ROZLYTREK 50mg film pellets in bag medication leaflet

Rozlytrek 50 mg film-coated granules in sachet

Each sachet contains 50 mg of entrectinib.

For the full list of excipients, see section 6.1.

Film-coated granules.

Brownish orange or greyish orange film-coated granules (approximately 2 mm in diameter) in sachet.

Neurotrophic tyrosine receptor kinase (NTRK) gene fusion

Rozlytrek as monotherapy is indicated for the treatment of adult and paediatric patients older than1 month with solid tumours that have a NTRK gene fusion,

* who have a disease that is locally advanced, metastatic or where surgical resection is likely toresult in severe morbidity, and

* who have not received a prior NTRK inhibitor

* who have no satisfactory treatment options (see sections 4.4 and 5.1).

ROS1 gene fusion

Rozlytrek as monotherapy is indicated for the treatment of adult patients with ROS1-positive,advanced non-small cell lung cancer (NSCLC) not previously treated with ROS1 inhibitors.

Treatment with Rozlytrek should be initiated by a physician experienced in the use of anticancermedicinal products.

Patient selection

NTRK gene fusion

A validated assay is required for the selection of patients with NTRK gene fusion-positive solidtumours. NTRK gene fusion-positive status must be established prior to initiation of Rozlytrek therapy(see section 5.1).

ROS1 gene fusion

A validated assay is required for the selection of adult patients with ROS1-positive NSCLC.

ROS1-positive status must be established prior to initiation of Rozlytrek therapy (see section 5.1).

Rozlytrek is available as hard capsules or film-coated granules.

The physician should prescribe the most appropriate pharmaceutical form according to the doserequired and patient needs.

* Rozlytrek film-coated granules are recommended for paediatric patients who have difficulty, orare unable, to swallow capsules but can swallow soft food and where the required dose is 50 mgor a multiple of 50 mg. Film-coated granules should be sprinkled on soft food.

* Patients who have difficulty or are unable to swallow capsules or who require enteraladministration (e.g., gastric or nasogastric) may receive treatment with Rozlytrek capsulesadministered as an oral suspension. Refer to the Rozlytrek hard capsules SmPC for prescribinginformation.

The recommended dose for adults is 600 mg entrectinib once daily.

Paediatric population > 6 months of age

The recommended dose for paediatric patients > 6 months of age is based on body surface area (BSA)(see Table 1).

Table 1: Recommended dosing for paediatric patients > 6 months

Body surface area (BSA)* Once daily dose/Number of sachets(granules)≤ 0.42 m2 250 mg/m2**0.43 m2 to 0.50 m2 100 mg (2 sachets)0.51 m2 to 0.80 m2 200 mg (4 sachets)0.81 m2 to 1.10 m2 300 mg (6 sachets)1.11 m2 to 1.50 m2 400 mg (8 sachets)≥ 1.51 m2 600 mg (12 sachets)

*BSA categories and recommended dosing in Table 1 are based on closely matching exposures to a target dose of 300 mg/m2

**To enable dosing increments of 10 mg, capsules prepared as an oral suspension may be used. Refer to the Rozlytrekcapsule SmPC for prescribing information.

Paediatric patients > 1 month to ≤ 6 months of age

The recommended dose for paediatric patients > 1 month to ≤ 6 months of age is 250 mg/m2 BSAentrectinib once daily, using capsules prepared as an oral suspension.

Capsules administered as an oral suspension (oral or enteral use) enable dosing increments of 10 mg.

The daily dose to be administered should be rounded to the nearest 10 mg increment. Refer to the

Rozlytrek hard capsules SmPC for prescribing information.

It is recommended that patients are treated with Rozlytrek until disease progression or unacceptabletoxicity.

If a planned dose of Rozlytrek is missed, patients can make up that dose unless the next dose is duewithin 12 hours.

When Rozlytrek is administered by individuals other than the healthcare professional (e.g., caregiversor parents) and partial or total vomiting/spitting occurs immediately after taking an administered dose,caregivers should consult the healthcare professional for the next steps.

Management of adverse reactions may require temporary interruption, dose reduction, ordiscontinuation of treatment with Rozlytrek, in case of specified adverse reactions (see Table 3) orbased on the prescriber’s assessment of the patient’s safety or tolerability.

For adults, the dose of Rozlytrek may be reduced up to 2 times, based on tolerability (see Table 2).

Rozlytrek treatment should be permanently discontinued if patients are unable to tolerate a dose of200 mg once daily.

For paediatric patients older than 1 month, the dose of Rozlytrek may be reduced up to 2 times, basedon tolerability (see Table 2).

Table 2: Dose reduction schedule for adult and paediatric patients

Starting dose First dose reduction Second dose reduction Permanentlyonce daily discontinue250 mg/m2 Reduce the once daily dose to Reduce the once daily Rozlytrek intwo thirds of the starting dose* dose to one third of the patients whostarting dose* are unable totolerate100 mg 50 mg or 100 mg once daily, 50 mg once daily Rozlytrek afteraccording to schedule** two dose200 mg 150 mg once daily 100 mg once daily reductions.

300 mg 200 mg once daily 100 mg once daily400 mg 300 mg once daily 200 mg once daily600 mg 400 mg once daily 200 mg once daily

*To enable dosing increments of 10 mg, capsules prepared as an oral suspension may be used. Refer to the Rozlytrekhard capsules SmPC for prescribing information.

**Monday (100 mg), Tuesday (50 mg), Wednesday (100 mg), Thursday (50 mg), Friday (100 mg), Saturday (50 mg),and Sunday (100 mg).

Recommendations for Rozlytrek dose modifications for adult and paediatric patients in case ofspecific adverse reactions are provided in Table 3 (see sections 4.4 and 4.8).

Table 3: Recommended Rozlytrek dose modifications for adverse reactions in adult andpaediatric patients

Adverse

Severity* Dosage modificationreaction

Symptomatic with middle tomoderate activity or exertion, * Withhold Rozlytrek until recovered to lessincluding where intervention is than or equal to Grade 1indicated (Grade 2 or 3) * Resume at reduced dose

Congestiveheart failure Severe with symptoms at rest, * Withhold Rozlytrek until recovered to lessminimal activity, or exertion than or equal to Grade 1or where intervention is * Resume at reduced dose or discontinue asindicated (Grade 4) clinically appropriate

Intolerable, but moderate * Withhold Rozlytrek until recovery to lesschanges interfering with than or equal to Grade 1 or to baselineactivities of daily living * Resume at same dose or reduced dose, as(Intolerable Grade 2) clinically needed

Cognitive Severe changes limiting * Withhold Rozlytrek until recovery to lessdisorders activities of daily living than or equal to Grade 1 or to baseline(Grade 3) * Resume at reduced dose

Urgent intervention indicated * For prolonged, severe, or intolerable events,for event (Grade 4) discontinue Rozlytrek as clinicallyappropriate

* Initiate urate-lowering medication

Hyperuricemia Symptomatic or Grade 4 * Withhold Rozlytrek until improvement ofsigns or symptoms

* Resume Rozlytrek at same or reduced dose

* Withhold Rozlytrek until recovered to

QTc 481 to 500 ms baseline

* Resume treatment at same dose

* Withhold Rozlytrek until QTc intervalrecovers to baseline

* Resume at same dose if factors that cause

QT interval QTc greater than 500 ms QT prolongation are identified andprolongation corrected

* Resume at reduced dose if other factors thatcause QT prolongation are not identified

Torsade de pointes;polymorphic ventriculartachycardia; signs/symptoms * Permanently discontinue Rozlytrekof serious arrhythmia

Adverse Severity* Dosage modificationreaction

* Withhold Rozlytrek until recovery to lessthan or equal to Grade 1 or to baseline

* Resume at same dose if resolution occurswithin 4 weeks

Grade 3

* Permanently discontinue if adverse reactiondoes not resolve within 4 weeks

* Resume at a reduced dose for recurrent

Grade 3 events that resolve within 4 weeks

* Withhold Rozlytrek until recovery to lessthan or equal to Grade 1 or to baseline

Transaminaseelevations * Resume at reduced dose if resolution occurswithin 4 weeks

Grade 4

* Permanently discontinue if adverse reactiondoes not resolve within 4 weeks

* Permanently discontinue for recurrent

Grade 4 events

ALT or AST greater than3 times ULN with concurrenttotal bilirubin greater than * Permanently discontinue Rozlytrek2 times ULN (in the absenceof cholestasis or haemolysis)

* Withhold Rozlytrek until recovery to less

Anaemia or than or equal to Grade 2 or to baselineneutropenia Grade 3 or 4

* Resume at the same dose or reduced dose,as clinically needed

* Withhold Rozlytrek until adverse reactionresolves or improves to recovery orimprovement to Grade 1 or baseline

Other clinically * Resume at the same or reduced dose, ifrelevant resolution occurs within 4 weeksadverse Grade 3 or 4

* Consider permanent discontinuation ifreactions adverse reaction does not resolve within4 weeks

* Permanently discontinue for recurrent

Grade 4 events

* Severity as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE)version 4.0.

Strong or moderate CYP3A inhibitors

The concomitant use of strong or moderate CYP3A inhibitors in adult and paediatric patients older than1 month should be avoided (see section 4.4).

For adults, if co-administration is unavoidable, the use of strong or moderate CYP3A inhibitors with

Rozlytrek should be limited to 14 days and the Rozlytrek dose should be reduced as follows:

* 100 mg once daily for use with strong CYP3A inhibitors (see section 4.5)

* 200 mg once daily for use with moderate CYP3A inhibitors.

After discontinuation of the concomitant strong or moderate CYP3A inhibitors, the Rozlytrek dose thatwas taken prior to initiating the strong or moderate CYP3A inhibitor can be resumed. A wash-out periodmay be required for CYP3A4 inhibitors with a long half-life (see section 4.5).

No dose adjustment is required in patients ≥ 65 years of age (see section 5.2).

No dose adjustment is recommended for patients with mild (Child-Pugh A), moderate (Child-Pugh B)or severe (Child-Pugh C) hepatic impairment (see section 5.2). Patients with severe hepaticimpairment should be carefully monitored for hepatic function and adverse reactions (see Table 3).

No dose adjustment is required in patients with mild or moderate renal impairment. Entrectinib has notbeen studied in patients with severe renal impairment (see section 5.2).

The safety and efficacy of entrectinib in paediatric patients 1 month of age and younger have not beenestablished. Currently available data are described in sections 4.8, 5.1 and 5.2, but no recommendationon a posology can be made.

Rozlytrek is for oral use.

Rozlytrek can be taken with or without food (see section 5.2) but should not be taken with grapefruit,grapefruit juice, or Seville oranges (see section 4.5).

The film-coated granules should be sprinkled on one or more spoonfuls of a soft food (e.g.,applesauce, yogurt, pudding) and taken within 20 minutes of mixing.

The patient should drink water after taking the film-coated granules to ensure the medicinal producthas been completely swallowed.

Patients should be instructed to not crush or chew the film-coated granules to avoid a bitter taste.

The contents of a sachet of film-coated granules should not be divided to prepare a smaller dose.

Detailed instructions on the administration of the film-coated granules are given in the Instructions for

Use (IFU) at the end of the package leaflet.

The film-coated granules are not suitable for enteral administration due to potential for clogging in thetubing. Refer to the Rozlytrek hard capsules SmPC for enteral (e.g., gastric or nasogastric tube)administration.

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

Efficacy across tumour types

The benefit of Rozlytrek has been established in single-arm trials encompassing a relatively smallsample of patients whose tumours exhibit NTRK gene fusions. Favourable effects of Rozlytrek havebeen shown based on overall response rate and response duration in a limited number of tumour types.

The effect may be quantitatively different depending on tumour type, as well as on concomitantgenomic alterations (see section 5.1). For these reasons, Rozlytrek should only be used if there are nosatisfactory treatment options (i.e., for which clinical benefit has not been established, or where suchtreatment options have been exhausted).

Cognitive disorders

Cognitive disorders, including confusion, mental status changes, memory impairment, andhallucinations, were reported in clinical trials with Rozlytrek (see section 4.8). Patients over the age of65 years experienced a higher incidence of these events than younger patients. Patients should bemonitored for signs of cognitive changes.

Based on the severity of cognitive disorders, Rozlytrek treatment should be modified as described in

Table 3 in section 4.2.

Patients should be counselled on the potential for cognitive changes with Rozlytrek treatment. Patientsshould be instructed not to drive or use machines until symptoms resolve if they experience cognitivedisorders (see section 4.7).

Fractures

Fractures have been reported in 29.7% (27/91) of paediatric patients treated with Rozlytrek in clinicaltrials (see section 4.8). Bone fractures mostly occurred in paediatric patients less than 12 years of ageand were localised in the lower extremity (with a predilection for femur, tibia, foot, and fibula). Inboth adult and paediatric patients, some fractures occurred in the setting of a fall or other trauma to theaffected area.

Fourteen paediatric patients had more than one occurrence of a fracture. Fractures resolved in themajority of paediatric patients (see section 4.8). Five paediatric patients had Rozlytrek treatmentinterrupted due to a fracture. Six paediatric patients discontinued treatment due to fractures.

Patients with signs or symptoms of fractures (e.g., pain, abnormal gait, changes in mobility, deformity)should be evaluated promptly.

Hyperuricemia

Hyperuricemia has been observed in patients treated with entrectinib. Serum uric acid levels should beassessed prior to initiating Rozlytrek and periodically during treatment. Patients should be monitoredfor signs and symptoms of hyperuricemia. Treatment with urate-lowering medicinal products shouldbe initiated as clinically indicated and Rozlytrek withheld for signs and symptoms of hyperuricemia.

Rozlytrek dose should be modified based on severity as described in Table 3 in section 4.2.

Congestive heart failure (CHF) has been reported 5.4% of patients across clinical trials with Rozlytrek(see section 4.8). These reactions were observed in patients with or without a history of cardiac diseaseand resolved in 63.0% of those patients upon institution of appropriate clinical management and/or

Rozlytrek dose reduction/interruption.

For patients with symptoms or known risk factors of CHF, left ventricular ejection fraction (LVEF)should be assessed prior to initiation of Rozlytrek treatment. Patients receiving Rozlytrek should becarefully monitored and those with clinical signs and symptoms of CHF, including shortness of breathor oedema, should be evaluated and treated as clinically appropriate.

Based on the severity of CHF, Rozlytrek treatment should be modified as described in Table 3 insection 4.2.

QTc interval prolongation

QTc interval prolongation has been observed in patients treated with Rozlytrek in clinical trials (seesection 4.8).

Use of Rozlytrek should be avoided in patients with a baseline QTc interval longer than 450 ms, inpatients with congenital long QTc syndrome, and in patients taking medicinal products that are knownto prolong the QTc interval.

Rozlytrek should be avoided in patients with electrolyte imbalances or significant cardiac disease,including recent myocardial infarction, congestive heart failure, unstable angina, andbradyarrhythmias. If, in the opinion of the treating physician, the potential benefits of Rozlytrek in apatient with any of these conditions outweigh the potential risks, additional monitoring should beperformed and a specialist consultation should be considered.

Assessment of ECG and electrolytes at baseline and after 1 month of treatment with Rozlytrek arerecommended. Periodic monitoring of ECGs and electrolytes as clinically indicated throughout

Rozlytrek treatment, are also recommended.

Based on the severity of QTc prolongation, Rozlytrek treatment should be modified as described in

Table 3 in section 4.2.

Rozlytrek may cause foetal harm when administered to a pregnant woman. Women of childbearingpotential must use highly effective contraception methods during treatment and up to 5 weeks after thelast dose of Rozlytrek.

Male patients with female partners of childbearing potential must use highly effective contraceptivemethods during treatment with Rozlytrek and for 3 months after the last dose (see sections 4.6 and5.3).

Co-administration of Rozlytrek with a strong or moderate CYP3A inhibitor increases entrectinibplasma concentrations (see section 4.5), which could increase the frequency or severity of adversereactions. Co-administration of Rozlytrek with a strong or moderate CYP3A inhibitor should beavoided. For adult patients if co-administration is unavoidable, the Rozlytrek dose should be reduced(see section 4.2).

During treatment with Rozlytrek, the consumption of grapefruit, grapefruit products, and Sevilleoranges should be avoided.

Co-administration of Rozlytrek with a strong or moderate CYP3A or P-gp inducer decreasesentrectinib plasma concentrations (see section 4.5), which may reduce efficacy of Rozlytrek, andshould be avoided.

This medicinal product contains less than 1mmol sodium (23 mg) per 600 mg dose, that is to sayessentially ‘sodium-free’.

Effects of entrectinib on other medicinal products

Effect of entrectinib on CYP substrates

Entrectinib is a weak inhibitor of CYP3A4. Co-administration of entrectinib 600 mg once daily withoral midazolam (a sensitive CYP3A substrate) in patients increased the midazolam AUC by 50% butreduced midazolam Cmax by 21%. Caution is advised when entrectinib is administered together withsensitive CYP3A4 substrates with a narrow therapeutic range (e.g., cisapride, cyclosporin, ergotamine,fentanyl, pimozide, quinidine, tacrolimus, alfentanil and sirolimus), due to the increased risk ofadverse drug reactions.

Effect of entrectinib on P-gp substrates

In vitro data suggest that entrectinib has inhibitory potential towards P-glycoprotein (P-gp).

Co-administration of a single 600 mg dose of entrectinib with digoxin (a sensitive P-gp substrate)increased digoxin Cmax by 28% and AUC by 18%. The renal clearance of digoxin was similar betweentreatments of digoxin alone and digoxin co-administered with entrectinib, indicating minimal effect ofentrectinib on renal clearance of digoxin.

The effect of entrectinib on digoxin absorption is not considered clinically relevant, but it is unknownwhether the effect of entrectinib may be larger on more sensitive oral P-gp substrates such asdabigatran etexilate.

Effect of entrectinib on BCRP substrates

Inhibition of BCRP was observed in in vitro studies.

The clinical relevance of this inhibition is unknown, but caution is advised when sensitive oral BCRPsubstrates (e.g. methotrexate, mitoxantrone, topotecan, lapatinib) are co-administered with entrectinib,due to the risk of increased absorption.

Effect of entrectinib on other transporter substrates

In vitro data indicate that entrectinib has weak inhibitory potential towards organic anion-transportingpolypeptide (OATP)1B1. The clinical relevance of this inhibition is unknown, but caution is advisedwhen sensitive oral OATP1B1 substrates (e.g. atorvastatin, pravastatin, rosuvastatin repaglinide,bosentan) are co-administered with entrectinib, due to the risk of increased absorption.

Effect of entrectinib on substrates of PXR regulated enzymes

In vitro studies indicate that entrectinib may induce pregnane X receptor (PXR) regulated enzymes(e.g. CYP2C family and UGT). Co-administration of entrectinib with CYP2C8, CYP2C9 or CYP2C19substrates (e.g. repaglinide, warfarin, tolbutamide or omeprazole) may decrease their exposure.

It is currently unknown whether entrectinib may reduce the effectiveness of systemically actinghormonal contraceptives. Therefore, women using systemically acting hormonal contraceptives areadvised to add a barrier method (see section 4.6).

Effects of other medicinal products on entrectinib

Based on in vitro data, CYP3A4 is the predominant enzyme mediating the metabolism of entrectiniband formation of its major active metabolite M5.

Effect of CYP3A or P-gp inducers on entrectinib

Co-administration of multiple oral doses of rifampin, a strong CYP3A inducer, with a single oral doseof entrectinib reduced entrectinib AUCinf by 77% and Cmax by 56%.

Co-administration of entrectinib with CYP3A/P-gp inducers (including, but not limited to,carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin, St. John's Wort [Hypericumperforatum], apalutamide, ritonavir, dexamethasone) should be avoided.

If co-administration of Rozlytrek with dexamethasone cannot be avoided, dexamethasone doserecommendations should be determined by the healthcare professional.

Effect of CYP3A or P-gp inhibitors on entrectinib

Co-administration of itraconazole, a strong CYP3A4 inhibitor, with a single oral dose of entrectinibincreased AUCinf by 600% and Cmax by 173%. Based on physiologically based pharmacokinetic(PBPK) modelling, a similar magnitude of the effect is expected in children as young as 2 years old.

Co-administration of strong and moderate CYP3A inhibitors (including, but not limited to, ritonavir,saquinavir, ketoconazole, itraconazole, voriconazole, posaconazole, grapefruit, or Seville oranges)should be avoided. If concurrent use of strong or moderate inhibitors of CYP3A4 is unavoidable, doseadjustment of entrectinib is required (see section 4.2).

Although, a marked effect of inhibitory P-gp medicinal products on entrectinib pharmacokinetics isnot expected, caution is advised when treatment with strong or moderate P-gp inhibitors (e.g.verapamil, nifedipine, felodipine, fluvoxamine, paroxetine) are co-administered with entrectinib due torisk of increased entrectinib exposure (see section 5.2).

Effect of medicinal products that increase gastric pH on entrectinib

Co-administration of a proton pump inhibitor (PPI), lansoprazole with a single 600 mg entrectinibdose reduced entrectinib AUC by 25% and Cmax by 23%.

No dose adjustments are required when entrectinib is co-administered with PPIs or other medicinesthat raise gastric pH (e.g., H2 receptor antagonists or antacids).

Interaction studies have only been performed in adults.

Female patients of childbearing potential should have medically supervised pregnancy testing prior toinitiating Rozlytrek therapy.

Female patients of childbearing potential must use highly effective contraceptive methods duringtreatment and for at least 5 weeks following the last dose of Rozlytrek.

It is currently unknown whether entrectinib may reduce the effectiveness of systemically actinghormonal contraceptives (see section 4.5). Therefore, women using systemically acting hormonalcontraceptives should be advised to add a barrier method.

Male patients with female partners of childbearing potential must use highly effective contraceptivemethods during treatment and for at least 3 months following the last dose of Rozlytrek (seesection 5.3).

There are no available data from the use of entrectinib in pregnant women. Based on animal studiesand its mechanism of action, entrectinib may cause foetal harm when administered to a pregnantwoman (see sections 4.4 and 5.3).

Rozlytrek is not recommended during pregnancy and in women of childbearing potential not usingcontraception.

Female patients receiving Rozlytrek should be advised of the potential harm to the foetus. Femalepatients should be advised to contact the doctor, should pregnancy occur.

It is unknown whether entrectinib or its metabolites are excreted in human milk. A risk to breast-fedchildren cannot be excluded. Breast-feeding should be discontinued during treatment with Rozlytrek.

No fertility studies in animals have been performed to evaluate the effect of entrectinib (seesection 5.3).

Rozlytrek has moderate influence on the ability to drive and use machines. Patients should beinstructed not to drive or use machines until the symptoms resolve, if they experience cognitiveadverse reactions, syncope, blurred vision, or dizziness, during treatment with Rozlytrek (seesections 4.4 and 4.8).

The most common adverse reactions (≥20%) were fatigue, constipation, diarrhoea, dizziness,dysgeusia, oedema, increased weight, anaemia, increased blood creatinine, nausea, dysaesthesia, pain,vomiting, pyrexia, arthralgia, increased aspartate aminotransferase and dyspnoea, cognitive disorders,cough, and increased alanine aminotransferase. The most frequent serious adverse reactions (≥2%)were lung infection (5.3%), fractures (4.1%), dyspnoea (3.6%), cognitive impairment (2.9%), pleuraleffusion (2.5%) and pyrexia (2.5%). Permanent discontinuation due to an adverse reaction occurred in6.0% of patients.

Table 4 summarises the adverse drug reactions (ADRs) occurring in 762 adult and 91 paediatricpatients treated with Rozlytrek in three clinical trials in adults (ALKA, STARTRK-1, and

STARTRK-2) and one clinical trial in paediatric patients (STARTRK-NG) and one clinical trial inadult and paediatric patients (TAPISTRY). The median duration of exposure was 8.6 months.

Table 5 includes paediatric patients from three clinical studies; STARTRK-NG, STARTRK-2 and

TAPISTRY. The median duration of exposure was 11.1 months. Paediatric data in the description ofselected adverse reactions reflect exposure to Rozlytrek in this expanded paediatric safety population(n=91). The safety profile observed in the expanded paediatric population was consistent with theknown paediatric safety profile from the integrated safety population in Table 4 below.

Adverse drug reactions are listed by MedDRA system organ class. The following categories offrequency have been used: very common ≥1/10, common (≥1/100 to <1/10), uncommon (≥1/1 000 to<1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000). Within each system organ class, theadverse reactions are presented in order of decreasing frequency.

Table 4: Adverse drug reactions occurring in adult and paediatric patients treated with

Rozlytrek in clinical trials (n=853)

System organ Adverse reaction All grades Frequencyclass (%) category Grade ≥3(all grades) (%)

Infections and Urinary tract infection 15.7 Very common 2.7infestations Lung infection1 14.4 Very common 6.1*

Blood and Anaemia 33.4 Very common 9.7lymphatic systemdisorders Neutropenia 15.8 Very common 6.1

Weight increased 34.1 Very common 10.6

Metabolism and Hyperuricemia 16.4 Very common 2.3nutritional Decreased appetite 13.0 Very common 0.7disorders Dehydration 6.6 Common 1.1

Tumour lysis syndrome 0.2 Uncommon 0.2*

Dizziness3 36.5 Very common 1.9

Dysgeusia 35.8 Very common 0.2

Dysaesthesia4 24.9 Very common 0.4

Cognitive disorders5 23.3 Very common 3.6

Nervous system Peripheral sensorydisorders neuropathy6 16.2 Very common 1.1

Headache 16.1 Very common 0.6

Ataxia7 15.1 Very common 1.5

Sleep disturbances8 12.8 Very common 0.4

Mood disorders9 9.4 Common 0.6

Syncope 5.0 Common 3.5

Eye disorders Vision blurred10 11.7 Very common 0.2

Congestive heartfailure11 5.4 Common 2.5*

Cardiac disorders Electrocardiogram QTcprolonged 3.6 Common 0.9

Myocarditis 0.2 Uncommon 0.1

Vasculardisorders Hypotension12 15.9 Very common 2.3

Respiratory, Dyspnoea 23.8 Very common 4.9*thoracic and Cough 21.1 Very common 0.4mediastinaldisorders Pleural effusion 6.0 Common 2.2

Constipation 42.3 Very common 0.4

Diarrhoea 37.9 Very common 2.2

Gastrointestinal Nausea 30.0 Very common 0.6disorders Vomiting 25.1 Very common 1.1

Abdominal pain 11.6 Very common 0.6

Dysphagia 10.7 Very common 0.6

Hepatobiliary AST increased 21.1 Very common 2.9disorders ALT increased 20.2 Very common 3.2

Skin and Rash13 13.4 Very common 1.2subcutaneous Photosensitivitytissue disorders reaction 1.9 Common 0

System organ Frequency

Adverse reaction All grades category Grade ≥3class (%) (all grades) (%)

Musculoskeletal Arthralgia 21.0 Very common 0.7and connective Myalgia 19.7 Very common 0.8tissue disorders Fractures14 11.3 Very common 3.4

Muscular weakness 10.4 Very common 1.3

Renal and urinary Blood creatinineincreased 31.5 Very common 1.2disorders Urinary retention15 10.4 Very common 0.6

General disorders Fatigue16 43.5 Very common 5.0and Oedema17 34.3 Very common 1.8administration Pain18 25.6 Very common 1.5site conditions Pyrexia 23.8 Very common 0.9

* Grades 3 to 5, inclusive of fatal adverse reactions (including 4 reactions of pneumonia, 3 reactions of dyspnoea,1 reaction of cardiac failure, and 1 reaction of tumour lysis syndrome).1 Lung infection (bronchitis, lower respiratory tract infection, lung infection, pneumonia, respiratory tract infection, upperrespiratory tract infection)2 Neutropenia (neutropenia, neutrophil count decreased)3 Dizziness (dizziness, vertigo, dizziness postural)4 Dysaesthesia (paresthesia, hyperesthesia, hypoesthesia, dysesthesia)5 Cognitive disorders (cognitive disorder, confusional state, memory impairment, disturbance in attention, amnesia, mentalstatus changes, hallucination, delirium, disorientation, brain fog, attention deficit hyperactivity disorder, ‘visualhallucination’,‘auditory hallucination’, mental impairment, mental disorder)6 Periphery sensory neuropathy (neuralgia, neuropathy peripheral, peripheral motor neuropathy, peripheral sensoryneuropathy)7 Ataxia (ataxia, balance disorder, gait disturbances)8 Sleep disturbances (hypersomnia, insomnia, sleep disorder, somnolence)9 Mood disorders (anxiety, affect lability, affective disorder, agitation, depressed mood, euphoric mood, mood altered,mood swings, irritability, depression, persistent depressive disorder, psychomotor retardation)10 Vision blurred (diplopia, vision blurred, visual impairment)11 Congestive heart failure (acute right ventricular failure, cardiac failure, cardiac failure congestive, chronic rightventricular failure, ejection fraction decreased, pulmonary oedema)12 Hypotension (hypotension, orthostatic hypotension)13 Rash (rash, rash maculopapular, rash pruritic, rash erythematous, rash papular)14 Fractures (acetabulum fracture, ankle fracture, avulsion fracture, bursitis, cartilage injury, clavicle fracture,compression fracture, femoral neck fracture, femur fracture, fibula fracture, foot fracture, fracture, fractured sacrum, handfracture, hip fracture, humerus fracture, ilium fracture, jaw fracture, joint injury, limb fracture, lower limb fracture,lumbar vertebral fracture, osteoporotic fracture, pathological fracture, pelvic fracture, rib fracture, spinal compressionfracture, spinal fracture, spondylolisthesis, sternal fracture, stress fracture, synovial rupture, thoracic vertebral fracture,tibia fracture, ulna fracture, wrist fracture)15 Urinary retention (urinary retention, urinary incontinence, urinary hesitation, micturition disorder, micturition urgency)16 Fatigue (fatigue, asthenia)17 Oedema (face oedema, fluid retention, generalised oedema, localised oedema, oedema, oedema peripheral, peripheralswelling)18 Pain (back pain, neck pain, musculoskeletal chest pain, musculoskeletal pain, pain in extremity)

Table 5: Adverse drug reactions occurring in paediatric patients treated with Rozlytrek inclinical trials (n=91)

System organ Infants and Children2 Adolescents3 All paediatricclass Frequency toddlers (n=55) (n=15) patients(n=21) (n=91)

Lung infection Urinary tract Urinary tract

Very (28.6%), infection infectioncommon Urinary tract (23.6%), Lung (19.8%),

Infections and infection infection Lung infectioninfestations (23.8%) (16.4%) (17.6%)

Lung

Common infection(6.7%)

Blood and Anaemia Anaemia Anaemia Anaemialymphatic Very (61.9%), (34.5%), (33.3%), (40.7%),system common Neutropenia Neutropenia Neutropenia Neutropeniadisorders (47.6%) (27.3%) (33.3%) (33.0%)

Weight Weight Weight Weightincreased increased increased increased(23.8%), (38.5%), (53.3%), (38.5%),

Very Decreased Decreased Decreased Decreased

Metabolism common appetite appetite appetite appetiteand nutritional (14.3%) (29.1%), (13.3%), (23.1%)disorders Dehydration Hyperuricem(12.7%) ia (13.3%)

Dehydration Hyperuricemia Dehydration

Common (4.8%), (3.6%) (8.8%),

Hyperuricemia Hyperuricemia(4.8%) (5.5%)

Headache Dysgeusia Headache(32.7%), (20%), (20.9%),

Mood Mood Mooddisorders disorders disorders(16.4%), (13.3%), (14.3%),

Very Sleep Cognitive Sleepcommon disturbances disorders disturbances(16.4%), (13.3%), (13.2%)

Dizziness Dysaesthesia(14.5%), (13.3%)

Ataxia

Nervous system (10.9%)disorders Mood Cognitive Headache Cognitivedisorders disorders (6.7%), disorders(9.5%), (9.1%), Sleep (9.9%),

Sleep Dysgeusia (9.1 disturbances Dizzinessdisturbances %), (6.7%), (8.8%),(9.5%), Dysaesthesia Peripheral Dysgeusia

Common Cognitive (5.5 %), sensory (8.8%),disorders Syncope neuropathy Ataxia(9.5%), (5.5 %), (6.7 %), (7.7 %),

Ataxia Peripheral Syncope Dysaesthesia(4.8 %), sensory (6.7%) (5.5%),

Peripheral neuropathy Peripheralsensory (5.5%) sensory

System organ Infants and Children2 Adolescents3 All paediatricclass Frequency toddlers (n=55) (n=15) patients(n=21) (n=91)neuropathy neuropathy(4.8 %), (5.5 %),

Syncope Syncope(4.8 %) (5.5%)

Vision blurred Vision Vision blurred

Eye disorders Common (7.3%) blurred (5.5%)(6.7%)

Congestive Congestive Congestiveheart failure heart failure heart failure(9.5%), (5.5%),

Cardiac (5.5%),

Common Electrocardiog Electrocardiogdisorders Electrocardiogram QT ram QT ram QTprolonged prolonged prolonged (5.5(9.5%) (5.5%) %)

Hypotension Hypotension Hypotension Hypotension

Vascular Common (9.5%) (7.3%) (6.7%) (7.7%)disorders

Cough Cough (40%) Cough Cough

Very (42.9%) (20%), (37.4%)

Respiratory, common Dyspnoeathoracic and (13.3%)mediastinal Dyspnoea Dyspnoea Pleural Dyspnoeadisorders (4.8%) (9.1%), effusion (8.8%),

Common Pleural (6.7%) Pleuraleffusion effusion(5.5%) (4.4%)

Vomiting Vomiting Nausea Vomiting(47.6%), (43.6%), (40%), (40.7%),

Diarrhoea Diarrhoea Constipation Diarrhoea(42.9%), (43.6%), (33.3%), (39.6%),

Very Constipation Constipation Vomiting (20 Constipationcommon (42.9%) (36.4%), %), (37.4 %),

Gastrointestina Nausea Diarrhoea Nauseal disorders (34.5%), (20%), (28.6 %),

Abdominal Abdominal Abdominalpain (25.5%) pain (13.3 pain (19.8%)%)

Abdominal

Common pain (9.5%),

Nausea(4.8%)

ALT increased AST increased AST AST increased(47.6%), (29.1%), increased (36.3%),

Hepatobiliary Very AST increased ALT (53.3%), ALT increaseddisorders common (42.9%) increased ALT (34.1%)(25.5%) increased(46.7%)

System organ Infants and Children2 Adolescents3 All paediatricclass Frequency toddlers (n=55) (n=15) patients(n=21) (n=91)

Skin and Rash (38.1%) Rash (21.8%) Rash (22%)subcutaneous Verytissue disorders common

Fractures Fractures Fractures(40%), (20%), (29.7%),

Very Arthralgia Muscular Arthralgiacommon (16.4%) weakness (11.0%)

Musculo- (13.3%),skeletal and Myalgiaconnective (13.3%)tissue disorders Fractures Muscular Arthralgia Muscular(9.5%) weakness (6.7%) weakness

Common (7.3%), (6.6%),

Myalgia Myalgia(7.3%) (6.6%)

Blood Blood Blood Bloodcreatinine creatinine creatinine creatinine

Very increased increased increased increased

Renal and common (19%) (34.5%), (46.7%) (33%),urinary Urinary Urinarydisorders retention retention(18.2%) (14.3%)

Urinary Urinary

Common retention retention(9.5%) (6.7%)

Pyrexia Pyrexia Pain Fatigue(61.9%) (50.9%), (33.3%), (28.6%),

Very Fatigue (40%), Pyrexia Pain (26.4%),common Pain (30.9%), (33.3%), Pyrexia

General Oedema Fatigue (50.5%),disorders and (14.5%) (20%) Oedemaadministration (11%)site conditions Pain (9.5%),

Oedema

Common (9.5%),

Fatigue(4.8%)% refers to all grades1Infant/toddlers (≥ 28 days to < 24 months): Grade ≥ 3 reactions reported were neutropenia, weight increased, lunginfection, anaemia, AST increased, abdominal pain, and urinary tract infection2Children (≥ 24 months to < 12 years): Grade ≥ 3 reactions reported were neutropenia, weight increased, fractures, lunginfection, anaemia, ALT increased, syncope, AST increased, ataxia, dyspnoea, abdominal pain, congestive heart failure,fatigue, headache, pain, pyrexia, urinary tract infection, arthralgia, cognitive disorders, constipation, cough, decreasedappetite, dehydration, hypotension, muscular weakness, oedema, and vomiting3Adolescents (≥ 12 to < 18 years of age): Grade ≥ 3 reactions reported were neutropenia, weight increased, fracture, lunginfection, and headache

Cognitive disorders

A variety of cognitive symptoms was reported across clinical trials (see section 4.4). These includedevents reported as cognitive disorders (6.4%), confusional state (6.2%), memory impairment (4.9%),disturbance in attention (4.1%), amnesia (2.3%), mental status changes (0.9%), hallucination (0.8%),delirium (0.8%), disorientation (0.5%), brain fog (0.4%), attention deficit hyperactivity disorder(0.2%), visual hallucination (0.2%), auditory hallucination (0.1%), mental impairment (0.1%) andmental disorder (0.1%). Grade 3 cognitive disorders were reported in 3.6% of patients. Adult patientswho had central nervous system (CNS) disease at baseline had a higher frequency of these adversereactions (30%) compared to those without CNS disease (22.6%). The median time to onset forcognitive disorders was 0.95 months. In the paediatric population, 2.2% (2/91) of patients experienceddisturbance in attention of Grade 1 severity and 2.2% (2/91) of patients experienced disturbance inattention of Grade 2 severity.

Fractures

Fractures were experienced by 9.1% (69/762) of adult patients and 29.7% (27/91) of paediatricpatients. 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 someadult patients. In both adult and paediatric patients, most fractures were hip or other lower extremityfractures (e.g., femoral or tibial shaft) and some fractures occurred in the setting of a fall or othertrauma.

The median time to fracture was 8.11 months (range: 0.26 months to 45.34 months) in adults.

Rozlytrek was interrupted in 26.1% of adults that experienced fractures. Eighteen adult patients had

Rozlytrek treatment interrupted and 2 adult patients discontinued Rozlytrek due to fractures. Rozlytrekdose was reduced for 2 adult patients due to fractures.

A total of 52 fracture events were reported in 27 paediatric patients, with 14 patients who experiencedmore than one occurrence of fracture. In paediatric patients, fractures mostly occurred in patients lessthan 12 years of age. Fractures resolved in 85.2% (23/27) of paediatric patients. The median time tofracture was 4.3 months (range: 2.0 months to 28.65 months) in paediatric patients. Twelve patientsexperienced Grade 2 fractures and 10 patients experienced Grade 3 fractures. Seven of the Grade 3fractures were serious. Rozlytrek was interrupted in 18.5% (5/27) of paediatric patients whoexperienced fractures. Six paediatric patients discontinued Rozlytrek due to fractures. Rozlytrek dosewas reduced for one paediatric patient.

Ataxia

Ataxia (including events of ataxia, balance disorder, and gait disturbances) was reported in 15.1% ofpatients. The median time to onset for ataxia was 0.5 months (range: 0.03 months to 65.48 months)and the median duration was 0.7 months (range: 0.03 months to 11.99 months). The majority ofpatients (55.8%) recovered from ataxia. Ataxia related adverse reactions were observed morefrequently in elderly patients (24.2%) compared to patients below 65 years of age (11.8%).

Syncope was reported in 5.0% of patients. In some patients, syncope was reported with concurrenthypotension, dehydration, or QTc prolongation and in other patients no other concurrent relatedconditions were reported.

QTc interval prolongation

Among the 853 patients who received entrectinib across clinical trials, 47 (7.2%) patients with at leastone post-baseline ECG assessment experienced QTcF interval prolongation of > 60 ms after startingentrectinib, and 27 (4.1%) patients had a QTcF interval of > 500 ms (see section 4.4).

Peripheral sensory neuropathy

Peripheral sensory neuropathy was reported in 16.2% of patients. The median time to onset was0.71 months (range 0.03 months to 81.97 months) and the median duration was 0.9 months (range:0.07 months to 41 months). 48.6% of patients recovered from peripheral neuropathy.

Eye disorders reported across clinical trials included vision blurred (9%), visual impairment (1.9%),and diplopia (1.8%). The median time to onset for eye disorders was 1.9 months (range: 0.03 monthsto 49.61 months). The median duration of eye disorders was 1.2 months (range 0.03 months to14.98 months). 54% of patients recovered from the eye disorder adverse reactions.

The overall safety profile of Rozlytrek in the paediatric population is generally similar to the safetyprofile in adults.

The safety of Rozlytrek in paediatric patients was established based on data from 91 paediatricpatients across 3 clinical trials (STARTRK-NG, STARTRK-2, and TAPISTRY). Of these, 21 patientswere 28 days to < 2 years old, 55 patients were ≥ 2 to < 12 years old, 15 patients were ≥ 12to < 18 years old.

Adverse reactions and laboratory abnormalities of Grade 3 or 4 severity occurring more frequently (atleast a 5% increased incidence) in paediatric patients compared to adult patients were neutropenia(19.8% vs 4.5%), weight increased (18.7% vs 9.6%), bone fractures (11% vs 2.5%), and lung infection(11% vs 5.5%). No Grade 5 events were observed in the 91 patients in the expanded paediatric safetypopulation. Grade 3 to 4 events that occurred at a frequency ≥ 5% were neutropenia (19.8%), weightincreased (18.7%), fractures (11%), lung infection (11%), and anaemia (8.8%).

The safety profile in each age group (infants and toddlers, children, and adolescents) is similar to theoverall safety profile of Rozlytrek in paediatric patients.

Among the 853 patients who received entrectinib across clinical trials, 227 (26.6%) patients were65 years or older and 53 (6.2%) were 75 years or older. The overall safety profile of entrectinib inelderly patients is similar to the safety profile observed in patients younger than 65 years of age.

Adverse reactions occurring more frequently (at least a 5% increased incidence) in the elderlycompared to patients less than 65 years old were dizziness (44.9% vs 33.4%), blood creatinineincreased (35.7% vs 30%), hypotension (19.8% vs 14.5%), and ataxia (24.2% vs 11.8%).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Patients who experience overdose should be closely supervised and supportive care instituted. Thereare no known antidotes for entrectinib.

Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors, ATC code: L01EX14

Entrectinib is an inhibitor of the tropomyosin receptor tyrosine kinases TRKA, TRKB and TRKC(encoded by the neurotrophic tyrosine receptor kinase [NTRK] genes NTRK1, NTRK2 and NTRK3,respectively), proto-oncogene tyrosine-protein kinase ROS (ROS1), and anaplastic lymphoma kinase(ALK), with IC50 values of 0.1 to 2 nM. The major active metabolite of entrectinib, M5, showedsimilar in vitro potency and activity against TRK, ROS1, and ALK.

Fusion proteins that include TRK, ROS1 or ALK kinase domains drive tumourigenic potential throughhyperactivation of downstream signalling pathways leading to unconstrained cell proliferation.

Entrectinib demonstrated in vitro and in vivo inhibition of cancer cell lines derived from multipletumour types, including subcutaneous and intracranial tumours, harbouring NTRK, ROS1, and ALKfusion genes.

Prior treatments with other drugs that inhibit the same kinases may confer resistance to entrectinib.

Resistance mutations in the TRK kinase domain identified following entrectinib discontinuationinclude NTRK1 (G595R, G667C) and NTRK3 (G623R, G623E and G623K). Resistance mutations inthe ROS1 kinase domain identified following entrectinib discontinuation include G2032R, F2004Cand F2004I.

The molecular causes for primary resistance to entrectinib are not known. It is therefore not known ifthe presence of a concomitant oncogenic driver in addition to an NTRK gene fusion affects the efficacyof TRK inhibition.

NTRK gene fusion-positive solid tumours

Efficacy in adult patients

The efficacy of Rozlytrek was evaluated in a pooled sub-group of adult patients with unresectable ormetastatic 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) or the multicentre multi-cohort,open-label clinical trial, TAPISTRY. To be included in the pooled subgroup, patients were required tohave confirmed NTRK gene fusion-positive solid tumours; measurable disease per Response

Evaluation Criteria in Solid Tumours (RECIST) v1.1; at least 12 months of follow-up from the firstpost-treatment initiation tumour assessment, and no prior therapy with a TRK inhibitor (patients withconcomitant driver mutations, where known, were excluded). Patients with primary CNS tumourswere assessed separately using Response Assessment in Neuro-Oncology Criteria (RANO). Patientsreceived Rozlytrek 600 mg orally once daily until unacceptable toxicity or disease progression. Theprimary efficacy endpoints were objective response rate (ORR) and duration of response (DOR) asevaluated by Blinded Independent Central Review (BICR) according to RECIST v1.1.

Efficacy was assessed in 242 adult patients with solid tumours with an NTRK gene fusion enrolled inthese trials. The baseline demographic and disease characteristics were: 47.5% males, median age of58 years (range 19 years to 92 years), 37.2% and 9.9% were 65 years or older and 75 years or olderrespectively, 49.4% white Caucasian, 36.5% Asian, 3.3% Hispanic or Latino and 61.9% neversmokers. The ECOG (Eastern Cooperative Oncology Group) performance status at baseline was0 (42.1%), 1 (50%), or 2 (7.9%). Most patients (95.5%) had metastatic disease [most common sitesbeing lung (62.8%), lymph nodes (49.2%), liver (33.1%), bone (31%), and brain (16.5%)], 4.5%patients had locally advanced disease. 76.9% and 52.5% of patients had received surgery andradiotherapy for their cancer, respectively. 71.5% patients had received prior systemic therapy for theircancer including chemotherapy (61.6%) and 37.2% patients had no prior systemic therapies formetastatic disease. The most common cancers were lung cancer (24.8%), sarcoma (19%), salivarygland tumours (15.7%), thyroid cancer (13.6%), colorectal cancer (7%), and breast cancer (7%). Theoverall median duration of follow-up was 35.1 months.

Efficacy results from patients with NTRK gene fusion-positive solid tumours are summarised in

Table 6.

Table 6: Overall efficacy by BICR in adults with NTRK gene fusion-positive solid tumours

Efficacy endpoint Rozlytrekn=242

Primary endpoints (BICR assessed; RECIST 1.1)

Objective response rate

Number of responses 152/242

ORR% (95% CI*) 62.8% (56.4, 68.9)

Complete response, n (%) 41 (16.9%)

Partial response, n (%) 111 (45.9%)

Duration of response**

Number (%) of patients with events 86/152 (56.6%)

Median, months (95% CI) 22 (16.6, 30.4)6-month durable response % (95% CI) 85% (80, 91)9-month durable response % (95% CI) 78% (71, 84)12-month durable response % (95% CI) 69% (62, 77)

*Confidence Intervals (CI) calculated using the Clopper-Pearson method.

**Median and event-free rates based on Kaplan-Meier estimates.

Objective response rate and duration of response by tumour type in adult patients with NTRK genefusion-positive solid tumours is presented in Table 7 below.

Table 7: Efficacy by tumour type in adults with NTRK gene fusion-positive solid tumours

ORR DOR

Tumour type Patients(n=242) n (%) 95% CI Range(months)

Sarcoma 46 29 (63) (47.6, 76.8) 2.8, 68.6*

Non-small cell lung cancer 60 38 (63.3) (49.9, 75.4) 3.1, 71.6

Salivary (MASC) 38 32 (84.2) (68.8, 94) 2.8, 73.5*

Breast cancer (secretory) 12 10 (83.3) (51.6, 97.9) 5.5, 69.9*

Breast cancer (non-secretory) 2 NE, PR NA 4.2

Breast cancer (NOS) 2 NE, NE NA NA

Breast cancer (Ductal) 1 PD NA NA

Thyroid cancer 33 20 (60.6) (42.1, 77.1) 5.6, 60.7

Colorectal cancer 17 6 (35.3) (14.2, 61.7) 5.6*, 24*

Neuroendocrine cancers 8 5 (62.5) (24.5, 91.5) 7.4, 31.1

Head and neck 5 3 (60.0) (14.7, 94.7) 4.0, 56.5*

Pancreatic cancer 6 4 (66.7) (22.3, 95.7) 5.6*, 12.9

Unknown primary cancer 3 1 (33.3) (0.8, 90.6) 9.1

Ovarian cancer 1 Non CR/PD NA NA

Endometrial carcinoma 1 PR NA 38.2

Cholangiocarcinoma 1 PR NA 9.3

Gastrointestinal cancer (other) 1 CR NA 30.4

Gastrointestinal cancer 1 PD NA NA(non CRC)

Neuroblastoma 1 NE NA NA

Prostate cancer 1 PD NA NA

Penile cancer 1 PD NA NA

Adrenal cancer 1 PD NA NA

*Censored

ORR: Objective Response Rate; DOR: Duration of Response; MASC: mammary analogue secretory carcinoma; NA: notapplicable due to small number or lack of response; NOS: not otherwise specified; CRC: colorectal cancer; CR: completeresponse; PR: partial response; PD: progressive disease; NE: not estimable.

Due to the rarity of NTRK gene fusion-positive cancers, patients were studied across multiple tumourtypes with a limited number of patients in some tumour types, causing uncertainty in the ORRestimate per tumour type. The ORR in the total population may not reflect the expected response in aspecific tumour type.

The ORR in 122 patients that had broad molecular characterisation before Rozlytrek treatment was59.8% (95% CI: 50.6, 68.6); of those, the ORR in 97 patients who had other genomic alterations inaddition to NTRK gene fusion was 55.7% (95% CI: 45.2, 65.8) and the ORR in 25 patients withoutother genomic alterations was 76% (95% CI: 54.9, 90.6).

Intracranial response

A BICR assessment resulted in a subgroup of 36 adult patients with CNS metastases at baseline,including 20 patients with measurable CNS lesions. Intracranial (IC) response assessed by BICRaccording to RECIST v1.1 was reported in 14 out of these 20 patients (7 CR and 7 PR), for an ORR of70% (95% CI: 45.7, 88.1) and median DOR of 19.7 months (95% CI: 7.4, 26.6). Five of these20 patients had received intracranial radiotherapy to the brain within 2 months prior to starting

Rozlytrek treatment.

Primary CNS tumour

Across the three trials, 16 adult patients with primary CNS tumours were treated with Rozlytrek with aminimum of 12 months of follow-up. Two out of the 16 adult patients had an objective responseassessed by BICR according to RANO.

Efficacy in paediatric patients

Efficacy of Rozlytrek was assessed in 44 paediatric patients with solid tumours that have a NTRK genefusion enrolled in STARTRK-NG or TAPISTRY.

To be included in the analysis, patients were required to have confirmed NTRK gene fusion-positivesolid tumours; at least 6 months of follow-up, no prior therapy with a TRK inhibitor, received at leastone dose of entrectinib and presenting with measurable or evaluable disease at baseline. Patientsreceived Rozlytrek doses from 20 mg to 600 mg once daily. The primary efficacy endpoint wasconfirmed ORR as evaluated by BICR according to RECIST v1.1 for extracranial tumours andaccording to RANO for primary CNS tumours. The secondary efficacy outcome measures includedduration of confirmed response as evaluated by BICR and time to first confirmed objective response(CR or PR).

The baseline demographic and disease characteristics were: 45.5% males, median age of 4 years(range: 2 months to 15 years), 52.3% white Caucasian, 34.1% Asian, and 9.1% Hispanic or Latino,with a median BSA of 0.73 m2 (range: 0.2-1.9 m2). At baseline, 23.8% of patients had metastaticdisease, 76.2% of patients had locally advanced disease, and 43.2% of patients had no prior systemictherapies for their cancer. The majority of patients had received treatment for their cancer includingsurgery (n=24), radiotherapy (n=8) and/or systemic therapy (n=25). The sites for metastatic diseaseincluded other (4 patients), brain (3 patients), and lung (3 patients). 45.5% of patients had primary

CNS tumours. The overall median duration of follow-up was 24.2 months.

Efficacy results from patients with NTRK gene fusion-positive solid tumours are summarised in

Table 8.

Table 8: Overall efficacy by BICR in paediatric patients with NTRK gene fusion-positive solidtumours

Efficacy endpoints Rozlytrekn=44

Primary endpoints**

Objective response rate

Number of responses 32/44

ORR% (95% CI***) 72.7% (57.21, 85.04)

Complete response, n (%) 20 (45.5%)

Partial response, n (%) 12 (27.3%)

Secondary endpoints**

DOR*

Number (%) of patients with events 6/32 (18.8%)

Median, months (95% CI) NE (25.4, NE)6-month durable response % (95% CI) 97% (90, 100)9-month durable response % (95% CI) 97% (90, 100)12-month durable response % (95% CI) 84% (70, 99)

NE = not estimable.

*Median and event-free rates based on Kaplan-Meier estimates.

**Includes patients with measurable or evaluable disease. BICR analysis by RECIST v1.1 for solid tumours(24 patients) and by RANO criteria for primary CNS tumours (20 patients).

***Confidence Intervals (CI) calculated using the Clopper-Pearson method.

Objective response rate and duration of response by tumour type in paediatric patients with NTRKgene fusion-positive solid tumours is presented in Table 9.

Table 9: Efficacy by tumour type in paediatric patients with NTRK gene fusion-positive solidtumours

ORR DOR

Tumour type Patients(n=44) n (%) 95% CI Range(months)

Primary CNS 20 10 (50) (27.2, 72.8) 5.5, 42.3*

Infantile fibrosarcoma 11 10 (90.9) (58.7, 99.8) 5.7*, 24*

Spindle Cell 8 8 (100.0) (63.1, 100) 5.4*, 23*

Sarcoma (other) 2 PR; Non-CR/Non-PD NA 3.7*

Melanoma 1 CR NA 42.4*

Kidney cancer 1 PR NA 9.2*

Thyroid cancer 1 CR NA 11.1*

*Censored

ORR: Objective Response Rate; DOR: Duration of Response; NA: not applicable due to small number or lack ofresponse; CR: complete response; PR: partial response; PD: progressive disease

Due to the rarity of NTRK gene fusion-positive cancers, patients were studied across multiple tumourtypes with a limited number of patients in some tumour types, causing uncertainty in the ORRestimate per tumour type. The ORR in the total population may not reflect the expected response in aspecific tumour type.

ROS1-positive NSCLC

The efficacy of Rozlytrek was evaluated in a pooled sub-group of patients with ROS1-positivemetastatic NSCLC who received Rozlytrek 600 mg orally once daily and were enrolled in one of threemulticentre single-arm, open-label clinical trials (ALKA, STARTRK-1, and STARTRK-2). To beincluded in the pooled sub-group, patients were required to have histologically confirmed, recurrent ormetastatic, ROS1-positive NSCLC, ECOG performance status ≤ 2, measurable disease per

RECIST v1.1, ≥ 6 months of follow-up, and no prior therapy with a ROS1 inhibitor. All patients wereassessed for CNS lesions at baseline.

The primary efficacy endpoints were ORR and DOR, as evaluated by BICR according to

RECIST v1.1. The secondary efficacy endpoints included PFS, OS, and in patients presenting with

CNS metastases at baseline - IC-ORR and IC-DOR (also evaluated by BICR using RECIST v1.1).

Efficacy was assessed in 161 patients with ROS1-positive NSCLC. The baseline demographic anddisease characteristics were: 35.4% males, median age of 54 years (range 20 years to 86 years), 24.2%and 4.3% were older than 65 years and 75 years of age, respectively, 44.1% white Caucasian, 45.3%

Asian, pct. 4.3%, Black, 2.6% Hispanic or Latino and 62.7% never smokers. The ECOG (Eastern

Cooperative Oncology Group) performance status at baseline was 0 (41%), 1 (49.1%), or 2 (9.9%).

Most patients (98.1%) had metastatic disease [most common sites being lymph nodes (69.6%), lung(50.3%) and brain (32.9%)], 1.9% patients had locally advanced disease and 37.3% patients had noprior systemic therapies for metastatic disease. ROS1 positivity was determined by NGS in 83% ofpatients, by FISH in 9% of patients, and by RT-PCR in 8% of patients. The overall median duration offollow-up from receipt of the first dose was 15.8 months.

Efficacy results from patients with ROS1-positive NSCLC are summarised in Table 10.

Table 10: Overall efficacy by BICR in patients with ROS1-positive NSCLC

Efficacy endpoint Rozlytrekn=161

Primary endpoints (BICR-assessed, RECIST 1.1)

Objective response rate

Number of responses 108/161

ORR% (95% CI***) 67.1% (59.25, 74.27)

Complete response, n (%) 14 (8.7%)

Partial response, n (%) 94 (58.4%)

Duration of response*

Number (%) of patients with events 48/108 (44.4%)

Range (months) 1.8**, 42.3**6-month durable response % (95% CI) 83% (76, 90)9-month durable response % (95% CI) 75% (67, 84)12-month durable response % (95% CI) 63% (53, 73)

Secondary endpoints (BICR-assessed, RECIST 1.1)

PFS*

Number (%) of patients with events 82/161 (50.9%)6-month PFS % (95% CI) 77% (70, 84)9-month PFS % (95% CI) 66% (58, 74)12-month PFS % (95% CI) 55% (47, 64)

Overall survival*

Number (%) of patients with events 38/161 (23.6%)6-month OS % (95% CI) 91% (87, 96)9-month OS % (95% CI) 86% (81, 92)12-month OS % (95% CI) 81% (74, 87)

*Event-free rates based on Kaplan-Meier estimates.

**Censored

***Confidence Intervals (CI) calculated using the Clopper-Pearson method.

In the ROS1 positive NSCLC efficacy evaluable patients with ≥ 12 months of follow-up (n=94), the

ORR was 73.4% (95% CI: 63.3, 82), the median DOR was 16.5 months (95% CI: 14.6, 28.6) andmedian PFS was 16.8 months (95% CI: 12, 21.4).

Intracranial response

A BICR assessment resulted in a subgroup of 46 ROS1-positive NSCLC patients with CNS metastasesat baseline including 24 patients with measurable CNS lesions. Intracranial response assessed by

BICR according to RECIST v1.1 was reported in 19 of these 24 patients (3 CR and 16 PR) for an

ORR of 79.2% (95% CI: 57.8, 92.9). The percentage of patients (95% CI) with DOR ≥ 6 months,≥ 9 months and ≥ 12 months was 76% (56, 97), 62% (38, 86), and 55% (29, 80), respectively(Kaplan-Meier estimates). Nine of these 24 patients had received intracranial radiotherapy to the brainwithin 2 months prior to starting Rozlytrek treatment.

This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. Thismeans that further evidence on this medicinal product is awaited.

The European Medicines Agency will review new information on this medicinal product at least everyyear and this SmPC will be updated as necessary.

The pharmacokinetic parameters for entrectinib and its major active metabolite (M5), have beencharacterised in patients with NTRK gene fusion-positive solid tumours and ROS1-positive NSCLCand healthy subjects. The pharmacokinetics of entrectinib and M5 are linear and are notdose-dependent or time-dependent. Steady state is achieved within one week for entrectinib and twoweeks for M5 following daily administration of Rozlytrek.

Entrectinib is a weak P-gp substrate based on in vitro data. The exact in vivo contribution of P-gp isunknown. M5 is a P-gp substrate. Entrectinib is not a substrate of BCRP but M5 is a substrate of

BCRP. Entrectinib and M5 are not substrates of OATP 1B1 or OATP1B3.

Following a single 600 mg oral administration of Rozlytrek to patients with NTRK genefusion-positive and ROS1-positive NSCLC under fed conditions, entrectinib was rapidly absorbedreaching time-to-maximum plasma concentration (Tmax) after approximately 4 to 6 hours. Based onpopulation pharmacokinetic analysis, steady-state was achieved within 5 days for entrectinib with600 mg once daily dosing.

No clinically significant effect of food on entrectinib bioavailability was observed.

In healthy adult subjects, the AUC and Cmax of Rozlytrek in the film-coated granule formulation wassimilar to that of the capsules. Rozlytrek capsules administered as a suspension with water or milk,given orally, or through a gastric or nasogastric tube, results in similar AUC and Cmax as capsulesswallowed whole.

Entrectinib and its major active metabolite M5 are highly bound to human plasma proteinsindependent of drug concentrations. In human plasma, entrectinib and M5 had similar protein bindingwith > 99% bound at a clinically relevant concentration.

After a single oral dose of entrectinib, the geometric mean volume of distribution (Vz/F) was 600 L,suggesting extensive distribution of the drug. Entrectinib demonstrated steady-state brain-to-plasmaconcentration ratios of 0.4 to 2.2 in multiple animal species (mice, rats, and dogs) at clinically relevantsystemic exposures.

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)and the direct N-glucuronide conjugate, M11, (formed by UGT1A4) are the two major circulatingmetabolites identified.

The population PK model estimated mean accumulation at steady-state following 600 mg once dailyadministration of entrectinib was 1.89 (±0.381) and 2.01 (±0.437) for M5. Following administration ofa single dose of [14C]-labelled entrectinib, 83% radioactivity was excreted in faeces (36% of the doseas unchanged entrectinib and 22% as M5) with minimal excretion in urine (3%).

Entrectinib and M5 account for approximately 73% of radioactivity in systemic circulation at Cmax,and approximately half of total radioactivity AUCinf.

Population PK analysis estimated apparent clearance CL/F was 19.6 L/h and 52.4 L/h for entrectiniband M5, respectively. The elimination half-lives of entrectinib and M5 were estimated to be 20 hoursand 40 hours, respectively.

Linearity/Non-linearity

Entrectinib has linear pharmacokinetics in the dose range of 100 mg to 600 mg.

The pharmacokinetics of entrectinib have been evaluated in 78 paediatric patients above one month ofage. In patients from > 1 month to ≤ 6 months the administered dose was 250 mg/m2; in patients> 6 months, the administered dose was 300 mg/m2 based on five BSA categories, with a maximumdose of 600 mg for children with ≥ 1.51 m2 body surface area (BSA).

Data obtained from population pharmacokinetic analyses show that in paediatric patients 6 years andolder, 300 mg Rozlytrek once daily dose for BSA range 0.81 m2 to 1.10 m2, 400 mg Rozlytrek oncedaily dose for BSA range 1.11 m2 to 1.50 m2, and 600 mg Rozlytrek once daily dose for BSA range≥ 1.51 m2 results in a similar systemic exposure attained in adults treated with 600 mg Rozlytrek oncedaily dose.

Data from non-compartmental analysis in patients from 1 month to < 6 years demonstrated thatsystemic exposure of the sum of entrectinib and M5 in paediatric patients receiving 250 mg/m2 or300 mg/m2 of Rozlytrek once daily were generally lower than the mean systemic exposure of adultpatients treated with 600 mg of Rozlytrek once daily. The recommended dose in this age category isbased on available efficacy and safety data.

No differences in entrectinib exposure were noted in patients older than 65 years and younger adultsbased on pharmacokinetic analysis.

Negligible amounts of entrectinib and the active metabolite M5 are excreted unchanged in urine(~3% of the dose) indicating that renal clearance plays a minor role in the elimination of entrectinib.

Based on population pharmacokinetic analyses, the pharmacokinetics of entrectinib are notsignificantly affected in renal impairment. The impact of severe renal impairment on thepharmacokinetics of entrectinib is unknown.

The pharmacokinetics of entrectinib were studied in subjects with mild (Child-Pugh A), moderate(Child-Pugh B) and severe (Child-Pugh C) hepatic impairment, relative to subjects with normalhepatic function. Following administration of a single oral dose of 100 mg entrectinib, the combined

AUClast of entrectinib and M5 showed no relevant change in the hepatic impaired groups compared tothe normal function group. The AUClast geometric mean ratio (90% CI) was 1.30 (0.889, 1.89) for themild, 1.24 (0.886, 1.73) for the moderate, and 1.39 (0.988, 1.95) for the severe hepatic impairedgroups compared to the normal hepatic function group. For the unbound entrectinib and M5, the

AUClast (fu) geometric mean ratio (90% CI) was 1.91 (1.21, 3.02) for the mild, 1.57 (1.06, 2.31) for themoderate, and 2.34 (1.57, 3.48) for the severe hepatic impaired groups compared to the normal hepaticfunction group. Although the effect of hepatic impairment on unbound PK parameters generallyfollowed a similar direction as total PK parameters, due to the high non-specific binding in buffer andhigh variability, results should be interpreted with caution.

In addition, it was also observed that the variability in systemic exposure was high and observedexposures overlapped across all the study groups (see section 4.2).

Effects of body weight, race and gender

No clinically significant differences in the pharmacokinetics of entrectinib were observed based onsex, race (Asian, Black and White) and body weight (4 kg to 130 kg).

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

Entrectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay butdemonstrated a potential for abnormal chromosome segregation (aneugenicity) in cultured humanperipheral blood lymphocytes. Entrectinib was not clastogenic or aneugenic in the in vivomicronucleus assay in rats and did not induce DNA damage in a comet assay in rats.

Dedicated fertility studies in animals have not been performed to evaluate the effect of entrectinib. Noadverse effects of entrectinib on male and female reproductive organs were observed in therepeat-dose toxicology studies in rats and dogs at approximately 2.4-fold and 0.6-fold, respectively,the human exposure by AUC at the recommended human dose.

In an embryo-foetal developmental study in rats, maternal toxicity (decreased body weight gain andfood consumption) and foetal malformations (including body closure defects and malformations of thevertebrae and ribs), were observed at 200 mg/kg/day of entrectinib which represents approximately2-fold the human exposure by AUC at the recommended dose. Dose-response dependent reducedfoetal body weight (low, middle and high dose) and reduced skeletal ossification (middle and highdose) were observed at exposures equivalent to < 2 times the human exposure by AUC at therecommended dose.

Entrectinib-related toxicities in repeat-dose studies in adult rats and dogs, and juvenile rats wereobserved in the central nervous system (convulsions, abnormal gait, tremors) at ≥ 0.2 times the humanexposures by Cmax at the recommended dose, skin (scabs/sores) and decreased red blood cellparameters at ≥ 0.1 times the human exposure by AUC at the recommended dose. In adult rats anddogs, effects on liver (increased ALT and hepatocellular necrosis) were observed at ≥ 0.6 times thehuman exposure by AUC at the recommended dose. In dogs, diarrhoea at ≥ 0.1 times the humanexposure by AUC at the recommended dose and prolongations of QT/QTc interval at ≥ 0.1 times thehuman exposure by Cmax at the recommended dose were also observed.

Juvenile rat toxicology study

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 adulthood in humans). In addition to CNS effects, ptosis andskin effects, decreased RBC parameters and effects on growth and development were observed in thedosing and recovery phases including decreased body weight gain and delayed sexual maturation (at≥ 4 mg/kg/day, approximately 0.1 times the human exposure by AUC at the recommended dose).

Deficits in neurobehavioural assessments including functional observational battery (decreasedlanding foot splay, decreased fore and hind limb grip strength that seemed to manifest later in age) andlearning and memory (at ≥ 8 mg/kg/day, approximately 0.2 times the human exposure by AUC at therecommended dose), and decreased femur length (at ≥ 16 mg/kg/day, approximately 0.3 times thehuman exposure by AUC at the recommended dose) were observed.

Microcrystalline cellulose (E460)

Tartaric acid (E334)

Silica, colloidal anhydrous (E551)

Croscarmellose sodium (E468)

Sodium stearyl fumarate

Mannitol (E421)

Magnesium stearate (E470b)

Titanium dioxide (E171)

Talc

Yellow iron oxide (E172)

Red iron oxide (E172)

Black iron oxide (E172)

Polyethylene glycol 3350

Polyvinyl alcohol (partially hydrolysed)

Not applicable.

2 years.

Do not store above 30°C.

Store in the original package in order to protect from moisture.

Rozlytrek film-coated granules are packaged in a PET/Alu/PE laminated foil sachet. Each cartoncontains 42 sachets.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Roche Registration GmbH

Emil-Barell-Strasse 179639 Grenzach-Wyhlen

Germany

EU/1/20/1460/003

Date of first authorisation: 31 July 2020

Date of latest renewal: 16 May 2024

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu