STUDY DESIGN

TRIDENT-1: a multicenter, single-arm, open-label, multicohort clinical trial1

PHASE 1: dose escalation (RP2D)1*

First 14 days: AUGTYRO 160 mg QD

Day 15 onward: AUGTYRO 160 mg BID

PHASE 2: dose expansion and efficacy cohorts1†

(Pooled population, inclusive of RP2D)

Flow chart arrows

TKI-naïve
(n=71)
 

1 prior TKI and no prior chemo‌⁠­therapy(n=56)

PRIMARY EFFICACY ENDPOINT:

  • ORR as assessed by BICR per RECIST v1.11

KEY SECONDARY ENDPOINTS:

  • DOR, PFS1,2
  • icORR according to modified RECIST v1.1, assessed by BICR1

INCLUSION CRITERIA:

  • ROS1+ locally advanced or metastatic NSCLC1
  • ECOG performance status ≤11
  • Measurable disease per RECIST v.1.11
  • ≥8 months from first dose1

EXCLUSION CRITERIA:

  • Patients with symptomatic brain metastases1
* Phase 1 was a dose escalation phase that determined the recommended Phase 2 dose (RP2D) at 160 mg once daily for 14 days and then 160 mg twice daily thereafter until disease progression or toxicity.1
† Phase 2 efficacy population included patients who received at least 1 dose of AUGTYRO.1

BASELINE CHARACTERISTICS

ROS1+ NSCLC population in TRIDENT-11

Baseline Patient Characteristics TKI-Naïve Patients (n=71) TKI-Pretreated Patients (n=56)
     Median age 57 (range: 28-80) 57 (range: 33-78)
Sex    
     Female 61% 68%
     Male 39% 32%
Race    
     Asian 68% 48%
     White 25% 45%
     Hispanic or Latino 4.2% 1.8%
     Black or African American 1.4% 1.8%
Never smoker 63% 64%
ECOG performance status of 1 66% 68%
Metastatic disease 94% 98%
CNS metastases by BICR 25% 43%
Adenocarcinoma 97% 95%

72% of TKI-naïve patients had no prior chemotherapy and/or immunotherapy treatment. All TKI-pretreated patients had received 1 prior TKI with no prior chemotherapy or immunotherapy.1‡

‡ 28% of TKI-naïve patients had up to 1 prior platinum-based chemotherapy and/or immunotherapy.1

DISCOVER THE EFFICACY DATA →

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

BICR=blinded independent central review; BID=twice daily; CNS=central nervous system; DOR=duration of response; ECOG=Eastern Cooperative Oncology Group; icORR=intracranial objective response rate; NSCLC=non-small cell lung cancer; ORR=objective response rate; PFS=progression-free survival; QD=once daily; RECIST=Response Evaluation Criteria In Solid Tumors; ROS1=proto-oncogene C-Ros1, receptor tyrosine kinase; RP2D=recommended Phase 2 dose; TKI=tyrosine kinase inhibitor.

References:
1. AUGTYRO [package insert]. Princeton, NJ. Bristol-Myers Squibb Company. 2. Cho BC, Camidge DR, Lin JJ, et al. Repotrectinib in patients with ROS1 fusion-positive non-small cell lung cancer: update from the pivotal phase 1/2 TRIDENT-1 trial. Presented at: 2023 World Conference on Lung Cancer; September 9-12, 2023; Singapore.


IMPORTANT SAFETY INFORMATION

SUMMARY OF WARNINGS AND PRECAUTIONS

AUGTYRO was assessed in 426 patients with ROS1+ NSCLC and other solid tumors in the TRIDENT-1 pivotal study and is associated with the following warnings and precautions: central nervous system (CNS) adverse reactions, interstitial lung disease (ILD)/pneumonitis, hepatotoxicity, myalgia with creatine phosphokinase (CPK) elevation, hyperuricemia, skeletal fractures, and embryo-fetal toxicity.

INDICATION

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

IMPORTANT SAFETY INFORMATION

Warnings and 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.
  • Ataxia, including gait disturbance and balance disorder, occurred in 28% of patients; Grade 3 ataxia occurred in 0.5%. 
  • 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.
  • 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.
  • 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%). 
  • 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

  • ILD/pneumonitis (pneumonitis [2.8%] and ILD [0.2%]) occurred in 3.1%; Grade 3 ILD/pneumonitis occurred in 1.2%.
  • 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

  • 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%.
  • 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. Myalgia occurred in 13% of patients, with Grade 3 in 0.7%. Concurrent increased CPK within a 7-day window was observed in 3.7% of patients.
  • 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

  • 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

  • Fractures occurred in 2.3% of patients and 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.
  • 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 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

  • Avoid concomitant use with P-gp inhibitors, strong or moderate CYP3A inducers, and strong or moderate CYP3A inhibitors. Discontinue CYP3A inhibitors for 3 to 5 elimination half-lives of the CYP3A inhibitor prior to initiating 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 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 Full U.S. Full Prescribing Information for AUGTYRO.

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