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tebentafusp
Tebentafusp is a bispecific antibody that consists of 2 domains: a soluble T-cell receptor (targeting domain) that targets gp100 peptides presented by HLA-A*02:01 on the uveal melanoma tumour cell surface, and a single-chain fragment of an anti-CD3 antibody (effector domain) that targets polyclonal T-cells. Once bound to the uveal melanoma tumour cell, an immune synapse is formed and T cells are redirected and activated to release inflammatory cytokines and cytolytic proteins. This results in direct lysis of uveal melanoma tumour cells (in vitro).
Linear, dose-proportional pharmacokinetics.
| Cross blood brain barrier? |
no |
| PPB |
no information available |
| Distribution Sites |
Does not distribute extensively. Preclinical biodistribution studies showed accumulation in highly vascular organs (e.g. heart, lung, liver, kidneys) was rapidly cleared between 8 to 24 hours. |
Expected to be to be degraded into small peptides and amino acids via catabolic pathways.
| Active metabolites |
unknown |
| Inactive metabolites |
unknown |
Based on molecular size, small amounts may be excreted in urine. Classical drug metabolic elimination not expected to be an important clearance mechanism for large proteins (monoclonal antibodies (mAbs), fusion proteins, etc.) such as tebentafusp.
| Half-life |
7.5 hours (terminal) |
- Uveal melanoma
Refer to the product monograph for a full list and details of approved indications
Emetogenic Potential:
The following adverse events occurred in ≥ 10% of metastatic uveal melanoma patients receiving tebentafusp in a randomized, open-label trial that compared first line treatment with tebentafusp vs. other systemic monotherapies (pembrolizumab, ipilimumab or dacarbazine). Severe or life-threatening adverse effects may also be included from other sources and post-marketing. Side effects that may be associated with CRS have been denoted with ^.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Hypertension (16%) (9% severe) | E | |||
| Hypotension (39%) (3% severe) ^ | I | ||||
| Tachycardia (10%) | E | ||||
| Dermatological | Other (47%) (Skin and hair colour changes) | E D | |||
| Rash, pruritus (83%) (18% severe) | E D | ||||
| Gastrointestinal | Abdominal pain (45%) | E | |||
| Anorexia, weight loss (18%) | E | ||||
| Constipation (18%) | E | ||||
| Diarrhea (25%) | E | ||||
| Nausea, vomiting (49%) (2% severe) ^ | I E | ||||
| General | Edema (45%) (including peripheral edema) | E | |||
| Fatigue (64%) (6% severe) | E | ||||
| Fever (76%) (4% severe) ^ | I E | ||||
| Hematological | Anemia (10%) (<1% severe) | E | |||
| Hepatobiliary | ↑ ALT (21%) ^ | I E D | |||
| ↑ AST (23%) ^ | I E D | ||||
| ↑ Bilirubin (11%) ^ | I E D | ||||
| Immune | Cytokine release syndrome (89%) (<1% severe) | I E | |||
| Metabolic / Endocrine | Abnormal electrolyte(s) (11%) ( ↓ PO4) | E | |||
| Musculoskeletal | Musculoskeletal pain (22%) | E | |||
| Nervous System | Dizziness (11%) | E | |||
| Headache (31%) ^ | I E | ||||
| Paresthesia (11%) | E | ||||
| Respiratory | Cough, dyspnea (18%) | E | |||
| Hypoxia (2%) ^ | I | ||||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common side effects for tebentafusp include cytokine release syndrome, rash, pruritus, fever, fatigue, nausea, vomiting, skin or hair hypo-/hyper-pigmentation, abdominal pain, edema, hypotension and headache. Some of these adverse effects may be associated with CRS.
Cytokine release syndrome (CRS) has been reported with tebentafusp (77% of patients, ≥ Grade 2) and may be life-threatening. Fever and hypotension were often the first indications of CRS, with fever being present in nearly all cases; other signs and symptoms include chills, nausea, vomiting, fatigue, headache, elevated transaminases (see below), and less commonly, hypoxia. Cardiac events have been reported, rarely, in association with CRS. The majority (84%) of CRS cases started on the day of infusion with a median time to resolution of 2 days. Sixty percent of patients experienced CRS (≥ Grade 2) with more than one infusion; patients should be monitored for at least 16 hours following the first infusions in the inpatient setting (including fluid status, vital signs, and oxygenation level) and appropriate therapy provided. Treatment may need to be withheld or discontinued depending on persistence and severity of CRS (see Dosing section).
Acute skin reactions, including rash, pruritis, erythema and cutaneous edema, have been reported commonly with tebentafusp infusion (91% of patients) and may be related to gp100 expression in normal melanocytes in the skin. Over two thirds of patients experienced either Grade 2 (44%) or Grade 3 (21%) skin reactions which typically occurred 1 day following the first 3 infusions and decreased in severity and frequency with subsequent dosing. The median time to improvement to ≤ Grade 1 was approximately 6 days. Patients should be monitored for skin reactions and treated appropriately (see Dosing section). Most symptoms resolved without the use of systemic corticosteroids.
Elevations in liver enzymes (ALT/AST) were observed in 65% of patients receiving tebentafusp and the majority occurred within the first 3 infusions. Most Grade 3 or 4 ALT/AST elevations improved within 7 days (to ≤ Grade 1). The majority of patients (95%) in the clinical trial had pre-existing liver metastasis, and severe cases were mostly related to CRS (8% of patients had an increase in LFTs ≥ Grade 3 outside of the setting of CRS). The median time to onset for events that occurred outside of the setting of CRS was 129 days.
Refer to protocol by which patient is being treated.
Screen for hepatitis B virus in all cancer patients starting systemic treatment. Refer to the hepatitis B virus screening and management guideline.
Patients must have a positive HLA-A*02:01 genotype status prior to treatment with tebentafusp.
IV fluids should be administered as necessary prior to starting tebentafusp infusion to reduce the risk of hypotension associated with CRS
Pre-medications (prophylaxis for CRS):
If previous Grade 3 CRS, or Grade 2 CRS that did not resolve within 2-3 hours :
- Administer corticosteroid (e.g. dexamethasone 4mg or equivalent) at least 30 minutes prior to next dose.
Intravenous: 20 mcg on Day 1
30 mcg on Day 8
68 mcg on Day 15, and once weekly thereafter
Note: Inpatient admission may be required for CRS monitoring (e.g. for the first 3 to 4 infusions). ST-QBP funding for ambulatory administration only.
***Coordination with local blood bank is required prior to administration as tebentafusp requires dilution with human albumin product (e.g., albumin 5%)***
|
Toxicity |
Grade |
Management/ Action |
|
CRS |
Grade 2*
|
Manage and treat symptoms as appropriate, including:
If symptoms do not resolve to Grade ≤1 within 2–3 hours, treat as Grade 3 |
|
Grade 3* |
Hold until CRS has resolved. Manage symptoms as per Grade 2 and:
Resume at same dose level** |
|
|
Grade 4* |
Discontinue. Administer IV corticosteroids (e.g., 2 mg/kg/day methylprednisolone or equivalent) Consider administering tocilizumab |
|
|
Acute skin reactions |
Grade 2 or 3 |
Hold until < Grade 1 or baseline Treat with systemic antihistamine and oral steroids as per local guidelines. If no response to oral steroids, consider IV corticosteroid (e.g., 2 mg/kg/day methylprednisolone or equivalent) Resume at same dose level** |
|
Grade 4 |
Discontinue. Administer IV corticosteroids (e.g., 2 mg/kg/day methylprednisolone or equivalent) |
|
|
↑ LFTs |
Grade 3 or 4 |
Hold*** If no improvement in 24 hours, administer IV corticosteroids Resume at same dose level if in Grade 3 CRS also occurred** Resume dose escalation (or same dose level if escalation complete) if Grade 3 CRS did not occur. |
|
Other adverse effects |
Grade 3 |
Hold*** Resume at same dose level** |
|
Grade 4 |
Discontinue |
*Based on ASTCT consensus grading of CRS criteria (Lee et.al 2019):
Grade 2 = temperature ≥ 38°C AND hypotension that responds to fluids and does not require vasopressors AND/OR hypoxia requiring low flow nasal cannula (delivery of oxygen ≤ 6L/min) or blow-by.
Grade 3 = temperature ≥ 38°C AND hypotension requiring a vasopressor with or without vasopressin AND/OR hypoxia requiring high flow nasal cannula (delivery of oxygen > 6L/min), face mask or non-rebreather mask or Venturi mask.
Grade 4 = temperature ≥ 38°C AND hypotension requiring multiple vasopressors (excluding vasopressin) AND/OR hypoxia requiring positive pressure (e.g. CPAP, BiPAP, intubation and mechanical ventilation)
**Do not escalate dose if severe (i.e. Grade 3) adverse reaction occurs during initial escalation. Dose escalation may resume once dose is tolerated.
***Do not restart until toxicities ≤ Grade 1 or baseline
No dose adjustment is required. Elevations in ALT and AST at baseline or during treatment did not impact tebentafusp pharmacokinetics.
| Creatinine Clearance (mL/min) | Tebentafusp Dose |
| ≥ 30 | No dose adjustment required |
| < 30 | No data available |
No dose adjustment is required. No overall differences in safety and efficacy were observed between patients ≥ 65 years of age compared to younger patients in the pivotal trial (in which 47% of patients were ≥ 65 years of age).
There was no significant effect of gender on tebentafusp clearance.
There was no significant effect of race on tebentafusp clearance.
The safety and efficacy of tebentafusp in children has not been established.
- Tebentafusp requires dilution with sodium chloride containing human albumin (e.g. 5%, 20% or 25%; concentration will vary depending on availability from local blood bank) to prevent adsorption to the infusion bag.
- Dilute human albumin in 100 mL 0.9% Sodium Chloride Injection to make a final albumin concentration between 225 to 275 mcg/mL. See product monograph for more information.
- Compatible with polyolefins [e.g. polyethylene (PE) and polypropylene (PP)] or polyvinyl chloride (PVC) infusion bags.
- DO NOT use a closed system transfer device for preparation of tebentafusp infusion.
- Do not flush needle/syringe on transfer when adding the required volume of tebentafusp to the human albumin and 0.9% Sodium Chloride preparation.
- Mix gently. Do not shake.
- Administer by IV infusion over 15 to 20 minutes, through a low protein binding 0.2 micron in-line filter infusion set.
- Do not mix or administer with other drugs.
- Flush the IV line with 0.9% Sodium Chloride after each dose.
- Monitor patients for at least 16 hours following the first infusions (in the inpatient setting). If no Grade ≥ 2 hypotension, monitor for at least 30 minutes following subsequent infusions (in the ambulatory care setting).
- Store unopened vials refrigerated (2°C to 8°C) and protect from light
- Patients who are hypersensitive to this drug or to any of its components.
- Severe CRS has occurred with tebentafusp; ensure infusions are administered where there is immediate access to medications and equipment required to manage CRS, and that patients are euvolemic prior to initiating infusion.
- Patients with significant cardiac disease were excluded from clinical trials. Patients with pre-existing cardiovascular disorders may be at increased risk for complications associated with CRS and should be monitored.
- Caution and monitor ECG in patients with history or predisposing factors to QT interval prolongation; cases of QT interval prolongation were reported following tebentafusp treatment.
- Patients with pre-existing adrenal insufficiency on maintenance systemic corticosteroids are at an increased risk of hypotension; consider adjusting corticosteroid dose.
Other Drug Properties:
-
Carcinogenicity:
Unknown
-
Genotoxicity:
Unknown
-
Fetotoxicity:
Unknown
Based on the mechanism of action, tebentafusp may cause fetal harm. No human or animal studies have been conducted to assess fetotoxicity but molecules of similar molecular weight can cross the placenta.
-
Teratogenicity:
Unknown
Tebentafusp is not recommended for use in pregnancy. Adequate contraception should be used by patients and their partners during treatment, and for at least 1 week after the last dose.
-
Lactation:
Breastfeeding is not recommended during treatment and for at least 1 week after the last dose. It is unknown if tebentafusp is excreted into human milk.
-
Fertility effects:
Unknown
Tebentafusp causes transient release of proinflammatory cytokines that may suppress CYP450 enzymes, especially during the first 24 hours following each of the first 3 doses. Monitor patients receiving concomitant CYP450 substrates, especially those that have a narrow therapeutic index, for increased substrate concentrations or toxicity.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| CYP 2C9 substrates (e.g. warfarin, meloxicam, fluvastatin) | ↑ substrate concentration and/or toxicity | cytokines may suppress CYP450 | Monitor and adjust dose of substrates with narrow therapeutic index (e.g. warfarin) if necessary |
| CYP3A4 substrates (e.g. cyclosporine, pimozide, tacrolimus, triazolo-benzodiazepines, dihydropyridine calcium-channel blockers, certain HMG-CoA reductase inhibitors) | ↑ substrate concentration and/or toxicity | cytokines may suppress CYP450 | Monitor and adjust dose of substrates with narrow therapeutic index (e.g. cyclosporine) if necessary |
| Anti-hypertensives | ↑ hypotension | Additive | Consider holding anti-hypertensives for 24 hours before/after tebentafusp infusion for the first 6 doses. |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
Refer to the hepatitis B virus screening and management guideline for monitoring during and after treatment.
| Monitor Type | Monitor Frequency |
|---|---|
Liver function tests (AST, ALT and total bilirubin) |
Baseline and as clinically indicated |
Creatinine |
Baseline and as clinically indicated |
CBC |
Baseline and as clinically indicated |
Clinical toxicity assessment for cytokine release syndrome (e.g. fever, hypotension, headache etc.), skin reactions, GI or cardiac effects. |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
| Monitor Type | Monitor Frequency |
|---|---|
ECG |
Baseline and as clinically indicated (especially during the first 3 weeks of treatment) for patients at risk of QT prolongation. |
High Cost Therapy Funding Program
- Tebentafusp (Inpatient) - Unresectable or Metastatic Uveal Melanoma
- Tebentafusp (Outpatient) - Unresectable or Metastatic Uveal Melanoma
Canada’s Drug and Health Technology Agency. CADTH Reimbursement Review Tebentafusp (Kimmtrak). Canadian Journal of Health Technologies. April 2023; 3 (4)
European Medicines Agency, 2022. Assessment Report Kimmtrak. Committee for Medicinal Products for Human Use (CHMP). February 24, 2022
KIMMTRAK® Full Prescribing Information. Immunocore Commercial LLC. Conshohocken, PA, US; January 25, 2022
Kimmtrak Product information. Immunocore Ireland Limited. Dublin, Ireland; April 22, 2022
KIMMTRAK® Tebentafusp Product Monograph. Medison Pharma Canada Inc. Toronto, Ontario; June 7, 2022
Lee W, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release Syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019;25:625-38.
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. 2020;26(22):5869-5878. doi:10.1158/1078-0432.CCR-20-1247
Nathan P, Hassel JC, Rutkowski P, et al. Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma. N Engl J Med. 2021 Sep 23;385(13):1196-1206. doi:10.1056/NEJMoa2103485
NCCN Practice Guidelines in Oncology (NCCN Guidelines) - Antiemesis v.2.2023. NCCN, 2023. Accessed October 11, 2023
Protocol for: Nathan P, Hassel JC, Rutkowski P, et al; IMCgp100-202 Investigators. Overall survival benefit with tebentafusp in metastatic uveal melanoma. N Engl J Med. 2021;385:1196-1206. doi:10.1056/NEJMoa2103485
Supplement to: Nathan P, Hassel JC, Rutkowski P, et al. Overall survival benefit with tebentafusp in metastatic uveal melanoma. N Engl J Med 2021;385:1196-206. doi: 10.1056/NEJMoa2103485
Tebentafusp: Drug information. Waltham, MA: Lexi-Comp Inc., 2023. https://online.lexi.com. Accessed October 10, 2023.
April 2024 Updated Mechanism of Action
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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