Consumer medicine information

Kimmtrak

Tebentafusp

BRAND INFORMATION

Brand name

Kimmtrak

Active ingredient

Tebentafusp

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Kimmtrak.

SUMMARY CMI

KIMMTRAK®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

▼ This medicine is new or being used differently. Please report side effects. See the full CMI for further details.

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine.

1. Why am I being given KIMMTRAK?

KIMMTRAK contains the active ingredient tebentafusp. KIMMTRAK is used to treat rare eye cancer called uveal melanoma.

For more information, see Section 1. Why am I being given KIMMTRAK? in the full CMI.

2. What should I know before I am given KIMMTRAK?

Do not use if you have ever had an allergic reaction to KIMMTRAK or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I am given KIMMTRAK? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with KIMMTRAK and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How will I be given KIMMTRAK?

KIMMTRAK will be given to you by a healthcare professional in a hospital or clinic through an infusion (drip) into your vein (intravenous) over 15-20 minutes.

More instructions can be found in Section 4. How will I be given KIMMTRAK? in the full CMI.

5. What should I know about being given KIMMTRAK?

Things you should do
  • Remind any doctor, dentist, pharmacist or nurse you visit that you have been given KIMMTRAK.
Driving or using machines
  • If you feel unwell whilst being treated with KIMMTRAK, you should not drive or operate machinery until you feel well again.

For more information, see Section 5. What should I know about being given KIMMTRAK? in the full CMI.

6. Are there any side effects?

Very common side effects include decreased appetite, prickling, tingling or numbness in any section of the body, cough, diarrhoea, stomach pain, chills, and abnormal blood tests.

Serious side effects include symptoms of cytokine release syndrome (CRS) such as fever, dizziness, light headedness, difficulty breathing, nausea, vomiting, fatigue, muscle pain, joint pain, swelling, low blood pressure, rapid heart rate, and headache.

Other serious side effects include itchy skin, rash, severe hives, peeling or flaking skin, swelling of body and/or skin around the eyes.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.

WARNING: CYTOKINE RELEASE SYNDROME
Cytokine Release Syndrome (CRS), which may be serious or life-threatening, can occur in patients receiving tebentafusp. Only administer in an appropriate setting. Monitor for at least 16 hours following each of the first three infusions, and then as clinically indicated.



FULL CMI

KIMMTRAK®

Active ingredient: tebentafusp

Consumer Medicine Information (CMI)

This leaflet provides important information about using KIMMTRAK. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using KIMMTRAK.

Where to find information in this leaflet:

1. Why am I being given KIMMTRAK?
2. What should I know before I am given KIMMTRAK?
3. What if I am taking other medicines?
4. How will I be given KIMMTRAK?
5. What should I know about being given KIMMTRAK?
6. Are there any side effects?
7. Product details

1. Why am I being given KIMMTRAK?

KIMMTRAK contains the active ingredient tebentafusp.

KIMMTRAK is an anticancer medicine. It is made from two different proteins that are fused together. One of these proteins recognises a target protein called ‘gp100’. Gp100 is found in large amounts in uveal melanoma cancer cells. Once the cancer cells are recognised, KIMMTRAK activates your immune system to destroy the cancer cells.

KIMMTRAK is used to treat a rare eye cancer called uveal melanoma.

KIMMTRAK is used when the uveal melanoma has grown despite local treatment, or has spread to other parts of the body.

2. What should I know before I am given KIMMTRAK?

Warnings

Do not use KIMMTRAK if:

  • You are allergic to tebentafusp, or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.

If you are not sure you are allergic to any of the ingredients, talk to your doctor or nurse before you are given KIMMTRAK.

Check with your doctor if you:

  • have any other medical conditions
  • take any medicines for any other condition
  • are pregnant or plan on getting pregnant

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

KIMMTRAK should not be used in pregnancy unless you and your doctor agree the benefit of taking this medicine outweighs any potential risks. Your doctor or nurse will give you a test for pregnancy before you start treatment with KIMMTRAK. If you become pregnant during KIMMTRAK treatment, inform your doctor or nurse immediately.

If you are female and of child-bearing age, you must use effective birth control to avoid becoming pregnant during KIMMTRAK treatment and for at least 1 week after your last dose. Discuss with your doctor the most appropriate methods of birth control.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

It is not known if KIMMTRAK passes into your breast milk. Discuss with your doctor whether the risks and benefits of breast-feeding your child outweigh the benefit of KIMMTRAK treatment and whether you should stop breast-feeding.

Use in children

KIMMTRAK should not be used in children under the age of 18 years. This is because there is limited information on how well it works in this age group.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect KIMMTRAK.

4. How will I be given KIMMTRAK?

How much KIMMTRAK is given:

  • This medicine will be given to you by a healthcare professional in a hospital or clinic
  • The recommended dose of KIMMTRAK is:
    - 1st dose: 20 micrograms
    - 2nd dose: 30 micrograms
    - 3rd dose: 68 micrograms
    - All further doses: 68 micrograms
  • You may be given fluids by infusion before each KIMMTRAK infusion to help prevent low blood pressure from cytokine release syndrome.

How KIMMTRAK is given

  • Your doctor or nurse will give you KIMMTRAK through an infusion (drip) into your vein (intravenous) over 15-20 minutes. You will be given KIMMTRAK once a week, for as long your doctor thinks treatment is benefitting you.
  • Your healthcare provider will keep you under observation during treatment and for at least 16 hours following your first three doses.
  • If the first three doses do not cause any serious or unmanageable side effects, your next doses may be given in a clinic. You will be monitored for any side effects during treatment and for at least 30 minutes after each dose.

If you miss an appointment for your next dose of KIMMTRAK

If you miss an appointment, arrange another visit as soon as possible with your doctor or nurse.

If you are given too much KIMMTRAK

As KIMMTRAK is given under the close supervision of a doctor or nurse, it is unlikely that you will be given too much. However, if you experience any side effects after receiving KIMMTRAK, tell your doctor or nurse immediately.

5. What should I know about being given KIMMTRAK?

Driving or using machines

Be careful before you drive or use any machines or tools until you know how KIMMTRAK affects you.

Tebentafusp is unlikely to affect your ability to drive or use machines. If you feel unwell whilst being treated with this medicine, you should not drive or operate machinery until you feel well again.

Drinking alcohol

Tell your doctor if you drink alcohol.

Your doctor will perform regular blood tests to check for very common side effects such as:

  • Increased levels of liver enzymes
  • Increased levels of bilirubin
  • Low levels of phosphate in the blood
  • Increased levels of pancreatic enzyme, lipase in the blood
  • Decreased levels of white blood cells in the blood
  • Abnormal blood tests.

Looking after your medicine

Your doctor, pharmacist or nurse is responsible for storing KIMMTRAK and disposing of any unused product correctly.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Gastrointestinal related:
  • Stomach pain
  • Diarrhoea
  • Indigestion
  • Decreased appetite
Nervous system related:
  • Unusual mood changes including anxiety
  • Prickling, tingling or numbness in any section of the body
General body related:
  • Cough
  • Chills
  • Mouth pain
  • Hair loss
  • Trouble sleeping
  • Excessve sweating during the night
  • Infection of nasal passages
  • Flu-like symptoms
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effects during or after treatmentWhat to do
Nervous system related:
  • Fever
  • Dizziness
  • Light headedness
  • Difficulty breathing
  • Fatigue
  • Headache
Gastrointestinal related:
  • Nausea
  • Vomiting
Body related:
  • Muscle pain
  • Joint pain
  • Swelling
Heart and blood related:
  • Low blood pressure
  • Rapid heart rate
Skin related:
  • Itchy skin
  • Rash
  • Severe hives
  • Peeling or flaking skin
  • Swelling of body and/or skin around the eyes.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What KIMMTRAK contains

Active ingredient
(main ingredient)		Tebentafusp
Other ingredients
(inactive ingredients)		Citric acid monohydrate
Dibasic sodium phosphate
Mannitol
Trehalose dihydrate
Polysorbate 20
Water for injections

Do not use this medicine if you are allergic to any of these ingredients.

What KIMMTRAK looks like

KIMMTRAK concentrate for solution for infusion is a clear, colourless to slightly yellowish solution in a single-dose vial.

The pack size is 1 glass vial per carton. (AUST R 375296).

Who distributes KIMMTRAK

Medison Pharma Australia Pty Ltd
1 Bligh Street
Sydney NSW 2000
Australia
Phone: 1800 566 020
Email: [email protected]
www.medisonpharma.com.au

This leaflet was prepared in June 2024.

Published by MIMS August 2024

BRAND INFORMATION

Brand name

Kimmtrak

Active ingredient

Tebentafusp

Schedule

S4

 

1 Name of Medicine

Tebentafusp.

2 Qualitative and Quantitative Composition

Each vial contains 0.1 milligrams of tebentafusp in 0.5 mL of concentrated solution for infusion.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Concentrated solution for infusion.
Sterile, preservative-free, clear, colourless to slightly yellowish solution in a single-dose vial.

4 Clinical Particulars

4.1 Therapeutic Indications

Kimmtrak is indicated for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma.

4.2 Dose and Method of Administration

Kimmtrak should be administered under the supervision of a physician experienced in the use of anti-cancer agents.

Dose.

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.
Give each dose by intravenous infusion over 15-20 minutes. Continue treatment with Kimmtrak until disease progression or unacceptable toxicity occurs.
Administer the first three doses of Kimmtrak in a healthcare setting with adequate resources (including 24-hour monitoring, medications and resuscitation equipment) to manage cytokine release syndrome (CRS). Monitor patients for CRS during infusion and for at least for 16 hours after infusion is complete (see Section 4.4 Special Warnings and Precautions for Use).
If the patient does not experience hypotension that is grade 2 or worse (requiring medical intervention) in association with the third infusion, subsequent doses can be administered in an appropriate outpatient/ambulatory care setting. Observe patients for a minimum of 30 minutes following each infusion.

Dose adjustments.

Dose modifications for Kimmtrak for adverse reactions are summarised in Table 1.

Method of administration.

Equipment. Gather the following equipment prior to preparing Kimmtrak for administration:
1 mL sterile syringes with graduations of 2 decimal places;
Sterile needles;
Locally sourced human albumin (see Table 2);
A 100 mL infusion bag containing sodium chloride 9 mg/mL (0.9%) solution for injection. The infusion bag should be constructed of polyvinyl chloride (PVC) or polyolefins (PO), such as polyethylene (PE) and polypropylene (PP);
A sterile, non-pyrogenic, low protein-binding 0.2 micron in-line filter infusion set.
Preparation. A two-step dilution process is required for preparation of the final Kimmtrak dose for infusion. Use aseptic technique for dilution and preparation of solutions for intravenous infusion. Visually inspect parenteral drug products and infusion bags for particulate matter and discoloration prior to administration, whenever solution and container permit.
Closed system transfer devices (CSTDs) must not be used for dose preparation of Kimmtrak solution for infusion.

Step 1: Prepare the infusion bag.

To prevent adsorption of tebentafusp to the infusion bag and other components of the drug delivery system, prepare a solution of 250 microgram/mL human albumin in 0.9% sodium chloride as follows:
1a. Using a 1 mL sterile syringe with graduations of 2 decimal places and a sterile needle, withdraw the calculated volume of source human albumin into the syringe (see Table 2 for calculation examples) and add to the 100 mL bag containing 0.9% sodium chloride solution for injection, to achieve a final human albumin concentration of 250 microgram/mL. Do not shake the infusion bag.
1b. Gently homogenise the 250 microgram/mL human albumin solution by completing the following steps:
i. Gently invert the infusion bag so that the bag is upside down, with the entry port positioned at the top. Then tap the side of the port tubing to ensure that any residual concentrated albumin solution is released into the bulk solution.
ii. Gently rotate the bag lengthwise (360 degrees: from upside-down to right-side-up, and back again) at least 5 times.
iii. Repeat (i) and (ii) an additional three times.

Step 2: Preparation of Kimmtrak solution for infusion.

Do not shake the Kimmtrak vial.
2a. Using a 1 mL syringe with graduations of 2 decimal places and a sterile needle, withdraw the required volume of Kimmtrak 200 micrograms/mL as per the dose required (see Table 3) and add to the prepared 100 mL infusion bag containing sodium chloride 9 mg/mL (0.9%) solution for injection plus human albumin (250 microgram/mL). Do not flush the needle and syringe on transfer.
2b. Each vial of Kimmtrak is for single use in one patient only. Discard any residue. Discard the vial containing the unused portion of Kimmtrak in accordance with local requirements.
2c. Gently mix the infusion bag by following the same procedure outlined in step 1b.
Administration. Immediately administer the diluted solution by intravenous infusion over 15-20 minutes through a dedicated intravenous line, using a sterile, non-pyrogenic, low protein binding 0.2 micron in-line filter infusion set. Administer the entire contents of the Kimmtrak infusion bag to the patient.
Kimmtrak does not contain a preservative. The infusion should be completed within 4 hours from the time of preparation. During the 4-hour window, the Kimmtrak infusion bag should remain below 30°C.
Upon completion of Kimmtrak infusion, flush the infusion line with an adequate volume of sterile sodium chloride 9 mg/mL (0.9%) solution for injection to ensure that the entire contents of the Kimmtrak infusion bag are administered.
Do not administer Kimmtrak as an intravenous push or bolus, or by any non-intravenous route of administration. Do not mix Kimmtrak with other drugs or administer other drugs through the same intravenous line.
Storage of diluted solution for infusion. If not used immediately, store diluted solution for infusion in a refrigerator at 2°C to 8°C and infuse within 24 hours from the time of preparation. The 24-hour window includes refrigerator storage time, the time taken for the infusion bag to re-equilibrate to room temperature (below 30°C) and the duration of the infusion.
Once removed from the refrigerator, do not refrigerate the Kimmtrak infusion bag again. Do not freeze. Discard unused Kimmtrak solution beyond the recommended storage time.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in Section 6.1 List of Excipients.

4.4 Special Warnings and Precautions for Use

Traceability.

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

Cytokine release syndrome (CRS).

CRS, which can be life threatening, occurred in patients receiving Kimmtrak (see Section 4.8 Adverse Effects (Undesirable Effects), Description of selected adverse reactions).
Manifestations of CRS may include fever, hypotension, hypoxia, chills, nausea, vomiting, rash, elevated transaminases, fatigue and headache. CRS has been associated with organ dysfunction, including hepatic, renal, pancreatic, cardiac, and pulmonary dysfunction.
Before initiating Kimmtrak infusion, ensure patients are euvolemic and that healthcare providers with adequate expertise and immediate access to medications and resuscitation equipment are available to manage CRS. For patients with pre-existing adrenal insufficiency on maintenance systemic corticosteroids, consider adjusting the corticosteroid dose to manage the risk of hypotension.
Closely monitor patients for signs or symptoms of CRS during and after infusions of Kimmtrak (see Section 4.2 Dose and Method of Administration). Monitor fluid status, vital signs and oxygenation level and provide appropriate therapy. Withhold or discontinue Kimmtrak depending on persistence and severity of CRS (see Section 4.2 Dose and Method of Administration, Table 1).

Skin reactions.

Skin reactions occurred in patients receiving Kimmtrak, including rash, pruritus, erythema and cutaneous oedema (see Section 4.8 Adverse Effects (Undesirable Effects), Description of selected adverse reactions).
Treat skin reactions with antihistamines and topical or systemic steroids based on persistence or severity of symptoms. Withhold or discontinue Kimmtrak depending on persistence and severity of skin reactions (see Section 4.2 Dose and Method of Administration, Table 1).

Elevated hepatic enzymes.

Elevation of hepatic enzymes occurred in patients receiving Kimmtrak (see Section 4.8 Adverse Effects (Undesirable Effects), Description of selected adverse reactions).
Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total blood bilirubin before and during treatment with Kimmtrak. Withhold Kimmtrak according to severity (see Section 4.2 Dose and Method of Administration, Table 1).

Use in hepatic impairment.

Dose adjustment is not necessary in patients with mild hepatic impairment. Tebentafusp has not been studied in patient with moderate to severe hepatic impairment (see Section 5.2 Pharmacokinetic Properties).

Use in renal impairment.

Dose adjustment is not necessary in patients with mild to moderate renal dysfunction. Tebentafusp has not been studied in patient with severe renal impairment (see Section 5.2 Pharmacokinetic Properties).

Use in the elderly.

Dose adjustment is not necessary for elderly patients (≥ 65 years of age).
Of the 245 patients with metastatic uveal melanoma treated with Kimmtrak in study IMCgp100-202, 47% were 65 years of age or older and 9% were 75 years of age or older. No meaningful differences in safety or efficacy were observed between patients ≥ 65 years of age compared to younger adult patients.

Paediatric use.

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

Effects on laboratory tests.

No data are available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No formal drug interaction studies have been performed with tebentafusp.
Kimmtrak treatment causes transient release of cytokines that may suppress CYP450 enzymes. The effect attenuates with repeat dosing of Kimmtrak, such that cytokine levels are highest during the 24-hour period after each of the first three doses. In patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, consider the possibility of interaction and 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

Effects on fertility.

No fertility studies have been conducted with tebentafusp. There are no data on the effect of tebentafusp on human fertility.
(Category C)
Based on the mechanism of action, Kimmtrak may cause foetal harm when administered to a pregnant person (see Section 5.1 Pharmacodynamic Properties). There are no data regarding the use of tebentafusp in pregnancy. No animal reproduction studies or developmental toxicity studies have been conducted with tebentfusp. Molecules of similar molecular weight can cross the placenta resulting in foetal exposure. Advise patients of the potential risk to a foetus.
Patients 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 patients of reproductive potential prior to initiating tebentafusp treatment.
 There is no information regarding the presence of tebentafusp in human milk, the effect on the breastfed child, or the effects on milk production. Because tebentafusp 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.

4.7 Effects on Ability to Drive and Use Machines

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

4.8 Adverse Effects (Undesirable Effects)

Summary of safety profile.

The safety of Kimmtrak was evaluated in study IMCgp100-202, a randomised (2:1), open-label, active-controlled trial in patients who had not received prior systemic therapy for metastatic or advanced uveal melanoma (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Patients received either Kimmtrak administered at 20 microgram intravenously on day 1, 30 microgram intravenously on day 8, 68 microgram intravenously on day 15, and 68 microgram intravenously once every week thereafter (n = 245) or investigator's choice treatment (n = 111). The median duration of exposure was 5.3 months (range: 0.3 to 33 months) in patients treated with Kimmtrak.
Serious adverse events occurred in 28% of patients who received Kimmtrak. Serious adverse events that occurred in > 2% of patients were cytokine release syndrome (10%), rashes (4.5%), pyrexia (2.4%), and hypotension (2%). One patient (0.4%) experienced a fatal adverse event (pulmonary embolism).
Adverse events led to permanent discontinuation in 3.3% of patients who received Kimmtrak. Adverse events that led to permanent discontinuation of Kimmtrak were anaphylactic reaction, brain oedema, cytokine release syndrome, fatigue, hepatotoxicity, hypotension, and nausea (each 0.4%).
Adverse events resulting in dose interruption occurred in 25% of patients who received Kimmtrak. Adverse events which required dose interruption in ≥ 2% of patients included fatigue (3.7%), lipase increased (2.9%), pyrexia (2.4%), alanine aminotransferase increase (2%), and aspartate aminotransferase increase (2%).
Adverse events leading to dose reduction occurred in 5% of patients who received Kimmtrak. Adverse events which required dose reduction in ≥ 2% of patients were cytokine release syndrome (2.4%), and rashes (2%).
The most common adverse events (≥ 30%) in patients who received Kimmtrak (see Table 4) were cytokine release syndrome, rash, pyrexia, pruritus, fatigue, nausea, chills, abdominal pain, oedema, hypotension, dry skin, headache and vomiting. The most common (≥ 50%) laboratory abnormalities in patients who received Kimmtrak were decreased lymphocyte count, increased creatinine, increased glucose, increased AST, increased ALT, decreased haemoglobin, and decreased phosphate.

Tabulated list of adverse reactions.

Table 4 summarises the adverse events observed in study IMCgp100-202.
Clinically relevant adverse reactions that occurred in < 20% of patients who received Kimmtrak included back pain, decreased appetite, constipation, hypertension, tachycardia or sinus tachycardia, dyspnoea, paraesthesia, dizziness, flushing, muscle spasms, myalgia, pain in extremity, alopecia, skin hyperpigmentation, influenza-like illness, oropharyngeal pain and night sweats.
Table 5 summarises selected laboratory abnormalities observed in study IMCgp100-202.

Description of selected adverse reactions.

Cytokine release syndrome (CRS).

In study IMCgp100-202, CRS of at least grade 2 severity occurred with Kimmtrak infusion at least once for 77% of patients, and 60% experienced it at least twice. In most cases, CRS started on the day of infusion. Fever was noted in nearly all cases of CRS, generally within the first 8 hours after Kimmtrak infusion.
Systemic corticosteroids were received by 23% of patients, supplemental oxygen was received by 8% of patients, and vasopressor treatment was received by 0.8% of patients to treat CRS during at least one infusion. Among cases that resolved, the median time to resolution of CRS was 2 days. CRS led to permanent treatment discontinuation in 1.2% of patients.

Acute skin reactions.

In study IMCgp100-202, acute skin reactions occurred in 91% of patients who received Kimmtrak, including rash (grouped term; 83%), pruritus (grouped term; 69%), erythema (25%) and cutaneous oedema (grouped term; 27%). Skin reactions were all grade 1 (28%), grade 2 (44%), or grade 3 (21%).
The frequency of acute skin reactions decreased after the first three Kimmtrak infusions. The rate of grade 3 reactions was 17% following dose 1; 10% following dose 2; 8% following dose 3; and 3% following dose 4. The median time to onset of acute skin reactions in patients receiving Kimmtrak was 1 day and median time to improvement to ≤ grade 1 was 6 days. There were no permanent discontinuations of Kimmtrak due to acute skin reactions.

Elevated hepatic enzymes.

In study IMCgp100-202, 95% of patients had liver metastasis at enrolment, and ALT/AST increases to ≥ grade 1 were observed in 65% of patients who received Kimmtrak. No deaths due to ALT/AST elevations were observed and more than 90% of patients were able to continue treatment beyond worst grade ALT/AST elevation. Most patients who experienced ALT/AST elevations (73%) did so within the first 3 infusions of Kimmtrak. Most patients (56%) who experienced grade 3 or 4 ALT/AST elevations had improvement to ≤ grade 1 within 7 days.
Elevations in bilirubin were reported in 27% of patients receiving Kimmtrak. In 58% of these cases, an increase in size of liver metastasis was seen at the tumour assessment that occurred closest to the date of bilirubin elevation (tumour assessments were scheduled 12 weekly).

Immunogenicity.

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralising antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
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 6-9 weeks after tebentafusp treatment. The ability of these binding ADA to neutralise tebentafusp is unknown. Tebentafusp clearance increased in patients with high titer ADAs (see Section 5.2 Pharmacokinetic Properties). Exploratory analyses with limited data were not suggestive of a relationship between the formation of ADA and the frequency or severity of hypersensitivity-related adverse reactions or decreased overall survival.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

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.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: antineoplastic agents; other antineoplastic agents, ATC code: L01XX75.

Mechanism of action.

Tebentafusp is a bispecific fusion protein, comprised of a T cell receptor (TCR) fused to an antibody fragment with specificity for the CD3 (cluster of differentiation 3) receptor, found on polyclonal T cells. The TCR has specificity for a gp100 peptide (expressed preferentially in melanoma cells) presented by human leukocyte antigen-A*02:01 (HLA-A*02:01).
In vitro, tebentafusp bound to HLA-A*02:01-positive uveal melanoma cells and activated polyclonal T cells to release inflammatory cytokines and cytolytic proteins, which results in direct lysis of uveal melanoma tumour cells.

Pharmacodynamic effects.

Lymphocyte counts declined the day after each of the first three tebentafusp doses and returned to baseline prior to subsequent doses.
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) were increased after each of the first three tebentafusp doses, peaking 8 to 24 hours after treatment and returning to baseline prior to subsequent doses. The intensity of cytokine elevation, and the proportion of patients in whom it occurred, decreased in subsequent treatment cycles.
The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of Kimmtrak have not been fully characterised.

Clinical trials.

Study IMCgp100-202 was a randomised, open-label, multicentre trial that enrolled patients with metastatic uveal melanoma who had a HLA-A*02:01 genotype according to a centrally-conducted clinical trial assay. Patients were excluded if they received previous systemic treatment or localised (liver-directed) therapy for metastatic uveal melanoma, however, prior surgical resection of oligometastatic disease was permitted. Patients with clinically significant cardiac disease and symptomatic or untreated brain metastasis were also excluded.
Patients were randomised (2:1) to either receive Kimmtrak by intravenous infusion at a dose of 20 microgram on day 1, 30 microgram on day 8, 68 microgram on day 15, and 68 microgram once every week thereafter (n = 252) or to receive investigator's choice (n = 126) of pembrolizumab, ipilimumab, or dacarbazine. Randomisation was stratified by lactate dehydrogenase (LDH) level at study entry. Across both arms, treatment was ceased on disease progression (unless the patient was otherwise deriving benefit), or for unacceptable toxicity.
The primary efficacy outcome was overall survival (OS). Additional efficacy outcomes were investigator-assessed progression free survival (PFS) and objective response rate (ORR) per RECIST v1.1.
The median age was 64 years (range 23 to 92 years); 87% of patients were White and 50% were female. Baseline ECOG performance status was 0 (73%) or 1 (21%) or 2 (0.3%); 36% had an elevated LDH level, and 94% had liver metastasis.
The efficacy results are summarised in Table 6 and Figure 1.
In the pre-specified subgroup analysis by LDH status, the HR for overall survival was 0.35 (95% CI: 0.21, 0.60) in the LDH ≤ ULN and 0.70 (95% CI: 0.46, 1.09) in the LDH ≥ ULN subgroup. In patients with ≤ 3 cm liver lesion diameter, treatment with tebentafusp showed improved OS compared to the investigator's choice treated group [HR = 0.36 (95% CI: 0.21, 0.61)].

5.2 Pharmacokinetic Properties

Absorption.

After a single dose administration, tebentafusp Cmax and AUC0-7d increased in an approximately dose-proportional manner, over a dose range of 20 microgram to 68 microgram (0.3 to 1 times the recommended dose). Following administration of tebentafusp at the recommended dose in patients with metastatic uveal melanoma, the steady-state geometric mean (% CV) Cmax was 13 nanogram/mL (35%) and AUC0-7d was 4.6 nanogram.day/mL (23%), with no accumulation.

Distribution.

The geometric mean (% CV) steady-state volume of distribution for tebentafusp is 7.56 L (24%).

Metabolism.

As a protein, tebentafusp is expected to be catabolised into small peptides and amino acids.

Excretion.

The geometric mean (% CV) clearance of tebentafusp is 16.4 L/d (25%) and the median terminal half-life is 7.5 hours (range: 6.8-7.5 hours).

Special populations.

Weight (43 to 163 kg), sex (48% female), age (23 to 91 years), mild to moderate renal impairment (creatinine clearance estimated by C-G formula [CLcr] of 30 to 89 mL/min), and mild hepatic impairment (elevated aspartate aminotransferase [AST] with normal total bilirubin [TB], or TB > 1 to 1.5 times the upper limit of normal [ULN] with any AST) had no clinically significant effect on the pharmacokinetics of tebentafusp.
Tebentafusp has not been studied in patients with severe renal impairment (CLcr < 30 mL/min) or in patients with moderate hepatic impairment (TB > 1.5 to 3 x ULN, any AST) or severe hepatic impairment (TB > 3 to 10 x ULN, any AST).

Immunogenicity.

Median titer in the ADA-positive subgroup was 8192 across the 67 treatment cycles. The exposure (AUC0-7 days) of tebentafusp decreased by 97% and terminal half-life decreased to 10-14 minutes in patients with ADA titers greater than 8192.

5.3 Preclinical Safety Data

Genotoxicity.

No genotoxicity studies have been conducted with tebentafusp.

Carcinogenicity.

No carcinogenicity studies have been conducted with tebentafusp.

6 Pharmaceutical Particulars

6.1 List of Excipients

Citric acid monohydrate, dibasic sodium phosphate, mannitol, trehalose dihydrate, polysorbate 20, water for injection.

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in Section 4.2 Dose and Method of Administration.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
For the in-use shelf life and storage conditions after vial opening and after dilution of the medicinal product, see Section 4.2 Dose and Method of Administration.

6.4 Special Precautions for Storage

Store at 2°C to 8°C. (Refrigerate. Do not freeze). Keep the vial in the outer carton in order to protect from light.

6.5 Nature and Contents of Container

Type I glass vial with a bromobutyl rubber stopper and an aluminium/plastic flip-off seal, containing 0.5 mL concentrated solution for infusion.
Pack size of 1 vial.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Tebentafusp is a bispecific gp100-targeted T cell receptor fusion protein with an approximate molecular weight of 77 kDa. Tebentafusp is produced by recombinant DNA technology in Escherichia coli cells.

CAS number.

1874157-95-5.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes