CAMBRIDGE, Mass. & OSAKA, Japan--(BUSINESS WIRE)--Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) today announced that new data for TAK-788 will be presented during an oral session at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting on Monday, June 3 at 10:12 a.m. CT in Chicago. Results from a Phase 1/2 first-in-human, open-label, multicenter study showed TAK-788 yielded a median progression-free survival (PFS) of 7.3 months and a confirmed objective response rate (ORR) of 43% in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumors harbor epidermal growth factor receptor (EGFR) exon 20 insertion mutations. These findings add to the collection of data featured at this year’s meeting from Takeda’s lung cancer portfolio, which also revealed key insights from sub-analyses of ALUNBRIG (brigatinib), including quality of life data from the Phase 3 ALTA-1L (ALK in Lung Cancer Trial of BrigAtinib in 1st Line) trial. TAK-788 is an investigational drug for which efficacy and safety have not been established. ALUNBRIG does not yet have regulatory approval for first-line therapy.
“We are thrilled to share promising, early results from TAK-788, an investigational therapy that has the potential to help advance the treatment of NSCLC patients with EGFR exon 20 insertion mutations,” said Phil Rowlands, Ph.D., Head, Oncology Therapeutic Area Unit, Takeda. “Furthermore, meaningful insights from our ongoing ALUNBRIG Phase 3 clinical trial, ALTA-1L, will be unveiled during the meeting. ALUNBRIG is the only treatment of its kind to report improved quality of life over another ALK tyrosine kinase inhibitor (TKI) as evidenced by patient-reported outcomes presented at ASCO. These findings build upon our ALTA-1L efficacy data and illustrate ALUNBRIG’s potential to provide a meaningful benefit for patient’s life quality.”
Results from the Phase 1/2 trial of TAK-788 will be presented on Monday, June 3 at 10:12 a.m. CT in Hall B1 of the McCormick Place Convention Center. A summary of key findings is provided below:
- The current analysis evaluated a total of 28 NSCLC patients with EGFR exon 20 insertions who were treated with the recommended Phase 2 dose (RP2D) of 160 mg once daily. More than 50% of patients had received three or more prior regimens and 61% had been previously treated with an immune-checkpoint inhibitor. The median time on treatment was 7.9 months ongoing.
- Among the total patients treated, including those with brain metastases at baseline, 43% (n=12/28) had a confirmed objective response and median PFS was 7.3 months. Patients without brain metastases at baseline had a confirmed objective response of 56% (n=9/16) and a median PFS of 8.1 months.
- The disease control rate was 86% (n=24/28) for the total patients treated and 100% for patients without brain metastases at baseline (n=16/16).
The safety profile of TAK-788 was manageable. For patients treated at
the 160 mg once daily dose:
- The most common any grade treatment-related adverse events (AEs) were diarrhea (85%), nausea (43%), rash (36%), vomiting (29%) and decreased appetite (25%).
- Most treatment-related AEs were Grade 1-2 and reversible.
- Forty percent experienced Grade ≥3 treatment-related AEs.
- The most common Grade ≥3 treatment-related AEs were diarrhea (18%), nausea (6%), increased lipase (6%), increased amylase (4%) and stomatitis (4%).
- Food instructions have been included in the ongoing study with the potential to improve gastrointestinal tolerability.
- At the time of the analysis, 50% of patients were still on treatment, and additional results will be presented at future congresses, including those from the recently opened Phase 2 pivotal extension cohort, EXCLAIM. The pivotal cohort was designed to evaluate the efficacy and safety of TAK-788 at 160 mg once daily in previously treated patients and will build upon the results seen in the Phase 1/2 trial.
“Results from this Phase 1/2 trial show that TAK-788 effectively treated NSCLC patients whose tumors harbor EGFR exon 20 insertion mutations and who had been previously treated with multiple prior therapies,” said Pasi A Jänne, M.D., Ph.D., Dana-Farber Cancer Institute. “These data represent an important development and demonstrate progress in addressing an unmet need for these patients, who currently have limited treatment options and no approved targeted therapies.”
For ALUNBRIG, Takeda presented three posters featuring results from ongoing trials of its clinical development program, which seeks to expand Takeda’s research of ALUNBRIG and optimize its use among patients with anaplastic lymphoma kinase-positive (ALK+) NSCLC.
Notably, two posters highlighted sub-analyses of the Phase 3 ALTA-1L trial in patients who had not received prior treatment with an ALK inhibitor:
- Results from an analysis of the validated patient-reported outcomes questionnaire EORTC QLQ-C30 showed that ALUNBRIG significantly improved the overall health-related quality of life (HRQoL) compared to crizotinib. Results also showed improvements for patients receiving ALUNBRIG across functional scales, with significant improvement seen for physical, emotional and cognitive functions. There was also observed improvement for symptom scales including fatigue, nausea and vomiting, appetite loss and constipation.
- Additionally, an investigation of outcomes in patients of Asian versus non-Asian heritage demonstrated that ALUNBRIG showed improvement in PFS compared to crizotinib for both patient subgroups. The safety profile of ALUNBRIG in these subgroups was consistent with what has been reported previously, with no new safety concerns. These findings add to the body of evidence evaluating ALUNBRIG in the first-line setting for patients with ALK+ NSCLC.
About EGFR Exon 20 Insertion-Mutant 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 Epidermal growth factor receptor (EGFR) is one of several unique, genetic alternations found in NSCLC that affects approximately 15-21% of all NSCLC patients.3,4 The exon refers to the location of the EGFR mutations, which can be found in exon 18, 19, 20 or 21. Exon 20 insertions are much less common than EGFR mutations in other exons, comprising approximately 6% of all EGFR-mutated lung tumors.5 Therefore, patients with NSCLC who harbor EGFR exon 20 insertion mutations make up a small proportion of the NSCLC population, and there are currently no targeted therapy options to treat them, as approved EGFR tyrosine kinase inhibitor (TKIs) were not designed for patients with this subtype of EGFR mutations.
TAK-788 is a potent and selective next-generation, small-molecule tyrosine kinase inhibitor (TKI) intelligently designed and under clinical investigation to inhibit epidermal growth factor receptor (EGFR) and human EGFR 2 (HER2) exon 20 mutations with selectivity over wild type (WT) EGFR. Non-clinical studies demonstrated antitumor activity against de novo mutations in EGFR including EGFR exon 20 insertions and the acquired resistance mutation T790M. In October 2018, the ongoing Phase 1/2 trial of TAK-788 was amended to add the pivotal extension cohort, EXCLAIM, 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 insertions and is currently actively recruiting.
The TAK-788 development program has started first in the non-small cell lung cancer (NSCLC) population and is expected to expand to additional underserved populations in other tumor types. TAK-788 is an investigational drug for which efficacy and safety have not been established.
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. Approximately three to five percent of patients with metastatic NSCLC have a rearrangement in the ALK gene.6,7,8
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.9
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.
- In July 2018, Health Canada approved ALUNBRIG for the treatment of adult patients with ALK+ metastatic NSCLC who have progressed on or who were intolerant to an ALK inhibitor (crizotinib).
- In November 2018, the European Commission (EC) granted marketing authorization for ALUNBRIG as a monotherapy for the treatment of adult patients with ALK+ advanced NSCLC previously treated with crizotinib. The FDA, Health Canada and EC approvals of ALUNBRIG were primarily based on results from the pivotal Phase 2 ALTA (ALK in Lung Cancer Trial of AP26113) 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.
The brigatinib 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. The comprehensive program includes the following clinical trials:
- 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.
For additional information on the brigatinib clinical trials, please visit www.clinicaltrials.gov.
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.
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%).
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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