Recommendation based on data from
registrational TRIDENT-1 and CARE trials, which demonstrated robust
responses and durable activity with repotrectinib in these patient
populations
If approved, repotrectinib has the potential
to be a best-in-class treatment for patients with advanced
ROS1-positive non-small cell lung cancer in the European
Union
Bristol Myers Squibb (NYSE: BMY) today announced that the
Committee for Medicinal Products for Human Use (CHMP) of the
European Medicines Agency (EMA) has recommended approval for
repotrectinib, a next-generation tyrosine kinase inhibitor (TKI),
as a treatment for adult patients with ROS1-positive advanced
non-small cell lung cancer (NSCLC) and for the treatment of adult
and pediatric patients 12 years of age and older with advanced
solid tumors expressing a NTRK gene fusion, and who have received a
prior NTRK inhibitor, or have not received a prior NTRK inhibitor
and treatment options not targeting NTRK provide limited clinical
benefit, or have been exhausted. The European Commission (EC),
which has the authority to approve medicines for the European Union
(EU), will now review the CHMP recommendation. The final EC
decision is expected in January 2025.
“Patients in the EU with ROS1-positive non-small cell lung
cancer and NTRK-positive solid tumors face a great unmet need for
new therapies that may improve their outcomes and address or delay
the difficult issue of treatment resistance,” said Joseph Fiore,
vice president, global program lead, repotrectinib, Bristol Myers
Squibb. “We look forward to the EC’s upcoming decision and to
potentially bringing this next-generation treatment to patients
with tumors harboring ROS1 or NTRK fusions in the EU.”
The positive opinion is based on results from the TRIDENT-1 and
CARE trials, in which repotrectinib demonstrated clinically
meaningful response rates in patients across ROS1-positive NSCLC
and NTRK-positive solid tumor cohorts, both as an initial targeted
treatment or after progression on a prior targeted treatment.
Durability of response was robust and intracranial responses were
observed in both settings, as well as in patients whose tumors
harbor common resistance mutations. The safety profile of
repotrectinib was well characterized and generally manageable with
routine standard-of-care treatments. The study remains ongoing to
assess long-term outcomes and additional endpoints across patient
populations with ROS1-positive advanced NSCLC and NTRK-positive
advanced solid tumors.
In November 2023 the U.S. Food and Drug Administration approved
Augtyro® (repotrectinib) for the treatment of adult patients with
locally advanced or metastatic ROS1-positive NSCLC. In June 2024
the U.S. Food and Drug Administration approved Augtyro for the
treatment of patients with NTRK-positive locally advanced or
metastatic solid tumors.
Bristol Myers Squibb thanks the patients and investigators
involved in the TRIDENT-1 and CARE clinical trials.
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
repotrectinib 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 and
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
repotrectinib 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). Patients less than 12 years of age will initially be
enrolled in Phase 1 to determine the RP2D for this age group.
Once the pediatric RP2D is determined, patients less than 12
years of age may be enrolled into Phase 2 of the study. Patients
ages 12 to 25 years will be directly enrolled into Phase 2
concurrent with Phase 1 enrollment. Phase 2 of the study will seek
to demonstrate the efficacy and anti-tumor activity of
repotrectinib 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 ROS1-Positive Lung
Cancer
Lung cancer is the leading cause of cancer deaths in the United
States. The two main types of lung cancer are non-small cell and
small cell. Non-small cell lung cancer (NSCLC) represents up to 85%
of diagnoses. Survival rates vary depending on the stage and type
of the cancer when diagnosed. ROS1 fusions are rare and occur in
about 1-2% of patients with NSCLC. With a median age of 50,
patients with tumors that are ROS1-positive tend to be younger than
the average lung cancer patient, more often female than male and
may have little to no smoking history. ROS1-positive lung cancer
tends to be aggressive and can often spread to the brain. ROS1
tyrosine kinase inhibitor (TKI) therapy is the current standard of
care for patients with a tumor harboring this gene alteration.
About NTRK-Positive Solid
Tumors
Neurotrophic tropomyosin receptor kinase (NTRK) are a family of
receptors involved in neural development. 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. These fusions lead to abnormal proteins, which may
cause cancer cells to grow. 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.
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 programs 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 Repotrectinib
Repotrectinib (TPX-0005, BMS-986472) is a next-generation
tyrosine kinase inhibitor (TKI) targeting ROS1- or NTRK-positive
advanced solid tumors, including non-small cell lung cancer
(NSCLC), where there remain significant unmet medical needs for
patients. Repotrectinib 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 primarily in adults and a Phase 1/2
trial in pediatric patients.
In June 2017, repotrectinib was granted an Orphan Drug
designation by the U.S. Food and Drug Administration (FDA). Since
then, repotrectinib 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.
Repotrectinib 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.
INDICATIONS
AUGTYRO® is indicated for the treatment of:
- adult patients with advanced 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 advanced, 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.
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, X (formerly 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 the CHMP opinion is not binding on the EC, that repotrectinib
may not receive regulatory approval for the 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 repotrectinib
for such indication will be commercially successful. 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.
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