Kimmtrak®
Tebentafusp-tebn, a bispecific gp100 peptide-HLA-directed CD3 T cell engager, is an antineoplastic agent.1
Tebentafusp-tebn is used for the treatment of HLA-A*02:01-positive adults with unresectable or metastatic uveal melanoma.1, 3 Tebentafusp has been designated an orphan drug by FDA for use in the treatment of uveal melanoma.2 Select patients for treatment based on HLA-A*02:01 genotyping; information on FDA-approved genotyping tests for HLA-A*02:01 is available at [Web].1
Efficacy of tebentafusp-tebn is based principally on the results of a randomized, open-label, multicenter study in 378 adults with HLA-A*02:01 genotype-positive metastatic uveal melanoma.1, 3 Patients enrolled had previously untreated metastatic disease.1, 3 Prior surgical resection of oligometastatic disease was permitted.1 Patients with clinically significant cardiac disease, symptomatic or untreated brain metastases, or patients receiving systemic immunosuppressive treatment were excluded.1 Patients were randomized (2:1) to receive IV tebentafusp-tebn or the investigator's choice of treatment with single agent pembrolizumab, ipilimumab, or dacarbazine.1, 3 Randomization was stratified according to lactate dehydrogenase (LDH) level at study entry.1, 3 Patients in the tebentafusp group received 20 mcg IV on day 1, 30 mcg IV on day 8, and 68 mcg IV on day 15 and weekly thereafter.1, 3 Patients were monitored overnight after treatment for the first 3 weeks during dose escalation.3 Treatment was continued in all patients until disease progression or unacceptable toxicity.1, 3 The primary endpoint was overall survival.1, 3 The median age of patients in the study was 64 years (range 23 to 92 years); 50% were female, 87% were White, 2.4% were Hispanic or Latino, 36% had elevated LDH, and 94% had liver metastases.1 Nearly all patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (73%) or 1 (21%).1 Among those in the control group, 82% received pembrolizumab, 13% received ipilimumab, and 6% received dacarbazine.3
At the data cutoff for the first prespecified interim analysis, the median duration of follow-up was 14.1 months and 150 deaths had occurred.3 The median duration of overall survival was 21.7 months in the tebentafusp group and 16 months in the control group.1, 3 Estimated overall survival at 1 year was 73% for patients receiving tebentafusp and 59% for those receiving a control regimen.3 Median progression-free survival was 3.3 months in the tebentafusp group and 2.9 months in the control group.1 Objective response rates (RECIST, version 1.1) in the tebentafusp and control groups were 9% and 5%, respectively.1, 3 Complete response occurred in 1 patient in the tebentafusp group.1 No patients in the control group achieved a complete response.1 Partial response occurred in 22 patients receiving tebentafusp and 6 patients receiving a control regimen.1
Although rare, uveal melanoma is the most common type of intraocular malignancy in adults.4, 5, 6, 7 Localized disease is treated with radiation or surgery; however, approximately 50% of patients will develop metastatic disease.4, 5, 6, 7, 9 There is no defined standard treatment for metastatic uveal melanoma; enrollment in a clinical trial is recommended.4, 5, 6, 7, 8, 9 Outside of a clinical trial, treatment for metastatic disease includes liver-directed therapy when appropriate or systemic treatment options used for the management of cutaneous melanoma.4, 5, 6, 7, 9 However, these systemic therapies have limited survival benefit and poor response rates.4, 5, 6, 7, 8, 9 Tebentafusp-tebn provides another option for the treatment of metastatic uveal melanoma.1, 9 The drug has been shown to improve overall survival compared with control regimens; however, objective tumor response rates remain low (9%) and treatment with the drug is limited to HLA-A*02:01-positive adults.1 3
Dispensing and Administration Precautions
Tebentafusp-tebn is administered by IV infusion through a dedicated line with a sterile, non-pyrogenic, low protein binding, 0.2 micron inline filter.1
Store unopened vials of tebentafusp-tebn in the original carton in the refrigerator at 2-8°C and protect from light until time of use.1 Do not freeze or shake the vials.1
A 2-step dilution process using aseptic technique is required for preparation of the final tebentafusp-tebn dose for infusion.1
Dilution - Step 1: Preparation of the Infusion Bag
Prepare an albumin (human) in 0.9% sodium chloride injection solution to prevent adsorption of tebentafusp to the infusion bag and other components of the drug delivery system.1 Using a 1 mL syringe with graduations of 2 decimal places and a sterile needle, withdraw the calculated volume of albumin into the syringe and add to a 100 mL 0.9% sodium chloride injection bag made of polyolefin (e.g., polyethylene [PE], polypropylene [PP]) or polyvinyl chloride (PVC) to provide a final albumin (human) concentration of 250 mcg/mL.1 See Table 1 for examples of calculated volumes to use for albumin 5% or 25% concentrations.1
Albumin (Human) Concentration | Albumin (Human) Volume for Addition to a 100 mL Bag of 0.9% Sodium Chloride Injection to Prepare a Concentration of 250 mcg/mL Albumin (Human) in 0.9% Sodium Chloride Injection |
|---|---|
5% (50 g/L) | 0.5 mL |
25% (250 g/L) | 0.1 mL |
To homogenize the solution, invert the infusion bag so the entry port is positioned on top and tap the side of the port to release any residual solution into the bulk solution.1 Gently rotate the bag lengthwise at least 5 times to mix the infusion.1 Do not shake the infusion bag.1 Repeat the inversion and rotation steps an additional 3 times.1
Dilution - Step 2: Preparation of the Tebentafusp-tebn Solution for Infusion
Use a 1 mL syringe with graduations of 2 decimal places and a sterile needle to withdraw the required volume of tebentafusp-tebn 100 mcg/0.5 mL for the required dose.1 See Table 2 for the volume of tebentafusp required for each treatment dose.1 Do not shake the vial.1 Add the tebentafusp to the 100 mL albumin (human) in 0.9% sodium chloride injection, USP infusion bag prepared in Step 1.1 Mix the infusion bag via the inversion and rotation procedure described in Step 1.1 Administer the diluted tebentafusp solution immediately.1 The preparation must be infused within 4 hours from the time of preparation including the duration of infusion.1 If not used immediately, store the tebentafusp infusion bag at 2-8°C and infuse within 24 hours from the time of preparation, including the storage time in the refrigerator, the time allowed for the infusion bag to reach room temperature, and the duration of the infusion.1 Once removed from the refrigerator, do not refrigerate the infusion bag again.1 Do not freeze.1
Day of Treatment | Tebentafusp-tebn Dose (mcg) | Tebentafusp-tebn Volume (mL) |
|---|---|---|
Day 1 | 20 | 0.1 |
Day 8 | 30 | 0.15 |
Day 15 and weekly thereafter | 68 | 0.34 |
Tebentafusp-tebn is administered by IV infusion over 15-20 minutes.1
For the treatment of HLA-A*02:01-positive unresectable or metastatic uveal melanoma, the recommended adult dosage of tebentafusp-tebn is 20 mcg IV on day 1, 30 mcg IV on day 8, 68 mcg IV on day 15, and 68 mcg IV once every week thereafter until disease progression or unacceptable toxicity occurs.1
The first 3 infusions must be administered in a healthcare setting where patients can be monitored during the infusion and for at least 16 hours after the infusion is complete.1 If the patient does not experience grade 2 or worse hypotension requiring medical intervention during or after the third infusion, subsequent doses can be administered in an ambulatory care setting where patients can be monitored for a minimum of 30 minutes following each infusion.1
Dosage Modification for Toxicity
No dosage reductions are recommended for tebentafusp-tebn.1 Interruption of therapy and/or discontinuation of tebentafusp may be necessary based on the severity of the adverse effect.1
For moderate cytokine release syndrome (CRS) defined as 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 CRS if hypotension and hypoxia do not improve within 3 hours or CRS worsens.1 If moderate CRS lasts 2-3 hours or is recurrent, premedicate with dexamethasone 4 mg or equivalent corticosteroid at least 30 minutes prior to the next dose.1
For severe CRS defined as 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 until CRS and sequelae have resolved.1 Administer an IV corticosteroid such as methylprednisolone 2 mg/kg/day or equivalent.1 Resume tebentafusp at the same dosage level (do not escalate if severe CRS occurred during initial dose escalation; resume escalation once dosage is tolerated).1 Premedicate with dexamethasone 4 mg or equivalent corticosteroid at least 30 minutes prior to the next dose.1
If life threatening CRS occurs, defined as 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 and administer an IV corticosteroid such as methylprednisolone 2 mg/kg/day or equivalent.1
If Grade 2 or 3 skin reactions occur, withhold tebentafusp until symptoms have resolved to Grade 0 or 1, or baseline.1 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).1 For persistent reactions not responding to oral steroids, consider IV corticosteroids such as methylprednisolone 2 mg/kg/day or equivalent.1 If Grade 4 skin reactions occur, permanently discontinue tebentafusp and administer an IV corticosteroid such as methylprednisolone 2 mg/kg/day or equivalent.1
If Grade 3 or 4 elevated liver enzymes occur, withhold tebentafusp until improvement to Grade 0 or 1, or baseline.1 Resume tebentafusp at the same dosage level if liver enzyme elevation occurred in the setting of Grade 3 CRS.1 Resume dose escalation if the next administration is tolerated and the patient is in the initial dose escalation phase.1 If liver enzyme elevation occurred outside the setting of Grade 3 CRS, resume escalation if the current dosage is less than 68 mcg or resume at the same dosage level if dose escalation has completed.1 Administer IV corticosteroids if liver enzymes have not improved within 24 hours.1
If other Grade 3 adverse reactions occur, withhold tebentafusp until symptoms have improved to Grade 0 or 1, or baseline.1 Resume therapy at the same dosage level.1 Do not escalate if other Grade 3 adverse reaction occurred during initial dose escalation; resume escalation once dosage is tolerated.1
If other Grade 4 adverse reactions occur, permanently discontinue tebentafusp.1
No dosage adjustment is necessary in patients with mild hepatic impairment as measured by total bilirubin and AST (total bilirubin ≤upper limit of normal (ULN) and AST >ULN or total bilirubin >1 to 1.5 times the ULN and any AST).1
The manufacturer makes no specific dosage recommendations for patients with 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; tebentafusp has not been studied in this population.1
No dosage adjustment is necessary in patients with mild or moderate renal impairment (creatinine clearance [Clcr] 30 to 89 mL/minute).1
The manufacturer makes no specific dosage recommendations for patients with severe renal impairment (Clcr<30 mL/minute); tebentafusp has not been studied in this population.1
No dosage adjustment is necessary.1
A boxed warning about the risk of cytokine release syndrome (CRS) is included in the prescribing information for tebentafusp-tebn.1 Cytokine release syndrome can be life-threatening and may include symptoms such as fever, hypotension, hypoxia, chills, nausea, vomiting, rash, elevated liver enzymes, fatigue, and headache.1 In the principle efficacy study, CRS occurred in 77% of patients receiving tebentafusp-tebn; 60% of patients experienced Grade 2 or higher CRS with more than 1 infusion and the median number of events was 2 (range: 1-12).1 Systemic steroids were administered in 23% of patients 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.1 The majority of CRS episodes started the day of infusion; median time to resolution was 2 days in the cases that resolved.1 Permanent discontinuation of therapy occurred in 1.2% of patients.1
Monitor patients for CRS for at least 16 hours following the first 3 tebentafusp-tebn infusions and then as clinically indicated.1 Healthcare providers should have immediate access to medications and resuscitative equipment to manage CRS.1 Patients should be euvolemic prior to initiating infusions.1 Monitor fluid status, vital signs, and oxygenation level and provide appropriate therapy.1 Withhold or discontinue tebentafusp depending on persistence and severity of CRS.1
Skin reactions are common in patients receiving tebentafusp-tebn.1 In the principle efficacy study, skin reactions occurred in 91% of patients receiving tebentafusp and included rash (83%), pruritus (69%), erythema (25%), and cutaneous edema (27%).1 Grade 2 and 3 skin reactions occurred in 44% and 21% of patients, respectively.1 The median time to onset of skin reactions was 1 day (range: 1-55 days).1 The median time to improvement to Grade 0 or 1 was 6 days.1
Monitor patients for skin reactions.1 Treat skin reactions with an antihistamine and topical or systemic steroids based on persistence and severity of symptoms.1 Withhold or permanently discontinue tebentafusp depending on the severity of skin reactions.1, 1
Tebentafusp-tebn can cause an increase in alanine aminotransferase (ALT) or aspartate aminotransferase (AST).1 Liver enzyme elevation occurred in 65% of patients receiving tebentafusp in the principle efficacy study; 0.4% of patients permanently discontinued treatment.1 The majority of patients with liver enzyme elevation experience an increase in ALT/AST with the first 3 tebentafusp infusions in the setting of CRS.1 Grade 3 or 4 ALT/AST elevations in these patients generally improve to Grade 0 or 1 within 7 days.1 Grade 3 or greater elevations in liver enzymes outside the setting of CRS occurred in 8% of patients receiving tebentafusp.1 The median time to onset for liver enzyme elevation in these patients was 129 days.1
Monitor ALT, AST, and total bilirubin prior to and during treatment with tebentafusp-tebn.1 Withhold tebentafusp for Grade 3 or 4 events and administer IV corticosteroids as indicated.1
Fetal/Neonatal Morbidity and Mortality
Tebentafusp-tebn may cause fetal harm based on its mechanism of action.1 There are no available data regarding the risk of tebentafusp use in pregnant women or animals to date.1
Pregnancy should be avoided during tebentafusp therapy.1 A pregnancy test should be performed prior to treatment.1 Advise pregnant women of the potential risk to the fetus.1 Females of reproductive potential should use effective contraception during treatment with tebentafusp and for 1 week after the last dose.1
Tebentafusp-tebn may cause fetal harm based on its mechanism of action.1 There are no tebentafusp data in pregnant women and no animal reproductive and developmental toxicity studies have been conducted to date.1 Molecules of similar weight can cross the placenta, exposing the fetus.1 Advise women of the potential risk to the fetus.1
It is not known whether tebentafusp-tebn distributes into milk in humans or animals or whether the drug has any effects on breastfed infants or on milk production.1 Because of the potential for serious adverse reactions to tebentafusp in breastfed infants, women should be advised to discontinue breastfeeding during tebentafusp therapy and for 1 week after the last dose.
Females and Males of Reproductive Potential
Tebentafusp-tebn may cause fetal harm.1 Perform pregnancy testing prior to initiating tebentafusp treatment.1 Females of reproductive potential should use effective contraception during treatment and for 1 week following the last dose.1
Safety and efficacy of tebentafusp-tebn have not been established in pediatric patients.1
No overall differences in safety or efficacy were observed between patients ≥65 years of age compared with younger adults.1 In the principle efficacy study, nearly half of the patients treated with tebentafusp-tebn were ≥65 years of age and 9% were ≥75 years of age.1
Mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin >1 to 1.5x ULN and any AST) does not have a clinically important effect on the pharmacokinetics of tebentafusp-tebn; however, the effects of moderate (total bilirubin >1.5 to 3x ULN, any AST) to severe (total bilirubin >3 to 10x ULN, any AST) hepatic impairment on the pharmacokinetics of tebentafusp-tebn have not been studied.1
Mild to moderate renal impairment (Clcr 30 to 89 mL/minute) does not have a clinically important effect on the pharmacokinetics of tebentafusp-tebn; however, the effects of severe renal impairment (Clcr<30 mL/minute) on the pharmacokinetics of tebentafusp-tebn have not been studied.1
The most common adverse reactions (occurring in ≥30%) are CRS, rash, pyrexia, pruritus, fatigue, nausea, chills, abdominal pain, edema, hypotension, dry skin, headache and vomiting.1 The most common laboratory abnormalities (occurring in ≥50%) are decreased lymphocyte count, increased creatinine, increased glucose, increased AST, increased ALT, decreased hemoglobin, and decreased phosphate.1
No formal drug interaction studies have been performed to date with tebentafusp-tebn.1
Drugs Affecting or Affected by Hepatic Microsomal Enzymes
Tebentafusp-tebn causes an increase in cytokines as part of its mechanism of action.1 Elevation of certain proinflammatory cytokines may suppress cytochrome P-450 enzyme activities.1 Peak cytokine elevation occurs 8-24 hours after tebentafusp-tebn infusion.1 Cytokine elevation occurs in fewer patients and with less intensity after the first 3 doses.1
Tebentafusp-tebn, a first-in-class bispecific glycoprotein 100 (gp100) peptide-human leukocyte antigen (HLA)-directed CD3 T cell engager, is an antineoplastic agent.1, 3, 10 Tebentafusp-tebn is a recombinant fusion protein composed of a T-cell receptor (TCR) arm and an anti-CD3 single chain variable fragment.1, 3, 10 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.1, 3, 10
Lymphocyte counts decline the day following the first 3 doses of tebentafusp-tebn and return to baseline prior to subsequent doses.1 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) increase during treatment.1 Peak levels occur 8 to 24 hours after tebentafusp infusion and return to baseline prior to subsequent doses.1 Cytokine elevation occurs in fewer patients with lesser intensity after the first 3 doses.1 Tebentafusp-tebn plasma concentrations increase in a dose proportional manner.1 The drug is expected to be catabolized into small peptides and amino acids and has a medial terminal half-life of 7.5 hours.1 Treatment emergent anti-drug antibodies (ADA) were detected in 29% of patients in the principle efficacy study.1, 3 The median ADA titer in the ADA-positive subgroup of patients was 8192 across 67 treatment cycles.1 Systemic exposure of tebentafusp-tebn decreased by 97% and the terminal half-life decreased to 10-14 minutes in patients with ADA titers greater than 8192.1 Limited data suggest ADAs have no clinically important effect on frequency or severity of hypersensitivity reactions or overall survival.1, 3 Age (23 to 91 years), weight (43 to 163 kg), and sex (48% female) do not have a clinically important effect on the pharmacokinetics of tebentafusp-tebn.1
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.
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.11 Contact Immunocore Commercial LLC or consult [Web] for specific availability information.11
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection Concentrate, for IV Infusion | 100 mcg/0.5 mL | Kimmtrak® | Immunocore |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions November 20, 2023. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Immunocore. KIMMTRAK® (TEBENTAFUSP) INTRAVENOUS prescribing information. Conshochoken, PA; 2022 Nov. [Web]
2. Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed January 5, 2023. [Web]
3. Nathan P, Hassel JC, Rutkowski P, et al. Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma. N Engl J Med. Sep 23 2021;385(13):1196-1206.
4. Jager MJ, Shields CL, Cebulla CM, et al. Uveal melanoma. Nat Rev Dis Primers. Apr 9 2020;6(1):24.
5. Comito F, Marchese PV, Ricci AD, et al. Systemic and liver-directed therapies in metastatic uveal melanoma: state-of-the-art and novel perspectives. Future Oncol. Nov 2021;17(33):4583-4606.
6. Orloff M, Seedor R, Sato T. Review of bi-specific therapies in uveal melanoma. Cancer Gene Ther. Mar 2 2022Orloff M, Seedor R, Sato T. Review of bi-specific therapies in uveal melanoma. Cancer Gene Ther. Mar 2 2022
7. Schank TE, Hassel JC. Tebentafusp for the treatment of metastatic uveal melanoma. Future Oncol. Feb 17 2022
8. Seth R, Messersmith H, Kaur V, et al. Systemic Therapy for Melanoma: ASCO Guideline. J Clin Oncol. Nov 20 2020;38(33):3947-3970.
9. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 761228Orig1s000 Multi-Discipline Review. From FDA website. [Web]
10. Middleton MR, McAlpine C, Woodcock VK, et al. Tebentafusp, A TCR/Anti-CD3 Bispecific Fusion Protein Targeting gp100, Potently Activated Antitumor Immune Responses in Patients with Metastatic Melanoma. Clin Cancer Res. Nov 15 2020;26(22):5869-5878.
11. Kimmtrak (tebentafusp-tebn) Distribution Information. Conshohocken, PA: Immunocore Commercial LLC; January 2023. [Web]