DESCRIPTION SECTION

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, preservative-free, 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.

CLINICAL PHARMACOLOGY SECTION

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.

12.2 Pharmacodynamics

Cemiplimab exposure-response relationships and the time course of pharmacodynamic response are not fully characterized.

12.3 Pharmacokinetics

Cemiplimab-rwlc pharmacokinetic data were collected in 1063 patients with various solid tumors. The pharmacokinetics of cemiplimab-rwlc were linear and dose proportional in the dose range of 1 mg/kg to 10 mg/kg LIBTAYO administered intravenously every 2 weeks.

At 350 mg every 3 weeks, the mean cemiplimab-rwlc concentrations (coefficient of variation, CV%) at steady-state ranged between a minimum concentration of 59 mg/L (47%) and a maximum concentration of 171 mg/L (27%). Steady-state exposure is achieved after 4 months of treatment.

In patients with CSCC, cemiplimab-rwlc steady-state exposure at 350 mg every 3 weeks was comparable to the exposure at 3 mg/kg every 2 weeks.

Distribution

The volume of distribution of cemiplimab-rwlc at steady state is 5.9 L (29%).

Elimination

Cemiplimab-rwlc clearance (CV%) after the first dose is 0.25 L/day (41%) and decreases over time by 11%, resulting in a steady-state clearance (CLss) (CV%) of 0.22 L/day (44%). The elimination half-life (CV%) at steady state is 22 days (42%).

Specific Populations

The following factors have no clinically important effect on the exposure of cemiplimab-rwlc in 1063 patients: 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=932), Asian (N=47), Black (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 (total bilirubin greater than 3.0 times the ULN).

12.6 Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of cemiplimab-rwlc or of other cemiplimab products.

During the treatment period ranging from 8 to 19 months in 5 clinical studies, the incidence of anti-cemiplimab-rwlc antibodies in LIBTAYO-treated patients was 2% (22/1029).

There was no identified clinically significant effect of anti-cemiplimab-rwlc antibodies on PK of LIBTAYO over the treatment duration ranging from 8 months to 19 months. Because of the low occurrence of anti-drug antibodies, the effect of these antibodies on the pharmacodynamics, safety, and/or effectiveness of LIBTAYO is unknown.

DOSAGE & ADMINISTRATION SECTION

Highlight: Administer LIBTAYO as an intravenous infusion over 30 minutes after dilution. (2.2)

• CSCC and BCC: 350 mg every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months. (2.2)
• NSCLC: 350 mg every 3 weeks until disease progression or unacceptable toxicity (2.2)

2 DOSAGE AND ADMINISTRATION

2.1 Patient Selection for NSCLC

Select patients with locally advanced or metastatic NSCLC for treatment with LIBTAYO as a single agent based on PD-L1 expression on tumor cells [see Clinical Studies (14.3)].

Information on FDA-approved tests for the detection of PD-L1 expression is available at: http://www.fda.gov/CompanionDiagnostics.

2.2 Recommended Dosage

Locally Advanced or Metastatic Basal Cell Carcinoma and Locally Advanced or Metastatic Cutaneous Squamous Cell Carcinoma

The recommended dosage of LIBTAYO is 350 mg administered as an intravenous infusion every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months.

Non-Small Cell Lung Cancer

The recommended dosage of LIBTAYO is 350 mg administered as an intravenous infusion every 3 weeks until disease progression or unacceptable toxicity.

Refer to the Prescribing Information for the agents administered in combination with LIBTAYO for recommended dosing information, as appropriate.

2.3 Dosage Modifications for Adverse Reactions

No dose reduction for LIBTAYO is recommended. In general, withhold LIBTAYO for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue LIBTAYO for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone equivalent per day within 12 weeks of initiating steroids.

Dosage modifications for LIBTAYO for adverse reactions that require management different from these general guidelines are summarized in Table 1.

2.4 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.

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 under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 10 days 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.

DOSAGE FORMS & STRENGTHS SECTION

Highlight: Injection: 350 mg/7 mL (50 mg/mL) solution in a single-dose vial. (3)

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.

CONTRAINDICATIONS SECTION

Highlight: None. (4)

4 CONTRAINDICATIONS

None.

USE IN SPECIFIC POPULATIONS SECTION

Highlight: Lactation: Advise not to breastfeed. (8.2)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

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

Animal Data

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.

8.2 Lactation

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.

8.3 Females and Males of Reproductive Potential

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)].

Females

Advise females of reproductive potential to use effective contraception during treatment with LIBTAYO and for at least 4 months after the last dose.

8.4 Pediatric Use

The safety and effectiveness of LIBTAYO have not been established in pediatric patients.

8.5 Geriatric Use

LIBTAYO as a Single Agent

Of the 1281 patients who received LIBTAYO as a single agent in clinical studies, 26% 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 358 patients with mCSCC or laCSCC who received LIBTAYO as a single agent in Study 1540, 30% were 65 years up to 75 years and 48% were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients.

Of the 138 patients with BCC who received LIBTAYO as a single agent in Study 1620, 27% were 65 years up to 75 years, and 31% 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.

ADVERSE REACTIONS SECTION

Highlight: LIBTAYO as a Single Agent:

• The most common adverse reactions (≥15%) are fatigue, musculoskeletal pain, rash, diarrhea, and anemia. (6.1)

LIBTAYO in Combination with Platinum-based Chemotherapy

• The most common adverse reactions (≥15%) are alopecia, musculoskeletal pain, nausea, fatigue, peripheral neuropathy, and decreased appetite. (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.

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)]
• Complications of Allogeneic HSCT [see Warnings and Precautions (5.3)]

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 as a single agent in 1281 patients in three open-label, single-arm, multicohort studies, and two open-label randomized multi-center studies. These studies included 384 patients with advanced CSCC (Studies 1540 and 1423), 138 patients with advanced BCC (Study 1620), 355 patients with NSCLC (Study 1624), and 404 patients with other advanced solid tumors. LIBTAYO was administered intravenously at doses of 3 mg/kg every 2 weeks (n=235), 350 mg every 3 weeks (n=1014), or other doses (n=32). Among the 1281 patients, 53% were exposed for 6 months or longer and 26% were exposed for one year or longer. In this pooled safety population, the most common adverse reactions (≥15%) were fatigue, musculoskeletal pain, rash, diarrhea, and anemia. The most common Grade 3-4 laboratory abnormalities (≥2%) were lymphopenia, anemia, hyponatremia, hypophosphatemia, increased aspartate aminotransferase, hypokalemia, hyperkalemia, and increased alanine aminotransferase.

In addition, the data below reflect exposure to LIBTAYO in combination with platinum-based chemotherapy in 312 patients with NSCLC enrolled in a randomized, active controlled trial (Study 16113).

Cutaneous Squamous Cell Carcinoma (CSCC)

Study 1540

The safety of LIBTAYO was evaluated in 358 patients with advanced CSCC (metastatic or locally advanced disease) in Study 1540 [see Clinical Studies (14.1)]. Of these 358 patients, 213 had mCSCC (nodal or distant) and 145 had laCSCC. Patients received LIBTAYO 3 mg/kg every 2 weeks (n=137) or 350 mg every 3 weeks (n=221) as an intravenous infusion until disease progression, unacceptable toxicity, or completion of planned treatment. The median duration of exposure was 40 weeks (1 week to 109 weeks).

Serious adverse reactions occurred in 41% of patients. Serious adverse reactions that occurred in at least 2% of patients were pneumonia (3.6%), skin infection (3.6%), and pneumonitis (2.8%). Fatal adverse reactions occurred in 5% of patients who received LIBTAYO, including deaths due to infections (2.2%).

Permanent discontinuation due to an adverse reaction occurred in 12% of patients. Adverse reactions resulting in permanent discontinuation in at least 2 patients were pneumonitis, rash, confusional state, general physical health deterioration, hemorrhage, liver function test abnormalities, and musculoskeletal pain.

Dosage interruptions of LIBTAYO due to an adverse reaction occurred in 36% of patients. Adverse reactions which required dosage interruption in ≥ 2% of patients included diarrhea, infusion-related reaction, upper respiratory tract infection, liver function test abnormalities, musculoskeletal pain, pneumonitis, and rash.

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

Vomiting is a composite term that includes hematemesis and vomiting

Upper respiratory tract infection is a composite term that includes upper respiratory tract infection, nasopharyngitis, sinusitis, influenza-like illness, rhinitis, influenza, viral upper respiratory tract infection, respiratory tract infection, influenza A virus test positive, and pharyngitis

Skin infection is a composite term that includes skin infection, cellulitis, fungal skin infection, and staphylococcal skin infection

Cough is a composite term that includes cough, productive cough, and upper airway cough syndrome

Headache is a composite term that includes headache, sinus headache, and migraine

Dizziness is a composite term that includes dizziness, vertigo, vertigo positional, and dizziness postural

Study 1423

In 26 patients with advanced CSCC treated with LIBTAYO in Study 1423 [see Clinical Studies (14.1)], safety data were consistent with those described above from Study 1540.

Basal Cell Carcinoma (BCC)

The safety of LIBTAYO was evaluated in 138 patients with advanced BCC (mBCC N=54, 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 45 weeks (range: 2.1 weeks to 98 weeks).

Serious adverse reactions occurred in 34% of patients. Serious adverse reactions that occurred in > 1.5% were diarrhea (3.6%), urinary tract infection (3.6%), pneumonia (2.9%), and hemorrhage (2.2%). Fatal adverse reactions occurred in 4.3% of patients who received LIBTAYO, including acute kidney injury (0.7%) and cachexia worsening due to colitis (0.7%).

Permanent discontinuation of LIBTAYO due to an adverse reaction occurred in 14% of patients. Adverse reactions resulting in permanent discontinuation of LIBTAYO in at least 2 patients were diarrhea, acute kidney injury, general physical health deterioration, and hepatitis.

Dosage interruptions of LIBTAYO due to an adverse reaction occurred in 40% of patients. Adverse reactions which required dosage interruptions in > 2% of patients included diarrhea, acute kidney injury, musculoskeletal pain, fatigue, fall, headache, infusion-related reaction, hemorrhage, pneumonitis, upper respiratory tract infection, and urinary tract infection.

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

The most common Grade 3 or 4 adverse reactions (> 2%) were hypertension, diarrhea, fatigue, musculoskeletal pain, hypokalemia, hyponatremia, pneumonia, urinary tract infection, visual impairment, and weight decreased. The most common (> 2%) laboratory abnormalities worsening from baseline to Grade 3 or 4 were lymphopenia and 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.

Rash is a composite term that includes rash maculo-papular, eczema, rash, dermatitis, erythema, dermatitis acneiform, rash pruritic, rash pustular, dermatitis bullous, dyshidrotic eczema, pemphigoid, rash erythematous, urticaria, nodular rash, and skin exfoliation

Upper respiratory tract infection is a composite term that includes upper respiratory tract infection, influenza-like illness, nasopharyngitis, rhinitis, sinusitis, viral rhinitis, pharyngitis, laryngitis, respiratory tract infection, influenza, viral upper respiratory tract infection, and influenza A virus test positive

Urinary tract infection is a composite term that includes urinary tract infection, cystitis, and urosepsis

Hemorrhage is a composite term that includes tumor hemorrhage, hematuria, epistaxis, eye hemorrhage, hemoptysis, hemorrhage intracranial, hemorrhagic diathesis, postmenopausal hemorrhage, rectal hemorrhage, skin hemorrhage, skin neoplasm bleeding, ulcer hemorrhage, vaginal hemorrhage, wound hemorrhage, and subcutaneous hematoma

Hypertension is a composite term that includes hypertension, blood pressure increased, and hypertensive crisis

Dyspnea is a composite term that includes dyspnea and dyspnea exertional

Acute kidney injury is a composite term that includes blood creatinine increased, acute kidney injury, renal failure, renal impairment, glomerular filtration rate decreased, and nephropathy toxic

Dizziness is a composite term that includes dizziness and vertigo

Peripheral neuropathy is a composite term that includes paresthesia, dysesthesia, hypoesthesia, peripheral motor neuropathy, burning sensation, neuralgia, and peripheral sensory neuropathy

Hypothyroidism is a composite term that includes hypothyroidism, blood thyroid stimulating hormone increased, and immune-mediated hypothyroidism

Liver function test abnormalities is a composite term that includes alanine aminotransferase increased, aspartate aminotransferase increased, bilirubin conjugated increased, blood alkaline phosphatase increased, blood bilirubin increased, and gamma-glutamyl transferase increased

Non-Small Cell Lung Cancer (NSCLC)

First-line treatment of NSCLC with LIBTAYO in Combination with Platinum-based Chemotherapy

The safety of LIBTAYO in combination with platinum-based chemotherapy was evaluated in 465 patients with locally advanced or metastatic NSCLC in Study 16113 [see Clinical Studies (14.3)]. Patients received LIBTAYO 350 mg every 3 weeks plus platinum-based chemotherapy every 3 weeks for 4 cycles (n=312), or placebo every 3 weeks plus platinum-based chemotherapy every 3 weeks for 4 cycles (n=153).

Among patients who received LIBTAYO, 70% were exposed for 6 months or longer and 35% were exposed for greater than one year. The safety population characteristics were: median age of 63 years (25 to 82 years), 41% of patients 65 or older, 86% male, 86% White, 14% Asian, 86% had metastatic disease and 14% had locally advanced disease and Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 (16%) and 1 (83%).

Serious adverse reactions occurred in 25% of patients. The most frequent serious adverse reactions that occurred in at least 2% of patients were pneumonia, anemia, and neutropenia. Fatal adverse reactions occurred in 6% of patients who received LIBTAYO in combination with chemotherapy, including death not otherwise specified (2.9%), sudden death (1.0%), acute hepatitis (0.3%), acute respiratory distress syndrome (0.3%), mesenteric artery thrombosis (0.3%), pneumonia (0.3%), pneumonitis (0.3%), and pulmonary hemorrhage (0.3%). LIBTAYO was permanently discontinued due to adverse reactions in 5% of patients. Adverse reactions resulting in permanent discontinuation in at least 2 patients were increased alanine aminotransferase and anemia.

Dosage interruptions of LIBTAYO due to an adverse reaction occurred in 33% of patients. Adverse reactions which required dosage interruptions in at least 2% of patients were anemia, pneumonia, neutropenia, thrombocytopenia, fatigue, COVID-19 infection, and pyrexia.

The most common (≥ 15%) adverse reactions were alopecia, musculoskeletal pain, nausea, fatigue, peripheral neuropathy, and decreased appetite. The most common Grade 3-4 laboratory abnormalities (≥ 2%) were anemia, neutropenia, lymphopenia, leukopenia, hyponatremia, thrombocytopenia, hyperglycemia, hypophosphatemia, increased alanine aminotransferase, hypocalcemia, hyperkalemia, hypermagnesemia, hypokalemia, and increased creatinine.

Table 6 summarizes the adverse reactions that occurred in ≥ 10% of patients and Table 7 summarizes Grade 3 or 4 laboratory abnormalities in patients receiving LIBTAYO and chemotherapy.

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

The safety of LIBTAYO was evaluated in 355 patients with locally advanced or metastatic NSCLC in Study 1624 [see Clinical Studies (14.3)]. Patients received LIBTAYO 350 mg every 3 weeks (n=355) or investigator's choice of chemotherapy (n=342), consisting of paclitaxel plus cisplatin or carboplatin; gemcitabine plus cisplatin or carboplatin; or pemetrexed plus cisplatin or carboplatin followed by optional pemetrexed maintenance. The median duration of exposure was 27.3 weeks (9 days to 115 weeks) in the LIBTAYO group and 17.7 weeks (18 days to 86.7 weeks) in the chemotherapy group. In the LIBTAYO group, 54% of patients were exposed to LIBTAYO for ≥ 6 months and 22% were exposed for ≥ 12 months.

The safety population characteristics were: median age of 63 years (31 to 79 years), 44% of patients 65 or older, 88% male, 86%White, 82% had metastatic disease and 18% had locally advanced disease, and ECOG performance score (PS) of 0 (27%) and 1 (73%).

LIBTAYO was permanently discontinued due to adverse reactions in 6% of patients; adverse reactions resulting in permanent discontinuation in at least 2 patients were pneumonitis, pneumonia, ischemic stroke, and increased aspartate aminotransferase. Serious adverse reactions occurred in 28% of patients. The most frequent serious adverse reactions in at least 2% of patients were pneumonia and pneumonitis.

Table 8 summarizes the adverse reactions that occurred in ≥ 10% of patients and Table 9 summarizes Grade 3 or 4 laboratory abnormalities in patients receiving LIBTAYO.

CLINICAL STUDIES SECTION

14 CLINICAL STUDIES

14.1 Cutaneous Squamous Cell Carcinoma (CSCC)

The efficacy of LIBTAYO in patients with metastatic (nodal or distant) cutaneous squamous cell carcinoma (mCSCC) or locally advanced CSCC (laCSCC) 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 Study 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 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 (Groups 1 and 2), or 350 mg every 3 weeks for up to 54 weeks (Group 3) in Study 1540. Treatment continued until progression of disease, unacceptable toxicity, or completion of planned treatment. Tumor response assessments were performed every 8 or 9 weeks. The major efficacy outcome measures were confirmed objective response rate (ORR), defined as complete response (CR) plus partial response (PR) as assessed by independent central review (ICR), and ICR-assessed duration of response (DOR). For patients with mCSCC 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 (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).

Study 1540

In the efficacy analysis of 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, 2% were Asian, 1% were Black or African American, and 1% were race unknown; 45% had ECOG PS 0 and 55% had ECOG PS 1; 34% received at least one prior anti-cancer systemic therapy; 81% 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 2.1 months (range: 1.7 to 22.8 months).

Efficacy results based on the final analysis of Study 1540 are presented in Table 10.

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.

14.2 Basal Cell Carcinoma (BCC)

The efficacy of LIBTAYO in 138 patients with advanced basal cell carcinoma (BCC) [unresectable locally advanced (laBCC) or metastatic (nodal or distant) (mBCC)] who had progressed on hedgehog pathway inhibitor (HHI) therapy, had not had an objective response after 9 months on HHI therapy, or were intolerant of prior HHI therapy was evaluated in Study 1620 (NCT03132636), an open-label, multi-center, non-randomized study. The study 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 therapy or other immune checkpoint inhibitor therapy; infection with HIV, hepatitis B or hepatitis C; or ECOG performance score (PS) ≥ 2.

Patients received LIBTAYO 350 mg every 3 weeks for up to 93 weeks until disease progression, unacceptable toxicity, or completion of planned treatment. Tumor assessments were performed every 9 weeks for the first 45 weeks of treatment and every 12 weeks thereafter. The major efficacy outcome measures were confirmed objective response rate (ORR) and duration of response (DOR) as assessed by independent central review (ICR). For patients with mBCC 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 (laBCC and mBCC), ORR was determined by a composite endpoint that 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. Of these, 39% had mBCC and 61% had laBCC. In patients with laBCC, the median age was 70 years (42 to 89 years); 67% were male; 68% were White and 32% were race not reported/unknown; 61% had ECOG PS 0 and 39% had ECOG PS 1; 83% had received at least 1 prior cancer-related surgery; and 50% had received prior radiotherapy. In patients with mBCC, the median age was 63.5 years (38 to 90 years); 70% were male; 87% were White and 13% were race not reported/unknown; 67% had ECOG PS 0 and 33% had ECOG PS 1; 85% had received at least 1 prior cancer-related surgery; and 59% had received prior radiotherapy. Among patients with mBCC, 35% had distant metastases only, 9% had nodal disease only, and 54% had both distant and nodal disease.

Efficacy results are presented in Table 11. For the responding patients, the median time to response was 3.1 months (range 2 to 10.5 months) for the mBCC group and 4.3 months (range 2.1 to 21.4 months) for the laBCC group.

14.3 Non-Small Cell Lung Cancer (NSCLC)

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

SPL MEDGUIDE SECTION

HOW SUPPLIED SECTION

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.

SPL UNCLASSIFIED SECTION

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)
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All rights reserved.