Takeda Pharmaceutical : European Commission Approves Takeda's ALUNBRIG as a First-Line Treatment for ALK+ NSCLC

Cambridge - 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.

About the ALTA-1L Trial

The Phase 3 ALTA-1L (ALK in Lung Cancer Trial of BrigAtinib in 1st 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-naive 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.

Takeda's Commitment to Oncology

Our core R&D mission is to deliver novel medicines to patients with cancer worldwide through our commitment to science, breakthrough innovation and passion for improving the lives of patients. Whether it's with our hematology therapies, our robust pipeline, or solid tumor medicines, we aim to stay both innovative and competitive to bring patients the treatments they need.

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, Rare Diseases, Neuroscience, and Gastroenterology (GI). 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.

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