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Takeda Announces Publication of ALUNBRIG™ (brigatinib) Pivotal Phase 2 ALTA Clinical Trial Data in Journal of Clinical Oncology

Takeda Pharmaceutical Company Limited (TSE: 4502) today announced that data from the pivotal Phase 2 ALTA (A LK in L ung Cancer T rial of A P26113) clinical trial evaluating ALUNBRIG™ (brigatinib) in patients with crizotinib-refractory anaplastic lymphoma kinase-positive (ALK+) locally advanced or metastatic non-small cell lung cancer (NSCLC) were published in the Journal of Clinical Oncology (DOI: 10.1200/JCO.2016.71.5904 Journal of Clinical Oncology) . The study found that, for the patients who received brigatinib at 180 mg once daily following a seven-day lead-in at 90 mg once daily, the Independent Review Committee (IRC) assessed confirmed objective response rate (ORR) was 53 percent. Additionally, 67 percent of patients with measurable brain metastases who received this dosing regimen achieved a confirmed intracranial objective response. Takeda recently received Accelerated Approval from the U.S. Food and Drug Administration (FDA) for ALUNBRIG for the treatment of 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.

“Given that half of ALK+ NSCLC patients treated with crizotinib will progress within one year, in many cases with cancer spreading to the brain, it is critical that we have new effective therapies that can address these mechanisms of resistance,” said presenting author Dong-Wan Kim, M.D., Ph.D., head of the Cancer Clinical Trials Center at the Seoul National University Hospital in South Korea. “The ALTA trial results offer clinicians important information on the efficacy and safety of brigatinib in patients who have progressed on crizotinib, and show brigatinib to be highly effective in this setting, both systemically and in the brain.”

“The publication of the Phase 2 ALTA trial results is an important milestone for the brigatinib clinical program, and we thank the patients, their families and caregivers, and the investigators for their participation in and dedication to this trial,” said David Kerstein, M.D., Oncology Clinical Research, Takeda, and an author of the publication. “We look forward to sharing additional ALUNBRIG data from our studies as we continue to develop the drug to address the unmet medical needs of patients with ALK+ NSCLC.”

ALTA, a two-arm, open-label, multicenter trial, enrolled 222 patients with locally advanced or metastatic ALK+ NSCLC who had progressed on crizotinib, the current standard of care for first line treatment in the metastatic setting. Patients were randomized one-to-one to receive either 90 mg of brigatinib once per day (90 mg; Arm A), or 180-mg once daily with a seven-day lead-in at 90 mg once daily (the 180 mg regimen; Arm B). In addition, patients were stratified by the presence of brain metastases at baseline and best response to prior treatment with crizotinib. The primary efficacy outcome measure was confirmed ORR according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as evaluated by the investigator. Secondary efficacy outcome measures included confirmed ORR as assessed by an Independent Review Committee (IRC), duration of response (DOR), progression free survival (PFS), intracranial ORR, intracranial DOR, overall survival, safety and tolerability.

As reported in the Journal of Clinical Oncology , the trial demonstrated:
Clinical Investigator Assessed Efficacy & Safety Data as of February 29, 2016, with last scan date for IRC assessments on May 16, 2016

  • Efficacy outcomes favored Arm B (the recommended dosing regimen in the full Prescribing Information) most notably in PFS and intracranial ORR.
    • With a median follow-up period of approximately 8 months (range (0.1-20.2 months), the IRC-assessed confirmed ORR was 48 percent in Arm A and 53 percent in Arm B. Investigator-assessed confirmed ORR was 45 percent in Arm A and 54 percent in Arm B.
    • The median DOR was 13.8 months in both arms as assessed by the IRC. The investigator assessed median DOR was 13.8 months in Arm A and 11.1 months in Arm B.
    • IRC-assessed median PFS was 9.2 months in Arm A and 15.6 months in Arm B. Investigator-assessed median PFS was 9.2 months and 12.9 in Arms A and B, respectively.
    • Responses in Arm B included a confirmed partial response in a patient with the ALK kinase domain G1202R mutation at baseline, that is associated with resistance to all approved tyrosine kinase inhibitors (TKIs).
    • Of the patients with measurable brain metastases at baseline, 42 percent (11/26) in Arm A and 67 percent (12/18) in Arm B achieved a confirmed intracranial OR by IRC assessment.
    • In patients with any brain metastases at baseline the median intracranial PFS as assessed by the IRC was 15.6 months and 12.8 months in Arms A and B, respectively.
  • The most common any-grade treatment-emergent adverse events (Arm A / Arm B) included gastrointestinal symptoms (nausea [33 percent / 40 percent]) diarrhea [19 percent / 38 percent]), headache [28 percent / 27 percent] and cough [18 percent / 34 percent]. The most common grade 3 or higher treatment-emergent adverse events (excluding neoplasm progression), were hypertension (6 percent / 6 percent), increased blood creatine phosphokinase (3 percent / 9 percent), pneumonia (3 percent / 5 percent) and increased lipase (4 percent / 3 percent). A subset of pulmonary adverse events with early onset occurred in six percent of all patients (grade ≥3 in 3 percent of patients); no such events with early onset occurred after dose escalation to 180 mg in Arm B.
  • The efficacy and safety data from the ALTA trial support future trials with the 180 mg once daily (with lead-in) regimen.

Data from ALTA were first presented at the 2016 Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Illinois, and updated at the International Association for the Study of Lung Cancer (IASLC) 17th World Conference on Lung Cancer (WCLC) in Vienna.

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. ALUNBRIG recently received Accelerated Approval from the U.S. Food and Drug Administration (FDA) for ALK+ 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 previously 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

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: Advise lactating women not to breastfeed during treatment with ALUNBRIG and for 1 week following the final dose.

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 .

Contact:

Takeda Pharmaceutical Company Limited
Japanese Media
Tsuyoshi Tada, +81 (0) 3-3278-2417
tsuyoshi.tada@takeda.com
or
Media outside Japan
Amy Atwood, +1-617-444-2147
amy.atwood@takeda.com
or
Liza Heapes, +1-617-621-2315
Liza.heapes@ariad.com

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