Supplemental Abbreviated Clinical Study Report
Protocol A8081001

CLINICAL STUDY REPORT SYNOPSISSYNOPSIS
Study Title: Phase 1 Safety, Pharmacokinetic And Pharmacodynamic Study Of
PF-02341066, A MET/HGFR Selective Tyrosine Kinase Inhibitor, Administered Orally To
Patients With Advanced Cancer
Study Number: Protocol A8081001
Regulatory Agency or Public Disclosure Identifier Number: 73,544
Study Phase: Phase 1
Name of Study Intervention: Crizotinib (PF-02341066)
Name of Sponsor/Company: Pfizer Inc.
CSR Version and Report Date:
Document Version
Supplemental CSR (sCSR) (Lastpatient last visit [LPLV]
19 January 2022) Version 1.0
Final CSR Version 1.0
Interim CSR (Amended
Preliminary Full Clinical Study
Report)Report Date
03 June 2022
19 February 2021
12 September 2011

Number of Study Center(s) and Investigator(s):Refer to Study 1001 final clinical study report (CSR) Synopsis, dated 19 February 2021, fordetails.
A list of study centers and investigators involved in this study is provided in the final CSR
Appendix 16.1.4.1.
Refer to the final CSR Appendix 16.1.11 for a list of publications based on this study.
Study Period:
The first patient first visit (FPFV) was on 19 April 2006, the LPLV was on 19 January 2022.
This study was neither discontinued nor interrupted.

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Supplemental Abbreviated Clinical Study Report
Protocol A8081001

CLINICAL STUDY REPORT SYNOPSIS
Rationale:
This sCSR was completed in order to summarize the safety data from the 2 patients(hereafter referred to as the “2 remaining patients”) still on crizotinib treatment at the time of
database snapshot on 30 July 2020 for the Study 1001 final CSR.
Objectives, Endpoints, and Statistical Methods:
Refer to Study 1001 final CSR Synopsis, dated 19 February 2021, for details.
Methodology:
Study 1001 was a Phase 1, open-label, multicenter study evaluating dose escalation, safety,
pharmacokinetics (PK), antitumor activity and pharmacodynamics of crizotinib administeredas an oral single agent to patients with advanced cancer (excluding leukemias).
Refer to Study 1001 final CSR Synopsis, dated 19 February 2021, for details.
At the time of the database snapshot date of the final CSR (30 July 2020), 2 patients with
MET exon 14-positive non-small cell lung cancer (NSCLC) were still on treatment.
The efficacy data have been fully reported in the previous CSRs including the final CSR,
dated 19 February 2021. These efficacy data were not updated in this report.
This CSR Synopsis summarizes the cumulative data from the 2 remaining patients still on
treatment at the time of database snapshot (30 July 2020) for the final CSR.
The LPLV for this sCSR was on 19 January 2022 with a database lock on 09 February 2022.
This sCSR presents listings and summary tables for the 2 remaining patients for patient
disposition at end of treatment, demographic characteristics, adverse events (AEs) andserious adverse events (SAEs), treatment duration, laboratory test values, and vital signs data.
Number of Patients (planned and analyzed):
Refer to Study 1001 final CSR Synopsis, dated 19 February 2021, for details.
Diagnosis and Main Criteria for Inclusion and Exclusion:
Refer to Study 1001 final CSR Synopsis, dated 19 February 2021, for details.
Study Interventions, Dose, Mode of Administration, and Batch Number(s):For 2 the remaining patients, crizotinib was provided as 50 mg or 100 mg tablets for oral
administration (Table S1) once daily (QD) or twice daily (BID) in continuous 28-day cycles.

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Supplemental Abbreviated Clinical Study Report
Protocol A8081001

CLINICAL STUDY REPORT SYNOPSIS
Refer to Study 1001 final CSR Synopsis, dated 19 February 2021, for details.
Table S1. Investigational Product Description
Investigational Product Description

Vendor Lot
Number

Pfizer Lot
NumberStrength/
Potency

DosageForm

Crizotinib 100mg Oval Tablet
Crizotinib 50mg Oval Tablet

19-DP-00006
19-DP-00005

19-000503
19-000502

100 mg
50 mg

TabletTabletDuration of Study Intervention:
Treatment was to continue until the occurrence of Response Evaluation Criteria in Solid
Tumors (RECIST)-defined disease progression or clinical deterioration, unacceptabletoxicity effects, or withdrawal from the study.
Summary of Results:
Both patients had permanently discontinued from study treatment; 1 patient because thestudy was terminated by the Sponsor and the second patient due to ‘other reasons’ (combined
use of prohibited medicines, clarithromycin and rifampicin, which were used for thetreatment of Mycobacterium avium complex infection). This combined use of the prohibited
medicines was assessed as important protocol deviation. No important protocol deviation wasreported for the second patient. None of the 2 remaining patients were considered
non-compliant.
Demographic and Other Baseline Characteristics:
The remaining 2 Japanese patients were 67 and 69 years old.
Refer to Study 1001 final CSR Synopsis, dated 19 February 2021, for details.
Exposure:
The durations of treatment for the 2 remaining patients were 29.9 and 40.0 months.
Efficacy:
Efficacy analyses for all patients are reported as per protocol in Study 1001 final CSR, dated
19 February 2021. There were no additional efficacy analyses for the 2 remaining patients.
Safety Results:
Both of the 2 remaining patients reported at least 1 treatment-related AE. One all-causality
SAE, which was not treatment-related, was reported for 1 (50.0%) patient. This SAE waspreviously reported in the final CSR, dated 19 February 2021. No new SAEs occurred since
the Study 1001 final CSR. No Grade 5 AEs were reported for the 2 remaining patients(Table S2).

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Supplemental Abbreviated Clinical Study Report
Protocol A8081001

CLINICAL STUDY REPORT SYNOPSIS
Table S2. Treatment-Emergent Adverse Events For Patients Who Were Ongoing
as of Data Snapshot of 30JUL2020 (All-Causality andTreatment-Related) (MET Exon 14 Alterations NSCLC) - Safety
Analysis Population
MET Exon 14 Alterations NSCLC, 250 mg BID(N=2)
All-Causality
Treatment-Related
132
83

Number of AEs
Number of patients, n (%)
With AEs
With SAEs aWith Grade 3 or 4 AEs
With Grade 5 AEs
With AEs associated with
Dose reduction
Temporary discontinuation

2 (100)1 (50.0)
2 (100)02 (100)0
1 (50.0)02 (100)2 (100)2 (100)2 (100)All-causality AEs that occurred in the 2 remaining patients were BRADYCARDIA, Bloodcreatine phosphokinase increased, Constipation, Diarrhoea, ELEVATED
TRANSAMINASES, Nausea, OEDEMA, and Vomiting. Treatment-related AEs that
occurred in the 2 remaining patients were BRADYCARDIA, Blood creatine phosphokinase
increased, Diarrhoea, ELEVATED TRANSAMINASES, Nausea, OEDEMA, and Vomiting.
All other all-causality or treatment-related AEs occurred in 1 patient each, respectively.
Most all-causality AEs in the 2 remaining patients were Grade 1 or Grade 2 in severity. One
patient had Grade 3 all-causality AEs of Hyperkalaemia, Hypoxia, and Pneumonia
pneumococcal which were not considered to be treatment-related. One patient had a Grade 4
treatment‑related AE of Lipase increased.
There were no AEs related to the Coronavirus Disease 2019 (COVID-19) pandemic.
There were no AEs leading to permanent treatment discontinuation for the 2 remaining
patients.
There were no dose reductions for either of the 2 remaining patients since the Study 1001
final CSR. Both patients did have a dose reduction prior to the data snapshot date for the
Study 1001 final CSR.
There were no temporary treatment discontinuations for either of the 2 remaining patients
since the Study 1001 final CSR. Both patients did have temporary treatment discontinuations
prior to the data snapshot date for the Study 1001 final CSR.
Neither of the 2 remaining patients had died.

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Supplemental Abbreviated Clinical Study Report
Protocol A8081001

CLINICAL STUDY REPORT SYNOPSIS
There were no new SAEs for the 2 remaining patients since the Study 1001 final CSR. One
patient had an SAE prior to the data snapshot date for the Study 1001 final CSR.
The review of the clinical laboratory test results from the 2 remaining patients indicated that
there were no new safety signals. No additional electrocardiograms (ECGs) were obtainedsince the data snapshot date for the final CSR for the 2 remaining patients. No other safety
data were reported for the 2 remaining patients.
Pharmacokinetic Results: (if applicable):
Not applicable
Pharmacodynamic Results: (if applicable):
Not applicable
Other Results: (if applicable):
Not applicable.
Conclusions:
Review of the safety data from the 2 remaining patients reported in this sCSR did not identify
any patterns of AEs indicative of a safety concern with the use of crizotinib. No new safetyissues were identified.

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Protocol A8081001

CLINICAL STUDY REPORT SYNOPSIS
Sponsor: Pfizer Inc.
Investigational Product: Crizotinib (PF-02341066)
Clinical Study Report Synopsis: Protocol A8081001
Protocol Title: Phase 1 Safety, Pharmacokinetic and Pharmacodynamic Study of
PF-02341066, A MET/HGFR Selective Tyrosine Kinase Inhibitor, Administered Orally toPatients With Advanced Cancer
Investigators: Refer to Appendix 16.1.4.1 for a list of investigators involved in this study.
Study Centers: Patients were enrolled at 16 centers in 4 countries; 11 centers in the UnitedStates; 3 centers in Japan; and 1 center each in Australia and South Korea (Republic ofKorea). Refer to Appendix 16.1.4.1 for a list of sites involved in this study.
Publications Based on the Study: Refer to Appendix 16.1.11 for a list of publications
based on this study.
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Study Initiation Date: First Patient First Visit (FPFV): 19 April 2006
Study Completion Date: Ongoing
Report Date: 19 February 2021
Previous Report Date: Not applicable
Phase of Development: Phase 1
Primary and Secondary Study Objectives and Endpoints:
Table S1Study Objectives and Endpoints

Objectives
Determine the safety profile of crizotinib including
identification of dose limiting toxicity (DLT),
maximum tolerated dose (MTD).
Determine the recommended Phase 2 doses(RP2D) and regimens of crizotinib.

Determine pharmacokinetics (PK) profile ofcrizotinib following oral administration including: Effect of food.
 Initial evaluation of crizotinib-related
CYP3A4 inhibition using midazolam (MDZ)
as a probe.








Endpoints
Incidence of DLT adverse events (AEs)within the first cycle (28 days) defined andgraded by the National Cancer Institute (NCI)
Common Terminology Criteria for Adverse
Events (CTCAE), version 3.0.
Number of patients with AEs and serious
adverse events (SAEs).
Plasma PK parameters of crizotinib and its
metabolites.
PK parameters of MDZ following a single
oral 2 mg dose before and after repeatedadministration of crizotinib.
Plasma PK parameters of crizotinib and its
metabolite(s) following multiple oral doses of

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Final Clinical Study Report
Protocol A8081001

CLINICAL STUDY REPORT SYNOPSIS





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Effect of the coadministration of rifampin or
itraconazole on the multiple-dose plasma PK
of crizotinib.
Document any evidence of anti-tumor activity ofcrizotinib.

Evaluate the effect of crizotinib on parameters
related to hypogonadism in males.

crizotinib alone and when coadministeredwith rifampin or itraconazole.
Objective response (by Response Evaluation
Criteria in Solid Tumors [RECIST] version
1.0 [RECIST version 1.1 for ALK-negative
non-small cell lung cancer (NSCLC)
cohorts]) for solid tumors and response
criteria for lymphomas and multiple
myelomas), duration of response, time toresponse, disease control rate at weeks 8 and16, progression-free survival (PFS), 6-month
PFS, overall survival (OS), probabilities ofsurvival at 6 and 12 months; others as
appropriate.

Measurements of blood testosterone and otherblood parameters associated with detecting
hypogonadism in males.

METHODS
Study Design:
Study A8081001 was a Phase 1, open-label, multicenter study evaluating dose escalation,
safety, PK, antitumor activity, and pharmacodynamics of crizotinib administered as an oral
single agent to patients with advanced cancer (excluding leukemias).
Starting with the FPFV on 19 April 2006, patients with advanced cancers (excluding
leukemias) were enrolled in the study. Patients were included in 12 different cohorts or
substudies (Figure S1) to study or establish:


A RP2D for crizotinib;Potential for CYP3A inhibition due to crizotinib using MDZ as a CYP3A4 substrateprobe;



Effect of genetic markers of ALK, ROS1, MET (amplification or presence of exon 14) on
crizotinib PK, safety and efficacy of crizotinib;Crizotinib drug-drug interaction (DDI) with rifampin and itraconazole;Crizotinib treatment effect on ophthalmological safety parameters, urinary 6
beta-hydroxycortisol/cortisol (6-OHC/C), and hypogonadism.

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Protocol A8081001

CLINICAL STUDY REPORT SYNOPSIS
Figure S1. Summary of All Cohorts

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a.

b.
c.

In the Interim CSR (see below), the RP2D cohorts consisted of cohorts with patients who had
ALK-negative NSCLC (referred to as ALK-negative NSCLC cohort #1 in this final Clinical Study Report[CSR]); ALK-positive NSCLC; and ALK-dependent tumors other than NSCLC and MET-dependent
tumors and who did not have ALK-positive or ALK-negative NSCLC (“RP2D Other” cohort).
Crizotinib dosing of ≤200 mg once a day (QD) or ≤300 mg twice a day (BID).
Crizotinib dosing from 300 mg QD to 800 mg once a day (QD).

To further evaluate the antitumor activity of crizotinib associated with MET amplification,
patients with MET-amplified NSCLC were further distinguished into categories based on
MET/CEP7 ratio: high-level MET gene amplified (MET/CEP7 ratio ≥4.0), medium-level
MET gene amplified (MET/CEP7 ratio >2.2 to <4.0), and low-level MET gene amplified(MET/CEP7 ratio ≥1.8 to ≤2.2).
This study was associated with several regulatory submissions and postmarketing
requirements/commitments for which individual reports were generated in the past. In thisfinal CSR, results from the previous reports (listed below) are summarized briefly and resultsof data collected subsequently are presented in detail.

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Protocol A8081001

CLINICAL STUDY REPORT SYNOPSIS
Previous reports referred to in this final CSR:

CCIInterim CSR, 12 September 2011



ALK-Negative Report, 16 February 2015

Rifampin DDI Report, 16 October 2015

ROS1-Positive CSR, 01 April 2016



Ophthalmology Report, 20 December 2016



Itraconazole DDI Report, 18 April 2017

ROS1-Positive Technical Report, 20 June 2019

Diagnosis and Main Criteria for Inclusion:
Key inclusion criteria:
1. Tumor eligibility: All cohorts except RP2D enriched population cohort: Histologically confirmed advanced
malignancies (except for leukemias) refractory to standard of care therapy, or for whom
no standard of care therapy was available.
 RP2D enriched population cohort: Histologically confirmed advanced malignancies thatmet 1 of the following criteria:o Positive for MET amplification by fluorescence in situ hybridization (FISH)
o Positive for ALK chromosomal translocations or gene amplificationo Positive for known MET kinase domain activating mutationso Chromosomal translocations/fusions that led to altered transcriptional regulationof MET and/or hepatocyte growth factor (HGF)
o Positive for chromosomal translocations at ROS1 geneo Other molecular changes for which there are data to suggest a biologic rationale
for crizotinib treatment, eg, TRK1 fusions
 ALK-negative NSCLC cohort #1: Histologically or cytologically proven diagnosis of
NSCLC that was locally advanced or metastatic and of the adenocarcinoma subtype(including mixed adenosquamous histology). Patients had to have received only 1 priorchemotherapy treatment and this regimen had to be platinum-based. All patients had
either to be non-smokers, ex-smokers or light smokers (≤10 pack-years).
 ALK-negative NSCLC cohort #2: In addition to the criteria for ALK-negative cohort #1,
patients had to be ALK-negative by the central laboratory.
2. Solid tumors had to have measurable disease as per RECIST v. 1.0. However, for theenriched population RP2D group, patients whose tumors were not measurable, could
have entered the study upon approval by the Sponsor. RECIST v. 1.1 was used toevaluate tumors for patients in the ALK-negative NSCLC cohorts.

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Final Clinical Study Report
Protocol A8081001

CLINICAL STUDY REPORT SYNOPSIS
3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. However,patients in the RP2D enriched population cohort or ALK-negative NSCLC cohorts with
an ECOG performance status of 2 could have entered the study upon agreement between
the investigator and Sponsor.
4. Adequate organ function.
Key exclusion criterion:
1. Major surgery, radiation therapy, or systemic anticancer therapy within 4 weeks ofstarting study treatment; within 2 weeks of starting study treatment for patients in the
RP2D enriched population or ALK-negative cohorts.
2. For MET-dependent tumors, prior therapy specifically directed against MET or HGF; for
ALK-dependent tumors, prior therapy specifically directed against ALK; for ROS1
dependent tumors, prior therapy specifically directed against ROS1.

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3. Patients with brain metastases, spinal cord compression, carcinomatous meningitis, or
leptomeningeal disease, unless appropriately treated and neurologically stable for at least
4 weeks (2 weeks for the RP2D enriched population cohort and the ALK-negative
NSCLC cohorts).
Study Treatment:
Crizotinib (Table S2) was administered orally QD or BID in continuous 28-day cycles,
except for 21-day cycles for patients in the ALK-negative NSCLC cohorts #1 and #2.
Treatment was to continue until the occurrence of RECIST-defined disease progression orclinical deterioration, unacceptable toxicity effects, or withdrawal from the study. The
various dosing regimens followed are described below.
Dose Escalation Cohorts:
 Low Dose escalation cohort: starting with 50 mg QD and escalating up to ≤300 mg BID
High Dose escalation cohort: starting with 300 mg QD and escalating up to ≤800 mg QD

Recommended Phase 2 Dose (RP2D) Cohorts
 All cohorts: 250 mg BID
DDI substudy Cohorts:
 MDZ substudy: MDZ 2 mg oral dose alone and coadministered with crizotinib:
100 mg QD, 250 mg BID, or 300 mg BID
Rifampin DDI: crizotinib 250 mg BID alone and coadministered with rifampin
600 mg QD

Itraconazole DDI: crizotinib 250 mg QD alone and coadministered with itraconazole 200
mg QD

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Protocol A8081001

CLINICAL STUDY REPORT SYNOPSIS
Investigational Product Description:
Crizotinib was provided as 50 mg or 100 mg tablets for oral administration (Table S2).
Commercially available MDZ, rifampin, and itraconazole (Sporanox®, 100 mg capsules;
USA: Janssen Pharmaceuticals, Inc.; Australia: Janssen-Cilag Pty Ltd) were supplied locallyby the study sites.
Table S2. Investigational Product Description

CCI

Investigational Product Description

Vendor Lot
Number

Pfizer Lot
NumberStrength/
Potency

DosageForm

Crizotinib 10mg #0 Gray/Gray PIC
Crizotinib 50mg #0 Gray/Gray PIC
Crizotinib 100mg #0 Gray/Gray PIC
Crizotinib 100mg #0 Gray/Gray PIC
Crizotinib 50mg Size 2 Light Gray/Gray PIC
Crizotinib 50mg #0 Gray/Gray PIC
Crizotinib 50mg #0 Gray/Gray PIC
Crizotinib 100mg Oval Tablet
Crizotinib 100mg Oval Tablet
Crizotinib 100mg Oval Tablet
Crizotinib 100mg Oval Tablet
Crizotinib 100mg Oval Tablet
Crizotinib 100mg Oval Tablet
Crizotinib 100mg Oval Tablet
Crizotinib 100mg Oval Tablet
Crizotinib 100mg Oval Tablet
Crizotinib 100mg Oval Tablet
Crizotinib 100mg Oval Tablet
Crizotinib 100mg Oval Tablet
Crizotinib 100mg Oval Tablet
Crizotinib 100mg #0 Gray/Gray PIC
Crizotinib 50mg Size 2 Light Gray/Gray PIC
Crizotinib 100mg #0 Gray/Gray PIC
Crizotinib 100mg #0 Gray/Gray PIC
Crizotinib 50mg Size 2 Light Gray/Gray PIC
Crizotinib 100mg Oval Tablet
Crizotinib 50mg Tablet
Crizotinib 50mg Tablet
Crizotinib 100mg Oval Tablet
Crizotinib 100mg #0 Gray/Gray PIC
Crizotinib 100mg #0 Gray/Gray PIC
Crizotinib 50mg Tablet
Crizotinib 100mg Oval Tablet
Crizotinib 50mg Tablet
Crizotinib 100mg Oval Tablet
Crizotinib 50mg Tablet
Crizotinib 100mg Oval Tablet
Crizotinib 100mg Oval Tablet
Crizotinib 50mg Tablet
Crizotinib 50mg Tablet
Crizotinib 50mg Tablet
Crizotinib 50mg Tablet

CA-1621005
CA-0100107
CA-0260207
080042080086
CA-1631005
080041
CM-0260211
CM-0270211
CM-13811
CM-02212
CM-0231213-106690
GR-SDM
GR-SDM
GR-SDM
GR-SDM
GR-SDM
GR-SDM
19-DP-00006
CA-0270208
CM-0090209
CM-0100209
CM-0260309
CM-0250309
CM-0530609
CM-0520609
CM-0970809
CM-1000809
CM-1090809
CM-1080809
CM-1791209
CM-1811209
CM-0210210
CM-0230210
CM-1520910
CM-1510910
CM-1570910
CM-0300211
CM-13511
CM-02012
13-106684

06-033836
07-051252
07-051590
08-068605
09-07296606-033845
08-067934
11-002370
11-002643
11-009235
12-001177
12-001191
13-106690
14-005965
14-00596616-000476
16-000477
17-001529
17-001530
19-000503
08-065179
09-074718
09-074818
09-075457
09-076000
09-076188
09-076189
09-077722
09-077725
09-078909
09-078997
10-080927
10-081002
10-082078
10-082080
10-088624
10-089144
10-089298
11-002655
11-008988
12-000937
13-106684

10 mg
50 mg
100 mg
100 mg
50 mg
50 mg
50 mg
100 mg
100 mg
100 mg
100 mg
100 mg
100 mg
100 mg
100 mg
100 mg
100 mg
100 mg
100 mg
100 mg
100 mg
50 mg
100 mg
100 mg
50 mg
100 mg
50 mg
50 mg
100 mg
100 mg
100 mg
50 mg
100 mg
50 mg
100 mg
50 mg
100 mg
100 mg
50 mg
50 mg
50 mg
50 mg

CapsuleCapsuleCapsuleCapsuleCapsuleCapsuleCapsuleTabletTabletTabletTabletTabletTabletTabletTabletTabletTabletTabletTabletTabletCapsuleCapsuleCapsuleCapsuleCapsuleTabletTabletTabletTabletCapsuleCapsuleTabletTabletTabletTabletTabletTabletTabletTabletTabletTabletTabletPFIZER CONFIDENTIAL
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Final Clinical Study Report
Protocol A8081001

CLINICAL STUDY REPORT SYNOPSIS
Table S2. Investigational Product Description

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Investigational Product Description

Vendor Lot
Number

Pfizer Lot
NumberStrength/
Potency

DosageForm

Crizotinib 50mg Tablet
Crizotinib 50mg Tablet
Crizotinib 50mg Tablet
Crizotinib 100mg #0 Gray/Gray PIC
Crizotinib 50mg #0 Gray/Gray PIC
Crizotinib 100mg Oval Tablet
Crizotinib 100mg Oval Tablet
Crizotinib 25mg/mL Oral Solution in 16 oz
HDPE Bottle (475mL)
Crizotinib 25mg/mL Oral Solution in 16 oz
HDPE Bottle (475mL)
Crizotinib 25mg/mL Oral Solution in 16 oz
HDPE Bottle (475mL)
Crizotinib 50mg Tablet

GR-SDM
GR-SDM
GR-SDM
CA-1740707
CA-0260208
CM-1801209
CM-0980809
K04021314-005964
16-000475
17-001528
07-058023
08-064662
10-081001
09-078261
13-107843

50 mg
50 mg
50 mg
100 mg
50 mg
100 mg
100 mg25 mg/ml

TabletTabletTabletCapsuleCapsuleTabletTabletSolution

K091615

15-006040

25 mg/ml

Solution

SW-LDM

16-004754

25 mg/ml

Solution

19-DP-00005

19-000502

50 mg

TabletEfficacy Evaluations:
Crizotinib treatment efficacy was evaluated on the basis of disease imaging assessments that
included computed tomography (CT) and magnetic resonance imaging (MRI) scans of thechest, abdomen, and pelvis, as well as brain and bone scans if deemed necessary. The
assessments were based on derived investigator tumor assessment and for certain cohorts
they were also reviewed by a centralized, independent radiological review for a certain
period of time during the study.
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and/or Other Evaluations:Patient blood samples were collected for PK analysis of crizotinib (and its metabolite, if
applicable) using standard bioanalytical methods. Series of PK samples were collectedstarting on Day −7, Cycle 1 Day 1 (C1D1), Cycle 1 Day 15 (C1D15), Cycle 2 Day 1 (C2D1),
and predose PK samples were collected on Day 1 of every other cycle up to Cycle 5(depending on the cohort). PK parameters were determined from plasma concentration-timedata using standard noncompartmental methods.
Safety Evaluations:
Safety evaluations included the standard procedures of clinical monitoring, vital signs (heartrate, blood pressure), physical examinations, ECOG performance status, 12-leadelectrocardiograms (ECGs), AEs, and safety laboratory tests; and also included determining
DLT and MTD of crizotinib treatment during the initial part of the study. In addition,
ophthalmologic examinations, urinary 6β-OHC/C measurements, and hypogonadism tests (inmale patients) were planned at specific timepoints for certain cohorts for a certain period
during the study.
Statistical Methods:
Analysis of objective response rate (ORR), duration of response (DR), time to tumor
response (TTR), and disease control rate (DCR) was performed for the response-evaluable
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Final Clinical Study Report
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CLINICAL STUDY REPORT SYNOPSIS(RE) population (all patients in the safety analysis population who have an adequate baseline
disease assessment). Analysis of PFS, OS, and probabilities of survival at 6 and 12 months
was performed on safety analysis (SA) population (all enrolled patients who receive at least
one dose of crizotinib on Cycle 1 Day 1).
ORR was defined as the percentage of patients with confirmed complete response (CR) or
confirmed partial response (PR) according to RECIST v. 1.0 (or RECIST v. 1.1 for
ALK-negative NSCLC cohorts), relative to the RE population. Confirmed responses were
those that persisted on repeat imaging study at least 4 weeks after the initial documentationof response. The point estimate of the ORR was provided along with the corresponding 95%
confidence interval (CI) using the exact method based on the F-distribution. The best overall
response (BOR) was also summarized. The BOR of stable disease could be assigned if stabledisease criteria were met at least once after the date of the first dose at a minimum interval of
6 weeks.

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DR was defined as the time (in months) from the first documentation of objective tumor
response (CR or PR) that was subsequently confirmed, to the first documentation of objective
tumor progression or death on-study due to any cause, whichever occurred first. DR was
calculated based on the RE population for the subgroup of patients with a confirmed
objective tumor response. DR was summarized using the Kaplan-Meier method. The
median event time (if appropriate) and 2-sided 95% CI for the median were provided.
TTR was defined as the time (in weeks) from the date of first dose to first documentation of
objective tumor response (CR or PR) that was subsequently confirmed. For patientsproceeding from PR to CR, the onset of PR was taken as the onset of response. TTR was
summarized using descriptive statistics.
DCR at Weeks 8 and 16 was defined as the percentage of patients with a confirmed CR,
confirmed PR or stable disease according to RECIST v. 1.0 based on the response at Weeks 8
and 16, relative to the RE population. DCR at Weeks 8 and 16 was analyzed in a similar way
to ORR.
PFS was defined as the time (in months) from the date of first dose to the date of the first
documentation of objective tumor progression or death on-study due to any cause, whicheveroccurred first. PFS in the SA population was summarized using the Kaplan-Meier method.
The median event time (and other quartiles) and 2-sided 95% CI for the median were
provided. The probability of PFS at 6 months was defined as the probability of being aliveand progression-free at 6 months after the date of first dose based on the Kaplan-Meierestimate. A 2-sided 95% CI for the log [-log(6-month PFS probability)] was calculated using
a normal approximation and then back-transformed to give a CI for the probability of PFS at
6 months itself.
OS was defined as time from the date of the first dose to the date of death due to any cause.
OS in the SA population was summarized using the Kaplan-Meier method. The median
event time (and other quartiles) and 2-sided 95% CI for the median were provided. The
PFIZER CONFIDENTIAL
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CLINICAL STUDY REPORT SYNOPSIS
probabilities of survival at 6 and 12 months were defined as the probability of survival at
6 months and 12 months, respectively, after the date of first dose based on the Kaplan-Meierestimate. A 2-sided 95% CI for the log [-log (6-month survival probability)] was calculatedusing a normal approximation and then back-transformed to give a CI for the probability ofsurvival at 6 months itself. The probability of survival at 12 months was estimated similarly.
PK concentrations of crizotinib are listed, summarized, and plotted for patients in the PK
analysis population. For summary statistics and mean/median plots by sampling time, thenominal PK sampling time was used; for individual patient plots by time, the actual PK
sampling time was used. Linear and semi-log plots of individual and median crizotinib
plasma concentrations were produced for each dose level and/or study days, as appropriate.
PK parameters, including but not limited to maximum plasma concentration (Cmax), area
under the plasma concentration-time curve (AUC) from time 0 hour to infinity (AUCinf) orfrom time 0 to time tau (AUC, and apparent clearance (CL/F), as appropriate, were
estimated using noncompartmental analysis. Descriptive statistics are provided for these PK
parameters by dose, including the number of patients (n), arithmetic mean, median, standard
deviation, coefficient of variation (CV), minimum, maximum, and geometric mean. Each
PK parameter was summarized by dose and included the set of summary statistics.
CCI

Plasma concentrations, predose plasma concentrations (Ctrough) and steady-state predose
concentrations (Ctrough,ss) of crizotinib were listed, summarized and/or plotted for patients in
the PK analysis populations. For summary statistics and mean/median plots by sampling
time, the nominal PK sampling time was used. Ctrough was the predose concentrationcollected on and after C1D15 between 3 hours and 0 hours before the morning dose on the
PK collection day (or 9 hours to 15 hours after the evening dose on the prior day in the caseof a missing morning dose on the PK collection day). Ctrough,ss was obtained by using thearithmetic mean of all evaluable Ctrough on and after C1D15 for each patient in the
PKP_Ctrough,ss population.
Safety data were summarized using the SA population. All AEs reported after initiation of
study drug (Cycle 1 Day 1) and pre-existing conditions that worsened during the treatment
period were considered as treatment-emergent adverse events. AEs were coded by systemorgan class (SOC) and preferred term (PT) according to Medical Dictionary for Regulatory
Activities (MedDRA) terminology (version 23.0). AE severity was graded according to NCI
CTCAE (version 3.0). Analyses were based on AEs, with the first dose date considered theC1D1 dose, and summarized by MedDRA SOC and PT. Certain PTs were analyzed inaggregate using CLUSTER terms (denoted by capital letters). Descriptive statistics were to
be presented for laboratory parameters, vital signs, ECGs, and ophthalmologic examination
data.

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CLINICAL STUDY REPORT SYNOPSISRESULTS
Patient Evaluation:
As of the database snapshot date of 30 July 2020, 596 patients were enrolled, 590 patientswere assigned to treatment, 578 patients received crizotinib treatment; 576 patients had
permanently discontinued treatment; and 2 patients were on treatment (Table S3).

CCI

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Table S3

Patient Evaluation Groups - All Enrolled Populations
Dose
Escalation

CCI

ALKNegative
#1
NSCLC

ALKNegative
#2
NSCLC

METAmplified
NSCLC

ROS1Positive
NSCLC

ALKPositive
NSCLC

MET
Exon 14Positive
NSCLC

Enriched
Other –
Other
Cancers

RP2D
MDZ
DDI
Substudy

Rifampin
DDI

Itraconazole
DDI

Total

Assigned to
70 d
48 b
19 a,b41 b
53 a
154 b,c85
67 b
14 b,c1821590
treatment, N
Treated
65
48
18
41
53
154
85 (100.0)
66
12
18
18
578
n (%)
(92.9)(100)(94.7)
(100)
(100)
(100)
(98.5)(85.7)(100)(85.7)(98.0)
Discontinued
65
48
18
41
53
154
83 (97.6)
66
12
18
18
576
n (%)
(92.9)(100)(94.7)
(100)
(100)
(100)
(98.5)(85.7)(100)(85.7)(97.6)
Ongoing000000
2 (2.4)0000
2 (0.3)n (%)
a Three (3) patients previously included in the ALK-negative NSCLC cohort #2 were retrospectively found to be ROS1-positive and were included in the
ROS1-positive NSCLC cohort instead of the ALK-negative cohort #2 in the final analyses.
b Patients enrolled in the RP2D Other cohort (N=50) of the Interim CSR are now included in the ALK-negative NSCLC cohort #1 (3 patients),
ALK-negative NSCLC cohort #2 (2 patients), MET-amplified NSCLC cohort (3 patients), ALK-positive NSCLC cohort (3 patients), Enriched Other – Other
Cancers (22 patients), and the MDZ DDI substudy (14 patients); and 3 patients enrolled in the RP2D Other cohort were not treated.
c Fourteen (14) patients under the RP2D MDZ DDI substudy and 1 patient under the ALK-positive NSCLC cohort were all previously included as RP2D
Other cohort in the MDZ DDI substudy in the Interim CSR.
d Nine (9) patients from the Dose Escalation cohort (4 at 100 mg QD and 5 at 300 mg BID crizotinib dose) received MDZ oral doses for evaluation ofpotential crizotinib-related CYP3A4 inhibition.

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Patient Disposition:
Patient disposition at the End of Treatment and based on the database snapshot of this final
CSR is presented by-cohort for the Low and High Dose escalation cohorts in Table S4, RP2D
cohorts in Table S5, and the DDI cohorts in Table S6. Patient disposition for the remaining
cohorts was reported previously as follows:

CCI

MDZ DDI substudy was initially conducted in 9 patients from the Low Dose escalation
cohort and later in an additional group of 14 patients from the RP2D Other cohort, asreported in the Interim CSR. Patient disposition was not separately analyzed for thissubstudy.

Food Effect substudy was conducted in 13 patients enrolled in the enriched RP2D cohort,
as reported in the Interim CSR. Patient disposition was not separately analyzed for thissubstudy.

Ophthalmology analysis subgroup patient disposition was reported in the Ophthalmology
Report. This included a total of 111 patients who were enrolled variously in the
ALK-negative NSCLC cohort #2, the ROS1-positive NSCLC cohort, the MET-amplified
NSCLC cohort, Enriched Other cohort, and Rifampin DDI substudy.

Table S4

Patient Disposition at End of Treatment; Dose Escalation Cohorts – Safety
Analysis Populations

Reason for discontinuation

Total discontinued
Reasons for discontinuation:
Adverse event
Progressive disease
Patient Died
Patient no longer willing to participate in
study
Other

Low Dose Escalation
CohortN=36n (%)
36 (100)

High Dose Escalation
CohortN=29n (%)
29 (100.0)

3 (8.3)23 (63.9)
0
6 (16.7)

4 (13.8)
16 (55.2)2 (6.9)4 (13.8)

4 (11.1)

3 (10.3)

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Table S5

Patient Disposition; RP2D Cohorts – Safety Analysis Populations

CCI

Total discontinued
Reasons fordiscontinuation:
Adverse event
Progressive disease
Patient Died
Patient no longer willingto participate in study
Lost to follow up
Withdrawn Due toPregnancy
Othera

ALK-Negative
NSCLC Cohort
#1
N=48
n (%)
48 (100)

ALK-Negative
NSCLC Cohort
#2
N=18
n (%)
18 (100.0)

METAmplified
NSCLC
N=41
n (%)
41 (100)

ROS1Positive
NSCLC
N=53
n (%)
53 (100.0)

ALKPositive
NSCLC
N=154
n (%)
154 (100%)

MET Exon 14Positive
NSCLC aN=85n (%)
83 (97.6)

Enriched Other– Other Cancers

4 (8.3)21 (43.8)8 (16.7)
3 (6.3)1 (5.6)
12 (66.7)
2 (11.1)
0

6 (14.6)
26 (63.4)
2 (4.9)0025 (47.2)
1 (1.9)8 (15.1)

14 (9.1)
94 (61.0)
11 (7.1)
7 (4.5)8 (9.4)29 (34.1)
7 (8.2)15 (17.6)

9 (13.6)
42 (63.6)
0
1 (1.5)0
1 (2.1)

0
0

0
0

0
0

0
0

1 (1.2)0

2 (3.0)011 (22.9)

3 (16.7)

7 (17.1)

19 (35.8)

28 (18.2)

23 (27.1)

12 (18.2)

In the MET exon 14-positive NSCLC group, 2 (2.4%) patients were on treatment at the database snapshot date.

PFIZER CONFIDENTIAL
Page 13N=66n (%)
66 (100)

Final Clinical Study Report
Protocol A8081001

CLINICAL STUDY REPORT SYNOPSIS
Table S6

Patient Disposition; DDI Substudies – Safety Analysis Populations
Crizotinib 250 mg BID +Rifampin 600 mg QD
N=18
n (%)
18 (100)

Crizotinib 250 mg QD +Itraconazole 200 mg QD a
N=18
n (%)
18 (100)

Total discontinued
Reasons for discontinuation:
Adverse event
3 (16.7)
2 (11.1)
Progressive disease
9 (50.0)
4 (22.2)
Patient no longer willing to participate in study
2 (11.1)
2 (11.1)Other
4 (22.2)
10 (55.6)
a In the Itraconazole DDI substudy, of the 21 enrolled patients, 18 patients were treated and were included in
the Safety Analysis population.

Patient Demographics:
Patient demographics were reported previously for the following cohorts/substudies:

Low Dose escalation cohort, ALK-positive NSCLC cohort, and MDZ DDI substudy in
the Interim CSR;

ALK-negative cohort #2 in the ALK-Negative Report;ROS1-positive NSCLC cohort in the ROS1-Positive CSR.

CCI

Summary of demographics for the remaining cohorts is presented in Table S7.
Table S7

Patient Demographics – Safety Analysis Populations

Number ofPatients

High Dose
Escalation
CohortSex, n (%)
Male
FemaleAge (years)
Mean
MedianRange
Standard
deviation
Age category
<65
years
≥65
years

METAmplified
NSCLC

MET
Exon 14Positive
NSCLC

Enriched
Other –
Other
Cancers

Rifampin
DDI
Substudy

Itraconazole
DDI
Substudy

N=29

ALKNegative
NSCLC
Cohort
#1
N=48

N=41

N=85

N=66

N=18

N=18

17 (58.6)
12 (41.4)

24 (50.0)
24 (50.0)

22 (53.7)
19 (46.3)

37 (43.5)
48 (56.5)

41 (62.1)
25 (37.9)9 (50.0)9 (50.0)

7 (38.9)
11 (61.1)

58.6
59.0
38-84
10.45

57.1
58.0
28-82
14.30

64.3
65.0
42-88
9.93

70.4
70.0
34–91
10.08

50.1
53.0
18-88
19.20

61.5
62.5
42-79
9.40

61.3
63.0
40-78
9.7

22 (75.9)30 (62.5)

20 (48.8)

18 (21.2)

51 (77.3)

12 (66.7)

9 (50.0)

7 (24.1)

18 (37.5)

21 (51.2)

67 (78.8)

15 (22.7)

6 (33.3)

9 (50.0)

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Table S7

Patient Demographics – Safety Analysis Populations

Number ofPatients

High Dose
Escalation
Cohort

ALKNegative
NSCLC
Cohort#1
N=48

METAmplified
NSCLC

MET
Exon 14Positive
NSCLC

Enriched
Other –
Other
Cancers

Rifampin
DDI
Substudy

Itraconazole
DDI
Substudy

N=41

N=85

N=66

N=18

N=18

35 (72.9)
1 (2.1)9 (18.8)
3 (6.3)38 (92.7)
2 (4.9)1 (2.4)060 (70.6)
2 (2.4)15 (17.6)
8 (9.4)49 (74.2)
4 (6.1)9 (13.6)4 (6.1)16 (88.9)
2 (11.1)
00

13 (72.2)
3 (16.7)
02 (11.1)

70.7
68.6

80.2
78.8

68.2
65.3

75.4
76.4

74.41
74.72

73.7
71.1

42.9-116.4

45.4-144.9

41.6-136.2

41.0- 127.1

49.0-129.9

44.2-111.7

20.93

16.93

19.62

18.03415.3

5 (12.2)

31 (36.5)

40 (60.6)NANA

34 (82.9)

53 (62.4)

22 (33.3)

NANA

2 (4.9)1 (1.2)4 (6.1)
ECOG Performance Status
14 (48.3)
20 (41.7)
13 (31.7)
21 (24.7)
21 (31.8)
015 (51.7)
24 (50.0)
23 (56.1)
62 (72.9)
32 (48.5)
1
0
4 (8.3)5 (12.2)2 (2.4)13 (19.7)2
NA = Not analyzed
a One patient had an ECOG Performance Status of 1 at screening and 2 at C1D1.

NANA

2 (11.1)
15 (83.3)
1 (5.6) a

5 (27.8)
13 (72.2)0

N=29Race, n (%)
25 (86.2)White
2 (6.9)Black
1 (3.4)Asian
1 (3.4)
Other
Body weight (kg)
82.26
Mean
81.90
Median46.40Range
141.10

CCI

Standard
20.37
18.89
deviation
Smoking classification, n (%)
Never
18 (62.1)
26 (54.2)
smokedEx10 (34.5)
21 (43.8)
smoker1 (3.4)1 (2.1)
SmokerEfficacy Results:
Efficacy analyses were reported previously as follows:

Low Dose escalation cohort and ALK-negative NSCLC cohort #1 in the Interim CSR;

ALK-positive NSCLC cohort in the Interim CSR and updated analyses published by
Camidge et al [Camidge et al. Lancet Oncol. 2012;13(10):1011-9];



ALK-negative NSCLC cohort #2 in the ALK-Negative Report;ROS1-positive NSCLC cohort in the ROS1-Positive CSR and ROS1-Positive Technical
Report.

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Efficacy data collected for the High Dose escalation cohort were not analyzed statisticallyand are provided as a patient listing in this final CSR. Among the 29 RE patients in the High
Dose escalation cohort, the BOR was stable disease for 5 patients.
Summary of efficacy analyses that were planned for the remaining cohorts is presented inTable S8.
Table S8

CCI

Efficacy Results Based on Derived Investigator Tumor
Assessment - Response-Evaluable Populations

Best overall
response, n (%)
Complete
response (CR)
Partial response(PR)
Stable disease
Early death, n(%)
Indeterminate
response, n (%)
Objective response
rate (CR+PR), n(%)
95% Exact CI
Duration of
Response; months;
median(95% CI) / n
Time to Tumor
Response; weeks;
median (range) / na
Progression-Free
Survival; months;
median (95%
CI) / nOverall Survival;
months; median(95% CI) / n
Survival
Probability at
Month 6, (95% CI)
Survival
Probability at

MET-Amplified
NSCLC
N = 38High-Level METAmplified NSCLC a
N = 21MET Exon 14Positive NSCLC
N = 85

Enriched Other –Other Cancers
N = 612 (5.3)2 (9.5)3 (3.5)

1 (1.6)

10 (26.3)

7 (33.3)

30 (35.3)

4 (6.6)

10 (26.3)
5 (13.2)

6 (28.6)
1 (4.8)35 (41.2)
1 (1.2)19 (31.1)

3 (7.9)2 (9.5)10 (11.8)

12 (31.6)

9 (42.9)33 (38.8)

5 (8.2)

17.5, 48.7

21.8, 66.0

28.4, 50.0

2.7, 18.1

5.2 (3.8, 12.2) / 10

5.2 (4.9, 12.0) / 8

9.1 (6.5, 12.9) / 23

NA

8.0 (7.1—23.6) /12

8.0 (7.6—23.6) / 9

7.6 (3.7—47.3) /33

NA

4.0 (1.9, 6.9) / 32

6.9 (3.4, 8.3) / 16

7.6 (5.6, 9.1) / 59NA

10.1 (7.1, 12.9) /33

11.0 (9.4, 16.3) /16

20.0 (13.2, 25.7) /46

NA

67.8% (51.1, 79.9)

80.2% (55.4, 92.1)

86.7% (77.3, 92.4)

NA37.1% (22.4, 51.8)

44.1% (22.1, 64.2)

66.0% (54.0, 75.5)

NA

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Month 12, (95%CI)
n = number of patients with the eventna = number of patients with CR or PR
NA = not analyzed.
a Patients with MET Amplification NSCLC, MET/CEP7 ratio cut off ≥4.

Pharmacokinetic Results:
Results from the PK analyses were reported previously as follows:

CCI

Low Dose escalation cohort, the MDZ DDI substudy, and the Food Effect substudy in theInterim CSR;

ROS1-positive NSCLC cohort in the ROS1-Positive CSR;

Rifampin and itraconazole DDI substudies in the Rifampin DDI Report and theItraconazole DDI Report, respectively.

No PK summary was planned for the ALK-negative NSCLC cohort #1.
A summary of plasma PK parameters of crizotinib in the High Dose escalation cohort ispresented in Table S9; summary tables for Ctrough of crizotinib in the ALK-negative NSCLC
cohort #2 and MET-amplified NSCLC cohort in Table S10 and Table S11, respectively;
summary tables for Ctrough and of mean steady-state predose concentrations (Ctrough, ss, mean) of
crizotinib in Asian and Non-Asian patients in the ALK-positive NSCLC cohort in Table S12
and Table S13, respectively; summary tables for Ctrough and Ctrough, ss of crizotinib in Asianand Non-Asian patients with MET exon 14-positive NSCLC in Table S14 and Table S15,
respectively; and a summary table for Ctrough in the Enriched Other – Other Cancers cohort inTable S16.
Table S9

Descriptive Summary of Plasma Pharmacokinetic Parameters of
Crizotinib in the High Dose Escalation Cohort – Study A8081001
Parameter Summary Statistics a by Crizotinib Treatment

Parameters,
Units

300 mg QD

400 mg QD

500 mg QD

650 mg QD

800 mg QD

N, n

6, 5

5, 5

3, 2

6, 6

8, 8

Tmax, h4.00 (2.00-6.00)

2.15 (1.00-6.00)

4.00 (2.00-8.00)

4.00 (1.98-6.00)

4.99 (2.15-6.13)

Cmax, ng/mLAUC,
ng*h/mL
AUCinf,ng*h/mL

184.7 (65)115.9 (85)146.6 (31)154.3 (30)270.9 (47)1731 (51)1377 (114)1300 (61)1906 (39)3423 (57)3457 (42)3078 (119)1480, 2990

3979.4 (39)7547 (76)

CL/F, L/h

86.77 (42)129.9 (119)167, 337

163.4 (39)106.0 (76)Day -7 (single dose)

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Table S9

Descriptive Summary of Plasma Pharmacokinetic Parameters of
Crizotinib in the High Dose Escalation Cohort – Study A8081001
Parameter Summary Statistics a by Crizotinib Treatment

Parameters,
Units

300 mg QD

400 mg QD

500 mg QD

650 mg QD

800 mg QD

Vz/F, L5352 (47)9444 (178)10400, 24200

9704 (62)6146 (94)t1/2, h43.12 (15)53.56 (39)43.0, 49.8

41.90 (20)40.76 (18)

3

3

5

4

5.13 (1.93-7.88)

5.17 (0.933-6.00)

4.00 (4.00-9.00)

5.98 (4.00-6.00)

5.03 (4.00-6.03)

Cmax, ng/mLAUC,
ng*h/mL

315.2 (50)215.5 (26)395.3 (16)379.2 (28)671.3 (76)4375 (34)2860, 4010 d

6655 (4)6362 (37)10480 (76) e

CL/F, L/h

68.57 (34)99.9, 140 d

75.13 (4)102.2 (37)2.836 (1.32- 4.02)

2.44, 4.18 d

4.159 (3.47-9.30)

3.328 (2.14-7.40)

76.31 (76) e
2.639 (1.83-15.7)

3

2

4

2

3.00 (1.00-5.95)

4.00 (2.08-6.00)

6.18, 9.00

4.30 (4.00-9.00)

4.00, 6.00

275.0 (28)248.2 (60)239, 450

419.8 (36)545, 899

4815 (23) b

3839 (65)4170, 9600

7273 (48)5800, 13100

57.45 (36)104.2 (65)52.1, 120

83.70 (59)60.9, 138

2.08, 13.9

2.739 (2.27-3.46) e

2.28, 2.88

Cycle 1 Day 15 (multiple doses)
6N
Tmax, hRac

CCI

Cycle 2 Day 1 (multiple doses)
6N
Tmax, hCmax, ng/mLAUC,
ng*h/mL
CL/F, L/h
Rac

3.195 (3.04-4.35) c

1.650 (1.27-5.63)e

N is the number of patients; n is the number of patients where terminal t1/2 was determined.
Note: individual values presented where N≤2.
a Geometric mean (% geometric CV) for all except: median (range) for Tmax and Rac, arithmetic mean(%CV) for t1/2.
b n=5
c n=4
d n=2
e n=3

Table S10 Predose Plasma Concentrations (Ctrough) of Crizotinib (ALK-Negative
NSCLC Cohort #2) - PKP_Ctrough Population
Day 29Day 57
Day 113(Cycle 2 Day 1)(Cycle 3 Day 1)(Cycle 5 Day 1)
N
954
Ctrough a, ng/mL
208.0 (55)209.2 (33)269.0 (46)
Summary statistics were calculated by setting concentration values below the lower limit of quantification tozero.
N is the number of non-missing concentration measurements collected on C1D15 or later.
a Presented as mean (% CV).

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Table S11 Predose Plasma Concentrations (Ctrough) of Crizotinib (MET-Amplified
NSCLC Cohort) - PKP_Ctrough Population
Day 15
Day 29Day 43
Day 57
Day 85
Day 113(Cycle 1(Cycle 2(Cycle 2(Cycle 3(Cycle 4(Cycle 5
Day 15)
Day 1)
Day 15)
Day 1)
Day 1)
Day 1)
N
6
19
7
11
4
15
Ctrough a, ng/mL
231.5 (21)264.9 (90)245.3 (29)240.3 (34)248.5 (26)221.0 (51)
Summary statistics were calculated by setting concentration values below the lower limit of quantification tozero.
N is the number of non-missing concentration measurements collected on C1D15 or later.
a Presented as mean (% CV).

Table S12 Summary of Predose Concentrations (Ctrough) of Crizotinib (ALK-Positive
NSCLC Cohort) - Study A8081001
Cycle 1 Day 1

Cycle 2 Day 1

Ctrough a (ng/mL)
Cycle 3 Day 126
1.9 (44)54
270.7 (51)51
261.0 (49)

Parameter

CCI

N
Crizotinib

Cycle 4 Day 1

Cycle 5 Day 1

52287.8 (43)41286.9 (44)

N is the number of observations for crizotinib.
a Geometric mean (% CV)

Table S13 Summary of Steady-State Mean Predose Concentrations (Ctrough, ss, mean) of
Crizotinib in Asian and Non-Asian Patients (ALK-Positive NSCLC Cohort)- Study A8081001
ParameterN
Crizotinib

Ctrough, ss, mean a (ng/mL)
Non-AsianAsian
23
350 (36.6)

88
260 (32.3)

All Patients111
276 (36.6)

N is the number of observations for crizotinib.
a Geometric mean (% CV)

Table S14 Predose Plasma Concentrations (Ctrough) of Crizotinib (MET Exon
14-Positive NSCLC) - PKP_Ctrough Population
Day 29Day 57
Day 113(Cycle 2 Day 1)(Cycle 3 Day 1)(Cycle 5 Day 1)
N
46
43
39
Ctrough a, ng/mL
279.9 (54)250.5 (68)209.1 (59)
Summary statistics were calculated by setting concentration values below the lower limit of quantification tozero.
N is the number of non-missing concentration measurements collected on C1D15 or later.
a Presented as mean (% CV).

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CLINICAL STUDY REPORT SYNOPSIS
Table S15 Mean Steady-State Predose Concentrations (Ctrough,ss) of Crizotinib (Asian,
Non-Asian and Overall) (MET Exon 14-Positive NSCLC) Following 250 mg
BID Crizotinib - PKP_Ctrough,ss Population

Ctrough,ss a, ng/mL

Asian
(N=5)

Non-Asian(N=46)

Total(N=51)

408.2 (53)234.4 (48)247.5 (51)

Summary statistics were calculated by setting concentration values below the lower limit of quantification tozero.
N is the number of observations for crizotinib.
a Presented as geometric mean (geometric % CV).

Table S16 Predose Plasma Concentrations (Ctrough) of Crizotinib (Enriched Other –Other Cancers) - PKP_Ctrough Population

CCI

Day 15(Cycle 1
Day 15)31
296.1 (51)

Day 29(Cycle 2
Day 1)
39
279.2 (62)

Day 43(Cycle 2
Day 15)19268.9 (44)

Day 57(Cycle 3
Day 1)
17302.7 (59)

Day 85(Cycle 4
Day 1)
9321.2 (44)

Day 113(Cycle 5
Day 1)
11
265.4 (63)N
Ctrough a,
ng/mL
Summary statistics were calculated by setting concentration values below the lower limit of quantification tozero.
N is the number of non-missing concentration measurements collected on C1D15 or later.
a Presented as mean (% CV).

Safety Results:
Safety analyses were reported previously as follows:

Low Dose escalation cohort, ALK-negative NSCLC cohort #1, and ALK-positive
NSCLC cohort in the Interim CSR;

ALK-negative NSCLC cohort #2 in the ALK-Negative Report;ROS1-positive NSCLC cohort in the ROS1-Positive CSR and ROS1-Positive Technical
Report.

Summary of safety analyses is presented by-cohort for the High Dose escalation cohort and
ALK-negative NSCLC cohorts #1 and #2 in Table S17; for the MET-amplified NSCLC,
ROS1-positive NSCLC, ALK-positive NSCLC, MET exon 14-positive NSCLC, andEnriched Other – Other Cancers cohorts in Table S18; and for the rifampin and itraconazole
DDI substudy cohorts in Table S19.

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CLINICAL STUDY REPORT SYNOPSIS
For the Low Dose escalation cohort, the MTD and RP2D of crizotinib were determined to be
250 mg BID; and for the High Dose escalation cohort, the QD MTD was determined to be
650 mg QD based on discussions with the investigators as both 650 mg QD and 800 mg QD
had 1 DLT each.
Table S17 Safety Results for Dose Escalation Cohorts and Other RP2D Cohorts –Safety Analysis Populations

CCI

Treatment duration,months; median (range)
All-Causality AEs, n (%)
AEs
SAEs aGrade 3 or 4 AEs
Grade 5 AEs
AEs associated withn (%)
Permanent
discontinuation
Dose reductions
Temporarydiscontinuation
Treatment-Related,n (%):
AEs
SAEs aGrade 3 or 4 AEs
Grade 5 AEs
AEs associated with:n (%)
Permanent
discontinuation
Dose reductions
Temporarydiscontinuation
Most Frequent (≥30%)
All-causality AEs(PT/CLUSTER Term)

High Dose escalation
cohortN = 291.12 (0—5.6)

ALK-negative NSCLC
cohort #1
N = 481.8 (0.1—49.0)

ALK-negative NSCLC
cohort #2
N = 181.3 (0.4—48.4)

28 (96.6)
11 (37.9)
17 (58.6)
4 (13.8)

47 (97.9)
22 (45.8)
31 (64.6)
14 (29.2)

18 (100)
9 (50.0)
14 (77.8)
3 (16.7)

6 (20.7)

12 (25.0)

3 (16.7)

2 (6.9)8 (27.6)

4 (8.3)
11 (22.9)

3 (16.7)
9 (50.0)25 (86.2)
0
4 (13.8)
043 (89.6)
1 (2.1)
13 (27.1)
1 (2.1)16 (88.9)
2 (11.1)
5 (27.8)
01 (3.4)4 (8.3)0

2 (6.9)3 (10.3)

4 (8.3)5 (10.4)

3 (16.7)
5 (27.8)

Constipation, Nausea,
VISION DISORDER,
Vomiting, and Fatigue

VISION DISORDER,
Vomiting, Fatigue,
Constipation, Nausea,
Diarrhoea, OEDEMA, and
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VISION DISORDER,
Constipation, Nausea,
Vomiting, and Fatigue

Final Clinical Study Report
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CLINICAL STUDY REPORT SYNOPSIS
Table S17 Safety Results for Dose Escalation Cohorts and Other RP2D Cohorts –Safety Analysis Populations

CCI

High Dose escalation
cohortN = 29ALK-negative NSCLC
cohort #1
N = 48

ALK-negative NSCLC
cohort #2
N = 18

Most Frequent (≥30%)
Treatment-related AEs(PT/CLUSTER Term)

VISION DISORDER,
Nausea, and Vomiting

VISION DISORDER,
Vomiting, Fatigue, Nausea,
and Diarrhoea

VISION DISORDER,
Nausea, and Vomiting

Most Frequent (≥5%)
All-Causality Grade 3
AEs (PT/CLUSTER
Term)

Vomiting, Nausea,
OEDEMA, CHEST PAIN,
and Fatigue

Vomiting, Fatigue, Nausea,
Decreased appetite,
DYSPNOEA, andHypophosphataemia

Hypophosphataemia b

Most Frequent (≥5%)
Treatment-related
Grade 3 AEs(PT/CLUSTER Term)

0

Fatigue,
Hypophosphataemia,
Nausea, and Vomiting

Hypophosphataemia b

Most Frequent(≥2 patients) AllCausality Grade 4 AEs(PT/CLUSTER Term)
Most Frequent(≥2 patients) Treatmentrelated Grade 4 AEs(PT/CLUSTER Term)

Cardiac arrest

PULMONARYEMBOLISM

PULMONARYEMBOLISM

000

Grade 5 All-Causality
AEs (PT/CLUSTER
Term)

Disease progression,
Hypoxic-ischaemic
encephalopathy

Disease progression,
Pneumonia, Cardiorespiratory arrest, Death,
Myocardial infarction,
Pneumothorax, and Small
cell lung cancer

Disease progression, Acuterespiratory failure, andRespiratory failure

Grade 5 TreatmentRelated AEs(PT/CLUSTER Term)

0

Death

0

Hypoalbuminemia, andalkaline phosphatase

Absolute lymphocytes,
absolute neutrophils,
hemoglobin;
hypophosphatemia,
alkaline phosphatase,hyponatremia, ALT andhypoalbuminemia

Absolute lymphocytes
and hypophosphatemia

0

0

0

Most Frequent (≥2
patients) ClinicalLaboratory Evaluation
shifts from Grade ≤2 atbaseline to maximum
Grade 3 postbaseline
Most Frequent(≥2 patients) ClinicalLaboratory Evaluation
shifts from Grade ≤2 at

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CLINICAL STUDY REPORT SYNOPSIS
Table S17 Safety Results for Dose Escalation Cohorts and Other RP2D Cohorts –Safety Analysis Populations
High Dose escalation
cohortN = 29ALK-negative NSCLC
cohort #1
N = 48

ALK-negative NSCLC
cohort #2
N = 182 (6.9) / 29

1 (2.2) / 45

02 (6.9) / 29

2 (4.5) / 440baseline to maximum
Grade 4 postbaseline
QTcF ≥500 msec;n (%) / NE
Increase from baseline in
QTcF ≥60 msec;n (%) / NE

NA = Not analyzed
NE = number of evaluable patientsa Seriousness was according to the investigator’s assessment.
b For this cohort, the frequency cutoff applied for this parameter was changed from “≥5%” (1 patient) to “≥2 patients”.

CCI

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CLINICAL STUDY REPORT SYNOPSIS
Table S18 Safety Results for Enriched RP2D Cohorts – Safety Analysis Populations

CCI

Treatment
duration, months;
median (range)
All-Causality AEs,n (%):
AEs
SAEs aGrade 3 or 4 AEs
Grade 5 AEs
AEs associatedwith: n (%)
Permanent
discontinuation
Dose reductions
Temporarydiscontinuation
Treatment-RelatedAEs, n (%):
AEs
SAEs aGrade 3 or 4 AEs
Grade 5 AEs
AEs associatedwith: n (%)
Permanent
discontinuation
Dose reductions
Temporarydiscontinuation

MET-Amplified
NSCLC
N = 41
3.3 (0.1—94.1)

ROS1-Positive
NSCLC
N = 5320.6 (0.5—97.9)

ALK-Positive NSCLC
N = 15413.1 (0.2—124.0)

MET Exon 14-Positive
NSCLC
N = 857.4 (0.4—51.1)

Enriched Other –Other Cancers
N = 66
1.8 (0.4—50.4)

41 (100)
25 (61.0)
33 (80.5)
10 (24.4)

53 (100)
24 (45.3)
36 (67.9)
10 (18.9)

154 (100.0)
75 (48.7)
104 (67.5)
27 (17.5)

85 (100.0)
54 (63.5)
65 (76.5)
15 (17.6)

66 (100)
29 (43.9)
40 (60.6)
14 (21.2)

9 (22.0)

1 (1.9)26 (16.9)

16 (18.8)

10 (15.2)

10 (24.4)
24 (58.5)

11 (20.8)
27 (50.9)

19 (12.3)
76 (49.4)

37 (43.5)
48 (56.5)

8 (12.1)
23 (34.8)

38 (92.7)
4 (9.8)20 (48.8)
1 (2.4)53 (100)
2 (3.8)19 (35.8)0152 (98.7)
12 (7.8)
52 (33.8)
1 (0.6)82 (96.5)
14 (16.5)
26 (30.6)
1 (1.2)63 (95.5)
8 (12.1)
17 (25.8)
04 (9.8)0

6 (3.9)7 (8.2)4 (6.1)9 (22.0)
12 (29.3)

11 (20.8)
14 (26.4)

19 (12.3)
38 (24.7)

34 (40.0)
24 (28.2)

8 (12.1)
13 (19.7)

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CLINICAL STUDY REPORT SYNOPSIS
Table S18 Safety Results for Enriched RP2D Cohorts – Safety Analysis Populations
MET-Amplified
NSCLC
N = 41

ROS1-Positive
NSCLC
N = 53

ALK-Positive NSCLCMost Frequent(≥30%) Allcausality AEs(PT/CLUSTERTerm)

OEDEMA, Diarrhoea,
Vomiting, Nausea, and
VISION DISORDERVISION DISORDER,
Nausea, OEDEMA,
Vomiting, Diarrhoea,
Constipation,
DIZZINESS,ELEVATEDTRANSAMINASES,
Fatigue,
NEUROPATHY,UPPERRESPIRATORYINFECTION,
DYSPNOEA, andDecreased appetite

VISION DISORDER,
Nausea, Diarrhoea,
OEDEMA, Vomiting,Constipation,
DIZZINESS, UPPERRESPIRATORYINFECTION, Fatigue,
NEUROPATHY, andDecreased appetiteOEDEMA, Diarrhoea,
Nausea, Constipation,
VISION DISORDER,
Fatigue, Vomiting,
NEUROPATHY,
DYSPNOEA, and
DIZZINESS

Nausea, Vomiting,Diarrhoea, VISIONDISORDER, Fatigue,
OEDEMA, andDecreased appetite

Most Frequent(≥30%) Treatmentrelated AEs(PT/CLUSTER
Term)

Diarrhoea, Vomiting,and OEDEMAVISION DISORDER,
Nausea, OEDEMA,
Diarrhoea, Vomiting,
ELEVATEDTRANSAMINASES,
and Constipation

VISION DISORDER,
Nausea, Diarrhoea,
OEDEMA, Vomiting, andConstipation

OEDEMA, Diarrhoea,
Nausea, VISIONDISORDER, andVomiting

Nausea, VISIONDISORDER,
Diarrhoea, andVomiting

N = 154

MET Exon 14-Positive
NSCLC
N = 85

Enriched Other –Other Cancers
N = 66CCI

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CLINICAL STUDY REPORT SYNOPSIS
Table S18 Safety Results for Enriched RP2D Cohorts – Safety Analysis Populations

CCI

Most Frequent(≥5%) AllCausality Grade 3
AEs(PT/CLUSTER
Term)

Most Frequent(≥5%) Treatmentrelated Grade 3
AEs(PT/CLUSTER
Term)
Most Frequent(≥2 patients) AllCausality Grade 4
AEs(PT/CLUSTER
Term)

MET-Amplified
NSCLC
N = 41
Hyponatraemia,
ANAEMIA,DYSPNOEA,
Pneumonia,
ELEVATEDTRANSAMINASES,
Hypophosphataemia,
Hypoxia, and
LYMPHOPENIAELEVATEDTRANSAMINAS
ES andLYMPHOPENIA

ROS1-Positive
NSCLC
N = 53Hypophosphataemia,
NEUTROPENIA,
DYSPNOEA,Headache, Vomiting,
ELEVATEDTRANSAMINASES,
and Syncope

Hypophosphataemia
and NEUTROPENIAPULMONARYEMBOLISM

PULMONARYEMBOLISM

ALK-Positive NSCLCMET Exon 14-Positive
NSCLC
N = 85
DYSPNOEA,
Pneumonia,
Hyponatraemia, Syncope,
ELEVATEDTRANSAMINASES,
Hypoxia, and Pleural
effusion

Enriched Other –Other Cancers
N = 66
Hyponatraemia,
ANAEMIA,ELEVATEDTRANSAMINASES,
Hypophosphataemia,
and NEUTROPENIANEUTROPENIA,
ELEVATEDTRANSAMINASES, andHypophosphatemia

DYSPNOEA,ELEVATEDTRANSAMINASES, and
INTERSTITIAL LUNGDISEASEELEVATEDTRANSAMINASESPULMONARYEMBOLISM,
ELEVATEDTRANSAMINASES,
NEUTROPENIA, Deepvein thrombosis,
Haemoptysis, Hypoxia,
INTERSTITIAL LUNGDISEASE, Pneumonia,
Respiratory failure, and
THROMBOCYTOPENIAPULMONARYEMBOLISM, Embolism,
Respiratory failure, Brain
oedema, andCerebrovascular accident

ANAEMIAN = 154
ELEVATEDTRANSAMINASES,
Hypophosphataemia,
NEUTROPENIA,
Pneumonia, ANAEMIA,
Syncope; DYSPNOEA,LYMPHOPENIA, andHyponatraemia

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CLINICAL STUDY REPORT SYNOPSIS
Table S18 Safety Results for Enriched RP2D Cohorts – Safety Analysis Populations
MET-Amplified
NSCLC
N = 41CCI

ROS1-Positive
NSCLC
N = 53

ALK-Positive NSCLC
N = 154
NEUTROPENIAMET Exon 14-Positive
NSCLC
N = 850

Enriched Other –Other Cancers
N = 66ANAEMIA

Most Frequent(≥2 patients)
Treatment-related
Grade 4 AEs(PT/CLUSTER
Term)

0

0

All-causality
Grade 5 AEs(PT/CLUSTER
Term)

Disease progression,
Pneumonia,
Encephalopathy,
INTERSTITIAL LUNGDISEASE, andRespiratory failure

Disease progression

Disease progression,
Pneumonia, Respiratory
failure, Aspergillus
infection, Disseminatedintravascular coagulation,
Pulmonary haemorrhage,
and Subcutaneous
emphysema

Disease progression,
INTERSTITIAL LUNGDISEASE, Respiratory
failure, Cardiac arrest,
Cardio-respiratory arrest,
Large intestinal
obstruction, Respiratoryarrest, and Subdural
haematoma

Disease progression,
Pneumonia, and Septic
shock

Treatment-Related
Grade 5 AEs(PT/CLUSTER
Term)

INTERSTITIAL LUNGDISEASE

0

Disseminatedintravascular coagulation

INTERSTITIAL LUNGDISEASE0

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CLINICAL STUDY REPORT SYNOPSIS
Table S18 Safety Results for Enriched RP2D Cohorts – Safety Analysis Populations

CCI

Most Frequent(≥2 patients)
Clinical Laboratory
Evaluation shifts
from Grade ≤2 atbaseline to
maximum Grade 3
postbaseline b

Most Frequent(≥2 patients)
Clinical Laboratory
Evaluation shifts
from Grade ≤2 atbaseline to
maximum Grade 4
postbaseline

MET-Amplified
NSCLC
N = 41
Absolute lymphocytes,
hemoglobin;
hypophosphatemia,
hyponatremia, ALT,
and hypoalbuminemia

ROS1-Positive
NSCLC
N = 53Absolute lymphocytes,
absolute neutrophils,WBCs;hypophosphatemia,
hyponatremia, ALT,
AST, hyperkalemia,
and hypoalbuminemia

0Absolute lymphocytes

ALK-Positive NSCLC
N = 154
Absolute lymphocytes,
absolute neutrophils,
WBCs, hemoglobin,platelets;
hypophosphatemia, ALT,
hyponatremia,
hyperglycemia, AST,
hypocalcemia,
hypoalbuminemia,
hypokalemia, and alkaline
phosphatase
Absolute lymphocytes,
absolute neutrophils, andALT

MET Exon 14-Positive
NSCLC
N = 85Absolute lymphocytes,
hemoglobin,
hyponatremia,
hypophosphatemia,
hyperkalemia, ALT, AST
and hyperglycemia,
alkaline phosphatase, andhypokalemia

Enriched Other –Other Cancers
N = 66
Absolute lymphocytes,
absolute neutrophils,
platelets, hyponatremia,
hypophosphatemia,
ALT, alkaline
phosphatase, AST,
hypoalbuminemia, andhypocalcemia

Absolute lymphocytes

Hemoglobin

QTcF ≥500 msec;
1 ( 2.6) / 39
2 (3.8) / 53
2 (1.3) / 154n (%) / NE
Increase from1 ( 2.6) / 39
2 (3.8) / 53
7 (4.5) / 154baseline in QTcF
≥60 msec; n (%) /NE
NE = number of evaluable patientsa Seriousness was according to investigator’s assessment.
b Hy’s Law criteria were met by 1 patient each in the ROS1-positive NSCLC and ALK-positive NSCLC cohort.

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5 (7.9) / 63

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CLINICAL STUDY REPORT SYNOPSIS
Table S19 Safety Results for Drug-Drug Interaction Cohorts - Safety Analysis
Populations
Crizotinib 250 mg BID +Rifampin 600 mg QD
N = 182.0 (1—13) cycles started

Crizotinib 250 mg QD +Itraconazole 200 mg QD
N = 1847.0 (7—331) days

18 (100)
6 (33.3)
9 (50.0)018 (100)
7 (38.9)
12 (66.7)
0

4 (22.2)07 (38.9)

3 (16.7)
1 (5.6)9 (50.0)

16 (88.9)
2 (11.1)
2 (11.1)
017 (94.4)
4 (22.2)
5 (27.8)
01 (5.6)0
3 (16.7)

1 (5.6)1 (5.6)4 (22.2)

Most Frequent (≥30%) All-Causality
AEs (PT/CLUSTER Term)

VISION DISORDER, Nausea,
Vomiting, Constipation,
Diarrhoea, Decreased appetite,
and Fatigue

Constipation, Nausea, VISIONDISORDER, DYSPNOEA,
Fatigue, Vomiting, Diarrhoea,
and OEDEMA

Most Frequent (≥30%) TreatmentRelated AEs (PT/CLUSTER Term)

VISION DISORDER, Nausea,
and Vomiting

Nausea, VISION DISORDER,
Vomiting, Constipation,
Diarrhoea, OEDEMA

Most Frequent (≥2 patients) AllCausality Grade 3 AEs(PT/CLUSTER Term)

Hypokalaemia

ANAEMIA, Ascites, Bloodalkaline phosphatase increased,
Deep vein thrombosis, andVomiting

Most Frequent (≥2 patients)
Crizotinib-Related Grade 3 AEs(PT/CLUSTER Term)

Hypokalaemia

0

Most Frequent (≥2 patients) AllCausality Grade 4 AEs(PT/CLUSTER Term)0Hyperuricaemia

Treatment exposure; median (range)
All-Causality AEs, n (%):
AEs
SAEs aGrade 3 or 4 AEs
Grade 5 AEs
AEs associated with: n (%)
Permanent discontinuation
Dose reductions
Temporary discontinuation

CCI

Treatment-related AEs b, n (%):
AEs
SAEs aGrade 3 or 4 AEs
Grade 5 AEs
AEs associated with: n (%)
Permanent discontinuation
Dose reductions
Temporary discontinuation

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CLINICAL STUDY REPORT SYNOPSIS

CCI

Most Frequent (≥2 patients)
Crizotinib-Related Grade 4 AEs(PT/CLUSTER Term)

00

Grade 5 AEs (PT/CLUSTER Term)

00

Most Frequent (≥2 patients) ClinicalLaboratory Evaluation shifts from
Grade ≤2 at baseline to maximum
Grade 3 postbaseline

Hyponatremia

Alkaline phosphatase

Most Frequent (≥2 patients) ClinicalLaboratory Evaluation shifts from
Grade ≤2 at baseline to maximum
Grade 4 postbaseline

00

QTcF ≥500 msec; n (%) / NE0
Increase from baseline in QTcF ≥60
0msec; n (%) / NE
NE = number of evaluable patientsa Seriousness was according to the investigator’s assessment.
b AEs related to crizotinib treatment only.

00

For the 8 hypogonadism parameters measured in this study, there was a reduction frombaseline in the levels of most parameters and the geometric mean of the ratio of C2D1/C1D1
calculated for evaluable patients was statistically significant (p values <0.05) for testosterone(0.47; p<0.0001), sex hormone-binding globulin (SHBG9 (0.24, p<0.0001), serum
luteinizing hormone (0.42; 0.0019), dihydroepiandosterone sulfate (0.85; p=0.0120), andestradiol (0.72; p=0.0133), but was not statistically significant for free testosterone (1.31;
p=0.0776), prolactin (0.89; p=0.3111), and follicle stimulating hormone (0.69; p=0.0508).
As there was no adjustment for multiple testing, these values should be viewed descriptively.
Abnormalities in clinical laboratory results or assessments of vital signs, ECGs, and physicalexaminations reported on crizotinib treatment were generally manageable by dosinginterruption, dose reduction, and/or standard medical therapy.

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CLINICAL STUDY REPORT SYNOPSISCONCLUSIONSIn the following subsections, conclusions drawn in previous reports that remained unchanged
are presented verbatim in italics and any updates made for the respective cohort as well as
conclusions for cohorts not previously reported, based on the database snapshot date for thisfinal CSR, are presented in regular font.
Safety and Efficacy:
Dose Escalation Cohorts


For the Low Dose escalation cohort, the MTD and RP2D of crizotinib were determined
to be 250 mg BID (Interim CSR).



For the High Dose escalation cohort, the QD MTD was determined to be 650 mg QD
based on discussions with the investigators as both 650 mg QD and 800 mg QD had
1 DLT each.

In the Low Dose escalation cohort, the best overall response was PR for 1 patient andwas stable disease for 11 patients (Interim CSR).



Efficacy data for the High Dose escalation cohort were listed but were not analyzed inthis final CSR.

CCI

ALK-Negative NSCLC Cohort #1


The AE profile for the ALK-negative NSCLC patients treated with crizotinib in the
ALK-negative NSCLC cohort #1 in this study was consistent with the established safety
profile of crizotinib.

Efficacy data for the ALK-negative NSCLC cohort #1 were listed but were not analyzed
in this final CSR.

ALK-Negative NSCLC Cohort #2
The following conclusions were drawn for the 21 patients included in the ALK-negative
NSCLC cohort #2, based on a data cutoff date of 24 June 2014, as reported in the
ALK-Negative Report, with updates made based on the database snapshot date for this finalCSR:The AE profile for the ALK-negative NSCLC patients treated with crizotinib in thisstudy was consistent with the established safety profile of crizotinib.

As expected, based on the mechanism of action of crizotinib, antitumor activity was much
lower in ALK-negative NSCLC patients than in ALK-positive NSCLC patients.

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CLINICAL STUDY REPORT SYNOPSIS

Eleven patients were known to have NSCLC that was negative for the 3 identified genetic
alterations targeted by crizotinib that were tested (ie, ALK fusion, ROS1 fusion, and MET
amplification).


CCI

No ALK-negative NSCLC patients achieved a CR, and 4 of 21 ALK-negative NSCLC
patients had a PR, for an ORR of 19.0% (95% CI: 5.4%, 41.9%). These 4 patients
included 1 patient with ROS1-positive NSCLC and 2 patients with unknown ROS1
and/or MET status.

In these 11 patients, 1 patient achieved a PR for an ORR of 9.1% (95% CI: 0.23%,
41.3%). Given the low response rate in a small sample size, this could potentiallyrepresent a patient with a false-negative ALK, ROS1, or MET test result or a patientwith yet another genetic alteration sensitive to inhibition by crizotinib that was nottested.



There did not appear to be any relationship between percent ALK positivity and best
overall response.



The ORR in ALK-negative NSCLC patients treated with a multi-targeted agent such as
crizotinib may reflect inadequate testing of all relevant genetic alterations rather thaninadequacy of a specific test for a single gene alteration or its cutoff.

MET-Amplified NSCLC CohortThe safety profile of crizotinib in patients with MET-amplified NSCLC was generally
consistent with the established safety profile of crizotinib.

Crizotinib provided meaningful clinical benefit in the high-level MET gene amplified
category as evidenced by objective responses that were rapid and durable, with complete
responses in some cases.
The ORR in the total MET-amplified NSCLC cohort (N=38) was 31.6%; 2 (5.3%)
patients had a CR, 10 (26.3%) patients had a PR, and a further 10 (26.3%) patients
had stable disease as their BOR. Median TTR was 8.0 weeks, median DR was
5.2 months, and median PFS was 4.0 months.

The highest ORR among the 3 MET amplification categories was observed in thehigh-level MET gene amplified category (N=21), which was 42.9% with 2 patients
who had a CR and 7 patients who had PR as their BOR; the median TTR was
8.0 weeks, median DR was 5.2 months, and median PFS was 6.9 months.

ROS1-Positive NSCLC Cohort

Crizotinib was generally well-tolerated and manageable by dosing interruption, dose
reduction, and/or standard medical therapy (ROS1-Positive CSR).

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Final Clinical Study Report
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CLINICAL STUDY REPORT SYNOPSIS

Crizotinib provided meaningful clinical benefit as evidenced by a high rate of objective
responses that were rapid, substantial, and durable, with complete response in somecases (ROS1-Positive CSR).
The ORR was 71.7% (N=53); 6 (11.3%) patients had a CR, 32 (60.4%) patients had a
PR, and a further 10 (18.9%) patients had stable disease as their BOR. Median TTR
was 7.9 weeks, and median PFS was 19.3 months (ROS1-Positive Technical Report).



The median DR was estimated to be approximately 25 months (ROS1-Positive
Technical Report).



The median OS was more than 4 years (ROS1-Positive Technical Report).

ALK-Positive NSCLC Cohort
The safety conclusions for the ALK-positive NSCLC cohort were initially drawn, based on
the database snapshot date of 01 November 2010, in the Interim CSR; minor updates weremade based on the database snapshot date for this final CSR.
CCIThe AE profile of crizotinib 250 mg BID orally was generally safe and well-tolerated,with the most frequent AEs in ALK-positive NSCLC patients of Grade 1 VISIONDISORDER, gastrointestinal events, including Nausea, Diarrhoea, Vomiting, andConstipation, and OEDEMA, which were all Grade 1 to Grade 3 in severity.



The incidence of severe and serious AEs and laboratory abnormalities reported on
crizotinib treatment was relatively low and generally manageable in this patient
population by dosing interruption, dose reduction, and/or standard medical therapy, withthe most frequently reported treatment-related SAEs in ALK-positive NSCLC patients of
ELEVATED TRANSAMINASES in 3 (1.9%) patients and RENAL CYST in 2 (1.3%)
patients.

The efficacy of crizotinib 250 mg BID in the ALK-positive advanced NSCLC cohort was
robust with an investigator-assessed ORR of 60.8%, durable with a median DR estimateof 49.1 weeks, and clinically meaningful with a median PFS estimate of 9.7 months(updates reported in Camidge et al [Camidge et al. Lancet Oncol. 2012;13(10):1011-9]).

Enriched Other Cohort
MET Exon 14-Positive NSCLC Patients

The safety profile of crizotinib in patients with MET exon 14-positive NSCLC was
generally consistent with the established safety profile of crizotinib.

Crizotinib provided meaningful clinical benefit as evidenced by objective responses thatwere rapid and durable, with complete responses in some cases.

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Final Clinical Study Report
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CLINICAL STUDY REPORT SYNOPSISThe ORR based on derived investigator tumor assessment was 38.8% (N=85);
3 (3.5%) patients had a CR, 30 (35.3%) patients had a PR, and a further 35 (41.2%)
patients had stable disease as their BOR. Median TTR was 7.6 weeks, median DR
was 9.1 months, median PFS was 7.6 months and median OS was 20.0 months.

Enriched Other – Other Cancers
The safety profile of crizotinib in other cancer patients (with molecular markers otherthan ALK-positive NSCLC and ROS1-positive NSCLC, that could confer sensitivity tocrizotinib), was generally consistent with the established safety profile of crizotinib.

The antitumor activity was lower than that observed for patients with ALK-positive and
ROS1-positive NSCLC.
The ORR was 8.2% (N=61); 1 (1.6%) patient had a CR, 4 (6.6%) patients had a PR,
and a further 19 (31.1%) patients had stable disease as their BOR.

Drug-Drug Interaction Cohorts
CCI

There were no new crizotinib safety signals when coadministered with rifampin during
the Rifampin DDI substudy (Rifampin DDI Report).



There were no new crizotinib safety signals when coadministered with itraconazole
during the Itraconazole DDI substudy.



Efficacy was not evaluated in the DDI cohorts.

Pharmacokinetics:
Dose Escalation and RP2D Cohorts
The following conclusions were drawn from crizotinib PK data that were available for:i) A total of 204 patients, 37 of whom were receiving crizotinib 50 to 200 mg QD or 200 to
300 mg BID in the Low Dose escalation cohort and 167 of whom were from the RP2D
cohorts, as reported in the Interim CSR, with updates made based on the database snapshot
date for this final CSR, andii) A total of 28 patients receiving crizotinib 300 to 800 mg QD in the High Dose escalation
cohort, which were combined with data from patients on QD dosing schedule in the Low
Dose escalation cohort, and other patients with different tumor types receiving crizotinib 250
mg BID, as reported in this final CSR:

After single oral doses of crizotinib, peak plasma concentrations were achieved
approximately 4 hours postdose, and the terminal elimination half-life was 42.4 hours;
food did not markedly change crizotinib systemic exposure (Interim CSR).

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Final Clinical Study Report
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CLINICAL STUDY REPORT SYNOPSIS

After multiple oral BID and QD doses of crizotinib, steady state was reached within
15 days (Interim CSR).



After multiple dosing, dose-proportional increases in crizotinib exposure were observed
over the dosing range of 200 to 300 mg BID and 100 to 800 mg QD.

There was no overt difference in crizotinib PK in patients with NSCLC with various geneabnormalities and other tumor types tested in this study.

Drug-Drug Interaction Cohorts

CCI

Crizotinib 250 mg BID increased the AUC of MDZ by 3.65-fold after repeatedadministration, indicating that crizotinib is a moderate CYP3A inhibitor (Interim CSR).



Coadministration of multiple doses of crizotinib 250 mg BID with rifampin (600 mg QD),
a strong CYP3A inducer, decreased steady-state AUCtau and Cmax of crizotinib by 84%
and 79%, respectively, compared to crizotinib treatment alone (Rifampin DDI Report).



Coadministration of crizotinib (250 mg QD) with itraconazole (200 mg QD), a strong
CYP3A inhibitor, increased steady-state AUCtau and Cmax of crizotinib by 57% and 33%,
respectively, compared to crizotinib administered alone (Itraconazole DDI Report).

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