Penpulimab

INDICATIONS AND USAGE Penpulimab-kcqx is a programmed death receptor-1 (PD-1)-blocking antibody indicated: in combination with either cisplatin or carboplatin and gemcitabine for the first-line treatment of adults with recurrent or metastatic non-keratinizing nasopharyngeal carcinoma (NPC) ( 1.1 ) as a single agent for the treatment of adults with metastatic non-keratinizing NPC with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy. ( 1.2 ) 1.1 First-line Treatment of Recurrent or Metastatic Non-Keratinizing Nasopharyngeal Carcinoma Penpulimab-kcqx, in combination with either cisplatin or carboplatin and gemcitabine, is indicated for the first-line treatment of adults with recurrent or metastatic non-keratinizing nasopharyngeal carcinoma (NPC). 1.2 Recurrent Metastatic Non-Keratinizing Nasopharyngeal Carcinoma Penpulimab-kcqx, as a single agent, is indicated for the treatment of adults with metastatic non-keratinizing NPC and disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy.

DOSAGE AND ADMINISTRATION Penpulimab-kcqx in combination with either cisplatin or carboplatin and gemcitabine: 200 mg intravenously over 60 minutes every 3 weeks until disease progression or a maximum of 24 months. ( 2.1 ) Penpulimab-kcqx as a single agent: 200 mg intravenously over 60 minutes every 2 weeks until disease progression or a maximum of 24 months. ( 2.2 ) Dilute prior to administration. ( 2.4 ) 2.1 Recommended Dosage of Penpulimab-kcqx in Combination with Either Cisplatin or Carboplatin and Gemcitabine – Every 3 Week Dosing First-line Treatment of Recurrent or Metastatic Nasopharyngeal Carcinoma The recommended dosage of penpulimab-kcqx is 200 mg administered as an intravenous infusion over 60 minutes every 3 weeks until disease progression or unacceptable toxicity, for a maximum of 24 months. Table 1 Order of Administration and Regimen for Penpulimab-kcqx in Combination with Either Cisplatin or Carboplatin and Gemcitabine Administer the regimen in the following order: penpulimab-kcqx first, gemcitabine second and cisplatin or carboplatin last. Drug and Dose Duration/ Timing of Treatment penpulimab-kcqx 200 mg intravenously Every 3 weeks for 6 cycles, and then every 3 weeks until unacceptable toxicity or disease progression for a maximum of 24 months gemcitabine 1000 mg/m 2 intravenously Every 3 weeks for 6 cycles cisplatin 80 mg/m 2 intravenously or carboplatin AUC 5 intravenously Every 3 weeks for 6 cycles 2.2 Recommended Dosage of Penpulimab-kcqx as a Single Agent – Every 2 Week Dosing Recurrent Metastatic Non-Keratinizing Nasopharyngeal Carcinoma The recommended dosage of penpulimab-kcqx is 200 mg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity, for a maximum of 24 months. 2.3 Dosage Modifications of Penpulimab-kcqx for Adverse Reactions No dose reduction for penpulimab-kcqx is recommended. In general, withhold penpulimab-kcqx for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue penpulimab-kcqx 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 or equivalent per day within 12 weeks of initiating steroids. Dosage modifications for penpulimab-kcqx in combination or penpulimab-kcqx as a single agent for adverse reactions that require management different from these general guidelines are summarized in Table 2 . Table 2 Recommended Dosage Modification for Adverse Reactions Adverse Reaction Severity* Dosage Modification Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1) ] Pneumonitis Grade 2 Withhold † 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 ‡ 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 † ALT or AST 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 * Based on Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 † Resume in patients with complete or partial resolution (Grades 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 10 mg per day or less (or equivalent) within 12 weeks of initiating steroids. ‡ If AST and ALT are less than or equal to ULN at baseline, withhold or permanently discontinue penpulimab-kcqx based on recommendations for hepatitis with no liver involvement. 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 2.4 Preparation and Administration Preparation and Storage of Diluted Solution Inspect the solution for particulate matter and discoloration. The solution is clear to slightly opalescent, colorless to yellowish. Discard the vial if the solution is cloudy, discolored, or contains visible particles. Dilute penpulimab-kcqx injection prior to intravenous administration. Withdraw the required volume from two vials of penpulimab-kcqx and transfer into an intravenous (IV) bag containing 100 mL or less of 0.9% Sodium Chloride Injection, USP. Gently invert the bag to mix the diluted solution . Do not shake. The final concentration of the diluted solution should be between 2 mg/mL to 5 mg/mL. Discard any unused portion left in the vial. The product does not contain a preservative. Administer diluted solution immediately once prepared. If diluted solution is not administered immediately the total time from dilution to the end of the infusion should not exceed 4 hours. Store the diluted solution up to 4 hours either at room temperature 20°C to 25°C (68°F to 77°F), or refrigerated at 2°C to 8°C (36°F to 46°F). Discard after 4 hours. Do not freeze. Administration Administer diluted solution intravenously over 60 minutes through an intravenous line containing a sterile, non-pyrogenic, low-protein binding 0.2 micron to 0.22 micron in-line or add-on filter. Do not co-administer other drugs through the same infusion line.

WARNINGS AND PRECAUTIONS Immune-Mediated Adverse Reactions ( 5.1 ) o 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 and hepatotoxicity, immune-mediated endocrinopathies, immune-mediated dermatologic adverse reactions, immune-mediated nephritis and renal dysfunction, immune-mediated dermatologic adverse reactions and solid organ transplant rejection. o Monitor for early identification and management. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. o Withhold or permanently discontinue penpulimab-kcqx based on severity and type of reaction. Infusion-Related Reactions: Interrupt, slow the rate of infusion, or permanently discontinue penpulimab-kcqx based on the severity of the reaction. ( 5.2 ) Complications of Allogeneic 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 to use effective contraception. ( 5.4 , 8.1 , 8.3 ) 5.1 Severe and Fatal Immune-Mediated Adverse Reactions Penpulimab-kcqx is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death-receptor 1 (PD-1) or the 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. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and can affect more than one body system simultaneously. Immune-mediated adverse reactions can occur at any time after starting treatment with a 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. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients 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 penpulimab-kcqx depending on severity [see Dosage and Administration (2) ] . In general, if penpulimab-kcqx requires interruption or discontinuation, administer systemic corticosteroid therapy (1 mg 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 [ see Dosage and A dministration (2) ] . Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. 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 Penpulimab-kcqx can cause immune-mediated pneumonitis. In patients treated with other PD-1/PD-L1 blocking antibodies, the incidence of pneumonitis is higher in patients who have received prior thoracic radiation. Penpulimab-kcqx in Combination with Either Cisplatin or Carboplatin and Gemcitabine Immune-mediated pneumonitis occurred in 0.7% (1/146) of patients receiving penpulimab-kcqx, which was a Grade 2 (0.7%) adverse reaction. Systemic corticosteroids were required in the patient. Pneumonitis led to withholding of penpulimab-kcqx in the patient. Penpulimab-kcqx as a Single Agent Immune-mediated pneumonitis occurred in 1.3% (5/372) of patients receiving penpulimab-kcqx, including Grade 3 (0.5%), Grade 2 (0.5%) and Grade 1 (0.3%) adverse reactions. Systemic corticosteroids were required in 80% (4/5) of patients with pneumonitis. Pneumonitis led to permanent discontinuation of penpulimab-kcqx in 0.8% (3/372). Pneumonitis resolved in 20% (1/5) of these patients. Immune -Mediated Colitis Penpulimab-kcqx can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus (CMV) infection/reactivation can occur in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Penpulimab-kcqx as a Single Agent Immune-mediated colitis occurred in 1.1% (4/372) of patients receiving penpulimab-kcqx, including Grade 2 (0.8%) and Grade 1 (0.3%) adverse reactions. Systemic corticosteroids were required in 75% (3/4) of patients with colitis. Colitis led to withholding of penpulimab-kcqx in 0.8% (3/372) of patients. Immune-Mediated Hepatitis and Hepatotoxicity Penpulimab-kcqx can cause immune-mediated hepatitis. Penpulimab-kcqx in Combination with Either Cisplatin or Carboplatin and Gemcitabine Immune-mediated hepatitis occurred in 0.7% (1/146) of patients receiving penpulimab-kcqx in combination with either cisplatin or carboplatin and gemcitabine, which was a Grade 2 (0.7%) adverse reaction. Systemic corticosteroids and withholding of penpulimab-kcqx were required in this patient. Penpulimab-kcqx as a Single Agent Immune-mediated hepatitis occurred in 3.8% (14/372) of patients receiving penpulimab-kcqx, including Grade 3 (0.8%), Grade 2 (1.3%) and Grade 1 (1.6%) adverse reactions. Systemic corticosteroids were required in 14% (2/14) of patients with hepatitis. Hepatitis led to permanent discontinuation of penpulimab-kcqx in 0.3% (1/372) and withholding of penpulimab-kcqx in 2.2% (8/372) of patients. Hepatitis resolved in 64% (9/14) of these patients. Immune-Mediated Endocrinopathies Adrenal Insufficiency Penpulimab-kcqx can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold penpulimab-kcqx depending on severity [see Dosage and Administration (2.2) ]. Hypophysitis Penpulimab-kcqx can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue penpulimab-kcqx depending on severity [see Dosage and Administration (2.2) ]. Thyroid Disorders: Penpulimab-kcqx can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement therapy for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue penpulimab-kcqx based on the severity [ see Dosage and Administration (2) ] . Penpulimab-kcqx in Combination with Either Cisplatin or Carboplatin and Gemcitabine Hyperthyroidism: Immune-mediated hyperthyroidism occurred in 2.1% (3/146) of patients receiving penpulimab-kcqx in combination with either cisplatin or carboplatin and gemcitabine, including Grade 2 (0.7%) and Grade 1 (1.4%) adverse reactions. Hypothyroidism: Immune-mediated hypothyroidism occurred in 16% (26/146) of patients receiving penpulimab-kcqx

CONTRAINDICATIONS None. None.(4)

ADVERSE REACTIONS The following adverse reactions are described in other sections of 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) ] Penpulimab-kcqx in combination with either cisplatin or carboplatin and gemcitabine : The most common adverse reactions (≥20%) were nausea, vomiting, hypothyroidism, constipation, decreased appetite, decreased weight, cough, COVID-19 infection, fatigue, rash, and pyrexia. (6.1) Penpulimab-kcqx as a single agent : The most common adverse reactions (≥20%) were anemia and hypothyroidism. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Akeso Biopharma Co., Ltd. at toll-free phone 833-662-5376 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to those observed in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in the WARNINGS AND PRECAUTIONS reflect exposure to penpulimab-kcqx in 146 patients in Study AK105-304 [see Clinical Studies (14.1) ] . Patients received 6 cycles every 3 weeks of intravenous penpulimab-kcqx 200 mg in combination with either cisplatin 80 mg/m 2 or carboplatin AUC 5 and gemcitabine 1000 mg/m 2 followed by single-agent penpulimab-kcqx 200 mg every 3 weeks until disease progression or a maximum of 24 months. Among the 146 patients who received penpulimab-kcqx in combination with either cisplatin or carboplatin and gemcitabine, 71% were exposed for 6 months or longer and 38% were exposed for greater than one year. In this safety population, the most common (≥ 20%) adverse reactions were nausea (58%), vomiting (55%), hypothyroidism (45%), constipation (41%), decreased appetite (36%), decreased weight (26%), cough (25%), COVID-19 infection (25%), fatigue (25%), rash (24%) and pyrexia (21%). The most common Grade 3 to 4 laboratory abnormalities (≥ 2%) were decreased lymphocytes (70%), decreased neutrophils (61%), decreased white blood cells (58%), decreased hemoglobin (49%), decreased platelets (33%), decreased potassium (14%), increased lipase (11%), increased ALT (8%), decreased sodium (7%), increased AST (6%), increased triglycerides (4.3%), decreased magnesium (4.2%), decreased CPK (4.1%), increased amylase (2.9%), increased potassium (2.8%), increased cholesterol (2.2%), increased calcium (2.1%) and increased blood bilirubin (2.1%). The data described in the WARNINGS AND PRECAUTIONS also reflect exposure to single-agent intravenous penpulimab-kcqx 200 mg every 2 weeks until disease progression or a maximum of 24 months in 372 patients in studies: AK105-101 [NCT03352531], AK-105-201 [NCT03722147], AK105-202 [see Clinical Studies (14.2)] , AK105-204 [NCT 04172506]. Among the 372 patients who received single-agent penpulimab-kcqx, 49% were exposed for 6 months or longer and 34% were exposed for at least one year. In this safety population, the most common (≥20%) adverse reactions were anemia (25%) and hypothyroidism (23%). The most common Grade 3 to 4 laboratory abnormalities (≥ 2%) were decreased lymphocytes (11%), increased GGT (9%), decreased phosphate (6%), decreased sodium (4.7%), increased aspartate aminotransferase (4.4%), increased alkaline phosphatase (4%), decreased hemoglobin (3.6%), increased bilirubin (2.7%), increased glucose (3%), increased triglycerides (2.8%), increased alanine aminotransferase (2.5%), increased magnesium (3.3%), and decreased platelets (2.5%). First line Recurrent or Metastatic Nasopharyngeal Carcinoma Study AK105-304 The safety of penpulimab-kcqx in combination with either cisplatin or carboplatin and gemcitabine was evaluated in Study AK105-304 [see Clinical Studies (14.1) ] . Patients received intravenous placebo or penpulimab-kcqx 200 mg every 3 weeks in combination with 6 cycles of either cisplatin 80 mg/m 2 or carboplatin AUC 5 and gemcitabine 1000 mg/m 2 every 3 weeks followed by placebo or penpulimab-kcqx 200 mg intravenously every 3 weeks until unacceptable toxicity, disease progression or a maximum of 24 months. Among patients who received penpulimab-kcqx, 71% were exposed for 6 months or longer and 38% were exposed for greater than one year. The median age of patients who received penpulimab-kcqx was 51 years (23 to 75 years); 82% were male; 97% were Asian, 3.4% were White; 2.1% were Hispanic or Latino, baseline Eastern Cooperative Oncology Group (ECOG) performance score was 0 (36%) or 1 (64%). Of the 146 patients, 69% of patients had received at least one prior systemic therapy and 100% of patients had received prior radiation therapy. Serious adverse reactions occurred in 51% of patients. The most frequent serious adverse reactions (≥2%) were thrombocytopenia (19%), decreased neutrophils (14%), decreased white blood cells (12%), anemia (8%), myelosuppression (3.4%), decreased sodium (2.7%), pneumonia (2.1%), and nausea (2.1%). Of the patients who received penpulimab-kcqx in combination with either cisplatin or carboplatin and gemcitabine, there was one fatal adverse reaction (0.7%) due to syndrome of inappropriate antidiuretic hormone secretion (SIADH). Permanent discontinuation of penpulimab-kcqx due to an adverse reaction occurred in 3.4% of patients. Adverse reactions which resulted in permanent discontinuation of penpulimab-kcqx were acute myocardial infarction, acute kidney injury, brain edema, diabetic ketoacidosis, increased potassium, increased lipase, and thrombocytopenia (0.7% each). Dose interruptions of penpulimab-kcqx due to an adverse reaction occurred in 64% of patients. Adverse reactions which required dose interruption in ≥ 2% of patients included COVID-19 (16%), anemia (16%), thrombocytopenia (14%), decreased white blood cells (14%), decreased neutrophils (10%), pneumonia (10%), increased alanine aminotransferase (3.4%), increased aspartate aminotransferase (2.7%), decreased sodium (2.7%), increased blood creatinine (2.7%), pyrexia (2.1%), and upper respiratory tract infection (2.1%). Table 3 summarizes the adverse reactions in Study AK105-304. Table 3 Adverse Reactions (≥ 10%) in Patients with Recurrent or Metastatic NPC Who Received Penpulimab-kcqx in Combination with Either Cisplatin or Carboplatin and Gemcitabine in Study AK105-304 Adverse Reaction Penpulimab-kcqx Cisplatin or Carboplatin and Gemcitabine N = 146 Placebo Cisplatin or Carboplatin and Gemcitabine N = 142 All Grades 1 (%) Grade 3 or 4 1 (%) All Grades 1 (%) Grade 3 or 4 1 (%) Gastrointestinal disorders Nausea 58 2.1 64 0 Vomiting 2 55 1.4 54 1.4 Constipation 41 0 44 0 Abdominal distension 12 0 6 0 Endocrine disorders Hypothyroidism 3 45 0 27 0 Metabolism and nutrition disorders Decreased appetite 36 0 39 0 Investigations Weight decreased 26 1.4 16 0 Respiratory, thoracic and mediastinal disorders Cough 4 25 0 16 0 Infections and infestations COVID-19 25 0 17 0.7 General disorders and administration site conditions Fatigue 5 25 1.4 22 0 Pyrexia 21 0 20 0.7 Malaise 10 0 8 0 Skin and subcutaneous tissue disorders Rash 6 24 1.4 20 0 Pruritus 11 0 11 0 Nervous system disorders Headache 15 0.7 10 0.7 Dizziness 7 14 0 15 0.7 Renal and urinary disorders Proteinuria 14 0 13 0 Acute kidney injury 8 13 1.4 4.9 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain 9 14 0.7 24 0 Psychiatric disorders Insomnia 12 0 10 0 1 Graded per NCI CTCAE v5.0 2 Includes retching 3 Includes blood thyroid stimulating hormone increased, secondary hypothyroidism 4 Includes productive cough, upper-airway cough syndrome 5 Includes asthenia 6 Includes dermatitis, dermatitis acneiform, drug eruption, eczema, rash maculo-papular, rash papular, rash pustular 7 Includes vertigo 8 Includes acute kidney injury, creatinine renal clearance decreased, glomerular fi

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. Penpulimab-kcqx injection is a humanized IgG1 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 murine tumor models, blocking PD-1 activity resulted in decreased tumor growth.