– Phase 1/2 Data Being Presented at the 2019 American Society of
Clinical Oncology (ASCO) Annual Meeting Demonstrated TAK-788 Extended
the Time Until Disease Progression or Death by More Than Seven Months –
– Takeda’s Growing Lung Portfolio is Driven by a Dedication to
Developing Innovative Therapies for People Living with NSCLC –
CAMBRIDGE, Mass. & OSAKA, Japan–(BUSINESS WIRE)–Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK)
today announced that new data for TAK-788 will be presented during an
oral session at the 2019 American Society of Clinical Oncology (ASCO)
Annual Meeting on Monday, June 3 at 10:12 a.m. CT in Chicago. Results
from a Phase 1/2 first-in-human, open-label, multicenter study showed
TAK-788 yielded a median progression-free survival (PFS) of 7.3 months
and a confirmed objective response rate (ORR) of 43% in patients with
locally advanced or metastatic non-small cell lung cancer (NSCLC) whose
tumors harbor epidermal growth factor receptor (EGFR) exon 20
insertion mutations. These findings add to the collection of data
featured at this year’s meeting from Takeda’s lung cancer portfolio,
which also revealed key insights from sub-analyses of ALUNBRIG
(brigatinib), including quality of life data from the Phase 3 ALTA-1L (ALK
in Lung Cancer Trial of BrigAtinib in 1st
Line) trial. TAK-788 is an investigational drug for which
efficacy and safety have not been established. ALUNBRIG does not yet
have regulatory approval for first-line therapy.
“We are thrilled to share promising, early results from TAK-788, an
investigational therapy that has the potential to help advance the
treatment of NSCLC patients with EGFR exon 20 insertion
mutations,” said Phil Rowlands, Ph.D., Head, Oncology Therapeutic Area
Unit, Takeda. “Furthermore, meaningful insights from our ongoing
ALUNBRIG Phase 3 clinical trial, ALTA-1L, will be unveiled during the
meeting. ALUNBRIG is the only treatment of its kind to report improved
quality of life over another ALK tyrosine kinase inhibitor (TKI) as
evidenced by patient-reported outcomes presented at ASCO. These findings
build upon our ALTA-1L efficacy data and illustrate ALUNBRIG’s potential
to provide a meaningful benefit for patient’s life quality.”
Results from the Phase 1/2 trial of TAK-788 will be presented on Monday,
June 3 at 10:12 a.m. CT in Hall B1 of the McCormick Place Convention
Center. A summary of key findings is provided below:
-
The current analysis evaluated a total of 28 NSCLC patients with EGFR
exon 20 insertions who were treated with the recommended Phase 2 dose
(RP2D) of 160 mg once daily. More than 50% of patients had received
three or more prior regimens and 61% had been previously treated with
an immune-checkpoint inhibitor. The median time on treatment was 7.9
months ongoing. -
Among the total patients treated, including those with brain
metastases at baseline, 43% (n=12/28) had a confirmed objective
response and median PFS was 7.3 months. Patients without brain
metastases at baseline had a confirmed objective response of 56%
(n=9/16) and a median PFS of 8.1 months. -
The disease control rate was 86% (n=24/28) for the total patients
treated and 100% for patients without brain metastases at baseline
(n=16/16). -
The safety profile of TAK-788 was manageable. For patients treated at
the 160 mg once daily dose:-
The most common any grade treatment-related adverse events (AEs)
were diarrhea (85%), nausea (43%), rash (36%), vomiting (29%) and
decreased appetite (25%). - Most treatment-related AEs were Grade 1-2 and reversible.
- Forty percent experienced Grade ≥3 treatment-related AEs.
-
The most common Grade ≥3 treatment-related AEs were diarrhea
(18%), nausea (6%), increased lipase (6%), increased amylase (4%)
and stomatitis (4%). -
Food instructions have been included in the ongoing study with the
potential to improve gastrointestinal tolerability.
-
The most common any grade treatment-related adverse events (AEs)
-
At the time of the analysis, 50% of patients were still on treatment,
and additional results will be presented at future congresses,
including those from the recently opened Phase 2 pivotal extension
cohort, EXCLAIM. The pivotal cohort was designed to evaluate the
efficacy and safety of TAK-788 at 160 mg once daily in previously
treated patients and will build upon the results seen in the Phase 1/2
trial.
“Results from this Phase 1/2 trial show that TAK-788 effectively treated
NSCLC patients whose tumors harbor EGFR exon 20 insertion
mutations and who had been previously treated with multiple prior
therapies,” said Pasi A Jänne, M.D., Ph.D., Dana-Farber Cancer
Institute. “These data represent an important development and
demonstrate progress in addressing an unmet need for these patients, who
currently have limited treatment options and no approved targeted
therapies.”
For ALUNBRIG, Takeda presented three posters featuring results from
ongoing trials of its clinical development program, which seeks to
expand Takeda’s research of ALUNBRIG and optimize its use among patients
with anaplastic lymphoma kinase-positive (ALK+) NSCLC.
Notably, two posters highlighted sub-analyses of the Phase 3 ALTA-1L
trial in patients who had not received prior treatment with an ALK
inhibitor:
-
Results from an analysis of the validated patient-reported outcomes
questionnaire EORTC QLQ-C30 showed that ALUNBRIG significantly
improved the overall health-related quality of life (HRQoL) compared
to crizotinib. Results also showed improvements for patients receiving
ALUNBRIG across functional scales, with significant improvement seen
for physical, emotional and cognitive functions. There was also
observed improvement for symptom scales including fatigue, nausea and
vomiting, appetite loss and constipation. -
Additionally, an investigation of outcomes in patients of Asian versus
non-Asian heritage demonstrated that ALUNBRIG showed improvement in
PFS compared to crizotinib for both patient subgroups. The safety
profile of ALUNBRIG in these subgroups was consistent with what has
been reported previously, with no new safety concerns. These findings
add to the body of evidence evaluating ALUNBRIG in the first-line
setting for patients with ALK+ NSCLC.
About EGFR Exon 20 Insertion-Mutant 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 Epidermal growth factor
receptor (EGFR) is one of several unique, genetic alternations found in
NSCLC that affects approximately 15-21% of all NSCLC patients.3,4
The exon refers to the location of the EGFR mutations, which can be
found in exon 18, 19, 20 or 21. Exon 20 insertions are much less common
than EGFR mutations in other exons, comprising approximately 6% of all
EGFR-mutated lung tumors.5 Therefore, patients with NSCLC who
harbor EGFR exon 20 insertion mutations make up a small proportion of
the NSCLC population, and there are currently no targeted therapy
options to treat them, as approved EGFR tyrosine kinase inhibitor (TKIs)
were not designed for patients with this subtype of EGFR mutations.
About TAK-788
TAK-788 is a potent and selective next-generation, small-molecule
tyrosine kinase inhibitor (TKI) intelligently designed and under
clinical investigation to inhibit epidermal growth factor receptor
(EGFR) and human EGFR 2 (HER2) exon 20 mutations with selectivity over
wild type (WT) EGFR. Non-clinical studies demonstrated antitumor
activity against de novo mutations in EGFR including EGFR exon 20
insertions and the acquired resistance mutation T790M. In October 2018,
the ongoing Phase 1/2 trial of TAK-788 was amended to add the pivotal
extension cohort, EXCLAIM, 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 insertions and is currently actively
recruiting.
The TAK-788 development program has started first in the non-small cell
lung cancer (NSCLC) population and is expected to expand to additional
underserved populations in other tumor types. TAK-788 is an
investigational drug for which efficacy and safety have not been
established.
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. Approximately three to
five percent of patients with metastatic NSCLC have a rearrangement in
the ALK gene.6,7,8
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.9
About ALUNBRIG® (brigatinib)
ALUNBRIG is a potent and selective next-generation tyrosine kinase
inhibitor (TKI) that was designed to target and inhibit the anaplastic
lymphoma kinase (ALK) fusion protein in non-small cell lung
cancer (NSCLC).
-
In April 2017, ALUNBRIG received Accelerated Approval from the U.S.
Food and Drug Administration (FDA) for anaplastic lymphoma
kinase-positive (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. -
In July 2018, Health Canada approved ALUNBRIG for the treatment of
adult patients with ALK+ metastatic NSCLC who have progressed on or
who were intolerant to an ALK inhibitor (crizotinib). -
In November 2018, the European Commission (EC) granted marketing
authorization for ALUNBRIG as a monotherapy for the treatment of adult
patients with ALK+ advanced NSCLC previously treated with crizotinib.
The FDA, Health Canada and EC approvals of ALUNBRIG were primarily
based on results from the pivotal Phase 2 ALTA (ALK in Lung
Cancer Trial of AP26113) 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.
The brigatinib 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. The comprehensive program includes the following clinical trials:
-
Phase 1/2 trial, which was designed to evaluate the safety,
tolerability, pharmacokinetics and preliminary anti-tumor activity of
ALUNBRIG. -
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. -
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. -
Phase 2 J-ALTA, single-arm, multicenter trial in Japanese patients
with ALK+ NSCLC, focusing on patients who have progressed on
alectinib. This trial is now enrolling. -
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 is now enrolling. -
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.
For additional information on the brigatinib 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
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. In particular, this press release contains forecasts and
management estimates related to the financial and operational
performance of Takeda, including statements regarding forecasts for
Revenue, Operating profit, Adjusted EBITDA, Profit before income taxes,
Net profit attributable to owners of Takeda, Basic earnings per share,
Amortization and impairment and other income/expense, Underlying
Revenue, Underlying Core Earnings margin, Underlying Core EPS and Net
Debt.
Contacts
Japanese Media
Kazumi Kobayashi
kazumi.kobayashi@takeda.com
+81
(0) 3-3278-2095
Media Outside Japan
Amanda Loder
amanda.loder@takeda.com
+1-212-259-0491