文案整理：Dr.
Jasmine Ding
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed
to use XALKORI® safely and effectively. See full prescribing information for
XALKORI.
XALKORI® (crizotinib) capsules, for oral use
Initial U.S. Approval: 2011
RECENT MAJOR CHANGES
Indications and Usage (1) 7/2017
Dosage and Administration, Patient Selection (2.1) 7/2017
INDICATIONS AND USAGE
XALKORI is a kinase inhibitor indicated for the treatment of
patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are
anaplastic lymphoma kinase (ALK) or ROS1-positive as detected by an
FDA-approved test
DOSAGE AND ADMINISTRATION
· Recommended Dose: 250 mg orally, twice daily. (2.2)
· Renal Impairment: 250 mg orally, once daily in patients
with severe renal impairment (creatinine clearance
5 WARNINGS AND PRECAUTIONS
. QT Interval Prolongation: Occurred in 2.1% of patients.
Monitor electrocardiograms and electrolytes in patients who have a history of
or predisposition for QTc prolongation, or who are taking medications that
prolong QT. Temporarily suspend, dose reduce, or permanently discontinue
XALKORI. (5.3)
· Bradycardia: XALKORI can cause bradycardia. Monitor heart
rate and blood pressure regularly. Temporarily suspend, dose reduce, or
permanently discontinue XALKORI. (5.4)
· Severe Visual Loss: Reported in 0.2% of patients.
Discontinue XALKORI in patients with severe visual loss. Perform an
ophthalmological evaluation. (5.5)
· Embryo-Fetal Toxicity: Can cause fetal harm. Advise
females of reproductive potential of the potential risk to a fetus and use of
effective contraception. (5.6, 8.1, 8.3)
ADVERSE REACTIONS
The most common adverse reactions (≥25%)
are vision disorders, nausea, diarrhea, vomiting, edema, constipation, elevated
transaminases, fatigue, decreased appetite, upper respiratory infection,
dizziness, and neuropathy.
(6) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer
Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
DRUG INTERACTIONS
· CYP3A Inhibitors: Avoid concurrent use of XALKORI with
strong CYP3A inhibitors. (7.1)
· CYP3A Inducers: Avoid concurrent use of XALKORI with
strong CYP3A inducers. (7.2)
· CYP3A Substrates: Avoid concurrent use of XALKORI with
CYP3A substrates with narrow therapeutic indices. (7.3)
USE IN SPECIFIC POPULATIONS
Lactation: Do not breastfeed while taking XALKORI. (8.2) See
17 for PATIENT COUNSELING INFORMATION and FDA‐approved
patient labeling. Revised: 7/2017
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
XALKORI is indicated for the treatment of patients with
metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic
lymphoma kinase (ALK) or ROS1-positive as detected by an FDA-approved test [see
Clinical Studies (14.1 and 14.2)].
2 DOSAGE AND ADMINISTRATION
2.1 Patient Selection
Select patients for the treatment of metastatic NSCLC with
XALKORI based on the presence of ALK or ROS1 positivity in tumor specimens [see
Indications and Usage (1) and Clinical Studies (14.1, 14.2)].
Information on FDA-approved tests for the detection of ALK
and ROS1 rearrangements in NSCLC is available at
http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm301431.htm.
2.2 Recommended Dosing The recommended dose of XALKORI is 250 mg orally, twice
daily until disease progression or no longer tolerated by the patient. The
recommended dose of XALKORI in patients with severe renal impairment
[creatinine clearance (CLcr)
Table 1. XALKORI Dose Modification – Hematologic Toxicitiesa
Grade 3 Withhold until recovery to Grade 2 or less, then
resume at the same dose schedule
Grade 4 Withhold until recovery to Grade 2 or less, then
resume at next lower dose a Except lymphopenia (unless associated with clinical
events, e.g., opportunistic infections).
Table 2. XALKORI Dose Modification – Non-Hematologic
Toxicities Criteria XALKORI Dosing Alanine aminotransferase (ALT) or aspartate
aminotransferase (AST) elevation greater than 5 times upper limit of normal
(ULN) with total bilirubin less than or equal to 1.5 times ULN Withhold until
recovery to baseline or less than or equal to 3 times ULN, then resume at
reduced dose. ALT or AST elevation greater than 3 times ULN with concurrent
total bilirubin elevation greater than 1.5 times ULN (in the absence of
cholestasis or hemolysis) Permanently discontinue. Any grade drug-related
interstitial lung disease/pneumonitis Permanently discontinue. QT corrected for
heart rate (QTc) greater than 500 ms on at least 2 separate electrocardiograms
(ECGs) Withhold until recovery to baseline or to a QTc less than 481 ms, then
resume at reduced dose. QTc greater than 500 ms or greater than or equal to 60
ms change from baseline with Torsade de pointes or polymorphic ventricular
tachycardia or signs/symptoms of serious arrhythmia Permanently discontinue.
Bradycardiaa (symptomatic, may be severe and medically significant, medical
intervention indicated) Withhold until recovery to asymptomatic bradycardia or
to a heart rate of 60 bpm or above. Evaluate concomitant medications known to
cause bradycardia, as well as antihypertensive medications. If contributing
concomitant medication is identified and discontinued, or its dose is adjusted,
resume at previous dose upon recovery to asymptomatic bradycardia or to a heart
rate of 60 bpm or above. If no contributing concomitant medication is
identified, or if contributing concomitant medications are not discontinued or
dose modified, resume at reduced dose upon recovery to asymptomatic bradycardia
or to a heart rate of 60 bpm or above. Bradycardiaa,b (life-threatening
consequences, urgent intervention indicated) Permanently discontinue if no
contributing concomitant medication is identified. If contributing concomitant
medication is identified and discontinued, or its dose is adjusted, resume at
250 mg once daily upon recovery to asymptomatic bradycardia or to a heart rate
of 60 bpm or above, with frequent monitoring. Visual Loss (Grade 4 Ocular
Disorder) Discontinue during evaluation of severe vision loss. a Heart rate
less than 60 beats per minute (bpm). b Permanently discontinue for recurrence.
Monitor complete blood counts including differential white blood cell counts
monthly and as clinically indicated, with more frequent repeat testing if Grade
3 or 4 abnormalities are observed, or if fever or infection occurs.
3 DOSAGE FORMS AND STRENGTHS
· 250 mg capsules: hard gelatin capsule, size 0, pink opaque
cap and body, with “Pfizer” on the cap and “CRZ 250” on the body.
· 200 mg capsules: hard gelatin capsule, size 1, white opaque
body and pink opaque cap, with “Pfizer” on the cap and “CRZ 200” on the body.
4 CONTRAINDICATIONS
None.
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
Drug-induced hepatotoxicity with fatal outcome occurred in 2
(0.1%) of the 1719 patients treated with XALKORI across clinical trials.
Concurrent elevations in alanine aminotransferase (ALT) or aspartate
aminotransferase (AST) greater than or equal to 3 times the upper limit of
normal (ULN) and total bilirubin greater than or equal to 2 times the ULN, with
normal alkaline phosphatase, occurred in 10 patients ((Elevations in ALT or AST
greater than 5 times the ULN occurred in 187 (11.2%) and 95 (5.7%) patients,
respectively. Seventeen patients (1.0%) required permanent discontinuation due
to elevated transaminases. Transaminase elevations generally occurred within
the first 2 months of treatment.
Monitor liver function tests, including ALT, AST, and total
bilirubin, every 2 weeks during the first 2 months of treatment, then once a
month, and as clinically indicated, with more frequent repeat testing for
increased liver transaminases, alkaline phosphatase, or total bilirubin in
patients who develop transaminase elevations. Temporarily suspend, dose reduce,
or permanently discontinue XALKORI as described in Table 2 [see Dosage and
Administration (2.3) and Adverse Reactions (6)].
5.2 Interstitial Lung Disease (Pneumonitis)
Severe, life-threatening, or fatal interstitial lung disease
(ILD)/pneumonitis can occur in patients treated with XALKORI. Across clinical
trials (n=1719), 50 XALKORI-treated patients (2.9%) had ILD of any grade, 18
patients (1.0%) had Grade 3 or 4 ILD, and 8 patients (0.5%) had fatal ILD.
Interstitial lung disease generally occurred within 3 months after the
initiation of XALKORI. Monitor patients for pulmonary symptoms indicative of
ILD/pneumonitis. Exclude other potential causes of ILD/pneumonitis, and
permanently discontinue XALKORI in patients diagnosed with drug-related
ILD/pneumonitis [see Dosage and Administration (2.3) and Adverse Reactions
(6)].
5.3 QT Interval Prolongation
QTc prolongation can occur in patients treated with XALKORI.
Across clinical trials, 34 of 1616 patients (2.1%) had QTcF (corrected QT for
heart rate by the Fridericia method) greater than or equal to 500 ms and 79 of
1582 patients (5.0%) had an increase from baseline QTcF greater than or equal
to 60 ms by automated machine-read evaluation of ECGs. 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 takingmedications that are known to prolong the QT
interval. Permanently discontinue XALKORI in patients who develop QTc greater
than 500 ms or greater than or equal to 60 ms change from baseline with Torsade
de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious
arrhythmia. Withhold XALKORI in patients who develop QTc greater than 500 ms on
at least 2 separate ECGs until recovery to a QTc less than or equal to 480 ms,
then resume XALKORI at a reduced dose as described in Table 2 [see Dosage and
Administration (2.3) and Clinical Pharmacology (12.2)].
5.4 Bradycardia
Symptomatic bradycardia can occur in patients receiving
XALKORI. Across clinical trials, bradycardia occurred in 219 (12.7%) 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.
Avoid using XALKORI in combination with other agents known to cause bradycardia
(e.g., beta-blockers, non-dihydropyridine calcium channel blockers, clonidine,
and digoxin) to the extent possible. Monitor heart rate and blood pressure
regularly. In cases of symptomatic bradycardia that is not life-threatening,
hold XALKORI until recovery to asymptomatic bradycardia or to a heart rate of
60 bpm or above, re-evaluate the use of concomitant medications, and adjust the
dose of XALKORI. Permanently discontinue for life-threatening bradycardia due
to XALKORI; however, if associated with concomitant medications known to cause
bradycardia or hypotension, hold XALKORI until recovery to asymptomatic
bradycardia or to a heart rate of 60 bpm or above, and if concomitant
medications can be adjusted or discontinued, restart XALKORI at 250 mg once
daily with frequent monitoring [see Dosage and Administration (2.3) and Adverse
Reactions (6)].
5.5 Severe Visual Loss
Across all clinical trials, the incidence of Grade 4 visual
field defect with vision loss was 0.2% (4/1719). Optic atrophy and optic nerve
disorder have been reported as potential causes of vision loss. Discontinue
XALKORI in patients with new onset of severe visual loss (best corrected vision
less than 20/200 in one or both eyes). Perform an ophthalmological evaluation
consisting of best corrected visual acuity, retinal photographs, visual fields,
optical coherence tomography (OCT) and other evaluations as appropriate for new
onset of severe visual loss. There is insufficient information to characterize
the risks of resumption of XALKORI in patients with a severe visual loss; a
decision to resume XALKORI should consider the potential benefits to the
patient.
5.6 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 [see
Use in Specific Populations (8.1, 8.3)]. Advise male patients 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
(8.3) and Nonclinical Toxicology (13.1)].
6 ADVERSE REACTIONS
The following adverse reactions are discussed in greater
detail in other sections of 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)] 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 section reflect exposure to
XALKORI in 1719 patients 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)
[see Warnings and Precautions (5)]. The data described below is based primarily
on 343 patients with ALK-positive metastatic NSCLC who received XALKORI 250 mg
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 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
The data in Table 3 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 in combination with
cisplatin 75 mg/m2 (n=91) or carboplatin at a dose calculated to produce an
area under the concentration-time curve (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 58 patients (34%) 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. 6 Reference ID: 4127887 Dose reductions due
to adverse reactions were required in 6.4% of XALKORI-treated patients. The
most frequent adverse reactions that led to dose reduction in these patients
were nausea (1.8%) and elevated transaminases (1.8%). Permanent discontinuation
of XALKORI treatment for adverse reactions was 8.2%. 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 3 and 4 summarize common adverse reactions and
laboratory abnormalities in XALKORI-treated patients.
Table 3. 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 (%) Cardiac Disorders
Electrocardiogram QT prolonged Bradycardiaa 6 14 2 1 2 1 0 0 Eye Disorders
Vision disorderb 71 1 10 0 Gastrointestinal Disorders Vomiting Diarrhea
Constipation Dyspepsia Dysphagia Abdominal painc Esophagitisd 46 61 43 14 10 26
6 2 2 2 0 1 0 2 36 13 30 2 2 12 1 3 1 0 0 1 0 0 General Disorders and
Administration Site Conditions Edemae Pyrexia 49 19 1 0 12 11 1 1 Infections
and Infestations Upper respiratory infectionf 32 0 12 1 Investigations
Increased weight 8 1 2 0 Musculoskeletal and Connective Tissue Disorders Pain
in extremity Muscle spasm 16 8 0 0 7 2 0 1 Nervous System Disorders Dizzinessg
Dysgeusia Headache 18 26 22 0 0 1 10 5 15 1 0 0 † Adverse reactions were graded
using NCI CTCAE version 4.0. Includes cases reported within the clustered
terms: a Bradycardia (Bradycardia, Sinus bradycardia). b Vision Disorder
(Diplopia, Photophobia, Photopsia, Reduced visual acuity, Blurred vision,
Vitreous floaters, Visual impairment). c Abdominal pain (Abdominal discomfort,
Abdominal pain, Lower abdominal pain, Upper abdominal pain, Abdominal
tenderness). d Esophagitis (Esophagitis, Esophageal ulcer). e Edema (Edema,
Peripheral edema, Face edema, Generalized edema, Local swelling, Periorbital
edema). f Upper respiratory infection (Nasopharyngitis, Pharyngitis, Rhinitis,
Upper respiratory tract infection). g Dizziness (Balance disorder, Dizziness,
Postural dizziness, Presyncope). 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).
Table 4. Laboratory Abnormalities with Grade 3
or 4 Incidence of ≥4% in XALKORI-Treated Patients in Study 1
Laboratory Abnormality XALKORI Any Grade (%) Grade 3-4 (%) Chemotherapy Any
Grade (%) Grade 3-4 (%) Hematology Neutropenia Lymphopenia 52 48 11 7 59 53 16
13 Chemistry ALT elevation AST elevation Hypophosphatemia 79 66 32 15 8 10 33
28 21 2 1 6 Additional laboratory test abnormality in patients treated with
XALKORI was an increase in creatinine (Any Grade: 99%; Grade 3: 2%; Grade 4:
0%) compared to the chemotherapy arm (Any Grade: 92%; Grade 3: 0%; Grade 4:
1%). Previously Treated ALK-Positive Metastatic NSCLC - Study 2 The data in
Table 5 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 64 patients (37.2%) treated with XALKORI and 40 patients (23.4%) 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 9 (5%) 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 ALT elevation (7.6%) including some patients with concurrent
AST elevation, 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%), ALT
and AST elevation (1.2%), dyspnea (1.2%), and pulmonary embolism (1.2%). Tables
5 and 6 summarize common adverse reactions and laboratory abnormalities in XALKORI-treated
patients. 9 Reference ID: 4127887 Table 5. 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 (%) Nervous System Disorders Dizzinessa Dysgeusia Syncope 22 26 3 1 0
3 8 9 0 0 0 0 Eye Disorders Vision disorderb 60 0 9 0 Cardiac Disorders
Electrocardiogram QT prolonged Bradycardiac 5 5 3 0 0 0 0 0 Investigations
Decreased weight 10 1 4 0 Gastrointestinal Disorders
Vomiting Nausea Diarrhea Constipation Dyspepsia 47 55 60 42 8 1 1 0 2 0 18 37
19 23 3 0 1 1 0 0 Infections and Infestations Upper respiratory infectiond 26 0
13 1 Respiratory, Thoracic and Mediastinal Disorders Pulmonary embolisme 6 5 2
2 General Disorders and Administration Site Conditions Edemaf 31 0 16 0 †
Adverse reactions were graded using NCI CTCAE version 4.0. Includes cases
reported within the clustered terms: a Dizziness (Balance disorder, Dizziness,
Postural dizziness). b Vision Disorder (Diplopia, Photophobia, Photopsia,
Blurred vision, Reduced visual acuity, Visual impairment, Vitreous floaters). c
Bradycardia (Bradycardia, Sinus bradycardia). d Upper respiratory infection
(Laryngitis, Nasopharyngitis, Pharyngitis, Rhinitis, Upper respiratory tract
infection). e Pulmonary embolism (Pulmonary artery thrombosis, Pulmonary
embolism). f Edema (Face edema, Generalized edema, Local swelling, Localized
edema, Edema, Peripheral edema, Periorbital edema). 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). 10 Reference ID: 4127887 Table 6. Laboratory Abnormalities with
Grade 3 or 4 Incidence of ≥4% in XALKORI-Treated Patients in
Study 2 Laboratory Abnormality XALKORI Any Grade (%) Grade 3-4 (%) Chemotherapy
Any Grade (%) Grade 3-4 (%) Hematology Neutropenia Lymphopenia 49 51 12 9 28 60
12 25 Chemistry ALT elevation AST elevation Hypokalemia Hypophosphatemia 76 61
18 28 17 9 4 5 38 33 10 25 4 0 1 6 Additional laboratory test abnormality in
patients treated with XALKORI was an increase in creatinine (Any Grade: 96%;
Grade 3: 1%; Grade 4: 0%) compared to the chemotherapy arm (Any Grade: 72%;
Grade 3: 0%; Grade 4: 0%).
ROS1-Positive Metastatic NSCLC - Study 3
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 Drug Reactions
Vision disorders
Vision disorders, most commonly visual impairment,
photopsia, blurred vision, or vitreous floaters, occurred in 1084 (63.1%) of
1719 patients. The majority (95%) of these patients had Grade 1 visual adverse
reactions. There were 13 (0.8%) patients with Grade 3 and 4 (0.2%) 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 435
(25%) of 1719 patients. Most events (95%) were Grade 1 or Grade 2 in severity.
Renal cysts
Renal cysts were experienced by 52 (3%) 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 impairment
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 11
Reference ID: 4127887 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
7 DRUG INTERACTIONS
7.1 Drugs That May Increase Crizotinib Plasma Concentrations
Coadministration of crizotinib with strong cytochrome P450 (CYP) 3A inhibitors
increases crizotinib plasma concentrations [see Clinical Pharmacology (12.3)].
Avoid concomitant use of strong CYP3A inhibitors, including but not limited to
atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone,
nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, and
voriconazole. Avoid grapefruit or grapefruit juice which may also increase
plasma concentrations of crizotinib. Exercise caution with concomitant use of
moderate CYP3A inhibitors.
7.2 Drugs That May Decrease Crizotinib Plasma Concentrations
Coadministration of crizotinib with strong CYP3A inducers decreases crizotinib
plasma concentrations [see Clinical Pharmacology (12.3)]. Avoid concomitant use
of strong CYP3A inducers, including but not limited to carbamazepine,
phenobarbital, phenytoin, rifabutin, rifampin, and St. John’s Wort.
7.3 Drugs Whose Plasma Concentrations May Be Altered By
Crizotinib Crizotinib inhibits CYP3A both in vitro and in vivo [see Clinical
Pharmacology (12.3)]. Avoid concomitant use of CYP3A substrates with narrow
therapeutic range, including but not limited to alfentanil, cyclosporine,
dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and
tacrolimus in patients taking XALKORI. If concomitant use of these CYP3A
substrates with narrow therapeutic range is required in patients taking
XALKORI, dose reductions of the CYP3A substrates may be required due to adverse
reactions.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy Risk Summary
Based on its mechanism of action, XALKORI can cause fetal
harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)].
There are no available data on the use of XALKORI during pregnancy. In animal
reproduction studies, oral administration of crizotinib in pregnant rats during
organogenesis at exposures similar to those expected with the maximum
recommended human dose resulted in embryotoxicity and fetotoxicity [see Data].
Advise pregnant women of the potential risk to a fetus. The estimated
background risk of major birth defects and miscarriage for the indicated
population is unknown. In the U.S. general population, the estimated background
risk of major birth defects and miscarriage in clinically recognized
pregnancies is 2 to 4% and 15 to 20%, respectively.
Animal Data Crizotinib was administered to pregnant rats and
rabbits during organogenesis to study the effects on embryo-fetal development.
Postimplantation loss was increased at doses ≥50
mg/kg/day (approximately 0.6 times the recommended human dose based on AUC) in
rats. No teratogenic effects were observed in rats at doses up to the
maternally toxic dose of 200 mg/kg/day (approximately 2.7 times the recommended
human dose based on AUC) or in rabbits at doses of up to 60 mg/kg/day
(approximately 1.6 times the recommended human dose based on AUC), though fetal
body weights were reduced at these doses.
8.2 Lactation Risk
Summary
There is no information regarding the presence of crizotinib
in human milk, the effects on the breastfed infant, or the effects on milk
production. Because of the potential for adverse reactions in breastfed
infants, do not breastfeed during treatment with XALKORI and for 45 days after
the final dose.
8.3 Females and Males of Reproductive Potential
Contraception Females XALKORI can cause fetal harm when administered to a
pregnant woman [see Use in Specific Populations (8.1)]. Advise females of
reproductive potential to use effective contraception during treatment with
XALKORI and for at least 45 days after the final dose. Males Because of the
potential for genotoxicity, 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 Nonclinical Toxicology (13.1)]. Infertility Based on
reproductive organ findings in animals, XALKORI may cause reduced fertility in
females and males of reproductive potential. It is not known whether these
effects on fertility are reversible [see Nonclinical Toxicology (13.1)]. 8.4
Pediatric Use The safety and efficacy of XALKORI in pediatric patients has not
been established. Animal Data Decreased bone formation in growing long bones
was observed in immature rats at 150 mg/kg/day following once daily dosing for
28 days (approximately 5.4 times the recommended human dose based on AUC).
Other toxicities of potential concern to pediatric patients have not been
evaluated in juvenile animals.
8.5 Geriatric Use
Of the total number of patients with ALK-positive metastatic
NSCLC in clinical studies of XALKORI (n=1669), 16% were 65 years or older and
3.8% were 75 years or older. No overall differences in safety or effectiveness
were observed between these patients and younger patients. Clinical studies of
XALKORI in patients with ROS1-positive metastatic NSCLC did not include
sufficient numbers of patients age 65 years and older to determine whether they
respond differently from younger patients.
8.6 Hepatic Impairment
XALKORI has not been studied in patients with hepatic
impairment. As crizotinib is extensively metabolized in the liver, hepatic
impairment is likely to increase plasma crizotinib concentrations. Clinical
studies excluded patients with AST or ALT greater than 2.5 times ULN, or
greater than 5 times ULN, if due to liver metastases. Patients with total
bilirubin greater than 1.5 times ULN were also excluded. Therefore, use caution
in patients with hepatic impairment [see Clinical Pharmacology (12.3)].
8.7 Renal Impairment
No starting dose adjustment is needed for patients with mild
(CLcr 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment based on a
population pharmacokinetic analysis. Increased exposure to crizotinib occurred
in patients with severe renal impairment
10 OVERDOSAGE
There have been no known cases of XALKORI overdose. There is
no antidote for XALKORI.
11 DESCRIPTION
XALKORI (crizotinib) is an oral receptor tyrosine kinase
inhibitor. The molecular formula for crizotinib is C21H22Cl2FN5O. The molecular
weight is 450.34 daltons. Crizotinib is described chemically as
(R)-3-[1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine.
Crizotinib is a white to pale-yellow powder with a pKa of
9.4 (piperidinium cation) and 5.6 (pyridinium cation). The solubility of
crizotinib in aqueous media decreases over the range pH 1.6 to pH 8.2 from greater
than 10 mg/mL to less than 0.1 mg/mL. The log of the distribution coefficient
(octanol/water) at pH 7.4 is 1.65. XALKORI capsules are supplied as printed
hard-shell capsules containing 250 mg or 200 mg of crizotinib together with
colloidal silicon dioxide, microcrystalline cellulose, anhydrous dibasic
calcium phosphate, sodium starch glycolate, magnesium stearate, and hard
gelatin capsule shells as inactive ingredients. The pink opaque capsule shell
components contain gelatin, titanium dioxide, and red iron oxide. The white
opaque capsule shell components contain gelatin and titanium dioxide. The
printing ink contains shellac, propylene glycol, strong ammonia solution,
potassium hydroxide, and black iron oxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Crizotinib is an inhibitor of receptor tyrosine kinases
including ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), ROS1 (c-ros),
and Recepteur d’Origine Nantais (RON). Translocations can affect the ALK gene
resulting in the expression of oncogenic fusion proteins. The formation of ALK
fusion proteins results in activation and dysregulation of the gene’s
expression and signaling which can contribute to increased cell proliferation
and survival in tumors expressing these proteins. Crizotinib demonstrated
concentration-dependent inhibition of ALK, ROS1, and c-Met phosphorylation in
cell-based assays using tumor cell lines and demonstrated antitumor activity in
mice bearing tumor xenografts that expressed echinoderm microtubule-associated
protein-like 4 (EML4)- or nucleophosmin (NPM)-ALK fusion proteins or c-Met.
12.2 Pharmacodynamics
Cardiac electrophysiology In an ECG substudy conducted in 52
patients with ALK-positive NSCLC who received crizotinib 250 mg twice daily,
the maximum mean QTcF (corrected QT by the Fridericia method) change from
baseline was 12.3 ms (2-sided 90% upper CI: 19.5 ms). An exposure-QT analysis
suggested a crizotinib plasma concentrationdependent increase in QTcF [see
Warnings and Precautions (5.3)]
12.3 Pharmacokinetics Absorption
Following a single oral dose, crizotinib was absorbed with
median time to achieve peak concentration of 4 to 6 hours. Following crizotinib
250 mg twice daily, steady state was reached within 15 days and remained
stable, with a median accumulation ratio of 4.8. Steady-state systemic exposure
[observed minimum concentration (Cmin) and AUC] appeared to increase in a
greater than dose-proportional manner over the dose range of 200-300 mg twice
daily. The mean absolute bioavailability of crizotinib was 43% (range: 32% to
66%) following a single 250 mg oral dose. A high-fat meal reduced crizotinib
AUC from time zero to infinity (AUCinf) and maximum observed plasma
concentration (Cmax) by approximately 14%. XALKORI can be administered with or
without food [see Dosage and Administration (2.2)
Distribution
The geometric mean volume of distribution (Vss) of
crizotinib was 1772 L following intravenous administration of a 50 mg dose,
indicating extensive distribution into tissues from the plasma. Binding of
crizotinib to human plasma proteins in vitro is 91% and is independent of drug
concentration. In vitro studies suggested that crizotinib is a substrate for
P-glycoprotein (P-gp). The blood-to-plasma concentration ratio is approximately
1.
Elimination
Following single doses of crizotinib, the mean apparent
plasma terminal half-life of crizotinib was 42 hours in patients. Following the
administration of a single 250 mg radiolabeled crizotinib dose to healthy
subjects, 63% and 22% of the administered dose was recovered in feces and
urine, respectively. Unchanged crizotinib represented approximately 53% and
2.3% of the administered dose in feces and urine, respectively. The mean
apparent clearance (CL/F) of crizotinib was lower at steady state (60 L/h) after
250 mg twice daily than after a single 250 mg oral dose (100 L/h), which was
likely due to autoinhibition of CYP3A by crizotinib after multiple dosing.
Metabolism
Crizotinib is predominantly metabolized by CYP3A4/5. The
primary metabolic pathways in humans were oxidation of the piperidine ring to
crizotinib lactam and O-dealkylation, with subsequent Phase 2 conjugation of
O-dealkylated metabolites. Specific populations Hepatic impairment: As
crizotinib is extensively metabolized in the liver, hepatic impairment is
likely to increase plasma crizotinib concentrations. However, XALKORI has not
been studied in patients with hepatic impairment. Clinical studies excluded
patients with ALT or AST greater than 2.5 times ULN or greater than 16
Reference ID: 4127887 5 times ULN if due to liver metastases. Patients with
total bilirubin greater than 1.5 times ULN were also excluded [see Use in
Specific Populations (8.6)]. The population pharmacokinetic analysis using the
data from approximately 1200 patients with cancer who received XALKORI
suggested that baseline total bilirubin (0.1 to 2.1 mg/dL) or AST levels (7 to
124 U/L) did not have a clinically relevant effect on the exposure of
crizotinib.
Renal impairment:
The pharmacokinetics of crizotinib were evaluated using the
population pharmacokinetic analysis in patients with mild (CLcr 60-89 mL/min,
n=433) and moderate (CLcr 30-59 mL/min, n=137) renal impairment. Mild or
moderate renal impairment has no clinically relevant effect on the exposure of
crizotinib. A study was conducted in 7 patients with severe renal impairment
(CLcr
Ethnicity:
No clinically relevant difference in the exposure of
crizotinib between Asian patients (n=523) and non-Asian patients (n=691).
Age: Age has no effect on the exposure of crizotinib based
on the population pharmacokinetic analysis. Body weight and gender: No
clinically relevant effect of body weight or gender on the exposure of
crizotinib based on the population pharmacokinetic analysis.
Drug interactions
Effect of Other Drugs on Crizotinib
Strong CYP3A inhibitors: Coadministration of a single 150 mg
oral dose of crizotinib with ketoconazole (200 mg twice daily), a strong CYP3A
inhibitor, increased crizotinib AUCinf and Cmax values by approximately
3.2-fold and 1.4-fold, respectively, compared to crizotinib alone. However, the
magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has
not been evaluated [see Drug Interactions (7.1)].
Strong CYP3A inducers: Coadministration of crizotinib (250
mg twice daily) with rifampin (600 mg once daily), a strong CYP3A inducer,
decreased crizotinib steady-state AUCtau and Cmax by 84% and 79%, respectively,
compared to crizotinib alone [see Drug Interactions (7.2)].
Gastric pH elevating medications: In healthy subjects,
coadministration of a single 250 mg oral dose of crizotinib following
administration of esomeprazole 40 mg daily for 5 days did not result in a
clinically relevant change in crizotinib exposure (AUCinf decreased by 10% and
no change in Cmax).
Effect of Crizotinib on Other Drugs CYP3A substrates:
Coadministration of crizotinib (250 mg twice daily for 28 days) in patients
increased the AUCinf of oral midazolam 3.7-fold compared to midazolam alone,
suggesting that crizotinib is a moderate inhibitor of CYP3A [see Drug
Interactions (7.3)].
Other CYP substrates: In vitro studies suggest that clinical
drug-drug interactions as a result of crizotinib-mediated inhibition of the
metabolism of substrates for CYP1A2, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 are
unlikely to occur.
Crizotinib is an inhibitor of CYP2B6 in vitro. Therefore,
crizotinib may increase plasma concentrations of coadministered drugs that are
predominantly metabolized by CYP2B6. An in vitro study suggests that clinical
drug-drug interactions as a result of crizotinib-mediated induction of the
metabolism of substrates for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A
are unlikely to occur.
UGT substrates: In vitro studies suggest that clinical
drug-drug interactions as a result of crizotinib-mediated inhibition of the
metabolism of drugs that are substrates for uridine diphosphate
glucuronosyltransferase (UGT)1A1, UGT1A4, UGT1A6, UGT1A9 or UGT2B7 are unlikely
to occur.
Substrates of transporters: Crizotinib inhibited P-gp in
vitro at clinically relevant concentrations. Therefore, crizotinib has the
potential to increase plasma concentrations of coadministered drugs that are
substrates of P-gp.
Crizotinib inhibited the hepatic uptake transporter, organic
cation transporter (OCT) 1, and renal uptake transporter, OCT2, in vitro at
clinically relevant concentrations. Therefore, crizotinib has the potential to
increase plasma concentrations of coadministered drugs that are substrates of
OCT1 or OCT2. Crizotinib did not inhibit the human hepatic uptake transport
proteins, organic anion transporting polypeptides (OATP) B1 or OATP1B3, or the
renal uptake transport proteins organic anion transporter (OAT) 1 or OAT3 in
vitro at clinically relevant concentrations.
Other transporters: Crizotinib did not inhibit the hepatic
efflux bile salt export pump transporter (BSEP) in vitro at clinically relevant
concentrations.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies with crizotinib have not been
conducted.
Crizotinib was
genotoxic in an in vitro micronucleus assay in Chinese Hamster Ovary cultures,
in an in vitro human lymphocyte chromosome aberration assay, and in in vivo rat
bone marrow micronucleus assays. Crizotinib was not mutagenic in vitro in the
bacterial reverse mutation (Ames) assay.
No specific studies with crizotinib have been conducted in
animals to evaluate the effect on fertility; however, crizotinib is considered
to have the potential to impair reproductive function and fertility in humans
based on findings in repeat-dose toxicity studies in the rat. Findings observed
in the male reproductive tract included testicular pachytene spermatocyte
degeneration in rats given greater than or equal to 50 mg/kg/day for 28 days
(greater than 1.7 times the recommended human dose based on AUC). Findings
observed in the female reproductive tract included single-cell necrosis of
ovarian follicles of a rat given 500 mg/kg/day (approximately 10 times the
recommended human dose based on body surface area) for 3 days.
14 CLINICAL STUDIES
14.1 ALK-Positive Metastatic NSCLC Previously Untreated
ALK-Positive Metastatic NSCLC - Study 1
The efficacy and safety of XALKORI for the treatment of
patients with ALK-positive metastatic NSCLC, who had not received previous
systemic treatment for advanced disease, was demonstrated in a randomized,
multicenter, open-label, active-controlled study (Study 1). Patients were
required to have ALK-positive NSCLC as identified by the FDA-approved assay,
Vysis ALK Break-Apart fluorescence in situ hybridization (FISH) Probe Kit,
prior to randomization. The major efficacy outcome measure was progression-free
survival (PFS) according to Response Evaluation Criteria in Solid Tumors
(RECIST) version 1.1 as assessed by independent radiology review (IRR)
committee. Additional efficacy outcome measures included objective response
rate (ORR) as assessed by IRR, duration of response (DOR), and overall survival
(OS). Patient-reported lung cancer symptoms were assessed at baseline and
periodically during treatment.
Patients were randomized to receive XALKORI (n=172) or
chemotherapy (n=171). Randomization was stratified by Eastern Cooperative
Oncology Group (ECOG) performance status (0-1, 2), race (Asian, non-Asian), and
brain metastases (present, absent). Patients in the XALKORI arm 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. Chemotherapy consisted of pemetrexed 500 mg/m2
with cisplatin 75 mg/m2 or carboplatin AUC of 5 or 6 mg·min/mL by intravenous
infusion every 3 weeks for up to 6 cycles. Patients in the chemotherapy arm
were not permitted to receive maintenance chemotherapy. At the time of
documented disease progression, as per independent radiology review, patients
randomized to chemotherapy were offered XALKORI.
The demographic characteristics of the overall study
population were 62% female, median age of 53 years, baseline ECOG performance
status 0 or 1 (95%), 51% White and 46% Asian, 4% current smokers, 32% past
smokers, and 64% never smokers. The disease characteristics of the overall
study population were metastatic disease in 98% of patients, 92% of patients’
tumors were classified as adenocarcinoma histology, 27% of patients had brain
metastases, and 7% received systemic chemotherapy as adjuvant or neoadjuvant
therapy. Of those randomized to chemotherapy, 70% received XALKORI after IRR
documented progression.
Study 1 demonstrated a statistically significant improvement
in PFS in the patients treated with XALKORI. The OS analysis conducted at the
time of the PFS analysis did not suggest a difference in survival between arms.
Table 7 and Figure 1 summarize the efficacy results. Exploratory
patient-reported symptom measures of baseline and post-treatment dyspnea,
cough, and chest pain suggested a delay in time to development of or worsening
of dyspnea, but not cough or chest pain, in patients treated with XALKORI as
compared to chemotherapy. The patient-reported delay in onset or worsening of
dyspnea may be an overestimation, because patients were not blinded to treatment
assignment.
Table 7. Previously Untreated ALK-Positive Metastatic NSCLC
- Efficacy Results XALKORI (N=172) Chemotherapy (N=171) Progression-Free
Survival (Based on IRR) Number of Events (%) 100 (58%) 137 (80%) Progressive
Disease 89 (52%) 132 (77%) Death 11 (6%) 5 (3%) Median, Months (95% CI) 10.9
(8.3, 13.9) 7.0 (6.8, 8.2) HR (95% CI)a 0.45 (0.35, 0.60) p-valueb
Figure 1. Kaplan-Meier Curves of Progression-Free Survival
as Assessed by IRR in Study 1
Previously Treated ALK-Positive Metastatic NSCLC - Study 2
The efficacy and safety of XALKORI as monotherapy for the
treatment of 347 patients with ALK-positive metastatic NSCLC, previously
treated with 1 platinum-based chemotherapy regimen, were demonstrated in a
randomized, multicenter, open-label, active-controlled study (Study 2). The
major efficacy outcome was PFS according to RECIST version 1.1 as assessed by
IRR. Additional efficacy outcomes included ORR as assessed by IRR, DOR, and OS.
Patients were randomized to receive XALKORI 250 mg orally
twice daily (n=173) or chemotherapy (n=174). Chemotherapy consisted of
pemetrexed 500 mg/m2 (if pemetrexed-naïve; n=99) or docetaxel 75 mg/m2 (n=72)
intravenously (IV) every 21 days. Patients in both treatment arms continued
treatment until documented disease progression, intolerance to therapy, or the
investigator determined that the patient was no longer experiencing clinical
benefit. Randomization was stratified by ECOG performance status (0-1, 2),
brain metastases (present, absent), and prior EGFR tyrosine kinase inhibitor
treatment (yes, no). Patients were required to have ALK-positive NSCLC as
identified by the FDA-approved assay, Vysis ALK Break-Apart FISH Probe Kit,
prior to randomization. At the time of the final analysis of overall survival,
154 (89%) patients randomized to the chemotherapy arm subsequently received
XALKORI.
The demographic characteristics of the overall study
population were 56% female, median age of 50 years, baseline ECOG performance
status 0 or 1 (90%), 52% White and 45% Asian, 4% current smokers, 33% past
smokers, and 63% never smokers. The disease characteristics of the overall
study population were metastatic disease in at least 95% of patients and at
least 93% of patients’ tumors were classified as adenocarcinoma histology.
Study 2 demonstrated a statistically significant improvement
in PFS in the patients treated with XALKORI. Table 8 and Figure 2 summarize the
efficacy results.
Table 8. Previously Treated ALK-Positive Metastatic NSCLC -
Efficacy Results XALKORI (N=173) Chemotherapy (N=174) Progression-Free Survival
(Based on IRR) Number of Events (%) 100 (58%) 127 (73%) Progressive Disease 84
(49%) 119 (68%) Death 16 (9%) 8 (5%) Median, Months (95% CI) 7.7 (6.0, 8.8)
3.0a (2.6, 4.3) HR (95% CI)b 0.49 (0.37, 0.64) p-valuec
Figure 2. Kaplan-Meier Curves of Progression-Free Survival
as Assessed by IRR in Study 2
14.2 ROS1-Positive Metastatic NSCLC The efficacy and safety
of XALKORI was investigated in a multicenter, single-arm study (Study 3), in
which patients with ROS1-positive metastatic NSCLC received XALKORI 250 mg
orally twice daily. Patients were required to have histologically-confirmed
advanced NSCLC with a ROS1 rearrangement, age 18 years or older, ECOG
performance status of 0, 1, or 2, adequate organ function, and measurable
disease. The efficacy outcome measures were ORR and DOR according to RECIST version
1.0 as assessed by IRR and investigator, with imaging performed every 8 weeks
for the first 60 weeks. Baseline demographic and disease characteristics were
female (56%), median age of 53 years, baseline ECOG performance status of 0 or
1 (98%), White (54%), Asian (42%), past smokers (22%), never smokers (78%),
metastatic disease (92%), adenocarcinoma (96%), no prior systemic therapy for
metastatic disease (14%), and prior platinum-based chemotherapy for metastatic
disease (80%). The ROS1 status of NSCLC tissue samples was determined by
laboratory-developed break-apart FISH (96%) or RT-PCR (4%) clinical trial
assays. For assessment by FISH, ROS1 positivity required that ≥15% of
a minimum of 50 evaluated nuclei contained a ROS1 gene rearrangement. Efficacy results
are summarized in Table 9. 23 Reference ID: 4127887 Table 9. ROS1-Positive
Metastatic NSCLC - Efficacy Results* Efficacy Parameters IRR (N=50)
Investigator-Assessed (N=50) Objective Response Rate (95% CI) 66% (51, 79) 72%
(58, 84) Complete Response, n 1 5 Partial Response, n 32 31 Duration of
Response Median, Months (95% CI) 18.3 (12.7, NR) NR (14.5, NR) IRR=independent
radiology review; CI=confidence interval; NR=not reached. * As assessed by
RECIST version 1.0.
16 HOW SUPPLIED/STORAGE AND HANDLING
· 250 mg capsules Hard gelatin capsule with pink opaque cap
and body, printed with black ink “Pfizer” on the cap, “CRZ 250” on the body;
available in: Bottles of 60 capsules: NDC 0069-8140-20
· 200 mg capsules Hard gelatin capsule with pink opaque cap
and white opaque body, printed with black ink “Pfizer” on the cap, “CRZ 200” on
the body; available in: Bottles of 60 capsules: NDC 0069-8141-20
Store at room temperature 20° to 25°C (68° to 77°F);
excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room
Temperature].
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling
(Patient Information).
Hepatotoxicity Inform patients to immediately report
symptoms of hepatotoxicity [see Warnings and Precautions (5.1)].
Interstitial Lung Disease (Pneumonitis)
Advise patients to immediately report any new or worsening
pulmonary symptoms [see Warnings and Precautions (5.2)].
Bradycardia Advise patients to report any symptoms of
bradycardia and to inform their healthcare provider about the use of any heart
or blood pressure medications [see Warnings and Precautions (5.4)].
Severe Visual Loss Inform patients of the potential risk of
severe visual loss and to immediately contact their healthcare provider if they
develop severe visual loss. Inform patients that visual changes such as
perceived flashes of light, blurry vision, light sensitivity, and floaters are
commonly reported adverse events and may occur while driving or operating
machinery. The onset of visual disorders most commonly occurs during the first
week of treatment [see Warnings and Precautions (5.5) and Adverse Reactions
(6)]. 24
Drug Interactions Inform patients to avoid grapefruit or
grapefruit juice while taking XALKORI.
Advise patients to inform their healthcare providers of all
concomitant medications, including prescription medicines, over-the-counter
drugs, vitamins, and herbal products [see Drug Interactions (7)].
Dosing and Administration Advise patients to take XALKORI
with or without food and swallow XALKORI capsules whole. If a patient misses a
dose, advise the patient to take it as soon as remembered unless it is less
than 6 hours until the next dose, in which case, advise the patient not to take
the missed dose.
If a patient vomits after taking a dose of XALKORI, advise
the patient not to take an extra dose, but to take the next dose at the regular
time.
Embryo-Fetal Toxicity Advise females of reproductive
potential of the potential risk to a fetus and to inform their healthcare
provider of a known or suspected pregnancy [see Warnings and Precautions (5.6)
and Use in Specific Populations (8.1)]. Advise females of reproductive
potential to use effective contraception during treatment with XALKORI and for
at least 45 days after the final dose [see Use in Specific Populations (8.3)].
Females and Males of
Reproductive Potential Advise females and males of reproductive potential of
the potential for reduced fertility from XALKORI [see Use in Specific
Populations (8.3) and Nonclinical Toxicology (13.1)].
Advise male patients 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 (8.3) and Nonclinical
Toxicology (13.1)].
Lactation Advise females not to breastfeed during treatment
with XALKORI and for 45 days after the final dose [see Use in Specific
Populations (8.2)].
Infertility Advise females and males of reproductive
potential of the potential for reduced fertility from XALKORI [see Use in
Specific Populations (8.3)].
This product’s labeling may have been updated. For full
prescribing information, please visit www.XALKORI.com.
