– ALUNBRIG has Potential to Expand its Indication in ALK+ Metastatic Non-Small Cell Lung Cancer –
– Prescription Drug User Fee Act (PDUFA) Target Action Date Set for June 23, 2020 –
CAMBRIDGE, Mass. & OSAKA, Japan-Friday 28 February 2020 [ AETOS Wire ]
(BUSINESS
WIRE)-- Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) today
announced that the U.S. Food and Drug Administration (FDA) has granted
priority review for the company’s supplemental New Drug Application
(sNDA) to expand the use of ALUNBRIG (brigatinib) as a first-line
treatment for patients with anaplastic lymphoma kinase-positive (ALK+)
metastatic non-small cell lung cancer (NSCLC) as detected by an
FDA-approved test. ALUNBRIG is a next-generation tyrosine kinase
inhibitor (TKI) that was designed to target and inhibit ALK genetic
alterations.
“ALK+ NSCLC is a rare and serious form of lung
cancer that is complex to treat. While progress has been made, unmet
needs still exist for the approximately 40,000 patients diagnosed with
this disease worldwide each year,” said Christopher Arendt, Head,
Oncology Therapeutic Area Unit, Takeda. “This is an important first step
in expanding treatment options for people with ALK+ metastatic NSCLC in
the U.S., and we look forward to continuing to work with regulatory
authorities around the world to bring ALUNBRIG to newly diagnosed
patients.”
The sNDA for ALUNBRIG as a first-line treatment is
based on results from the Phase 3 ALTA-1L trial, which is evaluating the
safety and efficacy of ALUNBRIG in patients with ALK+ locally advanced
or metastatic NSCLC who have not received prior treatment with an ALK
inhibitor compared to that of crizotinib in the same population. The
ALTA-1L trial met its primary endpoint with ALUNBRIG demonstrating
superiority in blinded independent review committee (BIRC)-assessed
progression-free survival (PFS) compared to crizotinib.
About the ALTA-1L Trial
The
Phase 3 ALTA-1L (ALK in Lung Cancer Trial of BrigAtinib in 1st Line)
trial of ALUNBRIG in adults is a global, ongoing, randomized,
open-label, comparative, multicenter trial, which enrolled 275 patients
(ALUNBRIG, n=137, crizotinib, n=138) with ALK+ locally advanced or
metastatic NSCLC who have not received prior treatment with an ALK
inhibitor. Patients received either ALUNBRIG, 180 mg once daily with
seven-day lead-in at 90 mg once daily, or crizotinib, 250 mg twice
daily.
The median age was 58 years in the ALUNBRIG arm and 60
years in the crizotinib arm. Twenty-nine percent of patients had brain
metastases at baseline in the ALUNBRIG arm versus 30% in the crizotinib
arm. Twenty-six percent of patients received prior chemotherapy for
advanced or metastatic disease in the ALUNBRIG arm versus 27% in the
crizotinib arm.
Blinded independent review committee
(BIRC)-assessed progression-free survival (PFS) was the primary
endpoint. Secondary endpoints included objective response rate (ORR) per
RECIST v1.1, intracranial ORR, intracranial PFS, overall survival (OS),
safety and tolerability.
The safety profile of ALUNBRIG in the ALTA-1L trial was generally consistent with the existing U.S. prescribing information.
About ALUNBRIG® (brigatinib)
ALUNBRIG
is a potent and selective next-generation tyrosine kinase inhibitor
(TKI) that was designed to target and inhibit anaplastic lymphoma kinase
(ALK) genetic alterations. In April 2017, ALUNBRIG received Accelerated
Approval from the U.S. 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 is currently approved in more than
40 countries, including the U.S., Canada and the European Union, for the
treatment of people living with ALK+ metastatic NSCLC who have taken
the medicine crizotinib, but their NSCLC has worsened or they cannot
tolerate taking crizotinib.
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.
About ALK+ NSCLC
Non-small cell lung cancer
(NSCLC) is the most common form of lung cancer, accounting for
approximately 85% of the estimated 1.8 million new cases of lung cancer
diagnosed each year worldwide, according to the World Health
Organization.1,2 Genetic studies indicate that chromosomal
rearrangements in anaplastic lymphoma kinase (ALK) are key drivers in a
subset of NSCLC patients.3 Approximately three to five percent of
patients with metastatic NSCLC have a rearrangement in the ALK
gene.4,5,6
Takeda is committed to continuing research and
development in NSCLC to improve the lives of the approximately 40,000
patients diagnosed with this serious and rare form of lung cancer
worldwide each year.7
Takeda’s Commitment to Lung Cancer
Takeda
is dedicated to expanding treatment options in the ALK+ NSCLC and
EGFR/HER2 mutant NSCLC treatment landscapes. Our comprehensive programs
include the following clinical trials to continue to address unmet needs
for people living with lung cancer:
ALUNBRIG
Phase
1/2 trial, which was designed to evaluate the safety, tolerability,
pharmacokinetics and preliminary anti-tumor activity of ALUNBRIG. This
trial has completed enrollment.
Pivotal Phase 2 ALTA trial
investigating the efficacy and safety of ALUNBRIG at two dosing regimens
in patients with ALK+ locally advanced or metastatic NSCLC who had
progressed on crizotinib. This trial has completed enrollment.
Phase 3 ALTA-1L, global, randomized trial assessing the efficacy and
safety of ALUNBRIG in comparison to crizotinib in patients with ALK+
locally advanced or metastatic NSCLC who have not received prior
treatment with an ALK inhibitor. This trial has completed enrollment.
Phase 2 J-ALTA, single-arm, multicenter trial in Japanese patients with
ALK+ NSCLC, focusing on patients who have progressed on alectinib. This
trial has completed enrollment.
Phase 2 ALTA 2, global,
single-arm trial evaluating ALUNBRIG in patients with advanced ALK+
NSCLC who have progressed on alectinib or ceritinib. This trial has
completed enrollment.
Phase 3 ALTA 3, global randomized trial
comparing the efficacy and safety of ALUNBRIG versus alectinib in
participants with ALK+ NSCLC who have progressed on crizotinib. This
trial is now enrolling.
TAK-788, a selective inhibitor of EGFR/HER2 mutations, currently being explored in EGFR exon 20 insertion mutations:
Phase 1/2 study evaluating the safety, pharmacokinetics and antitumor
activity of oral EGFR/HER2 inhibitor TAK-788 in patients with NSCLC.
This trial has completed enrollment.
Phase 2 EXCLAIM, pivotal
extension cohort of the Phase 1/2 trial, which was designed to evaluate
the efficacy and safety of TAK-788 at 160 mg once daily in previously
treated patients with EGFR exon 20 insertion mutations. This trial has
completed enrollment.
Phase 3 EXCLAIM 2, global, randomized study
evaluating the efficacy of TAK-788 as a first-line treatment compared
to platinum-based doublet chemotherapy in treatment-naïve patients with
locally advanced or metastatic NSCLC whose tumors harbor EGFR exon 20
insertion mutations. This trial is now enrolling.
Phase 1,
open-label, multicenter, dose-escalation study evaluating the safety,
tolerability and pharmacokinetics of TAK-788 in Japanese patients with
locally advanced or metastatic NSCLC. This trial has completed
enrollment.
Phase 2 J-EXCLAIM, open-label, multicenter, study
evaluating the efficacy of TAK-788 as a first-line treatment in Japanese
patients with locally advanced or metastatic NSCLC whose tumors harbor
EGFR exon 20 insertion mutations. This trial is now enrolling.
Phase 1, open-label, two-period, fixed-sequence study designed to
characterize drug-drug interaction between TAK-788 and either a strong
cytochrome P-450 (CYP)3A inhibitor, itraconazole (Part 1) or a strong
CYP3A inducer, rifampin (Part 2) in healthy adult subjects. This trial
is now enrolling.
For additional information on the ALUNBRIG and TAK-788 clinical trials, please visit www.clinicaltrials.gov.
ALUNBRIG 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 coadministration of ALUNBRIG with strong or moderate
CYP3A inhibitors. Avoid grapefruit or grapefruit juice as it may also
increase plasma concentrations of brigatinib. If coadministration of a
strong or moderate CYP3A inhibitor cannot be avoided, reduce the dose of
ALUNBRIG.
CYP3A Inducers: Avoid coadministration of ALUNBRIG
with strong or moderate CYP3A inducers. If coadministration of moderate
CYP3A inducers cannot be avoided, increase the dose of ALUNBRIG.
CYP3A
Substrates: Coadministration of ALUNBRIG with sensitive CYP3A
substrates, including hormonal contraceptives, can result in decreased
concentrations and loss of efficacy of sensitive 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:
Pregnancy Testing: Verify pregnancy status in females of reproductive potential prior to initiating ALUNBRIG.
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 effectiveness 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.
Hepatic or Renal Impairment:
No dose adjustment is recommended for patients with mild or moderate
hepatic impairment or mild or moderate renal impairment. Reduce the dose
of ALUNBRIG for patients with severe hepatic impairment or severe renal
impairment.
Please see the full U.S. Prescribing Information for ALUNBRIG at www.ALUNBRIG.com
About Takeda Pharmaceutical Company Limited
Takeda
Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) is a global,
values-based, R&D-driven biopharmaceutical leader headquartered in
Japan, committed to bringing Better Health and a Brighter Future to
patients by translating science into highly-innovative medicines. Takeda
focuses its R&D efforts on four therapeutic areas: Oncology,
Gastroenterology (GI), Rare Diseases and Neuroscience. We also make
targeted R&D investments in Plasma-Derived Therapies and Vaccines.
We are focusing on developing highly innovative medicines that
contribute to making a difference in people's lives by advancing the
frontier of new treatment options and leveraging our enhanced
collaborative R&D engine and capabilities to create a robust,
modality-diverse pipeline. Our employees are committed to improving
quality of life for patients and to working with our partners in health
care in approximately 80 countries and regions.
For more information, visit https://www.takeda.com
Important Notice
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Key Information—D. Risk Factors” in Takeda’s most recent Annual Report
on Form 20-F and Takeda’s other reports filed with the U.S. Securities
and Exchange Commission, available on Takeda’s website at:
https://www.takeda.com/investors/reports/sec-filings/ or at www.sec.gov.
Future results, performance, achievements or financial position of
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1 World Health Organization. Latest Global Cancer Data. https://www.who.int/cancer/PRGlobocanFinal.pdf. Accessed May 11, 2019.
2
American Cancer Society. What is Non-Small Cell Lung Cancer?
https://www.cancer.org/cancer/non-small-cell-lung-cancer/about/what-is-non-small-cell-lung-cancer.html.
Accessed May 11, 2019.
3 Kris MG, et al. JAMA, 2014;311:1998-2006.
4 Gainor JF, Varghese AM, Ou SH, et al. Clin Cancer Res. 2013;19(15):4273-81.
5 Koivunen JP, Mermel C, Zejnullahu K, et al. Clin Cancer Res. 2008; 14(13):4275-83.
6 Wong DW, Leung EL, So KK, et al. Cancer. 2009; 115(8):1723-33.
7 Chia PL, Mitchell P, Dobrovic A, John T. Clin Epidemiol, 2014;6:423-432.
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Contacts
Takeda Pharmaceutical Company Limited
Japanese Media
Kazumi Kobayashi
kazumi.kobayashi@takeda.com
+81 (0) 3-3278-2095
Media Outside Japan
Lauren Padovan
lauren.padovan@takeda.com
+1-617-444-1419
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