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XALKORI (crizotinib) Adverse Reactions

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Adverse Reactions

Adverse Drug Reaction Overview

The data described below reflect exposure to XALKORI in 1669 patients with ALK-positive advanced NSCLC who participated in randomized Phase 3 studies (Study A8081007 and A8081014) or in single-arm trials (Studies A8081001 and A8081005), and in 53 patients with ROS1-positive advanced NSCLC who participated in single arm Study 1001, for a total of 1722 patients. These patients received a starting oral dose of 250 mg taken twice daily continuously.

The most serious adverse drug reactions in 1722 patients with either ALK-positive or ROS1-positive advanced NSCLC are hepatotoxicity, ILD/pneumonitis, and QT interval prolongation (see WARNINGS AND PRECAUTIONS). The most common all-causality adverse events (≥10%) of XALKORI are vision disorder, nausea, diarrhea, vomiting, edema, constipation, elevated transaminases, fatigue, decreased appetite, upper respiratory infection, dizziness, neuropathy, cough, dyspnea, neutropenia, dysgeusia, abdominal pain, headache, pyrexia, chest pain, back pain, anemia, leukopenia, stomatitis, asthenia, rash, bradycardia, insomnia, pain in extremity, disease progression, and arthralgia.

Treatment-emergent all-causality bradycardia was experienced by 219 (13%) of 1722 patients treated with XALKORI in clinical trials of patients with either ALK-positive or ROS1-positive advanced NSCLC. The majority of these cases were Grade 1 or 2 in severity. A total of 259 (16%) of 1666 patients with at least 1 postbaseline vital sign assessment had a pulse heart rate <50 bpm.

Across all XALKORI clinical studies, approximately 2100 patients have received XALKORI at a starting dose of 250 mg twice daily across various tumor types, the most common being NSCLC. The safety profile for these patients was consistent with that observed for the 1722 patients with either ALK-positive or ROS1-positive NSCLC.

Clinical Trial Adverse Drug Reactions

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.

Previously Untreated ALK-Positive Metastatic NSCLC - Study A8081014

The data in Table 1 are derived from 343 patients with ALK-positive metastatic NSCLC who had not received previous systemic treatment for advanced disease who enrolled in a randomized, multicenter, open-label, active-controlled trial (Study A8081014).

The safety analysis population in Study A8081014 included 171 patients who received XALKORI and 169 patients who received chemotherapy (91 pemetrexed/ cisplatin or 78 pemetrexed/carpboplatin).

The median duration of study treatment was 10.9 months for patients in the XALKORI arm and 4.1 months for patients in the chemotherapy arm (a maximum of 6 cycles was permitted). Median duration of treatment was 5.2 months for patients who received XALKORI after cross over from chemotherapy. Across the 343 patients who were randomized to study treatment (340 received at least 1 dose of study treatment), the median age was 53 years; 87% of patients in the XALKORI arm and 81% of patients in the chemotherapy arm were younger than 65 years. A total of 61% of patients on XALKORI and 63% of chemotherapy patients were female. Forty-five percent (45%) of XALKORI-treated patients and 47% of chemotherapy-treated patients were Asian.

The most frequent (≥10%) all-causality ADRs for patients treated with XALKORI were vision disorder, diarrhea, nausea, edema, vomiting, constipation, elevated transaminases, decreased appetite, fatigue, dysgeusia, neutropenia, neuropathy, dizziness, bradycardia, dyspepsia, and rash.

The most common (≥1%) grade 3/4 all-causality ADRs for patients treated with XALKORI were elevated transaminases, neutropenia, fatigue, decreased appetite, diarrhea, vomiting, constipation, nausea, electrocardiogram QT prolonged, leukopenia, neuropathy, and bradycardia.

Serious adverse events were reported in 58 patients (33.9%) treated with XALKORI and 47 patients (27.8%) in the chemotherapy arm. The most frequent serious adverse events reported in patients treated with XALKORI were dyspnea (4.1%) and pulmonary embolism (2.9%). Fatal adverse events in XALKORI-treated patients occurred in 2.3% patients, consisting of septic shock, acute respiratory failure, and diabetic ketoacidosis.

Dose reductions due to adverse reactions were required in 11 (6.4%) of XALKORI-treated patients. The most frequent adverse reactions that led to dose reduction in these patients were nausea (1.8%) and elevated transaminases (1.8%).

Dose interruption/temporary discontinuation occurred in 44.3% of patients. The most frequent adverse events that led to dose interruption/temporary discontinuation were neutropenia (8.2%), alanine aminotransferase (6.0%), vomiting (4.8%), nausea (4.1%), aspartate aminotransferase increased (3.8%), pneumonia (3.2%), dyspnea (2.6%), neutrophil count decreased (2.5%), fatigue (2.1%), leukopenia (1.7%), oedema peripheral (1.7%), diarrhoea (1.4%), pyrexia (1.3%), decreased appetite (1.1%), and abdominal pain upper (1.0%).

In this study, 4.1% of patients permanently discontinued XALKORI treatment due to disease progression and 8.2% due to an adverse event. The most frequent adverse reactions that led to permanent discontinuation in XALKORI-treated patients were elevated transaminases (1.2%), hepatotoxicity (1.2%), and ILD (1.2%).

Table 1 summarizes common adverse events experienced by patients in both the XALKORI and chemotherapy arms of study A8081014.

Table 1. Adverse Drug Reactions Reported in Previously Untreated Patients with ALK-Positive NSCLC Who Received Crizotinib or Chemotherapy in Randomized Phase 3 Study A8081014*
 
Abbreviations: N=total number of patients; n=number of patients meeting prespecified criteria.
*
The percentages of adverse drug reactions were based on the data cutoff date of 30 Nov 2013, with the exception of Blood creatinine increased, for which frequency was based on the data cutoff date of 15 Jul 2014.
Event terms that represent the same medical concept or condition were grouped together and reported as single adverse reaction in the table above. Terms actually reported in the study up to the data cutoff date and contributing to the relevant adverse reaction are indicated in parenthesis, as listed below.
a
Neutropenia (Febrile neutropenia, Neutropenia, Neutrophil count decreased).
b
Leukopenia (Leukopenia, White blood cell count decreased).
c
Bradycardia (Bradycardia, Sinus bradycardia).
d
Vision Disorder (Diplopia, Photophobia, Photopsia, Vision blurred, Visual acuity reduced, Visual field defect, Visual impairment, Vitreous floaters).
e
Oesophagitis (Oesophagitis, Oesophageal ulcer)
f
Oedema (Face oedema, Generalised oedema, Local swelling, Localised oedema, Oedema, Oedema peripheral, Periorbital oedema).
g
There were no cases of hepatic failure in Study 1014.
h
Elevated Transaminases (Alanine aminotransferase increased, Aspartate aminotransferase increased, Gamma-glutamyltransferase increased, Hepatic function abnormal, Transaminases increased).
i
Blood testosterone decreased (Hypogonadism).
j
Neuropathy (Dysaesthesia, Gait disturbance, Hypoaesthesia, Muscular weakness, Neuralgia, Neuropathy peripheral, Neurotoxicity, Paraesthesia, Peripheral sensory neuropathy, Polyneuropathy, Sensory disturbance).
k
Dizziness (Balance disorder, Dizziness, Dizziness postural, Presyncope).
l
Renal Cyst (Renal cyst).
m
Blood creatinine increased (Blood creatinine increased).
n
Interstitial Lung Disease (Interstitial lung disease, Pneumonitis).

Adverse Reaction

Crizotinib

(N=171)

Chemotherapy

(N=169)

All Grades

n (%)

Grade 3/4

n (%)

All Grades

n (%)

Grade 3/4

n (%)

Blood and Lymphatic System Disorders

Neutropeniaa

Leukopeniab


36 (21)

12 (7)


19 (11)

3 (2)


51 (30)

26 (15)


26 (15)

9 (5)

Cardiac Disorders

Bradycardiac

Electrocardiogram QT prolonged

Syncope


23 (14)

10 (6)

1 (<1)


2 (1)

4 (2)

1 (<1)


1 (<1)

3 (2)

2 (1)


0 (0)

0 (0)

2 (1)

Eye Disorders

Vision disorderd

122 (71)

1 (<1)

16 (10)

0 (0)

Gastrointestinal Disorders
Oesophagitise

Vomiting

Diarrhea

Nausea
Constipation

Dyspepsia


10 (6)

78 (46)

105 (61)

95 (56)

74 (43)

23 (14)


3 (2)

3 (2)

4 (2)

2 (1)

3 (2)

0 (0)


1 (1)

60 (36)

22 (13)

99 (59)

51 (30)

4 (2)


0 (0)

5 (3)

1 (<1)

3 (2)

0 (0)

0 (0)

General Disorders and Administration Site Conditions
Fatigue
Oedemaf



49 (29)
83 (49)



5 (3)
1 (<1)



65 (39)
21 (12)



4 (2)
1 (<1)

Hepatobiliary Disordersg
Elevated transaminasesh

Blood alkaline phosphatase increased


61 (36)

4 (2)


24 (14)

0 (0)


22 (13)

2 (1)


4 (2)

0 (0)

Investigations

Blood testosterone decreasedi

1 (<1)

0 (0)

0 (0)

0 (0)

Metabolism and Nutrition Disorders

Decreased appetite


51 (30)


4 (2)


57 (34)


1 (<1)

Nervous System Disorders
Neuropathyj

Dizzinessk
Dysgeusia


35 (21)

31 (18)

45 (26)


2 (1)

0 (0)

0 (0)


38 (23)

17 (10)

9 (5)


0 (0)

2 (1)

0 (0)

Renal and Urinary Disorders
Renal cystl

Blood creatinine increasedm


8 (5)

8 (5)


0 (0)

0 (0)


1 (<1)

5 (3)


0 (0)

0 (0)

Respiratory, Thoracic and Mediastinal Disorders

Interstitial lung diseasen



2 (1)



1 (<1)



1 (<1)



0 (0)

Skin and Subcutaneous Tissue Disorders

Rash



18 (11)



0 (0)



19 (11)



0 (0)

Additional adverse events that were observed during the clinical trial included upper respiratory infection (32%), abdominal pain (26%), pyrexia (19%), pain in extremity (16%), asthenia (13%), dysphagia (10%), anemia (8%), and stomatitis (6%).

Previously Treated ALK-Positive Metastatic NSCLC (Study A8081007)

The safety analysis population in Study A8081007 included 172 patients who received XALKORI and 171 patients who received chemotherapy (99 pemetrexed, 72 docetaxel). The median duration of study treatment was 11 months for patients on XALKORI and 3 months for patients on chemotherapy).

The most frequent (≥10%) all-causality ADRs for patients treated with crizotinib were vision disorder, edema, diarrhea, nausea, vomiting, constipation, elevated transaminases, decreased appetite, neutropenia, fatigue, dizziness, dysgeusia, neuropathy, leukopenia, and rash.

The most common (≥1%) grade 3/4 all-causality ADRs for patients treated with XALKORI were elevated transaminases, neutropenia, leukopenia, syncope, pneumonia, electrocardiogram QT prolonged, decreased appetite, constipation, nausea, vomiting, and fatigue.

Serious adverse events occurred in 76 (44%) patients on XALKORI, the most common of which were disease progression, pneumonia, pulmonary embolism and dyspnoea and 42 (25%) patients on chemotherapy, the most common of which was febrile neutropenia. Fatal adverse events in XALKORI-treated patients occurred in 6.4% patients, consisting of arrhythmia, interstitial lung disease, pneumonitis, dyspnea, sepsis/acute respiratory distress syndrome, cognitive disorder, death, pneumonia, pulmonary embolism, respiratory failure, sudden death, pericardial effusion, tumor hemorrhage.

Dosing interruptions due to adverse events occurred in 76 (44%) patients on XALKORI, the most common of which were neutropenia, ALT/AST increased, nausea and vomiting, and 28 (16%) patients on chemotherapy, the most common of which were fatigue and dizziness. Dose reductions due to adverse events occurred in 30 (17%) patients on XALKORI, the most common of which were elevated transaminases, electrocardiogram QT prolonged and neutropenia, and 25 (15%) patients on chemotherapy, the most common of which were neutropenia, fatigue and mucosal inflammation.

In this study, 9.9% of patients permanently discontinued XALKORI treatment due to progression and 13.4% due to an adverse event. The most frequent adverse reactions that led to permanent discontinuation in XALKORI-treated patients were interstitial lung disease/pneumonitis (2.3%), dyspnea (1.7%), elevated transaminases (2.4%), pulmonary embolism (1.2%), and pneumonia (1.2%).

Table 2 compares adverse drug reactions, regardless of causality, experienced by patients in the XALKORI and chemotherapy arms of Study

Table 2. Adverse Drug Reactions Reported in Previously Treated Patients with ALK-Positive NSCLC Who Received XALKORI or Chemotherapy in Randomized Phase 3 Study A8081007*
a
Abbreviations: N=total number of patients; n=number of patients meeting prespecified criteria.
*
The percentages of adverse drug reactions were based on the data cutoff date of 30 Nov 2013, with the exception of Blood creatinine increased, for which frequency was based on the data cutoff date of 15 Jul 2014.
Event terms that represent the same medical concept or condition were grouped together and reported as single adverse reaction in the table above. Terms actually reported in the study up to the data cutoff date and contributing to the relevant adverse reaction are indicated in parenthesis, as listed below.
Neutropenia (Febrile neutropenia, Neutropenia, Neutrophil count decreased), Leukopenia (Leukopenia, White blood cell count decreased), Bradycardia (Bradyarrhythmia, Bradycardia, Heart rate decreased, Sinus arrest, Sinus bradycardia), Vision Disorder (Chromatopsia, Diplopia, Halo vision, Photophobia, Photopsia, Vision blurred, Visual acuity reduced, Visual brightness, Visual field defect, Visual impairment, Vitreous floaters), Oesophagitis (Oesophagitis), Oedema (Face oedema, Generalised oedema, Local swelling, Localised oedema, Oedema, Oedema peripheral, Periorbital oedema), Elevated Transaminases (Alanine aminotransferase, Alanine aminotransferase abnormal, Alanine aminotransferase increased, Aspartate aminotransferase, Aspartate aminotransferase abnormal, Aspartate aminotransferase increased, Gamma-glutamyltransferase abnormal, Gamma-glutamyltransferase increased, Hepatic function abnormal, Hepatic enzyme increased, Hepatic function abnormal, Hypertransaminasaemia, Liver function test abnormal, Transaminases, Transaminases abnormal, Transaminases increased), Upper respiratory infection (Laryngitis, Nasopharyngitis, Pharyngitis, Rhinitis, Upper respiratory tract infection), Blood testosterone decreased (Hypogonadism), Neuropathy (Acute polyneuropathy, Amyotrophy, Areflexia, Autoimmune neuropathy, Autonomic failure syndrome, Autonomic neuropathy, Axonal neuropathy, Biopsy peripheral nerve abnormal, Burning feet syndrome, Burning sensation, Decreased vibratory sense, Demyelinating polyneuropathy, Dysaesthesia, Electromyogram abnormal, Formication, Gait disturbance, Genital hypoaesthesia, Guillain-Barre syndrome, Hyperaesthesia, Hypoaesthesia,Hyporeflexia, Hypotonia, Ischaemic neuropathy, Loss of proprioception, Miller Fisher syndrome, Mononeuritis, Monomeuropathy, Mononeuropathy multiplex, Motor dysfunction, Multifocal motor neuropathy, Muscle atrophy, Muscular weakness, Myelopathy, Nerve conduction studies abnormal, Nerve degeneration, Neuralgia, Neuritis, Neuromuscular toxicity, Neuromyopathy, Neuropathy peripheral, Neuropathy vitamin B6 deficiency, Neurotoxicity, Paraesthesia, Peripheral motor neuropathy, Peripheral nerve lesion, Peripheral nerve palsy, Peripheral nervous system function test abnormal, Peripheral sensorimotor neuropathy, Peripheral sensory neuropathy, Peroneal muscular atrophy, Peroneal nerve palsy, Phrenic nerve paralysis, Polyneuropathy, Polyneuropathy chronic, Polyneuropathy idiopathic progressive, Radiation neuropathy, Sensorimotor disorder, Sensory disturbance, Sensory loss, Skin burning sensation, Temperature perception test decreased, Tinel’s sign, Toxic neuropathy, Ulnar neuritis), Dizziness (Balance disorder, Dizziness, Dizziness exertional, Dizziness postural, Presyncope), Renal Cyst (Renal abscess, Renal cyst, Renal cyst excision, Renal cyst haemorrhage, Renal cyst infection, Renal cyst ruptured), Blood creatinine increased (Blood creatinine increased), Interstitial Lung Disease (Acute interstitial pneumonitis, Acute lung injury, Acute respiratory distress syndrome, Alveolitis, Alveolitis allergic, Alveolitis necrotizing, Diffuse alveolar damage, Eosinophilic pneumonia, Eosinophilic pneumonia acute, Idiopathic pulmonary fibrosis, Interstitial lung disease, Pneumonitis, Pulmonary toxicity), Pulmonary embolism (Pulmonary artery thrombosis, Pulmonary embolism, Pulmonary thrombosis).
b
Adverse reaction incidences were not adjusted for the difference in duration of study treatment; median was 11 months for patients who received XALKORI and 3 months for patients who received chemotherapy.

Adverse Reactionb,

n (%)

XALKORI

(N=172)

Chemotherapy

(N=171)

All Grades

Grade 3/4

All Grades

Grade 3/4

Blood and Lymphatic System Disorders

Neutropeniaa

Leukopeniaa


54 (31)

38 (22)


24 (14)

7 (4)


40 (23)

23 (14)


33 (19)

12 (7)

Cardiac Disorders

Electrocardiogram QT prolonged

Bradycardiaa

Syncope


9 (5)

14 (8)

6 (4)


6 (4)

0 (0)

6 (4)


0 (0)

0 (0)

0 (0)


0 (0)

0 (0)

0 (0)

Eye Disorders

Vision disordera

108 (63)

0 (0)

15 (9)

0 (0)

Gastrointestinal Disorders
Oesophagitisa

Vomiting

Nausea

Diarrhea
Constipation

Dyspepsia


4 (2)

90 (52)
100 (58)
108 (63)
82 (48)
15 (9)


0 (0)

4 (2)
3 (2)
1 (1)
4 (2)
0 (0)


0 (0)

32 (19)
64 (37)
34 (20)
39 (23)
6 (4)


0 (0)

0 (0)
1(1)
1 (1)
0 (0)
0 (0)

General Disorders and Administration Site Conditions
Fatigue
Oedemaa



52 (30)
74 (43)



4 (2)
0 (0)



60 (35)
28 (16)



8 (5)
0 (0)

Hepatobiliary Disorders
Elevated transaminasesa

Blood alkaline phosphatase increased

Hepatic failure


74 (43)
17 (10)

1 (1)


31 (18)
1 (1)

1 (1)


25 (15)

6 (4)

0 (0)


4 (2)

0 (0)

0 (0)

Infections and Infestations

Upper Respiratory Infectiona

54 (31)

0 (0)

23 (14)

1 (1)

Investigations

Blood testosterone decreaseda

1 (<1)

0 (0)

0 (0)

0 (0)

Metabolism and Nutritional Disorders

Decreased appetite

Hypokalemia



55 (32)

15 (9)



5 (3)

8 (5)



47 (28)

5 (3)



3 (2)

0 (0)

Nervous System Disorder
Neuropathya

Dizzinessa
Dysgeusia


41 (24)
44 (26)

44 (26)


1 (1)
1 (1)

0 (0)


30 (18)
15 (9)
17 (10)


2 (1)
0 (0)
0 (0)

Renal and Urinary Disorders
Renal cysta

Blood creatinine increased a


8 (5)

13 (8)


0 (0)

0 (0)


1 (1)

3 (2)


0 (0)

0 (0)

Respiratory, Thoracic and Mediastinal Disorders

Interstitial lung diseasea

Pulmonary Embolisma



7 (4)

14 (8)



1 (1)

12 (7)



1 (1)

5 (3)



0 (0)

4 (2)

Skin and Subcutaneous Tissue Disorders

Rash



21 (12)



0 (0)



30 (18)



0 (0)

The following treatment-related Serious Adverse Events (SAEs) were reported in XALKORI clinical studies:

Common Clinical Trial Treatment-Related SAEs (≥1% to <10%):

Vomiting, Pneumonia, Alanine aminotransferase increased, Aspartate aminotransferase increased, Electrocardiogram QT prolonged, Interstitial lung disease

Uncommon Clinical Trial Treatment-Related SAEs (≥0.1% to <1%):

Febrile neutropenia, Neutropenia, Arrhythmia, Cardiac arrest, Abdominal pain upper, Diarrhoea, Nausea, Fatigue, Pyrexia, hepatic failure, Hepatitis, Decreased appetite, Hypokalaemia, Syncope, Renal cyst, Acute respiratory failure, Pneumonitis, Pulmonary artery thrombosis, Pulmonary thrombosis, Drug eruption, Pelvis venous thrombosis

Single-Arm Studies in ALK-Positive Advanced NSCLC (Studies A8081001 and A8081005)

The safety analysis population in Study A8081005 included 1063 patients with ALK-positive metastatic NSCLC who received XALKORI in a clinical trial. The median duration of treatment was 45 weeks. Dosing interruptions and dose reductions due to adverse events occurred in 476 (45%) patients and 192 (18%) of patients, respectively, in Study A8081005. The rate of adverse events resulting in permanent discontinuation was 202 (19%) patients. The most adverse reactions (≥25%) were vision disorder (60%), diarrhea (52%), nausea (56%), vomiting (53%), constipation (44%), edema (49%), elevated transaminases (30%), decreased appetite (30%), fatigue (30%), cough (27%), neuropathy (26%) and dyspnea (25%). The most common Grade 3 or 4 treatment-related adverse events (≥3%) were neutropenia, elevated transaminases and fatigue, hypophosphatemia, and leukopenia. The potentially serious adverse reactions of pneumonitis and QT interval prolongation are discussed in WARNINGS AND PRECAUTIONS.

The safety analysis population in Study A8081001 included 154 patients in the ALK rearranged expansion cohort who received XALKORI. The median duration of treatment was 57 weeks. Dosing interruptions and dose reductions due to adverse events occurred in 73 (47%) patients, most common of which were ALT increased, pyrexia and pneumonia, and 18 (12%) patients, most common of which was ALT increased, respectively. The rate of adverse events resulting in permanent discontinuation was 24 (16%), most common of which was pneumonitis. The most common treatment-related adverse reactions (≥ 25%) are consistent with Studies A8081007 and A8081005, and were vision disorder, nausea, diarrhea, vomiting, edema, constipation, dizziness, fatigue, decreased appetite, rash, and neuropathy. The most common Grade 3 or 4 adverse reactions (>3%) in Study A8081001 were elevated transaminases, neutropenia, syncope, nausea, vomiting, edema, fatigue, and neuropathy.

Six unexplained deaths (<1%) occurred during treatment with XALKORI in these studies.

Table 3 Adverse Drug Reactions Reported at a Very Common Frequency (≥10%) in Patients with ALK Positive Advanced NSCLC in Studies A8081001a* or A8081005a** – in at least 1 study
 
Abbreviations: RP2D: Recommended Phase 2 Dose N=total number of patients; n=number of patients meeting prespecified criteria.
*
The percentages of adverse drug reactions from Study 1001 were based on 119 patients with the data cutoff date of 15 September 2010, with the exception of Blood creatinine increased, for which the percentage was based on 154 patients with the data cutoff date of 15 Jul 2014.
**
The percentages of adverse drug reactions from Study 1005 were based on 934 patients with the data cutoff date of 15 February 2012, with the exception of Blood creatinine increased, for which the percentage was based on 1065 patients with the data cutoff date of 15 Jul 2014.

Event terms that represent the same medical concept or condition were grouped together and reported as single adverse reaction in the table above. Terms actually reported in the study up to the data cutoff date and contributing to the relevant adverse reaction are indicated in parenthesis, as listed below.
a
Study A8081001 used NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, and Study A8081005 used NCI CTCAE version 4.0
b
Cough (cough, productive cough), dizziness (balance disorder, dizziness, dizziness exertional, dizziness postural, presyncope), dyspnoea (dyspnoea, dyspnoea at rest, dyspnoea exertional, dyspnoea paroxysmal nocturnal, nocturnal dyspnoea, orthopnoea), edema (edema, edema peripheral, face oedema, generalized oedema, local swelling, localized oedema, oedema (edema), oedema peripheral (edema peripheral), periorbital oedema), elevated transaminases (alanine aminotransferase, alanine aminotransferase abnormal, alanine aminotransferase increased, aspartate aminotransferase, aspartate aminotransferase abnormal, aspartate aminotransferase increased, gamma-glutamyltransferase abnormal, gamma-glutamyltransferase increased, hepatic enzyme abnormal, hepatic enzyme increased, hepatic function abnormal, hypertransaminasaemia, liver function test abnormal, transaminases, transaminases abnormal, transaminases increased), blood creatinine increased (blood creatinine increased, creatinine renal clearance decreased), neuropathy (acute polyneuropathy, amyotrophy, areflexia, autoimmune neuropathy, autonomic failure syndrome, autonomic neuropathy, axonal neuropathy, biopsy peripheral nerve abnormal, burning feet syndrome, burning sensation, decreased vibratory sense, demyelinating polyneuropathy, dysaesthesia, electromyogram abnormal, formication, gait disturbance, genital hypoaesthesia, Guillain-Barre syndrome, hyperaesthesia, hypoaesthesia, hyporeflexia, hypotonia, ischaemic neuropathy, loss of proprioception, Miller Fisher syndrome, mononeuritis, mononeuropathy, mononeuropathy multiplex, motor dysfunction, multifocal motor neuropathy, muscle atrophy, muscular weakness, myelopathy, nerve conduction studies abnormal, nerve degeneration, neuralgia, neuritis, neuromuscular toxicity, neuromyopathy, neuropathy peripheral, neuropathy vitamin B6 deficiency, neurotoxicity, paraesthesia, peripheral motor neuropathy, peripheral nerve lesion, peripheral nerve palsy, peripheral nervous system function test abnormal, peripheral sensorimotor neuropathy, peripheral sensory neuropathy, peroneal muscular atrophy, peroneal nerve palsy, phrenic nerve paralysis, polyneuropathy, polyneuropathy chronic, polyneuropathy idiopathic progressive, radiation neuropathy, sensorimotor disorder, sensory disturbance, sensory loss, skin burning sensation, temperature perception test decreased, Tinel’s sign, toxic neuropathy, ulnar neuritis), neutropenia (febrile neutropenia, neutropenia, neutrophil count decreased), and vision disorder (diplopia, halo vision, photophobia, photopsia, vision blurred, visual field defect, visual impairment, vitreous floaters, visual acuity reduced, visual brightness).
c
Includes 6 Grade 5 events

Adverse Reaction,

n (%)

Study A8081001 RP2D (N=119)

Study A8081005 (N=934)

All Grades

Grade 3/4

All Grades

Grade 3/4

Blood and Lymphatic System Disorders

Neutropeniab

6 (5)

4 (3)

125 (13)

72 (8)

Eye Disorders

Vision disorderb

75 (63)

0 (0)

513 (55)

4 (<1)

Gastrointestinal Disorders

Nausea

Diarrhea
Vomiting

Constipation

Dyspepsia

59 (50)

57 (48)

48 (40)

45 (38)

14 (12)

1 (1)

1 (1)

1 (1)

1 (1)

0 (0)

476 (51)

432 (46)

433 (46)

356 (38)

55 (6)

18 (2)

11 (1)

12 (1)

4 (<1)
0 (0)

General Disorders and Administration Site Conditions

Edemab

Fatigue


43 (36)

30 (25)


1 (1)

3 (3)


360 (39)
239 (26)


13 (1)

28 (3)

Investigations

Elevated transminasesb


24 (20)


10 (8)


221 (24)


65 (7)

Renal and Urinary Disorders

Blood creatinine increasedb

3 (2)

0 (0)

102 (10)

4 (<1)

Metabolism and Nutritional Disorders

Decreased Appetite

28 (24)

1 (1)

228 (24)

7 (<1)

Nervous System Disorder

Dizzinessb

Neuropathyb

Dysgeusia

35 (29%)
24 (20)

10 (8)

0 (0)
1 (<1)

0 (0)

173 (19)
178 (19)

178 (19)

4 (<1)
9 (1)
0 (0)

Respiratory, Thoracic and Mediastinal Disorders

Dyspnoeabc

Coughb

22 (18)

16 (13)


6 (5)

1 (1)


184 (20) c

194 (21)


43 (5)

3 (<1)

Skin and Subcutaneous Tissue Disorders

Rash

21 (18)

0 (0)

89 (10)

1 (<1)

Table 4 Adverse Drug Reactions Reported at a Common Frequency (≥1% to <10%) in Patients with ALK-Positive Advanced NSCLC in Studies A8081001a* and A8081005a**- in at least 1 study
*
The percentages of adverse drug reactions from Study 1001 were based on 119 patients with the data cutoff date of 15 September 2010, with the exception of Blood creatinine increased, for which the percentage was based on 154 patients with the data cutoff date of 15 Jul 2014, and Oesophagitis and Blood testosterone decreased with the cutoff date of 30 Nov 2013.
**
The percentages of adverse drug reactions from Study 1005 were based on 934 patients with the data cutoff date of 15 February 2012, with the exception of Blood creatinine increased, for which the percentage was based on 1065 patients with the data cutoff date of 15 Jul 2014, and Oesophagitis and Blood testosterone decreased for which the percentage was based on 1063 patients with the cutoff date of 30 Nov 2013.
RP2D: Recommended Phase 2 Dose
a
Study A8081001 used NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, and Study A8081005 used NCI CTCAE version 4.0
b
Blood testosterone decreased (Blood testosterone decreased, Hypogonadism, Secondary hypogonadism); Bradycardia (bradyarrhythmia, bradycardia, heart rate decreased, sinus bradycardia, sinus arrest), interstitial lung disease (acute interstitial pneumonitis, acute lung injury, acute respiratory distress syndrome, alveolitis, alveolitis allergic, alveolitis fibrosing, alveolitis necrotising, diffuse alveolar damage, eosinophilic pneumonia, eosinophilic pneumonia acute, interstitial lung disease, pneumonitis, pulmonary toxicity), Oesophagitis (Oesophagitis, Oesophageal ulcer), renal cyst (renal abscess, renal cyst, renal cyst excision, renal cyst haemorrhage, renal cyst infection, renal cyst ruptured).
c
Includes 1 Grade 5 event

Adverse Reaction,

n (%)

Study A8081001 RP2D (N=119)

Study A8081005 (N=934)

All Grades

Grade 3/4

All Grades

Grade 3/4

Blood and Lymphatic System Disorders

Leukopenia

Lymphopenia

6 (5)

6 (5)

0 (0)

3(3)

58 (6)

34 (4)

14 (2)

25 (3)

Cardiac Disorders

Bradycardiab

Electrocardiogram QT Prolonged

8 (7)

1 (1)

0 (0)

0 (0)

57 (6)

25 (3)

2(<1)

11 (1)

Gastrointestinal

Oesophagitisb

3 (2)

0 (0)

16 (2)

0 (0)

Investigations

Blood testosterone decreasedb


15 (10)


0 (0)


11 (1)


1 (<1)

Renal and Urinary Disorders

Renal cystb

0 (0)

0 (0)

12 (1)

1 (<1)

Respiratory, Thoracic and Mediastinal Disorders

Interstitial lung diseasebc

3 (3)


3(3)


22 (2)c

8 (1)

Vascular Disorders

Hypotension

6 (5)

0 (0)

36 (4)

6 (<1)

The following treatment-related Serious Adverse Events (SAEs) were reported in XALKORI clinical studies:

Common Clinical Trial Treatment-Related SAEs (≥1% to <10%)

The following treatment-related SAE was reported with XALKORI treatment at a common frequency (≥1% to <10%): pneumonitis (2%).

Uncommon Clinical Trial Treatment-Related SAEs (≥0.1% to <1%)

The following treatment-related SAEs were reported with XALKORI treatment at an uncommon frequency (≥0.1% to <1%): alanine aminotransferase increased (0.4%), constipation (0.4%), death (0.4%), dyspnoea (0.4%), febrile neutropenia (0.4%), haematoma (0.4%), hepatic enzyme increased (0.4%), hypokalaemia (0.4%), hyponatraemia (0.4%), infection (0.4%), liver function test abnormality (0.4%), oedema peripheral (0.4%), oesophageal ulcer (0.4%), pneumonia (0.4%), renal abscess (0.4%), and supraventricular tachycardia (0.4%).

There were no clinical trial SAEs that occurred at a rare frequency (≤0.1%).

Single-Arm Study in ROS1-Positive Advanced NSCLC (ROS1 Rearranged Expansion Cohort from Study A8081001)

The safety analysis population in Study A8081001 included 53 patients with ROS1 positive NSCLC who received XALKORI. The median duration of treatment was 101 weeks. All-causality adverse events associated with dosing interruptions and dose reductions occurred in 24 (45%) patients and 6 (11%) patients, respectively. All-causality adverse events associated with permanent discontinuation from treatment occurred in 4 (8%) patients with ROS1-positive NSCLC in Study A8081001. The most common adverse reactions (≥25%) in patients with ROS1-positive NSCLC from Study A8081001 were consistent with those seen in patients with ALK-positive advanced NSCLC and were vision disorder, nausea, edema, vomiting, diarrhea, constipation, dizziness, elevated transaminases, fatigue, neuropathy, bradycardia, and rash. The most common Grade 3 or 4 adverse reactions (>3%) were neutropenia, syncope, vomiting, elevated transaminases, and electrocardiogram QT prolonged.

Electrocardiography and Haemodynamics

ECG evaluations were performed in all patients who received XALKORI 250 mg twice daily. Serial ECGs in triplicate were collected following a single dose and at steady state to evaluate the effect of XALKORI on QT intervals. Crizotinib 250 mg twice daily was associated with a statistically significant decrease in heart rate during steady-state treatment (see ADVERSE REACTIONS). At 6 hours post-dosing on Day 22 of treatment, heart rate was decreased by mean 15.9 beats per minute (90% CI: -17.9, -13.8) in 105 ALK-positive NSCLC patients in Study A8081005.

XALKORI 250 mg twice daily was also associated with a statistically significant prolongation of the QTcF interval (Fridericia-corrected QT interval) during steady-state treatment. At 6 hours post-dosing on Day 22 of treatment, the QTcF interval was prolonged by mean increase from baseline of 10.3 msec (90% CI: 7.3, 13.3). In clinical trials of patients with ALK-positive or ROS1-positive NSCLC (n=1722), electrocardiogram QT prolonged (all grades) was observed in 64 (3.7%) patients. QTcF greater than or equal to 500 msec on at least 2 separate ECGs was observed in 34 of 1619 (2.1%) patients with at least 1 postbaseline ECG assessment and a maximum increase from baseline QTcF greater than 60 msec was observed in 79 (5.0%) of 1585 patients with a baseline and at least 1 postbaseline ECG assessment.

An ECG substudy from Studies A8081005 and A8081007 using blinded manual ECG measurements was conducted in 52 ALK-positive NSCLC patients who received crizotinib 250 mg twice daily. A total of 11 (21.2%) patients and 1 (1.9%) patient had a maximum increase from baseline in QTcF of ≥30 msec to < 60 msec and ≥ 60 msec, respectively, and no patients had a maximum QTcF ≥ 480 msec in this analysis. The central tendency analysis indicated that the largest mean change from baseline in QTcF was 12.3 msec (90% CI: 5.1, 19.5) (least squares [LS] mean from Analysis of Variance [ANOVA]) and occurred at 6 hours post-dose on Cycle 2 Day 1 (steady state). All upper limits of the 90% CI for the LS mean change from baseline in QTcF at all Cycle 2 Day 1 time points were <20 msec. HR decreased with a maximum reduction of 17.8 (range: -51 to +9) beats per minutes after 8 hours on Cycle 2 Day 1 (last ECG collecting time point). Bradycardia was reported in 6 (9.2%) patients.

Pharmacokinetic/pharmacodynamic modeling indicated a concentration-dependent increase in QTcF and decrease in HR (see WARNINGS AND PRECAUTIONS, Cardiovascular & Monitoring and Laboratory Tests; DRUG INTERACTIONS; DOSAGE AND ADMINISTRATION).

Abnormal Hematologic and Clinical Chemistry Findings

Table 5a. Summary of Treatment-Emergent Laboratory Abnormalities with Grade 3 or 4 Incidence of ≥4% in XALKORI-Treated Patients with ALK-positive previously untreated NSCLC– Study A8081014

Laboratory Abnormality

XALKORI

Chemotherapy

Any Grade

(%)

Grade 3/4

(%)

Any Grade

(%)

Grade 3/4

(%)

Hematology

Neutropenia

52

11

59

16

Lymphopenia

48

7

53

13

Chemistry

ALT elevation

79

15

33

2

AST elevation

66

8

28

1

Hypophosphatemia

32

10

21

6

Additional laboratory test abnormality in patients treated with XALKORI was an increase in creatinine (Any Grade: 99%; Grade 3: 2%; Grade 4: 0%) compared to the chemotherapy arm (Any Grade: 92%; Grade 3: 0%; Grade 4: 1%).

Table 5b. Summary of Treatment-Emergent Laboratory Abnormalities with Grade 3 or 4 Incidence of ≥4% in XALKORI-Treated Patients with ALK-positive previously treated NSCLC – Study A8081007

Laboratory Abnormality

Crizotinib

Chemotherapy

Any Grade

(%)

Grade 3/4

(%)

Any Grade

(%)

Grade 3/4

(%)

Hematology

Neutropenia

52

15

28

12

Lymphopenia

58

15

55

24

White blood cell decreased

55

5

36

8

Chemistry

ALT elevation

79

18

40

5

AST elevation

69

9

33

1

Hyperglycemia

44

4

49

4

Hypokalemia

21

5

12

1

Hypophosphatemia

37

8

24

6

Additional laboratory test abnormality in patients treated with XALKORI was an increase in creatinine (Any Grade: 96%; Grade 3: 1%; Grade 4: 0%) compared to the chemotherapy arm (Any Grade: 72%; Grade 3: 0%; Grade 4: 0%).

Table 5c. Summary of Treatment-Emergent Laboratory Abnormalities with Shift to Grade 3 or 4 Incidence of ≥4% in XALKORI-Treated Patients with ALK-positive NSCLC– Study A8081005

Laboratory Abnormality

Shift to Any Grade

Shift to Grade 3/4

Hematology

Neutropenia

38%

8%

Lymphopenia

48%

15%

Chemistry

ALT elevation

67%

8%

Hypophosphatemia
Hyponatremia

30%
18%

8%

5%

Table 5d. Summary of Treatment-Emergent Laboratory Abnormalities with Shift to Grade 3 or 4 Incidence of ≥4% in XALKORI-Treated Patients with ALK-positive NSCLC – Study A8081001

Laboratory Abnormality

Shift to Any Grade

Shift to Grade 3/4

Hematology

Lymphopenia

35%

11%

Chemistry

ALT elevation

65%

5%

Hypophosphatemia
Hyponatremia
Hyperglycemia

42%
21%
44%

5%
5%
4%

Hepatic Laboratory Abnormalities

In clinical studies of XALKORI in patients with either ALK‑positive or ROS1-positive NSCLC, shifts to Grade 3 or 4 ALT, AST, and alkaline phosphatase were observed in 187 (11%), 95 (6%), and 33 (2%) patients, respectively. Patients should be monitored for hepatotoxicity and managed as recommended in WARNINGS AND PRECAUTIONS section.

Drug-induced hepatotoxicity, including hepatic failure, with fatal outcome has occurred in 2 (0.1%) of the 1722 patients treated with XALKORI across clinical trials. Concurrent elevations in ALT and/or AST ≥3 x ULN and total bilirubin ≥2 x ULN without significant elevations of phosphatase (Hy’s Law) have been observed in 8 (<1%) patients treated with XALKORI in clinical trials. Grade 3 or 4 ALT or AST elevations were observed in 187 (11%) and 95 (6%) of patients, respectively. Seventeen (1%) patients required permanent discontinuation from treatment associated with elevated transaminases. Concurrent elevations in ALT >3 x ULN and total bilirubin >2 x ULN without elevated alkaline phosphatase were detected in <1% patients in clinical trials. Liver function tests including ALT, AST, and total bilirubin should be monitored every 2 weeks during the first 2 months of treatment, then once a month and as clinically indicated, with more frequent repeat testing for Grades 2, 3 or 4 elevation. In patients who develop transaminase elevations, see Dose Modification section under DOSAGE AND ADMINISTRATION.

Renal Laboratory Abnormalities

In clinical studies of crizotinib in patients with ALK-positive advanced NSCLC, the estimated glomerular filtration rate (eGFR) decreased from a baseline median of 96.42 mL/min/1.73 m2 (n=1681) to a median of 80.23 mL/min/1.73 m2 at 2 weeks of treatment (n=1499). Median eGFR appeared to be relatively stable from 12 weeks of treatment (78.06 mL/min/1.73 m2, n=1338) through 104 weeks of treatment (75.45 mL/min/1.73 m2, n=315) and increased to 83.02 mL/min/1.73 m2 at 28 days after the last does of crizotinib (n=123).

Shifts to eGFR Grade 4 (15 to <30 mL/min/1.73 m2) or to eGFR Grade 5 (<15 mL/min/1.73 m2) were observed in 3% and <1% of patients, respectively.

Hematologic Effects

In clinical studies of XALKORI in patients with either ALK-positive or ROS1-positive advanced NSCLC, shifts to Grade 3 or 4 decreases in leukocytes and neutrophils were observed in 64 (4%) and 226 (13%) patients, respectively. Complete blood counts, including differential white blood cell counts, should be monitored as clinically indicated, with more frequent repeat testing if Grade 3 or 4 abnormalities are observed, or if fever or infection occurs. In patients who develop hematologic laboratory abnormalities, see Dose Modification section under DOSAGE AND ADMINISTRATION.

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