Retifanlimab-Dlwr

1 INDICATIONS AND USAGE ZYNYZ is a programmed death receptor-1 (PD-1)–blocking antibody indicated: Squamous Cell Carcinoma of the Anal Canal (SCAC) in combination with carboplatin and paclitaxel for the first-line treatment of adult patients with inoperable locally recurrent or metastatic squamous cell carcinoma of the anal canal (SCAC). ( 1.1 ) as a single agent for the treatment of adult patients with locally recurrent or metastatic SCAC with disease progression on or intolerance to platinum-based chemotherapy. ( 1.1 ) Merkel Cell Carcinoma (MCC) for the treatment of adult patients with metastatic or recurrent locally advanced Merkel cell carcinoma (MCC). ( 1.2 ) 1.1 Squamous Cell Carcinoma of the Anal Canal ZYNYZ, in combination with carboplatin and paclitaxel, is indicated for the first-line treatment of adult patients with inoperable locally recurrent or metastatic squamous cell carcinoma of the anal canal (SCAC). ZYNYZ, as a single agent, is indicated for the treatment of adult patients with locally recurrent or metastatic SCAC with disease progression on or intolerance to platinum‑based chemotherapy. 1.2 Merkel Cell Carcinoma ZYNYZ is indicated for the treatment of adult patients with metastatic or recurrent locally advanced Merkel cell carcinoma (MCC).

2 DOSAGE AND ADMINISTRATION The recommended dosage of ZYNYZ is 500 mg as an intravenous infusion over 30 minutes every 4 weeks. ( 2.1 ) See full prescribing information for dosage modifications for adverse reactions ( 2.2 ) and preparation and administration instructions. ( 2.3 ) 2.1 Recommended Dosage The recommended dosages of ZYNYZ are provided in Table 1. Administer ZYNYZ as an intravenous infusion after dilution, over 30 minutes, as recommended [see Dosage and Administration ( 2.3 )] . Table 1: Recommended Dosage of ZYNYZ Indication Recommended Dosage of ZYNYZ Duration of Treatment Combination Therapy Refer to the Prescribing Information for the agents administered in combination with ZYNYZ for recommended dosing information, as appropriate. Adult patients with inoperable locally recurrent or metastatic SCAC in combination with carboplatin and paclitaxel 500 mg every 4 weeks Until disease progression, unacceptable toxicity, or up to 12 months Monotherapy Adult patients with locally recurrent or metastatic SCAC with disease progression on or intolerance to platinum-based chemotherapy 500 mg every 4 weeks Until disease progression, unacceptable toxicity, or up to 24 months Adult patients with metastatic or recurrent locally advanced MCC 500 mg every 4 weeks Until disease progression, unacceptable toxicity, or up to 24 months 2.2 Dosage Modifications for Adverse Reactions No dose reduction of ZYNYZ is recommended. In general, withhold ZYNYZ for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue ZYNYZ 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 ZYNYZ for adverse reactions that require management different from these general guidelines are summarized in Table 2. Table 2: Recommended Dosage Modifications for Adverse Reactions AST = aspartate aminotransferase; ALT = alanine aminotransferase; DRESS = drug rash with eosinophilia and systemic symptoms; SJS = Stevens-Johnson syndrome; TEN = toxic epidermal necrolysis; ULN = upper limit of normal. Adverse Reaction Severity Toxicity graded per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5. ZYNYZ Dosage Modifications 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 resolution within 12 weeks of initiating steroids or inability to reduce prednisone to less than 10 mg/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 greater than 3 but no more than 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 greater 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 ZYNYZ 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 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 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 Grade 3 or suspected SJS, TEN, or DRESS Withhold Grade 4 or 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 prior to administration. ZYNYZ is a clear to slightly opalescent, colorless to pale yellow solution and is free of particles. Discard the vial if the solution is cloudy, discolored, or contains particulate matter. Do not shake the vial. Preparation Withdraw 20 mL (500 mg) of ZYNYZ from one vial and discard vial with any unused portion. Dilute ZYNYZ with either 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a final concentration between 1.4 mg/mL and 10 mg/mL. Use polyvinylchloride (PVC) and di-2-ethylhexyl phthalate (DEHP), polyolefin copolymer, polyolefin with polyamide, or ethylene vinyl acetate infusion bags. Mix diluted solution by gentle inversion. Do not shake. Visually inspect the infusion bag for particulate matter and discoloration prior to administration. Discard if the solution is discolored or contains particulate matter. Storage of diluted ZYNYZ solution Protect the diluted ZYNYZ solution from light during storage. Store diluted ZYNYZ solution: 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 24 hours from the time of preparation to the end of the infusion. If refrigerated, allow the diluted solution to come to room temperature prior to administration. The diluted solution must be administered within 4 hours (including infusion time) once it is removed from the refrigerator. Do not freeze or shake diluted solution. Administration Administer diluted ZYNYZ solution by intravenous infusion over 30 minutes through a polyethylene, polyurethane, or PVC with DEHP intravenous line containing a sterile, non‑pyrogenic, low-protein binding polyethersulfone, polyvinylidene fluoride, or cellulose acetate 0.2 micron to 5 micron in-line or add-on filter or 15 micron mesh in-line or add-on filter. Do NOT administer ZYNYZ as an intravenous push or bolus injection. Do not co‑administer other drugs through the same infusion line.

6 ADVERSE REACTIONS The following 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 )] ZYNYZ in Combination with Carboplatin and Paclitaxel In patients with SCAC, the most common (≥ 20%) adverse reactions are fatigue, peripheral neuropathy, nausea, alopecia, diarrhea, musculoskeletal pain, constipation, hemorrhage, rash, vomiting, decreased appetite, pruritus, and abdominal pain. ( 6.1 ) ZYNYZ as a Single Agent In patients with SCAC, the most common (≥ 10%) adverse reactions are fatigue, musculoskeletal pain, diarrhea, non-urinary tract infections, perineal pain, hemorrhage, urinary tract infection, rash, nausea, decreased appetite, constipation, abdominal pain, dyspnea, pyrexia, vomiting, cough, pruritus, hypothyroidism, headache, and decreased weight. ( 6.1 ) In patients with MCC, the most common (≥ 10%) adverse reactions are musculoskeletal pain, fatigue, pruritus, diarrhea, rash, pyrexia, nausea, and constipation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Incyte Corporation at 1-855-463-3463 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial 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 safety population described in Warnings and Precautions reflects exposure to ZYNYZ 500 mg as an intravenous infusion every 4 weeks in combination with carboplatin and paclitaxel in 154 patients with SCAC enrolled in the POD1UM-303 trial, and as a single agent in 94 patients with SCAC in the POD1UM-202 trial, 107 patients with MCC in the POD1UM-201 trial, and 251 patients with other solid tumors. All patients received ZYNYZ until disease progression or unacceptable toxicity; those in the POD1UM-202 and POD1UM-201 trials received ZYNYZ for up to 24 months and those in the POD1UM-303 trial received ZYNYZ for up to 12 months. The median duration of exposure of the pooled monotherapy population was 5.4 months (range: 1 day to 27 months). Squamous Cell Carcinoma of the Anal Canal (SCAC) Inoperable Locally Recurrent or Metastatic SCAC: ZYNYZ in Combination with Carboplatin and Paclitaxel The safety of ZYNYZ in patients with inoperable locally recurrent or metastatic SCAC was evaluated in 154 patients enrolled in the POD1UM-303 trial [see Clinical Studies ( 14.1 )] . Patients received ZYNYZ 500 mg or placebo intravenously every 4 weeks in combination with carboplatin and paclitaxel for 6 cycles followed by ZYNYZ 500 mg or placebo every 4 weeks until disease progression or unacceptable toxicity. Among patients who received ZYNYZ, the median duration of exposure was 7.4 months (range: 1 day to 14.6 months). Serious adverse reactions occurred in 47% of patients receiving ZYNYZ in combination with carboplatin and paclitaxel. The most frequent serious adverse reactions (≥ 2% of patients) were sepsis (3.2%), pulmonary embolism (3.2%), diarrhea (2.6%), and vomiting (2.6%). In patients receiving ZYNYZ in combination with carboplatin and paclitaxel, ZYNYZ was permanently discontinued due to an adverse reaction in 11% of patients. Adverse reactions that resulted in permanent discontinuation of ZYNYZ included immune-mediated enterocolitis (2 patients), warm autoimmune hemolytic anemia, hepatitis, adrenal insufficiency, blood bilirubin increased, AST increased, blood alkaline phosphatase increased, arthritis, encephalopathy, peripheral sensorimotor neuropathy, hypothyroidism, immune‑mediated cholangitis, pruritus, malaise, and rash (1 patient each). Dosage interruptions due to an adverse reaction, excluding temporary interruptions due to infusion-related reactions, occurred in 55% of patients who received ZYNYZ in combination with carboplatin and paclitaxel. Adverse reactions that resulted in dosage interruptions in ≥ 2% of patients were neutropenia, anemia, thrombocytopenia, leukopenia, fatigue, COVID-19, and urinary tract infection. The most common (≥ 20%) adverse reactions were fatigue, peripheral neuropathy, nausea, alopecia, diarrhea, musculoskeletal pain, constipation, hemorrhage, rash, vomiting, decreased appetite, pruritus, and abdominal pain. Table 3 and Table 4 summarize adverse reactions and laboratory abnormalities, respectively, that occurred in POD1UM-303. Table 3: Adverse Reactions in ≥ 10% of Patients with Inoperable Locally Recurrent or Metastatic SCAC Receiving ZYNYZ in Combination with Carboplatin and Paclitaxel with a Difference Between Arms of ≥ 5% for All Grades or ≥ 2% for Grades 3 or 4 vs Placebo in Combination with Carboplatin and Paclitaxel in POD1UM-303 ZYNYZ in Combination with Carboplatin and Paclitaxel (N = 154) Placebo in Combination with Carboplatin and Paclitaxel (N = 152) Adverse Reaction All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Gastrointestinal disorders Diarrhea Includes diarrhea, colitis, and frequent bowel movements. 49 5 41 7 Stomatitis Includes stomatitis, aphthous ulcer, cheilitis, mouth ulceration, and mucosal inflammation. 18 0 11 0 Nervous system disorders Peripheral neuropathy Includes peripheral neuropathy, paresthesia, peripheral sensory neuropathy, neuralgia, hypoesthesia, peripheral sensorimotor neuropathy, dysesthesia, peripheral motor neuropathy, and hyperesthesia. 56 5 52 2.6 Musculoskeletal and connective tissue disorders Musculoskeletal pain Includes arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, pain in extremity, and spinal pain. 40 2.6 34 0 Vascular disorders Hemorrhage Includes hemorrhage, anal hemorrhage, anal ulcer hemorrhage, conjunctival hemorrhage, epistaxis, gastrointestinal hemorrhage, genital hemorrhage, hematuria, hemoptysis, hemorrhoidal hemorrhage, lower gastrointestinal hemorrhage, lymph node hemorrhage, rectal hemorrhage, stoma site hemorrhage, tumor hemorrhage, urinary bladder hemorrhage, uterine hemorrhage, vaginal hemorrhage, and wound hemorrhage. 29 3.2 21 0 Skin and subcutaneous tissue disorders Rash Includes rash, eczema, dermatitis acneiform, dermatitis, rash erythematous, rash maculo-papular, rash papular, rash pustular, and rash pruritic. 29 1.3 16 0.7 Pruritus 24 0.6 7 0 Endocrine disorders Hypothyroidism 14 0.6 3.3 0 Graded according to NCI CTCAE v5.0. Table 4: Laboratory Abnormalities that Worsened from Baseline to Grade 3 or 4 Occurring in ≥ 1% of Patients with Inoperable Locally Recurrent or Metastatic SCAC Receiving ZYNYZ in Combination with Carboplatin and Paclitaxel in POD1UM-303 ZYNYZ in Combination with Carboplatin and Paclitaxel The denominator used to calculate the rate varied from 142 to 153 based on the number of patients with a baseline value and at least one post-treatment value. Placebo in Combination with Carboplatin and Paclitaxel Laboratory abnormality All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Hematology Decreased hemoglobin 91 20 92 24 Decreased leukocytes 88 44 90 40 Decreased neutrophils 79 52 78 39 Decreased lymphocytes 77 40 69 38 Decreased platelets 55 6 52 4 Chemistry Decreased albumin 37 2 29 1.3 Increased alanine aminotransferase 35 3.9 23 0.7 Increased aspartate aminotransferase 26 3.9 16 0 Increased alkaline phosphatase 26 2 25 0 Decreased potassium 24 5 16 2.6 Increased calcium 23 2 20 1.3 Increased lipase 18 4.9 15 0.7 Increased bilirubin 10 1.3 4.6 1.3 Graded according to NCI CTCAE v5.0. Platinum-refractory Intolerant Locally Recurrent or Metastatic SCAC: ZYNYZ as a Single Agent The safety of ZYNYZ in patients with platinum-refractory intolerant locally recurrent or metastatic SCAC was evaluated in 94 patients in the POD1UM‑202 trial [see Clinical Studies ( 14.1 )] . Patients received ZYNYZ 500 mg intravenously every 4 weeks until disease progression, unacceptable toxicity, or up to 24 months. The median duration of exposure was 2.8 months (range: 1 day to 27.1 months). Serious adverse reactions occurred in 40% of patients receiving ZYNYZ. The most frequent serious adverse reactions (≥ 2% of patients) were non-urinary tract infection, perineal pain, abdominal pain, anemia, hemorrhage, diarrhea, pyrexia, urinary tract infection, musculoskeletal pain, and dyspnea. Permanent discontinuation of ZYNYZ due to an adverse reaction occurred in 4.3% of patients. These adverse reactions included diarrhea, non-urinary tract infection, perineal pain, and rash. Dosage interruptions due to an adverse reaction occurred in 21% of patients who received ZYNYZ. Adverse reactions that resulted in dose delay in ≥ 2% of patients who received ZYNYZ were non-urinary tract infection, rash, diarrhea, abdominal pain, hemorrhage, musculoskeletal pain, pyrexia, and urinary tract infection. The most common (≥ 10%) adverse reactions that occurred in patients receiving ZYNYZ were fatigue, musculoskeletal pain, diarrhea, non-urinary tract infections, perineal pain, hemorrhage, urinary tract infection, rash, nausea, decreased appetite, constipation, abdominal pain, dyspnea, pyrexia, vomiting, cough, pruritus, hypothyroidism, headache, and decreased weight. Table 5 and Table 6 summarize adverse reactions and laboratory abnormalities, respectively, that occurred in POD1UM-202. Table 5: Adverse Reactions in ≥ 10% of Patients with Platinum-Refractory Locally Recurrent or Metastatic SCAC Receiving ZYNYZ in POD1UM-202 Adverse Reaction ZYNYZ (N = 94) All Grades (%) Grades 3-4 (%) General disorders and administration site conditions Fatigue Includes fatigue and asthenia. 42 7 Pyrexia 14 2.1 Musculoskeletal and connective tissue disorders Musculoskeletal pain Includes arthralgia, back pain, bone pain, musculoskeletal chest pain, myalgia, non-cardiac chest pain, osteoarthritis, pain in extremity, and spinal pain. 27 2.1 Gastrointestinal disorders Diarrhea Includes diarrhea, gastroenteritis, and immune-mediated enterocolitis. 23 2.1 Nausea 16 0 Constipation 15 0 Abdominal pain Includes abdominal pain, abdominal discomfort, and abdominal pain upper. 14 3.2 Vomiting 14 1.1 Infections and infestations Non-urinary tract infections Includes anal abscess, cellulitis, cholangitis, cholecystitis, cholecystitis acute, device related infection, herpes zoster, Lyme disease, pelvic infection, peritonitis, Pneumocystis jirovecii pneumonia, pneumonia, postoperative wound infection, pseudomonas infection, sepsis, skin infection, stoma site infection, and wound infection bacterial. 21 12 Urinary tract infection Includes urinary tract infection, cystitis, escherichia urinary tract infection, and pyelonephritis. 17 2.1 Reproductive system and breast disorders Perineal pain Includes anorectal discomfort, pelvic pain, proctalgia, and vulvovaginal discomfort. 19 7 Vascular disorders Hemorrhage Includes epistaxis, hematochezia, hematuria, proctitis hemorrhagic, rectal hemorrhage, stoma site hemorrhage, and vaginal hemorrhage. 19 3.2 Skin and subcutaneous tissue disorders Rash Includes rash, dermatitis, dermatitis acneiform, eczema, erythema, palmar-plantar erythrodysesthesia syndrome, rash erythematous, and rash maculo-papular. 16 2.1 Pruritus 12 0 Metabolism and nutrition disorders Decreased appetite Includes decreased appetite and hypophagia. 15 2.1 Respiratory, thoracic, and mediastinal disorders Dyspnea 14 3.2 Cough Includes cough and productive cough. 13 0 Endocrine disorders Hypothyroidism 10 0 Nervous system disorders Headache 10 0 Investigations Decreased weight 10 0 Graded according to NCI CTCAE v5.0. Table 6: Laboratory Abnormalities that Worsened from Baseline to Grade 3 or 4 Occurring in ≥ 1% of Patients with Platinum-Refractory Locally Recurrent or Metastatic SCAC Receiving ZYNYZ in POD1UM-202 Laboratory abnormality ZYNYZ The denominator used to calculate the rate varied from 59 to 87 based on the number of patients with a baseline value and at least one post-treatment value. All Grades (%) Grades 3-4 (%) Hematology Decreased hemoglobin 35 2.3 Decreased lymphocytes 33 6 Chemistry Decreased albumin 36 1.2 Increased aspartate aminotransferase 28 1.1 Decreased sodium 24 1.2 Increased triglycerides 19 3.4 Increased lipase 17 1.3 Increased alanine aminotransferase 16 1.1 Increased bilirubin 8 2.3 Graded according to NCI CTCAE v5.0. Merkel Cell Carcinoma (MCC) Metastatic or Recurrent Locally Advanced MCC: ZYNYZ as a Single Agent The safety of ZYNYZ was evaluated in 107 patients enrolled in the POD1UM-201 trial with metastatic or recurrent locally advanced MCC [see Clinical Studies (14.2)] . Patients received ZYNYZ 500 mg intravenously every 4 weeks until disease progression, unacceptable toxicity, or up to 24 months. The median duration of exposure was 10.3 months (range: 1 day to 25 months). Serious adverse reactions occurred in 26% of patients receiving ZYNYZ. The most frequent serious adverse reactions (≥ 2% of patients) were fatigue, arrhythmia, and pneumonitis. Permanent discontinuation of ZYNYZ due to an adverse reaction occurred in 21% of patients. These included asthenia, colitis, demyelinating polyneuropathy, diarrhea, drug hypersensitivity, eosinophilic fasciitis, hepatitis, hypophysitis, increased transaminases, infusion-related reaction, pancreatitis, polyarthritis, radiculopathy, toxic epidermal necrolysis, and tubulointerstitial nephritis (1 patient each). Dosage interruptions due to an adverse reaction occurred in 39% of patients who received ZYNYZ. Adverse reactions or laboratory abnormalities that required dosage interruption in > 2% of patients who received ZYNYZ were increased transaminases, increased lipase, increased amylase, and pyrexia. The most common (≥ 10%) adverse reactions that occurred in patients receiving ZYNYZ were musculoskeletal pain, fatigue, pruritus, diarrhea, rash, pyrexia, nausea, and constipation. Table 7 and Table 8 summarize adverse reactions and laboratory abnormalities, respectively, that occurred in POD1UM-201. Table 7: Adverse Reactions in ≥ 10% of Patients with Metastatic or Recurrent Locally Advanced MCC Receiving ZYNYZ in POD1UM-201 Graded according to NCI CTCAE v5.0. Adverse Reaction ZYNYZ (N = 107) All Grades (%) Grades 3-4 (%) Musculoskeletal and connective tissue disorders Musculoskeletal pain Includes arthralgia, back pain, bone pain, pain in extremity, neck pain, myalgia, and musculoskeletal chest pain. 37 3 General disorders and administration site conditions Fatigue Includes fatigue and asthenia. 33 1 Pyrexia 12 0 Skin and subcutaneous tissue disorders Pruritus 22 0 Rash Includes rash, dermatitis, dermatitis bullous, rash erythematous, rash maculo-papular, rash papular, rash pruritic, psoriasis, and toxic epidermal necrolysis. 17 2 Gastrointestinal disorders Diarrhea 19 0 Nausea 12 0 Constipation 11 0 Table 8: Laboratory Abnormalities that Worsened from Baseline to Grade 3 or 4 Occurring in > 1% of Patients with Metastatic or Recurrent Locally Advanced MCC Receiving ZYNYZ in POD1UM-201 Graded according to NCI CTCAE v5.0. ZYNYZ The denominator used to calculate the rate varied from 96 to 101 based on the number of patients with a baseline value and at least one post-treatment value. Laboratory Abnormality All Grades (%) Grades 3-4 (%) Hematology Decreased lymphocytes 31 11 Decreased neutrophils 14 3 Chemistry Increased lipase 39 5 Increased aspartate aminotransferase 28 3 Decreased sodium 27 3 Increased alanine aminotransferase 26 4 Increased alkaline phosphatase 22 2 Decreased potassium 15 2

12.3 Pharmacokinetics The pharmacokinetics of retifanlimab-dlwr were evaluated in patients with various solid tumors, including patients with SCAC and patients with MCC. Retifanlimab-dlwr exposures (maximum concentration [C max ] and area under the curve [AUC]) increased proportionally over a dosage range from 375 mg to 750 mg (0.75- to 1.5-fold of the approved recommended dose). Following administration of retifanlimab-dlwr at 500 mg every 4 weeks, steady-state concentrations were achieved at Cycle 6 (approximately 6 months) and systemic accumulation was 1.3-fold. Distribution The geometric mean volume of distribution at steady state for retifanlimab-dlwr is 6.0 L (coefficient of variation [CV]: 20%). Elimination The elimination half-life of retifanlimab-dlwr at steady state is 19 days (CV: 30%). Clearance of retifanlimab-dlwr after the first dose was 0.3 L/day (CV: 38%) and decreased over time by approximately 23%, resulting in a steady-state clearance of 0.23 L/day. Specific Populations The following factors have no clinically meaningful effect on the pharmacokinetics of retifanlimab-dlwr: age (18 to 94 years), sex, body weight (33 to 133 kg), race (White, Black, Asian), albumin level (17 to 54 g/L), Eastern Cooperative Oncology Group (ECOG) score (0 to 2), tumor burden (sum of the target lesion diameters: 0 to 360 mm), HIV status, renal function (estimated glomerular filtration rate ≥ 26 mL/min/1.73 m 2 ), or mild hepatic impairment (total bilirubin less than or equal to the ULN and AST greater than ULN or total bilirubin greater than ULN and less than or equal to 1.5 times ULN and any AST). The pharmacokinetics of retifanlimab-dlwr have not been studied in patients with moderate or severe hepatic impairment.