On September 26, 2018 Takeda Pharmaceutical Company Limited ( TSE: 4502 ) reported the test results Phase 3 HIGH-1L ( which stands for the LK in U UNG Cancer T rial Brig The tinibe in 1 to Linha) which demonstrated that ALUNBRIG reduced the risk of disease progression or death, known as progression-free survival (PFS), as assessed by the Independent Independent Review Committee (BIRC), by more than 50% when compared to crizotinib in adults with locally advanced or metastatic anaplastic positive kinase lymphoma (ALK +) with non-small cell lung cancer (NSCLC) (Press release, Takeda, SEP 26, 2018, View Source [SID1234529602]). The results of the first interim analysis of the ALTA-1L trial will be presented during the Presidential Symposium at the International Association for the Study of Lung Cancer (IASLC), the 19th World Conference on Lung Cancer (WCLC) in Toronto on Tuesday, September 2018. The data were also published simultaneously online in The New England Journal of Medicine . Currently, ALUNBRIG is not approved as first-line therapy for advanced ALK + NSCLC.
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ALTA-1L is a randomized, open, comparative, multicenter trial involving 275 patients with locally advanced or metastatic ALK + NSCLC who have not received prior treatment with an ALK inhibitor but may have received up to one prior chemotherapy regimen in advanced configuration. Patients were eligible for entry into the study based on locally determined ALK tests. Patients received ALUNBRIG 180 mg once daily and on the previous 7 days with 90 mg once daily or crizotinib 250 mg twice daily. Treatment with ALUNBRIG resulted in a higher PFS than crizotinib as assessed by an independent blind review committee (hazard ratio = 0.49 (95% confidence interval (CI), 0.33 to 0.74); log-rank p = 0, 0007), corresponding to a 51% reduction in the risk of disease progression or death. The safety profile associated with ALUNBRIG was generally consistent with existing US prescribing information.
"The treatment scenario for ALK + NSCLC NSCLC has undergone tremendous change in the last decade, and the ALTA-1L trial demonstrates that brigatinib has the potential to be a key player in the first-line setting," said Dr. Ross Camidge, MD , PhD, president of Joyce Zeff in Lung Cancer Research at the University of Colorado Cancer Center and principal investigator of ALTA-1L. "The ALTA-1L assay offers unique aspects, including the actual applicability of the data. The study design offered enrollment to a broader population, allowing patients to participate even though they had received prior chemotherapy and included patients based on the local standard ALK rapid test, as opposed to mandatory confirmation in a central laboratory. We look forward to continued follow-up, which will provide an even better understanding of the role of brigatinib in the evolving setting. "
"We are excited to share these long-awaited results with the lung cancer community," said David Kerstein MD, Global Clinical Leader for brigatinib and strategy leader of the Lung Cancer Clinical Portfolio, Takeda. "ALTA-1L data demonstrate that ALUNBRIG is superior to crizotinib in the first-line setting, reducing disease progression or death by more than half, with particularly pronounced activity in the brain. We would like to thank all the researchers and especially the patients and their caregivers who participated in this important clinical research. "
Brigatinib vs crizotinib in patients with ALK + NSCLC advanced with ALK inhibitor-Naïve: first report of a Phase 3 trial (ALTA-1L) (Presidential Symposium on Tuesday, September 25, at 8:30 am ET at the North Toronto Metro Building Convention Center, Plenary Hall)
Key findings, to be presented by Dr. Ross Camidge, MD, PhD, president of Joyce Zeff in Lung Cancer Research at the University of Colorado Cancer Center and principal investigator of ALTA-1L, include:
A total of 275 patients were randomized to brigatinib (n = 137) or crizotinib (n = 138). Mean age was 59 years (brigatinib, 58, crizotinib, 60) and 55% of the patients in the trial were female (brigatinib, 50%, crizotinib, 59%). Twenty-nine percent had brain metastases at the start of the study (brigatinib, 29%, crizotinib, 30%), with comparable pre-inscription rates for SNV (central nervous system) radiotherapy. Overall, 27% of patients received prior chemotherapy in the locally advanced or metastatic setting (brigatinib, 26%, crizotinib, 27%).
At the point of data cut for the first interim analysis (February 19, 2018), in a mean follow-up period of 11 and 9.3 months in the arm of brigatinib and arm of crizotinib, respectively, 95 patients (69%) in the arm of brigatinib and 59 patients (43%) in the arm of crizotinib remained in the study treatment.
The assay reached the pre-specified threshold for superiority in the primary endpoint at the first interim analysis. With a total of 99 events, the SLI evaluated by BIRC with brigatinib was superior to crizotinib (risk ratio, 0.49 (95% confidence interval (CI), 0.33 to 0.74, log-rank p = 0.0007).
Additional efficacy results are presented in the following table:
The safety profile associated with ALUNBRIG was generally consistent with existing US prescribing information.
Adverse events emerging from treatment of any degree that occurred more frequently with brigatinib than with crizotinib by more than five percentage points were increased creatine phosphokinase in the blood (brigatinib, 39% vs. crizotinib, 15%), cough (25% vs. 16%) hypertension (23% vs 7%) and increased lipase (19% vs 12%).
Adverse events emerging from treatment of any degree that occurred in a higher incidence with crizotinib than with brigatinib in more than five percentage points were nausea (crizotinib, 56% vs brigatinib, 26%), diarrhea (55% vs 49%), constipation ( 42% vs 15%), peripheral edema (39% vs 4%), vomiting (39% vs 18%), increased alanine aminotransferase (32% vs 19%), decreased appetite (20% vs 7%), (20% vs 1%), dysgeusia (19% vs 4%) and visual impairment (16% vs 0).
Treatment-emergent Grade 3 to 5 adverse events occurred in 61% of patients in the brigatinib arm and 55% of patients in the crizotinib arm. Increased creatine phosphokinase in the blood (16%), increased lipase (13%), hypertension (10%) and increased amylase (5%) were the most common emergent adverse events of grade 3 or higher treatment for brigatinib; and for crizotinib increased alanine aminotransferase (9%), increased aspartate aminotransferase (6%) and increased lipase (5%).
Interstitial lung disease / pneumonia occurred at any time in 4% (5/136) of patients in the arm of brigatinib and 2% (3/137) in the arm of crizotinib. Interstitial lung disease / pneumonia with early onset (defined 14 days after initiation of treatment) was observed in 3% of patients in the arm of brigatinib (beginning: days 3 to 8) and was not seen in the arm of crizotinib.
About the ALTA-1L test
The ALTA-1L phase 3 trial (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 have not received prior treatment with an ALK inhibitor. Patients received ALUNBRIG at the dose of 180 mg once daily after a seven-day preparation receiving 90 mg once daily or crizotinib at the dose of 250 mg twice daily. The progression-free survival (SLP) evaluated by the Independent Independent Review Committee (BIRC) was the primary objective. Secondary objectives included objective response rate (ORT) by RECIST v1.1, intracranial ORT, intracranial SLP, overall survival (OS), safety and tolerability. A total of approximately 198 PFS events were planned in the final analysis of the primary outcome to demonstrate a minimum of six months of improvement of PFS in relation to crizotinib. The trial was designed with two pre-specified interim analyzes for the primary endpoint – one in 50% of planned SLP events and one in 75% of planned SLP events.
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 cases of lung cancer 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 Drug Administration (FDA) for patients with metastatic ALK + NSCLC who 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). FDA and Health Canada approvals for ALUNBRIG were primarily based on the Phase 2 results of the ALTA trial (acronym forThe LK in U UNG Cancer T rial of the P26113).
ALUNBRIG has received the FDA’s innovative therapy designation for the treatment of critically ill ALK + patients whose tumors are resistant to crizotinib and the orphan designation of the FDA for the treatment of ALK + NSCLC, ROS1 + CPNPC and EGFR + CPNPC.
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:
The 1/2 phase assay was designed to assess ALUNBRIG’s safety, tolerability, pharmacokinetics, and preliminary antitumor activity
The pivotal phase 2 ALTA trial investigates the efficacy and safety of ALUNBRIG in two dosing regimens in patients with locally advanced or metastatic ALK + NSCLC who progressed with crizotinib
The ALTA-1L phase 3 trial is 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
The phase 2 trial is multicenter, single arm in Japanese patients with NSCLC + ALK, focusing on patients who progressed in alectinib
The overall phase 2 trial evaluates ALUNBRIG in patients with advanced ALK + NSCLC who progressed in alectinib or ceritinib
The randomized phase 3 global trial compared the efficacy and safety of ALUNBRIG versus alectinib in participants with ALK + NSCLC who progressed on crizotinib
For additional information on brigatinib’s clinical trials, visit www.clinicaltrials.gov .
IMPORTANT SAFETY INFORMATION (USA)
WARNINGS AND PRECAUTIONS
Interstitial lung disease (IPD) / pneumonia: Severe, life-threatening, and life-threatening pulmonary adverse reactions have been reported consistent with interstitial lung disease (IPD) / ALUNBRIG pneumonia. 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 and on the previous 7 days with 90 mg once daily). Adverse reactions consistent with IPD / pneumonia occurred initially (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 aggravated respiratory symptoms (eg, dyspnoea, cough, etc.), particularly during the first week of ALUNBRIG. Discontinue use of ALUNBRIG in any patient with new or aggravated 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, resume 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. For grade 1 or 2 PID / pneumonia, resume 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. For grade 1 or 2 PID / pneumonia, resume 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.
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 the patients in general. Check blood pressure before ALUNBRIG treatment. Monitor blood pressure after 2 weeks and thereafter at least monthly during ALUNBRIG treatment. Discontinue use of ALUNBRIG for grade 3 hypertension, regardless of optimal antihypertensive therapy. After resolution or improvement to grade 1 severity, resume 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 frequently 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 medications for those known to cause bradycardia. If a concomitant medication known to cause bradycardia is identified and discontinued or the dosage adjusted, resume the use of ALUNBRIG at the same dosage, after the reduction of symptomatic bradycardia; Otherwise, reduce ALUNBRIG dosage after reduction of symptomatic bradycardia. Stop ALUNBRIG for life-threatening bradycardia if the contribution of the 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 patients in the 90 → 180 group mg. Grade 3 macular edema and cataract occurred in one patient each 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 aggravated visual symptoms of grade 2 or greater severity. After resumption of grade 2 or 3 visual impairment for grade 1 grade or initial plateau, resume ALUNBRIG at a reduced dosage..
Elevated creatine phosphokinase (CPK): In ALTA, creatine phosphokinase (CPK) elevation occurred in 27% of patients receiving ALUNBRIG in the 90 mg group and 48% 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 resolution or reinstatement to grade 1 or baseline, resume ALUNBRIG at the same dosage or at a reduced dosage.
Elevation of pancreatic enzymes: In ALTA, amylase elevation 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, resume ALUNBRIG at the same dosage or with a reduced dosage.
Hyperglycemia: In ALTA, 43% of patients receiving ALUNBRIG experienced new or aggravated 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,
Embryofetal 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. Inform 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% of the total, 3.7% in the 90 mg group, and 7.3% in the 90 → 180 mg group) and IPD / pneumonia (4.6% of the 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 urinary sepsis (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 CYP3A inhibitors. Avoid grapefruit or grapefruit juice, as this may also increase the plasma concentrations of brigatinib. If concomitant use of a strong CYP3A inhibitor is unavoidable, reduce the dosage of ALUNBRIG.
CYP3A Inducers: Avoid the concomitant use of ALUNBRIG with strong CYP3A inducers.
CYP3A Substrates: Coadministration of ALUNBRIG with substrates of CYP3A, including hormonal contraceptives, may result in decreased concentrations and loss of efficacy of CYP3A substrates.
USE IN SPECIFIC POPULATIONS
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 : Women with reproductive capacity should be advised to use effective non-hormonal contraceptives during treatment with ALUNBRIG and for at least 4 months after final dosing. Advise men living with women with reproductive capacity to use effective contraceptives during ALUNBRIG treatment and for at least 3 months after final dosing.
Infertility : ALUNBRIG can cause fertility reduction in men.
Pediatric use: The safety and efficacy 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 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.