Cemiplimab-Rwlc

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 and up to 3 times the ULN Withhold AST or ALT increases to more than 8 times the ULN or Total bilirubin increases to more than 3 times the ULN Permanently discontinue Hepatitis with tumor involvement of the liver If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue LIBTAYO based on recommendations for hepatitis with no liver involvement Baseline AST or ALT is more than 1 and up to 3 times ULN and increases to more than 5 and up to 10 times ULN or Baseline AST or ALT is more than 3 and up to 5 times ULN and increases to more than 8 and up to 10 times ULN Withhold AST or ALT increases to more than 10 times ULN or Total bilirubin increases to more than 3 times ULN Permanently discontinue Endocrinopathies Grade 3 or 4 Withhold until clinically stable or permanently discontinue depending on severity Nephritis with Renal Dysfunction Grade 2 or 3 increased blood creatinine Withhold Grade 4 increased blood creatinine Permanently discontinue Exfoliative Dermatologic Conditions Suspected SJS, TEN, or DRESS Withhold Confirmed SJS, TEN, or DRESS Permanently discontinue Myocarditis Grade 2, 3 or 4 Permanently discontinue Neurological Toxicities Grade 2 Withhold Grade 3 or 4 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 2.4 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 the vial(s). Withdraw the required volume from the vial(s) of LIBTAYO and transfer into an intravenous (IV) bag containing 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 portion left in the vial(s). Storage of Diluted 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.

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 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 3 summarizes the adverse reactions that occurred in ≥10% of patients and Table 4 summarizes Grade 3 or 4 laboratory abnormalities worsening from baseline in ≥1% of patients receiving LIBTAYO. Table 3: Adverse Reactions in ≥10% of Patients with Advanced CSCC Receiving LIBTAYO in Study 1540 Adverse Reactions LIBTAYO N = 358 All Grades % Grades 3-4 % Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v.4.03 General and Administration Site Fatigue Fatigue is a composite term that includes fatigue and asthenia 38 2.2 Skin and Subcutaneous Tissue Rash Rash is a composite term that includes rash, rash maculo-papular, dermatitis, erythema, eczema, dermatitis bullous, rash erythematous, dermatitis acneiform, psoriasis, dermatitis contact, blister, pemphigoid, rash papular, hand dermatitis, skin exfoliation, autoimmune dermatitis, rash pruritic, rash macular, rash pustular, urticaria, dermatitis atopic, drug eruption, eczema asteatotic, skin reaction, dermatitis psoriasiform, eczema nummular, exfoliative rash, and immune-mediated dermatitis 34 1.7 Pruritus Pruritus is a composite term that includes pruritus and pruritus allergic 22 0.3 Actinic keratosis 10 0 Musculoskeletal and Connective Tissue Musculoskeletal pain Musculoskeletal pain is a composite term that includes arthralgia, back pain, myalgia, polyarthritis, pain in extremity, neck pain, non-cardiac chest pain, arthritis, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal stiffness, bone pain, immune-mediated arthritis, and spinal pain 33 2.5 Gastrointestinal Diarrhea Diarrhea is a composite term that includes diarrhea, colitis, and autoimmune colitis 26 1.1 Nausea 21 0 Constipation 13 0.3 Vomiting Vomiting is a composite term that includes hematemesis and vomiting 11 0.6 Infections and infestations Upper respiratory tract infection 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 14 1.1 Skin infection Skin infection is a composite term that includes skin infection, cellulitis, fungal skin infection, and staphylococcal skin infection 11 4.5 Respiratory Cough Cough is a composite term that includes cough, productive cough, and upper airway cough syndrome 12 0 Metabolism and Nutrition Decreased appetite 11 0.6 Nervous system disorders Headache Headache is a composite term that includes headache, sinus headache, and migraine 10 0 Dizziness Dizziness is a composite term that includes dizziness, vertigo, vertigo positional, and dizziness postural 10 0.3 Table 4: Grade 3 or 4 Laboratory Abnormalities Worsening from Baseline in ≥1% of Patients with Advanced CSCC Receiving LIBTAYO in 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 Toxicity graded per NCI CTCAE v. 4.03 Hematology Lymphopenia 7.0 Anemia 4.1 Electrolytes Hyponatremia 4.9 Hypophosphatemia 4.1 Hypercalcemia 2.0 Hypokalemia 1.5 Coagulation Increased INR 2.9 Chemistry Increased aspartate aminotransferase 1.5 Hypoalbuminemia 1.2 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. Adjuvant treatment of CSCC at high risk of recurrence C-POST study The safety of LIBTAYO was evaluated in patients with CSCC at high-risk of recurrence after surgery and radiation in the C-POST study [see Clinical Studies (14.1) ] . Patients were assigned to receive: LIBTAYO 350 mg (n=140) or placebo (n=140) intravenously every 3 weeks for 12 weeks, followed by 700 mg LIBTAYO or placebo intravenously every 6 weeks for an additional 36 weeks, or LIBTAYO 350 mg every 3 weeks (n=65) or placebo (n=64) for up to 48 weeks. Treatment continued until disease recurrence, unacceptable toxicity, or up to 48 weeks. The median duration of exposure was 48 weeks (range: 3 weeks to 52 weeks) in LIBTAYO-treated patients. Serious adverse reactions occurred in 18% of patients who received LIBTAYO. Serious adverse reactions that occurred in ≥1% of patients in the LIBTAYO arm were pneumonia (1.5%), rash (1.5%), diarrhea (1.5%), adrenal insufficiency (1%), and arrhythmia (1%). Permanent discontinuation due to an adverse reaction occurred in 10% of patients who received LIBTAYO. Adverse reactions resulting in permanent discontinuation in ≥1% of patients were alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, and adrenal insufficiency. Dosage interruptions due to an adverse reaction occurred in 22% of patients who received LIBTAYO. Adverse reactions leading to interruptions in ≥1% of patients included COVID-19, diarrhea, alanine aminotransferase increased, urinary tract infection, upper respiratory tract infection, aspartate aminotransferase increased, edema, dyspnea, pneumonitis, pneumonia, and rash. Table 5 summarizes the adverse reactions that occurred in ≥10% of patients and Table 6 summarizes Grade 3 or 4 laboratory abnormalities worsening from baseline in ≥1% of patients receiving LIBTAYO. Table 5: Adverse Reactions in ≥10% of Patients with CSCC at High Risk of Recurrence in the Adjuvant Setting Receiving LIBTAYO with a Difference Between Arms of ≥3% Compared to Placebo in C-POST study Adverse reactions Toxicity graded per NCI CTCAE v. 5. LIBTAYO N=205 Placebo N=204 All Grades % Grades 3-4 % All Grades % Grades 3-4 % Skin and subcutaneous tissue disorders Rash Includes multiple related terms 37 2 21 0 Pruritus 16 0.5 12 0 Endocrine disorders Hypothyroidism 12 0.5 2.9 0 Table 6: Laboratory Abnormalities Worsening from Baseline in ≥1% of Patients with CSCC at High Risk of Recurrence in the Adjuvant Setting Receiving LIBTAYO in C-POST Study Laboratory Abnormality LIBTAYO Placebo Grade 3-4 (%) The denominator used to calculate the rate varied from 201 to 203 based on the number of patients with a baseline value and at least one post-treatment value. Toxicity graded per NCI CTCAE v. 5 Hematology Lymphocyte count decreased 6 3 Chemistry Alanine aminotransferase increased 3.9 0 Aspartate aminotransferase increased 3 0.5 Alkaline phosphatase increased 1.5 0 Albumin decreased 1 0 Electrolytes Calcium decreased 1 1 Potassium decreased 1 0.5 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, musculoskeletal pain, acute kidney injury, 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 7 summarizes the adverse reactions that occurred in ≥10% of patients and Table 8 summarizes Grade 3 or 4 laboratory abnormalities worsening from baseline in ≥1% of patients receiving LIBTAYO. Table 7: Adverse Reactions in ≥10% of Patients with Advanced BCC Receiving LIBTAYO in Study 1620 Adverse Reactions LIBTAYO N = 138 All Grades % Grades 3-4 % Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v.4.03 General disorders and administration site conditions Fatigue Fatigue is a composite term that includes fatigue, asthenia, and malaise 50 4.3 Edema Edema is a composite term that includes peripheral edema, peripheral swelling, and face swelling 10 0.7 Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain is a composite term that includes arthralgia, back pain, pain in extremity, myalgia, neck pain, non-cardiac chest pain, arthritis, musculoskeletal chest pain, musculoskeletal stiffness, musculoskeletal discomfort, and spinal pain 36 2.9 Gastrointestinal disorders Diarrhea Diarrhea is a composite term that includes diarrhea, colitis, autoimmune colitis, and enterocolitis 33 4.3 Nausea 13 0.7 Abdominal pain Abdominal pain is a composite term that includes abdominal pain, abdominal pain upper, abdominal pain lower, and gastrointestinal pain 12 1.4 Constipation 12 0.7 Skin and subcutaneous tissue disorders Rash 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 30 0.7 Pruritus 19 0 Infections and infestations Upper respiratory tract infection 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 22 0 Urinary tract infection Urinary tract infection is a composite term that includes urinary tract infection, cystitis, and urosepsis 13 2.2 Vascular disorders Hemorrhage 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 18 0.7 Hypertension Hypertension is a composite term that includes hypertension, blood pressure increased, and hypertensive crisis 17 9 Metabolism and nutrition disorders Decreased appetite 14 1.4 Blood and lymphatic system disorders Anemia 14 0.7 Respiratory, thoracic, and mediastinal disorders Dyspnea Dyspnea is a composite term that includes dyspnea and dyspnea exertional 14 0 Renal and urinary disorders Acute kidney injury 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 14 0 Nervous system disorders Headache 13 1.4 Dizziness Dizziness is a composite term that includes dizziness and vertigo 12 0 Peripheral neuropathy Peripheral neuropathy is a composite term that includes paresthesia, dysesthesia, hypoesthesia, peripheral motor neuropathy, burning sensation, neuralgia, and peripheral sensory neuropathy 11 0 Endocrine disorders Hypothyroidism Hypothyroidism is a composite term that includes hypothyroidism, blood thyroid stimulating hormone increased, and immune-mediated hypothyroidism 12 0 Investigations Liver function test abnormalities 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 10 1.4 Table 8: Grade 3 or 4 Laboratory Abnormalities Worsening from Baseline in ≥1% of Patients with Advanced BCC Receiving LIBTAYO in Study 1620 Laboratory Abnormality Grade 3-4 (%) Percentages are based on the number of patients with at least 1 post-baseline value available for that parameter Toxicity graded per NCI CTCAE v. 4.03 Hematology Lymphopenia 2.9 Electrolytes Hyponatremia 2.9 Hypokalemia 1.5 Coagulation Activated partial thromboplastin time prolonged 1.9 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 9 summarizes the adverse reactions that occurred in ≥10% of patients and Table 10 summarizes Grade 3 or 4 laboratory abnormalities in patients receiving LIBTAYO and chemotherapy. Table 9: Adverse Reactions in ≥10% of Patients with Locally Advanced or Metastatic NSCLC Receiving LIBTAYO and Chemotherapy in Study 16113 Adverse Reactions LIBTAYO and Chemotherapy (N=312) Placebo and Chemotherapy (N=153) All Grades % Grades 3 or 4 % All Grades % Grades 3 or 4 % Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v. 4.03 Skin and subcutaneous tissue disorders Alopecia 37 0 43 0 Rash Rash is a composite term that includes rash, rash maculo-papular, dermatitis, psoriasis, rash papular, urticaria, dermatitis allergic, erythema, lichen planus, rash macular, rash pruritic, skin reaction, skin toxicity, skin exfoliation, and dermatitis acneiform 13 1.3 6 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain is a composite term that includes arthralgia, back pain, pain in extremity, non-cardiac chest pain, myalgia, bone pain, musculoskeletal pain, neck pain, musculoskeletal chest pain, arthritis, and spinal pain 30 1.6 36 0 Gastrointestinal disorders Nausea 25 0 16 0 Constipation 14 0.3 11 0 Vomiting 12 0 10 0 Diarrhea 11 1.3 7 0 General disorders and administration site conditions Fatigue Fatigue is a composite term that includes asthenia, fatigue, and malaise 23 3.8 18 2 Nervous system disorders Peripheral neuropathy Peripheral neuropathy is a composite term that includes peripheral sensory neuropathy, peripheral neuropathy, paresthesia, polyneuropathy, hypoesthesia, peripheral sensorimotor neuropathy, neuralgia, polyneuropathy in malignant disease, and toxic neuropathy 23 0 19 0 Metabolism and nutrition disorders Decreased appetite 17 1 12 0 Investigations Weight decreased 11 1.3 8 0 Respiratory, thoracic, and mediastinal disorders Dyspnea Dyspnea is a composite term that includes dyspnea and dyspnea exertional 13 2.2 7 0.7 Psychiatric disorders Insomnia 11 0 7 0 Table 10: Grade 3 or 4 Laboratory Abnormalities Worsening from Baseline in ≥1% of Patients with Locally Advanced or Metastatic NSCLC Receiving LIBTAYO and Chemotherapy in Study 16113 Laboratory Abnormality LIBTAYO and Chemotherapy Placebo and Chemotherapy Grades 3 or 4 (%) The denominator used to calculate the rate varied from 134 to 299 based on the number of patients with a baseline value and at least one post-treatment value. Toxicity graded per NCI CTCAE v. 4.03 Chemistry Hyperglycemia 4 1.5 Increased alanine aminotransferase 3 2.1 Increased creatinine 2 1.4 Hypoalbuminemia 1 0 Hematology Anemia 10 7 Neutrophil count decreased 10 8 Lymphocyte count decreased 7 8 White blood cell decreased 6 4.1 Platelet count decreased 4.7 0.7 Electrolytes Hyponatremia 6 4.1 Hypophosphatemia 3.4 7 Hypocalcemia 3 2.1 Hyperkalemia 2.7 2.7 Hypermagnesemia 2.4 2.8 Hypokalemia 2.3 1.4 Hypercalcemia 1.7 0.7 Hypernatremia 1 0 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 11 summarizes the adverse reactions that occurred in ≥10% of patients and Table 12 summarizes Grade 3 or 4 laboratory abnormalities in patients receiving LIBTAYO. Table 11: Adverse Reactions in ≥10% of Patients with Locally Advanced or Metastatic NSCLC Receiving LIBTAYO in Study 1624 Adverse Reactions LIBTAYO N=355 Chemotherapy N=342 All Grades % Grades 3-4 % All Grades % Grades 3-4 % Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v.4.03 Musculoskeletal and connective tissue disorders Musculoskeletal pain Musculoskeletal pain is a composite term that includes back pain, arthralgia, pain in extremity, musculoskeletal pain, musculoskeletal chest pain, bone pain, myalgia, neck pain, spinal pain, and musculoskeletal stiffness 26 0.6 27 1.5 Skin and subcutaneous tissue disorders Rash Rash is a composite term that includes rash, dermatitis, urticaria, rash maculo-papular, erythema, rash erythematous, rash pruritic, psoriasis, autoimmune dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis atopic, dermatitis bullous, drug eruption, dyshidrotic eczema, lichen planus, and skin reaction 15 1.4 6 0 Blood and lymphatic system disorders Anemia 15 3.4 50 16 General disorders and administration site conditions Fatigue Fatigue is a composite term that includes fatigue, asthenia, and malaise 14 1.1 26 2 Metabolism and nutrition disorders Decreased appetite 12 0.6 18 0.3 Infections and infestations Pneumonia Pneumonia is a composite term that includes atypical pneumonia, embolic pneumonia, lower respiratory tract infection, lung abscess, paracancerous pneumonia, pneumonia, pneumonia bacterial, and pneumonia klebsiella 11 5 12 5 Respiratory, thoracic, and mediastinal disorders Cough Cough is a composite term that includes cough and productive cough 11 0 8 0.3 Table 12: Grade 3 or 4 Laboratory Abnormalities Worsening from Baseline in ≥1% of Patients with Locally Advanced or Metastatic NSCLC Receiving LIBTAYO in Study 1624 Laboratory Abnormality LIBTAYO N=355 Chemotherapy N=342 Grades 3-4 Percentages are based on the number of patients with at least 1 post-baseline value available for that parameter % Toxicity graded per NCI CTCAE v. 4.03 Chemistry Increased aspartate aminotransferase 3.9 1.2 Increased alanine aminotransferase 2.7 0.3 Increased alkaline phosphatase 2.4 0.3 Increased blood bilirubin 2.1 0.3 Hypoalbuminemia 1.8 1.3 Increased creatinine 1.2 1.6 Hematology Lymphopenia 7 9 Anemia 2.7 16 Electrolytes Hyponatremia 6 7 Hyperkalemia 4.2 1.9 Hypocalcemia 3.9 3.4 Hypophosphatemia 2.4 4.1 Hypermagnesemia 2.1 1.6 Hypokalemia 1.5 2.2 Hypercalcemia 1.2 2.2

12.3 Pharmacokinetics Cemiplimab-rwlc pharmacokinetics were observed at steady state in patients with various solid tumors and are presented as mean (% coefficient of variation) unless otherwise specified. The pharmacokinetics of cemiplimab-rwlc increase in a dose proportional manner over the dose range of 1 mg/kg to 10 mg/kg (0.2 to 2 times the highest recommended approved dose; assuming a 70 kg patient) administered intravenously every 2 weeks. At a dosing regimen of 350 mg every 3 weeks, cemiplimab-rwlc minimum concentration is 59 mg/L (47%) and maximum concentration is 171 mg/L (27%). Steady-state is reached in about 4 months. At a dosing regimen of 350 mg every 3 weeks for 12 weeks followed by 700 mg every 6 weeks, cemiplimab-rwlc minimum concentration after 30 weeks is 50 mg/L (32%). Distribution The volume of distribution of cemiplimab-rwlc is 5.9 L (29%). Elimination Cemiplimab-rwlc clearance after the first dose is 0.25 L/day (41%) and decreases over time by 11%, resulting in a steady-state clearance of 0.22 L/day (44%). The elimination half-life is 22 days (42%). Specific Populations No clinically significant differences in the pharmacokinetics of cemiplimab-rwlc were observed based on age (27 to 96 years), race [White (N=932), Asian (N=47), Black (N=21)], sex, body weight (31 to 172 kg), cancer type, albumin level (20 to 93 g/L), renal function (creatinine clearance determined by Cockcroft-Gault) and hepatic function (total bilirubin ≥1 to 3× ULN). The effect of severe hepatic impairment (total bilirubin 3× ULN) on the pharmacokinetics of cemiplimab-rwlc is unknown.