Safety

Safety and Tolerability Studied in 219 Treated ALK+ NSCLC Patients

  • Serious adverse events occurred in 38% of patients in the 90-mg arm and 40% of patients in the 90180-mg arm. The most common serious adverse reactions were pneumonia (5.5% overall, 3.7% in the 90-mg arm, and 7.3% in the 90180-mg arm) and interstitial lung disease (ILD)/pneumonitis (4.6% overall, 1.8% in the 90-mg arm and 7.3% in the 90180-mg arm)
    • Fatal adverse reactions occurred in 3.7% of patients, consisting of pneumonia (2 patients), sudden death, dyspnea, respiratory failure, pulmonary embolism, bacterial meningitis, and urosepsis (1 patient each)
  • Most common adverse reactions (≥25% of any grade) in the 90-mg arm were nausea (33%), fatigue (29%), headache (28%), and dyspnea (27%) and in the 90180-mg arm were nausea (40%), diarrhea (38%), fatigue (36%), cough (34%), and headache (27%)
  • Median duration of treatment was 7.5 and 7.8 months in the 90-mg arm and 90180-mg arm, respectively

 

Discontinuation Rates

  • In ALTA, permanent discontinuation of ALUNBRIG® (brigatinib) due to adverse reactions occurred in 2.8% of patients in the 90-mg arm and 8.2% of patients in the 90180-mg arm
  • The most frequent adverse reactions that led to discontinuation were ILD/pneumonitis (0.9% in the 90-mg arm and 1.8% in the 90180-mg arm) and pneumonia (1.8% in the 90180-mg arm only)

 

Dose Modifications

  • 14% of patients required a dose reduction due to adverse reactions (7.3% in the 90-mg arm and 20% in the 90180-mg arm)
  • The most common adverse reaction that led to dose reduction was increased creatine phosphokinase (CPK) for both regimens (1.8% in the 90-mg arm and 4.5% in the 90180-mg arm)

 

Adverse Reactions in ≥10% (All Grades)a or ≥2% (Grades 3-4) of Patients by Dose Group in ALTA (N=219)

Adverse Reactions

90 mg once daily
(n=109)
90180 mg once daily
(n=110)
All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%)
Gastrointestinal Disorders        
Nausea 33 0.9 40 0.9
Diarrhea 19 0 38 0
Vomiting 24 1.8 23 0
Constipation 19 0.9 15 0
Abdominal painb 17 0 10 0
General Disorders and Administration Site Conditions        
Fatiguec 29 1.8 36 0
Pyrexia 14 0 6.4 0.9
Respiratory, Thoracic, and Mediastinal Disorders        
Cough 18 0 34 0
Dyspnead 27 2.8 21 1.8e
ILD/Pneumonitis 3.7 1.8 9.1 2.7
Hypoxia 0.9 0 2.7 2.7
Nervous System Disorders        
Headachef 28 0 27 0.9
Peripheral neuropathyg 13 0.9 13 1.8
Skin and Subcutaneous
Tissue Disorders
       
Rashh 15 1.8 24 3.6
Vascular Disorders        
Hypertension 11 5.5 21 6.4
Musculoskeletal and Connective Tissue Disorders        
Muscle spasms 12 0 17 0
Back pain 10 1.8 15 1.8
Myalgiai 9.2 0 15 0.9
Arthralgia 14 0.9 14 0
Pain in extremity 11 0 3.6 0.9
Metabolism and Nutrition Disorders        
Decreased appetite 22 0.9 15 0.9
Eye Disorders        
Visual disturbancej 7.3 0 10 0.9
Infections        
Pneumonia 4.6 2.8e 10 5.5e
Psychiatric Disorders        
Insomnia 11 0 7.3 0

aPer National Cancer Institute Common Terminology Criteria for Adverse Events. Version 4.0 (NCI CTCAE v4.0).
bIncludes abdominal distension, abdominal pain, and epigastric discomfort.
cIncludes asthenia and fatigue.
dIncludes dyspnea and exertional dyspnea.
eIncludes one Grade 5 event.
fIncludes headache and sinus headache.

gIncludes peripheral sensory neuropathy and paresthesia.
hIncludes acneiform dermatitis, exfoliative rash, rash, pruritic rash, and pustular rash.
iIncludes musculoskeletal pain and myalgia.
jIncludes diplopia, photophobia, blurred vision, reduced visual acuity, visual impairment, vitreous floaters, visual field defect, macular edema, and vitreous detachment.

Laboratory Abnormalities With Incidence of ≥20% (All Grades)a of Patients by Dose Group in ALTA (N=219)

Laboratory Abnormality

90 mg once daily
(n=109)
90180 mg once daily
(n=110)
All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%)
Chemistry        
Increased aspartate aminotransferase 38 0.9 65 0
Hyperglycemiab 38 3.7 49 3.6
Increased creatine phosphokinase 27 2.8 48 12
Increased lipase 21 4.6 45 5.5
Increased alanine aminotransferase 34 0 40 2.7
Increased amylase 27 3.7 39 2.7
Increased alkaline phosphatase 15 0.9 29 0.9
Decreased phosphorous 15 1.8 23 3.6
Prolonged activated partial thromboplastin time 22 1.8 20 0.9
Hematology        
Anemia 23 0.9 40 0.9
Lymphopenia 19 2.8 27 4.5

aPer NCI CTCAE v4.0.
bElevated blood insulin was also observed in both regimens.

 

ILD/Pneumonitis

  • Severe, life-threatening, and fatal pulmonary adverse reactions consistent with interstitial lung disease (ILD)/pneumonitis have occurred with ALUNBRIG
  • In ALTA, ILD/pneumonitis occurred in 3.7% of patients in the 90-mg arm and 9.1% of patients in the 90180-mg arm

 

Early in Treatment

  • In ALTA, 6.4% (14 of 219 treated patients) experienced reactions consistent with possible ILD within 9 days of initiation of ALUNBRIG (median onset was 2 days). None occurred after escalation to 180 mg, and 7 of the 14 patients were successfully re-treated with ALUNBRIG1
  • 2.7% of patients had Grade 3-4 events within the first 9 days of treatment

 

Recommendations for Management

  • Monitor for new or worsening respiratory symptoms (eg, dyspnea, cough, etc), particularly in the first week of initiating treatment with ALUNBRIG
  • Withhold ALUNBRIG in any patient with new or worsening respiratory symptoms, and promptly evaluate for ILD/pneumonitis or other causes of respiratory symptoms (eg, pulmonary embolism, tumor progression, and infectious pneumonia)
  • For Grade 1-2 adverse reactions, either resume ALUNBRIG with dose reduction as recommended 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

Reference: 1. Kim D-W, Tiseo M, Ahn M-J, et al. J Clin Oncol. 2017;35(22):2490-2498.

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