Public Disclosure Synopsis
Protocol A8081007 – 25 October 2016 Final

PFIZER INC.
These results are supplied for informational purposes only.
Prescribing decisions should be made based on the approved package insert.
GENERIC DRUG NAME: Crizotinib
COMPOUND NUMBER: PF-02341066
PROTOCOL NO.: A8081007

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PROTOCOL TITLE: Phase 3, Randomized, Open-Label Study of the Efficacy and Safetyof PF-02341066 Versus Standard-of-Care Chemotherapy (Pemetrexed or Docetaxel) in
Subjects With Advanced Non-Small Cell Lung Cancer (NSCLC) Harboring a Translocation
or Inversion Event Involving the Anaplastic Lymphoma Kinase (ALK) Gene Locus.
Study Centers: A total of 106 centers participated in the study in 21 countries: Australia(2 centers), Brazil (5 centers), Canada (3 centers), China (8 centers), France (6 centers),
Germany (9 centers), Greece (1 center), Hong Kong (2 centers), Hungary (2 centers), Ireland(2 centers), Italy (11 centers), Japan (10 centers), Republic of Korea (3 centers), Netherlands(1 center), Poland (3 centers), Russian Federation (2 centers), Spain [8 centers], Sweden[1 center], Taiwan [1 center], United Kingdom [4 centers], and United States (US;
22 centers). An additional 59 centers received study drug, but did not enroll subjects.
Study Initiation Date and Final Completion Dates:
Study initiation date: 18 September 2009
Study completion date: 05 January 2016
Phase of Development: Phase 3
Study Objectives:
Primary Objective:•

To demonstrate that crizotinib (Arm A) was superior to standard-of-carechemotherapy, pemetrexed or docetaxel (Arm B), in prolonging progression-freesurvival (PFS) in subjects with advanced NSCLC whose tumors harbor atranslocation or inversion event involving the ALK gene locus and who had received
only 1 prior chemotherapy regimen for advanced NSCLC and this regimen must havebeen platinum-based.

Secondary Objectives:•

To compare secondary measures of clinical efficacy including overall survival (OS),objective response rate (ORR), and disease control rate (DCR) between the
2 treatment arms, and evaluate duration of response (DR) and time to tumor response(TTR).

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Public Disclosure Synopsis
Protocol A8081007 – 25 October 2016 Final•

To assess the safety and tolerability of crizotinib compared to chemotherapy(pemetrexed or docetaxel).

•

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

•

To characterize the effects of crizotinib at therapeutic doses on QT interval in thissubject population.

•

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

•

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

•

To correlate modulation of soluble biomarkers to PK and outcome measures.

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METHODS
Study Design:This was a multinational, multicenter, randomized, open-label Phase 3 efficacy and safety
study of crizotinib vs standard-of-care chemotherapy (pemetrexed or docetaxel) in subjects
with previously treated NSCLC (with 1 prior platinum-based chemotherapy regimen) whose
tumors harbor ALK fusions.
The ALK break-apart fluorescence in-situ hybridization (FISH) assay was used to determine
ALK-positivity.
A total of 318 subjects were planned for randomization in a 1:1 ratio (2 arms) and to receive
crizotinib (Arm A) or chemotherapy (pemetrexed or docetaxel) (Arm B). Each treatment
cycle was defined as 21 days. Randomization was stratified by Eastern Cooperative
Oncology Group (ECOG) performance status (PS) (0-1, 2), brain metastases (present,
absent), and previous treatment with an epidermal growth factor receptor tyrosine kinase
inhibitor (EGFR-TKI) (yes or no).
After starting study drug, subjects were to continue with the assigned treatment until
Response Evaluation Criteria in Solid Tumors (RECIST, version [v] 1.1) - definedprogression of disease as assessed by the independent radiology review (IRR), unacceptabletoxicity, or consent withdrawal. Subjects continued treatment as assigned beyond the time of
RECIST-defined progression, as assessed by the IRR, at the discretion of the investigator if
the subject was perceived to be experiencing clinical benefit. In addition, subjects in the
chemotherapy arm, who had RECIST defined progression of disease, as assessed by the IRR,
had the option to enroll in A8081005 to receive crizotinib treatment if they met the safety
screening inclusion/exclusion criteria for crizotinib.
The complete schedule of events for all subjects is shown in Table 1. A reduced schedule ofevents for subjects in the crizotinib arm is shown in Table 2.

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Protocol A8081007 – 25 October 2016 Final

Table 1

Schedule of Activities
Study Treatment[1]Protocol Activities

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Screening≤28 Days PriortoRandomization
Baseline Documentation
Informed Consent[4]Medical/ Oncological History[5]Baseline Signs/Symptoms
Mandatory Tumor Tissue for Molecular Profiling[6]Physical Examination[7]ECOG Performance Status
Ophthalmologic Examination[8]Laboratory Studies
Hematology[9]Blood Chemistry[9]Coagulation[9]Dipstick Urinalysis and Urine Reflex Microscopy[10]12-lead ECG[11]Pregnancy Test (as appropriate)[12]
Disease Assessments
Tumor Assessments (including scans)[13]Other Clinical Assessments
Adverse Events and Hospitalizations[14]Concomitant Medications/Treatments[15]
EORTC QLQ-C30, QLQ-LC13, EQ-5D and
VSAQ-ALK[16]Multiple Gate Acquisition (MUGA) Scan or
Echocardiogram[17] (France, Ireland and any substudysite)
Contraception Check
Survival Follow-up[18]Cycles ≥ 2

Cycle 1
Day 1 (±2)[2]

End of Treatment

Day 15 (±2)

Day 1 (±2;except as
noted below)

End ofTreatment/
Withdrawal[3]X
X
Cycle 5, thenevery 4 cycles(France only)

X
X

X
X

X
X

X (Korea only)
Cycle 2X (Korea only)

Post
Treatment
Follow-up

X
X
X
X
X
X

(X)
X

X

X
X
X
X (Korea only)
X
X

(X)
(X)

X
X

X (Korea only)
X

X
every 6 weeks(±1 week)

X
X
X

X
X
X

X
X

X
X
X

X

X

X
X

X
X

X

Cycle 3, thenevery 4 cycles

X

X[12]

X[12]
X

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Protocol A8081007 – 25 October 2016 Final

Study Treatment[1]Protocol Activities
Screening

090177e18aa74a44\Approved\Approved On: 22-Nov-2016 12:34≤28 Days PriortoRandomization

Cycles ≥ 2

Cycle 1
Day 1 (±2)

Study Treatment
PF-02341066 (Crizotinib) (ie, Arm A only)
Pemetrexed or Docetaxel (ie, Arm B only)[19]
Special Laboratory Studies
Optional Blood Sample for Biomarkers and Optional
Tumor Tissue for Molecular Profiling (crizotinib arm
only)[20][2]

End of Treatment

Day 15 (±2)

Day 1 (±2;except as
noted below)

End ofTreatment/
Withdrawal[3]PostTreatment
Follow-up

Daily

Pharmacokinetics (PK) (crizotinib arm only)[21]

X

X

X

Cycle 2X

Cycles 2, 3,
5X( ) – if not performed within 7 days of study treatment.
Abbreviations: AE=adverse event; ALK=anaplastic lymphoma kinase; ALT=alanine aminotransferase; c-Met=hepatocyte growth factor receptor; CT=computed tomography;
ECG=electrocardiogram; EORTC=European Organization for the Research and Treatment of Cancer; EQ-5D=EuroQOL-5D; ECOG=Eastern Cooperative Oncology Group;
FISH=fluorescence in-situ hybridization; HGF=hepatocyte growth factor; MRI=magnetic resonance imaging; MUGA=multiple gated acquisition; OS=overall survival;
PK=pharmacokinetic; QLQ-C30= Quality of Life Questionnaire – Core 30 Questionnaire; QLQ-LC13=Quality of Life Questionnaire – Lung Cancer 13; RECIST=Response
Evaluation Criteria in Solid Tumors; SAE=serious adverse events; VSAQ-ALK=Visual Symptom Assessment Questionnaire-ALK
1Study Treatment: All cycles were 21 days in duration.
2
Cycle 1/Day 1: Blood chemistry, hematology, and physical examination were not to be required if acceptable screening assessment was performed within 7 days prior to thestart of study treatment.
3
End of Treatment/Withdrawal: These assessments were obtained if not completed during the previous 4 weeks on study (during the last 6 weeks for disease assessments).
4
Informed Consent: Was obtained prior to undergoing any trial specific procedure.
5
Medical/Oncological History: Included information on prior regimens.
6
Mandatory Tumor Tissue for Molecular Profiling: Paraffin block(s) of adequate size to allow if possible for at least 10 slides with cuts that were 5-microns thick. Thesesamples were used for the assessment of ALK gene fusion by FISH by the central laboratory.
7
Physical Examination: Examination of major body systems, height (at screening only); weight, blood pressure, and pulse rate (at baseline and on Day 1 of each cycle).
8
Ophthalmologic Examination: Visual acuity, slit lamp and fundoscopy were performed by an ophthalmologist. The ophthalmologic examination was repeated during thestudy when visual disturbances were observed and when there was an increase in the grade for visual disturbances. For all subjects enrolled in France, ophthalmology exams
were performed after the completion of every 4 cycles.
9
Hematology, Blood Chemistry and Coagulation: For crizotinib arm only: If ALT or AST ≥ Grade 3 and total bilirubin ≥ Grade 2, then liver function tests were repeatedwithin 48 hours and then repeated every 48-72 hours until ALT or 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 if additional laboratory tests were indicated, for example, additional testing to exclude
other causes of liver injury.
10
Dipstick urinalysis and Urine Reflex Microscopy: Urine reflex microscopy was performed if urine dipstick was positive for blood or protein.
11
12-lead ECG.
12
Pregnancy Test.

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Protocol A8081007 – 25 October 2016 Final

Study Treatment[1]Protocol Activities
Screening≤28 Days PriortoRandomization

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13

14

15

16

17
18

19
20

21

Cycle 1
Day 1 (±2)[2]

Day 15 (±2)

End of Treatment
Cycles ≥ 2
Day 1 (±2;except as
noted below)

End ofTreatment/
Withdrawal[3]PostTreatment
Follow-up

Tumor Assessments: CT or MRI was to include chest, brain, abdomen and pelvis at screening. Bone scan was performed at screening. Scans performed 6 weeks after
randomization had a +1 week allowance; all subsequent scans were performed at 6 week intervals (±1 week). Tumor Assessments should have continued every 6 weeks until
RECIST-defined disease progression confirmed by an independent radiology laboratory. If study drug was discontinued in the absence of confirmed RECIST-defined diseaseprogression, subjects remained on study until confirmation was received by the independent radiology laboratory.
Adverse Events and Hospitalizations: Subjects were followed for AEs from the time they signed the protocol-specific informed consent until at least 28 days after the lastdose of study treatment, or until all serious or study drug-related toxicities were resolved or were determined to be “chronic” or “stable”, whichever was later. Hospitalizations
were recorded from 28 days prior to the start of study treatment until the last day of study drug administration.
Concomitant Medications/Treatments: Concomitant medications and treatments were recorded from 28 days prior to the start of study treatment and up to 28 days post thelast dose of study treatment.
EORTC QLQ-C30, QLQ-LC13 EQ-5D, and VSAQ-ALK: Subjects were to complete the EORTC QLQ-C30, the QLQ-LC13, the EQ-5D, and the VSAQ-ALK
questionnaires at the clinic prior to any study or medical procedure. Subjects with visual disturbances ongoing at the End of Treatment visit were also to complete the
VSAQ-ALK at the 28 day follow-up visit after last dose. All self-assessment questionnaires were completed by the subjects while in the clinic and could not be taken home.
The VSAQ-ALK has been translated into different languages; however, if the VSAQ-ALK was not available in the subject’s preferred language, the subject did not need tocomplete this assessment.
MUGA Scan or Echocardiogram: MUGA scans or echocardiograms were required from selected sites for a total of 30 subjects/treatment arm.
Survival Follow-Up: After discontinuation of study treatment, post-study survival status was collected every 2 months until death or until the required number of OS events had
been reached, whichever was earlier. Included collection of information on subsequent anti-cancer therapies. Telephone contact was acceptable.
Pemetrexed or Docetaxel (ie, Arm B Only).
Optional Blood Sample for Biomarkers and Optional Tumor Tissue for Molecular Profiling (Crizotinib Arm Only): An optional blood sample was collected for soluble
biomarkers including c-Met ectodomain and HGF scatter factors, prior to dosing on Cycle 1 Day 1, Cycle 2 Day 1 (corresponding to the 2-6 hour post-dose PK sample) and endof treatment if a subject discontinued due to disease progression. An optional fresh tumor sample was collected at the end of treatment if a subject discontinued due to diseaseprogression.
Pharmacokinetics (Crizotinib Arm Only).

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Protocol A8081007 – 25 October 2016 Final

Table 2

Reduced Schedule of Activities for Subjects in the Crizotinib Arm
Protocol Activities

Study Treatment/Each Cycle[1]090177e18aa74a44\Approved\Approved On: 22-Nov-2016 12:34

Day 1 (±2; Except as Noted Below)
Baseline Documentation
Physical Examination[3]ECOG Performance Status
Ophthalmologic Examination[4]Laboratory Studies
Hematology[5]Blood Chemistry[5]Dipstick Urinalysis and Urine Reflex Microscopy[6]12-lead ECG[7]Female Subjects: Pregnancy Test (as appropriate)[8]Disease Assessments
Tumor Assessments (including scans)[9]Other Clinical Assessments
Adverse Events and Hospitalizations[10]Concomitant Medications/Treatments[11]
EORTC QLQ-C30, QLQ-LC13, EQ-5D and VSAQ-ALK[12]Multiple Gate Acquisition (MUGA) Scan or
Echocardiogram[13] (France and Ireland)
Contraception Check
Survival Follow-up[14]Study Treatment
PF-02341066
Special Laboratory Studies
Optional Blood Sample for Biomarkers and Optional
Tumor Tissue for Molecular Profiling[15]Pharmacokinetics (PK)[16]End of Treatment/
Withdrawal[2]X
X
Cycle 5, then every 4 cycles(France only)

X
X

X
X

X
X
X (Korea only, othercountries as clinicallyindicated)

X (Korea only, other countries as
clinically indicated)
Cycles 1 and 2 only
(X)

Post Treatment Follow-upX

As per local clinical practice
X
X
X

X
X
X

X
X

Cycle 3, then every 4 cycles
X

X
X

Twice daily

Cycle 2 (if applicable)
Cycles 2, 3, 5 (If applicable)

X

Abbreviations: ALT=alanine aminotransferase; c-Met=hepatocyte growth factor receptor; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group;
EORTC=European Organization for the Research and Treatment of Cancer; EQ-5D=EuroQol-5D; MUGA=Multiple Gated Acquisition; OS=overall survival; QLQ-PK:
Pharmacokinetics; C30=Quality of Life Questionnaire – Core 30 Questionnaire; QLQ-LC13=Quality of Life Questionnaire – Lung Cancer 13; SAE=serious adverse event;
VSAQ-ALK=Visual Symptom Assessment Questionnaire-Anaplastic Lymphoma Kinase.

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Protocol A8081007 – 25 October 2016 Final

1
2
3
4

5

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6
7
8
9
10

11

12

13
14

15

16

Study Treatment: Enough study drug for 2 cycles of treatment was dispensed at each clinic visit.
End of Treatment/Withdrawal: These assessments were obtained if not completed during the previous 4 weeks on study.
Physical Examination: Included an examination of major body systems, weight, blood pressure, and pulse rate (at each cycle visit, ie, Day 1 of that cycle).
Ophthalmologic Examination: Included visual acuity, slit lamp, and fundoscopy and should be performed by an ophthalmologist. The ophthalmologic examination was
repeated during the study when visual disturbances had been observed and when there was an increase in the grade for visual disturbances.
Hematology and Blood Chemistry: For subjects in the crizotinib arm only: If ALT ≥ Grade 3 and total bilirubin ≥ Grade 2, then liver function tests needed to be repeatedevery 48-72 hours until ALT ≤ Grade 2.
Dipstick Urinalysis and Urine Reflex Microscopy: Urine reflex microscopy was required if urine dipstick was positive for blood or protein.
12-lead ECG.
Pregnancy Test.
Tumor Assessments: The timing for tumor imaging could be completed per standard of care while receiving study treatment.
Adverse Events and Hospitalizations: Subjects were follow for adverse events from the time they signed the protocol-specific informed consent until at least 28 days
after the last dose of study treatment, or until all serious or study drug-related toxicities had resolved or were determined to be “chronic” or “stable”, whichever was later.
Concomitant Medications/Treatments: Concomitant medications and treatments were recorded from 28 days prior to the start of study treatment and up to 28 days after
the last dose of study treatment.
EORTC QLQ-C30, QLQ-LC13; EQ-5D, and VSAQ-ALK: Subjects were to complete the EORTC QLQ-C30, the QLQ-LC13, the EQ-5D, and the VSAQ-ALK
questionnaires at the clinic prior to any study or medical procedure. Subjects with visual disturbances ongoing at the End of Treatment visit were also to complete the
VSAQ-ALK at the 28 day follow-up visit after last dose. All self-assessment questionnaires were completed by the subjects while in the clinic and could not be taken
home. The VSAQ-ALK was translated into different languages. However, if the VSAQ-ALK was not available in the subject’s preferred language, the subject did notneed to complete this assessment.
MUGA Scan or Echocardiogram: MUGA scans or echocardiograms were required from selected sites for a total of 30 subjects/treatment arm.
Survival Follow-Up: After discontinuation of study treatment, post-study survival status was collected every 2 months until death or until the required number of OS
events had been reached, whichever was earlier. Included collection of information on subsequent anti-cancer therapies. Telephone contact was acceptable.
Optional Blood Sample for Biomarkers and Optional Tumor Tissue for Molecular Profiling (Crizotinib arm only): An optional blood sample was collected forsoluble biomarkers including c-Met ectodomain and HGF scatter factors, prior to dosing on Cycle 1 Day 1, Cycle 2 Day 1 (corresponding to the 2-6 hour post-dose PK
sample) and at end of treatment if a subject discontinued due to disease progression. An optional fresh tumor sample was collected at the end of treatment if a subject
discontinued due to disease progression.
Pharmacokinetics (Crizotinib arm only).

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Protocol A8081007 – 25 October 2016 Final

Number of Subjects (Planned and Analyzed):
Planned: 318 subjects.
Randomized and analyzed: 347 subjects and included in the Full Analysis (FA) population:
347 subjects (173 subjects in the crizotinib arm and 174 subjects in the chemotherapy arm).
Safety Analysis (SA) population: 343 treated subjects (172 treated with crizotinib and171 treated with chemotherapy).
Diagnosis and Main Criteria for Inclusion and Exclusion:
Subjects with histologically or cytologically proven diagnosis of NSCLC (locally advanced
or metastatic) with measurable tumors, who were positive for the ALK fusion gene andwhose disease had progressed after only 1 prior chemotherapy that included one platinum
drug, were included in the study.
Study Treatment:

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Subjects were randomized in a 1:1 ratio to receive crizotinib (Arm A) or chemotherapy(pemetrexed or docetaxel; Arm B).
Test Product, Dose and Mode of Administration:
Crizotinib tablets, 250 mg twice daily (BID), were administered orally at approximately thesame times each day on a continuous daily dosing schedule (i.e. no break in dosing). Cycles
were defined in 21-day periods to facilitate scheduling of visits and assessments. Subjects
were monitored closely for toxicity and the dose of crizotinib could have been reduced by 1
and, if needed, 2 dose levels depending on the type and severity of toxicity encountered(Dose Level -1 was 200 mg BID; Dose Level -2 was 250 mg once daily).
Reference Therapy, Dose and Mode of Administration:
Standard doses of chemotherapy (pemetrexed or docetaxel) were administered byintravenous (IV) infusion:•

Pemetrexed (500 mg/m2) was administered by IV infusion over 10 minutes or
according to institutional practices on Day 1 of a 21-day cycle.

•

Docetaxel (75 mg/m2) was administered by IV infusion over 1 hour or according toinstitutional practices on Day 1 of a 21-day cycle.

Efficacy, Pharmacokinetic and Pharmacodynamic Evaluations or Outcome Research
Endpoints:
Primary Endpoint:•

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

Secondary Endpoints:•

OS and survival probabilities at 6 and 12 months.

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Public Disclosure Synopsis
Protocol A8081007 – 25 October 2016 Final

•

ORR.

•

DCR at 6 and 12 weeks.

•

DR.

•

TTR.

•

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

•

Plasma concentrations of PF-02341066.

•

QTc.

•

Types of EML4-ALK fusion variants and ALK protein expression.

•

Plasma concentrations of soluble c-Met ectodomain and HGF scatter proteins.

•

TTD in patient reported pain, dyspnea, and cough.

•HRQoL, lung cancer disease/treatment-related symptoms, and general health status.

Safety Evaluations:
Safety evaluations included clinical monitoring, physical examinations, vital signs, ECOG
PS, ophthalmologic examinations, laboratory parameters (hematology, blood chemistry,
coagulation [screening only], urinalysis [introduced in Protocol Amendment 10: for subjects
enrolled in Korea, urinalysis was obtained at Day 1 of every cycle and at the End of
Treatment (EOT); for subjects enrolled in all other countries, urinalysis was repeated asclinically indicated – at the time of the initial diagnosis of a renal cyst], and pregnancy tests),
12-lead ECGs, AEs, concomitant medications/treatments, and multiple gated acquisition(MUGA) scans or echocardiograms. The safety evaluations were done as per the schedule
mentioned in Table 1 and Table 2.
Statistical Methods:
The full analysis (FA) population included all subjects who were randomized with study drug
assignment designated according to initial randomization. The FA population was theprimary population for evaluating time-to-event efficacy endpoints (ie, PFS and OS), ORR,
DCR, PROs, and subject characteristics.
The SA population included all subjects who received at least 1 dose of study medication,with treatment assignments designated according to actual study treatment received. The SA
population was the primary population for evaluating safety and treatment.
The PRO evaluable population was defined as the subjects from the FA population who
completed a baseline and at least 1 post baseline PRO assessment.
The PK concentration population was defined as all subjects in the SA population who had atleast 1 concentration following treatment with at least 1 dose of crizotinib.

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Protocol A8081007 – 25 October 2016 Final

Analysis of Efficacy Parameters:

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Primary Endpoint: PFS was defined as the time from the date of randomization to the date of
the first documentation of objective tumor progression or death on study due to any cause,
whichever occurred first. PFS was summarized using the FA population based on the IRR ofthe tumor imaging data. Differences in PFS between treatment arms were analyzed by
1-sided log-rank test stratified for baseline factors of ECOG PS (0-1 or 2), brain metastases(present or absent), and prior EGFR inhibitor treatment (yes or no). Estimates of the PFS
curves obtained from the Kaplan-Meier method were presented and displayed graphically.
The median event time (and other quartiles) and corresponding 2-sided 95% confidence
interval (CI) were provided for each treatment arm. Additionally, for each treatment arm, themedian PFS and a 2-sided 95% CI were provided for each level of the stratification variables
and for subgroups of other relevant subject baseline characteristics. Cox regression models,
adjusted for baseline stratification factors and other subject baseline characteristics, werefitted. The estimated hazard ratio (HR) and 2-sided 95% CI were provided. PFS was also
analyzed by an unstratified log-rank test.
Secondary Endpoints: OS was defined as the time from randomization to the date of death
due to any cause. Upon confirmation of progressive disease by the IRR, subjects in Arm B
had the opportunity to receive crizotinib by enrolling in a previous open-label, multicenter,single arm study (Phase 2, Open-Label Single Arm Study of the Efficacy And Safety of
PF-02341066 in subjects With Advanced Non-Small Cell Lung Cancer [NSCLC] Harboringa Translocation or Inversion Involving the ALK Gene Locus [NCT00932451]). For thesesubjects, survival follow-up data and follow-up systemic therapies were collected in theprevious study. Data from both study databases were used for analysis of OS and reported
under this study.
Differences in OS between treatment arms were analyzed by the 1-sided log-rank test
stratified for baseline factors. Estimates of the OS curves obtained from the Kaplan-Meiermethod were presented. OS curves were also displayed graphically. The median event time(and other quartiles) and corresponding 2-sided 95% CI for the event times were provided foreach treatment arm.
Cox regression models, adjusted for baseline stratification factors and other subject baselinecharacteristics, were fitted. The estimated HR and 2-sided 95% CI were provided.
Six-month and 1-year survival probabilities were estimated using the Kaplan-Meier method
together with the 2-sided 95% CI.
Subgroup analyses were provided for major baseline subject characteristics and for thebaseline stratification factors: median OS (and other quartiles) and 2-sided 95% CI were
estimated.
ORR was defined as the percent of subjects with complete response (CR) or partial response(PR) according to RECIST version 1.1 as assessed by the IRR, relative to the FA population.
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 test stratified for baseline
stratification factors and an unstratified test (2-sided Pearson). An analysis of ORR in the
SA population was performed with chemotherapy arm separated for pemetrexed andPage 10

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Protocol A8081007 – 25 October 2016 Final

docetaxel. Disagreement rates between ORR based on IRR and Investigator assessments oftumor responses were presented.
DR was defined as the time from the first documentation of objective tumor response (CR or
PR), as assessed by the IRR, to the first documentation of objective tumor progression, or todeath due to any cause, whichever occurred first. DR was summarized in the subgroup of
subjects with objective response from the FA population using the Kaplan-Meier method andwas graphically displayed. The median event time (and other quartiles) and 2-sided 95% CI
for the event times for each treatment arm were provided.
TTR was defined as the time from randomization to first documentation of objective tumor
response (CR or PR) as assessed by the IRR. For subjects proceeding from PR to CR, theonset of PR was taken as the onset of response. TTR was calculated for the subgroup of
subjects with objective tumor response. Descriptive statistics were provided.

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DCR at 6 and 12 weeks was defined as the percent of subjects with CR, PR or stable disease(SD) at 6 and 12 weeks as assessed by the IRR, relative to the FA population. The best
response of SD could have been assigned if SD criteria were met at least once after
randomization at a minimum interval of 6 weeks. DCR was summarized for each treatment
arm along with the corresponding exact 2-sided 95% CI using a method based on theF-distribution.
TTD in pain (pain in chest from quality of life questionnaire supplement module for Lung
Cancer [QLQ-LC13]), dyspnea (from QLQ-LC13), or cough (from QLQ-LC13) symptoms
was a composite endpoint and defined as the time from randomization to the earliest time thesubject’s scale scores showed a 10 point or greater increase after baseline in any of the
3 symptoms and was summarized using Kaplan-Meier methods. The median event time (andother quartiles) and corresponding 2-sided 95% CI for the event times were provided for eachtreatment arm. Treatment group comparison was performed using the unstratified log-rank
test. Descriptive statistics by treatment group were reported for the change from baseline foreach quality of life questionnaire-core 30 (QLQ-C30) and QLQ-LC13 domains and single
item scores, and European quality of life 5-dimensional (EuroQoL 5D) - visual analog scale(EQ-5D VAS). Change from baseline scores were compared between treatment arms using
repeated measures mixed effects modeling, with the baseline scores included as a covariate.
Safety data were analyzed using descriptive statistics.

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Protocol A8081007 – 25 October 2016 Final

RESULTS
Subject Disposition:
Based on the FA population, of the 347 subjects randomized into the study 172 subjects weretreated with crizotinib, 99 subjects were treated with pemetrexed, and 72 subjects weretreated with docetaxel.
End of Treatment (EOT):
All crizotinib- or chemotherapy-treated subjects permanently discontinued from study
treatment. The most frequent reasons for permanent discontinuation of study treatment ineither treatment arm were objective progression or relapse and global deterioration of healthstatus (Table 3).
Table 3

Subject Disposition at End of Treatment by Treatment Arm - Full Analysis090177e18aa74a44\Approved\Approved On: 22-Nov-2016 12:34

Number (%) of Subjects

Ongoing treatment
Randomized but not treated
Discontinued treatment
Reason for discontinuation fromtreatment:
Completed
Adverse event
Global deterioration of health status
Lost to follow-up
Objective progression or relapse
Protocol violation
Study terminated by sponsor
Subject died
Subject refused continued treatment
for reason other than adverse eventa
Other
Total
a

Crizotinib(N=173)n (%)
0
1 (<1.0)

Chemotherapy(N=174)n (%)
0
3 (1.7)

Total(N=347)n (%)
0
4 (1.2)017 (9.8)
57 (32.9)
057 (32.9)
00
12 (6.9)9 (5.2)0
19 (10.9)25 (14.4)
0105 (60.3)
1 (<1.0)04 (2.3)2 (1.1)036 (10.4)
82 (23.6)
0162 (46.7)
1 (<1.0)0
16 (4.6)
11 (3.2)

20 (11.6)
172 (99.4)

15 (8.6)
171 (98.3)

35 (10.1)
343 (98.8)

Abbreviations: AE=adverse event; CRF=case report form; CSR=clinical study report; N/n=number of subjects.
End of Treatment CRF reason “Subject No Longer Willing to Continue Treatment for Reason Other Than AE” wasmapped to “Subject Refused Continued Treatment for Reason Other Than Adverse Event”.

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Public Disclosure Synopsis
Protocol A8081007 – 25 October 2016 Final

End of Study:
All subjects discontinued from the study. The most common reason for discontinuation fromthe study was subject death (115 [66.5%] subjects) in the crizotinib arm and “other” reasons(mainly crossover to Study 1005) (144 [82.8%] subjects) in the chemotherapy arm (Table 4).
Table 4

Subject Disposition at End of Study by Treatment Arm - Full Analysis

Number (%) of Subjects
Reason for discontinuation from study
Completeda
Subject died
Study terminated by sponsor
Lost to follow-up
Subject refused further follow-up
Other
Total

Crizotinib(N=173)n (%)

Chemotherapy(N=174)
n (%)

Total
(N=347)n (%)

40 (23.1)
115 (66.5)
08 (4.6)5 (2.9)5 (2.9)173 (100)

4 (2.3)24 (13.8)
00
2 (1.1)144 (82.8)
174 (100)

44 (12.7)
139 (40.1)
08 (2.3)7 (2.0)149 (42.9)
347 (100)

090177e18aa74a44\Approved\Approved On: 22-Nov-2016 12:34

Reason for Discontinuation was based on the Subject Summary at End of Study page.
Abbreviations: CSR=clinical study report; N/n=number of subjects.
a“Completed study follow-up” was only applicable when the required number of events for overall survival had beenreported. At that time, the sponsor sent written notification to the clinical sites.

Data Sets Analyzed:
A summary of data sets analyzed is provided in Table 5.
Table 5

Data Sets Analyzed

Number randomized
Full analysis
Safety analysis
PRO evaluable
EORTC QLQ-C30
QLQ LC13
EQ-5D VAS
VSAQ-ALK evaluable population
PK evaluable

Crizotinib
173
173
172
162
165
164
164
101
152

Chemotherapy
174
174
171
151
163
162
161
104
NA

Total
347
347
343
313
328
326
325
205
152

Abbreviations: N=number of subjects; EORTC QLQ LC13 = European organization for the research and treatment ofcancer quality of life questionnaire–supplement module for Lung Cancer (LC13); EORTC QLQ C30 = European
organization for the research and treatment of cancer quality of life questionnaire-core 30; EQ-5D VAS = EuroQol 5Dvisual analog scale; VSAQ-ALK=Visual Symptom Assessment Questionnaire–ALK, EuroQol = European quality of life;
NA = not applicable; PK = pharmacokinetic; PRO = patient-reported outcomes.

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Public Disclosure Synopsis
Protocol A8081007 – 25 October 2016 Final

Demographic Characteristics:
A summary of demographic characteristics by treatment arm in the FA population isprovided in Table 6. Demographics were comparable between the 2 treatment arms.

090177e18aa74a44\Approved\Approved On: 22-Nov-2016 12:34

Table 6

Summary of Demographics by Treatment Arm – Full Analysis

Sex, n (%)
Male
FemaleAge (years)
Mean (standard deviation)MedianRange
Age category, n (%)<45 years
45-<55 years
55-<65 years≥65 years
Race, n (%)
White
Black
Asian
Racial designation for AsianJapanese
KoreanChineseOther
Other
Smoking classification, n (%)
Never smokedEx-smoker
Smoker
Not reportedaaCrizotinib(N=173)Chemotherapy(N=174)

Total(N=347)75 (43.4)
98 (56.6)

79 (45.4)
95 (54.6)

154 (44.4)
193(55.6)

50.3 (13.09)
51.0
22 – 8149.8 (13.03)
49.0
24 – 85

50.0 (13.04)
50.0
22 – 85

64 (37.0)
40 (23.1)
42 (24.3)
27 (15.6)

63 (36.2)
47 (27.0)41(23.6)
23 (13.2)

127 (36.6)
87 (25.1)
93 (23.9)50 (14.4)

90 (52.0)
2 (1.2)79 (45.7)

91(52.3)
3 (1.7)78 (44.8)181 (52.2)
5 (1.4)157 (45.2)

40 (23.1)
22 (12.7)
14 (8.1)
3 (1.7)2 (1.2)29 (16.7)
28 (16.1)
18 (10.3)
3 (1.7)2 (1.1)69 (19.9)50 (14.4)
32 (9.2)
6 (1.7)4 (1.2)108 (62.4)
59 (34.1)
5 (2.9)1 (<1.0)110 (63.2)
55 (31.6)
9 (5.2)0218 (62.8)
114 (32.9)
14 (4.0)
1 (<1.0)

Abbreviation: N/n=number of subjects.
Smoking status for 1 subject was not reported; the subject was randomized but not treated and some, but not all, baseline
information was collected.

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Public Disclosure Synopsis
Protocol A8081007 – 25 October 2016 Final

Efficacy Results:
Primary Endpoints:
Progression-Free Survival:
A summary of PFS based on the IRR assessment by treatment arm is provided in Table 7.
Crizotinib more than doubled median PFS compared to chemotherapy, with a median PFS of
7.7 months for 173 subjects randomized to crizotinib and 3.0 months for 174 subjects
randomized to chemotherapy. The HR comparing crizotinib with chemotherapy was 0.487(95% CI: 0.371, 0.638) with a p-value of <0.0001 (1-sided stratified log-rank test).

090177e18aa74a44\Approved\Approved On: 22-Nov-2016 12:34

Table 7

Summary of Progression-Free Survival Based on the Independent Radiology
Review Assessment by Treatment Arm – Full Analysis

Number with event, n (%)
Objective progression
Death without objective progression
Number censored, n (%)
No adequate baseline assessments
No on-study disease assessments
Given new anti-cancer treatment prior to tumor progression
Withdrew consent for follow-up
Lost to follow-up
Unacceptable gap (>14 weeks) between PD or death to the mostrecent prior adequate assessment
In follow-up for progression
No scans/data available
Probability of being event free at Month 6a
95% CIb
Kaplan-Meier estimate of time to event (months)
25% percentile (95% CI)c
50% percentile (95% CI)c
75% percentile (95% CI)c
Vs chemotherapy
Hazard ratiod
95% CI of hazard ratio
p-valuee

Crizotinib(N=173)100 (57.8)
84 (48.6)
16 (9.2)
73 (42.2)
03 (1.7)13 (7.5)
2 (1.2)0
1 (<1.0)

Chemotherapy(N=174)127 (73.0)
119 (68.4)
8 (4.6)47 (27.0)0
2 (1.1)13 (7.5)
00
2 (1.1)51 (29.5)
3 (1.7)58.2
49.7, 65.8

30 (17.2)0
30.0
22.7, 37.6

4.0 (2.9, 5.3)
7.7 (6.0, 8.8)
13.9 (11.1, 18.0)

1.4 (1.4, 1.6)
3.0 (2.6, 4.3)
7.0 (5.7, 9.8)

0.487
0.371-0.638<0.0001

Abbreviations: PD=progressive disease; CI=confidence interval; EGFR=epidermal growth factor receptor; TKI=tyrosine
kinase inhibitor; ECOG PS=Eastern Cooperative Oncology Group performance status; n/N=number of subjects; vs=versus.
a.
Estimated from the Kaplan-Meier curve.
b.
Calculated using the normal approximation to the log transformed cumulative hazard rate.
c.
Based on the Brookmeyer and Crowley method.
d.
Based on the Cox proportional hazards model stratified by ECOG PS score, brain metastases, prior EGFR-TKI treatment.
Assuming proportional hazards, a hazard ratio <1 indicates a reduction in hazard rate in favor of crizotinib.
e.
1-sided p-value from the log-rank test stratified by ECOG PS score, brain metastases, and prior EGFR-TKI treatment.

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Public Disclosure Synopsis
Protocol A8081007 – 25 October 2016 Final

A summary of PFS based on the IRR assessment by study treatment (crizotinib vspemetrexed and crizotinib vs docetaxel) is provided in Table 8. Subgroup analysis of
crizotinib vs pemetrexed and crizotinib vs docetaxel demonstrated superior PFS in the
crizotinib arm. The median PFS was 7.7 months for 172 subjects treated with crizotinib and4.2 months for 99 subjects treated with pemetrexed and 2.6 months for 72 subjects treatedwith docetaxel.

090177e18aa74a44\Approved\Approved On: 22-Nov-2016 12:34

Table 8

Summary of Progression-Free Survival Based on the Independent Radiology
Review Assessment by Study Treatment (Crizotinib Versus Pemetrexed andCrizotinib Versus Docetaxel) – Safety Analysis

Number with event, n (%)
Objective progression
Death without objective progression
Kaplan-Meier estimate of time to event (months)
Quartiles (95% CI)a
25% percentile (95% CI)c
50% percentile (95% CI)c
75% percentile (95% CI)c
Vs pemetrexed or docetaxel
Hazard ratiob
Hazard ratiob
95% CI of hazard ratio
p-valuec

Crizotinib(N=172)100 (58.1)
84 (48.8)
16 (9.3)

Pemetrexed(N=99)
72 (72.7)
67 (67.7)
5 (5.1)Docetaxel(N=72)
54 (75.0)
52 (72.2)
2 (2.8)4.0 (2.9, 5.3)
7.7 (6.0, 8.8)
13.9 (11.1, 18.0)

1.5 (1.4, 2.5)
4.2 (2.8, 5.7)
9.5 (6.7, 11.3)

1.4 (1.3, 1.6)
2.6 (1.6, 4.0)
5.5 (4.0, 7.0)

0.589
0.431-0.804
0.00040.298
0.207-0.428<0.0001

Abbreviations: CI=confidence interval; EGFR=epidermal growth factor receptor; TKI=tyrosine kinase inhibitor; ECOG
PS=Eastern Cooperative Oncology Group performance status; n/N=number of subjects; vs=versus.
a.
Based on the Brookmeyer and Crowley method.
b.
Based on the Cox proportional hazards model stratified by ECOG PS score, brain metastases, and prior EGFR-TKI
treatment. Assuming proportional hazards, a hazard ratio <1 indicates a reduction in hazard rate in favor of crizotinib.
c.
1-sided p-value from the log-rank test stratified by ECOG PS score, brain metastases, prior EGFR-TKI treatment.

Secondary endpoints:
Overall Survival:
A summary of OS by treatment arm is provided in Table 9. A total of 116 (67.1%) subjects
in the crizotinib arm and 126 (72.4%) subjects in the chemotherapy arm were known to havedied. Data of subjects not known to have died were censored at the time they were last
known to be alive. Among these, a total of 41 (23.7%) subjects in the crizotinib arm and 32(18.4%) subjects in the chemotherapy arm were in the follow-up for survival at the data
cutoff. There was no statistically significant improvement in OS for crizotinib vschemotherapy. There was, however, a numerical improvement in OS in the crizotinib arm(HR: 0.854; 95% CI: 0.661, 1.104 with a p-value of 0.1145; 1-sided stratified log-rank test).
The median OS was 21.7 months for crizotinib and 21.9 months for chemotherapy.
The survival probabilities at 6 months and 12 months were comparable in the 2 treatment
arms. The survival probabilities at 6 months were 86.6% (95% CI: 80.5%, 90.9%) and
83.8% (95% CI: 77.4%, 88.5%) for the crizotinib arm and the chemotherapy arm,
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Public Disclosure Synopsis
Protocol A8081007 – 25 October 2016 Finalrespectively; and the survival probabilities at 12 months were 70.4% (95% CI: 62.9%,
76.7%) and 66.7% (95% CI: 59.1%, 73.2%) for the crizotinib arm and the chemotherapy
arm, respectively.

090177e18aa74a44\Approved\Approved On: 22-Nov-2016 12:34

Table 9

Summary of Overall Survival by Treatment Arm- Full Analysis

Number of deaths, n (%)
Number censored, n (%)
Subject remains in follow-up
Subject no longer being followed for survival
Withdrew consent for follow-up
Lost to follow-up
Survival probability:aat 6 months (95% CI)b
at 12 months (95% CI)b
Kaplan-Meier estimate of time to event (month)
25% percentile (95% CI)c
50% percentile (95% CI)c
75% percentile (95% CI)c
Versus chemotherapy
Hazard ratiod
95% CI of hazard ratio
p-valuee

Crizotinib (N=173)
116 (67.1)
57 (32.9)
41 (23.7)
3 (1.7)5 (2.9)8 (4.6)

Chemotherapy (N=174)
126 (72.4)
48 (27.6)
32 (18.4)
5 (2.9)8 (4.6)3 (1.7)86.6 (80.5, 90.9)
70.4 (62.9, 76.7)

83.8 (77.4, 88.5)
66.7 (59.1, 73.2)

10.4 (8.0, 13.1)
21.7 (18.9, 30.5)
58.0 (47.4, NR)

9.8 (7.8, 11.5)
21.9 (16.8, 26.0)
51.3 (35.6, NR)

0.854
0.661-1.104
0.1145Abbreviations: CI=confidence interval; ECOG PS=Eastern Cooperative Oncology Group performance status; EGFRTKI=Epidermal growth factor receptor tyrosine kinase inhibitor; HR=hazard ratio; N/n=number of subjects; NR=not reached.
a
Estimated from the Kaplan-Meier curve.
bCalculated using the normal approximation to the log transformed cumulative hazard rate.
cBased on the Brookmeyer and Crowley Method.
dBased on the Cox Proportional hazards model stratified by ECOG PS, brain metastases, prior EGFR-TKI treatment.
Assuming proportional hazards, a HR less than 1 indicates a reduction in hazard rate in favor of crizotinib.
e1-sided p-value from the log-rank test stratified by ECOG PS, brain metastases, prior EGFR-TKI treatment.

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Public Disclosure Synopsis
Protocol A8081007 – 25 October 2016 Final

Objective Response Rate:
This study demonstrated a statistically significant improvement in ORR for crizotinib asassessed by the IRR. Crizotinib more than tripled ORR compared to chemotherapy with
ORRs of 65% (95% CI: 58%, 72%) for crizotinib and 20% (95% CI: 14%, 26%) for
chemotherapy with p<0.0001 (2-sided stratified Cochran-Mantel-Haenszel [CMH] test). A
summary of best overall response based on the IRR by treatment arm is provided in Table 10.
Table 10. Summary of Best Overall Response Based on the Independent Radiology
Review Assessment by Treatment Arm – Full Analysis090177e18aa74a44\Approved\Approved On: 22-Nov-2016 12:34

Crizotinib (N=173)
Best overall response, n (%)
Complete response
Partial response
Stable disease for at least 6 weeks
Objective progression
Early deathIndeterminate
Objective response rate (CR+PR), n (%)
95% Exact CIa
SD duration (months) b, n (%)
0 to <3 months
3 to <6 months
6 to <9 months
9 to <12 months≥12 months
Treatment comparison (vs chemotherapy)
Treatment difference in ORR ratec
95% CI of differencec
p-valued
Treatment comparison (vs chemotherapy)
Risk ratioe
95% CI of risk ratioe
p-valuee

Chemotherapy (N=174)

1 (<1.0)112 (64.7)
32 (18.5)
11 (6.4)
4 (2.3)13 (7.5)
113 (65.3)
57.7, 72.4

034 (19.5)
63 (36.2)
60 (34.5)
4 (2.3)13 (7.5)
34 (19.5)
13.9, 26.2

13 (40.6)
9 (28.1)
8 (25.0)
2 (6.3)0

23 (36.5)
24 (38.1)
10 (15.9)
1 (1.6)5 (7.9)45.8
36.6, 55.0
<0.0001
3.4
2.5, 4.7<0.0001

Best overall response was based on the independent radiology review.
Early death was death within 6 weeks (42 days) from randomization.
Abbreviations: CR=complete response; PR=partial response; CI=confidence interval; ORR=objective response rate;
EGFR=epidermal growth factor receptor; TKI=tyrosine kinase inhibitor; ECOG PS=Eastern Cooperative Oncology Group
performance status; SD=stable disease; vs=versus; N/n=number of subjects.
a.
Using exact method based on F-distribution.
b.
% was based on the number of SD subjects.
c.
Calculated based on a normal distribution.
d.
p-value was from a Pearson chi-square test.
e.
Calculated from Cochran-Mantel-Haenszel (CMH) test stratified by ECOG-PS score, brain metastases, and prior
EGFR-TKI treatment.

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Public Disclosure Synopsis
Protocol A8081007 – 25 October 2016 Final

Disease Control Rate:
Summary of Disease Control Rate at Week 6 and Week 12 Based on the Independent
Radiology Review Assessment by Treatment Arm is provided in Table 11.

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Table 11

Summary of Disease Control Rate at Week 6 and Week 12 Based on the
Independent Radiology Review Assessment by Treatment Arm – Full
Analysis

Disease control rate at Week 6, n (%)
95% exact CIa
Treatment comparison (vs chemotherapy)
Treatment difference in DCR rateb
95% CI of differenceb
p-valuec
Treatment comparison (vs chemotherapy)
Risk ratiod
95% CI of risk ratiod
p-valuee
Disease control rate at Week 12, n (%)
95% exact CIa
Treatment comparison (vs chemotherapy)
Treatment difference in DCR rateb
95% CI of differenceb
P valuec
Treatment comparison (vs chemotherapy)
Risk ratiod
95% CI of risk ratiod
p-valued

Crizotinib (N=173)
141 (81.5)
74.9, 87.0

Chemotherapy (N=174)
96 (55.2)
47.5, 62.7

26.3
16.9, 35.7
<0.0001
1.5
1.3, 1.7<0.0001111 (64.2)
56.5, 71.3

67 (38.5)
31.2, 46.2

25.7
15.5, 35.8
<0.0001
1.7
1.4, 2.1<0.0001

Abbreviations: CI=confidence interval; EGFR=epidermal growth factor receptor; TKI=tyrosine kinase inhibitor; ECOG
PS=Eastern Cooperative Oncology Group performance status; DCR=disease control rate; n/N=number of subjects.
a.
Using exact method based on F-distribution.
b.
Calculated based on a normal distribution.
c.
P-value was from a Pearson chi-square test.
d.
Calculated from Cochran-Mantel-Haenszel (CMH) test stratified by ECOG PS score, brain metastases, and prior
EGFR-TKI treatment.

Duration of Response:
Summary of Duration of Response Based on the Independent Radiology Review Assessment
by Treatment Arm is provided in Table 12.

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Public Disclosure Synopsis
Protocol A8081007 – 25 October 2016 Final

Table 12

Summary of Duration of Response Based on the Independent Radiology
Review Assessment by Treatment Arm – Full Analysis (Objective
Responders Only)
Crizotinib (N=173)

090177e18aa74a44\Approved\Approved On: 22-Nov-2016 12:34

Number of subjects with objective response (CR or PR), n (%)
Objective response (CR or PR) statusa, n (%)
With subsequent progression or death
Duration of response (weeks)b
Mean (standard deviation)MedianRange
Without subsequent progression or death
Kaplan-Meier estimates of duration of response (weeks)
25% percentile (95% CI)c
50% percentile (95% CI)c
75% percentile (95% CI)c113 (65.3)

Chemotherapy(N=174)34 (19.5)

61 (54.0)

20 (58.8)

25.4 (16.3)
19
2.1-72.4
52 (46.0)

17.3 (10.9)
14.2
3.0-43.6
14 (41.2)

17.7 (12.9, 23.1)
32.1 (26.4, 42.3)
61.4 (43.6, NR)

12.1 (7.0, 19.1)
24.4 (15.0, 36.0)
43.6 (25.1, 43.6)

Duration of response was the time from the date of first documentation of CR or PR to the date of first documentation of
objective disease progression or death due to any cause.
Abbreviations: CR=complete response; PR=partial response; CI=confidence interval; NR=not reached; N/n=number ofsubjects.
a.
% based on the number of subjects with objective response (CR or PR).
b.
Descriptive statistics are presented for subjects with subsequent progression or death.
c.
Based on the Brookmeyer and Crowley method.

Time to Tumor Response:
Summary of Time to Tumor Response Based on the Independent Radiology Review
Assessment by Treatment Arm is provided in Table 13.
Table 13

Summary of Time to Tumor Response Based on the Independent Radiology
Review Assessment by Treatment Arm – Full Analysis (Objective
Responders Only)
Crizotinib (N=173)

Chemotherapy (N=174)

113
8.6 (6.2)
6.3
4.4-48.4

34
16.9 (10.1)
12.6
5.0-37.1

15 (13.3)
76 (67.3)
17 (15.0)
1 (0.9)4 (3.5)5 (14.7)
9 (26.5)
5 (14.7)
5 (14.7)
10 (29.4)

Time to response (weeks)aN
Mean (standard deviation)MedianRange
Category (weeks)b
0 to <6
6 to <12
12 to <18
18 to <24
≥24

Time to response was the time from the randomization date to the first documentation of objective tumor response (CR or
PR).
Abbreviations: N=number of subjects; CR=complete response; PR=partial response.
a.
Descriptive statistics are presented for subjects with an event.
b.
Category was presented for subjects with an event.

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Public Disclosure Synopsis
Protocol A8081007 – 25 October 2016 FinalTime to Deterioration:
Summary of Time to Deterioration in Pain (in Chest), Dyspnea, or Cough (Composite
Endpoint) by Arm is provided in Table 14.

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Table 14

Summary of Time to Deterioration in Pain (in Chest), Dyspnea, or Cough(Composite Endpoint) by Arm – PRO Evaluable

Number with event, n (%)
Deterioration of symptom
Number censored, n (%)
No deterioration
Probability of being event free at Month 6a (95% CI b)
Kaplan-Meier estimate of time to event (months)
25% percentile (95% CI)c
50% percentile (95% CI)c
75% percentile (95% CI)c
Vs chemotherapy
Hazard ratiod
95% CI of hazard ratio
p-valuee

Crizotinib (N=162)
91 (56.5)
91 (56.5)
70 (43.5)
70 (43.5)
46.2 (37.6, 54.4)

Chemotherapy (N=151)
111 (74.0)
111 (74.0)
39 (26.0)
39 (26.0)
18.3 (11.5, 26.4)

1.3 (0.8, 1.6)
4.5 (3.0, 6.9)
18.7 (12.5, NR)

0.8 (0.8, 0.9)
1.4 (1.0, 1.6)
3.9 (2.4, 8.3)

0.497
0.373, 0.661<0.0001

Time to deterioration was defined as the first occurrence of a 10-point or more increase in scores from baseline in symptoms
of pain in chest (EORTC QLQ-LC13 pain in chest), cough (EORTC QLQ-LC13 cough), or dyspnea (EORTC QLQ-LC13
dyspnea); otherwise censored at date of last questionnaire. PRO evaluable subjects with either a missing baseline or followup symptom values are not included in summary.
Abbreviations: PRO=subject-reported outcomes; n/N=number of subjects; CI=confidence interval; NR=not reached;
Vs=versus; EORTC QLQ-LC13=European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire–
supplement module for Lung Cancer (LC13).
a.
Estimated from the Kaplan-Meier curve.
b.
Calculated using the normal approximation to the log transformed cumulative hazard rate.
c.
Based on the Brookmeyer and Crowley Method.
d.
Based 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.
e.
2-sided p-value from the unstratified log-rank test.

European Organization for the Research and Treatment of Cancer Quality of Life
Questionnaire-Core 30 (EORTC QLQ-C30).
The change from baseline scores were found to be significantly different between the
2 treatment arms, with a significantly greater improvement observed in the crizotinib arm
compared to the chemotherapy arm in global quality of life (p<0.0001), emotional
functioning (p<0.05), physical functioning (p<0.0001), role functioning (p<0.05), and social
functioning (p<0.05). The change from baseline scores for cognitive functioning between the
crizotinib and chemotherapy arms were not significantly different.
The change from baseline was found to be significantly different between the 2 treatment
arms, with a significantly greater improvement observed in the crizotinib arm compared tothe chemotherapy arm in appetite loss (p<0.05), dyspnea (p<0.0001), fatigue (p<0.0001),
insomnia (p<0.0001), and pain (p<0.0001). The change from baseline was found to bestatistically significantly different between the 2 treatment arms, with a significantly greater
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Public Disclosure Synopsis
Protocol A8081007 – 25 October 2016 Final

deterioration observed in the crizotinib arm compared to the chemotherapy arm forconstipation (p<0.05) and diarrhea (p<0.0001). The difference in change from baseline
scores between the crizotinib and chemotherapy arms was not statistically significant fornausea/vomiting.
European Organization for the Research and Treatment of Cancer Quality of Life
Questionnaire-Supplement Module for Lung Cancer (EORTC QLQ-LC13).
The change from baseline was found to be significantly different between the 2 treatment
arms, with a significantly greater improvement observed in the crizotinib arm compared tothe chemotherapy arm in alopecia (p<0.0001), coughing (p<0.0001), dyspnea (p<0.0001),
haemoptysis (p<0.05), pain in arm or shoulder (p<0.0001), pain in chest (p<0.0001), and painin other parts (p<0.0001). Significantly greater deterioration from baseline was observed in
the chemotherapy arm compared to crizotinib for the symptoms of peripheral
neuropathy (p<0.05), dysphagia (p<0.05), and sore mouth (p<0.001).

090177e18aa74a44\Approved\Approved On: 22-Nov-2016 12:34

European Quality of Life - 5 Dimensional (EQ-5D) Visual Analog Scale (VAS)
The EQ-5D VAS records the subjects self-rated general health status on a scale from 0 (worst
imaginable health state) to 100 (best imaginable health state). The results of the within
subjects analyses showed a statistically significant (p<0.05) improvement from baseline in
EQ-5D VAS scores in the crizotinib arm (Cycles 2 to 15) and no statistically significant
change from baseline in the chemotherapy arm. The change from baseline in EQ-5D VAS
scores was found to be statistically significantly different (p<0.001) between the 2 treatment
arms, with a statistically significantly greater improvement observed in the crizotinib arm
compared to the chemotherapy arm.
Visual Symptom Assessment Questionnaire
Subjects were instructed to complete Questions 2-7 of the VSAQ-ALK only if they indicatedthat they had a visual disturbance in Question 1 (“Have you experienced any visual
disturbances?”). The number of chemotherapy-treated subjects who had completed
Questions 2-7 of the VSAQ-ALK were much lower (n<20) than crizotinib-treated subjects as
the majority reported not having a visual disturbance on the first question. Completion ratesof all questions of the VSAQ-ALK questionnaire ranged from 59.6% to 93.1% for subjects
treated with crizotinib over the first 30 cycles and 62.8% to 84.2% for subjects treated withchemotherapy over the first 10 cycles.
A total of 31.3% to 63.4% of crizotinib-treated subjects (up to Cycle 30) and 16.7% to 26.7%
of chemotherapy-treated subjects (up to Cycle 10) had experienced visual disturbance.
Among crizotinib-treated subjects who reported experiencing a visual disturbance in the first
30 cycles, the majority (range: 73.9% to 100%) had event frequency of >1 day per week; atotal of 39.1% to 72.7%, 4.4% to 60.0% and 60.0% to 87.0% subjects had reported
occurrence of visual disturbances in the morning, afternoon and evening within the first
30 cycles, respectively.
Among chemotherapy-treated subjects, based on the first 10 cycles, the majority(range: 58.3% to 100%) of subjects had event frequency of >1 day per week; a total of 41.7%

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Public Disclosure Synopsis
Protocol A8081007 – 25 October 2016 Final

to 80.0%, 60.0% to 100% and 40.0% to 80.0% subjects had reported visual disturbances in
the morning, afternoon, and evening within the first 10 cycles, respectively.
Most crizotinib-treated and chemotherapy-treated subjects had reported that each event had
lasted for about ≤1 minute. The most commonly experienced visual disturbances incrizotinib-treated subjects were appearance of shimmering/flashing/trailing lights,
streamers/strings/floaters, and overlapping shadows/after images and inchemotherapy-treated subjects was hazy/blurry vision.
In crizotinib-treated subjects, the occurrence of visual disturbance had produced not at all or
little bothersome and most subjects indicated no or minimal impact (score 0 to 3) on daily
activities at each cycle.
Pharmacokinetic endpoints:
Summary of Predose Concentrations (Ctrough) of Crizotinib and its Metabolite, PF-06260182,
and PF-06260182 to Crizotinib Ratio, Following 250 mg BID Oral Dosing of Crizotinib isprovided in Table 15.

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Table 15

Summary of Predose Concentrations (Ctrough) of Crizotinib and its
Metabolite, PF-06260182, and PF-06260182 to Crizotinib Ratio, Following
250 mg BID Oral Dosing of Crizotinib
Ctrougha (ng/mL)

Parameter
Cycle 1 Day 1
15/13

Cycle 2 Day 1
62/55

Cycle 3 Day 1
61/59

Cycle 5 Day 1
47/46

Crizotinib

BLQ

293 (47)306 (41)291 (49)

PF-06260182
PF-06260182 tocrizotinib ratio

BLQ

81.3 (54)85.7 (54)87.1 (50)NA

0.267 (23)0.267 (28)0.291 (22)N/nNote: N=number of observations for crizotinib and n=number of observations for PF-06260182 and PF-06260182 tocrizotinib ratio. The PF-06260182 to crizotinib ratio for plasma concentrations was calculated by ([concentration of PF06260182]/[concentration of crizotinib])*([molecular weight of crizotinib (450.34)/molecular weight of PF-06260182(464.33)]).
Abbreviations: Ctrough=trough concentration; BID=twice daily; BLQ=below the lower limit of quantification;
CV=coefficient of variation; NA=not applicable.
a.
Geometric mean (%CV).

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Public Disclosure Synopsis
Protocol A8081007 – 25 October 2016 Final

Electrocardiograms:
The majority (88.4%) of crizotinib-treated subjects had maximum post-dose QTcF <450msec (Table 16). Eight crizotinib-treated subjects (5.2%) had QTcF ≥500 msec.
Table 16

Categorization of Electrocardiogram Data, Maximum Postdose (CrizotinibArm) - Safety Analysis
Crizotinib

Maximum QTcF
<450 msec
450 to <480 msec
480 to <500 msec
≥500 msec

N

n (%)

155
155
155
155

137 (88.4)
9 (5.8)1 (0.6)8 (5.2)

Table does not include subjects who participated in the ECG substudy. Abbreviations: N=number of subjects with a
postbaseline assessment; n=number of subjects; QTcF=corrected QT interval using Fridericia’s correction;
ECG=electrocardiogram.

Pharmacodynamic Results

090177e18aa74a44\Approved\Approved On: 22-Nov-2016 12:34

Molecular Profiling (ALK status)
Subjects NSCLC were determined to be ALK-positive by an investigational-use only (IUO)
diagnostic test from Abbott Molecular.
A summary of descriptive statistics for percentage of ALK-positive cells by the central
laboratory IUO test (Abbott Molecular) is provided in Table 17.
Mean and median percentages of ALK-positive cells were similar between the 2 treatment
arms.
Table 17

Descriptive Statistics for ALK Percentage of Positive Cells by Central
Laboratory Test by Treatment Arm – Full Analysis

ALK percentage of positive cells (%)
N
Mean (standard deviation)MedianRange

Crizotinib(N=173)Chemotherapy(N=174)173
57.4 (21.80)
58.0
15.0-98.0

173a59.5 (20.05)
58.0
15.0-98.0

ALK+ by IUO includes all enrolled subjects with IOU data and ALK+.
Abbreviations: N/n=number of subjects; ALK= anaplastic lymphoma kinase; IUO=investigational-use only;
FISH=fluorescence in-situ hybridization.
a.
One subject on chemotherapy was ALK+ identified by local laboratory only, using FISH.

Molecular Profiling Outcomes
Analyses investigating the relationship of ALK gene fusion to the presence of ALK protein
and fusion transcript have not been performed for technical reasons, including limited sample
stability.

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Public Disclosure Synopsis
Protocol A8081007 – 25 October 2016 Final

Biomarkers
Plasma concentrations of soluble c-Met ectodomain protein are provided in Table 18. No
statistically significant differences were observed in comparisons of on-treatment to baseline
values or between objective response categories.
Table 18

Plasma Concentration of Soluble c-Met Ectodomain Protein in the
Crizotinib Treatment Arm
Plasma concentration (ng/ml)
172
Mean
Standard Deviation
1428.3363.91683.0325.6
1751.8327.9

Number of samples analyzed (N)090177e18aa74a44\Approved\Approved On: 22-Nov-2016 12:34

Baseline (N=81)
Cycle 2 Day 1 6 hour post dose (N=69)
End of treatment (N=40)

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Public Disclosure Synopsis
Protocol A8081007 – 25 October 2016 Final

Safety Results:
Treatment-emergent adverse events due to all-causality and treatment-related aresummarized in Table 19. Almost all subjects experienced treatment-related AEs (95.3%
crizotinib-treated subjects, 83.8% pemetrexed -treated subjects and 95.8% docetaxel-treatedsubjects). A total of 13.4% of crizotinib-treated subjects, 9.1% of pemetrexed-treatedsubjects and 20.8% of docetaxel-treated subjects had treatment-related SAEs. None of thesafety analyses was adjusted for the longer duration of crizotinib treatment than the durationof chemotherapy treatment (median 48 and 13 weeks, respectively).

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Table 19

Treatment-Emergent Adverse Events by Treatment (All-Causality andTreatment-Related) – Safety Analysis

Number of AEs
Subjects with AEs
Subjects with SAEs
Subjects with Grade 3 or 4 AEs
Subjects with Grade 5 AEs
Subjects discontinued due toAEs
Subjects with dose reduced due
to AEsSubjects with temporary
discontinuation due to AEs

Crizotinib (N=172)n (%)
All-Causality Treatment-Related
2741
1499
172 (100.0)
164 (95.3)
80 (46.5)
23 (13.4)
111 (64.5)
67 (39.0)30 (17.4)
3 (1.7)34 (19.8)
11 (6.4)

Chemotherapy
All-Causality1430
169 (98.8)
42 (24.6)
82 (48.0)
7 (4.1)34 (19.9)

Treatment-Related
845
152 (88.9)
24 (14.0)
58 (33.9)
1 (0.6)21 (12.3)

29 (16.9)

26 (15.1)

24 (14.0)

23 (13.5)

83 (48.3)

64 (37.2)

28 (16.4)

17 (9.9)

Includes all AE data captured in the database.
Except for the Number of AEs, subjects counted only once per treatment group in each row.
SAEs - according to the investigator’s assessment.
MedDRA (v18.1) coding dictionary applied.
Abbreviations: AE=adverse event; CSR=clinical study report; MedDRA=Medical Dictionary for Regulatory Activities;
N/n=number of subjects; SAE=serious adverse event; v=version.

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Non-Serious adverse events (NSAEs):
NSAEs above the 5% threshold are summarized in Table 20.

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Table 20

Non-Serious adverse events (NSAEs):

Number (%) of Subjects:
All-Causality
Evaluable for adverse events
171 (99.42)
With adverse events
Number (%) of Subjects with Adverse Events by System Organ Class
and MedDRA (v18.1) Preferred Term
BLOOD AND LYMPHATIC SYSTEM
65 (37.79)
DISORDERS
Anaemia36 (20.93)
Leukopenia
24 (13.95)
Neutropenia
41 (23.84)
CARDIAC DISORDERS
9 (5.23)
Bradycardia
9 (5.23)
EYE DISORDERS
98 (56.98)
Lacrimation increased
1 (0.58)
Photopsia
21 (12.21)
Vision blurred
13 (7.56)
Visual impairment
74 (43.02)
GASTROINTESTINAL DISORDERS
158 (91.86)
Abdominal pain
18 (10.47)
Abdominal pain upper
17 (9.88)
Constipation
83 (48.26)
Diarrhoea
106 (61.63)
Dyspepsia
18 (10.47)
Dysphagia
9 (5.23)
Gastrooesophageal reflux disease
12 (6.98)
Nausea104 (60.47)

Crizotinibn (%)
Treatment-Related172
162 (94.19)

55 (31.98)

43 (25.15)

38 (22.22)

20 (11.63)
24 (13.95)
39 (22.67)
9 (5.23)
9 (5.23)
96 (55.81)

27 (15.79)
9 (5.26)
18 (10.53)
00
22 (12.87)
9 (5.26)
1 (0.58)
5 (2.92)
8 (4.68)
101 (59.06)
8 (4.68)
13 (7.60)
39 (22.81)
34 (19.88)
6 (3.51)
2 (1.17)060 (35.09)

23 (13.45)
9 (5.26)
16 (9.36)
00
6 (3.51)

21 (12.21)
10 (5.81)
73 (42.44)
145 (84.30)
10 (5.81)
62 (36.05)
94 (54.65)
11 (6.40)

94 (54.65)

Page 27

Chemotherapyn (%)
All-Causality
Treatment-Related171
157 (91.81)
136 (79.53)

1 (0.58)
4 (2.34)
2 (1.17)88 (51.46)
5 (2.92)
32 (18.71)
29 (16.96)
4 (2.34)

57 (33.33)

Public Disclosure Synopsis
Protocol A8081007 – 25 October 2016 Final

090177e18aa74a44\Approved\Approved On: 22-Nov-2016 12:34

Crizotinibn (%)
Stomatitis
Vomiting
GENERAL DISORDERS AND
ADMINISTRATION SITE CONDITIONSAsthenia
Chest pain
Fatigue
OedemaOedema peripheral
Pain
Pyrexia
INFECTIONS AND INFESTATIONS
Nasopharyngitis
Upper respiratory tract infection
INJURY, POISONING AND PROCEDURALCOMPLICATIONSFall
INVESTIGATIONS
Alanine aminotransferase increased
Aspartate aminotransferase increased
Blood alkaline phosphatase increased
Blood creatinine increased
Electrocardiogram QT prolonged
Neutrophil count decreased
Weight decreased
White blood cell count decreased
METABOLISM AND NUTRITION DISORDERS
Decreased appetite
Hyperglycaemia
Hypoalbuminaemia
Hypocalcaemia

9 (5.23)
88 (51.16)
132 (76.74)

8 (4.65)
79 (45.93)
92 (53.49)

31 (18.02)
15 (8.72)
51 (29.65)
15 (8.72)
59 (34.30)
10 (5.81)
41 (23.84)
50 (29.07)
32 (18.60)
24 (13.95)
11 (6.40)

18 (10.47)
31 (18.02)
11 (6.40)
50 (29.07)
9 (5.23)

11 (6.40)
103 (59.88)
72 (41.86)
55 (31.98)
18 (10.47)
13 (7.56)
9 (5.23)
15 (8.72)
21 (12.21)
16 (9.30)
79 (45.93)
56 (32.56)
12 (6.98)
16 (9.30)
13 (7.56)

88 (51.16)
68 (39.53)
51 (29.65)
12 (6.98)
10 (5.81)
14 (8.14)
12 (6.98)
15 (8.72)
46 (26.74)
37 (21.51)
10 (5.81)

Page 28

Chemotherapyn (%)
13 (7.60)
12 (7.02)
32 (18.71)
24 (14.04)
112 (65.50)
81 (47.37)
32 (18.71)
13 (7.60)
60 (35.09)
6 (3.51)
15 (8.77)
9 (5.26)
33 (19.30)
20 (11.70)
7 (4.09)14 (8.19)
3 (1.75)
3 (1.75)
46 (26.90)
21 (12.28)
17 (9.94)
6 (3.51)
3 (1.75)
09 (5.26)
8 (4.68)
13 (7.60)
56 (32.75)
46 (26.90)
9 (5.26)
1 (0.58)022 (12.87)
51 (29.82)
2 (1.17)7 (4.09)19 (11.11)

37 (21.64)
19 (11.11)
14 (8.19)
4 (2.34)
1 (0.58)
9 (5.26)
4 (2.34)
12 (7.02)
37 (21.64)
37 (21.64)
0Public Disclosure Synopsis
Protocol A8081007 – 25 October 2016 Final

090177e18aa74a44\Approved\Approved On: 22-Nov-2016 12:34

Crizotinibn (%)
Hypokalaemia
MUSCULOSKELETAL AND CONNECTIVE
TISSUE DISORDERS
Arthralgia
Back pain
Muscle spasms
Musculoskeletal pain
Myalgia
Neck pain
Pain in extremity
NERVOUS SYSTEM DISORDERS
Dizziness
Dysgeusia
Headache
Neuropathy peripheral
Paraesthesia
Peripheral sensory neuropathy
Visual perseveration
PSYCHIATRIC DISORDERS
Insomnia
RESPIRATORY, THORACIC AND
MEDIASTINAL DISORDERS
Cough
Dyspnoea
Epistaxis
Haemoptysis
Oropharyngeal pain
Productive coughPulmonary embolism
Rhinorrhoea
SKIN AND SUBCUTANEOUS TISSUE

15 (8.72)
63 (36.63)

Chemotherapyn (%)
5 (2.91)

15 (8.72)
30 (17.44)
9 (5.23)
14 (8.14)
5 (2.91)
11 (6.40)
20 (11.63)
100 (58.14)
34 (19.77)
45 (26.16)
46 (26.74)
5 (2.91)
13 (7.56)
9 (5.23)
12 (6.98)
19 (11.05)
19 (11.05)
72 (41.86)

3 (1.74)

2 (1.16)62 (36.05)
16 (9.30)
43 (25.00)
11 (6.40)

12 (6.98)

37 (21.51)
27 (15.70)
3 (1.74)
9 (5.23)
20 (11.63)
12 (6.98)
9 (5.23)
4 (2.33)
47 (27.33)

22 (12.79)

Page 29

5 (2.92)
54 (31.58)
20 (11.70)
11 (6.43)
4 (2.34)
6 (3.51)
19 (11.11)
5 (2.92)
10 (5.85)
55 (32.16)
13 (7.60)
17 (9.94)
26 (15.20)
10 (5.85)
7 (4.09)
6 (3.51)013 (7.60)
13 (7.60)
75 (43.86)
35 (20.47)
29 (16.96)
10 (5.85)
11 (6.43)
7 (4.09)8 (4.68)
2 (1.17)9 (5.26)
62 (36.26)

24 (14.04)
12 (7.02)

18 (10.53)

31 (18.13)
8 (4.68)
17 (9.94)
11 (6.43)

057 (33.33)

Public Disclosure Synopsis
Protocol A8081007 – 25 October 2016 Final
Crizotinib
n (%)

090177e18aa74a44\Approved\Approved On: 22-Nov-2016 12:34

DISORDERS
Alopecia
Dry skin
PruritusRash

21 (12.21)
10 (5.81)
12 (6.98)
23 (13.37)

Chemotherapyn (%)
5 (2.91)

18 (10.47)

Subjects are only counted once per treatment for each row.
MedDRA (v18.1) coding dictionary applied.

Page 3035 (20.47)
2 (1.17)7 (4.09)30 (17.54)

34 (19.88)

29 (16.96)

Public Disclosure Synopsis
Protocol A8081007 – 25 October 2016 Final

Serious Adverse Events (SAEs):
SAEs are summarized in Table 21.

090177e18aa74a44\Approved\Approved On: 22-Nov-2016 12:34

Table 21

Serious Adverse Events (SAEs):

Number (%) of Subjects:
All-Causality
Evaluable for adverse events
With adverse events80 (46.51)
Number (%) of Subjects with Adverse Events by System Organ Class
and MedDRA (v18.1) Preferred Term
BLOOD AND LYMPHATIC SYSTEM
6 (3.49)
DISORDERS
Anaemia2 (1.16)
Febrile neutropenia
1 (0.58)
Lymphadenopathy
1 (0.58)
Neutropenia
2 (1.16)
Thrombocytopenia
0
CARDIAC DISORDERS
6 (3.49)
Arrhythmia
1 (0.58)
Cardiac arrest
1 (0.58)
Cardiac tamponade
1 (0.58)
Coronary artery disease
1 (0.58)
Myocardial ischaemia
1 (0.58)
Pericardial effusion
1 (0.58)
Supraventricular tachycardia
0
Syncope1 (0.58)
GASTROINTESTINAL DISORDERS
7 (4.07)
Abdominal pain upper
1 (0.58)
Diarrhoea
1 (0.58)
Food poisoning
1 (0.58)
Haematemesis
1 (0.58)

Crizotinibn (%)
Treatment-Related172
23 (13.37)

2 (1.16)

14 (8.19)

14 (8.19)

01 (0.58)

2 (1.17)
12 (7.02)
02 (1.17)1 (0.58)
3 (1.75)00
1 (0.58)00
2 (1.17)1 (0.58)
04 (2.34)0000

2 (1.17)
12 (7.02)

1 (0.58)03 (1.74)
1 (0.58)
1 (0.58)00
1 (0.58)
2 (1.16)1 (0.58)
1 (0.58)

Page 31

Chemotherapyn (%)
All-Causality
Treatment-Related171
42 (24.56)
24 (14.04)

2 (1.17)1 (0.58)
1 (0.58)00
1 (0.58)

1 (0.58)02 (1.17)00Public Disclosure Synopsis
Protocol A8081007 – 25 October 2016 Final

090177e18aa74a44\Approved\Approved On: 22-Nov-2016 12:34

Crizotinibn (%)
Ileus paralytic
Intestinal perforation
Melaena
NauseaOesophageal stenosis
Stomatitis
Vomiting
GENERAL DISORDERS AND
ADMINISTRATION SITE CONDITIONSChest pain
Death
Disease progression
Fatigue
General physical health deterioration
Malaise
Mucosal inflammation
Product contamination microbial
Pyrexia
Sudden death
HEPATOBILIARY DISORDERS
Hepatic failure
Hepatitis
INFECTIONS AND INFESTATIONS
Cellulitis
Empyema
Extradural abscess
Gastroenteritis
Lower respiratory tract infection
Lung abscessLung infection

Chemotherapyn (%)

1 (0.58)
1 (0.58)01 (0.58)
1 (0.58)03 (1.74)

1 (0.58)

23 (13.37)
02 (1.16)18 (10.47)
1 (0.58)
1 (0.58)
1 (0.58)00
1 (0.58)
1 (0.58)
2 (1.16)1 (0.58)
1 (0.58)
19 (11.05)
2 (1.16)1 (0.58)
1 (0.58)
1 (0.58)
2 (1.16)
2 (1.16)
2 (1.16)1 (0.58)02 (1.16)00
1 (0.58)
2 (1.17)0
1 (0.58)02 (1.16)

10 (5.85)

4 (2.34)

1 (0.58)
1 (0.58)01 (0.58)
2 (1.16)1 (0.58)
1 (0.58)
2 (1.16)

Page 32

2 (1.17)03 (1.75)
1 (0.58)00
2 (1.17)1 (0.58)
1 (0.58)0000
6 (3.51)00002 (1.17)0
1 (0.58)

1 (0.58)01 (0.58)02 (1.17)1 (0.58)000Public Disclosure Synopsis
Protocol A8081007 – 25 October 2016 Final

090177e18aa74a44\Approved\Approved On: 22-Nov-2016 12:34

Crizotinib
n (%)
Pneumonia
Pneumonia bacterial
Pneumonia influenzal
SepsisUrinary tract infection
INJURY, POISONING AND PROCEDURALCOMPLICATIONS
Femur fracture
Spinal fracture
INVESTIGATIONS
Alanine aminotransferase increased
Aspartate aminotransferase increased
Blood glucose increased
Electrocardiogram QT prolonged
Haemoglobin
Neutrophil count decreased
White blood cell count decreased
METABOLISM AND NUTRITION DISORDERS
Decreased appetite
Hyperglycaemia
Hyperkalaemia
Hypoglycaemia
Hypokalaemia
MUSCULOSKELETAL AND CONNECTIVE
TISSUE DISORDERS
Back pain
Muscular weakness
Musculoskeletal pain
Spinal column stenosis

8 (4.65)
1 (0.58)
1 (0.58)
1 (0.58)02 (1.16)00

Chemotherapyn (%)
3 (1.75)
1 (0.58)00
1 (0.58)
1 (0.58)
1 (0.58)
1 (0.58)

2 (1.16)1 (0.58)

1 (0.58)
1 (0.58)
5 (2.91)
3 (1.74)
2 (1.16)1 (0.58)
1 (0.58)000
5 (2.91)
2 (1.16)1 (0.58)
1 (0.58)
2 (1.16)1 (0.58)

1 (0.58)
0
0
0
0
0
0
1 (0.58)
1 (0.58)
2 (1.17)
2 (1.17)1 (0.58)00
1 (0.58)
04 (2.33)
3 (1.74)
2 (1.16)1 (0.58)000
2 (1.16)
2 (1.16)1 (0.58)

4 (2.33)

3 (1.75)

2 (1.16)1 (0.58)01 (0.58)

2 (1.17)0
1 (0.58)
0Page 33

3 (1.75)000
1 (0.58)
1 (0.58)
1 (0.58)
1 (0.58)
1 (0.58)
0Public Disclosure Synopsis
Protocol A8081007 – 25 October 2016 Final

090177e18aa74a44\Approved\Approved On: 22-Nov-2016 12:34

Crizotinibn (%)
NEOPLASMS BENIGN, MALIGNANT AND
UNSPECIFIED (INCL CYSTS AND POLYPS)
Colon cancer
Colon cancer recurrent
Tumour haemorrhage
NERVOUS SYSTEM DISORDERS
Brain oedema
Cerebral cyst
Dizziness
Headache
Intracranial pressure increased
Lethargy
Paraesthesia
Presyncope
SeizurePSYCHIATRIC DISORDERS
Confusional state
Delirium
Mental status changes
RENAL AND URINARY DISORDERS
Renal cyst
Ureteric stenosis
RESPIRATORY, THORACIC AND
MEDIASTINAL DISORDERS
Acute respiratory distress syndrome
Acute respiratory failure
Cough
Dyspnoea
Interstitial lung disease
Organising pneumonia
Pleural effusion

Chemotherapy
n (%)

0

2 (1.17)000
10 (5.81)
1 (0.58)
1 (0.58)
1 (0.58)
1 (0.58)
2 (1.16)1 (0.58)
1 (0.58)
1 (0.58)
2 (1.16)
2 (1.16)0
1 (0.58)
1 (0.58)
2 (1.16)1 (0.58)
1 (0.58)

1 (0.58)
1 (0.58)
1 (0.58)
3 (1.75)000
2 (1.17)0000
1 (0.58)
1 (0.58)
1 (0.58)
0
0
0
0
0

0

0

1 (0.58)
1 (0.58)

23 (13.37)

6 (3.49)

1 (0.58)
1 (0.58)
1 (0.58)
6 (3.49)
3 (1.74)02 (1.16)1 (0.58)

3 (1.74)
0Page 34

10 (5.85)
0002 (1.17)0
1 (0.58)
3 (1.75)

1 (0.58)

1 (0.58)00
3 (1.75)00
1 (0.58)

Public Disclosure Synopsis
Protocol A8081007 – 25 October 2016 Final

090177e18aa74a44\Approved\Approved On: 22-Nov-2016 12:34

Crizotinib
n (%)
Pneumonitis
Pulmonary artery thrombosis
Pulmonary embolism
Pulmonary oedema
Respiratory failure
SKIN AND SUBCUTANEOUS TISSUEDISORDERSDrug eruption
SURGICAL AND MEDICAL PROCEDURES
Cancer surgery
VASCULAR DISORDERS
Deep vein thrombosis
Pelvic venous thrombosis

Chemotherapyn (%)

1 (0.58)
1 (0.58)
7 (4.07)0
1 (0.58)

1 (0.58)
1 (0.58)0000
3 (1.75)
1 (0.58)
000
1 (0.58)
1 (0.58)

1 (0.58)

1 (0.58)00

1 (0.58)
1 (0.58)
1 (0.58)
2 (1.16)1 (0.58)
1 (0.58)

1 (0.58)000
2 (1.17)
2 (1.17)00

1 (0.58)

Subjects are only counted once per treatment for each row.
MedDRA (v18.1) coding dictionary applied.

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2 (1.17)

Public Disclosure Synopsis
Protocol A8081007 – 25 October 2016 Final

Permanent discontinuations due to adverse events:
A summary of permanent treatment discontinuations due to AEs by treatment arm isprovided in Table 22.
Table 22

Treatment-emergent all-causality adverse events associated with permanent
discontinuation from treatment by treatment group (all cycles) – safety
analysis.

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MedDRA Preferred Term or Clustered Term

Crizotinib (N=172)n (%)
34 (19.8)8 (4.7)5 (2.9)4 (2.3)3 (1.7)2 (1.2)2 (1.2)2 (1.2)2 (1.2)1 (0.6)
1 (0.6)
1 (0.6)
1 (0.6)
1 (0.6)
1 (0.6)
1 (0.6)
1 (0.6)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0

Any AEs
Disease progression
Interstitial lung disease (ILD)
Dyspnoea
Elevated transaminases
Death
Hepatotoxicity
Pulmonary embolism
Pneumonia
Arrhythmia
Decreased appetite
Extradural abscessGI perforation
General physical health deterioration
Intracranial pressure increased
SepsisSudden death
Pleural effusion
Neutropenia
Asthenia
Fatigue
Neuropathy
Pericardial effusion
Anaemia
Acne
Alopecia
Cardiac failure
Cardiomyopathy
Cataract
Dermatitis allergic
Drug hypersensitivity
Lymphangitis
MelaenaTumour haemorrhage

Chemotherapy (N=171)n (%)
34 (19.9)
3 (1.8)1 (0.6)
1 (0.6)
0
0
0
0
0
0
0
0
0
2 (1.2)0
1 (0.6)0
4 (2.3)3 (1.8)2 (1.2)2 (1.2)2 (1.2)2 (1.2)1 (0.6)
1 (0.6)
1 (0.6)
1 (0.6)
1 (0.6)
1 (0.6)
1 (0.6)
1 (0.6)
1 (0.6)
1 (0.6)
1 (0.6)

MedDRA (v18.0) coding dictionary was applied.
Abbreviations: AE=adverse event; MedDRA=Medical Dictionary for Regulatory Activities; N/n=number of subjects;
v=version.

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Public Disclosure Synopsis
Protocol A8081007 – 25 October 2016 Final

Deaths:A summary of deaths reported during the study is provided in Table 23.
Table 23

Summary of Deaths by Treatment Group – (Safety Analysis)
Crizotinib(N=172)n (%)

All death causes
Within 28 days of last dose of study drug
More than 28 days after last dose of study drug
Death within 30 days of first dose of study drug
Death within 60 days of first dose of study drug

115 (66.9)
27 (15.7)
88 (51.2)
3 (1.7)
10 (5.8)

Chemotherapy(Without Crossover)(N=171)n (%)
124 (72.5)
6 (3.5)118 (69.0)
3 (1.8)9 (5.3)

Total(N=343)n (%)
239 (69.7)
33 (9.6)
206 (60.1)
6 (1.8)19 (5.5)

Data were based on the ‘Notice of Death’ CRF page.
Abbreviations: CRF=case report form; N/n=number of subjects.

The Grade 5 TEAE and treatment-related AEs are summarized in Table 24.

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Table 24

Grade 5 Treatment-Emergent Adverse Events by Treatment Arm (AllCausality and Treatment Related) – Safety Analysis Population
Crizotinib(N=172)n (%)
All-Causality Treatment-Related

Any AEsa
Disease progression
Interstitial lung disease
Dyspnoea
Death
Arrhythmia
Pulmonary embolism
Pneumonia
Respiratory failure
SepsisSudden death
Pericardial effusion
Tumour haemorrhage

30 (17.4)
18 (10.5)
3 (1.7)2 (1.2)2 (1.2)1 (0.6)
1 (0.6)
1 (0.6)
1 (0.6)
1 (0.6)
1 (0.6)00

3 (1.7)0
2 (1.2)00
1 (0.6)
0
0
0
0
0
0
0

Chemotherapy(N=171)n (%)
All-Causality Treatment-Related
7 (4.1)3 (1.8)0
1 (0.6)00
0
0
0
1 (0.6)0
1 (0.6)
1 (0.6)

1 (0.6)
0
0
0
0
0
0
0
0
1 (0.6)000

AE = adverse event; N = number of subjects in a treatment group; n = number of subjects with AEs associated with death;
NSCLC = non-small cell lung cancer.
a
One crizotinib-treated subject had 2 Grade 5 AEs - Acute respiratory distress syndrome and sepsis.

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Public Disclosure Synopsis
Protocol A8081007 – 25 October 2016 Final

090177e18aa74a44\Approved\Approved On: 22-Nov-2016 12:34

CONCLUSIONS:•

Crizotinib treatment resulted in a statistically significant, robust, and clinicallymeaningful improvement in PFS as compared to standard of care chemotherapy in thetreatment of subjects with previously treated advanced ALK-positive NSCLC(7.7 months vs 3.0 months, HR: 0.487, 1 sided p-value <0.0001).

•

Crizotinib treatment resulted in a clinically and statistically significant increase in
ORR compared to chemotherapy (65% vs 20%, 2 sided p-value <0.0001), with
objective responses that were rapid, with a median TTR of 6 weeks, and durable, witha median DR estimate of 32.1 weeks.

•

There was no statistically significant improvement in the secondary outcome of OS
for subjects randomized to receive crizotinib as compared to subjects randomized toreceive chemotherapy. There was, however, a numerical improvement in OS in the
crizotinib arm compared to the chemotherapy arm (HR: 0.854 [95% CI: 0.661,
1.104], 1 sided p-value 0.1145 [stratified log-rank test]). These OS analyses were notadjusted for the potentially confounding effects of crossover, as 154 (88.5%) subjects
in the chemotherapy arm subsequently received crizotinib treatment as follow-up
systemic therapy.

•

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

•

Patient-reported visual events were transient with minimal impact on daily activities.

•

Crizotinib treatment resulted in significantly greater improvement from baseline inpatient-reported key lung cancer symptoms and global QoL compared to thechemotherapy arm.

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