Augtyro is the only FDA-approved treatment
option for NTRK-positive tumors studied in both TKI-naïve
and TKI-pretreated patients across solid tumors,
demonstrating clinically meaningful response rates in the
TRIDENT-1 trial1
This accelerated approval marks the second
indication for Augtyro in the U.S.1
Bristol Myers Squibb (NYSE: BMY) today announced that the U.S.
Food and Drug Administration (FDA) has granted accelerated approval
of Augtyro™ (repotrectinib) 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.1 The
approval is based on results from the Phase 1/2 TRIDENT-1 study,
which evaluated Augtyro in adult patients with NTRK-positive solid
tumors.1 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
trials.1
“NTRK fusion-positive tumors can present challenges in the
clinical setting, which is why it is important that we have
additional treatment options for these patients,” said Alexander
Drilon, MD, TRIDENT-1 global trial lead and Chief of the Early Drug
Development Service at Memorial Sloan Kettering Cancer Center.2,3
“The FDA approval of repotrectinib adds an important tool to our
toolbox, offering oncologists a next-generation TKI that can be
used across a broad range of NTRK fusion-positive solid tumors for
both TKI-naïve and TKI-pretreated patients.”1
The TRIDENT-1 trial included both TKI-naïve (n=40) and
TKI-pretreated (n=48) patients with NTRK-positive locally
advanced/metastatic solid tumors collectively representing 15
different types of cancer.1 In TKI-naïve patients, with a median
follow up of 17.8 months, 58% (95% CI: 41 to 73) had a confirmed
objective response rate (cORR); of those, 43% experienced partial
responses (PR) and 15% had complete responses (CR).1,4 Of the
TKI-naïve responding patients, 83% were still in response at one
year with Augtyro. The median duration of response (mDOR) was not
yet reached. In TKI-pretreated patients, with a median follow up of
20.1 months, the cORR was 50% (95% CI: 35 to 65); of those, 50%
experienced PR and no patients achieved CR.1,4 Additionally, 42% of
TKI-pretreated responding patients were still in response at one
year with Augtyro.1 The mDOR was 9.9 months (95% CI: 7.4 to 13.0).1
Among those who had measurable central nervous system (CNS)
metastases at baseline, intracranial response was observed in 2 out
of 2 TKI-naïve patients and in 3 out of 3 TKI-pretreated
patients.1
Augtyro is associated with the following Warnings &
Precautions: central nervous system (CNS) effects, interstitial
lung disease (ILD)/pneumonitis, hepatotoxicity, myalgia with
creatine phosphokinase elevation, hyperuricemia, skeletal
fractures, and embryo-fetal toxicity.1 Please see Important Safety
Information below.
“Today’s FDA approval of Augtyro for patients with NTRK-positive
tumors adds to its indication in ROS1-positive NSCLC, showing its
clinical value for more people across multiple genetic markers,”
said Nick Botwood, senior vice president of Medical Oncology at
Bristol Myers Squibb.1 “Previously, there was not an FDA approved
treatment option for NTRK-positive cancers that was studied in both
TKI-naïve and TKI-pretreated patients across solid tumors. This
milestone helps address this area of unmet need and builds on
Bristol Myers Squibb’s longstanding legacy of bringing innovations
to individuals who are facing cancer and urgently seeking new
treatment options.”
“Cancer can be frightening regardless of the type, but having a
rare gene fusion driving it can be especially stressful and
isolating,” said Susan Spinosa, president and patient co-founder of
NTRKers, a patient advocacy group. “It’s exciting to know that
there’s a new targeted therapy option for patients with
NTRK-positive gene fusions, as this may offer hope to patients and
their loved ones navigating this difficult journey.”
Based on clinical and pharmacokinetic data, the recommended dose
for Augtyro for pediatric patients aged 12 years and older is the
same as for adults, 160 mg orally once daily for 14 days followed
by 160 mg twice daily until disease progression or unacceptable
toxicity.1 The safety and effectiveness of Augtyro have not been
established in pediatric patients younger than 12 years of age with
solid tumors who have an NTRK gene fusion.1 This is the second
indication for Augtyro in the U.S., following its full approval for
the treatment of adult patients with locally advanced or metastatic
ROS1-positive NSCLC in November 2023.1
Disclosure: Dr. Drilon has provided advisory and speaking
services to Bristol Myers Squibb.
About TRIDENT-1
TRIDENT-1 is a global, multicenter, single-arm, open-label,
multi-cohort Phase 1/2 clinical trial evaluating the safety,
tolerability, pharmacokinetics and anti-tumor activity of Augtyro
in patients with locally advanced or metastatic neurotrophic
tyrosine receptor kinase (NTRK) gene fusion-positive (NTRK1/2/3)
solid tumors.1,5 The trial excludes patients with symptomatic brain
metastases, among other exclusion criteria.1 Phase 1 of the trial
included the dose escalation that determined the recommended Phase
2 dose.5
Phase 2 of the trial in NTRK-positive locally
advanced/metastatic solid tumor cohorts has a primary endpoint of
objective response rate (ORR) as assessed by Blinded Independent
Central Review (BICR).5 Among others, key secondary endpoints
include duration of response (DOR) according to Response Evaluation
Criteria in Solid Tumors (RECIST v1.1) as assessed by BICR, and
intracranial response in patients with measurable brain
metastases.5
Select Safety Profile from
TRIDENT-1
The safety profile for Augtyro was evaluated in 426 patients who
received Augtyro in the TRIDENT-1 pivotal trial.1 Permanent
discontinuation of Augtyro due to an adverse reaction occurred in
7% of patients.1 There were no specific adverse reactions that
accounted for ≥1% of permanent discontinuations. Augtyro dosage was
interrupted due to an adverse reaction in 50% of patients, and dose
reductions due to an adverse reaction occurred in 38% of patients.1
Serious adverse reactions occurred in 35% of patients who received
Augtyro.1 Serious adverse reactions in ≥2% of patients included
pneumonia (6.3%), dyspnea (3.1%), pleural effusion (2.8%) and
hypoxia (2.6%).1 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.1 The most common (≥20%) adverse
reactions were dizziness (65%), dysgeusia (54%), peripheral
neuropathy (49%), constipation (38%), dyspnea (30%), fatigue (30%),
ataxia (28%), cognitive impairment (25%), muscular weakness (20%)
and nausea (20%).1 Grade 3 dizziness occurred in 2.8% of
patients.1
About NTRK-Positive Solid
Tumors
Neurotrophic tropomyosin receptor kinase (NTRK) are a family of
receptors involved in neural development.6 An NTRK gene fusion is
an alteration that occurs when a piece of the chromosome containing
the NTRK gene breaks off and joins with a gene on another
chromosome.7 These fusions lead to abnormal proteins, which may
cause cancer cells to grow.7 While NTRK gene fusions are rare in
patients with solid tumors, testing for NTRK gene fusions allows
for the identification of patients who may benefit from TRK
inhibitor therapy.8,9,10,11
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 the 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.
Bristol Myers Squibb: Creating a Better
Future for People with Cancer
Bristol Myers Squibb is inspired by a single vision —
transforming patients’ lives through science. The goal of the
company’s cancer research is to deliver medicines that offer each
patient a better, healthier life and to make cure a possibility.
Building on a legacy across a broad range of cancers that have
changed survival expectations for many, Bristol Myers Squibb
researchers are exploring new frontiers in personalized medicine
and, through innovative digital platforms, are turning data into
insights that sharpen their focus. Deep understanding of causal
human biology, cutting-edge capabilities and differentiated
research platforms uniquely position the company to approach cancer
from every angle.
Cancer can have a relentless grasp on many parts of a patient’s
life, and Bristol Myers Squibb is committed to taking actions to
address all aspects of care, from diagnosis to survivorship. As a
leader in cancer care, Bristol Myers Squibb is working to empower
all people with cancer to have a better future.
About Bristol Myers Squibb’s Patient
Access Support
Bristol Myers Squibb remains committed to providing assistance
so that cancer patients who need our medicines can access them and
expedite time to therapy.
BMS Access Support®, the Bristol Myers Squibb patient access and
reimbursement program, is designed to help appropriate patients
initiate and maintain access to BMS medicines during their
treatment journey. BMS Access Support offers benefit investigation,
prior authorization assistance, as well as co-pay assistance for
eligible, commercially insured patients. More information about our
access and reimbursement support can be obtained by calling BMS
Access Support at 1-800-861-0048 or by visiting
www.bmsaccesssupport.com.
About Bristol Myers
Squibb
Bristol Myers Squibb is a global biopharmaceutical company whose
mission is to discover, develop and deliver innovative medicines
that help patients prevail over serious diseases. For more
information about Bristol Myers Squibb, visit us at BMS.com or
follow us on LinkedIn, Twitter, YouTube, Facebook and
Instagram.
Cautionary Statement Regarding
Forward-Looking Statements
This press release contains “forward-looking statements” within
the meaning of the Private Securities Litigation Reform Act of 1995
regarding, among other things, the research, development and
commercialization of pharmaceutical products. All statements that
are not statements of historical facts are, or may be deemed to be,
forward-looking statements. Such forward-looking statements are
based on current expectations and projections about our future
financial results, goals, plans and objectives and involve inherent
risks, assumptions and uncertainties, including internal or
external factors that could delay, divert or change any of them in
the next several years, that are difficult to predict, may be
beyond our control and could cause our future financial results,
goals, plans and objectives to differ materially from those
expressed in, or implied by, the statements. These risks,
assumptions, uncertainties and other factors include, among others,
whether Augtyro™ (repotrectinib) for the indication described in
this release will be commercially successful, that any marketing
approvals, if granted, may have significant limitations on their
use, and that continued approval of Augtyro for such indication
described in this release may be contingent upon verification and
description of clinical benefit in confirmatory trials. No
forward-looking statement can be guaranteed. Forward-looking
statements in this press release should be evaluated together with
the many risks and uncertainties that affect Bristol Myers Squibb’s
business and market, particularly those identified in the
cautionary statement and risk factors discussion in Bristol Myers
Squibb’s Annual Report on Form 10-K for the year ended December 31,
2023, as updated by our subsequent Quarterly Reports on Form 10-Q,
Current Reports on Form 8-K and other filings with the Securities
and Exchange Commission. The forward-looking statements included in
this document are made only as of the date of this document and
except as otherwise required by applicable law, Bristol Myers
Squibb undertakes no obligation to publicly update or revise any
forward-looking statement, whether as a result of new information,
future events, changed circumstances or otherwise.
References
- Augtyro Prescribing Information. Augtyro U.S. Product
Information. Last updated: May 2024. Princeton, NJ: Bristol Myers
Squibb Company
- Hibar DP, Demetri GD, Peters S, et al. Real-world survival
outcomes in patients with locally advanced or metastatic NTRK
fusion-positive solid tumors receiving standard-of-care therapies
other than targeted TRK inhibitors. PLoS One.
2022;17(8):e0270571
- Gambella A, Senetta R, Collemi G, et al. NTRK fusions in
central nervous system tumors: a rare, but worthy target. Int J Mol
Sci. 2020;21(3):753
- B.J. Solomon, A. Drilon, J.J. Lin S, et al. Repotrectinib in
patients (pts) with NTRK fusion-positive (NTRK+) advanced solid
tumors, including NSCLC: Update from the phase I/II TRIDENT-1
trial. Presented at: ESMO Congress 2023; October 21, 2023; Madrid,
Spain.
- ClinicalTrials.gov: NCT03093116. A study of repotrectinib
(TPX-0005) in patients with advanced solid tumors harboring ALK,
ROS1, or NTRK1-3 rearrangements (TRIDENT-1). Available at
https://classic.clinicaltrials.gov/ct2/show/NCT03093116. Accessed
May 7, 2024
- Manea CA, Badiu DC, Ploscaru IC, et al. A review of NTRK
fusions in cancer. Ann Med Surg. 2022;79:103893
- National Cancer Institute. NCI Dictionary of Cancer Terms: NKRT
gene fusion. Available at
https://www.cancer.gov/publications/dictionaries/cancer-terms/def/ntrk-gene-fusion.
Accessed May 7, 2024
- European Society for Medical Oncology (ESMO). Epidemiology of
cancers with NTRK gene fusion. Available at
https://oncologypro.esmo.org/oncology-in-practice/anti-cancer-agents-and-biological-therapy/targeting-ntrk-gene-fusions/overview-of-cancers-with-ntrk-gene-fusion/ntrk-gene-fusions-as-oncogenic-drivers/epidemiology-of-cancers-with-ntrk-gene-fusion#:~:text=NTRK%20fusions%20have%20been%20reported,0.3%25%20across%20all%20tumour%20types.
Accessed May 7, 2024
- European Society for Medical Oncology (ESMO). Importance of
testing cancers for NTRK gene fusions. Available at
https://oncologypro.esmo.org/oncology-in-practice/anti-cancer-agents-and-biological-therapy/targeting-ntrk-gene-fusions/importance-of-testing-cancers-for-ntrk-gene-fusions.
Accessed May 7, 2024
- Hechtman JF. NTRK insights: best practices for pathologists.
Mod Pathol. 2022;35(3):298-305
- Hsiao SJ, Zehir A, Sireci AN, Aisner DL. Detection of tumor
NTRK gene fusions to identify patients who may benefit from
tyrosine kinase (TRK) inhibitor therapy. J Mol Diagn.
2019;21(4):553-571
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