Tebentafusp-tebn (Monograph)

Brand name: Kimmtrak
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Nov 20, 2023. Written by ASHP.

Introduction

Bispecific gp100 peptide-HLA-directed CD3 T cell engager; antineoplastic agent.

Uses for Tebentafusp-tebn

Uveal Melanoma

Treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma. Designated an orphan drug by FDA for treatment of uveal melanoma.

Tebentafusp-tebn Dosage and Administration

General

Pretreatment Screening

• Select patients for treatment based on positive HLA-A*02:01 genotype test; perform genotyping using an FDA-approved test ([Web]) with a whole blood sample.

• Perform pregnancy test in females of reproductive potential prior to initiating treatment.

• Evaluate ALT, AST, and total blood bilirubin prior to treatment.

• Ensure adequate hydration prior to each infusion.

Patient Monitoring

• Monitor patient during the infusion and for at least 16 hours after the infusion is complete for the first 3 infusions. If tolerated, for subsequent infusions, monitor patient for at least 30 minutes following the infusion.

• Monitor fluid status, vital signs, and oxygenation level.

• Monitor for signs or symptoms of cytokine release syndrome (CRS).

• Monitor ALT, AST, and total bilirubin during treatment.

• Monitor for skin reactions.

Premedication and Prophylaxis

• Patients who experience persistent or recurrent moderate or severe CRS: Administer dexamethasone 4 mg or equivalent corticosteroid at least 30 minutes prior to subsequent infusions.

Dispensing and Administration Precautions

• Ensure that healthcare providers administering tebentafusp have immediate access to medications and resuscitative equipment to manage CRS.

Administration

IV Administration

Administer IV through a dedicated line with a sterile, non-pyrogenic, low protein binding, 0.2 micron inline filter.

Flush with 0.9% sodium chloride injection following infusion.

A 2-step dilution process using aseptic technique is required to prepare the final dose for infusion.

Dilution - Step 1: Preparation of the Infusion Bag

Prepare an albumin (human) in 0.9% sodium chloride injection solution to prevent adsorption.

Withdraw calculated volume of albumin into a 1 mL syringe with graduations of 2 decimal places and sterile needle. See Table 1 for examples of calculated volumes for different albumin concentrations.

Add albumin to a 100 mL 0.9% sodium chloride injection bag made of polyolefin (e.g., polyethylene [PE], polypropylene [PP]) or polyvinyl chloride (PVC).

Invert infusion bag so the entry port is on top and tap side of port to release residual solution, then gently rotate lengthwise at least 5 times to mix infusion. Repeat inversion and rotation steps an additional 3 times.

Dilution - Step 2: Preparation of the Tabentafusp-tebn Solution for Infusion

Do not shake the vial. Withdraw required volume of tebentafusp-tebn (See Table 2).

Add tebentafusp-tebn to the 100 mL albumin (human) in 0.9% sodium chloride injection infusion bag prepared in Step 1. Mix the infusion bag via inversion and rotation procedure described in Step 1.

Administer immediately; infuse diluted solution within 4 hours from the time of preparation including duration of infusion. Infuse within 24 hours from time of preparation, including storage time in refrigerator, time allowed for infusion bag to reach room temperature, and duration of infusion.

Rate of Administration

Administer by IV infusion over 15-20 minutes.

Dosage

Adults

Uveal Melanoma

IV

20 mcg on day 1, 30 mcg on day 8, 68 mcg on day 15, and 68 mcg once weekly thereafter until disease progression or unacceptable toxicity occurs.

Dosage Modification for Toxicity

Dosage reduction not recommended. Interrupt therapy or discontinue treatment based on severity of adverse effect.

Cytokine Release Syndrome (CRS)

Moderate CRS (temperature ≥38°C with hypotension that responds to fluids OR hypoxia requiring low flow nasal canula [≤ 6 L/minute] or blow-by oxygen): Treat as severe if no improvement in hypotension or hypoxia occurs within 3 hours or CRS worsens. Premedicate with dexamethasone 4 mg or equivalent at least 30 minutes prior to the next dose for persistent (lasts 2-3 hours) or recurrent moderate CRS.

Severe CRS (temperature ≥38°C with hemodynamic instability requiring a vasopressor OR worsening hypoxia or respiratory distress requiring high flow nasal canula [>6 L/minute oxygen] or face mask): Withhold tebentafusp-tebn. Administer IV methylprednisolone 2 mg/kg/day or equivalent. Resume tebentafusp at the same dosage level (do not escalate if severe CRS occurred during initial dose escalation; resume escalation once dosage is tolerated). Premedicate with dexamethasone 4 mg or equivalent at least 30 minutes prior to next dose.

Life threatening CRS (temperature ≥38°C with hemodynamic instability requiring multiple vasopressors [excluding vasopressin] and worsening hypoxia or respiratory distress despite oxygen administration requiring positive pressure): Permanently discontinue tebentafusp-tebn. Administer IV methylprednisolone 2 mg/kg/day or equivalent.

Skin Reactions

Grade 2 or 3 skin toxicity: Withhold therapy until improvement to Grade 0 or 1, or baseline. Resume therapy at the same dosage level (do not escalate the dose if Grade 3 skin reactions occurred during initial dose escalations; resume escalation once the dosage is tolerated). Consider IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day) for persistent reactions not responsive to oral steroids.

Grade 4 skin toxicity: Permanently discontinue tebentafusp-tebn. Administer IV methylprednisolone 2 mg/kg/day or equivalent.

Elevated Liver Enzymes

Grade 3 or 4 liver enzyme elevation: Withhold therapy until improvement to Grade 0 or 1, or baseline. Resume therapy at the same dosage level if liver enzyme elevation occurred in the setting of Grade 3 CRS. Resume dose escalation if the next administration is tolerated and patient is in the initial dose escalation phase.

If liver enzyme elevation occurred outside the setting of Grade 3 CRS, resume dose escalation if in the initial dose escalation phase or resume at the same dosage level if dose escalation has completed.

Administer IV corticosteroids if liver enzymes have not improved within 24 hours.

Other Adverse Reactions

Grade 3 toxicity: Withhold therapy until improvement to Grade 0 or 1, or baseline. Resume therapy at the same dosage level. Do not escalate if other Grade 3 adverse reaction occurred during initial dose escalation; resume escalation once dosage is tolerated.

Grade 4 toxicity: Permanently discontinue therapy.

Special Populations

Hepatic Impairment

Mild hepatic impairment (total bilirubin ≤ULN and AST > ULN or total bilirubin >1 to 1.5 times ULN and any AST): No dosage adjustment required.

Moderate (total bilirubin >1.5 to 3 times ULN and any AST) or severe (total bilirubin >3 to 10 times ULN and any AST) hepatic impairment: No specific dosage recommendations.

Renal Impairment

Mild or moderate renal impairment (Cl_cr30 to 89 mL/minute): No dosage adjustment required.

Several renal impairment (CL_cr <30 mL/minute): No specific dosage recommendations.

Geriatric Use

No dosage adjustment required.

Related/similar drugs

melphalan, Kimmtrak, Hepzato, tebentafusp

Cautions for Tebentafusp-tebn

Contraindications

• None.

Warnings/Precautions

Warnings

Cytokine Release Syndrome

Risk of life-threatening cytokine release syndrome (CRS) (see Boxed Warning). Symptoms can include fever, hypotension, hypoxia, chills, nausea, vomiting, rash, elevated liver enzymes, fatigue, and headache.

Monitor patients for CRS for at least 16 hours following the first 3 infusions and then as clinically indicated. Ensure access to medications and resuscitative equipment during administration. Ensure patients are euvolemic prior to initiating infusions. Monitor fluid status, vital signs, and oxygenation level and provide appropriate therapy.

Withhold or discontinue tebentafusp depending on persistence and severity of CRS.

Skin Reactions

Skin toxicity is common; can present as rash, pruritus, erythema, or cutaneous edema.

Monitor for skin reactions. Treat with antihistamines and topical or systemic steroids based on persistence and severity of symptoms. Withhold or permanently discontinue tebentafusp depending on severity.

Elevated Liver Enzymes

Increased ALT and AST reported. Most often occurs during initial dose escalation phase in the setting of CRS. May also occur outside the setting of CRS.

Monitor ALT, AST, and total bilirubin prior to and during treatment. Withhold therapy for Grade 3 or 4 events and administer IV corticosteroids as indicated.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm based on mechanism of action. No human data or animal studies to date.

Perform pregnancy test in females of reproductive potential prior to treatment. Advise such females to use effective contraception during treatment and for 1 week after the last dose.

If used during pregnancy, apprise patient of potential fetal hazard.

Specific Populations

Pregnancy

May cause fetal harm.

Lactation

Not known whether distributed into human milk. Effects on breastfed infants and milk production unknown. Discontinue breastfeeding during therapy and for 1 week after the last dose.

Females and Males of Reproductive Potential

May cause fetal harm. Perform pregnancy testing prior to treatment. Advise females of reproductive potential to use effective contraception during treatment and for 1 week following the last dose.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No overall differences in safety or efficacy relative to younger patients.

Hepatic Impairment

Mild hepatic impairment does not have a clinically important effect on pharmacokinetics of tebentafusp. Effects of moderate to severe hepatic impairment not evaluated.

Renal Impairment

Mild to moderate renal impairment (Cl_cr 30 to 89 mL/minute) does not have a clinically important effect on pharmacokinetics of tebentafusp. Effects of severe renal impairment (Cl_cr <30 mL/minute) not evaluated.

Common Adverse Effects

Most common adverse reactions (≥30%): CRS, rash, pyrexia, pruritus, fatigue, nausea, chills, abdominal pain, edema, hypotension, dry skin, headache, vomiting.

Most common laboratory abnormalities (≥50%): decreased lymphocyte count, increased creatinine, increased glucose, increased AST, increased ALT, decreased hemoglobin, decreased phosphate.

Drug Interactions

Formal drug interaction studies not conducted.

Drugs Affecting or Affected by Hepatic Microsomal Enzymes

Elevation of certain proinflammatory cytokines may suppress CYP enzyme activities. Cytokine elevation peaks 8-24 hours after treatment and occurs with less intensity after the first 3 doses.

Tebentafusp-tebn Pharmacokinetics

Absorption

Plasma concentrations increase in a dose proportional manner.

Distribution

Extent

Molecular weight suggests may cross the placenta; not known whether distributed into human milk.

Elimination

Metabolism

Catabolized into small peptides and amino acids.

Half-life

Median terminal half-life 7.5 hours (range: 6.8 to 7.5 hours).

Special Populations

Age, weight, and sex do not have a clinically important effect on pharmacokinetics of tebentafusp.

Systemic exposure decreased by 97% and terminal half-life decreased to 10-14 minutes in patients with anti-drug antibody titers >8192.

Stability

Storage

Parenteral

Injection Concentrate, for IV Infusion

2–8°C in original package to protect from light. Do not freeze.

Diluted infusion solution: Infuse within 4 hours of preparation including duration of infusion. If not used immediately, store at 2–8°C and infuse within 24 hours from the time of preparation, including storage time in refrigerator, time allowed for infusion bag to reach room temperature, and duration of infusion. Do not return to refrigerator once removed. Do not freeze.

Actions

• Tebentafusp-tebn, a first-in-class bispecific glycoprotein 100 (gp100) peptide-human leukocyte antigen (HLA)-directed CD3 T cell engager, is an antineoplastic agent.

• Tebentafusp-tebn is a recombinant fusion protein composed of a T-cell receptor (TCR) arm and an anti-CD3 single chain variable fragment.

• The TCR arm targets the melanoma-associated antigen, gp100 presented by HLA-A*02:01, and the anti-CD3 T-cell engaging domain enables polyclonal activation of native T cells, which release cytokines and cytolytic proteins that target and kill gp100-expressing tumor cells.

Advice to Patients

• Inform patients of the risk of cytokine release syndrome (CRS), and to immediately contact their healthcare provider for signs and symptoms associated with CRS (e.g., pyrexia, hypotension, hypoxia, chills, nausea, vomiting, fatigue, or headache).

• Inform patients that rashes and skin reactions have occurred in patients who have received tebentafusp-tebn. Advise patients to contact their healthcare provider for signs and symptoms of progressive or intolerable skin reactions.

• Inform patients that elevations in liver enzymes have occurred in patients who have received tebentafusp-tebn. Advise patients to contact their healthcare provider for signs and symptoms of liver toxicity (e.g., right sided abdominal pain, jaundice, scleral icterus).

• Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform females of the risk to a fetus.

• Advise females of reproductive potential to use effective contraception while on tebentafusp-tebn and for 1 week after the last dose.

• Advise patients not to breastfeed during treatment with tebentafusp-tebn and for 1 week after the last dose.

• Advise patients to inform clinicians 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.

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.

Tebentafusp-tebn is obtained through specialty pharmacy distributors. Contact Immunocore Commercial LLC or consult [Web] for specific availability information.

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