− Updated Results Continue to Support the Efficacy and Safety Findings for ALUNBRIG with the 180 mg Dosing Regimen in Patients with Advanced ALK+ NSCLC Who Have Progressed on Crizotinib, Per Independent Review Committee:

• Median Progression-Free Survival (PFS) of 16.7 Months
• Sixty-Seven Percent of Patients with Measurable Brain Metastases at Baseline had an Intracranial Objective Response with a Median Duration of Intracranial Response of 16.6 Months –

− Data Will Be Presented in an Oral Session at the IASLC World Conference on Lung Cancer (WCLC) on Monday, October 16 at 4:30 p.m. JST

 

CAMBRIDGE, Mass. & OSAKA, Japan–(BUSINESS WIRE)– Takeda Pharmaceutical Company Limited (TSE: 4502) today announced that data from the pivotal Phase 2 ALTA (ALK in Lung Cancer Trial of AP26113) clinical trial evaluating ALUNBRIG^TM (brigatinib) in patients with locally advanced or metastatic anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC) who have progressed on crizotinib will be presented in an oral session at the International Association for the Study of Lung Cancer (IASLC) 18^th World Conference on Lung Cancer (WCLC) on Monday, October 16, 4:30 p.m.- 4:40 p.m. JST. The presentation will share updated safety and efficacy data from the trial as of February 21, 2017, which continue to support previously reported clinical results.

The randomized Phase 2 ALTA trial was designed to investigate the efficacy and safety of ALUNBRIG at two dosing regimens. Patients received either 90 mg of ALUNBRIG once daily (n = 112; 90 mg; Arm A) or 180 mg once daily following a seven-day lead-in of 90 mg once daily (n=110; 180 mg dosing regimen; Arm B).

“The data being presented at WCLC provide further evidence supporting the role of ALUNBRIG in the treatment of patients with advanced ALK-positive NSCLC,” said David Kerstein, M.D., Senior Medical Director and Global Clinical Lead for ALUNBRIG, Oncology Clinical Research, Takeda. “There continues to be an unmet need for the more than 30,000 patients diagnosed with this serious and rare form of lung cancer worldwide each year. We are encouraged by the updated data from the ALTA trial, which support the efficacy and safety of ALUNBRIG in a crizotinib-refractory population, at the dosing regimen that is being taken forward into ongoing and future clinical trials.”

“The updated data from the ALTA trial further support the clinical benefit of ALUNBRIG (brigatinib),” said Myung-Ju Ahn, M.D., Professor, Department of Hematology & Oncology, Samsung Medical Center. “I am especially encouraged by the efficacy seen in patients with brain metastases, cancer that has spread to the brain. The central nervous system is a common site for progression in this disease, with brain metastases occurring in up to 70 percent of patients after treatment with crizotinib. With the 180 mg dosing regimen of brigatinib, two-thirds of patients with measurable brain metastases had an intracranial response, with a median intracranial duration of response of 16.6 months.”

Brigatinib in Crizotinib-Refractory ALK+ NSCLC: Updated Efficacy and Safety Results From ALTA, a Randomized Phase 2 Trial (Abstract #8027, Oral Presentation on Monday, October 16, 4:30-4:40 p.m. at the PACIFICO Yokohama Convention Center, Rooms 301 & 302)

Follow-up data as of February 21, 2017, 17 months after the last patient enrolled; last brain scan was February 28, 2017.

Key findings, which will be presented by Dr. Myung-Ju Ahn, Samsung Medical Center, include:

• As of February 21, 2017, at a median follow-up period of 16.8 and 18.6 months in Arms A (90 mg once daily) and B (180 mg once daily following a seven-day lead-in of 90 mg once daily), respectively, 32 percent of patients in Arm A and 41 percent of patients in Arm B continued to receive ALUNBRIG.
• Investigator-assessed confirmed objective response rate (ORR), which was the primary endpoint, was 46 percent in Arm A and 55 percent in Arm B. Per Independent Review Committee (IRC), confirmed ORR was 51 percent in Arm A and 55 percent in Arm B.
• Investigator-assessed median duration of response (DOR) was 12 months in Arm A and 13.8 months in Arm B. IRC-assessed median DOR was 13.8 months in Arm A and 14.8 months in Arm B.
• Investigator-assessed median progression-free survival (PFS) was 9.2 months in Arm A and 15.6 months in Arm B. IRC-assessed median PFS was 9.2 months in Arm A and 16.7 months in Arm B.
• Median overall survival (OS) was not reached in Arm A and 27.6 months in Arm B. The one-year OS probability was 70 percent in Arm A and 80 percent in Arm B.
• Of the patients with measurable brain metastases at baseline (n=26 / n=18, Arm A / Arm B), 50 percent in Arm A and 67 percent in Arm B achieved a confirmed intracranial objective response by IRC assessment; median duration of intracranial response was not reached in Arm A and was 16.6 months in Arm B.
• In patients with any brain metastases at baseline the median intracranial PFS as assessed by the IRC was 12.8 months in Arm A and 18.4 months in Arm B.
• The most common grade ≥3 treatment-related adverse events (AEs) (Arm A / Arm B) included increased blood creatine phosphokinase (3 percent / 11 percent), hypertension (4 percent / 4 percent), increased lipase (4 percent / 4 percent), pneumonitis (2 percent / 4 percent), and rash (1 percent / 4 percent). Dose reduction (9 percent / 30 percent) or discontinuation (4 percent / 11 percent) due to any AEs was reported.
• The efficacy and safety data from the ALTA trial continue to support future trials with the 180 mg dosing regimen.

About the ALTA Trial

The Phase 2 ALTA (ALK in Lung Cancer Trial of AP26113) trial of brigatinib in adults is an ongoing, two-arm, open-label, multicenter trial, which enrolled 222 patients with locally advanced or metastatic ALK+ NSCLC who had progressed on crizotinib. Patients received either 90 mg of ALUNBRIG once daily (n=112) or 180 mg once daily following a seven-day lead-in of 90 mg once daily (n=110). Investigator-assessed confirmed objective response rate (ORR) per RECIST v1.1 was the primary endpoint. Secondary endpoints included IRC-assessed ORR, duration of response (DOR), intracranial ORR, intracranial PFS, safety and tolerability.

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 222,500 new cases of lung cancer diagnosed each year in the United States, according to the American Cancer Society. Genetic studies indicate that chromosomal rearrangements in anaplastic lymphoma kinase (ALK) are key drivers in a subset of NSCLC patients. Approximately two to eight percent of patients with metastatic NSCLC have a rearrangement in the ALK gene.

The central nervous system (CNS) is a frequent site for progression in ALK+ NSCLC, with brain metastases present in up to 70 percent of patients after treatment with crizotinib.

About ALUNBRIG^™ (brigatinib)

ALUNBRIG is a targeted cancer medicine discovered by ARIAD Pharmaceuticals, Inc., which was acquired by Takeda in February 2017. In April of 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.

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. A Marketing Authorization Application (MAA) for ALUNBRIG was submitted to the European Medicines Agency (EMA) in February 2017.

In the US, the recommended dosing regimen for ALUNBRIG is:

• 90 mg orally once daily for the first 7 days;
• if 90 mg is tolerated during the first 7 days, increase the dose to 180 mg orally once daily.

The ALTA 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. In addition to the ongoing Phase 1/2 and Phase 2 ALTA trial, brigatinib is also being studied in the Phase 3 ALTA 1L trial to assess its efficacy and safety in comparison to crizotinib in patients with locally advanced or metastatic ALK+ NSCLC who have not received prior treatment with an ALK inhibitor.

To learn more about ALUNBRIG, please visit www.ALUNBRIG.com or call 1-844-A1POINT (1-844-217-6468). 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 Prescribing Information for ALUNBRIG at www.ALUNBRIG.com

About Takeda Pharmaceutical Company

Takeda Pharmaceutical Company Limited 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 central nervous system therapeutic areas plus vaccines. Takeda conducts R&D both internally and with partners to stay at the leading edge of innovation. New innovative products, especially in oncology and gastroenterology, as well as our presence in Emerging Markets, fuel the growth of Takeda. More than 30,000 Takeda employees are committed to improving quality of life for patients, working with our partners in health care in more than 70 countries. For more information, visit http://www.takeda.com/news.

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.

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Contacts

Takeda Pharmaceutical Company Limited
Japanese Media
Tsuyoshi Tada, +81 (0) 3-3278-2417
tsuyoshi.tada@takeda.com
or
< b>Media outside Japan/EU
Shawn Goodman, +1-617-444-1250
Shawn.Goodman@takeda.com
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Kate Burd, +41 79 514 9533
kate.burd@takeda.com