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LORBRENA® (lorlatinib) Adverse Reactions

6 ADVERSE REACTIONS

The following adverse reactions are described elsewhere in the labeling:

6.1 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 practice.

The data in Warnings and Precautions reflect exposure to LORBRENA in 332 patients with ALK-positive or ROS1-positive, metastatic non-small cell lung cancer (NSCLC) enrolled in a multi-cohort, multinational, non-comparative, dose-finding, and activity-estimating trial (Study B7461001) who received LORBRENA at doses ranging from 10 mg to 200 mg daily in single or divided doses.

The data described below reflect exposure to LORBRENA in 295 patients with ALK-positive or ROS1-positive metastatic NSCLC who received LORBRENA 100 mg orally once daily in Study B7461001. The median duration of exposure to LORBRENA was 12.5 months (1 day to 35 months) and 52% received LORBRENA for ≥12 months. Patient characteristics were a median age of 53 years (19 to 85 years), age ≥65 years (18%), female (58%), White (49%), Asian (37%), and Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (96%).

The most common (≥20%) adverse reactions were edema, peripheral neuropathy, cognitive effects, dyspnea, fatigue, weight gain, arthralgia, mood effects, and diarrhea. Of the worsening laboratory values occurring in ≥20% of patients, the most common were hypercholesterolemia, hypertriglyceridemia, anemia, hyperglycemia, increased AST, hypoalbuminemia, increased ALT, increased lipase, and increased alkaline phosphatase.

Serious adverse reactions occurred in 32% of the 295 patients; the most frequently reported serious adverse reactions were pneumonia (3.4%), dyspnea (2.7%), pyrexia (2%), mental status changes (1.4%), and respiratory failure (1.4%). Fatal adverse reactions occurred in 2.7% of patients and included pneumonia (0.7%), myocardial infarction (0.7%), acute pulmonary edema (0.3%), embolism (0.3%), peripheral artery occlusion (0.3%), and respiratory distress (0.3%). Permanent discontinuation of LORBRENA for adverse reactions occurred in 8% of patients.

The most frequent adverse reactions that led to permanent discontinuation were respiratory failure (1.4%), dyspnea (0.7%), myocardial infarction (0.7%), cognitive effects (0.7%) and mood effects (0.7%). Approximately 48% of patients required dose interruption. The most frequent adverse reactions that led to dose interruptions were edema (7%), hypertriglyceridemia (6%), peripheral neuropathy (5%), cognitive effects (4.4%), increased lipase (3.7%), hypercholesterolemia (3.4%), mood effects (3.1%), dyspnea (2.7%), pneumonia (2.7%), and hypertension (2.0%). Approximately 24% of patients required at least 1 dose reduction for adverse reactions. The most frequent adverse reactions that led to dose reductions were edema (6%), peripheral neuropathy (4.7%), cognitive effects (4.1%), and mood effects (3.1%).

Tables 2 and 3 summarize common adverse reactions and laboratory abnormalities, respectively, in patients treated with LORBRENA in Study B7461001.

Table 2 Adverse Reactions Occurring in ≥10% of Patients in Study B7461001*
Adverse ReactionLORBRENA
(N=295)
All Grades
(%)
Grade 3 or 4
(%)
Abbreviations: NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; SOC=System organ class.
*
Adverse reactions were graded using NCI CTCAE version 4.0.
Mood effects (including affective disorder, affect lability, aggression, agitation, anxiety, depressed mood, depression, euphoric mood, irritability, mania, mood altered, mood swings, personality change, stress, suicidal ideation).
Peripheral neuropathy (including burning sensation, carpal tunnel syndrome, dysesthesia, formication, gait disturbance, hypoesthesia, muscular weakness, neuralgia, neuropathy peripheral, neurotoxicity, paresthesia, peripheral sensory neuropathy, sensory disturbance).
§
Cognitive effects (including events from SOC Nervous system disorders: amnesia, cognitive disorder, dementia, disturbance in attention, memory impairment, mental impairment; and also including events from SOC Psychiatric disorders: attention deficit/hyperactivity disorder, confusional state, delirium, disorientation, reading disorder).
Speech effects (including aphasia, dysarthria, slow speech, speech disorder)
#
Sleep effects (including abnormal dreams, insomnia, nightmare, sleep disorder, sleep talking, somnambulism)
Þ
Vision disorder (including blindness, diplopia, photophobia, photopsia, vision blurred, visual acuity reduced, visual impairment, vitreous floaters).
ß
Myalgia (including musculoskeletal pain, myalgia).
à
Edema (including edema, edema peripheral, eyelid edema, face edema, generalized edema, localized edema, periorbital edema, peripheral swelling, swelling).
è
Fatigue (including asthenia, fatigue).
ð
Upper respiratory infection (including fungal upper respiratory infection, upper respiratory infection, viral upper respiratory infection).
ø
Rash (including dermatitis acneiform, maculopapular rash, pruritic rash, rash).
Psychiatric
  Mood effects231.7
Nervous system
  Peripheral neuropathy472.7
  Cognitive effects§272.0
  Headache180.7
  Dizziness160.7
  Speech effects120.3
  Sleep effects#100
Respiratory
  Dyspnea275.4
  Cough180
Ocular
  Vision disorderÞ150.3
Gastrointestinal
  Diarrhea220.7
  Nausea180.7
  Constipation150
  Vomiting121
Musculoskeletal and connective tissue
  Arthralgia230.7
  Myalgiaß170
  Back pain130.7
  Pain in extremity130.3
General
  Edemaà573.1
  Fatigueè260.3
  Weight gain244.4
  Pyrexia120.7
Infections
  Upper respiratory tract infectionð120
Skin
  Rashø140.3

Additional clinically significant adverse reactions occurring at an incidence between 1% and 10% were hallucinations (7%).

Table 3 Worsening Laboratory Values Occurring in ≥20% of Patients in Study B7461001*
Laboratory AbnormalityLORBRENA
All Grades
(%)
Grade 3 or 4
(%)
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events.
N=number of patients who had at least one on-study assessment for the parameter of interest.
*
Grades using NCI CTCAE version 4.0.
N=292.
N=293.
§
N=291.
N=290.
#
N=284.
Chemistry
  Hypercholesterolemia9618
  Hypertriglyceridemia9018
  Hyperglycemia525
  Increased AST372.1
  Hypoalbuminemia§331.0
  Increased ALT282.1
  Increased lipase2410
  Increased alkaline phosphatase241.0
  Increased amylase#223.9
  Hypophosphatemia214.8
  Hyperkalemia211.0
  Hypomagnesemia210
Hematology
  Anemia524.8
  Thrombocytopenia230.3
  Lymphopenia223.4
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