Label: LIBTAYO- cemiplimab-rwlc injection
- NDC Code(s): 61755-008-01
- Packager: Regeneron Pharmaceuticals, Inc.
- Category: HUMAN PRESCRIPTION DRUG LABEL
- DEA Schedule: None
- Marketing Status: Biologic Licensing Application
Updated January 18, 2019
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- HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use LIBTAYO safely and effectively. See full prescribing information for LIBTAYO.
LIBTAYO ® (cemiplimab-rwlc) injection, for intravenous use
Initial U.S. Approval: 09/2018
INDICATIONS AND USAGE
LIBTAYO is a programmed death receptor-1 (PD-1) blocking antibody indicated for the treatment of patients with metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC who are not candidates for curative surgery or curative radiation. (1)
DOSAGE AND ADMINISTRATION
The recommended dosage of LIBTAYO is 350 mg as an intravenous infusion over 30 minutes every 3 weeks. (2.1)
DOSAGE FORMS AND STRENGTHS
Injection: 350 mg/7 mL (50 mg/mL) solution in a single-dose vial. (3)
WARNINGS AND PRECAUTIONS
- Severe and Fatal Immune-Mediated Adverse Reactions: Immune-mediated adverse reactions can occur in any organ system or tissue, including the following: immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatitis, immune-mediated endocrinopathies, immune-mediated dermatologic adverse reactions and immune-mediated nephritis and renal dysfunction. Monitor for symptoms and signs of immune-mediated adverse reactions. Evaluate clinical chemistries, including liver and thyroid function, at baseline and periodically during treatment. Withhold or permanently discontinue LIBTAYO and administer corticosteroids based on the severity of reaction. (2.2, 5.1)
- Infusion-Related Reactions: Interrupt, slow the rate of infusion or permanently discontinue based on severity of reaction. (2.2, 5.2)
- Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and use of effective contraception. (5.3, 8.1, 8.3)
Most common adverse reactions (incidence ≥ 20%) were fatigue, rash and diarrhea. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Regeneron at 1-877-542-8296 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
USE IN SPECIFIC POPULATIONS
Lactation: Advise not to breastfeed. (8.2)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
- FULL PRESCRIBING INFORMATION: CONTENTS*
- Sections or subsections omitted from the full prescribing information are not listed.
- 1 INDICATIONS AND USAGE
LIBTAYO is indicated for the treatment of patients with metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC who are not candidates for curative surgery or curative radiation.Close
- 2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage
The recommended dosage of LIBTAYO is 350 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity.
2.2 Dosage Modifications for Adverse Reactions
Withhold or discontinue LIBTAYO to manage adverse reactions as described in Table 1. No dose reduction of LIBTAYO is recommended.
Table 1: Recommended Dosage Modifications for Adverse Reactions Adverse Reaction Severity* LIBTAYO Dosage Modifications Severe and Fatal Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)] Pneumonitis Grade 2 Withhold† Grades 3 or 4 Permanently discontinue Colitis Grades 2 or 3 Withhold† Grade 4 Permanently discontinue Hepatitis If AST or ALT increases to more than 3 and up to 10 times the upper limit of normal (ULN) or if total bilirubin increases up to 3 times the ULN. Withhold† If AST or ALT increases to more than 10 times the ULN or total bilirubin increases to more than 3 times the ULN Permanently discontinue Endocrinopathies Grades 2, 3, or 4 Withhold if clinically necessary Other immune-mediated adverse reactions involving a major organ Grade 3 Withhold† Grade 4 Permanently discontinue Recurrent or persistent immune mediated adverse reactions
- Recurrent Grade 3 or 4
- Grade 2 or 3 persistent for 12 weeks or longer after last LIBTAYO dose
- Requirement for 10 mg per day or greater prednisone or equivalent lasting 12 weeks or longer after last LIBTAYO dose
Permanently discontinue Other Adverse Reactions Infusion-related reactions [see Warnings and Precautions (5.2)] Grade 1 or 2 Interrupt or slow the rate of infusion Grade 3 or 4 Permanently discontinue
2.3 Preparation and Administration
- Visually inspect for particulate matter and discoloration prior to administration. LIBTAYO is a clear to slightly opalescent, colorless to pale yellow solution that may contain trace amounts of translucent to white particles. Discard the vial if the solution is cloudy, discolored or contains extraneous particulate matter other than trace amounts of translucent to white particles.
- 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.
- 3 DOSAGE FORMS AND STRENGTHS
Injection: 350 mg/7 mL (50 mg/mL), clear to slightly opalescent, colorless to pale yellow solution that may contain trace amounts of translucent to white particles in a single-dose vial.Close
- 4 CONTRAINDICATIONS
- 5 WARNINGS AND PRECAUTIONS
5.1 Severe and Fatal Immune-Mediated Adverse Reactions
LIBTAYO is a monoclonal antibody that belongs to a class of drugs that binds to the programmed death receptor-1 (PD-1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response with the potential for breaking of peripheral tolerance and induction of immune-mediated adverse reactions. Important immune-mediated adverse reactions listed under Warnings and Precautions may not be inclusive of all possible immune-mediated reactions.
Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies.
Early identification and management are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor for symptoms and signs of immune-mediated adverse reactions. Evaluate clinical chemistries, including liver tests and thyroid function tests, at baseline and periodically during treatment. Institute medical management promptly to include specialty consultation as appropriate.
In general, withhold LIBTAYO for Grade 3 or 4 and certain Grade 2 immune-mediated adverse reactions. Permanently discontinue LIBTAYO for Grade 4 and certain Grade 3 immune-mediated adverse reactions [see Dosage and Administration (2.2)]. For Grade 3 or 4 and certain Grade 2 immune-mediated adverse reactions, administer corticosteroids (1 to 2 mg/kg/day prednisone or equivalent) or other appropriate therapy until improvement to Grade 1 or less followed by a corticosteroid taper over one month [see Dosage and Administration (2.2)]. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reaction is not controlled with corticosteroids. Institute hormone replacement therapy for endocrinopathies as warranted.
Immune-mediated pneumonitis occurred in 2.4% of 534 patients receiving LIBTAYO, including Grade 5 (0.2%), Grade 3 (0.7%) and Grade 2 (1.3%) [see Adverse Reactions (6.1)]. Pneumonitis led to permanent discontinuation of LIBTAYO in 1.3% of patients. Systemic corticosteroids were required in all patients with pneumonitis, including 85% who received prednisone ≥ 40 mg per day or equivalent. Pneumonitis resolved in 62% of patients.
Immune-mediated colitis occurred in 0.9% of 534 patients receiving LIBTAYO, including Grade 3 (0.4%) and Grade 2 (0.6%) [see Adverse Reactions (6.1)]. Colitis led to permanent discontinuation of LIBTAYO in 0.2% of patients. Systemic corticosteroids were required in all patients with colitis, including 60% who received prednisone ≥ 40 mg per day or equivalent. Colitis resolved in 80% of patients.
Immune-mediated hepatitis occurred in 2.1% of 534 patients receiving LIBTAYO, including Grade 5 (0.2%), Grade 4 (0.2%), and Grade 3 (1.7%) [see Adverse Reactions (6.1)]. Hepatitis led to permanent discontinuation of LIBTAYO in 0.9% of patients. Systemic corticosteroids were required in all patients with hepatitis, including 91% who received prednisone ≥ 40 mg per day or equivalent. Hepatitis resolved in 64% of patients.
Adrenal insufficiency occurred in 0.4% of 534 patients receiving LIBTAYO, including Grade 3 (0.2%), and Grade 2 (0.2%) [see Adverse Reactions (6.1)].
Hypophysitis, which can result in hypopituitarism, occurred in 0.2% of 534 patients receiving LIBTAYO, which consisted of one patient with Grade 3 hypophysitis.
Hypothyroidism occurred in 6% of 534 patients receiving LIBTAYO, including Grade 3 (0.2%) and Grade 2 (5.6%). No patients discontinued hormone replacement therapy.
Hyperthyroidism occurred in 1.5% of 534 patients receiving LIBTAYO, including Grade 3 (0.2%) and Grade 2 (0.4%). Hyperthyroidism resolved in 38% of patients.
Immune-Mediated Nephritis with Renal Dysfunction
Immune-mediated nephritis occurred in 0.6% of 534 patients receiving LIBTAYO, including Grade 3 (0.4%) and Grade 2 (0.2%) [see Adverse Reactions (6.1)]. Nephritis led to permanent discontinuation of LIBTAYO in 0.2% of patients. Systemic corticosteroids were required in all patients with nephritis, including 67% who received prednisone ≥ 40 mg per day or equivalent. Nephritis resolved in all patients.
Immune-Mediated Dermatologic Adverse Reactions
Immune-mediated dermatologic reactions, including erythema multiforme and pemphigoid, occurred in 1.7% of 534 patients receiving LIBTAYO, including Grade 3 (1.1%) and Grade 2 (0.6%) [see Adverse Reactions (6.1)]. In addition, SJS and TEN have been observed with LIBTAYO and with other products in this class. Systemic corticosteroids were required in all patients with dermatologic reactions, including 89% who received prednisone ≥ 40 mg per day or equivalent. Dermatologic reactions resolved in 33% of patients. Approximately 22% of patients had recurrence of dermatologic reactions after re-initiation of LIBTAYO.
Other Immune-Mediated Adverse Reactions
The following clinically significant immune-mediated adverse reactions occurred at an incidence of < 1% in 534 patients who received LIBTAYO [see Adverse Reactions (6.1)] 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.
Neurological: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome / myasthenia gravis, Guillain-Barre syndrome, nerve paresis, autoimmune neuropathy
Cardiovascular: Myocarditis, pericarditis, vasculitides
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 corticosteroids to reduce the risk of permanent vision loss.
Gastrointestinal: Pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis
Musculoskeletal and Connective Tissue: Myositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatica
Hematological and Immunological: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection
5.2 Infusion-Related Reactions
Severe infusion-related reactions (Grade 3) occurred in 0.2% of patients receiving LIBTAYO [see Adverse Reactions (6.1)]. Monitor patients for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion or permanently discontinue LIBTAYO based on severity of reaction [see Dosage and Administration (2.2)].
5.3 Embryo-Fetal Toxicity
Based on its mechanism of action, LIBTAYO can cause fetal harm when administered to a pregnant woman. 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. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with LIBTAYO and for at least 4 months after the last dose [see Use in Specific Populations (8.1, 8.3)].
- 6 ADVERSE REACTIONS
The following serious adverse reactions are described elsewhere in the labeling.
- Severe and Fatal Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)]
- Infusion-Related Reactions [see Warnings and Precautions (5.2)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described in WARNINGS AND PRECAUTIONS reflect exposure to LIBTAYO in 534 patients in two open-label, single-arm, multicohort studies (Study 1423 and Study 1540), including 98 patients with metastatic (nodal or distant) CSCC, 65 patients with locally advanced CSCC, and 371 patients with other advanced solid tumors. LIBTAYO as a single agent or in combination with chemotherapy or radiation was administered intravenously at doses of 1 mg/kg every 2 weeks (n=27), 3 mg/kg every 2 weeks (n=446), 3 mg/kg every 3 weeks (n=12), 10 mg/kg every 2 weeks (n=6), 200 mg every 2 weeks (n=20) or 350 mg every 3 weeks (n=23). Among the 534 patients, 38% were exposed for ≥ 6 months and 16% were exposed for ≥ 12 months.
The data described below reflect exposure to LIBTAYO in 163 patients with advanced CSCC (metastatic or locally advanced disease) in Study 1423 and Study 1540 [see Clinical Studies (14)]. Patients received LIBTAYO 1 mg/kg every 2 weeks (n=1), 3 mg/kg every 2 weeks (n=139) or 350 mg every 3 weeks (n=23) as an intravenous infusion until disease progression, unacceptable toxicity, or completion of planned treatment. The median duration of exposure was 20 weeks (3 days to 1.4 years).
The safety population characteristics were: median age of 71 years (38 to 96 years), 85% male, 96% white, and ECOG performance score (PS) of 0 (44%) or 1 (56%).
The most common adverse reactions reported in at least 20% of patients were fatigue, rash and diarrhea. The most common Grade 3-4 adverse reactions (≥ 2%) were cellulitis, sepsis, hypertension, pneumonia, musculoskeletal pain, skin infection, urinary tract infection and fatigue. LIBTAYO was permanently discontinued due to adverse reactions in 5% of patients; adverse reactions resulting in permanent discontinuation were pneumonitis, autoimmune myocarditis, hepatitis, aseptic meningitis, complex regional pain syndrome, cough, and muscular weakness. Serious adverse reactions occurred in 28% of patients. Serious adverse reactions that occurred in at least 2% of patients were cellulitis, sepsis, pneumonia, pneumonitis and urinary tract infection.
Table 2 summarizes the adverse reactions that occurred in ≥ 10% of patients and Table 3 summarizes Grade 3 and 4 laboratory abnormalities worsening from baseline in ≥ 1% of patients receiving LIBTAYO.
Table 2: Adverse Reactions in ≥ 10% of Patients with Advanced CSCC Receiving LIBTAYO in Study 1423 and Study 1540 Adverse Reactions LIBTAYO
- Rash is a composite term that includes rash maculopapular, rash, dermatitis, rash generalized, dermatitis bullous, drug eruption, erythema, rash erythematous, rash macular, rash pruritic, and skin reaction.
- Pruritus is a composite term that includes pruritus and pruritus allergic.
- Diarrhea is a composite term that includes diarrhea and colitis.
- Fatigue is a composite term that includes fatigue and asthenia.
- Musculoskeletal pain is a composite term that includes: musculoskeletal pain, back pain, myalgia, neck pain, pain in extremity.
Skin and Subcutaneous Tissue Rash* 25 1.2 Pruritus† 15 0 Gastrointestinal Diarrhea‡ 22 0.6 Nausea 19 0 Constipation 12 0.6 General and Administration Site Fatigue§ 29 2 Musculoskeletal and Connective Tissue Musculoskeletal pain¶ 17 3 Metabolism and Nutrition Decreased appetite 10 0 Table 3: Grade 3 or 4 Laboratory Abnormalities Worsening from Baseline in ≥ 1% of Patients with Advanced CSCC Receiving LIBTAYO in Study 1423 and Study 1540 Laboratory Abnormality Grade 3-4 (%)*
- Percentages are based on the number of patients with at least 1 post-baseline value available for that parameter.
Chemistry Increased aspartate aminotransferase 3 Increased INR 2 Hypoalbuminemia 1 Hematology Lymphopenia 7 Anemia 2 Electrolytes Hypophosphatemia 4 Hyponatremia 3 Hypercalcemia 1
As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to cemiplimab-rwlc in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
Anti-drug antibodies (ADA) were tested in 398 of 534 patients who received LIBTAYO and the incidence of cemiplimab-rwlc treatment-emergent ADAs was 1.3% using an electrochemiluminescent (ECL) bridging immunoassay; 0.3% were persistent ADA responses. In the patients who developed anti-cemiplimab-rwlc antibodies, there was no evidence of an altered pharmacokinetic profile of cemiplimab-rwlc.
- 8 USE IN SPECIFIC POPULATIONS
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.
Animal reproduction studies have not been conducted with LIBTAYO to evaluate its effect on reproduction and fetal development. A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. In murine models of pregnancy, blockade of PD-L1 signaling has been shown to disrupt tolerance to the fetus and to result in an increase in fetal loss; therefore, potential risks of administering LIBTAYO during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, there were no malformations related to the blockade of PD-1/PD-L1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 and PD-L1 knockout mice. Based on its mechanism of action, fetal exposure to cemiplimab-rwlc may increase the risk of developing immune-mediated disorders or altering the normal immune response.
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.
8.3 Females and Males of Reproductive Potential
Verify pregnancy status in females of reproductive potential prior to initiating LIBTAYO [see Use in Specific Populations (8.1)].
LIBTAYO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].
8.4 Pediatric Use
The safety and effectiveness of LIBTAYO have not been established in pediatric patients.
8.5 Geriatric Use
Of the 163 patients with metastatic and locally advanced CSCC who received LIBTAYO in clinical studies, 72% were 65 years or older and 37% were 75 years or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.
- 11 DESCRIPTION
Cemiplimab-rwlc is a human programmed death receptor-1 (PD-1) blocking antibody. Cemiplimab-rwlc is a recombinant human IgG4 monoclonal antibody that binds to PD-1 and blocks its interaction with PD-L1 and PD-L2. Cemiplimab-rwlc is produced by recombinant DNA technology in Chinese hamster ovary (CHO) cell suspension culture. Cemiplimab-rwlc has an approximate molecular weight of 146 kDa.
LIBTAYO (cemiplimab-rwlc) injection for intravenous use is a sterile, clear to slightly opalescent, colorless to pale yellow solution with a pH of 6. The solution may contain trace amounts of translucent to white particles.
Each vial contains 350 mg of cemiplimab-rwlc. Each mL contains cemiplimab-rwlc 50 mg, L-histidine (0.74 mg), L-histidine monohydrochloride monohydrate (1.1 mg), sucrose (50 mg), L-proline (15 mg), Polysorbate 80 (2 mg), and Water for Injection, USP.Close
- 12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Binding of the PD-1 ligands PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors.
Cemiplimab-rwlc is a recombinant human immunoglobulin G4 (IgG4) monoclonal antibody that binds to PD-1 and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth.
Cemiplimab-rwlc pharmacokinetic (PK) data were collected in 505 patients with various solid tumors, including 135 patients with CSCC. The PK of cemiplimab-rwlc was linear and dose proportional in the dose range of 1 mg/kg to 10 mg/kg administered intravenously every two weeks and 350 mg intravenously administered every three weeks.
After a dose of 350 mg LIBTAYO administered intravenously every 3 weeks, median steady-state concentrations (CV%) of cemiplimab-rwlc ranged between a maximum concentration (Cmax,ss) of 166 mcg/mL (28%) and a minimum concentration (Cmin,ss) of 59 mcg/mL (48%). Steady-state exposure is achieved after approximately 4 months of treatment.
Cemiplimab-rwlc clearance (CV%) after the first dose is 0.32 L/day (39%) and decreases over time by 34%, resulting in a steady-state clearance (CLss) (CV%) of 0.21 L/day (39%). The elimination half-life (CV%) at steady state is 19 days (30%).
The following factors have no clinically important effect on the exposure of cemiplimab-rwlc: age (27 to 96 years), sex, body weight (31 to 156 kg), race (White, Black, Asian and other), cancer type, albumin level (22 to 48 g/L), renal function (creatinine clearance determined by Cockcroft-Gault 25 mL/min or greater) and hepatic function (total bilirubin 0.35 to 45 µmol/L). LIBTAYO has not been studied in patients with moderate or severe hepatic impairment.
- 13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No studies have been performed to assess the potential of cemiplimab-rwlc for carcinogenicity or genotoxicity.
In a 3-month repeat-dose toxicology study in sexually mature cynomolgus monkeys, there were no cemiplimab-rwlc-related effects on fertility parameters (menstrual cycle, semen analysis, or testicular measurements) or in male or female reproductive organs at doses up to the highest dose tested, 50 mg/kg/week (approximately 5.5 to 25.5 times the human exposure based on AUC at the clinical dose of 350 mg once every 3 weeks).
13.2 Animal Toxicology and/or Pharmacology
In animal models, inhibition of PD-L1/PD-1 signaling increased the severity of some infections and enhanced inflammatory responses. M. tuberculosis–infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-L1 and PD-1 knockout mice and mice receiving PD-L1 blocking antibody have also shown decreased survival following infection with lymphocytic choriomeningitis virus.
- 14 CLINICAL STUDIES
The efficacy of LIBTAYO in patients with metastatic (nodal or distant) cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC who were not candidates for curative surgery or curative radiation was evaluated in two open-label, multi-center, non-randomized, multicohort studies: Study 1423 (NCT02383212) and 1540 (NCT02760498). Both studies excluded patients with autoimmune disease that required systemic therapy with immunosuppressant agents within 5 years; history of solid organ transplant; prior treatment with anti–PD-1/PD-L1 blocking antibodies or other immune checkpoint inhibitor therapy; infection with HIV, hepatitis B or hepatitis C; or ECOG performance score (PS) ≥ 2.
Patients received LIBTAYO 3 mg/kg intravenously every 2 weeks for up to 48 weeks in Study 1423 or up to 96 weeks in Study 1540. Treatment continued until progression of disease, unacceptable toxicity, or completion of planned treatment. Tumor response assessments were performed every 8 weeks. The major efficacy outcome measures were confirmed objective response rate (ORR), as assessed by independent central review (ICR) and ICR-assessed duration of response. For patients with metastatic CSCC without externally visible target lesions, ORR was determined by Response Evaluation Criteria in Solid Tumors (RECIST 1.1). For patients with externally visible target lesions (locally advanced and metastatic CSCC), ORR was determined by a composite endpoint that integrated ICR assessments of radiologic data (RECIST 1.1) and digital medical photography (WHO criteria). The efficacy analysis was conducted when all patients had the opportunity for at least 6 months of follow-up.
A total of 26 patients with CSCC were enrolled in Study 1423 and 82 patients were enrolled in Study 1540. Of these 108 patients, 75 had metastatic CSCC and 33 had locally advanced CSCC. The median age was 71 years (38 to 96 years); 85% were male; 97% were White; 43% had ECOG PS 0 and 57% had ECOG PS 1; 50% received at least one prior anti-cancer systemic therapy; 96% received prior cancer-related surgery; and 79% received prior radiotherapy. Among patients with metastatic CSCC, 69% had distant metastases and 31% had only nodal metastases.
Efficacy results are presented in Table 4.
Table 4: Efficacy Results for Study 1423 and Study 1540 Efficacy Endpoints* Metastatic CSCC
N = 75
Locally Advanced CSCC
N = 33
N = 108
CI: confidence interval; +: Denotes ongoing at last assessment Confirmed Objective Response Rate Objective response rate 46.7% 48.5% 47.2% (95% CI) (35.1%, 58.6%) (30.8%, 66.5%) (37.5%, 57.1%) Complete response (CR) rate† 5.3% 0% 3.7% Partial response (PR) rate 41.3% 48.5% 43.5% Duration of Response Range in months 2.8 – 15.2+ 1 – 12.9+ 1 – 15.2+ Patients with DOR ≥ 6 months, n % 21 (60%) 10 (63%) 31 (61%)
- 16 HOW SUPPLIED/STORAGE AND HANDLING
LIBTAYO (cemiplimab-rwlc) injection is a clear to slightly opalescent, colorless to pale yellow solution that may contain trace amounts of translucent to white particles. It is supplied in a carton containing 1 single-dose vial of:
- 350 mg/7 mL (50 mg/mL) (NDC 61755-008-01)
Store in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton. Protect from light. Do not freeze or shake.
- 17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Immune-Mediated Adverse Reactions
Advise patients that LIBTAYO can cause immune-mediated adverse reactions including the following [see Warnings and Precautions (5.1)]:
- Pneumonitis: Advise patients to contact their healthcare provider immediately for signs or symptoms of pneumonitis, including new or worsening symptoms of cough, chest pain, or shortness of breath.
- Colitis: Advise patients to contact their healthcare provider immediately for signs or symptoms of colitis, including diarrhea, blood or mucus in stools, or severe abdominal pain.
- Hepatitis: Advise patients to contact their healthcare provider immediately for signs or symptoms of hepatitis.
- Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, or type 1 diabetes mellitus.
- Nephritis: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis.
- Dermatologic Adverse Reactions: Advise patients to contact their healthcare provider immediately if they develop a new rash.
Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.2)].
Advise females of reproductive potential that LIBTAYO can cause harm to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1, 8.3)].
Advise females of reproductive potential to use effective contraception during treatment and for at least 4 months after the last dose of LIBTAYO [see Use in Specific Populations (8.3)].
Advise female patients not to breastfeed while taking LIBTAYO and for at least 4 months after the last dose [see Use in Specific Populations (8.2)].
- SPL UNCLASSIFIED SECTION
Regeneron Pharmaceuticals, Inc.
777 Old Saw Mill River Road
Tarrytown, NY 10591-6707
U.S. License No. 1760
Regeneron Pharmaceuticals, Inc. (Tarrytown, NY 10591) and
sanofi-aventis U.S. LLC (Bridgewater, NJ 08807)
©2019 Regeneron Pharmaceuticals, Inc. / sanofi-aventis U.S. LLC.
All rights reserved.
- MEDICATION GUIDE
- PRINCIPAL DISPLAY PANEL - 350 mg/7 mL Vial Carton
350 mg/7 mL (50 mg/mL)
For Intravenous Infusion After Dilution
Discard unused portion.
Do not use vial if seal is broken or missing.
Dispense the enclosed Medication Guide to each patient.
REGENERON ∣ SANOFI GENZYME
- INGREDIENTS AND APPEARANCE
Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:61755-008 Route of Administration INTRAVENOUS Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CEMIPLIMAB (UNII: 6QVL057INT) (CEMIPLIMAB - UNII:6QVL057INT) CEMIPLIMAB 50 mg in 1 mL Inactive Ingredients Ingredient Name Strength HISTIDINE (UNII: 4QD397987E) 0.74 mg in 1 mL HISTIDINE MONOHYDROCHLORIDE MONOHYDRATE (UNII: X573657P6P) 1.1 mg in 1 mL PROLINE (UNII: 9DLQ4CIU6V) 15 mg in 1 mL POLYSORBATE 80 (UNII: 6OZP39ZG8H) 2 mg in 1 mL SUCROSE (UNII: C151H8M554) 50 mg in 1 mL WATER (UNII: 059QF0KO0R) Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:61755-008-01 1 in 1 CARTON 09/28/2018 1 7 mL in 1 VIAL, SINGLE-USE; Type 0: Not a Combination Product Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA761097 09/28/2018 Labeler - Regeneron Pharmaceuticals, Inc. (194873139) Establishment Name Address ID/FEI Business Operations Regeneron Pharmaceuticals, Inc. 945589711 ANALYSIS(61755-008) , API MANUFACTURE(61755-008) , MANUFACTURE(61755-008)