Drug Detail:Libtayo (Cemiplimab-rwlc [ se-mip-li-mab ])
Drug Class: Anti-PD-1 and PD-L1 monoclonal antibodies (immune checkpoint inhibitors)
Highlights of Prescribing Information
LIBTAYO® (cemiplimab-rwlc) injection, for intravenous use
Initial U.S. Approval: 09/2018
Indications and Usage for Libtayo Injection
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)
Libtayo Injection 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)
Contraindications
None. (4)
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)
Adverse Reactions/Side Effects
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.
Revised: 3/2019
Full Prescribing Information
1. Indications and Usage for Libtayo Injection
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.
2. Libtayo Injection 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.
| 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 |
| 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.
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.
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.
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/Side Effects
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.
| Adverse Reactions | LIBTAYO N=163 |
|
|---|---|---|
| All Grades % | Grade 3-4 % |
|
|
||
| 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 |
| Laboratory Abnormality | Grade 3-4 (%)* |
|---|---|
|
|
| Chemistry | |
| Increased aspartate aminotransferase | 3 |
| Increased INR | 2 |
| Hypoalbuminemia | 1 |
| Hematology | |
| Lymphopenia | 7 |
| Anemia | 2 |
| Electrolytes | |
| Hypophosphatemia | 4 |
| Hyponatremia | 3 |
| Hypercalcemia | 1 |
6.2 Immunogenicity
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
11. Libtayo Injection 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.
12. Libtayo Injection - 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.
12.3 Pharmacokinetics
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.
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.
| Efficacy Endpoints* | Metastatic CSCC N = 75 | Locally Advanced CSCC N = 33 | Combined CSCC 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 is Libtayo Injection supplied
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)
17. Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
| This Medication Guide has been approved by the U.S. Food and Drug Administration. | Issued: September/2018 | ||
| MEDICATION GUIDE
LIBTAYO® (Lib-TIE-oh) (cemiplimab-rwlc) injection |
|||
| What is the most important information I should know about LIBTAYO?
LIBTAYO is a medicine that may treat a type of skin cancer by working with your immune system. LIBTAYO can cause your immune system to attack normal organs and tissues in any area of your body and can affect the way they work. These problems can sometimes become severe or life-threatening and can lead to death. These problems may happen anytime during treatment or even after your treatment has ended. Call or see your healthcare provider right away if you develop any symptoms of the following problems or these symptoms get worse: |
|||
| Lung problems (pneumonitis). Signs and symptoms of pneumonitis may include: | |||
|
|
|
|
| Intestinal problems (colitis) that can lead to tears or holes in your intestine. Signs and symptoms of colitis may include: | |||
|
|||
| Liver problems (hepatitis). Signs and symptoms of hepatitis may include: | |||
|
|
||
| Hormone gland problems (especially the adrenal glands, pituitary, thyroid, and pancreas). Signs and symptoms that your hormone glands are not working properly may include: | |||
|
|
||
| Kidney problems, including nephritis and kidney failure. Signs of these problems may include: | |||
|
|
||
| Skin problems. Signs of these problems may include: | |||
|
|
||
| Problems in other organs. Signs of these problems may include: | |||
|
|
||
|
|||
| Rejection of a transplanted organ. Your doctor should tell you what signs and symptoms you should report and monitor you, depending on the type of organ transplant that you have had. | |||
| Infusion (IV) reactions that can sometimes be severe and life-threatening. Signs of these problems may include: | |||
|
|
||
| Getting medical treatment right away may help keep these problems from becoming more serious. Your healthcare provider will check you for these problems during your treatment with LIBTAYO. Your healthcare provider may treat you with corticosteroid or hormone replacement medicines. Your healthcare provider may delay or completely stop treatment with LIBTAYO if you have severe side effects. | |||
| What is LIBTAYO?
LIBTAYO is a prescription medicine used to treat people with a type of skin cancer called cutaneous squamous cell carcinoma (CSCC) that has spread or cannot be cured by surgery or radiation. It is not known if LIBTAYO is safe and effective in children. |
|||
| Before you receive LIBTAYO, tell your healthcare provider about all your medical conditions, including if you: | |||
|
|||
| Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. | |||
| How will I receive LIBTAYO? | |||
|
|||
| What are the possible side effects of LIBTAYO? LIBTAYO can cause serious side effects, including: |
|||
|
|||
| The most common side effects of LIBTAYO include tiredness, rash and diarrhea. These are not all the possible side effects of LIBTAYO. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. |
|||
| General information about the safe and effective use of LIBTAYO.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. If you would like more information about LIBTAYO, talk with your healthcare provider. You can ask your healthcare provider for information about LIBTAYO that is written for health professionals. |
|||
| What are the ingredients of LIBTAYO?
Active ingredient: cemiplimab-rwlc Inactive ingredients: L-histidine, L-histidine monohydrochloride monohydrate, sucrose, L-proline, Polysorbate 80, and Water for Injection, USP. Manufactured by: Regeneron Pharmaceuticals, Inc. 777 Old Saw Mill River Road Tarrytown, NY 10591-6707 U.S. License No. 1760 Marketed by: Regeneron Pharmaceuticals, Inc. (Tarrytown, NY 10591) and sanofi-aventis U.S. LLC (Bridgewater, NJ 08807) For more information, call 1-877-542-8296 or go to www.libtayo.com ©2019 Regeneron Pharmaceuticals, Inc/sanofi-aventis U.S. LLC. All rights reserved. |
|||
| LIBTAYO
cemiplimab-rwlc injection |
||||||||||||||||||||
|
||||||||||||||||||||
|
||||||||||||||||||||
|
||||||||||||||||||||
|
||||||||||||||||||||
|
||||||||||||||||||||
| 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) | |
