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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 Reaction LORBRENA
(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 effects 23 1.7
Nervous system
  Peripheral neuropathy 47 2.7
  Cognitive effects§ 27 2.0
  Headache 18 0.7
  Dizziness 16 0.7
  Speech effects 12 0.3
  Sleep effects# 10 0
Respiratory
  Dyspnea 27 5.4
  Cough 18 0
Ocular
  Vision disorderÞ 15 0.3
Gastrointestinal
  Diarrhea 22 0.7
  Nausea 18 0.7
  Constipation 15 0
  Vomiting 12 1
Musculoskeletal and connective tissue
  Arthralgia 23 0.7
  Myalgiaß 17 0
  Back pain 13 0.7
  Pain in extremity 13 0.3
General
  Edemaà 57 3.1
  Fatigueè 26 0.3
  Weight gain 24 4.4
  Pyrexia 12 0.7
Infections
  Upper respiratory tract infectionð 12 0
Skin
  Rashø 14 0.3

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 Abnormality LORBRENA
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
  Hypercholesterolemia 96 18
  Hypertriglyceridemia 90 18
  Hyperglycemia 52 5
  Increased AST 37 2.1
  Hypoalbuminemia§ 33 1.0
  Increased ALT 28 2.1
  Increased lipase 24 10
  Increased alkaline phosphatase 24 1.0
  Increased amylase# 22 3.9
  Hypophosphatemia 21 4.8
  Hyperkalemia 21 1.0
  Hypomagnesemia 21 0
Hematology
  Anemia 52 4.8
  Thrombocytopenia 23 0.3
  Lymphopenia 22 3.4

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