Tevimbra Drug Information

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 . 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 or oxaliplatin ) and a fluoropyrimidine (5-FU or capecitabine ) or Platinum (cisplatin or oxaliplatin ) 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

Metabolism and Nutrition Disorders Decreased Appetite 44 6 39 2.2 Gastrointestinal Disorders

Diarrhea 28 4.3 24

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

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

Potassium decreased 33 10 29 2.8 Creatinine increased 33 2.5 25 1.6

Calcium decreased 29 6 24

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 . 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

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

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

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

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

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 . 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

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.

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.

Pregnancy Risk Summary Based on its mechanism of action, TEVIMBRA can cause fetal harm when administered to a pregnant woman . 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.

Pediatric Use The safety and effectiveness of TEVIMBRA have not been established in pediatric patients.