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    Indications

    AUGTYRO® (repotrectinib) is indicated for the treatment of adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC).

    AUGTYRO® (repotrectinib) is indicated for the treatment of adult and pediatric patients 12 years of age and older with solid tumors that:

    • have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion
    • are locally advanced or metastatic or where surgical resection is likely to result in severe morbidity, and
    • have progressed following treatment or have no satisfactory alternative therapy.

    This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial(s).

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Discover a path forward
with AUGTYRO (repotrectinib)

The next-generation TKI for ROS1+ NSCLC, approved for NTRK gene fusion+ solid tumors1,2

EFFICACY

ORR and DOR in TKI-naïve and ‑pretreated patients1*

Data from the pivotal TRIDENT-1 study*

Bar graph moving forward with arrow icon

ORR

PRIMARY ENDPOINT
Tiimer moving clockwise with arrow icon

DOR†

SECONDARY ENDPOINT
TKI-naïve (n=40)

Median follow-up in the TKI-naïve population: 17.8 months.3

58%

(95% CI: 41, 73; CR, 15%; PR, 43%)1*
mDOR

Not yet
reached

(95% CI: NE, NE)

83% of patients had DOR at 1 year1*
TKI-pretreated (n=48)

Median follow-up in the TKI-pretreated population: 20.1 months.3

50%

(95% CI: 35, 65; CR, 0%; PR, 50%)1*
mDOR

9.9

months

(95% CI: 7.4, 13.0)

42% of patients had DOR at 1 year
Bar graph moving forward with arrow icon

ORR

PRIMARY ENDPOINT

TKI-naïve (n=40)

Median follow-up in the TKI-naïve population: 17.8 months.3

58%

(95% CI: 41, 73; CR, 15%; PR, 43%)1*

TKI-pretreated (n=48)

Median follow-up in the TKI-pretreated population: 20.1 months.3

50%

(95% CI: 35, 65; CR, 0%; PR, 50%)1*

Timer moving clockwise with arrow icon

DOR†

SECONDARY ENDPOINT

TKI-naïve (n=40)
mDOR

Not yet
reached

(95% CI: NE, NE)

83% of patients had DOR at 1 year1*

TKI-pretreated (n=48)
mDOR

9.9

months

(95% CI: 7.4, 13.0)

42% of patients had DOR at 1 year

Intracranial response

SECONDARY ENDPOINT

Brain icon

icORR

SECONDARY ENDPOINT

in patients with measurable CNS metastases at baseline1*¶

2/2

TKI‑naïve patients

achieved intracranial response

3/3

TKI-pretreated patients

achieved intracranial response

  • Data from the pivotal TRIDENT-1 study, a Phase 1/2 multicenter, single-arm, open-label, multicohort clinical trial of AUGTYRO (160 mg orally once daily for 14 days, then increased to 160 mg twice daily until disease progression or unacceptable toxicity) in adult patients with locally advanced or metastatic NTRK gene fusion+ solid tumors. The major efficacy outcome measures were ORR and DOR according to RECIST v1.1 as assessed by BICR. Intracranial response according to modified RECIST v1.1 was assessed by BICR. The primary efficacy populations included 40 TRK TKI-naïve patients and 48 patients who received prior TRK TKI. Inclusion criteria: NTRK gene fusion+ (NTRK1/2/3) locally advanced or metastatic solid tumors; ECOG performance status ≤1; measurable disease per RECIST v.1.1. Key exclusion criteria: patients with symptomatic brain metastases.1
  • Median DOR (95% CI) are based on Kaplan-Meier estimates. DOR results are based on the updated data as of 15 October 2023. DOR landmark analysis is based on the observed DOR.1
  • One out of 2 TKI-naïve patients and 2 out of 3 TKI-pretreated patients received prior radiotherapy to the brain, all more than 2 months prior to study entry.1

Safety

Adverse reaction profile with AUGTYRO in the TRIDENT-1 study1

The safety population included 426 patients who were exposed to AUGTYRO1

7% of patients permanently
discontinued due to adverse reactions1

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.

Adverse Reaction1§
(≥10%) in patients taking AUGTYRO		 AUGTYRO (N=426)
All Grades, % Grade 3
or 4, %
Nervous system disorders
Dizzinessa 65 2.8
Dysgeusiab 54 0
Peripheral neuropathyc 49 1.4
Ataxiad 28 0.5
Cognitive impairmente 25 0.9
Headachef 19 0
Gastrointestinal disorders
Constipation 38 0.2
Nausea 20 0.7
Diarrhea 14 0.7
Vomiting 12 1.2
Respiratory, thoracic, and mediastinal disorders
Dyspneag 30 6
Coughh 18 0.2
Pneumoniai 11 6
General disorders
Fatiguej 30 1.2
Edemak 15 0.5
Decreased appetite 11 0.2
Musculoskeletal and connective tissue disorders
Muscular weakness 20 2
Myalgial 13 0.7
Metabolism and nutritional
Increased weight 16 3
Eye disorders
Vision disordersm 12 0.5
  • Based on NCI CTCAE v4.03.
  • Includes terms dizziness, vertigo, dizziness postural, dizziness exertional, vertigo positional.
  • Includes terms dysgeusia, ageusia, anosmia, hypogeusia.
  • Includes terms neuralgia, neuropathy peripheral, peripheral sensory neuropathy, dysesthesia, peripheral motor neuropathy, polyneuropathy, paresthesia, hypoesthesia, hyperesthesia.
  • Includes terms ataxia, gait disturbance, balance disorder, cerebellar ataxia and coordination abnormal.
  • 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, neurological decompensation.
  • Includes terms headache, migraine, tension headache.
  • Includes terms dyspnea and dyspnea exertional.
  • Includes terms productive cough, cough, and upper-airway cough syndrome.
  • Includes terms pneumonia, pneumonia aspiration, lower respiratory tract infection, pneumonia viral, pneumonia bacterial, lower respiratory tract infection bacterial, pneumonia klebsiella.
  • Includes terms fatigue and asthenia.
  • Includes terms generalized edema, periorbital edema, localized edema, face edema, edema peripheral, edema, eye edema, scrotal edema.
  • Includes terms myalgia, myositis, musculoskeletal discomfort, musculoskeletal pain.
  • 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, eyelid injury, eyelids pruritus, glaucoma, night blindness, ophthalmic herpes zoster.

BICR=blinded independent central review; CNS=central nervous system; CR=complete response; CTCAE=Common Terminology Criteria for Adverse Events; DOR=duration of response; ECOG=Eastern Cooperative Oncology Group; icORR=intracranial objective response rate; mDOR=median duration of response; NCI=National Cancer Institute; NE=not evaluable, endpoint not yet reached; NSCLC=non-small cell lung cancer; NTRK=neurotrophic tyrosine receptor kinase; ORR=objective response rate; PR=partial response; RECIST=Response Evaluation Criteria In Solid Tumors; ROS1=proto-oncogene C-Ros1, receptor tyrosine kinase; TKI=tyrosine kinase inhibitor.

References:

1. AUGTYRO [package insert]. Princeton, NJ. Bristol-Myers Squibb Company. 2. Drilon A, Ou SI, Cho BC, et al. Repotrectinib (TPX-0005) is a next-generation ROS1/TRK/ALK inhibitor that potently inhibits ROS1/TRK/ALK solvent-front mutations. Cancer Discov. 2018;8 (10):1227-1236. 3. Solomon B, Drilon A, Lin JJ, et al. Repotrectinib in patients with NTRK fusion-positive advanced solid tumors, including non-small cell lung cancer: updated from the phase 1/2 TRIDENT-1 trial. Presented at: ESMO Congress 2023; October 20-24, 2023; Madrid, Spain.

Prescribing Information Patient Information

IMPORTANT SAFETY INFORMATION AND INDICATIONS

INDICATIONS

AUGTYRO® is indicated for the treatment of:

  • adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC)
  • adult and pediatric patients 12 years of age and older with solid tumors that:
    • have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion,
    • are locally advanced or metastatic or where surgical resection is likely to result in severe morbidity, and
    • have progressed following treatment or have no satisfactory alternative therapy

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial(s).

IMPORTANT SAFETY INFORMATION

Warnings & Precautions

Central Nervous System Adverse Reactions

  • Among the 426 patients who received AUGTYRO in Study TRIDENT-1, a broad spectrum of central nervous system (CNS) adverse reactions including dizziness, ataxia, and cognitive disorders occurred in 77% of patients with Grade 3 or 4 events occurring in 4.5%.
  • Dizziness, including vertigo, occurred in 65%; 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 11% 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%. The median time to onset was 15 days (1 day to 1.4 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% 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% 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% required a dose reduction due to sleep disorders.
  • The incidences of CNS adverse reactions reported were similar in patients with and without CNS metastases.
  • 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.

Interstitial Lung Disease (ILD)/Pneumonitis

  • Among the 426 patients treated with AUGTYRO, ILD/pneumonitis (pneumonitis [2.8%] and ILD [0.2%]) occurred in 3.1%; Grade 3 ILD/pneumonitis occurred in 1.2%. The median time to onset was 45 days (19 days to 0.9 years). Dose interruption was required in 1.4% of patients, 0.5% required dose reduction, and 1.1% permanently discontinued AUGTYRO due to ILD/pneumonitis.
  • 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.

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 (range: 1 day to 1.9 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, every 2 weeks during the first month of treatment, then monthly thereafter and then as clinically indicated. Withhold and then resume at same or reduced dose upon improvement or permanently discontinue AUGTYRO based on the severity.

Myalgia with Creatine Phosphokinase (CPK) Elevation

  • 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 19 days (range: 1 day to 2 years). Concurrent increased CPK within a 7-day window was observed in 3.7% 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 every 2 weeks during the first month of treatment and 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 same or reduced dose upon improvement.

Hyperuricemia

  • Among the 426 patients treated with AUGTYRO, 21 patients (5%) experienced hyperuricemia reported as an adverse reaction, 0.7% experienced Grade 3 or 4 hyperuricemia. One patient without pre-existing gout required urate-lowering medication.
  • 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 same or reduced dose upon improvement, or permanently discontinue AUGTYRO based on severity.

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 71 days (range: 31 days to 1.4 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 less than 12 years of age.
  • 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.

Embryo-Fetal Toxicity

  • Based on literature reports in humans with congenital mutations leading to changes in tropomyosin receptor tyrosine kinase (TRK) signaling, findings from animal studies, and its mechanism of action, AUGTYRO can cause fetal harm when administered to a pregnant woman.
  • Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with AUGTYRO and for 2 months following the last dose, since AUGTYRO can render some hormonal contraceptives ineffective.
  • Advise male patients with female partners of reproductive potential to use effective contraception during treatment with AUGTYRO and for 4 months after the last dose.

Adverse Reactions

  • The safety of AUGTYRO was evaluated in 426 patients in TRIDENT-1. The most common adverse reactions (≥20%) were dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, fatigue, ataxia, cognitive impairment, muscular weakness, and nausea.

Drug Interactions

Effects of Other Drugs on AUGTYRO

Strong and Moderate CYP3A Inhibitors

  • Avoid concomitant use with strong or moderate CYP3A inhibitors. Concomitant use of AUGTYRO with a strong or a moderate CYP3A inhibitor may increase repotrectinib exposure, which may increase the incidence and severity of adverse reactions of AUGTYRO. Discontinue CYP3A inhibitors for 3 to 5 elimination half-lives of the CYP3A inhibitor prior to initiating AUGTYRO.

P-gp Inhibitors

  • Avoid concomitant use with P-gp inhibitors. Concomitant use of AUGTYRO with a P-gp inhibitor may increase repotrectinib exposure, which may increase the incidence and severity of adverse reactions of AUGTYRO.

Strong and Moderate CYP3A Inducers

  • Avoid concomitant use with strong or moderate CYP3A inducers. Concomitant use of AUGTYRO with a strong or moderate CYP3A inducer may decrease repotrectinib plasma concentrations, which may decrease efficacy of AUGTYRO.

Effects of AUGTYRO on other Drugs

Certain CYP3A4 Substrates

  • Avoid concomitant use unless otherwise recommended in the Prescribing Information for CYP3A substrates, where minimal concentration changes can cause reduced efficacy. If concomitant use is unavoidable, increase the CYP3A4 substrate dosage in accordance with approved product labeling.
  • Repotrectinib is a CYP3A4 inducer. Concomitant use of repotrectinib decreases the concentration of CYP3A4 substrates, which can reduce the efficacy of these substrates.

Contraceptives

  • Repotrectinib is a CYP3A4 inducer, which can decrease progestin or estrogen exposure to an extent that could reduce the effectiveness of hormonal contraceptives.
  • Avoid concomitant use of AUGTYRO with hormonal contraceptives. Advise females of childbearing potential to use an effective nonhormonal contraceptive.

Please see U.S. Full Prescribing Information for AUGTYRO.