Entrectinib

Entrectinib is an inhibitor of the tropomyosin receptor tyrosine kinases TRKA, TRKB and TRKC (encoded by NTRK1, NTRK2 and NTRK3), of proto-oncogene tyrosine-protein kinase ROS1 and of anaplastic lymphoma kinase (ALK), with IC50 values of 0.1 to 2 nM. Its major active metabolite, M5, has similar in vitro potency and activity against TRK, ROS1 and ALK.

Mechanism of Action

• Oncogenic fusion proteins: fusion proteins that contain TRK, ROS1 or ALK kinase domains drive tumour formation through hyperactivation of downstream signalling, which leads to unconstrained cell proliferation. Entrectinib competes with ATP at these kinases and blocks that signalling.
• Preclinical activity: it inhibited cancer cell lines from many tumour types, including subcutaneous and intracranial tumours, that carry NTRK, ROS1 or ALK fusion genes, in vitro and in vivo. It crosses the blood–brain barrier.
• Resistance: earlier treatment with other drugs that inhibit the same kinases may confer resistance. Resistance mutations in the TRK and ROS1 kinase domains have been identified after entrectinib was stopped; the causes of primary resistance are not known.

Pharmacokinetics

• Absorption: rapid; peak plasma levels about 4 to 6 hours after a single 600 mg dose, with steady state within about a week (M5: two weeks). Food has no clinically significant effect. In healthy adults the film-coated granules gave a similar AUC and Cmax to the capsules, and capsules given as a suspension (by mouth or by gastric or nasogastric tube) matched whole capsules.
• Distribution: entrectinib and M5 are more than 99% bound to plasma proteins. The volume of distribution (Vz/F) is about 600 L, suggesting extensive distribution.
• Metabolism: mainly by CYP3A4 (about 76%), with minor contributions from other CYPs and UGT1A4. The active metabolite M5 (formed by CYP3A4) and the N-glucuronide M11 (formed by UGT1A4) are the two major circulating metabolites.
• Elimination: after a radiolabelled dose about 83% of the radioactivity was in faeces and 3% in urine. Half-lives are about 20 hours for entrectinib and 40 hours for M5. Pharmacokinetics are linear and do not depend on dose or time.
• Special populations: no dose adjustment is needed for age 65 or over, for hepatic impairment of any Child-Pugh class, or for mild or moderate renal impairment (see Administration and Dosage).

Entrectinib is used as monotherapy. Before treatment, a validated assay must establish NTRK gene fusion status or ROS1 status.

• NTRK gene fusion-positive solid tumours: adults and paediatric patients older than 1 month with solid tumours that have an NTRK gene fusion, who have locally advanced or metastatic disease or where surgical resection is likely to cause severe morbidity, who have not received a prior NTRK inhibitor, and who have no satisfactory treatment options.
• ROS1-positive advanced non-small cell lung cancer (NSCLC): adults not previously treated with ROS1 inhibitors.

• Hypersensitivity to the active substance or to any of the excipients.

The safety data come from 853 patients (762 adults and 91 children) in five clinical studies, with a median exposure of 8.6 months. The most common reactions (20% or more) were fatigue, constipation, diarrhoea, dizziness, dysgeusia, oedema, increased weight, anaemia, increased blood creatinine, nausea, dysaesthesia, pain, vomiting, pyrexia, arthralgia, increased aspartate aminotransferase, dyspnoea, cognitive disorders, cough and increased alanine aminotransferase. The most frequent serious reactions (2% or more) were lung infection (5.3%), fractures (4.1%), dyspnoea (3.6%), cognitive impairment (2.9%), pleural effusion (2.5%) and pyrexia (2.5%). Treatment was permanently stopped because of a reaction in 6.0% of patients.

Very common (≥1/10): urinary tract infection, lung infection; anaemia, neutropenia; increased weight, hyperuricaemia, decreased appetite; dizziness, dysgeusia, dysaesthesia, cognitive disorders, sensory peripheral neuropathy, headache, ataxia, sleep disorders; blurred vision; hypotension; dyspnoea, cough; constipation, diarrhoea, nausea, vomiting, abdominal pain, dysphagia; increased aspartate and alanine aminotransferases; rash; arthralgia, myalgia, fractures, muscular weakness; increased blood creatinine, urinary retention; fatigue, oedema, pain, pyrexia.

Common (≥1/100 to <1/10): dehydration; mood disorders, syncope; congestive heart failure, QTc prolongation on the electrocardiogram; pleural effusion; photosensitivity reaction.

Uncommon (≥1/1,000 to <1/100): tumour lysis syndrome, myocarditis.

Fatal outcomes among grade 3 to 5 events included pneumonia (4), dyspnoea (3), heart failure (1) and tumour lysis syndrome (1). Fractures were reported in 29.7% (27/91) of the children treated; most resolved.

Entrectinib is metabolised mainly by CYP3A4, so strong modulators of this enzyme change its exposure a great deal.

• Strong or moderate CYP3A inhibitors (for example ritonavir, saquinavir, ketoconazole, itraconazole, voriconazole, posaconazole, grapefruit, Seville oranges): itraconazole raised entrectinib AUC by 600% and Cmax by 173%. Avoid the combination; if it cannot be avoided in an adult, limit it to 14 days and reduce the dose (see Administration and Dosage).
• CYP3A or P-gp inducers (carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin, St John’s wort, apalutamide, ritonavir, dexamethasone): rifampicin cut entrectinib AUC by 77% and Cmax by 56%. Avoid the combination; if dexamethasone cannot be avoided, the healthcare professional decides its dose.
• P-gp inhibitors (for example verapamil, nifedipine, felodipine, fluvoxamine, paroxetine): a marked effect is not expected, but caution is advised because entrectinib exposure may rise.
• Acid-reducing medicines: lansoprazole lowered entrectinib AUC by 25% and Cmax by 23%. No adjustment is needed with proton pump inhibitors, H2 blockers or antacids.
• Sensitive CYP3A4 substrates with a narrow therapeutic range (cisapride, ciclosporin, ergotamine, fentanyl, pimozide, quinidine, tacrolimus, alfentanil, sirolimus): entrectinib is a weak CYP3A4 inhibitor (midazolam AUC rose by 50%), so caution is advised.
• Transporter substrates: digoxin exposure rose slightly (Cmax 28%, AUC 18%), not considered clinically relevant, but the effect on more sensitive P-gp substrates such as dabigatran etexilate is unknown. Caution is advised with sensitive oral BCRP substrates (methotrexate, mitoxantrone, topotecan, lapatinib) and OATP1B1 substrates (atorvastatin, pravastatin, rosuvastatin, repaglinide, bosentan) because absorption may increase.
• CYP2C substrates: entrectinib may induce CYP2C enzymes and UGT, so exposure to CYP2C8, CYP2C9 and CYP2C19 substrates (for example repaglinide, warfarin, tolbutamide, omeprazole) may fall.
• Hormonal contraceptives: it is unknown whether entrectinib reduces their effect, so a barrier method should be added.
• QTc-prolonging medicines: use with entrectinib should be avoided (see Special Instructions).
• Food: avoid grapefruit, grapefruit juice and Seville oranges. Otherwise it can be taken with or without food.
• Interaction studies have been done only in adults.

Treatment is started by a physician experienced in the use of anticancer medicinal products, after NTRK gene fusion or ROS1 status has been established with a validated assay. Rozlytrek is for oral or enteral (gastric or nasogastric tube) use and can be taken with or without food, but not with grapefruit, grapefruit juice or Seville oranges. The prescriber chooses capsules or film-coated granules according to the dose required and the patient’s needs. Treatment continues until disease progression or unacceptable toxicity.

Recommended Dose

• Adults: 600 mg once daily (capsules).
• Children older than 6 months: once-daily dose by body surface area (BSA): up to 0.42 m², 250 mg/m²; 0.43–0.50 m², 100 mg; 0.51–0.80 m², 200 mg; 0.81–1.10 m², 300 mg; 1.11–1.50 m², 400 mg; 1.51 m² or more, 600 mg. The BSA bands are based on matching exposures to a target dose of 300 mg/m². For the 250 mg/m² band, capsules prepared as an oral suspension allow 10 mg dosing steps.
• Children older than 1 month up to 6 months: 250 mg/m² BSA once daily, using capsules prepared as an oral suspension (dose rounded to the nearest 10 mg).
• Children aged 1 month or younger: safety and efficacy have not been established, and no dose can be recommended.

Forms and How to Take Them

• Hard capsules (100 mg, 200 mg): for patients who can swallow whole capsules and need 100 mg or a multiple of 100 mg. Swallow whole; do not crush or chew.
• Capsules as an oral suspension: for patients who cannot swallow capsules or need enteral administration; prepared as described in section 6.6 of the SmPC. Give immediately and discard the suspension if not used within 2 hours. The patient drinks water afterwards; through a tube, the tube is flushed with water or milk afterwards.
• Film-coated granules (50 mg sachets): for children who cannot swallow capsules but can swallow soft food, when the dose is 50 mg or a multiple of 50 mg. Sprinkle on one or more spoonfuls of soft food (for example apple purée, yoghurt, pudding) and give within 20 minutes of mixing, then give water. Do not crush or chew the granules (bitter taste) and do not divide a sachet to make a smaller dose. Sachets per dose: 100 mg, 2; 200 mg, 4; 300 mg, 6; 400 mg, 8; 600 mg, 12.

Dose Reduction

The dose may be reduced up to twice according to tolerability (adults and children older than 1 month). Treatment is permanently discontinued if the patient cannot tolerate it after two reductions, and in adults if 200 mg once daily is not tolerated.

• 250 mg/m²: first reduction to two thirds of the starting dose, second to one third (capsules as suspension allow 10 mg steps).
• 100 mg: 50 mg or 100 mg once daily on alternating days (100 mg Monday, Wednesday, Friday and Sunday; 50 mg Tuesday, Thursday and Saturday), then 50 mg once daily.
• 200 mg: 150 mg, then 100 mg. 300 mg: 200 mg, then 100 mg. 400 mg: 300 mg, then 200 mg. 600 mg: 400 mg, then 200 mg.

Dose Modifications for Adverse Reactions

Treatment may be interrupted, reduced or stopped for the reactions below (NCI CTCAE grades) or on the prescriber’s assessment.

• Congestive heart failure: grade 2 or 3, withhold until grade 1 or lower, resume at a reduced dose. Grade 4, withhold until grade 1 or lower, then resume at a reduced dose or discontinue as clinically appropriate.
• Cognitive disorders: intolerable grade 2, withhold until grade 1 or baseline, resume at the same or a reduced dose. Grade 3, withhold, resume at a reduced dose. Grade 4, for prolonged, severe or intolerable events, discontinue as clinically appropriate.
• Hyperuricaemia (symptomatic or grade 4): start urate-lowering medicine, withhold until signs and symptoms improve, resume at the same or a reduced dose.
• QT interval prolongation: QTc 481–500 ms, withhold until baseline, resume at the same dose. QTc above 500 ms, withhold until baseline, resume at the same dose if the cause is found and corrected, otherwise at a reduced dose. Torsade de pointes, polymorphic ventricular tachycardia or signs of serious arrhythmia: discontinue permanently.
• Transaminase elevations: grade 3, withhold until grade 1 or baseline; resume at the same dose if resolved within 4 weeks (reduced dose for a recurrent grade 3 event that resolves within 4 weeks); discontinue if not resolved within 4 weeks. Grade 4, withhold; resume at a reduced dose if resolved within 4 weeks; discontinue if not resolved within 4 weeks or if grade 4 recurs. ALT or AST above 3 times the upper limit of normal with total bilirubin above 2 times (without cholestasis or haemolysis): discontinue permanently.
• Anaemia or neutropenia (grade 3 or 4): withhold until grade 2 or lower or baseline, resume at the same or a reduced dose.
• Other clinically relevant reactions (grade 3 or 4): withhold until grade 1 or baseline; resume at the same or a reduced dose if resolved within 4 weeks; consider permanent discontinuation if not resolved within 4 weeks; discontinue for recurrent grade 4.

With CYP3A Inhibitors

Avoid strong or moderate CYP3A inhibitors in adults and in children older than 1 month. If an adult cannot avoid them, limit use to 14 days and reduce entrectinib to 100 mg once daily with a strong inhibitor or 200 mg once daily with a moderate inhibitor. After the inhibitor is stopped, the previous dose can be resumed; a wash-out period may be needed for inhibitors with a long half-life.

Special Populations

• Elderly: no dose adjustment at 65 years or over (cognitive events were more frequent in this age group).
• Hepatic impairment: no dose adjustment in mild, moderate or severe impairment (Child-Pugh A, B or C); in severe impairment, monitor liver function and adverse reactions closely.
• Renal impairment: no adjustment in mild or moderate impairment; not studied in severe impairment.

Missed or Vomited Dose

A missed dose can be made up unless the next dose is due within 12 hours. If vomiting occurs straight after whole capsules, the dose may be repeated. If a caregiver gives the oral suspension and the child vomits or spits out part or all of the dose straight away, the caregiver should ask the healthcare professional what to do.

Efficacy Across Tumour Types

The benefit in NTRK fusion-positive tumours was established in single-arm trials in a relatively small number of patients, based on response rate and duration of response in a limited number of tumour types. The effect may differ by tumour type and by other genomic alterations, so entrectinib should be used only when there are no satisfactory treatment options.

Cognitive Disorders

Confusion, mental status changes, memory impairment and hallucinations were reported, more often in patients over 65. Patients should be monitored for cognitive changes, counselled about them, and told not to drive or use machines until symptoms resolve. Modify treatment as described under dose modifications.

Fractures

Fractures occurred in 29.7% (27/91) of children in clinical trials, mostly under 12 years of age and in the lower limb (femur, tibia, foot, fibula). Some followed a fall or other trauma, and 14 children had more than one fracture. Most resolved; five children had treatment interrupted and six stopped it because of fractures. Fractures also occurred in adults. Anyone with pain, abnormal gait, changed mobility or deformity should be evaluated promptly.

Hyperuricaemia

Serum uric acid should be measured before starting and periodically during treatment, with monitoring for signs and symptoms. Urate-lowering medicines are started as clinically indicated, and entrectinib is withheld for signs and symptoms.

Congestive Heart Failure

Congestive heart failure occurred in 5.4% of patients, with or without a history of heart disease, and resolved in 63.0% after management and/or dose reduction or interruption. In patients with symptoms or risk factors, left ventricular ejection fraction should be assessed before starting. Patients with shortness of breath or oedema should be evaluated and treated as appropriate.

QTc Interval Prolongation

QTc prolongation has been seen. Avoid entrectinib in patients with a baseline QTc above 450 ms, congenital long QT syndrome, electrolyte imbalance or significant heart disease (recent myocardial infarction, heart failure, unstable angina, bradyarrhythmias), and in patients taking medicines known to prolong QTc. If the physician judges that the benefit outweighs the risk, add monitoring and consider specialist advice. An ECG and electrolytes are recommended at baseline and after 1 month, then periodically.

Pregnancy, Contraception, Breastfeeding and Fertility

• Pregnancy test and contraception: women of childbearing potential need a medically supervised pregnancy test before starting and must use highly effective contraception during treatment and for at least 5 weeks after the last dose. Women using systemic hormonal contraceptives should add a barrier method.
• Men: male patients with female partners of childbearing potential must use highly effective contraception during treatment and for at least 3 months after the last dose.
• Pregnancy: no data in pregnant women; animal studies and the mechanism of action indicate that entrectinib may cause foetal harm. It is not recommended in pregnancy or in women of childbearing potential not using contraception. Patients should tell their doctor if pregnancy occurs.
• Breastfeeding: it is unknown whether entrectinib or its metabolites pass into human milk and a risk cannot be excluded, so breastfeeding should be stopped during treatment.
• Fertility: no animal fertility studies have been done.

Excipients

The capsules contain lactose (65 mg in the 100 mg capsule, 130 mg in the 200 mg capsule); patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take them. The 200 mg capsule contains sunset yellow FCF (E110), which may cause allergic reactions.

Effect on Driving

Rozlytrek has a moderate influence on the ability to drive and use machines. Patients with cognitive reactions, syncope, blurred vision or dizziness should not drive or use machines until the symptoms resolve.

• Capsules: keep in the original package with the bottle tightly closed to protect from moisture; no temperature limit is stated. The bottles are HDPE with a child-resistant, tamper-evident closure and silica gel desiccant in the cap (30 capsules of 100 mg or 90 capsules of 200 mg).
• Film-coated granules: do not store above 30 °C; keep in the original package to protect from moisture.
• Oral suspension made from capsules: do not store above 30 °C and use within 2 hours.

Capsules: 4 years. Film-coated granules: 2 years. Oral suspension prepared from the capsules: use immediately and discard if not used within 2 hours.

Prescription only (Rx), under restricted medical prescription (Annex II B of the marketing authorisation), and started by a physician experienced in the use of anticancer medicinal products. Rozlytrek is taken at home (capsules, granules or capsules as an oral suspension), so it is supplied to the patient or to the treating clinic on prescription.