Tislelizumab-jsgr (Monograph)

Brand name: Tevimbra
Drug class: Antineoplastic Agents

Introduction

Antineoplastic agent; humanized anti-programmed-death receptor-1 (anti-PD-1) monoclonal antibody.

Uses for Tislelizumab-jsgr

Esophageal Cancer

Used as a single agent for 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.

Gastric Cancer

Used in combination with platinum and fluoropyrimidine-based chemotherapy for the first-line treatment of adults with unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastroesophageal junction adenocarcinoma whose tumors express programmed death-ligand 1 (PD-L1) (≥1).

Tislelizumab-jsgr Dosage and Administration

General

Pretreatment Screening

Confirm pregnancy status of females of reproductive potential.
Evaluate liver function tests, S_cr concentrations, and thyroid function tests at baseline.
Select patients for the treatment of unresectable or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma based on the presence of PD-L1 in tumor specimens.

Patient Monitoring

Evaluate liver enzymes, S_cr, and thyroid function periodically during treatment.
Monitor patients closely for manifestations of underlying immune-mediated adverse effects.
Monitor patients for signs and symptoms of infusion-related reactions.
Monitor patients for hyperglycemia or other signs and symptoms of diabetes.

Administration

IV Administration

Administer by IV infusion after dilution.

Administer through an IV line with a sterile, nonpyrogenic, low-protein-binding, 0.2 or 0.22 micron in-line or add-on filter.

Do not administer as an IV push or single bolus injection.

Do not coadminister other drugs through the same infusion line.

Flush IV line at the end of infusion.

Dilution

Must dilute injection concentrate prior to administration. Visually inspect vials of tislelizumab-jsgr solution for particulate matter and discoloration prior to administration, whenever solution and container permit. Undiluted solution is a clear to slightly opalescent, colorless to slightly yellow solution.

To prepare solution for infusion, withdraw 20 mL of tislelizumab-jsgr from 2 vials (for a total of 200 mg in 20 mL).

Transfer solution to an IV infusion bag containing 0.9% sodium chloride injection to prepare a final concentration of 2–5 mg/mL.

Mix diluted solution by gentle inversion to avoid foaming or excessive shearing. Do not shake. Tislelizumab-jsgr vials are for single use only. Discard any unused portion left in the vial.

Rate of Administration

Administer initial infusion over 60 minutes. If tolerated, may administer all subsequent infusions over 30 minutes.

Dosage

Adults

Unresectable or Metastatic Esophageal Squamous Cell Carcinoma

IV

Recommended dosage (as a single agent): 200 mg as an IV infusion once every 3 weeks, until disease progression or unacceptable toxicity.

Unresectable or Metastatic HER2-negative Gastric or Gastroesophageal Junction Adenocarcinoma

IV

Recommended dosage (in combination with platinum and fluoropyrimidine-containing chemotherapy): 200 mg as an IV infusion once every 3 weeks, until disease progression or unacceptable toxicity.

Refer to the respective Prescribing Information for dosing information for the drugs administered in combination with tislelizumab-jsgr.

Dosage Modification for Adverse Reactions

If immune-mediated adverse effects occur, temporary interruption or discontinuance of therapy may be required (see Table 1). In general, withhold tislelizumab-jsgr for severe (grade 3) immune-mediated adverse reactions. Permanently discontinue therapy for life-threatening (Grade 4) immune-mediated adverse reactions or recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, and in patients where the corticosteroid dosage cannot be reduced to <10 mg of prednisone daily (or equivalent) within 12 weeks of initiating steroids.

Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or if unable to reduce prednisone to <10 mg per day (or equivalent) within 12 weeks of initiating steroids.

If AST and ALT are ≤ULN at baseline, withhold or permanently discontinue tislelizumab-jsgr based on recommendations for hepatitis with no liver involvement.

Table 1: Recommended Dosage Modifications for Adverse Reactions to Tislelizumab-jsgr1
Adverse Reaction	Dose Modification Based on Severity
Pneumonitis	Grade 2: Withhold therapy until recovery to Grade 0 or 1; may resume after corticosteroid taper Grade 3 or 4 or recurrent Grade 2: Permanently discontinue
Colitis	Grade 2 or 3: Withhold therapy until recovery to Grade 0 or 1; may resume after corticosteroid taper Grade 4: Permanently discontinue
Hepatitis with no tumor involvement of the liver	AST or ALT increases to >3 times and ≤8 times ULN or total bilirubin increases to >1.5 and ≤3 times ULN: Withhold therapy until recovery to Grade 0 or 1; may resume after corticosteroid taper AST or ALT increase to >8 times ULN or total bilirubin increases to >3 times ULN: Permanently discontinue
Hepatitis with tumor involvement of the liver	Baseline AST or ALT is >1 and ≤3 times ULN and increases to >5 and ≤10 times ULN, or baseline AST or ALT is >3 and ≤5 times ULN and increases to >8 and ≤10 times ULN: Withhold therapy until recovery to Grade 0 or 1; may resume after corticosteroid taper Baseline AST or ALT increases to >10 times ULN or total bilirubin increases to >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 therapy until recovery to Grade 0 or 1; may resume after corticosteroid taper Grade 4 increased blood creatinine: Permanently discontinue
Exfoliative dermatologic conditions	Grade 3, or suspected Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or drug rash with eosinophilia and systemic symptoms (DRESS): Withhold therapy until recovery to Grade 0 or 1; may resume after corticosteroid taper Grade 4, or confirmed SJS, TEN, or DRESS: Permanently discontinue
Myocarditis	Grade 2, 3, or 4: Permanently discontinue
Neurological toxicities	Grade 2: Withhold therapy until recovery to Grade 0 or 1; may resume after corticosteroid taper Grade 3 or 4: Permanently discontinue
Infusion-related reactions	Grade 1: Slow infusion rate by 50% Grade 2: Interrupt infusion; resume infusion if resolved or decreased to Grade 1, and slow rate of infusion by 50% of the previous rate Grade 3 or 4: Permanently discontinue

Special Populations

Hepatic Impairment

No specific dosage recommendations.

Renal Impairment

No specific dosage recommendations.

Geriatric Patients

No specific dosage recommendations.

Cautions for Tislelizumab-jsgr

Contraindications

None.

Warnings/Precautions

Immune-Mediated Adverse Reactions

Severe and fatal immune-mediated adverse reactions can occur at any time in any organ system or tissue.

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.

If an immune-mediated adverse effect is suspected, evaluate patient to exclude alternative etiologies including infection.

Withhold or permanently discontinue treatment depending on severity and promptly initiate appropriate management. If dose interruption or discontinuation required, administer systemic corticosteroids (1–2 mg/kg/day prednisone or equivalent) until improvement to ≤grade 1 and then initiate and continue a corticosteroid taper over at least 1 month.

Consider administration of other systemic immunosuppressants if reaction not controlled with corticosteroids.

Permanently discontinue therapy if there is not partial or complete resolution within 12 weeks of steroid initiation or if corticosteroid dosage is not able to be decreased to <10 mg of prednisone daily (or equivalent) within 12 weeks of steroid initiation.

Immune-mediated Pneumonitis

Immune-mediated pneumonitis, sometimes fatal, reported. Risk may be higher in patients who received prior thoracic radiation.

Withhold or permanently discontinue drug depending on severity.

Immune-mediated Colitis

Immune-mediated colitis reported.

Withhold or permanently discontinue drug depending on severity.

Immune-mediated Hepatitis

Immune-mediated hepatitis, sometimes fatal, reported.

Withhold or permanently discontinue drug depending on severity.

Immune-mediated Endocrinopathies

Immune-mediated endocrinopathies (e.g., hypophysitis, hypothyroidism, hyperthyroidism, adrenal insufficiency, thyroiditis, type 1 diabetes mellitus) reported.

Monitor for manifestations of adrenal insufficiency. In patients with grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold or permanently discontinue drug depending on severity.

Monitor for hypophysitis; symptoms may include headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as clinically indicated. Withhold or permanently discontinue drug depending on severity.

Evaluate thyroid function prior to initiation of therapy and periodically during therapy. Initiate hormone replacement or medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue drug depending on severity.

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold or permanently discontinue drug depending on severity.

Immune-mediated Nephritis with Renal Dysfunction

Immune-mediated nephritis reported. Evaluate serum creatinine concentrations prior to initiation of therapy and periodically during therapy.

Depending on severity, interrupt or discontinue therapy.

Immune-mediated Dermatologic Adverse Reactions

Immune-mediated rash or dermatitis including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or drug rash with eosinophilia and systemic symptoms (DRESS) reported. Administration of topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-bullous/exfoliative rash.

Withhold or permanently discontinue therapy depending on severity.

Other Immune-Mediated Adverse Reactions

Other immune-mediated adverse reactions affecting any organ system or tissue (including solid organ transplant rejection) have occurred; some reactions were severe or fatal.

Depending on severity, interrupt or discontinue therapy.

Infusion-related Reactions

Severe or life-threatening infusion-related reactions reported.

Monitor patients for signs and symptoms of infusion-related reactions.

Slow rate of infusion for mild (grade 1) and interrupt 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 tislelizumab-jsgr.

Complications of Allogeneic HSCT

Serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after treatment with tislelizumab-jsgr. 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).

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider benefits versus risks of treatment with a PD-1/PD-L1-blocking antibody prior to or after an allogeneic HSCT.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm. 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.

Avoid pregnancy during therapy. Confirm pregnancy status prior to initiation of therapy in females of reproductive potential. Such females should use effective contraception during therapy and for at least 4 months after drug discontinuance.

Immunogenicity

Treatment-emergent anti-drug antibodies (ADAs) and neutralizing antibodies reported in both the RATIONALE-302 and RATIONALE-305 studies.

Specific Populations

Pregnancy

May cause fetal harm based on animal studies. No available data on use in pregnant women. Human IgG₄ immunoglobulins are known to cross the placental barrier. Advise patients of the potential risk to a fetus.

Lactation

No information regarding the presence of tislelizumab-jsgr in human milk, its effects on the breastfed child, or on milk production. Advise women not to breastfeed during treatment and for 4 months after the last dose of the drug.

Females and Males of Reproductive Potential

May cause fetal harm. Verify pregnancy status in females of reproductive potential prior to initiating tislelizumab-jsgr.

Advise females of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of the drug.

Pediatric Use

Safety and effectiveness not established.

Geriatric Use

No differences in safety or effectiveness observed between geriatric patients and younger patients.

Hepatic Impairment

No differences in pharmacokinetics of tislelizumab-jsgr observed based on mild to moderate hepatic impairment. Effect of severe hepatic impairment on pharmacokinetics of tislelizumab is unknown.

Renal Impairment

No differences in pharmacokinetics of tislelizumab-jsgr observed based on mild to moderate renal impairment.

Common Adverse Effects

Most common adverse reactions (≥20%) as a single agent in patients with esophageal cancer: anemia, fatigue, musculoskeletal pain, decreased weight, cough.

Most common (≥20%) adverse reactions in combination with chemotherapy in patients with gastric or gastroesophageal junction adenocarcinoma: nausea, fatigue, decreased appetite, anemia, peripheral sensory neuropathy, vomiting, decreased platelet count, decreased neutrophil count, increased aspartate aminotransferase, diarrhea, abdominal pain, increased alanine aminotransferase, decreased white blood cell count, decreased weight, pyrexia.

Drug Interactions

No formal drug interaction studies have been performed to date.

Tislelizumab-jsgr Pharmacokinetics

Absorption

Onset

Steady state concentration of tislelizumab-jsgr is reached after 12 weeks of repeated dosing with an every 3-week regimen.

Distribution

Plasma Protein Binding

Not applicable.

Elimination

Metabolism

Expected to be catabolized by non-hepatic pathways.

Half-life

Half-life is 24 days.

Stability

Storage

Parenteral

Injection, for IV infusion

2–8°C in original carton to protect from light; do not freeze and do not shake.

Diluted solution may be stored at room temperature (20–25°C) for up to 4 hours or under refrigeration (2–8°C) for up to 20 hours after dilution, including preparation and infusion time. If refrigerated, allow diluted solution to come to room temperature prior to administration.

Actions

Humanized anti-programmed-death receptor-1 (anti-PD-1) monoclonal antibody.
Overexpression of PD-1 ligands on surface of tumor cells results in activation of PD-1 activity and suppression of cytotoxic T-cell activity.
Binds to the PD-1 receptor on T cells, which blocks interaction with PD-1 ligands (PD-L1 and PD-L2) and prevents PD-1 pathway mediated inhibition of the immune response.
Anti-tumor activity is focused on preventing inhibition of active T cell immune surveillance of tumors.

Advice to Patients

Advise patients to read the FDA-approved patient labeling (Medication Guide).
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 therapy. These reactions may include pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and dermatologic adverse reactions. Other immune-mediated adverse reactions involving any organ system can occur; advise patients to contact their healthcare provider immediately for any new or worsening signs or symptoms.
Advise patients to contact their healthcare provider immediately for symptoms of pneumonitis (e.g., new or worsening cough, chest pain, or shortness of breath).
Advise patients to contact their healthcare provider immediately for symptoms of colitis (e.g., diarrhea, severe abdominal pain).
Advise patients to contact their healthcare provider immediately for symptoms of hepatitis (e.g., jaundice, severe nausea or vomiting, pain on the right side of the abdomen, or easy bruising or bleeding).
Advise patients to contact their healthcare provider immediately for signs or symptoms of hypophysitis, adrenal insufficiency, hypothyroidism, hyperthyroidism, thyroiditis, or Type 1 diabetes mellitus.
Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis.
Advise patients to contact their healthcare provider immediately for any signs or symptoms of severe skin reactions, SJS, TEN, or DRESS.
Advise patients of the risk of solid organ transplant rejection and other transplant (including corneal graft) rejection and to contact their healthcare provider immediately for signs or symptoms of organ transplant rejection.
Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions.
Advise patients of the potential risk of post-allogeneic hematopoietic stem cell transplantation complications.
Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy. Advise females of reproductive potential to use effective contraception during treatment with tislelizumab-jsgr and for 4 months after the last dose.
Advise patients not to breastfeed during treatment with tislelizumab-jsgr and for 4 months after the last dose.
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Tislelizumab-jsgr is obtained through designated specialty pharmacies. Contact manufacturer or consult the website ([Web]) for specific availability information.