Tebentafusp

What is tebentafusp?

Tebentafusp (Kimmtrak®) is a first-in-class, intravenously administered, ImmTAC (Immune-Mobilising Monoclonal T-cell receptor Against Cancer) agent.

In 2022, tebentafusp gained widespread approval from a number of regulatory bodies including the FDA, MHRA, TGA, and the European Commission.

What is tebentafusp used for?

Tebentafusp is used to treat HLA-A*02:01 genotype-positive adult patients with unresectable or metastatic uveal melanoma. It is not approved for cutaneous melanoma; the main dermatological importance relates to the frequency of cutaneous side effects.

How does tebentafusp work?

Tebentafusp is composed of two fused domains: an engineered T-cell receptor (TCR) domain that binds uveal melanoma cells by recognising a gp100 peptide presented by HLA-A*02:01 (an antigen expressed strongly in melanoma cells but weakly in non-malignant melanocytes) and a CD3 single-chain antibody fragment domain that binds CD3+ polyclonal T cells.

When tebentafusp binds both domains, the T-cells are activated and release inflammatory cytokines and cytolytic proteins which results in direct lysis of melanoma cells.

Tebentafusp is also known as a bi-specific T-cell engaged (BiTE).

What are the contraindications and precautions with tebentafusp?

Contraindications:

• Hypersensitivity to tebentafusp

Permanently discontinue tebentafusp for any of the following:

• Grade 4 cytokine release syndrome (CRS)
• Grade 4 acute skin reactions
• Any other grade 4 clinically relevant adverse reactions

Withhold tebentafusp for any of the following:

• Grade 3 cytokine release syndrome (CRS)
• Grade 2 or 3 acute skin reactions
• Elevated liver enzymes (if severe)
• Any other severe or grade 3 clinically relevant adverse reactions
• QT interval prolongation (absolute value >500msec or increase of ≥60msec)

No data:

• Pregnancy
• Breast feeding
• Severe renal impairment
• Severe hepatic impairment

What are the dosing and monitoring requirements for tebentafusp?

Dosing

Tebentafusp is administered weekly by intravenous infusion:

• Week 1: 20mcg IVI
• Week 2: 30mcg IVI
• Week 3 and thereafter: 68mcg IVI

Monitoring

• First 3 doses (3 weeks): Overnight admission for 16 hours post-infusion monitoring, where the risk of CRS is greatest.
• Week 4 onwards: patients are monitored for 30 minutes following infusion.
• Local guidelines should be consulted for variations in monitoring requirements.

What are the benefits of tebentafusp?

• While immune-checkpoint inhibitors have resulted in major progress for the treatment of cutaneous melanoma, they are largely ineffective against metastatic uveal melanoma.
• Currently, tebentafusp is the only FDA and TGA approved immunotherapy for metastatic uveal melanoma. In trials, it resulted in an improved survival compared to standard care.

What are the disadvantages of tebentafusp?

• High rates of adverse effects
• Requirement for prolonged monitoring, even beyond the first 2 infusions

What are the side effects and risks of tebentafusp?

In clinical trials, the common side effects seen in ≥30% of cases include cytokine release syndrome (CRS) (89%), rash (83%), fever (76%), itch (68%), fatigue (64%), nausea (49%), chills (48%), hypo/hyperpigmentation (47%), abdominal pain (45%), oedema (45%), hypotension (39%), xerosis (31%), headache (31%) and vomiting (30%).

Cytokine release syndrome (CRS)

• CRS is a form of systemic inflammatory response syndrome (SIRS), caused by leukocyte (white blood cell) activation and release of large amounts of inflammatory cytokines.
• It usually manifests as fever and hypotension with or without hypoxia.
• Other symptoms of CRS may include chills, nausea, vomiting, fatigue, and headache.
• With tebentafusp, most cases of CRS occurred within an hour of the first 3 infusions with reducing severity following subsequent infusions despite increasing dose.

Cutaneous adverse effects of tebentafusp

As gp100 may be expressed by normal melanocytes, skin-related adverse effects are common (occurring in 94% of patients).

Most cutaneous adverse effects occur within a few hours of the infusion and are typically most severe with the first 3 infusions, reducing in severity thereafter.

The most common presentation is widespread confluent macular erythema, which may be accompanied by blistering and/or oedema. Other reported cutaneous reactions include:

• Dermatitis (acneiform, allergic, bullous, contact, seborrhoeic)
• Exfoliative rash
• Erythema multiforme
• Urticaria
• Psoriasiform reactions
• Maculopapular rash
• Vesicular/bullous rash
• Alopecia.

Other adverse effects

• Hepatic: Liver function derangements: elevated aspartate aminotransferase, alanine aminotransferase, bilirubin, gamma glutamyl transferase or alkaline phosphatase.
• Cardiac: sinus tachycardia, arrhythmia, QT prolongation, hypotension, hypertension, flushing.
• General: nasopharyngitis, night sweats, pyrexia, fatigue, chills.
• Oedema: periorbital, eyelid, pharyngeal, lip, face, peripheral.
• Drug interactions: Tebentafusp may release cytokines which suppress CYP450 enzymes, especially within the 24 hours following administration. Monitoring of drugs with a narrow therapeutic window such as warfarin is advised.
• GI: anorexia, oropharyngeal pain, nausea, vomiting, diarrhoea, abdominal pain, constipation, dyspepsia, elevated lipase or amylase.
• Electrolytes: hypomagnesaemia, hyponatraemia, hypocalcaemia, hypokalaemia, hypophosphataemia.
• Psychiatric: insomnia, anxiety.
• Neurological: headache, dizziness, paraesthesia, dysgeusia.
• Respiratory: cough, dyspnoea, hypoxia.
• Musculoskeletal: arthralgia, back pain, myalgia, muscle spasm.
• Haematological: anaemia, lymphopenia (usually transient and not clinically significant), elevated white cell count.
  Renal: elevated creatinine.

Approved datasheets are the official source of information for medicines, including approved uses, doses, and safety information. Check the individual datasheet in your country for information about medicines.

We suggest you refer to your national drug approval agency such as the Australian Therapeutic Goods Administration (TGA), US Food and Drug Administration (FDA), UK Medicines and Healthcare products regulatory agency (MHRA) / emc, and NZ Medsafe, or a national or state-approved formulary eg, the New Zealand Formulary (NZF) and New Zealand Formulary for Children (NZFC) and the British National Formulary (BNF) and British National Formulary for Children (BNFC).