Tebentafusp is a bispecific gp100 peptide-HLA-directed CD3 T cell engager used to treat unresectable or metastatic uveal melanoma. Tebentafusp is a gp100 peptide-HLA-directed CD3 T cell engager. It is a bispecific, fusion protein and first-in-class drug of immune-mobilizing monoclonal T cell receptors against cancer (ImmTACs), a recently developed cancer immunotherapy with a novel mechanism of action. ImmTACs bind to target cancer cells that express a specific antigen of interest and recruit cytotoxic T cells to lyse the cells, such as melanocytes.^[rx,rx]

Uveal melanoma is a rare ocular tumour with often poor prognosis and limited treatment options. Even after surgical ablation or removal of the ocular tumour, almost 50% of patients with uveal melanoma develop metastatic disease.^[rx] On January 26, 2022, tebentafusp was first approved by the FDA for the treatment of HLA-A*02:01-positive adults with unresectable or metastatic uveal melanoma. This approval marks the first bispecific T cell engager to be approved by the FDA to treat a solid tumour and being the first and only therapy for the treatment of unresectable or metastatic uveal melanoma to be approved by the FDA.^[rx] Tebentafusp was subsequently approved for the same indication in the EU in April 2022.^[rx]

Mechanism of action

Glycoprotein 100 (gp100) is a transmembrane glycoprotein highly expressed in melanoma cells and weakly expressed by normal melanocytes or other tissues. Gp100 is presented as a human leukocyte antigen (HLA)-peptide complex on the cell surface. Gp100 has a particularly high affinity for the HLA-A subtype HLA-A*02:01.^[rx,rx] HLAs are part of a protein complex that normally regulates immune function: natural T cell responses are initiated by the interaction between the T-cell receptor (TCR) and its peptide antigen, such as gp100, presented by HLA on the surface of a target cell.^[rx]

Tebentafusp is a bispecific gp100 peptide-HLA-A*02:01 directed T cell receptor CD3 T cell engager. It consists of a TCR targeting domain – or a TCR arm – fused to a single-chain variable fragment (scFv) anti-CD3 effector domain.^[rx] The TCR arm binds to a gp100 peptide bound to HLA-A on the uveal melanoma tumour cell surface. The anti-CD3 effector domain of tebentafusp engages and activates CD3+ T cells to inflammatory cytokines and cytolytic proteins, which results in direct lysis of uveal melanoma tumour cells.^[rx] The anti-CD3 fragment of the drug has a lower affinity, so the T cells are not stimulated unless tebentafusp has detected gp100.^[rx]

Tebentafusp is only effective in HLA-A*02:01-positive patients.^[rx,rx]

Tebentafusp is novel immunotherapy that causes cytotoxicity of cancer cells. Tebentafusp increased the 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) during the first three doses. The levels of cytokines and chemokines peaked between eight to 24 hours after treatment, and levels returned to baseline before subsequent doses. In subsequent treatment cycles, cytokine elevation occurred in fewer patients with lesser intensity than the first three doses. Tebentafusp also reduced lymphocyte counts after the first three doses, which returned to baseline before subsequent doses.^[rx] In phase III clinical trials, patients treated with tebentafusp showed a better overall survival rate compared to pembrolizumab, ipilimumab, or dacarbazine.^[rx]

Indications

• Tebentafusp, sold under the brand name Kimmtrak, is an anti-cancer medication used to treat uveal melanoma (eye cancer). Tebentafusp is a bispecific gp100 peptide-HLA-directed CD3 T cell engager.^[rx][rx]
• Tebentafusp is indicated for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma.
• Metastatic Uveal Melanoma (UM)
• Unresectable Uveal Melanoma

Use in Cancer

Tebentafusp-tebn is approved to treat:

• Uveal melanoma that cannot be removed by surgery or has spread to other parts of the body. It is used in adults who have the HLA-A*02:01 antigen.

Tebentafusp-tebn is also being studied in the treatment of other types of cancer.

Contraindications

• abnormal liver function tests
• pregnancy
• a patient who is producing milk and breastfeeding

Dosage

Strengths: tebn 100 mcg/0.5 mL

Malignant Melanoma

• 20 mcg IV on Day 1, 30 mcg IV on Day 8, 68 mcg IV on Day 15, and then 68 mcg IV once a week thereafter
• Duration of therapy: Until unacceptable toxicity or disease progression occurs
• Patient selection should be based on a positive human leukocyte antigen-A*02:01 (HLA-A*02:01) genotyping test.
• A US FDA-approved test for the detection of HLA-A*02:01 genotyping is not currently available.
• For the treatment of HLA-A*02:01-positive patients with unresectable or metastatic uveal melanoma

Dose Adjustments

No dosage reduction is recommended for this drug; the following dosage modifications are recommended for adverse reactions.

CYTOKINE RELEASE SYNDROME (CRS):

• MODERATE defined as temperature at least 38C (100.4F) with hypotension that responds to fluids (does not require vasopressors) OR hypoxia requiring low flow nasal canula (up to 6 L/min) or blow-by oxygen:
• If hypotension and hypoxia do not improve within 3 hours or CRS worsens, care should be escalated and signs/symptoms should be managed according to next higher level of severity.
• For moderate CRS that is persistent (lasting 2 to 3 hours) or recurrent, corticosteroid premedication (e.g., dexamethasone 4 mg or equivalent) should be administered at least 30 minutes before the next dose.
• SEVERE defined as temperature at least 38C with hemodynamic instability requiring a vasopressor (with or without vasopressin) OR worsening hypoxia or respiratory distress requiring high flow nasal canula (greater than 6 L/min oxygen) or face mask:
• This drug should be withheld until CRS and sequelae have resolved.
• IV corticosteroid (e.g., 2 mg/kg/day methylprednisolone or equivalent) should be administered.
• This drug should resume at the same dose level (i.e., should not escalate if severe CRS occurred during initial dose escalation; escalation should resume once dosage is tolerated).
• For severe CRS, corticosteroid premedication (e.g., dexamethasone 4 mg or equivalent) should be administered at least 30 minutes before the next dose.
• LIFE-THREATENING is defined as a temperature at least 38C with hemodynamic instability requiring multiple vasopressors (excluding vasopressin) OR worsening hypoxia or respiratory distress despite oxygen administration requiring positive pressure:
• This drug should be permanently discontinued.
• IV corticosteroids (e.g., 2 mg/kg/day methylprednisolone or equivalent) should be administered.

SKIN REACTIONS:

• Grade 2 or 3:
• This drug should be withheld until grade 1 or lower or baseline.
• This drug should resume at the same dose level (i.e., should not escalate if grade 3 skin reactions occurred during initial dose escalation; escalation should resume once the dosage is tolerated).
• For persistent reactions not responding to oral steroids, IV corticosteroids (e.g., 2 mg/kg/day methylprednisolone or equivalent) should be considered.
• Grade 4:
• This drug should be permanently discontinued.
• IV corticosteroids (e.g., 2 mg/kg/day methylprednisolone or equivalent) should be administered.

ELEVATED LIVER ENZYMES:

• Grade 3 or 4:
• This drug should be withheld until grade 1 or lower or baseline.
• This drug should resume at the same dose level if the elevated liver enzymes occur in the setting of grade 3 CRS; escalation should resume if next administration is tolerated.
• If the elevated liver enzymes occur outside the setting of grade 3 CRS, escalation should resume if the current dose is less than 68 mcg, or this drug should resume at the same dose level if escalation has completed.
• IV corticosteroids should be administered if no improvement within 24 hours.

OTHER ADVERSE REACTIONS:

• Grade 3:
• This drug should be withheld until grade 1 or lower or baseline.
• This drug should resume at same dose level (i.e., should not escalate if other grade 3 adverse reactions occurred during initial dose escalation; escalation should resume once dosage is tolerated).
• Grade 4:
• This drug should be permanently discontinued.

Grade is based on National Cancer Institute Common Terminology Criteria for Adverse Events.

Administration advice:

• Administer the first 3 infusions in an appropriate health care setting; monitor patients during the infusion and for at least 16 hours after the infusion is complete.
• If the patient does not have grade 2 or worse hypotension (requiring medical intervention) during or after the third infusion, administer subsequent doses in an appropriate ambulatory care setting; monitor patients for at least 30 minutes after each of these infusions.
• Administer the diluted solution immediately via IV infusion over 15 to 20 minutes through a dedicated IV line.
• Use a sterile, nonpyrogenic, low protein binding 0.2-micron in-line filter infusion set.
• Administer the entire contents of the infusion bag.
• Do not mix this drug with other drugs or administer other drugs through the same IV line.
• After the infusion is complete, flush the infusion line with an adequate volume of sterile 0.9% Sodium Chloride Injection, USP to ensure the entire contents of the infusion bag have been administered.

Reconstitution/preparation techniques:

• A 2-step dilution process is required to prepare the final dose for infusion.
• The manufacturer’s product information should be consulted.
• Compatible: Albumin (Human); 0.9% Sodium Chloride Injection, USP
• This drug should not be mixed with other drugs.

Monitoring:

• Dermatologic: For skin reactions
• Hepatic: ALT, AST, and total blood bilirubin (before starting and during therapy)
• Immunologic: For signs/symptoms of CRS (after administration)
• Investigations: Fluid status, vital signs, oxygenation level
• Read the US FDA-approved patient labeling (Patient Information).
• Immediately contact the health care provider if signs/symptoms associated with CRS (e.g., pyrexia, hypotension, hypoxia, chills, nausea, vomiting, fatigue, headache) occur.
• Contact health care provider if signs/symptoms of progressive/intolerable skin reactions develop.
• Contact health care provider if signs/symptoms of liver toxicity (e.g., right-sided abdominal pain, jaundice, scleral icterus) develop.
• Patients of childbearing potential: Notify your health care provider if you are pregnant or become pregnant; use effective contraception while receiving this drug and for 1 week after the last dose.
• Do not breastfeed during therapy and for 1 week after the last dose.

Side Effects

The Most Common

• rash
• skin redness, itching, or swelling
• lightening or darkening of the skin
• hair color changes or hair loss
• constipation
• swelling of the arms or legs
• decreased appetite
• pain in arms, legs, back, or joints
• mouth or throat pain
• pain or discomfort in right upper stomach area or yellowing of the skin or eyes
• Back pain
• burning, crawling, itching, numbness, prickling, “pins and needles”, or tingling feelings
• constipation
• difficulty in moving
• dry skin
• joint pain or swelling
• lightening of the normal skin color
• loss or thinning of the hair
• muscle aches, cramps, pain, or stiffness
• night sweats
• pain in the arms or legs
• runny nose
• shivering
• sore throat
• trouble sleeping

More common

• Blurred vision
• chills
• confusion
• diarrhea
• dizziness
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• faintness
• fast, pounding, or irregular heartbeat or pulse
• feeling of warmth
• fever
• general feeling of discomfort or illness
• headache
• muscle or joint pain
• nausea
• nervousness
• pounding in the ears
• rash, itching, or skin swelling
• redness of the face, neck, arms and occasionally, upper chest
• redness of the skin
• sweating
• unusual tiredness or weakness
• unusually warm skin
• vomiting

Rare

• Anxiety
• chest pain
• clay colored stools
• cough
• dark urine
• loss of appetite
• problems with movement, walking, or speech
• seizures
• stomach pain or tenderness
• swelling of the feet or lower legs
• trouble breathing
• yellow eyes or skin

Drug Interaction

Pregnancy and Lactation

US FDA pregnancy category: Not assigned.

Pregnancy

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 women. 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.

Lactation

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.