Tebentafusp-tebn
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Edzel Lorraine Co, DMD, MD[2]
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Black Box Warning
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WARNING: CYTOKINE RELEASE SYNDROME
See full prescribing information for complete Boxed Warning.
Cytokine Release Syndrome (CRS), which may be serious or lifethreatening, occurred in patients receiving KIMMTRAK. Monitor for at least 16 hours following first three infusions and then as clinically indicated.
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Overview
Tebentafusp-tebn is a bispecific gp100 peptide-HLA-directed CD3 T cell engager that is FDA approved for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma. There is a Black Box Warning for this drug as shown here. Common adverse reactions include cytokine release syndrome, rash, pyrexia, pruritus, fatigue, nausea, chills, abdominal pain, edema, hypotension, dry skin, headache and vomiting. The most common laboratory abnormalities (occurring in ≥50%) are decreased lymphocyte count, increased creatinine, increased glucose, increased aspartate aminotransferase, increased alanine aminotransferase, decreased hemoglobin, and decreased phosphate.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
The recommended dosage of KIMMTRAK administered intravenously is: • 20 mcg on Day 1 • 30 mcg on Day 8 • 68 mcg on Day 15 • 68 mcg once every week thereafter Treat patients until unacceptable toxicity or disease progression occur.
Administer the first three infusions of KIMMTRAK in an appropriate healthcare setting by intravenous infusion over 15-20 minutes. Monitor patients during the infusion and for at least 16 hours after the infusion is complete. If the patient does not experience Grade 2 or worse hypotension (requiring medical intervention) during or after the third infusion, administer subsequent doses in an appropriate ambulatory care setting, and monitor patients for a minimum of 30 minutes following each of these infusions.
Preparation and Administration
Preparation
• A 2-step dilution process is required for preparation of the final KIMMTRAK dose for infusion. • Use aseptic technique for dilution and preparation of intravenous infusion solutions. • Visually inspect parenteral drug products and infusion bags for particulate matter and discoloration prior to administration, whenever solution and container permit. Step 1: Preparation of the Infusion Bag To prevent adsorption of tebentafusp-tebn to the infusion bag and other components of the drug delivery system, prepare an Albumin (Human) in 0.9% Sodium Chloride Injection, USP solution as follows: a. Using a 1 mL syringe with graduations of 2 decimal places and a sterile needle, withdraw the calculated volume of Albumin (Human) into the syringe (see Table 2 below) and add to the 100 mL 0.9% Sodium Chloride Injection, USP bag constructed of polyolefins (PO) [such as polyethylene (PE) and polypropylene (PP)] or polyvinyl chloride (PVC) to make a final Albumin (Human) concentration of 250 mcg/mL.
b. Gently homogenize the prepared solution by completing the following steps: i. Invert the infusion bag so that the bag is upside down with the entry port positioned on top. Then tap the side of the port tubing to ensure that any residual solution is released into the bulk solution. ii. Mix the prepared solution by gently rotating the bag lengthwise 360 degrees from the inverted position at least 5 times. Do not shake the infusion bag. iii. Repeat (i) and (ii) an additional three times. Step 2- Preparation of KIMMTRAK Solution for Infusion a. Do not shake the KIMMTRAK vial. b. Using a 1 mL syringe with graduations of 2 decimal places and a sterile needle, withdraw the required volume of KIMMTRAK 100 mcg/ 0.5 mL as per the dose required and add to the prepared 100 mL infusion bag containing 0.9% Sodium Chloride Injection, USP plus Albumin (Human). c. Discard the single-dose vial containing the unused portion of KIMMTRAK in accordance with local requirements. Do not prepare more than one dose from the vial. d. Mix the infusion bag by following the same procedure outlined in Step 1b.
Off-Label Use and Dosage (Adult)
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Tebentafusp-tebn FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Contraindications
None
Warnings
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WARNING: CYTOKINE RELEASE SYNDROME
See full prescribing information for complete Boxed Warning.
Cytokine Release Syndrome (CRS), which may be serious or lifethreatening, occurred in patients receiving KIMMTRAK. Monitor for at least 16 hours following first three infusions and then as clinically indicated.
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- Cytokine Release Syndrome
Cytokine release syndrome (CRS), which may be life threatening, occurred in patients receiving KIMMTRAK. Manifestations of CRS may include fever, hypotension, hypoxia, chills, nausea, vomiting, rash, elevated transaminases, fatigue, and headache. CRS (≥ Grade 2) occurred in 77% of patients in Study IMCgp100-202 who received KIMMTRAK. Among patients who received KIMMTRAK, 23% received systemic corticosteroids for at least 1 infusion, 8% received supplemental oxygen during at least 1 infusion, and 0.8% received a vasopressor for at least 1 infusion. CRS led to permanent discontinuation in 1.2% of patients. In Study IMCg100-202, 60% of patients experienced ≥ Grade 2 CRS with more than 1 infusion, with the median number of events being 2 (range 1 - 12). The majority (84%) of episodes of CRS started the day of infusion. Among cases that resolved, the median time to resolution of CRS was 2 days. Ensure that healthcare providers administering KIMMTRAK have immediate access to medications and resuscitative equipment to manage CRS. Ensure patients are euvolemic prior to initiating the infusions. Closely monitor patients for signs or symptoms of CRS following infusions of KIMMTRAK Monitor fluid status, vital signs, and oxygenation level and provide appropriate therapy. Withhold or discontinue KIMMTRAK depending on persistence and severity of CRS.
- Skin Reactions
Skin reactions, including rash, pruritus, and cutaneous edema occurred in patients treated with KIMMTRAK. In study IMCgp100-202, skin reactions occurred in 91% of patients treated with KIMMTRAK, including Grade 2 (44%) and Grade 3 (21%) events. Skin reactions included rash (83%), pruritus (69%), erythema (25%), and cutaneous edema (27%). The median time to onset of skin reactions was 1 day (range: 1 – 55 days). The median time to improvement to ≤ Grade 1 was approximately 6 days. Monitor patients for skin reactions. If skin reactions occur, treat with antihistamine and topical or systemic steroids based on persistence and severity of symptoms. Withhold or permanently discontinue KIMMTRAK depending on the severity of skin reactions.
- Elevated Liver Enzymes
In Study IMC100-gp100-202, increases in alanine aminotransferase or aspartate aminotransferase were observed in 65% of patients treated with KIMMTRAK. In patients experiencing ALT/AST elevations, 73% initially occurred within the first 3 infusions with KIMMTRAK. Most patients experiencing Grade 3 or 4 ALT/AST elevations had improvement to ≤ Grade 1 within 7 days. For events that were observed outside the setting of CRS, the median time to onset was 129 days. Grade 3 or greater elevations in liver enzymes outside the setting of CRS occurred in approximately 8% of patients. Elevations in liver enzymes led to permanent discontinuation in 0.4% of patients receiving KIMMTRAK. Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total blood bilirubin prior to the start of and during treatment with KIMMTRAK. Withhold KIMMTRAK according to severity.
- Embryo-Fetal Toxicity
Based on the mechanism of action, KIMMTRAK may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with KIMMTRAK and for 1 week after the last dose.
Adverse Reactions
Clinical Trials Experience
• Cytokine Release Syndrome • Skin Reactions • Elevated Liver Enzymes
Postmarketing Experience
There is limited information regarding Tebentafusp-tebn Postmarketing Experience in the drug label.
Drug Interactions
Elevation of certain proinflammatory cytokines may suppress CYP450 enzyme activities.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Tebentafusp-tebn in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tebentafusp-tebn in women who are pregnant.
Labor and Delivery
Risk Summary Based on the mechanism of action, KIMMTRAK may cause fetal harm when administered to a pregnant woman. There are no available data with KIMMTRAK in pregnant woman. No animal reproductive and developmental toxicity studies have been conducted with KIMMTRAK. Molecules of similar molecular weight can cross the placenta resulting in fetal exposure. Advise women of the potential risk to the fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.
Nursing Mothers
Risk Summary There are no data on the presence of tebentafusp-tebn in human milk, the effect on the breastfed child, or the effects on milk production. Because tebentafusp-tebn may be excreted in human milk and because of the potential for serious adverse reactions in a breastfed child, advise patients not to breastfeed during treatment with KIMMTRAK and for at least 1 week after the last dose.
Pediatric Use
Safety and efficacy of KIMMTRAK have not been established in pediatric patients.
Geriatic Use
Of the 245 patients with metastatic uveal melanoma treated with KIMMTRAK on IMCgp100-202, 47% were 65 years of age and older and 9% were 75 years of age and older. No overall differences in safety or efficacy were observed between patients ≥ 65 years of age compared to younger adult patients.
Gender
There is no FDA guidance on the use of Tebentafusp-tebn with respect to specific gender populations.
Race
There is no FDA guidance on the use of Tebentafusp-tebn with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Tebentafusp-tebn in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Tebentafusp-tebn in patients with hepatic impairment.
Females of Reproductive Potential and Males
KIMMTRAK may cause fetal harm when administered to a pregnant woman
Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating KIMMTRAK treatment.
Contraception Females Advise female of reproductive potential to use effective contraception during treatment and for 1 week following the last dose of KIMMTRAK.
Immunocompromised Patients
There is no FDA guidance one the use of Tebentafusp-tebn in patients who are immunocompromised.
Administration and Monitoring
Administration
• Immediately administer the diluted solution via intravenous infusion over 15-20 minutes through a dedicated intravenous line. A sterile, non-pyrogenic, low protein binding 0.2 micron in-line filter infusion set should be used. Administer the entire contents of the KIMMTRAK infusion bag. • Administer the prepared infusion bag within 4 hours from the time of preparation including the duration of infusion. During the 4-hour window, the KIMMTRAK infusion bag should remain at room temperature. • If not used immediately, store the KIMMTRAK infusion bag in a refrigerator at 2°C to 8°C (36°F to 46°F) and infuse within 24 hours from the time of preparation, which includes the storage time in the refrigerator, the time allowed for equilibration of the infusion bag to room temperature, and the duration of the infusion. • Once removed from the refrigerator, do not refrigerate KIMMTRAK infusion bag again. Do not freeze. Discard unused KIMMTRAK solution beyond the recommended storage time. • Do not mix KIMMTRAK with other drugs or administer other drugs through the same intravenous line. • Upon completion of KIMMTRAK infusion, flush the infusion line with adequate volume of sterile 0.9% Sodium Chloride Injection, USP to ensure that the entire contents of the infusion bag are administered.
Monitoring
There is limited information regarding Tebentafusp-tebn Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Tebentafusp-tebn and IV administrations.
Overdosage
There is limited information regarding Tebentafusp-tebn overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Tebentafusp-tebn Pharmacology in the drug label.
Mechanism of Action
Tebentafusp-tebn is a bispecific gp100 peptide-HLA-A*02:01 directed T cell receptor CD3 T cell engager. The TCR arm binds to a gp100 peptide presented by human leukocyte antigen-A*02:01 (HLAA*02:01) on the cell surface of uveal melanoma tumor cells. In vitro, tebentafusp-tebn bound to HLA-A*02:01-positive uveal melanoma cells and activated polyclonal T cells to release inflammatory cytokines and cytolytic proteins, which results in direct lysis of uveal melanoma tumor cells.
Structure
Tebentafusp-tebn is a bispecific gp100 peptide-HLA-directed T cell receptor CD3 T cell engager. Tebentafusp-tebn has an approximate molecular weight of 77 kDa. Tebentafusp-tebn is produced by recombinant DNA technology in Escherichia coli cells. KIMMTRAK (tebentafusp-tebn) injection is supplied in a single-dose vial as a sterile, preservative-free, clear, colorless or slightly yellowish solution for intravenous administration by infusion. Each single-dose vial contains tebentafusp-tebn (100 mcg), citric acid monohydrate (0.95 mg), di-sodium hydrogen phosphate (2.91 mg), mannitol (5 mg), polysorbate 20 (0.1 mg) trehalose (25 mg), and water for injection, with a pH of 6.5.
Pharmacodynamics
Lymphocyte counts declined the day after the first 3 doses and returned to baseline prior to subsequent doses. Serum levels of cytokines (IFN-γ, TNFα, IL-2, IL-6, IL-10 and IL-1RA) and chemokines (CXCL9, CXCL10, CXCL11, hepatocyte growth factor, and monocyte chemoattractant protein-1) were increased during the first three doses of KIMMTRAK with peak levels between 8 to 24 hours after treatment with KIMMTRAK and levels returned to baseline prior to subsequent doses. In subsequent treatment cycles, cytokine elevation occurred in fewer patients with lesser intensity compared to the first 3 doses. The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of KIMMTRAK have not been fully characterized.
Pharmacokinetics
After a single dose administration, tebentafusp-tebn Cmax and AUC0-7d increased in an approximately dose proportional manner from 20 to 68 mg (0.3 to 1 times the approved recommended dose). Following administration of the approved recommended dosage in patients with metastatic uveal melanoma, the steady-state geometric mean (% CV) Cmax of tebentafusp-tebn is 13 ng/mL (34.6%) and AUC0-7d is 4.6 ng.day/mL (23%) with no accumulation.
Distribution Tebentafusp-tebn geometric mean (%CV) steady-state volume of distribution is 7.56 L (24%).
Elimination The geometric mean clearance of tebentafusp-tebn is 16.4 L/d (CV: 24.5%) and median terminal half-life is 7.5 hours (range: 6.8-7.5 hours).
Metabolism Tebentafusp-tebn is expected to be catabolized into small peptides and amino acids.
Specific Populations No clinically significant difference in the pharmacokinetics of tebentafusp-tebn were identified based on weight (43 to 163 kg), sex (48% female), age (23 to 91 years), or mild to moderate renal impairment based on creatinine clearance (CLcr) estimated by C-G formula (CLcr 30 to 89 mL/min) or mild hepatic impairment as measured by total bilirubin (TB) and aspartate aminotransferase (AST) (TB ≤ upper limit of normal (ULN) and AST > ULN or TB > 1 to 1.5x ULN and any AST). Tebentafusp-tebn has not been studied in patients with severe (CLcr < 30 mL/min) renal impairment or in patients with moderate (TB >1.5 to 3x ULN, any AST) to severe (TB > 3 to 10x ULN, any AST) hepatic impairment.
Immunogenicity Median titer in the ADA-positive subgroup was 8192 across the 67 treatment cycles. The exposure (AUC0-7 days) of tebentafusp-tebn decreased by 97% and terminal half-life decreased to 10-14 minutes in patients with ADA titers greater than 8192.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
No carcinogenicity or genotoxicity studies have been conducted with tebentafusp-tebn. No studies have been conducted to evaluate the effects of tebentafusp-tebn on fertility.
Clinical Studies
Study IMCgp100-202: First line metastatic uveal melanoma
KIMMTRAK was evaluated in IMCgp100-202, a randomized, open-label, multicenter trial (NCT03070392) that enrolled patients with metastatic uveal melanoma (N=378). Patients were required to be HLA-A*02:01 genotype positive identified by a central assay. Patients were excluded if they received prior systemic therapy for metastatic or advanced uveal melanoma or localized liver-directed therapy. Prior surgical resection of oligometastatic disease was permitted. Patients with clinically significant cardiac disease or the presence of symptomatic or untreated brain metastasis were excluded.
Patients were randomized (2:1) to receive KIMMTRAK weekly by intravenous infusion administered at 20 mcg intravenously on Day 1, 30 mcg intravenously on Day 8, 68 mcg intravenously on Day 15, and 68 mcg intravenously once every week thereafter (N=252) or Investigator’s choice (N=126) of pembrolizumab, ipilimumab, or dacarbazine. Randomization was stratified by lactate dehydrogenase (LDH) level at study entry. Across both arms, patients stopped treatment for disease progression, unless the patient was otherwise deriving benefit, or for unacceptable toxicity. The major efficacy outcome was overall survival (OS). Additional efficacy outcomes were investigatorassessed progression free survival (PFS) and objective response rate (ORR) per RECIST 1.1. The median age was 64 years (range 23 to 92 years); 50% were female; 87% were White, and 12% were unreported or unknown race. The reported ethnicity was Hispanic or Latino in 2.4% of patients. Baseline ECOG performance status was 0 (73%), 1 (21%), or 2 (0.3%); 36% had elevated LDH level; and 94% had liver metastasis.
How Supplied
Each KIMMTRAK (tebentafusp-tebn) injection carton (NDC 80446-401-01) contains:
One single-dose vial containing 100 mcg of tebentafusp-tebn in 0.5 mL of sterile, preservativefree, clear, colorless or slightly yellowish solution. The vial stopper is not made with natural rubber latex.
Storage
Store KIMMTRAK vials in the original carton refrigerated at 2°C to 8°C (36°F to 46°F) and protect from light until time of use. Do not freeze. Do not shake.
Images
Drug Images
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Package and Label Display Panel
Manufactured by: Immunocore Limited 92 Park Drive, Milton Park Abingdon, Oxfordshire United Kingdom, OX144RY License no: 2239 At: Baxter Oncology GmbH Kantstraβe 2 33790 Halle/Westfalen Germany For: Immunocore Commercial LLC 181 Washington Street, Conshohocken, PA, US {{#ask: Label Page::Tebentafusp-tebn |?Label Name |format=template |template=DrugLabelImages |mainlabel=- |sort=Label Page }}
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Cytokine Release Syndrome (CRS) Inform patients of the risk of 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).
Skin Reactions Inform patients that rashes and skin reactions have occurred in patients who have received KIMMTRAK. Advise patients to contact their healthcare provider for signs and symptoms of progressive or intolerable skin reactions.
Elevated Liver Enzymes Inform patients that elevations in liver enzymes have occurred in patients who have received KIMMTRAK. Advise patients to contact their healthcare provider for signs and symptoms of liver toxicity (e.g., right sided abdominal pain, jaundice, scleral icterus).
Embryo-Fetal Toxicity • 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 KIMMTRAK and for 1 week after the last dose.
Lactation • Advise patients not to breastfeed during treatment with KIMMTRAK and for 1 week after the last dose.
Precautions with Alcohol
Alcohol-Tebentafusp-tebn interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
Brand Names
KIMMTRAK®
Look-Alike Drug Names
There is limited information regarding Tebentafusp-tebn Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.