiplimab (seesection 4.8). Patients should be monitored for clinical signs and symptoms of HLH. If HLH isconfirmed, administration of cemiplimab should be discontinued and treatment for HLH initiated (seesection 4.2).

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

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 patientsexcluded from clinical studies, see section 5.1.

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

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

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

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

Animal reproduction studies have not been conducted with cemiplimab. There are no available data onthe 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 developingfoetus resulting in foetal death (see section 5.3).

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

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 whilebeing treated with cemiplimab and for at least 4 months after the last dose.

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

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

Immune-mediated adverse reactions can occur with cemiplimab. Most of these, including severereactions, 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 solidmalignancies who received cemiplimab monotherapy in 5 clinical studies. The median duration ofexposure to cemiplimab was 28 weeks (range: 2 days to 144 weeks).

Immune-mediated adverse reactions occurred in 21% of patients treated with cemiplimab in clinicaltrials 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% ofpatients. 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 insection 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 toxicepidermal necrolysis (TEN) have been reported in association with cemiplimab treatment (seesection 4.4).

Cemiplimab in combination with platinum‐based chemotherapy

The safety of cemiplimab in combination with platinum‐based chemotherapy has been evaluated in aclinical study of 465 patients with locally advanced or metastatic NSCLC. The median duration ofexposure was 38.5 weeks (10 days to 102.6 weeks) in the cemiplimab and chemotherapy group, and21.3 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 ofcemiplimab in 1.0% of patients. The most common immune-mediated adverse reactions werehypothyroidism (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 bloodthyroid stimulating hormone (1.6%) (see “Description of selected adverse reactions” below, Specialwarnings and precautions for use in section 4.4 and Recommended treatment modifications insection 4.2).

Adverse events were serious in 25.3% of patients.

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

Table 2 lists the incidence of adverse reactions in the monotherapy safety dataset and in patientstreated with cemiplimab in combination with chemotherapy. Adverse reactions are presented bysystem 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 alonemay occur during treatment with these medicinal products in combination.

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

Cemiplimab Monotherapy Cemiplimab in Combination with

Chemotherapy

System organ class Any Grade % Grade Any Grade % Grade

Preferred term 3-5 (%) 3-5 (%)

Upper respiratory tract Very common 10.9 0.4infectiona

Urinary tract infectionb Common 8.4 2.3

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 Not Known -- --lymphohistiocytosisd

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 Not known -- --rejectiond

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

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 Rare < 0.1 < 0.1encephalomyelitis

Chronic inflammatory Rare < 0.1 0demyelinatingpolyradiculoneuropathy

Keratitis Rare < 0.1 0

Uveitis Rare < 0.1 < 0.1

Myocarditisk Uncommon 0.5 0.3

Pericarditisl Uncommon 0.3 0.2

Hypertensionm Common 5.7 2.6

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

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

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

Hepatitist Common 2.7 1.8

Psychiatric Disorders

Insomnia Very common 10.9 0

Skin and subcutaneous skin disorders

Rashu Very common 21.4 1.6 Very common 12.5 1.3

Pruritusv Very common 12.7 0.2 Common 3.5 0

Actinic keratosis Common 3.7 0

Alopecia Very common 36.9 0

Musculoskeletal painw Very common 28.3 1.8 Very common 26.9 1.3

Arthritisx Uncommon 0.9 0.2 Common 1.0 0

Myositisy Uncommon 0.3 < 0.1

Muscular weakness Uncommon 0.2 0

Polymyalgia rheumatica Uncommon 0.2 0

Nephritisz Common 1.2 0.2 Common 2.6 0

Noninfective cystitis Not known -- --

Fatigueaa Very common 29.9 2.6 Very common 23.4 3.8

Pyrexiabb Common 8.7 0.2

Oedemacc Common 7.9 0.4

Alanine aminotransferase Common 4.6 0.5 Very common 16.3 2.2increased

Aspartate aminotransferase Common 4.4 0.7 Very common 14.7 0.3increased

Blood alkaline phosphatase Common 1.9 0.2 Common 4.5 0increased

Blood creatinine increased Common 1.6 0 Common 8.7 0

Blood thyroid stimulating Uncommon 0.8 0 Common 4.2 0hormone increased

Transaminases increased Uncommon 0.4 < 0.1

Blood bilirubin increased Uncommon 0.4 < 0.1 Common 1.6 0.3

Blood thyroid stimulating Rare < 0.1 0 Common 1.6 0hormone decreased

Weight decreased Very common 11.2 1.3

Gamma-glutamyltransferase Uncommon 0.6 0.3increased

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, bacterialurinary 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 pulmonaryfibrosis.q. Abdominal pain includes abdominal pain, abdominal pain upper, abdominal distension, abdominal painlower, 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. Hepatitis includes autoimmune hepatitis, immune-mediated hepatitis, hepatitis, hepatotoxicity,hyperbilirubinemia, hepatocellular injury, hepatic failure, and abnormal hepatic function.u. 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, erythemanodosum, skin reaction, skin toxicity, dermatitis exfoliative, dermatitis exfoliative generalised, dermatitispsoriasiform, erythema multiforme, exfoliative rash, immune-mediated dermatitis, lichen planus, andparapsoriasis.

v. Pruritus includes pruritus and allergic pruritus.w. Musculoskeletal pain includes arthralgia, back pain, pain in extremity, myalgia, neck pain, musculoskeletalchest pain, bone pain, musculoskeletal pain, spinal pain, musculoskeletal stiffness, and musculoskeletaldiscomfort.

x. Arthritis includes arthritis, polyarthritis, autoimmune arthritis, and immune-mediated arthritis.

y. Myositis includes myositis and dermatomyositis.z. Nephritis includes acute kidney injury, renal impairment, immune-mediated nephritis, nephritis, renalfailure, tubulointerstitial nephritis, and nephropathy toxic.aa. Fatigue includes fatigue, asthenia, and malaise.bb. Pyrexia includes pyrexia, hyperthermia, and hyperpyrexia.cc. Edema includes peripheral edema, face edema, peripheral swelling, face swelling, localised edema,generalised edema, and swelling.

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

These selected adverse reactions were consistent when cemiplimab was administered in monotherapyor 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-mediatedpneumonitis. Immune-mediated pneumonitis led to permanent discontinuation of cemiplimab in17 (1.3%) of 1281 patients. Among the 33 patients with immune-mediated pneumonitis, the mediantime to onset was 2.7 months (range: 7 days to 22.2 months) and the median duration of pneumonitiswas 1.1 months (range: 5 days to 16.9 months). Twenty-seven of the 33 patients (81.8%) receivedhigh-dose corticosteroids for a median of 15 days (range: 1 day to 5.9 months). Resolution ofpneumonitis 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 diarrhoeaor colitis led to permanent discontinuation of cemiplimab in 5 (0.4%) of 1281 patients. Among the25 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 was2.1 months (range: 4 days to 26.8 months). Nineteen of the 25 patients (76.0%) withimmune-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 in14 (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, including1 (< 0.1%) patient with Grade 5, 4 (0.3%) patients with Grade 4, and 21 (1.6%) patients with Grade 3immune-mediated hepatitis. Immune-mediated hepatitis led to permanent discontinuation ofcemiplimab in 18 (1.4%) of 1281 patients. Among the 31 patients with immune-mediated hepatitis, themedian time to onset was 2.8 months (range: 7 days to 22.5 months) and the median duration ofhepatitis was 2.3 months (range: 5 days to 8.7 months). Twenty-seven of the 31 patients (87.1%) withimmune-mediated hepatitis received high-dose corticosteroids for a median of 24 days (range: 2 daysto 3.8 months). Resolution of hepatitis had occurred in 12 (38.7%) of the 31 patients at the time of datacutoff.

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 tohypothyroidism. Among the 87 patients with hypothyroidism, the median time to onset was4.0 months (range: 15 days to 18.9 months) with a median duration of 9.2 months (range: 1 day to37.1 months). Resolution of hypothyroidism had occurred in 5 (5.7%) of the 87 patients at the time ofdata 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 discontinuedcemiplimab due to hyperthyroidism. Among the 39 patients with hyperthyroidism, the median time toonset 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 patientsat the time of data cutoff.

Thyroiditis occurred in 8 (0.6%) of 1281 patients receiving cemiplimab, including 4 (0.3%) patientswith Grade 2 thyroiditis. No patient discontinued cemiplimab due to thyroiditis. Resolution ofthyroiditis 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, including6 (0.5%) patients with Grade 3 adrenal insufficiency. One (< 0.1%) of 1281 patients discontinuedcemiplimab due to adrenal insufficiency. Among the 6 patients with adrenal insufficiency, the mediantime to onset was 7.5 months (range: 4.2 months to 18.3 months) and the median duration was2.9 months (range: 22 days to 6.1 months). Two of the 6 patients (33.3%) received high-dosecorticosteroids. Resolution of adrenal insufficiency had occurred in 1 (16.7%) of 6 patients at the timeof data cutoff.

Immune-mediated hypophysitis occurred in 7 (0.5%) of 1281 patients receiving cemiplimab, including3 (0.2%) patients with Grade 3 immune-mediated hypophysitis. One (< 0.1%) of 1281 patientsdiscontinued cemiplimab due to hypophysitis. Among the 7 patients with hypophysitis, the mediantime to onset was 7.4 months (range: 2.5 months to 10.4 months) with a median duration of2.7 months (range: 9 days to 34.9 months). Three of the 7 patients (42.9%) received high-dosecorticosteroids. Resolution of hypophysitis had occurred in 1 (14.3%) of 7 patients at the time of datacutoff.

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 receivingcemiplimab, 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 mediantime 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 skinadverse reactions received high-dose corticosteroids for a median of 10 days (range: 1 day to2.9 months). Resolution of skin reaction had occurred in 17 (70.8%) of 24 patients at the time of datacutoff.

Immune-mediated nephritis

Immune-mediated nephritis occurred in 9 (0.7%) of 1281 patients receiving cemiplimab, including1 (< 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%) of1281 patients. Among the 9 patients with immune-mediated nephritis, the median time to onset was2.1 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 receivedhigh-dose corticosteroids for a median of 18 days (range: 3 days to 1.3 months). Resolution ofnephritis 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 ofless than 1% (unless otherwise noted) of 1281 patients treated with cemiplimab monotherapy. Theevents were Grade 3 or less unless stated otherwise:

Nervous system disorders: Aseptic meningitis, paraneoplastic encephalomyelitis (Grade 5), chronicinflammatory demyelinating polyradiculoneuropathy, encephalitis, myasthenia gravis, peripheralneuropathya

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

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 polyarthritise includes myositis and dermatomyositis

f. reported in clinical studies outside the pooled dataset

The following additional immune-mediated adverse reactions were observed in patients receivingcombination therapy in clinical trials: vasculitis, Guillain-Barre syndrome, central nervous systeminflammation, 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 immunecheckpoint inhibitors, which might also occur during treatment with cemiplimab: coeliac disease,pancreatic exocrine insufficiency.

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

As with all therapeutic proteins, there is a potential for immunogenicity with cemiplimab. In clinicalstudies with 1029 patients treated with cemiplimab, 2.1% of patients developed treatment-emergentantibodies, with approximately 0.3% exhibiting persistent antibody responses. No neutralisingantibodies have been observed. There was no evidence of an altered pharmacokinetic or safety profilewith anti-cemiplimab antibody development.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

Pharmacotherapeutic group: Antineoplastic agents, PD-1/PD-L1 (Programmed cell death protein1/death ligand 1) inhibitors. ATC code: L01FF06

Cemiplimab is a fully human immunoglobulin G4 (IgG4) monoclonal antibody that binds to theprogrammed 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 antigenpresenting cells and may be expressed by tumour cells and/or other cells in the tumourmicroenvironment, results in inhibition of T cell function such as proliferation, cytokine secretion, andcytotoxic activity. Cemiplimab potentiates T cell responses, including anti-tumour responses, throughblockade of PD-1 binding to PD-L1 and PD-L2 ligands.

CSCC

The efficacy and safety of cemiplimab in patients with mCSCC (nodal or distant) or laCSCC whowere 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 thatenrolled 193 patients with mCSCC or laCSCC in Groups 1 to 3 with a combined median follow-uptime of 15.7 months total. Median duration of follow-up was 18.5 months for the mCSCC 3 mg/kgevery 2 weeks (Q2W) group (Group 1), 15.5 months for the laCSCC 3 mg/kg Q2W group (Group 2),17.3 months for the mCSCC 350 mg Q3W group (Group 3). In an additional cohort of 165 advanced

CSCC patients (mCSCC and laCSCC) dosed at 350 mg Q3W, the median duration of follow-up was8.7 months (Group 6).

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

In Study 1540, patients received cemiplimab intravenously (IV) until progression of disease,unacceptable toxicity or completion of planned treatment [3 mg/kg Q2W for 96 weeks (Groups 1 and2) or 350 mg Q3W for 54 weeks (Group 3)]. If patients with locally advanced disease showedsufficient response to treatment, surgery with curative intent was permitted. Tumour responseassessments were performed every 8 or 9 weeks (for patients receiving 3 mg/kg Q2W or 350 mg

Q3W, respectively). The primary efficacy endpoint of Study 1540 was confirmed objective responserate (ORR), as assessed by independent central review (ICR). For patients with mCSCC withoutexternally visible target lesions, ORR was determined by Response Evaluation Criteria in Solid

Tumours (RECIST 1.1). For patients with externally visible target lesions (laCSCC and mCSCC),

ORR was determined by a composite endpoint that integrated ICR assessments of radiologic data(RECIST 1.1) and digital medical photography (WHO criteria). The key secondary endpoint wasduration of response (DOR) by ICR. Other secondary endpoints included ORR and DOR byinvestigator assessment (IA), progression-free survival (PFS) by ICR and IA, overall survival (OS),complete response rate (CR) 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).

In the efficacy analysis of 193 patients with advanced CSCC from Study 1540 Groups 1 to 3, 115 hadmCSCC 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, and49 patients (25.4%) were less than 65 years. A total of 161 (83.4 %) patients were male, and187 (96.9%) patients were White; the ECOG PS was 0 (44.6%) and 1 (55.4%). Thirty-three and7/10 percent (33.7%) of patients had received at least 1 prior anti-cancer systemic therapy, 81.3% ofpatients had received prior cancer related surgery, and 67.9% of patients had received priorradiotherapy. Among patients with mCSCC, 76.5% had distant metastases, and 22.6% had only nodalmetastases.

Efficacy results based on the final analysis of Study 1540 Groups 1 to 3 are presented in Table 3.

Table 3: Efficacy results - Study 1540 - metastatic CSCC by dosing group, locallyadvanced CSCC

Efficacy endpoints mCSCC laCSCC mCSCCcemiplimab: cemiplimab: cemiplimab:3 mg/kg every 3 mg/kg every 350 mg every2 weeks 2 weeks 3 weeks(Group 1) (Group 2) (Group 3)(N=59) (N=78) (N=56)

ICR ICR ICR

Confirmed objective response rate(ORR)a

ORR 50.8% 44.9% 46.4%95% CI for ORR (37.5, 64.1) (33.6, 56.6) (33.0, 60.3)

Complete response (CR)b 20.3% 12.8% 19.6%

Partial response (PR) 30.5% 32.1% 26.8%

Stable disease (SD) 15.3% 34.6% 14.3%

Progressive disease (PD) 16.9% 12.8% 25.0%

Duration of response (DOR)

Medianc (months) NR 41.9 41.3(95% CI) (20.7, NE) (20.5, 54.6) (40.8, 46.3)

Range (months) 2.8-38.9 1.9-54.6 4.2-46.3

Patients with DOR ≥ 6 months, % 93.3% 88.6% 96.2%

Time to response (TTR)

Median (months) range (min:max) 1.9 2.1 2.1(1.7: 21.8) (1.8: 8.8) (2.0: 22.8)

Progression-free survival (PFS)a, c6 months 66.4% 72.4% 60.7%(95% CI) (52.5, 77.1) (60.1, 81.5) (46.7, 72.1)12 months 53.8% 60.8% 53.4%(95% CI) (40.0, 65.8) (47.8, 71.5) (39.5, 65.4)

Overall survival (OS)a, c12 months 81.3% 91.8% 72.5%(95% CI) (68.7, 89.2) (82.6, 96.2) (58.6, 82.5)

CI: Confidence interval; ICR: Independent Central Review; NR: Not reached; NE: Not evaluable.

a. In Groups 1, 2, and 3, median durations of follow-up were 18.5, 15.5, and 17.3 months, respectively.

b. Only includes patients with complete healing of prior cutaneous involvement; laCSCC patients in Study1540 required biopsy to confirm CR.

c. Based on Kaplan Meier estimates.

Efficacy and PD-L1 status

Clinical activity was observed regardless of tumour PD-L1 expression status.

BCC

The efficacy and safety of cemiplimab in patients with laBCC or mBCC who had progressed on HHItherapy, were intolerant of prior HHI therapy, or had no better than SD after 9 months on HHI therapy(exclusive of treatment breaks), were evaluated in Study 1620, an open-label, multi-centre,non-randomised study. The study excluded patients with autoimmune disease that required systemictherapy with immunosuppressant agents within 5 years; history of solid organ transplant; priortreatment with anti-PD-1/PD-L1 therapy or other immune checkpoint inhibitor therapy; infection with

HIV, hepatitis B or hepatitis C; or ECOG performance score (PS) ≥ 2.

Patients received cemiplimab 350 mg intravenously (IV) every 3 weeks for 5 cycles of 9 weeksfollowed by 4 cycles of 12 weeks up to 93 weeks of treatment. Treatment continued until diseaseprogression, unacceptable toxicity or completion of planned treatment. Tumour assessments wereperformed every 9 weeks during cycles 1 to 5 and every 12 weeks during cycles 6 to 9. The majorefficacy endpoints were confirmed ORR and DOR as assessed by ICR. Secondary efficacy outcomesincluded ORR and DOR by IA, PFS, OS, CR by ICR, and time to response. For patients with mBCCwithout externally visible target lesions, ORR was determined by RECIST 1.1. For patients withexternally visible target lesions (laBCC and mBCC), ORR was determined by a composite endpointthat integrated ICR assessments of radiologic data (RECIST 1.1) and digital medical photography(WHO criteria).

A total of 138 patients with advanced BCC were included in the efficacy analysis of Study 1620,84 patients with laBCC and 54 patients with mBCC.

In the laBCC group, the median age was 70.0 years (range: 42 to 89): 31 (37%) patients were <65years old and 53 (63%) were 65 years or older. A total of 56 (67%) were male and 57 (68%) were

White; the ECOG PS was 0 (61%) and 1 (39%); Eighty-three per cent (83%) of patients had receivedat least 1 prior cancer-related surgery and 35% of patients had > 3 prior cancer-related surgeries(median: 3.0 surgeries, range: 1 to 43); 50% of patients had received at least 1 prior anti-cancerradiotherapy (RT) (median: 1.0 RT, range: 1 to 6).

In the mBCC group, the median age was 63.5 years (range: 38 to 90): 27 (50%) patients were < 65years old and 27 (50%) were 65 years or older. A total of 38 (70%) were male and 47 (87%) were

White; the ECOG PS was 0 (67%) and 1 (33%); Eighty-five per cent (85%) of patients had received atleast 1 prior cancer-related surgery and 28% of patients had > 3 prior cancer-related surgeries (median:2.0 surgeries, range: 1 to 8); 59% of patients had received at least 1 prior anti-cancer radiotherapy(RT) (median: 1.0 RT, range: 1 to 4).

All 138 patients were previously treated with a HHI, and 12% (16/138) of patients were previouslytreated with both vismodegib and sonidegib (as separate lines of therapy). Of the 84 laBCC patients,71% (60/84) of patients discontinued HHI therapy due to disease progression, 38% (32/84) of patientsdiscontinued HHI therapy due to intolerance and 2% (2/84) discontinued solely due to lack ofresponse. Of the 54 mBCC patients, 76% (41/54) of patients discontinued HHI therapy due to diseaseprogression, 33% (18/54) of patients discontinued HHI therapy due to intolerance, and 6% (3/54)discontinued solely due to lack of response. Investigators could select more than one reason fordiscontinuation of prior HHI therapy for an individual patient.

Efficacy results are presented in Table 4.

Table 4: Efficacy results for Study 1620 in locally advanced and metastatic basal cellcarcinoma

Efficacy endpoints laBCC mBCCcemiplimab 350 mg every cemiplimab 350 mg every3 weeks 3 weeks

N=84 N=54

ICR ICR

Best overall response (BOR)a, b, c

Objective response rate 27 (32.1%) 12 (22.2%)(ORR: CR+ PR) (95% CI) (22.4, 43.2) (12.0, 35.6)

Complete response (CR) rated 6 (7.1%) 1 (1.9%)(95 % CI) (2.7, 14.9) (0.0, 9.9)

Partial response (PR) rate 21 (25.0%) 11 (20.4%)

Progressive disease (PD) rate 9 (10.7%) 16 (29.6%)

Duration of response (DOR) N=27 responders N=12 responders

Mediane (months) NR 16.7(95% CI) (15.5, NE) (9.8, NE)

Range (observed) (months) 2.1 - 36.8+ 9.0 - 25.8+

Patients with DOR ≥ 6 months, %e 88.5% 100.0%(95% CI) (68.4, 96.1) (100, 100)

Time to response (TTR) N=27 responders N=12 responders

Median (months) 4.3 3.1(Range) (2.1 - 21.4) (2.0 - 10.5)

CI: Confidence interval; +: Denotes ongoing at last assessment; ICR: Independent Central Review; NR: Notreached; NE: Not evaluable

a. Median duration of follow-up: laBCC: 15.9 months, mBCC: 8.4 months.

b. Includes 2 laBCC patients who met the inclusion criteria solely on the basis of “No better than stabledisease (SD) after 9 months on HHI therapy”. BOR results by ICR were SD for 1 patient and NE for 1patient.

c. Includes 3 mBCC patients who met the inclusion criteria solely on the basis of “No better than SD after9 months on HHI therapy”. BOR results by ICR were PR for 1 patient and SD for 2 patients.

d. Locally advanced BCC patients in Study 1620 required biopsy to confirm complete response.

e. Based on Kaplan Meier estimates.

Efficacy and PD-L1 status

Clinical activity was observed regardless of tumour PD-L1 expression status.

First-line treatment of NSCLC with cemiplimab as monotherapy

The efficacy and safety of cemiplimab compared with platinum-doublet chemotherapy in patients withlocally advanced NSCLC who were not candidates for definitive chemoradiation, or with metastatic

NSCLC who had tumour PD-L1 expression ≥ 50% using the PD-L1 IHC 22C3 pharmDx assay wereevaluated in Study 1624, a randomised, open-label, multi-centre study.

A total of 710 patients were enrolled.

The study excluded patients with EGFR, ALK or ROS1 genomic tumour aberrations, ECOGperformance score (PS) ≥ 2, medical conditions that required systemic immunosuppression,uncontrolled infection with hepatitis B (HBV) or hepatitis C (HCV) or human immunodeficiency virus(HIV), history of interstitial lung disease, who were never smokers or who had an autoimmune diseasethat required systemic therapy within 2 years of treatment. Treatment of brain metastases waspermitted, and patients could be enrolled if they had been adequately treated and had neurologicallyreturned to baseline for at least 2 weeks prior to randomisation. Radiological confirmation of stabilityor response was not required.

Randomisation was stratified by histology (non-squamous vs squamous) and geographic region(Europe, Asia, or Rest of World). Patients were randomised (1:1) to receive cemiplimab 350 mgintravenously (IV) every 3 weeks for up to 108 weeks or investigator’s choice of the followingplatinum-doublet chemotherapy regimens for 4 to 6 cycles: paclitaxel + cisplatin or carboplatin;gemcitabine + cisplatin or carboplatin; or pemetrexed + cisplatin or carboplatin followed by optionalpemetrexed maintenance (This regimen was not recommended for patients with squamous NSCLC).

Treatment with cemiplimab continued until RECIST 1.1-defined progressive disease, unacceptabletoxicity, or up to 108 weeks. Patients who experienced independent review committee (IRC)-assessed

RECIST 1.1-defined progressive disease on cemiplimab therapy were permitted to continue treatmentwith cemiplimab with an addition of 4 cycles of histology-specific chemotherapy until furtherprogression was observed. Patients who experienced IRC-assessed RECIST 1.1-defined progressivedisease on chemotherapy treatment were permitted to receive cemiplimab treatment until furtherprogression, unacceptable toxicity or up to 108 weeks. Of the 203 patients randomised to receivechemotherapy who had IRC-assessed RECIST 1.1-defined disease progression, 150 (73.9%) patientscrossed over to treatment with cemiplimab. Assessment of tumour status was performed every 9weeks. The primary efficacy endpoints were overall survival (OS) and progression-free survival (PFS)as assessed by blinded IRC using RECIST 1.1. A key secondary endpoint was objective response rate(ORR).

Among the 710 patients, baseline characteristics were: median age 63 years (45% were 65 or older),85% male, 86% White, an ECOG performance score 0 and 1 in 27% and 73% respectively, and 12%with history of brain metastasis. Disease characteristics were locally advanced (16%), metastatic(84%), squamous (44%) and non-squamous (56%).

The study showed statistically significant improvement in OS for patients randomised to cemiplimabas compared with chemotherapy.

Efficacy results are presented in Table 5, Figure 1 and Figure 2.

Table 5: Efficacy results for Study 1624 in non-small cell lung cancer

Efficacy endpointsa Cemiplimab Chemotherapy350 mg every 3 weeks N=354

N=356

Overall survival (OS)

Deaths n(%) 108 (30.3) 141 (39.8)

Median in months (95% CI)b 22.1 (17.7, NE) 14.3 (11.7, 19.2)

Hazard ratio (95% CI)c 0.68 (0.53, 0.87)p-Valued 0.0022

OS rate at 12 months (95% CI)b 70% (64, 75) 56% (49, 62)

Progression-free survival (PFS)

Events n(%) 201 (56.5) 262 (74.0)

Median in months (95% CI)b 6.2 (4.5, 8.3) 5.6 (4.5, 6.1)

Hazard ratio (95% CI)c 0.59 (0.49, 0.72)

PFS rate at 12 months (95% CI)b 38% (32, 44) 7% (4, 11)

Objective response rate (%)e

ORR (95% CI) 36.5 (31.5, 41.8) 20.6 (16.5, 25.2)

Complete response (CR) rate 3.1 0.8

Partial response (PR) rate 33.4 19.8

Duration of response N=130 responders N=73 responders

Median (months)b 21.0 6.0

Range (months) (1.9 +, 23.3+) (1.3+, 16.5+)

Patients with observed DOR ≥ 6 69% 41%months, %

CI: Confidence interval; NE: Not evaluable; +: Ongoing response

a. Median duration of follow-up: cemiplimab: 13.1 months; chemotherapy: 13.1 months

b. Based on Kaplan-Meier estimates

c. Based on stratified proportional hazards model

d. Based on a two-sided p-value

e. Based on Clopper-Pearson exact confidence interval

Figure 1: OS in Study 1624 in NSCLC

Figure 2: PFS in Study 1624 in NSCLC

First-line treatment of NSCLC with cemiplimab in combination with platinum-based chemotherapy

The efficacy and safety of cemiplimab in combination with platinum-based chemotherapy wereevaluated in Study 16113, a randomised, multi-centre, double-blind, active-controlled trial in466 patients with locally advanced NSCLC who were not candidates for definitive chemoradiation, orwith metastatic NSCLC, regardless of tumour PD-L1 expression status and who had not previouslyreceived systemic treatment for metastatic NSCLC. Testing for genomic tumour aberrations other than

EGFR, ALK or ROS1 was not mandatory for enrolment in Study 16113.

Patients with EGFR, ALK or ROS1 genomic tumour aberrations; a medical condition that requiredsystemic immunosuppression; active infection with hepatitis B (HBV) or hepatitis C (HCV),uncontrolled human immunodeficiency disease (HIV), or ongoing or recent autoimmune disease thatrequired systemic therapy were ineligible. Patients with a history of brain metastases were eligible ifthey had been adequately treated and had neurologically returned to baseline for at least 2 weeks priorto randomisation. Radiological confirmation of stability or response was not required.

Randomisation was stratified by histology (non-squamous vs squamous) and PD-L1 expression (< 1%versus 1% to 49% versus ≥ 50%) according to the VENTANA PD-L1 (SP263) assay. Patients wererandomised (2:1) to receive either cemiplimab 350 mg intravenously (IV) every 3 weeks for108 weeks plus platinum-based chemotherapy every 3 weeks for 4 cycles or placebo intravenously(IV) every 3 weeks for 108 weeks plus platinum-based chemotherapy every 3 weeks for 4 cycles.

Treatment with cemiplimab or placebo was continued until RECIST 1.1-defined progressive disease,unacceptable toxicity, or up to 108 weeks. Treatment with chemotherapy was given for 4 cyclesfollowed by maintenance of pemetrexed as clinically indicated or until RECIST 1.1-definedprogressive disease or unacceptable toxicity. Chemotherapy in Study 16113 consisted of carboplatinor cisplatin combined with paclitaxel or pemetrexed with mandatory maintenance for pemetrexedregimens. Assessment of tumour status was performed every 9 weeks beginning at week 9 during year1 and every 12 weeks beginning at week 55 during year 2. The primary efficacy endpoint was overallsurvival (OS). Key secondary endpoints as assessed by blinded IRC using RECIST 1.1, wereprogression-free survival (PFS), and objective response rate (ORR).

Among the 466 patients, 327 (70%) had tumours expressing PD-L1 (in ≥ 1% of tumour cells). Ofthese, 217 patients were in the cemiplimab and chemotherapy group and 110 patients were in theplacebo and chemotherapy group. The baseline characteristics of the 327 patients with tumoursexpressing PD-L1 in ≥ 1% of tumour cells were: median age 62 years (38% were 65 or older), 83%male, 87% White, an ECOG performance score 0 and 1 in 16% and 83% respectively, and 6% withhistory of brain metastasis; 51% of patients were current smokers, 34% were past smokers and 15%had never smoked (less than 100 cigarettes a lifetime). Disease characteristics were locally advanced(14%), metastatic (86%), squamous histology (45%), and non-squamous histology (55%).

At the primary analysis in the overall population with a median follow-up time of 16.4 months, thestudy showed a statistically significant improvement in OS for patients randomised to cemiplimab incombination with chemotherapy compared with placebo in combination with chemotherapy.

Efficacy results in patients whose tumours expressed PD-L1 ≥ 1% are presented in Table 6, Figure 3,and Figure 4.

Table 6: Efficacy results for Study 16113 in non-small cell lung cancer (patients with PD-L1expression ≥ 1%)acemiplimab and placebo and chemotherapy

Endpointsa chemotherapy N=110

N=217

Overall Survival (OS)

Deaths, n (%) 78 (35.9) 55 (50.0)

Median in months (95% CI)b 21.9 (17.3, NE) 12.6 (10.3, 16.4)

Hazard ratio (95% CI)c 0.55 (0.39, 0.78)

Progression-free Survival (PFS)

Events, n (%) 134 (61.8) 86 (78.2)

Median in months (95% CI)b 8.5 (6.7, 10.7) 5.5 (4.3, 6.2)

Hazard ratio (95% CI)c 0.48 (0.36, 0.63)

Objective Response Rate (ORR) (%)

ORR (95% CI)d 47.9 (41.1, 54.8) 22.7 (15.3, 31.7)

Complete response (CR) rate 2.8 0

Partial response (PR) rate 45.2 22.7

Duration of Response (DOR)

Median in monthsb (range) 15.6 (1.7, 18.7+) 4.9 (1.9, 18.8+)

CI: confidence interval; NE: Not evaluable; +: Ongoing response (Data cutoff - Jun 14, 2021)

a. Median duration of follow up: cemiplimab and chemotherapy: 15.9 months, placebo and chemotherapy:

16.1 months

b. Based on Kaplan-Meier method

c. Based on stratified proportional hazards model

d. Clopper-Pearson exact confidence interval

At the time of the pre-specified final analysis, patients whose tumours expressed PD-L1 ≥ 1%randomised to cemiplimab in combination with chemotherapy, at a median duration of follow-up of27.9 months, continued to show a clinically meaningful survival and progression free survival benefitcompared to chemotherapy alone.

Figure 3: OS in Study 16113 in NSCLC (patients with PD-L1 expression ≥ 1%) - (Final analysis)a

Hazard Ratio (95% CI) = 0.51 (0.38, 0.69)a Based on final OS analysis (Data cutoff Jun 14, 2022)

Figure 4: PFS in Study 16113 in NSCLC (patients with PD-L1 expression ≥ 1%) - (Finalanalysis)a

Hazard Ratio (95% CI) = 0.48 (0.37, 0.62)a Based on final PFS analysis (Data cutoff Jun 14, 2022)

Cervical Cancer

The efficacy and safety of cemiplimab were evaluated in patients with recurrent or metastatic cervicalcancer whose tumours progressed on or after platinum-based chemotherapy, with or withoutbevacizumab in Study 1676, a randomised, open-label, multi-centre study. Patients were enrolledregardless of PD-L1 tumour expression status. The study excluded patients with autoimmune diseasethat required systemic therapy with immunosuppressant agents within 5 years and prior treatment withanti-PD-1/PD-L1 therapy.

The stratification factors for the efficacy analysis were geographic region (North America, Asia, Restof World) and histology [squamous histology (SCC), adenocarcinoma/adenosquamous histologies(AC)]. Randomisation was also stratified by whether or not patients had received prior bevacizumabtreatment and their ECOG performance status. Patients were randomised (1:1) to receive cemiplimab350 mg intravenously every 3 weeks or investigator’s choice of intravenous chemotherapy amongpemetrexed, topotecan, irinotecan, gemcitabine, or vinorelbine, for up to 96 weeks.

Treatment continued until disease progression, unacceptable toxicity, or completion of plannedtreatment. Tumour assessments were performed every 6 weeks for the first 24 weeks and every12 weeks thereafter. The primary efficacy endpoint was OS in SCC followed by the total population.

Secondary endpoints included PFS, ORR according to RECIST 1.1, and DOR by investigatorassessment.

The median age was 51 years (22 to 87 years); 63% were White, 29% Asian, 3.5% Black; 49%received prior bevacizumab treatment, 47% had ECOG PS 0 and 53% had ECOG PS 1; 78% had SCCand 22% had AC, 94% had metastatic disease; 57% had 1 prior line of treatment in the recurrent ormetastatic setting and 43% had > 1 prior line of treatment in the recurrent or metastatic setting. Themedian duration of follow-up for the primary analysis in the total population was 18.2 months.

Cemiplimab showed a statistically significant improvement in OS in both SCC and total populationcompared to chemotherapy.

Efficacy results are presented in Table 7, Figure 5, and Figure 6.

Table 7: Efficacy results for Study 1676 in cervical cancer

Squamous histology (SCC) Total population(N=477) (N=608)cemiplimab chemotherapy cemiplimab chemotherapy350 mg every (n=238) 350 mg every (n=304)

Efficacyendpoints 3 weeks 3 weeks(n=239) (n=304)

Overall survival (OS)a

Deaths, n (%) 143 (59.8%) 161 (67.6%) 184 (60.5%) 211 (69.4%)

Median inmonths (95% 11.1 8.8 12.0 8.5

CI)b (9.2, 13.4) (7.6, 9.8) (10.3, 13.5) (7.5, 9.6)

Hazard ratio 0.73 0.69(95% CI)c (0.58, 0.91) (0.56, 0.84)p-valued 0.00306 0.00011

Progression-free survival (PFS) a

Events, n (%) 197 (82.4%) 214 (89.9%) 253 (83.2%) 269 (88.5%)

Median inmonths (95% 2.8 2.9 2.8 2.9

CI)b (2.6, 4.0) (2.7, 3.9) (2.6, 3.9) (2.7, 3.4)

Hazard ratio(95% CI)c 0.71 (0.58, 0.86) 0.75 (0.62, 0.89)p-valued 0.00026 0.00048

Objective response rate (%)a

ORR 17.6 6.7 6.3(95% CI)e (13.0, 23.0) (3.9, 10.7) 16.4 (12.5,21.1) (3.8, 9.6)

Duration of

Response N=42 N=16 N=50 N=19(DOR)a

Median(months)b 16.4 6.9 16.4 6.9(95% CI) (12.4, NE) (4.2, 7.7) (12.4, NE) (5.1, 7.7)

a. Median follow-up: 18.2 months. (Data cutoff - Jan 04, 2021)

b. Based on Kaplan-Meier estimates.

c. Based on stratified proportional hazards model stratified by histology and geographic region.

d. One-sided p-value based on stratified proportional hazards model (cemiplimab vs. chemotherapy).

e. Based on Clopper-Pearson exact confidence interval.

In an updated OS analysis (data cutoff Jan 04, 2022), at a median duration of follow-up of30.2 months, cemiplimab showed a continued survival benefit compared to chemotherapy (Hazard

Ratio (HR): 0.66, 95% CI [0.55, 0.79]) (see Figure 5).

Figure 5: OS in Study 1676 in cervical cancer - Total population (Updated analysis)a

a. Based on results from an updated OS analysis which was conducted one year after the primary analysis.

Figure 6: PFS in Study 1676 in cervical cancer - Total population (Primary Analysis)

Subgroup analyses:

In a subgroup analysis of overall survival by histology based on the updated exploratory OS analysis.the HR for the SCC group was 0.69 (95% CI: 0.56, 0.85) and the HR for the AC group was 0.55 (95%

CI: 0.36, 0.81).

An exploratory subgroup analysis was conducted on survival by tumour PD-L1 Tumour Cell (TC)expression status using a clinical trial assay (VENTANA PD-L1 SP263 Assay). Of the 608 enrolledpatients, 42% of patients had samples that were tested for PD-L1. Among these samples, 64% were

PD-L1 ≥ 1% and 36% were PD-L1 < 1%. At the updated exploratory OS analysis, with medianduration of follow-up of 30.2 months, the HR for the PD-L1 ≥ 1% group was 0.70 (95% CI: 0.48,1.01) and the HR for the PD-L1 < 1% group was 0.85 (95% CI: 0.53, 1.36).

Of the 1281 patients treated with cemiplimab monotherapy in clinical studies, 52.2% (669/1281) wereless than 65 years, 25.9% (332/1281) were 65 to less than 75 years, and 21.9% (280/1281) were75 years or older.

No overall differences in efficacy were observed between elderly patients and younger patients. Therewas a trend towards a higher frequency of serious adverse events and discontinuations due to adverseevents in patients 65 years and older compared with patients aged less than 65 years treated withcemiplimab monotherapy.

Of the 312 patients treated with cemiplimab in combination with chemotherapy, 59% (184/312) wereless than 65 years, 35.3% (110/312) were 65 to less than 75 years, and 5.8% (18/312) were 75 years orolder.

No overall differences in safety or efficacy were observed between elderly patients and youngerpatients treated with cemiplimab in combination with platinum-based chemotherapy.

The efficacy, safety and pharmacokinetics of cemiplimab were evaluated in 57 paediatric and youngadult patients with relapsed or refractory solid and CNS tumours, newly diagnosed diffuse intrinsicpontine glioma (DIPG), newly diagnosed high-grade glioma (HGG) or recurrent HGG in Study 1690.

The study, an open-label, multi-centre study, consisted of two phases, Phase 1 and Efficacy phase,conducted in parallel.

In Phase 1, the safety and pharmacokinetics of cemiplimab monotherapy were evaluated in 25 patients(0 to less than 18 years): 8 patients with relapsed or refractory solid tumours and 17 patients withrelapsed or refractory CNS tumours. Sixteen patients with solid or CNS tumour received a cemiplimabdose of 3 mg/kg every 2 weeks and 9 patients with CNS tumours received a cemiplimab dose of4.5 mg/kg every 2 weeks. In Efficacy phase, the efficacy and safety of cemiplimab in combinationwith radiotherapy were evaluated in 32 patients (3 to 25 years) with CNS tumours: 11 patients withnewly diagnosed DIPG, 12 patients with newly diagnosed HGG and 9 patients with recurrent HGG.

All patients 12 years and older received a cemiplimab dose of 3 mg/kg and patients aged 3 to less than12 years received a cemiplimab dose of 4.5 mg/kg every 2 weeks. Cemiplimab was administered via a30-minute intravenous infusion.

Efficacy of cemiplimab in combination with radiotherapy was not established in studied populationsas an improvement in OS or PFS was not demonstrated over historical data.

No new risks or safety signals were identified.

Concentration data from 1063 patients with various solid tumours who received intravenouscemiplimab were combined in a population PK analysis.

At 350 mg Q3W, the mean cemiplimab concentrations at steady-state ranged between a Ctrough of59 mg/l and a concentration at end of infusion (Cmax) of 171 mg/l. Steady-state exposure is achievedafter approximately 4 months of treatment.

Cemiplimab exposure at steady-state in patients with solid tumours is similar at 350 mg Q3W and at3 mg/kg Q2W.

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

Cemiplimab is primarily distributed in the vascular system with a volume of distribution atsteady-state (Vss) of 5.9 l. Median Tmax occurs at the end of the 30-minute infusion.

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

Clearance of cemiplimab is linear at doses of 1 mg/kg to 10 mg/kg every two weeks. Cemiplimabclearance after the first dose is approximately 0.25 l/day. The total clearance appears to decrease byapproximately 11% over time, resulting in a steady-state clearance (CLss) of 0.22 l/day; the decreasein CL is not considered clinically relevant. The within dosing interval half-life at steady-state is22 days.

At the dosing regimens of 1 mg/kg to 10 mg/kg every two weeks, pharmacokinetics of cemiplimabwere linear and dose proportional, suggesting saturation of the systemic target-mediated pathway.

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

Pharmacokinetics in paediatric patients were estimated based on an updated population PK modelcontaining PK data from 1227 adults with various solid tumours who received intravenous cemiplimabmonotherapy pooled with PK data from 55 paediatric to young adult patients aged 1 to 24 years whoreceived cemiplimab intravenously at 3 mg/kg or 4.5 mg/kg every 2 weeks, with or withoutradiotherapy. The exposure in paediatric patients was comparable to that in adults receivingcemiplimab intravenously 350 mg every 3 weeks, with slightly higher exposure seen for paediatricpatients 0 to less than 12 years old receiving 4.5 mg/kg every 2 weeks. Overall, the lowest predictedmedian Ctrough,ss and highest Cmax,ss for all paediatric patients was within the observed range for adultpatients receiving 350 mg intravenously every 3 weeks.

The effect of renal impairment on the exposure of cemiplimab was evaluated by a population PKanalysis in patients with mild (CLcr 60 to 89 ml/min; n= 396), moderate (CLcr 30 to 59 ml/min;n= 166), or severe (CLcr 15 to 29 ml/min; n= 7) renal impairment. No clinically important differencesin the exposure of cemiplimab were found between patients with renal impairment and patients withnormal renal function. Cemiplimab has not been studied in patients with CLcr < 21 ml/min (seesection 4.2).

The effect of hepatic impairment on the exposure of cemiplimab was evaluated by population PKanalysis in patients with mild hepatic impairment (n= 22) (total bilirubin [TB] greater than 1.0 to1.5 times the upper limit of normal [ULN] and any aspartate aminotransferase [AST]) and patientswith moderate hepatic impairment (n=3) (total bilirubin > 1.5 times ULN up to 3.0 times ULN) andany AST; no clinically important differences in the exposure of cemiplimab were found compared topatients with normal hepatic function. Cemiplimab has not been studied in patients with severe hepaticimpairment. There are insufficient data in patients with severe hepatic impairment for dosingrecommendations (see section 4.2).

No studies have been performed to test the potential of cemiplimab for carcinogenicity orgenotoxicity. 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 bymaintaining immunological tolerance and studies have shown that PD-1 receptor blockade results inearly termination of pregnancy. The increase of spontaneous abortion and/or resorption in animalswith restricted PD-L1 expression (knock-out or anti-PD-1/PD-L1 monoclonal antibodies) has beenshown in both mice and monkeys. These animal species have similar maternal-foetal interface to thatin humans.

L-histidine

L-histidine monohydrochloride monohydrate

Sucrose

L-proline

Polysorbate 80

Water for injections

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

Unopened vial4 years.

Once opened, the medicinal product should be diluted and infused immediately (see section 6.6 forinstructions on dilution of the medicinal product before administration).

From a microbiological point of view the prepared solution for infusion should be used immediately.

If diluted solution is not administered immediately, in-use storage times and conditions prior to use arethe responsibility of the user.

Chemical and physical in-use stability has been demonstrated as follows:

* at room temperature up to 25°C for no more than 8 hours from the time of infusionpreparation to the end of infusion.

Or

* under refrigeration at 2°C to 8°C for no more than 10 days from the time of infusionpreparation to the end of infusion. Allow the diluted solution to come to room temperatureprior to administration.

Do not freeze.

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.

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.

Preparation and administration

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

* Discard the vial if the solution is cloudy, discoloured or contains extraneous particulatematter 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 intravenousinfusion bag containing sodium chloride 9 mg/ml (0.9%) solution for injection or glucose50 mg/ml (5%) solution for injection. Mix the diluted solution by gentle inversion. Do notshake the solution. The final concentration of the diluted solution should be between1 mg/ml to 20 mg/ml.

* LIBTAYO is administered by intravenous infusion over 30 minutes through anintravenous line containing a sterile, non-pyrogenic, low-protein binding, in-line or add-onfilter (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 inaccordance with local requirements.

Regeneron Ireland Designated Activity Company (DAC)

One Warrington Place

Dublin 2, D02 HH27

Ireland

EU/1/19/1376/001

Date of first authorisation: 28 June 2019

Date of latest renewal: 01 July 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.