Repotrectinib

In vitro studies indicate that repotrectinib may induce pregnane X receptor (PXR) regulated enzymes that include CYP2C8, CYP2C9, CYP2C19 and UGT. In vitro data also indicate that repotrectinib inhibits CYP2C8, CYP2C9 and UGT1A1. The in vivo net effect of induction and inhibition, or its clinical relevance, is not known. Co-administration of repotrectinib with CYP2C8, CYP2C9 or CYP2C19 substrates (including but not limited to repaglinide, warfarin, tolbutamide or omeprazole) may alter their exposure.

Repotrectinib is a moderate CYP3A4 inducer. Co-administration of 160 mg repotrectinib once daily for 14 days followed by twice daily dosing for 7 days reduced AUC_0-inf by 69% and C_max by 48% of a single oral dose of midazolam (a CYP3A4 substrate). Caution is advised when CYP3A4 substrates (including but not limited to cisapride, cyclosporin, fentanyl, tacrolimus, alfentanil, sirolimus, everolimus, lovastatin, and simvastatin) are co-administered with repotrectinib, due to risk of therapeutic failure.

In vitro studies indicate that repotrectinib is a CYP2B6 inducer. Co-administration of repotrectinib with sensitive substrates of CYP2B6 substrates (including but not limited to bupropion, efavirenz) may decrease their exposure.

In vitro data indicate that repotrectinib inhibits P-gp, breast cancer resistant protein (BCRP), organic anion-transporting polypeptide (OATP1B1), multidrug and toxin extrusion protein (MATE1) and MATE2-K. Co-administration of AUGTYRO with sensitive substrates of P-gp (including but not limited to dabigatran etexilate, digoxin, edoxaban, or fexofenadine), BCRP (including but not limited to methotrexate, rosuvastatin, sulfasalazine), OATP1B1 (including but not limited to valsartan, statins), MATE1 or MATE2-K (including but not limited to metformin) may increase their exposure. The clinical relevance is unknown.

Co-administration of multiple oral doses of rifampicin (a strong CYP3A4 and P-gp inducer) with a single 160 mg repotrectinib dose reduced repotrectinib AUC_0-inf by 92% and C_max by 79%. Co-administration of repotrectinib with strong or moderate CYP3A4 or P-gp inducers (including but not limited to carbamazepine, phenytoin, rifampicin, St. John’s Wort - Hypericum perforatum, apalutamide, ritonavir) decreases repotrectinib plasma concentrations and should thus be avoided.

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

Repotrectinib has not been studied in patients with moderate (total bilirubin >1.5 to 3 times ULN) or severe (total bilirubin >3 times ULN) hepatic impairment, and repotrectinib should not be used in patients with moderate/severe hepatic impairment.

Repotrectinib is a moderate CYP3A4 inducer, which can decrease progestin or oestrogen exposure to an extent that could reduce the effectiveness of systemically acting hormonal contraceptives including oral contraceptives. Thus, women using systemically acting hormonal contraceptives are advised to use a barrier method.

There are no available data on repotrectinib use in pregnant women. Based on animal studies and its mechanism of action, repotrectinib may cause foetal harm when administered to pregnant women. Repotrectinib should not be used unless clinical condition of the woman requires treatment with repotrectinib. Women of childbearing potential have to use highly effective contraception.

It is unknown whether repotrectinib or its metabolites are excreted in human milk. A risk to the suckling child cannot be excluded. Breast-feeding should be discontinued during treatment with repotrectinib and for 10 days after the final dose.

Women of childbearing potential/Contraception in males and females

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

Female patients of childbearing potential must use highly effective contraception during treatment with repotrectinib and for at least 2 months following the final dose. Repotrectinib may reduce the effectiveness of systemically acting hormonal contraceptives including oral contraceptives. If hormonal contraception is used, females of childbearing potential should be advised to use an additional barrier method of contraception.

Fertility

No fertility studies have been conducted with repotrectinib. The effect of repotrectinib on male and female fertility is unknown.

Repotrectinib has moderate influence on the ability to drive and use machines. Patients should be advised of potential CNS effects and vision disorders with repotrectinib as these effects may influence the ability to drive and use machines. Patients should be advised not to drive or use machines if they are experiencing CNS adverse reactions and vision disorders.

Summary of the safety profile

The most common adverse reactions in adults were dizziness (65%), dysgeusia (57%), constipation (39%), paraesthesia (39%), anaemia (38%), and dyspnoea (31%). The most common serious adverse reactions were pneumonia (6.2%), dyspnoea (3.5%), pleural effusion (3.0%), pyrexia (1.2%), muscular weakness (1.1%), anaemia (1.1%), and pneumonitis (1.1%). Grade ≥ 3 adverse reactions occurred in 43% of patients and anaemia (8.8%), dyspnoea (6.7%), pneumonia (5.7%), blood creatine phosphokinase increased (3.4%), weight increased (3.2%), aspartate aminotransferase increased (2.7%), pleural effusion (2.3%), and neutrophil count decreased (2.1%) were the most frequently reported. Permanent discontinuation due to an adverse reaction occurred in 6.2% patients.

Tabulated list of adverse reactions

Tables 1 and 2 summarise the adverse reactions reported in patients treated with repotrectinib in the TRIDENT-1 study in adults (n=565) and in the CARE study (n=38) including paediatric patients respectively. These reactions are presented by system organ class and by frequency. Frequencies are defined as: 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 frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Unless otherwise stated, the frequencies of adverse reactions are based on all-cause adverse event frequencies identified in patients exposed to repotrectinib with a median duration of 7.6 months in clinical study.

Table 1. Adverse reactions occurring in adult patients treated with repotrectinib:

^a Hyperuricaemia (hyperuricaemia, increased blood uric acid)
^b Dizziness (dizziness, vertigo, dizziness postural, dizziness exertional, vertigo positional)
^c Ataxia (ataxia, gait disturbance, balance disorder, cerebellar ataxia, coordination abnormal, nystagmus)
^d Cognitive disorders (memory impairment, disturbance in attention, cognitive disorder, confusional state, delirium, amnesia, attention deficit hyperactivity disorder, aphasia, altered state of consciousness, depressed level of consciousness, bradyphrenia, delusion, dysgraphia, hallucination, intellectual disability, mental disorder, mental status changes, neurological decompensation)
^e Paraesthesia (paraesthesia, hypoaesthesia, dysaesthesia, burning sensation, anaesthesia, formication)
^f Peripheral sensory neuropathy (neuralgia, neuropathy peripheral, peripheral sensory neuropathy, peripheral motor neuropathy, peripheral sensorimotor neuropathy, polyneuropathy)
^g Sleep disorders (somnolence, insomnia, hypersomnia, sleep apnoea syndrome, sleep disorder, abnormal dreams, narcolepsy, obstructive sleep apnoea syndrome, snoring)
^h Dysgeusia (dysgeusia, taste disorder, ageusia, sensory disturbance, allodynia, hypogeusia, sensory loss)
ⁱ Vision disorders (vision blurred, visual impairment, dry eye, photophobia, visual field defect, conjunctivitis, diplopia, eye pain, periorbital oedema, asthenopia, cataract, eye haematoma, photosensitivity reaction, visual acuity reduced, vitreous floaters, blepharospasm, cataract nuclear, colour blindness, eye infection, eye oedema, eye swelling, eyelid disorder, eyelid injury, eyelids pruritus, glaucoma, iridocyclitis, myopia, night blindness, ophthalmic herpes zoster, orbital oedema)
^j Pneumonitis (pneumonitis, interstetial lung disease)
^k Skeletal fractures (foot fracture, rib fracture, pathological fracture, acetabulum fracture, ankle fracture, femur fracture, fibula fracture, spinal compression fracture, sternal fracture, upper limb fracture)

Table 2. Adverse reactions occurring in paediatric patients ≤18 years old treated with repotrectinib in CARE study*:

^a Hyperuricaemia (hyperuricaemia, increased blood uric acid)
^b Ataxia (gait disturbance, ataxia)
^c Cognitive disorders (aphasia, confusional state, memory impairment, attention deficit hyperactivity disorder, depressed level of consciousness)
^d Sleep disorders (somnolence, insomnia, obstructive sleep apnoea syndrome)
^e Dysgeusia (dysgeusia, allodynia)
^f Peripheral sensory neuropathy (peripheral sensory neuropathy, peripheral motor neuropathy)
^g Vision disorders (vision blurred, eye pain, hemianopia homonymous, photophobia, visual impairment)
^h Skeletal fractures (ankle fracture, foot fracture, stress fracture, fibula fracture, fracture, tibia fracture)
^* Frequencies include data from two adult patients

Description of selected adverse reactions

Dizziness

Among the 565 adult patients who received at least one dose of repotrectinib in TRIDENT-1, dizziness (including dizziness, vertigo, dizziness postural, dizziness exertional, and vertigo positional) were reported in 65.5% (370/565) of patients; Grade 3 dizziness was reported 3.2% (18/565) of patients.

The median time to onset was 7 days (range: 1 day to 2.1 years). Resolution occurred in 187 patients (50.5%) with a median time to resolution of 40.0 weeks (range: 0.1 weeks to 323.6+ weeks). Dose reduction was required in 11.5% (65/565) of patients, and 10.3% (58/565) required dose interruption of repotrectinib due to dizziness.

Ataxia

Ataxia (including ataxia, gait disturbances, balance disorder, cerebellar ataxia, and coordination abnormal) was reported in 29.0% (164/565) of patients; Grade 3 ataxia was reported in 0.5% (3/565) of patients. The median time to onset was 17 days (range: 1 day to 3.1 years). Resolution occurred in 85 patients (51.8%) with a median time to resolution of 28.4 weeks (range: 0.4+ weeks to 257.6+ weeks). Dose reduction was required in 7.6% (43/565) of patients, 5.0% (28/565) required dose interruptions and 0.2% (1/565) discontinued repotrectinib due to ataxia.

Cognitive disorders

Cognitive disorders were reported in 22.3% (126/565) of patients. Cognitive disorders included memory impairment (12.2%), disturbance in attention (10.3%), cognitive disorder (6.2%), confusional state (2.1%), delirium (1.2%), amnesia (0.9%), attention deficit hyperactivity disorder, aphasia (0.7% each), depressed level of consciousness (0.5%), altered state of consciousness, neurological decompensation (0.4% each), bradyphrenia, delusion, dysgraphia, hallucinations, intellectual disability, mental disorder, and mental status change (0.2% each); Grade 3 cognitive disorders were reported in 1.2% (7/565) of patients. The median time to onset of cognitive disorders was 37 days (range: 1 day to 2.1 years). Resolution occurred in 56 patients (44.4%) with a median time to resolution of 69.3 weeks (range: 0.1 weeks to 235.7+ weeks). Dose reduction was required in 1.9% (11/565) of patients, 1.6% (9/565) required dose interruption and 0.9% (5/565) of patients discontinued repotrectinib due to cognitive adverse reactions.

The incidences of reported CNS adverse reactions were similar in patients with or without CNS metastases.

Skeletal fractures

Skeletal fractures (including foot fracture, rib fracture, pathological fracture, acetabulum fracture, ankle fracture, femur fracture, fibula fracture, spinal compression fracture, sternal fracture, upper limb fracture) were reported in 3.5% (20/565) of patients; Grade 3 skeletal fractures were reported in 0.4% (2/565) of patients. The median time to onset was 5.6 months (range:10 days to 2.5 years). Resolution occurred in 10 patients (50.0%) with a median time to resolution of 40 weeks (range: 0.1 weeks to 220.9+ weeks). Dose interruption was required in 0.7% (4/565) of patients. Discontinuation of repotrectinib was required in 0.2% (1/565) of patients due to skeletal fractures.

Skeletal fractures (including ankle fracture, foot fracture, fracture, stress fracture, tibia fracture and fibula fracture) was reported in 18.4% (7/38) of paediatric patients; Grade 3 skeletal fractures were reported in 5.3% (2/38) of paediatric patients. The median time to onset was 4.2 months (range: 25 days to 16.9 months). Resolution occurred in 57.1% (4/7) patients with a time to resolution 10 days-6.7 months. Dose interruption was required in 10.5% (4/38) of patients. Discontinuation of repotrectinib was required in 2.6% (1/38) of paediatric patients due to skeletal fractures.

ILD/pneumonitis

Among the 565 patients treated with repotrectinib, ILD/pneumonitis was reported in 3.2% (18/565) of patients; Grade 3 ILD/pneumonitis was reported in 0.9% (5/565) of patients. The median time to onset was 56 days (18 days to 11.7 months). Resolution occurred in 12 patients (66.7%) with median time to resolution 7.4 weeks (range: 0.6 weeks to 67.7 weeks). Dose interruption was required in 1.4% (8/565) of patients, 0.5% (3/565) of patients required dose reduction, and 0.9% (5/565) of patients permanently discontinued repotrectinib due to ILD/pneumonitis.

Dyspnoea

Among the 565 patients treated with repotrectinib, dyspnoea occurred in 31.3% (177/565) of patients, with Grade 3 in 5.1% (29/565). Median time to onset of dyspnoea was 43 days (range: 1 day to 2.1 years). Resolution occurred in 75 patients (42.4%) with median time to resolution 35.6 weeks (range: 0.1 weeks to 269.1+ weeks). Dose reduction was required in 1.6% (9/565) of patients, 6.5% (37/565) required dose interruptions and 1.1% (6/565) of patients were required to discontinue repotrectinib due to dyspnoea.

Hepatotoxicity

Among the 565 patients treated with repotrectinib, increased alanine transaminase (ALT) occurred in 22.1% (125/565) patients, increased aspartate aminotransferase (AST) occurred in 20.9% (118/565), including Grade 3 increased ALT in 1.8% (10/565) and increased AST in 2.5% (14/565). The median time to onset was 19 days (range: 1 day to 2.9 years). Resolution occurred in 120 patients (78.9%) with median time to resolution 5 weeks (0.7+ weeks to 92.0+ weeks). Dose interruption was required in 3% (17/565) of patients, 1.2% (7/565) of patients required dose reduction.

Vision disorder

Among the 565 patients who received repotrectinib, vision changes occurred in 14.2 % (80/565) of patients, including Grade 3 vision disorder in 0.5% (3/565). Vision disorders included blurred vision (4.1%), visual impairment (2.3%), dry eye (1.6%). Resolution occurred in 34 patients (42.5%) with a range of time to resolution of 0.1 weeks to 226.9+ weeks. Dose interruption was required in 1.2% (7/565) of patients, 0.2% (1/565) of patients required dose reduction, and 0.2% (1/565) of patients permanently discontinued repotrectinib due to vision disorders.

Muscular weakness

Repotrectinib can cause muscle weakness with or without creatine phosphokinase (CPK) elevation. Among the 565 patients treated with repotrectinib, muscle weakness occurred in 21.6% (122/565) of patients, with Grade 3 in 1.9% (11/565). Median time to onset of muscle weakness was 39 days (range: 1 day to 3.4 years). Resolution occurred in 49 patients (40.2%) with median time to resolution 86.6 weeks (0.3 weeks to 236.6+ weeks). Dose interruption was required in 5.5% (31/565) of patients, 4.8% (27/565) of patients required dose reduction, and 0.9% (5/565) of patients permanently discontinued repotrectinib due to muscle weakness.

Paediatric population

The safety of repotrectinib was evaluated in 38 paediatric patients (including 22 paediatric patients <12 years of age, 14 paediatric patients 12-17 years of age and 2 patients ≥18 years of age) with advanced or metastatic tumours harbouring ALK, ROS1, or NTRK1-3 gene fusions in the phase I/II, open-label, single-arm, multicentre, multicohort CARE study. Of the 14 patients between the age of 12 and 17, 7 patients were NTRK positive.

Adverse reactions observed in paediatric patients were comparable in frequency and intensity to those observed in adults except skeletal fractures which were observed at a higher frequency in paediatric patients (18.4%) compared to adults (3.5%). No differences in the spectrum of adverse reactions reported in adults and the paediatric population were evident with no new or unexpected adverse reactions observed. The events reported in the adult population can also be observed in children and adolescents. The most frequent adverse reactions in paediatric patients were constipation, fatigue and headache. The most frequent Grade ≥3 adverse reactions in paediatric patients were weight increased, diarrhoea, and skeletal fractures.

Elderly

Of the 565 patients who received repotrectinib 25% were 65 years or older, and 6% were 75 years of age or older. The frequency of adverse reactions was generally similar for patients <65 years of age and patients ≥65 years of age. The frequencies of serious adverse reactions were higher in patients 65-75 years of age (48%) and ≥75 years of age (63%) compared to patients 18-65 years of age (37%). The most common serious adverse reactions in patients ≥65 years of age were pneumonia, dyspnoea, and pleural effusion. The rate of discontinuations was higher in patients 65-75 years of age (16%) and ≥75 years of age (23%) compared to patients 18-65 years of age (9%).