Preparation

• Do not shake.
• Withdraw 7 mL from a vial and dilute with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to a final concentration between 1 mg/mL to 20 mg/mL.
• Mix diluted solution by gentle inversion. Do not shake.
• Discard any unused medicinal product or waste material.

Storage of Infusion Solution

• Store at room temperature up to 25°C (77°F) for no more than 8 hours from the time of preparation to the end of the infusion or at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of preparation to the end of infusion.
• Allow the diluted solution to come to room temperature prior to administration.
• Do not freeze.

Administration

• Administer by intravenous infusion over 30 minutes through an intravenous line containing a sterile, in-line or add-on 0.2-micron to 5-micron filter.

Immune-Mediated Pneumonitis

LIBTAYO can cause immune-mediated pneumonitis. The definition of immune-mediated pneumonitis included the required use of systemic corticosteroids or other immunosuppressants and the absence of a clear alternate etiology. In patients treated with other PD-1/PD-L1 blocking antibodies the incidence of pneumonitis is higher in patients who have received prior thoracic radiation.

Immune-mediated pneumonitis occurred in 3.2% (26/810) of patients receiving LIBTAYO, including Grade 4 (0.5%), Grade 3 (0.5%), and Grade 2 (2.1%) adverse reactions. Pneumonitis led to permanent discontinuation of LIBTAYO in 1.4% of patients and withholding of LIBTAYO in 2.1% of the patients.

Systemic corticosteroids were required in all patients with pneumonitis. Pneumonitis resolved in 58% of the 26 patients. Of the 17 patients in whom LIBTAYO was withheld for pneumonitis, 9 reinitiated LIBTAYO after symptom improvement; of these, 3/9 (33%) had recurrence of pneumonitis.

Immune-Mediated Colitis

LIBTAYO can cause immune-mediated colitis. The definition of immune-mediated colitis included the required use of systemic corticosteroids or other immunosuppressants and the absence of a clear alternate etiology. The primary component of the immune-mediated colitis was diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis treated with PD-1/PD-L1 blocking antibodies. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.

Immune-mediated colitis occurred in 2.2% (18/810) of patients receiving LIBTAYO, including Grade 3 (0.9%) and Grade 2 (1.1%) adverse reactions. Colitis led to permanent discontinuation of LIBTAYO in 0.4% of patients and withholding of LIBTAYO in 1.5% of patients.

Systemic corticosteroids were required in all patients with colitis. Colitis resolved in 39% of the 18 patients. Of the 12 patients in whom LIBTAYO was withheld for colitis, 4 reinitiated LIBTAYO after symptom improvement; of these, 3/4 (75%) had recurrence of colitis.

Immune-Mediated Hepatitis

LIBTAYO can cause immune-mediated hepatitis. The definition of immune-mediated hepatitis included the required use of systemic corticosteroids or other immunosuppressants and the absence of a clear alternate etiology.

Immune-mediated hepatitis occurred in 2% (16/810) of patients receiving LIBTAYO, including fatal (0.1%), Grade 4 (0.1%), Grade 3 (1.4%), and Grade 2 (0.2%) adverse reactions. Hepatitis led to permanent discontinuation of LIBTAYO in 1.2% of patients and withholding of LIBTAYO in 0.5% of patients.

Systemic corticosteroids were required in all patients with hepatitis. Nineteen percent (19%) of these patients (3/16) required additional immunosuppression with mycophenolate. Hepatitis resolved in 50% of the 16 patients. Of the 5 patients in whom LIBTAYO was withheld for hepatitis, 3 patients reinitiated LIBTAYO after symptom improvement; of these, none had recurrence of hepatitis.

Immune-Mediated Endocrinopathies

Immune-Mediated Nephritis with Renal Dysfunction

LIBTAYO can cause immune-mediated nephritis. The definition of immune-mediated nephritis included the required use of systemic corticosteroids or other immunosuppressants and the absence of a clear alternate etiology.

Immune-mediated nephritis occurred in 0.6% (5/810) patients receiving LIBTAYO, including fatal (0.1%), Grade 3 (0.1%) and Grade 2 (0.4%) adverse reactions. Nephritis led to permanent discontinuation of LIBTAYO in 0.1% of patients and withholding of LIBTAYO in 0.4% of patients.

Systemic corticosteroids were required in all patients with nephritis. Nephritis resolved in 80% of the 5 patients. Of the 3 patients in whom LIBTAYO was withheld for nephritis, 2 reinitiated LIBTAYO after symptom improvement; of these, none had recurrence of nephritis.

Immune-Mediated Dermatologic Adverse Reactions

LIBTAYO can cause immune-mediated rash or dermatitis. The definition of immune-mediated dermatologic adverse reaction included the required use of systemic corticosteroids or other immunosuppressants and the absence of a clear alternate etiology. Exfoliative dermatitis, including Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and DRESS (Drug Rash with Eosinophilia and Systemic Symptoms), has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue LIBTAYO depending on severity [see Dosage and Administration (2.3)].

Immune-mediated dermatologic adverse reactions occurred in 1.6% (13/810) of patients receiving LIBTAYO, including Grade 3 (0.9%) and Grade 2 (0.6%) adverse reactions. Dermatologic adverse reactions led to permanent discontinuation of LIBTAYO in 0.1% of patients and withholding of LIBTAYO in 1.4% of patients.

Systemic corticosteroids were required in all patients with immune-mediated dermatologic adverse reactions. Immune-mediated dermatologic adverse reactions resolved in 69% of the 13 patients. Of the 11 patients in whom LIBTAYO was withheld for dermatologic adverse reaction, 7 reinitiated LIBTAYO after symptom improvement; of these 43% (3/7) had recurrence of the dermatologic adverse reaction.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of < 1% in 810 patients who received LIBTAYO or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions.

Cardiac/Vascular: Myocarditis, pericarditis, vasculitis

Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome / myasthenia gravis (including exacerbation), Guillain-Barre syndrome, nerve paresis, autoimmune neuropathy

Ocular: Uveitis, iritis, and other ocular inflammatory toxicities. Some cases can be associated with retinal detachment. Various grades of visual impairment to include blindness can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss.

Gastrointestinal: Pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis, stomatitis

Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatica

Endocrine: Hypoparathyroidism

Other (Hematologic/Immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Cutaneous Squamous Cell Carcinoma (CSCC)

The safety of LIBTAYO was evaluated in 219 patients with advanced CSCC (metastatic or locally advanced disease) in Study 1423 and Study 1540 [see Clinical Studies (14.1)]. Of these 219 patients, 131 had mCSCC (nodal or distant) and 88 had laCSCC. Patients received LIBTAYO 1 mg/kg every 2 weeks (n=1), 3 mg/kg every 2 weeks (n=162) or 350 mg every 3 weeks (n=56) as an intravenous infusion until disease progression, unacceptable toxicity, or completion of planned treatment. The median duration of exposure was 38 weeks (2 weeks to 110 weeks).

The safety population characteristics were: median age of 72 years (38 to 96 years), 83% male, 96% White, and European Cooperative Oncology Group (ECOG) performance score (PS) of 0 (44%) and 1 (56%).

Serious adverse reactions occurred in 35% of patients. Serious adverse reactions that occurred in at least 2% of patients were pneumonitis, cellulitis, sepsis, and pneumonia.

Permanent discontinuation due to an adverse reaction occurred in 8% of patients. Adverse reactions resulting in permanent discontinuation were pneumonitis, cough, pneumonia, encephalitis, aseptic meningitis, hepatitis, arthralgia, muscular weakness, neck pain, soft tissue necrosis, complex regional pain syndrome, lethargy, psoriasis, rash maculopapular, proctitis, and confusional state.

The most common (≥ 20%) adverse reactions were fatigue, rash, diarrhea, musculoskeletal pain, and nausea. The most common Grade 3 or 4 adverse reactions (≥ 2%) were cellulitis, anemia, hypertension, pneumonia, musculoskeletal pain, fatigue, pneumonitis, sepsis, skin infection, and hypercalcemia. The most common (≥ 4%) Grade 3 or 4 laboratory abnormalities worsening from baseline were lymphopenia, anemia, hyponatremia, and hypophosphatemia.

Table 2 summarizes the adverse reactions that occurred in ≥ 10% of patients and Table 3 summarizes Grade 3 or 4 laboratory abnormalities worsening from baseline in ≥ 1% of patients receiving LIBTAYO.

Basal Cell Carcinoma (BCC)

The safety of LIBTAYO was evaluated in 132 patients with advanced BCC (mBCC N=48, laBCC N=84) in an open-label, single-arm trial (Study 1620) [see Clinical Studies (14.2)]. Patients received LIBTAYO 350 mg every 3 weeks as an intravenous infusion for up to 93 weeks or until disease progression or unacceptable toxicity. The median duration of exposure was 42 weeks (range: 2.1 weeks to 94 weeks).

The safety population characteristics were: median age of 68 years (38 to 90 years), 67% male, 74% White, and ECOG performance score (PS) of 0 (62%) and 1 (38%).

Serious adverse reactions occurred in 32% of patients. Serious adverse reactions that occurred in > 1.5% (at least 2 patients) were urinary tract infection, colitis, acute kidney injury, adrenal insufficiency, anemia, infected neoplasm, and somnolence. Fatal adverse reactions occurred in 1.5% of patients who received LIBTAYO, including acute kidney injury and cachexia.

Permanent discontinuation of LIBTAYO due to an adverse reaction occurred in 13% of patients. Adverse reactions resulting in permanent discontinuation of LIBTAYO in > 1.5% (at least 2 patients) were colitis and general physical health deterioration.

Dosage delays of LIBTAYO due to an adverse reaction occurred in 34% of patients. Adverse reactions which required dosage delay in > 2% of patients (at least 3 patients) included blood creatinine increased, diarrhea, colitis, fatigue, headache, pneumonitis, and urinary tract infection.

The most common adverse reactions reported in at least 15% of patients were fatigue, musculoskeletal pain, diarrhea, rash, pruritus, and upper respiratory tract infection.

The most common Grade 3 or 4 adverse reactions (> 2%) were hypertension, colitis, fatigue, urinary tract infection, pneumonia, increased blood pressure, hypokalemia and visual impairment. The most common (> 3%) laboratory abnormality worsening from baseline to Grade 3 or 4 was hyponatremia.

Table 4 summarizes the adverse reactions that occurred in ≥ 10% of patients and Table 5 summarizes Grade 3 or 4 laboratory abnormalities worsening from baseline in ≥ 1% of patients receiving LIBTAYO.

Non-Small Cell Lung Cancer (NSCLC)

Risk Summary

Based on its mechanism of action, LIBTAYO can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of LIBTAYO 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 fetus resulting in fetal death (see Data). Human IgG4 immunoglobulins (IgG4) are known to cross the placenta; therefore, LIBTAYO has the potential to be transmitted from the mother to the developing fetus. Advise women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Risk Summary

There is no information regarding the presence of cemiplimab-rwlc in human milk, or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for at least 4 months after the last dose of LIBTAYO.

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating LIBTAYO [see Use in Specific Populations (8.1)].

Contraception

LIBTAYO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

LIBTAYO as a Single Agent

Of the 810 patients who received LIBTAYO as a single agent in clinical studies, 32% were 65 years up to 75 years and 22% were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients.

Of the 219 patients with mCSCC or laCSCC who received LIBTAYO as a single agent in clinical studies, 34% were 65 years up to 75 years and 41% were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients.

Of the 132 patients with BCC who received LIBTAYO as a single agent in Study 1620, 27% were 65 years up to 75 years, and 32% were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients.

LIBTAYO in combination with Platinum-based Chemotherapy

Of the 312 patients with NSCLC who received LIBTAYO in combination with platinum-based chemotherapy in Study 16113, 35% were 65 years up to 75 years and 6% were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients.

Distribution

The volume of distribution of cemiplimab-rwlc at steady state is 5.3 L (26%).

Elimination

Cemiplimab-rwlc clearance (CV%) after the first dose is 0.29 L/day (33%) and decreases over time by 29%, resulting in a steady-state clearance (CLss) (CV%) of 0.20 L/day (40%). The elimination half-life (CV%) at steady state is 20.3 days (29%).

Specific Populations

The following factors have no clinically important effect on the exposure of cemiplimab-rwlc: age (27 to 96 years), sex, body weight (31 to 172 kg), cancer type, albumin level (20 to 93 g/L), renal function (creatinine clearance determined by Cockcroft-Gault 21 mL/min or greater) and hepatic function (total bilirubin greater than 1.0 times up to 3.0 times the ULN). Race [White (N=931), Black (N=47), Asian (N=21)] appears to have no clinically important effect on the exposure of cemiplimab-rwlc. LIBTAYO has not been studied in patients with severe hepatic impairment.

Study 1540

Among the 193 patients with advanced CSCC enrolled in Study 1540 who received LIBTAYO at either 3 mg/kg every 2 weeks or 350 mg every three weeks, 115 had mCSCC and 78 had laCSCC. The median age was 72 years (38 to 96 years); 83% were male; 97% were White; 45% had ECOG PS 0 and 55% had ECOG PS 1; 34% received at least one prior anti-cancer systemic therapy; 90% received prior cancer-related surgery; and 68% received prior radiotherapy. Among patients with mCSCC, 77% had distant metastases and 23% had only nodal metastases.

For the responding patients presented in Table 10 below, the median time to response was 1.9 months (range: 1.7 to 9.1 months).

Efficacy results in patients who received 3 mg/kg every 2 weeks are presented in Table 10.

Study 1540: 350 mg every 3 weeks

In an additional cohort in Study 1540, 56 patients received cemiplimab-rwlc at a dose of 350 mg intravenously every 3 weeks for up to 54 weeks. With a median duration of follow-up of 8.0 months, the confirmed ORR was 41% (95% CI: 28, 55), and 65% of responders had a DOR ≥ 6 months.

Study 1423

Among 26 CSCC patients in Study 1423, 16 had mCSCC and 10 had laCSCC. The median age was 73 years (52 to 88 years); 81% of patients were male; 92% of patients were White; the ECOG PS was 0 (38%) and 1 (62%); 58% of patients had received at least 1 prior anti-cancer systemic therapy; 92% of patients had received prior cancer-related surgery and 81% had received prior radiotherapy. One patient in the mCSCC group was dosed at 1 mg/kg. The rest received 3 mg/kg every 2 weeks.

With a median duration of follow-up of 13.3 months, the confirmed ORR was 50% (95% CI: 30, 70); all responses were PRs. The median time to response was 1.9 months (range: 1.7 to 7.3 months) and 85% of responders had a DOR ≥ 6 months.

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

The efficacy of LIBTAYO in combination with platinum-based chemotherapy was evaluated in Study 16113 (NCT03409614), a randomized, multi-center, double-blind, active-controlled trial in 466 patients with locally advanced NSCLC who were not candidates for surgical resection or definitive chemoradiation or with metastatic NSCLC who had not previously received systemic treatment for metastatic NSCLC. Patients were eligible regardless of tumor PD-L1 expression status.

Patients with EGFR, ALK or ROS1 genomic tumor aberrations; a medical condition that required systemic immunosuppression; or ongoing or recent autoimmune disease that required systemic therapy were ineligible. Patients with a history of brain metastases were eligible if they had been adequately treated and had neurologically returned to baseline for at least 2 weeks prior to randomization.

Randomization 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 were randomized (2:1) to receive either:

• LIBTAYO 350 mg intravenously (IV) every 3 weeks for 108 weeks plus platinum-based chemotherapy every 3 weeks for 4 cycles, or
• placebo IV every 3 weeks for 108 weeks plus platinum-based chemotherapy every 3 weeks for 4 cycles.

Platinum-based chemotherapy in either arm consisted of carboplatin AUC of 5 or 6 and paclitaxel 200 mg/m2; cisplatin 75 mg/m2 and paclitaxel 200 mg/m2; carboplatin AUC of 5 or 6 and pemetrexed 500 mg/m2; or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2. Maintenance pemetrexed was mandatory for patients with non-squamous NSCLC who received a pemetrexed-containing chemotherapy regimen in the first 4 treatment cycles.

Study treatment continued until RECIST 1.1-defined progressive disease, unacceptable toxicity, or 108 weeks. Assessment of tumor status was performed every 9 weeks during year 1 and every 12 weeks after year 1. The major efficacy outcome measure was overall survival (OS). Additional efficacy outcome measures were progression-free survival (PFS) and overall response rate (ORR) as assessed by blinded independent central review (BICR).

The study population characteristics were: median age of 63 years (range: 25 to 84), 40% age 65 or older; 84% male; 87% White, 13% Asian. Fifteen percent had Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 and 84% had ECOG PS 1; 85% had metastatic disease and 15% had stage IIIB or IIIC disease and were not candidates for surgical resection or definitive chemoradiation per investigator assessment; 57% had non-squamous and 43% had squamous histology; and 7% had history of treated brain metastases at baseline.

The trial demonstrated a statistically significant improvement in OS for patients randomized to LIBTAYO in combination with chemotherapy compared with placebo in combination with chemotherapy.

Efficacy results are presented in Table 12 and Figure 1.

Figure 1: Kaplan-Meier Curves for OS from Study 16113

First-line treatment of NSCLC with LIBTAYO as a single agent

The efficacy of LIBTAYO was evaluated in Study 1624 (NCT03088540), a randomized, multi-center, open-label, active-controlled trial in 710 patients with locally advanced NSCLC who were not candidates for surgical resection or definitive chemoradiation, or with metastatic NSCLC.

Only patients whose tumors had high PD-L1 expression [Tumor Proportion Score (TPS) ≥ 50%] as determined by an immunohistochemistry assay using the PD-L1 IHC 22C3 pharmDx kit and who had not received prior systemic treatment for metastatic NSCLC were eligible.

Patients with EGFR, ALK or ROS1 genomic tumor aberrations; a medical condition that required systemic immunosuppression; autoimmune disease that required systemic therapy within 2 years of treatment; or who had never smoked were ineligible. Patients with a history of brain metastases were eligible if they had been adequately treated and had neurologically returned to baseline for at least 2 weeks prior to randomization.

Randomization was stratified by histology (non-squamous vs squamous) and geographic region (Europe vs Asia vs Rest of world). Patients were randomized (1:1) to receive LIBTAYO 350 mg intravenously (IV) every 3 weeks for up to 108 weeks or a platinum-doublet chemotherapy regimen for 4 to 6 cycles followed by optional pemetrexed maintenance for patients with non-squamous histology who received a pemetrexed containing regimen.

Treatment with LIBTAYO continued until RECIST 1.1-defined progressive disease, unacceptable toxicity, or up to 108 weeks. Patients who experienced IRC-assessed RECIST 1.1-defined progressive disease on LIBTAYO therapy were permitted to continue treatment with LIBTAYO (up to an additional 108 weeks) with the addition of 4 cycles of histology-specific chemotherapy until further progression was observed. Of the 203 patients randomized to receive chemotherapy who had IRC-assessed RECIST 1.1- defined disease progression, 150 (74%) patients crossed over to treatment with LIBTAYO. Assessment of tumor status was performed every 9 weeks. The major efficacy outcome measures were overall survival (OS) and progression-free survival (PFS). An additional efficacy outcome measure was overall response rate (ORR).

The study population characteristics were: median age of 63 years (range: 31 to 84), 45% age 65 or older; 85% male; 86% White, 11% Asian; and 0.6% Black. Nine percent were Hispanic or Latino. Twenty-seven percent had ECOG PS 0 and 73% had ECOG PS 1; 84% had metastatic disease and 16% had stage IIIB or IIIC disease and were not candidates for surgical resection or definitive chemoradiation per investigator assessment; 56% had non-squamous and 44% had squamous histology; and 12% had history of treated brain metastases at baseline.

The trial demonstrated a statistically significant improvement in OS and PFS for patients randomized to LIBTAYO as compared with chemotherapy.

Efficacy results are presented in Table 13 and Figure 2.

Figure 2: Kaplan-Meier Curve for OS from Study 1624