The following adverse reactions are discussed in greater detail in other sections of the labeling:
- Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
- Interstitial Lung Disease/Pneumonitis [see WARNINGS AND PRECAUTIONS]
- QT Interval Prolongation [see WARNINGS AND PRECAUTIONS]
- Bradycardia [see WARNINGS AND PRECAUTIONS]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Safety evaluation of XALKORI is based on more than 1200 patients with ALK-positive metastatic NSCLC who received XALKORI as monotherapy at a starting oral dose of 250 mg twice daily continuously.
The most common adverse reactions ( ≥ 25%) of XALKORI are vision disorder, nausea, diarrhea, vomiting, constipation, edema, elevated transaminases, and fatigue.
ALK-Positive Metastatic NSCLC-Study 1
The data in Table 3 are derived from 343 patients with ALK-positive metastatic NSCLC enrolled in a randomized, multicenter, active-controlled, open-label trial (Study 1). Patients in the XALKORI arm (n=172) received XALKORI 250 mg orally twice daily until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit. A total of 171 patients in the chemotherapy arm received pemetrexed 500 mg/m² (n=99) or docetaxel 75 mg/m² (n=72) by intravenous infusion every three weeks until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit. Patients in the chemotherapy arm received pemetrexed unless they had received pemetrexed as part of first-line or maintenance treatment.
The median duration of study treatment was 7.1 months for patients who received XALKORI and 2.8 months for patients who received chemotherapy. Across the 347 patients who were randomized to study treatment (343 received at least one dose of study treatment), the median age was 50 years; 84% of patients in the XALKORI arm and 87% of patients in the chemotherapy arm were younger than 65 years. A total of 57% of patients on XALKORI and 55% of chemotherapy patients were female. Forty-six percent (46%) of XALKORI-treated and 45% of chemotherapy-treated patients were from Asia.
Serious adverse reactions were reported in 64 patients (37.2%) treated with XALKORI and 40 patients (23.4%) in the chemotherapy arm. The most frequent serious adverse reactions reported in patients treated with XALKORI were pneumonia (4.1%), pulmonary embolism (3.5%), dyspnea (2.3%), and interstitial lung disease (ILD; 2.9%). Fatal adverse reactions in XALKORI-treated patients in Study 1 occurred in 9 (5%) patients, consisting of: acute respiratory distress syndrome, arrhythmia, dyspnea, pneumonia, pneumonitis, pulmonary embolism, ILD, respiratory failure, and sepsis.
Dose reductions due to adverse reactions were required in 16% of XALKORI-treated patients. The most frequent adverse reactions that led to dose reduction in the patients treated with XALKORI were alanine aminotransferase (ALT) elevation (7.6%) including some patients with concurrent aspartate aminotransferase (AST) elevation, QTc prolongation (2.9%), and neutropenia (2.3%).
Discontinuation of therapy in XALKORI-treated patients for adverse reactions was 17.0%. The most frequent adverse reactions that led to discontinuation in XALKORI-treated patients were ILD (1.7%), ALT and AST elevation (1.2%), dyspnea (1.2%), and pulmonary embolism (1.2%). Tables 3 and 4 summarize common Adverse Reactions and Laboratory Abnormalities in XALKORI-treated patients.
Table 3: Adverse Reactions Reported at a Higher Incidence ( ≥ 5% Higher for All Grades or ≥ 2% Higher for Grades 3/4) with XALKORI than Chemotherapy in Study 1
|Chemotherapy (Pemetrexed or Docetaxel)
|All Grades (%)||Grade 3/4 (%)||All Grades (%)||Grade 3/4 (%)|
|Nervous System Disorder|
|Electrocardiogram QT prolonged||5||3||0||0|
|Infections and Infestations|
|Upper respiratory infectiond||26||0||13||1|
|Respiratory, Thoracic and Mediastinal Disorders|
|General Disorders and Administration Site Conditions|
|Includes cases reported within the clustered terms:
aDizziness (Balance disorder, Dizziness, Dizziness postural)
bVision Disorder (Diplopia, Photophobia, Photopsia, Vision blurred, Visual acuity reduced, Visual impairment, Vitreous floaters)
cBradycardia (Bradycardia, Sinus bradycardia)
dUpper respiratory infection (Laryngitis, Nasopharyngitis, Pharyngitis, Rhinitis, Upper respiratory tract infection)
ePulmonary embolism (Pulmonary artery thrombosis, Pulmonary embolism)
fEdema (Face edema, Generalized edema, Local swelling, Localized edema, Edema, Edema peripheral, Periorbital edema)
Additional adverse reactions occurring at an overall incidence between 1% and 30% in patients treated with XALKORI included decreased appetite (27%), fatigue (27%), neuropathy (19%; dysesthesia, gait disturbance, hypoesthesia, muscular weakness, neuralgia, peripheral neuropathy, parasthesia, peripheral sensory neuropathy, polyneuropathy, burning sensation in skin), rash (9%), ILD (4%; acute respiratory distress syndrome, ILD, pneumonitis), renal cyst (4%), and hepatic failure (1%).
Table 4: Summary of Treatment-Emergent Laboratory Abnormalities with Grade 3 or 4 Incidence of ≥ 4% in XALKORI-Treated Patients
|Any Grade||Grade 3/4||Any Grade||Grade 3/4|
ALK-positive metastatic NSCLC-Study 2
The safety analysis population in Study 2 included 934 patients with ALK-positive metastatic NSCLC who received XALKORI in a clinical trial. The median duration of treatment was 23 weeks. Dosing interruptions and reductions due to treatment-related adverse events occurred in 23% and 12% of patients, respectively. The rate of treatment-related adverse events resulting in permanent discontinuation was 5%. The most common adverse reactions ( ≥ 25%) included vision disorder (55%), nausea (51%), vomiting (46%), diarrhea (46%), edema (39%), constipation (38%), and fatigue (26%).
Description Of Selected Adverse Drug Reactions
Vision disorders, most commonly visual impairment, photopsia, blurred vision, or vitreous floaters, occurred in 691 (56%) patients across clinical trials (n=1225). The majority (99%) of these patients had Grade 1 or 2 visual adverse reactions. Across clinical studies, one patient had a treatment-related grade 3 vision abnormality.
Based on the Visual Symptom Assessment Questionnaire (VSAQ-ALK), patients treated with XALKORI in Study 1 reported a higher incidence of visual disturbances compared to patients treated with chemotherapy. The onset of vision disorders generally started within the first week of drug administration. The majority of patients on the XALKORI arm in Study 1 ( > 50%) reported visual disturbances; these visual disturbances occurred at a frequency of 4-7 days each week, lasted up to 1 minute, and had mild or no impact (scores 0 to 3 out of a maximum score of 10) on daily activities as captured in a patient questionnaire.
Neuropathy, most commonly sensory in nature, occurred in 235 (19%) of 1225 patients. Most events (95%) were Grade 1 or Grade 2 in severity.
Renal cysts occurred in 7 (4%) patients treated with XALKORI and 1 (1%) patient treated with chemotherapy in Study 1. The majority of renal cysts in XALKORI-treated patients were complex. Local cystic invasion beyond the kidney occurred, in some cases with imaging characteristics suggestive of abscess formation. However, across clinical trials no renal abscesses were confirmed by microbiology tests.