1 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.

6 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 filtration rate decreased, renal failure, renal impairment 9 Includes arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, myalgia, neck pain, pain in extremity, spinal pain Table 4 summarizes the laboratory abnormalities in AK105-304.

Table 4 Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with Recurrent or Metastatic NPC Who Received Penpulimab-kcqx in Combination with Either Cisplatin or Carboplatin and Gemcitabine in Study AK105-304 Laboratory Abnormality Penpulimab-kcqx Cisplatin or Carboplatin /Gemcitabine 2 Placebo Cisplatin or Carboplatin /Gemcitabine 3 All Grades 1 (%) Grade 3 or 4 1 (%) All Grades 1 (%) Grade 3 or 4 1 (%) Hematology White blood cell decreased 99 58 97 58 Hemoglobin decreased 98 49 97 47 Lymphocytes decreased 93 70 89 58 Neutrophils decreased 92 61 95 65 Chemistry Magnesium decreased 69 4.2 58 3.6 Sodium decreased 62 7 58 7 Triglycerides increased 58 4.3 53 4.3 Aspartate aminotransferase increased 52 6 37 2.9 Cholesterol increased 49 2.2 46 0.7 Creatinine increased 48 1.4 39 0.7 Albumin decreased 47 0 44 1.4 Potassium decreased 45 14 31 3.6 Alanine aminotransferase increased 42 8 37 2.1 GGT increased 36 1.4 33 0.7 Alkaline phosphatase increased 32 0.7 30 0 Lipase increased 28 11 23 3.9 Chloride decreased 25 1.4 11 0 Serum amylase increased 23 2.9 17 0.7 Glucose decreased 22 1.4 20 0.7 Lipids increased 21 1.4 20 0.7 1 Toxicity graded according to NCI CTCAE v5.0.

2 The denominator used to calculate the rate varied from 102 to 146 based on the number of patients with a baseline value and at least one post-treatment value.

3 The denominator used to calculate the rate varied from 103 to 142 based on the number of patients with a baseline value and at least one post-treatment value.

Recurrent Metastatic Non-Keratinizing Nasopharyngeal Carcinoma Study AK105-202 The safety of penpulimab-kcqx as a single agent was evaluated in Study AK105-202 [see Clinical Studies (14.2) ].

Eligible patients had metastatic non-keratinizing NPC and had received prior platinum-based chemotherapy and at least one other line of therapy or had disease progression within 6 months of completion of platinum-based chemotherapy administered as neoadjuvant, adjuvant, or definitive chemoradiation treatment.

Patients received penpulimab-kcqx 200 mg intravenously every 2 weeks until unacceptable toxicity, disease progression, or a maximum of 24 months.

Among patients who received penpulimab-kcqx, 45% were exposed for 6 months or longer and 30% for exposed for greater than one year.

The median age of patients who received penpulimab-kcqx was 50 years (20 to 66 years); 76% were male; 100% were Asian, 100% had recurrent disease; baseline Eastern Cooperative Oncology Group (ECOG) performance score was 0 (31%) or 1 (69%).

All patients had received at least one prior systemic therapy and prior radiation.

Serious adverse reactions occurred in 22% of patients.

Serious adverse reactions in ≥1% were pneumonia (3.8%), pneumonitis (1.5%), respiratory failure (1.5%), rash (1.5%).

Fatal adverse reactions occurred in 1% of patients treated with penpulimab-kcqx, including a case each of pneumonitis, septic shock, colitis, and hepatitis.

Permanent discontinuation of penpulimab-kcqx due to an adverse reaction occurred in 3.8% of patients.

Adverse reactions which resulted in permanent discontinuation of penpulimab-kcqx in ≥1% were rash, hepatitis, herpes zoster, spinal cord compression and pleural effusion (0.8% each).

Dose interruptions of penpulimab-kcqx due to an adverse reaction occurred in 25% of patients.

Adverse reactions which required dose interruption in ≥ 1% of patients included hepatitis (6.2%), anemia (3.1%), pneumonia (3.1%), hypothyroidism (3.1%), rash (1.5%) and white blood cells decreased (1.5%).

Table 5 summarizes the adverse reactions in AK105-202.

Table 5 Adverse Reactions (≥ 10%) in Patients with Recurrent Metastatic Non-Keratinizing NPC Who Received Penpulimab-kcqx in Study AK105-202 Adverse Reaction Penpulimab-kcqx N = 130 All Grades 1 (%) Grade 3 or 4 1 (%) Endocrine disorders Hypothyroidism 2 39 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain 3 25 0.8 Investigations Weight decreased 19 1.5 General disorders and administration site conditions Pyrexia 15 0 Infections and infestations Upper respiratory tract infection 13 0.8 Respiratory, thoracic and mediastinal disorders Cough 4 11 0 Skin and subcutaneous tissue disorders Rash 5 11 2.3 1 Graded per NCI CTCAE v5.0 2 Includes blood thyroid stimulating hormone increased 3 Includes arthralgia, back pain, bone pain, musculoskeletal chest pain, neck pain, non-cardiac chest pain, pain in extremity 4 Includes productive cough 5 Includes dermatitis acneiform, eczema, pemphigoid Table 6 summarizes the laboratory abnormalities in AK105-202.

Table 6 Select Laboratory Abnormalities (≥20%) Worsening from Baseline in Patients with Recurrent Metastatic Non-Keratinizing NPC Who Received Penpulimab-kcqx in Study AK105-202 Laboratory Abnormality Penpulimab-kcqx All Grades 1 (%) 2 Grades 3 or 4 (%) Chemistry Creatinine increased 81 0 Phosphate decreased 47 8 Sodium decreased 46 6 Albumin decreased 45 0 Triglycerides increased 38 3.1 Alkaline phosphatase increased 35 5 Aspartate aminotransferase increased 33 3.9 GGT increased 34 8 Glucose increased 34 0 Magnesium decreased 28 0.8 Activated partial thromboplastin time prolonged 22 0 Alanine aminotransferase increased 20 3.9 Hematology Lymphocytes decreased 43 16 Hemoglobin decreased 36 4.7 1 Toxicity graded according to NCI CTCAE v5.0.

2 Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: penpulimab-kcqx (range of the patient number: 128 to130).