On November 28, 2018 Takeda Pharmaceutical Company Limited ( TSE: 4502 ) reported that the European Commission (EC) has granted marketing authorization for ALUNBRIG (brigatinib) as monotherapy for the treatment of adult patients with advanced non-small cell lung cancer (NSCLC), positive for anaplastic lymphoma kinase (ALK +), previously treated with crizotinib (Press release, Takeda, NOV 28, 2018, View Source [SID1234531685]). The decision is a consequence of the favorable opinion of the Committee for Medicinal Products for Human Use (CHMP) of September 20, 2018.

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"The introduction of targeted therapies has greatly improved the treatment of ALK + NSCLC, but for the approximately 70% of patients who experience progression with crizotinib with brain metastases, other therapeutic options are needed," said Enriqueta Felip, MD, PhD, chief of the Thoracic Oncology Unit of the Oncology Department of the Vall d’Hebron University Hospital in Barcelona. "The data from the ALTA trial, for the ALUNBRIG research, showed sustained efficacy results, both at the systemic and intracranial level, and a manageable safety profile. This resulted in the longest progression-free survival and longest survival reported in this scenario.

"The decision of the European Commission to approve ALUNBRIG for patients with NSCLC ALK + is a significant advance for European patients affected by this life-threatening disease," said Jesús Gómez-Navarro, MD, Vice President, Director of Oncology Clinical Research and Development at Takeda. . "This is the first time that a median progression-free survival of more than 16 months has been reported, as assessed by an independent review committee, and a median overall survival of 34 months in the post-crizotinib treatment scenario, which highlights the robustness of the HIGH trial data.

"Many people are unaware of the ALNC NSCLC and its nuances, including the fact that this type of lung cancer tends to affect people at a younger age, and that it is not associated with smoking," explained Stefania Vallone, president of Lung Cancer Europe. "These young patients are almost always in the prime of life and in the midst of raising their children, focusing on their careers and contributing to their community. The availability of new treatments to potentially extend the period without progression of the disease is very important and can not be underestimated. "

The approval of the European Commission is based on data from the global phase 2 HIGH trial, in which patients were randomly assigned to receive one of two dosing regimens of ALUNBRIG: 90 mg once a day (n = 112) or the recommended dosing regimen of 180 mg once a day, with an initial period of seven days with 90 mg once a day (n = 110). The results showed that of the patients who received the recommended dose regimen, 56% achieved an objective response rate (ORR), with a median response duration (DOR) of 15.7 months, according to the committee’s evaluation. of independent review (IRC). ALUNBRIG demonstrated a median progression-free survival (PFS) of 16.7 months, as assessed by the IRC,

The most frequent adverse reactions (≥25%) reported in patients treated with ALUNBRIG with the recommended dosage regimen of 180 mg were: increase in aspartate aminotransferase (AST), hyperglycemia, hyperinsulinemia, anemia, increase in creatine phosphokinase (CPK) , nausea, increased lipase, decreased lymphocyte count, increased alanine aminotransferase (ALT), diarrhea, increased amylase, fatigue, cough, headache, increased alkaline phosphatase, hypophosphatemia, abnormal increase in time of activated partial thromboplastin (APTT), rash, vomiting, dyspnea, hypertension, decreased red blood cell count, myalgia and peripheral neuropathy.The most frequent serious adverse reactions (≥2%) reported in patients treated with ALUNBRIG with the recommended dose regimen, in addition to the events related to the progression of the neoplasm, were: pneumonitis, pneumonia and dyspnea.

This decision of the European Commission means that ALUNBRIG has authorization for its commercialization for this indication in the 28 Member States of the European Union, and it is applicable in Norway, Liechtenstein and Iceland. For more information on the decision of the European Commission, visit the website of the European Medicines Agency: www.ema.europe.eu/ema .

About the HIGH trial
The HIGH phase 2 clinical trial ( A LK in L ung Cancer T rial of AP26113) of ALUNBRIG in adults is an ongoing two-group, open-label, multi-center trial that enrolled 222 patients with advanced or metastatic ALK + NSCLC whose disease has progressed despite treatment with crizotinib. Patients received either 90 mg of ALUNBRIG once per day (n = 112) or 180 mg once per day after an initial dose of 90 mg for seven days once per day (n = 110). The main endpoint was the confirmed objective response rate (ORR), evaluated by the researcher according to RECIST v1.1. Other key endpoints included the ORR assessed by the independent review committee (IRC), the duration of the response (DOR),

The results of the ALTA trial showed that of the patients who received the 180 mg dose regimen, 56% achieved an ORR according to the investigator’s evaluation, and 56% according to the IRC evaluation. The median of the DOR was 13.8 months according to the researcher’s evaluation, and 15.7 months according to the IRC evaluation. The median of the PFS was 15.6 months according to the researcher’s evaluation, and 16.7 months according to the IRC evaluation. In addition, of the patients with brain metastases measurable at baseline (n = 18), 67% achieved an intracranial ORR according to the IRC evaluation; the median duration of the intracranial response was 16.6 months according to the IRC evaluation. The median overall survival was 34.1 months.

Among the patients who received the 90 mg dose regimen, 46% achieved an ORR according to the investigator’s evaluation, and 51% according to the IRC evaluation. The median of the DOR was 12.0 months according to the researcher’s evaluation, and 16.4 months according to the IRC evaluation. The median of the PFS was 9.2 months according to the evaluation of both the researcher and the IRC. In addition, of the patients with brain metastases measurable at baseline (n = 26), 50% achieved an intracranial ORR according to the IRC evaluation; the median duration of the intracranial response was 9.4 months according to the evaluation of CRF. The median overall survival was 29.5 months

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 in the world, according to the World Health Organization. Genetic studies indicate that chromosomal rearrangements in the anaplastic lymphoma kinase (ALK) are key actors in a subset of patients with NSCLC. Approximately, between three and five percent of patients with metastatic NSCLC have a rearrangement in the ALK gene.

Takeda is committed to continuing research and development in the NSCLC to improve the lives of the approximately 40,000 patients diagnosed with this serious and rare form of lung cancer worldwide each year.

About ALUNBRIG (brigatinib)
ALUNBRIG is a targeted cancer 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. UU (FDA) for patients with ALK + metastatic NSCLC who experienced progression with crizotinib, or who are intolerant to it. This indication is approved according to the Accelerated Approval based on the response rate of the tumor and the duration of the response. Continued approval for this indication may be subject to verification and description of clinical benefit in a confirmatory study. In July 2018, Health Canada approved ALUNBRIG for the treatment of adult patients with ALK + metastatic NSCLC who experienced progression with an ALK inhibitor (crizotinib), or were intolerant of it. The ALUNBRIG FDA and Health Canada approvals were based primarily on the results of the HIGH phase 2 core study (A LK in L ung Cancer T rial of A P26113).

The FDA previously designated ALUNBRIG as an innovative therapy for the treatment of patients with ALK + NSCLC whose tumors are resistant to crizotinib. The FDA also provided the designation of orphan drug for the treatment of NSCLC ALK +, ROS1 + and NSCLC + NSCLC.

Brigatinib’s clinical development program further strengthens Takeda’s ongoing commitment to developing innovative therapies for people living with ALN + NSCLC worldwide and the healthcare professionals who treat them. The broad program includes the following clinical studies:

Phase 1/2 study, which was designed to evaluate the safety, tolerability, pharmacokinetics and preliminary antitumor activity of ALUNBRIG
Central phase 2 HIGH study investigating the efficacy and safety of ALUNBRIG in two dosing regimens in patients with locally advanced or metastatic ALK + NSCLC who had experienced progression with crizotinib
Phase 3, randomized, global ALTA-1L study, which evaluates the efficacy and safety of ALUNBRIG compared to crizotinib in patients with locally advanced or metastatic ALK + NSCLC who have not received prior treatment with an ALK inhibitor
Multicenter phase 2 and single group study in Japanese patients with ALK + NSCLC, concentrating on patients who have experienced progression with alectinib
Global, phase 2 and single group study evaluating ALUNBRIG in patients with ALK + NSCLC who have experienced progression with alectinib or ceritinib
A global randomized phase 3 study comparing the efficacy and safety of ALUNBRIG versus alectinib in participants with ALK + NSCLC who have experienced progression with crizotinib
For more information about brigatinib clinical trials, visit www.clinicaltrials.gov .

ALUNBRIG (brigatinib): IMPORTANT EUROPEAN SECURITY INFORMATION

SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Pulmonary adverse reactions :severe, life-threatening and fatal pulmonary adverse reactions can occur, including those with characteristics consistent with interstitial lung disease / pneumonitis. The majority of pulmonary adverse reactions were observed within the first 7 days of treatment. Grade 1-2 pulmonary adverse reactions resolved after discontinuation of treatment or dose modification. The increase in age and the shorter interval (less than 7 days) between the last dose of crizotinib and the first dose of ALUNBRIG were independently associated with a higher rate of these pulmonary adverse reactions. These factors must be taken into account when starting treatment with ALUNBRIG. Some patients experienced pneumonitis in a late phase of treatment with ALUNBRIG. Patients should be monitored for new or worsening respiratory symptoms (eg, dyspnea, cough, etc.), especially during the first week of treatment. Evidence of pneumonitis in any patient with worsening respiratory symptoms should be investigated promptly. If pneumonitis is suspected, the ALUNBRIG dose should be discontinued and the patient evaluated to rule out other causes of symptoms (eg, pulmonary embolism, tumor progression, and infectious pneumonia). The dose should be modified accordingly. Patients should be monitored for new or worsening respiratory symptoms (eg, dyspnea, cough, etc.), especially during the first week of treatment. Evidence of pneumonitis in any patient with worsening respiratory symptoms should be investigated promptly. If pneumonitis is suspected, the ALUNBRIG dose should be discontinued and the patient evaluated to rule out other causes of symptoms (eg, pulmonary embolism, tumor progression, and infectious pneumonia). The dose should be modified accordingly. Patients should be monitored for new or worsening respiratory symptoms (eg, dyspnea, cough, etc.), especially during the first week of treatment. Evidence of pneumonitis in any patient with worsening respiratory symptoms should be investigated promptly. If pneumonitis is suspected, the ALUNBRIG dose should be discontinued and the patient evaluated to rule out other causes of symptoms (eg, pulmonary embolism, tumor progression, and infectious pneumonia). The dose should be modified accordingly. Evidence of pneumonitis in any patient with worsening respiratory symptoms should be investigated promptly. If pneumonitis is suspected, the ALUNBRIG dose should be discontinued and the patient evaluated to rule out other causes of symptoms (eg, pulmonary embolism, tumor progression, and infectious pneumonia). The dose should be modified accordingly. Evidence of pneumonitis in any patient with worsening respiratory symptoms should be investigated promptly. If pneumonitis is suspected, the ALUNBRIG dose should be discontinued and the patient evaluated to rule out other causes of symptoms (eg, pulmonary embolism, tumor progression, and infectious pneumonia). The dose should be modified accordingly.

Hypertension: there have been cases of hypertension. Blood pressure should be checked regularly during treatment with ALUNBRIG. Hypertension should be treated according to the standard guidelines for controlling blood pressure. The heart rate should be checked more frequently in patients if the concomitant use of a medication known to cause bradycardia can not be avoided. For severe hypertension (≥ grade 3), ALUNBRIG should be discontinued until the hypertension has retreated to grade 1 or baseline. The dose should be modified accordingly.

Bradycardia: there have been cases of bradycardia. Caution should be exercised when ALUNBRIG is administered in combination with other agents known to cause bradycardia. The heart rate and blood pressure should be checked regularly. Treatment with ALUNBRIG should be discontinued if symptomatic bradycardia develops. Concomitant medications known to cause bradycardia should be evaluated. Once recovered, the dose should be modified accordingly. In case of life-threatening bradycardia, interrupt ALUNBRIG permanently if no concomitant medication is identified or in case of relapse. If any concomitant medication is identified, modify the dose accordingly.

Visual disorders: there have been visual disturbances with ALUNBRIG. Patients should be advised to report any visual symptoms. In case of severe, new or worsening visual symptoms, an ophthalmological evaluation and a dose reduction should be considered.

Elevation of creatine phosphokinase (CPK): cases of elevation of this enzyme have been reported. Advise patients to report any unexplained muscle pain, tenderness or weakness. Monitor CPK levels regularly during treatment. Depending on the severity of CPK elevation, stop treatment with ALUNBRIG and modify the dose accordingly.

Elevation of pancreatic enzymes : elevations of amylase and lipase have occurred. Lipase and amylase should be monitored regularly during treatment with ALUNBRIG. Based on the severity of the laboratory abnormalities, suspend ALUNBRIG and modify the dose accordingly.

Hepatotoxicity : Elevations of liver enzymes (aspartate aminotransferase, alanine aminotransferase) and bilirubin levels have occurred. Liver function should be evaluated, including AST, ALT and total bilirubin, before starting treatment with ALUNBRIG and, subsequently, every 2 weeks during the first 3 months of treatment. Thereafter, monitoring must be done periodically. Based on the severity of the laboratory abnormalities, suspend ALUNBRIG and modify the dose accordingly.

Hyperglycaemia : Elevations of serum glucose have occurred. Fasting serum glucose should be evaluated before starting treatment with ALUNBRIG and periodically thereafter. Antihyperglycemic treatment should be initiated or optimized as necessary. If adequate control of hyperglycemia can not be achieved with optimal medical treatment, discontinue ALUNBRIG until adequate control of hyperglycemia is achieved; after recovery, dose reduction can be considered or ALUNBRIG can be interrupted permanently.

Drug Interactions : The concomitant use of ALUNBRIG with potent CYP3A inhibitors should be avoided. If the concomitant use of potent inhibitors of CYP3A can not be avoided, reduce the dose of ALUNBRIG from 180 mg to 90 mg, or from 90 mg to 60 mg. After stopping the potent inhibitor of CYP3A, treatment with ALUNBRIG should be resumed with the dose that had been tolerated before initiating the potent inhibitor of CYP3A. The concomitant use of ALUNBRIG with potent and moderate inducers of CYP3A should be avoided.

Fertility : Women of childbearing age should be advised to use effective non-hormonal contraceptives during treatment with ALUNBRIG and for at least 4 months after the final dose. Men with female partners of childbearing age should be advised to use effective contraceptives during treatment and for at least 3 months after the last dose of ALUNBRIG.

Lactose : ALUNBRIG contains lactose monohydrate. Patients suffering from rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

ADVERSE EFFECTS
The most frequent adverse reactions (≥25%) reported in patients treated with ALUNBRIG in the recommended dose regimen were: increase in AST, hyperglycemia, hyperinsulinemia, anemia, increase in CPK, nausea, increase in lipase, decrease in lymphocyte count, increased ALT, diarrhea, increased amylase, fatigue, cough, headache, increased alkaline phosphatase, hypophosphatemia, increased APTT, rash, vomiting, dyspnea, hypertension, decreased blood cell count whites, myalgias and peripheral neuropathy.

The most frequent serious adverse reactions (≥2%) reported in patients treated with ALUNBRIG in the recommended dosage regimen, in addition to the events related to the progression of the neoplasm, were: pneumonitis, pneumonia and dyspnea.

SPECIAL POPULATIONS

Elderly patients: Limited data on the safety and efficacy of ALUNBRIG in patients aged 65 years and older suggest that dose adjustment is not necessary in this patient population. There is no data available on patients older than 85 years of age.

Hepatic insufficiency: it is not necessary to adjust the dose of ALUNBRIG in patients with mild hepatic impairment (Child-Pugh class A) or moderate hepatic insufficiency (Child-Pugh class B). For patients with severe hepatic impairment (Child-Pugh class C), a reduced initial dose of 60 mg once a day for the first 7 days, then 120 mg once a day is recommended.

Renal insufficiency: it is not necessary to adjust the dose of ALUNBRIG in patients with mild or moderate renal insufficiency (estimated glomerular filtration rate (eGFR) ≥30 ml / min). For patients with severe renal impairment (eGFR <30 ml / min), a reduced initial dose of 60 mg once a day for the first 7 days is recommended, then 90 mg once a day. Patients with severe renal impairment should be monitored closely for respiratory symptoms, new or worsening, and may indicate interstitial lung disease / pneumonitis (eg, dyspnea, cough, etc.), especially during the first week of treatment .

Pediatric population: the safety and efficacy of ALUNBRIG in patients under 18 years of age have not been established. No data available.

IMPORTANT SAFETY INFORMATION (US)
WARNINGS AND PRECAUTIONS

Interstitial lung disease (PID) / pneumonitis: there have been serious, life-threatening or fatal pulmonary adverse reactions that are congruent with interstitial lung disease (ILD) / pneumonitis with the use of ALUNBRIG. In the HIGH (HIGH) trial, there were cases of PID / pneumonitis in 3.7% of patients in the group with 90 mg (90 mg once a day) and in 9.1% of patients in the group with 90 → 180 mg (180 mg once a day with an initial period of seven days with a dose of 90 mg once a day). Adverse reactions consistent with a possible PID / pneumonitis occurred at an early stage (within 9 days after the start of ALUNBRIG use, the median to onset was 2 days) in 6.4% of patients, with 2.7% of reactions grade 3 to 4. Control the worsening of respiratory symptoms or the appearance of new symptoms (eg dyspnoea, cough, etc.), especially during the first week of treatment with ALUNBRIG. Suspend ALUNBRIG if the patient presents worsening of respiratory symptoms or new onset and immediately check for PID / pneumonitis or other causes of respiratory symptoms (eg, pulmonary embolism, tumor progression, and infectious pneumonia). For PID / Grade 1 or 2 pneumonitis, resume ALUNBRIG with a dose reduction after recovery or permanently suspend ALUNBRIG. Suspend ALUNBRIG definitely if PPE / grade 3 or 4 pneumonitis occurs or if PID / pneumonitis grade 1 or 2 reappears. eg, dyspnea, cough, etc.), especially during the first week of treatment with ALUNBRIG. Suspend ALUNBRIG if the patient presents worsening of respiratory symptoms or new onset and immediately check for PID / pneumonitis or other causes of respiratory symptoms (eg, pulmonary embolism, tumor progression, and infectious pneumonia). For PID / Grade 1 or 2 pneumonitis, resume ALUNBRIG with a dose reduction after recovery or permanently suspend ALUNBRIG. Suspend ALUNBRIG definitely if PPE / grade 3 or 4 pneumonitis occurs or if PID / pneumonitis grade 1 or 2 reappears. eg, dyspnea, cough, etc.), especially during the first week of treatment with ALUNBRIG. Suspend ALUNBRIG if the patient presents worsening of respiratory symptoms or new onset and immediately check for PID / pneumonitis or other causes of respiratory symptoms (eg, pulmonary embolism, tumor progression, and infectious pneumonia). For PID / Grade 1 or 2 pneumonitis, resume ALUNBRIG with a dose reduction after recovery or permanently suspend ALUNBRIG. Suspend ALUNBRIG definitely if PPE / grade 3 or 4 pneumonitis occurs or if PID / pneumonitis grade 1 or 2 reappears. Suspend ALUNBRIG if the patient presents worsening of respiratory symptoms or new onset and immediately check for PID / pneumonitis or other causes of respiratory symptoms (eg, pulmonary embolism, tumor progression, and infectious pneumonia). For PID / Grade 1 or 2 pneumonitis, resume ALUNBRIG with a dose reduction after recovery or permanently suspend ALUNBRIG. Suspend ALUNBRIG definitely if PPE / grade 3 or 4 pneumonitis occurs or if PID / pneumonitis grade 1 or 2 reappears. Suspend ALUNBRIG if the patient presents worsening of respiratory symptoms or new onset and immediately check for PID / pneumonitis or other causes of respiratory symptoms (eg, pulmonary embolism, tumor progression, and infectious pneumonia). For PID / Grade 1 or 2 pneumonitis, resume ALUNBRIG with a dose reduction after recovery or permanently suspend ALUNBRIG. Suspend ALUNBRIG definitely if PPE / grade 3 or 4 pneumonitis occurs or if PID / pneumonitis grade 1 or 2 reappears. tumor progression and infectious pneumonia). For PID / Grade 1 or 2 pneumonitis, resume ALUNBRIG with a dose reduction after recovery or permanently suspend ALUNBRIG. Suspend ALUNBRIG definitely if PPE / grade 3 or 4 pneumonitis occurs or if PID / pneumonitis grade 1 or 2 reappears. tumor progression and infectious pneumonia). For PID / Grade 1 or 2 pneumonitis, resume ALUNBRIG with a dose reduction after recovery or permanently suspend ALUNBRIG. Suspend ALUNBRIG definitely if PPE / grade 3 or 4 pneumonitis occurs or if PID / pneumonitis grade 1 or 2 reappears.

Hypertension: In the HIGH trial, cases of hypertension were reported in 11% of patients in the group receiving 90 mg of ALUNBRIG and in 21% of patients in the group with 90 → 180 mg. Grade 3 hypertension occurred in 5.9% of the total patients. Control blood pressure before treatment with ALUNBRIG. Keep track of blood pressure after 2 weeks and at least once a month during treatment with ALUNBRIG. Suspend ALUNBRIG if there is hypertension of grade 3 although there are optimal antihypertensive treatments. Once the situation is resolved or if it improves to grade 1 intensity, resume ALUNBRIG with a reduced dose.

Bradycardia: Bradycardia may occur due to the use of ALUNBRIG. In the ALTA trial, heart rates lower than 50 beats per minute (bpm) were detected in 5.7% of patients in the 90 mg group and in 7.6% of patients in the 90 → 180 mg group. Grade 2 bradycardia occurred in 1 (0.9%) patient in the 90 mg group. Check heart rate and blood pressure during treatment with ALUNBRIG. Control more frequently those patients who use concomitant medications that cause bradycardia and can not stop them. If symptomatic bradycardia develops, discontinue ALUNBRIG and review concomitant medications for those that cause bradycardia. If a concomitant medication that causes bradycardia is identified, if the dose is interrupted or adjusted, resume the use of ALUNBRIG in the same dose once the symptomatic bradycardia has resolved; otherwise, reduce the dose of ALUNBRIG once the symptomatic bradycardia has resolved. Suspend the use of ALUNBRIG in case of life-threatening bradycardia if concomitant medications are not identified that contribute to this.

Visual disorder: in the ALTA trial, adverse reactions leading to visual disturbances, including blurred vision, diplopia and diminished visual acuity, were reported in 7.3% of patients treated with ALUNBRIG in the 90 mg group and in 10% of the patients in the group with 90 → 180 mg. One patient with cataracts and another with grade 3 macular edema was detected in the group with 90 → 180 mg. Advise patients to report any symptoms of vision. Suspend ALUNBRIG and obtain an ophthalmological evaluation in patients with new or worsening vision symptoms with grade 2 or greater severity. Once the patient has recovered from visual disturbances of grade 2 or 3 and has returned to baseline or grade 1, resume the use of ALUNBRIG in a reduced dose. Suspend treatment with ALUNBRIG definitely if visual disturbances of grade 4 occur.

Elevation of creatine phosphokinase (CPK): in the ALTA trial, creatine phosphokinase (CPK) increased in 27% of patients receiving ALUNBRIG in the 90 mg group and 48% of the patients in the 90 mg → 180 mg group. The incidence of grade 3-4 CPK increase was 2.8% in the 90 mg group and 12% in the 90 → 180 mg group. A reduction in dose was made due to the increase in CPK in 1.8% of patients in the 90 mg group and in 4.5% of patients in the group with 90 → 180 mg. Advise patients to report if they have muscle pain, hypersensitivity or weakness without explanation. Control CPK levels during treatment with ALUNBRIG. Suspend ALUNBRIG if there is an increase in CPK grade 3 or 4.

Increase in pancreatic enzymes: in the ALTA trial, the increase in amylase was detected in 27% of the patients in the 90 mg group and in 39% of the patients in the 90 → 180 mg group. Lipase was increased in 21% of patients in the 90 mg group and in 45% of patients in the 90 → 180 mg group. Grade 3 or 4 amylase increased in 3.7% of patients in the 90 mg group and in 2.7% of patients in the 90 → 180 mg group. Elevation of grade 3 or 4 lipase was present in 4.6% of the patients in the 90 mg group and in 5.5% of the patients in the 90 → 180 mg group. Control lipase and amylase during treatment with ALUNBRIG..

Hyperglycemia: in the ALTA trial, 43% of patients who received ALUNBRIG presented hyperglycemia for the first time or worsening of previous hyperglycemia. According to the laboratory evaluation of fasting glucose levels, grade 3 hyperglycemia occurred in 3.7% of patients. Two of the 20 patients (10%) with diabetes or glucose intolerance at the beginning of the treatment initiated insulin treatment while receiving ALUNBRIG. Evaluate the fasting serum glucose level before beginning treatment with ALUNBRIG and control it periodically. Start or improve medication against hyperglycemia as needed. If proper control of hyperglycemia can not be obtained through optimal medical treatment,

Embryo-Fetal Toxicity: Based on its mechanism of action and the results obtained with animals, ALUNBRIG can cause fetal harm if administered to pregnant women. There are no clinical data on the use of ALUNBRIG in pregnant women. Inform pregnant women about the potential harm to the fetus. Counsel women with reproductive capacity who use effective non-hormonal contraceptives during treatment with ALUNBRIG and up to 4 months after taking the last dose. Counsel men with couples with reproductive capacity who use contraceptives during treatment and up to 3 months after taking the last dose of ALUNBRIG .

ADVERSE REACTIONS

Adverse reactions occurred in 38% of patients in the 90 mg group and in 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 PID / pneumonitis (4.6% overall, 1.8% in the group with 90 mg and 7.3% in the group with 90 → 180 mg). Fatal adverse reactions occurred in 3.7% of patients. These were: pneumonia (2 patients), sudden death, dyspnea, respiratory insufficiency, pulmonary embolism, bacterial meningitis and urosepsis (1 patient with each).

The most common adverse reactions (≥25%) in the 90 mg group were nausea (33%), fatigue (29%), headache (28%) and dyspnea (27%); in the group with 90 → 180 mg the most common reactions were nausea (40%), diarrhea (38%), fatigue (36%), cough (34%) and headache (27%).

DRUG INTERACTIONS

CYP3A inhibitors : avoid the concomitant use of ALUNBRIG with potent inhibitors of CYP3A. Avoid the consumption of grapefruit or grapefruit juice as this may increase the concentrations of brigatinib in plasma. If the concomitant use of ALUNBRIG with potent inhibitors of CYP3A can not be avoided, reduce the dose of ALUNBRIG.

Inducers of CYP3A : avoid the concomitant use of ALUNBRIG with potent inducers of CYP3A.

CYP3A substrates: the administration of ALUNBRIG together with substrates of CYP3A, including hormonal contraceptives, may cause a decrease in the concentration and loss of efficacy of CYP3A substrates.

USE IN SPECIFIC POPULATIONS

Pregnancy: ALUNBRIG can cause fetal harm. Inform women with reproductive capacity about possible risks to the fetus.

Lactation: there is no data on the secretion of brigatinib in human milk or its effects on the infant or the production of breast milk. Because of possible adverse reactions in breastfed infants, women are advised not to breastfeed during treatment with ALUNBRIG.

Women and men with reproductive capacity:

Contraception : advise women with reproductive capacity to use effective non-hormonal contraceptives during treatment with ALUNBRIG and at least 4 months after taking the last dose. Advise men with couples with reproductive capacity to use contraceptives during treatment and at least 3 months after taking the last dose of ALUNBRIG.

Infertility : ALUNBRIG can cause reduction of male fertility.

Pediatric use: the safety and efficacy of ALUNBRIG in pediatric patients have not been determined.

Geriatric use: the clinical studies of ALUNBRIG did not include a sufficient number of patients from 65 years of age to determine if they respond differently to younger patients. Of the 222 patients in ALTA, 19.4% were between 65 and 74 years old, and 4.1% were 75 years or older. No clinically relevant differences in safety or efficacy were observed between patients ≥65 and younger patients.

Hepatic or renal impairment: dose adjustment is not recommended in patients with mild hepatic impairment or with mild or moderate renal impairment. The safety of ALUNBRIG has not been studied in patients with moderate or severe hepatic impairment or with severe renal insufficiency.