− Updated Results Continue to Support the Efficacy and Safety
Findings for ALUNBRIG with the 180 mg Dosing Regimen in Patients
with Advanced ALK+ NSCLC Who Have Progressed on Crizotinib, Per
Independent Review Committee:
- Median Progression-Free Survival (PFS)
of 16.7 Months
- Sixty-Seven Percent of Patients with
Measurable Brain Metastases at Baseline had an Intracranial
Objective Response with a Median Duration of Intracranial Response
of 16.6 Months –
− Data Will Be Presented in an Oral Session at
the IASLC World Conference on Lung Cancer (WCLC) on Monday, October
16 at 4:30 p.m. JST –
Takeda Pharmaceutical Company Limited (TSE: 4502) today
announced that data from the pivotal Phase 2 ALTA (ALK
in Lung Cancer Trial
of AP26113) clinical trial evaluating ALUNBRIGTM
(brigatinib) in patients with locally advanced or metastatic
anaplastic lymphoma kinase-positive (ALK+) non-small cell lung
cancer (NSCLC) who have progressed on crizotinib will be presented
in an oral session at the International Association for the Study
of Lung Cancer (IASLC) 18th World Conference on Lung Cancer (WCLC)
on Monday, October 16, 4:30 p.m.- 4:40 p.m. JST. The presentation
will share updated safety and efficacy data from the trial as of
February 21, 2017, which continue to support previously reported
clinical results.
The randomized Phase 2 ALTA trial was designed to investigate
the efficacy and safety of ALUNBRIG at two dosing regimens.
Patients received either 90 mg of ALUNBRIG once daily (n = 112; 90
mg; Arm A) or 180 mg once daily following a seven-day lead-in of 90
mg once daily (n=110; 180 mg dosing regimen; Arm B).
“The data being presented at WCLC provide further evidence
supporting the role of ALUNBRIG in the treatment of patients with
advanced ALK-positive NSCLC,” said David Kerstein, M.D., Senior
Medical Director and Global Clinical Lead for ALUNBRIG, Oncology
Clinical Research, Takeda. “There continues to be an unmet need for
the more than 30,000 patients diagnosed with this serious and rare
form of lung cancer worldwide each year. We are encouraged by the
updated data from the ALTA trial, which support the efficacy and
safety of ALUNBRIG in a crizotinib-refractory population, at the
dosing regimen that is being taken forward into ongoing and future
clinical trials.”
“The updated data from the ALTA trial further support the
clinical benefit of ALUNBRIG (brigatinib),” said Myung-Ju Ahn,
M.D., Professor, Department of Hematology & Oncology, Samsung
Medical Center. “I am especially encouraged by the efficacy seen in
patients with brain metastases, cancer that has spread to the
brain. The central nervous system is a common site for progression
in this disease, with brain metastases occurring in up to 70
percent of patients after treatment with crizotinib. With the 180
mg dosing regimen of brigatinib, two-thirds of patients with
measurable brain metastases had an intracranial response, with a
median intracranial duration of response of 16.6 months.”
Brigatinib in Crizotinib-Refractory ALK+ NSCLC: Updated
Efficacy and Safety Results From ALTA, a Randomized Phase 2 Trial
(Abstract #8027, Oral Presentation on Monday, October 16, 4:30-4:40
p.m. at the PACIFICO Yokohama Convention Center, Rooms 301 &
302)
Follow-up data as of February 21, 2017, 17 months after the last
patient enrolled; last brain scan was February 28, 2017.
Key findings, which will be presented by Dr. Myung-Ju Ahn,
Samsung Medical Center, include:
- As of February 21, 2017, at a median
follow-up period of 16.8 and 18.6 months in Arms A (90 mg once
daily) and B (180 mg once daily following a seven-day lead-in of 90
mg once daily), respectively, 32 percent of patients in Arm A and
41 percent of patients in Arm B continued to receive ALUNBRIG.
- Investigator-assessed confirmed
objective response rate (ORR), which was the primary endpoint, was
46 percent in Arm A and 55 percent in Arm B. Per Independent Review
Committee (IRC), confirmed ORR was 51 percent in Arm A and 55
percent in Arm B.
- Investigator-assessed median duration
of response (DOR) was 12 months in Arm A and 13.8 months in Arm B.
IRC-assessed median DOR was 13.8 months in Arm A and 14.8 months in
Arm B.
- Investigator-assessed median
progression-free survival (PFS) was 9.2 months in Arm A and 15.6
months in Arm B. IRC-assessed median PFS was 9.2 months in Arm A
and 16.7 months in Arm B.
- Median overall survival (OS) was not
reached in Arm A and 27.6 months in Arm B. The one-year OS
probability was 70 percent in Arm A and 80 percent in Arm B.
- Of the patients with measurable brain
metastases at baseline (n=26 / n=18, Arm A / Arm B), 50 percent in
Arm A and 67 percent in Arm B achieved a confirmed intracranial
objective response by IRC assessment; median duration of
intracranial response was not reached in Arm A and was 16.6 months
in Arm B.
- In patients with any brain metastases
at baseline the median intracranial PFS as assessed by the IRC was
12.8 months in Arm A and 18.4 months in Arm B.
- The most common grade ≥3
treatment-related adverse events (AEs) (Arm A / Arm B) included
increased blood creatine phosphokinase (3 percent / 11 percent),
hypertension (4 percent / 4 percent), increased lipase (4 percent /
4 percent), pneumonitis (2 percent / 4 percent), and rash (1
percent / 4 percent). Dose reduction (9 percent / 30 percent) or
discontinuation (4 percent / 11 percent) due to any AEs was
reported.
- The efficacy and safety data from the
ALTA trial continue to support future trials with the 180 mg dosing
regimen.
About the ALTA Trial
The Phase 2 ALTA (ALK in Lung
Cancer Trial of AP26113) trial of
brigatinib in adults is an ongoing, two-arm, open-label,
multicenter trial, which enrolled 222 patients with locally
advanced or metastatic ALK+ NSCLC who had progressed on crizotinib.
Patients received either 90 mg of ALUNBRIG once daily (n=112) or
180 mg once daily following a seven-day lead-in of 90 mg once daily
(n=110). Investigator-assessed confirmed objective response rate
(ORR) per RECIST v1.1 was the primary endpoint. Secondary endpoints
included IRC-assessed ORR, duration of response (DOR), intracranial
ORR, intracranial PFS, safety and tolerability.
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. In April of 2017, ALUNBRIG received Accelerated Approval from
the U.S. Food and Drug Administration (FDA) for ALK+ metastatic
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 (U.S.)
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 LimitedJapanese
MediaTsuyoshi Tada, +81 (0)
3-3278-2417tsuyoshi.tada@takeda.comorMedia outside
Japan/EUShawn Goodman,
+1-617-444-1250Shawn.Goodman@takeda.comorEuropean MediaKate
Burd, +41 79 514 9533kate.burd@takeda.com