Takeda Presents Long-Term Data in ALK+ NSCLC Showing ALUNBRIG® (brigatinib) Continues to Demonstrate Superiority in the First-Line After Two Years of Follow-Up

Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) today announced updated data from the Phase 3 ALTA-1L trial, which evaluated ALUNBRIG versus crizotinib in adults with advanced anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC) who had not received a prior ALK inhibitor. Results show after more than two years of follow-up, ALUNBRIG reduced the risk of disease progression or death by 76% (hazard ratio [HR] = 0.24, 95% CI: 0.12–0.45) as assessed by investigators in newly diagnosed patients whose disease had spread to the brain at time of enrollment. ALUNBRIG also demonstrated a 57% (HR = 0.43, 95% CI: 0.31–0.61) reduction in risk of disease progression or death in all patients. These data will be presented during the Presidential Session at the 2019 European Society for Medical Oncology (ESMO) Asia Congress on Saturday, November 23 in Singapore.

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Results from the ALTA-1L trial were evaluated by two separate review bodies – study investigators and a blinded independent review committee (BIRC) – and results from both assessments were reported. At the data cutoff for the second interim analysis (June 28, 2019), the BIRC-assessed HR of progression-free survival (PFS), which is the primary endpoint, was 0.49 (95% CI: 0.35–0.68, log-rank P<0.0001), demonstrating a reduced risk of disease progression or death by 51%.

“Given the complexity of this disease and the expected longevity of the population, it is important for physicians to have multiple well-tolerated and durable treatment options to address the needs of their patients,” said D. Ross Camidge, M.D., Ph.D., Joyce Zeff Chair in Lung Cancer Research at the University of Colorado Cancer Center and the lead investigator of ALTA-1L. “With 25 months of follow up from the ALTA-1L trial, brigatinib continues to demonstrate overall and intracranial effectiveness, while also significantly improving quality of life compared to crizotinib, reinforcing its potential as a first-line therapy for ALK+ NSCLC.”

Additional data from the long-term analysis showed that newly diagnosed patients treated with ALUNBRIG benefited regardless of the presence or absence of brain metastases at baseline, which is one of the most common sites of first progression and associated with poor quality of life.

• ALUNBRIG demonstrated high and durable responses in the brain, with patients with baseline brain metastases having superior efficacy compared to crizotinib, as assessed by a BIRC, and an early separation of the PFS curves in these patients was observed.
  • ALUNBRIG reduced the risk of intracranial disease progression or death by 69% in patients with brain metastases at baseline (HR = 0.31, 95% CI: 0.17–0.56), with a median intracranial PFS of 24 months compared to 5.6 months with crizotinib. Median PFS for patients with brain metastases at baseline was not reached with ALUNBRIG and was 5.9 months with crizotinib, as assessed by investigators.
  • Confirmed intracranial objective response rate (ORR) for patients with measurable brain metastases at baseline was 78% (95% CI: 52.4–93.6) for patients treated with ALUNBRIG and 26% (95% CI: 10.2–48.4) for patients treated with crizotinib.
  • Median intracranial duration of response (DOR) in confirmed responders with measurable brain metastases at baseline was not reached (95% CI: 5.7–NE) with ALUNBRIG and was 9.2 months (95% CI: 3.9–9.2) with crizotinib.
• ALUNBRIG demonstrated consistent overall efficacy (intent to treat population) with a longer follow-up of 25 months.
  • Median PFS with ALUNBRIG was 29.4 months (95% CI: 21.2–NE) versus 9.2 months (95% CI: 7.4–12.9) with crizotinib, as assessed by investigators. The BIRC-assessed median PFS was 24.0 months (95% CI: 18.5–NE) for ALUNBRIG and 11.0 months (95% CI: 9.2–12.9) for crizotinib.
  • Confirmed ORR was 74% (95% CI: 65.5–80.9) for ALUNBRIG and 62% (95% CI: 52.9–69.7) for crizotinib as assessed by a BIRC.
  • Median DOR was not reached (95% CI: 19.4–NE) with ALUNBRIG and was 13.8 months (95% CI: 9.3–20.8) with crizotinib as assessed by a BIRC.
• Quality of life (QoL) for newly diagnosed ALK+ NSCLC patients was also evaluated, with results showing patients treated with ALUNBRIG experienced significant improvements in health-related QoL (HRQoL).
  • ALUNBRIG delayed median time to worsening in Global Health Score (GHS)/QoL score (≥10 point worsening in score) by 27 months versus 8 months with crizotinib.
  • Patients treated with ALUNBRIG had longer duration of improvement in GHS/ QoL, with duration of improvement not yet reached versus 12 months with crizotinib.
  • ALUNBRIG also delayed time to worsening and prolonged duration of improvement in multiple subscales such as fatigue, nausea and vomiting, appetite loss, and emotional and social functioning.

“At Takeda, we are committed to developing products that seek to advance the lung cancer treatment landscape and address the unmet needs of patients,” said Phil Rowlands, Head, Oncology Therapeutic Area Unit. “We are proud of the progress made thus far, including these updated results from the ALTA-1L trial, which show that ALUNBRIG delayed disease progression by more than two years and significantly reduced the risk of disease progression in patients with baseline brain metastasis. We look forward to submitting these data to regulatory authorities around the globe with the goal of making ALUNBRIG available to ALK+ NSCLC patients worldwide.”

“Individual treatment needs for patients with ALK+ NSCLC are diverse because cancer is not a one-size-fits-all disease,” said Bonnie Addario, Co-Founder, Board Chair, GO₂ Foundation for Lung Cancer. “Ongoing research and clinical trials such as ALTA-1L are critical to achieving our goal of improving outcomes and quality of life for patients early on in their treatment journey. We’re grateful for the patients, families and investigators who participated in this clinical trial, which shows meaningful results for those with newly diagnosed ALK+ NSCLC.”

The safety profile of ALUNBRIG in the ALTA-1L trial was generally consistent with the existing U.S. prescribing information.

• 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%).
• The frequency of early pulmonary events (interstitial lung disease/pneumonitis) in the ALTA-1L trial was slightly lower compared with the ALTA study in a post-crizotinib population.
• Pulmonary events at any time occurred in 5.1% of patients in the ALUNBRIG arm and 2.2% in the crizotinib arm.
• Discontinuations due to AEs occurred in 12.5% of patients in the ALUNBRIG arm and 8.8% in the crizotinib arm.
• ALUNBRIG is not currently approved for use in the first-line.

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 anaplastic lymphoma kinase-positive (ALK+) locally advanced or metastatic non-small cell lung cancer (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.

About ALUNBRIG^® (brigatinib)
ALUNBRIG is a potent and selective next-generation tyrosine kinase inhibitor (TKI) that was designed to target and inhibit the anaplastic lymphoma kinase (ALK) fusion protein in non-small cell lung cancer (NSCLC). In April 2017, ALUNBRIG received Accelerated Approval from the U.S. Food and Drug Administration (FDA) for anaplastic lymphoma kinase-positive (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 with ALK+ metastatic NSCLC whose disease has worsened during crizotinib treatment or they could not 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.

Takeda in Lung Cancer
Takeda is dedicated to expanding experience in the ALK+ NSCLC and EGFR exon 20 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.
• 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, 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 J-ALTA, single-arm, multicenter trial in Japanese patients with ALK+ NSCLC, focusing on patients who have progressed on alectinib. This trial is now enrolling.
• 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 is now enrolling.
• 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

• Phase 1/2 study evaluating the safety, pharmacokinetics and antitumor activity of oral EGFR/HER2 inhibitor TAK-788 in patients with NSCLC.
• 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 is closed to enrollment.
• Phase 3 EXCLAIM 2, global, randomized study evaluating the efficacy of TAK-788 as a first-line treatment compared to platinum-based chemotherapy in treatment-naïve patients with locally advanced or metastatic NSCLC whose tumors harbor EGFR exon 20 insertion mutations.
• 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 been fully enrolled.
• Phase 2, open label, single-arm study evaluating the efficacy of TAK-788 in treatment-naïve patients with locally advanced or metastatic NSCLC whose tumors harbor EGFR exon 20 insertion mutations.
• 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.

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

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

ALUNBRIG 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 coadministration of ALUNBRIG with strong or moderate CYP3A inhibitors. Avoid grapefruit or grapefruit juice as it may also increase plasma concentrations of brigatinib. If coadministration of a strong or moderate CYP3A inhibitor cannot be avoided, reduce the dose of ALUNBRIG.
CYP3A Inducers: Avoid coadministration of ALUNBRIG with strong or moderate CYP3A inducers. If coadministration of moderate CYP3A inducers cannot be avoided, increase the dose of ALUNBRIG.
CYP3A Substrates: Coadministration of ALUNBRIG with sensitive CYP3A substrates, including hormonal contraceptives, can result in decreased concentrations and loss of efficacy of sensitive 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:
Pregnancy Testing: Verify pregnancy status in females of reproductive potential prior to initiating ALUNBRIG.
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 effectiveness 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.

Hepatic or Renal Impairment: No dose adjustment is recommended for patients with mild or moderate hepatic impairment or mild or moderate renal impairment. Reduce the dose of ALUNBRIG for patients with severe hepatic impairment or severe renal impairment.

Please see the full U.S. Prescribing Information for ALUNBRIG at www.ALUNBRIG.com.

About Takeda Pharmaceutical Company Limited
Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) is a global, values-based, R&D-driven biopharmaceutical leader headquartered in Japan, committed to bringing Better Health and a Brighter Future to patients by translating science into highly-innovative medicines. Takeda focuses its R&D efforts on four therapeutic areas: Oncology, Gastroenterology (GI), Rare Diseases and Neuroscience. We also make targeted R&D investments in Plasma-Derived Therapies and Vaccines. We are focusing on developing highly innovative medicines that contribute to making a difference in people's lives by advancing the frontier of new treatment options and leveraging our enhanced collaborative R&D engine and capabilities to create a robust, modality-diverse pipeline. Our employees are committed to improving quality of life for patients and to working with our partners in health care in approximately 80 countries and regions.
For more information, visit https://www.takeda.com.

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² American Cancer Society. What is Non-Small Cell Lung Cancer? https://www.cancer.org/cancer/non-small-cell-lung-cancer/about/what-is-non-small-cell-lung-cancer.html. Accessed May 11, 2019.
³ Kris MG, et al. JAMA, 2014;311:1998-2006.
⁴ Gainor JF, Varghese AM, Ou SH, et al. Clin Cancer Res. 2013;19(15):4273-81.
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