LORBRENA (lorlatinib) 8 Adverse Reactions | Pfizer Medical Information

8.1 Adverse Reaction Overview

The pooled safety population described in the 7 WARNINGS AND PRECAUTIONS section reflects exposure to LORBRENA in 476 patients who received 100 mg LORBRENA once daily in Study B7461001 (N=327) and Study B7461006 (N=149). Among 476 patients who received LORBRENA, 75% were exposed for 6 months or longer and 61% were exposed for greater than 1 year. In this pooled safety population, the most frequent adverse reactions in ≥ 20% of 476 patients who received LORBRENA were edema (56%), peripheral neuropathy (44%), weight gain (31%), cognitive effects (28%), fatigue (27%), dyspnea (27%), arthralgia (24%), diarrhea (23%), mood effects (21%), and cough (21%). Temporary discontinuation occurred 245 (51.5%) of patients, dose reduction occurred in 117 (24.6%) of patients, and permanent discontinuation occurred in 44 (9.2%) of patients. The most frequent Grade 3-4 laboratory abnormalities in ≥ 20% of 476 patients who received LORBRENA were hypercholesterolemia (21%) and hypertriglyceridemia (21%).

Previously Untreated ALK-Positive Metastatic Non-small Cell Lung Cancer (Phase 3 Study B7461006)

The safety of LORBRENA was evaluated in 149 patients with ALK-positive non-small cell lung cancer (NSCLC) in randomized, open-label, active-controlled Phase 3 Study B7461006. The median duration of exposure to LORBRENA was 16.7 months (4 days to 34.3 months) and 76% received LORBRENA for at least 12 months. Patient characteristics were: median age of 59 years (47 to 68 years), age ≥65 years (35%), female (59%), White (49%), Asian (44%), and Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (96%).

The most frequent (≥20%) adverse reactions reported in patients treated with LORBRENA were edema, weight gain, peripheral neuropathy, cognitive effects, diarrhea, and dyspnea. Of the worsening laboratory values, the most frequent (≥30%) were hypertriglyceridemia, hypercholesterolemia, increased creatinine, increased gamma glutamyl transferase (GGT), increased AST, hyperglycemia, increased ALT, increased creatine phosphokinase (CPK), hypoalbuminemia, and anemia.

Serious adverse reactions occurred in 51 (34%) of the 149 patients treated with LORBRENA; the most frequently reported serious adverse reactions were pneumonia in 7 patients (4.7%), dyspnea in 4 patients (2.7%), respiratory failure in 4 patients (2.7%), cognitive effects in 3 patients (2.0%), and pyrexia in 3 patients (2.0%).

Fatal adverse reactions occurred in 7 (4.7%) of patients treated with LORBRENA and included pneumonia in 1 patient (0.7%), respiratory failure in 1 patient (0.7%), cardiac failure acute in 1 patient (0.7%), disease progression in 1 patient (0.7%), lung neoplasm malignant in 1 patient (0.7%), pulmonary embolism in 1 patient (0.7%), and death in 1 patient (0.7%).

Permanent discontinuation of LORBRENA due to adverse reactions occurred in 10 (6.7%) patients. The most frequent adverse reactions that led to permanent discontinuation of LORBRENA was cognitive effects in 2 patients (1.3%). Dose interruption was required in 73 (49%) patients treated with LORBRENA. The most frequent adverse reactions that led to dose interruptions of LORBRENA were hypertriglyceridemia in 11 patients (7.4%), edema in 8 patients (5.4%), pneumonia in 7 patients (4.7%), cognitive effects in 6 patients (4.0%), hypercholesterolemia in 5 patients (3.4%), and mood effects in 5 patients (3.4%). At least 1 dose reduction due to adverse reactions was required in 31 (21%) patients. The most frequent adverse reactions that led to dose reductions were edema in 8 patients (5.4%), hypertriglyceridemia in 6 patients (4.0%), and peripheral neuropathy in 5 patients (3.4%).

Previously Treated ALK-Positive Metastatic NSCLC (Phase 1/2 Study B7461001)

The data from B7461001 described below reflect exposure to LORBRENA in 295 adult patients with ALK positive or ROS1 positive metastatic NSCLC who received LORBRENA 100 mg orally once daily in Study B7461001. The majority of subjects (232 subjects, 78.6%) had been previously treated with 1 or more ALK or ROS1 TKIs.

The median duration of treatment was 12.5 months (range: 1 day to 35 months), the median age was 53 years (range: 19 to 85 years), and 18% of patients were older than 65 years. A total of 170 patients (58%) were female, 145 patients (49%) were White, and 108 patients (37%) were Asian.

The most frequent (≥ 20%) adverse reactions were edema, peripheral neuropathy, cognitive effects, dyspnea, fatigue, weight increased, arthralgia, mood effects and diarrhea.

Of the worsening laboratory values occurring in ≥ 20% of patients, the most frequent were hypercholesterolemia, hypertriglyceridemia, anemia, hyperglycemia, increased AST, hypoalbuminemia, increased ALT, lipase increased, and increased alkaline phosphatase.

Serious adverse reactions occurred in 95 (32%) of the 295 patients; the most frequently reported serious adverse reactions were pneumonia in 10 patients (3.4%), dyspnea in 8 patients (2.7%), pyrexia in 6 patients (2%), mental status changes in 4 patients (1.4%), and respiratory failure in 4 patients (1.4%). Fatal adverse reactions occurred in 8 patients (2.7%) and included pneumonia in 2 patients (0.7%), myocardial infarction in 2 patients (0.7%), acute pulmonary edema in 1 patient (0.3%), embolism in 1 patient (0.3%), peripheral artery occlusion in 1 patient (0.3%), and respiratory distress in 1 patient (0.3%). Permanent discontinuation of LORBRENA for adverse reactions occurred in 23 patients (8%).

The most frequent adverse reactions that led to permanent discontinuation were respiratory failure in 4 patients (1.4%), dyspnea in 2 patients (0.7%), myocardial infarction in 2 patients (0.7%), cognitive effects in 2 patients (0.7%) and mood effects in 2 patients (0.7%). Dose interruption was required in 142 patients (48%). The most frequent adverse reactions that led to dose interruptions were edema in 20 patients (7%), hypertriglyceridemia in 17 patients (6%), peripheral neuropathy in 15 patients (5%), cognitive effects in 13 patients (4.4%), increased lipase in 11 patients (3.7%), hypercholesterolemia in 10 patients (3.4%), mood effects in 9 patients (3.1%), dyspnea in 8 patients (2.7%), pneumonia in 8 patients (2.7%), and hypertension in 6 patients (2.0%). At least 1 dose reduction due to adverse reactions was required in 71 patients (24%). The most frequent adverse reactions that led to dose reductions were edema in 18 patients (6%), peripheral neuropathy in 14 patients (4.7%), cognitive effects in 12 patients (4.1%), and mood effects in 9 patients (3.1%).

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

Table 3 summarizes the most frequent adverse reactions in patients treated with LORBRENA in the Phase 3 study.

Table 3. Adverse Reactions (≥10% for all NCI CTCAE Grades or ≥2% for Grades 3-4) in Patients Treated with LORBRENA in Phase 3 Study B7461006*
Adverse Reaction	LORBRENA n=149		Crizotinib n=142
* Adverse reactions were graded using NCI CTCAE version 4.03. Abbreviations: NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; SOC=System organ class. a Mood effects (including affective disorder, affect lability, agitation, anger, anxiety, bipolar I disorder, depressed mood, depression, depressive symptom, euphoric mood, intentional self-injury, irritability, mood altered, mood swings, stress). b Peripheral neuropathy (including dysesthesia, gait disturbance, hypoesthesia, motor dysfunction, muscular weakness, neuralgia, neuropathy peripheral, paresthesia, peripheral motor neuropathy, peripheral sensory neuropathy). c Cognitive effects (including events from SOC Nervous system disorders: amnesia, cognitive disorder, disturbance in attention, memory impairment, mental impairment; and also including events from SOC Psychiatric disorders: confusional state, delirium, disorientation). d Sleep effects (including insomnia, nightmare, sleep disorder, somnambulism). e Vision disorder (including diplopia, photophobia, photopsia, vision blurred, visual acuity reduced, visual impairment, vitreous floaters). f Myalgia (including musculoskeletal pain, myalgia). g Edema (including edema, edema peripheral, eyelid edema, face edema, generalized edema, localized edema, periorbital edema, peripheral swelling, swelling). h Fatigue (including asthenia, fatigue). i Upper respiratory tract infection (including upper respiratory infection). j Rash (including dermatitis acneiform, maculopapular rash, rash).
Adverse Reaction	All Grades n (%)	Grade 3 or 4 n (%)	All Grades n (%)	Grade 3 or 4 n (%)
Psychiatric
Mood effects ^a	24 (16.1)	2 (1.3)	7 (4.9)	0
Nervous system
Peripheral neuropathy ^b	50 (33.6)	3 (2.0)	21 (14.8)	1 (0.7)
Cognitive effects ^c	32 (21.5)	3 (2.0)	8 (5.6)	0
Headache	25 (16.8)	0	25 (17.6)	1 (0.7)
Dizziness	16 (10.7)	0	20 (14.1)	0
Sleep effects ^d	17 (11.4)	2 (1.3)	14 (9.9)	0
Respiratory
Dyspnea	30 (20.1)	4 (2.7)	23 (16.2)	3 (2.1)
Cough	24 (16.1)	0	26 (18.3)	0
Respiratory failure	4 (2.7)	3 (2.0)	0	0
Vascular disorders
Hypertension	27 (18.1)	15 (10.1)	3 (2.1)	0
Ocular
Vision disorder ^e	27 (18.1)	0	56 (39.4)	1 (0.7)
Gastrointestinal
Diarrhea	32 (21.5)	2 (1.3)	74 (52.1)	1 (0.7)
Nausea	22 (14.8)	1 (0.7)	74 (52.1)	3 (2.1)
Constipation	26 (17.4)	0	42 (29.6)	1 (0.7)
Vomiting	19 (12.8)	1 (0.7)	55 (38.7)	2 (1.4)
Musculoskeletal and connective tissue
Arthralgia	28 (18.8)	1 (0.7)	16 (11.3)	0
Myalgia ^f	23 (15.4)	1 (0.7)	10 (7.0)	0
Back pain	22 (14.8)	1 (0.7)	16 (11.3)	0
Pain in extremity	26 (17.4)	0	12 (8.5)	0
General
Edema ^g	83 (55.7)	6 (4.0)	57 (40.1)	2 (1.4)
Weight gain	57 (38.3)	25 (16.8)	18 (12.7)	3 (2.1)
Fatigue ^h	29 (19.5)	2 (1.3)	46 (32.4)	4 (2.8)
Pyrexia	25 (16.8)	2 (1.3)	18 (12.7)	2 (1.4)
Chest pain	16 (10.7)	2 (1.3)	20 (14.1)	1 (0.7)
Infections
Upper respiratory tract infection ⁱ	17 (11.4)	1 (0.7)	11 (7.7)	2 (1.4)
Pneumonia	11 (7.4)	3 (2.0)	12 (8.5)	5 (3.5)
Bronchitis	10 (6.7)	3 (2.0)	3 (2.1)	0
Skin
Rash ^j	17 (11.4)	0	12 (8.5)	0

Table 4 summarizes the most frequent adverse reactions in patients treated with LORBRENA in the Phase 1/2 Study B7461001.

Table 4. Adverse Reactions Reported in ≥ 10% of Patients in Phase 1/2 Study B7461001*
Adverse Reaction	LORBRENA (N=295)
* Adverse reactions were graded using NCI CTCAE version 4.0. Event terms that represent the same medical concept or condition were grouped together and reported as a single adverse reaction in the table above. Terms actually reported in the studies up to the data cutoff date and contributing to the relevant adverse reaction are indicated in parentheses, as listed below. Abbreviations: NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events a Hypercholesterolemia (including blood cholesterol increased, hypercholesterolemia). b Hypertriglyceridemia including (blood triglycerides increased, hypertriglyceridemia). c 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). d 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). e 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, reading disorder). f Speech effects (including aphasia, dysarthria, slow speech, speech disorder) g Sleep effects (including abnormal dreams, insomnia, nightmare, sleep disorder, sleep talking, somnambulism) h Vision disorder (including diplopia, photophobia, photopsia, vision blurred, visual acuity reduced, visual impairment, vitreous floaters). i Myalgia (including musculoskeletal pain, myalgia). j Edema (including edema, edema peripheral, eyelid edema, face edema, generalized edema, localized edema, periorbital edema, peripheral swelling, swelling). k Fatigue (including asthenia, fatigue). l Upper respiratory infection (including fungal upper respiratory infection, upper respiratory infection, viral upper respiratory infection). m Rash (including dermatitis acneiform, maculopapular rash, pruritic rash, rash).
Adverse Reaction	All Grades n (%)	Grade 3-4 n (%)
Metabolism and nutrition disorders
Hypercholesterolemia^a	249 (84.4)	49 (16.6)
Hypertriglyceridemia^b	197 (66.8)	48 (16.3)
Psychiatric disorders
Mood effects^c	65 (22.0)	5 (1.7)
Nervous system disorders
Peripheral neuropathy^d	140 (47.5)	8 (2.7)
Cognitive effects^e	80 (27.1)	6 (2.0)
Headache	52 (17.6)	2 (0.7)
Dizziness	48 (16.3)	2 (0.7)
Speech effects^f	34 (11.5)	1 (0.3)
Sleep effects^g	29 (9.8)	0
Respiratory
Dyspnea	79 (26.8)	16 (5.4)
Cough	54 (18.3)	0
Eye disorders
Vision disorder^h	43 (14.6)	1 (0.3)
Gastrointestinal disorders
Diarrhea	64 (21.7)	2 (0.7)
Nausea	52 (17.6)	2 (0.7)
Constipation	45 (15.3)	0
Vomiting	34 (11.5)	3 (1.0)
Musculoskeletal and connective tissue disorders
Arthralgia	67 (22.7)	2 (0.7)
Myalgiaⁱ	50 (16.9)	0
Back pain	38 (12.9)	2 (0.7)
Pain in extremity	39 (13.2)	1 (0.3)
General disorders and administration site conditions
Edema^j	159 (53.9)	7 (2.4)
Fatigue^k	76 (25.8)	1 (0.3)
Pyrexia	36 (12.2)	2 (0.7)
Infections
Upper respiratory tract infection^l	36 (12.2)	0
Skin and subcutaneous tissue disorders
Rash^m	41 (13.9)	1 (0.3)
Investigations
Weight increased	71 (24.1)	13 (4.4)

8.2.1 Clinical Trial Adverse Reactions – Pediatrics

Not applicable

8.3 Less Common Clinical Trial Adverse Reactions

In Study B7461006, additional clinically significant adverse reactions occurring at an overall incidence between 1% and 10% in patients treated with LORBRENA included speech effects in 10 patients (6.7%) and psychotic effects in 5 patients (3.4%).

In study B7461001, additional clinically significant adverse reactions occurring at an overall incidence between 1% and 10% in patients treated with LORBRENA included psychotic effects in 21 patients (7%).

8.3.1 Less Common Clinical Trial Adverse Reactions – Pediatrics

Not applicable

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Clinical Trial Findings

Table 5 summarizes laboratory abnormalities in patients treated with LORBRENA in Phase 3 study B7461006.

Table 5 Worsening Laboratory Values Occurring in ≥20% of Patients in Phase 3 Study B7461006*
Laboratory Abnormality	LORBRENA n=149		Crizotinib n=142
* Grades using NCI CTCAE version 4.03. Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; CPK=creatine phosphokinase; GGT=gamma glutamyl transferase; NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; PTT=partial thromboplastin time. N=number of patients who had at least one on‑study assessment for the parameter of interest. a N=149 (LORBRENA). A N=141 (crizotinib). b N=148 (LORBRENA). B N=135 (crizotinib). c N=138 (LORBRENA).
Laboratory Abnormality	All Grades n (%)	Grade 3 or 4 n (%)	All Grades n (%)	Grade 3 or 4 n (%)
Chemistry
Hypertriglyceridemia ^a,A	142 (95)	33 (22)	38 (27)	0
Hypercholesterolemia ^a,A	136 (91)	29 (19)	17 (12)	0
Increased creatinine ^a,A	121 (81)	1 (0.7)	139 (99)	3 (2.1)
Increased GGT ^a,A	77 (52)	9 (6.0)	58 (41)	9 (6.4)
Increased AST ^a,A	71 (48)	3 (2.0)	105 (75)	5 (3.5)
Hyperglycemia ^a,A	71 (48)	10 (6.7)	38 (27)	3 (2.1)
Increased ALT ^a,A	65 (44)	4 (2.7)	105 (75)	6 (4.3)
Increased CPK ^a,A	58 (39)	3 (2.0)	90 (64)	7 (5.0)
Hypoalbuminemia ^a,A	53 (36)	1 (0.7)	86 (61.0)	9 (6.4)
Increased lipase ^a,A	42 (28.2)	11 (7.4)	48 (34)	7 (5.0)
Increased alkaline phosphatase ^a,A	35 (23)	0	70 (50)	1 (0.7)
Hyperkalemia ^a,A	32 (21)	2 (1.3)	38 (27)	3 (2.1)
Increased amylase ^b,A	30 (20)	2 (1.4)	45 (32)	2 (1.4)
Hematology
Anemia ^a,A	72 (48)	3 (2.0)	54 (38)	4 (2.8)
Activated PTT ^c,B	35 (25)	0	19 (14)	0
Lymphopenia ^a,A	34 (23)	4 (2.7)	61 (43)	8 (5.7)
Thrombocytopenia ^a,A	34 (23)	0	10 (7.1)	1 (0.7)

Table 6 summarizes laboratory abnormalities in patients treated with LORBRENA in Phase 1/2 Study B7461001.

Table 6. Worsening Laboratory Values Occurring in ≥20% of Patients in Phase 1/2 Study B7461001*
Laboratory Abnormality	LORBRENA
* Grades using NCI CTCAE version 4.0. 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. a N=292 b N=293. c N=291. d N=290. e N=284.
Laboratory Abnormality	All Grades n (%)	Grade 3 or 4 n (%)
Chemistry
Hypercholesterolemia^a	279 (96)	52 (18)
Hypertriglyceridemia^a	262 (90)	52 (18)
Hyperglycemia^b	151 (52)	15 (5)
Increased AST^a	108 (37)	6 (2.1)
Hypoalbuminemia^c	95 (33)	3 (1.0)
Increased ALT^a	82 (28)	6 (2.1)
Increased lipase^d	70 (24)	28 (10)
Increased alkaline phosphatase^a	70 (24)	3 (1.0)
Increased amylase^e	61 (22)	11 (3.9)
Hypophosphatemia^a	61 (21)	14 (4.8)
Hyperkalemia^b	61 (21)	3 (1.0)
Hypomagnesemia^a	60 (21)	0
Hematology
Anemia^b	152 (52)	14 (4.8)
Thrombocytopenia^b	67 (23)	1 (0.3)
Lymphopenia^a	63 (22)	10 (3.4)

8.5 Post-Market Adverse Reactions

Not applicable