Xalkori (Page 3 of 9)

5.3 QT Interval Prolongation

QTc prolongation can occur in patients treated with XALKORI. Across clinical trials in patients with NSCLC, 2.1% of 1616 patients had QTcF (corrected QT for heart rate by the Fridericia method) greater than or equal to 500 ms and 5% of 1582 patients had an increase from baseline QTcF greater than or equal to 60 ms by automated machine-read evaluation of ECGs.

​ In Study ADVL0912, QTc prolongation was reported as an adverse reaction in 4.1% of patients, including 8% of patients with ALCL and 7% of pediatric patients with IMT.

Avoid use of XALKORI in patients with congenital long QT syndrome. Monitor ECGs and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that are known to prolong the QT interval. Withhold, reduce dose, or permanently discontinue XALKORI for QT/QTc interval prolongation as recommended [see Dosage and Administration (2.4), Clinical Pharmacology (12.2)].

5.4 Bradycardia

Symptomatic bradycardia can occur in patients receiving XALKORI. Across clinical trials in patients with NSCLC, bradycardia occurred in 13% of 1719 patients treated with XALKORI. Grade 3 syncope occurred in 2.4% of XALKORI-treated patients and in 0.6% of the chemotherapy-treated patients [see Adverse Reactions (6.1)].

​ In Study ADVL0912, among 121 patients ages 1 to ≤21 years treated with XALKORI, bradycardia was reported in 14%, including Grade 3 bradycardia in 0.8% of patients. Of the 26 patients with ALCL treated with XALKORI, bradycardia (all Grade 1) was reported in 19%. Of the 14 pediatric patients with IMT treated with XALKORI, bradycardia was reported in 14% of patients, including Grade 3 bradycardia in 7% of patients.

Avoid using XALKORI in combination with other medications known to cause bradycardia (e.g., beta-blockers, nondihydropyridine-calcium channel blockers, clonidine, and digoxin) to the extent possible. Monitor heart rate and blood pressure regularly. If bradycardia occurs, re-evaluate for the use of concomitant medications known to cause bradycardia. Withhold, reduce dose, or permanently discontinue XALKORI for bradycardia as recommended [see Dosage and Administration (2.4)].

5.5 Severe Visual Loss

Across all clinical trials in patients with NSCLC, the incidence of Grade 4 visual field defect with visual loss was 0.2% of 1719 patients [see Adverse Reactions (6.1)]. Optic atrophy and optic nerve disorder have been reported as potential causes of visual loss.

​ In Study ADVL0912, visual disorders occurred in 46% of 121 patients with XALKORI, including 65% of 26 patients with ALCL and 50% of 14 patients with IMT. Of the 56 patients who experienced visual disorders, one pediatric patient with IMT experienced Grade 3 myopic optic nerve disorder. The most common visual symptoms were blurred vision and visual impairment.

​ Assessment of visual symptoms for all patients is recommended monthly during treatment. Report new visual symptoms to an eye specialist.

​ For pediatric and young adult patients with ALCL or IMT, obtain baseline and follow-up ophthalmologic examinations including retinal examination within 1 month of starting XALKORI and every 3 months thereafter. The ophthalmological evaluation should consist of best corrected visual acuity, retinal photographs, visual fields, optical coherence tomography (OCT), and other evaluations as appropriate [see Dosage and Administration (2.4) ​ , Adverse Reactions (6.1) ​ ] ​ .

​ Permanently discontinue XALKORI for Grade 3 or 4 ocular disorders or severe visual loss (best corrected vision less than 20/200 in one or both eyes) unless another cause is identified [see Dosage and Administration (2.4) ​ ] ​ . There is insufficient information to characterize the risks of resumption of XALKORI in patients who develop visual symptoms or visual loss. A decision to resume XALKORI should consider the potential benefits versus risks to the patient.

5.6 Gastrointestinal Toxicity in Pediatric and Young Adult Patients with ALCL or Pediatric Patients with IMT

​ XALKORI can cause severe gastrointestinal toxicities in pediatric and young adult patients with ALCL or pediatric patients with IMT [see Adverse Reactions (6.1) ​ ] ​ . In patients with ALCL (n=26), gastrointestinal toxicity occurred in 100% of patients; Grade 3 gastrointestinal toxicity occurred in 27% of patients and included diarrhea, nausea, vomiting, and stomatitis. In pediatric patients with IMT (n=14), vomiting occurred in 93%, nausea occurred in 86%, and diarrhea occurred in 64% of patients.

​ Provide standard antiemetic and antidiarrheal agents for gastrointestinal toxicities in pediatric and young adult patients with ALCL or pediatric patients with IMT. Antiemetics are recommended prior to and during treatment with XALKORI to prevent nausea and vomiting. If patients develop Grade 3 nausea lasting 3 days or Grade 3 or 4 diarrhea or vomiting despite maximum medical therapy, withhold XALKORI until resolved, and then resume at the next lower dose level. Consider supportive care such as hydration, electrolyte supplementation, and nutritional support as clinically indicated [see Dosage and Administration (2.4) ​ ] ​ .

5.7 Embryo-Fetal Toxicity

Based on its mechanism of action, XALKORI can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of crizotinib in pregnant rats during organogenesis at exposures similar to those observed with the maximum recommended human dose resulted in embryotoxicity and fetotoxicity. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with XALKORI and for at least 45 days following the final dose. Advise males with female partners of reproductive potential to use condoms during treatment with XALKORI and for at least 90 days after the final dose [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].

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 8 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 8 and 9 summarize common adverse reactions and laboratory abnormalities in XALKORI-treated patients.

Table 8. 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 Reaction	XALKORI (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 infection Þ	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
Dizziness ß	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 9. Laboratory Abnormalities with Grades 3–4 Occurring in ≥4% of XALKORI-Treated Patients in Study 1

	XALKORI		Chemotherapy
Laboratory Abnormality	Any 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 10 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 10 and 11 summarize common adverse reactions and laboratory abnormalities in XALKORI-treated patients.

Table 10. 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 Reaction	XALKORI (N=172)		Chemotherapy (Pemetrexed or Docetaxel) (N=171)
	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: † 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).
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
Edema Þ	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 11. Laboratory Abnormalities with Grades 3–4 Occurring in ≥4% of XALKORI-Treated Patients in Study 2

	XALKORI		Chemotherapy
Laboratory Abnormality	Any 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: 96%; Grade 3: 1%; Grade 4: 0%) compared to the chemotherapy arm (Any Grade: 72%; Grade 3: 0%; Grade 4: 0%).
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 12.

Table 12. Adverse Reactions in ≥20% of Patients with Systemic ALCL in Study ADVL0912

Adverse Reaction	XALKORI N=26
	All Grades (%)	Grade 3–4 (%)
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.
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 pain Þ	58	12
General Disorders
Fatigue	46	0
Pyrexia	38	0
Edema ß	27	0
Chills	23	0
Metabolism and Nutrition Disorders
Decreased appetite	42	0
Skin and Subcutaneous Disorders
Pruritus	35	0
Rash à	23	0
Infections
Upper respiratory tract infection è	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 13 and Table 14 summarize the adverse reactions and laboratory abnormalities, respectively, in Study ADVL0912.

Table 13. Adverse Reactions in ≥20% of Pediatric Patients with IMT Treated With XALKORI in Study ADVL0912

Adverse Reaction	XALKORI N=14
	All Grades (%)	Grade 3–4 (%)
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.
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
Pain Þ	29	0
Eye Disorders
Vision disorders ß	50	0
Musculoskeletal Disorders
Musculoskeletal pain à	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 14. Laboratory Abnormalities (≥15%) That Worsened from Baseline in Pediatric Patients with IMT Treated With XALKORI in Study ADVL0912

Laboratory Abnormality	XALKORI * , †
	Any Grade (%)	Grade 3–4 (%)
* 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.
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 [s ee 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.