4.1. Therapeutic indications

KIMMTRAK is indicated as monotherapy for the treatment of human leukocyte antigen (HLA)-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma.

4.2. Posology and method of administration

KIMMTRAK should be administered under the supervision of a physician experienced in the use of anti-cancer immunotherapy agents. Appropriate medicinal products, including anti‑IL‑6 treatment and resuscitation equipment should be available.

Posology

Patients treated with KIMMTRAK must have HLA-A*02:01 genotype determined by a validated HLA genotyping assay.

The recommended dose of KIMMTRAK is:

20 micrograms on Day 1

30 micrograms on Day 8

68 micrograms on Day 15

68 micrograms once every week thereafter (see section 6.6).

Continue treatment until disease progression or unacceptable toxicity. Atypical responses similar to immune checkpoint inhibitors have been observed. It is recommended to continue treatment for clinically stable patients with initial evidence of disease progression until disease progression is confirmed.

First three treatment doses

First three doses of KIMMTRAK should be administered in a hospital setting with overnight monitoring for signs and symptoms of CRS for at least 16 hours. Vital signs should be monitored pre-dose and at a minimum of every 4 hours until resolution of symptoms. If clinically indicated, more frequent monitoring or prolongation of hospitalisation should occur.

If patients experience Grade 3 or 4 hypotension during any of the first three KIMMTRAK infusions, patients should be monitored every hour for at least 4 hours in an outpatient setting for the next three infusions.

Subsequent treatment doses

After 68 mcg dose level is tolerated (i.e., absence of Grade ≥ 2 hypotension requiring medical intervention), subsequent doses can be administered in appropriate out-patient ambulatory care setting. Observe patients for a minimum of 30 minutes following each infusion.

Pre-medication

To minimize the risk of hypotension associated with cytokine release syndrome (CRS), administer intravenous fluids prior to starting KIMMTRAK infusion based on clinical evaluation and the volume status of the patient.

For patients with pre-existing adrenal insufficiency on maintenance systemic corticosteroids, consider adjusting the corticosteroid dose to manage the risk of hypotension.

Dose adjustments

Evaluate for and treat other causes of fever, hypoxia and hypotension. If CRS is suspected, identify and manage according to recommendations in Table 1. See Table 2 for management guidelines for acute skin reactions.

Table 1: CRS Grading and Management Guidance

CRS Grade*

Management

Grade 1

Temperature ≥ 38°C

No hypotension or hypoxia

Treat for symptoms as appropriate. Monitor for escalation in CRS severity

Grade 2

Temperature ≥ 38°C

Hypotension that responds to fluids and does not require vasopressors.

Oxygen requirement includes low flow nasal cannula (delivery of oxygen ≤ 6 L/min) or blow-by

Symptom management as per Grade 1 in addition to the following measures:

Administer bolus intravenous fluids as needed for hypotension

Manage oxygen requirement with supplemental oxygen and additional respiratory support as needed.

Increase monitoring to determine resolution or escalation in severity

If Grade 2 CRS symptoms do not rapidly improve to Grade ≤ 1 within 2‑3 hours, then treat as Grade 3

For Grade 2 CRS that is persistent (lasting 2‑3 hours) or recurrent (occurrence of ≥ Grade 2 CRS with more than one dose), administer corticosteroid premedication (e.g. dexamethasone 4 mg or equivalent) at least 30 minutes prior to next dose

Grade 3

Temperature ≥ 38°C

Require a vasopressor with or without vasopressin.

Require high flow nasal cannula (delivery of oxygen > 6 L/min), face mask or non-rebreather mask or Venturi mask

Management per Grade 2 and include the following measures:

Administer high-dose intravenous corticosteroid (e.g. 2 mg/kg/day methylprednisolone or equivalent)

Increase monitoring to determine resolution or escalation in severity

Consider administering tocilizumab.

Withhold KIMMTRAK until Grade ≤ 1. At next treatment, resume KIMMTRAK at same dose level (i.e. do not escalate) after appropriate risk versus benefit assessment and monitor patient accordingly. Once dose level is tolerated, can resume pre-planned dosing schedule

For Grade 3 CRS, administer corticosteroid premedication (e.g. dexamethasone 4 mg or equivalent) at least 30 minutes prior to next dose

Grade 4

Temperature ≥ 38°C

Require multiple vasopressors.

Requiring positive pressure (e.g. CPAP, BiPAP, intubation and mechanical ventilation).

Permanently discontinue KIMMTRAK

Administer intravenous corticosteroid (e.g., 2 mg/kg/day methylprednisolone or equivalent)

* Based on ASTCT consensus grading of CRS criteria (Lee et.al 2019).

Table 2: Recommended Management and Dose Modifications for Acute Skin Reactions and Elevated Liver Enzymes

Adverse Reactions

Severitya of Adverse Reaction

Management

Acute skin reactions

(see section 4.4)

Grade 2 or 3

Use local skin management and systemic antihistamine regimen.

Topical corticosteroid treatment can be considered for symptomatic rash that does not respond to anti-pruritic regimen.

Consider systemic steroids for persistent or severe symptoms.

Withhold KIMMTRAK until Grade ≤ 1

Resume KIMMTRAK at same dose level (i.e., do not escalate if Grade 3 skin reactions occurred during initial dose escalation; resume escalation once dosage is tolerated)

Grade 4

Permanently discontinue KIMMTRAK

Administer intravenous corticosteroid (e.g., 2 mg/kg/day methylprednisolone or equivalent)

Elevated liver enzymes (see section 4.4)

Grade 3 or 4a

Withhold KIMMTRAK until ≤ Grade 1 or baseline.

Resume KIMMTRAK at same dose level if the elevated liver enzymes occur in the setting of Grade 3 CRS; resume escalation if next administration is tolerated.

If the elevated liver enzymes occur outside the setting of Grade 3 CRS resume escalation if the current dose is less than 68 mcg, or resume at same dose level if dose escalation has completed

Administer intravenous corticosteroids if no improvement within 24 hours

Other clinically relevant adverse reactions

Grade 3a

Withhold KIMMTRAK until ≤ Grade 1 or baseline

Resume KIMMTRAK at same dose level (i.e., do not escalate if other Grade 3 adverse reaction occurred during initial dose escalation; resume escalation once dosage is tolerated)

Grade 4a

Permanently discontinue KIMMTRAK

a Based on National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 (NCI CTCAEv4.03).

Special populations

Paediatric population

The safety and efficacy of KIMMTRAK in children under the age of 18 years has not been established.

No data are available.

Elderly

No dose adjustment is required for elderly patients (≥ 65 years of age).

Renal impairment

Based on pharmacokinetic analyses, dose adjustment is not necessary in patients with mild to moderate renal impairment (see section 5.2). Patients with severe renal impairment have not been evaluated and should be treated with caution. No dose recommendations can be made for patients with severe renal impairment because of the lack of pharmacokinetic data.

Hepatic impairment

No dose adjustment is recommended for patients with mild hepatic impairment. KIMMTRAK has not been studied in patients with moderate or severe hepatic impairment at baseline (see section 5.2).

Cardiac disease

Patients with significant history of cardiac disease have not been evaluated. Patients with cardiac disease, QTc prolongation, or risk factors for cardiac failure should be monitored carefully.

Method of administration

KIMMTRAK is for intravenous use. The recommended infusion period is 15‑20 minutes.

KIMMTRAK requires dilution with sodium chloride 9 mg/mL (0.9 %) solution for injection containing human albumin for IV infusion. Each vial of KIMMTRAK is intended for use as single‑dose only. Do not shake the KIMMTRAK vial.

Use aseptic technique for dilution and preparation of dosing solutions.

Closed system transfer devices (CSTDs) must not be used for dose preparation of solution for infusion.

For instructions on dilution and administration of the medicinal product, see section 6.6.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Patient selection

When considering the use of KIMMTRAK as a monotherapy for unresectable or metastatic uveal melanoma, it is important that the HLA-A*02:01 positive status of a patient is determined.

Cytokine release syndrome (CRS)

CRS has occurred following KIMMTRAK infusions. Diagnosis of CRS following KIMMTRAK infusion was most frequently based on pyrexia followed by hypotension and infrequently hypoxia. Other commonly observed symptoms with CRS included chills, nausea, vomiting, fatigue, and headache.

Most patients experienced CRS following each of first three KIMMTRAK infusions, with decreasing severity and frequency. Nearly all cases of CRS started on the day of infusion. Early signs of CRS include increase in body temperature and hypotension which occur within the first 16 hours after KIMMTRAK infusion.

Monitor patients for signs or symptoms of CRS for at least 16 hours following first three infusions of tebentafusp in hospital setting with immediate access to medicinal products and resuscitative equipment to manage CRS. If CRS is observed, prompt treatment with supportive care including antipyretics, intravenous fluids or corticosteroids should be initiated to avoid escalation to severe or life-threatening events and monitoring should be continued until resolution (see section 4.2).

At subsequent doses, patients should be closely monitored for at least 30 minutes after treatment for early identification of signs and symptoms of CRS. Patients with co-morbidities, including certain cardiovascular disorders, may be at increased risk for sequalae associated with CRS.

Withhold or discontinue tebentafusp depending on persistence and severity of CRS (see section 4.2, Table 1).

Acute skin reactions

Acute skin reactions have been reported with KIMMTRAK infusion, which may be based on its mechanism of action and gp100 expression in normal melanocytes in the skin. Acute skin reactions mainly included rash, pruritus, erythema and cutaneous oedema.

Acute skin reactions typically occur following each of the first three KIMMTRAK infusions and decrease in severity and frequency with subsequent doses. No cases of Stevens-Johnson syndrome or toxic epidermal necrolysis were reported.

Acute skin reactions can be managed with antihistamine and topical corticosteroids. Consider systemic steroids for persistent or severe symptoms. For additional details on management of acute skin reaction, refer to clinical management as outlined in section 4.2, Table 2.

Elevated liver enzymes

Transient elevations in liver enzymes including aspartate transaminase/alanine aminotransferase (AST/ALT) and bilirubin have occurred following KIMMTRAK treatment. These elevations mainly occurred secondary to a CRS event and may also be attributed to underlying disease, liver metastasis, or disease progression. Cases of liver enzyme increase can be asymptomatic.

Monitor AST, ALT and total blood bilirubin prior to the start of and during treatment with KIMMTRAK. Withhold KIMMTRAK according to severity (see section 4.2, Table 2).

Cardiac Disease

Cardiac events such as sinus tachycardia and arrhythmia have been observed in patients who have received tebentafusp treatment (see section 4.8). Patients with pre‑existing cardiovascular disorders may be at increased risk for sequalae associated with CRS and should be monitored carefully. Any patient with signs or symptoms consistent with cardiac events should be evaluated and promptly treated. In addition, appropriate treatment should be administered for any underlying CRS as a precipitating factor.

Cases of QT interval prolongation were reported following tebentafusp treatment (see section 4.8). Tebentafusp treatment should be administered with caution in patients with history of or predisposition to QT interval prolongation and in patients who are taking medicinal products that are known to prolong QT interval.

An electrocardiogram (ECG) should be performed in all patients before and after tebentafusp treatment during the first 3 weeks of treatment and subsequently as clinically indicated. If QTcF exceeds 500 msec or increases by ≥ 60 msec from baseline value, tebentafusp treatment should be withheld and patients should be treated for any underlying precipitating factors including electrolyte abnormalities. Tebentafusp treatment should be resumed once QTcF interval improves to <500 msec or is < 60 msec from baseline value. Depending on persistence and severity of the cardiac event and any associated CRS, tebentafusp treatment should be withheld or discontinued (see section 4.2, Table 1).

4.5. Interaction with other medicinal products and other forms of interaction

No formal drug interaction studies have been performed with tebentafusp.

Initiation of KIMMTRAK treatment causes transient release of cytokines that may suppress CYP450 enzymes. The highest drug-drug interaction risk is during the first 24 hours of the first three doses of KIMMTRAK in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index. In these patients, monitor for toxicity (e.g., warfarin) or drug concentrations (e.g., cyclosporine). Adjust the dose of the concomitant drug as needed.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential should use effective contraception during treatment with tebentafusp and for at least 1 week after last dose of tebentafusp.

Verify pregnancy status in females of reproductive potential prior to initiating tebentafusp treatment.

Pregnancy

There are no data from the use of tebentafusp in pregnant women. Animal reproduction studies have not been conducted with tebentfusp (see section 5.3). Tebentafusp is not recommended during pregnancy and in women of childbearing potential not using contraception. The pregnancy status in females of reproductive potential should be verified prior to initiating tebentafusp treatment.

Breastfeeding

There is insufficient information on the excretion of tebentafusp/metabolites in human milk. A risk to the new-borns /infants cannot be excluded. Breast-feeding should be discontinued during treatment with tebentafusp.

Fertility

No fertility studies have been conducted with tebentafusp (see section 5.3). There are no data on the effect of tebentafusp on human fertility.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of safety profile

The most common adverse drug reactions (≥ 30 %) in patients treated with KIMMTRAK were cytokine release syndrome (89 %), rash (83 %), pyrexia (76 %), pruritus (69 %), fatigue (64 %), nausea (49 %), chills (48 %), hypo/hyperpigmentation (47 %), abdominal pain (45 %), oedema (45 %), hypotension (39 %), dry skin (31 %), headache (31 %) and vomiting (30 %).

The most common serious adverse reactions (≥ 2 %) in patients treated with KIMMTRAK were cytokine release syndrome (10 %), rashes (4.5 %), pyrexia (2.4 %), and hypotension (2 %).

The most common ≥ Grade 3 adverse reactions (≥ 2 %) in KIMMTRAK treated patients were rash (18 %), hypertension (8 %), hypotension (7 %), aspartate aminotransferase increased (6 %) blood phosphate decreased (5 %), pruritus (4.8 %), lipase increased (4.2 %), pyrexia (4 %), abdominal pain (3.7 %), blood bilirubin increased (3.4 %), lymphocyte count decreased (3.4 %), alanine aminotransferase increased (3.4 %), cytokine release syndrome (2.6 %), and gamma-glutamyltransferase increased (2.4 %).

The frequency of treatment discontinuation due to adverse reactions was 4 % in patients who received KIMMTRAK. The most common adverse reactions leading to discontinuation were cytokine release syndrome (0.4 %). No treatment-related deaths were reported.

Adverse reactions resulting in dose interruption occurred in 26 % of patients who received KIMMTRAK. The most common adverse reactions leading to dose interruption (≥ 2 %) included fatigue (3 %), pyrexia (2.7 %), alanine aminotransferase increase (2.4 %), aspartate aminotransferase increase (2.4 %). abdominal pain (2.1 %) and lipase increased (2.1 %).

Adverse reactions leading to dose reduction occurred in 4.3 % of patients who received KIMMTRAK. The most common adverse reactions (≥1 %) leading to dose reduction were cytokine release syndrome (1.9 %), and hypotension (1.1 %).

Tabulated list of adverse reactions

Table 3 summarizes adverse reactions that occurred in 378 metastatic uveal melanoma patients from two clinical studies (IMCgp100‑102 and IMCgp100‑202) that received the recommended dosing KIMMTRAK dosing regimen of 20 micrograms on Day 1, 30 micrograms on Day 8 and 68 micrograms on Day 15 and 68 micrograms weekly thereafter.

The adverse drug reaction frequency is listed by MedDRA System Organ Class (SOC) at the preferred term level. Frequencies of occurrence of adverse reactions are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 3: Adverse Reactions in Patients Treated with KIMMTRAK Monotherapy

Adverse Reactions

Infections and infestations

Common

Nasopharyngitis

Immune system disorders

Very common

Cytokine release syndrome1

Metabolism and nutrition disorders

Very common

Decreased appetite, hypomagnesaemia, hyponatraemia, hypocalcaemia, hypokalaemia

Uncommon

Tumour lysis syndrome

Psychiatric disorders

Very Common

Insomnia

Common

Anxiety

Nervous system disorders

Very common

Headache2, dizziness, paraesthesia

Common

Taste disorder

Cardiac disorders

Very common

Tachycardia9

Common

Arrhythmia2

Uncommon

Angina pectoris2

Vascular disorders

Very common

Hypotension2, flushing, hypertension

Respiratory, thoracic and mediastinal disorders

Very common

Cough, dyspnoea

Common

Oropharyngeal pain, hypoxia10

Gastrointestinal disorders

Very common

Nausea2, vomiting2, diarrhoea, abdominal pain6, constipation, dyspepsia

Skin and subcutaneous tissue disorders

Very common

Rash3, pruritus, dry skin, hypo-/ hyperpigmentation5, erythema

Common

Alopecia, night sweats

Musculoskeletal and connective tissue disorders

Very common

Arthralgia, back pain, myalgia, pain in extremity

Common

Muscle spasm

General disorders and administration site conditions

Very common

Pyrexia2, fatigue4, chills2, oedema7, influenza like illness

Investigations

Very common

Aspartate aminotransferase increased8, alanine aminotransferase increased8, blood bilirubin increased8, lipase increased8, anaemia8, lymphopenia8, hypophosphataemia8

Common

Amylase increased8, blood creatinine increased8, gamma glutamyl transferase increased8, white blood cell count increased8, blood alkaline phosphatase increased8

1 CRS was adjudicated using the ASTCT consensus grading of CRS criteria (Lee et.al 2019). Adjudicated CRS is provided in lieu of investigator reported CRS.

2 Some of the events may be associated with CRS or may be isolated reported events.

3 Includes blister, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, dermatitis contact, dermatosis, drug eruption, eczema, eczema eyelids, erythema multiforme, exfoliative rash, interstitial granulomatous dermatitis, lichenification, lichenoid keratosis, palmar-plantar erythrodysaesthesia syndrome, papule, psoriasis, rash, rash erythematous, rash generalised, rash macular, rash maculo-papular, rash papular, rash pruritic, rash vesicular, seborrhoea, seborrhoeic dermatitis, skin abrasion, skin erosion, skin exfoliation, skin irritation, skin plaque, solar dermatitis, toxic skin eruption, urticaria.

4 Includes fatigue and asthenia.

5 Includes achromotrichia acquired, ephelides, eyelash discolouration, eyelash hypopigmentation, hair colour changes, lentigo, pigmentation disorder, retinal depigmentation, skin depigmentation, skin discolouration, skin hyperpigmentation, skin hypopigmentation, solar lentigo, vitiligo.

6 Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness, epigastric discomfort, flank pain, gastrointestinal pain and hepatic pain.

7 Includes eye oedema, eye swelling, eyelid oedema, periorbital swelling, periorbital oedema, swelling of eyelid, pharyngeal oedema, lip oedema, lip swelling, face oedema, generalized oedema, localised oedema, oedema, oedema peripheral, peripheral swelling, swelling, swelling face.

8 Based on laboratory values; not all were reported as adverse events.

9 Includes tachycardia and sinus tachycardia.

10 Includes hypoxia and oxygen saturation decrease.

Description of selected adverse reactions

Cytokine release syndrome (CRS)

In clinical trial Study IMCgp100-202, cytokine release syndrome (adjudicated based on ASTCT consensus grading 2019) occurred in 89 % of KIMMTRAK-treated patients. The overall incidence of CRS included 12 % Grade 1, 76 % Grade 2 and 0.8 % Grade 3 events. The majority (84 %) of episodes of CRS started the day of infusion. The median time to resolution of CRS was 2 days.

CRS rarely (1.2 %) led to treatment discontinuation. All CRS symptoms were reversible and were managed with intravenous fluids, antipyretics, or a single dose of corticosteroid. Two patients (0.8 %) received tocilizumab.

For clinical management of CRS, see section 4.2, Table 1.

Acute skin reactions

In Study IMCgp100‑202, acute skin reactions occurred in 91% of patients treated with KIMMTRAK including any grade rash (83 %), pruritus (69%), erythema (25 %) and cutaneous oedema (27 %). Most skin reactions were Grade 1 (28 %) or 2 (44 %) and some KIMMTRAK-treated patients experienced Grade 3 (21 %) events.

Acute skin reactions typically occurred following each of the first three KIMMTRAK infusions, with decreasing frequency of ≥ Grade 3 reactions (dose 1; 17 %, dose 2; 10 %, dose 3; 8 %, dose 4; 3 %). The median time to onset of acute skin reactions was 1 day in the KIMMTRAK-treated patients and median time to improvement to ≤ Grade 1 was 6 days. There were no discontinuations of KIMMTRAK due to acute skin reactions.

For clinical management of acute skin reactions, see section 4.2, Table 2.

Elevated liver enzymes

In Study IMCgp100‑202 where 95 % of patients had pre-existing liver metastasis, ALT/AST increase to ≥ Grade 1 were observed in 65 % of patients treated with KIMMTRAK. More than 90 % of patients were able to continue treatment beyond worst grade ALT/AST elevation. In patients experiencing ALT/AST elevations, 73 % initially occurred within the first 3 infusions with KIMMTRAK. Most patients experiencing Grade 3 or 4 ALT/AST elevations had improvement to ≤ Grade 1 within 7 days.

Elevations in bilirubin have been reported in 27 % of patients and these were primarily associated with an increase in size of liver metastasis.

For clinical management of elevated liver enzymes, see section 4.2, Table 2.

Other laboratory abnormalities

In Study IMCgp100-202, decreased lymphocytes were reported in 91 % of patients treated with KIMMTRAK. Decreased lymphocytes Grade ≥ 3 was reported in 56 % of patients treated with KIMMTRAK. Decreases in lymphocytes count were transient and were most commonly (> 95% of cases) observed the day after the initial 3 KIMMTRAK doses.

The proportion of patients (≥ 3 %) who experienced a shift from baseline to a Grade 3 or 4 of other laboratory abnormalities were as follows: 3 % haemoglobin decreased, 4 % for amylase increased, 15 % for lipase increased.

Immunogenicity

Treatment-emergent anti-drug antibodies (ADA) against tebentafusp were detected in 33 % and 29 % of patients receiving tebentafusp across all doses in study IMCgp100‑102 and study IMCgp100‑202, respectively. The median onset time to ADA formation was 6 to 9 weeks after start of tebentafusp treatment. There was no evidence of ADA impact on safety or efficacy of tebentafusp, although the small number of patients who developed high titre ADA precludes firm conclusions regarding their clinical impact.

Neutralizing antibodies (Nab) against tebentafusp were detected in 19 % and 15 % of patients from studies IMCgp100‑102 and IMCgp100‑202, respectively, with a median time to onset of 12‑16 weeks. NAb responses were generally persistent, lasting longer than 20 weeks from first detection. The majority of NAb responses occurred in high titre ADA positive patients: 24/27 (89 %) patients with ADA titres greater than the median in study IMCgp100‑102 and 29/34 (85 %) patients with ADA titres greater than the median in study IMCgp100‑202. No association between NAb onset or titre and the safety or efficacy of tebentafusp was identified in either study.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is no information on overdose with tebentafusp. In case of overdose, patients should be closely monitored for signs or symptoms of adverse reactions and appropriate symptomatic treatment should be instituted immediately.