LIBTAYO

1 INDICATIONS AND USAGE LIBTAYO is a programmed death receptor-1 (PD-1) blocking antibody indicated: Cutaneous Squamous Cell Carcinoma (CSCC) for the treatment of adult patients with metastatic cutaneous squamous cell carcinoma (mCSCC) or locally advanced CSCC (laCSCC) who are not candidates for curative surgery or curative radiation. ( 1.1 ) for the adjuvant treatment of adult patients with CSCC at high risk of recurrence after surgery and radiation. ( 1.1 , 14.1 ) Basal Cell Carcinoma (BCC) for the treatment of adult patients with locally advanced or metastatic BCC (laBCC or mBCC) who have been previously treated with a hedgehog pathway inhibitor or for whom a hedgehog pathway inhibitor is not appropriate. ( 1.2 ) Non-Small Cell Lung Cancer (NSCLC) in combination with platinum‐based chemotherapy for the first‐line treatment of adult patients with non-small cell lung cancer (NSCLC) with no EGFR, ALK or ROS1 aberrations and is: locally advanced where patients are not candidates for surgical resection or definitive chemoradiation or metastatic. ( 1.3 ) as single agent for the first-line treatment of adult patients with NSCLC whose tumors have high PD-L1 expression [Tumor Proportion Score (TPS) ≥50%] as determined by an FDA-approved test, with no EGFR, ALK or ROS1 aberrations, and is: locally advanced where patients are not candidates for surgical resection or definitive chemoradiation or metastatic. ( 1.3 , 2.1 ) 1.1 Cutaneous Squamous Cell Carcinoma LIBTAYO is indicated for the treatment of adult patients with metastatic cutaneous squamous cell carcinoma (mCSCC) or locally advanced CSCC (laCSCC) who are not candidates for curative surgery or curative radiation. LIBTAYO is indicated for the adjuvant treatment of adult patients with CSCC at high risk of recurrence [see Clinical Studies (14.1) ] after surgery and radiation . 1.2 Basal Cell Carcinoma LIBTAYO is indicated for the treatment of adult patients with locally advanced or metastatic basal cell carcinoma (laBCC or mBCC) who have been previously treated with a hedgehog pathway inhibitor or for whom a hedgehog pathway inhibitor is not appropriate. 1.3 Non-Small Cell Lung Cancer LIBTAYO in combination with platinum‐based chemotherapy is indicated for the first‐line treatment of adult patients with non-small cell lung cancer (NSCLC) with no EGFR, ALK or ROS1 aberrations and is: locally advanced where patients are not candidates for surgical resection or definitive chemoradiation or metastatic. LIBTAYO as a single agent is indicated for the first-line treatment of adult patients with NSCLC whose tumors have high PD-L1 expression [Tumor Proportion Score (TPS) ≥50%] as determined by an FDA-approved test [see Dosage and Administration (2.1) ] , with no EGFR, ALK or ROS1 aberrations, and is: locally advanced where patients are not candidates for surgical resection or definitive chemoradiation or metastatic.

2 DOSAGE AND ADMINISTRATION Administer LIBTAYO as an intravenous infusion over 30 minutes after dilution. ( 2.2 ) Metastatic and locally advanced CSCC and BCC: 350 mg every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months. ( 2.2 ) Adjuvant treatment of CSCC at high risk of recurrence after surgery and radiation: 350 mg every 3 weeks for 12 weeks followed by 700 mg every 6 weeks until disease recurrence, unacceptable toxicity, or up to 48 weeks of total therapy, or 350 mg every 3 weeks until disease recurrence, unacceptable toxicity, or up to 48 weeks of total therapy. ( 2.2 ) NSCLC: 350 mg every 3 weeks until disease progression or unacceptable toxicity. ( 2.2 ) 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 The recommended dosages of LIBTAYO are presented in Table 1. Refer to the Prescribing Information for the agents administered in combination with LIBTAYO for recommended dosing information, as appropriate. Table 1: Recommended Dosages of LIBTAYO as a Single Agent or in Combination with Other Agents Indication Recommended dosage of LIBTAYO as an intravenous infusion Duration of Treatment Adults with metastatic cutaneous squamous cell carcinoma (mCSCC) or locally advanced CSCC (laCSCC) 350 mg every 3 weeks Until disease progression, unacceptable toxicity, or up to 24 months. Adjuvant treatment of adult patients with CSCC at high risk of recurrence after surgery and radiation 350 mg every 3 weeks for 12 weeks, followed by 700 mg every 6 weeks Or 350 mg every 3 weeks Until disease recurrence, unacceptable toxicity, or up to 48 weeks. Adults with locally advanced basal cell carcinoma (laBCC) or metastatic BCC (mBCC) 350 mg every 3 weeks Until disease progression, unacceptable toxicity, or up to 24 months. Adults with non-small cell lung cancer (NSCLC) Single-agent or in combination with platinum-based chemotherapy 350 mg every 3 weeks Until disease progression or unacceptable toxicity. 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 2. Table 2: Recommended Dosage Modifications for Adverse Reactions Adverse Reaction Severity Based on National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 Dosage Modifications ALT=alanine aminotransferase, AST=aspartate aminotransferase, ULN=upper limit of normal, SJS=Stevens-Johnson Syndrome, TEN=toxic epidermal necrolysis, DRESS=Drug Rash with Eosinophilia and Systemic Symptoms Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1) ] Pneumonitis Grade 2 Withhold Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone to less than 10 mg per day (or equivalent) within 12 weeks of initiating steroids. Grade 3 or 4 Permanently discontinue Colitis Grade 2 or 3 Withhold Grade 4 Permanently discontinue Hepatitis with no tumor involvement of the liver AST or ALT increases to more than 3 and up to 8 times ULN or Total bilirubin increases to more than 1…

5 WARNINGS AND PRECAUTIONS Immune-Mediated Adverse Reactions ( 5.1 ) Immune-mediated adverse reactions, which may be severe or fatal, 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, immune-mediated nephritis and renal dysfunction, and solid organ transplant rejection. Monitor for early identification and management. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. Withhold or permanently discontinue LIBTAYO based on the severity of reaction. ( 2.3 ) Infusion-Related Reactions: Interrupt, slow the rate of infusion, or permanently discontinue based on severity of reaction. ( 2.3 , 5.2 ) Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT): Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after being treated with a PD-1/PD-L1 blocking antibody. ( 5.3 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and use of effective contraception. ( 5.4 , 8.1 , 8.3 ) 5.1 Severe and Fatal Immune-Mediated Adverse Reactions LIBTAYO is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Important immune-mediated adverse reactions listed under Warnings and Precautions may not include all possible severe and fatal immune-mediated reactions. The incidence and severity of immune-mediated adverse reactions were similar when LIBTAYO was administered as a single agent or in combination with chemotherapy. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting PD-1/PD-L1 blocking antibody. 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. Immune-mediated adverse reactions affecting more than one body system can occur simultaneously. Early identification and management of immune‐mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate. Withhold or permanently discontinue LIBTAYO depending on severity [see Dosage and Administration (2.3) ] . In general, if LIBTAYO requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroids. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below. Immune-Mediated Pneumonitis LIBTAYO can cause immune-mediated pneumonitis. The definition of immune-mediated pneumonitis included the required use of systemic corticosteroids or other immunosuppressants…

4 CONTRAINDICATIONS None. None. ( 4 )

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.

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) ] Most common adverse reactions (≥15%): LIBTAYO as a single agent in mCSCC or laCSCC, m BCC or laBCC, and NSCLC with high PD-L1 expression : Fatigue, musculoskeletal pain, rash, diarrhea, and anemia. ( 6.1 ) LIBTAYO as a single agent in adjuvant CSCC at high risk of recurrence: Rash and pruritus. ( 6.1 ) LIBTAYO in combination with platinum-based chemotherapy in NSCLC: 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. 6.1 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 with advanced cancers 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. The data below also reflect exposure to LIBTAYO as a single agent (either 350 mg every 3 weeks for 12 weeks followed by 700 mg every 6 weeks for 36 weeks or 350 mg every 3 weeks for 48 weeks) in the adjuvant setting in 205 patients with CSCC at high risk of recurrence after treatment with surgery and radiation (C-POST study), and LIBTAYO 350 mg every 3 weeks 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…