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 1^st Line) trial, demonstrating that ALUNBRIG reduced the risk of disease progression or death, known as progression-free survival (PFS), as assessed by a blinded independent review committee (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 had not received a prior ALK inhibitor. Findings from 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 once daily, 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), corresponding to 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 design offered enrollment to 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 confirmation at a central lab. We look forward to further 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 especially the patients and their caregivers 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 advanced or 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

• 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 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%).
  • 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 the ALTA-1L Trial

The Phase 3 ALTA-1L (ALK in Lung Cancer Trial of BrigAtinib in 1^st 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 once daily, 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) per RECIST 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 demonstrate a minimum of six months PFS improvement over crizotinib. The trial is designed with two pre-specified interim analyses for the primary endpoint – one at approximately 50 percent of planned PFS events and one at approximately 75 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 rearrangement in 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 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). The FDA and Health Canada 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, 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/pneumonitis occurred early (within 9 days of initiation of ALUNBRIG; median onset was 2 days) in 6.4% of patients, with Grade 3 to 4 reactions occurring in 2.7%. Monitor for new or worsening respiratory symptoms (e.g., dyspnea, cough, etc.), particularly during the first week of initiating ALUNBRIG. Withhold ALUNBRIG in any patient with new or worsening respiratory symptoms, and promptly evaluate for ILD/pneumonitis or other causes of respiratory symptoms (e.g., pulmonary embolism, tumor progression, and infectious pneumonia). For Grade 1 or 2 ILD/pneumonitis, either resume ALUNBRIG with dose reduction after recovery to baseline or permanently discontinue ALUNBRIG. Permanently discontinue ALUNBRIG for Grade 3 or 4 ILD/pneumonitis or recurrence of Grade 1 or 2 ILD/pneumonitis.

Hypertension: In ALTA, hypertension was reported in 11% of patients in the 90 mg group who received ALUNBRIG and 21% of patients in the 90→180 mg group. Grade 3 hypertension occurred in 5.9% of patients overall. Control blood pressure prior to treatment with ALUNBRIG. Monitor blood pressure after 2 weeks and at least monthly thereafter during treatment with ALUNBRIG. Withhold ALUNBRIG for Grade 3 hypertension despite optimal antihypertensive therapy. Upon resolution or improvement to Grade 1 severity, resume ALUNBRIG at a reduced dose. Consider permanent discontinuation of treatment with ALUNBRIG for Grade 4 hypertension or recurrence of Grade 3 hypertension. Use caution when administering ALUNBRIG in combination with antihypertensive agents that cause bradycardia.

Bradycardia: Bradycardia can occur with ALUNBRIG. In ALTA, heart rates less than 50 beats per minute (bpm) occurred in 5.7% of patients in the 90 mg group and 7.6% of patients in the 90→180 mg group. Grade 2 bradycardia occurred in 1 (0.9%) patient in the 90 mg group. Monitor heart rate and blood pressure during treatment with ALUNBRIG. Monitor patients more frequently if concomitant use of drug known to cause bradycardia cannot be avoided. For symptomatic bradycardia, withhold ALUNBRIG and review concomitant medications for those known to cause bradycardia. If a concomitant medication known to cause bradycardia is identified and discontinued or dose adjusted, resume ALUNBRIG at the same dose following resolution of symptomatic bradycardia; otherwise, reduce the dose of ALUNBRIG following resolution of symptomatic bradycardia. Discontinue ALUNBRIG for life-threatening bradycardia if no contributing concomitant medication is identified.

Visual Disturbance: In ALTA, adverse reactions leading to visual disturbance including blurred vision, diplopia, and reduced visual acuity, were reported in 7.3% of patients treated with ALUNBRIG in the 90 mg group and 10% of patients in the 90→180 mg group. Grade 3 macular edema and cataract occurred in one patient each in the 90→180 mg group. Advise patients to report any visual symptoms. Withhold ALUNBRIG and obtain an ophthalmologic evaluation in patients with new or worsening visual symptoms of Grade 2 or greater severity. Upon recovery of Grade 2 or Grade 3 visual disturbances to Grade 1 severity or baseline, resume ALUNBRIG at a reduced dose. Permanently discontinue treatment with ALUNBRIG for Grade 4 visual disturbances.

Creatine Phosphokinase (CPK) Elevation: In ALTA, creatine phosphokinase (CPK) elevation occurred in 27% of patients receiving ALUNBRIG in the 90 mg group and 48% of patients in the 90 mg→180 mg group. The incidence of Grade 3‑4 CPK elevation was 2.8% in the 90 mg group and 12% in the 90→180 mg group. Dose reduction for CPK elevation occurred in 1.8% of patients in the 90 mg group and 4.5% in the 90→180 mg group. Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor CPK levels during ALUNBRIG treatment. Withhold ALUNBRIG for Grade 3 or 4 CPK elevation. Upon resolution or recovery to Grade 1 or baseline, resume ALUNBRIG at the same dose or at a reduced dose.

Pancreatic Enzyme Elevation: In ALTA, amylase elevation occurred in 27% of patients in the 90 mg group and 39% of patients in the 90→180 mg group. Lipase elevations occurred in 21% of patients in the 90 mg group and 45% of patients in the 90→180 mg group. Grade 3 or 4 amylase elevation occurred in 3.7% of patients in the 90 mg group and 2.7% of patients in the 90→180 mg group. Grade 3 or 4 lipase elevation occurred in 4.6% of patients in the 90 mg group and 5.5% of patients in the 90→180 mg group. Monitor lipase and amylase during treatment with ALUNBRIG. Withhold ALUNBRIG for Grade 3 or 4 pancreatic enzyme elevation. Upon resolution or recovery to Grade 1 or baseline, resume ALUNBRIG at the same dose or at a reduced dose.

Hyperglycemia: In ALTA, 43% of patients who received ALUNBRIG experienced new or worsening hyperglycemia. Grade 3 hyperglycemia, based on laboratory assessment of serum fasting glucose levels, occurred in 3.7% of patients. Two of 20 (10%) patients with diabetes or glucose intolerance at baseline required initiation of insulin while receiving ALUNBRIG. Assess fasting serum glucose prior to initiation of ALUNBRIG and monitor periodically thereafter. Initiate or optimize anti-hyperglycemic medications as needed. If adequate hyperglycemic control cannot be achieved with optimal medical management, withhold ALUNBRIG until adequate hyperglycemic control is achieved and consider reducing the dose of ALUNBRIG or permanently discontinuing ALUNBRIG.

Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animals, ALUNBRIG can cause fetal harm when administered to pregnant women. There are no clinical data on the use of ALUNBRIG in pregnant women. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with ALUNBRIG and for at least 4 months following the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose of ALUNBRIG.

ADVERSE REACTIONS

Serious adverse reactions occurred in 38% of patients in the 90 mg group and 40% of patients in the 90→180 mg group. The most common serious adverse reactions were pneumonia (5.5% overall, 3.7% in the 90 mg group, and 7.3% in the 90→180 mg group) and ILD/pneumonitis (4.6% overall, 1.8% in the 90 mg group and 7.3% in the 90→180 mg group). Fatal adverse reactions occurred in 3.7% of patients and consisted of pneumonia (2 patients), sudden death, dyspnea, respiratory failure, pulmonary embolism, bacterial meningitis and urosepsis (1 patient each).

The most common adverse reactions (≥25%) in the 90 mg group were nausea (33%), fatigue (29%), headache (28%), and dyspnea (27%) and in the 90→180 mg group were nausea (40%), diarrhea (38%), fatigue (36%), cough (34%), and headache (27%).

DRUG INTERACTIONS

CYP3A Inhibitors: Avoid concomitant use of ALUNBRIG with strong CYP3A inhibitors. Avoid grapefruit or grapefruit juice as it may also increase plasma concentrations of brigatinib. If concomitant use of a strong CYP3A inhibitor is unavoidable, reduce the dose of ALUNBRIG.

CYP3A Inducers: Avoid concomitant use of ALUNBRIG with strong CYP3A inducers.

CYP3A Substrates: Coadministration of ALUNBRIG with CYP3A substrates, including hormonal contraceptives, can result in decreased concentrations and loss of efficacy of CYP3A substrates.

USE IN SPECIFIC POPULATIONS

Pregnancy: ALUNBRIG can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus.

Lactation: There are no data regarding the secretion of brigatinib in human milk or its effects on the breastfed infant or milk production. Because of the potential adverse reactions in breastfed infants, advise lactating women not to breastfeed during treatment with ALUNBRIG.

Females and Males of Reproductive Potential:

Contraception: Advise females of reproductive potential to use effective non-hormonal contraception during treatment with ALUNBRIG and for at least 4 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ALUNBRIG and for at least 3 months after the final dose.

Infertility: ALUNBRIG may cause reduced fertility in males.

Pediatric Use: The safety and efficacy of ALUNBRIG in pediatric patients have not been established.

Geriatric Use: Clinical studies of ALUNBRIG did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. Of the 222 patients in ALTA, 19.4% were 65-74 years and 4.1% were 75 years or older. No clinically relevant differences in safety or efficacy were observed between patients ≥65 and younger patients.

Hepatic or Renal Impairment: No dose adjustment is recommended for patients with mild hepatic impairment or mild or moderate renal impairment. The safety of ALUNBRIG in patients with moderate or severe hepatic impairment or severe renal impairment has not been studied.

Please see the full 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 in oncology 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 life for patients, working with Takeda’s partners in 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.

Contacts:

Takeda Pharmaceutical Company Limited

Japanese Media Kazumi Kobayashi [email protected] +81 3 3 278 2095              European Media Kate Burd [email protected] +41 79 514 9533

Media outside Japan/EU Amanda Loder [email protected] +1-212-259-0491