Public Disclosure Synopsis
Protocol A8081005 – 27 Oct 2016 – Final

PFIZER INC.
These results are supplied for informational purposes only.
Prescribing decisions should be made based on the approved package insert.
GENERIC DRUG NAME / COMPOUND NUMBER: Crizotinib / PF-02341066
PROTOCOL NO.: A8081005
PROTOCOL TITLE:
Phase 2, Open-label, Single Arm Study of the Efficacy and Safety of PF-02341066 in
Subjects with Advanced Non-Small-Cell Lung Cancer (NSCLC) Harboring a Translocation
or Inversion Involving the Anaplastic Lymphoma Kinase (ALK) Gene Locus.
Study Centers:
A total of 143 centers in 22 countries enrolled subjects in this study; 47 in the United Sates(US), 10 each in Italy and Japan, 9 each in China, France, Germany and Spain, 6 in Brazil
and the United Kingdom, 3 each in Australia, Canada, Hong Kong, South Korea and Taiwan,
2 each in Bulgaria, Greece, Hungary, Poland and Russian Federation and 1 each in Ireland,
Netherlands and Sweden. An additional 34 centers received study drug, but did not enroll
subjects.
Study Initiation Date and Study Completion Date:
Study Initiation Date: 07 January 2010.
Study Completion Date: 29 December 2015.
Phase of Development: Phase 2.
Study Objectives:
Primary Objectives

To assess the antitumor efficacy of oral single-agent crizotinib administered tosubjects with advanced NSCLC after failure of at least 1 line of chemotherapy andharbor a translocation or inversion event involving the ALK gene locus as measured
by objective response rate (ORR).



To assess the safety and tolerability of oral crizotinib.

Secondary Objectives

To assess secondary measures of clinical efficacy including overall survival (OS),duration of response (DR), time to tumor response (TTR), disease control rate (DCR)
at 6 and 12 weeks, and progression-free survival (PFS);

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Protocol A8081005 – 27 Oct 2016 – Final

To determine pharmacokinetics (PK) in this subject population using population
pharmacokinetic (popPK) methods and explore correlations between PK, response,
and/or safety findings;

To explore the relationship of ALK gene fusion to the presence of ALK protein andfusion transcript;

To correlate changes from Baseline in expression of biomarkers in signaling
pathways (including Janus kinase [JAK]/signal transducers and activators oftranscription [STAT], mitogen-activated protein kinase [MEK]/extracellular signalregulated kinase [ERK], and phosphatidyl inositol-3-kinase [PI3K]/protein kinase B[AKT] pathways) to PK and outcome measures;To assess patient-reported outcomes of health-related quality of life (QoL),
disease/treatment-related symptoms of lung cancer, and general health status;

To evaluate the effect of crizotinib on the QT interval (QTc);



To identify and evaluate potential pharmacogenomic (PG) markers for possible
association with selected observed toxicities, i.e., potential markers of adverse hepaticand renal drug reactions.

METHODS
Study Design:This was a multicenter, multinational, open-label, single arm, Phase 2 study to assess theantitumor efficacy and safety of crizotinib administered to subjects with advanced NSCLC
after failure of at least 1 line of chemotherapy and whose tumors harbored a translocation or
inversion event involving the ALK gene locus.
Only ALK fusion-positive (ALK-positive) NSCLC subjects were enrolled in the study.
Fluorescence in situ hybridization (FISH) was the primary assay used to detect ALK fusion
events in tumor samples. An investigational-use only (IUO) population and a non-IUO
population subjects are defined as FISH ALK-positive based on the central laboratory andlocal assay testing only, respectively.
Crizotinib (250 mg) was administered orally twice daily (BID) at approximately the sametimes each day using a continuous dosing schedule. To facilitate visits and assessments,
treatment cycles were defined as 21-day periods. Radiographic tumor assessments including
brain scans for objective tumor response and progression were performed at 6-weekintervals, and after 10 cycles, assessments may have been performed at 12-week intervals.
Bone scans were required at screening. Repeat bone and brain scans were performed in caseof bone metastases at Baseline and if new bone metastases were suspected.
An electrocardiogram (ECG) substudy was conducted to further evaluate the effect of
crizotinib on corrected QTc and to evaluate a potential crizotinib concentration-QTc
relationship. A PK substudy was also performed to evaluate single-dose and multiple-dose

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Protocol A8081005 – 27 Oct 2016 – Final

PK profiles of crizotinib and its metabolite (PF-06260182) in a fasted state in Chinese
subjects for the PK substudy. The details of the PK assessments for this substudy weresummarized in a separate report. A single dose of crizotinib (250 mg) was administered
7 days prior to the start of Cycle 1 (Day-7), after which subjects began receiving multiple,
continuous crizotinib doses (i.e., 250 mg BID from Day 1 of Cycle 1). Table 1 and Table 2
provide an overview of the schedule of activities.

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Protocol A8081005 – 27 Oct 2016 – Final

Table 1: Subject Evaluation Schedule/Schedule of Time and Events
Screening a
Protocol Activities

Baseline Documentation
Informed Consent e
Medical/Oncological History f
Baseline Signs/Symptoms
Mandatory Tumor Tissue for Molecular Profiling g
Physical Examination h
ECOG Performance Status
Ophthalmologic Examination iLaboratory Studies
Hematology j
Blood Chemistry j
Urinalysis Dipstick and Reflex Microscopy j
Coagulation j
12-lead ECG k
Female Subjects: Pregnancy Test (as Appropriate) l
Disease Assessments
Tumor Assessments (Including Scans) m
Other Clinical Assessments
Contraceptive Check (as Appropriate)
Adverse Eventsn
Concomitant Medications/Treatmentso
EORTC QLQ-C30, QLQ-LC13, EQ-5D and VSAQALKp
MUGA Scan or Echocardiogram (France and Ireland
only)
Survival Follow-upq≤28 Days Prior
to Dosing

Study Treatment b
End of Treatment
Cycle 1
Cycles ≥2
Cycles >10
Day 1
Day 15
Day 1 (±2;Visits on alternate End of Rx/ Post Rx(±2) c(±2)
except as noted cycles Day 1 (±4; Withdrawal d Followbelow)
except as notedup
below)

X
X
X
X
X
X
X

X
X
X (Korea only)
X
X
X

(X)
X

(X)
(X)
X
(Korea
only)

X
X

X

X
X
X
X

X
X
X

X

X
X

X
X
Cycle 5, thenevery 4 cycles(France only)

X
X
France only: every
4 cyclesX
X

X
X
Korea only:X
All countries u

Xj
Xj
Korea only:X
All countries uX
X
Korea only:X
All countries u

Cycle 2Xl

Xl

X

every 6 weeks(±1 week)

every 12 weeks(±1 week)

X

X
X
X
X

X
X
X
X

X
X
X
X

Cycle 3, thenevery 4 cycles

every 4 cycles

X
X
X

X

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Protocol A8081005 – 27 Oct 2016 – Final

Screening a
Protocol Activities

Study Treatment
Crizotinib
Special Laboratory Studies
Optional Tumor Tissue for Molecular Profilingr
Pharmacokineticss
Optional Blood Sample for Pharmacogenomicst≤28 Days Prior
to Dosing

Study Treatment b
End of Treatment
Cycle 1
Cycles ≥2
Cycles >10
Day 1
Day 15
Day 1 (±2;Visits on alternate End of Rx/ Post Rx(±2) c(±2)
except as noted cycles Day 1 (±4; Withdrawal d Followbelow)
except as notedup
below)
Twice Daily

X
X
X

Cycle 2
Cycles 2, 3, 5

X

Source: Protocol.
( ) – if not performed within 7 days of the first dose of crizotinib.
Abbreviations: ALK=anaplastic lymphoma kinase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CT=computed tomography; DNA=deoxyribonucleic acid;
EC=Ethics Committee; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EORTC QLQ-C30=European Organization for the Research and Treatment ofCancer Quality of Life Questionnaire - Core 30 Questionnaire; EQ-5D=EuroQol-5D; FISH=fluorescence in situ hybridization; HLA-DQA1*02:01=Major histocompatibility
complex, class 2, DQ alpha 1*02:01; IRB=Institutional Review Board; K2EDTA=dipotassium ethylenediamine tetraacetic acid; MRI=magnetic resonance imaging;
MUGA=multiple gate acquisition; PK=pharmacokinetic; PKD1=polycystic kidney disease 1; PKD2=polycystic kidney disease 2; QLQ-LC13=Quality of Life Questionnaire –Lung Cancer 13; QTc=corrected QT; Rx=treatment; VHL=von Hippel-Lindau; VSAQ-ALK=Visual Symptom Assessment Questionnaire – Anaplastic Lymphoma Kinase.
a. Screening: Subjects who were treated on Arm B of Study A8081007 did not need to be re-screened if they had required laboratory tests and physical examination within
3 weeks of scheduled Day 1 of Cycle 1 dosing.
b. Study Treatment: All assessments were performed prior to dosing with study drugs unless otherwise indicated. Acceptable time windows for performing each assessment aredescribed in the column headings. All cycles were 3 weeks in duration. Upon the IRB/EC approval of Amendment 11 and after Cycle 10, clinic visits could have been reduced toevery other cycle. Sufficient study drug for 2 cycles of treatment was dispensed at each clinic visit. During the non-clinical visit cycles, the Investigator was responsible for
ensuring the subject contacted the clinical site in order to provide an update of adverse events and concomitant medications.
c. Cycle 1/Day 1: Blood chemistry, hematology, urinalysis, and physical examination not required if acceptable screening assessment was performed within 7 days prior to thestart of study treatment.
d. End of Treatment/Withdrawal: These assessments were obtained if not completed during the previous 4 weeks on-study (during the last 6 weeks for disease assessments).
e. Informed Consent: Obtained prior to undergoing any trial specific procedure.
f. Medical/Oncological History: Included information on prior regimens.
g. Mandatory Tumor Tissue for Molecular Profiling: For subjects not previously screened in Study A8081007, paraffin block (s) of adequate size to allow if possible for at least
10 slides with cuts that were 5 microns thick were used. If no block was available, then the sites were to try to obtain, if possible, at least 10 slides with cuts that were 5 microns
thick. Archived or fresh tumor samples were acceptable. These samples were used for the assessment of ALK gene fusion by FISH. Samples could have been tested at the site
local laboratory but samples (blocks or slides enough if possible for 10 slides of 5 microns thick) were sent to the central laboratory for confirmation of ALK fusion by FISH. For
those subjects enrolled based upon Amendment 10 and lacking sufficient or appropriate tissue for FISH testing by the central laboratory, other ALK testing results could have been
acceptable but had to be discussed and approved on a case-by-case basis by the Sponsor. Tumor samples could also have been used for analysis of the presence of ALK protein
and ALK fusion transcripts. The mandatory tumor tissue could have been completed outside the 28-day screening window.
h. Physical Examination: Included an examination of major body systems, height (at screening only), weight, blood pressure and pulse rate (at Baseline and on Day 1 of eachcycle).
i. Ophthalmologic Examination: Included visual acuity, slit lamp, and fundoscopy, and was performed by an ophthalmologist. The ophthalmologic examination was repeatedduring the study when visual disturbances were observed and when there was an increase in the grade for visual disturbances. For all subjects enrolled in France, ophthalmology

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Protocol A8081005 – 27 Oct 2016 – Final

Screening a
Protocol Activities≤28 Days Prior
to Dosing

Study Treatment b
End of Treatment
Cycle 1
Cycles ≥2
Cycles >10
Day 1
Day 15
Day 1 (±2;Visits on alternate End of Rx/ Post Rx(±2) c(±2)
except as noted cycles Day 1 (±4; Withdrawal d Followbelow)
except as notedup
below)

exams were performed after the completion of every 4 cycles.
j. Hematology, Blood Chemistry, Coagulation, and Urinalysis: If ALT or AST ≥ Grade 3 or ALT or AST ≥ Grade 2 and total bilirubin ≥ Grade 2, repeat ALT or AST and total
bilirubin were obtained within 48 hours and then repeated every 48-72 hours until ALT/AST < Grade 1. A 4 mL serum sample obtained just prior to the first dose of study drug
(Day -7) was stored frozen on-site through completion of the study for possible use as a Baseline reference if additional laboratory tests were indicated, for example, additional
testing to exclude other causes of liver injury. Reflex Microscopy was required if urine dipstick was positive for blood or protein. Upon IRB/EC approval of Amendment 15 andafter Cycle 10, laboratory tests (at least: ALT/AST/alkaline phosphatase/total bilirubin) were also performed on Day 1 of each cycle. Such tests could be done locally (preferably
at the clinical site’s local laboratory).
k. 12-lead ECG: Triplicate ECG measurements (approximately 2 minutes apart) were measured at all time points, except a single ECG measurement at screening. The ECG on
Day 1 of Cycles 1 and 2 was obtained at 0 hour (predose) and 2-6 hours following morning crizotinib dosing. ECGs were performed immediately before PK blood draws at
respective time points. If the QTc was prolonged (>500 msec), then the ECG was read by a cardiologist at the site for confirmation. At selected clinical sites, an ECG substudy
was conducted.
l. Pregnancy Test: All female subjects of childbearing potential were required to have a negative pregnancy test at screening. The test was repeated whenever one menstrual
cycle was missed during the active treatment period or a potential pregnancy was otherwise suspected, and could also have been repeated as per request of IRB/ECs or if requiredby local regulations.
m. Tumor Assessments: CT or MRI included chest, brain, abdomen and pelvis at screening. A bone scan was also required at screening. All subsequent scans were based on acalendar schedule beginning from the date of first dose of crizotinib. Scans performed 6 weeks after the first dose of crizotinib had a +1 week allowance; all subsequent scans
were performed at 6 week intervals (±1 week), and after 10 cycles were performed at 12-week intervals (±1 week). Brain was included in subsequent tumor assessments if asubject had brain metastases, otherwise brain was only evaluated when clinically indicated. Repeat bone scans were required every 12 weeks only if bone metastases were present
at Baseline otherwise a repeat bone scan was required only if new bone metastases were suspected. A bone scan was also required at the time of determination of response forsubjects who had bone metastases. For subjects that crossed over from Arm B on Study A8081007, repeat brain and bone scans were required if the scans were not obtained
within the appropriate screening window. CT or MRI scan was also performed whenever disease progression was suspected (eg, symptomatic deterioration). If renal cysts wereobserved, active surveillance with appropriate imaging was performed at the time of renal cyst diagnosis and thereafter following the same schedule as for tumor imaging. All
images were reviewed by an independent radiology laboratory until written notification by the Sponsor.
n. Adverse Events: subjects were followed for adverse events from the time they signed the informed consent until at least 28 days after the last dose of study treatment, or until
all serious or study drug-related toxicities resolved or were determined to be “chronic” or “stable”, whichever was later. Serious adverse events were monitored and reported fromthe time that the subject provided informed consent as described in the protocol.
o. Concomitant Medications/Treatments: Concomitant medications and treatments were recorded from 28 days prior to the start of study treatment and up to 28 days post thelast dose of study treatment.
p. EORTC QLQ-C30, QLQ-LC13 EQ-5D, and VSAQ-ALK: Subjects completed the EORTC QLQ-C30, the QLQ-LC13, the EQ-5D, and the VSAQ-ALK questionnaires at theclinic prior to any study or medical procedure. Subjects with visual disturbances ongoing at End of Treatment visit had also to complete the VSAQ-ALK at the 28-day Follow-up
visit after last dose. All self-assessment questionnaires had to be completed by the subjects while in the clinic and could not be taken home. The VSAQ-ALK was translated into
different languages. However, if the VSAQ-ALK was not available in the subject’s preferred language, the subject did not need to complete this assessment.
q. Survival Follow-Up: After discontinuation of study treatment, post-study survival status was collected every 2 months until death or until 12 months after the last subject had
discontinued study treatment. This included collection of information on subsequent anticancer therapies. Telephone contact was acceptable.
r. Optional Tumor Tissue for Molecular Profiling: Paraffin block (s) of adequate size to allow for at least 10 slides if possible with cuts that were 5 microns thick. If no block
was available, then at least 10 slides, if possible, with cuts that were 5 microns were acceptable. Archived or fresh tumor samples were acceptable for screening. A tumor

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Protocol A8081005 – 27 Oct 2016 – Final

Screening a≤28 Days Prior
to DosingProtocol Activities

Study Treatment b
End of Treatment
Cycle 1
Cycles ≥2
Cycles >10
Day 1
Day 15
Day 1 (±2;Visits on alternate End of Rx/ Post Rx(±2) c(±2)
except as noted cycles Day 1 (±4; Withdrawal d Followbelow)
except as notedup
below)

specimen was only needed at the End of Treatment, if a subject discontinued due to disease progression.
s. Pharmacokinetics: Subjects enrolled in the ECG substudy only: refer to protocol for further details regarding concurrent PK sampling on Cycles 1, 2, 3, and 5, Day 1. For allother subjects, PK plasma samples were collected prior to and 2-6 hours following morning crizotinib dosing (effective from the original protocol to Amendment 10); PK plasma
samples were no longer required after Amendment 11 was approved locally, except for the subjects enrolled in the ECG substudy. At each sampling time point, 2 mL of blood
was drawn into K2EDTA tubes. Unused plasma sample remaining after completion of PK assessments could also have been used to investigate biomarkers (eg, protein or
circulating nucleic acid markers) of potential relevance to the mechanism of crizotinib, the development of resistance to crizotinib, or the identification of subjects who might
benefit from treatment with crizotinib. Additionally, blood samples could have been requested from subjects experiencing unexpected or serious adverse events.
t. Optional Blood Sample for Pharmacogenomics: A single 4 mL blood sample was collected for the analysis of DNA sequence variation in genes that could affect the PK of
crizotinib, or that could be associated with adverse drug reactions. Examples of genes that may affect PK include, but may not be limited to, genes encoding drug metabolizing
enzymes and transporters. Genes that may be associated with specific adverse events include, but may not be limited to, HLA-DQA1*02:01 for liver toxicities and PKD1, PKD2and VHL for renal toxicities.
u. As clinically indicated.

Table 2: Reduced Schedule of Activities
Protocol Activities

Physical Examination[3]Study Treatment[1]Visits on Day 1 of Alternate
Cycles (±4; except as noted
below)X

Blood Pressure and Pulse Rate

X

Ophthalmologic Examination[4]France only: every 4 cycles
All countries: X[4]End of Treatment
End of Txt/
Post Txt FollowWithdrawal[2]upX
X

Laboratory Studies
X

Hematology and Blood Chemistry, excluding Liver Functions Tests(LFTs)[5]
LFTs: ALT/AST/alkaline phosphatase/total bilirubin[5]Urinalysis dipstick and Reflex Microscopy[6]Female subjects: Pregnancy Test (as appropriate)[7]X

Day 1 of each cycle (±4)

X

Korea only: X(all other countries: as clinicallyindicated)
X[7]Korea only: X (allother countries: asclinically indicated)
X[7]

X

X

Contraceptive Check (as appropriate)
Disease Assessments
Tumor Assessments [8]As per local clinical practice

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Protocol A8081005 – 27 Oct 2016 – Final

Protocol Activities

Study Treatment[1]Visits on Day 1 of Alternate
Cycles (±4; except as noted
below)End of Treatment
End of Txt/
Post Txt FollowWithdrawal[2]upOther Clinical Assessments
Adverse Events[9]Concomitant Medications/Treatments[10]Multiple Gate Acquisition (MUGA) Scan or Echocardiogram (France only)

X
X
France only: every 4 cycles

X
X

X
X

Study Treatment
PF-02341066

Twice daily

Survival Follow-up [11]Source: Protocol. Abbreviations: Txt=treatment.
Footnotes for Schedule of Activities
1. All assessments should be performed prior to dosing with study medications unless otherwise indicated. All cycles are 3 weeks in duration. Sufficient study
medication for 2 cycles of treatment will be dispensed at each clinic visit. During the non-clinical visit cycles, the Investigator is responsible for ensuring the subject
contacts the clinical site in order to provide an update of adverse events and concomitant medications.
2. End of Treatment/Withdrawal: Obtain blood pressure, pulse rate, laboratory tests (including LFTs), and physical examination if not completed during the previous
4 weeks on study.
3. Physical Examination: Includes an examination of major body systems and weight.
4. Ophthalmologic Examination: Includes visual acuity, slit lamp, and fundoscopy, and should be performed by an ophthalmologist. The ophthalmologic examination
should be repeated during the study when visual disturbances have been observed and when there is an increase in the grade for visual disturbances. For all subjects
enrolled in France, ophthalmology exams will be performed after the completion of every 4 cycles.
5. Hematology, Blood Chemistry, and Urinalysis: Required tests are listed in Appendix 1 of the protocol. Where possible, laboratory tests should be performed at theclinical site’s local laboratory. Where that is not possible, subjects will provide the laboratory test results carried out at a non-clinical site laboratory, eg, by telephone,and bring a copy of the laboratory test results at the next cycle visit; process depends on local medical practice. The copy of the laboratory test results must be retainedin the subject’s file at the clinical site for documentation purposes. If ALT or AST ≥ grade 3 or ALT or AST ≥ grade 2 and total bilirubin ≥grade 2, obtain repeat
ALT or AST and total bilirubin within 48 hours and then repeat every 48-72 hours until ALT/AST < Grade 1.
6. Reflex Microscopy required if urine dipstick is positive for blood or protein.
7. Pregnancy Test: All female subjects of childbearing potential are required to repeat the test whenever one menstrual cycle is missed during the active treatment
period or a potential pregnancy is otherwise suspected, and the test may also be repeated as per request of IRB/ECs or if required by local regulations.
8. Tumor Assessments: Will be repeated at the frequency as per local clinical practice, and will no longer be recorded on the CRF. However, tumor assessment
information should be retained in the subject’s file for documentation purposes
9. Adverse Events: subjects must be followed for adverse events with the frequency as per local clinical practice until at least 28 days after the last dose of study
treatment, or until all serious or study drug-related toxicities have resolved or are determined to be “chronic” or “stable”, whichever is later. Serious adverse eventsshould be monitored and reported from the time that the subject provides informed consent as described in the protocol.
10. Concomitant Medications/Treatments: Concomitant medications and treatments will be recorded up to 28 days post the last dose of study treatment.
11. NOTE: Post-study survival status is no longer required.

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Number of Subjects (Planned and Analyzed):
Approximately 1100 subjects were projected to be enrolled into this trial. A total of 1069
subjects were enrolled and 1066 subjects received at least1 dose of crizotinib and were
included in the safety analysis (SA) population. Three subjects who were enrolled but nottreated were withdrawn from the study before receiving treatment because they were noteligible and were mistakenly entered into the interactive voice response system. A total of
144 (13.5%) subjects of Study A8081007, including 143 subjects from the chemotherapy arm
and 1 subject initially erroneously randomized in the crizotinib arm but not treated, wereenrolled in A8081005 study to receive treatment with crizotinib.
Main Inclusion Criteria:

Eligible female or male subjects ≥18 years of age (for subjects enrolled in Japan:
consent from a legally acceptable representative was required for all subjects who
were under 20 years old).



Have histologically or cytologically proven diagnosis of NSCLC that was locallyadvanced or metastatic; at least 1 prior treatment for locally advanced or metastatic
disease.



Positive for translocation or inversion events involving the ALK gene locus asdetermined by the ALK break apart FISH assay. Upon local approval of Protocol
Amendment 10, positive ALK test results from other methods such as
immunohistochemistry (IHC) or reverse transcriptase polymerase chain reaction(RT-PCR) testing may have also been acceptable after discussion and approval by theSponsor.



Randomized to Arm B (pemetrexed or docetaxel) of Study A8081007 and was
discontinued from treatment due to response evaluation criteria in solid tumors(RECIST) version 1.1-defined progression of disease as determined by independentradiology review or ineligible for Study A8081007 due to not meeting therequirement for prior treatment for advanced disease, or ECOG performance status 3or the laboratory or RECIST eligibility criteria (but must meet all eligibility criteria of
this protocol).



Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS)score of 0 to 3 and an adequate organ function as defined in the protocol.



Subjects with brain metastases were eligible if asymptomatic or, if treated, were
neurologically stable for at least 2 weeks.

Study Treatment:
Crizotinib 250 mg (two 100 mg tablets and one 50 mg tablet) was administered orally BID
on a continuous dosing schedule at the same time each day. Cycles were defined in 21-day
periods to facilitate scheduling of visits and assessments.

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Subjects were monitored closely for toxicity and the dose of crizotinib was adjusted for
toxicity. Intra-subject dose reduction by 1 and, if needed, 2 dose levels was allowed
depending on the type and severity of toxicity encountered (Dose Level 1 was 200 mg BID,
and Dose Level 2 was 250 mg once daily [QD]). Subjects were instructed that if they
vomited any time after taking a dose, then they should not “make it up” with an extra dose,
but instead, they should resume subsequent doses as prescribed. Any missed dose was taken
up to 6 hours prior to the next scheduled dose, otherwise it was skipped, and dosing was
resumed with subsequent doses as prescribed.

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Efficacy, Outcomes Research, Pharmacokinetic and Pharmacodynamic Endpoints:
Efficacy Endpoints:
Primary Endpoints:


ORR.



Type, incidence, severity, seriousness and relationship to study medications ofadverse events (AEs) and any laboratory abnormalities.

Secondary Endpoints:
OS, DR, TTR, DCR at 6 and 12 weeks, and PFS.



Plasma concentrations of PF-02341066.

Types of echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion
variants and ALK protein expression.

Protein expression of identified biomarkers in serial tumor samples from surgery orbiopsy, when available.



Health-related QoL, lung cancer disease/treatment-related specific symptoms, andgeneral health status.



QTc.



Genotype of alleles possibly associated with adverse hepatic or renal drug reactions,eg, major histocompatibility complex, class 2, DQ alpha 1*02:01 (HLA-DQAI*2:01),
polycystic kidney disease 1 (PKD1), polycystic kidney disease 2 (PKD2), and vonHippel-Lindau (VHL).

Safety Evaluations:
Safety evaluations included reporting of AEs, serious adverse events, periodic physicalexaminations (major body systems, weight and height [at screening only]), clinical laboratory
parameters (hematology, blood chemistry, coagulation [screening only], urinalysis[introduced in Protocol Amendment 11: for subjects enrolled in Korea, urinalysis was
obtained at Day 1 of every cycle and at the End of Treatment (EOT); for subjects enrolled in
all other countries, urinalysis was repeated as clinically indicated – at the time of the initialdiagnosis of a renal cyst]), vital signs (blood pressure [BP], and pulse rate), pregnancy
testing, electrocardiogram (12-lead electrocardiogram [ECG]), multiple gated acquisition(MUGA) scan or echocardiogram analysis (France and Ireland only), ECOG PS, concomitant
medications, follow-up systemic therapies, and ophthalmologic examination (visual acuity,
slit lamp and fundoscopy).

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Statistical Methods:
The main purpose of this study was to characterize antitumor efficacy and safety of
PF-02341066 in this study population. Hence, no specific hypothesis tests were planned. No
specific statistical decision rule was applied.
Determination of Sample Size
The goal of the primary analysis of objective response was to estimate ORR including a 95%
confidence interval (CI). No specific hypothesis tests were planned. The sample size was set
at 250 subjects, which was considered adequate to estimate ORR and its 95% CI, in case thetrue ORR ranged from 30% to 50%. Subsequently final sample size was projected as 1100
subjects in order to understand the possible genetic mechanisms for specific AEs, to accountfor subjects crossing over to this study, and to meet country-specific regulatory requirements.
Electrocardiogram Substudy
Based upon the standard deviation (std. dev) of change from Baseline of QT interval using
Fridericia’s correction (QTcF) of 16 msec (Study 1001), a total sample size of 40 subjects
from either Study 1007 (crizotinib arm) or Study 1005 had been deemed sufficient for greaterthan 90% probability that all 5 boundaries of upper one-sided 95% CIs for the change fromBaseline of QTc at all 5 QTc sampling time points on Cycle 2 Day 1 were under 20 msec,
assuming the true change from Baseline in QTc was 10 msec.
Analysis Populations
A SA population was defined as all subjects who were enrolled and received ≥1 dose of
study drug (excluding Day -7 PK dosing for subjects enrolled into the China PK substudy).
The following specific population data sets were analyzed:

SA (ALK-positive by IUO) population, defined as all subjects in the SA population
who were FISH ALK-positive by the central laboratory.



SA (ALK-positive by non-IUO) population, defined as all subjects in the SA
population who were ALK-positive by local assay testing only (i.e., other than by thecentral laboratory).

Response-Evaluable (RE) (ALK-positive by IUO) population, defined as all subjects
in the SA ALK-positive by IUO population who had adequate Baseline tumor
assessments.

RE (ALK-positive by non-IUO) population, defined as all subjects in the SA
ALK-positive by non-IUO population who had adequate Baseline tumor assessments.

PRO-Evaluable population, defined as the subjects from the SA population who
completed a Baseline PRO assessment and ≥1 post-Baseline PRO assessment.



PK concentration population, defined as all subjects in the SA population who had≥1 concentration measurement following treatment.
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All Genotyped population, defined as all subjects in the SA population who had≥1 genotype result.



PG Evaluable population, defined as subjects in the All Genotyped population who
had an HLA genotype result and who were designated as an alanine aminotransferase(ALT) Case or Control. ALT Cases were defined as those subjects with a Baseline
ALT of ≤1x Upper Limit Of Normal (ULN) and at least one on treatment ALT
assessment of >3x ULN; ALT Controls represented those subjects with Baseline andon-treatment assessments of ALT of ≤1x ULN.

Ophthalmologic Examination Evaluable population, defined as subjects from the SA
population who reported visual disturbances and who had the required postdose
ophthalmologic examination. These subjects had at least one of the following: 1)
Baseline (performed during the screening period) and ≥1 post-Baseline visual acuity
exam, or 2) Baseline and ≥1 post-Baseline slit lamp examination, or 3) Baseline and≥1 post-Baseline fundoscopy.



ECG-Evaluable population (non-ECG substudy), defined as subjects from the SA
population who had a Baseline (last ECG prior to Cycle 1 Day 1 dose) and ≥1 postBaseline ECG measurement and were not included in the ECG substudy.



ECG-Evaluable population (ECG substudy), defined as subjects from the SA
population and had at least 1 required Cycle 2 Day 1 ECG measurement performedby the core ECG laboratory.

Analysis of Efficacy Parameters
Primary analyses of endpoints dependent on tumor assessments (ORR, DCR, DR, TTR and
PFS) were based on investigator assessment of tumor data.
Primary Endpoint
Derived Tumor Assessment:
The derived tumor assessment (i.e., Best Overall Response) was based on the target lesion
measurements, non-target lesion assessments, and new lesion records provided by theinvestigator, independent of the overall response category provided by the investigator.
The ORR was defined as the percent of subjects with a confirmed complete response (CR) or
partial response (PR) according to RECIST v 1.1, relative to the RE population.
The ORR was estimated and 95% exact CI for the true ORR was provided. Waterfall plots
displaying the best percentage change in tumor size by BOR were presented.
Stable disease (SD) was categorized according to duration in several time intervals,
specifically, 0 to <3 months, 3 to <6 months, 6 to <9 months, 9 to <12 months, and ≥12months.

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ORR was also analyzed by age group (<65 years, ≥65 years), gender, race (white, black,
Japanese, Korean, Chinese, other Asians, and other races), race group (Asian and non-Asian),
Baseline ECOG PS (0, 1, 2, and 3), and number of prior systemic regimens (1, 2, 3, and >3).
Secondary Endpoints
PFS and OS were analyzed in the SA (ALK-positive by IUO) and the SA (ALK positive by
non-IUO) populations.
Estimates of PFS and OS curves obtained from the Kaplan-Meier method were presented
graphically. The median event time (and other quartiles) and corresponding 2-sided 95% CI
were provided. For OS, the 6-month and 1-year survival probabilities were estimated using
the Kaplan-Meier method.
TTR and DR were summarized by descriptive statistics in the RE populations of subjects
with a confirmed CR or PR. The Kaplan-Meier method was also used for DR. The DCRs
were provided at 6 and 12 weeks.
Endpoint definitions:
PFS was defined as the time from the date of the Cycle 1 Day 1 dose to the date of the first
documentation of objective tumor progression or death on study due to any cause, whicheveroccurred first. PFS (in months) was calculated as (first event date −Cycle 1 Day 1 dose
date+1)/30.4.
OS was defined as the time from the Cycle 1 Day 1 dose to the date of death due to any
cause. OS (in months) was calculated as (date of death − date of Cycle 1 Day 1
dose+1)/30.4. For subjects who were alive/lost to follow-up, the OS was censored on the lastdate that subjects were known to be alive. Subjects lacking data beyond the date of the
Cycle 1 Day 1 dose had their OS censored at the date of the Cycle 1 Day 1 dose.
Six-month and 1-year survival probabilities were defined as the probabilities of survival at
6 months and 1 year, respectively, after the date of the Cycle 1 Day 1 dose based on the
Kaplan-Meier estimate.
DR was defined as the time from the first documentation of objective tumor response (CR orPR) that was subsequently confirmed, to the first documentation of objective tumor
progression or to death on study due to any cause, whichever occurred first. DR (in weeks)
was calculated as (first date of PD or death −first date of CR or PR that was subsequently
confirmed+1)/7.02. DR was only calculated for the subgroup of subjects from the RE
population with a confirmed objective tumor response. Censoring for DR was identical tothe censoring rules for PFS.
TTR was defined as the time (in weeks) from the date of Cycle 1 Day 1 dose to first
documentation of objective tumor response (CR or PR) that was subsequently confirmed.
For subjects proceeding from PR to CR, the onset of PR was taken as the onset of response.
TTR (weeks) was calculated as (first event date − Cycle 1 Day 1 dose date+1)/7.02. TTR
was calculated for the RE population in the subgroup of subjects with a confirmed objective
tumor response.
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DCR at 6 and 12 weeks was defined as the percentage of subjects in the RE population with aconfirmed CR, confirmed PR, or SD (according to RECIST v 1.1) at 6 weeks and 12 weeks,
respectively.
Covariates and Subpopulations:
The primary and secondary endpoints were analyzed in certain subpopulations, such as, agegroup, gender, race groups, and ECOG PS.
Analysis of Pharmacokinetic and Pharmacodynamic Parameters
Pharmacokinetic Analysis
All subjects who have ≥ 1 measurement of PF-02341066 or PF-06260182 at the time ofreporting were included in PK analysis.
Predose concentrations for crizotinib, its metabolite PF-06260182, and ratio of PF-06260182
to crizotinib were summarized before the reporting data cut-off. All crizotinib and its
metabolite PF-06260182 plasma concentration data were listed by subject, by actual
collection time and day in clinical study report.
Population Pharmacokinetic Analysis (PopPK)The plasma concentration data from this study were pooled with data from other crizotinib
studies, as appropriate, for popPK analyses and reported separately.
Pharmacodynamic Analysis
Concentration-QTc modeling
Concentration-QTc modeling analysis was conducted using the ECG data from this study
and/or combined data with other clinical studies of crizotinib and reported separately.
Molecular Profiling Outcomes
Analyses investigating the relationship of ALK gene fusion to the presence of ALK protein
and fusion transcript have not been performed for technical reasons, including limited sample
stability.
Biomarker Analysis
Analyses of change from Baseline in the expression of biomarkers relevant to signaling
pathways were not performed because paired Baseline and on-treatment (Cycle 2) tumor
tissue required for the analysis, which were to be collected on an optional basis, were notavailable.
Pharmacokinetic/Pharmacodynamic Modeling
PopPK/pharmacodynamic analyses were performed based on emerging clinical response datafrom this study, and safety data from this study and other crizotinib studies. The analyses
were reported separately.

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Analysis of Pharmacogenomic Parameters
PG markers included genotypes of alleles possibly associated with hepatic toxicity, including
HLA-DQA1*02:01, HLA-DQB1*02:02, HLA-DRB1*07:01 and human tenascin XB(TNXB)/rs12153855. Complete genotyping of polymorphic alleles involving the HLA gene
locus, including, MHC class I HLA-A, B, C, and MHC class II HLA-DP, DQ, DR loci, wasperformed.
Summary of Type of ALK Testing
ALK marker status by central laboratory was tabulated vs ALK marker status from alaboratory developed test, when both were available.
Descriptive statistics were also presented for the percentage of ALK-positive cells in the
SA – ALK Positive by IUO population and in the RE - ALK Positive by IUO population.
In addition, a subject listing of ALK percentage positivity and BOR based on derived tumor
assessment was presented for the RE - ALK Positive by IUO population. Bar graphs/box
plots of ALK percentage positivity by BOR were also provided for this group of subjects.
AEs
Subjects were followed-up for AEs from the time they signed the informed consent until atleast 28 days after the last dose of study treatment, or until all serious or study drug-related
toxicities resolved or were determined “chronic” or “stable”, whichever was later.
Analyses of Other Parameters
The subscales of the EORTC QLQ-C30 and QLQ-LC13 were scored based on the EORTC
scoring manual. The transformed scores range from 0-100. Higher scores indicate higher(“worse”) symptom severity, higher (“better”) functioning, and better global QoL. Negativechange from Baseline scores indicate an improvement in symptoms, decreased functioning,or decreased QoL, while positive change scores indicate an increase in functioning or
increased QoL and deterioration in symptoms.

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Protocol A8081005 – 27 Oct 2016 – Final

RESULTS
Subject Disposition and Demography:
In this study, 1066 subjects received at least 1 dose of crizotinib and all subjects (100%)
discontinued study treatment. The most common reason for study discontinuations wasdeath reported in 726 (68.1%) subjects (Table 3).
Table 3:

Subject Disposition (SA Population)
Crizotinib 250 mg BID

Number (%) of Subjects

1066

Treated1066

Completed0

Discontinued

1066 (100.0)

Discontinuations from study
Subjects died

726 (68.1)

Completeda244 (22.9)

Lost to follow-up

22 (2.1)

Other

5 (0.5)

Subjects refused further follow-up

69 (6.5)

Abbreviations: BID=twice daily; N/n=number of subjects; SA=safety analysis.
a“Completed” were those subjects who were on treatment or on survival follow-up upon achievement of the PrimaryCompletion Date, when the Sponsor sent written notification to the clinical sites that survival follow up was no longer
required.

Demographic Characteristics
A summary of demographic characteristics by treatment arm in the FA population isprovided in Table 4.

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Table 4:

Demographic Characteristics (SA Population)

Parameter

Crizotinib 250 mg BID
N=1066

Sex, n (%)
Male
FemaleAge (years)
Mean (std. dev)
MedianRange<65, n (%)≥65, n (%)
Race, n (%)
White
Black
Asian
Racial designation for AsianJapanese
KoreanChineseOther
Other
Smoking classification, n (%)
Never smokedEx-smoker
Smoker465 (43.6)
601 (56.4)
52.2 (12.33)
52.0
19 – 84894 (83.9)
172 (16.1)
532 (49.9)
20 (1.9)495 (46.4)
81 (7.6)
144 (13.5)
252 (23.6)
18 (1.7)
19 (1.8)702 (65.9)
321 (30.1)
43 (4.0)

Abbreviations: BID=twice daily; CSR=clinical study report; N/n=number of subjects; SA=safety analysis;
std dev=standard deviation.

Efficacy, Outcomes Research, Pharmacokinetic and Pharmacodynamic Results:
Efficacy Results
Primary Endpoint:
ORR
A summary of best overall response in the [RE (ALK-positive by IUO) and RE(ALK-positive by non-IUO)] study populations is provided in Table 5. Based on the derived
tumor assessment in both populations, [RE (ALK-positive by IUO) and RE (ALK-positive
by non-IUO)], ORR was 54.1% (95% CI: 50.8, 57.4) and 40.5% (95% CI: 32.8, 48.6),
respectively.
Table 5:

Best Overall Response (RE [ALK-positive by IUO] and [ALK-positive by
non-IUO] Populations)
RE [ALK-positive by IUO]
Crizotinib 250 mg BID
N=908
n (%)

RE [ALK-positive by non-IUO]
Crizotinib 250 mg BID
N=158
n (%)

Complete Response

11 (1.2)

1 (<1.0)

Partial Response

480 (52.9)

63 (39.9)Best Overall Response

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RE [ALK-positive by IUO]
Crizotinib 250 mg BID
N=908
n (%)
251 (27.6)

RE [ALK-positive by non-IUO]
Crizotinib 250 mg BID
N=158
n (%)
46 (29.1)

Objective progression

90 (9.9)28 (17.7)

Early death37 (4.1)

10 (6.3)

Indeterminate

39 (4.3)

10 (6.3)

Stable Disease

Objective response rate (CR + PR)

491 (54.1)

64 (40.5)[50.8, 57.4][32.8, 48.6]

0 to <3 months

65 (25.9)

5 (10.9)

3 to <6 months

79 (31.5)

14 (30.4)

6 to <9 months

33 (13.1)

8 (17.4)

9 to <12 months

16 (6.4)

8 (17.4)≥12 months

58 (23.1)

11 (23.9)

95% exact CI [%] a
SD duration (months) b

Abbreviations: ALK=anaplastic lymphoma kinase; BID=twice daily; CI=confidence interval; IUO=investigational-use only;
N/n=number of subjects; CR=complete response; PR=partial response; RE=response-evaluable; SD=stable disease.
Best Overall Response was based on the derived tumor assessment. Early death was death within 42 days (6 weeks) fromfirst dose. The RE population was defined as all subjects in the safety analysis set who had an adequate Baseline diseaseassessment.
a.
Used exact method based on F-distribution.
b.
Percentage was based on the number of SD subjects.

Secondary Endpoints:
DR
DR in the [RE (ALK-positive by IUO) and RE (ALK-positive by non-IUO)] study
populations is summarized in Table 6. The median DR of the [RE (ALK-positive by IUO)]
subjects was 11.8 months (95% CI: 10.4, 12.8). The median DR of the [RE (ALK-positive
by non-IUO)] was 9.5 months (95% CI: 6.9, 15.2).
Table 6:

Duration of Response, Objective Responders Only (RE [ALK-positive by
IUO] and [ALK-positive by non-IUO] Populations)
RE [ALK-positive by IUO]
Crizotinib 250 mg BID
N=908
n (%)
491 (54.1)

RE [ALK-positive by
non-IUO]
Crizotinib 250 mg BID
N=158
n (%)
64 (40.5)

Subsequent progression or death

373 (76.0)

43 (67.2)

Without subsequent progression or death

118 (24.0)

21 (32.8)

5.5 [4.9, 5.7]

4.4 [4.2, 8]

Subjects with a response (CR or PR)
Status after responsea

Kaplan-Meier Estimates of Duration of
Response (Months)
25th percentile (95%CI)b

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Protocol A8081005 – 27 Oct 2016 – Final
RE [ALK-positive by IUO]

50th percentile (95%CI)b

Crizotinib 250 mg BID
N=908
n (%)
11.8 [10.4, 12.8]

RE [ALK-positive by
non-IUO]
Crizotinib 250 mg BID
N=158
n (%)
9.5 [6.9, 15.2]

75th percentile (95%CI)b

25 [20, 27.4]

20.8 [12.5, NR]

Abbreviations: ALK=anaplastic lymphoma kinase; BID=twice daily; CI=confidence interval; CR=complete response;
IUO=investigational-use only; N/n=number of subjects; NR=not reported, not reached; PR=partial response; RE=response
evaluable.
Tumor assessment was based on the derived tumor assessment.
Duration of response was the time from the date of first documentation of CR or PR to the date of first documentation of
objective progression or death due to any cause.
a.
Percent was based on the number of subjects with confirmed objective response (CR or PR).
b.
Based on the Brookmeyer and Crowley Method.

TTR
TTR in the [RE (ALK-positive by IUO) and RE (ALK-positive by non-IUO)] study
populations are summarized in Table 7.
Table 7:

TTR, Objective Responders Only (RE [ALK-positive by IUO] and[ALK-positive by non-IUO] Populations)
RE [ALK-positive by IUO]
Crizotinib 250 mg BID
N=908
n (%)

RE [ALK-positive by non-IUO]
Crizotinib 250 mg BID
N=158
n (%)

491

64

10.3 (13.2)

9.5 (9.9)

6.1

6.3

2.7-164

4.7-65.9

0 - <690 (18.3)

19 (29.7)

6 - <12304 (61.9)

35 (54.7)

12 - <14

28 (5.7)5 (7.8)14 - <24

40 (8.2)

3 (4.7)≥24

29 (5.9)2 (3.1)Time to tumor response (weeks)aN
Mean (std. dev)
MedianRange
Category (weeks)bAbbreviations: ALK=anaplastic lymphoma kinase; BID=twice daily; IUO=investigational-use only; N/n=number ofsubjects; RE=response evaluable; std. dev=standard deviation.
Time to response was the time from the date of first dose to the first documentation of objective tumor response (CR or PR)
that was subsequently confirmed. Best overall response was based on the derived tumor assessment.
a.
Descriptive statistics are presented for subjects with an event.
b.
Category is presented for subjects with an event.

DCR
The DCRs at Week 6 and Week 12 are presented in Table 8.

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Protocol A8081005 – 27 Oct 2016 – Final

Table 8:

Disease Control Rates at Week 6 and Week 12 (RE [ALK-positive by IUO]
and [ALK-positive by non-IUO] Populations)

Disease Control Rate at Week 6

RE [ALK-positive by IUO]
Crizotinib 250 mg BID
N=908
n (%) [95% CI] a
742 (81.7) [79.0, 84.2]

RE [ALK-positive by non-IUO]
Crizotinib 250 mg BID
N=158
n (%) [95% CI] a
110 (69.6) [61.8, 76.7]

Disease Control Rate at Week 12

643 (70.8) [67.7, 73.8]

97 (61.4) [53.3, 69.0]

Abbreviations: ALK=anaplastic lymphoma kinase; BID=twice daily; CI=confidence interval; IUO=investigational-use only;
N/n=number of subjects; RE=response evaluable.
Tumor assessment was based on the derived tumor assessment.
aUsed exact method based on F-distribution.

PFS
A summary of PFS is provided in Table 9. The median PFS was 8.4 months in the SA(ALK-positive by IUO) population, and it was 6.9 months in the SA (ALK-positive by
non-IUO) population, respectively.
Table 9:Progression-Free Survival (SA [ALK-positive by IUO] and [ALK-positive
by non-IUO] Populations)
SA [ALK-positive by
IUO]
Crizotinib 250 mg BID
N=908
n (%)
702 (77.3)

SA [ALK-positive by
non-IUO]
Crizotinib 250 mg BID
N=158
n (%)
119 (75.3)

Objective progression

614 (67.6)

100 (63.3)

Death without objective progression

88 (9.7)

19 (12.0)

206 (22.7)

39 (24.7)

No adequate Baseline assessments00

No on-study disease assessments

7 (<1.0)

1 (<1.0)

Given new anticancer treatment prior to tumor
progression

85 (9.4)

17 (10.8)

Off treatment prior to progression

41 (4.5)9 (5.7)

Withdrew consent for follow-up

0

0

Lost to follow-up

2 (<1.0)0

Unacceptable gap (>14 weeks) between PD or
Death to the most recent prior adequate assessment

16 (1.8)

3 (1.9)In follow-up for progression

55 (6.1)

9 (5.7)61.1 [57.7, 64.3]

55.2 [46.6, 62.9]

4.1 [3.7, 4.2]

2.6 [1.4, 4.0]

8.4 [7.1, 9.7]

6.9 [5.6, 9.4]

Number with Event
Type of Event

Number CensoredReason for Censorship

Probability of Being Event Free at Month 6[95% CI] baKaplan-Meier Estimates of Time to Event (month)
25th percentile (95%CI)cth

50 percentile (95%CI)cPage 21

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Protocol A8081005 – 27 Oct 2016 – Final
SA [ALK-positive by
IUO]
Crizotinib 250 mg BID
N=908
n (%)
20.6 [17.7, 22.7]

75th percentile (95%CI)c

SA [ALK-positive by
non-IUO]
Crizotinib 250 mg BID
N=158
n (%)
15.2 [10.9, 20.2]

Abbreviations: ALK=anaplastic lymphoma kinase; BID=twice daily; CI=confidence interval; IUO=investigational-use only;
N/n=number of subjects; PD=progressive disease; SA=safety analysis.
Tumor assessment was based on the derived tumor assessment.
a.
Estimated from the Kaplan-Meier curve.
b.
Calculated using the normal approximation to the log-transformed cumulative hazard function.
c.
Based on the Brookmeyer and Crowley method.

OS and Probability of Survival
An overview of OS and survival probabilities at 6 months and 12 months is provided inTable 10. The median OS was 21.8 months (95% CI: 19.4, 24.0) and the probabilities ofsurvival at 6 months and 1 year were 81.7% (95% CI: 79.0, 84.0) and 66.5% (95% CI: 63.3,
69.5), respectively, in the SA (ALK positive by IUO) population.
The median OS was 16.9 months (95% CI: 13.4, 21.5) and the probabilities of survival at
6 months and 1 year were 77.5% (95% CI: 70.1, 83.3) and 62.4% (95% CI: 54.3, 69.6),
respectively, in the SA (ALK positive by non-IUO) population.
Table 10: OS (SA [ALK-positive by IUO] and [ALK-positive by non-IUO]
Populations)

Number of Deaths

SA [ALK-positive by
IUO]
Crizotinib 250 mg BID
N=908
n (%)
594 (65.4)

SA [ALK-positive by
non-IUO]
Crizotinib 250 mg BID
N=158
n (%)
115 (72.8)

Number Censored314 (34.6)

43 (27.2)

237 (26.1)

35 (22.2)

00

58 (6.4)

8 (5.1)

Reason for Censorship
Subject remains in follow-up
Subject no longer being followed for survival
Withdrew consent for follow-up
Lost to follow-upaProbability of Survival at 6 Months (95% CI)b

Probability of Survival at 12 Months a (95% CI) b

19 (2.1)

081.7 [79.0, 84.0]

77.5 [70.1, 83.3]

66.5 [63.3, 69.5]

62.4 [54.3, 69.6]

Kaplan-Meier Estimates of Time to Event (month)
Quartiles (95% CI)c25th percentile (95% CI)c

8.5 [7.6, 9.7]

7.7 [4.2, 10.3]

thc21.8 [19.4, 24.0]

16.9 [13.4, 21.5]

thc

58.1 [49.3, NR]

40.0 [32.7, NR]

50 percentile (95% CI)
75 percentile (95% CI)

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Protocol A8081005 – 27 Oct 2016 – Final
SA [ALK-positive by
IUO]
Crizotinib 250 mg BID
N=908
n (%)

SA [ALK-positive by
non-IUO]
Crizotinib 250 mg BID
N=158
n (%)

Abbreviations: ALK=anaplastic lymphoma kinase; BID=twice daily; CI=confidence interval; IUO=investigational-use only;
N/n=number of subjects; NR=not reported, not reached; SA=safety analysis.
Subjects in follow-up include subjects still on treatment.
In follow-up as of data cut-off.
a.
Estimated from the Kaplan-Meier curve.
b.
Derived from the CI for the log-transformed cumulative hazard function.
c.
Based on the Brookmeyer and Crowley method.

Patient-Reported Outcomes:
European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30
and QLQ-LC13 Scale Scores
EORTC QLQ-C30 Global Quality of LifeA statistically significant (95% CI excluded 0) and clinically meaningful (≥10-point)
improvement from Baseline was observed for global QoL (Cycles 3 to 14).
A majority of the subjects had either an improved (42.5% of subjects) or stable (38.5% ofsubjects) score in global QoL over the course of therapy (including all Cycles).
EORTC QLQ-C30 Functioning Domains
A majority of the subjects had improved or stable scores in the functioning domains over thecourse of therapy (included all Cycles).
Symptoms (EORTC QLQ-C30)
A statistically significant and clinically meaningful improvement (ie, decrease) fromBaseline (up to and including Cycle 30) was observed early and maintained at several cycles
in patient-reported symptoms of appetite loss, dyspnoea, fatigue, insomnia and pain.
Clinically significant worsening of symptoms (i.e., increases) were reported in constipationand diarrhoea scales.
The symptoms that had the highest percentage (≥40%) of subjects ‘improved’ from Baseline
were pain (48.2%), fatigue (46.2%), insomnia (43.0%), and dyspnoea (42.1%). The
symptoms that had the highest percentage (≥40%) of subjects ‘worsening’ from Baseline
were constipation (43.9%) and diarrhoea (43.8%) (Table 11).
Symptoms (EORTC QLQ-LC13)
A statistically significant and clinically meaningful improvement (i.e., decrease) fromBaseline (up to and including Cycle 30) was observed early and maintained at several cycles
in patient-reported symptoms of alopecia, coughing, dyspnoea, pain in arm or shoulder, pain
in chest, and pain in other parts.
The symptoms that had the highest percentage (≥40%) of subjects ‘improved’ from Baseline
were coughing (51.0%), dyspnoea (41.3%), and pain in other parts (40.8%).

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Table 11: Change in EORTC (QLQ-C30 and QLQ-LC13) Scales (PRO-Evaluable
Population)

EORTC QLQ-C30
Functional Scales QLQ-C30

Symptom Scales/Items QLQ-C30

Symptom Scales/Items QLQ-LC13

Global QoL
Physical functioning
Role functioning
Emotional functioning
Cognitive functioning
Social functioning
Fatigue
Nausea and vomitingPain
Dyspnoea
Insomnia
Appetite loss
Constipation
Diarrhoea
Financial difficulties
Dyspnoea
Coughing
Haemoptysis
Sore mouth
Dysphagia
Peripheral neuropathy
Alopecia
Pain in chest
Pain in arm or shoulder
Pain in other parts

Crizotinib 250 mg BID
N=976
Improved a
Stable b
Worsening c
n (%)
n (%)
n (%)
415 (42.5)
376 (38.5)
179 (18.3)
333 (34.1)
506 (51.8)
136 (13.9)
342 (35.0)415 (42.5)
217 (22.2)
338 (34.6)
509 (52.2)
122 (12.5)
234 (24.0)
525 (53.8)
212 (21.7)
403 (41.3)
375 (38.4)
191 (19.6)
451 (46.2)
364 (37.3)
160 (16.4)
213 (21.8)
507 (51.9)
255 (26.1)
470 (48.2)
392 (40.2)
113 (11.6)
411 (42.1)
408 (41.8)
154 (15.8)
420 (43.0)
396 (40.6)
159 (16.3)
355 (36.4)
420 (43.0)
200 (20.5)
185 (19.0)
356 (36.5)
428 (43.9)
104 (10.7)
438 (44.9)
427 (43.8)
249 (25.5)
553 (56.7)
167 (17.1)
403 (41.3)
430 (44.1)
139 (14.2)
498 (51.0)
343 (35.1)
132 (13.5)
89 (9.1)
863 (88.4)
21 (2.2)
119 (12.2)
744 (76.2)
111 (11.4)
149 (15.3)
701 (71.8)
123 (12.6)
216 (22.1)
518 (53.1)
238 (24.4)
274 (28.1)
565 (57.9)
132 (13.5)
359 (36.8)
524 (53.7)
90 (9.2)352 (36.1)
498 (51.0)
120 (12.3)
398 (40.8)
396 (40.6)
159 (16.3)

Abbreviations: BID=twice daily; EORTC QLQ-C30=European Organization for the Research and Treatment of Cancer
Quality of Life Questionnaire – Core 30 Questionnaire; n/N=number of subjects; PRO=patient-reported outcome;
QoL=quality of life; QLQ-C30=Quality of Life Questionnaire – Core 30 Questionnaire; QLQ-LC13=Quality of Life
Questionnaire – Lung Cancer 13.
%=(n/N)*100.
a.
A subject with at least a 10-point improvement in the average of mean changes was improved.
b.
A subject who was neither improved nor worsened was stable.
c.
A subject with at least a 10-point deterioration in the average of mean changes was worsened.

EuroQol five dimensions questionnaire (EQ-5D)
EQ-5D visual analog score (VAS)
A statistically significant (95% CI excluded 0) improvement in health status as measured by
the EQ-5D VAS scores was observed as early as Cycle 2, and this improvement wasmaintained through Cycle 30.(Table 12).

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Protocol A8081005 – 27 Oct 2016 – Final

Table 12: Summary of mean Change from Baseline of EQ-5D VAS (Cycles 1 to 30 andEOT; PRO-Evaluable Population)

Time Point
Cycle 2/Day 1
Cycle 3/Day 1
Cycle 4/Day 1
Cycle 5/Day 1
Cycle 6/Day 1
Cycle 7/Day 1
Cycle 8/Day 1
Cycle 9/Day 1
Cycle 10/Day 1
Cycle 11/Day 1
Cycle 12/Day 1
Cycle 13/Day 1
Cycle 14/Day 1
Cycle 15/Day 1
Cycle 16/Day 1
Cycle 17/Day 1
Cycle 18/Day 1
Cycle 19/Day 1
Cycle 20/Day 1
Cycle 21/Day 1
Cycle 22/Day 1
Cycle 23/Day 1
Cycle 24/Day 1
Cycle 25/Day 1
Cycle 26/Day 1
Cycle 27/Day 1
Cycle 28/Day 1
Cycle 29/Day 1
Cycle 30/Day 1
EOT

n
926
875
826
804
771
728
693
667
633
573
409
512
351
461
289
417
244
372
219
339
179
310
154
299
128
272
120
249
108
450

Median
5.00
5.00
8.00
9.00
8.50
7.00
9.00
9.00
7.00
7.00
8.00
8.00
10.00
5.00
5.00
5.00
5.00
6.00
6.00
5.00
5.00
4.50
5.00
4.00
6.50
2.50
5.00
2.00
6.00
0.00

Mean
5.72
8.57
10.01
10.38
10.17
9.91
10.35
10.69
10.34
10.09
9.69
9.74
10.93
8.71
8.47
7.99
7.62
8.17
8.03
6.96
6.59
5.53
7.61
4.97
8.54
5.24
7.93
5.05
8.07
0.09

Crizotinib 250 mg BID(N=974)SD
95% CI
17.51(4.59, 6.85)
18.82(7.32, 9.82)
19.73(8.66, 11.36)
19.85(9, 11.75)
20.38(8.73, 11.61)
19.76(8.47, 11.35)
19.22(8.92, 11.78)
19.82(9.18, 12.19)
19.15(8.85, 11.84)
19.72(8.48, 11.71)
18.81(7.86, 11.52)
19.64(8.04, 11.45)
18.67(8.97, 12.89)
20.53(6.83, 10.59)
20.66(6.08, 10.87)
20.8(5.99, 9.99)
19.86(5.11, 10.12)
18.92(6.24, 10.1)
18.45(5.57, 10.48)
18.71(4.96, 8.95)
18.97(3.79, 9.39)
19.5(3.35, 7.71)
19.58(4.49, 10.73)
17.98(2.92, 7.01)
18.97(5.22, 11.86)
17.61(3.13, 7.34)
19.53(4.4, 11.46)
17.07(2.92, 7.18)
19.95(4.27, 11.88)
23.92(-2.13, 2.31)

Abbreviations: Med=median, SD=standard deviation. EOT=End of Treatment. EOT is based on the actual CRF visit label.
Visit windows were applied for the EQ-5D data with the expected Day 1 of each cycle as the midpoint.

Visual Symptom Assessment Questionnaire (VSAQ-ALK) Results Summary
The results of the first question on the VSAQ-ALK, “Have You Experienced any Visual
Disturbances?” in the SA population up to and including Cycle 30 are presented in Table 13.
At Baseline, 16.0% of subjects reported experiencing a visual disturbance. During the first
30 cycles, 27.4% to 64.5% of subjects reported experiencing a visual disturbance, with thehighest proportion at Cycle 2 and the lowest at Cycle 30 (Table 13).
Subjects were instructed to complete the remaining questions on the VSAQ-ALK only if they
had a visual disturbance.

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Public Disclosure Synopsis
Protocol A8081005 – 27 Oct 2016 – Final

Table 13: Visual Symptom Assessment Question 1: Have You Experienced any Visual
Disturbances? (Cycles 1 to 30 and EOT; SA Population)
Time Point
Baseline
Cycle 2 / Day 1
Cycle 3 / Day 1
Cycle 4 / Day 1
Cycle 5 / Day 1
Cycle 6 / Day 1
Cycle 7 / Day 1
Cycle 8 / Day 1
Cycle 9 / Day 1
Cycle 10 / Day 1
Cycle 11 / Day 1
Cycle 12 / Day 1
Cycle 13 / Day 1
Cycle 14 / Day 1
Cycle 15 / Day 1
Cycle 16 / Day 1
Cycle 17 / Day 1
Cycle 18 / Day 1
Cycle 19 / Day 1
Cycle 20 / Day 1
Cycle 21 / Day 1
Cycle 22 / Day 1
Cycle 23 / Day 1
Cycle 24 / Day 1
Cycle 25 / Day 1
Cycle 26 / Day 1
Cycle 27 / Day 1
Cycle 28 / Day 1
Cycle 29 / Day 1
Cycle 30 / Day 1
EOT

Crizotinib 250 mg BID
N=1066
Total
N+
821
798
768
754
743
731
699
670
653
621
565
403
507
354
468
296
418
249
378
221
344
181
312
155
302
130
276
118
249
106
428

Yes
n (%)
131 (16.0)
515 (64.5)
434 (56.5)
394 (52.3)
365 (49.1)
357 (48.8)
320 (45.8)
293 (43.7)
284 (43.5)
265 (42.7)
227 (40.2)
173 (42.9)
209 (41.2)
147 (41.5)
183 (39.1)
129 (43.6)
156 (37.3)
100 (40.2)
139 (36.8)
86 (38.9)
134 (39.0)
71 (39.2)
109 (34.9)
54 (34.8)
108 (35.8)
40 (30.8)
90 (32.6)
37 (31.4)
76 (30.5)
29 (27.4)
168 (39.3)

No
n (%)
690 (84.0)
283 (35.5)
334 (43.5)
360 (47.7)
378 (50.9)374 (51.2)
379 (54.2)
377 (56.3)
369 (56.5)
356 (57.3)
338 (59.8)
230 (57.1)
298 (58.8)
207 (58.5)
285 (60.9)
167 (56.4)
262 (62.7)
149 (59.8)
239 (63.2)
135 (61.1)
210 (61.0)
110 (60.8)
203 (65.1)
101 (65.2)
194 (64.2)
90 (69.2)
186 (67.4)
81 (68.6)
173 (69.5)
77 (72.6)
260 (60.7)

Abbreviations: BID=twice daily; CRF=case report form; EOT=End of Treatment; N/N+n=number of subjects; SA=safety
analysis; VSAQ=visual symptom assessment questionnaire.
Baseline was Cycle 1 Day 1.
%=(n/N+)*100, N+ was the number of subjects who had completed the first question.
EOT was based on the actual CRF visit label.
Visit windows were applied for the VSAQ data with the expected Day 1 of each cycle as the midpoint.

Pharmacokinetic Results:
Secondary endpoints
Plasma concentrations of crizotinib (PF-02341066) and its metabolite PF-06260182
Summary of predose concentrations of crizotinib and its metabolite, PF-06260182, andPF-06260182 to crizotinib ratio, following 250 mg BID oral dosing of crizotinib is provided
in Table 14.

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Public Disclosure Synopsis
Protocol A8081005 – 27 Oct 2016 – Final

Table 14: Plasma concentrations of crizotinib (PF-02341066) and its metabolite
PF-06260182, and PF-06260182 to crizotinib ratio, following 250 mg BID
oral dosing of crizotinib

Cycle 1 Day 1 (N=13, 13, 13)
Cycle 2 Day 1 (N=447, 431, 430)
Cycle 3 Day 1 (N=398, 385, 385)
Cycle 5 Day 1 (N=297, 290, 290)

Predose Plasma Concentrationsa ng/mL (%)
Crizotinib (PF-02341066)
PF-06260182
PF-06260182 to
N=906
N=904
crizotinib ratio
1.95 (55)0.00601 (167)0.00416 (157)279 (46)76.2 (79)0.263 (55)297 (44)80.8 (58)0.264 (31)294 (48)
81.4 (61)0.266 (31)

N is the number of observations for crizotinib above limit of quantification.
Abbreviations: BID=twice daily; CV=coefficient of variation; PK=pharmacokinetic.
a
Geometric mean (%CV).
The PF-06260182 to crizotinib ratio for plasma concentrations was calculated by ([concentration of
PF-06260182]/[concentration of crizotinib])*([molecular weight of crizotinib (450.34)/molecular weight of PF-06260182(464.33)])

Pharmacodynamic Results:
Secondary endpoints
Molecular Profiling (ALK Status)
ALK-positivity was determined by the IUO test in 908 subjects. The mean percentage of
ALK-positive cells was 59.49% (Table 15).
Table 15: Descriptive Statistics for ALK Percentage of Positive Cells by Central
Laboratory Test (SA [ALK-positive by IUO] Population)
Crizotinib 250 mg BID
N=908

Number of Subjects
Percent of ALK-Positive Tumor Cells (%)
n
Mean (standard deviation)MedianRange

908
59.49 (21.18)
60.00(15.00-100.00)

Abbreviations: ALK=anaplastic lymphoma kinase; BID=twice daily; IUO=investigational-use only; N/n=number ofsubjects; SA=safety analysis.
ALK-positive by IUO included all enrolled subjects with IUO results indicating ALK-positivity.

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Public Disclosure Synopsis
Protocol A8081005 – 27 Oct 2016 – Final

Molecular Profiling Outcomes
Analyses investigating the relationship of ALK gene fusion to the presence of ALK protein
and fusion transcript have not been performed for technical reasons, including limited sample
stability.
Biomarkers
Analyses of change from Baseline in the expression of biomarkers relevant to signaling
pathways were not performed because paired Baseline and on-treatment (Cycle 2) tumor
tissue required for the analysis, which were collected on an optional basis, were notavailable.
Pharmacogenomic Results:
Assessment of Candidate Gene Alleles
The frequencies of the 4 candidate gene alleles, HLA-DQA1*02:01, HLA-DQB1*02:02,
HLA-DRB1*07:01 and TNXB/rs12153855, among ALT Cases and ALT Controls weresimilar (Table 16), with no statistically significant differences observed that would support orsuggest any predictive (i.e., diagnostic) value of these markers in identifying subjects who
may be at increased risk for hepatic toxicity.
Table 16: ALT Case-Control Analysis of Pre-Defined Candidate Genetic Variants (PG
Evaluable Population)
Number of Participants Analyzed
Genetic Variants
HLA-DQA1*02:01
HLA-DQB1*02:02
HLA-DRB1*07:01
TNXB/rs12153855

Crizotinib 250 mg BID ALT Cases
74
(%)
20.3
17.6
20.3
10.8

Crizotinib 250 mg BID ALT Controls
115
(%)
20.0
16.5
20.0
16.5

Abbreviations: ALT=alanine aminotransferase; CI=confidence interval; HLA=major histocompatibility complex;
N/n=number of subjects; PG=pharmacogenomic; TNXB=human tenascin XB gene; ULN=upper limit of normal.
%=(n/N)*100. N=total (N=74 for ALT Cases; N=115 for ALT Controls).
ALT Cases are defined as those subjects with a Baseline ALT of ≤1x ULN and at least one on-treatment ALT assessment of>3x ULN, and ALT controls represent those subjects with Baseline and on-treatment assessments of ALT of ≤1x ULN.

Exploratory Assessment of Additional Gene Alleles
The frequency of 2 additional HLA gene alleles, HLA-B*57:01 and HLA-DRB1*15:01,
were also similar between ALT Cases and ALT Controls (Table 17), with no statisticallysignificant associations observed that would support or suggest any predictive (i.e.,diagnostic) value of these markers in identifying subjects who may be at increased risk forhepatic toxicity.

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Public Disclosure Synopsis
Protocol A8081005 – 27 Oct 2016 – Final

Table 17: ALT Case-Control Analysis of Additional HLA Genetic Variants (PG
Evaluable Population)
Number of Participants Analyzed
Genetic Variants

Crizotinib 250 mg BID ALT Cases
74(%)

Crizotinib 250 mg BID ALT Controls
115(%)

HLA-B*57:01
HLA-DRB1*15:01

2.7
17.6

4.3
20.9

Abbreviations: ALT=alanine aminotransferase; CI=confidence interval; HLA=major histocompatibility complex;
N/n=number of subjects; PG=pharmacogenomic; TNXB=human tenascin XB gene; ULN=upper limit of normal.
%=(n/N)*100. N=total (N=74 for ALT Cases; N=115 for ALT Controls).
ALT Cases are defined as those subjects with a Baseline ALT of ≤1x ULN and at least one on-treatment ALT assessment of>3x ULN, and ALT controls represent those subjects with Baseline and on-treatment assessments of ALT of ≤1x ULN.

Safety Results:
Primary Endpoint
Percentage of subjects with adverse Events
Treatment-emergent adverse events due to all causality and treatment-related are summarizedin Table 18. Almost all subjects experienced treatment-related AEs (96%) and 11.5% of all
subjects experienced treatment-related SAEs. A total of 5.7% of subjects permanently
discontinued due to treatment related AEs.
Table 18: Treatment-Emergent (All Causality and Treatment-Related) Adverse
Events – SA Population

No. of AEs
Subjects with AEs
Subjects with serious AEs
Subjects with Grade 3 or 4 AEs
Subjects with Grade 5 AEs
Subjects with permanent discontinuation due to AEs
Subjects s with dose reduction due to AEs
Subjects with temporary discontinuation due to AEs

Crizotinib 250 mg BID
N=1066n (%)
All causality
Treatment related
16367
8644
1061 (99.5)
1023 (96.0)
539 (50.6)
123 (11.5)
699 (65.6)
428 (40.2)
242 (22.7)
17 (1.6)215 (20.2)
61 (5.7)
209 (19.6)
196 (18.4)
509 (47.7)
331 (31.1)

Abbreviations: AE=adverse event; BID=twice daily; CSR=clinical study report; N/n=number of subjects; SA=safety
analysis.

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Public Disclosure Synopsis
Protocol A8081005 – 27 Oct 2016 – Final

Secondary endpoints
Electrocardiograms (ECGs)
ECGs were obtained from all subjects during the study. Most subjects had a maximum QTcF
interval <480 msec (97.5%) (Table 19).
Table 19: Percentage of subjects with maximum Postdose QTcF Intervals (Except
ECG Substudy Group) – SA Population
Crizotinib 250 mg BID
N=999
n (%)
Maximum QTcF Interval (msec)<450
450 - <480
480 - <500≥500

897 (89.8)
77 (7.7)
10 (1.0)
15 (1.5)

Abbreviations: BID=twice daily; N/n=number of subjects; QTcF=corrected QT interval for heart rate using Fridericia’s
correction formula SA=safety analysis.
%=(n/N)•100.
N=number of subjects having a post-Baseline assessment.
n=number of subjects within category.

Serious Adverse Events
Serious adverse events are summarized in Table 20.
Table 20: Treatment-Emergent Serious Adverse Events by System Organ Class andPreferred Term (All causalities and treatment related)
Crizotinib 250 mg BID

Number (%) of Subjects:
Evaluable for adverse events
With adverse events
Number (%) of Subjects with Adverse Events by:
System Organ Class and
MedDRA (v 18.1) Preferred Term
BLOOD AND LYMPHATIC SYSTEM DISORDERS
Anaemia
Basophilia
Eosinophilia
Febrile neutropenia
Leukocytosis
Monocytosis
Thrombocytopenia
Thrombocytosis
CARDIAC DISORDERS
Acute myocardial infarction
Angina pectoris
Angina unstable
Atrial fibrillation

Page 30

All causalities (%)

Treatment
related (%)

1066
539 (50.56)

1066
123 (11.54)

13 (1.22)
4 (0.38)
1 (0.09)
1 (0.09)
6 (0.56)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)36 (3.38)
2 (0.19)
2 (0.19)
1 (0.09)
3 (0.28)

5 (0.47)
1 (0.09)
1 (0.09)
4 (0.38)
1 (0.09)
1 (0.09)
6 (0.56)

1 (0.09)

Public Disclosure Synopsis
Protocol A8081005 – 27 Oct 2016 – Final
Crizotinib 250 mg BID
All causalities (%)
Bradycardia
Cardiac arrest
Cardiac failure
Cardiac failure congestive
Cardiac tamponade
Coronary artery stenosis
CyanosisLeft ventricular failure
Myocardial infarction
Myocarditis
Palpitations
Pericardial effusion
Pericarditis
Supraventricular tachycardia
SyncopeTachycardia
EYE DISORDERS
Cataract
Glaucoma
Optic atrophy
Retinal detachment
Vision blurred
Vitreous haemorrhage
GASTROINTESTINAL DISORDERS
Abdominal pain
Abdominal wall haematoma
Ascites
ColitisConstipation
Diarrhoea
Diarrhoea haemorrhagic
Dysphagia
Gastric ulcer
Gastritis
Gastrointestinal haemorrhage
Ileus
Intestinal obstruction
Intestinal perforation
NauseaOesophageal stenosis
Oesophagitis
Pancreatic atrophy
Pancreatitis
Pancreatitis acute
Peptic ulcer haemorrhage
Peritoneal disorder
Rectal haemorrhage
Retroperitoneal haemorrhage
Small intestinal obstruction
Subileus
Upper gastrointestinal haemorrhage
Vomiting

1 (0.09)
2 (0.19)
2 (0.19)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)
2 (0.19)
1 (0.09)
1 (0.09)
7 (0.66)
1 (0.09)
1 (0.09)
6 (0.56)
2 (0.19)
7 (0.66)
2 (0.19)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)52 (4.88)
6 (0.56)
1 (0.09)
1 (0.09)
1 (0.09)
3 (0.28)
4 (0.38)
1 (0.09)
7 (0.66)
1 (0.09)
1 (0.09)
3 (0.28)
3 (0.28)
1 (0.09)
1 (0.09)9 (0.84)
1 (0.09)
2 (0.19)
1 (0.09)
3 (0.28)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)
6 (0.56)

Page 31

Treatment
related (%)
1 (0.09)
1 (0.09)

1 (0.09)

1 (0.09)
1 (0.09)
2 (0.19)
1 (0.09)
1 (0.09)12 (1.13)

1 (0.09)
1 (0.09)
2 (0.19)
1 (0.09)
1 (0.09)
2 (0.19)
1 (0.09)
4 (0.38)
1 (0.09)

1 (0.09)

Public Disclosure Synopsis
Protocol A8081005 – 27 Oct 2016 – Final
Crizotinib 250 mg BID

GENERAL DISORDERS AND ADMINISTRATION SITE
CONDITIONSAsthenia
Chest discomfort
Chest pain
ChillsCondition aggravatedDeath
Device dislocation
Disease progression
Fatigue
Gait disturbance
General physical health deterioration
Generalised oedema
Mass
Multi-organ failure
Oedema peripheral
Pain
Pyrexia
Vascular stent thrombosis
HEPATOBILIARY DISORDERS
Cholecystitis
Drug-induced liver injury
Hepatic failure
Hepatitis
Hepatocellular injury
Hepatotoxicity
IMMUNE SYSTEM DISORDERS
Contrast media allergy
INFECTIONS AND INFESTATIONS
Abdominal abscess
Abscess limb
Appendicitis
Bacteraemia
Bone abscess
Bronchitis
Candiduria
Cellulitis
Chest wall abscess
Clostridium difficile infection
Cystitis
Diverticulitis
Empyema
Gastroenteritis
Herpes zoster
Infection
Infectious pleural effusion
Infective spondylitis
Lower respiratory tract infection
Lung abscessLung infection
Lymphangitis

Page 32

All causalities (%)

Treatment
related (%)

192 (18.01)

14 (1.31)

7 (0.66)
2 (0.19)5 (0.47)
1 (0.09)
2 (0.19)8 (0.75)
1 (0.09)135 (12.66)
4 (0.38)
1 (0.09)9 (0.84)
3 (0.28)
1 (0.09)
1 (0.09)
7 (0.66)
1 (0.09)18 (1.69)
1 (0.09)11 (1.03)
1 (0.09)
3 (0.28)
2 (0.19)
1 (0.09)
1 (0.09)
3 (0.28)
1 (0.09)
1 (0.09)
162 (15.20)
1 (0.09)
1 (0.09)8 (0.75)
2 (0.19)
1 (0.09)
2 (0.19)
1 (0.09)13 (1.22)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)
6 (0.56)
3 (0.28)
1 (0.09)
2 (0.19)
1 (0.09)
3 (0.28)
1 (0.09)14 (1.31)
1 (0.09)

1 (0.09)
3 (0.28)
1 (0.09)
1 (0.09)
2 (0.19)
1 (0.09)
5 (0.47)

9 (0.84)
3 (0.28)
1 (0.09)
1 (0.09)
1 (0.09)
3 (0.28)
15 (1.41)
1 (0.09)

2 (0.19)

3 (0.28)

Public Disclosure Synopsis
Protocol A8081005 – 27 Oct 2016 – Final
Crizotinib 250 mg BID
All causalities (%)
Meningitis
Metapneumovirus infection
Oesophageal candidiasis
Osteomyelitis chronic
Peritonitis
Pneumonia
Pneumonia bacterial
Pneumonia fungal
Pneumonia staphylococcal
Pyelonephritis
Renal abscess
Renal cyst infection
Respiratory tract infection
Sepsis
Septic shock
Skin infection
Soft tissue infection
Staphylococcal sepsis
Upper respiratory tract infection
Urinary tract infection
Urinary tract infection bacterial
Viral infection
Viral upper respiratory tract infection
Wound infection
INJURY, POISONING AND PROCEDURAL COMPLICATION
Ankle fracture
Bone fissure
Craniocerebral injury
Dislocation of vertebra
Fall
Femoral neck fracture
Femur fracture
Hip fracture
Humerus fracture
Joint dislocation
Lower limb fracture
Overdose
Pelvic fracture
Postoperative wound complication
Radiation necrosis
Radiation pneumonitis
Radius fracture
Road traffic accident
Spinal compression fracture
Subdural haemorrhage
Traumatic haematoma
Upper limb fracture
Wound dehiscence

Page 33

1 (0.09)
1 (0.09)
2 (0.19)
1 (0.09)
1 (0.09)74 (6.94)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.1)2 (0.19)
2 (0.19)5 (0.47)
8 (0.75)
4 (0.38)
4 (0.38)
1 (0.09)
1 (0.09)
7 (0.66)
7 (0.66)
1 (0.09)
1 (0.09)
1 (0.09)
2 (0.19)31 (2.91)
2 (0.19)
1 (0.09)
1 (0.09)
1 (0.09)
6 (0.56)
4 (0.38)
4 (0.38)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)
2 (0.19)
2 (0.19)
2 (0.19)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)

Treatment
related (%)

6 (0.56)

1 (0.09)
2 (0.19)

1 (0.09)

1 (0.09)

Public Disclosure Synopsis
Protocol A8081005 – 27 Oct 2016 – Final
Crizotinib 250 mg BID
All causalities (%)
INVESTIGATIONS
Alanine aminotransferase increased
Blood albumin decreased
Blood bilirubin increased
Blood creatinine increased
Blood lactate dehydrogenase increased
C-reactive protein increased
Electrocardiogram QT prolonged
Hepatic enzyme increased
Troponin I increased
METABOLISM AND NUTRITION DISORDERS
Decreased appetite
Dehydration
Failure to thrive
Fluid retention
Hypercalcaemia
Hyperglycaemia
Hyperkalaemia
Hypoalbuminaemia
Hypocalcaemia
Hypoglycaemia
Hypokalaemia
Hypomagnesaemia
Hyponatraemia
Hypophosphataemia
MUSCULOSKELETAL AND CONNECTIVE TISSUEDISORDERS
Arthralgia
Back pain
Bursitis
Chest wall mass
Joint swelling
Lumbar spinal stenosis
Muscular weakness
Musculoskeletal pain
Myalgia
Myopathy
Neck pain
Osteoarthritis
Pain in extremity
Pathological fracture
Spinal column stenosis
Spondylolisthesis
Systemic lupus erythematosus

Page 34

13 (1.22)
5 (0.47)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)24 (2.25)
3 (0.28)
4 (0.38)
2 (0.19)
1 (0.09)
1 (0.09)
2 (0.19)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)
5 (0.47)
1 (0.09)
4 (0.38)
1 (0.09)27 (2.53)
2 (0.19)5 (0.47)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)
2 (0.19)
3 (0.28)
1 (0.09)
1 (0.09)
2 (0.19)
1 (0.09)
2 (0.19)5 (0.47)
1 (0.09)
1 (0.09)
1 (0.09)

Treatment
related (%)
10 (0.94)
5 (0.47)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)8 (0.75)
1 (0.09)
2 (0.19)
1 (0.09)

1 (0.09)
2 (0.19)
1 (0.09)
3 (0.28)

1 (0.09)

1 (0.09)

1 (0.09)

Public Disclosure Synopsis
Protocol A8081005 – 27 Oct 2016 – Final
Crizotinib 250 mg BID

NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED(INCLUDING CYSTS AND POLYPS)
Basal cell carcinoma
Breast cancer
Gallbladder cancer
Malignant melanoma
Metastases to meninges
Neoplasm malignant
Neuroendocrine tumour
Plasma cell myeloma
Prostate cancer
Small cell lung cancer
Squamous cell carcinoma of skin
NERVOUS SYSTEM DISORDERS
Aphasia
AtaxiaBrain oedema
Cerebellar infarction
Cerebral haemorrhage
Cerebral infarction
Cerebrovascular accident
ChoreaComa
Depressed level of consciousness
Dizziness
Dysarthria
Generalised tonic-clonic seizure
Haemorrhage intracranial
Headache
Intracranial pressure increased
Ischaemic stroke
Nervous system disorder
Neurological decompensation
Paraplegia
Peripheral motor neuropathy
Peripheral sensorimotor neuropathy
Peripheral sensory neuropathy
Pyramidal tract syndrome
SeizureSpinal cord compression
Transient ischaemic attack
TremorVocal cord paralysis
PSYCHIATRIC DISORDERS
Completed suicide
Confusional state
Depression
Disorientation
Mania
Mental status changes
Suicide attempt

Page 35

All causalities (%)

Treatment
related (%)

12 (1.13)

4 (0.38)

1 (0.09)
1 (0.09)
1 (0.09)
2 (0.19)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)
2 (0.19)49 (4.60)
2 (0.19)
1 (0.09)
3 (0.28)
1 (0.09)
4 (0.38)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)
2 (0.19)
2 (0.19)
1 (0.09)
1 (0.09)
4 (0.38)
1 (0.09)
1 (0.09)
2 (0.19)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)9 (0.84)
2 (0.19)
3 (0.28)
1 (0.09)
2 (0.19)
14 (1.31)
1 (0.09)
7 (0.66)
3 (0.28)
1 (0.09)
1 (0.09)
2 (0.19)
1 (0.09)

1 (0.09)
1 (0.09)

1 (0.09)
2 (0.19)
3 (0.28)

1 (0.09)

1 (0.09)
1 (0.09)

1 (0.09)
1 (0.09)

Public Disclosure Synopsis
Protocol A8081005 – 27 Oct 2016 – Final
Crizotinib 250 mg BID
All causalities (%)
RENAL AND URINARY DISORDERS
Acute kidney injury
Dysuria
Haematuria
Hydronephrosis
Nephrolithiasis
Renal cyst
Renal cyst haemorrhage
Renal failure
Ureteral polyp
Urinary retention
Urinary tract obstruction
REPRODUCTIVE SYSTEM AND BREAST DISORDERS
Benign prostatic hyperplasia
Pelvic pain
RESPIRATORY, THORACIC AND MEDIASTINALDISORDERS
Acute respiratory distress syndrome
Acute respiratory failure
Alveolitis
Asphyxia
Atelectasis
Bronchial hyperreactivity
Chronic obstructive pulmonary disease
Cough
Dyspnoea
Epistaxis
Haemoptysis
Haemothorax
HypoxiaInterstitial lung disease
Lung infiltration
Oropharyngeal pain
Pleural effusion
Pleuritic pain
Pneumonia aspiration
Pneumonitis
Pneumothorax
Pulmonary arterial hypertension
Pulmonary artery thrombosis
Pulmonary embolism
Pulmonary haemorrhage
Pulmonary oedema
Pulmonary thrombosis
Rales
Respiratory failure
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
Paraneoplastic pemphigus
Rash
SURGICAL AND MEDICAL PROCEDURES
Pleural decortication

Page 36

29 (2.72)
5 (0.47)2(0.19)1 (0.09)
2 (0.19)
2 (0.19)
13 (1.22)
1 (0.09)
1 (0.09)
1 (0.09)
2 (0.19)
1 (0.09)
2 (0.19)
1 (0.09)
1 (0.09)143 (13.41)
1 (0.09)
3 (0.28)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)
3 (0.28)
39 (3.66)
1 (0.09)
3 (0.28)
1 (0.09)
4 (0.38)
5 (0.47)
1 (0.09)
1 (0.09)14 (1.31)
1 (0.09)
4 (0.38)
17 (1.59)
8 (0.75)
1 (0.09)
2 (0.19)26 (2.44)
1 (0.09)
1 (0.09)
1 (0.09)
2 (0.19)17 (1.59)
2 (0.19)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)

Treatment
related (%)
17 (1.59)
3 (0.28)

1 (0.09)13 (1.22)

30 (2.81)

1 (0.09)

6 (0.56)
1 (0.09)
2 (0.19)
1 (0.09)14 (1.31)

4 (0.38)

1 (0.09)
1 (0.09)
1 (0.09)

Public Disclosure Synopsis
Protocol A8081005 – 27 Oct 2016 – Final
Crizotinib 250 mg BID
All causalities (%)
VASCULAR DISORDERS
Deep vein thrombosis
Embolism
Haematoma
Hypotension
Hypovolaemic shock
Orthostatic hypotension
Peripheral arterial occlusive disease
Peripheral embolism
Phlebitis
Superior vena cava syndrome
Thrombophlebitis
Thrombosis
Vasculitis
Vena cava thrombosis
Venous thrombosis

41 (3.85)
14 (1.31)
1 (0.09)
3 (0.28)
1 (0.09)
1 (0.09)
1 (0.09)
1 (0.09)
2 (0.19)
1 (0.09)
4 (0.38)
1 (0.09)
5 (0.47)
1 (0.09)
2 (0.19)4 (0.38)

Treatment
related (%)
8 (0.75)
4 (0.38)
1 (0.09)
1 (0.09)
1 (0.09)

1 (0.09)
1 (0.09)

Subjects are only counted once per treatment for each row.
Includes data up to 9999 days after last dose of study drug.
MedDRA (v 18.1) coding dictionary applied.

Non-Serious Adverse events:
Non-serious adverse events are summarized in Table 21. Vision disorder, nausea, vomiting,and diarrhoea were the most common treatment related AEs.
Table 21: Treatment-Emergent Non-Serious Adverse Events by System Organ Classand Preferred Term (All Causalities and treatment related) in > 5% of
Subjects
Crizotinib 250 mg BID
All causalities (%)
Treatment related (%)
Number (%) of Subjects:
Evaluable for adverse events
With adverse events
Number (%) of Subjects with Adverse Events by:
System Organ Class and
MedDRA (v18.1) Preferred Term
BLOOD AND LYMPHATIC SYSTEMDISORDERS
Anaemia
Leukopenia
Lymphopenia
Neutropenia
CARDIAC DISORDERS
Bradycardia
EYE DISORDERS
Photopsia
Vision blurred
Visual impairment

Page 371066
1038 (97.37)

1066
991 (92.96)

332 (31.14)

242 (22.70)

138 (12.95)
101 (9.47)
71 (6.66)
180 (16.89)
93 (8.72)
93 (8.72)
587 (55.07)
96 (9.01)
80 (7.50)
460 (43.15)

74 (6.94)
92 (8.63)
169 (15.85)
74 (6.94)
74 (6.94)
557 (52.25)
92 (8.63)
64 (6.00)
443 (41.56)

Public Disclosure Synopsis
Protocol A8081005 – 27 Oct 2016 – Final

GASTROINTESTINAL DISORDERS
Abdominal pain
Abdominal pain upper
Constipation
Diarrhoea
Dyspepsia
Dysphagia
NauseaVomiting
GENERAL DISORDERS AND
ADMINISTRATION SITE CONDITIONSAsthenia
Chest pain
Fatigue
OedemaOedema peripheral
Pyrexia
INFECTIONS AND INFESTATIONS
Nasopharyngitis
Upper respiratory tract infection
Urinary tract infection
INJURY, POISONING AND PROCEDURALCOMPLICATIONSFall
INVESTIGATIONS
Alanine aminotransferase increased
Aspartate aminotransferase increased
Blood alkaline phosphatase increased
Blood creatinine increased
Blood lactate dehydrogenase increased
Neutrophil count decreased
Weight decreased
Weight increased
White blood cell count decreased
METABOLISM AND NUTRITION DISORDERS
Decreased appetite
Hyperglycaemia
Hypoalbuminaemia
Hypocalcaemia
Hypokalaemia
Hyponatraemia
MUSCULOSKELETAL AND CONNECTIVE
TISSUE DISORDERS
Arthralgia
Back pain
Muscle spasms
Muscular weakness
Musculoskeletal pain
Pain in extremity

Page 38

Crizotinib 250 mg BID
All causalities (%)
Treatment related (%)
933 (87.52)
872 (81.80)
118 (11.07)
57 (5.35)
106 (9.94)
68 (6.38)
475 (44.56)
368 (34.52)
548 (51.41)
498 (46.72)
81 (7.60)
56 (5.25)
603 (56.57)
546 (51.22)
565 (53.00)
496 (46.53)
754 (70.73)

562 (52.72)

156 (14.63)
105 (9.85)
326 (30.58)
96 (9.01)
450 (42.21)
181 (16.98)
278 (26.08)
113 (10.60)
145 (13.60)
62 (5.82)

93 (8.72)
226 (21.20)
68 (6.38)
356 (33.40)

59 (5.53)
59 (5.53)
551 (51.69)
302 (28.33)
233 (21.86)
76 (7.13)
105 (9.85)
60 (5.63)
84 (7.88)
109 (10.23)
98 (9.19)
98 (9.19)
488 (45.78)
326 (30.58)
55 (5.16)
98 (9.19)
99 (9.29)
77 (7.22)
54 (5.07)418 (39.21)
131 (12.29)
184 (17.26)
79 (7.41)
57 (5.35)
74 (6.94)
137 (12.85)

387 (36.30)
287 (26.92)
224 (21.01)
68 (6.38)
80 (7.50)
94 (8.82)
226 (21.20)
226 (21.20)

Public Disclosure Synopsis
Protocol A8081005 – 27 Oct 2016 – Final
Crizotinib 250 mg BID
All causalities (%)
Treatment related (%)
541 (50.75)
340 (31.89)
265 (24.86)
150 (14.07)
213 (19.98)
206 (19.32)
214 (20.08)
74 (6.94)
65 (6.10)
83 (7.79)
190 (17.82)
76 (7.13)
136 (12.76)

NERVOUS SYSTEM DISORDERS
Dizziness
Dysgeusia
HeadacheHypoaesthesia
Paraesthesia
PSYCHIATRIC DISORDERS
Anxiety
Insomnia
RESPIRATORY, THORACIC AND
MEDIASTINAL DISORDERS
Cough
Dyspnoea
Haemoptysis
Oropharyngeal pain
Productive cough
SKIN AND SUBCUTANEOUS TISSUEDISORDERS
Alopecia
PruritusRash

470 (44.09)
260 (24.39)
224 (21.01)
55 (5.16)
75 (7.04)
71 (6.66)
244 (22.89)

95 (8.91)

67 (6.29)
84 (7.88)
134 (12.57)

95 (8.91)

Subjects are only counted once per treatment for each row.
Includes data up to 9999 days after last dose of study drug.
MedDRA (v 18.1) coding dictionary applied.

Deaths:A total of 727 deaths reported due to all causes during the study and the most common causeof deaths was disease under study in 653 subjects (61.3%). Overall, 236 (22.1%) subjects
died during treatment (ie, ≤28 days after the last dose of study drug), and 491 (46.1%)
subjects died >28 days after the last dose of study drug (Table 22).
Table 22: Deaths - SA population
Crizotinib 250 mg BID
N=1066n (%)
727 (68.2)
236 (22.1)
491 (46.1)
44 (4.1)
76 (7.1)

Deaths from all causes
Within 28 days of last dose of study drug
More than 28 days after last dose of study drug
Deaths within 30 days of first dose of study drug
Deaths within 60 days of first dose of study drug
Cause of death a
Disease under study
Study drug toxicity
Unknown b
Other

653 (61.3)
12 (1.1)
31 (2.9)34 (3.2)

Summary of death data was based on the NOD CRF page.
Abbreviations: BID=twice daily; CRF=case report form; N/n=number of subjects; NOD=Notice of Death; SA=safety
analysis.
aMore than 1 cause of death may have been reported.
b
Unknown cause of death included “Not Reported”.

Page 39

Public Disclosure Synopsis
Protocol A8081005 – 27 Oct 2016 – Final

Grade 5 treatment-related AEs:
In total, 17 (1.6%) subjects experienced Grade 5 treatment related AEs with the mostcommon being interstitial lung disease (Table 23: Overview of Grade 5 Treatment-Related
Adverse Events – SA PopulationTable 23).
Table 23: Overview of Grade 5 Treatment-Related Adverse Events – SA Population
Crizotinib 250 mg BID
N=1066n (%)
17 (1.6)

MedDRA Preferred Term or Clustered Term
Any AEInterstitial lung disease
Pneumonia
Death
Hepatotoxicity
Lung infection
Dyspnoea
Pulmonary embolism
Cardiac arrest

4 (0.4)3 (0.3)3 (0.3)2 (0.2)2 (0.2)1 (0.1)1 (0.1)1 (0.1)

MedDRA v18.1 coding dictionary was applied.
Abbreviations: AE=adverse event; BID=twice daily; MedDRA=Medical Dictionary for Regulatory Activities; N/n=numberof subjects; SA=safety analysis; v=version.

Permanent Discontinuations Associated With AEs
All-causality and treatment-related AEs associated with permanent discontinuation oftreatment, which occurred at a frequency ≥1% (ie, ≥11 subjects), are presented in Table 24.
Table 24: Treatment-Emergent Adverse Events in ≥1% of Subjects Associated with
Permanent Discontinuation from Treatment (All Causality andTreatment-Related) – SA Population
MedDRA Preferred Term or
Clustered Term
Any all causality AEsa
Disease progression
Pneumonia
Interstitial lung disease
Dyspnoea
Any treatment related AEsa
Interstitial lung disease

Grade 110 (0.9)00
3 (0.3)0
10 (0.9)
3 (0.3)

Grade 28 (0.8)00
2 (0.2)2 (0.2)3 (0.3)2 (0.2)

Crizotinib 250 mg BID
N=1066n (%)
Grade 3 Grade 4
Grade 540 (3.8)
23 (2.2)
134 (12.6)
00
52 (4.9)
3 (0.3)1 (0.1)14 (1.3)
3 (0.3)3 (0.3)5 (0.5)3 (0.3)2 (0.2)4 (0.4)23 (2.2)
11 (1.0)
14 (1.3)
3 (0.3)3 (0.3)3 (0.3)Total
215 (20.2)
52 (4.9)18 (1.7)
16 (1.5)
11 (1.0)61 (5.7)
14 (1.3)

AEs ordered by descending frequency of occurrence in total number of subjects.
Data were based on AE CRF page.
MedDRA (v18.1) coding dictionary was applied.
Abbreviations: AE=adverse event; BID=twice daily; CRF=case report form; MedDRA=Medical Dictionary forRegulatory Activities; N/n=number of subjects; SA=safety analysis; v=version.
a
Any AE columns also include AEs that occurred in <1% of subjects.

Page 40

Public Disclosure Synopsis
Protocol A8081005 – 27 Oct 2016 – Final

CONCLUSIONS:Crizotinib 250 mg orally BID had clinically meaningful antitumor activity as asingle-agent in subjects with ALK-positive advanced NSCLC after failure of at least
1 line of chemotherapy, with a derived tumor assessment ORR of 54.1% (95% CI:
50.8, 57.4) in the ALK-positive by IUO population and responses that were rapid,
with a median TTR of 6.1 weeks, and durable with a median DR of 11.8 months.

Crizotinib had a clinically meaningful median PFS of 8.4 months (95% CI: 7.1, 9.7),
a median OS of 21.8 months (95% CI: 19.4, 24.0), and probabilities of survival at
6 months and 12 months of 81.7% and 66.5%, respectively.

Crizotinib had a side effect profile with AEs that were generally tolerable andmanageable by dosing interruption, dose reduction, and/or standard medical therapy,
as the most common treatment-related AEs were visual and gastrointestinal in nature,
which have been mostly mild to moderate in severity. Patient-reported visual eventswere transient with minimal impact on daily activities.



Crizotinib treatment resulted in statistically significant and clinically meaningfulimprovements from Baseline in key patient-reported lung cancer symptoms andpatient-reported global QoL.



There were no statistically significant associations observed that would support orsuggest any predictive (ie, diagnostic) value of the 4 candidate gene alleles(HLA-DQA1*02:01, HLA-DQB1*02:02, HLA-DRB1*07:01, and
TNXB/rs12153855) and of the 2 additional exploratory gene alleles (HLA-B*57:01
and HLA-DRB1*15:01) in identifying subjects who may be at increased risk forhepatic toxicity.

Page 41