CAMBRIDGE, Mass. & OSAKA, Japan -Saturday 7 March 2020 [ AETOS Wire ]
–
If Approved by the European Medicines Agency, ALUNBRIG Would Become an
Important First-Line Treatment Option for ALK+ NSCLC Patients –
– Positive Opinion is Based
on Data from Phase 3 ALTA-1L Trial, in which ALUNBRIG Demonstrated
Superiority in both Overall and Intracranial Efficacy Compared to
Crizotinib –
(BUSINESS WIRE)-- Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK)
today announced that the European Medicines Agency’s (EMA) Committee
for Medicinal Products for Human Use (CHMP) adopted a positive opinion
recommending the approval of ALUNBRIG (brigatinib) as a monotherapy for
the treatment of adult patients with anaplastic lymphoma kinase-positive
(ALK+) advanced non-small cell lung cancer (NSCLC) previously not
treated with an ALK inhibitor. ALUNBRIG is a next-generation tyrosine
kinase inhibitor (TKI) that was designed to target and inhibit ALK
genetic alterations.
“Because of the complex nature of ALK+
NSCLC and the way in which the disease often spreads to the brain, it is
essential for physicians to have treatment options that demonstrate
both overall and intracranial effectiveness,” said Professor Sanjay
Popat, Consultant Medical Oncologist, Royal Marsden NHS Foundation
Trust. “In the ALTA-1L trial, brigatinib demonstrated significant
responses in the brain and consistent overall efficacy compared to
crizotinib. If approved by the EMA, brigatinib has the potential to
become an important option for the first-line treatment of ALK+ advanced
NSCLC patients in Europe.”
This opinion is based on data from the
Phase 3 ALTA-1L trial, which is evaluating the safety and efficacy of
ALUNBRIG compared to crizotinib in patients with ALK+ locally advanced
or metastatic NSCLC who have not received prior treatment with an ALK
inhibitor. Results from the trial showed ALUNBRIG demonstrated
superiority compared to crizotinib with significant responses observed
in patients with baseline brain metastases. After more than two years of
follow-up, ALUNBRIG reduced the risk of intracranial disease
progression or death by 69% in patients with brain metastases at
baseline (hazard ratio [HR] = 0.31, 95% CI: 0.17–0.56), as assessed by a
blinded independent review committee (BIRC), and 76% (HR = 0.24, 95%
CI: 0.12–0.45), as assessed by investigators. ALUNBRIG also demonstrated
consistent overall efficacy (intent to treat population), with a median
progression-free survival (PFS) more than two times longer than that
with crizotinib at 24.0 months (95% CI: 18.5–NE) versus 11.0 months (95%
CI: 9.2–12.9) for crizotinib, as assessed by BIRC, and 29.4 months (95%
CI: 21.2–NE) versus 9.2 months (95% CI: 7.4–12.9), as assessed by
investigators.
The safety profile of ALUNBRIG in the
ALTA-1L trial was generally consistent with the existing European
summary of product characteristics (SmPC). The most common
treatment-emergent adverse events (TEAEs) Grade ≥3 in the ALUNBRIG arm
were increased CPK (24.3%), increased lipase (14.0%) and hypertension
(11.8%); and for crizotinib were increased ALT (10.2%), increased AST
(6.6%), and increased lipase (6.6%).
“Developing safe and effective treatment
options for cancer is a top priority for Takeda, and we continue to
look for ways to address the unmet needs of the lung cancer community,”
said Christopher Arendt, Head, Oncology Therapeutic Area Unit, Takeda.
“Today’s positive CHMP opinion is an important step towards bringing
ALUNBRIG to people living with ALK+ advanced NSCLC, and we look forward
to continuing to work with the EMA as they review the application for
ALUNBRIG as a first-line treatment of patients with this serious and
rare form of lung cancer.”
“ALK+ NSCLC is a rarer form of lung
cancer, and the needs of people impacted by it are multiple,” said
Stefania Vallone, President of Lung Cancer Europe (LuCE). “Despite
progress in recent years, there remains a need for additional first-line
treatment options for the approximately 10,000 people with ALK+ NSCLC
in Europe.”
The positive opinion for ALUNBRIG will
now be reviewed by the European Commission (EC) for Commission Decision.
ALUNBRIG is currently not approved as a therapy for first-line ALK+
NSCLC.
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 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 European
summary of product characteristics (SmPC).
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 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
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:
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® (brigatinib): EUROPEAN IMPORTANT SAFETY INFORMATION
SPECIAL WARNINGS AND PRECAUTIONS FOR USE
Pulmonary Adverse Reactions: Severe,
life-threatening, and fatal pulmonary adverse reactions, including
those with features consistent with ILD/pneumonitis, can occur. Most
pulmonary adverse reactions were observed within the first 7 days of
treatment. Grade 1-2 pulmonary adverse reactions resolved with
interruption of treatment or dose modification. Increased age and
shorter interval (less than 7 days) between the last dose of crizotinib
and the first dose of ALUNBRIG were independently associated with an
increased rate of these pulmonary adverse reactions. Consider these
factors when initiating treatment with ALUNBRIG. Some patients
experienced pneumonitis later in treatment with ALUNBRIG. Patients
should be monitored for new or worsening respiratory symptoms (e.g.,
dyspnoea, cough, etc.), particularly in the first week of treatment.
Evidence of pneumonitis in any patient with worsening respiratory
symptoms should be promptly investigated. If pneumonitis is suspected,
the dose of ALUNBRIG should be withheld, and the patient evaluated for
other causes of symptoms (e.g., pulmonary embolism, tumour progression,
and infectious pneumonia). The dose should be modified accordingly.
Hypertension has
occurred. Blood pressure should be monitored regularly during treatment
with ALUNBRIG. Hypertension should be treated according to standard
guidelines to control blood pressure. Heart rate should be monitored
more frequently in patients if concomitant use of a medication known to
cause bradycardia cannot be avoided. For severe hypertension (≥ Grade
3), ALUNBRIG should be withheld until hypertension has recovered to
Grade 1 or to baseline. The dose should be modified accordingly.
Bradycardia has
occurred. Caution should be exercised when administering ALUNBRIG in
combination with other agents known to cause bradycardia. Heart rate and
blood pressure should be monitored regularly. Treatment with ALUNBRIG
should be withheld if symptomatic bradycardia occurs. Concomitant
medications known to cause bradycardia should be evaluated. Upon
recovery, dose should be modified accordingly. In case of
life-threatening bradycardia, permanently discontinue ALUNBRIG if no
contributing concomitant medication is identified or in the case of
recurrence. If contributing concomitant medication is identified, modify
dose accordingly.
Visual Disturbance has
occurred with ALUNBRIG. Patients should be advised to report any visual
symptoms. For new or worsening severe visual symptoms, an ophthalmologic
evaluation and dose reduction should be considered.
Creatine Phosphokinase (CPK) Elevation has
been reported. Advise patients to report any unexplained muscle pain,
tenderness, or weakness. Monitor CPK levels regularly during treatment.
Based on the severity of the CPK elevation, withhold treatment with
ALUNBRIG and modify dose accordingly.
Pancreatic Enzyme Elevation: Elevations
of amylase and lipase have occurred. Lipase and amylase should be
monitored regularly during treatment with ALUNBRIG. Based on the
severity of the laboratory abnormalities, withhold ALUNBRIG and modify
dose accordingly.
Hepatotoxicity: Elevations
of hepatic enzymes (aspartate aminotransferase, alanine
aminotransferase) and bilirubin have occurred. Liver function, including
AST, ALT and total bilirubin should be assessed prior to the initiation
of ALUNBRIG and then every 2 weeks during the first 3 months of
treatment. Thereafter, monitoring should be performed periodically.
Based on the severity of the laboratory abnormalities, withhold ALUNBRIG
and modify dose accordingly.
Hyperglycemia: Elevations
of serum glucose have occurred. Fasting serum glucose should be
assessed prior to initiation of ALUNBRIG and monitored periodically
thereafter. Antihyperglycaemic treatment should be initiated or
optimised as needed. If adequate hyperglycaemic control cannot be
achieved with optimal medical management, ALUNBRIG should be withheld
until adequate hyperglycaemic control is achieved; upon recovery
reducing the dose may be considered or ALUNBRIG may be permanently
discontinued.
Drug interactions: Concomitant
use of ALUNBRIG with strong CYP3A inhibitors should be avoided. If
concomitant use of strong CYP3A inhibitors cannot be avoided, reduce
dose of ALUNBRIG from 180 mg to 90 mg, or from 90 mg to 60 mg. After
discontinuation of a strong CYP3A inhibitor, ALUNBRIG should be resumed
at the dose that was tolerated prior to the initiation of the strong
CYP3A inhibitor. The concomitant use of ALUNBRIG with strong and
moderate CYP3A inducers should be avoided.
Fertility: Women of
childbearing potential should be advised to use effective non-hormonal
contraception during treatment with ALUNBRIG and for at least 4 months
following the final dose. Men with female partners of childbearing
potential should be advised to use effective contraception during
treatment and for at least 3 months after the last dose of ALUNBRIG.
Lactose: ALUNBRIG
contains lactose monohydrate. Patients with rare hereditary problems of
galactose intolerance, total lactase deficiency or glucose-galactose
malabsorption should not take this medication.
UNDESIRABLE EFFECTS
The most common adverse reactions (≥
25%) reported in patients treated with ALUNBRIG at the recommended
dosing regimen were increased AST, hyperglycaemia, hyperinsulinaemia,
anaemia, increased CPK, nausea, increased lipase, decreased lymphocyte
count, increased ALT, diarrhoea, increased amylase, fatigue, cough,
headache, increased alkaline phosphatase, hypophosphataemia, increased
APTT, rash, vomiting, dyspnoea, hypertension, decreased white blood cell
count, myalgia, and peripheral neuropathy.
The most common serious adverse
reactions (≥ 2%) reported in patients treated with ALUNBRIG at the
recommended dosing regimen other than events related to neoplasm
progression were pneumonitis, pneumonia, and dyspnoea.
SPECIAL POPULATIONS
Elderly patients: The
limited data on the safety and efficacy of ALUNBRIG in patients aged 65
years and older suggest that a dose adjustment is not required in
elderly patients. There are no available data on patients over 85 years
of age.
Hepatic impairment: No
dose adjustment of ALUNBRIG is required for patients with mild hepatic
impairment (Child-Pugh class A) or moderate hepatic impairment
(Child-Pugh class B). A reduced starting dose of 60 mg once daily for
the first 7 days, then 120 mg once daily is recommended for patients
with severe hepatic impairment (Child-Pugh class C).
Renal impairment: No
dose adjustment of ALUNBRIG is required for patients with mild or
moderate renal impairment (estimated glomerular filtration rate (eGFR) ≥
30 mL/min). A reduced starting dose of 60 mg once daily for the first 7
days, then 90 mg once daily is recommended for patients with severe
renal impairment (eGFR < 30 mL/min). Patients with severe renal
impairment should be closely monitored for new or worsening respiratory
symptoms that may indicate ILD/pneumonitis (e.g., dyspnoea, cough, etc.)
particularly in the first week.
Paediatric population: The safety and efficacy of ALUNBRIG in patients less than 18 years of age have not been established. No data are available.
ALUNBRIG 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.
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).
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.
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.
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.
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, Rare Diseases, Neuroscience, and Gastroenterology (GI). 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.
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, Rare Diseases, Neuroscience, and Gastroenterology (GI). 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.
For more information, visit https://www.takeda.com.
Important Notice
For the purposes of this notice, “press release” means this document, any oral presentation, any question and answer session and any written or oral material discussed or distributed by Takeda Pharmaceutical Company Limited (“Takeda”) regarding this release. This press release (including any oral briefing and any question-and-answer in connection with it) is not intended to, and does not constitute, represent or form part of any offer, invitation or solicitation of any offer to purchase, otherwise acquire, subscribe for, exchange, sell or otherwise dispose of, any securities or the solicitation of any vote or approval in any jurisdiction. No shares or other securities are being offered to the public by means of this press release. No offering of securities shall be made in the United States except pursuant to registration under the U.S. Securities Act of 1933, as amended, or an exemption therefrom. This press release is being given (together with any further information which may be provided to the recipient) on the condition that it is for use by the recipient for information purposes only (and not for the evaluation of any investment, acquisition, disposal or any other transaction). Any failure to comply with these restrictions may constitute a violation of applicable securities laws.
For the purposes of this notice, “press release” means this document, any oral presentation, any question and answer session and any written or oral material discussed or distributed by Takeda Pharmaceutical Company Limited (“Takeda”) regarding this release. This press release (including any oral briefing and any question-and-answer in connection with it) is not intended to, and does not constitute, represent or form part of any offer, invitation or solicitation of any offer to purchase, otherwise acquire, subscribe for, exchange, sell or otherwise dispose of, any securities or the solicitation of any vote or approval in any jurisdiction. No shares or other securities are being offered to the public by means of this press release. No offering of securities shall be made in the United States except pursuant to registration under the U.S. Securities Act of 1933, as amended, or an exemption therefrom. This press release is being given (together with any further information which may be provided to the recipient) on the condition that it is for use by the recipient for information purposes only (and not for the evaluation of any investment, acquisition, disposal or any other transaction). Any failure to comply with these restrictions may constitute a violation of applicable securities laws.
The companies in which Takeda directly
and indirectly owns investments are separate entities. In this press
release, “Takeda” is sometimes used for convenience where references are
made to Takeda and its subsidiaries in general. Likewise, the words
“we”, “us” and “our” are also used to refer to subsidiaries in general
or to those who work for them. These expressions are also used where no
useful purpose is served by identifying the particular company or
companies.
Forward-Looking Statements
This press release and any materials distributed in connection with this press release may contain forward-looking statements, beliefs or opinions regarding Takeda’s future business, future position and results of operations, including estimates, forecasts, targets and plans for Takeda. Without limitation, forward-looking statements often include words such as “targets”, “plans”, “believes”, “hopes”, “continues”, “expects”, “aims”, “intends”, “ensures”, “will”, “may”, “should”, “would”, “could” “anticipates”, “estimates”, “projects” or similar expressions or the negative thereof. Forward-looking statements in this document are based on Takeda’s estimates and assumptions only as of the date hereof. Such forward-looking statements do not represent any guarantee by Takeda or its management of future performance and involve known and unknown risks, uncertainties and other factors, including but not limited to: the economic circumstances surrounding Takeda’s global business, including general economic conditions in Japan and the United States; competitive pressures and developments; changes to applicable laws and regulations; the success of or failure of product development programs; decisions of regulatory authorities and the timing thereof; fluctuations in interest and currency exchange rates; claims or concerns regarding the safety or efficacy of marketed products or product candidates; the timing and impact of post-merger integration efforts with acquired companies; and the ability to divest assets that are not core to Takeda’s operations and the timing of any such divestment(s), any of which may cause Takeda’s actual results, performance, achievements or financial position to be materially different from any future results, performance, achievements or financial position expressed or implied by such forward-looking statements. For more information on these and other factors which may affect Takeda’s results, performance, achievements, or financial position, see “Item 3. 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 Takeda could differ materially from those expressed in or implied by the forward-looking statements. Persons receiving this press release should not rely unduly on any forward-looking statements. Takeda undertakes no obligation to update any of the forward-looking statements contained in this press release or any other forward-looking statements it may make, except as required by law or stock exchange rule. Past performance is not an indicator of future results and the results of Takeda in this press release may not be indicative of, and are not an estimate, forecast or projection of Takeda’s future results.
This press release and any materials distributed in connection with this press release may contain forward-looking statements, beliefs or opinions regarding Takeda’s future business, future position and results of operations, including estimates, forecasts, targets and plans for Takeda. Without limitation, forward-looking statements often include words such as “targets”, “plans”, “believes”, “hopes”, “continues”, “expects”, “aims”, “intends”, “ensures”, “will”, “may”, “should”, “would”, “could” “anticipates”, “estimates”, “projects” or similar expressions or the negative thereof. Forward-looking statements in this document are based on Takeda’s estimates and assumptions only as of the date hereof. Such forward-looking statements do not represent any guarantee by Takeda or its management of future performance and involve known and unknown risks, uncertainties and other factors, including but not limited to: the economic circumstances surrounding Takeda’s global business, including general economic conditions in Japan and the United States; competitive pressures and developments; changes to applicable laws and regulations; the success of or failure of product development programs; decisions of regulatory authorities and the timing thereof; fluctuations in interest and currency exchange rates; claims or concerns regarding the safety or efficacy of marketed products or product candidates; the timing and impact of post-merger integration efforts with acquired companies; and the ability to divest assets that are not core to Takeda’s operations and the timing of any such divestment(s), any of which may cause Takeda’s actual results, performance, achievements or financial position to be materially different from any future results, performance, achievements or financial position expressed or implied by such forward-looking statements. For more information on these and other factors which may affect Takeda’s results, performance, achievements, or financial position, see “Item 3. 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 Takeda could differ materially from those expressed in or implied by the forward-looking statements. Persons receiving this press release should not rely unduly on any forward-looking statements. Takeda undertakes no obligation to update any of the forward-looking statements contained in this press release or any other forward-looking statements it may make, except as required by law or stock exchange rule. Past performance is not an indicator of future results and the results of Takeda in this press release may not be indicative of, and are not an estimate, forecast or projection of Takeda’s future results.
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.
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
Kazumi Kobayashi
kazumi.kobayashi@takeda.com
+81 (0) 3-3278-2095
Media Outside Japan
Lauren Padovan
lauren.padovan@takeda.com
+1-617-444-1419
