On September 22, 2018 Takeda Pharmaceutical Company Limited ( TSE: 4502 ) reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending full approval of ALUNBRIG (brigatinib) as part of a monotherapy for the treatment of adult patients with anaplastic lymphoma (ALK +) kinase positive, advanced non-small cell lung cancer (NSCLC) and previously treated with crizotinib. ALUNBRIG is a tyrosine kinase inhibitor (TKI), designed to target and inhibit the ALK mutation in NSCLC (Press release, Takeda, SEP 22, 2018, View Source [SID1234529524]). Approximately 3% to 5% of patients with NSCLC worldwide have the ALK mutation. If the opinion of the CHMP is confirmed and the European Commission approves the ALUNBRIG, it will be the only ALK inhibitor available in the European Union as a dose of one tablet per day, which can be taken with or without food.
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The Randomized Phase 2 ALTA trial was designed to investigate the efficacy and safety of ALUNBRIG in patients with locally advanced or metastatic ALK + NSCLC who presented progress with crizotinib. Patients were randomized to receive one of two ALUNBRIG regimens: ALUNBRIG 90 mg once daily (n = 112) or 180 mg once daily with induction from 7 days to 90 mg once daily (n = 110) .
"ALK + NSCLC is a serious, life-threatening disease that affects approximately 40,000 people worldwide each year, with many patients progressing or failing to respond to first-line treatment," said Stefania Vallone, president, Lung Cancer Europe . "For Europeans with ALK + NSCLC, there remains a significant need not met by new and effective treatment options."
"Although ALK inhibitors have shown tremendous growth over this period of treatment over the past decade, another targeted therapy option available for ALK + NSCLC treatment has been awaited with anticipation and anticipation," said Enriqueta Felip, MD, PhD, chief of the Thoracic Oncology Unit, Department of Oncology at the Vall d’Hebron University Hospital in Barcelona. "With a median progression free survival of 16.7 months and an overall survival of 34.1 months, ALUNBRIG demonstrated impressive results, representing new progress for ALK + NSCLC treatment in this setting."
"The ALTA trial established ALUNBRIG as a possible second-line treatment option for ALK + NSCLC, demonstrating significant efficacy with a manageable safety profile," said Jesús Gómez-Navarro, MD, vice president, chief of Clinical Research and Development in Oncology in Takeda. "With 16.7 months of progression-free median survival, the longest of any ALK inhibitors to be reported in this setting, ALUNBRIG offers great potential for patients who progressed with crizotinib. Today’s positive opinion brings us closer to the ultimate goal of advancing the treatment paradigm for the considerable number of critically ill ALK + patients treated with crizotinib who live in Europe.
As part of this submission, the CHMP also analyzed data from the first interim review of the Phase 3 ALTA-1L trial, which fulfilled its main objective as evidence of support. In ALTA-1L, treatment with ALUNBRIG resulted in a statistically and clinically significant improvement in progression-free survival (PFS) versus crizotinib, as assessed by an independent blind review committee. The safety profile associated with ALUNBRIG has generally been consistent with previous studies and with labeling approved in the USA and Canada.
The CHMP’s positive opinion on ALUNBRIG will now be reviewed by the European Commission, which has the authority to approve medicines for use in the 28 member states of the European Union, as well as in Norway, Liechtenstein and Iceland.
About the ALTA test
The Phase 2 ALTA (acronym for A LK in L ung Cancer T rial of AP26113) in adults is a multicenter, open, randomized, continuous, multi-center trial involving 222 patients with locally advanced or metastatic ALK + NSCLC who progressed on crizotinib. Patients received ALUNBRIG at a dose of 90 mg once daily (n = 112) or 180 mg once daily with induction of seven days at 90 gm once daily (n = 110). The confirmed objective response rate (ORT), evaluated by the investigator according to RECIST v1.1, was the primary endpoint. Additional major endpoints included ORT, independent response committee (IRR), duration of response (DOR), progression-free survival (PFS), intracranial ORT, intracranial DOR, safety and tolerability.
The results of the ALTA trial demonstrated that, of the patients who received the 180 mg dosing regimen, 56% achieved an objective response rate as measured by the investigator and 56% by the CRI assessment. The median DOR was 13.8 months, as assessed by the investigator, and 15.7 months for the IRC evaluation. The median SLP was 15.6 months, as assessed by the investigator, and 16.7 months by the IRC evaluation. In addition, of the patients with measurable brain metastases at baseline (n = 18), 67% achieved intracranial ORR due to CRI; the median duration of intracranial response was 16.6 months by the CRI assessment. Median overall survival was 34.1 months, as assessed by the investigator.
The most frequent (≥ 25%) adverse reactions reported in ALUNBRIG-treated patients on the 180 mg dosing regimen were increased aspartate aminotransferase (AST), hyperglycemia, hyperinsulinemia, anemia, increased creatine phosphokinase (CPK), nausea, increased lipase, decreased lymphocyte count, increased alanine aminotransferase (ALT), diarrhea, increased amylase, fatigue, cough, headache, increased alkaline phosphatase, hypophosphataemia, increased abnormal activated partial thromboplastin time (APTT), rash, vomiting, dyspnoea, hypertension, decreased blood cell count, myalgia, and peripheral neuropathy.
About the ALTA-1L test
The Phase 3 ALTA-1L (acronym for A LK in L ung Cancer T rial of Brig A tinibe in 1 to Linha) in adults is an open, randomized, continuous, multicenter, global trial involving 275 patients with locally advanced or metastatic ALK + NSCLC who did not receive prior treatment with an ALK inhibitor. Patients received ALUNBRIG at the dose of 180 mg once daily with induction from 7 days to 90 mg once daily, or crizotinib at the dose of 250 mg twice daily. Progression-free survival (SLP) evaluated by the Independent Review Committee (IRC) was the primary endpoint. Secondary endpoints included objective response rate (ORT) according to RECIST v1.1, intracranial ORT, intracranial SLP, overall survival (OS), safety, and tolerability. A total of approximately 198 SLP events were planned in the final analysis of the primary endpoint to demonstrate a minimum of six months of improvement of SLP over crizotinib. The assay was developed with two pre-specified intermediate analyzes for the primary endpoint – one in approximately 50% of the planned PFS events and one in approximately 75% of the planned events of the SLP.
About CPNPC ALK +
Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for about 85% of the estimated 1.8 million new lung cancer cases diagnosed each year worldwide, according to the Organization World Health Organization. Genetic studies indicate that chromosomal rearrangements in anaplastic lymphoma (ALK) kinase are fundamental motivators in a subset of patients with NSCLC. About 3% to 5% of patients with metastatic NSCLC have a rearrangement in the ALK gene.
Takeda is committed to continuing research and development at CPNPC to enhance the lives of the approximately 40,000 patients diagnosed with this severe and rare form of lung cancer worldwide each year.
About ALUNBRIG (brigatinib)
ALUNBRIG is a cancer-fighting drug discovered by ARIAD Pharmaceuticals, Inc., which was acquired by Takeda in February 2017. In April 2017, ALUNBRIG received accelerated approval from the US Food and Drug Administration (FDA) for patients with ALK + metastatic NSCLC, which have progressed or are intolerant to crizotinib. This indication was approved from accelerated approval, based on the tumor response rate and duration of response. Continuous approval for this indication may be conditional upon verification and description of clinical benefits in a confirmatory trial. In July 2018, Health Canada approved ALUNBRIG for the treatment of adult patients with metastatic ALK + NSCLC, who progressed or who were intolerant of an ALK inhibitor (crizotinib). ALUNBRIG’s approvals by the FDA and Health Canada were based primarily on the results of the ALTA Phase 2 trial (acronym forThe LK in U UNG Cancer T rial of the P26113).
ALUNBRIG has received the Breakthrough Therapy (FDA) designation of the FDA for the treatment of patients with critically ill ALK + NSCLC whose tumors are resistant to crizotinib and has been granted the Orphan Drug Designation by the FDA for the treatment of ALK + NSCLC, ROS1 + NSCLC and CPNPC EGFR +.
The brigatinib clinical development program further enhances Takeda’s continued commitment to the development of innovative therapies for people living with ALK + NSCLC worldwide and healthcare professionals who treat this disease. The comprehensive program includes the following clinical trials:
Phase 1/2 trial, which was designed to assess ALUNBRIG’s safety, tolerability, pharmacokinetics and antitumor activity
A phase 2 ALTA pivotal trial investigating the efficacy and safety of ALUNBRIG in two dosing regimens in patients with locally advanced or metastatic ALK + NSCLC who progressed with crizotinib
Phase 3 ALTA-1L trial, a randomized, global trial evaluating the efficacy and safety of ALUNBRIG in relation to crizotinib in patients with locally advanced or metastatic ALK + NSCLC who did not receive prior treatment with an ALK inhibitor
Single-phase, multicenter, phase 2 study in Japanese patients with ALK + NSCLC, focusing on patients who progressed in alectinib
A single-arm global phase 2 study evaluating ALUNBRIG in patients with advanced ALK + NSCLC who progressed in alectinib or ceritinib
A global randomized phase 3 trial comparing the efficacy and safety of ALUNBRIG versus alectinib in participants with ALK + NSCLC who progressed in crizotinib
For more information on brigatinib’s clinical trials, visit www.clinicaltrials.gov .
IMPORTANT SAFETY INFORMATION (USA)
WARNINGS AND PRECAUTIONS
Interstitial lung disease (IPD) / pneumonia: fatal life-threatening pulmonary adverse events consistent with interstitial lung disease (IPD) / pneumonia occurred with ALUNBRIG. In the ALTA trial, IPD / pneumonia 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). once daily with induction from 7 days to 90 mg once daily). Adverse reactions consistent with IPD / pneumonia occurred earlier (in 9 days after ALUNBRIG started, 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 (eg, dyspnoea, cough, etc.), particularly during the first week of ALUNBRIG. Discontinue ALUNBRIG in any patient with new or worsening respiratory symptoms and immediately assess whether there is an IPD / pneumonia or other causes of respiratory symptoms (eg, pulmonary embolism, tumor progression, and infectious pneumonia). For Grade 1 or 2 PID / pneumonia, restart ALUNBRIG with dosage reduction after recovering the initial level or permanently discontinuing ALUNBRIG. Permanently discontinue ALUNBRIG for grade 3 or 4 PID / pneumonia or recurrence of grade 1 or 2 IPD / pneumonia. restart the ALUNBRIG with reduction of the dosage, after recovering the initial level or interrupt ALUNBRIG permanently. Permanently discontinue ALUNBRIG for grade 3 or 4 PID / pneumonia or recurrence of grade 1 or 2 IPD / pneumonia. restart the ALUNBRIG with reduction of the dosage, after recovering the initial level or interrupt ALUNBRIG permanently. Permanently discontinue ALUNBRIG for grade 3 or 4 PID / pneumonia or recurrence of grade 1 or 2 IPD / pneumonia.
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. In general, grade 3 hypertension occurred in 5.9% of the patients. Check blood pressure before ALUNBRIG treatment. Monitor blood pressure after 2 weeks and at least monthly thereafter during treatment with ALUNBRIG. Discontinue use of ALUNBRIG for grade 3 hypertension despite optimal antihypertensive therapy. After resolution or improvement to grade 1 severity, restart ALUNBRIG at a reduced dosage. Consider stopping ALUNBRIG treatment for grade 4 hypertension or recurrence of grade 3 hypertension.
Bradycardia: bradycardia may occur with ALUNBRIG. At ALTA, heart rates below 50 beats per minute (bpm) occurred in 5.7% of the patients in the 90 mg group and 7.6% of the patients in the 90 → 180 mg group. Grade 2 bradycardia occurred in 1 (0.9%) patient in the 90 mg group. Monitor your heart rate and blood pressure during ALUNBRIG treatment. Monitor patients more often if it is not possible to avoid the concomitant use of medication known to cause bradycardia. For symptomatic bradycardia, discontinue ALUNBRIG and review the concomitant use of medicines for those known to cause bradycardia. If a concomitant medication known to cause bradycardia is identified and discontinued or the dosage adjusted, restart ALUNBRIG at the same dosage, after symptomatic bradycardia has subsided; Otherwise, reduce ALUNBRIG dosage after reduction of symptomatic bradycardia. Stop ALUNBRIG for life-threatening bradycardia if the contribution of a concomitant medication is not identified.
Visual disturbance: in ALTA, adverse reactions that caused visual disturbance, including blurred vision, diplopia and reduced visual acuity, were recorded in 7.3% of patients treated with ALUNBRIG in the 90 mg group and 10% of the patients in the 90 → 180 group mg. Grade 3 macular edema and cataract occurred in one patient in each case in the 90 → 180 mg group. Advise patients to report any visual symptoms. Discontinue ALUNBRIG and obtain an ophthalmologic evaluation in patients with new or worsening grade 2 or greater severity of visual symptoms. After grade 2 or 3 visual impairment is restored for grade 1 or initial plateau pain, restart ALUNBRIG at a reduced dosage..
Elevated creatine phosphokinase (CPK): in ALTA, elevated creatine phosphokinase (CPK) 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 or 4 CPK elevation was 2.8% in the 90 mg group and 12% in the 90 → 180 mg group. The reduction in CPK elevation was observed 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 pain, tenderness, or muscle weakness. Monitor CPK levels during treatment with ALUNBRIG. Discontinue ALUNBRIG if CPK grade 3 or 4 is elevated. After resolving or restoring to grade 1 or the initial plateau, restart ALUNBRIG at the same dosage or at a reduced dosage.
Elevation of pancreatic enzymes: in ALTA, increased amylase occurred in 27% of patients in the 90 mg group and 39% in the 90 → 180 mg group. Lipase elevations occurred in 21% of the patients in the 90 mg group and 45% of the patients in the 90 → 180 mg group. Elevation of grade 3 or 4 amylase occurred in 3.7% of patients in the 90 mg group and 2.7% in the 90 → 180 mg group. Elevation of grade 3 or 4 lipase occurred in 4.6% of patients in the 90 mg group and 5.5% in the 90 → 180 mg group. Monitor lipase and amylase during treatment with ALUNBRIG. Discontinue use of ALUNBRIG if there is elevation of pancreatic enzymes to grade 3 or 4. After resolution or recovery to grade 1 or baseline, restart ALUNBRIG at the same dosage or with a reduced dosage.
Hyperglycemia: in ALTA, 43% of patients receiving ALUNBRIG experienced new or worsening hyperglycemia. Grade 3 hyperglycemia, based on the laboratory evaluation of fasting serum glucose levels, occurred in 3.7% of the patients. Two of 20 (10%) patients with diabetes or glucose intolerance at the initial level requested the start of insulin use while receiving ALUNBRIG. Analyze fasting serum glucose before ALUNBRIG starts and then monitor periodically. Initiate or optimize antihyperglycemic medications as needed. If adequate control of hyperglycaemia can not be achieved with optimal medical management,
Embryo-fetal toxicity : Based on its mechanism of action and findings in animals, ALUNBRIG can cause fetal injury when administered to pregnant women. There are no clinical data on the use of ALUNBRIG in pregnant women. Advise the pregnant women about the potential risk to the fetus. Advise women with reproductive capacity to use effective non-hormonal contraceptives during treatment with ALUNBRIG and for at least 4 months after the final dose. Advise men with reproductive partners to use effective contraceptives during treatment and for at least 3 months after the last dose of ALUNBRIG .
ADVERSE REACTIONS
Serious adverse reactions occurred in 38% of the patients in the 90 mg group and 40% of the 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 IPD / pneumonia (4.6% in total , 1.8% in the 90 mg group and 7.3% in the 90 → 180 mg group). Fatal adverse reactions occurred in 3.7% of the patients and consisted of pneumonia (2 patients), sudden death, dyspnea, respiratory arrest, 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 dyspnoea (27%), and in the group of 90 → 180 mg (40%), diarrhea (38%), fatigue (36%), cough (34%) and headache (27%).
DRUG INTERACTIONS
CYP3A Inhibitors : Avoid the concomitant use of ALUNBRIG with strong inhibitors of CYP3A. Avoid grapefruit juice or grapefruit as fruit, as it may also increase plasma concentrations of brigatinib. If concomitant use of a strong inhibitor of CYP3A is unavoidable, reduce ALUNBRIG dosage.
CYP3A Inducers: Avoid the concomitant use of ALUNBRIG with strong CYP3A inducers.
CYP3A Substrates: Co-administration of ALUNBRIG with substrates of CYP3A, including hormonal contraceptives, may result in decreased concentrations and loss of efficacy of CYP3A substrates.
USE ON SPECIFIC GROUPS
Pregnancy: ALUNBRIG can harm the fetus. Advise women with reproductive capacity about the potential risk to the fetus.
Lactation: There are no data regarding the secretion of brigatinib in human milk or its effect on the suckling baby or milk production. Due to potential adverse reactions in lactating infants, advise women not to breastfeed during treatment with ALUNBRIG.
Men and women with reproductive capacity:
Contraception : advise women with reproductive potential to use effective non-hormonal contraceptives during ALUNBRIG treatment and for at least 4 months after final dosing. Advise men living with women in reproductive capacity to use effective contraceptives during treatment with ALUNBRIG and for at least 3 months after the final dosing.
Infertility : ALUNBRIG can cause fertility reduction in men.
Pediatric use: The safety and efficacy of ALUNBRIG in pediatric patients has not been established.
Geriatric Use: ALUNBRIG clinical studies did not include sufficient patients aged 65 years or older to determine whether they responded differently from younger patients. Of the 222 patients in the ALTA, 19.4% were 65 to 74 years and 4.1% of 75 years or older. No clinically relevant difference in safety or efficacy was observed between patients 65 years of age and older and younger patients.
Hepatic or renal impairment: no dosage 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.