Tebentafusp

Tebentafusp redirects T cells against uveal melanoma. It is a soluble protein built on a T-cell receptor: one end binds a peptide of gp100 (a protein highly expressed in melanoma cells) presented by HLA-A*02:01 on the tumour surface, and the other end binds CD3 on T cells. Because it depends on presentation by HLA-A*02:01, it acts only in patients who carry that HLA type.

Mechanism of Action

• Targeting domain: the T-cell-receptor end binds with high affinity to a gp100 peptide presented by HLA-A*02:01 on the surface of uveal melanoma cells.
• Effector domain: the anti-CD3 antibody fragment binds CD3 on polyclonal T cells. Its affinity is lower, so T cells are not stimulated unless tebentafusp has found gp100 on a tumour cell.
• Immune synapse: binding to the tumour cell and to a T cell forms an immune synapse, which redirects and activates polyclonal T cells regardless of their native receptor specificity. The activated T cells release inflammatory cytokines and cytolytic proteins that lyse the tumour cells directly.
• gp100 in normal tissue: gp100 is highly expressed in melanoma cells and weakly in normal melanocytes. The SmPC links acute skin reactions to gp100 expression in normal skin melanocytes.
• Pharmacodynamic effects: lymphocyte counts fall transiently, without clinical significance, the day after each of the first three doses and return to baseline before later doses. Proinflammatory cytokines and chemokines rise transiently after the first three doses, peaking 8 to 24 hours after treatment and returning to baseline before later doses.

Pharmacokinetics

• Absorption and exposure: given intravenously. Pharmacokinetics appear linear and dose-proportional between 20 and 68 micrograms. After weekly infusions in metastatic uveal melanoma, peak concentrations of 4.2–13.7 ng/mL were reached at the end of the infusion (0.5 hours), and there was no accumulation with weekly dosing at the target doses.
• Distribution: tebentafusp does not distribute extensively; its volume of distribution (5.25 L) is comparable to blood volume.
• Metabolism: the metabolic pathway has not been characterised; like other protein therapeutics, it is expected to be degraded into small peptides and amino acids.
• Elimination: excretion is not fully characterised. Its size is close to the glomerular filtration threshold, so small amounts may be excreted in urine. The terminal half-life is 6 to 8 hours.
• Special populations: body weight (43–163 kg), sex, race and age (23–91 years) have no significant effect on clearance. There are no formal studies in renal or hepatic impairment. Mild to moderate renal impairment (creatinine clearance 30–89 mL/min) had no impact on safety or efficacy, data in moderate impairment are limited (below 5% of patients) and there is no information for severe impairment (below 30 mL/min). Raised ALT or AST at baseline or on treatment did not affect pharmacokinetics.

• Uveal melanoma: as monotherapy for human leukocyte antigen (HLA)-A*02:01-positive adults with unresectable or metastatic uveal melanoma. The patient’s HLA-A*02:01 genotype must be determined by a validated HLA genotyping assay.

• Hypersensitivity to tebentafusp or to any of the excipients.

The safety data come from 378 patients with metastatic uveal melanoma in two clinical studies (IMCgp100-102 and IMCgp100-202) who received the recommended regimen. The most common reactions were cytokine release syndrome (88%), rash (85%), pyrexia (79%), pruritus (72%), fatigue (66%), nausea (56%), chills (55%), abdominal pain (49%), oedema (49%), hypo/hyperpigmentation (48%), hypotension (43%), dry skin (35%), vomiting (34%) and headache (32%). Adverse reactions led to permanent discontinuation in 4% of patients, most often because of cytokine release syndrome.

Very common (≥1/10): cytokine release syndrome; decreased appetite, hypomagnesaemia, hyponatraemia, hypocalcaemia, hypokalaemia; insomnia; headache, dizziness, paraesthesia; tachycardia; hypotension, flushing, hypertension; cough, dyspnoea; nausea, vomiting, diarrhoea, abdominal pain, constipation, dyspepsia; rash, pruritus, dry skin, hypo/hyperpigmentation (including vitiligo and skin or hair colour changes), erythema; arthralgia, back pain, myalgia, pain in extremity; pyrexia, fatigue (including asthenia), chills, oedema (including eyelid, periorbital and facial swelling), influenza-like illness; raised aspartate aminotransferase, raised alanine aminotransferase, raised blood bilirubin, raised lipase, anaemia, decreased lymphocyte count, decreased blood phosphate, raised blood creatinine.

Common (≥1/100 to <1/10): nasopharyngitis; anxiety; taste disorder; arrhythmia, atrial fibrillation; oropharyngeal pain, hypoxia; alopecia, night sweats; muscle spasm; raised amylase, raised gamma-glutamyltransferase, raised white blood cell count, raised alkaline phosphatase, raised blood glucose.

Uncommon (≥1/1,000 to <1/100): tumour lysis syndrome; angina pectoris, cardiac failure; QT prolongation on the electrocardiogram.

Some events, such as headache, tachycardia, hypotension, hypoxia, nausea, vomiting, pyrexia and chills, may be associated with cytokine release syndrome or reported in isolation. Acute skin reactions and cardiac events (sinus tachycardia, arrhythmia, QT prolongation) are the other important reactions (see Special Instructions).

No formal drug interaction studies have been performed.

• CYP450 substrates: starting tebentafusp causes a transient release of cytokines that may suppress CYP450 enzymes. The highest risk is in the first 24 hours of each of the first three doses in patients taking CYP450 substrates, particularly those with a narrow therapeutic index. These patients should be monitored for toxicity (for example with warfarin) or drug concentrations (for example with ciclosporin), and the dose of the concomitant medicine adjusted as needed.
• QT-prolonging medicines: tebentafusp should be given with caution to patients taking medicinal products known to prolong the QT interval (see Special Instructions).
• Systemic corticosteroids: in patients with adrenal insufficiency on maintenance corticosteroids, adjusting the corticosteroid dose should be considered to manage the risk of hypotension.

Kimmtrak is given under the direction and supervision of a physician experienced in the use of anti-cancer agents who is prepared to manage cytokine release syndrome (CRS) in an environment where full resuscitation facilities are immediately available. Hospitalisation is recommended for at least the first three infusions. The patient’s HLA-A*02:01 genotype must be determined with a validated HLA genotyping assay before treatment.

Recommended Dose

• Dose escalation: 20 micrograms on day 1, 30 micrograms on day 8 and 68 micrograms on day 15, then 68 micrograms once every week.
• Duration: while the patient derives clinical benefit and there is no unacceptable toxicity.
• Infusion: the concentrate is diluted in sodium chloride 9 mg/mL (0.9%) solution for injection containing human albumin and infused intravenously over 15 to 20 minutes. Each vial is single-dose, and the vial must not be shaken. Dilution instructions are in section 6.6 of the SmPC.
• Premedication: intravenous fluids are given before starting the infusion, according to clinical evaluation and the patient’s volume status, to reduce the risk of hypotension linked to CRS. In patients with pre-existing adrenal insufficiency on maintenance systemic corticosteroids, adjusting the corticosteroid dose should be considered.

Monitoring After Infusion

• First three doses: given in hospital with overnight monitoring for signs and symptoms of CRS for at least 16 hours. Vital signs are checked before the dose and at least every 4 hours until symptoms resolve; monitoring is more frequent or hospitalisation longer if clinically indicated. If grade 3 or 4 hypotension occurs during any of the first three infusions, the next three infusions are followed by hourly monitoring for at least 4 hours in an outpatient setting.
• Later doses: once the 68 microgram dose is tolerated (no grade 2 or higher hypotension needing medical intervention), doses can be given in an appropriate outpatient ambulatory care setting, with observation for at least 60 minutes after each infusion. For patients treated as outpatients for at least 3 months without interruptions longer than 2 weeks, post-infusion monitoring may be shortened to a minimum of 30 minutes.

Dose Adjustments

No dose reductions are recommended; Kimmtrak is withheld or discontinued to manage adverse reactions.

• Grade 1 CRS (temperature ≥38 °C, no hypotension or hypoxia): continue treatment with symptomatic support and monitor for escalation.
• Grade 2 CRS (hypotension responding to fluids, or oxygen by low-flow nasal cannula or blow-by): continue treatment, give bolus intravenous fluids and oxygen as needed. If hypotension and hypoxia do not improve within 3 hours or CRS worsens, give a high-dose intravenous corticosteroid (for example methylprednisolone 2 mg/kg/day or equivalent). For persistent or recurrent grade 2 CRS, give corticosteroid premedication (for example dexamethasone 4 mg or equivalent) at least 30 minutes before the next dose.
• Grade 3 CRS (vasopressor needed, or high-flow oxygen, face mask or similar): withhold until CRS and its sequelae have resolved; give a high-dose intravenous corticosteroid and tocilizumab as needed (dosed by body weight, see the SmPC). Resume at the same dose level, without escalating if grade 3 CRS occurred during initial dose escalation, and give corticosteroid premedication (for example dexamethasone 4 mg or equivalent) at least 30 minutes before the next dose.
• Grade 4 CRS (multiple vasopressors or positive-pressure ventilation): discontinue permanently and give an intravenous corticosteroid (for example methylprednisolone 2 mg/kg/day or equivalent).
• Acute skin reactions, grade 2: withhold until grade 1 or baseline; give an antipruritic regimen (for example a non-sedating long-acting antihistamine), a topical corticosteroid for symptomatic rash that does not respond, and systemic steroids for persistent symptoms. Resume escalation if the current dose is below 68 micrograms, or resume at the same dose if escalation is complete.
• Acute skin reactions, grade 3: withhold until grade 1 or baseline; give topical and oral corticosteroids, and consider an intravenous corticosteroid if oral steroids do not work. Resume at the same dose level, without escalating if the grade 3 reaction occurred during initial dose escalation.
• Acute skin reactions, grade 4: discontinue permanently and give an intravenous corticosteroid.

Special Populations

• Elderly: no dose adjustment (65 years and over).
• Renal impairment: no adjustment for mild to moderate impairment. No dose recommendation can be made for severe impairment because of lack of pharmacokinetic data, so dosing should be done with caution and careful monitoring.
• Hepatic impairment: no dose adjustment based on ALT or AST levels is recommended.
• History of cardiac disease: Kimmtrak has not been studied in patients with a history of significant cardiac disease; patients with cardiac disease, QT prolongation or risk factors for cardiac failure should be monitored carefully.
• Children and adolescents: safety and efficacy below 18 years have not been established; no data are available.

HLA-A*02:01 Genotype Requirement

Tebentafusp acts only in patients who are HLA-A*02:01-positive. Every patient must have the HLA-A*02:01 genotype determined with a validated HLA genotyping assay before treatment is given.

Traceability

The name and batch number of the administered biological medicinal product should be clearly recorded.

Cytokine Release Syndrome

Most patients had CRS after tebentafusp infusions. It was most often diagnosed on pyrexia, followed by hypotension and, infrequently, hypoxia; chills, nausea, vomiting, fatigue and headache were also common. CRS has been associated with organ dysfunction, including hepatic, renal, pancreatic, cardiac and pulmonary dysfunction. It usually began on the day of infusion and resolved after a median of 2 days; the rise in temperature generally occurred within 8 hours of the infusion. CRS led to discontinuation in 1.2% of patients. Patients are monitored for at least 16 hours after the first three infusions in hospital, with immediate access to medicines and resuscitation equipment. If CRS occurs, prompt supportive care (antipyretics, intravenous fluids, tocilizumab or corticosteroids) is started and monitoring continues until resolution. Patients with co-morbidities, including cardiovascular disorders, may be at higher risk of its consequences, and treatment is withheld or discontinued depending on persistence and severity.

Acute Skin Reactions

Acute skin reactions (mainly rash, pruritus, erythema and cutaneous oedema) may relate to the mechanism of action and to gp100 expression in normal melanocytes. They typically followed each of the first three infusions and became less severe and less frequent over time; most resolved without systemic corticosteroids or long-term sequelae. They are managed with antihistamines and topical corticosteroids, with systemic steroids considered for persistent or severe symptoms, and may need temporary delays of later infusions.

Cardiac Disease and QT Prolongation

Sinus tachycardia and arrhythmia have been seen, and patients with pre-existing cardiovascular disorders should be monitored carefully. Any patient with signs or symptoms of a cardiac event is evaluated and treated promptly, including treatment of any underlying CRS. Cases of QT prolongation have been reported, so tebentafusp is given with caution to patients with a history of, or predisposition to, QT prolongation or who take medicines known to prolong the QT interval. An electrocardiogram is performed before and after treatment during the first 3 weeks and then as clinically indicated. If QTcF exceeds 500 msec or rises by 60 msec or more from baseline, treatment is withheld and any precipitating factors, including electrolyte abnormalities, are treated; it is resumed once QTcF is below 500 msec or less than 60 msec above baseline.

Pregnancy, Breastfeeding and Fertility

• Contraception and pregnancy status: women of childbearing potential should use effective contraception during treatment and for at least 1 week after the last dose, and pregnancy status should be verified before treatment starts.
• Pregnancy: there are no data from pregnant women and no animal reproduction studies. Tebentafusp is not recommended during pregnancy or in women of childbearing potential not using contraception.
• Breastfeeding: there is insufficient information on excretion in human milk and a risk to the infant cannot be excluded, so breast-feeding should be discontinued during treatment.
• Fertility: no fertility studies have been conducted; the effect on male and female fertility is unknown.

Excipients

The medicine contains less than 1 mmol (23 mg) of sodium per mL, so it is essentially sodium-free.

Effect on Driving

Tebentafusp has no or negligible influence on the ability to drive and use machines.

Store and transport refrigerated at 2–8 °C. Keep the vial in the outer carton to protect from light. Kimmtrak is held under cold-chain handling until it is diluted, and storage after dilution is described under Shelf Life.

Unopened vial: 3 years. From a microbiological point of view, once opened the medicinal product should be diluted and infused immediately. After preparation of the infusion solution, chemical and physical in-use stability has been shown for 24 hours at 2–8 °C; from a microbiological point of view the product should be used immediately, and otherwise in-use storage times and conditions are the responsibility of the user.

Prescription only (Rx), on restricted medical prescription. Kimmtrak is given under the supervision of a physician experienced in anti-cancer agents who can manage cytokine release syndrome with full resuscitation facilities immediately available, and hospitalisation is recommended for at least the first three infusions. It is used only in patients whose HLA-A*02:01 genotype has been confirmed by a validated assay. It is given as an intravenous infusion, so it is supplied to the hospital or clinic that administers it, under refrigerated (2–8 °C) cold-chain handling.