On October 23, 2018 Takeda Pharmaceutical Company Limited ( TSE: 4502 ) reported that Phase 3 ALTA-1L ( A LK in L ung Cancer Trial of Brig A tinib in 1 st L ine, Brig A tinib first-line treatment of lung cancer in the ALK trial of intracranial efficacy data showed anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC) Among patients, ALUNBRIG (brigatinib) had better intracranial progression-free survival (PFS) and intracranial objective response rate (ORR) than crizotinib (Press release, Takeda, OCT 23, 2018, View Source [SID1234530062]). The above secondary endpoint data will be presented at the 2018 Conference of the European Congress of Oncology (ESMO) (Free ESMO Whitepaper) in Munich, Germany on October 19th (Friday) at 2:00 pm. These results further support ALUNBRIG as a promising therapeutic for ALK+ locally advanced or metastatic NSCLC adult patients who have not previously used ALK inhibitors. ALUNBRIG is currently not approved for first-line treatment of advanced ALK+ NSCLC.
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Royal Marsden Hospital Oncologist Sanjay Popat, PhD, FRCP said: "ALK+ NSCLC often spreads to the brain, so having a choice that clearly demonstrates both brain and body effectiveness is critical for doctors and their patients. The ALTA-1L trial showed that brigitinib treatment is significantly superior to crizotinib in delaying the progression of brain disease, and we look forward to sharing this clinical evidence with the medical community at ESMO (Free ESMO Whitepaper)."
The first interim analysis of the ALTA-1L trial showed that the intracranial PFS of ALUNBRIG was significantly better than crizotinib, and the risk ratio of intention to treat (ITT) population [HR]: 0.42, 95% confidence interval [CI]: 0.24−0.70; Log-rank P = 0.0006, HR with baseline brain metastasis: 0.27, 95% CI: 0.13−0.54; log-rank P <0.0001. In the population with brain metastases at baseline, the risk of intracranial progression or death in ALUNBRIG decreased by 73%. As of this first interim analysis, the timing of intracranial PFS analysis in patients without baseline brain metastasis is not yet mature.
The results also showed that the intracranial ORR of the ALUNBRIG treatment group was superior to crizotinib. Patients with measurable baseline brain metastases obtained a confirmed intracranial OR rate of 78% in the ALUNBRIG group and 29% in the crizotinib group. Patients with unrecognized baseline brain metastases obtained a confirmed intracranial OR rate of 67% in the ALUNBRIG group and 17% in the crizotinib group.
In addition, ALUNBRIG simultaneously delayed central nervous system (CNS) progression (without previous systemic progression) and systemic progression (without previous CNS progression), significantly better than crizotinib. Baseline factors associated with CNS, such as the proportion of patients with brain metastases at baseline, the average number of brain metastases, previous brain radiation therapy, and the type of patients included, the proportion of patients in both groups was balanced. The ALUNBRIG security in the ALTA-1L trial is generally consistent with the existing US version of the prescribing information.
David Kerstein, MD, global clinical director and clinical lineup strategy director for Brigatinib, said: "CNS lesions are a heavy burden for ALK+ NSCLC patients. The additional intracranial efficacy results from the ALTA-1L trial are based on previous reports of ALUNBRIG. The activity of crizotinib in patients with brain metastases highlights Takeda’s commitment to research, which aims to improve outcomes in patients with this serious disease."
The results of the above data were recently reported during the 19th World Congress of Lung Cancer Conference (WCLC) President of the International Society for the Study of Lung Cancer (IASLC). The results showed that the blinded independent review committee of the ALUNBRIG treatment group evaluated PFS better than crosazole. Tinidine, which is equivalent to a 51% lower risk of disease progression or death (HR: 0.49, 95% CI: 0.33−0.74); log-rank P = 0.0007).
The incidence of adverse events in the 3 to 5 degree treatment was 61% in the brigitinib group and 55% in the crizotinib group. The most common adverse events occurred in 3 or more degrees of treatment, brigitinib group: elevated creatine phosphokinase (16%), elevated lipase (13%), hypertension (10%), amylase High (5%); crizotinib group: alanine aminotransferase increased (9%), aspartate aminotransferase increased (6%), lipase increased (5%).
About the ALTA-1L test, the
application of ALUNBRIG in the third phase of ALTA-1L ( A LK in L ung Cancer T rial of Brig A tinib in 1 st L ine, Brig A tinib first-line treatment of ALK in lung cancer test) is ongoing. A global, multicenter, open, randomized, controlled trial enrolled 275 patients with locally advanced or metastatic ALK+ NSCLC who had not previously used ALK inhibitors. The patient received ALUNBRIG 180 mg once daily (7 days introduction period 90 mg once daily) or crizotinib 250 mg twice daily. The primary endpoint was progression-free survival (PFS) assessed by the blind independent review board (BIRC). Secondary endpoints included objective response rate (ORR) (according to RECIST v1.1), intracranial ORR, intracranial PFS, overall survival (OS), safety, and tolerability. As planned, PFS should achieve a minimum of 6 months over crizotinib, and the final endpoint analysis would require approximately 198 PFS events. The trial presupposes two primary endpoint interim analyses, one in the planned PFS event reaching approximately 50%, and the other in the planned PFS event reaching approximately 75%.
ABOUT ALK+ NSCLC
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, which accounts for about 85% of the world’s approximately 1.8 million newly diagnosed lung cancer cases each year, according to the World Health Organization. Genetic studies have shown that chromosomal recombination of anaplastic lymphoma kinase (ALK) is a key driver in a subset of NSCLC patients. Approximately 3 to 5% of patients with metastatic NSCLC have ALK gene rearrangements.
Takeda is committed to continuous research and development in the field of NSCLC to improve the lives of patients. About 40,000 patients worldwide are diagnosed with this serious and rare type of lung cancer every year.
About ALUNBRIG (brigatinib)
ALUNBRIG ALUNBRIG is a targeted anticancer drug discovered by ARIAD Pharmaceuticals, Inc., which was acquired by Takeda in February 2017. In April 2017, ALUNBRIG was recently approved by the US Food and Drug Administration (FDA) for the treatment of ALK+ metastatic NSCLC that progressed during crizotinib administration or was unable to tolerate crizotinib. The basis for the accelerated approval of this indication is the rate of tumor remission and duration of remission. The continued approval of this indication is subject to a confirmatory trial to validate and describe the clinical benefits. In July 2018, Health Canada approved ALUNBRIG for the treatment of ALK+metastatic NSCLC adult patients who progressed or were intolerant during the administration of the ALK inhibitor (cizotinib). Mainly based on FDA approved by Health Canada and is pivotal ALUNBRIG 2 ALTA ( A LK in L UNG Cancer T Rial of A P26113, A P26113 lung clinical trials A LK) test results.
ALUNBRIG has received FDA breakthrough drug certification for the treatment of crizotinib-resistant ALK+ NSCLC patients, which is also approved by the FDA orphan drug for the treatment of ALK+ NSCLC, ROS1+ and EGFR+ NSCLC.
The brigatinib clinical development program further strengthens Takeda’s long-standing commitment to developing innovative therapeutics for ALK+ NSCLC patients worldwide and treating their healthcare professionals. This comprehensive program includes the following clinical trials:
Phase 1/2 trial to assess the safety, tolerability, pharmacokinetics, and initial antitumor activity of ALUNBRIG
A phase 2 pivotal ALTA trial to evaluate the efficacy and safety of the ALUNBRIG two-dose regimen in patients with ALK+ locally advanced or metastatic NSCLC who progressed during crizotinib administration
Phase 3 ALTA-1L global randomized trial comparing the efficacy and safety of ALUNBRIG with crizotinib in patients with ALK+ locally advanced or metastatic NSCLC who have not previously used ALK inhibitors
A two-stage, single-group, multicenter trial of Japanese ALK+ NSCLC patients with a focus on patients who progressed during the use of alectinib
Phase 2 global single-group trial to evaluate ALUNBRIG for advanced ALK+ NSCLC patients who progressed during the use of alectinib or ceritinib
Phase 3 global randomized trial comparing the efficacy and safety of ALUNBRIG and alectinib in patients with ALK+ NSCLC who progressed during crizotinib administration
For further information on brigitinib clinical trials, please visit www.clinicaltrials.gov .
Important safety information (US)
Warnings and precautions
Interstitial lung disease (ILD)/interstitial inflammation: ALUNBRIG can cause severe, life-threatening and lethal pulmonary adverse events consistent with interstitial lung disease (ILD)/pulmonary interstitial inflammation. In the ALTA (ALTA) trial, the incidence of ILD/pulmonary interstitial inflammation was 3.7% in the 90 mg group (9 mg once daily) and 90 to 180 mg in the group (180 mg once daily, 7 days in the introduction period of 90 mg). Once a day) is 9.1%. 6.4% of patients had an adverse reaction with ILD/pulmonary interstitial inflammation in the early stage (within 9 days after ALUNBRIG was activated; median onset within 2 days), and 2.7% showed a 3 to 4 degree response. New or worsening of respiratory symptoms (eg, difficulty breathing, coughing, etc.) should be monitored, especially during the first week of ALUNBRIG activation. Once patients have new or worsening respiratory symptoms, ALUNBRIG should be suspended and other causes of ILD/pulmonary interstitial or respiratory symptoms (eg, pulmonary embolism, tumor progression, and infectious pneumonia) should be assessed immediately. For 1 or 2 degrees of ILD/Pulmonary Interstitial, you can restart ALUNBRIG or permanently disable ALUNBRIG after returning to baseline. For 3 or 4 degrees ILD/pulmonary interstitial inflammation, or 1 or 2 degrees of ILD/pulmonary interstitial recurrence, ALUNBRIG should be permanently discontinued.
Hypertension: In the ALTA trial, the reported rate of hypertension was 11% in the ALUNBRIG 90 mg group and 21% in the 90→180 mg group. Overall, 5.9% of patients developed 3 degrees of hypertension. Blood pressure should be controlled before ALUNBRIG treatment. Blood pressure should be monitored after 2 weeks of ALUNBRIG treatment, at least once a month. For 3 degrees of hypertension, ALUNBRIG should be suspended even if the best antihypertensive medication is taken. After the relief of hypertension, or the severity is improved to 1 degree, ALUNBRIG can be restarted in a reduced amount. For the recurrence of 4 degrees of hypertension or 3 degrees of hypertension, consider permanently discontinuing ALUNBRIG treatment. ALUNBRIG should be used with caution in combination with antihypertensive drugs that cause bradycardia.
Bradycardia: ALUNBRIG can cause bradycardia. In the ALTA trial, heart rate was less than 50 hops per minute (bpm), 5.7% in the 90 mg group, and 7.6% in the 90→180 mg group. One patient (0.9%) in the 90 mg group developed a 2 degree bradycardia. Heart rate and blood pressure should be monitored during ALUNBRIG treatment. If it is unavoidable to combine drugs known to cause bradycardia, the frequency of monitoring should be increased. For symptomatic bradycardia, ALUNBRIG should be suspended and checked for any combination of drugs known to cause bradycardia. If a combination of drugs known to cause bradycardia is found and the dose has been discontinued or adjusted, ALUNBRIG may be restarted at the original dose after bradycardia relief; otherwise, ALUNBRIG dose should be reduced after symptomatic bradycardia relief . For life-threatening bradycardia, ALUNBRIG should be discontinued if no comorbid combination is found.
Visual impairment: In the ALTA trial, the rate of adverse reactions (including blurred vision, diplopia, and visual acuity) caused by visual impairment was 7.3% in the ALUNBRIG 90 mg treatment group and 10% in the 90→180 mg group. 3 degree macular edema and cataract occurred in 1 case in each group of 90→180 mg. Patients should be informed to report any visual symptoms. If the patient has a new or worsened visual condition of 2 degrees or more, ALUNBRIG should be suspended and an ophthalmologic assessment should be performed. If the 2 or 3 degree visual impairment returns to 1 degree or the baseline severity, ALUNBRIG can be restarted in a reduced amount. For 4 degree visual impairment, ALUNBRIG should be permanently disabled.
Increase in creatine phosphokinase (CPK): In the ALTA trial, elevated creatine phosphokinase (CPK) was 27% in the ALUNBRIG 90 mg treatment group and 48% in the 90→180 mg group. The incidence of CPK increased by 3-4 degrees, 2.8% in the 90 mg group and 12% in the 90→180 mg group. The decrease in the amount of CPK was 1.8% in the 90 mg group and 4.5% in the 90→180 mg group. Patients should be informed to report any unexplained muscle pain, tenderness or weakness. CPK levels should be monitored during ALUNBRIG treatment. For a 3 or 4 degree CPK rise, ALUNBRIG should be suspended. To be relieved or restored to 1 degree or baseline, ALUNBRIG can be restarted at the original dose or decrement.
Increased pancreatic enzyme: In the ALTA test, amylase increased by 27% in the 90 mg group and 39% in the 90→180 mg group. The increase in lipase was 21% in the 90 mg group and 45% in the 90→180 mg group. The increase in amylase at 3 or 4 degrees was 3.7% in the 90 mg group and 2.7% in the 90→180 mg group. Those with elevated 3 or 4 degrees of lipase were 4.6% in the 90 mg group and 5.5% in the 90→180 mg group. Lipase and amylase should be monitored during ALUNBRIG treatment. For 3 or 4 degrees of pancreatic enzyme elevation, ALUNBRIG should be suspended. To be relieved or restored to 1 degree or baseline, ALUNBRIG can be restarted at the original dose or decrement.
Hyperglycemia: In the ALTA trial, 43% of patients who received ALUNBRIG developed new or worsening hyperglycemia. 3.7% of patients developed 3-degree hyperglycemia (laboratory assessment based on fasting blood glucose levels). Of the 20 patients with diabetes or glucose intolerance at baseline, 2 (10%) required insulin to be activated during ALUNBRIG. Fasting blood glucose should be assessed before ALUNBRIG is enabled and should be monitored periodically. Enable or adjust hypoglycemic agents as necessary. If the optimal drug treatment does not adequately control blood glucose, ALUNBRIG should be suspended until the blood glucose is fully controlled. ALUNBRIG reduction or permanent withdrawal may also be considered.
Embryo fetal toxicity: According to its mechanism of action and animal studies, pregnant women taking ALUNBRIG can cause fetal damage. Lack of clinical data on the use of ALUNBRIG in pregnant women. The pregnant woman should be informed of the potential risk of the drug to the fetus. Women of childbearing age should be informed of effective non-hormonal contraception during ALUNBRIG treatment and at least 4 months after the last dose. Men with a female partner of childbearing age should be informed of effective contraception during treatment and at least 3 months after the last dose.
Adverse reactions
The incidence of serious adverse reactions was 38% in the 90 mg group and 40% in the 90→180 mg group. The most common serious adverse reactions were pneumonia (65% overall, 3.7% in the 90 mg group, 7.3% in the 90→180 mg group) and ILD/Pulmonary Interstitial (the overall incidence was 4.6%, 90 mg). The group incidence rate was 1.8%, and the 90→180 mg group was 7.3%). 3.7% of patients had fatal adverse reactions, including pneumonia (2 cases), sudden death, dyspnea, respiratory failure, pulmonary embolism, bacterial meningitis, and urinary sepsis (1 case each).
The most common (≥25%) adverse reactions, 90 mg were nausea (33%), fatigue (29%), headache (28%), and dyspnea (27%), and 90→180 mg was nausea (40%) Diarrhea (38%), fatigue (36%), cough (34%) and headache (27%).
medicine interactions
CYP3A inhibitors : ALUNBRIG should be avoided in combination with potent CYP3A inhibitors. Grapefruit or grapefruit juice can also increase the plasma concentration of brigitinib and should be avoided. If it cannot be avoided in combination with a potent CYP3A inhibitor, ALUNBRIG should be reduced.
CYP3A inducer : ALUNBRIG should be avoided in combination with a potent CYP3A inducer.
CYP3A Substrate: The combination of ALUNBRIG and CYP3A substrate (including hormonal contraceptives) can cause a decrease in the concentration and failure of the CYP3A substrate.
Special population medication
Pregnant women: ALUNBRIG can cause fetal damage. The potential risk of the drug to the fetus should be informed to women of childbearing age.
Lactation: No data on the effect of brigitinib on breast milk secretion or on breast-fed infants or breast milk production. Breastfeeding women are advised not to breastfeed during ALUNBRIG treatment due to potential adverse effects in breastfed infants.
Men and women of childbearing age:
Contraception : Women of childbearing age should be informed of effective non-hormonal contraception during ALUNBRIG treatment and at least 4 months after the last dose.
Infertility : ALUNBRIG can cause male fertility to decline.
Pediatric Use: The safety and efficacy of ALUNBRIG in children is not established.
Geriatric Use: The ALUNBRIG clinical study did not include a sufficient number of patients aged 65 years and older to determine if their remission differed from that of younger patients. Of the 222 patients with ALTA, 19.4% were between 65-74 years old and 4.1% were 75 years or older. There were no clinically significant differences in the safety or efficacy of patients ≥65 years of age and younger patients.
Hepatic or renal dysfunction: Patients with mild liver damage or mild or moderate renal impairment are not recommended to adjust the dose. The safety of ALUNBRIG in patients with moderate or severe liver damage or severe renal impairment has not been studied.