Entrectinib

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

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

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 CYP2C19 substrates (e.g. repaglinide, warfarin, tolbutamide or omeprazole) may decrease their exposure.

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

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

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

Co-administration of entrectinib with a strong or moderate CYP3A or P-gp inducer decreases entrectinib plasma concentrations, which may reduce efficacy of entrectinib, and should be avoided.

Co-administration of multiple oral doses of rifampin, a strong CYP3A inducer, with a single oral dose of entrectinib reduced entrectinib AUC_inf by 77% and C_max 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-Hypericum perforatum-, apalutamide, ritonavir) should be avoided.

Although, a marked effect of inhibitory P-gp medicinal products on entrectinib pharmacokinetics is not 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 to risk of increased entrectinib exposure.

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 C_max by 28% and AUC by 18%. The renal clearance of digoxin was similar between treatments of digoxin alone and digoxin co-administered with entrectinib, indicating minimal effect of entrectinib on renal clearance of digoxin.

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

Co-administration of entrectinib with a strong or moderate CYP3A inhibitor increases entrectinib plasma concentrations, which could increase the frequency or severity of adverse reactions.

The concomitant use of strong or moderate CYP3A inhibitors in adult and paediatric patients older than 1 month should be avoided.

For adults, if co-administration is unavoidable, the use of strong or moderate CYP3A inhibitors with entrectinib should be limited to 14 days and the entrectinib dose should be reduced as follows:

• 100 mg once daily for use with strong CYP3A inhibitors
• 200 mg once daily for use with moderate CYP3A inhibitors.

After discontinuation of the concomitant strong or moderate CYP3A inhibitors, the entrectinib dose that was taken prior to initiating the strong or moderate CYP3A inhibitor can be resumed. A wash-out period may be required for CYP3A4 inhibitors with a long half-life.

Co-administration of itraconazole, a strong CYP3A4 inhibitor, with a single oral dose of entrectinib increased AUC_inf by 600% and C_max 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, dose adjustment of entrectinib is required.

Entrectinib has not been studied in patients with severe renal impairment.

Patients with severe hepatic impairment should be carefully monitored for hepatic function and adverse reactions.

It is currently unknown whether entrectinib may reduce the effectiveness of systemically acting hormonal contraceptives. Therefore, women using systemically acting hormonal contraceptives are advised to add a barrier method.

There are no available data from the use of entrectinib in pregnant women. Based on animal studies and its mechanism of action, entrectinib may cause foetal harm when administered to a pregnant woman.

Entrectinib is not recommended during pregnancy and in women of childbearing potential not using contraception.

Female patients receiving entrectinib should be advised of the potential harm to the foetus. Female patients 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-fed children cannot be excluded. Breast-feeding should be discontinued during treatment with entrectinib.

Women of childbearing potential/Contraception in males and females

Female patients of childbearing potential should have medically supervised pregnancy testing prior to initiating entrectinib therapy.

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

It is currently unknown whether entrectinib may reduce the effectiveness of systemically acting hormonal contraceptives. Therefore, women using systemically acting hormonal contraceptives should be advised to add a barrier method.

Male patients with female partners of childbearing potential must use highly effective contraceptive methods during treatment and for at least 3 months following the last dose of entrectinib.

Fertility

No fertility studies in animals have been performed to evaluate the effect of entrectinib.

Entrectinib has moderate influence on the ability to drive and use machines. Patients should be instructed not to drive or use machines until the symptoms resolve, if they experience cognitive adverse reactions, syncope, blurred vision, or dizziness, during treatment with entrectinib.

Summary of the safety profile

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%), pleural effusion (2.5%) and pyrexia (2.5%). Permanent discontinuation due to an adverse reaction occurred in 6.0% of patients.

Tabulated list of adverse reactions

Table 1 summarises the adverse drug reactions (ADRs) occurring in 762 adult and 91 paediatric patients treated with entrectinib 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 in adult and paediatric patients (TAPISTRY). The median duration of exposure was 8.6 months.

Table 2 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 of selected adverse reactions reflect exposure to entrectinib in this expanded paediatric safety population (n=91). The safety profile observed in the expanded paediatric population was consistent with the known paediatric safety profile from the integrated safety population in Table 1 below.

Adverse drug reactions are listed by MedDRA system organ class. The following categories of frequency 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, the adverse reactions are presented in order of decreasing frequency.

Table 1. Adverse drug reactions occurring in adult and paediatric patients treated with entrectinib in clinical trials (n=853):

^* 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, upper respiratory 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, mental status changes, hallucination, delirium, disorientation, brain fog, attention deficit hyperactivity disorder, ‘visual hallucination’,‘auditory hallucination’, mental impairment, mental disorder)
⁶ Periphery sensory neuropathy (neuralgia, neuropathy peripheral, peripheral motor neuropathy, peripheral sensory neuropathy)
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 right ventricular 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, hand fracture, 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 compression fracture, 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, peripheral swelling)
¹⁸ Pain (back pain, neck pain, musculoskeletal chest pain, musculoskeletal pain, pain in extremity)

Table 2. Adverse drug reactions occurring in paediatric patients treated with entrectinib in clinical trials (n=91):

% refers to all grades
¹ Infant/toddlers (≥28 days to <24 months): Grade ≥3 reactions reported were neutropenia, weight increased, lung infection, anaemia, AST increased, abdominal pain, and urinary tract infection
² Children (≥24 months to <12 years): Grade ≥3 reactions reported were neutropenia, weight increased, fractures, lung infection, 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, decreased appetite, dehydration, hypotension, muscular weakness, oedema, and vomiting
³ Adolescents (≥12 to <18 years of age): Grade ≥3 reactions reported were neutropenia, weight increased, fracture, lung infection, and headache

Description of selected adverse reactions

Cognitive disorders

A variety of cognitive symptoms was reported across clinical trials. These included events 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%) and mental disorder (0.1%). Grade 3 cognitive disorders were reported in 3.6% of patients. Adult patients who had central nervous system (CNS) disease at baseline had a higher frequency of these adverse reactions (30%) compared to those without CNS disease (22.6%). The median time to onset for cognitive disorders was 0.95 months. In the paediatric population, 2.2% (2/91) of patients experienced disturbance in attention of Grade 1 severity and 2.2% (2/91) of patients experienced disturbance in attention of Grade 2 severity.

Fractures

Fractures were experienced by 9.1% (69/762) of adult patients and 29.7% (27/91) of paediatric patients. 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) and some fractures occurred in the setting of a fall or other trauma.

The median time to fracture was 8.11 months (range: 0.26 months to 45.34 months) in adults. Entrectinib was interrupted in 26.1% of adults that experienced fractures. Eighteen adult patients had entrectinib treatment interrupted and 2 adult patients discontinued entrectinib due to fractures. Entrectinib dose 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 experienced more than one occurrence of fracture. In paediatric patients, fractures mostly occurred in patients less than 12 years of age. Fractures resolved in 85.2% (23/27) of paediatric patients. The median time to fracture was 4.3 months (range: 2.0 months to 28.65 months) in paediatric patients. Twelve patients experienced Grade 2 fractures and 10 patients experienced Grade 3 fractures. Seven of the Grade 3 fractures were serious. Entrectinib was interrupted in 18.5% (5/27) of paediatric patients who experienced fractures. Six paediatric patients discontinued entrectinib due to fractures. Entrectinib dose was reduced for one paediatric patient.

Ataxia

Ataxia (including events of ataxia, balance disorder, and gait disturbances) was reported in 15.1% of patients. 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 of patients (55.8%) recovered from ataxia. Ataxia related adverse reactions were observed more frequently in elderly patients (24.2%) compared to patients below 65 years of age (11.8%).

Syncope

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

QTc interval prolongation

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

Peripheral sensory neuropathy

Peripheral sensory neuropathy was reported in 16.2% of patients. The median time to onset was 0.71 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

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 months to 49.61 months). The median duration of eye disorders was 1.2 months (range 0.03 months to 14.98 months). 54% of patients recovered from the eye disorder adverse reactions.

Paediatric population

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

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

Adverse reactions and laboratory abnormalities of Grade 3 or 4 severity occurring more frequently (at least 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 safety population. Grade 3 to 4 events that occurred at a frequency ≥5% were neutropenia (19.8%), weight increased (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 the overall safety profile of entrectinib in paediatric patients.

Elderly

Among the 853 patients who received entrectinib across clinical trials, 227 (26.6%) patients were 65 years or older and 53 (6.2%) were 75 years or older. The overall safety profile of entrectinib in elderly 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 elderly compared to patients less than 65 years old were dizziness (44.9% vs 33.4%), blood creatinine increased (35.7% vs 30%), hypotension (19.8% vs 14.5%), and ataxia (24.2% vs 11.8%).