XALKORI® Adverse Reactions

(crizotinib)

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

•
Hepatotoxicity [see Warnings and Precautions (5.1)]
•
Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.2)]
•
QT Interval Prolongation [see Warnings and Precautions (5.3)]
•
Bradycardia [see Warnings and Precautions (5.4)]
•
Severe Visual Loss [see Warnings and Precautions (5.5)]
•
Gastrointestinal Toxicity in Pediatric and Young Adult Patients with ALCL or Pediatric Patients with IMT [see Warnings and Precautions (5.6)]

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 clinical practice.

The data in the Warnings and Precautions reflect exposure to XALKORI in 1719 patients with NSCLC who received XALKORI 250 mg twice daily enrolled on Studies 1 (including an additional 109 patients who crossed over from the control arm), 2, 3, a single-arm trial (n=1063) of ALK-positive NSCLC, and an additional ALK-positive NSCLC expansion cohort of a dose finding study (n=154). The data also reflect exposure to XALKORI in 121 patients ages 1 to ≤21 years with relapsed or refractory tumors, including 26 patients with systemic ALCL and 14 pediatric patients with IMT, in a single-arm trial (Study ADVL0912). The data are also described for 7 adult patients with IMT treated with XALKORI in a single-arm trial (Study A8081013).

ALK- or ROS1-Positive Metastatic NSCLC

The data described below is based primarily on 343 patients with ALK-positive metastatic NSCLC who received XALKORI 250 mg orally twice daily from 2 open-label, randomized, active-controlled trials (Studies 1 and 2). The safety of XALKORI was also evaluated in 50 patients with ROS1-positive metastatic NSCLC from a single-arm study (Study 3).

The most common adverse reactions (≥25%) of XALKORI in patients with NSCLC are vision disorders, nausea, diarrhea, vomiting, edema, constipation, elevated transaminases, fatigue, decreased appetite, upper respiratory infection, dizziness, and neuropathy.

Previously Untreated ALK-Positive Metastatic NSCLC - Study 1 (PROFILE 1014)

The data in Table 9 are derived from 340 patients with ALK-positive metastatic NSCLC who had not received previous systemic treatment for advanced disease who received treatment in a randomized, multicenter, open-label, active-controlled trial (Study 1). Patients in the XALKORI arm (n=171) 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 169 patients in the chemotherapy arm received pemetrexed 500 mg/m2 with cisplatin 75 mg/m2 (n=91) or carboplatin at a dose calculated to produce an AUC of 5 or 6 mg×min/mL (n=78). Chemotherapy was given by intravenous infusion every 3 weeks for up to 6 cycles, in the absence of dose-limiting chemotherapy-related toxicities. After 6 cycles, patients remained on study with no additional anticancer treatment, and tumor assessments continued until documented disease progression.

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. Median duration of treatment was 5.2 months for patients who received XALKORI after cross over from chemotherapy. Across the 340 patients who were treated in Study 1, the median age was 53 years; 16% of patients were older than 65 years. A total of 62% of patients were female and 46% were Asian.

Serious adverse events were reported in 34% of patients treated with XALKORI. 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 6% 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%).

Permanent discontinuation of XALKORI treatment for adverse reactions was 8%. 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%).

Tables 9 and 10 summarize common adverse reactions and laboratory abnormalities in XALKORI-treated patients.

Table 9. 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*
Adverse ReactionXALKORI
(N=171)		Chemotherapy
(Pemetrexed/Cisplatin or Pemetrexed/Carboplatin)
(N=169)
All Grades
(%)		Grade 3–4
(%)		All Grades
(%)		Grade 3–4
(%)
*
Adverse reactions were graded using NCI CTCAE version 4.0.
Includes cases reported within the clustered terms:
†
Bradycardia (Bradycardia, Sinus bradycardia).
‡
Vision Disorder (Diplopia, Photophobia, Photopsia, Reduced visual acuity, Blurred vision, Vitreous floaters, Visual impairment).
§
Abdominal pain (Abdominal discomfort, Abdominal pain, Lower abdominal pain, Upper abdominal pain, Abdominal tenderness).
Esophagitis (Esophagitis, Esophageal ulcer).
#
Edema (Edema, Peripheral edema, Face edema, Generalized edema, Local swelling, Periorbital edema).
Þ
Upper respiratory infection (Nasopharyngitis, Pharyngitis, Rhinitis, Upper respiratory tract infection).
ß
Dizziness (Balance disorder, Dizziness, Postural dizziness, Presyncope).

Cardiac

  Bradycardia†

14

1

1

0

  Electrocardiogram QT prolonged

6

2

2

0

Eye

  Vision disorder‡

71

1

10

0

Gastrointestinal

  Diarrhea

61

2

13

1

  Vomiting

46

2

36

3

  Constipation

43

2

30

0

  Abdominal pain§

26

0

12

0

  Dyspepsia

14

0

2

0

  Dysphagia

10

1

2

1

  Esophagitis

6

2

1

0

General

  Edema#

49

1

12

1

  Pyrexia

19

0

11

1

Infections

  Upper respiratory infectionÞ

32

0

12

1

Investigations

  Increased weight

8

1

2

0

Musculoskeletal and Connective Tissue

  Pain in extremity

16

0

7

0

  Muscle spasm

8

0

2

1

Nervous System

  Dysgeusia

26

0

5

0

  Headache

22

1

15

0

  Dizzinessß

18

0

10

1

Additional adverse reactions occurring at an overall incidence between 1% and 60% in patients treated with XALKORI included nausea (56%), decreased appetite (30%), fatigue (29%), neuropathy (21%; gait disturbance, hypoesthesia, muscular weakness, neuralgia, neuropathy peripheral, paresthesia, peripheral sensory neuropathy, polyneuropathy, sensory disturbance), rash (11%), renal cyst (5%), ILD (1%; ILD, pneumonitis), syncope (1%), and decreased blood testosterone (1%; hypogonadism).

Clinically relevant adverse reactions in <1% of patients who received XALKORI included photosensitivity (0.3%).

Table 10. Laboratory Abnormalities with Grades 3–4 Occurring in ≥4% of XALKORI-Treated Patients in Study 1
XALKORIChemotherapy
Laboratory AbnormalityAny Grade
(%)		Grade 3–4
(%)		Any Grade
(%)		Grade 3–4
(%)
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%).

Hematology

  Neutropenia

52

11

59

16

  Lymphopenia

48

7

53

13

Chemistry

  Increased ALT

79

15

33

2

  Increased AST

66

8

28

1

  Hypophosphatemia

32

10

21

6

Previously Treated ALK-Positive Metastatic NSCLC - Study 2 (PROFILE 1007)

The data in Table 11 are derived from 343 patients with ALK-positive metastatic NSCLC enrolled in a randomized, multicenter, active-controlled, open-label trial (Study 2). 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 3 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 1 dose of study treatment), the median age was 50 years; 14% of patients were older than 65 years. A total of 56% of patients were female and 45% of patients were Asian.

Serious adverse reactions were reported in 37% of patients treated with XALKORI and 23% of patients 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 ILD (2.9%). Fatal adverse reactions in XALKORI-treated patients in Study 2 occurred in 5% of 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 increased ALT (8%) including some patients with concurrent increased AST, QTc prolongation (2.9%), and neutropenia (2.3%).

XALKORI was discontinued for adverse reactions in 15% of patients. The most frequent adverse reactions that led to discontinuation of XALKORI were ILD (1.7%), increased ALT and AST (1.2%), dyspnea (1.2%), and pulmonary embolism (1.2%).

Tables 11 and 12 summarize common adverse reactions and laboratory abnormalities, respectively, in XALKORI-treated patients.

Table 11. 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 2*
*
Adverse reactions were graded using NCI CTCAE version 4.0.
Includes cases reported within the clustered terms:
†
Dizziness (Balance disorder, Dizziness, Postural dizziness).
‡
Vision Disorder (Diplopia, Photophobia, Photopsia, Blurred vision, Reduced visual acuity, Visual impairment, Vitreous floaters).
§
Bradycardia (Bradycardia, Sinus bradycardia).
Upper respiratory infection (Laryngitis, Nasopharyngitis, Pharyngitis, Rhinitis, Upper respiratory tract infection).
#
Pulmonary embolism (Pulmonary artery thrombosis, Pulmonary embolism).
Þ
Edema (Face edema, Generalized edema, Local swelling, Localized edema, Edema, Peripheral edema, Periorbital edema).

Adverse Reaction

XALKORI
(N=172)

Chemotherapy
(Pemetrexed or Docetaxel)
(N=171)

All Grades
(%)

Grade 3–4
(%)

All Grades
(%)

Grade 3–4
(%)

Nervous System

  Dysgeusia

26

0

9

0

  Dizziness†

22

1

8

0

  Syncope

3

3

0

0

Eye

  Vision disorder‡

60

0

9

0

Cardiac

  Electrocardiogram QT prolonged

5

3

0

0

  Bradycardia§

5

0

0

0

Investigations

  Decreased weight

10

1

4

0

Gastrointestinal

  Diarrhea

60

0

19

1

  Nausea

55

1

37

1

  Vomiting

47

1

18

0

  Constipation

42

2

23

0

  Dyspepsia

8

0

3

0

Infections

  Upper respiratory infection

26

0

13

1

Respiratory, Thoracic and Mediastinal

  Pulmonary embolism#

6

5

2

2

General

  EdemaÞ

31

0

16

0

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, paresthesia, peripheral sensory neuropathy, polyneuropathy, burning sensation in skin), rash (9%), ILD (4%; acute respiratory distress syndrome, ILD, pneumonitis), renal cyst (4%), esophagitis (2%), hepatic failure (1%), and decreased blood testosterone (1%; hypogonadism).

Clinically relevant adverse reactions in <1% of patients who received XALKORI included photosensitivity (0.4%).

Table 12. Laboratory Abnormalities with Grades 3–4 Occurring in ≥4% of XALKORI-Treated Patients in Study 2
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%).

XALKORI

Chemotherapy

Laboratory Abnormality

Any Grade
(%)

Grade 3–4
(%)

Any Grade
(%)

Grade 3–4
(%)

Hematology

  Lymphopenia

51

9

60

25

  Neutropenia

49

12

28

12

Chemistry

  Increased ALT

76

17

38

4

  Increased AST

61

9

33

0

  Hypophosphatemia

28

5

25

6

  Hypokalemia

18

4

10

1

ROS1-Positive Metastatic NSCLC - Study 3 (PROFILE 1001)

The safety profile of XALKORI from Study 3, which was evaluated in 50 patients with ROS1-positive metastatic NSCLC, was generally consistent with the safety profile of XALKORI evaluated in patients with ALK-positive metastatic NSCLC (n=1669). Vision disorders occurred in 92% of patients in Study 3; 90% were Grade 1 and 2% were Grade 2. The median duration of exposure to XALKORI was 34.4 months.

Description of Selected Adverse Reactions in Patients with Metastatic NSCLC

Vision disorders: Vision disorders, most commonly visual impairment, photopsia, blurred vision, or vitreous floaters, occurred in 63% of 1719 patients. The majority (95%) of these patients had Grade 1 visual adverse reactions. There were 0.8% of patients with Grade 3 and 0.2% of patients with Grade 4 visual impairment. Based on the Visual Symptom Assessment Questionnaire (VSAQ-ALK), patients treated with XALKORI in Studies 1 and 2 reported a higher incidence of visual disturbances compared to patients treated with chemotherapy. The onset of vision disorder generally was within the first week of drug administration. The majority of patients on the XALKORI arms in Studies 1 and 2 (>50%) reported visual disturbances which 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 the VSAQ-ALK questionnaire.

Neuropathy: Neuropathy, most commonly sensory in nature, occurred in 25% of 1719 patients. Most events (95%) were Grade 1 or Grade 2 in severity.

Renal cysts: Renal cysts were experienced by 3.0% of 1719 patients. 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.

Renal toxicity: 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 (n=1499) in patients with ALK-positive advanced NSCLC who received XALKORI in clinical trials. No clinically relevant changes occurred in median eGFR from 12 to 104 weeks of treatment. Median eGFR slightly increased (83.02 mL/min/1.73 m2) 4 weeks after the last dose of XALKORI. Overall, 76% of patients had a decrease in eGFR to <90 mL/min/1.73 m2, 38% had a decrease to eGFR to <60 mL/min/1.73 m2, and 3.6% had a decrease to eGFR to <30 mL/min/1.73 m2.

Relapsed or Refractory, Systemic ALK-Positive ALCL - Study ADVL0912

The safety of XALKORI was evaluated in Study ADVL0912 [see Clinical Studies 14.2], which included 26 patients with relapsed or refractory, systemic ALCL after at least one systemic therapy. Eligible patients were 1 to ≤21 years of age and were required to have an absolute neutrophil count ≥1000/mm3 (750/mm3 if bone marrow was involved), platelet count ≥75,000/mm3 (25,000/mm3 if bone marrow was involved), creatinine clearance ≥70ml/min/1.73m2, and QTc ≤480 msec. The study excluded patients with ALT >2.5 times upper limit of normal (ULN), bilirubin ≤1.5 times ULN, and central nervous system tumors.

Patients with ALCL received XALKORI 165 mg/m2 or 280 mg/m2 orally twice daily until disease progression or unacceptable toxicity. The median duration of exposure was 5.4 months (range 1.8, 82.3 months), with 46% of patients treated for at least 6 months and 35% of patients treated for at least 12 months.

Serious adverse reactions occurred in 35% of patients with ALCL treated with XALKORI. The most frequent serious adverse reactions were neutropenia (12%) and hypotension (8%).

Dose interruptions and dose reductions occurred in 77% and 19% of patients with ALCL, respectively. XALKORI was discontinued for an adverse reaction in 8% of patients.

The most common adverse reactions (≥35%), excluding laboratory abnormalities, were diarrhea, vomiting, nausea, vision disorder, headache, musculoskeletal pain, stomatitis, fatigue, decreased appetite, pyrexia, abdominal pain, cough, and pruritis.

The most common Grade 3 or 4 laboratory abnormalities (≥15%) included neutropenia, lymphopenia, and thrombocytopenia. Grade 4 laboratory abnormalities (≥15%) included neutropenia (62%), lymphopenia (35%), and thrombocytopenia (19%).

Selected adverse reactions are summarized in Table 13.

Table 13. Adverse Reactions in ≥20% of Patients with Systemic ALCL in Study ADVL0912
Adverse reactions were graded using NCI CTCAE version 4.0.
*
Derived from laboratory values collected in Cycle 1 and adverse reaction data.
†
Includes neutrophil count decreased.
‡
Includes lymphocyte count decreased.
§
Includes platelet count decreased.
Includes oral pain, oropharyngeal pain, stomatitis.
#
Includes blurred vision, visual impairment, photophobia, photopsia, reduced visual acuity, vitreous floaters, cyanopsia, heterophoria, visual field defect.
Þ
Includes arthralgia, back pain, myalgia, non-cardiac chest pain, pain in extremity.
ß
Includes peripheral edema, face edema, periorbital edema, localized edema.
à
Includes rash maculopapular, rash pustular.
è
Includes upper respiratory tract infection, pharyngitis, rhinitis, sinusitis.

Adverse Reaction

XALKORI
N=26

All Grades
(%)

Grade 3–4
(%)

Blood and Lymphatic System Disorders*

  Neutropenia†

100

77

  Lymphopenia‡

58

38

  Anemia

54

3.8

  Thrombocytopenia§

38

19

Gastrointestinal Disorders

  Diarrhea

92

12

  Vomiting

92

3.8

  Nausea

77

3.8

  Abdominal Pain

50

0

  Stomatitis

46

8

  Constipation

31

0

Renal Disorders*

  Blood creatinine increased

100

0

Investigations*

  ALT increased

81

3.8

  AST increased

65

3.8

  Hypocalcemia

62

3.8

  Hypoalbuminemia

54

0

  Hyperglycemia

46

0

  Hypomagnesemia

46

0

  Hypoglycemia

35

0

  Hypokalemia

31

3.8

  Hypermagnesemia

27

0

  Hyperkalemia

23

0

Nervous System Disorders

  Headache

58

3.8

  Dysgeusia

23

0

  Dizziness

23

0

Eye Disorders

  Vision disorders#

65

0

Musculoskeletal Disorders

  Musculoskeletal painÞ

58

12

General Disorders

  Fatigue

46

0

  Pyrexia

38

0

  Edemaß

27

0

  Chills

23

0

Metabolism and Nutrition Disorders

  Decreased appetite

42

0

Skin and Subcutaneous Disorders

  Pruritus

35

0

  Rashà

23

0

Infections

  Upper respiratory tract infectionè

31

0

Respiratory Disorders

  Cough

35

0

  Rhinitis allergic

23

0

Vascular Disorders

  Hypertension

31

0

Clinically relevant adverse reactions in <20% of patients treated with XALKORI included:

•
Cardiac disorders: Bradycardia (19%), electrocardiogram QT prolonged (8%)
•
Vascular disorders: Hypotension (19%)
•
Investigations: Alkaline phosphatase increase (19%), hypernatremia (19%), GGT increase (8%), hyponatremia (12%), hyperuricemia (12%), hypophosphatemia (12%)
•
Nervous system disorders: Peripheral neuropathy (12%)
•
Gastrointestinal disorders: Esophagitis (8%)
•
Blood and lymphatic disorders: Febrile neutropenia (3.8%)
•
Musculoskeletal disorders: Muscular weakness (8%)
•
Renal disorders: Acute renal injury (8%)

Unresectable, Recurrent, or Refractory ALK-Positive IMT

Study ADVL0912

The safety of XALKORI was evaluated in Study ADVL0912 [see Clinical Studies (14.3)] that included 14 pediatric patients with unresectable, recurrent, or refractory IMT.

Pediatric patients with IMT received XALKORI 280 mg/m2 orally twice daily until disease progression or unacceptable toxicity. Two patients received a lower dose. The median duration of treatment with XALKORI was 20.5 months.

Serious adverse reactions occurred in 7% of pediatric patients with IMT treated with XALKORI. The most frequent serious adverse reaction was neutropenia and hypotension (7% for each).

Dose interruptions due to an adverse reaction occurred in 71% of patients. Dose reductions due to an adverse reaction occurred in 29% of patients. Permanent discontinuation occurred in 29% of patients.

The most common adverse reactions (≥35%) were vomiting, nausea, diarrhea, abdominal pain, rash, vision disorder, upper respiratory tract infection, cough, pyrexia, musculoskeletal pain, fatigue, edema, constipation, and headache.

The most common Grade 3 or 4 laboratory abnormality (>15%) was neutropenia.

Table 14 and Table 15 summarize the adverse reactions and laboratory abnormalities, respectively, in Study ADVL0912.

Table 14. Adverse Reactions in ≥20% of Pediatric Patients with IMT Treated With XALKORI in Study ADVL0912
Adverse reactions were graded using NCI CTCAE version 4.0.
*
Includes abdominal pain and abdominal pain upper.
†
Includes oral pain and oropharyngeal pain.
‡
Includes upper respiratory tract infection, pharyngitis, rhinitis.
§
Includes cough and productive cough.
Includes rash maculopapular, rash pustular, dermatitis acneiform.
#
Includes face edema, localized edema, periorbital edema, peripheral edema.
Þ
Includes pain, bone pain, ear pain.
ß
Includes photophobia, photopsia, vision blurred, visual impairment, vitreous floaters.
à
Includes arthralgia, myalgia, non-cardiac chest pain, pain in extremity.

Adverse Reaction

XALKORI
N=14

All Grades
(%)

Grade 3–4
(%)

Gastrointestinal Disorders

  Vomiting

93

0

  Nausea

86

0

  Diarrhea

64

7

  Abdominal pain*

57

0

  Constipation

36

0

  Stomatitis†

29

0

Infections

  Upper respiratory tract infection‡

64

0

  Skin Infection

29

0

Respiratory Disorders

  Cough§

64

0

  Rhinitis allergic

29

0

Skin and Subcutaneous Disorders

  Rash

57

0

General Disorders

  Pyrexia

50

0

  Fatigue

43

0

  Edema#

36

7

  PainÞ

29

0

Eye Disorders

  Vision disordersß

50

0

Musculoskeletal Disorders

  Musculoskeletal painà

43

0

Nervous System Disorders

  Headache

36

0

Metabolism and Nutrition Disorders

  Decreased appetite

29

0

Vascular Disorders

  Hypotension

21

7

Clinically relevant adverse reactions in <20% of pediatric patients with IMT treated with XALKORI included:

Cardiac disorders: Bradycardia (14%), electrocardiogram QT prolonged (7%)

Gastrointestinal disorders: Dyspepsia (14%), esophagitis (7%)

Vascular disorders: Hypertension (14%)

Nervous system disorders: Peripheral neuropathy (7%)

Blood and lymphatic disorders: Febrile neutropenia (7%)

Musculoskeletal disorders: Muscular weakness (7%)

Table 15. Laboratory Abnormalities (≥15%) That Worsened from Baseline in Pediatric Patients with IMT Treated With XALKORI in Study ADVL0912
*
The incidence is based on the number of patients who had both a baseline and at least one on-study laboratory measurement and varied from 13 to 14.
†
Laboratory abnormality data were only collected for the 1st cycle (28 days) of treatment for the duration of the study.

Laboratory Abnormality

XALKORI*,†

Any Grade
(%)

Grade 3–4
(%)

Chemistry

  Increased creatinine

100

0

  Decreased calcium

36

0

  Increased magnesium

23

0

  Decreased phosphate

15

0

Hematology

  Decreased neutrophils

64

36

Hepatic

  Increased ALT

36

0

Study A8081013

The safety of XALKORI for adult patients with ALK-positive IMT was evaluated in Study A8081013 [see Clinical Studies (14.3)] that included 7 patients with IMT with a median age of 38 years (range 23 to 73). The safety profile of this patient group was generally consistent with the safety profile of XALKORI evaluated in patients with ALK-positive or ROS1-positive NSCLC.

The most frequent adverse reactions (≥20%) were vision disorders, nausea, and edema.

6.2 Postmarketing Experience

The following additional adverse reaction has been identified during post-approval use of XALKORI. Because this reaction is reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

Investigations: Increased blood creatine phosphokinase

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Adverse Reactions

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

•
Hepatotoxicity [see Warnings and Precautions (5.1)]
•
Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.2)]
•
QT Interval Prolongation [see Warnings and Precautions (5.3)]
•
Bradycardia [see Warnings and Precautions (5.4)]
•
Severe Visual Loss [see Warnings and Precautions (5.5)]
•
Gastrointestinal Toxicity in Pediatric and Young Adult Patients with ALCL or Pediatric Patients with IMT [see Warnings and Precautions (5.6)]

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 clinical practice.

The data in the Warnings and Precautions reflect exposure to XALKORI in 1719 patients with NSCLC who received XALKORI 250 mg twice daily enrolled on Studies 1 (including an additional 109 patients who crossed over from the control arm), 2, 3, a single-arm trial (n=1063) of ALK-positive NSCLC, and an additional ALK-positive NSCLC expansion cohort of a dose finding study (n=154). The data also reflect exposure to XALKORI in 121 patients ages 1 to ≤21 years with relapsed or refractory tumors, including 26 patients with systemic ALCL and 14 pediatric patients with IMT, in a single-arm trial (Study ADVL0912). The data are also described for 7 adult patients with IMT treated with XALKORI in a single-arm trial (Study A8081013).

ALK- or ROS1-Positive Metastatic NSCLC

The data described below is based primarily on 343 patients with ALK-positive metastatic NSCLC who received XALKORI 250 mg orally twice daily from 2 open-label, randomized, active-controlled trials (Studies 1 and 2). The safety of XALKORI was also evaluated in 50 patients with ROS1-positive metastatic NSCLC from a single-arm study (Study 3).

The most common adverse reactions (≥25%) of XALKORI in patients with NSCLC are vision disorders, nausea, diarrhea, vomiting, edema, constipation, elevated transaminases, fatigue, decreased appetite, upper respiratory infection, dizziness, and neuropathy.

Previously Untreated ALK-Positive Metastatic NSCLC - Study 1 (PROFILE 1014)

The data in Table 9 are derived from 340 patients with ALK-positive metastatic NSCLC who had not received previous systemic treatment for advanced disease who received treatment in a randomized, multicenter, open-label, active-controlled trial (Study 1). Patients in the XALKORI arm (n=171) 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 169 patients in the chemotherapy arm received pemetrexed 500 mg/m2 with cisplatin 75 mg/m2 (n=91) or carboplatin at a dose calculated to produce an AUC of 5 or 6 mg×min/mL (n=78). Chemotherapy was given by intravenous infusion every 3 weeks for up to 6 cycles, in the absence of dose-limiting chemotherapy-related toxicities. After 6 cycles, patients remained on study with no additional anticancer treatment, and tumor assessments continued until documented disease progression.

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. Median duration of treatment was 5.2 months for patients who received XALKORI after cross over from chemotherapy. Across the 340 patients who were treated in Study 1, the median age was 53 years; 16% of patients were older than 65 years. A total of 62% of patients were female and 46% were Asian.

Serious adverse events were reported in 34% of patients treated with XALKORI. 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 6% 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%).

Permanent discontinuation of XALKORI treatment for adverse reactions was 8%. 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%).

Tables 9 and 10 summarize common adverse reactions and laboratory abnormalities in XALKORI-treated patients.

Table 9. 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*
Adverse ReactionXALKORI
(N=171)		Chemotherapy
(Pemetrexed/Cisplatin or Pemetrexed/Carboplatin)
(N=169)
All Grades
(%)		Grade 3–4
(%)		All Grades
(%)		Grade 3–4
(%)
*
Adverse reactions were graded using NCI CTCAE version 4.0.
Includes cases reported within the clustered terms:
†
Bradycardia (Bradycardia, Sinus bradycardia).
‡
Vision Disorder (Diplopia, Photophobia, Photopsia, Reduced visual acuity, Blurred vision, Vitreous floaters, Visual impairment).
§
Abdominal pain (Abdominal discomfort, Abdominal pain, Lower abdominal pain, Upper abdominal pain, Abdominal tenderness).
Esophagitis (Esophagitis, Esophageal ulcer).
#
Edema (Edema, Peripheral edema, Face edema, Generalized edema, Local swelling, Periorbital edema).
Þ
Upper respiratory infection (Nasopharyngitis, Pharyngitis, Rhinitis, Upper respiratory tract infection).
ß
Dizziness (Balance disorder, Dizziness, Postural dizziness, Presyncope).

Cardiac

  Bradycardia†

14

1

1

0

  Electrocardiogram QT prolonged

6

2

2

0

Eye

  Vision disorder‡

71

1

10

0

Gastrointestinal

  Diarrhea

61

2

13

1

  Vomiting

46

2

36

3

  Constipation

43

2

30

0

  Abdominal pain§

26

0

12

0

  Dyspepsia

14

0

2

0

  Dysphagia

10

1

2

1

  Esophagitis

6

2

1

0

General

  Edema#

49

1

12

1

  Pyrexia

19

0

11

1

Infections

  Upper respiratory infectionÞ

32

0

12

1

Investigations

  Increased weight

8

1

2

0

Musculoskeletal and Connective Tissue

  Pain in extremity

16

0

7

0

  Muscle spasm

8

0

2

1

Nervous System

  Dysgeusia

26

0

5

0

  Headache

22

1

15

0

  Dizzinessß

18

0

10

1

Additional adverse reactions occurring at an overall incidence between 1% and 60% in patients treated with XALKORI included nausea (56%), decreased appetite (30%), fatigue (29%), neuropathy (21%; gait disturbance, hypoesthesia, muscular weakness, neuralgia, neuropathy peripheral, paresthesia, peripheral sensory neuropathy, polyneuropathy, sensory disturbance), rash (11%), renal cyst (5%), ILD (1%; ILD, pneumonitis), syncope (1%), and decreased blood testosterone (1%; hypogonadism).

Clinically relevant adverse reactions in <1% of patients who received XALKORI included photosensitivity (0.3%).

Table 10. Laboratory Abnormalities with Grades 3–4 Occurring in ≥4% of XALKORI-Treated Patients in Study 1
XALKORIChemotherapy
Laboratory AbnormalityAny Grade
(%)		Grade 3–4
(%)		Any Grade
(%)		Grade 3–4
(%)
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%).

Hematology

  Neutropenia

52

11

59

16

  Lymphopenia

48

7

53

13

Chemistry

  Increased ALT

79

15

33

2

  Increased AST

66

8

28

1

  Hypophosphatemia

32

10

21

6

Previously Treated ALK-Positive Metastatic NSCLC - Study 2 (PROFILE 1007)

The data in Table 11 are derived from 343 patients with ALK-positive metastatic NSCLC enrolled in a randomized, multicenter, active-controlled, open-label trial (Study 2). 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 3 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 1 dose of study treatment), the median age was 50 years; 14% of patients were older than 65 years. A total of 56% of patients were female and 45% of patients were Asian.

Serious adverse reactions were reported in 37% of patients treated with XALKORI and 23% of patients 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 ILD (2.9%). Fatal adverse reactions in XALKORI-treated patients in Study 2 occurred in 5% of 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 increased ALT (8%) including some patients with concurrent increased AST, QTc prolongation (2.9%), and neutropenia (2.3%).

XALKORI was discontinued for adverse reactions in 15% of patients. The most frequent adverse reactions that led to discontinuation of XALKORI were ILD (1.7%), increased ALT and AST (1.2%), dyspnea (1.2%), and pulmonary embolism (1.2%).

Tables 11 and 12 summarize common adverse reactions and laboratory abnormalities, respectively, in XALKORI-treated patients.

Table 11. 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 2*
*
Adverse reactions were graded using NCI CTCAE version 4.0.
Includes cases reported within the clustered terms:
†
Dizziness (Balance disorder, Dizziness, Postural dizziness).
‡
Vision Disorder (Diplopia, Photophobia, Photopsia, Blurred vision, Reduced visual acuity, Visual impairment, Vitreous floaters).
§
Bradycardia (Bradycardia, Sinus bradycardia).
Upper respiratory infection (Laryngitis, Nasopharyngitis, Pharyngitis, Rhinitis, Upper respiratory tract infection).
#
Pulmonary embolism (Pulmonary artery thrombosis, Pulmonary embolism).
Þ
Edema (Face edema, Generalized edema, Local swelling, Localized edema, Edema, Peripheral edema, Periorbital edema).

Adverse Reaction

XALKORI
(N=172)

Chemotherapy
(Pemetrexed or Docetaxel)
(N=171)

All Grades
(%)

Grade 3–4
(%)

All Grades
(%)

Grade 3–4
(%)

Nervous System

  Dysgeusia

26

0

9

0

  Dizziness†

22

1

8

0

  Syncope

3

3

0

0

Eye

  Vision disorder‡

60

0

9

0

Cardiac

  Electrocardiogram QT prolonged

5

3

0

0

  Bradycardia§

5

0

0

0

Investigations

  Decreased weight

10

1

4

0

Gastrointestinal

  Diarrhea

60

0

19

1

  Nausea

55

1

37

1

  Vomiting

47

1

18

0

  Constipation

42

2

23

0

  Dyspepsia

8

0

3

0

Infections

  Upper respiratory infection

26

0

13

1

Respiratory, Thoracic and Mediastinal

  Pulmonary embolism#

6

5

2

2

General

  EdemaÞ

31

0

16

0

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, paresthesia, peripheral sensory neuropathy, polyneuropathy, burning sensation in skin), rash (9%), ILD (4%; acute respiratory distress syndrome, ILD, pneumonitis), renal cyst (4%), esophagitis (2%), hepatic failure (1%), and decreased blood testosterone (1%; hypogonadism).

Clinically relevant adverse reactions in <1% of patients who received XALKORI included photosensitivity (0.4%).

Table 12. Laboratory Abnormalities with Grades 3–4 Occurring in ≥4% of XALKORI-Treated Patients in Study 2
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%).

XALKORI

Chemotherapy

Laboratory Abnormality

Any Grade
(%)

Grade 3–4
(%)

Any Grade
(%)

Grade 3–4
(%)

Hematology

  Lymphopenia

51

9

60

25

  Neutropenia

49

12

28

12

Chemistry

  Increased ALT

76

17

38

4

  Increased AST

61

9

33

0

  Hypophosphatemia

28

5

25

6

  Hypokalemia

18

4

10

1

ROS1-Positive Metastatic NSCLC - Study 3 (PROFILE 1001)

The safety profile of XALKORI from Study 3, which was evaluated in 50 patients with ROS1-positive metastatic NSCLC, was generally consistent with the safety profile of XALKORI evaluated in patients with ALK-positive metastatic NSCLC (n=1669). Vision disorders occurred in 92% of patients in Study 3; 90% were Grade 1 and 2% were Grade 2. The median duration of exposure to XALKORI was 34.4 months.

Description of Selected Adverse Reactions in Patients with Metastatic NSCLC

Vision disorders: Vision disorders, most commonly visual impairment, photopsia, blurred vision, or vitreous floaters, occurred in 63% of 1719 patients. The majority (95%) of these patients had Grade 1 visual adverse reactions. There were 0.8% of patients with Grade 3 and 0.2% of patients with Grade 4 visual impairment. Based on the Visual Symptom Assessment Questionnaire (VSAQ-ALK), patients treated with XALKORI in Studies 1 and 2 reported a higher incidence of visual disturbances compared to patients treated with chemotherapy. The onset of vision disorder generally was within the first week of drug administration. The majority of patients on the XALKORI arms in Studies 1 and 2 (>50%) reported visual disturbances which 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 the VSAQ-ALK questionnaire.

Neuropathy: Neuropathy, most commonly sensory in nature, occurred in 25% of 1719 patients. Most events (95%) were Grade 1 or Grade 2 in severity.

Renal cysts: Renal cysts were experienced by 3.0% of 1719 patients. 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.

Renal toxicity: 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 (n=1499) in patients with ALK-positive advanced NSCLC who received XALKORI in clinical trials. No clinically relevant changes occurred in median eGFR from 12 to 104 weeks of treatment. Median eGFR slightly increased (83.02 mL/min/1.73 m2) 4 weeks after the last dose of XALKORI. Overall, 76% of patients had a decrease in eGFR to <90 mL/min/1.73 m2, 38% had a decrease to eGFR to <60 mL/min/1.73 m2, and 3.6% had a decrease to eGFR to <30 mL/min/1.73 m2.

Relapsed or Refractory, Systemic ALK-Positive ALCL - Study ADVL0912

The safety of XALKORI was evaluated in Study ADVL0912 [see Clinical Studies 14.2], which included 26 patients with relapsed or refractory, systemic ALCL after at least one systemic therapy. Eligible patients were 1 to ≤21 years of age and were required to have an absolute neutrophil count ≥1000/mm3 (750/mm3 if bone marrow was involved), platelet count ≥75,000/mm3 (25,000/mm3 if bone marrow was involved), creatinine clearance ≥70ml/min/1.73m2, and QTc ≤480 msec. The study excluded patients with ALT >2.5 times upper limit of normal (ULN), bilirubin ≤1.5 times ULN, and central nervous system tumors.

Patients with ALCL received XALKORI 165 mg/m2 or 280 mg/m2 orally twice daily until disease progression or unacceptable toxicity. The median duration of exposure was 5.4 months (range 1.8, 82.3 months), with 46% of patients treated for at least 6 months and 35% of patients treated for at least 12 months.

Serious adverse reactions occurred in 35% of patients with ALCL treated with XALKORI. The most frequent serious adverse reactions were neutropenia (12%) and hypotension (8%).

Dose interruptions and dose reductions occurred in 77% and 19% of patients with ALCL, respectively. XALKORI was discontinued for an adverse reaction in 8% of patients.

The most common adverse reactions (≥35%), excluding laboratory abnormalities, were diarrhea, vomiting, nausea, vision disorder, headache, musculoskeletal pain, stomatitis, fatigue, decreased appetite, pyrexia, abdominal pain, cough, and pruritis.

The most common Grade 3 or 4 laboratory abnormalities (≥15%) included neutropenia, lymphopenia, and thrombocytopenia. Grade 4 laboratory abnormalities (≥15%) included neutropenia (62%), lymphopenia (35%), and thrombocytopenia (19%).

Selected adverse reactions are summarized in Table 13.

Table 13. Adverse Reactions in ≥20% of Patients with Systemic ALCL in Study ADVL0912
Adverse reactions were graded using NCI CTCAE version 4.0.
*
Derived from laboratory values collected in Cycle 1 and adverse reaction data.
†
Includes neutrophil count decreased.
‡
Includes lymphocyte count decreased.
§
Includes platelet count decreased.
Includes oral pain, oropharyngeal pain, stomatitis.
#
Includes blurred vision, visual impairment, photophobia, photopsia, reduced visual acuity, vitreous floaters, cyanopsia, heterophoria, visual field defect.
Þ
Includes arthralgia, back pain, myalgia, non-cardiac chest pain, pain in extremity.
ß
Includes peripheral edema, face edema, periorbital edema, localized edema.
à
Includes rash maculopapular, rash pustular.
è
Includes upper respiratory tract infection, pharyngitis, rhinitis, sinusitis.

Adverse Reaction

XALKORI
N=26

All Grades
(%)

Grade 3–4
(%)

Blood and Lymphatic System Disorders*

  Neutropenia†

100

77

  Lymphopenia‡

58

38

  Anemia

54

3.8

  Thrombocytopenia§

38

19

Gastrointestinal Disorders

  Diarrhea

92

12

  Vomiting

92

3.8

  Nausea

77

3.8

  Abdominal Pain

50

0

  Stomatitis

46

8

  Constipation

31

0

Renal Disorders*

  Blood creatinine increased

100

0

Investigations*

  ALT increased

81

3.8

  AST increased

65

3.8

  Hypocalcemia

62

3.8

  Hypoalbuminemia

54

0

  Hyperglycemia

46

0

  Hypomagnesemia

46

0

  Hypoglycemia

35

0

  Hypokalemia

31

3.8

  Hypermagnesemia

27

0

  Hyperkalemia

23

0

Nervous System Disorders

  Headache

58

3.8

  Dysgeusia

23

0

  Dizziness

23

0

Eye Disorders

  Vision disorders#

65

0

Musculoskeletal Disorders

  Musculoskeletal painÞ

58

12

General Disorders

  Fatigue

46

0

  Pyrexia

38

0

  Edemaß

27

0

  Chills

23

0

Metabolism and Nutrition Disorders

  Decreased appetite

42

0

Skin and Subcutaneous Disorders

  Pruritus

35

0

  Rashà

23

0

Infections

  Upper respiratory tract infectionè

31

0

Respiratory Disorders

  Cough

35

0

  Rhinitis allergic

23

0

Vascular Disorders

  Hypertension

31

0

Clinically relevant adverse reactions in <20% of patients treated with XALKORI included:

•
Cardiac disorders: Bradycardia (19%), electrocardiogram QT prolonged (8%)
•
Vascular disorders: Hypotension (19%)
•
Investigations: Alkaline phosphatase increase (19%), hypernatremia (19%), GGT increase (8%), hyponatremia (12%), hyperuricemia (12%), hypophosphatemia (12%)
•
Nervous system disorders: Peripheral neuropathy (12%)
•
Gastrointestinal disorders: Esophagitis (8%)
•
Blood and lymphatic disorders: Febrile neutropenia (3.8%)
•
Musculoskeletal disorders: Muscular weakness (8%)
•
Renal disorders: Acute renal injury (8%)

Unresectable, Recurrent, or Refractory ALK-Positive IMT

Study ADVL0912

The safety of XALKORI was evaluated in Study ADVL0912 [see Clinical Studies (14.3)] that included 14 pediatric patients with unresectable, recurrent, or refractory IMT.

Pediatric patients with IMT received XALKORI 280 mg/m2 orally twice daily until disease progression or unacceptable toxicity. Two patients received a lower dose. The median duration of treatment with XALKORI was 20.5 months.

Serious adverse reactions occurred in 7% of pediatric patients with IMT treated with XALKORI. The most frequent serious adverse reaction was neutropenia and hypotension (7% for each).

Dose interruptions due to an adverse reaction occurred in 71% of patients. Dose reductions due to an adverse reaction occurred in 29% of patients. Permanent discontinuation occurred in 29% of patients.

The most common adverse reactions (≥35%) were vomiting, nausea, diarrhea, abdominal pain, rash, vision disorder, upper respiratory tract infection, cough, pyrexia, musculoskeletal pain, fatigue, edema, constipation, and headache.

The most common Grade 3 or 4 laboratory abnormality (>15%) was neutropenia.

Table 14 and Table 15 summarize the adverse reactions and laboratory abnormalities, respectively, in Study ADVL0912.

Table 14. Adverse Reactions in ≥20% of Pediatric Patients with IMT Treated With XALKORI in Study ADVL0912
Adverse reactions were graded using NCI CTCAE version 4.0.
*
Includes abdominal pain and abdominal pain upper.
†
Includes oral pain and oropharyngeal pain.
‡
Includes upper respiratory tract infection, pharyngitis, rhinitis.
§
Includes cough and productive cough.
Includes rash maculopapular, rash pustular, dermatitis acneiform.
#
Includes face edema, localized edema, periorbital edema, peripheral edema.
Þ
Includes pain, bone pain, ear pain.
ß
Includes photophobia, photopsia, vision blurred, visual impairment, vitreous floaters.
à
Includes arthralgia, myalgia, non-cardiac chest pain, pain in extremity.

Adverse Reaction

XALKORI
N=14

All Grades
(%)

Grade 3–4
(%)

Gastrointestinal Disorders

  Vomiting

93

0

  Nausea

86

0

  Diarrhea

64

7

  Abdominal pain*

57

0

  Constipation

36

0

  Stomatitis†

29

0

Infections

  Upper respiratory tract infection‡

64

0

  Skin Infection

29

0

Respiratory Disorders

  Cough§

64

0

  Rhinitis allergic

29

0

Skin and Subcutaneous Disorders

  Rash

57

0

General Disorders

  Pyrexia

50

0

  Fatigue

43

0

  Edema#

36

7

  PainÞ

29

0

Eye Disorders

  Vision disordersß

50

0

Musculoskeletal Disorders

  Musculoskeletal painà

43

0

Nervous System Disorders

  Headache

36

0

Metabolism and Nutrition Disorders

  Decreased appetite

29

0

Vascular Disorders

  Hypotension

21

7

Clinically relevant adverse reactions in <20% of pediatric patients with IMT treated with XALKORI included:

Cardiac disorders: Bradycardia (14%), electrocardiogram QT prolonged (7%)

Gastrointestinal disorders: Dyspepsia (14%), esophagitis (7%)

Vascular disorders: Hypertension (14%)

Nervous system disorders: Peripheral neuropathy (7%)

Blood and lymphatic disorders: Febrile neutropenia (7%)

Musculoskeletal disorders: Muscular weakness (7%)

Table 15. Laboratory Abnormalities (≥15%) That Worsened from Baseline in Pediatric Patients with IMT Treated With XALKORI in Study ADVL0912
*
The incidence is based on the number of patients who had both a baseline and at least one on-study laboratory measurement and varied from 13 to 14.
†
Laboratory abnormality data were only collected for the 1st cycle (28 days) of treatment for the duration of the study.

Laboratory Abnormality

XALKORI*,†

Any Grade
(%)

Grade 3–4
(%)

Chemistry

  Increased creatinine

100

0

  Decreased calcium

36

0

  Increased magnesium

23

0

  Decreased phosphate

15

0

Hematology

  Decreased neutrophils

64

36

Hepatic

  Increased ALT

36

0

Study A8081013

The safety of XALKORI for adult patients with ALK-positive IMT was evaluated in Study A8081013 [see Clinical Studies (14.3)] that included 7 patients with IMT with a median age of 38 years (range 23 to 73). The safety profile of this patient group was generally consistent with the safety profile of XALKORI evaluated in patients with ALK-positive or ROS1-positive NSCLC.

The most frequent adverse reactions (≥20%) were vision disorders, nausea, and edema.

6.2 Postmarketing Experience

The following additional adverse reaction has been identified during post-approval use of XALKORI. Because this reaction is reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

Investigations: Increased blood creatine phosphokinase

Prescribing Information
Download Prescribing Information

Health Professional Information

Adverse Reactions

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

•
Hepatotoxicity [see Warnings and Precautions (5.1)]
•
Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.2)]
•
QT Interval Prolongation [see Warnings and Precautions (5.3)]
•
Bradycardia [see Warnings and Precautions (5.4)]
•
Severe Visual Loss [see Warnings and Precautions (5.5)]
•
Gastrointestinal Toxicity in Pediatric and Young Adult Patients with ALCL or Pediatric Patients with IMT [see Warnings and Precautions (5.6)]

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 clinical practice.

The data in the Warnings and Precautions reflect exposure to XALKORI in 1719 patients with NSCLC who received XALKORI 250 mg twice daily enrolled on Studies 1 (including an additional 109 patients who crossed over from the control arm), 2, 3, a single-arm trial (n=1063) of ALK-positive NSCLC, and an additional ALK-positive NSCLC expansion cohort of a dose finding study (n=154). The data also reflect exposure to XALKORI in 121 patients ages 1 to ≤21 years with relapsed or refractory tumors, including 26 patients with systemic ALCL and 14 pediatric patients with IMT, in a single-arm trial (Study ADVL0912). The data are also described for 7 adult patients with IMT treated with XALKORI in a single-arm trial (Study A8081013).

ALK- or ROS1-Positive Metastatic NSCLC

The data described below is based primarily on 343 patients with ALK-positive metastatic NSCLC who received XALKORI 250 mg orally twice daily from 2 open-label, randomized, active-controlled trials (Studies 1 and 2). The safety of XALKORI was also evaluated in 50 patients with ROS1-positive metastatic NSCLC from a single-arm study (Study 3).

The most common adverse reactions (≥25%) of XALKORI in patients with NSCLC are vision disorders, nausea, diarrhea, vomiting, edema, constipation, elevated transaminases, fatigue, decreased appetite, upper respiratory infection, dizziness, and neuropathy.

Previously Untreated ALK-Positive Metastatic NSCLC - Study 1 (PROFILE 1014)

The data in Table 9 are derived from 340 patients with ALK-positive metastatic NSCLC who had not received previous systemic treatment for advanced disease who received treatment in a randomized, multicenter, open-label, active-controlled trial (Study 1). Patients in the XALKORI arm (n=171) 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 169 patients in the chemotherapy arm received pemetrexed 500 mg/m2 with cisplatin 75 mg/m2 (n=91) or carboplatin at a dose calculated to produce an AUC of 5 or 6 mg×min/mL (n=78). Chemotherapy was given by intravenous infusion every 3 weeks for up to 6 cycles, in the absence of dose-limiting chemotherapy-related toxicities. After 6 cycles, patients remained on study with no additional anticancer treatment, and tumor assessments continued until documented disease progression.

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. Median duration of treatment was 5.2 months for patients who received XALKORI after cross over from chemotherapy. Across the 340 patients who were treated in Study 1, the median age was 53 years; 16% of patients were older than 65 years. A total of 62% of patients were female and 46% were Asian.

Serious adverse events were reported in 34% of patients treated with XALKORI. 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 6% 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%).

Permanent discontinuation of XALKORI treatment for adverse reactions was 8%. 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%).

Tables 9 and 10 summarize common adverse reactions and laboratory abnormalities in XALKORI-treated patients.

Table 9. 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*
Adverse ReactionXALKORI
(N=171)		Chemotherapy
(Pemetrexed/Cisplatin or Pemetrexed/Carboplatin)
(N=169)
All Grades
(%)		Grade 3–4
(%)		All Grades
(%)		Grade 3–4
(%)
*
Adverse reactions were graded using NCI CTCAE version 4.0.
Includes cases reported within the clustered terms:
†
Bradycardia (Bradycardia, Sinus bradycardia).
‡
Vision Disorder (Diplopia, Photophobia, Photopsia, Reduced visual acuity, Blurred vision, Vitreous floaters, Visual impairment).
§
Abdominal pain (Abdominal discomfort, Abdominal pain, Lower abdominal pain, Upper abdominal pain, Abdominal tenderness).
Esophagitis (Esophagitis, Esophageal ulcer).
#
Edema (Edema, Peripheral edema, Face edema, Generalized edema, Local swelling, Periorbital edema).
Þ
Upper respiratory infection (Nasopharyngitis, Pharyngitis, Rhinitis, Upper respiratory tract infection).
ß
Dizziness (Balance disorder, Dizziness, Postural dizziness, Presyncope).

Cardiac

  Bradycardia†

14

1

1

0

  Electrocardiogram QT prolonged

6

2

2

0

Eye

  Vision disorder‡

71

1

10

0

Gastrointestinal

  Diarrhea

61

2

13

1

  Vomiting

46

2

36

3

  Constipation

43

2

30

0

  Abdominal pain§

26

0

12

0

  Dyspepsia

14

0

2

0

  Dysphagia

10

1

2

1

  Esophagitis

6

2

1

0

General

  Edema#

49

1

12

1

  Pyrexia

19

0

11

1

Infections

  Upper respiratory infectionÞ

32

0

12

1

Investigations

  Increased weight

8

1

2

0

Musculoskeletal and Connective Tissue

  Pain in extremity

16

0

7

0

  Muscle spasm

8

0

2

1

Nervous System

  Dysgeusia

26

0

5

0

  Headache

22

1

15

0

  Dizzinessß

18

0

10

1

Additional adverse reactions occurring at an overall incidence between 1% and 60% in patients treated with XALKORI included nausea (56%), decreased appetite (30%), fatigue (29%), neuropathy (21%; gait disturbance, hypoesthesia, muscular weakness, neuralgia, neuropathy peripheral, paresthesia, peripheral sensory neuropathy, polyneuropathy, sensory disturbance), rash (11%), renal cyst (5%), ILD (1%; ILD, pneumonitis), syncope (1%), and decreased blood testosterone (1%; hypogonadism).

Clinically relevant adverse reactions in <1% of patients who received XALKORI included photosensitivity (0.3%).

Table 10. Laboratory Abnormalities with Grades 3–4 Occurring in ≥4% of XALKORI-Treated Patients in Study 1
XALKORIChemotherapy
Laboratory AbnormalityAny Grade
(%)		Grade 3–4
(%)		Any Grade
(%)		Grade 3–4
(%)
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%).

Hematology

  Neutropenia

52

11

59

16

  Lymphopenia

48

7

53

13

Chemistry

  Increased ALT

79

15

33

2

  Increased AST

66

8

28

1

  Hypophosphatemia

32

10

21

6

Previously Treated ALK-Positive Metastatic NSCLC - Study 2 (PROFILE 1007)

The data in Table 11 are derived from 343 patients with ALK-positive metastatic NSCLC enrolled in a randomized, multicenter, active-controlled, open-label trial (Study 2). 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 3 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 1 dose of study treatment), the median age was 50 years; 14% of patients were older than 65 years. A total of 56% of patients were female and 45% of patients were Asian.

Serious adverse reactions were reported in 37% of patients treated with XALKORI and 23% of patients 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 ILD (2.9%). Fatal adverse reactions in XALKORI-treated patients in Study 2 occurred in 5% of 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 increased ALT (8%) including some patients with concurrent increased AST, QTc prolongation (2.9%), and neutropenia (2.3%).

XALKORI was discontinued for adverse reactions in 15% of patients. The most frequent adverse reactions that led to discontinuation of XALKORI were ILD (1.7%), increased ALT and AST (1.2%), dyspnea (1.2%), and pulmonary embolism (1.2%).

Tables 11 and 12 summarize common adverse reactions and laboratory abnormalities, respectively, in XALKORI-treated patients.

Table 11. 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 2*
*
Adverse reactions were graded using NCI CTCAE version 4.0.
Includes cases reported within the clustered terms:
†
Dizziness (Balance disorder, Dizziness, Postural dizziness).
‡
Vision Disorder (Diplopia, Photophobia, Photopsia, Blurred vision, Reduced visual acuity, Visual impairment, Vitreous floaters).
§
Bradycardia (Bradycardia, Sinus bradycardia).
Upper respiratory infection (Laryngitis, Nasopharyngitis, Pharyngitis, Rhinitis, Upper respiratory tract infection).
#
Pulmonary embolism (Pulmonary artery thrombosis, Pulmonary embolism).
Þ
Edema (Face edema, Generalized edema, Local swelling, Localized edema, Edema, Peripheral edema, Periorbital edema).

Adverse Reaction

XALKORI
(N=172)

Chemotherapy
(Pemetrexed or Docetaxel)
(N=171)

All Grades
(%)

Grade 3–4
(%)

All Grades
(%)

Grade 3–4
(%)

Nervous System

  Dysgeusia

26

0

9

0

  Dizziness†

22

1

8

0

  Syncope

3

3

0

0

Eye

  Vision disorder‡

60

0

9

0

Cardiac

  Electrocardiogram QT prolonged

5

3

0

0

  Bradycardia§

5

0

0

0

Investigations

  Decreased weight

10

1

4

0

Gastrointestinal

  Diarrhea

60

0

19

1

  Nausea

55

1

37

1

  Vomiting

47

1

18

0

  Constipation

42

2

23

0

  Dyspepsia

8

0

3

0

Infections

  Upper respiratory infection

26

0

13

1

Respiratory, Thoracic and Mediastinal

  Pulmonary embolism#

6

5

2

2

General

  EdemaÞ

31

0

16

0

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, paresthesia, peripheral sensory neuropathy, polyneuropathy, burning sensation in skin), rash (9%), ILD (4%; acute respiratory distress syndrome, ILD, pneumonitis), renal cyst (4%), esophagitis (2%), hepatic failure (1%), and decreased blood testosterone (1%; hypogonadism).

Clinically relevant adverse reactions in <1% of patients who received XALKORI included photosensitivity (0.4%).

Table 12. Laboratory Abnormalities with Grades 3–4 Occurring in ≥4% of XALKORI-Treated Patients in Study 2
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%).

XALKORI

Chemotherapy

Laboratory Abnormality

Any Grade
(%)

Grade 3–4
(%)

Any Grade
(%)

Grade 3–4
(%)

Hematology

  Lymphopenia

51

9

60

25

  Neutropenia

49

12

28

12

Chemistry

  Increased ALT

76

17

38

4

  Increased AST

61

9

33

0

  Hypophosphatemia

28

5

25

6

  Hypokalemia

18

4

10

1

ROS1-Positive Metastatic NSCLC - Study 3 (PROFILE 1001)

The safety profile of XALKORI from Study 3, which was evaluated in 50 patients with ROS1-positive metastatic NSCLC, was generally consistent with the safety profile of XALKORI evaluated in patients with ALK-positive metastatic NSCLC (n=1669). Vision disorders occurred in 92% of patients in Study 3; 90% were Grade 1 and 2% were Grade 2. The median duration of exposure to XALKORI was 34.4 months.

Description of Selected Adverse Reactions in Patients with Metastatic NSCLC

Vision disorders: Vision disorders, most commonly visual impairment, photopsia, blurred vision, or vitreous floaters, occurred in 63% of 1719 patients. The majority (95%) of these patients had Grade 1 visual adverse reactions. There were 0.8% of patients with Grade 3 and 0.2% of patients with Grade 4 visual impairment. Based on the Visual Symptom Assessment Questionnaire (VSAQ-ALK), patients treated with XALKORI in Studies 1 and 2 reported a higher incidence of visual disturbances compared to patients treated with chemotherapy. The onset of vision disorder generally was within the first week of drug administration. The majority of patients on the XALKORI arms in Studies 1 and 2 (>50%) reported visual disturbances which 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 the VSAQ-ALK questionnaire.

Neuropathy: Neuropathy, most commonly sensory in nature, occurred in 25% of 1719 patients. Most events (95%) were Grade 1 or Grade 2 in severity.

Renal cysts: Renal cysts were experienced by 3.0% of 1719 patients. 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.

Renal toxicity: 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 (n=1499) in patients with ALK-positive advanced NSCLC who received XALKORI in clinical trials. No clinically relevant changes occurred in median eGFR from 12 to 104 weeks of treatment. Median eGFR slightly increased (83.02 mL/min/1.73 m2) 4 weeks after the last dose of XALKORI. Overall, 76% of patients had a decrease in eGFR to <90 mL/min/1.73 m2, 38% had a decrease to eGFR to <60 mL/min/1.73 m2, and 3.6% had a decrease to eGFR to <30 mL/min/1.73 m2.

Relapsed or Refractory, Systemic ALK-Positive ALCL - Study ADVL0912

The safety of XALKORI was evaluated in Study ADVL0912 [see Clinical Studies 14.2], which included 26 patients with relapsed or refractory, systemic ALCL after at least one systemic therapy. Eligible patients were 1 to ≤21 years of age and were required to have an absolute neutrophil count ≥1000/mm3 (750/mm3 if bone marrow was involved), platelet count ≥75,000/mm3 (25,000/mm3 if bone marrow was involved), creatinine clearance ≥70ml/min/1.73m2, and QTc ≤480 msec. The study excluded patients with ALT >2.5 times upper limit of normal (ULN), bilirubin ≤1.5 times ULN, and central nervous system tumors.

Patients with ALCL received XALKORI 165 mg/m2 or 280 mg/m2 orally twice daily until disease progression or unacceptable toxicity. The median duration of exposure was 5.4 months (range 1.8, 82.3 months), with 46% of patients treated for at least 6 months and 35% of patients treated for at least 12 months.

Serious adverse reactions occurred in 35% of patients with ALCL treated with XALKORI. The most frequent serious adverse reactions were neutropenia (12%) and hypotension (8%).

Dose interruptions and dose reductions occurred in 77% and 19% of patients with ALCL, respectively. XALKORI was discontinued for an adverse reaction in 8% of patients.

The most common adverse reactions (≥35%), excluding laboratory abnormalities, were diarrhea, vomiting, nausea, vision disorder, headache, musculoskeletal pain, stomatitis, fatigue, decreased appetite, pyrexia, abdominal pain, cough, and pruritis.

The most common Grade 3 or 4 laboratory abnormalities (≥15%) included neutropenia, lymphopenia, and thrombocytopenia. Grade 4 laboratory abnormalities (≥15%) included neutropenia (62%), lymphopenia (35%), and thrombocytopenia (19%).

Selected adverse reactions are summarized in Table 13.

Table 13. Adverse Reactions in ≥20% of Patients with Systemic ALCL in Study ADVL0912
Adverse reactions were graded using NCI CTCAE version 4.0.
*
Derived from laboratory values collected in Cycle 1 and adverse reaction data.
†
Includes neutrophil count decreased.
‡
Includes lymphocyte count decreased.
§
Includes platelet count decreased.
Includes oral pain, oropharyngeal pain, stomatitis.
#
Includes blurred vision, visual impairment, photophobia, photopsia, reduced visual acuity, vitreous floaters, cyanopsia, heterophoria, visual field defect.
Þ
Includes arthralgia, back pain, myalgia, non-cardiac chest pain, pain in extremity.
ß
Includes peripheral edema, face edema, periorbital edema, localized edema.
à
Includes rash maculopapular, rash pustular.
è
Includes upper respiratory tract infection, pharyngitis, rhinitis, sinusitis.

Adverse Reaction

XALKORI
N=26

All Grades
(%)

Grade 3–4
(%)

Blood and Lymphatic System Disorders*

  Neutropenia†

100

77

  Lymphopenia‡

58

38

  Anemia

54

3.8

  Thrombocytopenia§

38

19

Gastrointestinal Disorders

  Diarrhea

92

12

  Vomiting

92

3.8

  Nausea

77

3.8

  Abdominal Pain

50

0

  Stomatitis

46

8

  Constipation

31

0

Renal Disorders*

  Blood creatinine increased

100

0

Investigations*

  ALT increased

81

3.8

  AST increased

65

3.8

  Hypocalcemia

62

3.8

  Hypoalbuminemia

54

0

  Hyperglycemia

46

0

  Hypomagnesemia

46

0

  Hypoglycemia

35

0

  Hypokalemia

31

3.8

  Hypermagnesemia

27

0

  Hyperkalemia

23

0

Nervous System Disorders

  Headache

58

3.8

  Dysgeusia

23

0

  Dizziness

23

0

Eye Disorders

  Vision disorders#

65

0

Musculoskeletal Disorders

  Musculoskeletal painÞ

58

12

General Disorders

  Fatigue

46

0

  Pyrexia

38

0

  Edemaß

27

0

  Chills

23

0

Metabolism and Nutrition Disorders

  Decreased appetite

42

0

Skin and Subcutaneous Disorders

  Pruritus

35

0

  Rashà

23

0

Infections

  Upper respiratory tract infectionè

31

0

Respiratory Disorders

  Cough

35

0

  Rhinitis allergic

23

0

Vascular Disorders

  Hypertension

31

0

Clinically relevant adverse reactions in <20% of patients treated with XALKORI included:

•
Cardiac disorders: Bradycardia (19%), electrocardiogram QT prolonged (8%)
•
Vascular disorders: Hypotension (19%)
•
Investigations: Alkaline phosphatase increase (19%), hypernatremia (19%), GGT increase (8%), hyponatremia (12%), hyperuricemia (12%), hypophosphatemia (12%)
•
Nervous system disorders: Peripheral neuropathy (12%)
•
Gastrointestinal disorders: Esophagitis (8%)
•
Blood and lymphatic disorders: Febrile neutropenia (3.8%)
•
Musculoskeletal disorders: Muscular weakness (8%)
•
Renal disorders: Acute renal injury (8%)

Unresectable, Recurrent, or Refractory ALK-Positive IMT

Study ADVL0912

The safety of XALKORI was evaluated in Study ADVL0912 [see Clinical Studies (14.3)] that included 14 pediatric patients with unresectable, recurrent, or refractory IMT.

Pediatric patients with IMT received XALKORI 280 mg/m2 orally twice daily until disease progression or unacceptable toxicity. Two patients received a lower dose. The median duration of treatment with XALKORI was 20.5 months.

Serious adverse reactions occurred in 7% of pediatric patients with IMT treated with XALKORI. The most frequent serious adverse reaction was neutropenia and hypotension (7% for each).

Dose interruptions due to an adverse reaction occurred in 71% of patients. Dose reductions due to an adverse reaction occurred in 29% of patients. Permanent discontinuation occurred in 29% of patients.

The most common adverse reactions (≥35%) were vomiting, nausea, diarrhea, abdominal pain, rash, vision disorder, upper respiratory tract infection, cough, pyrexia, musculoskeletal pain, fatigue, edema, constipation, and headache.

The most common Grade 3 or 4 laboratory abnormality (>15%) was neutropenia.

Table 14 and Table 15 summarize the adverse reactions and laboratory abnormalities, respectively, in Study ADVL0912.

Table 14. Adverse Reactions in ≥20% of Pediatric Patients with IMT Treated With XALKORI in Study ADVL0912
Adverse reactions were graded using NCI CTCAE version 4.0.
*
Includes abdominal pain and abdominal pain upper.
†
Includes oral pain and oropharyngeal pain.
‡
Includes upper respiratory tract infection, pharyngitis, rhinitis.
§
Includes cough and productive cough.
Includes rash maculopapular, rash pustular, dermatitis acneiform.
#
Includes face edema, localized edema, periorbital edema, peripheral edema.
Þ
Includes pain, bone pain, ear pain.
ß
Includes photophobia, photopsia, vision blurred, visual impairment, vitreous floaters.
à
Includes arthralgia, myalgia, non-cardiac chest pain, pain in extremity.

Adverse Reaction

XALKORI
N=14

All Grades
(%)

Grade 3–4
(%)

Gastrointestinal Disorders

  Vomiting

93

0

  Nausea

86

0

  Diarrhea

64

7

  Abdominal pain*

57

0

  Constipation

36

0

  Stomatitis†

29

0

Infections

  Upper respiratory tract infection‡

64

0

  Skin Infection

29

0

Respiratory Disorders

  Cough§

64

0

  Rhinitis allergic

29

0

Skin and Subcutaneous Disorders

  Rash

57

0

General Disorders

  Pyrexia

50

0

  Fatigue

43

0

  Edema#

36

7

  PainÞ

29

0

Eye Disorders

  Vision disordersß

50

0

Musculoskeletal Disorders

  Musculoskeletal painà

43

0

Nervous System Disorders

  Headache

36

0

Metabolism and Nutrition Disorders

  Decreased appetite

29

0

Vascular Disorders

  Hypotension

21

7

Clinically relevant adverse reactions in <20% of pediatric patients with IMT treated with XALKORI included:

Cardiac disorders: Bradycardia (14%), electrocardiogram QT prolonged (7%)

Gastrointestinal disorders: Dyspepsia (14%), esophagitis (7%)

Vascular disorders: Hypertension (14%)

Nervous system disorders: Peripheral neuropathy (7%)

Blood and lymphatic disorders: Febrile neutropenia (7%)

Musculoskeletal disorders: Muscular weakness (7%)

Table 15. Laboratory Abnormalities (≥15%) That Worsened from Baseline in Pediatric Patients with IMT Treated With XALKORI in Study ADVL0912
*
The incidence is based on the number of patients who had both a baseline and at least one on-study laboratory measurement and varied from 13 to 14.
†
Laboratory abnormality data were only collected for the 1st cycle (28 days) of treatment for the duration of the study.

Laboratory Abnormality

XALKORI*,†

Any Grade
(%)

Grade 3–4
(%)

Chemistry

  Increased creatinine

100

0

  Decreased calcium

36

0

  Increased magnesium

23

0

  Decreased phosphate

15

0

Hematology

  Decreased neutrophils

64

36

Hepatic

  Increased ALT

36

0

Study A8081013

The safety of XALKORI for adult patients with ALK-positive IMT was evaluated in Study A8081013 [see Clinical Studies (14.3)] that included 7 patients with IMT with a median age of 38 years (range 23 to 73). The safety profile of this patient group was generally consistent with the safety profile of XALKORI evaluated in patients with ALK-positive or ROS1-positive NSCLC.

The most frequent adverse reactions (≥20%) were vision disorders, nausea, and edema.

6.2 Postmarketing Experience

The following additional adverse reaction has been identified during post-approval use of XALKORI. Because this reaction is reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

Investigations: Increased blood creatine phosphokinase

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