Takeda to Present Positive Data from ALUNBRIG® (brigatinib) ALTA-1L Trial Showing a Reduction in Risk of Disease Progression or Death of More Than 50 Percent Versus Crizotinib in First-Line Advanced ALK+ NSCLC

– ALTA-1L Met its Primary Endpoint Showing Superiority in Blinded Independent Review Committee-Assessed Progression-Free Survival Compared to Crizotinib

Data Will Be Presented During the Presidential Symposium at the 19th World Conference on Lung Cancer (WCLC) with Simultaneous Publication in The New England Journal of Medicine

Cambridge, Mass. and Osaka, Japan, September 25, 2018 – Takeda Pharmaceutical Company Limited (TSE: 4502) today announced results from the Phase 3 ALTA-1L (ALK in Lung Cancer   Trial of BrigAtinib in 1st Line) trial, demonstrating that ALUNBRIG reduced the risk of disease progression or death, known as progression-free survival (PFS), as assessed by a blindedindependent reviewcommittee (BIRC), by more than fifty percent compared to crizotinib in adults with anaplastic lymphoma kinase-positive (ALK+) locally advanced or metastatic non-small cell lung cancer (NSCLC) who hadnot received a prior ALK inhibitor. Findingsfrom the first interim analysis of the ALTA-1L trial will be presented during the Presidential Symposium at the International Association for the Study of Lung Cancer (IASLC)19th World Conference on Lung Cancer (WCLC) in Toronto on Tuesday, September 25, 2018. The data were also simultaneously published online in The New England Journal of Medicine. ALUNBRIG is currently not approved as first-line therapy for advanced ALK+ NSCLC.

ALTA-1L is a global, randomized, open-label, comparative, multicenter trial, which enrolled 275 patients with ALK+ locally advanced or metastatic NSCLC who have not received prior treatment with an ALK inhibitor but may have received up to one prior   regimen of chemotherapy in the advanced setting. Patients were eligible for study entry on the basis of locally determined ALK testing. Patients received either ALUNBRIG, 180 mg once daily with seven-day lead-in at 90 mg oncedaily, or crizotinib,250 mg twice daily. Treatment with ALUNBRIG resulted in superior PFS compared to crizotinib as assessed by a blinded independent review committee (hazard ratio = 0.49 [95 percent confidence interval(CI), 0.33 to 0.74]; log-rank p=0.0007), correspondingto a 51 percent reduction in the risk of disease progression or death. The safety profile associated with ALUNBRIG was generally consistent with the existing U.S.prescribing information.

"The ALK+ NSCLC treatment landscape has experienced tremendous change over the last decade, and the ALTA-1L trial demonstrates that brigatinib has the potential to be a key player in the first-line setting," said D. Ross Camidge, MD, PhD, Joyce Zeff   Chair in Lung Cancer Research at the University of Colorado Cancer Center and the lead investigator of ALTA-1L. "The ALTA-1L trial offers unique aspects, including the real-world applicability of the data. The study's designoffered enrollmentto a broader population by allowing patients to participate even if they had received prior chemotherapy and enrolled patients based on local standard of care ALK testing as opposed to mandating confirmationat a central lab. We look forward tofurther follow-up, which will provide even better understanding of the role of brigatinib in the evolving landscape."

"We are thrilled to share these highly anticipated results with the lung cancer community," said David Kerstein MD, Global Clinical Lead for Brigatinib and Lung Cancer Clinical Portfolio Strategy Lead, Takeda. "The ALTA-1L data demonstrate that ALUNBRIG   is superior to crizotinib in the first-line setting, reducing disease progression or death by more than half, with particularly pronounced activity in the brain. We would like to thank all the investigators, and especiallythe patients and theircaregivers who participated in this important clinical research."

Brigatinib vs Crizotinib in Patients with ALK Inhibitor-Naïve Advanced ALK+ NSCLC: First Report of a Phase 3 Trial (ALTA-1L) (Presidential Symposium on Tuesday, September 25, 8:30 a.m. ET at the Metro Toronto Convention Centre North Building, Plenary Hall)

Key findings, which will be presented by D. Ross Camidge, MD, PhD, Joyce Zeff Chair in Lung Cancer Research at the University of Colorado Cancer Center and lead investigator of ALTA-1L, include:   

  • A total of 275 patients were randomized to either brigatinib (n=137) or crizotinib (n=138). The median age was 59 years (brigatinib, 58; crizotinib, 60) and 55% of patients in the trial were female (brigatinib, 50%; crizotinib 59%). Twenty-nine percent had brain metastases at baseline (brigatinib, 29%; crizotinib, 30%), with comparable pre-enrollment CNS radiotherapy rates. Overall, 27% of patients had prior chemotherapy in the locally advancedor metastatic setting (brigatinib,  26%; crizotinib, 27%).
  • At the data cutoff for the first interim analysis (February 19, 2018), at a median follow-up period of 11.0 and 9.3 months in the brigatinib arm and crizotinib arm, respectively, 95 patients (69%) in the brigatinib arm and 59 patients (43%) in the crizotinib arm remained on study treatment.
  • The trial has met the pre-specified threshold for superiority in the primary endpoint at the first interim analysis. With a total of 99 events, BIRC-assessed PFS with brigatinib was superior to crizotinib (hazard ratio, 0.49 [95% confidence interval (CI), 0.33 to 0.74]; log-rank p=0.0007).
  • Additional efficacy outcomes are presented in the table below:

ALTA-1L Efficacy Results

Efficacy Endpoint                 Brigatinib                 Crizotinib
Intention-to-treat population                 n=137                 n=138
BIRC-assessed PFS                                    
Median, months (95% CI)                 NR (NR to NR)                 9.8 (9.0 to 12.9)
12-month estimate (95% CI)                 67% (56% to 75%)                 43% (32% to 53%)
Hazard ratio (95% CI)                 0.49 (0.33 to 0.74)
Log-rank p-value                 0.0007
Investigator-assessed PFS                                    
Median, months (95% CI)                 NR (NR to NR)                 9.2 (7.4 to 12.9)
12-month estimate (95% CI)                 69% (59% to 76%)                 40% (30% to 50%)
Hazard ratio (95% CI)                 0.45 (0.30 to 0.68)
Log-rank p-value                 0.0001
BIRC-assessed confirmed ORR (95% CI)                 71% (62% to 78%)                 60% (51% to 68%)
P-value                 0.07
BIRC-assessed overall ORR (objective response at 1 or more assessments) (95% CI)                 76% (68% to 83%)                 73% (65% to 80%)
Patients with BIRC-assessed brain metastases at baseline
                  n=43                 n=47
Intracranial PFS                                    
Median, months (95% CI)                

NR (11.0 to NR)

 

                5.6 (4.1 to 9.2)
12-month estimate (95% CI)                

67% (47% to 80%)

 

                21% (6% to 42%)
Hazard ratio (95% CI)                

0.27 (0.13 to 0.54)

 

Log-rank p-value                

<0.0001

 

Patients with BIRC-assessed measurable brain metastases at baseline
                 

N=18

               

N=21

Confirmed intracranial ORR (95% CI)                

78% (52% to 94%)

               

29% (11% to 52%)

P-value                

0.0028

 

Overall intracranial ORR (objective response at 1 or more assessments) (95% CI)                 83% (59% to 96%)                 33% (15% to 57%)

  NR = Not reached

  CI = Confidence Interval

  PFS= Progression-Free Survival

  ORR= Objective Response Rate   

  • Any grade treatment-emergent adverse events that occurred at a higher incidence with brigatinib than with crizotinib by more than five percentage points were increased blood creatine phosphokinase (brigatinib, 39% vs crizotinib, 15%), cough (25% vs 16%), hypertension (23% vs 7%), and increased lipase (19% vs 12%).The safety profile associated with ALUNBRIG was generally consistent with the existing U.S. prescribing information.    
  • Any grade treatment-emergent adverse events that occurred at a higher incidence with crizotinib than with brigatinib by more than five percentage points were nausea (crizotinib, 56% vs brigatinib, 26%), diarrhea (55% vs 49%), constipation (42% vs 15%), peripheral edema (39% vs 4%), vomiting (39% vs 18%), increased alanine aminotransferase (32% vs 19%), decreased appetite (20% vs 7%), photopsia (20% vs 1%),dysgeusia (19% vs 4%), and visual impairment (16% vs 0).
  • Grade 3 to 5 treatment-emergent adverse events occurred in 61% of the patients in the brigatinib arm and 55% of the patients in the crizotinib arm. Most common grade 3 or greater treatment-emergent adverse events for brigatinib were increased blood creatine phosphokinase (16%), increased lipase (13%), hypertension (10%), and increased amylase (5%); and for crizotinib were increased alanine aminotransferase (9%),increased aspartate aminotransferase (6%), and increased lipase  (5%).
  • Interstitial lung disease/pneumonitis at any time occurred in 4% (5/136) of patients in the brigatinib arm and 2% (3/137) in the crizotinib arm. Interstitial lung disease/pneumonitis with early onset (defined as within 14 days of treatment initiation) was observed in 3% of patients in the brigatinib arm (onset: Days 3 to 8) and was not observed in the crizotinib arm.

ABOUT THEALTA-1L TRIAL

The Phase 3 ALTA-1L (ALK inLung CancerTrial ofBrigAtinib in 1st Line) trial of ALUNBRIG in adults is a global, ongoing, randomized, open-label, comparative, multicenter trial,   which enrolled 275 patients 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 oncedaily, or crizotinib,250 mg twice daily. Blinded Independent Review Committee (BIRC)-assessed progression-free survival (PFS) was the primary endpoint. Secondary endpoints included objective response rate (ORR) perRECIST v1.1, intracranial ORR, intracranial PFS,overall survival (OS), safety and tolerability. A total of approximately 198 PFS events are planned at the final analysis of the primary endpoint in order to demonstratea minimum of six months PFS improvement over crizotinib. The trial is designedwith two pre-specified interim analyses for the primary endpoint – one at approximately 50 percent of planned PFS events and one at approximately75 percent of planned PFS events.

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 1.8 million new cases of lung cancer diagnosed each year worldwide, according to the World Health Organization. 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 rearrangementin the ALK gene.

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.

ABOUT ALUNBRIG® (BRIGATINIB)

ALUNBRIG is a targeted cancer medicine discovered by ARIAD Pharmaceuticals, Inc., which was acquired by Takeda in February 2017. In April 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 maybe contingent uponverification 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 progressedon or who were intolerant to an ALK inhibitor(crizotinib). The FDA and Health Canada approvals of ALUNBRIG were primarily based on results from the pivotal Phase 2 ALTA (ALK inLung CancerTrialofAP26113) 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, a 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 single-arm, multicenter trial in Japanese patients with ALK+ NSCLC, focusing on patients who have progressed on alectinib
  • Phase 2 global, single-arm trial evaluating ALUNBRIG in patients with advanced ALK+ NSCLC who have progressed on alectinib or ceritinib
  • Phase 3 global randomized trial comparing the efficacy and safety of ALUNBRIG versus alectinib in participants with ALK+ NSCLC who have progressed on crizotinib

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/pneumonitisoccurred 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 firstweek of initiating ALUNBRIG. Withhold ALUNBRIG in any patient with new or worsening respiratory symptoms, and promptly evaluate for ILD/pneumonitis or other causes of respiratorysymptoms (e.g., pulmonary embolism, tumor progression, and infectiouspneumonia). 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 1or 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. Uponresolution or improvementto 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 cautionwhen administering ALUNBRIG in combination with antihypertensiveagents 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 ALUNBRIGand 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 thesame dose following resolution of symptomaticbradycardia; otherwise, reduce the dose of ALUNBRIG following resolution of symptomatic bradycardia. Discontinue ALUNBRIG for life-threatening bradycardia if no contributingconcomitant 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 patientswith new or worseningvisual symptoms of Grade 2 or greater severity. Upon recovery of Grade 2 or Grade 3 visual disturbances to Grade1 severity or baseline, resume ALUNBRIG at a reduced dose. Permanently discontinuetreatment with ALUNBRIG for Grade 4 visualdisturbances.

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 Grade3‑4 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 unexplainedmuscle 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 doseor 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 groupand 5.5% of patientsin 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 reduceddose.

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. Initiateor optimize anti-hyperglycemicmedications as needed. If adequate hyperglycemic control cannot be achieved with optimal medical management, withhold ALUNBRIG until adequate hyperglycemic control is achieved and considerreducing the dose of ALUNBRIG or permanently discontinuingALUNBRIG.

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 femalepartners of reproductivepotential 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, respiratoryfailure, 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 U.S. Prescribing Information for ALUNBRIG at www.ALUNBRIG.com

ABOUT TAKEDA PHARMACEUTICAL COMPANY

Takeda Pharmaceutical Company Limited (TSE: 4502) 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 neuroscience therapeutic areas plus vaccines. Takeda conducts R&D both internally and with partners to stay at the leading edge of innovation. Innovative products,especially inoncology and gastroenterology, as well as Takeda's presence in emerging markets, are currently fueling the growth of Takeda. Approximately 30,000 Takeda employees are committed to improving quality of lifefor patients, working with Takeda's partnersin health care in more than 70 countries. For more information, visit https://www.takeda.com/newsroom/.

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.

Media Contacts:

Takeda Pharmaceutical Company Limited 

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