Consumer medicine information

Rozlytrek

Entrectinib

BRAND INFORMATION

Brand name

Rozlytrek

Active ingredient

Entrectinib

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Rozlytrek.

What is in this leaflet

This leaflet answers some common questions about Rozlytrek. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Rozlytrek against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Rozlytrek is used for

Rozlytrek is used to treat adults with a type of lung cancer called non-small cell lung cancer. It is used if your cancer:

  • is 'ROS1-positive' – this means your cancer cells have an alteration in a gene called ROS1 and
  • is advanced or has spread to another part of your body (metastatic)

Rozlytrek is also used to treat children (12 years and older), adolescents and adults with cancer that is ‘NTRK fusion-positive’. This means that your cancer cells have an alteration in one of the NTRK genes. Rozlytrek is used when the cancer is advanced or has spread to another part of your body (metastatic) and other treatments have not worked or are not suitable for you.

Rozlytrek contains the active ingredient entrectinib.

Rozlytrek belongs to a group of medicines called anti-neoplastic (or anti-cancer) agents which are used to treat cancer.

Rozlytrek works by blocking the action of enzymes which have an alteration in them. This is due to the alteration in the NTRK or ROS1 genes that make them. The altered enzymes encourage the cancer cells to grow.

Rozlytrek may slow down or stop the cancer growing. It may also help to shrink your cancer.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

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

Before you take Rozlytrek

When you must not take it

Do not take Rozlytrek if you have an allergy to:

  • any medicine containing entrectinib
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not take this medicine if you are pregnant. It may affect your developing baby if you take it during pregnancy.

Do not breast-feed if you are taking this medicine. It is not known if entrectinib passes into breast milk. There is a possibility that your baby may be affected.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • heart problems such as a conditional called ‘prolonged QT interval’. This is shown on an electrocardiogram (ECG). Or a condition called 'congestive heart failure'.
  • heart failure – an inability for your heart to adequately pump blood to supply oxygen to the body
  • an inherited problem called ‘galactose intolerance’, ‘congenital lactase deficiency’ or ‘glucose-galactose malabsorption’. Rozlytrek contains lactose (a type of sugar). If you have been told by your doctor that you cannot tolerate or digest some sugars, talk to your doctor before taking this medicine.
  • liver or kidney problems

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding. Your doctor can discuss with you the risks and benefits involved.

Rozlytrek may be harmful to an unborn baby when taken by a pregnant woman. You should not take Rozlytrek while you are pregnant.

If you are a woman who could become pregnant, use highly effective contraception (birth control) during treatment, and for at least 5 weeks after taking the last capsule.

If you are the male partner of a woman who could become pregnant, use highly effective contraception during treatment, and for at least 3 months after taking the last capsule.

Talk to your doctor about the right methods of contraception for you and your partner.

Tell your doctor if you are planning to start breast-feeding. It is not recommended that you breastfeed while taking Rozlytrek.

If you have not told your doctor about any of the above, tell him/ her before you start taking Rozlytrek.

Taking other medicines

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

Rozlytrek and other medicines may interfere with each other. These include:

  • nilotinib, topotecan, lapatinib and mitoxantrone used to treat cancer
  • everolimus used to treat cancer or used to prevent the body’s immune system from rejecting a transplanted organ
  • sirolimus used to prevent the body’s immune system from rejecting a transplanted organ
  • St. John’s Wort, a herbal medicine for depression
  • ritonavir and saquinavir used to treat AIDS/HIV
  • ketoconazole, itraconazole, voriconazole and posaconazole used to treat fungal infections
  • phenytoin, carbamazepine and phenobarbital, anti-epileptics used to treat seizures or fits
  • rifampicin and rifabutin used to treat tuberculosis and other infectious diseases

These medicines may be affected by Rozlytrek or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take Rozlytrek

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

How much to take

Your doctor will tell you how many capsules you need to take each day. This may depend on your condition, whether you are taking any other medicines and whether you experience side effects.

For adults, the normal dose of Rozlytrek is three 200 mg capsules taken daily (total dose 600 mg).

For children and adolescents, the dose will be calculated by the doctor based on the patient's weight and height.

How to take it

Swallow the capsules whole with a full glass of water. Do not open or dissolve the capsules.

The capsules can be taken with or without food.

If you vomit immediately after taking a dose of Rozlytrek, take another dose.

When to take it

Take your medicine at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

How long to take it

Continue taking your medicine for as long as your doctor tells you.

Do not stop taking this medicine without talking to your doctor first.

It is important to take Rozlytrek every day for as long as your doctor prescribes it for you.

If you forget to take it

If it is more than 12 hours until your next dose, take the missed dose as soon as you remember.

If it is less than 12 hours until your next dose, do not take the missed dose. Then take your next dose at the usual time.

Do not take a double dose to make up for the dose that you missed.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (Australia - telephone 13 11 26; New Zealand - telephone 0800 764 766 or 0800 POISON) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Rozlytrek. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Keep telephone numbers for these places handy.

If you are not sure what to do, contact your doctor or pharmacist.

While you are taking Rozlytrek

Things you must do

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

Use highly effective contraception to prevent pregnancy while you are being treated with Rozlytrek.

Women must avoid pregnancy during treatment with Rozlytrek and for at least 5 weeks after taking the last capsule. Men must avoid fathering a child during treatment with Rozlytrek and for at least 3 months after taking the last capsule.

If you or your partner become pregnant while taking this medicine, tell your doctor immediately.

Keep all of your doctor's appointments so that your progress can be checked. Your doctor will monitor your progress and check for side effects. If necessary, your doctor may decide to reduce your dose, temporarily interrupt your treatment or stop it altogether.

Things you must not do

Do not take Rozlytrek to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or lower the dosage without checking with your doctor.

Things to be careful of

Be careful driving or operating machinery until you know how Rozlytrek affects you. This medicine may cause confusion, hallucinations, fainting, blurred vision or dizziness in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous. Children should be careful when riding bicycles or climbing trees.

Do not drink grapefruit juice or eat grapefruit during your treatment with Rozlytrek. It may increase the amount of the medicine in your blood to a harmful level.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Rozlytrek.

This medicine helps most people with cancer, but it may have unwanted side effects. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • feeling tired
  • pain including headache or head pain, or joint or muscle pain or pain or discomfort in limbs or bones
  • fever
  • constipation
  • diarrhoea
  • feeling sick (nausea) or being sick (vomiting), or stomach pain
  • difficulty in swallowing
  • changes in taste
  • an abnormal or unpleasant sense of touch
  • numbness or weakness of the arms and legs
  • loss of muscle coordination, being unsteady when walking
  • symptoms of anaemia such as tiredness, headaches, being short of breath when exercising, dizziness and looking pale
  • weight gain
  • loss of appetite
  • dehydration
  • muscle weakness
  • bone fractures
  • lung infection
  • urinary tract infection
  • blurred vision
  • rash
  • swelling or puffiness of the skin
  • disturbances in your sleep pattern

If any of the following happen, tell your doctor immediately:

  • signs of heart problems (heart failure) such as persistent coughing or wheezing, shortness of breath, and swelling in your legs or arms (fluid retention)
  • feeling dizzy or light-headed as this may be a sign of an abnormal heart rhythm or low blood pressure
  • feeling confused, changes in mood, having memory problems or seeing things that are not there (hallucinations)
  • loss of consciousness or fainting
  • symptoms of a condition called tumour lysis syndrome, including nausea or vomiting, muscle cramps or twitches, decreased urination, irritability, sudden uncontrolled fits (seizures).

Your doctor may lower your dose, stop your treatment for a short time or stop your treatment completely.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

Some of these side effects can only be found when your doctor does tests from time to time to check your progress (for example, decreased while blood cell count, increase in blood creatinine, increase in blood liver enzymes, increase uric acid in blood).

After using Rozlytrek

Storage

Keep the capsules in the bottle until it is time to take them. If you take the capsules out of the bottle they may not keep well.

Keep the bottle tightly closed to protect from moisture. Store in a cool dry place where the temperature stays below 30°C.

Do not store Rozlytrek or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

Rozlytrek 100 mg capsules are yellow with “ENT 100” imprinted in blue on the side. Rozlytrek 100 mg capsules are supplied in bottles of 30 capsules.

Rozlytrek 200 mg capsules are orange with “ENT 200” imprinted in blue on the side. Rozlytrek 200 mg capsules are supplied in bottles of 90 capsules.

Ingredients

Rozlytrek capsules contain 100 mg or 200 mg of entrectinib as the active ingredient.

The capsules also contain:

  • lactose
  • microcrystalline cellulose
  • tartaric acid
  • hypromellose
  • crospovidone
  • magnesium stearate
  • silicon dioxide

The capsule shell contains:

  • hypromellose
  • titanium dioxide
  • iron oxide yellow (100 mg capsule only)
  • sunset yellow FCF (200 mg capsule only)

The printing ink contains:

  • shellac
  • propylene glycol
  • strong ammonia solution
  • indigo carmine aluminium lake

This medicine does not contain sucrose or gluten.

Manufacturer

Rozlytrek is distributed in Australia by:

Roche Products Pty Limited
ABN 70 000 132 865
Level 8, 30 - 34 Hickson Road
Sydney NSW 2000
AUSTRALIA

Medical enquiries: 1800 233 950

Please check with your pharmacist for the latest Consumer Medicine Information.

Australian Registration Numbers:

100 mg AUST R 318003

200 mg AUST R 318002

Rozlytrek is distributed in New Zealand by:

Roche Products (NZ) Limited
PO Box 109113 Newmarket
Auckland 1149
NEW ZEALAND

Medical enquiries: 0800 276 243

This leaflet was prepared on 11 February 2022

Published by MIMS April 2022

BRAND INFORMATION

Brand name

Rozlytrek

Active ingredient

Entrectinib

Schedule

S4

 

1 Name of Medicine

Entrectinib.

2 Qualitative and Quantitative Composition

Each 100 mg hard capsule contains 100 mg entrectinib.
Each 200 mg hard capsule contains 200 mg entrectinib.
Entrectinib has the molecular formula C31H34F2N6O2. The molecular weight is 560.6. The chemical name is N-{5-[(3,5-difluorophenyl) methyl]-1H-indazol-3-yl}-4-(4-methylpiperazin-1-yl)-2-[(oxan-4-yl)amino]benzamide. The solubility in aqueous media decreases over the range pH 1.2 to pH 8.0.

Excipients with known effect.

Each 100 mg hard capsule contains 65 mg lactose. Each 200 mg hard capsule contains 130 mg lactose. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Hard capsule.
Rozlytrek 100 mg are size 2 hard capsules with yellow body and cap with "ENT 100" imprinted in blue on the body.
Rozlytrek 200 mg are size 0 hard capsules with orange body and cap with "ENT 200" imprinted in blue on the body.

4 Clinical Particulars

4.1 Therapeutic Indications

Non-small cell lung cancer (NSCLC).

Rozlytrek is indicated for the treatment of adult patients with advanced non-small cell lung cancer (NSCLC) whose tumours are ROS1-positive.

Solid tumours.

Rozlytrek is indicated for the treatment of adult and paediatric patients 12 years of age and older with solid tumours that:
have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation;
are metastatic or where surgical resection is likely to result in severe morbidity; and
have either progressed following treatment or have no satisfactory alternative therapy.
This indication was approved via the provisional approval pathway, based on objective response rate and duration of response in single-arm trials. Full registration for this indication depends on verification and description of clinical benefit in confirmatory trials.

4.2 Dose and Method of Administration

General.

Method of administration. Rozlytrek can be taken with or without food. Capsules should be swallowed whole. Capsules must not be opened or dissolved.
Patient selection.

Solid tumours.

A validated assay is required for the selection of patients with NTRK fusion-positive locally advanced or metastatic solid tumours. NTRK fusion-positive status should be established prior to initiation of Rozlytrek therapy.

NSCLC.

A validated assay is required for the selection of patients with ROS1-positive locally advanced or metastatic NSCLC. ROS1-positive status should be established prior to initiation of Rozlytrek therapy.

Dosage.

Adults. The recommended dose of Rozlytrek for adults is 600 mg given orally, once daily (see Section 5.2 Pharmacokinetic Properties).
Paediatric patients. The recommended dose of Rozlytrek for paediatric patients is based on body surface area (BSA) as shown in Table 1 (see Section 5.2 Pharmacokinetic Properties).
Duration of treatment. It is recommended that patients are treated with Rozlytrek until disease progression or unacceptable toxicity.
Delayed or missed doses. If a planned dose of Rozlytrek is missed, patients can make up that dose unless the next dose is due within 12 hours. If vomiting occurs immediately after taking a dose of Rozlytrek, patients may repeat that dose.
Dose modifications for adverse reactions. Management of adverse reactions may require temporary interruption, dose reduction, or discontinuation of treatment with Rozlytrek.
Recommended dose reductions are provided in Table 2. The dose of Rozlytrek may be reduced up to 2 times, after which Rozlytrek treatment should be permanently discontinued if patients are unable to tolerate the lowest reduced dose.
Recommended dose modifications for specific adverse reactions are provided in Table 3. See Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects).
Dose modifications for specific medicine interactions.

Strong or moderate CYP3A inhibitors.

Avoid concomitant use of strong or moderate CYP3A inhibitors with Rozlytrek (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
For adults and for paediatric patients 12 years and older who have a BSA greater than 1.50 m2, if the concomitant use of strong or moderate CYP3A inhibitors with Rozlytrek cannot be avoided, the Rozlytrek dose should be reduced to:
100 mg once daily if it is a strong CYP3A inhibitor; and
200 mg once daily if it is a moderate CYP3A inhibitor.
After discontinuation of a strong or moderate CYP3A inhibitor, and after an appropriate wash-out period (3 to 5 times the elimination half-life of the CYP3A inhibitor), the Rozlytrek dose that was taken prior to initiating the CYP3A inhibitor can be resumed.
For paediatric patients 12 years and older who have a BSA less than or equal to 1.50 m2, the concomitant use of strong or moderate CYP3A inhibitors with Rozlytrek should be avoided altogether.
Avoid grapefruit products during treatment with Rozlytrek, as they contain inhibitors of CYP3A.

Strong or moderate CYP3A inducers.

Avoid concomitant use of Rozlytrek with strong or moderate CYP3A inducers in adult and paediatric patients (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Drugs that prolong the QT interval.

Avoid co-administration of Rozlytrek with other products known to prolong the QT/QTc interval (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Dosing in special populations.

Paediatric populations.

Dosage for patients is based on body surface area (mg/m2) (see Table 1 for paediatric dosing).

Renal impairment.

No dose adjustment is required in patients with mild or moderate renal impairment (CLcr 30 to < 90 mL/min calculated by Cockcroft-Gault equation). Rozlytrek has not been studied in patients with severe renal impairment (CLcr < 30 mL/min). However, since entrectinib elimination via the kidney is negligible, no dose adjustment is required in patients with severe renal impairment (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

Hepatic impairment.

No dose adjustment is required in patients with underlying mild (Child-Pugh A), moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment, based on a study in subjects with hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties). Patients with severe hepatic impairment should be carefully monitored for hepatic function and adverse reactions.

4.3 Contraindications

Rozlytrek is contraindicated in patients with a known hypersensitivity to entrectinib or any of the excipients.

4.4 Special Warnings and Precautions for Use

Congestive heart failure.

Congestive heart failure (CHF) has been reported across clinical trials with Rozlytrek (see Section 4.8 Adverse Effects (Undesirable Effects)). These reactions were observed in patients with or without a history of cardiac disease and resolved upon treatment with diuretics and/or dose reduction/interruption of Rozlytrek. Assess left ventricular ejection fraction (LVEF) prior to initiation of Rozlytrek in patients with symptoms or known risk factors for CHF. Monitor patients for clinical signs and symptoms of CHF, including shortness of breath and oedema. For patients with myocarditis, with or without a decreased ejection fraction, MRI or cardiac biopsy may be required to make the diagnosis. For patients with new onset or worsening CHF, withhold Rozlytrek, institute appropriate medical management, and reassess LVEF. Based on the severity of CHF, modify Rozlytrek treatment as described in Table 3 (see Section 4.2 Dose and Method of Administration).

Central nervous system effects.

A broad spectrum of central nervous system (CNS) adverse reactions were reported in clinical trials with Rozlytrek, including cognitive impairment, mood disorders, dizziness and sleep disturbances (see Section 4.8 Adverse Effects (Undesirable Effects)). Monitor for signs of CNS adverse reactions, and advise patients and caregivers of these risks with Rozlytrek. Advise patients not to drive or operate hazardous machinery if they are experiencing CNS adverse reactions (see Section 4.7 Effects on Ability to Drive and Use Machines). Based on the severity of the CNS effects, modify Rozlytrek treatment as described in Table 3 (see Section 4.2 Dose and Method of Administration).

Skeletal fractures.

Rozlytrek increases the risk of fractures (see Section 4.8 Adverse Effects (Undesirable Effects), Description of selected adverse drug reactions). Promptly evaluate patients with signs or symptoms (e.g. pain, changes in mobility, deformity) of fractures. In both adult and paediatric patients, some fractures occurred in the setting of a fall or other trauma to the affected area; in paediatric patients, some fractures occurred with no trauma. There are no data on the effects of Rozlytrek on healing of known fractures and risk of future fractures. In the majority of paediatric patients treatment was continued with Rozlytrek and the fracture healed (see Section 4.8 Adverse Effects (Undesirable Effects)).

Hepatotoxicity.

Hepatic transaminase elevation was frequently reported in entrectinib clinical trials (see Section 4.8 Adverse Effects (Undesirable Effects)), and hepatotoxicity is a known effect of other ROS1 inhibitors. Monitor liver function tests, including ALT and AST, every 2 weeks during the first month of treatment, then monthly thereafter, and as clinically indicated. Based on the severity of hepatic enzyme elevation, modify Rozlytrek treatment as described in Table 3 (see Section 4.2 Dose and Method of Administration).

Hyperuricaemia.

Hyperuricaemia was frequently reported in entrectinib clinical trials (see Section 4.8 Adverse Effects (Undesirable Effects)), and 34% of cases required medical intervention to reduce serum urate. Assess serum urate prior to initiating Rozlytrek and periodically during treatment. Monitor patients for signs and symptoms of hyperuricaemia. Initiate treatment with urate-lowering medications as clinically indicated and withhold Rozlytrek for signs and symptoms of hyperuricaemia, as described in Table 3 (see Section 4.2 Dose and Method of Administration).

QTc interval prolongation.

QT interval prolongation was observed in patients treated with Rozlytrek in clinical trials (see Section 4.8 Adverse Effects (Undesirable Effects)). Monitor patients who have QTc interval prolongation or are at significant risk of developing it, including patients with congenital long QT syndrome, clinically significant bradyarrhythmias, severe or poorly controlled heart failure and patients taking medications that are associated with QT interval prolongation. Assess QT interval and electrolytes at baseline and periodically during treatment, adjusting frequency based upon risk factors such as congestive heart failure, electrolyte abnormalities, or concomitant medications. Based on the severity of any QT interval prolongation observed, modify Rozlytrek treatment as described in Table 3 (see Section 4.2 Dose and Method of Administration).

Vision disorders.

Vision changes were reported in 21% of patients treated with Rozlytrek in clinical trials (see Section 4.8 Adverse Effects (Undesirable Effects)). For patients with new visual changes or changes that interfere with activities of daily living, modify Rozlytrek treatment as described in Table 3 (see Section 4.2 Dose and Method of Administration).

Paediatric use.

There is limited clinical experience with Rozlytrek in paediatric patients. Rozlytrek had effects on growth and development in juvenile rats (see Section 5.3 Preclinical Safety Data).
The effectiveness of Rozlytrek in paediatric patients (12 years of age and older) was established based on extrapolation of data from three open-label, single-arm clinical trials in adult patients with solid tumours harboring an NTRK gene fusion (ALKA, STARTRK-1, and STARTRK-2) and pharmacokinetic data in paediatric patients enrolled in STARTRK-NG. Rozlytrek doses based on body surface area in paediatric patients 12 years and older resulted in similar systemic exposure compared to that in adults who received a Rozlytrek dose of 600 mg (see Section 4.2 Dose and Method of Administration; Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special populations).
The safety of Rozlytrek was evaluated in paediatric patients with unresectable or metastatic solid tumours with a NTRK gene fusion enrolled in one of three multi-centre, open-label clinical trials: STARTRK-NG (n=68); TAPISTRY (n=21) and STARTRK-2 (n=2). Patients received Rozlytrek 20 mg to 600 mg based on body surface area (BSA) orally or via enteral feeding tube once daily in 4-week cycles until unacceptable toxicity or disease progression. Among patients who received Rozlytrek, 62.6% were exposed for 6 months or longer and 48.4% were exposed for greater than one year.
The median age of paediatric patients who received Rozlytrek was 6 years (range: 0 to 17 years); 49.5% were female; 62.6% were White, 26.4% Asian, 5.5% Black or African American, and 5.5% were other races.
The overall safety profile was generally similar with that observed for adults. Rozlytrek was associated with a higher incidence of skeletal fractures in the paediatric patients compared to adult patients (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects), Description of selected adverse drug reactions).
The safety and effectiveness of Rozlytrek in paediatric patients with ROS1-positive NSCLC have not been established.

Use in hepatic impairment.

The pharmacokinetics of entrectinib were studied in subjects with hepatic impairment due to cirrhosis and subjects with normal hepatic function. Following administration of a single oral dose of 100 mg entrectinib, the AUCinf geometric mean ratio (90% CI) of entrectinib were 1.57 (1.03, 2.41) for the mild (Child-Pugh A), 1.54 (1.06, 2.24) for the moderate (Child-Pugh B), and 1.80 (1.22, 2.66) for the severe (Child-Pugh C) hepatic impaired groups compared to the normal hepatic function group. The combined AUClast of entrectinib and M5 showed no relevant change in the hepatic impaired groups compared to the normal hepatic function group. The AUClast geometric mean ratio (90% CI) were 1.30 (0.889, 1.89) for the mild, 1.24 (0.886, 1.73) for the moderate, and 1.39 (0.988, 1.95) for the severe hepatic impaired groups compared to the normal hepatic function group. For the unbound entrectinib and M5, the AUClast (fu) geometric mean ratio (90% CI) were 1.91 (1.21, 3.02) for the mild, 1.57 (1.06, 2.31) for the moderate, and 2.34 (1.57, 3.48) for the severe hepatic impaired groups compared to the normal hepatic function group. Although the effect of hepatic impairment on unbound PK parameters generally followed a similar direction as total PK parameters, due to the high non-specific binding in buffer and high variability, results should be interpreted with caution. In addition to the modest increases in entrectinib exposure observed, the variability in systemic exposure was high and observed exposures overlapped across all the study groups (also see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Use in renal impairment.

Rozlytrek has not been studied in patients with severe (CLcr < 30 mL/min) renal impairment (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Use in the elderly.

Of the 355 patients who received Rozlytrek across clinical trials, 25% were 65 years or older, and 5% were 75 years of age or older. Clinical studies of Rozlytrek did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients.

Effects on laboratory tests.

See Section 4.8 Adverse Effects (Undesirable Effects), Laboratory abnormalities.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effects of entrectinib on other drugs.

CYP substrates.

Co-administration of a single 600 mg Rozlytrek dose with oral midazolam (a sensitive CYP3A substrate) in patients increased the midazolam AUC by 50% but reduced midazolam Cmax by 21%. See Section 4.2 Dose and Method of Administration, Dose modifications for specific medicine interactions.

Transporter substrates.

Co-administration of a single 600 mg Rozlytrek dose with oral digoxin (a sensitive P-glycoprotein (P-gp) substrate) in patients increased digoxin Cmax by 28% and AUC by 18%.
In vitro data indicates:
Entrectinib is not a substrate of P-gp or BCRP, but M5 is a substrate of both.
Entrectinib and M5 are not substrates of OATP1B1 or OATP1B3.

Oral contraceptives.

Physiologically-based pharmacokinetic simulation does not predict a significant effect of entrectinib on the pharmacokinetics of ethinyl oestradiol.

Effects of other drugs on entrectinib.

CYP3A inducers.

Co-administration of a single oral 600 mg dose of entrectinib with rifampicin (a strong CYP3A inducer) reduced entrectinib AUCinf by 77% and Cmax by 56%. Co-administration of a moderate CYP3A inducer with Rozlytrek is predicted to reduce AUC0-tau by 56% and Cmax by 43%. See Section 4.2 Dose and Method of Administration, Dose modifications for specific medicine interactions.

CYP3A inhibitors.

Co-administration of a single oral 100 mg dose of entrectinib with itraconazole (a strong CYP3A4 inhibitor) increased entrectinib AUCinf by 504% (6-fold) and Cmax by 73%. Coadministration of a moderate CYP3A inhibitor with Rozlytrek is predicted to increase entrectinib AUC0-tau by 3-fold and Cmax by 2.9-fold. See Section 4.2 Dose and Method of Administration, Dose modifications for specific medicine interactions.

Medicinal products that increase gastric pH.

Co-administration of a single oral 600 mg dose of entrectinib with lansoprazole (a proton pump inhibitor [PPI]) decreased entrectinib AUCinf by 25% and Cmax by 23%.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Dedicated toxicological fertility studies of entrectinib have not been performed. In general toxicology studies, with the exception of dose-dependent decreases in prostate weight in male dogs, no effects of entrectinib on reproductive organs were observed in rats or dogs at doses resulting in exposures up to approximately 3.2 times the human exposure (AUC) at the recommended human dose (600 mg).
(Category D)
There are no available data on the use of Rozlytrek in pregnant women, but based on its mechanism of action, findings in animal studies (see below), and published clinical case reports of inherited NTRK pathway deficiencies (see below), Rozlytrek can cause embryo-fetal harm when administered to a pregnant woman. Advise all patients, including pregnant women, of the potential harm to a fetus.

Human data.

Published reports of individuals with congenital mutations in TRK pathway proteins suggest that decreases in TRK-mediated signalling are correlated with obesity, developmental delays, cognitive impairment, insensitivity to pain, and anhidrosis.

Animal data.

Administration of entrectinib to pregnant rats during the period of organogenesis at a dose of 200 mg/kg (resulting in exposures up to 2.7 times the human exposure (AUC) at the 600 mg dose) resulted in maternal toxicity (decreased body weight gain and food consumption) and resulted in fetal malformations including body closure defects (omphalocele and gastroschisis) and malformations of the vertebrae, ribs and limbs (micromelia and adactyly), but did not result in embryolethality. Lower fetal weights and reduced skeletal ossification occurred at doses ≥ 12.5 and 50 mg/kg, respectively (resulting in exposures equivalent to 0.2 and 0.9 times the human exposure (AUC) at the 600 mg dose, respectively).

Contraception in male and female patients.

Rozlytrek can cause embryo-fetal harm when administered to a pregnant woman. Advise all patients of the potential harm to a fetus. Test for pregnancy in females of reproductive potential prior to initiating Rozlytrek. Advise female patients of reproductive potential to use highly effective contraceptive methods during treatment with Rozlytrek and for at least 5 weeks following the last dose.
Advise male patients with female partners of reproductive potential to use highly effective contraceptive methods during treatment with Rozlytrek and for 3 months following the last dose.
 There are no data on the presence of entrectinib or its metabolites in human milk or their effects on either the breastfed child or on milk production. Because of the potential for harm to the breastfed child, advise a lactating woman to discontinue breastfeeding during treatment with Rozlytrek and for 7 days after the last dose.

4.7 Effects on Ability to Drive and Use Machines

Rozlytrek may influence the ability to drive and use machines. Advise patients not to drive or operate hazardous machinery if they are experiencing CNS adverse reactions (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

The safety profile of Rozlytrek was characterised in a group of 355 patients, including 172 (48%) patients exposed for 6 months or longer and 84 (24%) patients exposed for 1 year or longer. Rozlytrek was studied in one dose-finding trial in adults [ALKA (n = 57)], one dose-finding and activity-estimating trial in adults [STARTRK-1 (n = 76)], one dose-finding and activity-estimating trial in paediatric and adult patients [STARTRK-NG (n = 16)], and one single arm, activity-estimating trial in adults [STARTRK-2 (n = 206)].
The population characteristics were: median age 55 years (range: 4 to 86 years); 5% (n = 17) were less than 18 years of age; 55% were female; and 66% were White, 23% were Asian, and 5% were Black; 3% were Hispanic/Latino. The most common tumours (≥ 5%) were lung (56%), sarcoma (8%), and colon (5%). ROS1 gene fusions were present in 42% and NTRK gene fusions were present in 20%. Most adults (75%) received Rozlytrek 600 mg orally once daily. The doses ranged from 100 mg/m2 to 1600 mg/m2 once daily in adults and 250 mg/m2 to 750 mg/m2 once daily in paediatric patients. Rozlytrek is not indicated for paediatric patients less than 12 years of age (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use).
Serious adverse reactions occurred in 39% of patients. The most frequent serious adverse reactions (≥ 2%) were pneumonia (3.9%), dyspnoea (3.7%), pleural effusion (3.4%), sepsis (2.5%), pulmonary embolism (2.3%), respiratory failure (2%), and pyrexia (2%).
Grade 3 or 4 adverse reactions occurred in 60% of patients; the most common (≥ 2%) were lung infection (5%), increased weight (7%), dyspnoea (6%), fatigue/asthenia (5%), cognitive disorders (4.5%), syncope (2.5%), pulmonary embolism (3.4%), hypoxia (3.4%), pleural effusion (3.1%), hypotension (2.8%), diarrhoea (2%), and urinary tract infection (2.5%).
Fatal events included dyspnoea (0.6%), pneumonia (0.6%), sepsis (0.6%), completed suicide (0.3%), large intestine perforation (0.3%) and tumour lysis syndrome (0.3%). One patient developed Grade 4 myocarditis after one dose of Rozlytrek which resolved after discontinuation of Rozlytrek and administration of high-dose corticosteroids.
Permanent discontinuation due to an adverse reaction occurred in 9% of patients who received Rozlytrek. The most frequent adverse reactions (< 1% each) that resulted in permanent discontinuation were pneumonia, cardio-respiratory arrest, dyspnoea, and fatigue.
Dose interruptions due to adverse reactions occurred in 46% of patients. The most frequent adverse reactions (≥ 2%) that resulted in interruption were increased blood creatinine (4%), fatigue (3.7%), anaemia (3.1%), diarrhoea (2.8%), pyrexia (2.8%), dizziness (2.5%), dyspnoea (2.3%), nausea (2.3%), pneumonia (2.3%), cognitive disorder (2%) and neutropenia (2%).
Dose reductions due to adverse reactions occurred in 29% of patients who received Rozlytrek. The most frequent adverse reactions resulting in dose reductions (≥ 1%) were dizziness (3.9%), increased blood creatinine (3.1%), fatigue (2.3%), anaemia (1.7%), and increased weight (1.4%).
The most common adverse reactions (≥ 20%) were fatigue, constipation, dysgeusia, oedema, dizziness, diarrhoea, nausea, dysaesthesia, dyspnoea, myalgia, cognitive impairment, increased weight, cough, vomiting, pyrexia, arthralgia and vision disorders.

Tabulated summary of adverse drug reactions from clinical trials.

Table 4 summarises the most common adverse drug reactions (ADRs) occurring in adult and paediatric patients treated with Rozlytrek.
Clinically relevant adverse reactions that occurred in ≤ 10% of patients include dysphagia (10%), fall (8%), pleural effusion (8%), fractures (6%), hypoxia (4.2%), pulmonary embolism (3.9%), syncope (3.9%), congestive heart failure (3.4%), and QT prolongation (3.1%).

Description of selected adverse drug reactions.

Congestive heart failure (CHF).

Among the 355 patients who received Rozlytrek across clinical trials, congestive heart failure (CHF) occurred in 3.4% of patients, including Grade 3 (2.3%). In clinical trials, cardiac monitoring was conducted using electrocardiograms (ECGs) and echocardiograms or multigated acquisition (MUGA) scans at baseline and at specified time points during treatment with Rozlytrek. Study eligibility criteria excluded patients with symptomatic CHF, myocardial infarction, unstable angina, or coronary artery bypass graft within 3 months of study entry. Among the 12 patients with CHF, the median time to onset was 2 months (range: 11 days to 12 months). Rozlytrek was interrupted in 6 of these patients (50%) and discontinued in 2 of these patients (17%). CHF resolved in 6 patients (50%) following interruption or discontinuation of Rozlytrek and institution of appropriate medical management. In addition, myocarditis in the absence of CHF was documented in 0.3% of patients. Also see Section 4.4 Special Warnings and Precautions for Use.

Central nervous system effects.

Among the 355 patients who received Rozlytrek across clinical trials, 96 (27%) experienced cognitive impairment; symptoms occurred within 3 months of starting Rozlytrek in 74 (77%). Cognitive impairment included cognitive disorders (8%), confusional state (7%), disturbance in attention (4.8%), memory impairment (3.7%), amnesia (2.5%), aphasia (2.3%), mental status changes (2%), hallucinations (1.1%), and delirium (0.8%). Grade 3 cognitive adverse reactions occurred in 4.5% of patients. Among the 96 patients with cognitive impairment, 13% required a dose reduction, 18% required dose interruption and 1% discontinued Rozlytrek due to cognitive adverse reactions.
Among the 355 patients who received Rozlytrek across clinical trials, 36 (10%) experienced mood disorders. The median time to onset of mood disorders was 1 month (range: 1 day to 9 months). Mood disorders occurring in ≥ 1% of patients included anxiety (4.8%), depression (2.8%) and agitation (2%). Grade 3 mood disorders occurred in 0.6% of patients. One completed suicide was reported 11 days after treatment had ended. Among the 36 patients who experienced mood disorders, 6% required a dose reduction, 6% required dose interruption and no patients discontinued Rozlytrek due to mood disorders.
Dizziness occurred in 136 (38%) of the 355 patients. Among the 136 patients who experienced dizziness, Grade 3 dizziness occurred in 2.2% of patients. Ten percent of patients required a dose reduction, 7% required dose interruption and 0.7% discontinued Rozlytrek due to dizziness.
Among the 355 patients who received Rozlytrek across clinical trials, 51 (14%) experienced sleep disturbances. Sleep disturbances included insomnia (7%), somnolence (7%), hypersomnia (1.1%), and sleep disorder (0.3%). Grade 3 sleep disturbances occurred in 0.6% of patients. Among the 51 patients who experienced sleep disturbances, 6% required a dose reduction and no patients discontinued Rozlytrek due to sleep disturbances.
The incidence of CNS adverse reactions was similar in patients with and without CNS metastases; however, the incidence of dizziness (38% vs 31%), headache (21% vs 13%), paraesthesia (20% vs 6%), balance disorder (13% vs 4%), and confusional state (11% vs 2%) appeared to be increased in patients with CNS metastases who had received prior CNS irradiation (N = 90) compared to those who did not (N = 48). Patients who had brain metastases at baseline had a higher frequency of these events (39%) compared to those without brain metastases (25%).
Also see Section 4.4 Special Warnings and Precautions for Use.

Skeletal fractures.

In an expanded safety population that included 762 adult patients and 91 paediatric patients who received Rozlytrek across clinical trials, 9.1% of adult patients and 29.7% of paediatric patients experienced fractures. In adult and paediatric patients, some fractures occurred in the setting of a fall or other trauma to the affected area; in paediatric patients some fractures occurred with no trauma. In general, there was inadequate assessment for tumour involvement at the site of fracture; however, radiologic abnormalities possibly indicative of tumour involvement were reported in some adult patients. In both adult and paediatric patients, most fractures were hip or other lower extremity fractures (e.g. femoral or tibial shaft). In two paediatric patients, bilateral femoral neck fractures occurred. A total of 52 fracture events were reported in 27 paediatric patients, with 14 patients who experienced more than one occurrence of fracture. Among the 27 paediatric patients who experienced fractures, 24 patients were less than 12 years of age. Fractures resolved in 85.2% (23/27) of paediatric patients. The median time to fracture was 8.11 months (range 0.26 to 45.3 months) in adults and 4.3 months (range: 2.0 months to 28.7 months) in paediatric patients. Rozlytrek was interrupted in 26.1% of adults and 18.5% of paediatric patients who experienced fractures. Six paediatric patients discontinued treatment and one patient reduced the dose of Rozlytrek due to fractures. Twelve paediatric patients experienced Grade 2 fractures and 10 patients experienced Grade 3 fractures. Two adult patients discontinued treatment and 2 patients reduced the dose due to fractures. Thirty-six adult patients experienced Grade 2 fractures and nineteen adult patients experienced Grade 3 fractures. Also see Section 4.4 Special Warnings and Precautions for Use.

Hepatotoxicity.

Among the 355 patients who received Rozlytrek, increased AST of any grade occurred in 42% of patients and increased ALT of any grade occurred in 36%. Grade 3 - 4 increased AST or ALT occurred in 2.5% and 2.8% of patients, respectively; the incidence may be underestimated as 4.5% of patients had no post-treatment liver function tests (see Table 6). The median time to onset of increased AST was 2 weeks (range: 1 day to 29.5 months). The median time to onset of increased ALT was 2 weeks (range: 1 day to 9.2 months). Increased AST or ALT leading to dose interruptions or reductions occurred in 0.8% and 0.8% of patients, respectively. Rozlytrek was discontinued due to increased AST or ALT in 0.8% patients. Also see Section 4.4 Special Warnings and Precautions for Use.

Hyperuricaemia.

Among 355 patients who received Rozlytrek across clinical trials, 32 patients (9%) experienced hyperuricaemia reported as adverse reactions with symptoms, as well as elevated uric acid levels. Grade 4 hyperuricaemia occurred in 1.7% of patients, including one patient who died due to tumour lysis syndrome. Among the 32 patients with hyperuricaemic adverse reactions, 34% required urate-lowering medication to reduce uric acid levels, 6% required dose reduction and 6% required dose interruption. Hyperuricaemia resolved in 73% of patients following initiation of urate-lowering medication without interruption or dose reduction of Rozlytrek. No patients discontinued Rozlytrek due to hyperuricaemia. Also see Section 4.4 Special Warnings and Precautions for Use.

QT interval prolongation.

Among the 355 patients who received Rozlytrek across the clinical trials, 3.1% of patients with at least one post-baseline ECG assessment experienced QTcF interval prolongation of > 60 millisec after starting Rozlytrek and 0.6% had a QTcF interval > 500 millisec (see Section 4.4 Special Warnings and Precautions for Use; Section 5.1 Pharmacodynamic Properties).

Vision disorders.

Among the 355 patients who received Rozlytrek across clinical trials, vision changes occurred in 21% of patients, including Grade 1 (82%), Grade 2 (14%) and Grade 3 (0.8%). Vision disorders occurring in ≥ 1% included blurred vision (8.7%), photophobia (5.1%), diplopia (3.1%), visual impairment (2%), photopsia (1.3%), cataract (1.1%), and vitreous floaters (1.1%). Also see Section 4.4 Special Warnings and Precautions for Use.

Weight gain.

Increased weight was reported by around a quarter of adult patients, 7% at grade 3 severity (an increase of more than 20% from baseline). Fluid retention or oedema was co-reported for a number of cases and may have contributed to weight gain. Among 30 paediatric patients treated with entrectinib for various NTRK-positive cancers, six (20%) reported grade 3 weight increase.

Safety in paediatric patients.

Serious adverse reactions occurred in 49.5% of paediatric patients who received Rozlytrek. Serious adverse reactions in > 2% of patients included skeletal fractures (13.2%), pyrexia (7.7%), pneumonia (5.5%), hydrocephalus (5.5%), device related infection (3.3%), hypoxia (3.3%), gait disturbance (2.2%), pain (2.2%), upper respiratory infection (2.2%), dyspnoea (2.2%), headache (2.2%), fall (2.2%), vomiting (2.2%), sepsis (2%) and infection (2%).
Permanent discontinuation of Rozlytrek due to an adverse reaction occurred in 12.1% of paediatric patients. Adverse reactions which resulted in permanent discontinuation of Rozlytrek in > 2% of patients included skeletal fracture. Dosage interruptions of Rozlytrek due to an adverse reaction occurred in 41.8% of patients. Adverse reactions which required dosage interruption in > 2% of patients included pneumonia, COVID-19 and urinary tract infection.
Dose reductions of Rozlytrek due to an adverse reaction occurred in 26.4% of patients. Adverse reactions which required dose reductions in > 2% of patients included increased weight and increased blood creatinine.
Table 5 summarises the adverse reactions in STARTRK-NG (n=68), TAPISTRY (n=21) and STARTRK-2 (n=2).
Clinically relevant adverse reactions in < 20% of paediatric patients who received Rozlytrek included pruritus, urinary incontinence, eye pain, photophobia, abdominal pain, urinary tract infection and nasal congestion.

Laboratory abnormalities.

Table 6 summarises the laboratory abnormalities that most commonly worsened from baseline in adult and paediatric patients treated with Rozlytrek.
Table 7 summarises the laboratory abnormalities in STARTRK-NG (n=68), TAPISTRY (n=6) and STARTRK-2 (n=2) in paediatric patients treated with Rozlytrek.
Other clinically relevant laboratory abnormalities in patients who received Rozlytrek included decreased phosphorous.

Reporting of suspected adverse reactions.

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 experience with overdose in clinical trials with Rozlytrek. Patients who experience overdose should be closely supervised and supportive care instituted. There are no known antidotes for Rozlytrek.
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 agent, tyrosine kinase inhibitor, ATC code: L01EX14.

Mechanism of action.

Entrectinib is an inhibitor of the tropomyosin receptor tyrosine kinases (TRK) TRKA, TRKB and TRKC (encoded by the neurotrophic tyrosine receptor kinase [NTRK] genes NTRK1, NTRK2 and NTRK3, respectively), proto-oncogene tyrosine-protein kinase ROS1 (ROS1; encoded by the gene ROS1), and anaplastic lymphoma kinase (ALK; encoded by the gene ALK) with IC50 values of 0.1 to 2 nanoM. Entrectinib also inhibits JAK2 and TNK2 with IC50 values > 5 nanoM. The major active metabolite of entrectinib, M5, showed similar in vitro activity against TRK, ROS1 and ALK.
Fusion proteins that include TRK, ROS1 or ALK kinase domains can drive tumourigenic potential through hyperactivation of downstream signalling pathways leading to unconstrained cell proliferation. Entrectinib inhibits the TRK kinases, ROS1 and ALK, leading to inhibition of downstream signalling pathways, cell proliferation and induction of tumour cell apoptosis. Entrectinib demonstrated in vitro and in vivo inhibition of cancer cell lines derived from multiple tumour types harbouring NTRK, ROS1 and ALK fusion genes.
Entrectinib demonstrated steady-state brain-to-plasma concentration ratios of 0.4 - 2.2 in multiple animal species (mice, rats and dogs) and demonstrated in vivo anti-tumour activity in mice with intracranial implantation of TRKA- and ALK-driven tumour cell lines.

Cardiac electrophysiology.

Across clinical trials, 355 patients who received Rozlytrek (at doses ranging from 100 mg to 2600 mg daily under fasting or fed conditions; 75% received 600 mg orally once daily) had at least one post-baseline ECG assessment. Amongst this group, 3.1% experienced QTcF prolongation of more than 60 millisec past their baseline after starting Rozlytrek, and 0.6% had a post-baseline QTc interval longer than 500 millisec (see Section 4.4 Special Warnings and Precautions for Use).

Clinical trials.

ROS1-positive NSCLC. The efficacy of Rozlytrek was evaluated in a pooled subgroup of patients with ROS1-positive metastatic NSCLC who received Rozlytrek at various doses and schedules (90% received Rozlytrek 600 mg orally once daily) and were enrolled in one of three multicentre, single-arm, open-label clinical trials: ALKA, STARTRK-1 and STARTRK-2. To be included in this pooled subgroup, patients were required to have histologically confirmed, recurrent or metastatic, ROS1-positive NSCLC, ECOG performance status ≤ 2, measurable disease per RECIST v1.1, ≥ 18 months of follow-up from first post-treatment tumour assessment, and no prior therapy with a ROS1 inhibitor. Identification of ROS1 gene fusion in tumour specimens was prospectively determined in local laboratories using either a fluorescence in situ hybridization (FISH), next-generation sequencing (NGS), or polymerase chain reaction (PCR) laboratory-developed tests. All patients were assessed for CNS lesions at baseline. The primary efficacy outcome measures were overall response rate (ORR) and duration of response (DOR) according to RECIST v1.1 as assessed by blinded independent central review (BICR). Intracranial response according to RECIST v1.1 was assessed by BICR. Tumour assessments with imaging were performed every 8 weeks.
Efficacy was assessed in 92 patients with ROS1-positive NSCLC. The median age was 53 years (range: 27 to 86); female (65%); White (48%), Asian (45%), Black (5%); and Hispanic or Latino (2.4%); never smoked (59%); and ECOG performance status 0 or 1 (88%). Ninety-nine percent of patients had metastatic disease, including 42% with CNS metastases; 96% had adenocarcinoma; 65% received prior platinum-based chemotherapy for metastatic or recurrent disease or had progressed in less than 6 months following platinum-based adjuvant or neoadjuvant therapy. ROS1 positivity was determined by NGS in 79%, FISH in 16%, and PCR in 4%. Twenty-five percent had central laboratory confirmation of ROS1 positivity using an analytically validated RNA-based NGS test.
Efficacy results from patients with ROS1-positive NSCLC are summarised in Table 8.
Of the 92 patients with ROS1-positive NSCLC in the efficacy evaluable analysis set, 10 had measurable CNS metastases at baseline as assessed by BICR and had not received radiation therapy to the brain within 2 months prior to study entry. Responses in intracranial lesions were observed in 7 of these 10 patients.
NTRK fusion-positive solid tumours.

Efficacy in adult patients.

The efficacy of Rozlytrek was evaluated in a pooled subgroup of adult patients with unresectable or metastatic solid tumours with a NTRK gene fusion enrolled in one of three multicentre, single-arm, open-label clinical trials: ALKA, STARTRK-1 and STARTRK-2. To be included in this pooled subgroup, patients were required to have progressed following systemic therapy for their disease, if available, or would have required surgery causing significant morbidity for locally advanced disease; measurable disease per RECIST v1.1; at least 2 years of follow-up from first post-treatment tumour assessment of Rozlytrek; and no prior therapy with a TRK inhibitor. Patients received Rozlytrek at various doses and schedules (94% received Rozlytrek 600 mg orally once daily) until unacceptable toxicity or disease progression. Identification of positive NTRK gene fusion status was prospectively determined in local laboratories or a central laboratory using various nucleic acid-based tests. The major efficacy outcome measures were ORR and DOR, as determined by a BICR according to RECIST v1.1. Intracranial response according to RECIST v1.1 as evaluated by BICR. Tumour assessments with imaging were performed every 8 weeks.
Efficacy was assessed in the first 54 adult patients with solid tumours with an NTRK gene fusion enrolled into these trials. The median age was 58 years (range: 21 to 83); female (59%); White (80%), Asian (13%) and Hispanic or Latino (7%); and ECOG performance status 0 (43%) or 1 (46%). Ninety-six percent of patients had metastatic disease, including 22% with CNS metastases, and 4% had locally advanced, unresectable disease. All patients had received prior treatment for their cancer including surgery (n=43), radiotherapy (n=36), or systemic therapy (n=48). Forty patients (74%) received prior systemic therapy for metastatic disease with a median of 1 prior systemic regimen and 17% (n=9) received 3 or more prior systemic regimens. The most common cancers were sarcoma (24%), lung cancer (19%), salivary gland tumours (13%), breast cancer (11%), thyroid cancer (9%), and colorectal cancer (7%). A total of 52 (96%) patients had an NTRK gene fusion detected by NGS and 2 (4%) had an NTRK gene fusion detected by other nucleic acid-based tests. Eighty-three percent of patients had central laboratory confirmation of NTRK gene fusion using an analytically validated RNA-based NGS test.
Efficacy results from patients with NTRK-positive solid tumours are summarised in Table 9. See Tables 10 and 11.
Among the subset of patients who received prior systemic therapy for metastatic disease, the ORR was 53%, similar to that seen in the overall population.
Among the 54 adult patients, 4 had measurable CNS metastases at baseline as assessed by BICR and had not received radiation therapy to the brain within 2 months of study entry. Responses in intracranial lesions were observed in 3 of these 4 patients.

5.2 Pharmacokinetic Properties

The pharmacokinetics of entrectinib and its pharmacologically active major circulating metabolite (M5) were characterised in adult patients with ROS1-positive NSCLC, NTRK gene fusion-positive solid tumours and, and healthy subjects. The pharmacokinetics of entrectinib and M5 are linear and are not dose-dependent or time-dependent. Steady state is achieved within one week for entrectinib and two weeks for M5 following daily administration of Rozlytrek. The pharmacokinetic parameters for entrectinib and M5 are described in Table 12.

Absorption.

The maximum entrectinib plasma concentration was reached 4 to 6 hours after oral administration of a 600 mg dose.

Effect of food.

A high-fat (approximately 50% of total caloric content), high-calorie (approximately 800 to 1000 calories) meal did not have a significant effect on entrectinib exposure.

Distribution.

Entrectinib and its major active metabolite M5 are both > 99% bound to human plasma proteins in vitro.
The estimated volume of distribution (V/F) of 551 L and 81.1 L for entrectinib and M5, respectively.

Metabolism.

Entrectinib is metabolised predominantly by CYP3A4 (~76%). Minor contributions from several other CYPs and UGT1A4 were estimated at < 25% in total. The active metabolite M5 (formed by CYP3A4) is the only major active circulating metabolite identified. M5 has similar pharmacological potency to entrectinib in vitro and circulating M5 exposures at steady-state in patients were 40% of the corresponding entrectinib exposure.

Excretion.

Following administration of a single oral dose of [14C]-labelled entrectinib, 83% of radioactivity was excreted in faeces (36% of the dose as unchanged entrectinib and 22% as M5) with minimal excretion in urine (3%).
The estimated apparent clearance (CL/F) was 19.6 L/h and 52.4 L/h for entrectinib and M5, respectively. The elimination half-lives of entrectinib and M5 were estimated to be 20 and 40 hours, respectively.

Pharmacokinetics in special populations.

No clinically significant differences in the pharmacokinetics of entrectinib were observed based on age (12 years to 86 years), sex, race (White, Asian and Black), body weight (32 to 130 kg), mild to moderate renal impairment (CLcr 30 to < 90 mL/min) and hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use).

Paediatric population (12 years and older).

In paediatric patients 12 years and older, the predicted systemic exposures for body surface area-based doses of 600 mg (BSA > 1.50 m2), 500 mg (BSA of 1.11 to 1.50 m2) and 400 mg (BSA of 0.91 to 1.10 m2) are comparable to the exposure in adults at the 600 mg dose.

5.3 Preclinical Safety Data

Genotoxicity.

Entrectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay; however, an in vitro assay in cultured human peripheral blood lymphocytes did demonstrate a potential for abnormal chromosome segregation (aneugenicity). Entrectinib was not clastogenic or aneugenic in the in vivo micronucleus assay in rats and did not induce DNA damage in a comet assay in rats.

Carcinogenicity.

No carcinogenicity studies have been performed to establish the carcinogenic potential of entrectinib.

Juvenile animal toxicity.

In a 13-week juvenile rat toxicology study, animals were dosed daily from post-natal day 7 to day 97 (approximately equivalent to neonate to 16 years of age in humans). Entrectinib resulted in:
decreased body weight gain and delayed sexual maturation at doses ≥ 4 mg/kg/day (approximately 0.06 times the human exposure (AUC) at the 600 mg dose);
deficits in neurobehavioral assessments including functional observational battery and learning and memory (at doses ≥ 8 mg/kg/day, approximately 0.14 times the human exposure at the 600 mg dose); and
decreased femur length at doses ≥ 16 mg/kg/day (approximately 0.18 times the human exposure at the 600 mg dose).
Also see Section 4.4 Special Warnings and Precautions for Use, Paediatric use.

6 Pharmaceutical Particulars

6.1 List of Excipients

Capsule content.

Lactose, microcrystalline cellulose, tartaric acid, hypromellose, crospovidone, magnesium stearate, colloidal anhydrous silica.

Capsule shell.

Hypromellose, titanium dioxide, iron oxide yellow (100 mg capsule only), sunset yellow FCF (200 mg capsule only).

Printing ink.

Shellac, propylene glycol, strong ammonia solution, indigo carmine aluminium lake.

6.2 Incompatibilities

Not applicable.

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.

6.4 Special Precautions for Storage

Store below 30°C. Keep capsules in the original bottle. Keep the bottle tightly closed to protect from moisture.
This medicine should not be used after the expiry date (EXP) shown on the pack.

6.5 Nature and Contents of Container

Rozlytrek hard capsules are packaged in white high-density polyethylene bottles with desiccant and a child-resistant screw cap.
100 mg hard capsules are supplied in bottles of 30 capsules.
200 mg hard capsules are supplied in bottles of 90 capsules.

6.6 Special Precautions for Disposal

The release of pharmaceuticals in the environment should be minimised. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided.
In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

1108743-60-7.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes