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 unrese...
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-authorized 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 o...
How Supplied TEVIMBRA injection is a clear to slightly opalescent, colorless to slightly yellow solution supplied in a carton containing one single-dose vial, available as follows: Strength NDC 100 mg/10 mL (10 mg/mL) 72579-121-01 150 mg/15 mL (10 mg/mL) 72579-125-00 Storage Store in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze. Do not shake.
www.fda.gov/CompanionDiagnosticswww.fda.gov/medwatch
www.TEVIMBRA.comTEVIMBRA, 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).
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.
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).
TEVIMBRA, in combination with zanidatamab-hrii and fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment for adults with HER2-positive (IHC 3+ or IHC 2+/ISH+) unresectable locally advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma as detected by an FDA-authorized test [see Dosage and Administration (2.1)].
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-authorized 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-authorized 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.
Select patients for the first-line treatment of HER2-positive unresectable locally advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma based on HER2-positive status from tumor specimens, as detected by an FDA-authorized test [see Clinical Studies (14)]. Information on FDA-authorized tests for HER2 protein expression in gastric, gastroesophageal junction, or esophageal adenocarcinoma at: www.fda.gov/CompanionDiagnostics
The recommended dosages of TEVIMBRA administered intravenously as a single agent or in combination with other therapeutic agents are presented in Table 1.
| Indication | Recommended Dosage of TEVIMBRA | Duration/Timing of Treatment |
|---|---|---|
| Esophageal Squamous Cell Carcinoma OR First-Line HER2-Negative Gastric Cancer OR First-Line HER2-Positive Gastric, Gastroesophageal Junction, or Esophageal Adenocarcinoma | 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, including premedication requirements, as appropriate.
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 of each of the individual therapeutic agents used in combination with TEVIMBRA for dosage modification recommendations.
| Adverse Reaction | Severity of Adverse Reaction* | 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† |
| 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‡ | 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§ | |
| Grade 3 or 4 | Permanently discontinue | |
* Based on Common Terminology Criteria for Adverse Events (CTCAE) Version 4.
† 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 TEVIMBRA based on recommendations for hepatitis with no liver involvement.
§ Resume infusion if resolved or decreased to Grade 1, and slow rate of infusion by 50% of the previous rate.
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:
Storage of Diluted Solution
This product does not contain any preservatives. If not used immediately, store the TEVIMBRA diluted solution either:
Protect diluted solution from light during storage. Do not freeze the diluted solution.
Administration
Injection: 100 mg/10 mL (10 mg/mL) and 150 mg/15 mL (10 mg/mL) clear to slightly opalescent, colorless to slightly yellow solution in a single-dose vial.
None.
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.
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.
Other: Myocarditis-myositis-myasthenia gravis (or myasthenia-like) overlap syndrome, reported as the co-occurrence of either two or all three adverse 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)].
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.
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)].
The following clinically significant adverse reactions are discussed in more detail in other sections of the label:
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:
or
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.
| 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* | 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 |
* Represents a composite of multiple, related preferred terms.
| Laboratory Abnormality | TEVIMBRA + Chemotherapy*
(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 |
* 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.
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/m2 every 3 weeks or 80-100 mg/m2 weekly, docetaxel 75 mg/m2 every 3 weeks, or irinotecan 125 mg/m2 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.
| 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* | 28 | 2 | 46 | 6 |
| Pyrexia | 16 | 0.4 | 14 | 0 |
| Musculoskeletal and Connective Tissue Disorders | ||||
| Musculoskeletal pain† | 24 | 1 | 25 | 1 |
| Investigations | ||||
| Weight decreased | 23 | 1 | 19 | 0 |
| Respiratory, Thoracic and Mediastinal Disorders | ||||
| Cough‡ | 22 | 0.4 | 16 | 0.4 |
| Metabolism and Nutrition Disorders | ||||
| Decreased appetite | 16 | 0.4 | 35 | 4 |
| Infections and Infestations | ||||
| Pneumonia§ | 16 | 6 | 12 | 7 |
| Gastrointestinal Disorders | ||||
| Constipation | 15 | 0 | 19 | 0.4 |
| Nausea | 14 | 0.4 | 30 | 3 |
| Diarrhea¶ | 13 | 1 | 32 | 7 |
| Dysphagia | 11 | 6 | 8 | 3 |
| Abdominal pain# | 11 | 0.8 | 16 | 2 |
| Vomiting | 11 | 0.8 | 20 | 4 |
| Endocrine Disorders | ||||
| Hypothyroidism♠ | 13 | 0.4 | 0.8 | 0 |
| Skin and Subcutaneous Tissue Disorders | ||||
| Rash♥ | 13 | 0.4 | 6 | 0 |
| Vascular Disorders | ||||
| Hemorrhage♦ | 12 | 2 | 10 | 3 |
* Fatigue includes asthenia, fatigue, malaise.
† 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.
‡ Cough includes productive cough, cough.
§ Pneumonia includes pneumonia aspiration, pneumonia, pneumonia bacterial, lower respiratory tract infection.
¶ Diarrhea includes diarrhea, colitis.
# Abdominal pain includes abdominal pain upper, abdominal pain, abdominal discomfort, abdominal pain lower, gastrointestinal pain.
♠ Hypothyroidism includes hypothyroidism, blood thyroid stimulating hormone increased.
♥ Rash includes dermatitis, dermatitis acneiform, dermatitis allergic, eczema, erythema, psoriasis, rash, rash follicular, rash maculo-papular, rash pruritic.
♦ 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.
| TEVIMBRA* | 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 |
* 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.
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:
or
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.
| 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* | 16 | 1.6 | 7 | 0 |
| Pruritus | 10 | 0.2 | 3.2 | 0 |
| Endocrine Disorders | ||||
| Hypothyroidism* | 13 | 0.2 | 2.8 | 0 |
* Represents a composite of multiple, related preferred terms.
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.
| Laboratory Abnormality | TEVIMBRA + Chemotherapy*
(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 |
* 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.
Other Clinically Important Laboratory Abnormalities Occurring in <20% include:
Creatinine increased, potassium increased, glucose decreased, sodium increased, lymphocytes increased, hemoglobin increased.
First-Line Treatment of HER2-Positive Unresectable Locally Advanced or Metastatic Gastric, Gastroesophageal Junction, or Esophageal Adenocarcinoma (GEA)
The safety of TEVIMBRA in combination with zanidatamab-hrii and chemotherapy for the treatment of GEA was evaluated in 596 patients in HERIZON-GEA-01. Patients received TEVIMBRA 200 mg by intravenous infusion every 3 weeks with zanidatamab-hrii 1800 mg (<70 kg) or 2400 mg (≥70kg ) and investigator's choice of a fluoropyrimidine- and platinum-based chemotherapy (CAPOX or FP), or trastuzumab 8 mg/kg loading dose (Cycle 1 Day 1) followed by 6 mg/kg intravenous infusion every 3 weeks and investigator's choice of CAPOX or FP. Patients were treated until disease progression or unacceptable toxicity [see Clinical Studies (14.3)].
The median duration of exposure was 9.0 months (range: 0.0 to 44.9 months) in TEVIMBRA-treated patients.
Serious adverse reactions occurred in 59% of patients who received TEVIMBRA in combination with zanidatamab-hrii and chemotherapy; the most frequent serious adverse reactions (≥2%) were diarrhea (17%), infusion-related reactions (5%), vomiting (4.8%), hypokalemia (4.4%), acute kidney injury (3.7%), pneumonia (3.7%), nausea (2.4%), decreased appetite (2.4%), and anemia (2.4%). Fatal adverse reactions occurred in 2.4% of patients who received TEVIMBRA in combination with zanidatamab-hrii and chemotherapy including acute kidney injury (N=2), cardiac failure, diarrhea, dehydration, hypovolemic shock, and intestinal obstruction (all N=1).
Permanent discontinuation of TEVIMBRA due to an adverse reaction occurred in 17% of patients. Adverse reactions which resulted in permanent discontinuation in ≥1% of patients were diarrhea or colitis (3.7%), pneumonitis (2.7%), rash (2.0%), and immune-mediated hepatitis (1.3%).
Dosage interruptions of TEVIMBRA due to an adverse reaction occurred in 60% of patients. Adverse reactions which required dosage interruptions in ≥2% of patients were diarrhea, neutrophil count decreased, platelet count decreased, anemia, decreased appetite, hypokalemia, asthenia, COVID-19, fatigue, ejection fraction decreased, influenza, pyrexia, and vomiting.
The most common (≥20%) adverse reactions for TEVIMBRA in combination with zanidatamab-hrii and chemotherapy, including laboratory abnormalities, were: diarrhea (83%), nausea (56%), anemia (47%), decreased appetite (46%), vomiting (44%), hypokalemia (39%), fatigue (37%), rash (36%), decreased neutrophil count (35%), decreased platelet count (31%), peripheral neuropathy (27%), infusion-related reaction (25%), and increased aspartate aminotransferase (21%).
Adverse reactions and laboratory abnormalities are listed in Table 9 and Table 10, respectively.
| Adverse Reaction* | TEVIMBRA with Zanidatamab-hrii and Chemotherapy N=294 | Trastuzumab with Chemotherapy N=302 | ||
|---|---|---|---|---|
| All Grades (%) | Grade 3 or higher (%) | All Grades (%) | Grade 3 or higher (%) | |
| Gastrointestinal Disorders | ||||
| Diarrhea† | 83 | 26 | 53 | 14 |
| Nausea | 56 | 8 | 48 | 3 |
| Vomiting‡ | 44 | 6 | 34 | 4.3 |
| Metabolism and Nutrition Disorders | ||||
| Decreased appetite | 46 | 8 | 36 | 6 |
| General Disorders and Administration Site Conditions | ||||
| Fatigue§ | 37 | 7 | 30 | 6 |
| Skin and Subcutaneous Tissue Disorders | ||||
| Rash¶ | 36 | 5 | 25 | 5 |
| Pruritus | 17 | 0.7 | 3.6 | 0 |
| Injury, Poisoning and Procedural Complications | ||||
| Infusion-related reaction | 25 | 1.7 | 13 | 0.7 |
| Investigations | ||||
| Ejection fraction decreased# | 12 | 3.1 | 7 | 1.3 |
* Graded per CTCAE version 5.
† Diarrhea includes colitis, diarrhea, enteritis, enterocolitis and enterocolitis hemorrhagic.
‡ Vomiting includes hematemesis and vomiting.
§ Fatigue includes asthenia and fatigue.
¶ Rash includes rash, rash maculo-papular, dermatitis, palmar plantar erythrodysesthesia syndrome, rash pustular, urticaria, dermatitis acneiform, rash erythematous.
# Ejection fraction decreased includes cardiac failure, ejection fraction decreased, left ventricular dysfunction and right ventricular failure.
| Laboratory Abnormalities | TEVIMBRA with Zanidatamab-hrii and Chemotherapy N=294 | Trastuzumab with Chemotherapy N=302 | ||
|---|---|---|---|---|
| All Grades (%) | Grade 3 or 4 (%) | All Grades (%) | Grade 3 or 4 (%) | |
| Hematology | ||||
| Hemoglobin decreased | 97 | 19 | 92 | 16 |
| Chemistry | ||||
| Blood calcium decreased | 62 | 1.7 | 56 | 1.7 |
| Potassium decreased | 61 | 27 | 38 | 12 |
| Sodium decreased | 43 | 2 | 35 | 1 |
| Blood magnesium decreased | 42 | 0.3 | 24 | 0 |
| Creatinine increased | 34 | 4.1 | 21 | 2.3 |
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.
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.
Risk Summary
There is no information regarding the presence of tislelizumab-jsgr in human milk, or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 4 months after the last dose of TEVIMBRA.
TEVIMBRA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].
Pregnancy Testing
Verify pregnancy status in females of reproductive potential prior to initiating TEVIMBRA [see Use in Specific Populations (8.1)].
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with TEVIMBRA and for 4 months after the last dose of TEVIMBRA.
The safety and effectiveness of TEVIMBRA have not been established in pediatric patients.
TEVIMBRA as a Single Agent
Of the 255 patients who were treated with TEVIMBRA for previously treated unresectable or metastatic ESCC in the clinical study RATIONALE-302, 98 (38%) were 65 years and older and 13 (5%) were 75 years and older. No overall differences in safety or effectiveness were observed between elderly patients and younger patients.
TEVIMBRA in Combination with Chemotherapy
Of the 324 patients who were treated with TEVIMBRA and platinum-containing chemotherapy as first-line treatment for unresectable advanced or metastatic ESCC in the clinical study RATIONALE-306, 149 (46%) were 65 years and older and 13 (4%) were 75 years and older. No overall differences in safety or effectiveness were observed between elderly patients and younger patients.
Of the 498 patients who were treated with TEVIMBRA in combination with platinum-containing chemotherapy for G/GEJ adenocarcinoma in the clinical study RATIONALE-305, 161 (32%) were 65 years and older, and 28 (6%) were 75 years and older. No overall differences in safety or effectiveness were observed between elderly patients and younger patients.
TEVIMBRA in Combination with Zanidatamab-hrii and Chemotherapy
Of the 302 patients who received TEVIMBRA in combination with zanidatamab-hrii and chemotherapy for GEA, there were 139 (46%) patients 65 years of age and older, 106 (35%) were 65 to 74 years old, and 33 (11%) were 75 years and older.
There was a higher incidence of Grade ≥3 adverse reactions observed in patients 65 years of age and older (87%) as compared to younger patients (80%). The incidence of Grade 3 or 4 diarrhea was higher in patients 65 years and older (32%) compared to patients younger than 65 years (20%). There was an increased incidence of fatal adverse reactions in patients 65 years and older (4.4%), including acute kidney injury (N=2), cardiac failure, dehydration, hypovolemic shock and intestinal obstruction (all N=1), compared to younger patients (0.6%), including diarrhea (N=1).
Tislelizumab-jsgr is a programmed death receptor-1 (PD-1)–blocking antibody. Tislelizumab-jsgr is an Fc-engineered humanized monoclonal IgG4 kappa antibody with an approximate molecular weight of 147 kDa. Tislelizumab-jsgr is produced in recombinant Chinese hamster ovary (CHO) cells.
TEVIMBRA (tislelizumab-jsgr) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly yellow solution for intravenous use, supplied in single-dose vials. Each mL of TEVIMBRA solution contains tislelizumab-jsgr monoclonal antibody (10 mg), citric acid monohydrate (0.42 mg), histidine (1.72 mg), L-histidine hydrochloride monohydrate (0.82 mg), polysorbate 20 (0.2 mg), sodium citrate (5.93 mg), trehalose (65.04 mg), and Water for Injection, USP. The pH is 6.5.
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.
Tislelizumab-jsgr 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. Tislelizumab-jsgr decreased tumor growth in xenograft models and a human PD-1 transgenic mouse model.
The tislelizumab-jsgr exposure-response relationship for efficacy and safety and time course of pharmacodynamic response has not been fully characterized.
Pharmacokinetic parameters are presented as geometric mean (% CV) unless otherwise specified.
The peak concentration (Cmax) and area under the plasma concentration versus time curve (AUC) of tislelizumab-jsgr increased dose proportionally in the dose range of 0.5 (0.2 times the approved recommended dosage in a 70 kg patient) to 10 mg/kg (3.5 times the approved recommended dosage in a 70 kg patient).
The steady-state AUCtau of tislelizumab-jsgr is 1,283 mcg/mL∙day (28.7%) and the Cmax is 110 mcg/mL (22.2%) following the approved recommended dosage. Steady-state concentration of tislelizumab-jsgr is reached after 12 weeks of repeated dosing with an every 3-week regimen and the systemic accumulation was 2.14-fold.
Distribution
The tislelizumab-jsgr steady-state total volume of distribution is 6.42 L (32.6%).
Elimination
The tislelizumab-jsgr total clearance is 0.153 L/day (29.5%) and the terminal half-life (t½) is 24 days (31%).
Specific Populations
No clinically significant differences in the pharmacokinetics of tislelizumab-jsgr were observed based on age (range: 18 to 90 years), weight (range: 32 to 130 kg), race (White, Asian, or Black), mild to moderate renal impairment (CLcr ≥30 mL/min, estimated by Cockcroft-Gault), mild to moderate hepatic impairment (total bilirubin ≤3 times ULN and any AST, estimated by NCI criteria). The effect of severe hepatic impairment (total bilirubin >3 times ULN and any AST), severe renal impairment (CLcr 15-29 mL/min), or end-stage renal disease (CLcr <15 mL/min) on the pharmacokinetics of tislelizumab-jsgr is unknown.
The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of tislelizumab-jsgr products.
In patients who received tislelizumab-jsgr in RATIONALE-306 for up to 26 months, the incidence of anti-tislelizumab antibodies was 22% (66/300). Among the anti-tislelizumab antibody-positive patients, the incidence of neutralizing antibodies was 1.5% (1/66).
In patients who received tislelizumab-jsgr in RATIONALE-302 for up to 22 months, the incidence of anti-tislelizumab antibodies was 14.5% (32/221). Among the anti-tislelizumab antibody-positive patients, the incidence of neutralizing antibodies was 3.1% (1/32).
In patients who received tislelizumab-jsgr in RATIONALE-305 throughout the treatment period and in the ADA analysis set, the incidence of anti-tislelizumab antibodies was 22.7% (108/475). Among the anti-tislelizumab antibody-positive patients, the incidence of neutralizing antibodies was 5.6% (6/108).
There was no significant effect of anti-drug antibodies on the pharmacokinetics of tislelizumab-jsgr. The effect of anti-drug antibodies on pharmacodynamics, safety, or effectiveness of tislelizumab-jsgr has not been fully characterized.
No studies have been performed to assess the potential of tislelizumab-jsgr for carcinogenicity or genotoxicity.
In a 3-month repeat-dose toxicology study in cynomolgus monkeys, there were no notable effects in the male and female reproductive organs; however, most animals in the study were not sexually mature.
In animal models, inhibition of PD-L1/PD-1 signaling resulted in an increased severity of some infections and enhanced inflammatory responses. Mycobacterium tuberculosis–infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-1 blockade using a primate anti–PD-1 antibody was also shown to exacerbate M. tuberculosis infection in rhesus macaques. PD-L1 and PD-1 knockout mice have also shown decreased survival following infection with lymphocytic choriomeningitis virus.
First-line Treatment of Unresectable or Metastatic Esophageal Carcinoma (ESCC) in Patients Whose Tumors Express PD-L1 (≥1)
The efficacy of TEVIMBRA, in combination with chemotherapy, was evaluated in RATIONALE-306 (NCT03783442), a global, randomized, placebo-controlled, double-blind study in patients with unresectable, recurrent, or metastatic esophageal squamous cell carcinoma (ESCC).
Patients were enrolled regardless of their PD-L1 expression level. PD-L1 expression was evaluated at a central laboratory using the Ventana PD-L1 (SP263) assay that identified PD-L1 staining on both tumor and tumor-associated immune cells (Tumor Area Positivity or TAP). A retrospective scoring of tumor PD-L1 status using Combined Positive Score (CPS) was also conducted using the PD-L1–stained tumor specimens used for randomization.
Patients should not have received prior systemic therapy for advanced or metastatic disease. A treatment-free interval of at least 6 months was required if there was prior neoadjuvant/adjuvant therapy with platinum-based chemotherapy. The trial excluded patients who had active leptomeningeal disease or uncontrolled brain metastasis, active autoimmune disease, a medical condition requiring systemic corticosteroids or immunosuppressants, or evidence of fistula or complete esophageal obstruction not amenable to treatment.
Patients were randomized (1:1) to receive either TEVIMBRA 200 mg every 3 weeks or placebo in combination with investigator's choice of chemotherapy (ICC) on a 21-day cycle. Patients received TEVIMBRA until disease progression assessed by the investigator per RECIST v1.1, or until unacceptable toxicity. The chemotherapy doublet regimen consists of:
or
Cross-over between treatment arms or between fluoropyrimidine and paclitaxel during the study treatment period was not allowed.
Patient randomization was stratified by geographic region (Asia [excluding Japan] versus Japan versus Rest of World), prior definitive therapy (yes versus no), and investigator choice of chemotherapy (ICC; platinum with fluoropyrimidine versus platinum with paclitaxel).
Tumor assessments were performed every 6 weeks for the first 48 weeks, then every 9 weeks thereafter.
The primary efficacy outcome measure was overall survival (OS) in the Intent-to-Treat (ITT) population. Secondary outcome measures included progression-free survival (PFS), objective response rate (ORR), and duration of response (DoR) as assessed by the investigator per RECIST v1.1. Additional analyses of efficacy outcome measures were also conducted based on PD-L1 TAP ≥1% and CPS ≥1.
A total of 649 patients were randomized. The trial population characteristics were median age 64 years (range: 26 to 84 years), 48% were ≥65 years of age, 87% were male, 75% were Asian, and 24% were White. Eighty-six percent had metastatic disease and 14% had locally advanced disease; 99.8% of patients had histological confirmation of squamous cell carcinoma. Baseline ECOG performance status was 0 (33%) or 1 (67%). Thirty-four percent of patients had tumors that expressed PD-L1 TAP ≥10%, 74% had PD-L1 TAP ≥1%, and 74% had PD-L1 CPS ≥1. Fifty-five percent of patients received platinum (cisplatin or oxaliplatin) and paclitaxel-containing regimens, and 45% received platinum (cisplatin or oxaliplatin) and fluoropyrimidine-containing regimens.
RATIONALE-306 demonstrated a statistically significant improvement in OS for patients randomized to TEVIMBRA in combination with chemotherapy compared to placebo in combination with chemotherapy. Exploratory analysis of OS in the population with TAP <1% population and in the CPS <1 population showed hazard ratios of 1.34 (95% CI 0.73, 2.46) and 1.52 (95% CI 0.81, 2.84), respectively, indicating that the improvement in the ITT population was primarily attributed to the results observed in the subgroup of patients with PD-L1 ≥1.
Efficacy results are shown in Table 11, Figure 1, and Figure 2.
| Endpoint | TEVIMBRA + Chemotherapy (N=231) | Placebo + Chemotherapy (N=250) | TEVIMBRA + Chemotherapy (N=233) | Placebo + Chemotherapy (N=247) |
|---|---|---|---|---|
| PD-L1 TAP ≥1% | PD-L1 CPS ≥1 | |||
| CI = confidence interval; HR = hazard ratio. | ||||
| Overall Survival (OS) | ||||
| Deaths n (%) | 141 (61) | 177 (70.8) | 141 (61) | 175 (71) |
| Median (months)* (95% CI) | 16.8 (15.3, 20.8) | 9.6 (8.9, 11.8) | 16.8 (15.3, 20.8) | 9.6 (8.9, 11.8) |
| HR† (95% CI) | 0.66 (0.53, 0.82) | 0.65 (0.52,0.81) | ||
| Progression-Free Survival (PFS) | ||||
| Events, n (%) | 152 (66) | 199 (80) | 153 (66) | 195 (79) |
| Median (months)* (95% CI) | 7.2 (6.8, 8.5) | 5.5 (4.5, 5.8) | 7.1 (6.8, 8.3) | 5.5 (4.5, 5.8) |
| HR† (95% CI) | 0.56 (0.45, 0.70) | 0.57 (0.46, 0.71) | ||
| Objective Response Rate (ORR)‡ | ||||
| Responders, n | 134 | 90 | 134 | 89 |
| ORR, % | 58 | 36 | 58 | 36 |
| 95% CI§ | (51, 65) | (30, 42) | (51, 64) | (30, 42) |
| Complete response (CR), n (%) | 11 (4.8) | 5 (2) | 11 (4.7) | 5 (2) |
| Partial response, n (%) | 123 (53) | 85 (34) | 123 (53) | 84 (34) |
| Duration of Response (DoR) | ||||
| Median DoR (months)* (95% CI) | 7.2 (6.2, 9.6) | 5.7 (4.4, 7.3) | 7.6 (6.6, 9.7) | 5.6 (4.4, 7.3) |
* Medians were estimated by Kaplan-Meier method with 95% CIs estimated using the method of Brookmeyer and Crowley.
† Estimated by Cox proportional hazards model.
‡ Confirmed responses.
§ Exact Clopper-Person-2-sided CI.
Figure 1: Kaplan-Meier Curve for Overall Survival in RATIONALE-306 (PD-L1 TAP ≥1%)
Figure 2: Kaplan-Meier Curve for Overall Survival in RATIONALE-306 (PD-L1 CPS ≥1)
Efficacy results from the exploratory retrospective analysis with CPS scoring were generally consistent with the efficacy results for TAP subgroups detailed in Table 11 and Figure 1.
Previously Treated Unresectable or Metastatic Esophageal Squamous Cell Carcinoma (ESCC)
RATIONALE-302 (NCT03430843) was a multicenter, randomized (1:1), open-label trial in 512 adult patients with unresectable advanced or metastatic ESCC who progressed on or after prior systemic chemotherapy.
Patients were enrolled regardless of their tumor PD-L1 expression level. PD-L1 expression was evaluated at a central laboratory using the Ventana PD-L1 (SP263) assay that identified PD-L1 staining on both tumor and tumor-associated immune cells (TAP). The trial excluded patients who received a prior immune checkpoint inhibitor, 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 tumor.
Patients were randomized (1:1) to receive either TEVIMBRA 200 mg every 3 weeks or investigator's choice of chemotherapy (ICC), all given intravenously: paclitaxel 135-175 mg/m2 every 3 weeks or 80 to 100 mg/m2 weekly, docetaxel 75 mg/m2 every 3 weeks, or irinotecan 125 mg/m2 on Days 1 and 8 of every 3-week cycle. Patients were treated until disease progression assessed by the investigator or unacceptable toxicity.
Randomization was stratified by geographic region (Asia [excluding Japan] vs Japan vs US/EU), ECOG performance status (0 vs 1), and ICC option. Tumor assessments were conducted every 6 weeks for the first 6 months, then every 9 weeks until disease progression.
The major efficacy outcome measure was overall survival (OS) in the Intent-to-Treat (ITT) population. Additional efficacy outcome measures were investigator-assessed progression-free survival (PFS), overall response rate (ORR), and duration of response (DoR) per RECIST v1.1.
A total of 512 patients were enrolled and randomized to TEVIMBRA (n=256) or ICC (n=256) (irinotecan [46%], paclitaxel [33%], or docetaxel [21%]). Of the 512 patients, 142 (28%) had PD-L1 ≥10%, 222 (43%) had PD-L1 <10%, and 148 (29%) had unknown baseline PD-L1 status.
The trial population characteristics were: median age of 62 years (range: 35 to 86), 38% age ≥65; 84% male; 19% White and 80% Asian; 95% had metastatic disease. All patients had received at least one prior anti-cancer systemic therapy. Baseline ECOG performance status was 0 (25%) or 1 (75%).
RATIONALE-302 demonstrated a statistically significant improvement in OS for patients randomized to TEVIMBRA as compared with ICC. OS results by PD-L1 CPS level (<1 and ≥1) were not studied.
Efficacy results are shown in Table 12 and Figure 3.
| Endpoint | TEVIMBRA (N=256) | ICC (N=256) |
|---|---|---|
| CI = confidence interval, ORR = objective response rate. | ||
| Overall Survival | ||
| Deaths n (%) | 197 (77) | 213 (83.2) |
| Median (months)* (95% CI) | 8.6 (7.5, 10.4) | 6.3 (5.3, 7) |
| Hazard ratio† (95% CI) | 0.7 (0.57, 0.85) | |
| p-value‡ | 0.0001 | |
| Progression-Free Survival | ||
| Disease progression or death (%) | 223 (87.1) | 180 (70.3) |
| Median (months)* (95% CI) | 1.6 (1.4, 2.7) | 2.1 (1.5, 2.7) |
| Hazard ratio† (95% CI) | 0.83 (0.67, 1.01) | |
| Objective Response Rate§ | ||
| ORR (%) (95% CI) | 15.2 (11.1, 20.2) | 6.6 (3.9, 10.4) |
| Complete response n (%) | 5 (2) | 1 (0.4) |
| Partial response n (%) | 34 (13.3) | 16 (6.3) |
| Duration of Response | ||
| Median (months)* (95% CI) | 10.3 (6.5, 13.2) | 6.3 (2.8, 8.5) |
* Estimated using Kaplan-Meier method.
† Based on Cox regression model stratified by baseline ECOG status and ICC option.
‡ One-sided p-value based on log-rank test stratified by ECOG performance status and ICC option.
§ Confirmed response.
Figure 3: Kaplan-Meier Curve for Overall Survival in RATIONALE-302 (ITT)
Previously Untreated, Unresectable, or Metastatic HER2-Negative Gastric or Gastroesophageal Junction (G/GEJ) Adenocarcinoma in Patients Whose Tumors Express PD-L1 (≥1)
RATIONALE-305 (NCT03777657) was a randomized, multicenter, placebo-controlled, double-blind trial in patients with HER2-negative previously untreated unresectable or metastatic G/GEJ adenocarcinoma.
Patients were enrolled regardless of their tumor PD-L1 expression level, which was evaluated prospectively at a central laboratory using the VENTANA PD-L1 (SP263) assay that identified PD-L1 staining on both tumor and tumor-associated immune cells (TAP). A retrospective scoring of tumor PD-L1 status using Combined Positive Score (CPS) was also conducted using the PD-L1-stained tumor specimens used for randomization.
The trial excluded patients who had active leptomeningeal disease or uncontrolled brain metastasis, and patients with active autoimmune disease or history of autoimmune diseases, or a medical condition requiring systemic corticosteroids or immunosuppressants.
Patients were randomized to receive either TEVIMBRA 200 mg every 3 weeks or placebo in combination with investigator's choice of chemotherapy on a 21-day cycle. TEVIMBRA (or placebo) was administered until disease progression or unacceptable toxicity.
The chemotherapy doublets regimen consisted of:
or
Cross-over between treatment arms was not allowed.
Patient randomization was stratified by geographic region (China [including Taiwan], vs Japan and South Korea vs rest of the world, including US and Europe); PD-L1 expression (PD-L1 TAP score ≥5% vs PD-L1 TAP score <5%); presence of peritoneal metastasis (yes vs no); and ICC option (oxaliplatin plus capecitabine vs cisplatin plus 5-FU).
Tumor assessments were performed every 6 weeks for the first 48 weeks and thereafter approximately every 9 weeks.
The primary efficacy outcome measures were OS in the PD-L1 TAP score ≥5% population and in the Intent-to-Treat (ITT) population. Secondary outcome measures included progression-free survival (PFS), objective response rate (ORR), and duration of response (DoR) as assessed by the investigator per RECIST v1.1. Additional analyses of efficacy outcome measures were also conducted based on PD-L1 TAP ≥1% and CPS ≥1.
A total of 997 patients were randomized. The trial population characteristics were median age 61 years (range: 23 to 86 years), 35% ≥65 years of age, 69% male; 75% Asian, 22% White, and 0% Black or African American. Eighty percent had primary stomach tumor; 89% had PD-L1 TAP ≥1% and 86% had PD-L1 CPS ≥1, and 99% of patients had metastatic disease at baseline. Baseline ECOG performance status was 0 (32%) or 1 (68%). Ninety-three percent of patients received CAPOX and 7% received FP.
RATIONALE-305 demonstrated a statistically significant improvement in OS for patients randomized to TEVIMBRA in combination with chemotherapy compared with placebo plus chemotherapy in the PD-L1 TAP ≥5% population and in the ITT population. Exploratory analyses of OS in the TAP <1% population and in the CPS <1 population showed hazard ratios of 0.98 (95% CI: 0.64, 1.50) and 1.01 (95% CI: 0.66, 1.52) respectively, indicating that the improvement in the ITT population was primarily attributed to the results observed in the subgroup of patients with PD-L1 ≥1.
Efficacy results are summarized in Table 13, Figure 4, and Figure 5.
| Endpoint | TEVIMBRA + Chemotherapy (N=432) | Placebo + Chemotherapy (N=453) | TEVIMBRA + Chemotherapy (N=420) | Placebo + Chemotherapy (N=434) |
|---|---|---|---|---|
| PD-L1 TAP ≥1% | PD-L1 CPS ≥1 | |||
| Abbreviations: CI = confidence interval, HR = hazard ratio, ORR = objective response rate. | ||||
| Overall Survival | ||||
| Deaths n (%) | 318 (74) | 370 (82) | 308 (73) | 356 (82) |
| Median (months)* (95% CI) | 15 (13.3, 16.7) | 12.8 (12.1, 14.1) | 15.1 (13.6, 17.2) | 12.9 (12.1, 14.1) |
| HR† (95% CI) | 0.78 (0.67, 0.90) | 0.78 (0.67, 0.91) | ||
| Progression-Free Survival | ||||
| Events, n (%) | 316 (73) | 364 (80) | 303 (72) | 348 (80) |
| Median‡ (months) (95% CI) | 6.9 (5.7, 7.2) | 5.9 (5.6, 6.9) | 7 (5.7, 7.7) | 6.4 (5.6, 6.9) |
| HR† (95% CI) | 0.78 (0.67, 0.91) | 0.77 (0.66, 0.90) | ||
| Objective Response Rate‡ | ||||
| ORR, n | 206 | 186 | 204 | 183 |
| ORR, % | 48 | 41 | 49 | 42 |
| 95% CI (%)§ | (43, 53) | (37, 46) | (44, 53) | (37, 47) |
| Complete response, n (%) | 15 (3.5) | 15 (3.3) | 16 (3.8) | 16 (3.7) |
| Partial response, n (%) | 191 (44) | 171 (38) | 188 (45) | 167 (38) |
| Duration of Response | ||||
| Median (months)* (95% CI) | 8.6 (7.8, 10.4) | 7.2 (5.8, 8.3) | 8.6 (7.8, 10.4) | 7.2 (5.8, 8.5) |
* Medians were estimated by Kaplan-Meier method with 95% CIs estimated using the method of Brookmeyer and Crowley.
† Estimated by Cox proportional hazards model.
‡ Based on confirmed response.
§ Exact Clopper-Pearson 2-sided confidence interval.
Figure 4: Kaplan-Meier Curve for Overall Survival in RATIONALE-305 (PD-L1 TAP ≥1%)
Figure 5: Kaplan-Meier Curve for Overall Survival in RATIONALE-305 (PD-L1 CPS ≥1)
An exploratory subgroup analysis of OS in 40 patients with MSI-H tumors irrespective of PD-L1 status showed a HR of 0.66 (0.3, 1.43).
First-Line Treatment of HER2-Positive (IHC3+/ IHC2+/ISH+) Unresectable Locally Advanced or Metastatic Gastric, Gastroesophageal Junction, or Esophageal Adenocarcinoma
The efficacy of TEVIMBRA in combination with zanidatamab-hrii and fluoropyrimidine- and platinum-containing chemotherapy for the treatment of GEA was evaluated in HERIZON-GEA-01 (NCT05152147), a randomized, multicenter, 3-arm, open-label, active-comparator study.
Patients had untreated, unresectable locally advanced/metastatic, HER2-positive (IHC 3+ or IHC 2+/ISH+) per central testing, an ECOG PS of 0 or 1, and adequate organ function, including left ventricular ejection fraction (LVEF) ≥50%. Patients were enrolled regardless of their PD-L1 expression.
Randomization was stratified by geographic region (Asian, EU/North America, Rest of World), HER2 status (3+ IHC staining, 2+ IHC staining with ISH-positivity), and Eastern Cooperative Oncology Group (ECOG) performance status (0, 1).
Patients were randomized to receive one of the following treatment arms, each with investigator's choice of a fluoropyrimidine- and platinum-containing chemotherapy – CAPOX (capecitabine 1,000 mg/m2 administered orally twice a day from the evening of Day 1 to the morning of Day 15 of each 21-day cycle plus oxaliplatin 130 mg/m2 administered intravenously on Day 1 of each 21-day cycle) or FP (5-Fluorouracil 800 mg/m2/day administered as continuous intravenous infusion on Days 1 to 5 of each 21-day cycle plus cisplatin 80 mg/m2 administered intravenously on Day 1 of each 21-day cycle) for at least 6 cycles:
Treatment with TEVIMBRA and zanidatamab-hrii continued in each arm until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Efficacy assessments were based on patients randomized to the TEVIMBRA plus zanidatamab-hrii and chemotherapy versus the trastuzumab and chemotherapy arms.
The dual major efficacy endpoints were progression-free survival (PFS) assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) and overall survival (OS). Additional efficacy outcome measures included objective response rate (ORR) and duration of response (DoR).
A total of 914 patients were enrolled into the HERIZON-GEA-01 trial with 610 patients randomized to the TEVIMBRA and control arms. Of these patients, 434 had gastric adenocarcinoma, 134 had gastroesophageal junction adenocarcinoma, and 42 had esophageal adenocarcinoma. The trial population characteristics were median age 64 years (range: 21 to 84 years), 47% ≥65 years of age, 79% male; 55% Asian, 40% White, 2% American Indian or Alaskan Native, and 1.6% of other or multiple races; 40% ECOG performance status of 0 or 60% performance status of 1.
HERIZON-GEA-01 demonstrated a statistically significant improvement in OS and PFS for patients randomized to TEVIMBRA plus zanidatamab-hrii and chemotherapy arm, compared with the trastuzumab plus chemotherapy arm.
Efficacy results are shown in Table 14, Figure 6, and Figure 7.
| TEVIMBRA + Zanidatamab-hrii and Chemotherapy N=302 | Trastuzumab + Chemotherapy N=308 | |
|---|---|---|
| Abbreviations: CI = confidence interval. | ||
| Overall Survival* | ||
| Deaths (%) | 134 (44%) | 170 (55%) |
| Median, months | 26.4 | 19.2 |
| (95% CI) | (21.5, 30.3) | (16.8, 21.8) |
| Hazard ratio (95% CI)† | 0.72 (0.57, 0.90) | |
| p-value‡ | 0.0043 | |
| Progression-Free Survival* | ||
| Number of events (%) | 154 (51%) | 196 (64%) |
| Median, months | 12.4 | 8.1 |
| (95% CI) | (9.8, 18.5) | (7.0, 8.9) |
| Hazard ratio (95% CI)† | 0.63 (0.51, 0.78) | |
| p-value‡ | <0.0001 | |
| Objective Response Rate (ORR) | ||
| ORR (95% CI)§ | 67% (61, 72) | 63% (57, 68) |
| Complete response rate | 20% | 12% |
| Partial response rate | 47% | 50% |
| Duration of Response (DoR)* | N=202 | N=193 |
| Median in months (95% CI) | 18.9 (12.1, 37.7) | 8.3 (6.8, 10.1) |
* Estimates per Kaplan-Meier method.
† Hazard ratio and 95% CIs were calculated stratified by geographic region, HER2 status, and ECOG performance status.
‡ The p-values were calculated by stratified log-rank test.
§ Two-sided 95% exact confidence interval using the Clopper-Pearson method.
In prespecified exploratory analyses comparing TEVIMBRA + zanidatamab-hrii + chemotherapy (Arm C) and trastuzumab + chemotherapy (Arm A) in the HER2 IHC3+ population, the PFS HR was 0.54 (95% CI: 0.43, 0.69), with a median 16.1 months (95% CI: 10.9, 22.0) in Arm C and 7.6 months (6.9, 8.5) in Arm A; the OS HR was 0.70 (95% CI: 0.55, 0.91), with a median 27.3 months (95% CI: 22.3, NE) in Arm C and 19.8 months (95% CI: 16.2, 22.8) in Arm A. In the HER2 IHC2+/ISH+ population, the PFS HR was 1.08 (95% CI: 0.65, 1.78), with a median 8.6 months (95% CI: 6.7, 11.1) in Arm C and 10.0 months (95% CI: 6.9, 18.4) in Arm A; the OS HR was 0.83 (95% CI: 0.50, 1.39), with a median 21.5 months (95% CI: 16.0, 26.4) in Arm C and 18.7 months (95% CI: 13.6, 23.1) in Arm A.
Figure 6: Kaplan-Meier Plot of Overall Survival in HERIZON-GEA-01
Figure 7: Progression Free Survival Curve in HERIZON-GEA-01
How Supplied
TEVIMBRA injection is a clear to slightly opalescent, colorless to slightly yellow solution supplied in a carton containing one single-dose vial, available as follows:
| Strength | NDC |
|---|---|
| 100 mg/10 mL (10 mg/mL) | 72579-121-01 |
| 150 mg/15 mL (10 mg/mL) | 72579-125-00 |
Storage
Store in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light.
Do not freeze. Do not shake.
Advise patients to read the FDA-approved patient labeling (Medication Guide).
Immune-Mediated Adverse Reactions
Inform patients of the risk of immune-mediated adverse reactions that may be severe or fatal, may occur after discontinuation of treatment, and may require corticosteroid treatment and interruption or discontinuation of TEVIMBRA. These reactions may include:
Infusion-Related Reactions
Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.2)].
Complications of Allogeneic Hematopoietic Stem Cell Transplantation Complications
Advise patients of potential risk of post-allogeneic hematopoietic stem cell transplantation complications (HSCT) [see Warnings and Precautions (5.3)].
Embryo-Fetal Toxicity
Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.4), Use in Specific Populations (8.1, 8.3)].
Advise females of reproductive potential to use effective contraception during treatment with TEVIMBRA and for 4 months after the last dose [see Warnings and Precautions (5.4) , Use in Specific Populations (8.1, 8.3)].
Lactation
Advise women not to breastfeed during treatment with TEVIMBRA and for 4 months after the last dose [see Use in Specific Populations (8.2)].
Manufactured by:
BeOne Medicines USA, Inc.
Pennington, NJ 08534
U.S. License No. 2400
TEVIMBRA® is a registered trademark owned by BeOne Medicines I GmbH or its affiliates.
© BeOne Medicines I GmbH, 2026. All Rights Reserved.
| Medication Guide TEVIMBRA® (teh-vim-brah) (tislelizumab-jsgr) injection | |||
|---|---|---|---|
| This Medication Guide has been approved by the U.S. Food and Drug Administration. | Revised: 8/2026 | ||
| What is the most important information I should know about TEVIMBRA? TEVIMBRA is a medicine that may treat certain cancers by working with your immune system. TEVIMBRA can cause your immune system to attack normal organs and tissues in any area of your body and can affect the way they work. These problems can sometimes become severe or life-threatening and can lead to death. You can have more than one of these problems at the same time. These problems may happen anytime during treatment or even after your treatment has ended. Call or see your healthcare provider right away if you develop any new or worsening symptoms, including: Lung problems | |||
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Intestinal problems
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Problems can also happen in other organs and tissues. These are not all of the signs and symptoms of immune system problems that can happen with TEVIMBRA. Call or see your healthcare provider right away for new or worsening symptoms, which may include:
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| Rejection of a transplanted organ or tissue. Your healthcare provider should tell you what signs and symptoms you should report and monitor you, depending on the type of organ or tissue transplant that you have had. Complications, including graft-versus-host-disease (GVHD), in people who have received a bone marrow (stem cell) transplant that uses donor stem cells (allogeneic). These complications can be serious and can lead to death. These complications may happen if you underwent transplantation either before or after being treated with TEVIMBRA. Your healthcare provider will monitor you for these complications. Getting medical treatment right away may help keep these problems from becoming more serious. Your healthcare provider will check you for these problems during your treatment with TEVIMBRA. Your healthcare provider may treat you with corticosteroid or hormone replacement medicines. Your healthcare provider may also need to delay or completely stop treatment with TEVIMBRA if you have severe side effects. | |||
| What is TEVIMBRA? TEVIMBRA is a prescription medicine used to treat adults with:
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Before receiving TEVIMBRA, tell your healthcare provider about all of your medical conditions, including if you:
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How will I receive TEVIMBRA?
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| What are the possible side effects of TEVIMBRA? TEVIMBRA may cause serious side effects. See "What is the most important information I should know about TEVIMBRA?" The most common side effects of TEVIMBRA when used in combination with platinum-containing chemotherapy include: | |||
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| The most common side effects of TEVIMBRA when used alone include: | |||
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| The most common side effects of TEVIMBRA in combination with platinum and fluoropyrimidine-based chemotherapy include: | |||
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| The most common side effects of TEVIMBRA in combination with zanidatamab-hrii and fluoropyrimidine and platinum-based chemotherapy include: | |||
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| These are not all the possible side effects of TEVIMBRA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. | |||
| General information about the safe and effective use of TEVIMBRA. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your healthcare provider or pharmacist for more information about TEVIMBRA that is written for health professionals. | |||
| What are the ingredients in TEVIMBRA? Active ingredient: tislelizumab-jsgr Inactive ingredients: citric acid monohydrate, histidine, L-histidine hydrochloride monohydrate, polysorbate 20, sodium citrate, trehalose, and Water for Injection. Manufactured by: BeOne Medicines USA, Inc. Pennington, NJ 08534 U.S. License No. 2400 TEVIMBRA® is a registered trademark owned by BeOne Medicines I GmbH or its affiliates. © BeOne Medicines I GmbH, 2026. All Rights Reserved. For more information, call 1-833-969-2463 or go to www.TEVIMBRA.com | |||
NDC 72579-121-01
Rx only
TEVIMBRA®
tislelizumab-jsgr
injection
100 mg/10 mL
(10 mg/mL)
For Intravenous Infusion
After Dilution
Dispense with Medication Guide
One 10 mL single-dose vial
Discard unused portion
NDC 72579-125-00
Rx only
TEVIMBRA®
tislelizumab-jsgr
injection
150 mg/15 mL
(10 mg/mL)
For Intravenous Infusion
After Dilution
Dispense with Enclosed
Medication Guide
One 15 mL single-dose vial
Discard unused portion
| Resource | Code type | Value | Equivalent identifiers | Source image |
|---|---|---|---|---|
| Data code | Data Matrix | 133139 | tevimbra-08.jpg |
| Product concept | Relation | Version | Effective |
|---|---|---|---|
| 6c17a59c-7e5f-4962-9bd9-f8862385434c | Product name | 1 | 20250124 |
| 0ca1d589-929b-4b33-bc5b-1d84abdafa6a | Product name | 1 | 20150324 |
| fc363c46-397b-4476-ac0f-70e43e8e4592 | Product name | 1 | 20150324 |
| Package NDC | Billing unit | Product NDC | DailyMed indexing SPL | SPL version | Effective |
|---|---|---|---|---|---|
| 72579-121-01 | ML - Milliliter | 72579-121 | 6c0c38de-cf9d-4f24-948e-5f7b79b3fe34 | 1 | 2024-09-09 |
Every source-derived product name is available through these pages.
| Product NDC | Package NDC |
|---|---|
| 72579-121 | 72579-121-01 |
| 72579-125 | 72579-125-00 |
| BLA | Proprietary name | Proper name | License type | Status | Latest source |
|---|---|---|---|---|---|
| 761232 | Tevimbra | tislelizumab-jsgr | 351(a) | Rx | 2026-09-01 |
Every source-derived ingredient row is available through these pages.
| Name | UNII | Kind |
|---|---|---|
| TISLELIZUMAB | 0KVO411B3N | ACTIB |
| CITRIC ACID MONOHYDRATE | 2968PHW8QP | IACT |
| HISTIDINE | 4QD397987E | IACT |
| POLYSORBATE 20 | 7T1F30V5YH | IACT |
| SODIUM CITRATE, UNSPECIFIED FORM | 1Q73Q2JULR | IACT |
| TREHALOSE | B8WCK70T7I | IACT |
| WATER | 059QF0KO0R | IACT |
| TISLELIZUMAB | 0KVO411B3N | ACTIB |
| CITRIC ACID MONOHYDRATE | 2968PHW8QP | IACT |
| HISTIDINE | 4QD397987E | IACT |
| POLYSORBATE 20 | 7T1F30V5YH | IACT |
| SODIUM CITRATE, UNSPECIFIED FORM | 1Q73Q2JULR | IACT |
| TREHALOSE | B8WCK70T7I | IACT |
| WATER | 059QF0KO0R | IACT |
| Version | Effective date | Source | Hydrated |
|---|---|---|---|
| 14 | 2026-08-31 | daily-update | 2026-09-04 01:01:45 |
| 13 | 2026-05-22 | daily-update | 2026-07-17 21:46:21 |
| 12 | 2026-02-04 | full-release | 2026-05-31 21:58:49 |
| 10 | 2025-12-12 | monthly-update | 2026-06-03 17:48:05 |
OpenFDA label data provides additional search and identifier links. DailyMed’s Structured Product Label is the canonical label on FDA.report. Matching records are deduplicated before they are shown below.
| Brand | Generic | Manufacturer | SPL set ID | Effective date | Available safety fields | Join |
|---|---|---|---|---|---|---|
| TEVIMBRA | TISLELIZUMAB-JSGR | BeOne Medicines USA, Inc. | 08ef1e3e-496f-4b0b-94ee-fbba3cc1985a | 2026-08-31 | Warnings, Adverse reactions | 72579-125-00 72579-121-01 72579-121 72579-125 72579012101 72579012500 08ef1e3e-496f-4b0b-94ee-fbba3cc1985a |
Adverse event summaries are temporarily unavailable. Other product information remains available.