Preparation

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. TEVIMBRA is a clear to slightly opalescent, colorless to slightly yellow solution. Discard the vial if the solution is cloudy, discolored, or contains visible particles. Do not shake the vial.

Prepare the solution for infusion as follows:

• Withdraw 20 mL of TEVIMBRA from two vials of TEVIMBRA (for a total of 200 mg in 20 mL).
• Transfer solution into an intravenous infusion bag containing 0.9% Sodium Chloride Injection, USP to prepare an infusion solution with a final concentration of 2 mg/mL to 5 mg/mL.
• Mix diluted solution by gentle inversion to avoid foaming or excessive shearing of the solution. Do not shake.
• TEVIMBRA is for single use only. Discard any unused portion left in the vial.

Storage of Diluted Solution

This product does not contain any preservatives. If not used immediately, store the TEVIMBRA diluted solution either:

• At room temperature at 20°C to 25°C (68°F to 77°F) for no more than 4 hours, including preparation and infusion duration. Discard after 4 hours.
• Under refrigeration at 2°C to 8°C (36°F to 46°F) for up to 20 hours, including preparation and infusion duration. Allow the diluted solution to come to room temperature prior to administration. Discard after 20 hours.

Do not freeze the diluted solution.

Administration

• Administer diluted solution by intravenous infusion through an intravenous line with a sterile, nonpyrogenic, low protein–binding 0.2 micron or 0.22 micron in-line or add-on filter.
• The initial infusion should be delivered over 60 minutes. If tolerated, all subsequent infusions may be administered over 30 minutes.
• Do NOT coadminister other drugs through the same infusion line.
• Do NOT administer TEVIMBRA as an intravenous push or single bolus injection.
• Flush the intravenous line at the end of infusion.

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 4.9% (96/1972) of patients receiving TEVIMBRA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (1.6%), and Grade 2 (1.9%) adverse reactions. Pneumonitis led to permanent discontinuation of TEVIMBRA in 38 (1.9%) patients and withholding of TEVIMBRA in 32 (1.6%) patients.

Seventy-four (77.1%) of the 96 patients received systemic corticosteroids. Sixty-five (67.7%) of the 96 patients received high-dose systemic corticosteroids. Immune-mediated pneumonitis resolved in 50% of the 96 patients. Of the 32 patients in whom TEVIMBRA was withheld for pneumonitis, 20 (62.5%) reinitiated TEVIMBRA after symptom improvement; of these, 2 (10%) 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% (16/1972) of patients receiving TEVIMBRA, including Grade 3 (0.3%) and Grade 2 (0.4%) adverse reactions. Colitis led to permanent discontinuation of TEVIMBRA in 4 (0.2%) patients and withholding of TEVIMBRA in 5 (0.3%) patients. Twelve (75%) of the 16 patients received systemic corticosteroids. Eight (50%) of the 16 patients received high-dose systemic corticosteroids. Two (12.5%) of the 16 patients received immunosuppressive treatment. Immune-mediated colitis resolved in 93.8% of the 16 patients. All 5 patients in whom TEVIMBRA was withheld for colitis reinitiated TEVIMBRA after symptom improvement; of these, none of the patients had recurrence of colitis.

Immune-Mediated Hepatitis

TEVIMBRA can cause immune-mediated hepatitis, which can be fatal.

Immune-mediated hepatitis occurred in 1.2% (24/1972) of patients receiving TEVIMBRA, including fatal (0.1%), Grade 4 (0.2%), Grade 3 (0.5%), and Grade 2 (0.4%) adverse reactions. Immune-mediated hepatitis led to permanent discontinuation in 3 (0.2%) patients and withholding of TEVIMBRA in 13 (0.7%) patients. Eighteen (75%) of the 24 patients received systemic corticosteroids. Thirteen (54.2%) of the 24 patients received high-dose systemic corticosteroids. Two (8.3%) of the 24 patients received immunosuppressive treatment. Immune-mediated hepatitis resolved in 70.8% of the 24 patients. Of the 13 patients in whom TEVIMBRA was withheld for hepatitis, 7 (53.8%) reinitiated TEVIMBRA after symptom improvement; of these, none of the patients had recurrence of hepatitis.

Immune-Mediated Endocrinopathies

Immune-Mediated Nephritis with Renal Dysfunction

TEVIMBRA can cause immune-mediated nephritis, which can be fatal.

Immune-mediated nephritis with renal dysfunction occurred in 0.3% (6/1972) of patients receiving TEVIMBRA, including Grade 3 (0.1%) and Grade 2 (0.2%) adverse reactions. TEVIMBRA was permanently discontinued in 1 (0.1%) patient and treatment was withheld in 3 (0.2%) patients. Three (50%) patients received systemic corticosteroids. Three (50%) of the 6 patients received high-dose systemic corticosteroids. Nephritis with renal dysfunction resolved in 33.3% of the 6 patients. Of the 3 patients in whom TEVIMBRA was withheld for nephritis, 2 (66.7%) reinitiated TEVIMBRA after symptom improvement; of these, one (50%) patient 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), toxic epidermal necrolysis (TEN), have been reported, some with fatal outcomes. 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 15.3% (301/1972) of patients receiving TEVIMBRA, including Grade 4 (0.1%), Grade 3 (0.9%), and Grade 2 (3.5%) adverse reactions. Dermatologic adverse reactions led to permanent discontinuation of TEVIMBRA in 2 (0.1%) patients and withholding of TEVIMBRA in 18 (0.9%) patients, thirty (10%) of the 301 patients received systemic corticosteroids. Thirteen (4.3%) of the 301 patients received high-dose systemic corticosteroids. Immune-mediated dermatologic adverse reactions resolved in 63.1% of the 301 patients. Of the 18 patients in whom TEVIMBRA was withheld for dermatologic adverse reactions, 15 (83.3%) reinitiated TEVIMBRA after symptom improvement; of these, 1 (6.7%) patient had recurrence of immune-mediated dermatologic adverse reaction.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of less than 1% each in patients who received TEVIMBRA: myositis, myocarditis, arthritis, polymyalgia rheumatica, encephalitis, myasthenia gravis, Sjogren's syndrome, and pericarditis.

The following additional clinically significant immune-mediated adverse reactions have been reported with other PD-1/PD-L1 blocking antibodies, including severe or fatal cases.

Cardiac/Vascular: 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 can occur. 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.

Musculoskeletal and Connective Tissue: Polymyositis, rhabdomyolysis and associated sequelae including renal failure.

Endocrine: Hypoparathyroidism.

Other (Hematologic/Immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection.

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 2 and Table 3, respectively.

Treatment of Previously Untreated Unresectable or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma (G/GEJ)

The safety of TEVIMBRA in combination with chemotherapy was evaluated in RATIONALE-305, a randomized, multicenter, double-blind, placebo-controlled trial in patients with previously untreated unresectable or metastatic G/GEJ adenocarcinoma [see Clinical Studies (14.2)].

Patients were randomized (1:1) to receive either TEVIMBRA 200 mg by intravenous infusion over 30-60 minutes every 3 weeks or placebo plus a platinum and fluoropyrimidine-based chemotherapy. The chemotherapy regimens consisted of:

• Oxaliplatin 130 mg/m2 IV on Day 1 for up to 6 cycles and capecitabine 1000 mg/m2 orally twice daily for 14 consecutive days of every 3-week cycle.

or

• Cisplatin 80 mg/m2 IV, Day 1, and 5-FU (5-fluorouracil) 800 mg/m2/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 4 and Table 5, respectively.

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.

Other Clinically Important Laboratory Abnormalities Occurring in <20% include:

Creatinine increased, potassium increased, glucose decreased, sodium increased, lymphocytes increased, hemoglobin increased.

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 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

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.

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating TEVIMBRA [see Use in Specific Populations (8.1)].

Contraception

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 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.

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.

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 (Tumor Area Positivity or 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 6 and Figure 1.

Figure 1: Kaplan-Meier Curve for Overall Survival in RATIONALE-302 (ITT)

Previously Untreated, Unresectable, or Metastatic HER2-Negative Gastric or Gastroesophageal Junction (G/GEJ) Adenocarcinoma 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:

• CAPOX: Oxaliplatin 130 mg/m2 IV on Day 1 for up to 6 cycles and capecitabine 1000 mg/m2 orally twice daily for 14 consecutive days. Capecitabine treatment could be continued beyond 6 cycles.

or

• FP: Cisplatin 80 mg/m2 IV, Day 1, and 5-FU 800 mg/m2/day IV continuous infusion over 24 hours daily Day 1-5. Cisplatin and 5-FU were given for up to 6 cycles.

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 7, Figure 2, and Figure 3.

Figure 2: Kaplan-Meier Curve for Overall Survival in RATIONALE-305 (PD-L1 TAP ≥1%)

TIS+C, Tislelizumab + Chemotherapy; PBO+C, Placebo + Chemotherapy.

Figure 3: Kaplan-Meier Curve for Overall Survival in RATIONALE-305 (PD-L1 CPS ≥1)

TIS+C, Tislelizumab + Chemotherapy; PBO+C, Placebo + Chemotherapy;

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).