Public Disclosure Synopsis
Protocol A8081014 – 17 September 2014 – 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 and/or COMPOUND NUMBER: Crizotinib/PF-02341066
PROTOCOL NO.: A8081014
PROTOCOL TITLE: Phase 3, Randomized, Open-Label Study of the Efficacy and Safetyof Crizotinib Versus Pemetrexed/Cisplatin or Pemetrexed/Carboplatin in Previously
Untreated Subjects With Non-Squamous Carcinoma of the Lung Harboring a Translocation
or Inversion Event Involving the Anaplastic Lymphoma Kinase (ALK) Gene Locus.
Study Centers: This was a multicenter study conducted at 169 centers in 31 countries.
Twenty-eight in United States, 16 in Italy, 15 in Japan, 9 each in Spain, and France, 8 each inAustralia, Belgium, and China, 7 in Germany, 5 each in Brazil, Canada, and United
Kingdom, 4 each in Portugal, Russia, Taiwan, and Singapore, 3 each in Chile, Finland,
Korea, Netherlands, Ukraine and Switzerland, 2 each in Hong Kong, India, and South Africa,and 1 each in Austria, Ireland, Luxembourg, Mexico, Peru, and Norway.
Study Initiation Date and Primary Completion or Final Completion Dates:
Study Initiation Date = 13 January 2011
Final Completion Date = Ongoing at data cutoff 30 November 2013
Phase of Development: Phase 3
Study Objectives:
Primary Objective

To demonstrate that crizotinib (Arm A) is superior to first-line chemotherapy,
pemetrexed/cisplatin or pemetrexed/carboplatin (Arm B), in prolonging PFS in subjects
with advanced non-squamous Non-Small Cell Lung Cancer (NSCLC) whose tumors
harbor a translocation or inversion event involving the Anaplastic Lymphoma Kinase(ALK) gene locus.

Secondary Objectives


To compare secondary measures of clinical efficacy including Objective Response Rate
(ORR), Overall Survival (OS), disease control rate (DCR) at 12 weeks, and times tooverall, intracranial and extracranial progression (Time to Overall Progression [TTP],
Time to Intracranial Progression [IC-TTP], Time to Extracranial Progression [EC-TTP])
between the 2 treatment arms and to evaluate OS at 1 year and 18 months, duration of
response (DR), and time to tumor response (TTR).

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Protocol A8081014 – 17 September 2014 – Final







To evaluate the safety and tolerability of crizotinib compared to chemotherapy(pemetrexed/cisplatin or pemetrexed/carboplatin).
To evaluate PK of crizotinib (including its active moieties, if appropriate) in this subject
population using population PK (POPPK) methods and explore correlations between PK,
response and/or safety findings, Arm A only.
To correlate ALK gene fusion variants to outcome measures.
To compare patient-reported outcomes (PRO) of health-related quality of life,
functioning, disease/treatment-related symptoms of lung cancer, and general health status
in both treatment arms.
To assess health care resource utilization (HCRU) with respect to hospitalization(ie, length of stay, frequency) and concomitant medication use for select adverse events(AEs) (eg, hematologic events).

METHODS
Study Design:This is an open label, multicenter, randomized, Phase 3, efficacy and safety study ofcrizotinib versus [vs] first line chemotherapy, ie, pemetrexed/cisplatin or
pemetrexed/carboplatin, in subjects with ALK positive, non-squamous NSCLC.
A total of 334 subjects were planned to be randomized in a 1:1 ratio to receive crizotinib or
chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin). The choice of platinum
doublet chemotherapy in the chemotherapy arm was made by the investigator. Eachtreatment cycle was defined as 3 weeks (21 days). Randomization was stratified by Eastern
Cooperative Oncology Group (ECOG) performance status (PS) (0-1 or 2), race (Asian or
non-Asian), and brain metastases (presence or absence).
Subjects were to continue in the assigned treatment arm until Response Evaluation Criteria in
Solid Tumors (RECIST; Version 1.1) defined progressive disease (PD), as determined byindependent radiology review (IRR), unacceptable toxicity, death, or consent withdrawal.
In the crizotinib arm, subjects could continue crizotinib treatment beyond the time of
RECIST defined PD, as determined by IRR, at the discretion of the investigator if the subject
was perceived to be experiencing clinical benefit. In the chemotherapy arm, subjects could be
dosed for up to 6 cycles of chemotherapy as long as they met the chemotherapy retreatment
criteria. If a subject completed the 6 cycles of chemotherapy, he/she was to remain in the
study with no additional treatment (ie, maintenance therapy was not permitted) and withongoing tumor assessments until RECIST defined PD, as determined by IRR. Once subjects
in the chemotherapy arm had RECIST defined PD, as determined by IRR, they were allowed
to cross over to receive crizotinib treatment providing they met the safety screening
inclusion/exclusion criteria for crizotinib.
The schedule of activities is shown in Table 1.

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Protocol A8081014 – 17 September 2014 – Final

Table 1: Schedule of Activities
Protocol Activities

Screeninga
28 Days Prior
to DosingBaseline Documentation
Informed consente
Medical/oncological historyf
Baseline signs/symptoms
Mandatory tumor tissue for molecular profilingg
Optional tumor tissue for molecular profiling(Arm A and crossover)hPhysical examinationi
ECOG performance status
Ophthalmologic examinationj

Study Treatmentb
Cycle 1
Day 1 (2)c Day 7 Day 15
(1)
(2)

End of Treatment

Cycles 2
Day 1 (2; 7 for Imaging)

End ofTreatment/
Withdrawald

Post
Treatment
Follow-Up

X
X
X
X
X
X
X

(X)
X

X
X
Cycle 5 and every 4 cycles
thereafter - France only;
End of every cycle – India only;
All subjects – anytime there was achange in CTCAE grade

X (Korea only);
all subjects asclinicallyindicated
(X)
(X)
(X)
X in triplicate

X (Korea only); all subjects asclinically indicated

X

X
X

Laboratory studies
Urinalysis -– protein/blood by dipstick (all subjects);
reflex microscopy if dipstick positive (all subjects)kHematologyl
Blood chemistryl
Coagulationl
12-lead ECGm
Pregnancy test (as appropriate)nDisease Assessments
Tumor assessments (including scans)oOther clinical assessments
Adverse events and hospitalizationsp
Concomitant medications/treatmentsq
EORTC QLQ-C30 and QLQ-LC13r
VSAQ-ALK and EQ-5Ds

X
X
X
X
X single
X

X
X

X
X

X (Cycles 2, 3) in triplicate
X

X

X
X

X
X

X (Korea only)

X
X
X
X

X

Page 3X
X
X

X (every 6  1 week; every 12 
1 week for crossover or crizotinib
past progression subjects)

X

X

X
X
X
X

X
X
X
X

X
X

Public Disclosure Synopsis
Protocol A8081014 – 17 September 2014 – Final

Protocol Activities

Screeninga
28 Days Prior
to Dosing

MUGA scan or echocardiogramt
Survival follow-upu
Study treatment
Study randomization
Vitamin premedication
Crizotinib (Arm A and crossover)Cisplatin and pemetrexed (Arm B option)
Carboplatin and pemetrexed (Arm B option)
Special laboratory studies
Pharmacokinetics (Arm A only)v
Optional blood sample for pharmacogenomics(crizotinib-treated subjects only)w
Hypogonadism laboratory testsx(males on crizotinib [Arm A and those crossing overfrom Arm B])
Hypogonadism laboratory testsx(males on chemotherapy [Arm B])
DXA scany(males on crizotinib [Arm A and those crossing overfrom Arm B])
DXA scany(males on chemotherapy [Arm B])

Study Treatmentb
Cycle 1
Day 1 (2)c Day 7 Day 15
(1)
(2)

X

Cycles 2
Day 1 (2; 7 for Imaging)

End of Treatment
End ofTreatment/
Withdrawald

Post
Treatment
Follow-Up

Cycle 3, then every 4 cycles
X

X (Day -7 to
Day 0)X (commencing
Day -7 until endof Cycle 6)Once or Twice Daily
X (6 cycle maximum)X (6 cycle maximum)

X
X
X

X (Cycles 2, 3, 5)

X
X

X

X

X

X (Cycle 2 Day 1, Cycle 5 Day 1,
Cycle 7 Day 1,
and every 4 cycles thereafter)
X (Cycle 2 Day 1, Cycle 5 Day 1)
X (Cycle 7 Day 1)yXXX
X see footnote yfor details
XyX

Abbreviations: AE=adverse event; ALK=anaplastic lymphoma kinase; ALT=alanine transaminase; Arm A=crizotinib arm; Arm B=chemotherapy arm; AST=aspartatetransaminase; CT=computed tomography; CTCAE=Common Terminology Criteria for Adverse Events; DNA=deoxyribonucleic acid; DXA=dual energy X-ray absorptiometry;
EORTC=European Organization for the Research and Treatment of Cancer; EQ-5D=EuroQol-5D; FISH=fluorescence in-situ hybridization; ECG=electrocardiogram;
ECOG=Eastern Cooperative Oncology Group; IEC=Independent Ethics Committee; IRB=Institutional Review Board; K2EDTA=dipotassium ethylenediamine tetraacetic acid;
MRI=magnetic resonance imaging; MUGA=multiple gated acquisition; NCI=National Cancer Institute; PD=progressive disease; PK=pharmacokinetic; QLQ-C30=Quality ofLife Questionnaire-Core 30; QLQ-LC13=Quality of Life Questionnaire-Supplement Module for Lung Cancer (LC13); QTc=corrected QT interval; RECIST=Response
Evaluation Criteria in Solid Tumors; ULN=upper limit of normal; VSAQ-ALK=Visual Symptom Assessment Questionnaire-ALK.
a
Screening: For Arm B subjects who crossed over to receive crizotinib treatment, screening laboratory tests were ideally to be performed within the previous 5 days, whereas
the physical examination, ECOG performance status, and pregnancy test did not need to be repeated if these were performed within 21 days of the previous evaluation.
Screening ECG was to be repeated. The results of these tests had to meet eligibility criteria in order for the subject to receive crossover crizotinib treatment. Screening

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Protocol A8081014 – 17 September 2014 – Final

b

c
d

e
f
g

h
i
j

k

l

ophthalmology examination and mandatory tumor tissue for molecular profiling did not need to be repeated.
Study Treatment: All assessments were to be performed prior to dosing with study treatment unless otherwise indicated. Every effort was to be made to start study treatment
within 2 days of randomization to ensure comparability of the 2 treatment arms and the time of treatment start after randomization. Acceptable time windows for performing
each assessment are described in the column headings. All cycles were 21 days in duration.
Once the primary endpoint (progression-free survival) for the study has been summarized and reported in this clinical study report, ongoing subjects in Arm A or thosesubjects who crossed over to receive crizotinib treatment will only need to visit the study site every other cycle for study assessments instead of every cycle. Hematology andblood chemistry tests will still be required in the non-visit cycle ie, approximately 3 weeks after previous laboratory testing, but can be done locally. Enough study treatment
for 2 cycles of treatment will be dispensed at each site visit. During the non-visit cycle, subjects are to telephone the study site to provide an update of adverse events andconcomitant medications and to provide results of the local laboratory tests.
Cycle 1/Day 1: Blood chemistry, hematology, coagulation, and physical examination were not required if an acceptable screening assessment was performed within 7 days
prior to the start of study treatment.
End of Treatment/Withdrawal: These assessments were to be obtained, if not completed, during the previous 4 weeks on study (during the last 6 weeks for diseaseassessments). The end of treatment visit was usually scheduled for 28 days post last dose of study treatment or when the decision was taken to provide alternative anticancer
therapy, whichever was sooner. For male subjects only: all attempts were to be made to obtain the blood sample for hypogonadism assessment and DXA scan for bonemineral density and muscle mass assessment at least 4 weeks after the last dose of study treatment if possible and prior to the commencement of new anticancer therapy.
Informed Consent: Had to be obtained prior to undergoing any study-specific procedure.
Medical/Oncological History: To include information on smoking history, prior regimens, and tumor marker status.
Mandatory Tumor Tissue for Molecular Profiling: Paraffin block(s) were to be of adequate size to allow, if possible, at least 10 slides with cuts that were 5 microns thick.
If no block was available, then the sites were to try to obtain at least 10 slides with cuts that were 5 microns thick. Archived or fresh tumor samples obtained according to theinstitutional practice for biopsy were acceptable. These samples were used for the assessment of ALK gene fusion by FISH by the central laboratory. Tumor samples thatwere sent directly to the central laboratory for testing could also be tested by FISH by a secondary laboratory for concordance. Tumor samples could also be used for analysisof the presence of ALK protein and ALK fusion transcripts. The mandatory tumor tissue sample could be completed outside the 28-day screening window.
Optional Tumor Tissue for Molecular Profiling (Arm A and crossover): An optional fresh tumor sample was to be collected at the end of treatment if a subject
discontinued due to PD. This included subjects who crossed over from Arm B to crizotinib.
Physical Examination: Included an examination of major body systems (at screening and on Day 1 of each cycle), height (at screening only), body weight, blood pressure,and pulse rate (on Day 1 of each cycle).
Ophthalmologic Examination: Included visual acuity, fundoscopy, and slit lamp, and was to be performed by an ophthalmologist. The ophthalmologic examination was tobe repeated during the study when visual disturbances had been observed, when there had been a reported change in CTCAE grade, or as clinically indicated. For all subjects
enrolled in France, ophthalmology examinations were to be performed after the completion of every 4 cycles. For all subjects enrolled in India, ophthalmology examinations
were to be performed after the completion of every cycle.
Dipstick Urinalysis and Reflex Microscopy: In Korea (after Protocol Amendment 4), repeat examinations were to be completed at Day 1 of every cycle and at the end oftreatment; all other countries were to perform examinations as clinically indicated, eg, upon diagnosis of renal cysts. Reflex microscopy was required if urine dipstick was
positive for blood or protein.
Hematology, Blood Chemistry, and Coagulation: For subjects on crizotinib treatment: liver function tests were to be repeated within 48 hours if the following wasobserved and repeated weekly until recovery to baseline levels:- if a subject entered the study with AST or ALT and total bilirubin baseline values within the normal range who subsequently presented with AST or ALT ≥3 x ULN
concurrent with total bilirubin ≥2 x ULN with no evidence of hemolysis and an alkaline phosphatase ≤2 ULN or not available,- OR if a subject entered the study with pre-existing AST or ALT baseline values above the normal range who subsequently presented with AST or ALT ≥2 times the baseline
values and ≥3 x ULN, or ≥8 x ULN (whichever was smaller) concurrent, in subjects with pre-existing values of total bilirubin above the normal range, with a total
bilirubin increased by 1 x ULN, or >3 x ULN (whichever was smaller).
During this time, crizotinib treatment was to be withheld and recommenced if appropriate after consulting dose-modification. A 4 mL serum sample obtained just prior to thefirst dose of study treatment was to be stored frozen on-site through completion of the study for possible use as a baseline reference should additional laboratory tests beindicated, eg, additional testing to exclude other causes for liver injury.

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Protocol A8081014 – 17 September 2014 – Final

m

n

o

p

q
r

s

t
u

12-lead ECG: All subjects were required to have a single ECG measurement at screening. Triplicate ECG measurements (approximately 2 minutes apart) were to bemeasured at all later time points with all 3 measurements obtained within a 10-minute time window for each time point. ECGs were to be performed immediately before PK
blood draws at respective time points. After Protocol Amendment 6, additional triplicate ECG measurements were required in all subjects randomized to Arm A. ECGs were
to be obtained at 0 hour (predose) on Day 1 of Cycles 1, 2, and 3. Subsequent ECGs were to be taken at 3 and 5 hours after morning crizotinib dosing on Day 1 of Cycles 1,
2, and 3. After Protocol Amendment 6, all ECG tracings were to be sent electronically to a core ECG laboratory for blinded manual interval measurements. For Arm B
subjects and subjects crossing over to crizotinib from Arm B (triplicate ECG assessments), ECGs were to be obtained at 0 hour (prior to the start of dosing) on Day 1 ofCycles 1, 2, and 3. For all subjects, if the QTc was prolonged (>500 msec), then the ECG was to be read by a cardiologist at the site for confirmation (to look for spurious QT
effects). Additional ECGs were to be performed as clinically indicated.
Pregnancy Test: All female subjects of child-bearing potential were required to have a negative pregnancy test at screening. The test was to be repeated whenever
1 menstrual cycle was missed during treatment or a potential pregnancy was otherwise suspected, and again at end of treatment. Pregnancy tests could also be repeated at therequest of IRB/IECs or if required by local regulations.
Tumor Assessments: CT or MRI was to include chest, abdomen and pelvis (CAP) at all time points. Bone scintigraphy/bone scans and brain scans/head CT/MRI were also
required at screening. All subsequent scans were based on a calendar schedule beginning from the date of randomization. The first post-randomization scan was to be
performed at 6 weeks (+1 week); all subsequent scans could be performed at 6 weeks (±1 week). The brain was to be included in subsequent tumor assessments if a subject
had brain metastases; otherwise, the brain was to be evaluated every 12 weeks. Bone metastases, if present at baseline, were to be followed on study by separate
CT/MRI/scan or X-ray every 6 weeks if the metastases were outside the CAP field of imaging. In all subjects, repeat bone scintigraphy/bone scans were required every 12
weeks to monitor for new lesions. A CT or MRI scan was also to be performed whenever PD was suspected (eg, symptomatic deterioration). All scans were to be sent to anindependent radiology laboratory for a blinded RECIST review. Tumor assessments were to continue until PD had been determined by the independent radiologist, which
included those subjects who had stopped treatment for reasons other than PD but remained on study. Crossover subjects and subjects continuing crizotinib therapy after
independent radiology review had declared PD were to continue to have tumor assessments; however, these no longer required central independent radiology review. The
tumor assessments after central review progression had been declared were to be performed every 12 weeks ± 1 week.
Adverse Events and Hospitalizations: Subjects were to be followed for adverse events and hospitalizations 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 treatment-related toxicities had resolved or were determined to be “chronic” or “stable”, whichever
was later. Serious adverse events were to be monitored and reported from the time that the subject provided informed consent. Hospitalizations were to be recorded from28 days prior to the start of study treatment and up to 28 days post the last dose of study treatment. Adverse events were graded using NCI CTCAE Version 4.
Concomitant Medications/Treatments: Concomitant medications and treatments were to be recorded from 28 days prior to the start of study treatment and up to 28 days
post the last dose of study treatment.
EORTC QLQ-C30 and QLQ-LC13: Subjects were to complete all EORTC QLQ-C30 and QLQ-LC13 self-assessment questionnaires in the study site at the specified time
points with the exception of the Day 7 assessment. The Day 7 assessment could be completed at home and was to be given to subjects along with completion
guidelines/on-site training at the Cycle 1/Day 1 visit (baseline). At Cycle 1/Day 1, site staff (eg, site coordinators) were to instruct subjects that the Day 7 assessment was tobe completed without help from friends or family members and also recommend that this assessment be completed in the morning. On Day 7 (or the day prior), a member ofthe site staff was to call to remind subjects to complete the assessment that day and to return completed questionnaires at their next visit (Day 15). All other scheduledassessments of the EORTC QLQ-C30 and QLQ-LC13 could not be taken home and were to be completed in the site prior to any other study or medical procedures.
Questionnaires were also to be completed in crossover subjects at the same specified time points.
VSAQ-ALK and EQ-5D: Subjects were to complete the VSAQ-ALK and the EQ-5D questionnaires at the study site prior to any study or medical procedure. All
self-assessment questionnaires were to be completed by the subjects while at the site and could not be taken home. Translation of the VSAQ-ALK into different languages
was undertaken and many language versions were available. However, if the VSAQ-ALK was not available in the subject’s preferred language, the subject did not need tocomplete this assessment. Questionnaires were also to be completed by crossover subjects at the same specified time points.
MUGA Scan or Echocardiogram: MUGA scans or echocardiograms were to be obtained from all subjects until sufficient data were available to discontinue collecting fromnewly enrolled subjects. The rationale for discontinuing this procedure will be provided to the IRB/IEC along with the amended protocol.
Survival Follow Up: After discontinuation of study treatment and/or confirmed PD, post-study survival status was to be collected every 2 months until death or until
18 months after the randomization of the last subject (End of Study definition). This included collection of information on subsequent anticancer therapies. Telephone
contact was acceptable.

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Protocol A8081014 – 17 September 2014 – Finalv

Pharmacokinetics (Arm A only; not crossover subjects): At 2-6 hours (3 and 5 hours after amendment 6) post AM crizotinib dose on Cycle 1 Day 1, 0 (predose) and 2-6 (3and 5 hours after amendment 6) post AM crizotinib dose on Day 1 in Cycles 2, 3 and 5, 3 mL of blood was to be drawn into a K2EDTA tube. Additional PK samples could becollected if the subject experienced a serious and/or unexpected adverse event.
w
Optional Blood sample for Pharmacogenomics: A 2-mL blood sample was to be collected for the analysis of DNA sequence variation in genes that may affect the PK of
crizotinib, or that may be associated with specific adverse events or toxicities related to crizotinib.
xHypogonadism Laboratory Tests (male subjects only, both treatment arms): All male subjects enrolled after Protocol Amendment 6 were to undergo hypogonadism
laboratory tests. In subjects’ crossing over to crizotinib from Arm B, the schedule of laboratory tests used in Arm A was to be repeated. Male subjects enrolled in Arm B
after Protocol Amendment 6 could optionally also undergo hypogonadism laboratory tests after appropriate informed consent at the time of crossover to crizotinib therapy.
Blood draws had to be done between 08:00 and 11:00. If a decrease of ≥25% from baseline was observed in total testosterone or free testosterone, a repeat laboratory analysisof both these parameters had to be performed at the next study site visit to confirm hypogonadism.
yDual-energy X-ray Absorptiometry (DXA) Scans for Bone Mineral Density and Muscle Mass Measurements: All male subjects enrolled after Protocol Amendment 6
were to undergo a baseline DXA scan. Subsequent DXA scans were to be performed based upon the following schedule:
Arm A/and subjects crossing over to crizotinib from Arm B: DXA scans were to be performed at Cycle 7/Day 1 and again at end of treatment unless a previous DXA
scan was performed within the last 2 months.
Arm B: A DXA scan was to be performed at the end of treatment visit and a repeat (re-baseline) DXA scan was needed if there was a gap of more than 2 months between the endof chemotherapy treatment in Arm B and crossover to crizotinib. Male subjects enrolled in Arm B after Protocol Amendment 6 could optionally also undergo DXA scans after
appropriate informed consent at the time of crossover to crizotinib therapy

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Protocol A8081014 – 17 September 2014 – Final

Number of Subjects (Planned and Analyzed):
A total of 334 subjects were planned to be enrolled in the study.
Analyzed in randomized phase: A total of 343 subjects were randomized and included in the
Full Analysis (FA) population (172 in the crizotinib arm and 171 in the chemotherapy arm).
Of these, 340 treated subjects had at least 1 dose of study medication and were included in
the Safety Analysis (SA) population (171 in the crizotinib arm and 169 in the chemotherapyarm).
Diagnosis and Main Criteria for Inclusion:
Male or female subjects were to be 18 years of age or older; have histologically or
cytologically proven diagnosis of locally advanced, not suitable for local treatment, recurrent,or metastatic non-squamous NSCLC; positive for translocation or inversion events involving
the ALK gene locus as determined by an ALK break-apart FISH test; have had no priorsystemic treatment for locally advanced or metastatic disease (except prior adjuvant
chemotherapy for Stage I-III or combined modality chemotherapy radiation for locallyadvanced disease if completed >12 months prior to documented PD); tumors must have hadmeasurable disease as per RECIST, version 1.1; and ECOG PS 0-2.
Study Treatment:
Subjects were randomized in a 1:1 ratio to receive either crizotinib or first-line chemotherapy(pemetrexed/cisplatin or pemetrexed/carboplatin).
Test ProductCrizotinib capsules, 250 mg twice daily (BID), were to be administered orally atapproximately the same time each day on a continuous daily dosing schedule. Cycles were
defined in 21 day periods to facilitate scheduling of visits and assessments. In order to keep
the treatment conditions similar between treatment arms, subjects in the crizotinib arm werealso required to take folic acid, 350-1000 µg, orally daily beginning approximately 7 days
before the first dose of crizotinib and continuing daily for up to 3 weeks after the first dose of
crizotinib. Similarly, Vitamin B12, 1000 µg, was to be injected intramuscularly approximately
7 days before the first dose of crizotinib only.
Reference Therapy
Standard doses of chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin) were to beadministered by intravenous (IV) infusion according to standard of care:

Pemetrexed (500 mg/m2) was to be administered by intravenous (IV) infusion over 10
minutes or according to institutional administration timing.

Cisplatin (75 mg/m2) was to be administered by infusion after adequate hydration,according to institutional practices, beginning approximately 30 minutes after the endof the pemetrexed infusion.

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Protocol A8081014 – 17 September 2014 – Final

Carboplatin (at a dose calculated to produce an area under the concentration time
curve [AUC] of 5 or 6 mgmin/mL) was to be administered by infusion, according toinstitutional practices, beginning approximately 30 minutes after the end of thepemetrexed infusion.

In order to reduce treatment-related hematologic and gastrointestinal toxicities, subjects wererequired to take folic acid, 350-1000 μg, orally daily beginning approximately 7 days before
the first dose of pemetrexed and continuing daily until 3 weeks after the last dose ofpemetrexed. In addition, Vitamin B12, 1000 μg, was to be injected intramuscularly (oraccording to local standard of care or local regulations) approximately 7 days before the firstdose of pemetrexed and repeated approximately every 9 weeks until discontinuation ofchemotherapy.
In order to reduce cutaneous reactions, subjects were also required to take a corticosteroid
equivalent to 4 mg dexamethasone given orally BID on the day before, the day of, and the
day after pemetrexed dosing. Intramuscular, intraperitoneal, or IV administration of a
corticosteroid with the same total dose as oral dexamethasone was allowed per country
regulations and according to institutional practices.
Efficacy, Pharmacodynamics, Pharmacokinetic Outcomes Research Endpoints:
Primary Endpoint

PFS based on RECIST Version 1.1 (determined by IRR).

Secondary Endpoints

ORR (determined by IRR), OS, Disease Control Rate (DCR) at 12 weeks, TTP, IC-TTP,
EC-TTP, OS at 1 year and 18 months, DR and TTR.

Type, incidence, severity, seriousness, and relationship to study treatments of AEs andany laboratory abnormalities.



Plasma concentrations of crizotinib (including its active moieties, if appropriate).

Proportions of subjects with each of the 8 ALK fusion variants of the EML4-ALK fusion.

Time to Deterioration (TTD) in pain in chest, dyspnea, or cough subject-reported disease
symptoms.



Subject-reported global quality of life, disease/treatment-related symptoms, and general
health status.



HCRU with respect to hospitalizations and concomitant medication use for select AEs(eg, hematologic events).

The observation period for the efficacy endpoints was from randomization until progressive
disease (PD; as determined by IRR) or initiation of subsequent antitumor therapy in the

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Protocol A8081014 – 17 September 2014 – Finalabsence of PD or death, whichever came first. For OS, the observation period was fromrandomization to death or the last date the subject was known to be alive in the absence ofdeath.
Safety Evaluations:
Safety evaluations included AEs, laboratory parameters (hematology, coagulation, urinalysis,
and clinical chemistry), physical examinations including vital signs, measurement of bodyweight, ECOG PS, 12-lead electrocardiograms (ECGs), multiple gated acquisition (MUGA)
scans or echocardiograms (ECHO), and ophthalmologic examinations. Hypogonadism
evaluation (for male subjects) including total and free testosterone levels and dual energy
X-ray absorptiometry (DXA) scan was included in Protocol Amendment 6.
Patient Reported Outcomes:
Global quality of life, functioning, lung cancer specific disease/treatment-related symptoms,
and general health status were assessed using the European Organization for the Research
and Treatment of Cancer (EORTC) quality of life questionnaire Core 30 (QLQ C30), itscorresponding quality of life questionnaire supplement module for lung cancer LC13 (QLQ
LC13), and the EuroQol 5D (EQ 5D) questionnaire. Subjects were to be asked to complete
the self-administered EORTC QLQ C30 and QLQ LC13 at baseline, Cycle 1 Day 7 and Day
15, and then Day 1 of each subsequent cycle until end of treatment/withdrawal.
Statistical Methods:
The following population sets were used:
Full Analysis (FA) Population:
The FA population included all subjects who were randomized with study treatment
assignment designated according to the initial randomization. The FA population was theprimary population for evaluating efficacy endpoints, subject characteristics, and subject
disposition.
Safety Analysis (SA) Population:
The SA population included all randomized subjects who received at least 1 dose of study
treatment, with treatment assignments designated according to actual study treatment
received during the first cycle. The SA population was the primary population for safety andtreatment evaluations; in addition, this population was used when summarizing efficacy databy treatment group (ie, by chemotherapy regimen: pemetrexed/cisplatin or
pemetrexed/carboplatin).
Pharmacokinetic (PK) Analysis Population:
The PK concentration population (also referred to as the PK evaluable population) included
any subject in the SA population who had at least 1 plasma concentration of crizotinib or its
metabolite, PF-06260182, determined following crizotinib treatment as of the data cutoff

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Public Disclosure Synopsis
Protocol A8081014 – 17 September 2014 – Finaldate. The plasma predose (0 hours) concentration population included any subject in the PKconcentration population who had at least 1 predose (0 hours) concentration (troughconcentration [Ctrough]) of crizotinib or PF-06260182, with actual sample collection times
between -1.2 to 0 hours prior to morning dosing.
PRO Evaluable Population:
The PRO evaluable population included all subjects from the FA population who completeda baseline (last PRO assessment prior to randomization day) and at least 1 postbaseline PRO
assessment prior to crossover or end of randomized study treatment. The PRO evaluable
population was the primary population for the analysis of change from baseline scores and
TTD in subject reported pain in chest, dyspnea, or cough.
ALK Gene Fusion Variant Evaluable Population:
The ALK gene fusion variant evaluable population was defined as subjects from the FA
population who had a result from EML4-ALK gene fusion variant testing of either norearrangement, or 1 of 9 results reflecting 8 specific rearrangements (V1, V2, V3a, V3b,
V3a/b, V4, V5a, V6, and V7). Testing for ALK gene fusion variants was performed using the
Response Genetics, Inc. EML4 ALK RT PCR gene fusion test (the polymerase chain
reaction [PCR] test).
Pharmacogenomics Evaluable Population:
The pharmacogenomics evaluable population was defined as subjects from the SA
population in the crizotinib group who provided a blood sample for pharmacogenomics
analysis at baseline (Day 1 of Cycle 1).
Subjects in the chemotherapy arm who had RECIST-defined PD, as determined by IRR,
were allowed to cross over to receive crizotinib treatment, providing they met safety
screening inclusion/exclusion criteria for crizotinib therapy. The following analysis
subgroups were included: subjects randomized crizotinib (subgroup 1), subjects randomized
to chemotherapy (subgroup 2), and subjects randomized to chemotherapy who crossed overto receive crizotinib (subgroup 3). However, analyses based on subgroup 3 have not beenpresented in the disclosure document as these are not the primary or secondary endpoints ofthe study.
Primary Efficacy Analysis
PFS based on RECIST Version 1.1 (determined by IRR)
PFS was defined as the time from the date of randomization to the date of the first
documentation of objective tumor progression (by IRR) or death on study due to any cause,
whichever occurred first. The study was to be considered positive if the 1-sided log-rank testfor PFS, stratified for baseline stratification factors (ECOG PS, race, brain metastases), wassignificant at the 0.0247 level. Estimates of the PFS curves obtained from the Kaplan-Meiermethod were presented. The median event time (and other quartiles) and corresponding
2-sided 95% confidence intervals (CIs) were provided for each treatment arm and treatment
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Protocol A8081014 – 17 September 2014 – Finalgroup, where appropriate. The Cox regression model, stratified for baseline stratification
factors, was fitted. The estimated hazard ratio (HR) and 2-sided 95% CIs were provided.
Secondary Efficacy Analyses
ORR (determined by IRR), OS, DCR at 12 weeks, TTP, IC-TTP, EC-TTP, OS at 1 year and18 months, Duration of Response (DR) and TTR
ORR was defined as the percentage of subjects with complete response (CR) or partial
response (PR) according to RECIST Version 1.1, as determined by IRR. ORR was
summarized for each treatment arm along with the corresponding exact 2-sided 95% CI using
a method based on the F distribution. ORR between the 2 treatment arms was comparedusing a 2-sided Cochran Mantel Haenszel test stratified for baseline stratification factors(ECOG PS, race, brain metastases) and a 2-sided unstratified test (eg, Pearson). Treatment
difference of ORR and its 95% CI based on the normal distribution were provided.
OS was defined as the time from randomization to the date of death due to any cause.
One-year and 18-month survival probabilities were defined as the probabilities of survival at
1 year and 18 months, respectively, after the date of randomization based on the
Kaplan-Meier estimate. Differences in OS between treatment arms were analyzed by a
1-sided log-rank test stratified for baseline stratification factors (ECOG PS, race, brain
metastases). Estimates of the OS curves obtained from the Kaplan-Meier method were
presented. The Cox regression model, stratified for baseline stratification factors, was fitted.
The estimated hazard ratio (HR) and 2-sided 95% CIs were provided.
DCR at 12 weeks was defined as the percentage of subjects with CR, PR, or stable disease at
12 weeks according to RECIST Version 1.1, as determined by IRR. A 2-sided unstratified
test (eg Pearson) was used to compare DCR between the two treatment arms.
TTP was defined as the time from randomization to first documentation of objective tumor
progression (by IRR). Differences between treatment arms were analyzed by the unstratified
log rank test. IC-TTP was defined as the time from randomization to first documentation of
objective intracranial disease progression, based on either new brain metastases orprogression of existing brain metastases. EC-TTP was defined as the time fromrandomization to first documentation of objective extracranial disease progression, based oneither new extracranial lesions or progression of existing extracranial lesions.
DR was defined as the time from the first documentation of objective tumor response (CR or
PR), as determined by IRR, to the first documentation of objective tumor progression or todeath due to any cause, whichever occurred first. DR was summarized for the subgroup of
responders (CR and PR) using the Kaplan-Meier method.
TTR was defined as the time from randomization to first documentation of objective tumor
response (CR or PR), as determined by IRR. TTR was summarized in the subgroup of
responders (CR and PR) using descriptive statistics.

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Protocol A8081014 – 17 September 2014 – Final

Patient-Reported Outcomes (TTD in pain in chest, dyspnea, or cough subject reported
disease symptoms and subject reported global quality of life, disease/treatment-related
symptoms, and general health status)
Time to deterioration (TTD) in pain in chest, dyspnea, or cough symptoms (fromQLQ-LC13) was a composite endpoint, defined as the time from randomization to theearliest date the subject’s scale scores showed a 10-point or greater increase after baseline inany of these 3 symptoms. TTD analyses for the composite endpoint and each of the 3
pre-specified symptoms were summarized using Kaplan-Meier methods. The estimatedKaplan-Meier plots were provided for the composite and each symptom within it, and theunstratified 2-sided log-rank test was the primary method to compare the time to first
deterioration between the 2 treatment arms. The median time and 2-sided 95% CI for the
median was also provided based on the Brookmeyer Crowley method. To compare actual
scores and change from baseline scores between treatment arms, repeated measures
mixed-effects modelling was carried out for the EORTC QLQ-C30, QLQ-LC13 domain andsingle-item scores, and the EQ-5D visual analogue scale. In the chemotherapy arm, data untilcrossover to crizotinib or end of treatment (maximum 6 cycles) were included in the analyses
and 2-sided p-values were reported that were not adjusted for multiple testing.
Pharmacokinetic analysis
Plasma concentrations of crizotinib and its metabolite PF-06260182
Predose (0 Hour) plasma concentrations of crizotinib, its metabolite PF-06260182, and the
PF-06260182-to-crizotinib ratio were summarized using descriptive statistics.
Pharmacodynamic analysis
Proportions of subjects with each of the 8 ALK fusion variants of the EML4 ALK fusion
ALK gene fusion variant analysis data were summarized using descriptive statistics. For each
ALK variant separately and for subjects with no identified ALK rearrangement, best
objective response and ORR were summarized for each treatment arm with thecorresponding exact 2-sided 95% CI using a method based on the F distribution.
Health care resource utilization analysis
HCRU with respect to hospitalizations and concomitant medication use for select AEs (eg,hematologic events)
Data regarding hospitalizations, the causality of AEs associated with the hospitalization, andconcomitant medication use were summarized.
SafetyType, incidence, severity, seriousness, and relationship to study treatments of AEs and any
laboratory abnormalities

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Protocol A8081014 – 17 September 2014 – Final

Safety data were analyzed in the SA population. All AEs were coded using Medical
Dictionary for Regulatory Activities (MedDRA) Version 16.1. The severity of all AEs wasgraded by the investigator using National Cancer Institute Common Terminology Criteria for
Adverse Events (NCI CTCAE) Version 4.0. Safety data (AEs, laboratory parameters, vital
signs, ECOG PS, ECGs, MUGA scans or ECHO, and ophthalmologic examinations) weresummarized using descriptive statistics.
RESULTS
Subject Disposition and Demography:
Subject disposition data is summarized in Table 2. A total of 172 subjects were randomized
to the crizotinib arm and 171 were randomized to the chemotherapy arm. Fifty-two (30.2%)
subjects in the crizotinib arm and 54 (31.6%) subjects in the chemotherapy arm (including
the crossover phase) were discontinued from the study. The most common reason for
discontinuation from the study in both treatment arms was death (44 subjects in the crizotinibarm and 46 subjects in the chemotherapy arm.
Table 2: Subject Disposition and Subjects Analyzed by Treatment Arm
Crizotinibn (%)

Chemotherapy
n (%)

Total
n (%)

172

171

343

Treated

171

169

340

Completed

00

Randomized to study treatment

Discontinued from study0a

52 (30.2)

54 (31.6)

Subject Died

44

46

90

Lost to Follow-Up

0

2

2

Subject Refused Further Follow-up

7

5

12

Other

106 (30.9)

1

1

2

119 (69.2)

115 (67.3)a234 (68.2)

Randomized not treated

1 (0.6)2 (1.2)3 (0.9)Full analysis population

172 (100)

171 (100)

343 (100)

Safety analysis population

171 (99.4)

169 (98.8)

340 (99.1)

EORTC QLQ-C30 and QLQ-LC13

166 (96.5)

163 (95.3)

329 (95.9)

EQ-5D

160 (93.0)

160 (93.6)

320 (93.3)

169 (98.3)

NA

169 (49.3)

Ongoing in study at date of cutoff

PRO evaluable population

PK concentration population

ALK variant evaluable population
70 (40.7)
78 (45.6)
148 (43.1)
Abbreviations: n=number of subjects; ALK=anaplastic lymphoma kinase; EORTC=European Organization for
the Research and Treatment of Cancer; EQ-5D=EuroQol-5D; n=number of subjects; NA=not applicable;
PK=pharmacokinetic; PRO=patient-reported outcome; QLQ-C30=Quality of Life Questionnaire-Core 30;
QLQ-LC13=Quality of Life Questionnaire-Supplement Module for Lung Cancer (LC13).
a
Includes data before and after crossover to crizotinib for those subjects who crossed over to receive
crizotinib treatment.

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Protocol A8081014 – 17 September 2014 – Final

Subject demographic data is presented in Table 3. Demographic characteristics werecomparable between the 2 treatment arms in the FA population.
Table 3: Demographic Characteristics by Treatment Arm - Full Analysis Population
Crizotinib(N=172)

Chemotherapy(N=171)

Total(N=343)Male

68 (39.5)

63 (36.8)

131 (38.2)

Female104 (60.5)

108 (63.2)

212 (61.8)

50.9 (11.9)

52.9 (13.1)

51.9 (12.6)<45 years

56 (32.6)

44 (25.7)

100 (29.2)

45-<55 years

52 (30.2)

46 (26.9)

98 (28.6)

55-<65 years

41 (23.8)

49 (28.7)

90 (26.2)≥65 years

23 (13.4)

32 (18.7)

55 (16.0)

Never smoked

106 (61.6)

112 (65.5)

218 (63.6)

Ex-smoker

56 (32.6)

54 (31.6)

110 (32.1)

Smoker10 (5.8)5 (2.9)15 (4.4)

Sex, n (%)

Age, years
Mean (SD)Age category, n (%)

Smoking classification, n (%)

Abbreviations: n/N=number of subjects; SD=standard deviation

Efficacy, Pharmacokinetic, Pharmacodynamic, or Outcomes Research Results:
Primary Efficacy Endpoint
PFS based on RECIST Version 1.1 (determined by IRR)PFS based on IRR review is presented in Table 4. The required number of PFS events for the
final analysis was achieved and a data cutoff of 30 November 2013 was used. The study met
its primary objective of demonstrating that crizotinib significantly prolongs PFS compared to
first-line platinum-based chemotherapy, as assessed by IRR. The median PFS was
10.9 months for 172 subjects randomized to crizotinib and 7.0 months for 171 subjects
randomized to chemotherapy. The Hazard ratio comparing crizotinib with chemotherapy
was 0.454 (95% CI: 0.346, 0.596), with a p-value of <0.0001 (1-sided stratified log-ranktest).

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Protocol A8081014 – 17 September 2014 – Final

Table 4: Progression-Free Survival Based on Independent Radiology Review by
Treatment Arm (Stratified) - Full Analysis Population

Number with event, n (%)

Crizotinib(N=172)100 (58.1)

Chemotherapy(N=171)a137 (80.1)

Objective progression

89 (51.7)

132 (77.2)

Death without objective progression

11 (6.4)

5 (2.9)72 (41.9)

34 (19.9)02 (1.2)Given new anticancer treatment prior to tumor progression

12 (7.0)

6 (3.5)

Withdrew consent for follow-up

3 (1.7)6 (3.5)02 (1.2)

In follow-up for progression

56 (32.6)

18 (10.5)

No scans/data available

1 (<1.0)0

5.4 (4.0, 6.8)

4.0 (2.8, 5.3)

Number censored, n (%)
No on-study disease assessments

Unacceptable gap (>14 weeks) between PD or death to the mostrecent prior adequate assessment

Kaplan-Meier estimates of time to event, months
25% quartile (95% CI)bb

10.9 (8.3, 13.9)

7.0 (6.8, 8.2)

75% quartile (95% CI)bNR (15.7, NR)

10.8 (9.5, 11.2)

50% quartile (95% CI)
Versus chemotherapy
Hazard ratioc

0.454

95% CI of hazard ratio(0.346, 0.596)dp-value<0.0001
Abbreviations: CI=confidence interval; N=number of subjects; NR=not reached; PD=progressive disease.
a Only includes data before crossover to crizotinib for those subjects who crossed over to receive crizotinib
treatment.
b.Based on the Brookmeyer and Crowley method.
c Based on the Cox Proportional hazards model stratified by ECOG PS, race group, and brain metastases.
Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of
crizotinib.
d One-sided p-value from log-rank test stratified by ECOG PS, race group, and brain metastases.

Secondary Efficacy Endpoints
Overall Survival and Survival Probabilities at 1 Year and 18 Months
Analyses of the secondary efficacy endpoints supported the primary PFS outcome. At thetime of the PFS analysis, a total of 44 (25.6%) subjects in the crizotinib arm and 46 (26.9%)
subjects in the chemotherapy arm were known to have died. With only 26% of OS events atthe time of the final PFS analysis and 120 subjects randomized to chemotherapy receiving
subsequent crizotinib treatment, the median OS was not reached in either treatment arm.
There was, however, a numerical improvement in OS in the crizotinib arm (HR: 0.821; 95%
CI: 0.536, 1.255; p value=0.1804). The 1 year and 18 month survival probabilities were

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Protocol A8081014 – 17 September 2014 – Finalsimilar between the treatment arms: 84% and 69%, respectively, for crizotinib and 79% and67%, respectively, for chemotherapy (Table 5).
Table 5: Summary of Overall Survival by Treatment Arm (Stratified) - Full Analysis
Population

Number of deaths, n (%)

Crizotinib(N=172)44 (25.6)

Chemotherapy(N=171)a46 (26.9)

Number censored, n (%)

128 (74.4)

125 (73.1)

119 (69.2)

115 (67.3)

Subject no longer being followed for survival

2 (1.2)3 (1.8)

Withdrew consent for follow-up

7 (4.1)5 (2.9)02 (1.2)at Month 12 (95% CI)c

83.5 (76.7, 88.5)

78.6 (71.3, 84.2)

c68.6 (59.5, 76.1)

67.3 (58.1, 74.9)

Reason for censorship, n (%):
Subject remains in follow-up

Lost to follow-upbSurvival probability:

at Month 18 (95% CI)

Kaplan-Meier estimates of time to event, months
25% quartile (95% CI)d15.5 (12.5, 26.5)

14.9 (8.8, 23.0)

d

NR

NR

75% quartile (95% CI)dNR

NR

50% quartile (95% CI)
Versus chemotherapy
Hazard ratioe

0.821

95% CI of hazard ratio(0.536, 1.255)fp-value
0.1804Abbreviations: CI=confidence interval; N=number of subjects; NR=not reached.
aIncludes events before and after crossover to crizotinib for those subjects who crossed over to receive
crizotinib treatment.
b
Estimated from the Kaplan-Meier curve.
cCalculated using the normal approximation to the log transformed cumulative hazard rate.
dBased on the Brookmeyer and Crowley method.
eBased on the Cox Proportional hazards model stratified by ECOG PS, race group, and brain metastases.
Assuming proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of
crizotinib.
fOne-sided p-value from the log-rank test stratified by ECOG PS, race group, and brain metastases.

Objective Response Rate
The study demonstrated a statistically significant (2-sided p value <0.0001) improvement in
IRR-assessed ORR for crizotinib compared with chemotherapy, with ORRs of 74% (95% CI:
67%, 81%) in the crizotinib arm and 45% (95% CI: 37%, 53%) in the chemotherapy arm(Table 6).

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Protocol A8081014 – 17 September 2014 – Final

Table 6: Best Overall Response Based on Independent Radiology Review by Treatment
Arm - Full Analysis Population

Objective response rate (CR + PR), n (%)

Crizotinib(N=172)128 (74.4)

Chemotherapy(N=171)a77 (45.0)

95% exact CIb(67.2, 80.8)(37.4, 52.8)

Treatment comparison versus chemotherapy
Treatment difference in ORR
95% CI of difference

29.4

c

(19.5, 39.3)

dp-value<0.0001
Early death is within 6 weeks (42 days) from randomization.
Abbreviations: CI=confidence interval; ECOG=Eastern Cooperative Oncology Group; N=number of subjects;
ORR=objective response rate; PS=performance status.
a
Only includes data before crossover to crizotinib for those subjects who crossed over to receive crizotinib
treatment.
bUsing exact method based on F distribution.
c
Calculated based on a normal distribution.
dP-value is from a 2-sided Pearson chi-square test.

Time to Tumor Response
The responses on crizotinib treatment were rapid and durable with a median TTR of 6.1
weeks. In the chemotherapy arm, the median TTR was 12.1 weeks (Table 7).
Table 7: Time to Tumor Response Based on Independent Radiology Review by
Treatment Arm (Objective Responders Only) - Full Analysis Population
Crizotinib(N=172)

Chemotherapy(N=171)a128

77

8.2 (5.2)

13.2 (7.7)

6.1

12.1

Time to response, weeksnMean (SD)MedianRange
2.7-41.4
5.1-36.7
Abbreviations: n/N=number of subjects; SD=standard deviation.
aOnly includes data before crossover to crizotinib for those subjects who crossed over to receive crizotinib
treatment.

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Protocol A8081014 – 17 September 2014 – Final

Duration of Response
The median DR estimate, using the Kaplan-Meier method, was 49.0 weeks (95% CI: 35.1,
60.0 weeks) for crizotinib and 22.9 weeks (95% CI: 18.0, 25.1 weeks) for chemotherapy(Table 8).
Table 8: Duration of Response Based on Independent Radiology Review by Treatment
Arm (Objective Responders Only) - Full Analysis Population
Crizotinib(N=172)128 (74.4)

Chemotherapy(N=171)a77 (45.0)

25% quartile (95% CI)b23.1 (18.1, 26.9)

11.7 (11.3, 17.1)

b49.0 (35.1, 60.0)

22.9 (18.0, 25.1)

Subjects with objective response (CR or PR), n (%)
Kaplan-Meier estimates of duration of response, weeks
50% quartile (95% CI)

75% quartile (95% CI) b
NR (69.6, NR)
36.4 (25.4, 47.9)
Abbreviations: CI=confidence interval; N=number of subjects; NR=not reached.
aOnly includes data before crossover to crizotinib for those subjects who crossed over to receive crizotinib
treatmentbBased on the Brookmeyer and Crowley method.

Disease Control Rate
At Week 12, crizotinib had a greater DCR compared to chemotherapy: 79% (95% CI: 72%,84%) for crizotinib and 68% (95% CI: 61%, 75%) for chemotherapy, p-value=0.0381(2-sided Pearson test) (Table 9).
Table 9: Summary of Disease Control Rate at Week 12 Based on Independent
Radiology Review Assessment by Treatment Arm - Full Analysis Population

Disease Control Rate at Week 12, n (%)

Crizotinib(N=172)135 (78.5)

Chemotherapy(N=171)a117 (68.4)

95% exact CIb(71.6, 84.4)(60.9, 75.3)

Treatment Comparison (vs Chemotherapy)
Treatment Difference in DCR
95% CI of Difference

10.067c(0.8, 19.4)

dP-value
0.0381Abbreviations: CI=confidence interval; DCR=disease control rate; N=number of subjects;aOnly includes data before crossover to crizotinib for those subjects who crossed over to receive crizotinib
treatmentbUsing exact method based on F distributioncCalculated based on a normal distributiondP-value is from a 2-sided Pearson chi-square test.

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Protocol A8081014 – 17 September 2014 – FinalTime to Progression
Median TTP was 13.6 months in the crizotinib arm and 7.0 months in the chemotherapy arm.
The HR comparing crizotinib with chemotherapy was 0.441 (95% CI: 0.335, 0.582), with ap-value <0.0001 (1-sided unstratified log-rank test) (Table 10).
Table 10: Summary of Time to Progression Based on Independent Radiology Review
Assessment by Treatment Arm (Unstratified) - Full Analysis Population
Crizotinib(N=172)

Chemotherapy(N=171)aKaplan-Meier estimates of Time to Progression, months
25% quartile (95% CI)b

5.6 (5.0, 7.0)

4.2 (3.1, 5.4)

50% quartile (95% CI)b13.6 (8.5, 15.0)

7.0 (6.8, 8.3)

75% quartile (95% CI)b

NR (17.7, NR)

11.0 (9.6, 11.4)

Versus Chemotherapy
Hazard Ratioc

0.441

95% CI of Hazard Ratio(0.335, 0.582)

dP-value<0.0001
Abbreviations: CI=confidence interval; HR=hazard ratio; N=number of subjects; NR=not reached.
aOnly includes data before crossover to crizotinib for those subjects who crossed over to receive crizotinib
treatment.
bBased on the Brookmeyer and Crowley method.
cBased on the Cox proportional hazards model. Assuming proportional hazards, a HR less than 1 indicates a
reduction in hazard rate in favor of crizotinib.
dOne-sided p-value from the unstratified log-rank test.

Time to Intracranial and Extracranial Progression
Time to IC-TTP and EC-TTP are shown in Table 11and Table 12 respectively. The
improvement in TTP was observed when only extracranial lesions were evaluated; median
EC-TTP was 15.2 months in the crizotinib arm and 7.2 months in the chemotherapy arm(HR: 0.387; 95% CI: 0.286, 0.524; p-value <0.0001). Median IC-TTP was not reached in the
crizotinib arm and was 17.8 months in the chemotherapy arm. There was a numericalimprovement in IC-TTP in the crizotinib arm (HR: 0.595; 95% CI: 0.338, 1.048; 1-sided
p-value=0.0347).

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Protocol A8081014 – 17 September 2014 – Final

Table 11: Summary of Time to Intracranial Progression Based on Independent
Radiology Review Assessment by Treatment Arm (Unstratified) - Full Analysis
Population
Crizotinib(N=172)

Chemotherapy(N=171)aKaplan-Meier estimates of Time to Intracranial Progression, months
25% quartile (95% CI)b15.0 (13.6, NR)

11.2 (8.5, 17.8)

50% quartile (95% CI)bNR

17.8 (13.9, NR)

75% quartile (95% CI) b

NR

NR (17.8, NR)

Versus Chemotherapy
Hazard Ratioc

0.595

95% CI of Hazard Ratio(0.338, 1.048)dP-value
0.0347Abbreviations: CI=confidence interval; HR=hazard ratio; N=number of subjects; NR=not reached.
aOnly includes data before crossover to crizotinib for those subjects who crossed over to receive crizotinib
treatment.
bBased on the Brookmeyer and Crowley method.
cBased on the Cox proportional hazards model. Assuming proportional hazards, a HR less than 1 indicates a
reduction in hazard rate in favor of Crizotinib. A hazard ratio greater than 1 indicates a reduction in hazard
rate in favor of chemotherapy.
dOne-sided p-value from the unstratified log-rank test.

Table 12: Summary of Time to Extracranial Progression Based on Independent
Radiology Review Assessment by Treatment Arm (Unstratified) - Full
Analysis Population
Crizotinib(N=172)

Chemotherapy(N=171)aKaplan-Meier estimates of Time to Extracranial Progression, months
25% quartile (95% CI)b

6.8 (5.4, 8.3)

4.5 (4.0, 5.7)

50% quartile (95% CI)b15.2 (12.6, 21.9)

7.2 (6.9, 8.5)

75% quartile (95% CI)b

NR

11.1 (9.8, 12.4)

Versus Chemotherapy
Hazard Ratioc

0.387

95% CI of Hazard Ratio(0.286, 0.524)

dP-value<0.0001
Abbreviations: CI=confidence interval; HR=hazard ratio; N=number of subjects; NR=not reached.
aOnly includes data before crossover to crizotinib for those subjects who crossed over to receive crizotinib
treatmentbBased on the Brookmeyer and Crowley method.
cBased on the Cox proportional hazards model. Assuming proportional hazards, a HR less than 1 indicates a
reduction in hazard rate in favor of Crizotinib. A hazard ratio greater than 1 indicates a reduction in hazard
rate in favor of chemotherapy.
dOne-sided p-value from the unstratified log-rank test

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Protocol A8081014 – 17 September 2014 – Final

Patient Reported OutcomesTime to Deterioration
A statistically significantly longer TTD was observed in the crizotinib arm than in the
chemotherapy arm (2.1 months vs 0.5 months; HR: 0.615; Hochberg adjusted log-rank
2-sided p-value=0.0017) in the composite endpoint that included pain in chest, dyspnea, or
cough symptoms (Table 13).
Table 13: Time to Deterioration in Pain (in Chest), Dyspnea, or Cough by Treatment
Arm - PRO Evaluable Population
Crizotinib(N=166)

Chemotherapy(N=163)a

25% quartile (95% CI)b0.3 (0.3, 0.5)

0.3 (0.3, 0.3)

50% quartile (95% CI)

b2.1 (1.4, 4.3)

0.5 (0.4, 0.7)

75% quartile (95% CI)b

NR (11.1, NR)

3.4 (2.0, NR)

Kaplan-Meier estimates of time to event, months

Versus chemotherapy
Hazard ratioc

0.615

95% CI of hazard ratio(0.472, 0.802)dp-value
0.0004Abbreviations: CI=confidence interval; NR=not reached; N=number of subjects;aOnly includes data before crossover to crizotinib for those subjects who crossed over to receive crizotinib
treatment.
bBased on the Brookmeyer and Crowley method.
cBased on the Cox Proportional hazards model. Assuming proportional hazards, a hazard ratio less than 1
indicates a reduction in hazard rate in favor of crizotinib.
dTwo-sided p-value from the unstratified log-rank test.

EORTC QLQ C30
Overall, a statistically significantly (all 2-sided p-values <0.001) greater improvement frombaseline was observed in the crizotinib arm compared with the chemotherapy arm in global
quality of life, emotional functioning, physical functioning, role functioning, and social
functioning (Table 14).
A statistically significantly greater improvement (p-values <0.001) was observed in the
crizotinib arm compared to the chemotherapy arm in appetite loss, dyspnea, fatigue,
insomnia, and pain. Statistically significantly greater deterioration was observed in the
crizotinib arm for diarrhea (p-value <0.001). A statistically significantly greater deterioration
was observed in the chemotherapy arm compared to the crizotinib arm for nausea andvomiting (p-value <0.05) (Table 15).

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Protocol A8081014 – 17 September 2014 – Final

Table 14: Crizotinib versus Chemotherapy Overall Difference in Change From
Baselinea Scores in QLQ-C30 Domain by Treatment Arm (Mixed Model
Analysis) - PRO Evaluable Population
Value

95% CIb

p-valueb

QLQ-C30 Global QoL

13.8303(10.74,16.92)<.0001QLQ-C30 Cognitive Functioning

3.3532(0.60,6.11)

0.0170QLQ-C30 Emotional Functioning

7.5165(4.57,10.46)<.0001QLQ-C30 Physical Functioning

10.4035(7.48,13.32)<.0001QLQ-C30 Role Functioning

15.5513(11.29,19.81)<.0001QLQ-C30 Social Functioning

8.7641(4.69,12.84)<.0001

Crizotinib vs Chemotherapy Overall

Abbreviations: CI=confidence interval; QLQ-C30= Quality of Life Questionnaire-Core 30.
a
From a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time
interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose areincluded as random effects).
b
P-values and confidence intervals are not adjusted for multiplicity.

Table 15: Crizotinib versus Chemotherapy Overall Difference in Change From
Baselinea Scores in QLQ-C30 Symptoms by Treatment Arm (Mixed Model
Analysis) - PRO Evaluable Population
Value

95% CIb

p-valueb

QLQ-C30 Appetite loss

-13.4976(-18.03,-8.97)<.0001QLQ-C30 Constipation-4.4336(-9.00,0.13)

0.0570QLQ-C30 Diarrhea

12.4906(8.98,16.00)<.0001QLQ-C30 Dysponea-13.4622(-17.20,-9.73)<.0001QLQ-C30 Fatigue-14.9987(-18.52,-11.48)<.0001QLQ-C30 Financial Difficulties-0.8186(-4.56,2.92)

0.6681QLQ-C30 Insomnia-10.0430(-14.22,-5.87)<.0001QLQ-C30 Nausea and Vomiting-3.4446(-6.84,-0.05)

0.0468QLQ-C30 Pain

-9.9277(-13.23,-6.62)<.0001

Crizotinib vs Chemotherapy Overall

Abbreviations: CI=confidence interval; QLQ-C30= Quality of Life Questionnaire-Core 30.
a
From a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time
interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose areincluded as random effects).
b
P-values and confidence intervals are not adjusted for multiplicity.

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Protocol A8081014 – 17 September 2014 – Final

EORTC QLQ-LC13
A statistically significantly greater improvement observed in the crizotinib arm compared tothe chemotherapy arm for alopecia (p-value <0.05), coughing (p-value <0.001), dyspnea(p-value <0.001), pain in arm or shoulder (p-value <0.001), pain in chest (p-value <0.001),
and pain in other parts (p-value <0.001). Statistically significantly greater deterioration
observed for peripheral neuropathy (p-value <0.05) (Table 16).
Table 16: Crizotinib versus Chemotherapy Overall Difference in Change From
Baselinea Scores in QLQ-LC30 Symptoms by Treatment Arm (Mixed Model
Analysis) - PRO Evaluable Population
Value

95% CIb

p-valueb

QLQ-LC13 Alopecia-4.8149(-8.52,-1.11)

0.0108QLQ-LC13 Coughing-8.3926(-12.06,-4.72)<.0001QLQ-LC13 Dysphagia

0.6651(-1.78,3.11)

0.5938QLQ-LC13 Dyspnoea-9.0080(-11.96,-6.06)<.0001QLQ-LC13 Haemoptysis-0.8828(-1.82,0.06)

0.0656

QLQ-LC13 Pain in Arm or Shoulder-6.0475(-9.22,-2.88)

0.0002

QLQ-LC13 Pain in Chest-8.0959(-11.35,-4.84)<.0001QLQ-LC13 Pain in Other Parts-6.7717(-10.24,-3.31)

0.0001QLQ-LC13 Peripheral Neuropathy

3.3521(0.11,6.59)

0.0427

QLQ-LC13 Sore Mouth-2.1521(-5.00,0.69)

0.1382

Crizotinib vs Chemotherapy Overall

Abbreviations: CI=confidence interval; QLQ-LC30=Quality of Life Questionnaire-Supplement Module forLung Cancer (LC13).
a
From a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time
interaction, and baseline EORTC QLQ-LC30 subscale baseline score (intercept and time from first dose areincluded as random effects).
b
P-values and confidence intervals are not adjusted for multiplicity.

Pharmacokinetic Endpoint
Plasma concentrations of crizotinib (including its metabolite, PF-06260182)
Plasma concentration of crizotinib and its metabolite PF-06260182 are presented in Table 17.
The plasma concentrations of crizotinib and PF-06260182 appeared to reach the steady state
within the first cycle after repeated oral administration of crizotinib 250 mg BID. The
geometric mean predose concentrations (Ctrough) of crizotinib and its metabolites were similar
across Day 1 of Cycles 2, 3, and 5.

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Protocol A8081014 – 17 September 2014 – Final

Table 17: Predose Concentrations (Ctrough) of Crizotinib and its Metabolite,
PF-06260182, and PF-06260182 to Crizotinib Ratios Following 250 mg BID
Oral Dosing of Crizotinib
N/nCrizotinib Ctrough, ng/mLa

PF-06260182 Ctrough, ng/mLaCycle 2 Day 1

Cycle 3 Day 1

Cycle 5 Day 1

91/100

85/94

82/86

324.2 (39)320.9 (40)308.2 (39)98.4 (46)99.0 (49)92.9 (55)PF-06260182 to Crizotinib ratio
0.302 (25)0.300 (25)0.290 (25)Abbreviations: BID=twice daily; Ctrough=trough concentration; CV=coefficient of variation; n=number ofobservations for PF-06260182; N=number of observations for crizotinib and PF-06260182 to crizotinib ratio.
aGeometric mean (%CV).

Pharmacodynamic Endpoint
ALK Gene Fusion Variant Analysis
The proportion of subjects with each of the EML4-ALK fusion variants is presented in Table
18. Overall 88 subjects (59.5% of the evaluable population) were with no rearrangement,
39 (26.4%) with a V1 rearrangement, 11 (7.4%) with a V2 rearrangement, 2 (1.4%) with aV3a rearrangement and 8 (5.4%) with a V3a/b rearrangement. No V3b, V4, V5a, V6, or V7
rearrangements were observed. Among the 60 subjects with an ALK gene rearrangement,
V1, V2, and V3 rearrangements represented 65.0%, 18.3%, and 16.7% of cases, respectively.
ORR, based on IRR, within treatment arm, was comparable between the ALK variant groups.
However, the analysis is limited by the small sample size and large 95% CI.

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Protocol A8081014 – 17 September 2014 – Final

Table 18: Best Overall Response Based on Independent Radiology Review by
Treatment Arm and EML4-ALK Gene Fusion Variant - ALK Variant
Evaluable Population
Crizotinib(N=70)

EML4-ALK genefusion variantb

Chemotherapy(N=78)a

Subjects withvariant, n (%)

ORR (CR + PR)n (%)(95% CI)c

Subjects withvariant, n (%)

ORR (CR + PR)n (%)(95% CI)cV1

19 (27.1)

16 (84.2)(60.4, 96.6)

20 (25.6)

9 (45.0)(23.1, 68.5)

V2

5 (7.1)5 (100)(47.8, 100)

6 (7.7)

2 (33.3)(4.3, 77.7)

V3a

1 (1.4)0NA

1 (1.3)

1 (100)(2.5, 100)V3a/b

3 (4.3)3 (100)(29.2, 100)

5 (6.4)3 (60.0)(14.7, 94.7)

No rearrangement

42 (60.0)30 (71.4)
46 (59.0)
20 (43.5)(28.9, 58.9)(55.4, 84.3)
Abbreviations: ALK=anaplastic lymphoma kinase; CI=confidence interval; CR=complete response;
EML4=echinoderm microtubule-associated protein-like 4; n/N=number of subjects; NA=not applicable;
ORR=objective response rate; PR=partial response.
aOnly includes data before crossover to crizotinib for those subjects who crossed over to receive crizotinib
treatment.
bVariants V4, V5a, V6, and V7 were not detected.
cUsing exact method based on F distribution.

Health care resource utilization analysis
Approximately 33% of subjects had a hospital admission while on treatment in the crizotinibarm. In the chemotherapy arm, during the period of chemotherapy treatment (maximum of 6
cycles) and prior to actual crossover to receive crizotinib treatment, approximately 34% ofsubjects were hospitalized. The median length of stay was 8 days in the crizotinib arm and 9days in the chemotherapy arm (Table 19)

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Protocol A8081014 – 17 September 2014 – Final

Table 19: Hospitalizations by Treatment Arm - Full Analysis Population
Crizotinib(N=172)

Chemotherapy(N=171)a57 (33.1)

58 (33.9)

94105

11.8 (11.3)

16.4 (40.9)89Hospital admissionsb
Number (%) of subjects who had hospital admissions
Number of hospitalization eventsc
Length of stay per event, days:
Mean (SD)Median

Range
1-64
1-410
Data are based on the 'Hospitalization Status' from the Adverse Event case report form page.
Subjects can have multiple hospitalization events.
Abbreviations: N=number of subjects; SD=standard deviation.
a
The chemotherapy arm only includes data prior to crossover to crizotinib for those subjects who crossed
over to receive crizotinib treatment. For subjects who completed 6 cycles of chemotherapy without
progression and later crossed over to receive crizotinib treatment, the chemotherapy arm includes the
hospitalization events that occurred between end of chemotherapy treatment and actual crossover tocrizotinib.
b
The follow-up period for hospitalization events could vary between the treatment arms and the events are
not adjusted for duration of study treatment.
cMore than 1 hospitalization event could be associated with a single subject.

Safety Results:
This section presents treatment-emergent adverse events (all-causality AEs andtreatment-related AEs). The duration of study treatment was longer in the crizotinib arm(median 47 weeks) than in the chemotherapy arm (median 18 weeks). The AE analyses
presented below were not adjusted for the longer duration of study treatment for the
crizotinib arm compared with the chemotherapy arm.
Adverse events (AEs)
The treatment-emergent non-serious AEs reported in >=5% of subjects in any of thetreatment arm by preferred term and by system organ class (all causality andtreatment-related) are summarized in Table 20.
Overall, 168 (98.2%) subjects in the crizotinib group and 165 subjects (97.6%) subjects inthe chemotherapy group experienced all causality treatment-emergent, non-serious AEs.
Meaningfully different incidences of all-causality non-serious AEs were considered to be
those that were reported with an incidence of ≥10% of subjects in either treatment arm andhad a ≥5% absolute difference between treatment arms. All causality non-serious AEs ofvisual impairment, abdominal pain, abdominal pain upper, constipation, diarrhoea,
dyspepsia, vomiting, oedema peripheral, pyrexia, nasopharyngitis, upper respiratory tract
infection, aspartate aminotransferase increased, alanine aminotransferase increased, pain in
extremity, dizziness, dysgeusia, headache, paraesthesia, insomnia, and cough, were reportedwith a meaningfully higher frequency in the crizotinib arm than in the chemotherapy arm. All

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Public Disclosure Synopsis
Protocol A8081014 – 17 September 2014 – Finalcausality non-serious AEs of anaemia, asthenia, fatigue, neutrophil, platelet count decreased,
were reported with a meaningfully higher frequency in the chemotherapy arm than in the
crizotinib arm.
Overall, 166 (97.1%) subjects in the crizotinib group and 153 subjects (90.5%) subjects inthe chemotherapy group experienced treatment-emergent, treatment-related,
treatment-emergent, non-serious AEs. Treatment-related AEs reported by ≥30% of subjects
included visual impairment, constipation, diarrhoea, vomiting, oedema peripheral, andalanine aminotransferase increased in the crizotinib arm, and decreased appetite and fatigue
in the chemotherapy arm. Nausea reported in ≥30% of subjects in both the crizotinib andchemotherapy arms.
Table 20: Treatment-Emergent Non-Serious Adverse Events Reported in ≥5% Subjects
in Any of the Treatment Arm by System Organ Class and Preferred Term
(All Causalities and Treatment-Related) - Safety Analysis Set
System Organ Class

Crizotinib(N=171)n (%)

Preferred Term

Chemotherapy(N=169)n (%)

All
Causalities
168 (98.2)

Treatment
related166 (97.1)

All
Causalities
165 (97.6)

Treatment
related153 (90.5)

42 (24.6)

32 (18.7)

71 (42.0)

66 (39.1)

14 (8.2)5 (2.9)28 (16.4)

4 (2.3)3 (1.8)28 (16.4)

51 (30.2)
16 (9.5)
36 (21.3)

43 (25.4)
16 (9.5)
35 (20.7)

Thrombocytopenia

1 (0.6)0

14 (8.3)

13 (7.7)

Cardiac disorders

16 (9.4)

13 (7.6)

00

Bradycardia

16 (9.4)

13 (7.6)

00

Ear and labyrinth disorders

4 (2.3)2 (1.2)10 (5.9)9 (5.3)Tinnitus

4 (2.3)2 (1.2)10 (5.9)9 (5.3)Eye disorders

122 (71.3)

118 (69.0)

22 (13.0)

6 (3.6)

Conjunctivitis

3 (1.8)0

10 (5.9)0Photopsia

17 (9.9)

17 (9.9)5 (3.0)2 (1.2)

Vision blurred

13 (7.6)

12 (7.0)

5 (3.0)2 (1.2)Visual impairment

97 (56.7)

96 (56.1)

5 (3.0)3 (1.8)Vitreous floaters

11 (6.4)

11 (6.4)

1 (0.6)0

Gastrointestinal disorders

160 (93.6)

151 (88.3)

129 (76.3)

117 (69.2)

Abdominal pain

21 (12.3)

18 (10.5)

8 (4.7)5 (3.0)Abdominal pain upper

25 (14.6)

17 (9.9)

10 (5.9)5 (3.0)Constipation

74 (43.3)

55 (32.2)

50 (29.6)

33 (19.5)

Diarrhoea

104 (60.8)

97 (56.7)

21 (12.4)

14 (8.3)

Dyspepsia

23 (13.5)

15 (8.8)

4 (2.4)2 (1.2)

Any AEs
Blood and lymphatic systemdisordersAnaemia
Leukopenia
Neutropenia

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Public Disclosure Synopsis
Protocol A8081014 – 17 September 2014 – Final
System Organ Class

Crizotinib(N=171)n (%)

Preferred Term

Chemotherapy(N=169)n (%)

All
Causalities
168 (98.2)

Treatment
related166 (97.1)

All
Causalities
165 (97.6)

Treatment
related153 (90.5)

Dysphagia

17 (9.9)02 (1.2)0

Gastrooesophageal reflux disease

13 (7.6)

9 (5.3)5 (3.0)3 (1.8)

Nausea94 (55.0)

85 (49.7)

99 (58.6)

94 (55.6)

Stomatitis

11 (6.4)

11 (6.4)

17 (10.1)

16 (9.5)

Vomiting
General disorders andadministration site conditions
Asthenia

78 (45.6)

68 (39.8)

57 (33.7)

50 (29.6)

127 (74.3)

87 (50.9)109 (64.5)

85 (50.3)

22 (12.9)

14 (8.2)

41 (24.3)

34 (20.1)

Chest pain

17 (9.9)013 (7.7)

0

Fatigue

49 (28.7)

41 (24.0)

65 (38.5)

55 (32.5)

Mucosal inflammation

1 (0.6)

1 (0.6)9 (5.3)9 (5.3)

Oedema peripheral

80 (46.8)

54 (31.6)

10 (5.9)4 (2.4)Pyrexia32 (18.7)

0

17 (10.1)

0Infections and infestations

50 (29.2)

0

18 (10.7)

0Nasopharyngitis

22 (12.9)

05 (3.0)0Upper respiratory tract infection

35 (20.5)

013 (7.7)

0

Investigations
Alanine aminotransferase
increased
Aspartate aminotransferase
increased
Electrocardiogram QT prolonged

88 (51.5)

62 (36.3)

51 (30.2)

42 (24.9)

54 (31.6)

52 (30.4)

20 (11.8)

18 (10.7)

40 (23.4)

38 (22.2)

16 (9.5)

15 (8.9)

10 (5.8)03 (1.8)0

Neutrophil count decreased

8 (4.7)8 (4.7)17 (10.1)

17 (10.1)

Platelet count decreased

1 (0.6)

1 (0.6)18 (10.7)

18 (10.7)

Weight decreased

11 (6.4)0

6 (3.6)0

Weight increased

14 (8.2)04 (2.4)0White blood cell count decreased
Metabolism and nutrition
disorders
Decreased appetite

9 (5.3)9 (5.3)12 (7.1)

12 (7.1)

61 (35.7)

38 (22.2)

66 (39.1)

60 (35.5)50 (29.2)

38 (22.2)

57 (33.7)

51 (30.2)

Hypoalbuminaemia

14 (8.2)02 (1.2)0

Hypomagnesaemia
Musculoskeletal and connective
tissue disorders
Arthralgia

2 (1.2)1 (0.6)

12 (7.1)

10 (5.9)67 (39.2)

9 (5.3)46 (27.2)

0

14 (8.2)

0

11 (6.5)

0Back pain

23 (13.5)

0

21 (12.4)0Bone pain

10 (5.8)

04 (2.4)0

Any AEs

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Public Disclosure Synopsis
Protocol A8081014 – 17 September 2014 – Final
System Organ Class

Crizotinib(N=171)n (%)

Preferred Term

Chemotherapy(N=169)n (%)

All
Causalities
168 (98.2)

Treatment
related166 (97.1)

All
Causalities
165 (97.6)

Treatment
related153 (90.5)

Muscle spasms

14 (8.2)

9 (5.3)2 (1.2)0

Musculoskeletal pain

15 (8.8)07 (4.1)

0

Pain in extremity

27 (15.8)

0

12 (7.1)

0

Nervous system disorders

86 (50.3)

66 (38.6)

52 (30.8)31 (18.3)

Dizziness

27 (15.8)

19 (11.1)

15 (8.9)

7 (4.1)

Dysgeusia

45 (26.3)

41 (24.0)

9 (5.3)8 (4.7)

Headache36 (21.1)

9 (5.3)25 (14.8)

4 (2.4)

Neuropathy peripheral

2 (1.2)2 (1.2)11 (6.5)

10 (5.9)

Paraesthesia

19 (11.1)

13 (7.6)

7 (4.1)6 (3.6)

Peripheral sensory neuropathy

5 (2.9)5 (2.9)10 (5.9)9 (5.3)

Psychiatric disorders

23 (13.5)

9 (5.3)22 (13.0)

3 (1.8)

Anxiety

6 (3.5)0

9 (5.3)0Insomnia
Respiratory, thoracic andmediastinal disordersCough

19 (11.1)

9 (5.3)15 (8.9)

3 (1.8)54 (31.6)

047 (27.8)

035 (20.5)

028 (16.6)

0

Dyspnoea

23 (13.5)

023 (13.6)0Haemoptysis
Skin and subcutaneous tissue
disorders
Alopecia

10 (5.8)06 (3.6)031 (18.1)

24 (14.0)

38 (22.5)

34 (20.1)

12 (7.0)

4 (2.3)17 (10.1)

15 (8.9)

Pruritus

6 (3.5)5 (2.9)10 (5.9)9 (5.3)

Any AEsRash
18 (10.5)
16 (9.4)
19 (11.2)
18 (10.7)
Abbreviation: MedDRA=medical dictionary for regulatory activities.
The MedDRA preferred term of syncope is reported under the system organ class of cardiac disorders.
MedDRA (v16.1) coding dictionary applied.

Serious Adverse Events (SAEs)
SAEs by preferred term and by system organ class (all-causality and treatment-related) aresummarized in Table 21.
All causality SAEs were reported for 58 (33.9%) subjects in crizotinib arm and 47 (27.8%)
subjects in chemotherapy arm. Most commonly reported all causality SAEs (≥2% of subjects
in either treatment arm) were vomiting (1.2% in crizotinib and 2.4% in chemotherapy),
disease progression (8.8% in crizotinib and 0.6% in chemotherapy), dyspnea (4.1% in
crizotinib and 2.4% in chemotherapy), pleural effusion (1.2% in crizotinib and 3.0% inPage 30

Public Disclosure Synopsis
Protocol A8081014 – 17 September 2014 – Finalchemotherapy) and pulmonary embolism (2.1% in crizotinib and 4.1% in chemotherapy), andconvulsion (0% in crizotinib, 3.0% in chemotherapy).
Treatment-related SAEs were reported for 18 (10.5%) subjects in crizotinib arm and 15(8.9%) subjects in chemotherapy arm. Most commonly reported (≥1% of subjects in either
treatment arm) treatment-related SAEs were febrile neutropenia (none in crizotinib and 1.2%
in chemotherapy), diarrhoea (1.2% in crizotinib and 0.6% in chemotherapy), nausea (1.8% in
crizotinib and 0.6% in chemotherapy), oesophagitis (1.8% in crizotinib and none inchemotherapy), vomiting (1.2% in crizotinib and 2.4% in chemotherapy), general physicalhealth deterioration (none in crizotinib and 1.2% in chemotherapy), pyrexia (0.6% in
crizotinib and 1.2% in chemotherapy), dehydration (none in crizotinib and 1.2% inchemotherapy), renal cyst (1.2% in crizotinib and none in chemotherapy), pulmonary
embolism ( none in crizotinib and 1.2% in chemotherapy).
Table 21: Treatment-Emergent Serious Adverse Events Reported in Subjects by System
Organ Class and Preferred Term (All Causalities and Treatment-Related) Safety Analysis Set
System Organ Class

Crizotinib(N=171)n (%)

Preferred Term

Chemotherapy(N=169)n (%)

All
Causalities
58 (33.9)

Treatment
related18 (10.5)

All
Causalities
47 (27.8)

Treatment
related15 (8.9)00

3 (1.8)3 (1.8)0000

1 (0.6)2 (1.2)1 (0.6)2 (1.2)

Cardiac disorders

4 (2.3)0

7 (4.1)2 (1.2)Atrial fibrillation

1 (0.6)0

1 (0.6)0

Atrioventricular block

1 (0.6)

0

0

0

0

0

1 (0.6)0

2 (1.2)000Cardiotoxicity

00

1 (0.6)

1 (0.6)

Pericardial effusion00

1 (0.6)0

Pericarditis

00

1 (0.6)0

Syncope002 (1.2)1 (0.6)

Gastrointestinal disorders

11 (6.4)

9 (5.3)7 (4.1)6 (3.6)

Abdominal pain

1 (0.6)

1 (0.6)00Constipation00

1 (0.6)

1 (0.6)

Diarrhoea

2 (1.2)2 (1.2)1 (0.6)

1 (0.6)Dysphagia

00

1 (0.6)0

Haemorrhoids

1 (0.6)000Intestinal obstruction

2 (1.2)1 (0.6)00

Any AEs
Blood and lymphatic systemdisordersAnaemia
Febrile neutropenia

Cardiac arrest
Cardiac tamponade

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Public Disclosure Synopsis
Protocol A8081014 – 17 September 2014 – Final
System Organ Class

Crizotinib(N=171)n (%)

Preferred Term

Chemotherapy(N=169)n (%)

Any AEsAll
Causalities
58 (33.9)

Treatment
related18 (10.5)

All
Causalities
47 (27.8)

Treatment
related15 (8.9)

Nausea3 (1.8)3 (1.8)1 (0.6)

1 (0.6)

Oesophageal ulcer

1 (0.6)

1 (0.6)00

Oesophagitis

3 (1.8)3 (1.8)00Vomiting
General disorders andadministration site conditions
Chest pain

2 (1.2)2 (1.2)4 (2.4)4 (2.4)17 (9.9)

2 (1.2)5 (3.0)3 (1.8)00

1 (0.6)0Disease progression

15 (8.8)

01 (0.6)0

Fatigue
General physical healthdeterioration
Oedema peripheral

1 (0.6)

1 (0.6)000

2 (1.2)2 (1.2)1 (0.6)000

Pyrexia

1 (0.6)

1 (0.6)2 (1.2)2 (1.2)

Hepatobiliary disorders

2 (1.2)1 (0.6)2 (1.2)0

Bile duct obstruction00

1 (0.6)0

1 (0.6)

0

0

0

0

0

1 (0.6)0

Drug-induced liver injury

1 (0.6)

1 (0.6)00

Infections and infestations

15 (8.8)

1 (0.6)3 (1.8)0Abdominal abscess

1 (0.6)

1 (0.6)00Bronchitis

00

1 (0.6)0

Cellulitis

2 (1.2)0

0

0

Hepatitis B

1 (0.6)0

0

0

Lower respiratory tract infection

2 (1.2)000Lung infection

1 (0.6)000Periodontitis

1 (0.6)00

0Pneumonia

3 (1.8)0

1 (0.6)0

Pulmonary sepsis

1 (0.6)0

00

Respiratory tract infection

1 (0.6)0

1 (0.6)0

Sepsis1 (0.6)000

Septic shock

2 (1.2)000Upper respiratory tract infection

1 (0.6)000Urinary tract infection
Injury, poisoning and procedural
complications
Overdose

1 (0.6)

0

0

0

0

0

2 (1.2)000

1 (0.6)0Cholecystitis
Cholecystitis acutePage 32

Public Disclosure Synopsis
Protocol A8081014 – 17 September 2014 – Final
System Organ Class

Crizotinib(N=171)n (%)

Preferred Term

Chemotherapy(N=169)n (%)

All
Causalities
58 (33.9)

Treatment
related18 (10.5)

All
Causalities
47 (27.8)

Treatment
related15 (8.9)00

1 (0.6)0

1 (0.6)

1 (0.6)00

1 (0.6)

1 (0.6)00

1 (0.6)

1 (0.6)00

4 (2.3)2 (1.2)3 (1.8)3 (1.8)2 (1.2)1 (0.6)

0

0

0

0

2 (1.2)2 (1.2)Diabetic ketoacidosis

1 (0.6)0

0

0

Hypokalaemia

1 (0.6)0

0

0

Hyponatraemia

1 (0.6)

1 (0.6)

1 (0.6)

1 (0.6)

Hypoproteinaemia
Musculoskeletal and connective
tissue disorders
Arthritis

1 (0.6)0

1 (0.6)0

4 (2.3)0

2 (1.2)0

1 (0.6)000Bone pain

1 (0.6)

0

0

0

0

0

1 (0.6)0Muscular weakness

1 (0.6)000Osteonecrosis

1 (0.6)000Rotator cuff syndrome00

1 (0.6)0Spinal column stenosis

1 (0.6)0

0

0

Nervous system disorders

6 (3.5)1 (0.6)7 (4.1)1 (0.6)

Altered state of consciousness

1 (0.6)0

0

0Central nervous system lesion

1 (0.6)000Convulsion00

5 (3.0)1 (0.6)

Headache2 (1.2)1 (0.6)0

0

Loss of consciousness

1 (0.6)000Multiple sclerosis

1 (0.6)000Partial seizures00

1 (0.6)

0Transient ischaemic attack00

1 (0.6)0

Psychiatric disorders

1 (0.6)0

1 (0.6)0Completed suicide00

1 (0.6)0

Hypomania

1 (0.6)000Renal and urinary disorders

3 (1.8)2 (1.2)2 (1.2)1 (0.6)00

1 (0.6)0

Any AEs
Rib fracture
Investigations
Alanine aminotransferase
increased
Aspartate aminotransferase
increased
Metabolism and nutrition
disorders
Decreased appetite
Dehydration

Muscle spasms

Haematuria

Page 33

Public Disclosure Synopsis
Protocol A8081014 – 17 September 2014 – Final
System Organ Class

Crizotinib(N=171)n (%)

Preferred Term

Chemotherapy(N=169)n (%)

All
Causalities
58 (33.9)

Treatment
related18 (10.5)

All
Causalities
47 (27.8)

Treatment
related15 (8.9)

2 (1.2)2 (1.2)

0

0

0

0

1 (0.6)

1 (0.6)

1 (0.6)000

16 (9.4)

3 (1.8)19 (11.2)

2 (1.2)1 (0.6)000Asthma00

1 (0.6)0

Dyspnoea

7 (4.1)1 (0.6)4 (2.4)0

Haemoptysis

00

2 (1.2)0

Hydropneumothorax

00

1 (0.6)0Interstitial lung disease

1 (0.6)

1 (0.6)00Lung infiltration00

1 (0.6)0Pleural effusion

2 (1.2)05 (3.0)000

1 (0.6)0

Pneumonitis

1 (0.6)

1 (0.6)00

Pulmonary embolism

5 (2.9)0

7 (4.1)2 (1.2)

Pulmonary oedema

00

1 (0.6)0

Vascular disorders

2 (1.2)0

1 (0.6)0

Deep vein thrombosis

1 (0.6)0

1 (0.6)0

Any AEs
Renal cyst
Renal failure acute
Urinary retention
Respiratory, thoracic andmediastinal disorders
Acute respiratory failure

Pleurisy

Orthostatic hypotension
1 (0.6)000Abbreviation: MedDRA=medical dictionary for regulatory activities.
The MedDRA preferred term of syncope is reported under the system organ class of cardiac disorders.
MedDRA (v16.1) coding dictionary applied.

Permanent discontinuations due to AEs
All withdrawals due to AEs regardless of causality by system organ class and preferred terms
are summarized in Table 22. Permanent discontinuations from study treatment were similar
between the 2 treatment arms; 21 (12.3%) subjects in the crizotinib arm and 24 (14.2%)
subjects in the chemotherapy arm.

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Public Disclosure Synopsis
Protocol A8081014 – 17 September 2014 – Final

Table 22: Treatment-Emergent All Causality Adverse Events Associated With
Permanent Discontinuation From Treatment by Treatment Arm - Safety
Analysis Population
System Organ Class
Preferred Term

Crizotinib(N=171)n (%)
21 (12.3)

Chemotherapy(N=169)an (%)
24 (14.2)

01 (0.6)0

1 (0.6)0

3 (1.8)

Cardiac arrest

0

1 (0.6)

Cardiotoxicity

0

1 (0.6)0

1 (0.6)2 (1.2)2 (1.2)0

1 (0.6)

Intestinal obstruction

1 (0.6)0

Nausea1 (0.6)00

1 (0.6)7 (4.1)3 (1.8)

Disease progression

7 (4.1)1 (0.6)

Fatigue
Hepatobiliary disorders0

2 (1.2)2 (1.2)1 (0.6)

Bile duct obstruction0

1 (0.6)

Drug-induced liver injury

1 (0.6)0

Hepatocellular injury
Infections and infestations

1 (0.6)0

2 (1.2)0

1 (0.6)0

1 (0.6)0

2 (1.2)5 (3.0)2 (1.2)1 (0.6)0

2 (1.2)

Platelet count decreased
Musculoskeletal and connective tissue disorders0

2 (1.2)0

1 (0.6)Arthralgia
Metabolism and nutrition disorders01 (0.6)

1 (0.6)0

Diabetic ketoacidosis
Psychiatric disorders

1 (0.6)00

2 (1.2)Completed suicide0

1 (0.6)0

1 (0.6)

1 (0.6)2 (1.2)Azotaemia01 (0.6)

Renal cyst

1 (0.6)0

Any AE associated with permanent treatment discontinuation;
Blood and lymphatic system disorders
Febrile neutropenia
Cardiac disorders

Syncope
Gastrointestinal disorders
Abdominal pain

Vomiting
General disorders and administration site conditions

Pulmonary sepsis
Septic shock
Investigations
Alanine aminotransferase increased
Blood creatinine increased

Depression
Renal and urinary disorders

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Public Disclosure Synopsis
Protocol A8081014 – 17 September 2014 – Final
System Organ Class
Preferred Term
Renal failure acuteRespiratory, thoracic and mediastinal disorders
Acute respiratory failure
Dyspnoea
Haemoptysis

Crizotinib(N=171)n (%)
0

Chemotherapy(N=169)an (%)
1 (0.6)4 (2.3)4 (2.4)1 (0.6)00

1 (0.6)0

1 (0.6)

Interstitial lung disease

1 (0.6)0Pleural effusion

1 (0.6)0

Pneumonitis

1 (0.6)00

2 (1.2)

Pulmonary embolism
Abbreviation: MedDRA=medical dictionary for regulatory activities.
MedDRA (v16.1) coding dictionary applied.

Deaths:Grade 5 all-causality AEs were reported for 20 (11.7%) subjects in the crizotinib arm and4 (2.4%) subjects in the chemotherapy arm (before crossover). The most commonly reported
Grade 5 all-causality AE in the crizotinib arm was Disease progression (16 [9.4%] subjects).
No Grade 5 all-causality AEs in the crizotinib arm or in the chemotherapy arm (while on
chemotherapy) were considered to be treatment-related (Table 23).

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Public Disclosure Synopsis
Protocol A8081014 – 17 September 2014 – Final

Table 23: Treatment-Emergent Adverse Events Associated With Death on Study(Grade 5) by Treatment Arm - All-Causality and Treatment-Related (All
Cycles) - Safety Analysis Population
MedDRA Preferred Term

Any Grade 5 AE:

Crizotinib
Chemotherapy(N=171)(N=169)aAll-Causality Treatment- All-Causality TreatmentRelated
Related
n (%)
n (%)
n (%)
n (%)
20 (11.7)
04 (2.4)0Disease progression

16 (9.4)b0

1 (0.6)0

Septic shock

2 (1.2)00

0Acute respiratory failure

1 (0.6)000

Diabetic ketoacidosis

1 (0.6)000

Cardiac arrest

0

0

1 (0.6)0Completed suicide00

1 (0.6)0

Haemoptysis
00
1 (0.6)0
MedDRA Version 16.1 coding dictionary applied.
Abbreviations: AE=adverse event; MedDRA=Medical Dictionary for Regulatory Activities; n/N=number ofsubjects.
a
Only includes data before crossover to crizotinib for those subjects who crossed over to receive crizotinib
treatment.
b
Two subjects are included although the Grade 5 events of Disease progression occurred >28 days after thelast dose of crizotinib (29 days and 185 days, respectively).

Clinical laboratory and other safety evaluations
Abnormal values in the clinical laboratory data that the investigator determined to beclinically significant were reported as AEs that were summarized in previous sections. Other
safety parameters (blood pressure, ECGs, and MUGA scans/Echocardiograms, andophthalmologic evaluations) did not reveal any new safety concerns. Due to the low numberof subjects with results for DXA analysis and hypogonadism laboratory parameters, no clear
conclusion can be made.
CONCLUSIONS:Crizotinib treatment resulted in a statistically significant, robust, and clinicallymeaningful improvement in IRR-assessed PFS as compared with platinum-based
chemotherapy in the treatment of subjects with previously untreated ALK-positive,
advanced non-squamous NSCLC (median PFS 10.9 months vs 7.0 months; HR: 0.454;
1-sided p-value <0.0001).
 Crizotinib treatment resulted in a clinically and statistically significant improvement in
IRR-assessed ORR compared with chemotherapy (74% vs 45%; 2-sided
p-value <0.0001), with objective responses that were rapid in onset (median TTR
6 weeks) and durable (median DR estimate 49.0 weeks).

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Public Disclosure Synopsis
Protocol A8081014 – 17 September 2014 – Final









Crizotinib treatment resulted in a clinically and statistically significant improvement in
TTP compared with chemotherapy (median 13.6 months vs 7.0 months; HR: 0.441;
1-sided p-value <0.0001). This improvement in TTP was also observed when only
extracranial lesions were evaluated (HR: 0.387; 1-sided p-value <0.0001). There was a
numerical improvement in IC-TTP in the crizotinib arm (HR: 0.595; 1-sided
p-value=0.0347).
With only 26% of OS events, median OS was not reached in either treatment arm. There
was a numerical improvement in OS in the crizotinib arm (HR: 0.821; 1-sided
p-value=0.1804). The 1-year and 18-month survival probabilities were similar between
the treatment arms; for crizotinib they were 84% and 69%, respectively, and forchemotherapy they were 79% and 67%, respectively. These OS analyses were notadjusted for the potentially confounding effects of crossover, as 120 chemotherapy
subjects (70.2%) received subsequent crizotinib treatment.
Crizotinib had a distinct side effect profile that was generally tolerable and manageable
by dosing interruption, dose reduction, and/or standard medical therapy.
Crizotinib treatment significantly delayed TTD in the composite endpoint of lung cancer
symptoms that included pain in chest, cough, or dyspnea (HR: 0.615; 2-sided
p-value=0.0017).
Crizotinib treatment resulted in statistically significantly (2-sided p-value<0.05) greater
overall improvement from baseline in patient-reported key lung cancer symptoms ofcoughing, dyspnea, and pain in chest, physical functioning, global quality of life, andgeneral health status as compared with the chemotherapy arm.

Page 38

Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – 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 AND/OR COMPOUND NUMBER: Crizotinib(PF-02341066)
PROTOCOL NO.: A8081014
PROTOCOL TITLE: Phase 3, Randomized, Open-Label Study of the Efficacy and Safetyof Crizotinib Versus Pemetrexed/Cisplatin or Pemetrexed/Carboplatin in Previously
Untreated Patients With Non-Squamous Carcinoma of the Lung Harboring a Translocation
or Inversion Event Involving the Anaplastic Lymphoma Kinase (ALK) Gene Locus
Study Centers: This was a multicenter study conducted at 101 centers in 27 countries:
Australia and France (6 centers), Belgium, Canada, Germany, Republic of Korea, Singapore
and Switzerland (3 centers each), Brazil, Hong Kong, Russian Federation, Taiwan andUnited Kingdom (UK) (2 centers each), China (7 centers), Italy (12 centers), Japan(11 centers), Spain (9 centers), Finland, Ireland, Luxembourg, Mexico, Netherlands, Norway,
Portugal, South Africa and Ukraine (1 center each) and United States (US; 13 centers). An
additional 70 centers received study drug, but did not randomize patients.
Study Initiation, Date and Primary Completion and Final Completion Dates:
Study Initiation Date: 13 January 2011
Primary Completion Date: 30 November 2013
Study Completion Date: 30 November 2016
Phase of Development: Phase 3
Study Objectives:
Primary objectives:•

To demonstrate that crizotinib (Arm A) was superior to first-line chemotherapy,
pemetrexed/cisplatin or pemetrexed/carboplatin (Arm B), in prolonging progressionfree survival (PFS) in patients with advanced non-squamous non-small cell lungcancer (NSCLC) whose tumors harbor a translocation or inversion event involving
the anaplastic lymphoma kinase (ALK) gene locus.

Secondary objectives:•

To compare secondary measures of clinical efficacy including objective response rate(ORR), overall survival (OS), disease control rate (DCR) at 12 weeks, and time tooverall progression (TTP), time to intracranial progression (IC-TTP), time to
extracranial progression (EC-TTP) between the 2 treatment arms and to evaluate OS
at 1 year and 18 months, duration of response (DR), and time to tumor response(TTR).
1

Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Final•

To evaluate the safety and tolerability of crizotinib compared to chemotherapy(pemetrexed/cisplatin or pemetrexed/carboplatin).

•

To evaluate pharmacokinetics (PK) of crizotinib (including its active moieties, if
appropriate) in this patient population using population PK (POPPK) methods andexplore correlations between PK, response and/or safety findings, Arm A only.

•

To correlate anaplastic lymphoma kinase (ALK) gene fusion variants to outcome
measures.

•

To compare patient-reported outcome (PRO) of health-related quality of life,
disease/treatment-related symptoms of lung cancer, and general health status in both
treatment arms.

•

To assess health care resource utilization (HCRU) with respect to hospitalization (ie,length of stay, frequency) and concomitant medication use for select adverse events(AEs) (eg, hematologic events).

METHODS
Study Design:This was an open-label, multicenter, randomized, Phase 3, efficacy and safety study ofcrizotinib vs first-line chemotherapy, ie, pemetrexed/cisplatin or pemetrexed/carboplatin, inpatients with ALK-positive, non-squamous NSCLC. The Vysis ALK Break Apart
fluorescence in-situ hybridization (FISH) test was used to determine ALK positivity.
A total of 334 patients were planned to be randomized in a 1:1 ratio to receive crizotinib or
chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin). In the chemotherapy arm,the choice of platinum-doublet chemotherapy was made by the investigator.
Each treatment cycle was defined as 3 weeks (21 days). The sample size was calculated
based on the primary endpoint of PFS.
Randomization was stratified by Eastern Cooperative Oncology Group (ECOG) performancestatus (PS) (0-1 or 2), race group (Asian or non-Asian), and brain metastases (presence orabsence).
Patient were to continue in the assigned treatment arm until Response Evaluation Criteria in
Solid Tumors (RECIST; Version 1.1)-defined progressive disease (PD) as determined byindependent radiology review (IRR), unacceptable toxicity, death, or consent withdrawal.
In the crizotinib arm, patients could continue crizotinib treatment beyond the time of
RECIST-defined PD, as determined by IRR, at the discretion of the investigator if the patient
was perceived to be experiencing clinical benefit.
In the chemotherapy arm, patients could be dosed for up to 6 cycles of chemotherapy as longas they met the chemotherapy retreatment criteria. If a patient completed the 6 cycles ofchemotherapy, he/she remained in the study with no additional treatment (ie, maintenance2

Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Finaltherapy was not permitted) and with ongoing tumor assessments until RECIST-defined PD,
as determined by IRR.
Once patients in the chemotherapy arm had RECIST-defined PD, as determined by IRR, they
were allowed to cross over to receive crizotinib treatment provided they met the safety
screening inclusion/exclusion criteria for crizotinib (eg, laboratory parameters and ECG
readings).
The complete schedule of activities is shown in Table 1. After amendment 9, Table 1 applied
to patients in the chemotherapy arm, until PD was confirmed by IRR and patients whocrossed over from chemotherapy arm for the first 10 cycles of crizotinib treatment. A
reduced schedule of events for patients in the crizotinib arm and patients who crossed overfrom chemotherapy arm after 10 cycles of crizotinib treatment is shown in Table 2.
In the chemotherapy arm, for patients who did not cross over to crizotinib after PD was
confirmed by IRR, only information on survival status was required.

3

Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Final

Table 1.

Schedule of Activities:
Protocol Activities

Screeninga

Study Treatmentb

End of Treatment

Cycle 1
Cycles ≥2≤28 Days Prior Day 1 (±2)c Day 7 Day 15 Day 1 (±2; ±7 for Imaging)
to Dosing(±1) (±2)
Baseline Documentation
Informed consente
Medical/oncological historyf
Baseline signs/symptoms
Mandatory tumor tissue for molecular profilingg
Optional tumor tissue for molecular profiling(Arm A and crossover)hPhysical examinationi
ECOG performance status

Ophthalmologic examinationj

End ofTreatment/
Withdrawald

Post
Treatment
Follow-Up

X
X
X
X
X
X
X

(X)
X

X
X
Cycle 5 and every 4 cycles
thereafter - France only;
End of every cycle – India
only;
All patients – anytime there
was a change in CTCAE grade

X (Koreaonly); allpatients asclinicallyindicated
(X)
(X)
(X)
X in triplicate
X
X predose

X (Korea only); all patients asclinically indicated

X

X
X

Laboratory studies
Urinalysis -– protein/blood by dipstick (allpatients); reflex microscopy if dipstick positive(all patients)k
Hematologyl
Blood chemistryl
Coagulationl
12-lead ECGm
Contraceptive check (as applicable)nPregnancy test (female patients)o

X

X
X
X
X single
XX

4

X (Korea only)

X
X

X
X

X
X

X (Cycles 2, 3) in triplicate
X
X

X
X

X

Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Final

Screeninga

Protocol Activities

Study Treatmentb

Cycle 1
Cycles ≥2≤28 Days Prior Day 1 (±2)c Day 7 Day 15 Day 1 (±2; ±7 for Imaging)
to Dosing(±1) (±2)

End of Treatment
End ofTreatment/
Withdrawald

Post
Treatment
Follow-Up

X

X

X
X
X
X

X
X

Disease Assessments
Tumor assessments (including scans)p

Other clinical assessments
Adverse events and hospitalizationsq
Concomitant medications/treatmentsr
EORTC QLQ-C30 and QLQ-LC13s
VSAQ-ALK and EQ-5Dt
MUGA scan or echocardiogramu
Survival follow-upv
Study treatment
Study randomization

Vitamin premedication
Crizotinib (Arm A and crossover)Cisplatin and pemetrexed (Arm B option)
Carboplatin and pemetrexed (Arm B option)
Special laboratory studies
Pharmacokinetics (Arm A only)w
Optional blood sample for pharmacogenomics(crizotinib-treated patients only)x
Hypogonadism laboratory testsy(males on crizotinib [Arm A and those crossing
over from Arm B])
Hypogonadism laboratory testsy(males on chemotherapy [Arm B])

X (every 6±1 week; every
12±1 week for crossover or
crizotinib past progression
patients)

X

X
X

X
X
X
X

X

X
X
X

X

X
X
X
X
Cycle 3, then every 4 cycles

X
X (Day -7 to
Day 0)
X(commencing
Day -7 until
end of Cycle 6)Once or twice daily
X (6 cycle maximum)X (6 cycle maximum)

X
X
X

X (Cycles 2, 3, 5)

X
X

X

X

X

5

X (Cycle 2 Day 1, Cycle 5
Day 1, Cycle 7 Day 1,
and every 4 cycles thereafter)
X (Cycle 2 Day 1, Cycle 5
Day 1)

X
X

Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Final

Protocol Activities

Screeninga

Study Treatmentb

Cycle 1
Cycles ≥2≤28 Days Prior Day 1 (±2)c Day 7 Day 15 Day 1 (±2; ±7 for Imaging)
to Dosing(±1) (±2)
DXA scanz(males on crizotinib [Arm A and those crossing
over from Arm B])
DXA scanz(males on chemotherapy [Arm B])

X (Cycle 7 Day 1)zX

End of Treatment
End ofTreatment/
Withdrawald

Post
Treatment
Follow-Up

X (see footnotez
for details)
Xz

X

Abbreviations: AE=adverse event; ALK=anaplastic lymphoma kinase; ALT=alanine transaminase; Arm A=crizotinib arm; Arm B=chemotherapy arm; AST=aspartatetransaminase; CT=computed tomography; CTCAE=Common Terminology Criteria for Adverse Events; DNA=deoxyribonucleic acid; DXA=dual energy X-ray absorptiometry;
EC=Ethics Committee; EORTC=European Organization for the Research and Treatment of Cancer; EQ-5D=EuroQol-5D; FISH=fluorescence in-situ hybridization;
ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; IRB=Institutional Review Board; K2EDTA=dipotassium ethylenediamine tetraacetic acid;
MRI=magnetic resonance imaging; MUGA=multiple gated acquisition; NCI=National Cancer Institute; PD=progressive disease; PK=pharmacokinetic; QLQ-C30=Quality ofLife Questionnaire-Core 30; QLQ-LC13=Quality of Life Questionnaire-Supplement Module for Lung Cancer (LC13); QTc=corrected QT interval; RECIST=Response
Evaluation Criteria in Solid Tumors; ULN=upper limit of normal; VSAQ-ALK=Visual Symptom Assessment Questionnaire-ALK
a Screening: For Arm B patients who crossed over to receive crizotinib treatment, screening laboratory tests were ideally performed within the previous 5 days, whereas thephysical examination, ECOG performance status, and pregnancy test did not need to be repeated if these were performed within 21 days of the previous evaluation.
Screening ECG was repeated. The results of these tests had to meet eligibility criteria in order for the patient to receive crossover crizotinib treatment. Screening
ophthalmology examination and mandatory tumor tissue for molecular profiling did not need to be repeated.
b Study Treatment: All assessments were performed prior to dosing with study treatment unless otherwise indicated. Every effort was made to start study treatment within
2 days of randomization to ensure comparability of the 2 treatment arms and the time of treatment start after randomization. Acceptable time windows for performing each
assessment were described in the column headings. All cycles were 21 days in duration. Once the primary endpoint (progression-free survival) for the study had beensummarized and reported in the final clinical study report, ongoing patients in Arm A or those patients who crossed over to receive crizotinib treatment only needed to visit
the study site every other cycle for study assessments instead of every cycle. Hematology and blood chemistry tests were still required in the non-visit cycleie, approximately 3 weeks after previous laboratory testing, but could be done locally. Enough study treatment for 2 cycles of treatment was to be dispensed at each site
visit. During the non-visit cycle, the investigator was responsible for ensuring the patients contacted the study site to provide an update of adverse events and concomitant
medications and to provide results of the local laboratory tests.
c Cycle 1/Day 1: Blood chemistry, hematology, coagulation, and physical examination were not required if an acceptable screening assessment was performed within 7 days
prior to the start 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 diseaseassessments). The end of treatment visit was usually scheduled for 28 days post last dose of study treatment or when the decision was taken to provide alternative
anticancer therapy, whichever was sooner. For male patients only: all attempts were made to obtain the blood sample for hypogonadism assessment and DXA scan for bonemineral density and muscle mass assessment at least 4 weeks after the last dose of study treatment if possible and prior to the commencement of new anticancer therapy.
e Informed Consent: Had to be obtained prior to undergoing any study-specific procedure.
f Medical/Oncological History: To include information on smoking history, prior regimens, and tumor marker status.
g Mandatory Tumor Tissue for Molecular Profiling: Paraffin block(s) were of adequate size to allow, if possible, at least 10 slides with cuts that were 5 microns thick. If
no block was available, then the sites were to try to obtain at least 10 slides with cuts that were 5 microns thick. Archived or fresh tumor samples obtained according to theinstitutional practice for biopsy were acceptable. These samples were used for the assessment of ALK gene fusion by FISH by the central laboratory. Tumor samples thatwere sent directly to the central laboratory for testing could also be tested by FISH by a secondary laboratory for concordance. Tumor samples could also be used for6

Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Finalanalysis of the presence of ALK protein and ALK fusion transcripts. The mandatory tumor tissue sample could be completed outside the 28-day screening window.
Optional Tumor Tissue for Molecular Profiling (Arm A and crossover): An optional fresh tumor sample was collected at the end of treatment if a patient discontinued
due to PD. This included patients who crossed over from Arm B to crizotinib.
i Physical Examination: Included an examination of major body systems (at screening and on Day 1 of each cycle), height (at screening only), body weight, blood pressure,and pulse rate (on Day 1 of each cycle).
j Ophthalmologic Examination: Included visual acuity, fundoscopy, and slit lamp, and was performed by an ophthalmologist. The ophthalmologic examination was
repeated during the study when visual disturbances had been observed, when there had been a reported change in CTCAE grade, or as clinically indicated. For all patientsenrolled in France, ophthalmology examinations were performed after the completion of every 4 cycles. For all patients enrolled in India, ophthalmology examinations
were performed after the completion of every cycle.
k Dipstick Urinalysis and Reflex Microscopy: In Korea (after Protocol Amendment 4), repeat examinations were completed at Day 1 of every cycle and at the end oftreatment; all other countries were to perform examinations as clinically indicated, eg, upon diagnosis of renal cysts. Reflex microscopy was required if urine dipstick was
positive for blood or protein.
l Hematology, Blood Chemistry, and Coagulation: For patients on crizotinib treatment: 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 to be repeated every 48-72 hours until ALT/AST Grade ≤1. A 4-mL serum sample obtained
just prior to the first dose of study medication was stored frozen on site through completion of the study for possible use as a baseline reference should additional laboratory
tests be indicated for example additional testing to exclude other causes for liver injury.
m 12-lead ECG: All patients were required to have a single ECG measurement at screening. Triplicate ECG measurements (approximately 2 minutes apart) were measured at
all later time points with all 3 measurements obtained within a 10-minute time window for each time point. ECGs were performed immediately before PK blood draws at
respective time points. Additional triplicate ECG measurements were required in all patients randomized to Arm A. ECGs were obtained at 0 hour (predose) on Day 1 ofCycles 1, 2, and 3. Subsequent ECGs were taken at 3 and 5 hours after morning crizotinib dosing on Day 1 of Cycles 1, 2, and 3. All ECG tracings were sent electronicallyto a core ECG laboratory for blinded manual interval measurements. For Arm B patients and patients crossing over to crizotinib from Arm B (triplicate ECG assessments),
ECGs were obtained at 0 hour (prior to the start of dosing) on Day 1 of Cycles 1, 2, and 3. For all patients, if the QTc was prolonged (>500 msec), then the ECG was readby a cardiologist at the site for confirmation (to look for spurious QT effects). Additional ECGs were performed as clinically indicated.
n Contraceptive Check: Male and female patients of childbearing potential and at risk for pregnancy had to agree to use 2 highly effective methods of contraception
throughout the study and for at least 90 days after the last dose of crizotinib. Male patients randomized to Arm B were used a highly effective method of contraception
for 180 days after the last dose of pemetrexed.
o Pregnancy Test: All female patients of childbearing potential were required to have a negative pregnancy test at screening. The test was repeated whenever 1 menstrual
cycle was missed during treatment or a potential pregnancy was otherwise suspected, and again at end of treatment. Pregnancy tests could also be repeated at the request of
IRB/ECs or if required by local regulations. Pregnancy tests were routinely repeated at every treatment cycle, at the end of treatment, and additionally whenever
1 menstrual cycle was missed or when potential pregnancy was otherwise suspected. In the case of a positive confirmed pregnancy, the patient was withdrawn from study
medication but could remain in the study. Additional pregnancy tests could also have been undertaken if requested by IRBs/ECs or if required by local regulations.
p Tumor Assessments: CT or MRI was to include chest, abdomen, and pelvis (CAP) at all time points. Bone scintigraphy/bone scans and brain scans/head CT/MRI werealso required at screening. All subsequent scans were based on a calendar schedule beginning from the date of randomization. The first post-randomization scan was
performed at 6 weeks (+1 week); all subsequent scans could be performed at 6 weeks (±1 week). The brain was included in subsequent tumor assessments if a patient hadbrain metastases; otherwise, the brain was evaluated every 12 weeks. Bone metastases, if present at baseline, were followed on study by separate CT/MRI/scan or X-ray
every 6 weeks if the metastases were outside the CAP field of imaging. In all patients, repeat bone scintigraphy/bone scans were required every 12 weeks to monitor for
new lesions. A CT or MRI scan was also performed whenever PD was suspected (eg, symptomatic deterioration). All scans were sent to an independent radiology
laboratory for a blinded RECIST review. Tumor assessments were to continue until PD had been determined by the independent radiologist, which included those patients
who had stopped treatment for reasons other than PD but remained on study. Crossover patients and patients continuing crizotinib therapy after independent radiology
review had declared PD were to continue to have tumor assessments; however, these no longer required central independent radiology review. The tumor assessments after
central review progression had been declared were performed every 12 weeks ± 1 week.
q Adverse Events and Hospitalizations: Patients were followed for adverse events and hospitalizations 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 treatment-related toxicities had resolved or were determined to be “chronic” or “stable”, whichever wash7

Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Finallater. Serious adverse events were monitored and reported from the time that the patient provided informed consent. Hospitalizations were recorded from 28 days prior to
the start of study treatment and up to 28 days post the last dose of study treatment. Adverse events were graded using NCI CTCAE Version 4.
r 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
the last dose of study treatment.
s EORTC QLQ-C30 and QLQ-LC13: Patients were to complete all EORTC QLQ-C30 and QLQ-LC13 self-assessment questionnaires in the study site at the specified time
points with the exception of the Day 7 assessment. The Day 7 assessment could be completed at home and was given to patients along with completion guidelines/on-sitetraining at the Cycle 1/Day 1 visit (baseline). At Cycle 1/Day 1, site staff (eg, site coordinators) was to instruct patients that the Day 7 assessment was to be completed
without help from friends or family members and also recommend that this assessment be completed in the morning. On Day 7 (or the day prior), a member of the site staff
was to call to remind patients to complete the assessment that day and to return completed questionnaires at their next visit (Day 15). All other scheduled assessments of the
EORTC QLQ-C30 and QLQ-LC13 could not be taken home and were completed in the site prior to any other study or medical procedures. Questionnaires were also
completed in crossover patients at the same specified time points.
t VSAQ-ALK and EQ-5D: Patients were to complete the VSAQ-ALK and the EQ-5D questionnaires at the study site prior to any study or medical procedure. All
self-assessment questionnaires were completed by the patients while at the site and could not be taken home. Translation of the VSAQ-ALK into different languages wasundertaken and many language versions were available. However, if the VSAQ-ALK was not available in the patient’s preferred language, the patient did not need tocomplete this assessment. Questionnaires were also completed by crossover patients at the same specified time points.
u MUGA Scan or Echocardiogram: MUGA scans or echocardiograms were obtained from all patients until sufficient data were available to discontinue collecting fromnewly enrolled patients. The rationale for discontinuing this procedure was to be provided to the IRB/EC along with the amended protocol.
v Survival Follow-Up: After discontinuation of study treatment and/or confirmed PD, post-study survival status was collected every 2 months until death or until 36 months
after the randomization of the last patient (End of Study definition). This included collection of information on subsequent anticancer therapies. Telephone contact was
acceptable.
w Pharmacokinetics (Arm A only; not crossover patients): At each sampling time point, 3 mL of blood was drawn into a K2EDTA tube. Additional PK samples could becollected if the patient experienced a serious and/or unexpected adverse event.
x Optional Blood Sample for Pharmacogenomics: A 2-mL blood sample was collected for the analysis of DNA sequence variation in genes that may affect the PK of
crizotinib, or that may be associated with specific adverse events or toxicities related to crizotinib.
y Hypogonadism Laboratory Tests (male patients only, both treatment arms): All male patients enrolled undergone hypogonadism laboratory tests. In patients crossing
over to crizotinib from Arm B, the schedule of laboratory tests used in Arm A was repeated. Male patients enrolled in Arm B optionally also undergone hypogonadism
laboratory tests after appropriate informed consent at the time of crossover to crizotinib therapy. Blood draws had been done between 08:00 and 11:00. If a decrease of≥25% from baseline was observed in total testosterone or free testosterone, a repeat laboratory analysis of both these parameters had been performed at the next study site
visit to confirm hypogonadism.
z Dual-energy X-ray Absorptiometry (DXA) Scans for Bone Mineral Density and Muscle Mass Measurements: All male patients enrolled after undergone a baseline
DXA scan. Subsequent DXA scans were performed based upon the following schedule:
Arm A/and patients crossing over to crizotinib from Arm B: DXA scans were performed at Cycle 7/Day 1 and again at end of treatment unless a previous DXA scan
was performed within the last 2 months.
Arm B: A DXA scan was performed at the end of treatment visit and a repeat (re-baseline) DXA scan was needed if there was a gap of more than 2 months between the endof chemotherapy treatment in Arm B and crossover to crizotinib. Male patients enrolled in Arm B also undergone DXA scans after appropriate informed consent at the timeof crossover to crizotinib therapy.

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Protocol A8081014 – 31 Oct 2017 – Final

Table 2.

Reduced Schedule of Activities for Patients in the Crizotinib Arm and Patients Who Crossed Over From
Chemotherapy Arm After 10 Cycles of Crizotinib Treatment:
Study Treatmenta

Protocol Activities

End of Treatment

Cycles >10
Visits on Day 1 (±4) of Alternate
Cycles (Except as Noted Below)

End of Treatment/
Withdrawalb

X
X
France only: every 4 cycles
All countries: Xd

X
X

Physical examinationc
Blood pressure and pulse rate
Ophthalmologic examinationd
Laboratory Studies
Hematology and blood chemistry, excluding liver function testse
Liver function testse
Urinalysis dipstick and reflex microscopyf.

X
Day 1 of each cycle
Korea only: X(all other countries: as clinicallyindicated)

Contraceptive check (as appropriate)g
Pregnancy test (female patients)hTumor assessmentsi

X
Xg

Other Clinical Assessments
Adverse eventsj
Concomitant medications/treatmentsk
EORTC QLQ-C30, QLQ-LC13l
VSAQ-ALK and EQ-5Dm
MUGA scan or echocardiogram
Hypogonadism laboratory tests (males on crizotinib [Arm A and thosecrossing over from Arm B])
DXA scan (males on crizotinib [Arm A and crossover from Arm B])
Survival follow-upn
Study Treatment
Crizotinib (Arm A and crossover from Arm B)

X
X
X
X
every 4 cycles
every 4 cycles

X
X
Korea only: X(all other countries:
as clinicallyindicated)
XXg
As per local clinical practice

Post Treatment
Follow-up

X
X
X
X

X

X
X

X
X
X

Twice daily

Abbreviations: ALK=anaplastic lymphoma kinase; ALT=alanine transaminase; Arm A=crizotinib arm; Arm B=chemotherapy arm; AST=aspartate transaminase; CRF=case reportform; DXA=dual energy X-ray absorptiometry; EC=Ethics Committee; EORTC=European Organization for the Research and Treatment of Cancer; EQ-5D=EuroQol-5D;

9Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Final

MUGA=multiple gated acquisition; IRB=Institutional Review Board; QLQ-C30=Quality of Life Questionnaire-Core 30; QLQ-LC13=Quality of Life Questionnaire-Supplement
Module for Lung Cancer (LC13); VSAQ-ALK=Visual Symptom Assessment Questionnaire-ALK
a All assessments were performed prior to dosing with study medications unless otherwise indicated. All cycles were 21 days in duration. Enough study medication for 2 cyclesof treatment was dispensed at each clinic visit. During the non-clinic visit cycles, the investigator was responsible for ensuring the patient contacted the clinical site in order toprovide an update of adverse events and concomitant medications.
b End of Treatment/Withdrawal: Blood pressure, pulse rate, laboratory tests (including liver function tests), and physical examination were obtained if not completed during
the previous 4 weeks on study.
c Physical Examination: Included an examination of major body systems, body weight, blood pressure, and pulse rate.
d 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 had been observed and when there was an increase in the grade for visual disturbances. For all patients enrolled in France,
ophthalmology examination was performed after the completion of every 4 cycles.
e Hematology, Blood Chemistry, and Urinalysis: Where possible, laboratory tests were performed at the clinical site’s local laboratory. Where that was not possible, patientswere provide the laboratory test results carried out at a non-clinic site laboratory, eg, by telephone, and bring a copy of the laboratory test results at the next cycle visit; processdepended on local medical practice. The copy of the laboratory test results had to be retained in the patient’s file at the clinical site for documentation purposes. Liver function
tests included ALT, AST, alkaline phosphatase, and total bilirubin. If ALT or AST Grade ≥3, or ALT or AST Grade ≥2 and total bilirubin Grade≥ 2, repeat ALT or AST andtotal bilirubin within 48 hours were to be obtained and then to be repeated every 48-72 hours until ALT/AST Grade ≤1.
f Reflex microscopy was required if urine dipstick was positive for blood or protein.
g Contraceptive Check: Male and female patients of childbearing potential and at risk for pregnancy had agreed to use 2 highly effective methods of contraception throughout
the study and for at least 90 days after the last dose of crizotinib.
h Pregnancy Test: For women of childbearing potential, a serum or urine pregnancy test was routinely repeated at every treatment cycle, at the end of treatment, andadditionally whenever 1 menstrual cycle was missed or when potential pregnancy was otherwise suspected. In the case of a positive confirmed pregnancy, the patient waswithdrawn from study medication. Additional pregnancy tests were also be undertaken if requested by IRBs/ECs or if required by local regulations.
i Tumor Assessments: Repeated at the frequency as per local clinical practice.
j For serious adverse events, the active reporting period to the Sponsor or its designated representative began from the time that the patient provided informed consent, which
was obtained prior to the patient’s participation in the study, ie, prior to undergoing any study related procedure and/or receiving investigational product, through and including
28 calendar days after the last administration of the investigational product. Adverse events (serious and non-serious) were to be recorded on the CRF from the time the patient
had taken at least 1 dose of study medication through the patient’s last visit.
k Concomitant Medications/Treatments: Concomitant medications and treatments were recorded up to 28 days post the last dose of study medication.
l EORTC QLQ-C30, QLQ-LC13: Completed only during cycle visits.
m VSAQ-ALK and EQ-5D: Completed only during cycle visits.
n Survival Follow-up: After discontinuation of study treatment and/or confirmed progression of disease, post study survival status was collected every 2 months until death oruntil 36 months after the randomization of the last patient (End of Study definition). Included collection of information on subsequent anticancer therapies. Telephone contact
was acceptable.

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Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Final

Number of patients (Planned and Analyzed):
Total number of patients planned = 334
Total number of patients randomized (full analysis [FA] population) = 343 (higher than theplanned number because at screening, all patients who signed an informed consent form wererandomized to study treatment if they met the study entry criteria).
Number of patients randomized to crizotinib arm = 172
Number of patients randomized to chemotherapy arm = 171
About 128 patients crossed over from the chemotherapy arm to receive crizotinib after
randomization phase.
Diagnosis and Main Criteria for Inclusion and Exclusion:
Inclusion criteria:•

Proven diagnosis of locally advanced not suitable for local treatment, recurrent or
metastatic non squamous NSCLC•

Positive for translocation or inversion events involving the ALK gene locus•

ECOG PS 0-2•

No prior systemic treatment for locally advanced or metastatic disease; Patients withbrain metastases only if treated and neurologically stable with no ongoing
requirement for corticosteroids•

Evidence of a personally signed and dated informed consent document andwillingness and ability to comply with scheduled visits, treatment plans, laboratory
tests, and other study procedures including completion of PRO measures•

18 years of age or older with the exception of India which has an upper age limit of
65 years old

Exclusion criteria:•

Current treatment on another therapeutic clinical trial.

•

Prior therapy directly targeting ALK.

•

Any of the following within the 3 months prior to starting study treatment:
myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass
graft, congestive heart failure, or cerebrovascular accident including transientischemic attack. Appropriate treatment with anticoagulants is permitted.

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Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Final•

Ongoing cardiac dysrhythmias of NCI CTCAE Grade >=2, uncontrolled atrial
fibrillation of any grade, or QTc interval >470 msec.

•

Pregnancy or breastfeeding.

•

Use of drugs or foods that are known potent CYP3A4 inducers/inhibitors.
Concurrent use of drugs that are CYP3A4 substrates with narrow therapeutic indices.

•

Known human immunodeficiency virus (HIV) infection•

Known grade 3 or 4 interstitial fibrosis or interstitial lung disease•

Other severe acute or chronic medical conditions (including severe gastrointestinal
conditions such as diarrhea or ulcer) or psychiatric conditions, or laboratory
abnormalities that would impart, in the judgment of the investigator and/or sponsor,
excess risk associated with study participation or study drug administration, andwhich would, therefore, make the patient inappropriate for entry into this study

Study Treatment:
Each treatment cycle (crizotinib or chemotherapy) was defined as 3 weeks (21 days).
Test product therapy: At each visit according to the schedule of treatment administration,
crizotinib 250 mg or 200 mg capsules were provided packed in high-density polyethylene
bottles. Crizotinib capsules, at a starting dose of 250 mg twice daily (BID), wereadministered orally at approximately the same time each day on a continuous daily dosing
schedule.
Reference Therapy (chemotherapy): Standard doses of chemotherapy (commerciallyavailable pemetrexed/cisplatin or pemetrexed/carboplatin) were administered by intravenous(IV) infusion according to standard of care.
•

Pemetrexed (500 mg/m2) was administered by IV infusion over 10 minutes or
according to institutional administration timing.

•

Cisplatin (75 mg/m2) was administered by IV infusion after adequate hydration,according to institutional practices, began approximately 30 minutes after the end of
the pemetrexed infusion.

•

Carboplatin (at a dose calculated to produce an area under the concentration-time
curve [AUC] of 5 or 6 mg.min/mL) was administered by IV infusion, according toinstitutional practices, began approximately 30 minutes after the end of thepemetrexed infusion.

In both therapy, in order to keep the treatment conditions similar between treatment arms andto reduce treatment-related hematologic and gastrointestinal toxicities, all patients had an
intramuscular Vitamin B12 1000 μg injection and oral once daily folic acid, 350-1000 μg pre-12

Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Finaltreatment approximately 7 days before the first dose of crizotinib and continued daily for up
to 3 weeks after the first dose of crizotinib.
Also to reduce cutaneous reactions, patients received corticosteroid (equivalent to 4 mg
dexamethasone) orally BID on the day before, the day of, and the day after pemetrexed
dosing. Intramuscular, intraperitoneal, or IV administration of a corticosteroid with the same
total dose as oral dexamethasone was allowed per country regulations and according toinstitutional practices.
Patients were monitored closely for toxicity and the dose of crizotinib was reduced by 1 and,if needed, 2 dose level(s) depending on the type and severity of toxicity encountered (DoseLevel -1 was 200 mg BID; Dose Level -2 was 250 mg once daily).
Efficacy, Pharmacokinetic, Pharmacodynamic, and PRO Endpoints:
The primary endpoint:•

PFS based on RECIST v1.1 (determined by the IRR assessment).

Secondary endpoints:•

ORR (determined by IRR), OS, survival probabilities at 1 year and 18 months, DCR
at 12 weeks, TTP, IC-TTP, EC-TTP, DR and TTR.

•

Plasma concentration of crizotinib (including its active moieties, if appropriate).

•

Proportions of patients with each of the 8 ALK fusion variants of the EML4-ALK
fusion.

•Time to Deterioration (TTD) in pain in chest, dyspnea, or cough patient-reported
disease symptoms.

•

PRO Evaluations: Global quality of life, functioning, lung cancer-specificdisease/treatment-related symptoms, and general health status.

•

Health care resource utilization (HCRU) was assessed based on hospitalization data(ie, length of stay, frequency) and concomitant medication use.

Safety Evaluations:
Safety evaluations included the following assessments:
•

AEs

•

Laboratory parameters (hematology, coagulation, and clinical chemistry)•

Physical examinations including vital signs

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Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Final•

12-lead electrocardiograms (ECGs), multiple gated acquisition (MUGA) scans or
echocardiograms (ECHO)•

Ophthalmologic examinations•

Hypogonadism evaluation including total and free testosterone levels and dual energy
X-ray absorptiometry (DXA) scan.

All observed or volunteered adverse events (AEs), regardless of treatment group or suspectedcausal relationship to the study treatment, were to be recorded on the CRF. AEs were to beclassified by type, incidence, severity (graded by NCI CTCAE Version 4.0), timing,
seriousness, and relatedness.
AEs were summarized as per the preferred terms and clustered terms. Clustered terms and
MedDRA preferred terms within each clustered term are presented in Table 3. Not all
MedDRA preferred terms within each clustered term were actually reported in this study.
Clustered terms are presented using capital letters while MedDRA preferred terms are writtenwith only the first letter capitalized.
Table 3Clustered Terms and Preferred Terms Within Each Clustered Term

Clustered Term

Preferred Terms

Abdominal discomforta; Abdominal paina; Abdominal pain lowera; Abdominal pain
uppera; Abdominal tendernessa
ANAEMIA
Anaemiaa; Anaemia macrocytic; Anaemia megaloblastic; Haemoglobin;
Haemoglobin decreaseda; Hyperchromic anaemia; Hypochromic anaemiaa;
Hypoplastic anaemia; Microcytic anaemia; Normochromic normocytic anaemiaa
BLOOD CREATININE
Blood creatinine abnormal; Blood creatinine increaseda; Creatinine renal clearance
INCREASED
abnormal; Creatinine renal clearance decreased; Glomerular filtration rateabnormal; Glomerular filtration rate decreased
BLOOD TESTOTERONE Androgen deficiency; Blood gonadotrophin abnormal; Blood gonadotrophin
DECREASED
decreased; Blood gonadotrophin increased; Blood testosterone abnormal; Bloodtestosterone decreaseda; Blood testosterone free decreased; Gonadotrophin
deficiency; Hypogonadisma; Hypogonadism male; Saliva testosterone abnormal;
Saliva testosterone decreased; Secondary hypogonadism
BRADYCARDIA
Bradyarrhythmiaa; Bradycardiaa; Heart rate decreased; Sinus arrest; Sinus
bradycardiaa
CARDIAC FAILURE
Acute left ventricular failure; Acute right ventricular failure; Cardiac failurea;
Cardiac failure acute; Cardiac failure chronic; Cardiac failure congestive; Cardiac
failure high output; Cardiopulmonary failure; Chronic left ventricular failure;
Chronic right ventricular failure; Ejection fraction decreaseda; Left ventricular
failurea; Pulmonary oedemaa; Right ventricular failure; Ventricular failure
CHEST PAIN
Chest discomforta; Chest paina; Musculoskeletal chest paina; Non-cardiac chest
paina
CHOLESTASIS
Bilirubin conjugated; Bilirubin conjugated abnormal; Bilirubin conjugatedincreaseda; Bilirubin excretion disorder; Blood bilirubina; Blood bilirubin
abnormal; Blood bilirubin increaseda; Cholestasis; Cholestatic liver injury;
Hepatitis cholestatic; Hyperbilirubinaemiaa; Jaundicea; Jaundice cholestatic;
Jaundice hepatocellular; Ocular icterus; Yellow skin
COUGH
Cougha; Productive cougha
ABDOMINAL PAIN

DIZZINESS

Balance disordera; Dizzinessa; Dizziness exertional; Dizziness posturala;
Presyncopea

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Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Final
Clustered Term

Preferred Terms

DYSPNOEA

Dyspnoeaa; Dyspnoea at resta; Dyspnoea exertionala; Dyspnoea paroxysmal
nocturnal; Nocturnal dyspnoea; Orthopnoeaa

ELEVATEDTRANSAMINASE

Alanine aminotransferase; Alanine aminotransferase abnormal; Alanine
aminotransferase increaseda; Aspartate aminotransferase; Aspartate
aminotransferase abnormal; Aspartate aminotransferase increaseda; Gammaglutamyltransferase abnormal; Gamma-glutamyltransferase increaseda; Hepatic
enzyme abnormal; Hepatic enzyme increased; Hepatic function abnormala;Hypertransaminasaemia; Liver function test abnormal; Liver function test
increased; Transaminases; Transaminases abnormal; Transaminases increaseda

GASTROINTESTINAL(GI) PERFORATION

Anastomotic ulcer perforation; Diverticular perforation; Duodenal perforation;
Duodenal ulcer perforation; Duodenal ulcer perforation, obstructive; Gastricperforation; Gastric ulcer perforation; Gastric ulcer perforation, obstructive;
Gastrointestinal anastomotic leak; Gastrointestinal perforation; Gastrointestinal
ulcer perforation; Ileal perforation; Ileal ulcer perforation; Intestinal perforation;
Intestinal ulcer perforation; Jejunal perforation; Jejunal ulcer perforation; Large
intestinal ulcer perforation; Large intestine perforation; Peptic ulcer perforation;
Peptic ulcer perforation, obstructive; Perforated peptic ulcer oversewing;
Perforated ulcer; Rectal perforation; Small intestinal perforation; Small intestinal
ulcer perforation

HEPATOTOXICITY

Acute hepatic failure; Cholestatic liver injury; Coma hepatic; Drug-induced liver
injurya; Hepatic encephalopathy; Hepatic failure; Hepatic necrosis; Hepatic
steatosis; Hepatitis fulminant; Hepatocellular injurya; Hepatorenal failure;Hepatorenal syndrome; Hepatotoxicity; Liver disorder; Liver injury; Mixed liver
injury; Subacute hepatic failure

INTERSTITIAL LUNGDISEASE

Acute interstitial pneumonitis; Acute lung injury; Acute respiratory distresssyndromea; Alveolitis; Alveolitis allergic; Alveolitis necrotising; Diffuse alveolar
damage; Eosinophilic pneumonia; Eosinophilic pneumonia acute; Idiopathic
pulmonary fibrosis; Interstitial lung diseasea; Pneumonitisa; Pulmonary toxicity

LEUKOPENIA

Leukopeniaa; White blood cell count decreaseda

LYMPHOPENIA

Lymphocyte count decreaseda; Lymphopeniaa

NEUROPATHY

Acute polyneuropathy; Amyotrophy; Areflexia; Autoimmune neuropathy;
Autonomic failure syndrome; Autonomic neuropathy; Axonal neuropathy; Biopsy
peripheral nerve abnormal; Burning feet syndrome; Burning sensation; Decreased
vibratory sense; Demyelinating polyneuropathy; Dysaesthesiaa; Electromyogram
abnormal; Formication; Gait disturbancea; Genital hypoaesthesia; Guillain-Barre
syndrome; Hyperaesthesia; Hypoaesthesiaa; Hyporeflexia; Hypotonia; Ischaemic
neuropathy; Loss of proprioception; Miller Fisher syndrome; Mononeuritis;
Mononeuropathy; Mononeuropathy multiplex; Motor dysfunction; Multifocal
motor neuropathy; Muscle atrophy; Muscular weaknessa; Myelopathy; Nerve
conduction studies abnormal; Nerve degeneration; Neuralgiaa; Neuritis;
Neuromuscular toxicity; Neuromyopathy; Neuropathy peripherala; Neuropathy
vitamin B6 deficiency; Neurotoxicitya; Paraesthesiaa; Peripheral motor neuropathy;
Peripheral nerve lesion; Peripheral nerve palsy; Peripheral nervous system function
test abnormal; Peripheral sensorimotor neuropathy; Peripheral sensory
neuropathya; Peroneal nerve palsy; Phrenic nerve paralysis; Polyneuropathy;
Polyneuropathy chronic; Polyneuropathy idiopathic progressive; Radiationneuropathy; Sensorimotor disorder; Sensory disturbancea; Sensory loss; Skinburning sensation; Small fibre neuropathy; Temperature perception test decreased;

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Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Final
Clustered Term

Preferred Terms
Tinels sign; Toxic neuropathy; Ulnar neuritis

NEUTROPENIA

Febrile neutropeniaa; Neutropeniaa; Neutrophil count decreaseda

OEDEMAEye swellinga; Face oedemaa; Generalised oedemaa; Local swellinga; Localised
oedemaa; Oedemaa; Oedema peripherala; Periorbital oedemaa

OESOPHAGITIS

Erosive oesophagitis; Necrotising oesophagitis; Oesophageal perforation;
Oesophageal rupture; Oesophageal ulcera; Oesophageal ulcer haemorrhage;
Oesophageal ulcer perforation; Oesophagitisa; Oesophagitis haemorrhagic;
Oesophagitis ulcerative

PULMONARYEMBOLISMRADIATION NDUCEDINTERSTITIAL LUNGDISEASERENAL CYST

Pulmonary artery thrombosisa; Pulmonary embolisma; Pulmonary thrombosis

STOMATITIS

Pulmonary radiation injury; Radiation alveolitis; Radiation fibrosis - lung;
Radiation pneumonitisa
Renal abscess; Renal cysta; Renal cyst excision; Renal cyst haemorrhage; Renal
cyst infection; Renal cyst rupture
Cheilitisa; Glossitisa; Glossodyniaa; Mouth ulcerationa; Mucosal inflammationa;
Oral pain; Oropharyngeal discomfort; Oropharyngeal paina; Stomatitisa

THROMBOCYTOPENIA Platelet count decreaseda; Thrombocytopeniaa
UPPER RESPIRATORYINFECTION

Laryngitis; Nasopharyngitisa; Pharyngitisa; Rhinitisa; Upper respiratory tract
infectiona

VISION DISORDER

Chromatopsia; Diplopiaa; Halo vision; Photophobiaa; Photopsiaa; Vision blurreda;
Visual acuity reduceda; Visual brightness; Visual impairmenta; Visualperseverationa; Vitreous floatersa

VISUAL LOSS

Amaurosis; Amaurosis fugax; Blindnessa; Blindness cortical; Blindness day;Blindness transient; Blindness unilateral; Hemianopia; Hemianopia heteronymous;
Hemianopia homonymous; Night blindness; Optic atrophy; Optic ischaemic
neuropathy; Optic nerve disordera; Optic neuropathy; Quadrantanopia;
Retinopathya; Sudden visual loss; Toxic optic neuropathy; Tunnel vision; Visualcortex atrophy; Visual field defecta; Visual pathway disorderaActual treatment emergent adverse event (TEAE) data reported.

Abnormal laboratory test results were considered AEs if they were associated withsymptoms; required additional diagnostic testing or medical/surgical intervention; led to achange in study dosing or discontinuation from the study, significant additional concomitantdrug treatment, or other therapy; and/or were otherwise considered to be an AE by theinvestigator or Sponsor. Baseline tumor-related signs and symptoms were to be recorded as
AEs during the study if they worsened in severity or increased in frequency.
Statistical Methods:
Analysis Populations:
Full Analysis (FA) Population: All patients who were randomized with study treatment
assignment designated according to the initial randomization. The FA population was the16

Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Final

primary population for evaluating efficacy endpoints (except as otherwise specified), patientcharacteristics, and patient disposition.
Safety Analysis (SA) Population: All randomized patients who received at least 1 dose of
study treatment, with treatment assignments designated according to actual study treatment
received during the first cycle. The SA population was the primary population for safety andtreatment evaluations; in addition, this population was used when summarizing efficacy databy treatment group (ie, by chemotherapy regimen).
PK evaluable population: Included any patient in the SA population who had at least
1 plasma concentration of crizotinib or its metabolite, PF-06260182, determined following
crizotinib treatment as of the data cutoff date. The plasma predose (0 hours) concentration
population included any patient in the PK concentration population who had at least 1
predose (0 hours) concentration (trough concentration [Ctrough]) of crizotinib or PF06260182, with actual sample collection times between -1.2 to 0 hours prior to morning
dosing.
PRO Evaluable Population: All patients from the FA population who completed a baseline(last PRO assessment prior to randomization day) and at least 1 post-baseline PRO
assessment prior to crossover or end of randomized study treatment. The PRO evaluable
population was the primary population for the analysis of change from baseline scores and
TTD in patient-reported pain in chest, dyspnea, or cough.
ALK Gene Fusion Variant Evaluable Population: The ALK gene fusion variant evaluable
population was defined as patients from the FA population who had a result from ALK genefusion variant testing of either no rearrangement, or 1 of 9 results reflecting 8 specificrearrangements (V1, V2, V3a, V3b, V3a/b, V4, V5a, V6, V7).
Pharmacogenomics Evaluable Population: The pharmacogenomics evaluable population was
defined as patients from the SA population in the crizotinib group who provided a blood
sample for pharmacogenomics analysis at baseline (Day 1 of Cycle 1).
Subgroups analysis: Patients in the chemotherapy arm who had RECIST-defined PD, as
determined by IRR, were allowed to cross over to receive crizotinib treatment, providing
they met safety screening inclusion/exclusion criteria for crizotinib therapy. The following
analysis subgroups were included:--

Patients randomized to crizotinib (subgroup 1)
Patients randomized to chemotherapy (subgroup 2): All data up to and including
the day prior to the first dose of crizotinib treatment were included, unlessotherwise specified, with the exception of OS that was calculated form the day ofrandomization to death independently from when it occurred;
Patients randomized to chemotherapy who crossed over to receive crizotinib(subgroup 3)

Unless otherwise noted, efficacy, safety, and PRO comparisons were based on data from
Subgroups 1 and 2. For Subgroup 3, safety data were summarized descriptively from thefirst dose of crizotinib.
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Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Final

Analysis of Efficacy Parameters:
Primary Efficacy Analysis:
PFS was defined as the time from the date of randomization to the date of the first
documentation of objective tumor progression (by IRR) or death on study due to any
cause, whichever occurred first. The study was to be considered positive if the
1-sided log-rank test for PFS, stratified for baseline stratification factors (ECOG PS,
race, brain metastases), was significant at the level determined at the time of the final
analysis (p-value ≤0.0247) with an O’Brien-Fleming stopping rule in favor of thecrizotinib arm. Estimates of the PFS curves obtained from the Kaplan-Meier method
were presented and displayed graphically. The median event time (and otherquartiles) and corresponding 2-sided 95% CI were provided for each treatment arm.
Additionally, for each treatment arm the median PFS and corresponding 2-sided 95%
CI were provided for each level of the stratification variables. The Cox regression
model, stratified for baseline stratification factors, was fitted. The estimated HR and
2-sided 95% CI were provided.
Secondary Efficacy Analysis:•

ORR was defined as the percentage of patients with CR or PR according to RECISTVersion 1.1, as determined by IRR, relative to the FA population.
ORR was summarized in the FA population based on IRR of tumor data. The ORR
was summarized for each treatment arm along with the corresponding exact 2-sided
95% CI using a method based on the F-distribution. ORR between the 2 treatment
arms was compared using a 2-sided Cochran-Mantel-Haenszel (CMH) test stratified
for baseline stratification factors (ECOG PS, race group, brain metastases) and a2-sided unstratified test (eg, Pearson). Treatment difference of ORR and its 95% CI
based on the normal distribution were provided. Best overall response was also
summarized for patients in subgroup 3.

•

DCR at 12 weeks was defined as the percentage of patients with CR, PR, or stabledisease at 12 weeks according to RECIST Version 1.1, as determined by IRR. DCR
at Week 12 was analyzed similarly as described for ORR. An unstratified test (eg,Pearson) was used to compare DCR between the 2 treatment arms.

•

DR was defined as the time from the first documentation of objective tumor response(CR or PR), as determined by IRR, to the first documentation of objective tumor
progression or to death due to any cause, whichever occurred first. DR was
summarized for the subgroup of responders (CR and PR) in the FA population using
the Kaplan-Meier method and was displayed graphically. The median event time and2-sided 95% CI for the median for each treatment arm were provided. DR was also
summarized for patients in subgroup 3.

•

TTR was defined as the time from randomization to first documentation of objective
tumor response (CR or PR), as determined by IRR. TTR was summarized in the18

Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Final

subgroup of responders (CR and PR) from the FA population using descriptive
statistics. In addition, TTR was summarized for patients in subgroup 3 treatment arm.
•

TTP was defined as the time from randomization to first documentation of objective
tumor progression, as determined by IRR. TTP was calculated for the FA populationand for subgroups of patients with or without brain metastases at baseline.
Differences between treatment arms were analyzed by the unstratified log rank test.
Estimates of the curves obtained from the Kaplan-Meier method were presented andalso displayed graphically. The median event time (and other quartiles) andcorresponding 2-sided 95% CI were provided for each treatment arm. The estimatedHR and 2-sided 95% CI were provided.

•

IC-TTP was defined as the time from randomization to first documentation of
objective intracranial disease progression, based on either new brain metastases orprogression of existing brain metastases, as determined by IRR. IC-TTP was
calculated and analyzed for the FA population and for subgroups of patients with andwithout brain metastases at baseline as described for TTP. For the subgroup ofpatients without brain metastases at baseline, only the new brain metastases wereconsidered events.

•

EC-TTP was defined as the time from randomization to first documentation of
objective extracranial disease progression, based on either new extracranial lesions orprogression of existing extracranial lesions, as determined by IRR. EC-TTP was
calculated and analyzed for the FA population and for the subgroups of patients withand without brain metastases at baseline as described for TTP.

•

OS was defined as the time from randomization to the date of death due to any cause.
Differences in OS between treatment arms were analyzed by a 1-sided log rank test
stratified for baseline stratification factors (ECOG PS, race group, brain metastases).
Estimates of the OS curves obtained from the Kaplan Meier method were presented
and displayed graphically. The median event time (and other quartiles), if achieved,and corresponding 2-sided 95% CI were provided for each treatment arm. The Cox
regression model, stratified for baseline stratification factors, was fitted. The
estimated HR and 2-sided 95% CI were provided. In addition, Cox regression
models, adjusted for baseline stratification factors and other patient baselinecharacteristics, were fitted. The estimated HR and 2-sided 95% CI were provided.
Subgroup analyses were provided for baseline patient and disease characteristics:
median OS (and other quartiles) and 2-sided 95% CI were estimated.

•

One-year and 18-months survival probabilities were defined as the probabilities ofsurvival at 1 year and 18 months, respectively, after the date of randomization basedon the Kaplan Meier estimate. Estimated by using the Kaplan Meier method and a2-sided 95% CI for the log [-log(1-year survival probability)] was calculated using anormal approximation and then back transformed to give a CI for the 1-year survival
probability itself.

•

Patient-Reported Outcomes: Time to deterioration (TTD) in pain in chest, dyspnea, or
cough symptoms (from QLQ-LC13) was a composite endpoint, defined as the time19

Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Finalfrom randomization to the earliest date the patient’s scale scores showed a 10-point or
greater increase after baseline in any of these 3 symptoms. TTD analyses for thecomposite endpoint and each of the 3 pre-specified symptoms were summarizedusing Kaplan-Meier methods. The estimated Kaplan-Meier plots were provided forthe composite and each symptom within it, and the unstratified 2-sided log-rank test
was the primary method to compare the time to first deterioration between the
2 treatment arms. The median time and 2-sided 95% CI for the median was also
provided based on the Brookmeyer Crowley method. To assess change from baseline
scores between treatment arms, repeated measures mixed-effects modelling was
carried out for the EORTC QLQ-C30, QLQ-LC13 domain and single-item scores,
and the EQ-5D visual analogue scale. Descriptive statistics were reported for each
item of the VSAQ-ALK. All analyses considered only data up to the time ofcrossover or end of randomization study treatment for patients randomized tochemotherapy.
•

Pharmacodynamic analysis: ALK gene fusion variant analysis data were summarizedusing descriptive statistics. For each ALK variant separately and for patients with noidentified ALK rearrangement, best objective response and ORR were summarized
for each treatment arm with the corresponding exact 2-sided 95% CI using a method
based on the F distribution. PFS was presented for those ALK gene variant groups
for which there were 10 or more patients per treatment arm, which included the ALK
variant V1 and the no variant rearrangement groups.

•

Health care resource utilization analysis: Data regarding hospitalizations, thecausality of AEs associated with the hospitalization, and concomitant medication use
were summarized.

Pharmacokinetic analysis:
The PK concentration population included any patient in the SA population who had at least
1 plasma concentration of crizotinib or its metabolite, PF 06260182, determined following
crizotinib treatment. For each patient, the mean steady state trough concentration (Ctrough, ss,mean) was derived as the arithmetic mean of all available plasma predose concentrations(Ctrough) of that patient on Day 1 of Cycles 2, 3 and 5 after at least 14 consecutive days of
crizotinib dosing (250 mg BID) prior to the PK sample collection time. The PF 06260182 tocrizotinib ratio for plasma concentrations was calculated. Trough concentrations weresummarized using descriptive statistics.
Safety analysis:
Safety data were analyzed in the SA population. All AEs were coded using Medical
Dictionary for Regulatory Activities (MedDRA) Version 19.1. The severity of all AEs wasgraded by the investigator using National Cancer Institute Common Terminology Criteria for
Adverse Events (NCI CTCAE) Version 4.0. Because the frequency of certain medical
concepts or conditions may have been underestimated by reliance on single MedDRA
preferred terms, certain preferred terms were analyzed in aggregate using clustered terms.

20

Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Final

Treatment-emergent AEs were summarized by MedDRA preferred term and by pre-definedclustered terms (shown in capital letters).
AEs of special interest included the following preferred terms or clustered terms:
ELEVATED TRANSAMINASES, HEPATOTOXICITY, INTERSTITIAL LUNGDISEASE, Electrocardiogram QT prolonged, BRADYCARDIA, VISION DISORDER,
gastrointestinal events (Diarrhoea, Nausea, Vomiting, and Constipation), RENAL CYST,OEDEMA, BLOOD CREATININE INCREASED, and Syncope.
The impact of treatment duration on the observed AE profile was evaluated including
considerations for time to onset of selected events (based on the results of previous crizotinib
clinical studies) and/or calculations of incidence rates per person-years of exposure.
Incidence rate per person-years of exposure was the ratio of total number of patients
reporting an event which occurred within 28 days from the last dose of study treatment
relative to person-years exposure. Person-years of exposure was calculated as the sum of
individual patient-years at risk (sum of time to onset for patients with the event, time to
28 days after last dose for patients alive without the event, or time to death for patients whodied within 28 days after the last dose without the event) divided by 365.25.
Safety data (AEs, laboratory parameters, vital signs, ECOG PS, ECGs, MUGA scans or
ECHO, and ophthalmologic examinations) were analyzed using descriptive statistics. Due tothe low number of patients with hypogonadism and DXA data, the results were only listed bypatient. Summaries of AEs associated with permanent treatment discontinuation, temporary
treatment discontinuation, or dose reduction, serious AEs (SAEs) and deaths, vital signs,
ECGs, and shifts in grade of laboratory parameter results were also produced for subgroup 3
RESULTS
Patient Disposition:
Of the 343 patients in the FA population, 172 patients were randomized to the crizotinib arm,and 171 patients were randomized to the chemotherapy arm (Table 4). A total of
144 patients randomized to chemotherapy received crizotinib after the randomization phase:
128 patients through the crossover process and 16 patients as follow-up therapy.
The most common reasons for discontinuation from the study in both treatment arms werestudy completion (81 [47.1%] patients in the crizotinib arm and 69 [40.4%] patients in the
chemotherapy arm) and patient death (71 [41.3%] patients in the crizotinib arm and 81[47.4%] patients in the chemotherapy arm) (Table 4).

21

Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Final

Table 4

Patient Disposition and patients Analyzed by Treatment Arm - - Full
Analysis Population

Randomized to study treatment
TreatedCompletedb

Randomized not treatedcDiscontinued from study
Patient Died

a
b

c
d

Crizotinibn (%)

Chemotherapya
n (%)

Total
n (%)

172

171

343

171

169

340

81 (47.1)

69 (40.4)

150 (43.7)

1 (0.6)2 (1.2)3 (0.9)90 (52.3)

100 (58.5)

190 (55.4)

71 (41.3)

81 (47.4)

152 (44.3)

Lost to Follow-Up

4 (2.3)5 (2.9)9 (2.6)

Patient Refused Further Follow-up

12 (7.0)

13 (7.6)

25 (7.3)

Otherd3 (1.7)1 (0.6)4 (1.2)

Includes data before and after crossover to crizotinib for those patients who crossed over to receive crizotinib treatment.
“Completed” refers either to those patients who switched to commercial supplies of crizotinib or those patients who
were in survival follow-up, when the Sponsor sent written End of Study notification to the clinical sites.
Reason for discontinuation is based on the Patient Summary at End of Study case report form page.
Other reasons for discontinuation from study in the crizotinib arm were: investigator decision because patient was
unable to fulfil the study procedures due to a deterioration in health; last follow-up required per protocol (18 months
after last randomization), no follow-up; patient did not sign ICD for extension of follow-up from 18 to 36 months.
Other reason for discontinuation of study in the chemotherapy was investigator decision (not specified)

Data Sets Analyzed:
Analysis population details were presented in Table 5.
Table 5

Data Sets Analyzed by Treatment Arm
Crizotinibn (%)

Chemotherapya
n (%)

Total
n (%)

Full analysis population

172 (100)

171 (100)

343 (100)

Safety analysis population

171 (99.4)

169 (98.8)

340 (99.1)

EORTC QLQ-C30 and QLQ-LC13

166 (96.5)

163 (95.3)

329 (95.9)

EQ-5D

160 (93.0)

160 (93.6)

320 (93.3)

VSAQ-ALK

158 (91.9)

153 (89.5)

311 (90.7)

PK concentration population

169 (98.3)

NA

169 (49.3)

ALK variant evaluable population

70 (40.7)

78 (45.6)

148 (43.1)

PRO evaluable population

Abbreviations: ALK=anaplastic lymphoma kinase; EORTC=European Organization for the Research and Treatment ofCancer; EQ-5D=EuroQol-5D; n=number of patients; NA=not applicable; PK=pharmacokinetic; PRO=patient-reported
outcome; QLQ-C30=Quality of Life Questionnaire-Core 30; QLQ-LC13=Quality of Life Questionnaire-Supplement
Module for Lung Cancer (LC13); VSAQ-ALK=Visual Symptom Assessment Questionnaire-ALK.

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Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Final

Patient demographic characteristics:
Demographic characteristics were comparable between the 2 treatment arms in the FA
population (Table 6).
Table 6

Demographic Characteristics by Treatment Arm Full Analysis Population
Crizotinib(N=172)

Chemotherapy(N=171)

Total(N=343)Sex, n (%)
Male

68 (39.5)

63 (36.8)

131 (38.2)

Female104 (60.5)

108 (63.2)

212 (61.8)

50.9 (11.9)

52.9 (13.1)

51.9 (12.6)

Median

52.0

54.0

53.0

Range
Age category, n (%)

22-76

19-78

19-78

<45 years

56 (32.6)

44 (25.7)

100 (29.2)

45-<55 years

52 (30.2)

46 (26.9)

98 (28.6)

55-<65 years

41 (23.8)

49 (28.7)

90 (26.2)≥65 years

23 (13.4)

32 (18.7)

55 (16.0)

White

91 (52.9)

85 (49.7)

176 (51.3)

Black

0

4 (2.3)4 (1.2)Age, years
Mean (SD)Race, n (%)

AsianJapanese77 (44.8)
14 (8.1)

80 (46.8)
18 (10.5)157 (45.8)
32 (9.3)

Korean30 (17.4)

26 (15.2)

56 (16.3)

Chinese27 (15.7)

32 (18.7)

59 (17.2)

Other Asian

6 (3.5)4 (2.3)10 (2.9)

Other
Body weight, kg

4 (2.3)2 (1.2)6 (1.7)

Mean (SD)66.3 (14.1)

64.7 (15.1)

65.5 (14.6)

Median

64.3

62.5

63.0

43.0-118.0

35.8-126.0

35.8-126.0

Never smoked

106 (61.6)

112 (65.5)

218 (63.6)

Ex-smoker

56 (32.6)

54 (31.6)

110 (32.1)

Smoker10 (5.8)5 (2.9)15 (4.4)

Range
Smoking classification, n (%)

Abbreviations: n/N=number of patients; SD=standard deviation.

23

Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Final

Efficacy, Pharmacokinetic, Pharmacodynamic, and PRO Results:
Primary Efficacy Endpoint:
PFS based on RECIST Version 1.1 (determined by IRR):
The study met its primary objective by demonstrating that crizotinib significantly prolonged
PFS compared with first-line chemotherapy, as assessed by IRR. The median PFS was
10.9 months for 172 patients randomized to crizotinib and 7.0 months for 171 patientsrandomized to chemotherapy (Table 7). The HR comparing crizotinib with chemotherapy
was 0.454 (95% CI: 0.346, 0.596), with a p-value of <0.0001 (1-sided stratified log-ranktest). Of the 172 patients randomized to crizotinib, 100 (58.1%) patients had diseaseprogression or death, and 56 (32.6%) patients are still in follow-up. Of the 171 patientsrandomized to chemotherapy, 137 (80.1%) patients had disease progression or death, and 18(10.5%) patients are still in follow-up.
Table 7

Progression-Free Survival Based on Independent Radiology Review by
Treatment Arm (Stratified) - Full Analysis Population
Crizotinib(N=172)100 (58.1)

Chemotherapy(N=171)a137 (80.1)

Objective progression

89 (51.7)

132 (77.2)

Death without objective progression

11 (6.4)

5 (2.9)72 (41.9)

34 (19.9)02 (1.2)Given new anticancer treatment prior to tumor progression

12 (7.0)

6 (3.5)

Withdrew consent for follow-up

3 (1.7)6 (3.5)02 (1.2)

In follow-up for progression

56 (32.6)

18 (10.5)

No scans/data available

1 (<1.0)0

Number with event, n (%)

Number censored, n (%)
No on-study disease assessments

Unacceptable gap (>14 weeks) between PD or death to themost recent prior adequate assessment

Kaplan-Meier estimates of time to event, months
25% quartile (95% CI)b

5.4 (4.0, 6.8)

4.0 (2.8, 5.3)

50% quartile (95% CI)

b10.9 (8.3, 13.9)

7.0 (6.8, 8.2)

75% quartile (95% CI)b

NR (15.7, NR)

10.8 (9.5, 11.2)

95% CI of hazard ratio(0.346, 0.596)

Versus chemotherapy
Hazard ratioc

0.454

p-valued<0.0001

Abbreviations: CI=confidence interval; N=number of patients; NR=not reached; PD=progressive disease.
a Only includes data before crossover to crizotinib for those patients who crossed over to receive crizotinib treatment.
b.Based on the Brookmeyer and Crowley method.
c Based on the Cox Proportional hazards model stratified by ECOG PS, race group, and brain metastases. Assuming
proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of crizotinib.
d One-sided p-value from log-rank test stratified by ECOG PS, race group, and brain metastases.

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Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Final

Secondary Efficacy Endpoint:
Objective Response Rate:
In ORR, for crizotinib, a statistically significant improvement was observed with ap-value <0.0001 (2-sided CMH chi-square test stratified by ECOG PS, brain metastases, andrace group) (Table 8). The ORRs were 74% (95% CI: 67%, 81%) in the crizotinib arm and
45% (95% CI: 37%, 53%) in the chemotherapy arm.
Table 8

Best Overall Response Based on Independent Radiology Review by
Treatment Arm - Full Analysis Population
Crizotinib(N=172)

Chemotherapy(N=171)aComplete response (CR)

3 (1.7)2 (1.2)

Partial response (PR)125 (72.7)

75 (43.9)

Stable disease

29 (16.9)

63 (36.8)

Objective progression

8 (4.7)21 (12.3)

Early death

4 (2.3)4 (2.3)

Indeterminate

3 (1.7)6 (3.5)128 (74.4)

77 (45.0)(67.2, 80.8)(37.4, 52.8)

Best response, n (%)

Objective response rate (CR + PR), n (%)
95% exact CIbTreatment comparison versus chemotherapy
Treatment difference in ORR
95% CI of difference
p-value29.4

c(19.5, 39.3)

d<0.0001

Treatment comparison versus chemotherapy
Risk ratio (%)f
95% CI of risk ratio (%)
p-value

1.664
f(1.379, 2.007)

f<0.0001

Early death is within 6 weeks (42 days) from randomization.
Abbreviations: CI=confidence interval; ECOG=Eastern Cooperative Oncology Group; N=number of patients;
ORR=objective response rate; PS=performance status.
a
Only includes data before crossover to crizotinib for those patients who crossed over to receive crizotinib treatment.
bUsing exact method based on F distribution.
c
Calculated based on a normal distribution.
dP-value is from a 2-sided Pearson chi-square test.
f Calculated from a 2-sided Cochran-Mantel-Haenszel chi-square test stratified by ECOG PS, brain metastases, and racegroup.

Overall Survival and Survival Probabilities at 1 Year and 18 Months:
A total of 71 (41.3%) patients in the crizotinib arm and 81 (47.4%) patients in the
chemotherapy arm were known to have died in the FA population (Table 9). With 41.3%
and 47.4% of OS events at the end of the study in the crizotinib and chemotherapy arms,
respectively, and 144 (84.2%) patients randomized to the chemotherapy arm receiving
subsequent crizotinib treatment (128 patients through the crossover process and 16 patients25

Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Finalas follow-up therapy), there was a numerical improvement in OS in the crizotinib arm
compared to the chemotherapy arm (HR: 0.760; [95% CI: 0.548, 1.053]; 1 sided stratified log
rank test p value=0.0489) that did not reach statistical significance. The median OS, using
the Kaplan-meier method, was not reached [NR] (95% CI: 45.8 months, NR) for crizotinib
and was 47.5 months (95% CI: 32.2, NR) for chemotherapy.
The survival probabilities at 1 year and 18 months were similar between the 2 treatment
arms. The survival probabilities at 1 year were 83.5% (95% CI: 77.0%, 88.3%) and 78.4%(95% CI: 71.3%, 83.9%) for crizotinib and chemotherapy arms, respectively, and the survival
probabilities at 18 months were 71.5% (95% CI: 64.0%, 77.7%) and 66.6% (95% CI: 58.8%,
73.2%) for crizotinib and chemotherapy arms, respectively.
Table 9

Summary of Overall Survival by Treatment Arm (Stratified) - Full Analysis
Population

Number of deaths, n (%)

Crizotinib(N=172)71 (41.3)

Chemotherapy(N=171)a81 (47.4)

Number censored, n (%)

101 (58.7)

90 (52.6)

Patient no longer being followed for survival

85 (49.4)

72 (42.1)

Withdrew consent for follow-up

12 (7.0)

13 (7.6)

Lost to follow-up

4 (2.3)5 (2.9)at Month 12 (95% CI)c

83.5 (77.0, 88.3)

78.4 (71.3, 83.9)

at Month 18 (95% CI)c71.5 (64.0, 77.7)

66.6 (58.8, 73.2)

25% percentile (95% CI)d16.7 (12.6, 20.8)

13.1 (8.8, 17.7)

50% percentile (95% CI)dNR (45.8, NR)

47.5 (32.2, NR)

75% percentile (95% CI)

d

NR

NR

Reason for censorship, n (%):

b

Survival probability:

Kaplan-Meier estimates of time to event, months:

Versus chemotherapy: Hazard ratio

e

0.760

95% CI of hazard ratio
p-value

0.548 - 1.053

f0.0489Abbreviations: CI=confidence interval; ECOG=Eastern Cooperative Oncology Group; n/N=number of patients; NR=notreached; PS=performance statusa
Includes events before and after crossover to crizotinib for those patients who crossed over to receive crizotinib
treatment.
b
Estimated from the Kaplan-Meier curve.
cCalculated using the normal approximation to the log transformed cumulative hazard function.
dBased on the Brookmeyer and Crowley method.
eBased on the Cox Proportional hazards model stratified by ECOG PS, race, and brain metastases. Assuming
proportional hazards, a hazard ratio less than 1 indicates a reduction in hazard rate in favor of crizotinib; a hazard ratio
greater than 1 indicates a reduction in hazard rate in favor of chemotherapy.
fOne-sided p-value from the log-rank test stratified by ECOG PS, race group, and brain metastases

26

Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – FinalTime to Tumor Response:
The responses on crizotinib treatment were rapid and durable with a median TTR of
6.1 weeks. In the chemotherapy arm, the median TTR was 12.1 weeks (Table 10).
Table 10

Time to Tumor Response Based on Independent Radiology Review by
Treatment Arm (Objective Responders Only) - Full Analysis Population
Crizotinib(N=172)

Chemotherapy(N=171)a128

77

8.2 (5.2)

13.2 (7.7)

Median

6.1

12.1

Range

2.7-41.4

5.1-36.7

0-<6 weeks

24 (18.8)

11 (14.3)

6-<12 weeks

81 (63.3)

24 (31.2)

12-<18 weeks

15 (11.7)

22 (28.6)

18-<24 weeks

5 (3.9)8 (10.4)≥24 weeks

3 (2.3)12 (15.6)

Time to response, weeksnMean (SD)

Category, n (%)

Abbreviations: n/N=number of patients; SD=standard deviation.
aOnly includes data before crossover to crizotinib for those patients who crossed over to receive crizotinib treatment.

Duration of Response:
The median DR, estimate using the Kaplan-Meier method, was 49.0 weeks (95% CI: 35.1,
60.0 weeks) for crizotinib and 22.9 weeks (95% CI: 18.0, 25.1 weeks) for chemotherapy(Table 11).
Table 11

Duration of Response Based on Independent Radiology Review by
Treatment Arm (Objective Responders Only) - Full Analysis Population
Crizotinib(N=172)128 (74.4)

Chemotherapy(N=171)a77 (45.0)

With subsequent progression or death70 (54.7)

68 (88.3)

Without subsequent progression or death58 (45.3)

9 (11.7)

25% quartile (95% CI)c23.1 (18.1, 26.9)

11.7 (11.3, 17.1)

c49.0 (35.1, 60.0)

22.9 (18.0, 25.1)

75% quartile (95% CI) c

NR (69.6, NR)

36.4 (25.4, 47.9)

Patients with objective response (CR or PR), n (%)
Objective response (CR or PR) status, n (%)bKaplan-Meier estimates of duration of response, weeks
50% quartile (95% CI)

Abbreviations: CI=confidence interval; N=number of patients; NR=not reached.
aOnly includes data before crossover to crizotinib for those patients who crossed over to receive crizotinib treatmentb% is based on the number of patients with objective response (CR or PR).
C
Based on the Brookmeyer and Crowley method.

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Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Final

Disease Control Rate:
At Week 12, crizotinib had a greater DCR compared to chemotherapy: 79% (95% CI: 72%,84%) for crizotinib and 68% (95% CI: 61%, 75%) for chemotherapy, p-value=0.0381(2-sided Pearson chi square test) (Table 12).
Table 12

Summary of Disease Control Rate at Week 12 Based on Independent
Radiology Review Assessment by Treatment Arm - Full Analysis Population

Disease Control Rate at Week 12, n (%)

Crizotinib(N=172)135 (78.5)

Chemotherapy(N=171)a117 (68.4)

95% exact CIb(71.6, 84.4)(60.9, 75.3)

Treatment Comparison (vs Chemotherapy)
Treatment Difference in DCR
95% CI of Difference
P-value

10.067c(0.8, 19.4)

d0.0381Abbreviations: CI=confidence interval; DCR=disease control rate; N=number of patients;aOnly includes data before crossover to crizotinib for those patients who crossed over to receive crizotinib treatmentbUsing exact method based on F distributioncCalculated based on a normal distributiondP-value is from a 2-sided Pearson chi-square test.

Time to Progression
Median TTP was 13.6 months in the crizotinib arm and 7.0 months in the chemotherapy arm.
The HR comparing crizotinib with chemotherapy was 0.441 (95% CI: 0.335, 0.582), with ap-value <0.0001 (1-sided unstratified log-rank test) (Table 13).
Table 13

Summary of Time to Progression Based on Independent Radiology Review
Assessment by Treatment Arm (Unstratified) - Full Analysis Population

Number of patients with event n (%)

Crizotinib(N=172)89 (51.7)

Chemotherapy(N=171)a132 (77.2)

Number of patients censored n (%)

83 (48.3)

39 (22.8)

Kaplan-Meier estimates of Time to Progression, months
25% quartile (95% CI)c

5.6 (5.0, 7.0)

4.2 (3.1, 5.4)

50% quartile (95% CI)c13.6 (8.5, 15.0)

7.0 (6.8, 8.3)

75% quartile (95% CI)cNR (17.7, NR)

11.0 (9.6, 11.4)

Versus Chemotherapy
Hazard Ratiod

0.441

95% CI of Hazard Ratio
P-value(0.335, 0.582)e<0.0001

Abbreviations: CI=confidence interval; HR=hazard ratio; N=number of patients; NR=not reached.
aOnly includes data before crossover to crizotinib for those patients who crossed over to receive crizotinib treatment.
bCalculated using the normal approximation to the log transformed cumulative hazard ratecBased on the Brookmeyer and Crowley method.
dBased on the Cox proportional hazards model. Assuming proportional hazards, a HR less than 1 indicates a reduction in28

Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Finalehazard rate in favor of crizotinib.
One-sided p-value from the unstratified log-rank test.

Time to Intracranial and Extracranial Progression
Time to IC-TTP and EC-TTP are shown in Table 14 and Table 15 respectively. The
improvement in TTP was observed when only extracranial lesions were evaluated; median
EC TTP was 15.2 months in the crizotinib arm and 7.2 months in the chemotherapy arm(HR: 0.387; 95% CI: 0.286, 0.524; 1-sided p-value <0.0001). Median IC TTP was notreached in the crizotinib arm and was 17.8 months in the chemotherapy arm. There was a
numerical improvement in IC-TTP in the crizotinib arm (HR: 0.595; 95% CI: 0.338, 1.048;
1-sided p-value=0.0347).
Table 14

Summary of Time to Intracranial Progression Based on Independent
Radiology Review Assessment by Treatment Arm (Unstratified) - Full
Analysis Population
Crizotinib(N=172)

Chemotherapy(N=171)aKaplan-Meier estimates of Time to Intracranial Progression, months
25% quartile (95% CI)b15.0 (13.6, NR)

11.2 (8.5, 17.8)

50% quartile (95% CI)b

NR

17.8 (13.9, NR)

75% quartile (95% CI)bNR

NR (17.8, NR)

Versus Chemotherapy
Hazard Ratioc

0.595

95% CI of Hazard Ratio(0.338, 1.048)

P-valued

0.0347Abbreviations: CI=confidence interval; HR=hazard ratio; N=number of patients; NR=not reached.
aOnly includes data before crossover to crizotinib for those patients who crossed over to receive crizotinib treatment.
bBased on the Brookmeyer and Crowley method.
cBased on the Cox proportional hazards model. Assuming proportional hazards, a HR less than 1 indicates a reduction inhazard rate in favor of Crizotinib. A hazard ratio greater than 1 indicates a reduction in hazard rate in favor ofchemotherapy.
dOne-sided p-value from the unstratified log-rank test.

Table 15

Summary of Time to Extracranial Progression Based on Independent
Radiology Review Assessment by Treatment Arm (Unstratified) - Full
Analysis Population
Crizotinib(N=172)

Chemotherapy(N=171)aKaplan-Meier estimates of Time to Extracranial Progression, months
25% quartile (95% CI)b

6.8 (5.4, 8.3)

4.5 (4.0, 5.7)

50% quartile (95% CI)b15.2 (12.6, 21.9)

7.2 (6.9, 8.5)

75% quartile (95% CI)b

NR

11.1 (9.8, 12.4)

Versus Chemotherapy
Hazard Ratioc

0.387

95% CI of Hazard Ratio
P-value(0.286, 0.524)d<0.000129

Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Final
Abbreviations: CI=confidence interval; HR=hazard ratio; N=number of patients; NR=not reached.
aOnly includes data before crossover to crizotinib for those patients who crossed over to receive crizotinib treatmentb
Based on the Brookmeyer and Crowley method.
cBased on the Cox proportional hazards model. Assuming proportional hazards, a HR less than 1 indicates a reduction inhazard rate in favor of Crizotinib. A hazard ratio greater than 1 indicates a reduction in hazard rate in favor ofchemotherapy.
dOne-sided p-value from the unstratified log-rank test

Patient Reported Outcomes:
Time to Deterioration
A statistically significantly longer TTD was observed in the crizotinib arm than in the
chemotherapy arm (2.1 months vs 0.5 months; HR: 0.591; Hochberg adjusted log-rank
2-sided p-value=0.0005) in the composite endpoint that included pain in chest, dyspnea, or
cough symptoms (Table 16).
Table 16

Time to Deterioration in Pain (in Chest), Dyspnea, or Cough by Treatment
Arm - PRO Evaluable Population

Number with event, n (%)

Crizotinib(N=166)111 (66.9)

Chemotherapy(N=163)a123 (75.5)

Number censored, n (%)

55 (33.1)

40 (24.5)

25% quartile (95% CI)b0.3 (0.3, 0.5)

0.3 (0.3, 0.3)

50% quartile (95% CI)

b2.1 (0.8, 4.2)

0.5 (0.4, 0.7)

75% quartile (95% CI)b16.7 (7.7, NR)

2.9 (1.5, NR)

Kaplan-Meier estimates of time to event, months

Versus chemotherapy
Hazard ratioc

0.591

95% CI of hazard ratio
p-value(0.452, 0.773)d0.0002Abbreviations: CI=confidence interval; NR=not reached; N=number of patients;aOnly includes data before crossover to crizotinib for those patients who crossed over to receive crizotinib treatment.
bBased on the Brookmeyer and Crowley method.
cBased on the Cox Proportional hazards model. Assuming proportional hazards, a hazard ratio less than 1 indicates a
reduction in hazard rate in favor of crizotinib.
dTwo-sided p-value from the unstratified log-rank test.

EORTC QLQ C30
Overall, a statistically significantly (all 2-sided p-values <0.001) greater improvement frombaseline was observed in the crizotinib arm compared with the chemotherapy arm in global
quality of life, emotional functioning, physical functioning, role functioning, and social
functioning (Table 17).
A statistically significantly greater improvement (p-values <0.001) was observed in the
crizotinib arm compared to the chemotherapy arm in appetite loss, dyspnea, fatigue,
insomnia, and pain. Statistically significantly greater deterioration was observed in the
crizotinib arm for diarrhea (p-value <0.001). A statistically significantly greater deterioration30

Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Final

was observed in the chemotherapy arm compared to the crizotinib arm for nausea andvomiting (p-value <0.05) (Table 18).
Table 17

Crizotinib versus Chemotherapy Overall Difference in Change From
Baselinea Scores in QLQ-C30 Domain by Treatment Arm (Mixed Model
Analysis) - PRO Evaluable Population
Value

95% CIa

p-valueb

QLQ-C30 Global QoL

13.8303(10.74,16.92)<.0001QLQ-C30 Cognitive Functioning

3.3532(0.60,6.11)

0.0170QLQ-C30 Emotional Functioning

7.5165(4.57,10.46)<.0001QLQ-C30 Physical Functioning

10.4035(7.48,13.32)<.0001QLQ-C30 Role Functioning

15.5513(11.29,19.81)<.0001QLQ-C30 Social Functioning

8.7641(4.69,12.84)<.0001

Crizotinib vs Chemotherapy Overall

Abbreviations: CI=confidence interval; QLQ-C30= Quality of Life Questionnaire-Core 30.
a
From a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, andbaseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).
b
P-values and confidence intervals are not adjusted for multiplicity.

Table 18

Crizotinib versus Chemotherapy Overall Difference in Change From
Baselinea Scores in QLQ-C30 Symptoms by Treatment Arm (Mixed Model
Analysis) - PRO Evaluable Population
Value

95% CIa

p-valueb

QLQ-C30 Appetite loss

-13.4976(-18.03,-8.97)<.0001QLQ-C30 Constipation-4.4336(-9.00,0.13)

0.0570QLQ-C30 Diarrhea

12.4906(8.98,16.00)<.0001QLQ-C30 Dysponea-13.4622(-17.20,-9.73)<.0001

Crizotinib vs Chemotherapy Overall

QLQ-C30 Fatigue-14.9987(-18.52,-11.48)<.0001QLQ-C30 Financial Difficulties-0.8186(-4.56,2.92)

0.6681QLQ-C30 Insomnia-10.0430(-14.22,-5.87)<.0001QLQ-C30 Nausea and Vomiting-3.4446(-6.84,-0.05)

0.0468QLQ-C30 Pain

-9.9277(-13.23,-6.62)<.0001Abbreviations: CI=confidence interval; QLQ-C30= Quality of Life Questionnaire-Core 30.
a
From a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, andbaseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).
b
P-values and confidence intervals are not adjusted for multiplicity.

EORTC QLQ-LC13
A statistically significantly greater improvement observed in the crizotinib arm compared tothe chemotherapy arm for alopecia (p-value <0.05), coughing (p-value <0.001), dyspnea(p-value <0.001), pain in arm or shoulder (p-value <0.001), pain in chest (p-value <0.001),
and pain in other parts (p-value <0.001). Statistically significantly greater deterioration
observed for peripheral neuropathy (p-value <0.05) (Table 19).
31

Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Final

Table 19

Crizotinib versus Chemotherapy Overall Difference in Change From
Baselinea Scores in QLQ-LC30 Symptoms by Treatment Arm (Mixed Model
Analysis) - PRO Evaluable Population
Value

95% CIa

p-valueb

QLQ-LC13 Alopecia-4.8149(-8.52,-1.11)

0.0108QLQ-LC13 Coughing-8.3926(-12.06,-4.72)<.0001QLQ-LC13 Dysphagia

0.6651(-1.78,3.11)

0.5938QLQ-LC13 Dyspnoea-9.0080(-11.96,-6.06)<.0001

Crizotinib vs Chemotherapy Overall

QLQ-LC13 Haemoptysis-0.8828(-1.82,0.06)

0.0656

QLQ-LC13 Pain in Arm or Shoulder-6.0475(-9.22,-2.88)

0.0002

QLQ-LC13 Pain in Chest-8.0959(-11.35,-4.84)<.0001QLQ-LC13 Pain in Other Parts-6.7717(-10.24,-3.31)

0.0001QLQ-LC13 Peripheral Neuropathy

3.3521(0.11,6.59)

0.0427

QLQ-LC13 Sore Mouth-2.1521(-5.00,0.69)

0.1382Abbreviations: CI=confidence interval; QLQ-LC30=Quality of Life Questionnaire-Supplement Module for Lung Cancer(LC13).
a
From a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, andbaseline EORTC QLQ-LC30 subscale baseline score (intercept and time from first dose are included as random effects).
b
P-values and confidence intervals are not adjusted for multiplicity.

EORTC EQ-5D VAS:
A statistically significantly (p-value <0.05) greater improvement was observed in EQ-5D
VAS general health status scores in the crizotinib arm compared to the chemotherapy arm(Table 20).
Table 20

Mixed Model Analysis Summary Tables by Arm for EORTC EQ-5D
VAS (Change from Baseline Score) - PRO evaluable
Estimated Change from Baselinea
Value

95% CIa

p-value

At Cycle 2 Day 1

4.2887(1.26,7.32)

0.0056At Cycle 3 Day 1

4.5730(1.62,7.53)

0.0024At Cycle 4 Day 1

4.8573(1.92,7.80)

0.0012At Cycle 5 Day 1

5.1416(2.15,8.14)

0.0008At Cycle 6 Day 1

5.4259(2.31,8.54)

0.0006

Crizotinib vs Chemotherapy Overall

3.9908(0.81,7.17)

0.0139Time point
Crizotinib vs ChemotherapyaFrom a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, andbaseline EQ-5D VAS subscale baseline score (intercept and time from first dose are included as random effects).

32

Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Final

EQ-5D Index:
A statistically significantly (p-value <0.05) greater improvement was observed in EQ-5D
index scores in the crizotinib arm compared to the chemotherapy arm. The overall EQ-5D
index score was also found to be statistically significantly higher in the crizotinib arm
compared to the chemotherapy arm (p-value <0.001) (Table 21).
Table 21

Mixed Model Analysis Summary Tables by Arm for EORTC EQ-5D
Index (Change from Baseline Score) - PRO evaluable
Estimated Change from Baselinea
Value

95% CIa

p-value

At Cycle 2 Day 1

0.1005(0.06,0.14)<.0001At Cycle 3 Day 1

0.08880(0.05,0.13)<.0001At Cycle 4 Day 1

0.07710(0.04,0.11)

0.0001At Cycle 5 Day 1

0.06540(0.03,0.10)

0.0008At Cycle 6 Day 1

0.05370(0.01,0.09)

0.0085

Crizotinib vs Chemotherapy Overall

0.1128(0.07,0.16)<.0001Time point
Crizotinib vs ChemotherapyaFrom a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, andbaseline EQ-5D VAS subscale baseline score (intercept and time from first dose are included as random effects).

Visual Symptom Assessment Questionnaire
Data from the first 60 cycles were presented as subsequent cycles which had fewer patientsand thus limited interpretation of the summary data.
In response to the first question, 17.4% to 67.1% of patients reported experiencing a visual
disturbance (up to Cycle 60) in the crizotinib arm and 12.8% to 20.8% in the chemotherapyarm (up to Cycle 6).
Most patients reported each event lasting ≤1 minute in both the crizotinib and chemotherapy
arms.
•

The most commonly experienced visual disturbances in the crizotinib arm wereappearance of shimmering/flashing/trailing lights, appearance of
streamers/strings/floaters, and appearance of overlapping shadows/after images.

•

The most commonly experienced visual disturbance in the chemotherapy arm washazy/blurry vision.

Among patients reporting an experience with a visual disturbance in the crizotinib arm, mostpatients reported that visual effects were not at all or a little bothersome and most patients
indicated no or minimal impact (scores 0 to 3) on daily activities at each cycle.
Pharmacokinetic Endpoint
33

Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Final

Plasma concentrations of crizotinib (including its metabolite, PF-06260182)
Trough plasma concentration of crizotinib and its metabolite PF-06260182 are presented inTable 22. The plasma concentrations of crizotinib and PF-06260182 appeared to reach thesteady state within the first cycle after repeated oral administration of crizotinib 250 mg BID.
The geometric mean predose concentrations (Ctrough) of crizotinib and its metabolites weresimilar across Day 1 of Cycles 2, 3, and 5.
Table 22

Predose Concentrations (Ctrough) of Crizotinib and its Metabolite,
PF-06260182, and PF-06260182 to Crizotinib Ratios Following 250 mg BID
Oral Dosing of Crizotinib

N/nCrizotinib Ctrough, ng/mLa

PF-06260182 Ctrough, ng/mLa

PF-06260182 to Crizotinib ratioaCycle 2 Day 1

Cycle 3 Day 1

Cycle 5 Day 1

91/100

85/94

82/86

324.2 (39)320.9 (40)308.2 (39)98.4 (46)99.0 (49)92.9 (55)0.302 (25)0.300 (25)0.290 (25)Abbreviations: BID=twice daily; Ctrough=trough concentration; CV=coefficient of variation; n=number of observations for
PF-06260182; N=number of observations for crizotinib and PF-06260182 to crizotinib ratio.
aGeometric mean (%CV).

Pharmacodynamic Endpoint
ALK Gene Fusion Variant Analysis
The proportion of patients with each of the EML4-ALK fusion variants is presented inTable 23. Overall 88 patients (59.5% of the evaluable population) were with norearrangement, 39 (26.4%) with a V1 rearrangement, 11 (7.4%) with a V2 rearrangement,
2 (1.4%) with a V3a rearrangement and 8 (5.4%) with a V3a/b rearrangement. No V3b, V4,
V5a, V6, or V7 rearrangements were observed. Among the 60 patients with an ALK generearrangement, V1, V2, and V3 rearrangements represented 65.0%, 18.3%, and 16.7% ofcases, respectively.
ORR, based on IRR, within treatment arm, was comparable between the ALK variant groups.
However, the analysis is limited by the small sample size and large 95% CI.
Table 23

Best Overall Response Based on Independent Radiology Review by
Treatment Arm and EML4-ALK Gene Fusion Variant - ALK Variant
Evaluable Population
Crizotinib(N=70)

EML4-ALK genefusion variantb

Chemotherapy(N=78)aPatients withvariant, n (%)

ORR (CR + PR)n (%)(95% CI)cPatients withvariant, n (%)

ORR (CR + PR)n (%)(95% CI)cV1

19 (27.1)

16 (84.2)(60.4, 96.6)

20 (25.6)

9 (45.0)(23.1, 68.5)

V2

5 (7.1)5 (100)(47.8, 100)

6 (7.7)

2 (33.3)(4.3, 77.7)

34

Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Final
Crizotinib(N=70)

EML4-ALK genefusion variantb

Chemotherapy(N=78)aPatients withvariant, n (%)

ORR (CR + PR)n (%)(95% CI)cPatients withvariant, n (%)

ORR (CR + PR)n (%)(95% CI)cV3a

1 (1.4)0NA

1 (1.3)

1 (100)(2.5, 100)V3a/b

3 (4.3)3 (100)(29.2, 100)

5 (6.4)3 (60.0)(14.7, 94.7)

No rearrangement

42 (60.0)30 (71.4)(55.4, 84.3)

46 (59.0)

20 (43.5)(28.9, 58.9)

Abbreviations: ALK=anaplastic lymphoma kinase; CI=confidence interval; CR=complete response; EML4=echinoderm
microtubule-associated protein-like 4; n/N=number of patients; NA=not applicable; ORR=objective response rate;
PR=partial response.
aOnly includes data before crossover to crizotinib for those patients who crossed over to receive crizotinib treatment.
bVariants V4, V5a, V6, and V7 were not detected.
cUsing exact method based on F distribution.

Health care resource utilization analysis
There were 127 hospitalization events for 69 patients in the crizotinib arm and 107
hospitalization events for 62 patients in the chemotherapy arm Median length of hospital stay
was 8 days (range, 1-114 days) in the crizotinib arm and 9 days (range, 1-410 days) in the
chemotherapy arm. Two (1.16%) readmissions were reported in the crizotinib arm and nonein the chemotherapy arm. Of note, the analysis of hospitalizations was not adjusted for the
longer duration of crizotinib treatment than the duration of chemotherapy treatment,
precluding meaningful conclusions (Table 24).
Table 24

Hospitalizations by Treatment Arm - Full Analysis Population
Crizotinib(N=172)

Chemotherapy(N=171)a69 (40.12)

62 (36.26)

127

107

12.6(14.27)

16.8(40.75)

Median

8

9

Range

1-114

1-410

Hospital admissionsb
Number (%) of patients who had hospital admissionsc

Number of hospitalization events
Length of stay per event, days:
Mean (SD)

Data are based on the 'Hospitalization Status' from the Adverse Event case report form page.
Patients can have multiple hospitalization events.
Abbreviations: N=number of patients; SD=standard deviation.
a
The chemotherapy arm only includes data prior to crossover to crizotinib for those patients who crossed over to receive
crizotinib treatment. For patients who completed 6 cycles of chemotherapy without progression and later crossed overto receive crizotinib treatment, the chemotherapy arm includes the hospitalization events that occurred between end of
chemotherapy treatment and actual crossover to crizotinib.
b
The follow-up period for hospitalization events could vary between the treatment arms and the events are not adjusted
for duration of study treatment.
cMore than 1 hospitalization event could be associated with a single patient35

Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Final

Safety Results:
The AE profile remains consistent with the known AE profile for crizotinib from otherpreviously reported crizotinib studies. Except for the analysis of exposure-adjusted incidence
rates of selected AEs and exposure-adjusted incidence rates for Grade 5 AEs, none of the AE
analyses were adjusted for the longer duration of study treatment for the crizotinib arm
compared with the chemotherapy arm (median 63.9 weeks and 18.0 weeks, respectively).
Brief Summary of Adverse Events:
A summary of all-causality AEs and treatment-related AEs (crizotinib vs chemotherapy) bytreatment arm is provided in Table 25. The analyses of AEs were not adjusted for the longer
study treatment duration in the crizotinib arm than in the chemotherapy arm, except for the
analysis of the exposure-adjusted incidence rates, per 1000 person-years of exposure, ofselected AEs of special interest and exposure-adjusted incidence rates for Grade 5 AEs.
Table 25

Treatment-Emergent Adverse Events by Treatment Arm – All-Causality
and Treatment-Related - Safety Analysis Population
Crizotinib(N=171)

Number of patientsb
With AEsc

With SAEs
With Grade 3 or 4 AEs
With Grade 5 AEs
With AEs associated with:dPermanent discontinuation
Dose reduction
Temporary discontinuation

Chemotherapy(N=169)aAll
Causalitiesn (%)

Treatment
relatedn (%)

All
Causalitiesn (%)

Treatment
relatedn (%)

170 (99.4)
71 (41.5)

168 (98.2)
22 (12.9)

168 (99.4)
49 (29.0)

156 (92.3)
15 (8.9)106 (62.0)
23 (13.5)

70 (40.9)
090 (53.3)
4 (2.4)67 (39.6)
026 (15.2)

9 (5.3)24 (14.2)

14 (8.3)

18 (10.5)
83 (48.5)

14 (8.2)
66 (38.6)

14 (8.3)
55 (32.5)

14 (8.3)
47 (27.8)

Abbreviations: AE=adverse event; n/N=number of patients; SAE=serious adverse eventa
Only includes data before crossover to crizotinib for those patients who crossed over to receive crizotinib treatment.
bPatients are counted only once per treatment in each row.
c
According to the investigator assessment.
d
AEs associated with permanent discontinuation are based on the AE case report form page; the AE may not be thepatient’s primary reason for discontinuation, as documented on the End of Treatment case report form

Non-serious adverse events (NSAE):
The treatment-emergent NSAEs reported in ≥5% of patients in any of the treatment arm bypreferred term and by system organ class (all causality and treatment related) are summarizedin (Table 26).

36

Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Final

Table 26

Treatment-Emergent Non-Serious Adverse Events Reported in ≥5%patients in Any of the Treatment Arm by System Organ Class and Preferred
Term (All Causalities and Treatment-Related) - Safety Analysis Set

System Organ Class

Crizotinib(N=171)n (%)

Preferred Term

Chemotherapy(N=169)n (%)

All
Causalities
169 (98.8)
47 (27.5)

Treatment
related167 (97.7)
38 (22.2)

All
Causalities
164 (97.0)
71 (42.0)

Treatment
related151 (89.3)
66 (39.1)

18 (10.5)

7 (4.1)53 (31.4)

43 (25.4)

Leukopenia

8 (4.7)7 (4.1)16 (9.5)

16 (9.5)

Neutropenia

32 (18.7)

31 (18.1)

36 (21.3)

35 (20.7)

Thrombocytopenia
Cardiac disorders

1 (0.6)31 (18.1)

25 (14.6)

14 (8.3)
1 (0.6)

13 (7.7)-

Bradycardia

22 (12.9)

17 (9.9)--

Sinus bradycardia

10 (5.8)9 (5.3)1 (0.6)-

Ear and labyrinth disorders

4 (2.3)2 (1.2)10 (5.9)9 (5.3)Tinnitus

4 (2.3)2 (1.2)10 (5.9)9 (5.3)Eye disorders

122 (71.3)

119 (69.6)

12 (7.1)

6 (3.6)

Photopsia

18 (10.5)

18 (10.5)

2 (1.2)2 (1.2)

Vision blurred

13 (7.6)

12 (7.0)

5 (3.0)2 (1.2)Visual impairment

98(57.3)

96 (56.1)

5 (3.0)3 (1.8)Vitreous floaters

11 (6.4)

11 (6.4)

1 (0.6)-

Gastrointestinal disorders

162 (94.7)

152 (88.9)

131 (77.5)

117 (69.2)

Abdominal distension

11 (6.4)-

1 (0.6)-

Abdominal pain

25 (14.6)

22 (12.9)8 (4.7)5 (3.0)Abdominal pain upper

27 (15.8)

20 (11.7)

10 (5.9)5 (3.0)Constipation

78 (45.6)

55 (32.2)

51 (30.2)

33 (19.5)

Diarrhoea

111 (64.9)

100 (58.5)

22 (13.0)

14 (8.3)

Dyspepsia

27 (15.8)

17 (9.9)5 (3.0)2 (1.2)Dysphagia

19 (11.1)-

3 (1.8)-Gastrooesophageal reflux disease

14 (8.2)

10 (5.8)

6 (3.6)3 (1.8)

Nausea100 (58.5)

87 (50.9)

98 (58.0)

93 (55.0)

Stomatitis

13 (7.6)

12 (7.0)

17 (10.1)

16 (9.5)

Vomiting

87 (50.9)

69 (40.4)

57 (33.7)

51 (30.2)

General disorders andadministration site conditions
Asthenia

134 (78.4)

98 (57.3)

112 (66.3)

86 (50.9)

28 (16.4)

17 (9.9)40 (23.7)

34 (20.1)

Chest pain

21 (12.3)-

14 (8.3)-

Fatigue54 (31.6)

45 (26.3)

66 (39.1)

56 (33.1)

Any AEs
Blood and lymphatic systemdisordersAnaemia37

Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Final
System Organ Class

Crizotinib(N=171)n (%)

Preferred Term

Chemotherapy(N=169)n (%)

Any AEs
Influenza like illness

All
Causalities
169 (98.8)
10 (5.8)

Treatment
related167 (97.7)-

All
Causalities
164 (97.0)
1 (0.6)

Treatment
related151 (89.3)-

Mucosal inflammation

2 (1.2)1 (0.6)9 (5.3)9 (5.3)

Oedema peripheral

89 (52.0)

68 (39.8)

12 (7.1)

5 (3.0)Pain

9 (5.3)-5 (3.0)-Pyrexia40 (23.4)-

17 (10.1)-

Infections and infestations

77 (45.0)-30 (17.8)-

Bronchitis

11 (6.4)-

2 (1.2)-

Conjunctivitis

3 (1.8)-10 (5.9)-

Nasopharyngitis

30 (17.5)-5 (3.0)-Rhinitis

9 (5.3)-2 (1.2)-Upper respiratory tract infection

41 (24.0)-

13 (7.7)-

Urinary tract infection

10 (5.8)-

2 (1.2)-

Investigations

97 (56.7)

76 (44.4)

53 (31.4)

42 (24.9)

Alanine aminotransferase
increased
Aspartate aminotransferase
increased
Blood bilirubin increased

59 (34.5)

58 (33.9)

21 (12.4)

18 (10.7)47 (27.5)

45 (26.3)

16 (9.5)

14 (8.3)

9 (5.3)-2 (1.2)-

Blood creatinine increased

9 (5.3)-5 (3.0)-Electrocardiogram QT prolonged

11 (6.4)

9 (5.3)2 (1.2)2 (1.2)

Neutrophil count decreased

14 (8.2)

14 (8.2)

17 (10.1)

17 (10.1)

Platelet count decreased

1 (0.6)

1 (0.6)19 (11.2)

18 (10.7)

Weight decreased

12 (7.0)-

5 (3.0)-Weight increased

16 (9.4)-

4 (2.4)-White blood cell count decreased

11 (6.4)

11 (6.4)

12 (7.1)

12 (7.1)

Metabolism and nutrition
disorders
Decreased appetite

78 (45.6)

47 (27.5)

69 (40.8)

61 (36.1)

59 (34.5)

40 (23.4)

58 (34.3)

52 (30.8)

Hypoalbuminaemia

19 (11.1)

9 (5.3)2 (1.2)2 (1.2)

Hypocalcaemia

10 (5.8)-

1 (0.6)-

Hypomagnesaemia

3 (1.8)2 (1.2)13 (7.7)

10 (5.9)

Hypophosphataemia

10 (5.8)-

2 (1.2)-

Hypoproteinaemia

10 (5.8)---

Musculoskeletal and connective
tissue disorders
Arthralgia

98 (57.3)

25 (14.6)

55 (32.5)

8 (4.7)25 (14.6)

9 (5.3)

11 (6.5)

4 (2.4)

Back pain

35 (20.5)-

20 (11.8)-

38

Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Final
System Organ Class

Crizotinib(N=171)n (%)

Preferred Term

Chemotherapy(N=169)n (%)

Any AEs
Bone pain

All
Causalities
169 (98.8)
12 (7.0)

Treatment
related167 (97.7)-

All
Causalities
164 (97.0)
4 (2.4)Treatment
related151 (89.3)-

Flank pain

9 (5.3)-2 (1.2)-

Muscle spasms

17 (9.9)

11 (6.4)

2 (1.2)-

Muscle weakness

9 (5.3)-4 (2.4)-

Musculoskeletal chest pain

10 (5.8)-

5 (3.0)-Musculoskeletal pain

21 (12.3)-

8 (4.7)-

Myalgia

14 (8.2)-

6 (3.6)-

Neck pain

11 (6.4)-

2 (1.2)-Pain in extremity

44 (25.7)

10 (5.8)

14 (8.3)5 (3.0)

Nervous system disorders

101 (59.1)

69 (40.4)

53 (31.4)

32 (18.9)

Dizziness

35 (20.5)

20 (11.7)

15 (8.9)

7 (4.1)

Dysgeusia

45 (26.3)

41 (24.0)

9 (5.3)8 (4.7)

Headache48 (28.1)

13 (7.6)

25 (14.8)

3 (1.8)

Neuropathy peripheral

4 (2.3)2 (1.2)12 (7.1)

10 (5.9)

Paraesthesia

29 (17.0)

16 (9.4)8 (4.7)7 (4.1)

Peripheral sensory neuropathy

6 (3.5)6 (3.5)10 (5.9)9 (5.3)

Psychiatric disorders

31 (18.1)

10 (5.8)

22 (13.0)

3 (1.8)

Anxiety

10 (5.8)-9 (5.3)-

Insomnia

23 (13.5)

10 (5.8)

15 (8.9)

3 (1.8)Respiratory, thoracic andmediastinal disorders
Cough

78 (45.6)-

59 (34.9)-

44 (25.7)-

28 (16.6)-

Dyspnoea

31 (18.1)-

23 (13.6)-

Haemoptysis

11 (6.4)-

6 (3.6)-

Oropharyngeal pain

14 (8.2)-

8 (4.7)-

Productive cough15 (8.8)-8 (4.7)-

Skin and subcutaneous tissue
disorders
Alopecia40 (23.4)

29 (17.0)

39 (23.1)

34 (20.1)

16 (9.4)

4 (2.3)17 (10.1)

15 (8.9)

Pruritus

9 (5.3)8 (4.7)

10 (5.9)9 (5.3)Rash

22 (12.9)

19 (11.1)

20 (11.8)

18 (10.7)

Abbreviation: MedDRA=medical dictionary for regulatory activities. “-”: Frequency below 5% threshold
MedDRA (v19.1) coding dictionary applied.

39

Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Final

Serious Adverse events (SAE):
The treatment-emergent SAEs of patients in any of the treatment arm by preferred term andby system organ class (all causality and treatment related) are summarized in (Table 27).
Table 27

Treatment-Emergent Serious Adverse Events Reported in patients by
System Organ Class and Preferred Term (All Causalities and TreatmentRelated) - Safety Analysis Set

System Organ Class

Crizotinib(N=171)n (%)

Preferred Term

Chemotherapy(N=169)n (%)

All
Causalities
71 (41.5)
1 (0.6)

Treatment
related22 (12.9)0All
Causalities
49 (29.0)
3 (1.8)Treatment
related15 (8.9)
3 (1.8)00

1 (0.6)

1 (0.6)

Febrile neutropenia
Lymphadenopathy mediastinal
Cardiac disorders01 (0.6)5 (2.9)00
1 (0.6)2 (1.2)0
7 (4.1)2 (1.2)0
2 (1.2)Atrial fibrillation

1 (0.6)0

1 (0.6)0

Atrioventricular block

1 (0.6)0

0

0Bradycardia

1 (0.6)

1 (0.6)00

Cardiac arrest

0

0

1 (0.6)0

Cardiac tamponade

2 (1.2)000Myocardial ischaemia

00

1 (0.6)

1 (0.6)

Pericardial effusion00

1 (0.6)0

Pericarditis

00

1 (0.6)0

Syncope002 (1.2)1 (0.6)

Gastrointestinal disorders

13 (7.6)

9 (5.3)7 (4.1)6 (3.6)

Abdominal pain

1 (0.6)

1 (0.6)00Colitis1 (0.6)000Constipation00

1 (0.6)

1 (0.6)

Diarrhoea

2 (1.2)2 (1.2)1 (0.6)

1 (0.6)Dysphagia

00

1 (0.6)0

Haemorrhoids

1 (0.6)000Intestinal obstruction

2 (1.2)1 (0.6)00

Nausea4 (2.3)3 (1.8)1 (0.6)

1 (0.6)

Oesophageal ulcer

1 (0.6)

1 (0.6)00

Oesophagitis

3 (1.8)3 (1.8)00Vomiting

3 (1.8)2 (1.2)4 (2.4)4 (2.4)General disorders and administration site
conditions

23 (13.5)

2 (1.2)5 (3.0)3 (1.8)Any AEs
Blood and lymphatic system disorders
Anaemia40

Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Final
System Organ Class

Crizotinib(N=171)n (%)

Preferred Term

Chemotherapy(N=169)n (%)

All
Causalities
71 (41.5)
2 (1.2)Treatment
related22 (12.9)0All
Causalities
49 (29.0)0Treatment
related15 (8.9)
0

Chest pain

1 (0.6)0

1 (0.6)0Death

1 (0.6)000Disease progression

18 (10.5)

01 (0.6)0

Fatigue

1 (0.6)

1 (0.6)

0

0

0

0

2 (1.2)2 (1.2)

Oedema peripheral

1 (0.6)000

Pyrexia

1 (0.6)

1 (0.6)2 (1.2)2 (1.2)

Hepatobiliary disorders

3 (1.8)1 (0.6)2 (1.2)0

Bile duct obstruction00

1 (0.6)0

2 (1.2)

0

0

0

0

0

1 (0.6)0

Drug-induced liver injury

1 (0.6)

1 (0.6)00

Infections and infestations

24 (14.0)

3 (1.8)3 (1.8)0Abdominal abscess

1 (0.6)

1 (0.6)00Arthritis bacterial

1 (0.6)0

0

0

Atypical pneumonia

1 (0.6)000Bronchitis

00

1 (0.6)0

Cellulitis

2 (1.2)0

0

0

Hepatitis B

1 (0.6)000Influenza

1 (0.6)0

0

0

Lower respiratory tract infection

2 (1.2)000Lung infection

1 (0.6)0

0

0

Neutropenic sepsis

1 (0.6)

1 (0.6)00Periodontitis

1 (0.6)000Peritonitis

1 (0.6)00

0Pneumonia

3 (1.8)0

1 (0.6)0

Pulmonary sepsis

1 (0.6)00

0

Pyelonephritis

1 (0.6)0

00

Respiratory tract infection

2 (1.2)0

1 (0.6)0

Respiratory tract infection viral

1 (0.6)0

0

0

Sepsis2 (1.2)1 (0.6)00

Septic shock

2 (1.2)000Skin infection

1 (0.6)0

0

0

Any AEs
Asthenia

General physical health deterioration

Cholecystitis
Cholecystitis acute41

Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Final
System Organ Class

Crizotinib(N=171)n (%)

Preferred Term

Chemotherapy(N=169)n (%)

All
Causalities
71 (41.5)
1 (0.6)

Treatment
related22 (12.9)0All
Causalities
49 (29.0)0Treatment
related15 (8.9)02 (1.2)000Injury, poisoning and procedural
complications
Overdose00

2 (1.2)000

1 (0.6)0

Rib fracture00

1 (0.6)0Investigations

1 (0.6)

1 (0.6)00Alanine aminotransferase increased

1 (0.6)

1 (0.6)0

0

Aspartate aminotransferase increased

1 (0.6)

1 (0.6)00Metabolism and nutrition disorders

4 (2.3)2 (1.2)3 (1.8)3 (1.8)Decreased appetite

2 (1.2)1 (0.6)

0

0

0

0

2 (1.2)2 (1.2)Diabetic ketoacidosis

1 (0.6)0

0

0

Hypokalaemia

1 (0.6)0

0

0

Hyponatraemia

1 (0.6)

1 (0.6)

1 (0.6)

1 (0.6)

Hypoproteinaemia

1 (0.6)0

0

0

Musculoskeletal and connective tissue
disorders
Arthritis

7 (4.1)0

2 (1.2)0

2 (1.2)000Bone pain

1 (0.6)000Flank pain

1 (0.6)

0

0

0

0

0

1 (0.6)0Muscular weakness

2 (1.2)000Osteonecrosis

1 (0.6)000Rotator cuff syndrome00

1 (0.6)0Spinal column stenosis

1 (0.6)

0

0

0

0

0

1 (0.6)00

0

1 (0.6)0

Nervous system disorders

10 (5.8)

1 (0.6)7 (4.1)1 (0.6)

Altered state of consciousness

1 (0.6)0

0

0Central nervous system lesion

1 (0.6)0

00Cervicobrachial syndrome

1 (0.6)0

0

0Dizziness

1 (0.6)0

0

0

Headache

3 (1.8)1 (0.6)0

0

Loss of consciousness

1 (0.6)0

0

0

Any AEs
Upper respiratory tract infection
Urinary tract infection

Dehydration

Muscle spasms

Neoplasms benign, malignant andunspecified (incl cysts and polyps)
Thyroid adenoma

42

Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Final
System Organ Class

Crizotinib(N=171)n (%)

Preferred Term

Chemotherapy(N=169)n (%)

All
Causalities
71 (41.5)
1 (0.6)

Treatment
related22 (12.9)0All
Causalities
49 (29.0)0Treatment
related15 (8.9)0Paraesthesia

1 (0.6)000Partial seizures00

1 (0.6)0

1 (0.6)0

5 (3.0)1 (0.6)00

1 (0.6)0Pregnancy, puerperium and perinatal
conditions
Unintended pregnancy

1 (0.6)00

0

1 (0.6)000

Psychiatric disorders

1 (0.6)0

1 (0.6)0Completed suicide00

1 (0.6)0

Hypomania

1 (0.6)000Renal and urinary disorders

5 (2.9)3 (1.8)2 (1.2)1 (0.6)00

1 (0.6)

1 (0.6)

1 (0.6)0

0

0

Haematuria

00

1 (0.6)0

Renal cyst

3 (1.8)3 (1.8)00Urinary retention

1 (0.6)0

0

0

Reproductive system and breast disorders

1 (0.6)4 (2.3)00

Uterine prolapse

1 (0.6)0

00

Respiratory, thoracic and mediastinal
disorders
Acute respiratory distress17(9.9)4 (2.3)20 (11.8)

2 (1.2)1 (0.6)00

0Acute respiratory failure

1 (0.6)000Asthma00

1 (0.6)0

Dyspnoea

7 (4.1)2 (1.2)4 (2.4)0

Haemoptysis

00

2 (1.2)0

1 (0.6)

1 (0.6)

1 (0.6)0Lung infiltration00

1 (0.6)0Pleural effusion

2 (1.2)05 (3.0)000

1 (0.6)0

Pneumonitis

1 (0.6)

1 (0.6)0

0

Pneumothorax

00

1 (0.6)0

Pulmonary embolism

5 (2.9)0

7 (4.1)2 (1.2)

Pulmonary oedema

00

1 (0.6)0

Vascular disorders

6 (3.5)1 (0.6)

1 (0.6)0

Aortic dissection

1 (0.6)0

0

0

Any AEs
Multiple sclerosis

SeizureTransient ischaemic attack

Acute kidney injury
DysuriaInterstitial lung disease

Pleurisy

43

Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Final
System Organ Class

Crizotinib(N=171)n (%)

Preferred Term

Chemotherapy(N=169)n (%)

All
Causalities
71 (41.5)
1 (0.6)

Treatment
related22 (12.9)0All
Causalities
49 (29.0)
1 (0.6)

Treatment
related15 (8.9)
0

Embolism

1 (0.6)

1 (0.6)00Orthostatic hypotension

1 (0.6)00

0

Phlebitis

1 (0.6)0

0

0

Superior vena cava syndrome

1 (0.6)0

0

0

Any AEs
Deep vein thrombosis

Abbreviation: MedDRA=medical dictionary for regulatory activities.
The MedDRA preferred term of syncope is reported under the system organ class of cardiac disorders.
MedDRA (v19.1) coding dictionary applied.

Permanent discontinuations due to AEs:
The percentages of patients with all-causality AEs associated with permanent discontinuationfrom study treatment were similar between the 2 treatment arms; 26 (15.2%) patients in the
crizotinib arm and 24 (14.2%) patients in the chemotherapy arm (Table 28).
Table 28

Treatment Emergent All Causality Adverse Events Associated With
Permanent Discontinuation From Treatment by Treatment Arm Safety
Analysis Population

MedDRA Preferred Term or Clustered Term

Any AE associated with permanent treatment discontinuation
Disease progression*

ELEVATED TRANSAMINASES
INTERSTITIAL LUNG DISEASE*HEPATOTOXICITY*

Crizotinib(N=171)n (%)
26 (15.2)

Chemotherapy(N=169)an (%)
24 (14.2)

7 (4.1)1 (0.6)3 (1.8)1 (0.6)3 (1.8)02 (1.2)0Acute respiratory failure

1 (0.6)0

Diabetic ketoacidosis
Intestinal obstruction

1 (0.6)0

1 (0.6)0

Nausea1 (0.6)0Pleural effusion

1 (0.6)0

Pulmonary sepsis

1 (0.6)0

Pyrexia
RENAL CYST*

1 (0.6)0

1 (0.6)0

Septic shock

1 (0.6)0

Superior vena cava syndrome
Unintended pregnancy

1 (0.6)0

1 (0.6)00

2 (1.2)0

2 (1.2)BLOOD CREATININE INCREASED*

Fatigue44

Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Final
MedDRA Preferred Term or Clustered Term

PULMONARY EMBOLISM*
THROMBOCYTOPENIA*
ABDOMINAL PAIN*

Acute kidney injury
Arthralgia

Crizotinib(N=171)n (%)
0

Chemotherapy(N=169)an (%)
2 (1.2)0

2 (1.2)0

1 (0.6)0

1 (0.6)0

1 (0.6)

Azotaemia01 (0.6)

Bile duct obstruction0

1 (0.6)

Cardiac arrest
Completed suicide0

1 (0.6)0

1 (0.6)

DYSPNOEA
Depression0

1 (0.6)0

1 (0.6)

Haemoptysis
Myocardial ischaemia

01 (0.6)0

1 (0.6)NEUTROPENIA

0

1 (0.6)

Syncope
Vomiting

01 (0.6)0

1 (0.6)**

MedDRA Version 19.1 coding dictionary applied.
Abbreviations: AE=adverse event; MedDRA=Medical Dictionary for Regulatory Activities; n/N=number ofpatients*
Clustered Termsa
Only includes data before crossover to crizotinib for those patients who crossed over to receive crizotinib treatment.

Deaths:A total of 23 (13.5%) patients in the crizotinib arm and 4 (2.4%) patients in the
chemotherapy arm died on study treatment or within 28 days of their last dose of study drug
(Table 29). Grade 5 all-causality AEs were reported for 23 (13.5%) patients in the crizotinibarm and 4 (2.4%) patients in the chemotherapy arm (before crossover) (Table 29). The mostcommonly reported Grade 5 all-causality AE in the crizotinib arm was Disease progression(18 [10.5%] patients).
Table 29

Treatment-Emergent Adverse Events Associated With Death on Study(Grade 5) by Treatment Arm - All-Causality and Treatment-Related (All
Cycles) - Safety Analysis Population

MedDRA Preferred Term

Any Grade 5 AE:

Crizotinib
Chemotherapy(N=171)(N=169)aAll-Causality Treatment- All-Causality TreatmentRelated
Related
n (%)
n (%)
n (%)
n (%)
23 (13.5)
04 (2.4)0Disease progression

18 (10.5)

01 (0.6)0

Septic shock

2 (1.2)00

0Acute respiratory failure

1 (0.6)

0

0

0

Death

1 (0.6)0045

Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Final
MedDRA Preferred Term

Diabetic ketoacidosis

Crizotinib
Chemotherapy(N=171)(N=169)aAll-Causality Treatment- All-Causality TreatmentRelated
Related
n (%)
n (%)
n (%)
n (%)
1 (0.6)000

Cardiac arrest

0

0

1 (0.6)0Completed suicide00

1 (0.6)0

Haemoptysis

00

1 (0.6)0

MedDRA Version 19.1 coding dictionary applied.
Abbreviations: AE=adverse event; MedDRA=Medical Dictionary for Regulatory Activities; n/N=number of patients.
aOnly includes data before crossover to crizotinib for those patients who crossed over to receive crizotinib treatment.

Clinical laboratory and other safety evaluations:
More Grade 3/4 hematology results were observed in the chemotherapy arm (before
crossover) than in the crizotinib arm. In the crizotinib arm, the most common shifts (≥ 5%of the patients) from Grade ≤2 to Grade 3/4 were for absolute neutrophils (14.7%) andlymphopenia (10.6%). In the chemotherapy arm, the most common shifts (≥5% of patients)from Grade ≤2 to Grade ¾ were for absolute neutrophils (17.6%), lymphopenia (11.5%),
anemia (10.9%), white blood cells (9.7%), and platelets (8.5%).
Chemistry data indicated shifts from Grade ≤2 at baseline to Grade 3/4 post baseline bytreatment arm. In the crozitinib arm, the most common shifts (≥5% of patients) from Grade≤2 to Grade 3/4 were for ALT (14.6%), hypophosphatemia (13.6%), and AST (8.2%). In
the chemotherapy arm, the most common shifts (≥5% of patients) from Grade ≤2 to Grade
3/4 were for hypophosphatemia (6.8%) and hyponatremia (6.7%).
Other safety parameters (blood pressure, ECGs, and MUGA scans/Echocardiograms, andophthalmologic evaluations) did not reveal any new safety concerns. Due to the low numberof subjects with results for DXA analysis and hypogonadism laboratory parameters, no clear
conclusion can be made.

46

Public Disclosure Synopsis
Protocol A8081014 – 31 Oct 2017 – Final

CONCLUSIONS:•

Crizotinib treatment resulted in a statistically significant, robust, and clinicallymeaningful improvement in IRR-assessed PFS as compared with platinum-based
chemotherapy in the treatment of patients with previously untreated ALK-positive,
advanced non-squamous NSCLC (median PFS 10.9 months vs 7.0 months; HR:
0.454; 1-sided p-value <0.0001).

•

Crizotinib treatment resulted in a clinically and statistically significant improvementin IRR-assessed ORR compared with chemotherapy (74% vs 45%; 2-sided p-value<0.0001), with objective responses that were rapid in onset (median TTR 6 weeks)
and durable (median DR estimate 49.0 weeks).

•

Crizotinib treatment resulted in a clinically and statistically significant improvementin IRR-assessed TTP compared with chemotherapy (median 13.6 months vs
7.0 months; HR: 0.441; 1-sided p-value <0.0001). This improvement in TTP was
also observed when only extracranial lesions were evaluated (HR: 0.387; 1-sided
p-value <0.0001). There was a numerical improvement in IC-TTP in the crizotinibarm (HR: 0.595; 1-sided p-value=0.0347).

•

Crizotinib had a distinct side effect profile that was generally tolerable andmanageable by dosing interruption, dose reduction, and/or standard medical therapy.

•

Crizotinib treatment significantly delayed TTD in the composite endpoint of lungcancer symptoms that included pain in chest, cough, or dyspnea (HR: 0.591; 2-sided
p-value=0.0005).

•

Crizotinib treatment resulted in statistically significantly (2-sided p-value<0.05)
greater improvement from baseline in patient-reported key lung cancer symptoms ofcoughing, dyspnea, and pain in chest, physical functioning, global QoL, and general
health status as compared with the chemotherapy arm.

•

There was a numerical improvement in secondary endpoint of OS in the crizotinibarm as compared to the chemotherapy arm (HR: 0.760 [95% CI: 0.548, 1.053];
1-sided stratified log-rank test p-value=0.0489), although this improvement was notstatistically significant. These OS analyses were not adjusted for the potentiallyconfounding effects of crossover, as 144 (84.2%) patients in the chemotherapy arm
received crizotinib treatment as follow-up systemic therapy.

47