Application based on results from the
TRIDENT-1 and CARE trials, in which Augtyro demonstrated clinically
meaningful response rates
If approved, Augtyro will provide a new,
next-generation option for patients with NTRK-positive locally
advanced or metastatic solid tumors who have high unmet medical
needs
The U.S. Food and Drug Administration
assigned a target action date of June 15, 2024
Bristol Myers Squibb (NYSE: BMY) today announced that the U.S.
Food and Drug Administration (FDA) has accepted the supplemental
New Drug Application (sNDA) for 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, and are locally advanced or metastatic or where
surgical resection is likely to result in severe morbidity. The
filing acceptance is based on results from the registrational Phase
1/2 TRIDENT-1 trial (adult patients with NTRK-positive solid
tumors) and CARE study (pediatric patients with NTRK-positive solid
tumors). The FDA granted the application Priority Review status and
assigned a Prescription Drug User Fee Act (PDUFA) goal date of June
15, 2024.
“While great advancements have been made over the last decade,
patients with NTRK-positive locally advanced or metastatic solid
tumors still experience significant unmet needs. New and effective
treatment options that may improve durability of response and
address resistance to existing tyrosine kinase inhibitors are
critical to helping patients with these aggressive tumors,” said
Joseph Fiore, vice president, global program lead, Augtyro, Bristol
Myers Squibb. “We look forward to working closely with the FDA on
the review of our application for Augtyro for this tumor-agnostic
indication and potentially offering patients with NTRK-positive
disease a new, durable treatment option.”
The filing was based on the results from the TRIDENT-1 and CARE
trials. In the TRIDENT-1 study, Augtyro demonstrated clinically
meaningful response rates in patients with NTRK-positive locally
advanced or metastatic solid tumors. Durability of response was
robust, including among patients whose tumors harbor common
resistance mutations, and intracranial responses were observed.
Augtyro showed a safety profile that was well tolerated and
generally manageable. The study remains ongoing to assess long-term
outcomes and additional endpoints. Results from TRIDENT-1 were
supported by data from the CARE study, which evaluates Augtyro in
pediatric and young adult patients with locally advanced or
metastatic solid tumors harboring ALK, ROS1 or NTRK1-3 gene
alterations. Additionally, in November 2023 the U.S. Food and Drug
Administration approved Augtyro for the treatment of adult patients
with locally advanced or metastatic ROS1-positive non-small cell
lung cancer NSCLC.
Bristol Myers Squibb thanks the patients and investigators
involved with the TRIDENT-1 and CARE clinical trials.
Turning Point Therapeutics is a wholly owned subsidiary of the
Bristol-Myers Squibb Company. As of August 2022, Bristol Myers
Squibb acquired the company, including its asset repotrectinib.
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 advanced solid tumors, including non-small cell
lung cancer (NSCLC). Phase 1/2 includes patients with locally
advanced or metastatic solid tumors harboring ROS1 or NTRK fusions.
Additional analyses of the trial are still being conducted;
asymptomatic central nervous system (CNS) metastases are allowed.
The trial excludes patients with symptomatic brain metastases,
among other exclusion criteria. Phase 1 of the trial included the
dose escalation that determined the recommended Phase 2 dose.
Phase 2 of the trial has a primary endpoint of overall response
rate (ORR). Key secondary endpoints include duration of response
(DOR) according to Response Evaluation Criteria in Solid Tumors
(RECIST v1.1) as assessed by Blinded Independent Central Review
(BICR), progression-free survival (PFS), and intracranial response
in six distinct expansion cohorts, including tyrosine kinase
inhibitor (TKI)-naïve and TKI-pretreated patients with
ROS1-positive locally advanced or metastatic NSCLC and
NTRK-positive locally advanced or metastatic solid tumors.
About CARE
CARE is a Phase 1/2 open-label, safety, tolerability,
pharmacokinetics and anti-tumor activity clinical trial evaluating
Augtyro in pediatric and young adult patients with locally advanced
or metastatic solid tumors harboring ALK, ROS1 or NTRK1-3 gene
alterations.
Phase 1 of the study aims to evaluate the safety and
tolerability at different dose levels. Phase 1 of the trial has
primary endpoints of dose limiting toxicities (DLTs) and pediatric
recommended Phase 2 dose (RP2D). Secondary endpoints include
overall response rate (ORR), clinical benefit rate (CBR), time to
response (TTR), duration of response (DOR) and intracranial ORR
(IC-ORR). Phase 2 of the study will seek to demonstrate the
efficacy and anti-tumor activity of Augtyro in pediatric and young
adult patients. The primary endpoint of Phase 2 is ORR and
secondary endpoints include CBR, TTR, DOR, IC-ORR, progression-free
survival (PFS), central nervous system PFS (CNS-PFS) and overall
survival (OS).
About NTRK-Positive Solid
Tumors
Neurotrophic tropomyosin kinase receptors (NTRK) are a family of
receptors involved in neural development. NTRK gene fusions can
play a role in the development of cancer. They are rare in patients
with solid tumors with less than 1% of patients testing positive,
though may be more frequent in patients with secretory breast
cancer, infantile fibrosarcoma, thyroid cancer, gastrointestinal
stromal tumors, spitzoid tumors and infantile fibrosarcoma, among
other cancers. Per international treatment guidelines, targeted
agents are part of the treatment armamentarium for patients with a
tumor harboring this gene alteration.
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 Augtyro
Augtyro (TPX-0005, BMS-986472) is a next-generation tyrosine
kinase inhibitor (TKI) targeting ROS1-positive or NTRK-positive
locally advanced or metastatic solid tumors, including non-small
cell lung cancer (NSCLC), where there remain significant unmet
medical needs for patients. Augtyro was designed to improve
durability of response and with favorable properties for human
brain penetration to enhance intracranial activity. It is being
studied in a registrational Phase 1/2 trial in adults (TRIDENT-1)
and a Phase 1/2 trial in pediatric patients (CARE).
Augtyro has demonstrated clinically meaningful results and was
granted three Breakthrough Therapy Designations (BTDs) by the FDA
for the treatment of patients with: ROS1-positive metastatic NSCLC
who have not been treated with a ROS1 TKI; ROS1-positive metastatic
NSCLC who have been previously treated with one ROS1 TKI and who
have not received prior platinum-based chemotherapy; and advanced
solid tumors that have an NTRK gene fusion who have progressed
following treatment with one or two prior tropomyosin receptor
kinase (TRK) TKIs (with or without prior chemotherapy) and have no
satisfactory alternative treatments.
Augtyro was also previously granted four fast-track designations
in patients with: ROS1-positive advanced NSCLC who have been
treated with disease progression following one prior line of
platinum-based chemotherapy and one prior line of a ROS1 TKI;
ROS1-positive advanced NSCLC who have not been treated with a ROS1
TKI; ROS1-positive advanced NSCLC who have been previously treated
with one ROS1 TKI and who have not received prior platinum-based
chemotherapy; and advanced solid tumors that have an NTRK gene
fusion who have progressed following treatment with at least one
prior line of chemotherapy and one or two prior TRK TKIs and have
no satisfactory alternative treatments. Augtyro was also granted an
Orphan Drug designation by the U.S. Food and Drug Administration
(FDA).
INDICATION
AUGTYROTM (repotrectinib) is indicated for the treatment of
adult patients with locally advanced or metastatic ROS1-positive
non-small cell lung cancer (NSCLC).
Warnings &
Precautions
IMPORTANT SAFETY INFORMATION
Central Nervous System Adverse Reactions
- Among the 351 patients who received AUGTYRO in the TRIDENT-1
study, a broad spectrum of central nervous system (CNS) adverse
reactions including dizziness, ataxia, and cognitive disorders
occurred in 75% with Grade 3 or 4 events occurring in 4%.
Dizziness, including vertigo, occurred in 64% and Grade 3 dizziness
occurred in 2.8% of patients. The median time to onset was 6 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 29% of the 351 patients; Grade 3 ataxia occurred in
0.3%. The median time to onset was 15 days (1 day to 1.4 years).
Dose interruption was required in 6% of patients, 8% required dose
reduction and one patient (0.3%) permanently discontinued AUGTYRO
due to ataxia.
- Cognitive disorder, including memory impairment and disturbance
in attention, occurred in 23% of the 351 patients. Cognitive
disorders included memory impairment (13%), disturbance in
attention (11%), and confusional state (2%); Grade 3 cognitive
disorders 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, 1.7% required dose
reduction and 0.6% permanently discontinued AUGTYRO due to
cognitive adverse reactions.
- Mood disorders occurred in 6% of the 351 patients. Mood
disorders occurring in >1% of patients included anxiety (2.8%),
irritability (1.1%), and depression (1.4%); Grade 4 mood disorders
(mania) occurred in 0.3% of patients. Dose interruption was
required in 0.3% of patients and 0.3% required a dose reduction due
to mood disorders.
- Sleep disorders including insomnia and hypersomnia occurred in
15% of the 351 patients. Sleep disorders observed in >1% of
patients were somnolence (8%), insomnia (6%) and hypersomnia
(1.1%). Dose interruption was required in 0.9% of patients, and
0.3% 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 351 patients treated with AUGTYRO, ILD/pneumonitis
(pneumonitis [2.6%] and interstitial lung disease [0.3%]) occurred
in 2.9%; Grade 3 ILD/pneumonitis occurred in 1.1%. The median time
to onset was 45 days (19 days to 0.9 years). Dose interruption was
required in 1.4% of patients, 0.6% 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 351 patients treated with AUGTYRO, increased alanine
transaminase (ALT) occurred in 35%, increased aspartate
aminotransferase (AST) occurred in 40%, including Grade 3 or 4
increased ALT in 2% and increased AST in 2.6%. 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 1.4% of patients, respectively.
Hyperbilirubinemia leading to dose interruptions occurred in
0.6%.
- Monitor liver function tests, including ALT, AST and bilirubin,
every 2 weeks during the first month of treatment, then monthly
thereafter and 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
- Among the 351 patients treated with AUGTYRO, myalgia occurred
in 13% of patients, with Grade 3 in 0.6%. 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 351 patients treated with AUGTYRO, 18 patients (5%)
experienced hyperuricemia reported as an adverse reaction, 0.9%
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 351 adult patients who received AUGTYRO, fractures
occurred in 2.3%. Fractures involved the ribs (0.6%), feet (0.6%),
spine (0.3%), acetabulum (0.3%), sternum (0.3%), and ankles (0.3%).
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.
- 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
- Among 351 patients who received AUGTYRO for ROS1-positive NSCLC
and other solid tumors in the TRIDENT-1 trial, the most common
(>20%) adverse reactions were dizziness (64%), dysgeusia (50%),
peripheral neuropathy (47%), constipation (37%), dyspnea (30%),
ataxia (29%), fatigue (29%), cognitive disorders (23%), and nausea
(20%).
- In a subset of 264 patients who received AUGTYRO for
ROS1-positive NSCLC, the most common (≥20%) adverse reactions were
dizziness (63%), dysgeusia (48%), peripheral neuropathy (47%),
constipation (36%), dyspnea (30%), ataxia (28%), fatigue (24%),
cognitive disorders (23%), and muscular weakness (21%).
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 to use an effective nonhormonal contraceptive.
Please see U.S. Full Prescribing Information for AUGTYRO
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,
that Augtyro (repotrectinib) may not receive regulatory approval
for the additional indication described in this release in the
currently anticipated timeline or at all, that any marketing
approvals, if granted, may have significant limitations on their
use, and, if approved, whether such treatment for such additional
indication described in this release will be commercially
successful. No forward-looking statement can be guaranteed. It
should be noted that acceptance of the application does not change
the standards for FDA approval. 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.
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