Augtyro Product Monograph

RECENT MAJOR LABEL CHANGES

Table of Contents

Certain sections or subsections that are not applicable at the time of the preparation of the most recent authorized product monograph are not listed.

RECENT MAJOR LABEL CHANGES .......................................................................................... 2

Table of Contents ................................................................................................................. 2

Part 1: Healthcare Professional Information.......................................................................... 4

1. 1.

   Indications..................................................................................................................... 4

   1.1. Pediatrics .................................................................................................................... 4

   1.2. Geriatrics .................................................................................................................... 4

2. 2. Contraindications .......................................................................................................... 4
3. 4.

   Dosage and Administration ............................................................................................ 4

   4.1. Dosing Considerations ............................................................................................... 4

   4.2. Recommended Dose and Dosage Adjustment .......................................................... 4

   4.4. Administration ........................................................................................................... 7

   4.5. Missed Dose ............................................................................................................... 7

4. 5. Overdose ....................................................................................................................... 7
5. 6. Dosage Forms, Strengths, Composition, and Packaging .................................................. 7
6. 7.

   Warnings and Precautions ............................................................................................. 8

   Carcinogenesis and Genotoxicity ........................................................................................... 8

   Hepatic/Biliary/Pancreatic ..................................................................................................... 8

   Monitoring and Laboratory Tests ........................................................................................... 8

   Musculoskeletal ...................................................................................................................... 8

   Neurologic .............................................................................................................................. 9

   Ophthalmologic .................................................................................................................... 10

   Reproductive Health ............................................................................................................. 10

   Respiratory ........................................................................................................................... 11

   7.1. Special Populations .................................................................................................. 11

   7.1.1. Pregnancy ......................................................................................................... 11

   7.1.2. Breastfeeding ................................................................................................... 12

   7.1.3. Pediatrics .......................................................................................................... 12

   7.1.4. Geriatrics .......................................................................................................... 12

7. 8.

   Adverse Reactions ....................................................................................................... 12

   8.1. Adverse Reaction Overview ..................................................................................... 12

   8.2. Clinical Trial Adverse Reactions ............................................................................... 13

   8.3. Less Common Clinical Trial Adverse Reactions ........................................................ 14

   8.4. Abnormal Laboratory Findings: Hematologic, Clinical Chemistry, and Other Quantitative Data ................................................................................................................. 14

8. 9.

   Drug Interactions ......................................................................................................... 15

   9.2. Drug Interactions Overview ..................................................................................... 15

   9.4. Drug-Drug Interactions ............................................................................................ 16

   9.5. Drug-Food Interactions ............................................................................................ 18

   9.6. Drug-Herb Interactions ............................................................................................ 18

   9.7. Drug-Laboratory Test Interactions........................................................................... 18

9. 10.

   Clinical Pharmacology .................................................................................................. 18

   10.1. Mechanism of Action ............................................................................................... 18

   10.2. Pharmacodynamics .................................................................................................. 18

   10.3. Pharmacokinetics ..................................................................................................... 19

10. 11. Storage, Stability, and Disposal .................................................................................... 20

Part 2: Scientific Information .............................................................................................. 21

1. 13. Pharmaceutical Information ........................................................................................ 21
2. 14.

   Clinical Trials ............................................................................................................... 21

   14.1. Clinical Trials by Indication ...................................................................................... 21

3. 16. Non-Clinical Toxicology ................................................................................................ 23

Patient Medication Information ......................................................................................... 24

Part 1: Healthcare Professional Information

1. Indications

AUGTYRO (repotrectinib capsules) is indicated for:

• Treatment of adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC).

1.1. Pediatrics

Pediatrics (< 18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

1.2. Geriatrics

Geriatrics (> 65 years of age): No overall differences in safety and efficacy were reported between elderly patients (≥ 65 years) and younger patients (< 65 years).

2. Contraindications

AUGTYRO is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 Dosage Forms, Strengths, Composition, and Packaging.

4. Dosage and Administration

4.1. Dosing Considerations

Select patients with locally advanced or metastatic NSCLC for treatment with AUGTYRO based on the presence of ROS1 rearrangement(s) in tumour specimens (see 14 Clinical Trials).

Prior to initiating AUGTYRO, discontinue strong and moderate CYP3A inhibitors for 3 to 5 elimination half-lives of the CYP3A inhibitor (see 9 Drug Interactions and 10 Clinical Pharmacology).

4.2. Recommended Dose and Dosage Adjustment

The recommended dosage of AUGTYRO is 160 mg orally once daily for 14 days, then increase to 160 mg twice daily until disease progression or unacceptable toxicity.

AUGTYRO may be taken with or without food.

Dosage Modifications for Adverse Reactions

The recommended dosage reductions of AUGTYRO for the management of adverse reactions are provided in Table 1:

Table 1 - Recommended Dose Reductions for AUGTYRO Adverse Reactions

Recommended dosage modifications of AUGTYRO for the management of adverse reactions are provided in Table 2.

Table 2 - Recommended Dosage Modifications for AUGTYRO Adverse Reactions

*Graded per Common Terminology Criteria for Adverse Events V4.03

Special Populations

Pediatrics

Health Canada has not authorized an indication for pediatric use (see 1.1 Pediatrics).

Geriatrics

No dose adjustment is recommended for patients aged 65 years or older (see 10.3 Pharmacokinetics).

Renal Impairment

No dose adjustment is recommended for patients with mild or moderate renal impairment (eGFR 30 to

90 mL/min). The recommended dosage of repotrectinib has not been established in patients with severe renal impairment or kidney failure (eGFR < 30 mL/min), or patients on dialysis.

Hepatic Impairment

No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin > upper limit of normal [ULN] to 1.5 × ULN or AST > ULN). The recommended dosage of repotrectinib has not been established in patients with moderate (total bilirubin >1.5 to 3 x ULN with any AST) or severe (total bilirubin > 3 x ULN with any AST) hepatic impairment (see 10.3 Pharmacokinetics, Special Populations and Conditions).

4.4. Administration

Instruct patients to swallow capsules whole at the same time every day as prescribed. Do not open, crush, chew, or dissolve the contents of the capsule.

4.5. Missed Dose

If a dose is missed or if a patient vomits at any time after taking a dose, instruct patients to resume subsequent doses as prescribed. Two doses should not be taken at the same time.

5. Overdose

1. 6. Dosage Forms, Strengths, Composition, and Packaging

Table 3 – Dosage Forms, Strengths, and Composition

Description

40 mg: White opaque cap, and body, hard shell capsules, filled with a white to off-white powder which may appear as a plug. “REP 40” is imprinted in blue text on the cap. Supplied in bottles of 60 and 120 capsules.

160 mg: Blue opaque cap and body, hard shell capsules, filled with a white to off-white powder which may appear as a plug. “REP 160” is imprinted in white text on the cap. Supplied in bottles of 14 and 60 capsules.

7. Warnings and Precautions

Carcinogenesis and Genotoxicity

See 16 Non-Clinical Toxicology.

Hepatic/Biliary/Pancreatic

Hepatotoxicity

AUGTYRO can cause hepatotoxicity.

Among the 426 patients treated with AUGTYRO, increased alanine transaminase (ALT) occurred in 38%, increased aspartate aminotransferase (AST) occurred in 41%, including Grade 3 or 4 increased ALT in 3.3% and increased AST in 2.9%. The median time to onset of increased ALT or AST was 15 days (1 day to 2 years). Increased ALT or AST leading to dose interruptions or reductions occurred in 2.8% and 1.2% of patients, respectively. Hyperbilirubinemia leading to dose interruptions occurred in 0.5%.

Monitor liver function tests, including ALT, AST and bilirubin as clinically indicated. Withhold and then resume at the same or reduced dose upon improvement, or permanently discontinue AUGTYRO based on the severity (see 4.2 Recommended Dose and Dosage Adjustment).

Monitoring and Laboratory Tests

Hyperuricemia

AUGTYRO can cause hyperuricemia.

Among the 426 patients treated with AUGTYRO, 21 patients (5%) experienced hyperuricemia reported as an adverse reaction and 0.7% of patients experienced Grade 3 or 4 hyperuricemia.

Monitor serum uric acid levels prior to initiating AUGTYRO and periodically during treatment. Initiate treatment with urate-lowering medications as clinically indicated. Withhold and then resume at the same or reduced dose upon improvement, or permanently discontinue AUGTYRO based on severity (see 4.2 Recommended Dose and Dosage Adjustment).

Musculoskeletal

Skeletal Fractures

AUGTYRO can cause skeletal fractures.

Among 426 adult patients who received AUGTYRO, fractures occurred in 2.3%. Fractures involved the ribs (0.5%), feet (0.5%), spine (0.2%), acetabulum (0.2%), sternum (0.2%), and ankles (0.2%). Some fractures occurred at sites of disease and prior radiation therapy. The median time to fracture was 129 days (31 days to 2.1 years). AUGTYRO was interrupted in 0.3% of patients.

Of 26 evaluable patients in an ongoing open-label study in pediatric patients, fractures occurred in one 12-year-old patient (ankle/foot) and one 10-year-old patient (stress fracture). AUGTYRO was interrupted in both patients. AUGTYRO is not approved for use in pediatric patients (see 1.1 Pediatrics).

Promptly evaluate patients with signs or symptoms (e.g., pain, changes in mobility, deformity) of fractures. There are no data on the effects of AUGTYRO on healing of known fractures and risk of future fractures.

Myalgia

AUGTYRO can cause myalgia with or without creatine phosphokinase (CPK) elevation.

Among the 426 patients treated with AUGTYRO, myalgia occurred in 13% of patients, with Grade 3 in 0.7%. Median time to onset of myalgia was 26 days (1 day to 2 years). Concurrent increased CPK within a 7-day window was observed in 3.5% of patients. AUGTYRO was interrupted in one patient with myalgia and concurrent CPK elevation.

Advise patients to report any unexplained muscle pain, tenderness, or weakness.

Monitor serum CPK levels during AUGTYRO treatment and monitor CPK levels as needed in patients reporting unexplained muscle pain, tenderness, or weakness. Initiate supportive care as clinically indicated. Based on severity, withhold and then resume AUGTYRO at the same or reduced dose upon improvement (see 4.2 Recommended Dose and Dosage Adjustment).

Neurologic

Central Nervous System Effects

AUGTYRO can cause central nervous system (CNS) adverse reactions.

Among the 426 patients who received AUGTYRO in Study TRIDENT-1, a broad spectrum of CNS adverse reactions including dizziness, ataxia, and cognitive disorders occurred in 77% of patients, with Grade 3 or 4 events occurring in 4.5% of patients.

Dizziness, including vertigo, occurred in 65% of patients; Grade 3 dizziness occurred in 2.8% of patients. The median time to onset was 7 days (1 day to 1.4 years). Dose interruption was required in 9% of patients, and 12% required dose reduction of AUGTYRO due to dizziness.

Ataxia, including gait disturbance and balance disorder, occurred in 28% of patients; Grade 3 ataxia occurred in 0.5% of patients. The median time to onset was 15 days (1 day to 1.6 years). Dose interruption was required in 5% of patients, 8% required dose reduction, and one patient (0.2%) permanently discontinued AUGTYRO due to ataxia.

Cognitive impairment, including memory impairment and disturbance in attention, occurred in 25% of patients. Cognitive impairment included memory impairment (15%), disturbance in attention (12%), and confusional state (2%); Grade 3 cognitive impairment occurred in 0.9% of patients. The median time to onset of cognitive disorders was 37 days (1 day to 1.4 years). Dose interruption was required in 2% of patients, 2.1% required dose reduction, and 0.5% patients permanently discontinued AUGTYRO due to cognitive adverse reactions.

Mood disorders occurred in 6% of patients. Mood disorders occurring in > 1% of patients included anxiety (2.6%); Grade 4 mood disorders (mania) occurred in 0.2% of patients. Dose interruption was required in 0.2% of patients and 0.2% of patients required a dose reduction due to mood disorders.

Sleep disorders including insomnia and hypersomnia occurred in 18% of patients. Sleep disorders observed in > 1% of patients were somnolence (9%), insomnia (6%) and hypersomnia (1.6%). Dose interruption was required in 0.7% of patients, and 0.2% of patients required a dose reduction due to sleep disorders.

The incidences of CNS adverse reactions observed were similar in patients with and without CNS metastases.

Advise patients and caregivers of the risk of CNS adverse reactions with AUGTYRO. Advise patients not to drive or use machines if they are experiencing CNS adverse reactions. Withhold and then resume at same or reduced dose upon improvement, or permanently discontinue AUGTYRO based on severity (see 4.2 Recommended Dose and Dosage Adjustment).

Peripheral Neuropathy

Among the 426 patients who received AUGTYRO, peripheral neuropathy occurred in 49% of patients, including Grade 3 peripheral neuropathy in 1%. Peripheral neuropathy included paresthesia (34%), neuralgia (12%), neuropathy peripheral (4%), and peripheral sensory neuropathy 4%). The median time to onset was 13 days (1 day to 2.3 years). Dose interruption was required in 2.8% of patients, 3.3% of patients required dose reduction, and 0.2% of patients permanently discontinued AUGTYRO due to peripheral neuropathy.

Advise patients and caregivers of the risk of peripheral neuropathy with AUGTYRO. Advise patients not to drive or use machines if they are experiencing peripheral neuropathy. Withhold and then resume at same or reduced dose upon improvement, or permanently discontinue AUGTYRO based on severity (see 4.2 Recommended Dose and Dosage Adjustment).

Ophthalmologic

Vision Disorders

Among the 426 patients who received AUGTYRO, vision disorders occurred in 12% of patients, including Grade 3 vision disorder in 1%. Vision disorders included blurred vision (4%), visual impairment (2%), dry eye (1%). The median time to onset was 39 days (2 days to 1.8 years). Dose interruption was required in 0.9% of patients, 0.2% of patients required dose reduction, and 0.2% of patients permanently discontinued AUGTYRO due to vision disorders.

Advise patients and caregivers of the risk of vision disorders with AUGTYRO. Advise patients not to drive or use machines if they are experiencing vision impairment. Withhold and then resume at same or reduced dose upon improvement, or permanently discontinue AUGTYRO based on severity (see 4.2 Recommended Dose and Dosage Adjustment).

Reproductive Health

• Fertility

Dedicated fertility studies were not conducted with repotrectinib. There were no effects on male and female reproductive organs observed in general repeat-dose toxicology studies of up to 3 months conducted in rats and monkeys, at any dose level tested, equivalent to approximately 3 times the human exposure at the 160 mg twice daily dose, based on AUC.

• Teratogenic Risk

Based on literature reports in humans with congenital mutations leading to changes in tropomyosin receptor kinase (TRK) signaling, findings from animal studies, and its mechanism of action, AUGTYRO can cause fetal harm when administered to a pregnant woman.

There are no available data on AUGTYRO use in pregnant women. Administration of repotrectinib to pregnant rats resulted in fetal malformations at predicted maternal exposures approximately 0.3 times the human exposure at the 160 mg twice daily dose based on body surface area (BSA) (see 16 Non-Clinical Toxicology).

Pregnancy Testing

Verify the pregnancy status of females of childbearing potential prior to initiating AUGTYRO.

Contraception

Males

Advise male patients with female partners of childbearing potential to use effective contraception during treatment with AUGTYRO and for 4 months following the last dose.

Females

Advise pregnant women of the potential risk to a fetus. Advise female patients of childbearing potential to use highly effective non-hormonal contraception during treatment with AUGTYRO and for 2 months following the final dose. AUGTYRO can decrease the efficacy of hormonal contraceptives (see 9.4 Drug-Drug Interactions).

Respiratory

Interstitial Lung Disease (ILD)/Pneumonitis

AUGTYRO can cause ILD/pneumonitis.

Among the 426 patients treated with AUGTYRO, ILD/pneumonitis (pneumonitis [2.8%] and ILD [0.2%]) occurred in 3.1% of patients; Grade 3 ILD/pneumonitis occurred in 1.2% of patients. The median time to onset was 48 days (19 days to 1 year). Dose interruption was required in 1.4% of patients, 0.5% of patients required dose reduction, and 0.9% of patients permanently discontinued AUGTYRO due to ILD/pneumonitis.

Advise patients to report symptoms of ILD/pneumonitis, which may include shortness of breath, cough, wheezing, chest pain or tightness, and hemoptysis. Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. Immediately withhold AUGTYRO in patients with suspected ILD/pneumonitis and permanently discontinue AUGTYRO if ILD/pneumonitis is confirmed, (see 4.2 Recommended Dose and Dosage Adjustment).

7.1. Special Populations

7.1.1. Pregnancy

There are no available data on AUGTYRO use in pregnant women. Advise women of childbearing potential and pregnant women of the potential risk to a fetus.

Data

Human Data

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

Animal Data

In an embryo-fetal development study, once daily oral administration of repotrectinib to pregnant rats during the period of organogenesis from gestation day 6 to 17 resulted in maternal effects of increased body weight and skin abrasions/ulcerations at doses ≥ 6 mg/kg, fetal malformations of malrotated hindlimbs, and lower fetal body weights at doses ≥ 12 mg/kg (approximately 0.3 times the recommended dose of 160 mg twice daily based on BSA). No embryolethality was observed.

7.1.2. Breastfeeding

There are no data on the presence of AUGTYRO in human milk or its effects on either the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children from AUGTYRO, advise a lactating woman to discontinue breastfeeding during treatment with AUGTYRO and for 10 days after the final dose.

7.1.3. Pediatrics

The safety and effectiveness of AUGTYRO in pediatric patients with ROS1-positive NSCLC has not been established.

7.1.4. Geriatrics

Of the 426 patients who received AUGTYRO, 19% were 65 to 74 years old, and 6% were 75 years of age or older. A higher proportion of subjects ≥ 75 years of age reported higher events of ataxia (65%) than subjects in the younger age subgroups; 40% in subjects ≥ 65 to < 75 and 23% in subjects 18 to <65 years. There were no clinically meaningful differences in safety and efficacy between patients less than 65 years of age and patients 65 years of age or older.

8. Adverse Reactions

8.1. Adverse Reaction Overview

The pooled safety population described in 7 Warnings and Precautions and summarized in this overview reflects exposure to AUGTYRO in 426 patients with ROS1-positive NSCLC and other solid tumours in the TRIDENT-1 study. Patients received AUGTYRO at a dose of 160 mg orally once daily for the first 14 days, then increased to 160 mg orally twice daily until disease progression or unacceptable toxicity. Of these patients, 48% were exposed for at least 6 months and 28% were exposed for greater than 1 year.

Most patients had a least one treatment-emergent adverse reaction. The most frequently reported adverse reactions (≥ 20%) were dizziness (65%), dysgeusia (54%), peripheral neuropathy (49%) constipation (38%), anemia (38%), dyspnea (30%), fatigue (30%), ataxia (28%), cognitive disorders (25%) ALT increased (23%), AST increased (21%), muscular weakness (20%), and nausea (20%).

Serious adverse reactions occurred in 35% of patients who received AUGTYRO. Serious adverse reactions in ≥ 2% of patients included pneumonia (6.3%), dyspnea (3.1%), pleural effusion (2.8%), and hypoxia (2.6%). Fatal adverse reactions occurred in 3.5% of patients who received AUGTYRO including pneumonia, pneumonia aspiration, cardiac arrest, sudden cardiac death, cardiac failure, hypoxia, dyspnea, respiratory failure, tremor, and disseminated intravascular coagulation.

Permanent discontinuation of AUGTYRO due to an adverse reaction occurred in 7% of patients. There were no specific adverse reactions that accounted for ≥ 1% of permanent discontinuations.

Dosage interruptions of AUGTYRO due to an adverse reaction occurred in 50% of patients. Adverse reactions that required dosage interruption in ≥ 2% of patients were dizziness, dyspnea, muscular weakness, ataxia, pneumonia, peripheral neuropathy, anemia, and vomiting.

Dose reductions of AUGTYRO due to an adverse reaction occurred in 38% of patients. Adverse reactions that required dosage reductions in ≥ 2% of patients included dizziness, ataxia, muscular weakness, peripheral neuropathy, and cognitive impairment.

8.2. Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. Therefore, the frequencies of adverse reactions observed in the clinical trials may not reflect frequencies observed in clinical practice and should not be compared to frequencies reported in clinical trials of another drug.

TRIDENT-1

This section describes the safety of AUGTYRO, evaluated in 320 patients with ROS1-positive NSCLC in the TRIDENT-1 study. Patients received AUGTYRO at a dose of 160 mg orally once daily for the first 14 days, then increased to 160 mg orally twice daily until disease progression or unacceptable toxicity. Patients with a history of ILD, drug-related pneumonitis, significant, uncontrolled, active cardiovascular disease, or prolonged QTc interval were excluded from enrollment in this trial. Among patients who received AUGTYRO, 48% were exposed for at least 6 months, and 28% were exposed for greater than 1 year (see 14 Clinical Trials).

The median age of patients who received AUGTYRO was 55 years (range: 27-93 years); 79% of patients were ≥ 18 years to < 65 years. Of the 320 patients, 62% were female, 49% Asian, 43% white, 2.8% Black, 0.3 % American Indian or Alaskan Native, 0.6% Native Hawaiian or Other Pacific Islander, and 4.3% not reported or unknown. Table 4 summarizes the adverse reactions reported in patients with ROS1-positive NSCLC from the TRIDENT-1 study.

Table 4 – Adverse Reactions (≥ 10%) in Patients with ROS1-positive NSCLC Who Received AUGTYRO in TRIDENT-1

1 Based on NCI CTCAE v4.03

1. a. Includes terms dizziness, vertigo, dizziness postural, dizziness exertional
2. b. Includes terms dysgeusia, ageusia, anosmia, hypogeusia
3. c. Includes terms neuralgia, neuropathy peripheral, peripheral sensory neuropathy, dysesthesia, peripheral motor neuropathy, polyneuropathy, paresthesia, hypoesthesia, hyperesthesia
4. d. Includes terms ataxia, gait disturbance, balance disorder, cerebellar ataxia and nystagmus
5. e. Includes terms memory impairment, disturbance in attention, cognitive disorder, confusional state, amnesia, attention deficit hyperactivity disorder, delirium, altered state of consciousness, aphasia, delusion, depressed level of consciousness, hallucination, mental status changes, bradyphrenia, and dysgraphia
6. f. Includes terms headache, migraine, tension headache
7. g. Includes terms dyspnea and dyspnea exertional
8. h. Includes terms productive cough, cough, and upper-airway cough syndrome
9. i. Includes terms pneumonia, pneumonia aspiration, lower respiratory tract infection, pneumonia viral, pneumonia bacterial, lower respiratory tract infection bacterial, pneumonia klebsiella
10. j. Includes terms fatigue and asthenia
11. k. Includes terms generalized edema, periorbital edema, localized edema, face edema, edema peripheral, edema, eye edema, scrotal edema, and orbital edema
12. l. Includes terms myalgia, myositis, musculoskeletal discomfort, musculoskeletal pain
13. m. Includes terms vision blurred, dry eye, visual impairment, visual field defect, cataract, conjunctivitis, eye pain, photophobia, photosensitivity reaction, visual acuity reduced, vitreous floaters, blepharospasm, color blindness, diplopia, eye hematoma, eye swelling, eyelid disorder, eyelids pruritus, glaucoma, asthenopia

8.3. Less Common Clinical Trial Adverse Reactions

Clinically relevant adverse reactions occurring in < 10% of patients receiving AUGTYRO were pyrexia (7.8%), fall (2.8%), vomiting (9.7%), skeletal fractures (2.5%), and decreased appetite (8.4%).

8.4. Abnormal Laboratory Findings: Hematologic, Clinical Chemistry, and Other Quantitative Data

Clinical Trial Findings

Table 5 summarizes the laboratory abnormalities.

Table 5 – Laboratory Abnormalities (≥ 20%) Worsening from Baseline in Patients with ROS1-positive NSCLC Who Received AUGTYRO in TRIDENT-1

1. a. The denominator used to calculate the rate varied from 178 to 319 based on the number of patients with a baseline value and at least one post-treatment value.
2. b. Based on NCI CTCAE v4.03

9. Drug Interactions

9.2. Drug Interactions Overview

Effects of other agents on repotrectinib

P-gp and CYP3A inhibitors: Avoid concomitant use of AUGTYRO with P-gp inhibitors or strong or moderate CYP3A inhibitors, which increases repotrectinib exposure and may increase the risk of adverse reactions with AUGTYRO (see 9.4 Drug-Drug Interactions).

CYP3A inducers: Avoid concomitant use of AUGTYRO with strong or moderate CYP3A inducers, which decreases repotrectinib exposure and may reduce the efficacy of AUGTYRO (see 9.4 Drug-Drug Interactions).

Effects of repotrectinib on other agents

Certain CYP3A Substrates: Repotrectinib is a CYP3A4 inducer. Avoid concomitant use of AUGTYRO with CYP3A substrates, which can reduce the efficacy of these substrates. If concomitant use is unavoidable, increase the CYP3A4 substrate in accordance with its approved labelling (see 9.4 Drug-Drug Interactions).

Hormonal contraceptives: Repotrectinib is a CYP3A4 inducer. Avoid concomitant use of AUGTYRO with hormonal contraceptives, which may reduce their efficacy (see 7 Warnings and Precautions, Reproductive Health and 9.4 Drug-Drug Interactions).

9.4. Drug-Drug Interactions

The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction.

Table 6 – Established or Potential Drug-Drug Interactions

Legend: CT = Clinical Trial; T= Theoretical.

Effects of repotrectinib on Other Drugs

CYP substrates

Based on the in vitro studies, repotrectinib induces, CYP2B6, CYP2C8, CYP2C9 and CYP2C19 and inhibits CYP2C8 and CYP2C9. The in vivo net effect of induction and inhibition, or its clinical relevance, is not known. Co-administration of AUGTYRO with CYP2B6, CYP2C8 or CYP2C9 or CYP2C19 substrates may alter their exposure.

Other Metabolic Pathways substrates

Based on in vitro studies, repotrectinib exhibits inhibitory potential toward UGT1A1. The in vivo net effect of this inhibition, or its clinical relevance, is not known.

Transporter substrates

In vitro data indicate that repotrectinib inhibits P-gp, breast cancer resistant protein (BCRP), organic anion-transporting polypeptide (OATP1B1), multidrug and toxin extrusion protein 2 (MAT2-K). Co-administration of AUGTYRO with sensitive substrates of P-gp, BCRP, OATP1B1 or MATE2-K may increase their exposure. The clinical relevance is unknown.

Repotrectinib is a substrate for P-gp and a potential substrate for MATE2-K and BCRP.

9.5. Drug-Food Interactions

AUGTYRO can be administered with or without food (see 10.3 Pharmacokinetics, Absorption). Grapefruit or grapefruit juice is a CYP3A inhibitor. Co-administration of Grapefruit or grapefruit juice with AUGTYRO should be avoided (see 9.4 Drug-Drug Interactions).

9.6. Drug-Herb Interactions

St. John’s Wort (hypericum perforatum) is a strong CYP3A inducer. Co-administration of St. John’s Wort with AUGTYRO should be avoided (see 9.4 Drug-Drug Interactions).

9.7. Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10. Clinical Pharmacology

10.1. Mechanism of Action

Repotrectinib is an inhibitor of proto-oncogene tyrosine-protein kinase ROS1 (ROS1), anaplastic lymphoma kinase (ALK) and the tropomyosin receptor tyrosine kinases (TRKs) TRKA, TRKB, and TRKC.

Fusion proteins that include ROS1 kinase domains can drive tumourigenic potential through hyperactivation of downstream signaling pathways leading to unconstrained cell proliferation. Repotrectinib has demonstrated anti-tumour activity in cell lines expressing the targeted fusion oncogenes ROS1 and corresponding solvent-front mutations (ROS1^G2032R, ROS1^D2033N and ROS1^L2026M). Repotrectinib binds inside the boundary of the ATP-binding pocket and avoids steric interference from both solvent front and gatekeeper mutations.

10.2. Pharmacodynamics

Repotrectinib exposure-response relationships and the time course of pharmacodynamic responses are unknown.

Cardiac Electrophysiology

AUGTYRO does not cause a mean increase in the QTc interval > 20 milliseconds (ms) at 160 mg QD followed by 160 mg BID, the approved recommended dosage.

10.3. Pharmacokinetics

Table 7 – Summary of Repotrectinib Pharmacokinetic Parameters in Adult Patients with Solid Tumours

Abbreviations: AUC_0-24 = Area under the plasma concentration-time curve from time 0 to 24 hours post-dose; C_max = maximum observed plasma drug concentration; T_max = time to reach Cmax.

Note: Geometric mean (geometric CV%) statistics are presented except for T_max median (range).

Fed indicates the administration of repotrectinib with a high-fat meal (approximately 800-1000 calories, 50% fat).

The pharmacokinetic (PK) parameters for repotrectinib have been characterized in patients with NTRK gene fusion-positive solid tumours, ROS1-positive NSCLC, and in healthy subjects. Repotrectinib C_max and AUC_0-inf increases approximately dose proportional (but less than linear with estimated slopes of 0.78 and 0.70, respectively) over the single dose range of 40 mg to 240 mg (0.25 to 1.5 times the approved recommended dosage). Steady state PK was time-dependent with an autoinduction of CYP3A4. Steady state is achieved within 14 days of daily administration of 160 mg of repotrectinib.

Absorption

The geometric mean (CV%) absolute bioavailability of repotrectinib is 45.7% (19.6%). Peak repotrectinib concentration occurred at approximately 2-3 hours post a single oral dose of 40 mg to 240 mg (0.25 to 1.5 times the approved recommended dosage) under fasted conditions.

Food Effect

Following high-fat and low-fat meals in healthy subjects, the total AUC of repotrectinib was approximately 42% and 36% higher and C_max was 110% and 124% higher, respectively, as compared with those under fasted conditions. T_max was delayed by about 2.0 h to 3.0 h. These changes in exposure are not considered to be clinically meaningful.

Distribution

The geometric mean (CV%) apparent volume of distribution (Vz/F) was 432 L (55.9%) in patients with cancer following a single 160 mg oral dose of repotrectinib. Repotrectinib binding to plasma protein was 95.4% in vitro. The blood-to-plasma ratio was 0.56 in vitro.

Metabolism

Repotrectinib is primarily metabolized by CYP3A4 followed by secondary glucuronidation.

Elimination

Repotrectinib elimination is time-dependent due to autoinduction of CYP3A4. The repotrectinib mean terminal half-life is approximately 60.7 hours for patients with cancer following a single dose. The steady state repotrectinib terminal half-life is approximately 40.3 hours for patients with cancer. The geometric mean (CV%) apparent oral clearance (CL/F) was 15.9 L/h (45.5%) in patients with cancer following a single 160 mg oral dose of repotrectinib.

Excretion

Following a single oral 160 mg dose of radiolabeled repotrectinib, 4.84% (0.56% as unchanged) was recovered in urine and 88.8% (50.6% unchanged) in feces.

Special populations and conditions

• Pediatrics

A population-PK model for repotrectinib was developed using data collected from adult and pediatric patients (16 children <12 years, 8 adolescents ≥12 to <18 years, and 502 adults). Based on population PK simulations, pediatric patients 12 years and older are predicted to have comparable systemic exposure as that of adults when administered the adult dose of 160 mg once daily for 14 days, followed by 160 mg twice daily.

Health Canada has not authorized an indication for pediatric use (see 1.1 Pediatrics).

• Geriatrics

No clinically significant differences in the pharmacokinetics of repotrectinib were identified based on age (18 years to 93 years).

• Sex

No clinically significant differences in the pharmacokinetics of repotrectinib were identified based on gender.

• Race

No clinically significant differences in the pharmacokinetics of repotrectinib were identified based on race (White 50%, Asian 38%, Black 7%).

• Hepatic Insufficiency

The effect of hepatic impairment on the pharmacokinetics of repotrectinib was evaluated by population PK analysis in patients. No clinically significant differences in the pharmacokinetics of repotrectinib were found between patients with mild hepatic impairment (total bilirubin > 1.0 to 1.5 times ULN or AST > ULN) and patients with normal hepatic function. Pharmacokinetics of repotrectinib has not been established in patients with moderate (total bilirubin > 1.5 to 3 x ULN with any AST) or severe (total bilirubin > 3 x ULN with any AST) hepatic impairment.

• Renal Insufficiency

The effect of renal impairment on the pharmacokinetics of repotrectinib was evaluated by a population PK analysis in patients. No clinically significant differences in the pharmacokinetics of repotrectinib were found between patients with mild or moderate (eGFR 30 to 90 mL/min) renal impairment and patients with normal renal function. Repotrectinib has not been studied in patients with severe renal impairment (eGFR < 30 mL/min).

1. 11. Storage, Stability, and Disposal

Store at room temperature (15°C to 30°C).

Part 2: Scientific Information

13. Pharmaceutical Information

Drug Substance

Proper/Common name: repotrectinib

Chemical name: (3R,11S)-6-Fluoro-3,11-dimethyl-10-oxa-2,13,17,18,21-pentaazatetracyclo[13.5.2.0^4,9.0^18,22]docosa-1(21),4,6,8,15(22),16,19-heptaen-14-one.

Molecular formula and molecular mass: C₁₈H₁₈FN₅O₂ and 355.37 g/mol

Figure 1 : Structural formula

Physicochemical properties: Repotrectinib is a white to off-white powder. Repotrectinib is practically insoluble in water and aqueous buffer, sparingly soluble in methanol and ethanol and freely soluble in N, N dimethylformamide (DMF)

Polymorphic Form: N-1 (previously designated as Form A)

14. Clinical Trials

14.1. Clinical Trials by Indication

ROS1-Positive Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC)

The efficacy of AUGTYRO was evaluated in TRIDENT-1, a Phase 1/2, multicenter, single-arm, open-label, multi-cohort, clinical trial. Eligible patients were required to have ROS1-positive locally advanced or metastatic NSCLC, ECOG performance status ≤1, measurable disease per RECIST v 1.1, ≥14 months follow-up from first dose. All patients were assessed for CNS lesions at baseline and patients with symptomatic brain metastases were excluded from the trial. Identification of ROS1 gene fusions in tumour specimens was prospectively determined in local laboratories using next-generation sequencing (NGS), polymerase chain reaction (PCR) or fluorescence in situ hybridization (FISH) tests. All ROS1-positive patients by local FISH testing required central laboratory confirmation of ROS1 fusion using an analytically validated NGS test. ROS1 fusions were identified by NGS in 51%, FISH in 26%, and PCR in 23%. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR) according to RECIST v1.1 as assessed by blinded independent central review (BICR). Intracranial response according to modified RECIST v1.1 was assessed by BICR. Tumour assessments with imaging were performed every 8 weeks.

The efficacy populations from pooled Phase 1 and Phase 2, included 71 ROS1 TKI-naïve patients (8 from phase 1 and 63 from phase 2) who received up to 1 prior line of platinum-based chemotherapy and/or immunotherapy and 56 patients (3 from phase 1 and 53 from phase 2) who received 1 prior ROS1 TKI with no prior platinum-based chemotherapy or immunotherapy. Patients from phase 1 received AUGTYRO at various doses (range 40 mg orally once daily to 200 mg twice daily), while patients from phase 2 received AUGTYRO 160 mg orally once daily for 14 days, then increased to 160 mg twice daily until disease progression or unacceptable toxicity.

Among the 71 ROS1 TKI-naïve patients, the median age was 57 years (range: 28 to 80); female (60.6%); Asian (67.6%), White (25.4%), Hispanic or Latino ethnicity (4.2%), Black or African American (1.4%), never smoked (63.4%); and ECOG performance status of 1 at baseline (66.2%). At baseline, 94.4% patients had metastatic disease, 25.4% patients had CNS metastases by BICR; 97.2% had adenocarcinoma; 28.2% patients had prior chemotherapy consisting of platinum-based chemotherapy for locally advanced or metastatic disease.

Among the 56 patients who had received 1 prior ROS1 TKI (crizotinib 82.1%, entrectinib 16.1%, and ceritinib 1.8%) with no prior platinum-based chemotherapy, the median age was 57 years (range: 33 – 78); female (67.9%); Asian (48.2%), White (44.6%), Black or African American and Hispanic or Latino ethnicity (1.8% each); never smoked (64.3%); and ECOG performance status of 1 at baseline (67.9%). At baseline, 98.2% patients had metastatic disease, 46.4% with CNS metastases by BICR, and 94.6% had adenocarcinoma.

Efficacy results are summarized in Table 8.

Table 8 – Efficacy Results in Patients with ROS1-Positive NSCLC per BICR Assessment

1. a. Median DOR (95% CI) and landmark analysis are based on Kaplan-Meier estimates.
2. b. with one (1) prior TKI and no chemotherapy

Abbreviations: CI = confidence interval; NE = not evaluable; “+” indicates ongoing response

Sixty-three TKI-naïve patients and 53 TKI pretreated patients received the recommended dose. The median duration of treatment was 17.3 weeks for TKI-Naive and 8.3 weeks for TKI-pretreated patients. The median Time to Response was 1.8 months for TKI-naïve patients and TKI pre-treated patients (ranges 0.9, 5.5; 1.6, 3.6, respectively).

Among the 9 ROS1 inhibitor naïve patients with measurable brain metastases at baseline as assessed by BICR (2 patients had CNS intervention within 60 days of first dose of study treatment), responses in intracranial lesions were observed in 8 of these 9 patients, with 1 patient achieving a complete response and 7 patients achieving a partial response. Among the 13 patients who had received 1 prior ROS1 inhibitor with no prior platinum-based chemotherapy with measurable brain metastases at baseline as assessed by BICR (7 patients had CNS intervention within 60 days of first dose of study treatment), responses in intracranial lesions were observed in 5 of these 13 patients, with all patients achieving a partial response.

16. Non-Clinical Toxicology

General toxicology

Repeat dose toxicity studies

Following repeat-dose oral administration of repotrectinib daily for up to 3 months in rats and monkeys, the main toxicities observed were CNS effects (i.e., ataxia, tremors) in rats at approximately 2.1 times the human exposure based on AUC at the recommended clinical dose; skin scabs/ulceration in rats, bone marrow hypocellularity in rats and monkeys, and gastrointestinal tract effects (i.e., emesis, watery feces, and minimal subacute/chronic inflammation and/or minimal to mild mucosal gland hyperplasia in the large intestines) in monkeys at exposure margins that were below the human exposure based on AUC at the recommended clinical dose.

Genotoxicity

Repotrectinib was genotoxic in an in vitro assay in human lymphoblastoid TK6 cells and in vivo in the rat bone marrow micronucleus assay, via an aneugenic mechanism of action. Repotrectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay.

Carcinogenicity

Carcinogenicity studies with repotrectinib were not conducted.

Reproductive and developmental toxicology

In an embryo-fetal development study in rats, teratogenic effects (fetal external malformation of malrotated hindlimbs), decreased fetal body weights, and maternal effects (skin scabbing/abrasions in cervical and thoracic regions, and increased body weight) were observed in pregnant rats at approximately 0.3 times the recommended clinical dose based on BSA (see 7 Warnings and Precautions, Reproductive Health).

Juvenile toxicity

The effects of repotrectinib in juvenile rats were investigated in a definitive (PND 12 to PND 70) repeat-dose juvenile toxicity study. Decreased body weight gain and decreased femur length were observed at approximately 0.04 and 0.1 times the human exposure based on AUC at the recommended clinical dose, respectively.