TEVIMBRA

1 INDICATIONS AND USAGE TEVIMBRA is a programmed death receptor-1 (PD-1)-blocking antibody indicated for: Esophageal Cancer in combination with platinum-containing chemotherapy for the first-line treatment of adults with unresectable or metastatic esophageal squamous cell carcinoma (ESCC) whose tumors express PD-L1 (≥1). ( 1.1 ) as a single agent in adults with unresectable or metastatic esophageal squamous cell carcinoma (ESCC) after prior systemic chemotherapy that did not include a PD-(L)1 inhibitor. ( 1.1 ) Gastric Cancer in combination with platinum and fluoropyrimidine-based chemotherapy in adults for the first line treatment of unresectable or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 (≥1). ( 1.2 ) 1.1 Esophageal Cancer First-Line Treatment of Esophageal Squamous Cell Carcinoma TEVIMBRA, in combination with platinum-containing chemotherapy, is indicated for the first-line treatment of adults with unresectable or metastatic esophageal squamous cell carcinoma (ESCC) whose tumors express PD-L1 (≥1). Previously Treated Esophageal Squamous Cell Carcinoma TEVIMBRA, as a single agent, is indicated for the treatment of adults with unresectable or metastatic esophageal squamous cell carcinoma (ESCC) after prior systemic chemotherapy that did not include a PD-(L)1 inhibitor. 1.2 Gastric Cancer TEVIMBRA, in combination with platinum and fluoropyrimidine-based chemotherapy, is indicated for the first-line treatment of adults with unresectable or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma (G/GEJ) whose tumors express PD-L1 (≥1).

2 DOSAGE AND ADMINISTRATION Recommended Dosage: Esophageal Cancer 150 mg every 2 weeks or 200 mg every 3 weeks or 300 mg every 4 weeks or 400 mg every 6 weeks in combination with platinum-containing chemotherapy for first-line treatment of unresectable or metastatic ESCC. ( 2.2 ) 150 mg every 2 weeks or 200 mg every 3 weeks or 300 mg every 4 weeks or 400 mg every 6 weeks as a single agent for treatment of unresectable or metastatic ESCC. ( 2.2 ) Gastric Cancer 150 mg every 2 weeks or 200 mg every 3 weeks or 300 mg every 4 weeks or 400 mg every 6 weeks in combination with platinum and fluoropyrimidine-based chemotherapy. ( 2.2 ) 2.1 Patient Selection Select patients for the first-line treatment of unresectable or metastatic esophageal squamous cell carcinoma based on the presence of PD-L1 in tumor specimens [see Clinical Studies (14.1) ]. An FDA-approved companion diagnostic for the detection of PD-L1 in patients with unresectable or metastatic esophageal squamous cell carcinoma is not available. Select patients for the first-line treatment of unresectable or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma (G/GEJ) based on the presence of PD-L1 in tumor specimens [see Clinical Studies (14.2) ] . An FDA-approved companion diagnostic for the detection of PD-L1 in patients with unresectable or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma (G/GEJ) is not available. 2.2 Recommended Dosage The recommended dosages of TEVIMBRA administered intravenously as a single agent or in combination with other therapeutic agents are presented in Table 1. Table 1: Recommended Dosages for TEVIMBRA as a Single Agent or in Combination with Other Therapeutic Agents Indication Recommended Dosage of TEVIMBRA Duration/Timing of Treatment ESCC OR First-Line Gastric Cancer 150 mg every 2 weeks OR 200 mg every 3 weeks OR 300 mg every 4 weeks OR 400 mg every 6 weeks Until disease progression or unacceptable toxicity. Refer to the respective Prescribing Information for each therapeutic agent administered in combination with TEVIMBRA for the recommended dosage information, as appropriate. 2.3 Dosage Modifications for Adverse Reactions No dose reduction of TEVIMBRA is recommended. In general, withhold TEVIMBRA for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue TEVIMBRA 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 [see Warnings and Precautions (5.1) ] . Dosage modifications for TEVIMBRA for adverse reactions that require management different from these general guidelines are summarized in Table 2 . Refer to the respective Prescribing Information for dosage modifications for the platinum and fluoropyrimidine agent administered in combination with TEVIMBRA. Table 2: Recommended Dosage Modifications for Adverse Reactions Adverse Reaction Severity of Adverse Reaction Based on Common Terminology Criteria for Adverse Events (CTCAE) Version 4. 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 (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. Grade 3 or 4 or recurrent Grade 2 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, withhold or permanently discontinue TEVIMBRA 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 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 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 Slow infusion rate by 50% Grade 2 Interrupt infusion Resume infusion if resolved or decreased to Grade 1, and slow rate of infusion by 50% of the previous rate. Grade 3 or 4 Permanently discontinue 2.4 Preparation and Administration Preparation Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. TEVIMBRA is a clear to slightly opalescent, colorless to slightly yellow solution. Discard the vial if the solution is cloudy, discolored, or contains visible particles. Do not shake the vial. Prepare the solution for infusion as follows: Withdraw the required volume of TEVIMBRA from the vial(s). Transfer solution into an intravenous infusion bag containing 0.9% Sodium Chloride Injection, USP to prepare an infusion solution with a final concentration of 2 mg/mL to 5 mg/mL. Mix diluted solution by gentle inversion to avoid foaming or excessive shearing of the solution. Do not shake. TEVIMBRA is for single use only. Discard any unused portion left in the vial. Storage of Diluted Solution This product does not contain any preservatives. If not used immediately, store the TEVIMBRA diluted solution either: At room temperature at 20°C to 25°C (68°F to 77°F) for up to 4 hours, including preparation and infusion duration. Discard after 4 hours. Under refrigeration at 2°C to 8°C (36°F to 46°F) for up to 10 days (240 hours), including preparation and infusion duration. Allow the diluted solution to come to room temperature prior to administration. Discard after 10 days (240 hours). Protect diluted solution from light during storage. Do not freeze the diluted solution. Administration Administer diluted solution by intravenous infusion through an intravenous line with a sterile, nonpyrogenic, low protein binding 0.2 micron or 0.22 micron in-line or add-on filter. For 150 mg and 200 mg doses, administer the initial infusion over 60 minutes. If tolerated, all subsequent infusions may be administered over 30 minutes. For 300 mg doses, administer the initial infusion over 90 minutes. If tolerated, administer the second infusion over 60 minutes. If the second infusion is tolerated, administer subsequent infusions over 30 minutes. For 400 mg doses, administer the initial infusion over 120 minutes. If tolerated, administer the second infusion over 60 minutes. If the second infusion is tolerated, administer subsequent infusions over 30 minutes. Do NOT coadminister other drugs through the same infusion line. Do NOT administer TEVIMBRA as an intravenous push or single bolus injection. Flush the intravenous line at the end of infusion.

4 CONTRAINDICATIONS None. None. ( 4 )

5 WARNINGS AND PRECAUTIONS Immune-Mediated Adverse Reactions : ( 5.1 ) 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, immune-mediated endocrinopathies, immune-mediated nephritis with renal dysfunction, immune-mediated dermatologic adverse reactions, and solid organ transplant rejection. Monitor for early identification and management. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. Withhold or permanently discontinue TEVIMBRA based on the severity of reaction. Infusion-Related Reactions : Slow the rate of infusion, interrupt, or permanently discontinue based on severity of infusion reaction. ( 5.2 ) Complications of Allogeneic Hematopoietic Stem Cell Transplantation (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 TEVIMBRA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or 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. 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 TEVIMBRA depending on severity [see Dosage and Administration (2.2) ] . In general, if TEVIMBRA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 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. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroids. 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 TEVIMBRA can cause immune-mediated pneumonitis, which can be fatal. 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. Immune-mediated pneumonitis occurred in 4.7% (113/2390) of patients receiving TEVIMBRA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (1.4%), and Grade 2 (1.9%) adverse reactions. Pneumonitis led to permanent discontinuation of TEVIMBRA in 44 (1.8%) patients and withholding of TEVIMBRA in 40 (1.7%) patients. Eighty-one (71.7%) of the 113 patients received systemic corticosteroids. Seventy-four (65.5%) of the 113 patients received high-dose systemic corticosteroids. Immune-mediated pneumonitis resolved in 48.7% of the 113 patients. Of the 40 patients in whom TEVIMBRA was withheld for pneumonitis, 26 (65%) reinitiated TEVIMBRA after symptom improvement; of these, 5 (19%) patients had recurrence of pneumonitis. Immune-Mediated Colitis TEVIMBRA can cause immune-mediated colitis, which can be fatal. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis treated with PD-1/PD-L1 blocking antibodies. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 0.8% (19/2390) of patients receiving TEVIMBRA, including Grade 3 (0.3%) and Grade 2 (0.4%) adverse reactions. Colitis led to permanent discontinuation of TEVIMBRA in 5 (0.2%) patients and withholding of TEVIMBRA in 10 (0.4%) patients. Seventeen (89.5%) of the 19 patients received systemic corticosteroids. Twelve (63.2%) of the 19 patients received high-dose systemic corticosteroids. Two (10.5%) of the 19 patients received immunosuppressive treatment. Immune-mediated colitis resolved in 89.5% of the 19 patients. Of the 10 patients in whom TEVIMBRA was withheld for colitis, 9 (90%) reinitiated TEVIMBRA after symptom improvement; of these, 2 (22%) patients had recurrence of colitis. Immune-Mediated Hepatitis TEVIMBRA can cause immune-mediated hepatitis, which can be fatal. Immune-mediated hepatitis occurred in 1.3% (30/2390) of patients receiving TEVIMBRA, including Grade 4 (0.3%), Grade 3 (0.6%), and Grade 2 (0.3%) adverse reactions. Immune-mediated hepatitis led to permanent discontinuation in 6 (0.3%) patients and withholding of TEVIMBRA in 19 (0.8%) patients. Twenty-five (83.3%) of the 30 patients received systemic corticosteroids. Twenty-four (80%) of the 30 patients received high-dose systemic corticosteroids. Two (6.7%) of the 30 patients received immunosuppressive treatment. Immune-mediated hepatitis resolved in 66.7% of the 30 patients. Of the 19 patients in whom TEVIMBRA was withheld for hepatitis, 7 (37%) reinitiated TEVIMBRA after symptom improvement; of these, 1 (14%) patient had recurrence of hepatitis. Immune-Mediated Endocrinopathies Adrenal Insufficiency TEVIMBRA can cause immune-mediated adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold TEVIMBRA depending on severity [see Dosage and Administration (2.2) ] . Immune-mediated adrenal insufficiency occurred in 0.5% (12/2390) of patients receiving TEVIMBRA, including Grade 4 (0.04%), Grade 3 (0.2%), and Grade 2 (0.3%) adverse reactions. Adrenal insufficiency did not lead to permanent discontinuation of TEVIMBRA. TEVIMBRA was withheld in 10 (0.4%) patients. All 12 patients received systemic corticosteroids. Three (25%) of the 12 patients received high-dose systemic corticosteroids. Adrenal insufficiency resolved in 25% of the 12 patients. Of the 10 patients in whom TEVIMBRA was withheld for adrenal insufficiency, 8 (80%) reinitiated TEVIMBRA after symptom improvement; of these, none of the patients had recurrence of adrenal insufficiency. Hypophysitis TEVIMBRA 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 clinically indicated. Withhold or permanently discontinue TEVIMBRA depending on severity [see Dosage and Administration (2.2) ] . Hypophysitis/hypopituitarism occurred in 0.3% (6/2390) of patients receiving TEVIMBRA; all were Grade 2 (0.3%). Hypophysitis did not lead to permanent discontinuation of TEVIMBRA. TEVIMBRA was withheld in 1 (0.04%) patient. Five (83.3%) of the 6 patients received systemic corticosteroids. One (17%) of the 6 patients received high-dose systemic corticosteroids. Hypophysitis/hypopituitarism resolved in 17% of the 6 patients. For the 1 patient where TEVIMBRA was withheld for hypophysitis/hypopituitarism, there was no recurrence of hypophysitis/hypopituitarism. Thyroid Disorders TEVIMBRA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue TEVIMBRA depending on severity [see Dosage and Administration (2.2) ] . Thyroiditis: Immune-mediated thyroiditis occurred in 1% (25/2390) of patients receiving TEVIMBRA, including Grade 2 (0.5%) adverse reactions. Thyroiditis did not lead to permanent discontinuation of TEVIMBRA. TEVIMBRA was withheld in 5 (0.2%) patients. Two (8%) of the 25 patients received systemic corticosteroids. Thyroiditis resolved in 36% of the 25 patients. All 5 patients in whom TEVIMBRA was withheld for thyroiditis reinitiated TEVIMBRA after symptom improvement; of these, 1 (20%) patient had recurrence of thyroiditis. Hyperthyroidism: Immune-mediated hyperthyroidism occurred in 4.9% (118/2390) of patients receiving TEVIMBRA, including Grade 3 (0.04%) and Grade 2 (0.9%) adverse reactions. Hyperthyroidism led to the permanent discontinuation of TEVIMBRA in 1 (0.04%) patient and withholding of TEVIMBRA in 7 (0.3%) patients. Three (2.5%) of the 118 patients received systemic corticosteroids. Hyperthyroidism resolved in 76.3% of the 118 patients. Of the 7 patients in whom TEVIMBRA was withheld for hyperthyroidism, 5 (71.4%) reinitiated TEVIMBRA after symptom improvement; of these, none of the patients had recurrence of hyperthyroidism. Hypothyroidism: Immune-mediated hypothyroidism occurred in 12.5% (299/2390) of patients receiving TEVIMBRA, including Grade 4 (0.04%), Grade 3 (0.04%), and Grade 2 (6.7%) adverse reactions. TEVIMBRA was permanently discontinued in 2 (0.1%) patients and treatment was withheld in 12 (0.5%) patients. Two (0.7%) of the 299 patients received systemic corticosteroids. One hundred ninety-five patients received hormone replacement therapy. Hypothyroidism resolved in 34.4% of the 299 patients. The majority (83.6%) of patients with hypothyroidism required long-term thyroid hormone replacement. Of the 12 patients in whom TEVIMBRA was withheld for hypothyroidism, 11 (91.7%) reinitiated TEVIMBRA after symptom improvement; of these, 2 (18.2%) patients had recurrence of hypothyroidism. Type 1 Diabetes Mellitus, Which Can Present with Diabetic Ketoacidosis Diabetes mellitus has been reported with PD-1/PD-L1 blocking antibodies. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold or permanently discontinue TEVIMBRA depending on severity [see Dosage and Administration (2.2) ] . Diabetes mellitus occurred in 0.7% (16/2390) of patients receiving TEVIMBRA, including Grade 4 (0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) adverse reactions. TEVIMBRA was permanently discontinued in 4 (0.2%) patients, and TEVIMBRA treatment was withheld in 4 (0.2%) patients. Fourteen of the 16 patients received insulin therapy for diabetes mellitus. Diabetes mellitus resolved in 12.5% of the 16 patients. Of the 4 patients in whom TEVIMBRA was withheld for diabetes mellitus, 1 (25%) patient reinitiated TEVIMBRA after symptom improvement. Immune-Mediated Nephritis with Renal Dysfunction TEVIMBRA can cause immune-mediated nephritis, which can be fatal. Immune-mediated nephritis with renal dysfunction occurred in 0.2% (5/2390) of patients receiving TEVIMBRA, including Grade 3 (0.04%) and Grade 2 (0.1%) adverse reactions. TEVIMBRA was permanently discontinued in 1 (0.04%) patient and treatment was withheld in 3 (0.1%) patients. Three (60%) out of 5 patients received systemic corticosteroids. Three (60%) of the 5 patients received high-dose systemic corticosteroids. Nephritis with renal dysfunction resolved in 40% of the 5 patients. Of the 3 patients in whom TEVIMBRA was withheld for nephritis, 2 (66.7%) reinitiated TEVIMBRA after symptom improvement and no patients had recurrence of nephritis. Immune-Mediated Dermatologic Adverse Reactions TEVIMBRA can cause immune-mediated rash or dermatitis. Cases of severe cutaneous adverse reactions (SCARs), including exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), have been reported, some with fatal outcome. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue TEVIMBRA depending on severity [see Dosage and Administration (2.2) ] . Immune-mediated dermatologic adverse reactions occurred in 13% (311/2390) of patients receiving TEVIMBRA, including Grade 4 (0.1%), Grade 3 (1.1%), and Grade 2 (3.4%) adverse reactions. Stevens-Johnson syndrome occurred in 1 (0.04%) patient. Dermatologic adverse reactions led to permanent discontinuation of TEVIMBRA in 3 (0.1%) patients and withholding of TEVIMBRA in 30 (1.3%) patients. Forty-four (14.1%) of the 311 patients received systemic corticosteroids. Nineteen (6.1%) of the 311 patients received high-dose systemic corticosteroids. Immune-mediated skin reactions resolved in 66.9% of the 311 patients. Of the 30 patients in whom TEVIMBRA was withheld for dermatologic adverse reactions, 26 (86.7%) reinitiated TEVIMBRA after symptom improvement; of these, 3 (12%) patients had recurrence of immune-mediated dermatologic adverse reactions. Other Immune-Mediated Adverse Reactions The following clinically significant immune-mediated adverse reactions occurred at an incidence of less than 1% in 2390 patients who received TEVIMBRA or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis , vasculitis. Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barre syndrome, nerve paresis, autoimmune neuropathy. Ocular: Uveitis, iritis, and other ocular inflammatory toxicities. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada–like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss. Gastrointestinal: Pancreatitis including increases in serum amylase and lipase levels, gastritis, duodenitis, stomatitis. Musculoskeletal and Connective Tissue: Myositis/polymyositis/dermatomyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatica. Endocrine: Hypoparathyroidism. Other (Hematologic/Immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenia, solid organ transplant rejection, other transplant (including corneal graft) rejection. 5.2 Infusion-Related Reactions TEVIMBRA can cause severe or life-threatening infusion-related reactions. Infusion-related reactions occurred in 4.7% (113/2390) patients receiving TEVIMBRA, including Grade 3 or higher (0.2%) reactions. Monitor patients for signs and symptoms of infusion-related reactions. Slow the rate of infusion for mild (Grade 1) and interrupt the infusion for moderate (Grade 2) infusion-related reactions. For severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions, stop infusion and permanently discontinue TEVIMBRA [see Dosage and Administration (2.2) ] . 5.3 Complications of Allogeneic HSCT Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT. 5.4 Embryo-Fetal Toxicity Based on its mechanism of action, TEVIMBRA can cause fetal harm when administered to a pregnant woman. Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus resulting in fetal death. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TEVIMBRA and for 4 months after the last dose [see Use in Specific Populations (8.1 , 8.3) ] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in more detail in other sections of the label: Severe and fatal immune-mediated adverse reactions [see Warnings and Precautions (5.1) ] Infusion-related reactions [see Warnings and Precautions (5.2) ] Most common adverse reactions (≥20%), including laboratory abnormalities, were: TEVIMBRA in combination with platinum-containing chemotherapy: decreased neutrophil count, decreased sodium, increased glucose, anemia, fatigue, decreased appetite, increased AST, decreased potassium, increased serum creatinine, decreased calcium, increased ALT, diarrhea, stomatitis, and vomiting. ( 6.1 ) TEVIMBRA as a single agent: increased glucose, decreased hemoglobin, decreased lymphocytes, decreased sodium, decreased albumin, increased alkaline phosphatase, anemia, fatigue, increased AST, musculoskeletal pain, decreased weight, increased ALT, and cough. ( 6.1 ) TEVIMBRA in combination with platinum and fluoropyrimidine-based chemotherapy: nausea, fatigue, decreased appetite, anemia, peripheral sensory neuropathy, vomiting, decreased platelet count, decreased neutrophil count, increased aspartate aminotransferase, diarrhea, abdominal pain, increased alanine aminotransferase, decreased white blood cell count, decreased weight, and pyrexia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact BeOne Medicines at 1-877-828-5596 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 pooled safety population described in WARNINGS AND PRECAUTIONS reflect exposure to TEVIMBRA as a single agent in 2390 patients enrolled in three randomized open-label, active-controlled studies (BGB-A317-301, RATIONALE-302, BGB-A317-303) and six open-label, single-arm studies (BGB-A317-209, BGB-A317-208, BGB-A317-204, BGB-A317-203, BGB-A317-102, BGB-A317_Study_001), which enrolled 307 patients with esophageal squamous cell carcinoma and 2083 patients with advanced or recurrent tumors. TEVIMBRA was administered at a dose of 200 mg intravenously once every 3 weeks, except in study BGB-A317_Study_001 where patients also received other dosage regimens. Among the 2390 patients, 38% were exposed for longer than 6 months, and 23% were exposed for longer than 12 months. First-line Treatment of Unresectable or Metastatic Esophageal Carcinoma (ESCC) The safety of TEVIMBRA in combination with chemotherapy was evaluated in RATIONALE-306, a randomized, placebo-controlled, multicenter, double-blind trial in patients with unresectable, advanced, or metastatic ESCC [see Clinical Studies (14.1) ] . Patients were randomized (1:1) to receive either TEVIMBRA 200 mg by intravenous infusion over 30-60 minutes every 3 weeks or placebo plus a chemotherapy doublet regimen. The chemotherapy doublet regimens consisted of: Platinum (cisplatin [60 to 80 mg/m 2 IV, on Day 1] or oxaliplatin [130 mg/m 2 IV, on Day 1]) and a fluoropyrimidine (5-FU [750 to 800 mg/m 2 IV, on Day 1 to 5] or capecitabine [1000 mg/m 2 orally twice daily, on Day 1 to 14]) or Platinum (cisplatin [60 to 80 mg/m 2 IV, on Day 1 or 2] or oxaliplatin [130 mg/m 2 IV, on Day 1 or 2]) and (paclitaxel 175 mg/m 2 IV, on Day 1) Patients were treated until disease progression or unacceptable toxicity. The median duration of exposure was 6.4 months (range: 0.1 to 38.3 months) in TEVIMBRA-treated patients. Serious adverse reactions occurred in 48% of patients receiving TEVIMBRA in combination with chemotherapy. The most frequent serious adverse reactions (≥2%) were pneumonia (5.2%), dysphagia (5.2%), diarrhea (2.2%), fatigue (2.2%), and esophageal stenosis (2.2%). Fatal adverse reactions occurred in 8% of patients who received TEVIMBRA in combination with chemotherapy. Permanent discontinuation of TEVIMBRA due to adverse reactions occurred in 13% of patients. The adverse reaction which resulted in discontinuation in ≥2% of patients was pneumonitis (2.2%). Dosage interruptions of TEVIMBRA due to adverse reactions occurred in 52% of patients. Adverse reactions which required dosage interruption in ≥2% of patients were neutrophil count decreased (7%), fatigue (6%), pneumonia (6%), anemia (4.3%), neutropenia (4.3%), white blood cell count decreased (4.3%), rash (3.7%), dysphagia (2.8%), platelet count decreased (2.8%), pyrexia (2.8%), and diarrhea (2.2%). The most common (≥20%) adverse reactions including laboratory abnormalities were decreased neutrophil count, decreased sodium, increased glucose, anemia, fatigue, decreased appetite, increased AST, decreased potassium, increased serum creatinine, decreased calcium, increased ALT, diarrhea, stomatitis, and vomiting. Adverse reactions and laboratory abnormalities are listed in Table 3 and Table 4, respectively. Table 3: Adverse Reactions (≥10%) in Patients with ESCC Receiving TEVIMBRA + Chemotherapy with a Difference Between Arms of ≥5% for All Grades or ≥2% for Grades 3 and 4 vs Placebo + Chemotherapy in RATIONALE-306 Adverse Reaction TEVIMBRA + Chemotherapy N=324 Placebo + Chemotherapy N=321 All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Blood and Lymphatic System Disorders Anemia 61 17 56 16 Neutropenia 16 7 15 10 General Disorders and Administration Site Conditions Fatigue Represents a composite of multiple, related preferred terms. 45 9 45 4.7 Metabolism and Nutrition Disorders Decreased Appetite 44 6 39 2.2 Gastrointestinal Disorders Diarrhea 28 4.3 24 1.9 Stomatitis 22 4 16 2.2 Vomiting 22 1.5 27 2.5 Dysphagia 14 6 11 4 Skin and Subcutaneous Tissue Disorders Rash 19 4 9 0.3 Pruritus 13 0.3 7 0 Endocrine Disorders Hypothyroidism 11 0 6 0 Table 4: Select Laboratory Abnormalities Worsening From Baseline Occurring in ≥10% of Patients Receiving TEVIMBRA in Combination with Chemotherapy in RATIONALE-306 with a Difference Between Arms of ≥5% for All Grades or ≥2% for Grades 3 and 4 vs Placebo + Chemotherapy in RATIONALE-306 Laboratory Abnormality TEVIMBRA + Chemotherapy The denominator used to calculate the rate varied from 132 to 323 based on the number of patients with a baseline value and at least one post-treatment value. (N=324) Placebo + Chemotherapy (N=321) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hematology Neutrophils decreased 75 41 75 46 Chemistry Sodium decreased 67 19 62 11 Glucose increased 65 7 61 5 AST increased 36 3.4 27 1.3 Potassium decreased 33 10 29 2.8 Creatinine increased 33 2.5 25 1.6 Calcium decreased 29 6 24 4.4 ALT increased 28 3.1 22 1.6 Previously Treated Unresectable Advanced or Metastatic Esophageal Squamous Cell Carcinoma (ESCC) The safety of TEVIMBRA was evaluated in RATIONALE-302, a randomized, active-controlled, open-label, multicenter study in 255 patients with unresectable advanced, recurrent or metastatic ESCC [see Clinical Studies (14.1) ] . The trial excluded patients who had brain or leptomeningeal metastases that were symptomatic or required treatment, active autoimmune disease, a medical condition requiring systemic corticosteroids or immunosuppressants, or apparent tumor invasion of organs adjacent to the esophageal site. Patients received TEVIMBRA 200 mg by intravenous infusion over 30-60 minutes every 3 weeks or investigator's choice: paclitaxel 135-175 mg/m 2 every 3 weeks or 80-100 mg/m 2 weekly, docetaxel 75 mg/m 2 every 3 weeks, or irinotecan 125 mg/m 2 on Days 1 and 8 of every 3-week cycle . Patients were treated until disease progression or unacceptable toxicity. The median duration of exposure was 2.8 months (range: 0.2 to 28.3 months) in TEVIMBRA-treated patients and 1.5 months (range: 0.2 to 19.2 months) in paclitaxel, docetaxel, or irinotecan-treated patients. Serious adverse reactions occurred in 41% of patients; the most frequent serious adverse reactions (≥2%) were pneumonia, dysphagia, hemorrhage, pneumonitis (including pneumonitis and immune-mediated pneumonitis), and esophageal obstruction. Fatal adverse reactions occurred in 7% of patients who received TEVIMBRA, including the following which occurred in more than one patient: pneumonia/pneumonitis (5 patients), hemorrhage (3 patients), and death due to an unknown cause (3 patients). Permanent discontinuation of TEVIMBRA due to an adverse reaction occurred in 19% of patients. Adverse reactions which resulted in permanent discontinuation in ≥1% of patients were hemorrhage, pneumonitis (including pneumonitis and immune-mediated pneumonitis), and pneumonia. Dosage interruptions of TEVIMBRA due to an adverse reaction occurred in 23% of patients. Adverse reactions which required dosage interruptions in ≥2% of patients were pneumonia, pneumonitis, and fatigue. The most common (≥20%) adverse reactions were anemia, fatigue, musculoskeletal pain, decreased weight, and cough. Adverse reactions and laboratory abnormalities are listed in Table 5 and Table 6, respectively. Table 5: Adverse Reactions (≥10%) in Patients With ESCC Receiving TEVIMBRA in RATIONALE-302 Adverse Reaction TEVIMBRA (N=255) ICC (N=240) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) ICC = investigator's choice of chemotherapy Blood Disorders Anemia 31 6 45 11 General Disorders Fatigue Fatigue includes asthenia, fatigue, malaise. 28 2 46 6 Pyrexia 16 0.4 14 0 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain Musculoskeletal pain includes musculoskeletal pain, spinal pain, arthralgia, back pain, neck pain, musculoskeletal chest pain, myalgia, pain in extremity, non-cardiac chest pain, bone pain, arthritis. 24 1 25 1 Investigations Weight decreased 23 1 19 0 Respiratory, Thoracic and Mediastinal Disorders Cough Cough includes productive cough, cough. 22 0.4 16 0.4 Metabolism and Nutrition Disorders Decreased appetite 16 0.4 35 4 Infections and Infestations Pneumonia Pneumonia includes pneumonia aspiration, pneumonia, pneumonia bacterial, lower respiratory tract infection. 16 6 12 7 Gastrointestinal Disorders Constipation 15 0 19 0.4 Nausea 14 0.4 30 3 Diarrhea Diarrhea includes diarrhea, colitis. 13 1 32 7 Dysphagia 11 6 8 3 Abdominal pain Abdominal pain includes abdominal pain upper, abdominal pain, abdominal discomfort, abdominal pain lower, gastrointestinal pain. 11 0.8 16 2 Vomiting 11 0.8 20 4 Endocrine Disorders Hypothyroidism Hypothyroidism includes hypothyroidism, blood thyroid stimulating hormone increased. 13 0.4 0.8 0 Skin and Subcutaneous Tissue Disorders Rash Rash includes dermatitis, dermatitis acneiform, dermatitis allergic, eczema, erythema, psoriasis, rash, rash follicular, rash maculo-papular, rash pruritic. 13 0.4 6 0 Vascular Disorders Hemorrhage Hemorrhage includes tumor hemorrhage, upper gastrointestinal hemorrhage, gastrointestinal hemorrhage, hemoptysis, esophageal hemorrhage, hematuria, gastric hemorrhage, epistaxis, tracheal hemorrhage, gingival bleeding, pulmonary hemorrhage, procedural hemorrhage, rectal hemorrhage, stoma site hemorrhage. 12 2 10 3 Table 6: Laboratory Abnormalities Worsening From Baseline Occurring in ≥10% of Patients Receiving TEVIMBRA in RATIONALE-302 TEVIMBRA The denominator used to calculate the rate varied from 136 to 240 based on the number of patients with a baseline value and at least one post-treatment value. ICC Laboratory Abnormality All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Chemistry Glucose increased 46 4 40 2 Sodium decreased 34 9 36 8 Albumin decreased 33 0.8 37 1 Alkaline phosphatase increased 32 3 15 0.5 AST increased 27 0.8 12 0.5 ALT increased 23 0.8 15 1 Phosphate decreased 15 4 20 3 Creatine kinase increased 13 1 2 0 Potassium decreased 13 1 15 3 Bilirubin increased 11 2 8 0.5 Glucose decreased 10 0.4 10 0.5 Hematology Hemoglobin decreased 45 6 61 10 Lymphocytes decreased 43 11 60 28 Platelets decreased 11 1 11 0.9 Leukocytes decreased 10 0.8 66 31 Treatment of Previously Untreated Unresectable or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma (G/GEJ) The safety of TEVIMBRA in combination with chemotherapy was evaluated in RATIONALE-305, a randomized, multicenter, double-blind, placebo-controlled trial in patients with previously untreated unresectable or metastatic G/GEJ adenocarcinoma [see Clinical Studies (14.2) ] . Patients were randomized (1:1) to receive either TEVIMBRA 200 mg by intravenous infusion over 30-60 minutes every 3 weeks or placebo plus a platinum and fluoropyrimidine-based chemotherapy. The chemotherapy regimens consisted of: Oxaliplatin 130 mg/m 2 IV on Day 1 for up to 6 cycles and capecitabine 1000 mg/m 2 orally twice daily for 14 consecutive days of every 3-week cycle or Cisplatin 80 mg/m 2 IV, Day 1, and 5-FU (5-fluorouracil) 800 mg/m 2 /day IV continuous infusion over 24 hours daily Day 1-5, every 3 weeks for up to 6 cycles Patients were treated until disease progression or unacceptable toxicity. The median duration of exposure was 5.91 months (range: 0.1 to 47 months) in TEVIMBRA-treated patients. Serious adverse reactions occurred in 42% of patients receiving TEVIMBRA in combination with chemotherapy. The most frequent serious adverse drug reactions (≥2%) were pneumonia (3.6%), decreased platelet count (3.2%), gastrointestinal hemorrhage (3%), and colitis (2.2%). Fatal adverse reactions occurred in 4.2% of patients who received TEVIMBRA in combination with chemotherapy; events occurring in 2 or more patients were death, sepsis, pneumonia, pulmonary embolism, and respiratory failure. Permanent discontinuation of TEVIMBRA due to an adverse reaction occurred in 16% of patients. Adverse drug reactions which resulted in permanent discontinuation in ≥1% of patients were death, fatigue, and pneumonitis. Dosage interruption of TEVIMBRA due to an adverse drug reaction occurred in 49% of patients. Adverse drug reactions which required dosage interruption in ≥2% of patients were decreased platelet count (12%), decreased neutrophil count (10%), neutropenia (6%), decreased white blood cell count (6%), increased AST (4.8%), increased ALT (3.8%), increased blood bilirubin (3%), COVID-19 (3%), thrombocytopenia (2.8%), leukopenia (2.6%), pneumonitis (2.2%), and pneumonia (2%). The most common (≥20%) adverse reactions, including laboratory abnormalities, for TEVIMBRA in combination with chemotherapy were nausea, fatigue, decreased appetite, anemia, peripheral sensory neuropathy, vomiting, decreased platelet count, decreased neutrophil count, increased aspartate aminotransferase, diarrhea, abdominal pain, increased alanine aminotransferase, white blood cell count decreased, decreased weight, and pyrexia. Adverse reactions and laboratory abnormalities are listed in Table 7 and Table 8, respectively. Table 7: Adverse Reactions (≥10%) in Patients with G/GEJ Receiving TEVIMBRA + Chemotherapy with a Difference Between Arms of ≥5% for All Grades or ≥2% for Grades 3 and 4 vs Placebo + Chemotherapy in RATIONALE-305 Adverse Drug Reaction TEVIMBRA + Chemotherapy (N=498) Placebo + Chemotherapy (N=494) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) General Disorders and Administration Site Conditions Pyrexia 20 1.6 14 0.6 Skin and Subcutaneous Tissue Disorders Rash Represents a composite of multiple, related preferred terms. 16 1.6 7 0 Pruritus 10 0.2 3.2 0 Endocrine Disorders Hypothyroidism 13 0.2 2.8 0 Other Clinically Important Adverse Reactions Occurring in Less Than 10% include : Stomatitis, infusion-related reaction, dyspnea, hepatitis, hyperthyroidism, pneumonitis, hyperglycemia, myalgia, diabetes mellitus, pancreatitis, arthritis, Sjogren's syndrome, thyroiditis, adrenal insufficiency, hypophysitis, myasthenia gravis, uveitis, myocarditis, pericarditis, colitis, vitiligo, myositis, and nephritis. Table 8: Select Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of Patients Receiving TEVIMBRA + Chemotherapy with a Difference Between Arms of ≥5% for All Grades or ≥2% for Grades 3 and 4 vs Placebo + Chemotherapy in RATIONALE-305 Laboratory Abnormality TEVIMBRA + Chemotherapy The denominator used to calculate the rate varied from 480 to 494 based on the number of patients with a baseline value and at least one post-treatment value. (N=498) Placebo + Chemotherapy (N=494) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Abbreviations: ALT = alanine aminotransferase, AST = aspartate amino transferase. Chemistry AST increased 58 6 56 3 Sodium decreased 42 7 36 5 ALT increased 41 4.8 36 2 Potassium decreased 33 9 28 6 Hematology Lymphocytes decreased 53 12 46 9 Other Clinically Important Laboratory Abnormalities Occurring in <20% include : Creatinine increased, potassium increased, glucose decreased, sodium increased, lymphocytes increased, hemoglobin increased. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of TEVIMBRA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, toxic epidermal necrolysis (including fatal cases). Immune system disorders: Immune-mediated cystitis.

8.1 Pregnancy Risk Summary Based on its mechanism of action, TEVIMBRA can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . There are no available data on the use of TEVIMBRA in pregnant women. Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus resulting in fetal death (see Data ) . Human IgG4 immunoglobulins (IgG4) are known to cross the placental barrier; therefore, tislelizumab-jsgr has the potential to be transmitted from the mother to the developing fetus. Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Animal reproduction studies have not been conducted with TEVIMBRA to evaluate its effect on reproduction and fetal development. A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. In murine models of pregnancy, blockade of PD-L1 signaling has been shown to disrupt tolerance to the fetus and to result in an increase in fetal loss; therefore, potential risks of administering TEVIMBRA during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, there were no malformations related to the blockade of PD-1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 and PD-L1 knockout mice. Based on its mechanism of action, fetal exposure to tislelizumab-jsgr may increase the risk of developing immune-mediated disorders or altering the normal immune response.