− New Dosing Option Will Reduce Pill Burden for
Patients Living with ALK+ Non-Small Cell Lung Cancer −
− 180 mg Tablets and Previously Approved 90 mg
Tablets Will Be Available Later this Year −
Takeda Pharmaceutical Company Limited (TSE:4502) today announced
that the U.S. Food and Drug Administration (FDA) has approved the
supplemental new drug application (sNDA) for ALUNBRIG® (brigatinib)
180 mg tablets. ALUNBRIG received Accelerated Approval from the FDA
in April 2017 for the treatment of patients with anaplastic
lymphoma kinase-positive (ALK+) metastatic non-small cell lung
cancer (NSCLC) who have progressed on or are intolerant to
crizotinib. This indication is approved under Accelerated Approval
based on tumor response rate and duration of response. Continued
approval for this indication may be contingent upon verification
and description of clinical benefit in a confirmatory trial. The
recommended dosing regimen for ALUNBRIG is 90 mg orally once daily
for the first seven days and if tolerated, the dose is then
increased to 180 mg orally once daily.
“Initially ALUNBRIG was only available in 30 mg tablets. This
meant that patients who were taking ALUNBRIG had to take three
pills (to equal 90 mg) daily or six pills (to equal 180 mg) daily,”
said Ryan Cohlhepp, PharmD, Vice President, U.S. Commercial, Takeda
Oncology. “With the approval of a 180 mg tablet, ALUNBRIG has
become the only ALK inhibitor available as a one tablet per day
dose that can be taken with or without food.”
“Today’s approval of the ALUNBRIG 180 mg tablets will reduce
pill burden for patients taking ALUNBRIG for advanced ALK+ NSCLC,”
said Mohammad Jahanzeb, M.D., F.A.C.P, Professor of Clinical
Medicine, Hematology and Oncology at University of Miami's Miller
School of Medicine. “As a physician, having a 180 mg tablet
available for my patients may help them better manage their
treatment schedule.”
The recommended dosing regimen was supported by the results of
the pivotal Phase 2 ALTA (ALK in Lung Cancer
Trial of AP26113) trial. This two-arm, open-label,
multicenter trial of 222 patients with locally advanced or
metastatic ALK+ NSCLC who had progressed on crizotinib found that,
of the patients who received the recommended dosing regimen (90→180
mg), 53 percent achieved a confirmed objective response (OR) as
assessed by an Independent Review Committee (IRC). Additionally, 67
percent of patients with measurable brain metastases who received
this dosing regimen achieved a confirmed intracranial OR by IRC
assessment. In ALTA, serious adverse reactions occurred in 38% of
patients in the 90 mg group and 40% of patients in the 90→180 mg
group. Overall, the most common serious adverse reactions were
pneumonia and interstitial lung disease (ILD)/pneumonitis. Fatal
adverse reactions occurred in 3.7% of patients and consisted of
pneumonia (2 patients), sudden death, dyspnea, respiratory failure,
pulmonary embolism, bacterial meningitis and urosepsis (1 patient
each). At the recommended dosing regimen, the most common adverse
reactions (≥25%) with ALUNBRIG were nausea, diarrhea, fatigue,
cough, and headache. The ALTA trial is ongoing and updated data
will be presented at the 18th World Conference on Lung Cancer of
the International Association for the Study of Lung Cancer, October
15-18, in Yokohama, Japan.
About ALK+ NSCLC
Non-small cell lung cancer (NSCLC) is the most common form of
lung cancer, accounting for approximately 85 percent of the
estimated 222,500 new cases of lung cancer diagnosed each year in
the United States, according to the American Cancer Society.
Genetic studies indicate that chromosomal rearrangements in
anaplastic lymphoma kinase (ALK) are key drivers in a subset of
NSCLC patients. Approximately two to eight percent of patients with
metastatic NSCLC have a rearrangement in the ALK gene.
The central nervous system (CNS) is a frequent site for
progression in ALK+ NSCLC, with brain metastases present in up to
70 percent of patients after treatment with crizotinib.
About ALUNBRIG® (brigatinib)
ALUNBRIG is a targeted cancer medicine discovered by ARIAD
Pharmaceuticals, Inc., which was acquired by Takeda in February
2017. ALUNBRIG recently received Accelerated Approval from the U.S.
Food and Drug Administration (FDA) for ALK+ NSCLC patients who have
progressed on or are intolerant to crizotinib. This indication is
approved under Accelerated Approval based on tumor response rate
and duration of response. Continued approval for this indication
may be contingent upon verification and description of clinical
benefit in a confirmatory trial.
ALUNBRIG received Breakthrough Therapy Designation from the FDA
for the treatment of patients with ALK+ NSCLC whose tumors are
resistant to crizotinib, and was granted Orphan Drug Designation by
the FDA for the treatment of ALK+ NSCLC, ROS1+ and EGFR+ NSCLC. A
Marketing Authorization Application (MAA) for ALUNBRIG was
submitted to the European Medicines Agency (EMA) in February
2017.
In the US, the recommended dosing regimen for ALUNBRIG is:
• 90 mg orally once daily for the first 7 days;
• if 90 mg is tolerated during the first 7 days, increase the
dose to 180 mg orally once daily.
The ALTA clinical development program further reinforces
Takeda’s ongoing commitment to developing innovative therapies for
people living with ALK+ NSCLC worldwide and the healthcare
professionals who treat them. In addition to the ongoing Phase 1/2
and Phase 2 ALTA trial, brigatinib is also being studied in the
Phase 3 ALTA 1L trial to assess its efficacy and safety in
comparison to crizotinib in patients with locally advanced or
metastatic ALK+ NSCLC who have not received prior treatment with an
ALK inhibitor.
To learn more about ALUNBRIG, please visit www.ALUNBRIG.com or
call 1-844-A1POINT (1-844-217-6468). For additional information on
the brigatinib clinical trials, please visit
www.clinicaltrials.gov.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Interstitial Lung Disease (ILD)/Pneumonitis: Severe,
life-threatening, and fatal pulmonary adverse reactions consistent
with interstitial lung disease (ILD)/pneumonitis have occurred with
ALUNBRIG. In Trial ALTA (ALTA), ILD/pneumonitis occurred in 3.7% of
patients in the 90 mg group (90 mg once daily) and 9.1% of patients
in the 90→180 mg group (180 mg once daily with 7-day lead-in at 90
mg once daily). Adverse reactions consistent with possible
ILD/pneumonitis occurred early (within 9 days of initiation of
ALUNBRIG; median onset was 2 days) in 6.4% of patients, with Grade
3 to 4 reactions occurring in 2.7%. Monitor for new or worsening
respiratory symptoms (e.g., dyspnea, cough, etc.), particularly
during the first week of initiating ALUNBRIG. Withhold ALUNBRIG in
any patient with new or worsening respiratory symptoms, and
promptly evaluate for ILD/pneumonitis or other causes of
respiratory symptoms (e.g., pulmonary embolism, tumor progression,
and infectious pneumonia). For Grade 1 or 2 ILD/pneumonitis, either
resume ALUNBRIG with dose reduction after recovery to baseline or
permanently discontinue ALUNBRIG. Permanently discontinue ALUNBRIG
for Grade 3 or 4 ILD/pneumonitis or recurrence of Grade 1 or 2
ILD/pneumonitis.
Hypertension: In ALTA, hypertension was reported in 11%
of patients in the 90 mg group who received ALUNBRIG and 21% of
patients in the 90→180 mg group. Grade 3 hypertension occurred in
5.9% of patients overall. Control blood pressure prior to treatment
with ALUNBRIG. Monitor blood pressure after 2 weeks and at least
monthly thereafter during treatment with ALUNBRIG. Withhold
ALUNBRIG for Grade 3 hypertension despite optimal antihypertensive
therapy. Upon resolution or improvement to Grade 1 severity, resume
ALUNBRIG at a reduced dose. Consider permanent discontinuation of
treatment with ALUNBRIG for Grade 4 hypertension or recurrence of
Grade 3 hypertension. Use caution when administering ALUNBRIG in
combination with antihypertensive agents that cause
bradycardia.
Bradycardia: Bradycardia can occur with ALUNBRIG. In
ALTA, heart rates less than 50 beats per minute (bpm) occurred in
5.7% of patients in the 90 mg group and 7.6% of patients in the
90→180 mg group. Grade 2 bradycardia occurred in 1 (0.9%) patient
in the 90 mg group. Monitor heart rate and blood pressure during
treatment with ALUNBRIG. Monitor patients more frequently if
concomitant use of drug known to cause bradycardia cannot be
avoided. For symptomatic bradycardia, withhold ALUNBRIG and review
concomitant medications for those known to cause bradycardia. If a
concomitant medication known to cause bradycardia is identified and
discontinued or dose adjusted, resume ALUNBRIG at the same dose
following resolution of symptomatic bradycardia; otherwise, reduce
the dose of ALUNBRIG following resolution of symptomatic
bradycardia. Discontinue ALUNBRIG for life-threatening bradycardia
if no contributing concomitant medication is identified.
Visual Disturbance: In ALTA, adverse reactions leading to
visual disturbance including blurred vision, diplopia, and reduced
visual acuity, were reported in 7.3% of patients treated with
ALUNBRIG in the 90 mg group and 10% of patients in the 90→180 mg
group. Grade 3 macular edema and cataract occurred in one patient
each in the 90→180 mg group. Advise patients to report any visual
symptoms. Withhold ALUNBRIG and obtain an ophthalmologic evaluation
in patients with new or worsening visual symptoms of Grade 2 or
greater severity. Upon recovery of Grade 2 or Grade 3 visual
disturbances to Grade 1 severity or baseline, resume ALUNBRIG at a
reduced dose. Permanently discontinue treatment with ALUNBRIG for
Grade 4 visual disturbances.
Creatine Phosphokinase (CPK) Elevation: In ALTA, creatine
phosphokinase (CPK) elevation occurred in 27% of patients receiving
ALUNBRIG in the 90 mg group and 48% of patients in the 90 mg→180 mg
group. The incidence of Grade 3 4 CPK elevation was 2.8% in the 90
mg group and 12% in the 90→180 mg group. Dose reduction for CPK
elevation occurred in 1.8% of patients in the 90 mg group and 4.5%
in the 90→180 mg group. Advise patients to report any unexplained
muscle pain, tenderness, or weakness. Monitor CPK levels during
ALUNBRIG treatment. Withhold ALUNBRIG for Grade 3 or 4 CPK
elevation. Upon resolution or recovery to Grade 1 or baseline,
resume ALUNBRIG at the same dose or at a reduced dose.
Pancreatic Enzyme Elevation: In ALTA, amylase elevation
occurred in 27% of patients in the 90 mg group and 39% of patients
in the 90→180 mg group. Lipase elevations occurred in 21% of
patients in the 90 mg group and 45% of patients in the 90→180 mg
group. Grade 3 or 4 amylase elevation occurred in 3.7% of patients
in the 90 mg group and 2.7% of patients in the 90→180 mg group.
Grade 3 or 4 lipase elevation occurred in 4.6% of patients in the
90 mg group and 5.5% of patients in the 90→180 mg group. Monitor
lipase and amylase during treatment with ALUNBRIG. Withhold
ALUNBRIG for Grade 3 or 4 pancreatic enzyme elevation. Upon
resolution or recovery to Grade 1 or baseline, resume ALUNBRIG at
the same dose or at a reduced dose.
Hyperglycemia: In ALTA, 43% of patients who received
ALUNBRIG experienced new or worsening hyperglycemia. Grade 3
hyperglycemia, based on laboratory assessment of serum fasting
glucose levels, occurred in 3.7% of patients. Two of 20 (10%)
patients with diabetes or glucose intolerance at baseline required
initiation of insulin while receiving ALUNBRIG. Assess fasting
serum glucose prior to initiation of ALUNBRIG and monitor
periodically thereafter. Initiate or optimize anti-hyperglycemic
medications as needed. If adequate hyperglycemic control cannot be
achieved with optimal medical management, withhold ALUNBRIG until
adequate hyperglycemic control is achieved and consider reducing
the dose of ALUNBRIG or permanently discontinuing ALUNBRIG.
Embryo-Fetal Toxicity: Based on its mechanism of action
and findings in animals, ALUNBRIG can cause fetal harm when
administered to pregnant women. There are no clinical data on the
use of ALUNBRIG in pregnant women. Advise pregnant women of the
potential risk to a fetus. Advise females of reproductive potential
to use effective non-hormonal contraception during treatment with
ALUNBRIG and for at least 4 months following the final dose. Advise
males with female partners of reproductive potential to use
effective contraception during treatment and for at least 3 months
after the last dose of ALUNBRIG.
ADVERSE REACTIONS
Serious adverse reactions occurred in 38% of patients in the 90
mg group and 40% of patients in the 90→180 mg group. The most
common serious adverse reactions were pneumonia (5.5% overall, 3.7%
in the 90 mg group, and 7.3% in the 90→180 mg group) and
ILD/pneumonitis (4.6% overall, 1.8% in the 90 mg group and 7.3% in
the 90→180 mg group). Fatal adverse reactions occurred in 3.7% of
patients and consisted of pneumonia (2 patients), sudden death,
dyspnea, respiratory failure, pulmonary embolism, bacterial
meningitis and urosepsis (1 patient each).
The most common adverse reactions (≥25%) in the 90 mg group were
nausea (33%), fatigue (29%), headache (28%), and dyspnea (27%) and
in the 90→180 mg group were nausea (40%), diarrhea (38%), fatigue
(36%), cough (34%), and headache (27%).
DRUG INTERACTIONS
CYP3A Inhibitors: Avoid concomitant
use of ALUNBRIG with strong CYP3A inhibitors. Avoid grapefruit or
grapefruit juice as it may also increase plasma concentrations of
brigatinib. If concomitant use of a strong CYP3A inhibitor is
unavoidable, reduce the dose of ALUNBRIG.
CYP3A Inducers: Avoid concomitant
use of ALUNBRIG with strong CYP3A inducers.
CYP3A Substrates: Coadministration
of ALUNBRIG with CYP3A substrates, including hormonal
contraceptives, can result in decreased concentrations and loss of
efficacy of CYP3A substrates.
USE IN SPECIFIC POPULATIONS
Pregnancy: ALUNBRIG can cause fetal harm. Advise females
of reproductive potential of the potential risk to a fetus.
Lactation: There are no data regarding the secretion of
brigatinib in human milk or its effects on the breastfed infant or
milk production. Because of the potential adverse reactions in
breastfed infants, advise lactating women not to breastfeed during
treatment with ALUNBRIG.
Females and Males of Reproductive Potential:
Contraception: Advise females of
reproductive potential to use effective non-hormonal contraception
during treatment with ALUNBRIG and for at least 4 months after the
final dose. Advise males with female partners of reproductive
potential to use effective contraception during treatment with
ALUNBRIG and for at least 3 months after the final dose.
Infertility: ALUNBRIG may cause
reduced fertility in males.
Pediatric Use: The safety and efficacy of ALUNBRIG in
pediatric patients have not been established.
Geriatric Use: Clinical studies of ALUNBRIG did not
include sufficient numbers of patients aged 65 years and older to
determine whether they respond differently from younger patients.
Of the 222 patients in ALTA, 19.4% were 65-74 years and 4.1% were
75 years or older. No clinically relevant differences in safety or
efficacy were observed between patients ≥65 and younger
patients.
Hepatic or Renal Impairment: No dose adjustment is
recommended for patients with mild hepatic impairment or mild or
moderate renal impairment. The safety of ALUNBRIG in patients with
moderate or severe hepatic impairment or severe renal impairment
has not been studied.
Please see the full Prescribing Information for ALUNBRIG
at www.ALUNBRIG.com
About Takeda Pharmaceutical Company
Takeda Pharmaceutical Company Limited is a global, research and
development-driven pharmaceutical company committed to bringing
better health and a brighter future to patients by translating
science into life-changing medicines. Takeda focuses its R&D
efforts on oncology, gastroenterology and central nervous system
therapeutic areas plus vaccines. Takeda conducts R&D both
internally and with partners to stay at the leading edge of
innovation. New innovative products, especially in oncology and
gastroenterology, as well as our presence in Emerging Markets, fuel
the growth of Takeda. More than 30,000 Takeda employees are
committed to improving quality of life for patients, working with
our partners in health care in more than 70 countries. For more
information, visit http://www.takeda.com/news.
Additional information about Takeda is available through its
corporate website, www.takeda.com, and additional information about
Takeda Oncology, the brand for the global oncology business unit of
Takeda Pharmaceutical Company Limited, is available through its
website, www.takedaoncology.com.
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Takeda Pharmaceutical Company LimitedAmy Atwood,
+1-617-444-2147amy.atwood@takeda.com