Safety and Tolerability Studied in 219 Treated ALK+ NSCLC Patients
The safety of ALUNBRIG® (brigatinib) was evaluated in 219 patients with locally advanced or metastatic ALK-positive non-small cell lung cancer who received at least 1 dose of ALUNBRIG in ALTA after experiencing disease progression on crizotinib.
- Serious adverse reactions occurred in 38% of patients in the 90-mg arm and 40% of patients in the 90→180-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 90→180-mg arm) and interstitial lung disease (ILD)/pneumonitis (4.6% overall, 1.8% in the
90-mgarm and 7.3% in the 90→180-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
90→180-mgarm 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 90→180-mg arm, respectively
- 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 90→180-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 90→180-mg arm) and pneumonia (1.8% in the 90→180-mg arm only)
- 14% of patients required a dose reduction due to adverse reactions (7.3% in the 90-mg arm and 20% in the 90→180-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 90→180-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
|90→180 mg once daily
|General Disorders and Administration Site Conditions|
|Respiratory, Thoracic and Mediastinal Disorders|
|Nervous System Disorders|
|Skin and Subcutaneous Tissue Disorders|
|Musculoskeletal and Connective Tissue Disorders|
|Pain in extremity||11||0||3.6||0.9|
|Metabolism and Nutrition Disorders|
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
|90→180 mg once daily
|Increased aspartate aminotransferase||38||0.9||65||0|
|Increased creatine phosphokinase||27||2.8||48||12|
|Increased alanine aminotransferase||34||0||40||2.7|
|Increased alkaline phosphatase||15||0.9||29||0.9|
|Prolonged activated partial thromboplastin time||22||1.8||20||0.9|
aPer NCI CTCAE v4.0.
bElevated blood insulin was also observed in both regimens.
- 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 90→180-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
- Kim DW, Tiseo M, Ahn MJ, et al. J Clin Oncol. 2017;35(22):2490-2498.