– Approval Based on Positive Results from the Phase 3 ALTA-1L Trial Showing ALUNBRIG Demonstrated Superior Overall and Intracranial Effectiveness over Crizotinib in the First-line Setting –

– Expanded Indication Provides Additional First-Line Treatment Option for the Approximately 10,000 People with ALK+ NSCLC in Europe –

CAMBRIDGE, Mass. & OSAKA, Japan--(BUSINESS WIRE)--Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) today announced that the European Commission (EC) extended the current marketing authorization of ALUNBRIG (brigatinib) to include use as a monotherapy for the treatment of adult patients with anaplastic lymphoma kinase-positive (ALK+) advanced non-small cell lung cancer (NSCLC) previously not treated with an ALK inhibitor. This decision follows a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) on February 27, 2020.

“Patients with ALK+ NSCLC, particularly those who have developed brain metastases, have been in need of additional treatment options that are proven effective in the first-line setting,” said Professor Sanjay Popat, Consultant Medical Oncologist, Royal Marsden NHS Foundation Trust. “As brigatinib has shown superiority compared to crizotinib in this setting, including in patients whose disease has spread to the brain, this approval is an important advancement for these patients and gives physicians in the European Union another choice when addressing the needs of ALK+ NSCLC patients.”

“At Takeda, our commitment to patients drives us as we seek to advance care and address the unmet needs of the lung cancer community,” said Teresa Bitetti, President, Global Oncology Business Unit, Takeda. “We are proud of the positive results ALUNBRIG has demonstrated in the first-line setting, including strong overall and intracranial efficacy, and look forward to making ALUNBRIG available to newly diagnosed ALK+ NSCLC patients in Europe.”

“ALK+ NSCLC is a complex and nuanced disease, and people with this form of lung cancer may benefit from the availability of a variety of treatment options,” said Stefania Vallone, President of Lung Cancer Europe (LUCE). “We welcome the availability of additional treatment options that may benefit the European cancer community and patients with this serious and rare form of the disease, with the hope that they will soon be accessible to patients across Europe.”

The approval is based on results from the Phase 3 ALTA-1L trial, which evaluated the safety and efficacy of ALUNBRIG compared to crizotinib in patients with ALK+ locally advanced or metastatic NSCLC who have not received prior treatment with an ALK inhibitor. Results from the trial showed ALUNBRIG demonstrated superiority compared to crizotinib with significant anti-tumor activity observed in patients with baseline brain metastases. After more than two years of follow-up, ALUNBRIG reduced the risk of intracranial disease progression or death by 69% in patients with brain metastases at baseline (hazard ratio [HR] = 0.31, 95% CI: 0.17–0.56), as assessed by a blinded independent review committee (BIRC), and reduced the risk of disease progression or death by 76% in patients with brain metastases at baseline (HR = 0.24, 95% CI: 0.12–0.45), as assessed by investigators. ALUNBRIG also demonstrated consistent overall efficacy (intent to treat population), with a median progression-free survival (PFS) more than two times longer than that with crizotinib at 24.0 months (95% CI: 18.5–NE) versus 11.0 months (95% CI: 9.2–12.9) for crizotinib, as assessed by BIRC, and 29.4 months (95% CI: 21.2–NE) versus 9.2 months (95% CI: 7.4–12.9), as assessed by investigators.

The safety profile of ALUNBRIG in the ALTA-1L trial was generally consistent with the existing European summary of product characteristics (SmPC). The most common treatment-emergent adverse events (TEAEs) Grade ≥3 in the ALUNBRIG arm were increased CPK (24.3%), increased lipase (14.0%) and hypertension (11.8%); and for crizotinib were increased ALT (10.2%), AST (6.6%) and lipase (6.6%).

This decision by the European Medicines Agency means that ALUNBRIG is now approved for marketing of this indication in all European Union member states, in addition to Norway, Liechtenstein and Iceland. For further details about the decision, please visit the European Medicines Agency website: www.ema.europa.eu/ema.

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 (ALUNBRIG, n=137, crizotinib, n=138) 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.

The median age was 58 years in the ALUNBRIG arm and 60 years in the crizotinib arm. Twenty-nine percent of patients had brain metastases at baseline in the ALUNBRIG arm versus 30% in the crizotinib arm. Twenty-six percent of patients received prior chemotherapy for advanced or metastatic disease in the ALUNBRIG arm versus 27% in the crizotinib arm.

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.

The safety profile of ALUNBRIG in the ALTA-1L trial was generally consistent with the existing European summary of product characteristics (SmPC).

About ALUNBRIG^® (brigatinib)

ALUNBRIG is a potent and selective next-generation tyrosine kinase inhibitor (TKI) that was designed to target and inhibit anaplastic lymphoma kinase (ALK) genetic alterations. In April 2017, ALUNBRIG received Accelerated Approval from the U.S. 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 is currently approved in more than 40 countries, including the U.S., Canada and the European Union, for the treatment of people living with ALK+ metastatic NSCLC who have taken the medicine crizotinib, but their NSCLC has worsened or they cannot tolerate taking crizotinib.

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.

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.³ Approximately three to five percent of patients with metastatic NSCLC have a rearrangement in the ALK gene.^4,5,6

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.⁷

Takeda in Lung Cancer

Takeda is dedicated to expanding treatment options in the ALK+ NSCLC and EGFR/HER2 mutant NSCLC treatment landscapes. Our comprehensive programs include the following clinical trials to continue to address unmet needs for people living with lung cancer:

ALUNBRIG

• Phase 1/2 trial, which was designed to evaluate the safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of ALUNBRIG. This trial has completed enrollment.
• 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. This trial has completed enrollment.
• 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. This trial has completed enrollment.
• Phase 2 J-ALTA, single-arm, multicenter trial in Japanese patients with ALK+ NSCLC, focusing on patients who have progressed on alectinib. This trial has completed enrollment.
• 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 has completed enrollment.
• 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.

TAK-788, a selective inhibitor of EGFR/HER2 mutations, currently being explored in patients with EGFR exon 20 insertion mutations:

• Phase 1/2 study evaluating the safety, pharmacokinetics and antitumor activity of oral EGFR/HER2 inhibitor TAK-788 in patients with NSCLC. This trial has completed enrollment.
• Phase 2 EXCLAIM, pivotal extension cohort of the Phase 1/2 trial, 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 insertion mutations. This trial has completed enrollment.
• Phase 3 EXCLAIM 2, global, randomized study evaluating the efficacy of TAK-788 as a first-line treatment compared to platinum-based doublet chemotherapy in treatment-naïve patients with locally advanced or metastatic NSCLC whose tumors harbor EGFR exon 20 insertion mutations. This trial is now enrolling.
• Phase 1, open-label, multicenter, dose-escalation study evaluating the safety, tolerability and pharmacokinetics of TAK-788 in Japanese patients with locally advanced or metastatic NSCLC. This trial has completed enrollment.
• Phase 2 J-EXCLAIM, open-label, multicenter, study evaluating the efficacy of TAK-788 as a first-line treatment in Japanese patients with locally advanced or metastatic NSCLC whose tumors harbor EGFR exon 20 insertion mutations. This trial is now enrolling.
• Phase 1, open-label, two-period, fixed-sequence study designed to characterize drug-drug interaction between TAK-788 and either a strong cytochrome P-450 (CYP)3A inhibitor, itraconazole (Part 1) or a strong CYP3A inducer, rifampin (Part 2) in healthy adult subjects. This trial is now enrolling.

For additional information on the ALUNBRIG and TAK-788 clinical trials, please visit www.clinicaltrials.gov.

ALUNBRIG^® (brigatinib): GLOBAL IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

Hypersensitivity to the active substance or to any of the excipients of ALUNBRIG is contraindicated

SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Pulmonary Adverse Reactions: Severe, life-threatening, and fatal pulmonary adverse reactions, including those with features consistent with ILD/pneumonitis, has been reported with ALUNBRIG. Most pulmonary adverse reactions were observed within the first 7 days of treatment. Grade 1-2 pulmonary adverse reactions resolved with interruption of treatment or dose modification. Increased age and shorter interval (less than 7 days) between the last dose of crizotinib and the first dose of ALUNBRIG were independently associated with an increased rate of these pulmonary adverse reactions. Consider these factors when initiating treatment with ALUNBRIG. Some patients experienced pneumonitis later in treatment with ALUNBRIG. Monitor for new or worsening respiratory symptoms (e.g., dyspnea, cough, etc.) in the first week of treatment. Promptly investigate signs of pneumonitis in any patient with worsening respiratory symptoms. If pneumonitis is suspected, withhold ALUNBRIG, and evaluate patient for other symptoms (e.g., pulmonary embolism, tumor progression, and infectious pneumonia).

Hypertension has been reported with ALUNBRIG. Monitor blood pressure regularly during treatment with ALUNBRIG. Treat hypertension according to standard guidelines to control blood pressure. Monitor heart rate more frequently in patients if concomitant use of a medicinal product known to cause bradycardia cannot be avoided. For severe hypertension (≥ Grade 3), ALUNBRIG should be withheld until hypertension has recovered to Grade 1 or to baseline. The dose should be modified accordingly.

Bradycardia has been reported with ALUNBRIG. Use caution when administering ALUNBRIG in combination with other agents known to cause bradycardia. Monitor heart rate and blood pressure regularly. If symptomatic bradycardia occurs, withhold ALUNBRIG and evaluate concomitant medications 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. In case of life-threatening bradycardia, if no contributing concomitant medication is identified or in case of recurrence, discontinue ALUNBRIG.

Visual Disturbance was reported with ALUNBRIG. Advise patients to report any visual symptoms. Withhold ALUNBRIG and obtain an ophthalmologic evaluation in patients with new or worsening visual symptoms.

Creatine Phosphokinase (CPK) Elevation has been reported with ALUNBRIG. Advise patients to report any unexplained muscle pain, tenderness, or weakness. Monitor CPK levels regularly during treatment. Withhold ALUNBRIG for Grade 3 or 4 CPK elevation. Based on the severity of the CPK elevation, and if associated with muscle pain or weakness, treatment with brigatinib should be withheld, and the dose modified accordingly.

Pancreatic Enzyme Elevation: Elevations of amylase and lipase have been reported with ALUNBRIG. Monitor lipase and amylase regularly. Withhold ALUNBRIG for Grade 3 or 4 pancreatic enzyme elevation. Based on the severity of the laboratory abnormalities, treatment with brigatinib should be withheld, and the dose modified accordingly.

Hyperglycemia: Elevations of serum glucose have occurred in patients treated with ALUNBRIG. Assess fasting serum glucose prior to initiation of ALUNBRIG and monitor periodically thereafter. Antihyperglycemic medications should be initiated or optimized as needed. If cannot control hyperglycemia with optimal medical management, withhold ALUNBRIG until adequate hyperglycemic control is achieved. Upon recovery, consider reducing the ALUNBRIG dose or permanently discontinue 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

The most common adverse reactions (≥ 25%) reported in patients treated with ALUNBRIG at the recommended dosing regimen were increased AST, increased CPK, hyperglycaemia, increased lipase, hyperinsulinaemia, anaemia, diarrhea, increased ALT, increased amylase, anemia, nausea, fatigue, hypophosphatemia, decreased lymphocyte count, cough, rash, increased alkaline phosphatas, increased APTT, myalgia, headache, hypertension, white blood count decreased, dyspnea and vomiting.

The most common serious adverse reactions (2%) reported in patients treated with ALUNBRIG at the recommended dosing regimen other than events related to neoplasm progression included pneumonitis, pneumonia, and dyspnoea.

DRUG INTERACTIONS

CYP3A Inhibitors: Avoid concomitant use of ALUNBRIG with strong CYP3A inhibitors. If concomitant use of a strong CYP3A inhibitor cannot be avoided, reduce the dose of ALUNBRIG. After discontinuation of strong CYP3A inhibitor, resume ALUNBRIG dose tolerated prior to the initiation of the strong CYP3A inhibitor. No dose adjustment is required for ALUNBRIG in combination with moderate CYP3A inhibitors. Monitor patients closely when coadminister ALUNBRIG with moderate CYP3A inhibitors. Avoid grapefruit or grapefruit juice as it may also increase plasma concentrations of ALUNBRIG. Concomitant use of ALUNBRIG with moderate CYP3A inhibitors should be avoided. If concomitant use of moderate CYP3A inhibitors cannot be avoided, reduce the dose of ALUNBRIG. After discontinuation of a moderate CYP3A inhibitor, resume ALUNBRIG at the dose that was tolerated prior to the initiation of the moderate CYP3A inhibitor.

CYP2C8 Inhibitors: No dose adjustment is required for ALUNBRIG when coadministered with strong CYP2C8 inhibitors

P-gp and BCRP Inhibitors: No dose adjustment is required for ALUNBRIG coadministered with P-gp and BCRP inhibitors.

CYP3A Inducers: Avoid concomitant use of ALUNBRIG with strong and moderate CYP3A inducers. If concomitant use of moderate CYP3A inducers cannot be avoided, the dose of ALUNBRIG may be increased in 30 mg increments after 7 days of treatment with the current dose as tolerated, up to a maximum of twice the dose that was tolerated prior to the initiation of the moderate CYP3A inducer. After discontinuation of a moderate CYP3A inducer, resume the dose of ALUNBRIG to the dose that was tolerated prior to the initiation of the moderate CYP3A inducer.

CYP3A Substrates: Clinical drug-drug interaction studies with sensitive CYP3A substrates have not been conducted. ALUNBRIG may reduce plasma concentrations of coadministered and induce other enzymes and transporters (e.g., CYP2C, P-gp).

Transporter Substrates: ALUNBRIG inhibits P-gp, BCRP, OCT1, MATE1, and MATE2K in vitro. Coadministration of ALUNBRIG Transporter substrates may increase their plasma concentrations. Monitored patients closely when coadminister ALUNBRIG with substrates of these transporters with a narrow therapeutic index (e.g., digoxin, dabigatran, methotrexate).

SPECIAL PATIENT POPULATIONS

Women of childbearing potential/Contraception in males and females: Advised women of childbearing age not to become pregnant and advise men not to father a child during treatment with ALUNBRIG. Advised women of reproductive potential to use effective non hormonal contraception during treatment with ALUNBRIG and for at least 4 months following the final dose. Advised men with female partners of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose of ALUNBRIG.

Pregnancy: ALUNBRIG can cause fetal harm. There are no clinical data on the use of ALUNBRIG in pregnant women. ALUNBRIG should not be used during pregnancy unless the clinical condition of the mother requires treatment. If used during pregnancy, or if patient becomes pregnant while taking ALUNBRIG, advise patient of the potential harm to fetus.

Breast feeding: There are no data regarding the secretion of ALUNBRIG in human milk. Breastfeed should be stopped during treatment with ALUNBRIG.

Infertility: ALUNBRIG may cause reduced fertility in males.

Elderly Patients: The limited data on the safety and efficacy of ALUNBRIG in patients aged 65 years and older suggest that a dose adjustment is not required in elderly patients. There are no available data on patients over 85 years of age.

Hepatic Impairment: No dose adjustment of ALUNBRIG is required for patients with mild hepatic impairment (Child Pugh class A) or moderate hepatic impairment (Child Pugh class B). Reduce the dose of ALUNBRIG by approximately 50% (i.e., from 180 mg to 90 mg, or from 90 mg to 60 mg) for patients with severe renal impairment

Renal Impairment: No dose adjustment of ALUNBRIG is required for patients with mild or moderate renal impairment (estimated glomerular filtration rate (eGFR) ≥ 30 mL/min). The dose of brigatinib should be reduced by approximately 40% (i.e., from 180 mg to 120 mg, 120 mg to 90 mg, or from 90 mg to 60 mg) for patients with severe hepatic impairment (Child-Pugh class C

Pediatric Patients: The safety and efficacy of ALUNBRIG in patients less than 18 years of age have not been established.

For US Prescribing Information: https://www.alunbrig.com/assets/pi.pdf

For European Union Summary of Product Characteristics: https://www.ema.europa.eu/en/medicines/human/EPAR/alunbrig

For Canada Product Monograph: https://www.takeda.com/siteassets/en-ca/home/what-we-do/our-medicines/product-monographs/alunbrig/alunbrig-pm-en.pdf

ALUNBRIG 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.

Contacts

Japanese Media
Kazumi Kobayashi

[email protected]
+81 (0) 3-3278-2095

Media outside Japan
Lauren Padovan

[email protected]
+1 (617) 444-1419

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