Cosibelimab

12.1. Mechanism of Action PD-L1 may be expressed on tumor cells and tumor-infiltrating immune cells and can contribute to the inhibition of the anti-tumor immune response in the tumor microenvironment. Binding of PD-L1 to the PD-1 and B7.1 receptors found on T cells and antigen presenting cells suppresses cytotoxic T-cell activity, T-cell proliferation, and cytokine production. Cosibelimab-ipdl binds PD-L1 and blocks the interaction between PD-L1 and its receptors PD-1 and B7.1. This interaction releases the inhibitory effects of PD-L1 on the anti-tumor immune response. Cosibelimab-ipdl has also been shown to induce antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro.

1. INDICATIONS AND USAGE UNLOXCYT is indicated for the treatment of adults with metastatic cutaneous squamous cell carcinoma (mCSCC) or locally advanced CSCC (laCSCC) who are not candidates for curative surgery or curative radiation. UNLOXCYT is a programmed death ligand-1 (PD-L1) blocking antibody indicated for the treatment of adults with metastatic cutaneous squamous cell carcinoma (mCSCC) or locally advanced CSCC (laCSCC) who are not candidates for curative surgery or curative radiation.

2. DOSAGE AND ADMINISTRATION The recommended dosage of UNLOXCYT is 1,200 mg as an intravenous infusion over 60 minutes every 3 weeks. ( 2.1 ) 2.1. Recommended Dosage The recommended dosage of UNLOXCYT is 1,200 mg administered as an intravenous infusion over 60 minutes every 3 weeks until disease progression or unacceptable toxicity. 2.2. Dose Modifications for Adverse Reactions No dose reductions of UNLOXCYT are recommended. In general, withhold UNLOXCYT for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue UNLOXCYT 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 a prednisone equivalent of 10 mg or less per day within 12 weeks of initiating steroids. Dosage modifications for UNLOXCYT for adverse reactions that require management different from these general guidelines are summarized in Table 1. Table 1: Recommended Dose Modifications for Adverse Reactions Adverse Reaction Severity Based on National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), Version 5. UNLOXCYT Dosage Modifications ALT = alanine aminotransferase; AST = aspartate aminotransferase; DRESS: drug rash with eosinophilia and systemic symptoms; SJS: Stevens-Johnson Syndrome; TEN: toxic epidermal necrolysis; ULN: upper limit of normal. 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 corticosteroid to a prednisone equivalent of 10 mg/day or less 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 ULN Withhold AST or ALT increases to more than 8 times ULN or Total bilirubin increases to more than 3 times ULN Permanently discontinue Hepatitis with tumor involvement of the liver If AST and ALT are less than or equal to ULN at baseline in patients with liver involvement, withhold or permanently discontinue UNLOXCYT based on recommendations for hepatitis with no tumor involvement of the liver. 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 Depending on clinical severity, consider withholding for Grade 2 endocrinopathy until symptom improvement with hormone replacement. Resume once acute symptoms have resolved. 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 2.3. Preparation and Administration Visually inspect the vial for particulate matter and discoloration. UNLOXCYT is clear to opalescent, colorless to yellow or slightly brown. Discard the vial if visible particles are observed. Do not shake the vial. Preparation for Intravenous Infusion: Add 20 mL (1,200 mg) of UNLOXCYT to a 250 mL intravenous infusion bag containing 0.9% Sodium Chloride Injection. UNLOXCYT is compatible with an infusion bag made of polyolefin or polyvinyl chloride. Mix diluted solution by gentle inversion. Do not shake . Discard any unused portion left in the vial. Storage of Infusion Solution: The prepared infusion solution may be stored either: At room temperature up to 25°C (77°F) for no more than 24 hours from the time of preparation until the end of infusion. Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from time of preparation until end of infusion. If refrigerated, allow the diluted solution to come to room temperature prior to administration. Discard after 24 hours. Do not freeze. Administration: Visually inspect the infusion bag for particulate matter and discoloration prior to administration. Discard if the solution is discolored or contains particulate matter. Administer

6. ADVERSE REACTIONS The following clinically significant 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) ] The most common adverse reactions (≥10%) were fatigue, musculoskeletal pain, rash, diarrhea, hypothyroidism, constipation, nausea, headache, pruritus, edema, localized infection, and urinary tract infection. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800- 818-4555 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The pooled safety population described in WARNINGS AND PRECAUTIONS reflects exposure to UNLOXCYT as a single agent in 223 patients in two open-label, single-arm, multicohort studies, including 141 patients with advanced CSCC and 82 patients with other solid tumors and hematologic malignancies. UNLOXCYT was administered intravenously at doses of 800 mg every 2 weeks (n=174), 1,200 mg every 3 weeks (n=35), or other doses (n=14). Among the 223 patients, 54% were exposed for ≥24 weeks and 17% were exposed for ≥72 weeks. The safety of UNLOXCYT was evaluated in Study CK-301-101 in 141 patients with metastatic or locally advanced disease CSCC [see Clinical Studies (14) ] . Patients received UNLOXCYT 800 mg every 2 weeks (n=115) or 1,200 mg every 3 weeks (n=26) as an intravenous infusion until disease progression or unacceptable toxicity. The median duration of exposure was 36 weeks (2 weeks to 3.7 years). Serious adverse reactions occurred in 31% of advanced patients with CSCC who received UNLOXCYT. The most frequent serious adverse reactions (≥ 2% of patients) were sepsis (2.8%), pneumonia (2.8%) and pyrexia (2.1%). Permanent discontinuation of UNLOXCYT due to an adverse reaction occurred in 8% of patients. Adverse reactions resulting in permanent discontinuation of UNLOXCYT were COVID-19, COVID-19 pneumonia, sepsis, ulcerative keratitis, tumor thrombosis, axillary pain, paresthesia, cholestasis, hepatic cytolysis, wound hemorrhage, neck pain, pemphigoid, and eye pain (1 patient each). Dosage interruptions due to an adverse reaction occurred in 36% of patients who received UNLOXCYT. The adverse reaction that required dosage interruption in ≥ 2% of patients who received UNLOXCYT was COVID-19 (2%). The most common (≥ 10%) adverse reactions were fatigue, musculoskeletal pain, rash, diarrhea, hypothyroidism, constipation, nausea, headache, pruritus, edema, localized infection, and urinary tract infection. Table 2 and Table 3 summarize adverse reactions and laboratory abnormalities, respectively in CK-301-101. Table 2: Adverse Reactions in ≥ 10% of Patients with Metastatic or Locally Advanced CSCC Receiving UNLOXCYT in Study CK-301-101 UNLOXCYT N = 141 % System Organ Class Preferred Term All Grades % Grade 3 or 4 % Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v.4.03 (or later version) General disorders and administrative site conditions Fatigue Represents a composite of multiple related terms 33 3 Edema 11 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain 25 3 Skin and subcutaneous tissue disorders Rash 23 1 Pruritus 12 0 Endocrine disorder Hypothyroidism 14 0 Gastrointestinal disorders Diarrhea 14 0 Nausea 13 0 Constipation 13 0 Nervous system disorders Headache 12 0 Infections and infestations Localized infection 10 0.7 Urinary tract infection 10 0 Table 3: Laboratory Abnormalities that Worsened from Baseline to Grade 3 or 4 Occurring in ≥ 1% of Patients with Metastatic or Locally Advanced CSCC Receiving UNLOXCYT in Study CK-301-101 Laboratory Abnormality UNLOXCYT (N = 141) All Grades % The denominator used to calculate the rate varied from 122-140 based on the number of patients with a baseline value and at least one post-treatment value. Grade 3 or 4 % Toxicity graded per NCI CTCAE v5 Hematology Hemoglobin decreased 45 4 Lymphocytes decreased 41 6 Platelets decreased 14 1 Leukocytes decreased 10 1 Chemistry Sodium decreased 38 5 Alkaline phosphatase increased 26 1 Alanine transferase increased 25 4 Lipase increased 25 3 Aspartate transaminase increased 24 3 Potassium increased 23 3 Calcium increased 14 2