A Phase III, Open-Label, Randomized Study to Evaluate the Efficacy and Safety of Adjuvant Alectinib Versus Adjuvant Platinum-Based Chemotherapy in Patients With Completely Resected Stage IB (Tumors Equal to or Larger Than 4cm) to Stage IIIA Anaplastic Lymphoma Kinase Positive Non-Small Cell Lung Cancer
Phase: PHASE3
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: Hoffmann-La Roche

 
Official Title: 
A Phase III, Open-Label, Randomized Study to Evaluate the Efficacy 
and Safety of Adjuvant Alectinib Versus Adjuvant Platinum-Based 
Chemotherapy in Patients With Completely Resected Stage IB 
(Tumors Equal to or Larger Than 4 cm) to Stage IIIA Anaplastic 
Lymphoma Kinase Positive Non-Small Cell Lung Cancer 
NCT Number: 
NCT03456076 
Document Date: 
Protocol Amendment Version 7: 16-December-2021 
 
 
 

PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered.
Alectinib—F. Hoffmann-La Roche Ltd
Protocol BO40336, Version 7
PROTOCOL
TITLE:
A PHASE III, OPEN-LABEL, RANDOMIZED STUDY 
TO EVALUATE THE EFFICACY AND SAFETY OF 
ADJUVANT ALECTINIB VERSUS ADJUVANT 
PLATINUM-BASED CHEMOTHERAPY IN 
PATIENTS WITH COMPLETELY RESECTED 
STAGE Ib (TUMORS4 cm) TO STAGE IIIa
ANAPLASTIC LYMPHOMA KINASEPOSITIVE 
NONSMALL-CELL LUNG CANCER
PROTOCOL NUMBER:
BO40336
VERSION NUMBER:
7
EUDRACT NUMBER:
2017-004331-37
IND NUMBER:
111,723
TEST PRODUCT:
Alectinib (RO5424802)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
See electronic date stamp below
Company Signatory
Approver's Name
Title
Date and Time (UTC)
16-Dec-2021 22:27:11

Alectinib—F. Hoffmann-La Roche Ltd
2/Protocol BO40336, Version 7
PROTOCOL HISTORY
Protocol
Version
Date Final
6
10 March 2021
5
26 November 2019
4
8 November 2019
3
23 April 2018
2 (E.U.)
10 April 2018
1
5 February 2018

Alectinib—F. Hoffmann-La Roche Ltd
3/Protocol BO40336, Version 7
PROTOCOL AMENDMENT, VERSION 7: 
RATIONALE
Protocol BO40336 has been amended primarily to update the management guidline of 
hemolytic anemia for patients treated with alectinib. Changes to the protocol, along with 
a rationale for each change, are summarized below:

Management guideline of hemolytic anemia for patients treated with alectinib has 
been updated (Section 5.1.7.3).

Hematologic findings from alectinib toxicity studies in animals have been provided 
to the section describing the risks associated with alectinib (Section 5.1.1.3).  

Management guidelines of bradycardia for patients treated with alectinib has been 
updated in line with the alectinib label (Section 5.1.7.3).  

Benefit-risk assessment for COVID-19 infection and COVID-19 vaccines has been 
included (Section 1.3.1).

Text relating to the collection of radiographic images and the potential independent 
review by an imaging review facility have been added (Section 4.5.6, Section 7.5, 
Section 9.5, Appendix 1 and Appendix 2). 

Any references to the Medical Monitor’s approval of the protocol-specific criteria or 
procedures are removed from the protocol. The Medical Monitor may be consulted 
for advice or clarification, but all medical decisions are the responsibility of the 
Investigator (Section 4.1.2, Section 4.3.2.2, and Section 5.1.7.2).

The minimum requirement of Creatinine Clearance (CrCL) has been clarified when 
the pemetrexed is given to the patient together with cisplatin. The patient’s CrCl 
must be60 mL/min before the next dose of cisplatin admistration due to its 
dose-related and cumulative renal insufficiency (Section 4.3.2.2). 

Vinorelbine preparation by syringe has been removed from the protocol following 
United States Prescribing Information (USPI) update, in order to reduce the 
potential for unintended intrathecal administration which causes death or severe 
neurological injury (Section 4.3.2.2).

Text relating to data reporting of COVID-19 vaccination in the medical history 
and/or in the concomitant medication section has been added (Section 4.5.2, 
Appendix 1 and Appendix 2).  

It has been clarified that, if the patient stops disease assessment, the patient will 
be contacted for disease recurrence status if no recurrence occurs as long as the 
patient hasn’t withdrawn from the study (Section 4.6.1).

The most common adverse effects for pemetrexed has been updated in line with 
the updated pemetrexed EU Summary of Product Characteristics, where multiple 
tables of adverse drug events have been consolidated into one table containing 
data from the pivotal clinical trials and the post marketing period (Section 5.1.4). 

It has been clarified that Long-Term Follow-Up should be conducted after the first 
documented disease recurrence or new primary NSCLC, until death, loss to 
follow-up, or study termination by the Sponsor (Appendix 1 and Appendix 2).

Alectinib—F. Hoffmann-La Roche Ltd
4/Protocol BO40336, Version 7
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information for Version 7 appears in Book Antiqua italics.  
This amendment represents cumulative changes to the original protocol.

Alectinib—F. Hoffmann-La Roche Ltd
5/Protocol BO40336, Version 7
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM ..........................................15
PROTOCOL SYNOPSIS ....................................................................................16
1.
BACKGROUND .......................................................................................... 28
1.1
Background on Anaplastic Lymphoma 
Kinase-Positive NonSmall-Cell Lung Cancer....................... 28
1.2
Background on Alectinib........................................................ 29
1.2.1
Study NP28761 ..................................................................... 29
1.2.2
Study NP28673 ..................................................................... 30
1.2.3
Study MO29750 (ALUR)........................................................ 31
1.2.4
Study BO28984 (ALEX)......................................................... 34
1.3
Study Rationale and BenefitRisk Assessment..................... 36
1.3.1
COVID-19 BenefitRisk Assessment..................................... 38
1.3.2
COVID-19 Vaccines .............................................................. 38
2.
OBJECTIVES AND ENDPOINTS ............................................................... 38
3.
STUDY DESIGN......................................................................................... 41
3.1
Description of the Study......................................................... 41
3.2
End of Study and Length of Study......................................... 44
3.3
Rationale for Study Design.................................................... 44
3.3.1
Rationale for Alectinib Dose and Schedule............................ 44
3.3.2
Rationale for Open-Label Design of the Study ...................... 45
3.3.3
Rationale for Patient Population and Analysis 
Groups................................................................................... 46
3.3.4
Rationale for Control Group................................................... 48
3.3.5
Rationale for PK Sample Collection Schedule....................... 48
3.3.6
Rationale for Biomarker Assessments................................... 49
3.3.7
Rationale for Patient-Reported Outcome 
Assessments ......................................................................... 50
4.
MATERIALS AND METHODS .................................................................... 50
4.1
Patients.................................................................................. 50
4.1.1
Inclusion Criteria.................................................................... 50
4.1.2
Exclusion Criteria................................................................... 52

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4.5.7.1
Samples for Pharmacokinetic Assessments.......................... 69
4.5.7.2
Samples for Biomarker Assessments.................................... 70
4.5.8
Electrocardiograms................................................................ 72
4.5.9
Patient-Reported Outcomes .................................................. 73
4.5.9.1
SF-36v2................................................................................. 73
4.5.9.2
EQ-5D-5L .............................................................................. 73
4.5.10
Optional Samples for Research Biosample 
Repository ............................................................................. 73
4.5.10.1
Overview of the Research Biosample Repository.................. 73
4.5.10.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 74
4.5.10.3
Sample Collection.................................................................. 74
4.5.10.4
Confidentiality........................................................................ 75
4.5.10.5
Consent to Participate in the Research 
Biosample Repository............................................................ 75
4.5.10.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 76
4.5.10.7
Monitoring and Oversight....................................................... 76
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 76
4.6.1
Study Treatment Discontinuation........................................... 76
4.6.2
Patient Discontinuation from Study........................................ 77
4.6.3
Study Discontinuation............................................................ 78
4.6.4
Site Discontinuation............................................................... 78
5.
ASSESSMENT OF SAFETY....................................................................... 78
5.1
Safety Plan ............................................................................ 78
5.1.1
Risks Associated with Alectinib ............................................. 79
5.1.1.1
Interstitial Lung Disease ........................................................ 79
5.1.1.2
Hepatotoxicity........................................................................ 79
5.1.1.3
Anemia .................................................................................. 80
5.1.1.4
Gastrointestinal Disorders ..................................................... 80
5.1.1.5
Skin Disorders ....................................................................... 81
5.1.1.6
Vision Disorders .................................................................... 81
5.1.1.7
Edema ................................................................................... 81

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5.1.5
Risks Associated with Cisplatin ............................................. 87
5.1.5.1
Nephrotoxicity........................................................................ 88
5.1.5.2
Ototoxicity.............................................................................. 88
5.1.5.3
Hematologic Toxicities........................................................... 88
5.1.5.4
Gastrointestinal Toxicities...................................................... 89
5.1.5.5
Vascular Toxicities................................................................. 89
5.1.5.6
Serum Electrolyte Disturbances ............................................ 89
5.1.5.7
Hyperuricemia ....................................................................... 89
5.1.5.8
Neurotoxicity.......................................................................... 90
5.1.5.9
Ocular Toxicity....................................................................... 90
5.1.5.10
Anaphylactic-Like Reactions.................................................. 90
5.1.5.11
Hepatotoxicity........................................................................ 90
5.1.5.12
Other Events.......................................................................... 91
5.1.5.13
Embryo-Fetal Toxicity............................................................ 91
5.1.5.14
Carcinogenic Potential........................................................... 91
5.1.6
Risks Associated with Carboplatin......................................... 91
5.1.6.1
Hematologic Toxicities........................................................... 91
5.1.6.2
Nephrotoxicity........................................................................ 92
5.1.6.3
Ototoxicity.............................................................................. 92
5.1.6.4
Gastrointestinal Toxicities...................................................... 92
5.1.6.5
Neurotoxicity.......................................................................... 92
5.1.6.6
Ocular Toxicity....................................................................... 93
5.1.6.7
Allergic Reactions.................................................................. 93
5.1.6.8
Hepatotoxicity........................................................................ 93
5.1.6.9
Embryo-Fetal Toxicity............................................................ 93
5.1.6.10
Other Toxicities...................................................................... 93
5.1.7
Management of Patients who Experience 
Adverse Events with Alectinib................................................ 94
5.1.7.1
Dose Modifications ................................................................ 94
5.1.7.2
Treatment Interruption ........................................................... 94
5.1.7.3
Management Guidelines........................................................ 94
5.1.8
Management of Patients who Experience 
Adverse Events with Vinorelbine ........................................... 99

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5.1.9
Management of Patients who Experience 
Adverse Events with Gemcitabine......................................... 99
5.1.10
Management of Patients who Experience 
Adverse Events with Pemetrexed.......................................... 99
5.1.10.1
Non-Hematologic Toxicity.................................................... 100
5.1.11
Management of Patients who Experience 
Adverse Events with Cisplatin ............................................. 100
5.1.12
Management of Patients who Experience 
Adverse Events with Carboplatin......................................... 100
5.1.12.1
Hematologic Toxicities......................................................... 100
5.2
Safety Parameters and Definitions ...................................... 100
5.2.1
Adverse Events ................................................................... 101
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor).................................................................... 101
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................. 102
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 102
5.3.1
Adverse Event Reporting Period ......................................... 102
5.3.2
Eliciting Adverse Event Information..................................... 103
5.3.3
Assessment of Severity of Adverse Events ......................... 103
5.3.4
Assessment of Causality of Adverse Events ....................... 104
5.3.5
Procedures for Recording Adverse Events.......................... 105
5.3.5.1
Infusion-Related Reactions.................................................. 105
5.3.5.2
Diagnosis versus Signs and Symptoms............................... 105
5.3.5.3
Adverse Events that are Secondary to Other 
Events.................................................................................. 106
5.3.5.4
Persistent or Recurrent Adverse Events.............................. 106
5.3.5.5
Abnormal Laboratory Values ............................................... 107
5.3.5.6
Abnormal Vital Sign Values ................................................. 107
5.3.5.7
Abnormal Liver Function Tests............................................ 108
5.3.5.8
Deaths ................................................................................. 108
5.3.5.9
Preexisting Medical Conditions............................................ 109
5.3.5.10
Lack of Efficacy or Recurrence of NSCLC........................... 109
5.3.5.11
Hospitalization or Prolonged Hospitalization........................ 109

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5.3.5.12
Cases of Overdose, Medication Error, Drug 
Abuse, or Drug Misuse ........................................................ 110
5.3.5.13
Patient-Reported Outcome Data ......................................... 112
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 112
5.4.1
Emergency Medical Contacts.............................................. 113
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest................... 113
5.4.2.1
Events that Occur prior to Study Drug Initiation................... 113
5.4.2.2
Events that Occur after Study Drug Initiation....................... 113
5.4.3
Reporting Requirements for Pregnancies............................ 114
5.4.3.1
Pregnancies in Female Patients.......................................... 114
5.4.3.2
Pregnancies in Female Partners of Male Patients............... 114
5.4.3.3
Abortions ............................................................................. 115
5.4.3.4
Congenital Anomalies/Birth Defects .................................... 115
5.5
Follow-Up of Patients after Adverse Events ........................ 115
5.5.1
Investigator Follow-Up......................................................... 115
5.5.2
Sponsor Follow-Up .............................................................. 115
5.6
Adverse Events that Occur after the Adverse 
Event Reporting Period........................................................ 116
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 116
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 117
6.1
Determination of Sample Size ............................................. 117
6.2
Summaries of Conduct of Study.......................................... 118
6.3
Summaries of Demographic and Baseline 
Characteristics..................................................................... 118
6.4
Efficacy Analyses ................................................................ 119
6.4.1
Primary Efficacy Endpoint.................................................... 119
6.4.2
Secondary Efficacy Endpoints............................................. 120
6.4.3
Exploratory Efficacy Endpoints............................................ 120
6.5
Safety Analyses................................................................... 120
6.6
Pharmacokinetic Analyses................................................... 122
6.7
Exploratory Biomarker Analysis........................................... 122

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6.8
Exploratory Patient-Reported Outcome Analyses ............... 123
6.9
Interim Analysis ................................................................... 123
6.9.1
Planned Interim Analysis ..................................................... 123
6.9.2
Optional Interim Analysis..................................................... 124
7.
DATA COLLECTION AND MANAGEMENT ............................................. 125
7.1
Data Quality Assurance....................................................... 125
7.2
Electronic Case Report Forms............................................. 125
7.3
Source Data Documentation................................................ 126
7.4
Use of Computerized Systems ............................................ 126
7.5
Retention of Records........................................................... 127
8.
ETHICAL CONSIDERATIONS.................................................................. 127
8.1
Compliance with Laws and Regulations .............................. 127
8.2
Informed Consent................................................................ 127
8.3
Institutional Review Board or Ethics Committee.................. 129
8.4
Confidentiality...................................................................... 129
8.5
Financial Disclosure ............................................................ 130
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 130
9.1
Study Documentation .......................................................... 130
9.2
Protocol Deviations.............................................................. 130
9.3
Management of Study Quality ............................................. 130
9.4
Site Inspections ................................................................... 131
9.5
Administrative Structure....................................................... 131
9.6
Publication of Data and Protection of Trade 
Secrets ................................................................................ 132
9.7
Protocol Amendments ......................................................... 132
10. REFERENCES ......................................................................................... 134

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LIST OF TABLES
Table 1
Summary of Efficacy Results from Studies NP28761 
and NP28673.............................................................................. 31
Table 2
Objectives and Corresponding Endpoints................................... 39
Table 3
Biomarkers for Exploratory Research ......................................... 43
Table 4
Doses and Suggested Infusion Times for Administration of 
Vinorelbine in Combination with Cisplatin or Carboplatin............ 57
Table 5
Doses and Suggested Infusion Times for Administration of
Gemcitabine in Combination with Cisplatin or Carboplatin ......... 58
Table 6
Doses and Suggested Infusion Times for Administration of 
Pemetrexed in Combination with Cisplatin or Carboplatin .......... 58
Table 7
Premedication for Pemetrexed Plus Platinum-Based 
Chemotherapy ............................................................................ 59
Table 8
Guidelines for Management of Risks, Adverse Events, and 
Selected Laboratory Abnormalities with Alectinib ....................... 95
Table 9
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................. 104
Table 10
Causal Attribution Guidance ..................................................... 105
LIST OF FIGURES
Figure 1
Primary Efficacy Endpoint:  Kaplan-Meier Plot of 
Investigator-Assessed Progression-Free Survival in 
ALURITT Population ............................................................... 33
Figure 2
Primary Efficacy Endpoint:  Kaplan-Meier Plot of 
Investigator-Assessed Progression-Free Survival in 
ALEXITT Population................................................................ 35
Figure 3
Study Schema............................................................................. 44
LIST OF APPENDICES
Appendix 1
Schedule of Activities:  Alectinib Arm........................................ 139
Appendix 2
Schedule of Activities:  Patients Randomized to 
Chemotherapy .......................................................................... 144
Appendix 3
Schedule of Pharmacokinetic Assessments for Patients 
Randomized to Alectinib ........................................................... 148
Appendix 4
Schedule of Biomarker Samples............................................... 149
Appendix 5
List of Substrates, Inhibitors, and Inducers of 
Drug-Metabolizing Enzymes and Transporters......................... 150

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Appendix 6
Eastern Cooperative Oncology Group Performance Status 
Scale......................................................................................... 151
Appendix 7
Formulae for the Calculation of QTcF and RR.......................... 152
Appendix 8
SF-36v2Health Survey........................................................... 153
Appendix 9
EuroQol 5-Dimension, 5-Level Questionnaire........................... 159

Alectinib—F. Hoffmann-La Roche Ltd
15/Protocol BO40336, Version 7
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE III, OPEN-LABEL, RANDOMIZED STUDY 
TO EVALUATE THE EFFICACY AND SAFETY OF 
ADJUVANT ALECTINIB VERSUS ADJUVANT 
PLATINUM-BASED CHEMOTHERAPY IN 
PATIENTS WITH COMPLETELY RESECTED 
STAGE Ib (TUMORS4 cm) TO STAGE IIIa 
ANAPLASTIC LYMPHOMA KINASEPOSITIVE 
NONSMALL-CELL LUNG CANCER
PROTOCOL NUMBER:
BO40336
VERSION NUMBER:
7
EUDRACT NUMBER:
2017-004331-37
IND NUMBER:
111,723
TEST PRODUCT:
Alectinib (RO5424802)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by your local study monitor.

Alectinib—F. Hoffmann-La Roche Ltd
16/Protocol BO40336, Version 7
PROTOCOL SYNOPSIS
TITLE:
A PHASE III, OPEN-LABEL, RANDOMIZED STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF ADJUVANT 
ALECTINIB VERSUS ADJUVANT PLATINUM-BASED 
CHEMOTHERAPY IN PATIENTS WITH COMPLETELY RESECTED 
STAGE Ib (TUMORS4 CM) TO STAGE IIIa ANAPLASTIC 
LYMPHOMA KINASEPOSITIVE NONSMALL-CELL LUNG 
CANCER
PROTOCOL NUMBER:
BO40336
VERSION NUMBER:
7
EUDRACT NUMBER:
2017-004331-37
IND NUMBER:
111,723
TEST PRODUCT:
Alectinib (RO5424802)
PHASE:
III
INDICATION:
Anaplastic Lymphoma KinasePositive NonSmall-Cell Lung Cancer
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the efficacy and safety of alectinib compared with platinum-based 
chemotherapy in patients with completely resected Stage Ib (tumors4 cm) to Stage IIIa, 
anaplastic lymphoma kinase (ALK)positive nonsmall-cell lung cancer (NSCLC).  Specific 
objectives and corresponding endpoints for the study are outlined below.
The primary and secondary efficacy objectives will be analyzed in the intent-to-treat (ITT) 
population of randomized patients with resected Stage Ib (tumors 4 cm) to Stage IIIa NSCLC
and in the subpopulation of patients with resected Stage IIIIIa NSCLC.
Disease-free survival (DFS) as an endpoint does not distinguish between the location of the first 
documented recurrence of disease or new primary NSCLC.  Descriptive statistics 
(i.e., frequencies and percentages) will be used to explore the first site of recurrence of disease 
or new primary NSCLC.
Primary Efficacy Objective
Corresponding Endpoint
To evaluate the efficacy of alectinib 
compared with platinum-based 
chemotherapy in patients with completely 
resected Stage Ib (tumors 4 cm) to 
Stage IIIa, ALK-positive NSCLC
DFS, defined as the time from randomization to the 
first documented recurrence of disease or new 
primary NSCLCas determined by the investigator 
through use of an integrated assessment of 
radiographic data, biopsy sample results (if clinically 
feasible), and clinical statusor death from any 
cause, whichever occurs first
Secondary Efficacy Objective
Corresponding Endpoint
To evaluate the efficacy of alectinib 
compared with platinum-based 
chemotherapy in patients with completely 
resected Stage Ib (tumors 4 cm) to 
Stage IIIa, ALK-positive NSCLC
OS, defined as the time from randomization to death 
from any cause

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Exploratory Efficacy Objectives
Corresponding Endpoints
To evaluate DFS rates for patients in the
alectinib arm compared with patients in 
the platinum-based chemotherapy arm
DFS rates at landmark timepoints of 3, 4, and 
5 years
To evaluate the effects of demographics 
and baseline prognostic characteristics 
on duration of DFS for patients in the
alectinib arm compared with patients in 
the platinum-based chemotherapy arm
Effects of demographics (e.g., age, sex, and 
race/ethnicity) and baseline prognostic 
characteristics (e.g., disease stage, smoking 
history, and ECOG Performance Status) on 
duration of DFS by subgroup analyses
To evaluate the location of the first 
documented recurrence of disease or 
new primary NSCLC for patients in the
alectinib arm compared with patients in 
the platinum-based chemotherapy arm
The location of the first documented recurrence of 
disease or new primary NSCLC
Safety Objective
Corresponding Endpoints
To evaluate the safety and tolerability of 
alectinib compared with platinum-based 
chemotherapy in patients with 
completely resected Stage Ib 
(tumors 4 cm) to Stage IIIa, 
ALK-positive NSCLC
Incidence of adverse events, with severity 
determined through use of NCI CTCAE v5.0

Safety laboratory values

Vital signs

ECG
Pharmacokinetic Objectives
(Alectinib Arm Only)
Corresponding Endpoint
To characterize the pharmacokinetics of 
alectinib and its major metabolite(s) in 
patients with completely resected 
Stage Ib (tumors 4 cm) to Stage IIIa, 
ALK-positive NSCLC
At Japanese sites only:  
To characterize the pharmacokinetics of 
alectinib and its major metabolite(s) in 
Japanese patients

Plasma concentrations of alectinib and its 
major metabolite(s) at specified timepoints
Exploratory Biomarker Objective
Corresponding Endpoint
To investigate molecular mechanisms of 
resistance to alectinib in patients with 
completely resected Stage Ib 
(tumors 4 cm) to Stage III, 
ALK-positive NSCLC

Relationship between biomarkers in blood 
and tumor tissue and efficacy (DFS)
Exploratory Patient-Reported Outcome 
Objectives
Corresponding Endpoints
To document the impact of alectinib 
compared with platinum-based 
chemotherapy on patients' quality of life 
and daily function
To document health utilities for 
pharmacoeconomic modeling

Mean change from baseline in PCS, MCS, 
and the PF scale as measured by their 
corresponding scores of the SF-36v2

Health utilities as evaluated through the 
EQ-5D-5L
ALK anaplastic lymphoma kinase; DFS disease-free survival; ECOG Eastern Cooperative 
Oncology Group; MCS mental component summary; NCI CTCAE National Cancer Institute 
Common Terminology Criteria for Adverse Events; NSCLC nonsmall-cell lung cancer; 
OS overall survival; PCS physical component summary; PF physical function.

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Study Design
Description of Study
This randomized, active-controlled, multicenter, open-label, Phase III study is designed to 
investigate the efficacy and safety of alectinib compared with platinum-based chemotherapy in 
the adjuvant setting.  The primary endpoint of the study is DFS as assessed by investigator, 
while OS is a secondary endpoint.
This study will comprise approximately 200 centers in around 30 countries worldwide.  
Central randomization will be performed via an interactive voice or Web-based response system 
(IxRS).  Randomized patients will be stratified by extent of disease (Stage Ib [tumors 4 cm] vs. 
Stage II vs. Stage IIIa) and ethnicity (Asian vs. non-Asian).  Relevant instruction will be provided 
to each study site by the IxRS provider.
Patients with completely resected (negative margins), histologically-confirmed Stage Ib
(tumors 4 cm) to Stage IIIa NSCLC as per the Union Internationale Contre le Cancer 
(UICC)/American Joint Committee on Cancer (AJCC) 7th edition with documented ALK-positive 
disease as assessed by a U.S. Food and Drug Administration (FDA)-approved and Conformité 
Européenne (CE)-marked test and meeting all required eligibility criteria, will be randomized in a 
1:1 fashion.
Staging must occur in accordance with the UICC/AJCC 7th edition and not the 8th edition.  
Patients with Stage Ib NSCLC with tumors4 cm per the 7th edition classification have been 
shown to experience more modest benefit from adjuvant chemotherapy treatment than patients 
with Stage IIIIIa NSCLC, and this has been taken into consideration for recruitment capping, 
stratification, and statistical analysis of the primary endpoint.
Patients in the experimental arm will receive alectinib at 600 mg orally twice a day (BID) taken 
with food for 24 months.
Patients in the control arm will receive one of the protocol-specified platinum-based 
chemotherapy regimens (including all required premedications and permitted concomitant 
medications) according to the local prescribing information.  Protocol-defined platinum-based 
chemotherapy regimens include:

Cisplatin 75 mg/m2 on Day 1 plus vinorelbine 25 mg/m2 on Days 1 and 8

Cisplatin 75 mg/m2 on Day 1 plus gemcitabine 1250 mg/m2 on Days 1 and 8

Cisplatin 75 mg/m2 on Day 1 plus pemetrexed 500 mg/m2 on Day 1
Platinum-based chemotherapy will be provided for 4 cycles, with each cycle lasting 21 days.  
In case of intolerability to a cisplatin-based regimen, carboplatin can be administered instead of 
cisplatin in one of the above combinations.
Post-operative radiation therapy (PORT) is not allowed as a treatment option.  
Therefore, patients with Stage IIIa N2 NSCLC who, in the investigator's opinion, should receive 
PORT, are excluded from the study.
Study drug (alectinib or platinum-based chemotherapy) will be administered until completion of 
treatment period (24 months for alectinib and 4 cycles for chemotherapy), recurrence of 
disease, unacceptable toxicity, withdrawal of consent, or death, whichever occurs first.  Patients
who complete a study treatment regimen or discontinue treatment prior to disease recurrence 
(e.g., due to unacceptable toxicity) will continue to be followed until disease recurrence.  
After disease recurrence, patients will be treated at the discretion of the investigator according 
to local clinical practice.  No crossover in the adjuvant setting will be allowed between the 
2 arms.
Approximately 255 patients will be enrolled into the study over a planned competitive 
recruitment period of approximately 38 months.  Patients inappropriately randomized into the 
study will not be replaced.  The primary DFS analysis will be conducted after approximately 
89 DFS events in the Stage IIIIIa subpopulation have been observed.  This is expected to 
occur approximately 60 months after the first patient is randomized.  Data collection will 
continue for each patient until death or study closure, whichever occurs first.
An independent Data Monitoring Committee (iDMC) will be established to monitor the progress 
of the study and ensure that the safety of patients enrolled in the study is not compromised.

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All randomized patients will undergo regular, scheduled visits until disease recurrence, death, 
withdrawal from the study, or study termination, whichever occurs first.  Regular safety 
assessments will be performed for both arms during treatment.  The safety follow-up visit will be 
performed 28 days after last dose of alectinib or 28 days after the end of the last cycle of
platinum-based chemotherapy.  For the first 12 weeks (3 months), regular safety assessment 
visits will be scheduled at baseline and every 3 weeks (i.e., 1 chemotherapy cycle) for both 
arms.  Additional visits will be scheduled for patients in the alectinib arm at Weeks 2, 4, 8, and 
10 to allow for more frequent CPK and liver function assessments.  Phone calls for safety 
monitoring of patients in the chemotherapy arm will be performed at the same timepoints 
(Weeks 2, 4, 8, and 10).  From Week 12, patients in the alectinib arm will continue to be 
monitored for safety until treatment discontinuation every 6 weeks until Week 48 and every 
12 weeks from Week 4996.  Scheduled disease assessments will be performed for both arms 
at baseline, every 12 weeks for the first 2 years, every 24 weeks during Years 35, and 
annually thereafter until disease recurrence, death, loss to follow-up, consent withdrawal, or 
study termination by the Sponsor, whichever occurs first.  If clinically indicated, unscheduled 
assessments can be performed at any time.  Positive efficacy results at an interim analysis will 
not influence the timing of disease assessments during the study.
For all patients, plasma samples for exploratory biomarker research will be obtained at baseline, 
every 3 weeks for the first 12 weeks, every 12 weeks from Weeks 1396, every 24 weeks
during years 35, and annually thereafter until disease recurrence.  Tumor samples will be 
obtained at study entry and upon disease recurrence for biomarker analysis. 
Plasma samples will also be obtained for patients randomized to the alectinib arm pre-dose at 
baseline, every 3 weeks for the first 12 weeks, and every 12 weeks until Week 96 for 
pharmacokinetic (PK) analysis.  At participating Japanese sites that can perform serial/intensive 
PK sampling, serial/intensive PK samples will be collected from a subset of Japanese patients 
receiving alectinib (approximately the first 6 patients who consent to participate to the 
serial/intensive PK sample collection) to facilitate the PK assessment in this population.  
The option to participate in the intensive Japanese PK profiling will be offered to these patients 
until at least 6 evaluable patients, as per protocol, have provided a reliable and complete PK 
profile.  Therefore, more than 6 patients may participate in the serial/intensive PK assessment.  
However, the study team will make all efforts to provide complete profiles to the sites within the 
shortest timeframe.
Number of Patients
Approximately 255 patients are expected to enroll in this study in approximately 200 sites 
globally.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 18 at time of signing Informed Consent Form

Complete resection of histologically-confirmed Stage Ib (tumor4 cm) to Stage IIIa
(T23 N0, T13 N1, T13 N2, T4 N01) NSCLC as per UICC/AJCC, 7th edition, with 
negative margins, at 412 weeks before enrollment
Accepted types of resection include any of the following:  lobectomy, sleeve 
lobectomy, bilobectomy, or pneumonectomy.
Resection by segmentectomy or wedge resection is not allowed.
N3 disease is not allowed.

If mediastinoscopy was not performed preoperatively, it is expected that, at a minimum, 
mediastinal lymph node systematic sampling will have occurred
Systematic sampling is defined as removal of at least 1 representative lymph node at 
specified levels.
Complete mediastinal lymph node dissection (MLND) is preferred.  Mediastinal lymph 
node dissection entails resection of all lymph nodes at those same levels.

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For patients who have undergone a right thoracotomy, sampling or MLND is required 
at Levels 4 and 7; for those who have undergone a left thoracotomy, sampling or 
MLND is required at Levels 5 and/or 6 and 7.
Exceptions will be granted for the following situations:
If patients have documented N2 disease in 1 level (per the UICC/AJCC staging 
system, 7th edition), not all levels need to be sampled.
If the preoperative staging imaging results (contrast computed tomography [CT] and 
positron emission tomography [PET] scans) do not suggest evidence of disease in the 
mediastinum, the patient may be considered eligible even if N2 nodal sampling was 
not performed per surgeon’s decision.

Documented ALK-positive disease according to an FDA-approved and CE-marked test

Eligible to receive a platinum-based chemotherapy regimen according to the local labels or 
guidelines

Eastern Cooperative Oncology Group (ECOG) Performance Status of Grade 0 or 1

Adequate hematologic function, defined by the following laboratory test results, obtained 
within 3 days prior to initiation of study treatment:
Platelet count100109/L
ANC1500/L
Hemoglobin9 g/dL

Adequate renal function, defined by the following laboratory test results, obtained within 
3 days prior to initiation of study treatment:
Serum creatinine 1.5upper limit of normal (ULN) and
Creatinine clearance (CrCl) 60 mL/min

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods with a failure rate of 1% per year 
during the treatment period and for at least 90 days after the last dose of alectinib or 
according to local labels or guidelines for chemotherapy
A woman is considered to be of childbearing potential if she is post-menarchal, has 
not reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and is not permanently infertile due to 
surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as 
determined by the investigator (e.g., Müllerian agenesis).
Examples of contraceptive methods with a failure rate of 1% per year include bilateral 
tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, and copper intrauterine devices.  
Hormonal contraceptive methods must be supplemented by a barrier method.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception.
Women of childbearing potential must have a negative serum pregnancy test result 
prior to randomization (maximum of 3 days) and within 10 days of the first dose of 
study drug.  First dose of study drug (alectinib or chemotherapy) must be administered 
within 7 days from randomization.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, and agreement to refrain from donating sperm, as defined below:
With female partners of childbearing potential, men must remain abstinent or use a 
condom plus an additional contraceptive method that together result in a failure rate of 
1% per year during the treatment period and for at least 90 days after the last dose of 
alectinib or according to local labels or guidelines for chemotherapy.  Men must refrain 
from donating sperm during this same period.

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With pregnant female partners, men must remain abstinent or use a condom during 
the treatment period and for at least 90 days after the last dose of alectinib or 
according to local labels or guidelines for chemotherapy to avoid exposing the embryo.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception.

Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, 
and other study procedures
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Pregnant or breastfeeding, or intending to become pregnant during the study or within 
90 days after the last dose of alectinib or according to local labels or guidelines for 
chemotherapy

Prior adjuvant radiotherapy for NSCLC
Radiotherapy in the neo-adjuvant setting is allowed and must be completed at least 
4 weeks prior to initiation of study treatment.

Prior exposure to systemic anti-cancer therapy
Anti-cancer therapy for an early stage of malignancy with curative intent, provided
that the last dose received was more than 5 years prior to enrollment, may be allowed.
The Medical Monitor could be consulted.

Prior exposure to ALK inhibitors

Stage IIIa N2 patients that, in the investigator's opinion, should receive PORT are excluded 
from the study
Post-operative radiation therapy is not allowed in the study.

Known sensitivity to any component of study drug (alectinib or planned chemotherapy) to 
which the patient may be randomized
This includes, but is not limited to, patients with galactose intolerance, a congenital 
lactase deficiency, or glucose-galactose malabsorption.

Malignancies other than NSCLC within 5 years prior to enrollment, except for curatively 
treated basal cell carcinoma of the skin, early gastrointestinal (GI) cancer by endoscopic 
resection, in situ carcinoma of the cervix, ductal carcinoma in situ, papillary thyroid cancer, 
or any cured cancer that is considered to have no impact on DFS or OS for the current 
NSCLC

Any GI disorder that may affect absorption of oral medications, such as malabsorption 
syndrome or status postmajor bowel resection

Liver disease characterized by any of the following:
ALT and AST 3ULN
or
Impaired excretory function or synthetic function or other conditions of decompensated liver 
disease such as coagulopathy, hepatic encephalopathy, hypoalbuminemia, ascites, or 
bleeding from esophageal varices
or
Active viral or active autoimmune, alcoholic, or other types of acute hepatitis.
Active viral hepatitis B is defined as having positive hepatitis B surface antigen 
(HBsAg). 
Patients with past hepatitis B virus (HBV) infection or resolved HBV infection 
(hepatitis B core antibody [HBcAb] – HbcAb-positive, but negative HBsAg) are eligible 
only if the HBV DNA test is negative.

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Patients positive for hepatitis C virus (HCV) antibody are eligible only if PCR is 
negative for HCV RNA.

Japanese patients participating in the serial/intensive PK sample collection only:
administration of strong/potent CYP450 3A inhibitors or inducers within 14 days prior to the 
first dose of study treatment and while on treatment with alectinib up to Week 3

Any exclusion criteria based on local labels or guidelines for chemotherapy

Patients with symptomatic bradycardia

History of organ transplant

Known HIV positivity or AIDS-related illness

Any clinically significant concomitant disease or condition that could interfere withor for 
which the treatment might interfere withthe conduct of the study or the absorption of oral 
medications or that would pose an unacceptable risk to the patients in this study, in the 
opinion of the Principal Investigator

Any psychological, familial, sociological, or geographical condition potentially hampering 
compliance with the study protocol requirements and/or follow-up procedures; those 
conditions should be discussed with the patient before trial entry.
End of Study
This study is event-driven with a recruitment period of approximately 3 years.  The required 
number of events for the primary analysis of the primary endpoint is expected to occur 
approximately 60 months after the first patient has been enrolled. Patients are to be treated 
until completion of the treatment period (24 months for alectinib and 4 cycles [21-day cycles] of 
platinum-based chemotherapy), recurrence of disease, unacceptable toxicity, withdrawal of 
consent, or death, whichever occurs first.
Length of Study
The final survival follow-up analysis will be conducted at approximately 5 years after the 
last patient is enrolled.  The study will formally end once the final survival follow-up analysis 
has been completed.
Investigational Medicinal Products
The investigational medicinal products (IMPs) for this study are alectinib and platinum-based 
chemotherapies.
Test Product (Investigational Drug)
Alectinib 600 mg (four 150-mg capsules) should be administered orally BID with food in the 
morning and evening.  First dose of study drug should be administered as soon as possible 
after randomization and no later than 7 days after randomization.  Treatment will continue until 
completion of treatment period (24 months), disease recurrence, unacceptable toxicity, 
withdrawal of consent, or death, whichever occurs first.
If a planned dose of alectinib is missed, patients can make up that dose unless the next dose is 
due within 6 hours.  If vomiting occurs after taking a dose of alectinib, patients should take the 
next dose at the scheduled time.  Patients should not take two doses at the same time to make 
up for a missed dose.
The patient will record their daily dose and time in a diary (Patient Dosing Diary).
Comparator
Platinum-based chemotherapy will be provided for 4 cycles, with each cycle lasting 21 days.  
Investigators can choose one of the permitted platinum-based chemotherapy regimens, which 
include the following:

Cisplatin 75 mg/m2 on Day 1 plus vinorelbine 25 mg/m2 on Days 1 and 8

Cisplatin 75 mg/m2 on Day 1 plus gemcitabine 1250 mg/m2 on Days 1 and 8

Cisplatin 75 mg/m2 on Day 1 plus pemetrexed 500 mg/m2 on Day 1

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First dose of study drug should be administered as soon as possible after randomization, taking 
required premedication into account, and no later than 7 days after randomization.  
Treatment will continue until completion of treatment period (4 cycles), recurrence of disease, 
unacceptable toxicity, withdrawal of consent, or death, whichever occurs first.
Institutions should follow their standard administration regiments (e.g., administration sequence 
or time) for the chemotherapy treatment.  Patients must receive adequate premeditations, 
anti-emetic treatments, and IV hydration for platinum-based treatments according to the local 
standard of care and prescribing information.
Platinum-based chemotherapy cycles may be delayed for safety reasons; however, if 
interrupted for more than 21 days 1 cycle), the cycle is considered a skipped cycle.  This does 
not prevent investigator from completing 4 cycles.
The selected cisplatin-based chemotherapy regimen should remain the same for all cycles.  
For patients who experience unacceptable toxicity with cisplatin, carboplatin can be used.  The 
investigator should inform the Medical Monitor of the switch from a cisplatin-based regimen 
to a carboplatin-based regimen.
Statistical Methods
Primary Analysis
The primary and secondary efficacy analyses will be performed for all randomized patients 
(ITT population) and for the Stage IIIIIa subpopulation.  The same analysis methods will be 
applied for both the ITT population and the Stage IIIIIa subpopulation.
Safety analyses will be performed on all randomized patients who received at least 1 dose of 
study medication.
Determination of Sample Size
Approximately 255 patients are expected to be randomized into the study.  The number of 
Stage Ib patients will be capped at 25% to ensure that at least 75% of all randomized patients 
will have Stage IIIIIa disease.  The resulting ITT population of all patients randomized will 
include a minimum of 191 patients in the Stage IIIIIa subpopulation.
Recruitment is assumed to happen at a rate of 0.034 patients per site per month, with a total of 
approximately 200 sites.  Detailed recruitment is as follows:

Months 12:  1 patient per month

Month 3:  2 patients per month

Month 4:  3 patients per month

Months 56:  4 patients per month

Months 79:  5 patients per month

Months 1012:  7 patients per month

Month 13 onwards:  8 patients per month
Based on these assumptions, enrollment will take approximately 38 months to complete.
The sample size and the number of events required to demonstrate efficacy with regard to the 
primary efficacy endpoint DFS at the primary analysis are based on the following assumptions:

Overall 2-sided significance level of 0.05 in the Stage IIIIIa subpopulation and the 
ITT population

80% power to detect a hazard ratio (HR)0.55, corresponding to an improvement in 
median DFS from 3055 months for patients receiving alectinib compared with 
chemotherapy in the Stage IIIIIa subpopulation

80% power to detect an HR 0.58 corresponding to an improvement in median DFS from 
3662 months for patients receiving alectinib compared with chemotherapy in the ITT 
population

One interim analysis for DFS when approximately 67% of the total DFS events have 
occurred, with use of the Lan-DeMets approximation to the O'Brien-Fleming boundaries

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Based on these assumptions, the primary DFS analysis will be conducted after approximately 
89 DFS events in the Stage IIIIIa subpopulation have been observed.  This is predicted to 
occur approximately 60 months (5 years) after the first patient is randomized.
The focus of this clinical trial is hypothesis testing, testing superiority of alectinib compared with 
chemotherapy with respect to DFS.  To control the overall level of significance at a 2-sided error 
rate of 0.05, comparisons with respect to DFS between the alectinib and chemotherapy arms 
within the Stage IIIIIa subpopulation and the ITT population will be conducted hierarchically as 
follows:

Disease-free survival (DFS) in the Stage IIIIIa subpopulation will be first tested at an 
overall 2-sided -level of 0.05.  If the 2-sided p-value corresponding to the stratified log-rank 
test is less than 0.0464 at the primary analysis (in order to adjust for 1 interim analysis for 
efficacy), the null hypothesis will be rejected, and it will be concluded that alectinib prolongs 
duration of DFS relative to chemotherapy in the Stage IIIIIa subpopulation.  
Stopping boundaries will be adjusted depending on the actual number of DFS events.

If alectinib significantly prolongs DFS in the Stage IIIIIa subpopulation, then DFS in the 
ITT population will be tested at an overall 2-sided -level of 0.05.  If the 2-sided p-value 
corresponding to the stratified log-rank test is less than 0.0463 at the primary analysis 
(in order to adjust for 1 interim analysis for efficacy), the null hypothesis will be rejected, and 
it will be concluded that alectinib prolongs duration of DFS relative to chemotherapy in the 
ITT population.  Stopping boundaries will be adjusted depending on the actual number of 
DFS events.
If alectinib has no significant effect on DFS in the Stage IIIIIa subpopulation, then DFS in the 
ITT population will not be tested.
Interim Analyses
There is 1 interim analysis for efficacy planned in the study for DFS.  The interim analysis will be 
conducted after approximately 67% of events have been observed in the 
Stage IIIIIa subpopulation.  Based on the assumptions described in the protocol, this relates to 
approximately 59 DFS events for the Stage IIIIIa subpopulation.  This is predicted to occur 
approximately 44 months after the first patient is randomized (i.e., approximately 16 months 
before the primary analysis), although the exact timing of this analysis will depend on the actual 
number of DFS events in the Stage IIIIIa subpopulation, but irrespective of the number of DFS 
events observed in the ITT population.
To control the type I error, the stopping boundaries for the DFS interim and primary analyses 
are to be computed with use of the Lan-DeMets approximation to the O'Brien-Fleming 
boundaries.  In the Stage IIIIIa subpopulation, the stopping boundary for early rejection of the 
null hypothesis for an overall 2-sided 5% significance level is HR 0.52 (p 0.0118).  In the 
ITT population, the stopping boundary for early rejection of the null hypothesis for an overall 
2-sided 5% significance level is HR 0.55 (p 0.0121).  If less than 67% of DFS events in the 
ITT population have been observed at the time of reaching the required events for the interim 
analysis in the Stage IIIIIa subpopulation, the stopping boundaries will be adjusted depending 
on the actual number of DFS events observed in the ITT population.  However, the ITT interim 
analysis would only take place in the case of early rejection of the null hypothesis in the
Stage IIIIIa subpopulation.
An external iDMC will evaluate safety data on an ongoing basis and review the data from the 
interim analysis.  All summaries and analyses by treatment arm for the iDMC's review will be 
prepared by an external independent data coordinating center.  Members of the iDMC will be 
external to the Sponsor and will follow a charter that outlines their roles and responsibilities.  
Any outcomes of these reviews that affect study conduct will be communicated in a timely 
manner to the investigators for notification of the Institutional Review Board (IRB)/Ethics 
Committee (EC).  A detailed plan will be included in the iDMC Charter.
Positive efficacy results at the interim analysis will not change the conduct of the study and 
timing of disease assessments.

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AJCC
American Joint Committee on Cancer
ALK
anaplastic lymphoma kinase
ARDS
acute respiratory distress syndrome
AUC
area under the concentrationtime curve
BID
twice a day
BICR
blinded independent central review
Cmax
maximum observed concentration
CE
Conformité Européenne (European Conformity)
COVID-19
coronavirus disease 2019
CrCl
creatinine clearance
CT
computed tomography (scan)
DAT
direct anti-globulin test
DFS
disease-free survival
DLT
dose-limiting toxicity
EC
Ethics Committee
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
EGFR
epidermal growth factor receptor
ESMO
European Society for Medical Oncology
EU-SmPC
Summary of Product Characteristics (European Union)
FDA
U.S. Food and Drug Administration
GFR
glomerular filtration rate
GGT
gamma-glutamyl transferase
GI
gastrointestinal
HBV
hepatitis B virus
HCV
hepatitis C virus
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HIPAA
Health Insurance Portability and Accountability Act
HR
hazard ratio
HRQoL
health-related quality of life
HUS
hemolytic-uremic syndrome
ICH
International Council on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use

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Abbreviation
Definition
iDMC
independent Data Monitoring Committee
IHC
immunohistochemistry
ILD
interstitial lung disease
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
IRC
Independent Review Committee
IRF
Independent Review Facility
ITT
intent-to-treat (population)
IxRS
interactive voice or Web-based response system
KRAS
Kirsten rat sarcoma viral oncogene homolog
LACE
Lung Adjuvant Cisplatin Evaluation
MCS
mental component summary
MET
mesenchymal-epithelial transition factor
MLND
mediastinal lymph node dissection
MN
mobile nursing
MRI
magnetic resonance imaging
NCCN
National Comprehensive Cancer Network
NCI CTCAE
National Cancer Institute Common Terminology Criteria for 
Adverse Events
NGS
next-generation sequencing
NSAID
nonsteroidal anti-inflammatory drug
NSCLC
nonsmall-cell lung cancer
ORR
objective response rate
OS
overall survival
PCS
physical component summary
PET
positron emission tomography (scan)
P-gp
P-glycoprotein
PFS
progression-free survival
PK
pharmacokinetic
PORT
post-operative radiotherapy treatment
PRES
posterior reversible encephalopathy syndrome
PRO
patient-reported outcome
QTcF
QT interval corrected with use of Fridericia’s formula
RBR
Research Biosample Repository
RP2D
recommended Phase II dose
SAP
Statistical Analysis Plan

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Abbreviation
Definition
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SDF
survival distribution function
SLS
sodium lauryl sulfate
UK-SmPC
Summary of Product Characteristics (United Kingdom)
TKI
tyrosine kinase inhibitor
tmax
time to maximum observed concentration
UICC
Union Internationale Contre le Cancer
ULN
upper limit of normal
USPI
United States Prescribing Information
WES
whole-exome sequencing
WGS
whole-genome sequencing

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1.
BACKGROUND
1.1
BACKGROUND ON ANAPLASTIC LYMPHOMA 
KINASE-POSITIVE NONSMALL-CELL LUNG CANCER
Cancer is a major cause of death worldwide and was responsible for 8.8 million deaths 
in 2015 according to the World Health Organization (WHO 2017), with nonsmall-cell 
lung cancer (NSCLC) being the leading cause of cancer-related mortality worldwide.
The highest estimated age-standardized incidence rates of NSCLC in men are reported 
in Central and Eastern Europe as 53.5 per 100,000 and in Eastern Asia as 50.4 per 
100,000. In women, the incidence rates are generally lower, with the highest estimated 
rates in Northern America (33.8 per 100,000), Northern Europe (23.7 per 100,000), and 
Eastern Asia (19.2 per 100,000; GLOBOCAN 2012).
Survival rates for lung cancer tend to be lower than other common cancers because of 
its late diagnosis and limited availability of effective treatments. Around 60% of patients 
diagnosed with NSCLC already have advanced (Stage IIIb) or metastatic (Stage IV) 
disease, whereas approximately 30% are diagnosed with early-stage disease 
(Stage I or II) and approximately 10% with Stage IIIa. The 5-year survival rate for 
advanced and metastatic disease is very poor with the reported range between 1%5%. 
For early stages, the 5-year survival rates are reported to be higher, ranging between 
14%70%, depending on the extent of the disease at diagnosis and available treatment 
options (Ravdin and Davis 2006; American Cancer Society [ACS] 2016; 
Cancer Research UK 2017).
Conventional anti-cancer therapies are far from satisfactory, and there is an unmet 
medical need for the development of new therapies for NSCLC. Progress in the 
identification of genetic mutations or chromosomal rearrangements in epidermal growth 
factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), 
mesenchymal-epithelial transition (MET) factor, and other genes has provided new 
opportunities to use targeted therapeutic agents for the treatment of advanced and 
metastatic NSCLC, when the tumor is identified as having these mutations 
(Katayama et al. 2011; Doebele et al. 2012).
Approximately 4%5% of NSCLC cases have been shown to harbor the echinoderm
microtubule-associated protein-like 4 anaplastic lymphoma kinase (ALK) fusion gene as 
a result of a chromosomal inversion at 2p21 and 2p23 (Choi et al. 2010; Ou et al. 2012; 
Paik et al. 2012; Blackhall et al. 2014).
In the advanced and metastatic setting, there are currently 4 approved treatments for 
patients with ALK-positive NSCLC that have been shown to provide clinical benefit and 
favorable tolerability compared with the previously used standard of care, 
platinumbased chemotherapy for patients with ALK-positive NSCLC.

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Crizotinib (Xalkori; Pfizer, Inc.) was the first ALK inhibitor approved and registered for 
the treatment of advanced and metastatic ALK-positive NSCLC (Sahu et al. 2013;
Shaw et al. 2013). Crizotinib was granted approval for first-line treatment of patients 
with ALK-positive NSCLC with advanced or metastatic disease based on the results of 
the Phase III PROFILE 1014 study, which showed a significantly longer progression-free 
survival (PFS) for patients treated with crizotinib as compared with platinum-based 
chemotherapy (median PFS: 10.9 months vs. 7.0 months) in patients with previously 
untreated ALK-positive NSCLC. Since then, second-generation ALK inhibitors like 
alectinib, ceritinib, and brigatinib have been granted marketing authorization as first- or 
second-line treatment for advanced and metastatic ALK-positive NSCLC.
Despite advancements in the use of targeted therapies in advanced and metastatic 
NSCLC, none of the currently available targeted treatments have been approved in the 
adjuvant setting. For patients diagnosed with early-stage NSCLC (Stages IIIIa), 
complete resection of the tumor is the preferred treatment option. For patients with 
resected Stage Ib (tumors 4 cm) to IIIa, adjuvant therapy has been shown to be of 
benefit following complete resection (Pignon et al. 2008).  In this setting, the current 
standard of care is platinum-based chemotherapy according to the 
National Comprehensive Cancer Network (NCCN 2017) and European Society for 
Medical Oncology (ESMO) guidelines (Postmus et al. 2017).
1.2
BACKGROUND ON ALECTINIB
Alectinib (also referred to as RO5424802 or CH5424802) is a small-molecule, highly
selective and potent oral next-generation ALK inhibitor with a benzo[b]carbazole
scaffold.
The clinical development program for alectinib to date includes 2 single-arm Phase I/II 
studies in patients with advanced or metastatic ALK-positive NSCLC who have failed 
crizotinib treatment:  Study NP28761/AF-002JG (hereafter referred to as 
Study NP28761), which was conducted in United States and Canada, and
Study NP28673, which was conducted globally.
The clinical development program also includes the following randomized Phase III 
studies. The ALUR study (Study MO29750) was conducted globally and compares
alectinib head-to-head with chemotherapy in patients who have failed both 
platinum-based chemotherapy and crizotinib treatment. In addition, 3 studies are being 
conducted to compare alectinib head-to-head with crizotinib in treatment-naive patients 
with advanced or metastatic disease: 1) the ALEX study (Study BO28984), being 
conducted globally, 2) the J-ALEX study, being conducted in Japan, and 3) the 
ALESIA study, being conducted in China.
1.2.1
Study NP28761
Study NP28761 was a multicenter, open-label, 2-part study of alectinib in patients with 
Stage IIIbIV, ALK-positive NSCLC who had progressed on crizotinib therapy.  A total of 

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134 patients were enrolled in the study, including 47 patients in the Phase I 
dose-escalation portion and 87 patients in the Phase II portion.  In Phase I, alectinib 
administered at 600 mg twice a day (BID) was chosen as the recommended 
Phase II dose (RP2D) on the basis of safety, tolerability, pharmacokinetic (PK), and 
efficacy data (Gadgeel et al. 2014).
The study met its primary objective of demonstrating a clinically meaningful and 
statistically significant Independent Review Committee (IRC)-assessed objective 
response rate (ORR).  The results of other secondary endpoints were supportive of the 
primary analyses, including investigator-assessed ORR (Shaw et al. 2016).
1.2.2
Study NP28673
Study NP28673 was a multicenter, open-label study of alectinib in patients with NSCLC 
who had progressed on crizotinib therapy.  During the conduct of Part 1 (Phase I) of this 
study, the RP2D was confirmed to be 600 mg BID in Study NP28761.  Therefore, Part 1 
was not concluded, and patients enrolled in Part 1 were merged into Part 2 (Phase II).
A total of 138 patients with Stage IIIbIV, ALK-positive NSCLC were enrolled in the 
Phase II part of the study.
The study met its primary objective of demonstrating a clinically meaningful and 
statistically significant ORR based on IRC assessments.  The co-primary objective of 
IRC-assessed ORR in the subgroup of chemotherapy-pretreated patients, although not 
met, was clinically meaningful.  The results of other secondary endpoints were 
supportive of the primary analyses, including investigator-assessed ORR
(Ou et al. 2016).
Updated safety and efficacy data were generated using a data cutoff date of 
22 January 2016 for Study NP28761 and 1 February 2016 for Study NP28673 and 
confirmed the results from the primary analysis for all endpoints (see Table 1).
In the pooled safety data analysis from Studies NP28761 and NP28673, almost all 
patients (98.8%) reported at least 1 adverse event. Adverse events occurring with an 
incidence of 20% of patients were constipation (36%), fatigue (32%), peripheral edema 
(29%), myalgia (25%), nausea (22%), and cough (21%). There were 100 of 253 patients 
(39.5%) with at least 1 adverse event Grade 3. The following Grade 3 events were 
reported in 2% of the patients: increased blood CPK (4%), dyspnea (4%), increased 
ALT (3%), increased AST (3%), hypertriglyceridemia (2%), and anemia (2%).
For additional details, refer to the Alectinib Investigator's Brochure.

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Table 1
Summary of Efficacy Results from Studies NP28761 and NP28673
Endpoint
Study
(Cutoff Date)
NP28761
Phase II
(22 January 2016)
NP28673
Phase II
(1 February 2016)
ORR (IRC) in RE population
N67 a
N122 a
No. responders (%)
35 (52.2%)
62 (50.8%)
95% CI b
(39.7%, 64.6%)
(41.6%, 59.9%)
ORR (Investigator) in RE population
N87
N138
No. responders (%)
46 (52.9%)
71 (51.4%)
95% CI b
(41.9%, 63.7%)
(42.8%, 60.0%)
C-ORR (IRC) in patients with 
measurable CNS lesions at baseline 
based on RECIST
N16
N34
No. responders (%)
12 (75.0%)
20 (58.8%)
95% CI
(47.6%, 92.7%)
(40.7%, 75.4%)
PFS (IRC)
N87
N138
Median, months
8.2
8.9
95% CI
(6.3, 12.6)
(5.6, 12.8)
C-ORRCNS objective response rate; IRCIndependent Review Committee; ORRobjective 
response rate; PFSprogression-free survival; REresponse evaluable; RECIST Response 
Evaluation Criteria in Solid Tumors.
a There were 20 patients (Study NP28761) and 16 patients (Study NP28673) who did not have 
measurable disease at baseline according to the IRC and therefore, were not included in the 
IRC RE population.
b Equivalent to a test of the null hypothesis that the ORR was equal to 35% vs. the alternative 
hypothesis that the ORR was not equal to 35% (lower boundary of CI35%), using an exact 
Clopper-Pearson CI.
1.2.3
Study MO29750 (ALUR)
Study MO29750 (ALUR) was a randomized, multicenter, open-label, Phase III study of 
alectinib versus standard chemotherapy (pemetrexed or docetaxel) in patients with 
advanced, recurrent, or metastatic ALK-positive Stage IIIbIV NSCLC previously treated 
with platinum-based chemotherapy and crizotinib.  At the time of the primary analysis of 
ALUR (data cutoff:  26 January 2017), 107 patients had been randomized, 72 patients to 
alectinib and 35 patients to chemotherapy (2:1 randomization).
The ALUR study met its primary endpoint of demonstrating a statistically significant and 
clinically meaningful improvement in investigator-assessed PFS with alectinib compared 
with chemotherapy in the intent-to-treat (ITT) population (see Figure 1).  Treatment with 
alectinib reduced the risk of disease progression or death by 85% compared with 

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chemotherapy, as shown by a stratified hazard ratio (HR)0.15 (95% CI: 0.08 to 0.29; 
p0.001).  The estimated median PFS was 8.2 months longer in the alectinib arm 
(9.6 months vs. 1.4 months for chemotherapy).

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Figure 1
Primary Efficacy Endpoint:  Kaplan-Meier Plot of Investigator-Assessed Progression-Free Survival in 
ALURITT Population
ITTintent-to-treat.

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The results for the secondary endpoints were in line with those for the primary endpoint.  
In particular, for the key secondary endpoint of the study, alectinib demonstrated a 
statistically significant and clinically meaningful improvement in IRC-assessed CNS ORR
for patients with measurable CNS metastases at baseline.
In spite of a median treatment duration in the alectinib arm that was 3 times longer than 
the chemotherapy arm, a lower proportion of alectinib-treated patients experienced 
adverse events (any grade:  77% alectinib vs. 85% chemotherapy).  In addition, when 
compared with patients who received chemotherapy, fewer patients treated with alectinib 
experienced severe adverse events (Grade 3), adverse events leading to 
discontinuation of study drug, and adverse events leading to dose reduction; however, 
more patients treated with alectinib experienced adverse events leading to dose 
interruption.
Refer to the Alectinib Investigator's Brochure for details on nonclinical and clinical 
studies.
1.2.4
Study BO28984 (ALEX)
Study BO28984 (ALEX) was a randomized, multicenter, open-label, Phase III 
head-to-head trial comparing alectinib and crizotinib in patients with treatment-naive,
ALK-positive advanced or recurrent (Stage IIIb) or metastatic (Stage IV) NSCLC. A total 
of 303 patients were randomized to crizotinib (N151) or alectinib (N152).
The study met its primary objective (data cutoff: 9 February 2017) to demonstrate 
superiority of alectinib over crizotinib with respect to investigator-assessed PFS in the 
first-line setting of advanced ALK-positive NSCLC (see Figure 2).  Alectinib significantly 
reduced the risk of disease progression or death by 53% compared with crizotinib, as 
shown by a stratified HR0.47 (95% CI: 0.34 to 0.65; p0.0001).  At the time of the 
cutoff, median duration of PFS was 11.1 months with crizotinib and had not been 
reached with alectinib.

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Figure 2
Primary Efficacy Endpoint:  Kaplan-Meier Plot of Investigator-Assessed Progression-Free Survival in
ALEXITT Population
IRCIndependent Review Committee; ITTintent-to-treat.
Notes:  Hazard ratio was estimated by Cox regression. Stratified hazard ratio and p-value are stratified for covariates race (Asian vs. non-Asian) 
and CNS metastases at baseline by IRC.
Data cutoff:  9 February 2017.

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The key secondary efficacy endpoints of IRC-assessed PFS and time to CNS 
progression, tested in the pre-specified hierarchy, were statistically significant with a 
HR0.50 (95% CI: 0.36 to 0.70) for IRC-assessed PFS and a cause-specific HR0.16 
(95% CI: 0.10 to 0.28) for time to CNS progression by IRC.
Based on case reports from ALEX, acute kidney injury and increased weight have been 
identified as new adverse drug reactions for alectinib. Despite the longer treatment 
duration in the alectinib arm compared with the crizotinib arm, alectinib appeared to be 
tolerated better than crizotinib, as shown by the lower incidence of adverse events that 
were treatment-related, Grade 3 in severity, and led to treatment interruptions and 
dose reductions. For additional details, refer to the Alectinib Investigator's Brochure.
1.3
STUDY RATIONALE AND BENEFITRISK ASSESSMENT
Over 40% of patients with newly diagnosed NSCLC present with an early stage of 
disease (Stage IIIIa).  For these patients, resection of the tumor, if clinically feasible, is 
preferred.  Despite complete resection, recurrence develops in up to 70% of patients 
(Ponn et al. 2005).  For patients with Stage IIIIIa disease and among a subset of 
patients with Stage Ib disease in whom the tumor is 4 cm in size at baseline, adjuvant 
platinum-based chemotherapy administered following resection has been shown to 
provide additional, although limited, benefit.  Over a median follow-up period of 
5.2 years, comparing chemotherapy with no chemotherapy, the HR for overall survival 
(OS) was 0.89 (95% CI: 0.82 to 0.96; p0.005), corresponding to a 5-year survival 
benefit of 5.4% from chemotherapy and a 5-year disease-free survival (DFS) benefit of 
5.8% over best supportive care (Pignon et al. 2008).
However, platinum-based chemotherapy has consistently been associated with 
significant toxicity, such as febrile neutropenia, myelosuppression, nausea, alopecia, 
nephropathy, and neuropathy.  Thus, in addition to the modest treatment benefit 
reported for the platinum-based chemotherapy, the regimens are generally not 
well-tolerated, resulting in issues with treatment compliance (Pignon et al. 2008).
In the metastatic setting, targeted therapies such as erlotinib and gefitinib for patients 
with EGFR-mutated proteins and crizotinib and alectinib for patients with ALK-positive 
NSCLC have replaced the less efficacious and more toxic chemotherapy regimens in 
molecularly selected populations (Solomon et al. 2014; Ou et al. 2016; Shaw et al. 2016; 
Peters et al. 2017).  In the adjuvant setting, the CTONG 1104 trial conducted in 
patients with EGFR-activating mutations was successful in demonstrating benefit with 
adjuvant gefitinib over platinum-based chemotherapy, suggesting that targeted therapies 
can provide meaningful clinical benefit in adjuvant NSCLC when administered to 
properly selected patient populations (Wu et al. 2017).

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In a randomized double-blind Phase III trial (ADAURA), patients with resected EGFR 
mutation–positive NSCLC who received osimertinib had significantly longer DFS than 
those who received placebo (Wu et al. 2020). The ADAURA study results led to the
U.S. Food and Drug Administration’s (FDA) approval of osimertinib as the adjuvant 
therapy for EGFR mutation–positive NSCLC after tumor resection. In addition, a study 
of adjuvant crizotinib (Xalkori) is ongoing in patients with Stage IbIIIa, resected, 
ALK-positive NSCLC, as part of the Adjuvant Lung Cancer Enrichment Marker 
Identification and Sequencing Trials (ALCHEMIST) scheme.  No data from the 
ALCHEMIST study are available to report at this time.
Primary analysis of 2 global Phase III studies in ALK-positive advanced or metastatic 
(Stage IIIbIV) NSCLC revealed a statistically significant and clinically meaningful 
benefit of alectinib compared with crizotinib in the first-line setting (ALEX) and compared 
with docetaxel or pemetrexed following recurrence on prior platinum-based 
chemotherapy and crizotinib (Study MO29750 [ALUR]; Novello et al. 2017; 
Peters et al. 2017).  Both studies met their primary endpoints of investigator-assessed 
PFS.  These results demonstrate a robust clinical benefit of alectinib, with a 53% and 
85% reduction in the risk of a PFS event versus the comparator in ALEX and ALUR, 
respectively.  Alectinib was better tolerated than crizotinib in ALEX and chemotherapy 
(docetaxel or pemetrexed) in ALUR, despite a substantially longer duration of treatment 
in the alectinib arm in both studies.
More detailed background information on the clinical efficacy of alectinib is presented in 
Section 1.2. Background information on the clinical safety of alectinib is presented in 
Section 1.2, Section 5.1, and the Alectinib Investigator's Brochure in more detail.
Identified and potential risks associated with alectinib treatment will be closely monitored 
throughout the clinical program. Patients' safety during the study is ensured by targeting 
the most appropriate patient population through inclusion/exclusion criteria, stringent 
safety monitoring by the Sponsor, and an independent Data Monitoring Committee 
(iDMC), as well as by protocol-specified study drug modification criteria 
(see Section 5.1.7).
In summary, a high unmet need remains for novel therapies that can provide greater
clinical benefit with a more favorable safety profile than the current standard of care of 
platinum-based chemotherapy in the adjuvant setting. Overall, alectinib has shown 
meaningful benefit as well as an acceptable safety profile in a diverse population of 
advanced or metastatic ALK-positive NSCLC, including in patients who are 
treatment-naive and patients who have not received benefit from crizotinib treatment 
with or without prior chemotherapy.  Furthermore, given the emerging data from targeted 
therapies in the post-operative setting of NSCLC, alectinib shows a potential of being 
beneficial for the adjuvant treatment of ALK-positive NSCLC. This would be consistent 
with the current treatment paradigm observed in the metastatic setting where, in the 
presence of actionable mutations or rearrangements of oncogene drivers such as EGFR

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and ALK, targeted therapy is the recommended treatment of choice and has replaced 
chemotherapy by providing superior efficacy and a more tolerable safety profile.
1.3.1
COVID-19 BenefitRisk Assessment
In the setting of the coronavirus disease 2019 (COVID-19) pandemic, patients with
comorbidities, including those with cancer, are a more vulnerable population, with the
potential for more severe clinical outcomes from COVID-19. However, it is unclear 
whether or how cancer therapies such as chemotherapy and targeted therapy impact the 
incidence or severity of COVID-19. Based on its safety profile and mechanism of 
action, it is not anticipated that the treatment used in this study will increase the risk 
of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 
Clinical trials with the treatment in this study have been ongoing during this pandemic 
and, although the study numbers are small, enrolled patients have not shown any 
increased risk of developing COVID-19 symptoms.
1.3.2
COVID-19 Vaccines
Based on the published mechanism of action of the COVID-19 vaccines and the known 
mechanism of action of alectinib, there is no scientific rationale to expect that 
COVID-19 vaccines will affect the efficacy of alectinib and chemotherapy. Based on a 
specific benefit-risk assessment, taking into account the available relevant information, 
the approved non-live COVID-19 vaccines may and should be administered in patients 
who are in the study, as long as there is no other contraindication (e.g., known 
hypersensitivity to a vaccine component).
Investigators should share with patients' primary healthcare providers relevant 
information regarding any potential effect of respective study drugs on the response to
COVID-19 vaccination, as applicable. Also, patients should contact the investigators
or site staff, when they are invited to receive a COVID-19 vaccine deployed in their
region. The decision to vaccinate a patient should be based on a patient’s SARS-CoV-2
infection/complication risk, general health condition, severity of underlying 
malignancy, and regional epidemiology of COVID-19. COVID-19 vaccines should be 
administered in accordance with their respective prescribing information and applicable 
immunization guidelines.
After COVID-19 vaccination, one should continue to observe the applicable 
epidemiologic/public health and hygiene measures, during the pandemic, along with per
protocol safety measures and assessments, in order to minimize the risk, but also to
appropriately identify and assess potential adverse reactions (e.g., nausea, diarrhea, 
myalgia) possibly shared by vaccines and study drugs.
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy and safety of alectinib compared with 
platinum-based chemotherapy in patients with completely resected Stage Ib 

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(tumors4 cm) to Stage IIIa, ALKpositive NSCLC.  Specific objectives and 
corresponding endpoints for the study are outlined in Table 2.
The primary and secondary efficacy objectives will be analyzed in the ITT population of 
randomized patients with resected Stage Ib (tumors 4 cm) to Stage IIIa NSCLC and in
the subpopulation of patients with resected Stage IIIIIa NSCLC.
Disease-free survival as an endpoint does not distinguish between the location of the 
first documented recurrence of disease or new primary NSCLC.  Descriptive statistics 
(i.e., frequencies and percentages) will be used to explore the first site of recurrence of 
disease or new primary NSCLC.
Table 2
Objectives and Corresponding Endpoints
Primary Efficacy Objective
Corresponding Endpoint
To evaluate the efficacy of alectinib 
compared with platinum-based 
chemotherapy in patients with completely 
resected Stage Ib (tumors4 cm) to 
Stage IIIa, ALK-positive NSCLC
DFS, defined as the time from randomization to 
the first documented recurrence of disease or 
new primary NSCLCas determined by the 
investigator through use of an integrated 
assessment of radiographic data, biopsy sample 
results (if clinically feasible), and clinical 
statusor death from any cause, whichever 
occurs first
Secondary Efficacy Objective
Corresponding Endpoint
To evaluate the efficacy of alectinib 
compared with platinum-based 
chemotherapy in patients with completely 
resected Stage Ib (tumors4 cm) to 
Stage IIIa, ALK-positive NSCLC
OS, defined as the time from randomization to 
death from any cause
Exploratory Efficacy Objectives
Corresponding Endpoints
To evaluate DFS rates for patients in the 
alectinib arm compared with patients in 
the platinum-based chemotherapy arm
DFS rates at landmark timepoints of 3, 4, and 
5 years
To evaluate the effects of demographics 
and baseline prognostic characteristics on 
duration of DFS for patients in the
alectinib arm compared with patients in 
the platinum-based chemotherapy arm
Effects of demographics (e.g., age, sex, and 
race/ethnicity) and baseline prognostic 
characteristics (e.g., disease stage, smoking 
history, and ECOG Performance Status) on 
duration of DFS by subgroup analyses

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Table 2
Objectives and Corresponding Endpoints (cont.)
Exploratory Efficacy Objectives (cont.)
Corresponding Endpoints (cont.)
To evaluate the location of the first 
documented recurrence of disease or new 
primary NSCLC for patients in the
alectinib arm compared with patients in 
the platinum-based chemotherapy arm
The location of the first documented 
recurrence of disease or new primary NSCLC
Safety Objective
Corresponding Endpoints
To evaluate the safety and tolerability of 
alectinib compared with platinum-based 
chemotherapy in patients with completely
resected Stage Ib (tumors4 cm) to
Stage IIIa, ALK-positive NSCLC
Incidence of adverse events, with severity 
determined through use of NCI CTCAE v5.0
Safety laboratory values
Vital signs
ECG
Pharmacokinetic Objectives
(Alectinib Arm Only)
Corresponding Endpoint
To characterize the pharmacokinetics of 
alectinib and its major metabolite(s) in 
patients with completely resected Stage Ib
(tumors 4 cm) to Stage IIIa, ALK-positive 
NSCLC
At Japanese sites only: To characterize 
the pharmacokinetics of alectinib and its 
major metabolite(s) in Japanese patients
Plasma concentrations of alectinib and its 
major metabolite(s) at specified timepoints
Exploratory Biomarker Objective
Corresponding Endpoint
To investigate molecular mechanisms of 
resistance to alectinib in patients with 
completely resected Stage Ib
(tumors 4 cm) to Stage IIIa, ALK-positive 
NSCLC
Relationship between biomarkers in blood 
and tumor tissue (listed in Table 3) and 
efficacy (DFS)
Exploratory Patient-Reported Outcome 
Objectives
Corresponding Endpoints
To document the impact of alectinib 
compared with platinum-based 
chemotherapy on patients' quality of life 
and daily function
To document health utilities for 
pharmacoeconomic modeling
Mean change from baseline in PCS, MCS, 
and the PF scale as measured by their 
corresponding scores of the SF-36v2
Health utilities as evaluated through the 
EQ-5D-5L
ALKanaplastic lymphoma kinase; DFSdisease-free survival; ECOGEastern Cooperative 
Oncology Group; MCSmental component summary; NCI CTCAENational Cancer Institute 
Common Terminology Criteria for Adverse Events; NSCLCnonsmall-cell lung cancer; 
PCSphysical component summary; PFphysical function.

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3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
This randomized, active-controlled, multicenter, open-label, Phase III study is designed 
to investigate the efficacy and safety of alectinib compared with platinum-based 
chemotherapy in the adjuvant setting.  The primary endpoint of the study is DFS as 
assessed by the investigator, while OS is a secondary endpoint.
This study will be conducted at approximately 200 centers in around 30 countries 
worldwide. Central randomization will be performed via an interactive voice or 
Web-based response system (IxRS). Randomized patients will be stratified by extent of 
disease (Stage Ib [tumors4 cm] vs. Stage II vs. Stage IIIa) and ethnicity (Asian vs. 
non-Asian). Relevant instructions will be provided to each study site by the IxRS 
provider.
Patients with completely resected (negative margins), histologically-confirmed Stage Ib
(tumors4 cm) to Stage IIIa NSCLC as per the Union Internationale Contre le 
Cancer (UICC)/American Joint Committee on Cancer (AJCC) 7th edition
(Detterbeck et al. 2009), with documented ALK-positive disease as assessed by a
FDAapproved and Conformité Européenne (CE)-marked test and meeting all required 
eligibility criteria, will be randomized in a 1:1 fashion.
Staging must occur in accordance with the UICC/AJCC 7th edition and not the 
8th edition. Patients with Stage Ib NSCLC with tumors 4 cm per the 7th edition 
classification have been shown to experience more modest benefit from adjuvant 
chemotherapy treatment than patients with Stage IIIIIa NSCLC, and this has been 
taken into consideration for recruitment capping, stratification, and statistical analysis of 
the primary endpoint.
Patients in the experimental arm will receive alectinib at 600 mg orally BID taken with 
food for 24 months.
Patients in the control arm will receive one of the protocol-specified platinum-based 
chemotherapy regimens (including all required premedications and permitted 
concomitant medications) according to the local prescribing information.
Protocol-defined platinum-based chemotherapy regimens include:

Cisplatin 75 mg/m2 on Day 1 plus vinorelbine 25 mg/m2 on Days 1 and 8

Cisplatin 75 mg/m2 on Day 1 plus gemcitabine 1250 mg/m2 on Days 1 and 8

Cisplatin 75 mg/m2 on Day 1 plus pemetrexed 500 mg/m2 on Day 1
Platinum-based chemotherapy will be provided for 4 cycles, with each cycle lasting 
21 days. In case of intolerability to a cisplatin-based regimen, carboplatin can be 
administered instead of cisplatin in one of the above combinations.

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Post-operative radiation therapy (PORT) is not allowed as a treatment option. 
Therefore, patients with Stage IIIa N2 NSCLC who, in the investigator's opinion, should 
receive PORT, are excluded from the study.
Study drug (alectinib or platinum-based chemotherapy) will be administered until the 
completion of the treatment period (24 months for alectinib and 4 cycles for 
chemotherapy), recurrence of disease, unacceptable toxicity, withdrawal of consent, or
death, whichever occurs first.  Patients who complete a study treatment regimen or 
discontinue treatment prior to disease recurrence (e.g., due to unacceptable toxicity) will 
continue to be followed until disease recurrence. After disease recurrence, patients will 
be treated at the discretion of the investigator according to local clinical practice.
No crossover in the adjuvant setting will be allowed between the 2 arms.
Approximately 255 patients will be enrolled into the study over a planned competitive 
recruitment period of approximately 38 months. Patients inappropriately randomized 
into the study will not be replaced. The primary DFS analysis will be conducted after 
approximately 89 DFS events in the Stage IIIIIa subpopulation have been observed.  
This is expected to occur approximately 60 months after the first patient is randomized.
Data collection will continue for each patient until death or study closure, whichever 
occurs first.
An iDMC will be established to monitor the progress of the study and ensure that the
safety of patients enrolled in the study is not compromised (see Section 5.1).
All randomized patients will undergo regular, scheduled visits until disease recurrence, 
death, withdrawal from the study, or study termination, whichever occurs first.  
Regular safety assessments will be performed for both arms during treatment.
The safety follow-up visit will be performed 28 days after the last dose of alectinib or 
28 days after the end of the last cycle of platinum-based chemotherapy. For the first 
12 weeks (3 months), regular safety assessment visits will be scheduled at baseline and 
every 3 weeks (i.e., 1 chemotherapy cycle) for both arms.  Additional visits will be 
scheduled for patients in the alectinib arm at Weeks 2, 4, 8, and 10 to allow for more 
frequent CPK and liver function assessments.  Phone calls for safety monitoring of 
patients in the chemotherapy arm will be performed at the same timepoints (Weeks 2, 4, 
8, and 10). From Week 12, patients in the alectinib arm will continue to be monitored for 
safety until treatment discontinuation every 6 weeks until Week 48 and every 12 weeks 
from Week 4996. Scheduled disease assessments will be performed for both arms at 
baseline, every 12 weeks for the first 2 years, every 24 weeks during Years 35, and 
annually thereafter until disease recurrence, death, loss to follow-up, consent 
withdrawal, or study termination by the Sponsor, whichever occurs first. If clinically 
indicated, unscheduled assessments can be performed at any time. Positive efficacy 
results at an interim analysis, as described in Section 6.9, will not influence the timing of 
disease assessments during the study.

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For all patients, plasma samples for exploratory biomarker research will be obtained at 
baseline, every 3 weeks for the first 12 weeks, every 12 weeks from Weeks 1396, 
every 24 weeks during Years 35, and annually thereafter until disease recurrence.  
Tumor samples will be obtained at study entry and upon disease recurrence for 
biomarker analysis (see Table 3).
Plasma samples will also be obtained for patients randomized to the alectinib arm 
pre-dose at baseline, every 3 weeks for the first 12 weeks, and every 12 weeks until 
Week 96 for PK analysis. At participating Japanese sites that can perform 
serial/intensive PK sampling, serial/intensive PK samples will be collected from a subset 
of Japanese patients receiving alectinib (approximately the first 6 patients who consent 
to participate in the serial/intensive PK sample collection) to facilitate the PK assessment 
in this population (see Appendix 3). The option to participate in the intensive Japanese
PK profiling will be offered to these patients until at least 6 evaluable patients, as per 
protocol, have provided a reliable and complete PK profile. Therefore, more than 
6 patients may participate in the serial/intensive PK assessment. However, the study 
team will make all efforts to provide complete profiles to the sites within the shortest 
timeframe.
Table 3
Biomarkers for Exploratory Research
Sample Type
Timing
Proposed Biomarkers
Plasma
At baseline and every 3 weeks for the 
first 12 weeks, every 12 weeks from 
Weeks 1396, every 24 weeks during 
Years 35, and annually thereafter until 
disease recurrence
ALK rearrangements/mutations and 
other genes and gene mutations 
involved in resistance, and 
circulating tumor nucleic acids for 
MRD and early recurrence
Tumor tissue
At study entry and at disease
recurrence
Confirmatory central ALK testing 
(at baseline only), and ALK
rearrangements/mutations and other 
genes and gene mutations involved 
in resistance
ALKanaplastic lymphoma kinase; MRDminimal residual disease.
Figure 3 presents an overview of the study design.  A schedule of activities is provided in
Appendix 1 and Appendix 2.

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Figure 3
Study Schema
ALKanaplastic lymphoma kinase positive; BID twice a day; ECOG Eastern Cooperative 
Oncology Group (Performance Status); Inv.investigator; NSCLC nonsmall-cell lung cancer; 
R1:1 1:1 randomization.
3.2
END OF STUDY AND LENGTH OF STUDY
This study is event-driven with a recruitment period of approximately 3 years. 
The required number of events for the primary analysis of the primary endpoint is 
expected to occur approximately 60 months after the first patient has been enrolled. 
Patients are to be treated until completion of the treatment period (24 months for 
alectinib and 4 cycles [21-day cycles] of platinum-based chemotherapy), recurrence of 
disease, unacceptable toxicity, withdrawal of consent, or death, whichever occurs first.
The final survival follow-up analysis will be conducted at approximately 5 years after the 
last patient is enrolled.  The study will formally end once the final survival follow-up 
analysis has been completed.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Alectinib Dose and Schedule
The 600 mg BID dosing regimen of alectinib was established as the RP2D based on 
safety, tolerability, PK, and anti-tumor activity from the dose-escalation part of the 
Phase I/II Study NP28761. This dosing regimen has been approved in most countries, 
based on the results of the pivotal Phase II Studies NP28761 and NP28673 in the 
crizotinib-progressed or intolerant population. The justification of the global alectinib 
600 mg BID clinical dosing regimen in the ALK inhibitornaive population is supported by 
the observed efficacy and safety results (Peters et al. 2017) and the cumulative available 
data on alectinib pharmacokinetics and exposure-response from the global patient 
population in the ALEX study (Hsu et al. 2017).
The protocol-defined 2-year treatment duration is supported by efficacy and safety data 
reported from the ALEX study, in which alectinib was compared with crizotinib in the 
first-line metastatic setting. In this trial, IRC-assessed median PFS in the alectinib arm 
was shown to be 25.7 months [95% CI: 19.9 months, NE], whereas 
investigator-assessed median PFS was not reached at the time of primary analysis. 

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The median treatment duration with alectinib was 17.9 months at the time of the data 
cutoff, with 55% of patients in the alectinib arm still receiving treatment 
(Peters et al. 2017).  It is anticipated that the mature median treatment duration will 
exceed 24 months.  The safety analysis from ALEX was consistent with that reported in 
previous studies and compared favorably with that of crizotinib despite the long 
treatment duration (Ou et al. 2016; Shaw et al. 2016).  The results were confirmed at the 
time of an updated analysis, reporting a median alectinib exposure of 20.6 months 
(range: 032 months).  Despite the longer duration of treatment, the overall 
characteristics, types, and severities of adverse events from the updated analysis were 
consistent with those from the primary analysis, and no new or unexpected safety 
findings were identified.
Various clinical trials have been initiated in the adjuvant setting for NSCLC, comparing 
tyrosine kinase inhibitors (TKIs) with either placebo or chemotherapy. The TKI treatment 
duration in these trials is typically 2 or 3 years (Goss et al. 2013; Kelly et al. 2015).  
Most recently, results of the Phase III trial CTONG 1104, which compared gefitinib 
administered for 24 months versus 4 cycles of cisplatin plus vinorelbine in patients with 
EGFR mutationpositive NSCLC in the adjuvant setting, showed that targeted therapies 
can be of benefit in a properly selected NSCLC population.  In the trial, patients 
experienced significantly longer DFS in the gefitinib arm compared with platinum-based 
chemotherapy, with a HR0.60 (95% CI: 0.42 to 0.87; p0.005).  In addition, Grade3 
adverse events were less common with gefitinib than with platinum-based chemotherapy 
(12.3% vs. 48.3%, respectively), allowing for the conclusion that the 2-year treatment 
duration with gefitinib was beneficial and safe in the adjuvant setting in this 
molecularly-selected population (Wu et al. 2017).
Cumulatively, alectinib 600 mg BID administered with food has been chosen as the 
optimal therapeutic dose level with the best balance between efficacy and safety.
Clinical data from the metastatic setting have shown that patients can be effectively and 
safely treated with alectinib for 2 years, and results from clinical trials of TKI treatment 
for NSCLC in the adjuvant setting have shown that a 2-year treatment duration is 
effective and shows a favorable safety profile in comparison with platinum-based 
chemotherapy.
Therefore, the protocol-defined experimental treatment will be 600 mg alectinib BID with 
food for 24 months administered orally.
3.3.2
Rationale for Open-Label Design of the Study
The open-label design of the study was chosen because alectinib is administered orally,
whereas the comparator chemotherapies are administered intravenously. Furthermore, 
infusion times for the different chemotherapy regimens may vary. Blinding of treatments 
in this scenario would place undue burden on both patients and investigators.

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3.3.3
Rationale for Patient Population and Analysis Groups
The study population will consist of patients who have undergone complete resection
with negative margins (R0) of histologically-confirmed Stage Ib (tumors4 cm) to 
Stage IIIa NSCLC as per UICC/AJCC, 7th edition. Patients will be randomized to 
receive either alectinib or platinum-based chemotherapy.
Post-operative radiotherapy treatment will not be allowed in the study. Post-operative 
radiotherapy treatment for patients with Stage I and II NSCLC has not been shown to 
provide additional benefit, while for patients with Stage IIIa N2 disease (R0), the benefit 
of PORT is not fully established. This is reflected in the recently published 
American Society of Clinical Oncology/Cancer Care Ontario guidelines on the use of 
PORT in the adjuvant setting where radiotherapy for patients with Stage IIIa N2 (R0) is 
not recommended for routine use, and it is advised that the benefits and risks of 
providing PORT for these patients should be carefully evaluated on a case-by-case 
basis (Kris et al. 2017).
In addition, PORT is associated with side effects that can appear during the treatment 
itself and/or up to 36 months after completion of treatment (Saynak et al. 2010; 
Patel et al. 2014; Radiology.org 2017). As per NCCN guidelines, PORT for patients with 
Stage IIIa N2 disease (R0) should only be provided following completion of adjuvant 
treatment, as its administration before or during adjuvant treatment could significantly 
delay, if not compromise, the planned adjuvant therapy.
However, because of the 24-month treatment duration for patients randomized to 
alectinib in the current study, delivery of PORT following adjuvant treatment may delay 
radiotherapy by at least 2 years, which may not be clinically meaningful.  Thus, to 
prevent a potential under-treatment of patients randomized to the alectinib arm, as well 
as potential imbalances in efficacy and safety reporting between the 2 treatment arms, 
patients with Stage IIIa N2 disease that, in the investigator's opinion, could benefit from 
PORT, should not be enrolled in the study.
Patients will have ALK-positive disease as determined in accordance with local testing 
using an FDA-approved and CE-marked test, and ALK positivity will also be confirmed 
retrospectively by central testing. If local ALK testing is not available, patients can be 
tested centrally using the Ventana immunohistochemistry (IHC) assay.
The Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis, comparing outcomes of 
adjuvant platinum-based treatment with best supportive care following complete 
resection of NSCLC, identified a variation in the magnitude of benefit between the 
different disease stages. The results indicated that patients with Stages II and III 
NSCLC (HR0.83 for each) experienced notable treatment benefit, while a more 
moderate effect was observed for patients with Stage Ib (HR0.93) and a potential 
deleterious effect in Stage Ia (HR1.40; Pignon et al. 2008). In the Cancer and 
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Stage Ib NSCLC, a survival advantage was not observed with platinum-based 
chemotherapy in the ITT (Stage Ib) population.  However, an exploratory analysis 
demonstrated a survival difference in favor of adjuvant chemotherapy for patients who 
had tumors4 cm in diameter (HR0.69 [95% CI: 0.48 to 0.99]; Strauss et al. 2008).
Due to the potential variation in benefit with disease stage, with the strongest effect seen 
in Stages II and III and more moderate effects observed in earlier stages, the primary 
efficacy endpoint of investigator-assessed DFS will be tested using a hierarchical
fixed-sequencing approach, testing patients with Stage IIIIIa first, followed by the 
ITT population, which includes patients with Stage Ib (tumors4 cm) to IIIa
(per UICC/AJCC, 7th edition). Stratification based on disease stage will be performed at 
randomization to ensure an equal distribution of patients with different disease stages 
between the treatment arms. In addition, efforts will be taken to ensure that at least 75% 
of the patients will have Stage IIIIIa disease by capping the number of patients with 
Stage Ib disease (as per UICC/AJCC, 7th edition) at 25%, a ratio consistent with what 
has been reported for the distribution of early-stage NSCLC 
(Decision Resources Group 2014).
The study is a global trial and, in order to ensure the applicability of the study data to a 
global population, efforts will be taken to ensure that no more than 75% of the subjects 
are of Asian race. To assess the generalizability of data from an Asian ALK-positive
NSCLC population to a global population, a comprehensive literature search was 
conducted to review and compare key demographic and clinical characteristics in 
studies conducted in Asian populations with those conducted in non-Asian patients.  
The overall results of the literature review suggest similar patterns in Asian and 
non-Asian cohorts with regard to main baseline characteristics of ALK-positive NSCLC.  
In line with the results of the literature review, a recent publication (Nishio et al. 2017) 
comparing outcomes for Asian vs. non-Asian subgroups from the crizotinib studies, 
PROFILE 1007 and 1014, indicates that the baseline characteristics for the 2 groups 
were similar.
Results from alectinib studies conducted in the metastatic setting indicate a comparable 
efficacy outcome, safety profile, and PK profile for alectinib in the Asian and non-Asian 
population.  In the ALEX study evaluating alectinib versus crizotinib in the first-line
setting, 138 of 303 patients (45%) enrolled were Asian. A subgroup analysis of the 
primary endpoint of investigator-assessed PFS showed very consistent results in the 
Asian and non-Asian populations with PFS HRs0.46 (95% CI: 0.28 to 0.75) and 
0.49 (95% CI: 0.32 to 0.75), respectively. This consistency was confirmed in the PFS 
subgroup analysis according to the IRC, with HRs0.49 (95% CI: 0.30 to 0.79) and 
0.56 (95% CI: 0.36 to 0.87) in the Asian and non-Asian populations, respectively.  A total 
of 69 of 138 Asian patients (50%) enrolled in the ALEX study received alectinib 
treatment. The safety subgroup analysis showed that race did not substantially 
influence the type and rate of adverse events reported. The most common event terms 
reported in each subgroup (Asian and non-Asian) were consistent with the overall 

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population, and overall differences in the incidence rate between Asian and non-Asian 
populations were small (generally 10% absolute difference).
3.3.4
Rationale for Control Group
Platinum-based chemotherapy is considered the standard of care for adjuvant treatment 
of NSCLC following resection according to NCCN and ESMO guidelines (NCCN 2017; 
Postmus et al. 2017).  In this comparative study, the control arm will receive one of the 
protocol-defined, platinum-based chemotherapies, which includes cisplatin plus 
vinorelbine, cisplatin plus gemcitabine, and cisplatin plus pemetrexed.
The platinum-based chemotherapy regimen for patients randomized to the control arm 
will be chosen by investigator from the protocol-defined regimens according to local 
clinical practice.  In case of intolerability to a cisplatin-based regimen, carboplatin can be 
administered instead of cisplatin in one of the above combinations. As per NCCN and 
ESMO guidelines, platinum-based chemotherapy will be provided for 4 cycles, with each 
cycle lasting 21 days.  The chemotherapy doses defined in the protocol are in line with 
recommendations in the NCCN guidelines.
The benefit provided by platinum-based chemotherapy in the adjuvant setting has been 
shown in a number of adjuvant NSCLC trials and has been summarized in a pooled 
analysis performed by the LACE Collaborative Group (Pignon et al. 2008).  Results from 
the pooled LACE analysis indicated an increase in DFS and OS benefit at 5 years of
5.8% and 5.4%, respectively, compared with best supportive care. No significant 
difference in benefit was seen between the various chemotherapy regimens used.
However, the platinum-based treatments are associated with significant side effects that 
can result in poor compliance.
There remains a high unmet need in patients with resectable NSCLC for more effective 
adjuvant therapies with a manageable and well-tolerated safety profile. Considering the 
robust efficacy data and acceptable safety profile observed with for alectinib in the 
metastatic setting, a head-to-head comparison between alectinib and platinum-based
chemotherapy is warranted.
3.3.5
Rationale for PK Sample Collection Schedule
To date, the pharmacokinetics of alectinib have been characterized in crizotinib-naive 
patients with NSCLC who have failed to benefit from chemotherapy (Study AF-001JP), 
in patients who have failed to benefit from both chemotherapy and crizotinib treatment 
(Studies NP28761 and NP28673), and in patients with previously untreated, advanced 
ALK-positive NSCLC (ALEX and J-ALE).  To better understand the pharmacokinetics of 
alectinib by identifying variables affecting exposure and to further support the 
development of a robust population PK characterization of alectinib, pharmacokinetics 
will be assessed in this study. This study will include PK assessment of alectinib in 
patients with completely resected Stage Ib (tumors4 cm) to Stage IIIa, ALK-positive 
NSCLC by collecting samples from all patients randomized to the alectinib arm. For a 

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subset of patients randomized at Japanese sites (approximately the first 6 patients), 
serial/intensive PK samples will be collected to facilitate the PK assessment in this 
population in support of the optimal use of alectinib in the Japanese population, including 
identification of the appropriate alectinib dosing regimen in the adjuvant population in 
Japan.
The data collected from this study will enable a more robust understanding of alectinib 
pharmacokinetics in this global population and support optimal use of alectinib therapy,
including investigation and potential identification of sources of variability, influencing 
alectinib pharmacokinetics and/or response to alectinib therapy.
3.3.6
Rationale for Biomarker Assessments
Several molecular mechanisms of resistance to crizotinib and other ALK inhibitors have 
been reported in the literature: secondary mutations in the ALK gene (e.g., gatekeeper 
mutation), increased copy number of the ALK gene, increased expression of ALK
mRNA, and ALK-independent resistance mechanisms through activation of other 
oncogenic genes and pathways such as EGFR, cKIT, MET or KRAS (e.g., increased 
copy number, increased phosphorylation, or point mutations; Katayama et al. 2011; 
Doebele et al. 2012; Kim et al. 2013; Lin et al. 2017). Recently, the effects of different 
ALK variants on the efficacy of crizotinib were explored (Yoshida et al. 2016).
To investigate molecular mechanisms of resistance to ALK inhibitors and the ALK
mutation status, as well as to explore the effect on efficacy by different ALK variants, 
tumor samples will be collected before treatment and at the time of recurrence to 
perform targeted sequencing on nucleic acids. A panel of known cancer genes and ALK
rearrangements will be used for targeted sequencing.
The amount of circulating tumor nucleic acids shed into the bloodstream by the tumor 
can be used to detect early tumor recurrence. Additionally, gene rearrangements and 
somatic mutations in cancer genes appearing from drug resistance in ALK and other 
cancer-related genes can be detected in circulating tumor nucleic acids and monitored in 
plasma (Forshew et al. 2012). Tumor nucleic acids are shed into circulation in amounts 
that allow direct sequencing. Plasma samples will be collected before treatment and at 
defined timepoints during treatment to monitor for circulating tumor nucleic acids, gene 
rearrangements, and mutations in ALK and other cancer-related genes likely to be 
involved in resistance to ALK inhibitors. Information from mutated genes in the tumor 
will be correlated with mutations detected in plasma circulating tumor nucleic acids.
Determination of ALK positivity will be performed at sites by an FDA-approved and 
CE-marked test or by central Ventana ALK IHC. Local ALK-positive test results will be 
confirmed retrospectively by central Ventana ALK IHC testing. For exploratory 
purposes, other methods to determine ALK positivity (e.g., reverse transcription-PCR) 
may also be used. Currently, ALK positivity for fusions can only be determined in tissue 
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sequencing. As tissue sampling is difficult and tissue biopsy sample sizes from lung 
cancer patients are very small, testing of several important biomarkers is challenging. 
Many patients with NSCLC may not have enough tumor tissue available and therefore,
cannot be tested for some biomarkers such as ALK. Plasma ALK assays analyzing
circulating tumor nucleic acids will enable more patients with NSCLC to be tested for 
ALK fusions and may also be used to monitor changes in ALK rearrangements during 
ALK inhibitor treatment. Information from plasma ALK assays will be used to investigate 
the use of circulating tumor nucleic acids from plasma as a surrogate for tumor tissue for 
diagnostic purposes.
3.3.7
Rationale for Patient-Reported Outcome Assessments
The benefits associated with treatment in the post-resection adjuvant setting must be 
weighed with its residual short- and long-term impact on patients' health-related quality 
of life (HRQoL) and function (Myrdal et al. 2001; Brunelli et al. 2007; Ostroff et al. 2011).
In this study, patient-reported outcome (PRO) data will be collected from patients using 
the SF-36v2Health Survey, which yields 2 component summary scores (i.e., physical 
and mental) and 8 health domains (i.e., physical functioning, role-physical, bodily pain, 
general health, vitality, social functioning, role-emotional, and mental health) that provide 
a generic assessment of HRQoL. In addition, in order to inform pharmacoeconomic 
modeling, health-status utility scores will be collected using the EQ-5D-5L
Questionnaire.
4.
MATERIALS AND METHODS
4.1
PATIENTS
The target population for this trial is approximately 255 patients with completely resected 
Stage Ib (tumors4 cm) to Stage IIIa ALKpositive NSCLC.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form

Age 18 at time of signing Informed Consent Form

Complete resection of histologically-confirmed Stage Ib (tumor 4 cm) to 
Stage IIIa (T23 N0, T13 N1, T13 N2, T4 N01) NSCLC as per UICC/AJCC,
7th edition, with negative margins, at 412 weeks before enrollment
Accepted types of resection include any of the following: lobectomy, sleeve 
lobectomy, bilobectomy, or pneumonectomy.
Resection by segmentectomy or wedge resection is not allowed.
N3 disease is not allowed.

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
If mediastinoscopy was not performed preoperatively, it is expected that, at a 
minimum, mediastinal lymph node systematic sampling will occurred
Systematic sampling is defined as removal of at least 1 representative lymph 
node at specified levels.
Complete mediastinal lymph node dissection (MLND) is preferred. 
Mediastinal lymph node dissection entails resection of all lymph nodes at those 
same levels.
For patients who have undergone a right thoracotomy, sampling or MLND is 
required at Levels 4 and 7; for those who have undergone a left thoracotomy, 
sampling or MLND is required at Levels 5 and/or 6 and 7.
Exceptions will be granted for the following situations:
If patients have documented N2 disease in 1 level (per the UICC/AJCC staging 
system, 7th edition), not all levels need to be sampled.
If the preoperative staging imaging results (contrast computed tomography [CT]
and positron emission tomography [PET] scans) do not suggest evidence of 
disease in the mediastinum, the patient may be considered eligible even if N2
nodal sampling was not performed per the surgeon’s decision.

Documented ALK-positive disease according to an FDA-approved and CE-marked 
test

Eligible to receive a platinum-based chemotherapy regimen according to the local 
labels or guidelines

Eastern Cooperative Oncology Group (ECOG) Performance Status of Grade 0 or 
1

Adequate hematologic function, defined by the following laboratory test results, 
obtained within 3 days prior to initiation of study treatment:
Platelet count 100109/L
ANC1500/L
Hemoglobin 9 g/dL

Adequate renal function, defined by the following laboratory test results, obtained 
within 3 days prior to initiation of study treatment:
Serum creatinine1.5upper limit of normal (ULN) and
Creatinine clearance (CrCl) 60 mL/min

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods with a failure rate of 1% 
per year during the treatment period and for at least 90 days after the last dose of 
alectinib or according to local labels or guidelines for chemotherapy
A woman is considered to be of childbearing potential if she is post-menarchal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes,

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and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices.  Hormonal contraceptive methods must be supplemented by a barrier 
method.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.
Women of childbearing potential must have a negative serum pregnancy test 
result prior to randomization (maximum of 3 days) and within 10 days of the 
first dose of study drug. First dose of study drug (alectinib or chemotherapy) 
must be administered within 7 days from randomization.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures, and agreement to refrain from donating sperm, as 
defined below:
With female partners of childbearing potential, men must remain abstinent or 
use a condom plus an additional contraceptive method that together result in a 
failure rate of 1% per year during the treatment period and for at least 90 days 
after the last dose of alectinib or according to local labels or guidelines for
chemotherapy.  Men must refrain from donating sperm during this same period.
With pregnant female partners, men must remain abstinent or use a condom 
during the treatment period and for at least 90 days after the last dose of 
alectinib or according to local labels or guidelines for chemotherapy to avoid 
exposing the embryo.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.

Willingness and ability to comply with scheduled visits, treatment plans, laboratory 
tests, and other study procedures
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Pregnant or breastfeeding, or intending to become pregnant during the study or 
within 90 days after the last dose of alectinib or according to local labels or 
guidelines for chemotherapy

Prior adjuvant radiotherapy for NSCLC
Radiotherapy in the neo-adjuvant setting is allowed and must be completed at 
least 4 weeks prior to initiation of study treatment.

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
Prior exposure to systemic anti-cancer therapy
Anti-cancer therapy for an early stage of malignancy with curative intent, 
provided that the last dose received was more than 5 years prior to enrollment, 
may be allowed. The Medical Monitor could be consulted. 

Prior exposure to ALK inhibitors

Stage IIIa N2 patients that, in the investigator's opinion, should receive PORT are 
excluded from the study
Post-operative radiation therapy is not allowed in the study.

Known sensitivity to any component of study drug (alectinib or planned 
chemotherapy) to which the patient may be randomized
This includes, but is not limited to, patients with galactose intolerance, a 
congenital lactase deficiency, or glucose-galactose malabsorption.

Malignancies other than NSCLC within 5 years prior to enrollment, except for 
curatively treated basal cell carcinoma of the skin, early gastrointestinal (GI) 
cancer by endoscopic resection, in situ carcinoma of the cervix, ductal carcinoma 
in situ, papillary thyroid cancer, or any cured cancer that is considered to have no
impact on DFS or OS for the current NSCLC

Any GI disorder that may affect absorption of oral medications, such as 
malabsorption syndrome or status postmajor bowel resection

Liver disease characterized by any of the following:
ALT and AST3ULN
or
Impaired excretory function or synthetic function or other conditions of 
decompensated liver disease such as coagulopathy, hepatic encephalopathy, 
hypoalbuminemia, ascites, or bleeding from esophageal varices
or
Active viral or active autoimmune, alcoholic, or other types of acute hepatitis.
Active viral hepatitis B is defined as having positive hepatitis B surface antigen 
(HBsAg).
Patients with past hepatitis B virus (HBV) infection or resolved HBV infection 
(hepatitis B core antibody [HBcAb] – HbcAb-positive, but negative HBsAg) are 
eligible only if the HBV DNA test is negative.
Patients positive for hepatitis C virus (HCV) antibody are eligible only if PCR is 
negative for HCV RNA.

Japanese patients participating in the serial/intensive PK sample collection only:
administration of strong/potent CYP450 3A inhibitors or inducers within 14 days 
prior to the first dose of study treatment and while on treatment with alectinib up to 
Week 3 (see Appendix 5)

Any exclusion criteria based on local labels or guidelines for chemotherapy

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
Patients with symptomatic bradycardia

History of organ transplant

Known HIV positivity or AIDS-related illness

Any clinically significant concomitant disease or condition that could interfere 
withor for which the treatment might interfere withthe conduct of the study or 
the absorption of oral medications or that would pose an unacceptable risk to the 
patients in this study, in the opinion of the Principal Investigator

Any psychological, familial, sociological, or geographical condition potentially 
hampering compliance with the study protocol requirements and/or follow-up 
procedures; those conditions should be discussed with the patient before trial entry
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING
This is an open-label trial in which approximately 255 patients will be randomly assigned 
in a 1:1 allocation ratio to the two treatment arms via a block-stratified randomization 
procedure over a planned recruitment period of approximately 3 years.
Randomization will guard against systematic selection bias and should ensure the 
compatibility of the treatment groups. To assist balance in prognostic factors, 
randomization will be stratified by race (Asian vs. non-Asian) and disease stage 
(Stage Ib [tumors 4 cm] vs. Stage II vs. Stage III). Central randomization and drug 
allocation will be performed and managed via an IxRS. Relevant instruction will be 
provided to each study site by the IxRS provider.
Study site personnel and patients will be unblinded to treatment assignment information
during the study.  The Sponsor and its agents will be blinded to treatment assignment
information, with the exception of individuals who require access to treatment 
assignments to fulfill critical tasks in their job roles to be performed during the clinical 
trial.
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal products (IMPs) for this study are alectinib and 
platinum-based chemotherapies.
4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
Alectinib
Alectinib comes in a capsule dosage form containing the following active ingredient:  
9-ethyl-6, 6-dimethyl-8-[4-(morpholin-4-yl) piperidin-1-yl]-11-oxo-
6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride.
Each capsule contains 150 mg alectinib (as free base) along with lactose monohydrate, 
carboxymethylcellulose calcium, hydroxypropyl cellulose, sodium lauryl sulfate (SLS), 
and magnesium stearate as excipients.

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Alectinib capsules should be stored in accordance with the storage instructions on the 
label.
The formulation contains SLS (also known as sodium dodecyl sulfate) as an excipient. 
This excipient is known to be potentially associated with GI adverse events such as 
nausea, vomiting, diarrhea, and abdominal pain.
Alectinib will be supplied by the Sponsor as capsules in vials.  For information on the 
formulation and handling of alectinib, see the Alectinib Investigator's Brochure.
4.3.1.2
Platinum-Based Chemotherapy
Cisplatin, pemetrexed, vinorelbine, gemcitabine, and carboplatin will be supplied by the 
Sponsor and used in the commercially available formulation where allowed by local 
regulations.
For information on the formulation, packaging, and handling of cisplatin, pemetrexed, 
vinorelbine, gemcitabine, and carboplatin, please refer to the United States Prescribing 
Information (USPI), Summary of Product Characteristics (SmPC), local prescribing 
information or local guidelines for each drug.
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.1.
Any overdose or incorrect administration of any of the study treatments should be noted 
on the Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of any of the study treatments 
should be recorded on the Adverse Event eCRF.
Guidelines for dose reduction and treatment interruption or discontinuation for patients 
who experience adverse events are provided in Sections 5.1.75.1.12.
4.3.2.1
Alectinib
Alectinib 600 mg (four 150-mg capsules) should be administered orally BID with food in 
the morning and evening. The first dose of study drug should be administered as soon 
as possible after randomization and no later than 7 days after randomization. 
Treatment will continue until completion of treatment period (24 months), disease
recurrence, unacceptable toxicity, withdrawal of consent, or death, whichever occurs 
first.
If a planned dose of alectinib is missed, patients can make up that dose unless the next 
dose is due within 6 hours. If vomiting occurs after taking a dose of alectinib, patients 
should take the next dose at the scheduled time. Patients should not take 2 doses at the 
same time to make up for a missed dose.
The patient will record their daily dose and time in a diary (Patient Dosing Diary).

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4.3.2.2
Platinum-Based Chemotherapy
Platinum-based chemotherapy will be provided for 4 cycles, with each cycle lasting 
21 days. Investigators can choose one of the permitted platinum-based chemotherapy 
regimens, which include the following:

Cisplatin 75 mg/m2 on Day 1 plus vinorelbine 25 mg/m2 on Days 1 and 8

Cisplatin 75 mg/m2 on Day 1 plus gemcitabine 1250 mg/m2 on Days 1 and 8

Cisplatin 75 mg/m2 on Day 1 plus pemetrexed 500 mg/m2 on Day 1
The first dose of study drug should be administered as soon as possible after 
randomization, taking the required premedication into account, and no later than 7 days 
after randomization. Treatment will continue until completion of treatment period 
(4 cycles), recurrence of disease, unacceptable toxicity, withdrawal of consent, or death, 
whichever occurs first.
Institutions should follow their standard administration regimens (e.g., administration 
sequence or time) for the chemotherapy treatment. Patients must receive adequate 
premeditations, anti-emetic treatments, and IV hydration for platinum-based treatments
according to the local standard of care and prescribing information.
Platinum-based chemotherapy cycles may be delayed for safety reasons; however, if 
interrupted for more than 21 days1 cycle), the cycle is considered a skipped cycle.
This does not prevent investigator from completing 4 cycles.
The selected cisplatin-based chemotherapy regimen should remain the same for all 
cycles. For patients who experience unacceptable toxicity with cisplatin, carboplatin can 
be used. The investigator should inform the Medical Monitor of the switch from a 
cisplatin-based regimen to a carboplatin-based regimen.
Cisplatin plus Vinorelbine
Table 4 lists the doses and the suggested infusion times for vinorelbine plus 
platinum-based treatments at Cycle 1. Doses for subsequent cycles can be modified in 
case of toxicities. Chemotherapy infusion times may be adapted in accordance with 
local standard of care.

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Table 4
Doses and Suggested Infusion Times for Administration of 
Vinorelbine in Combination with Cisplatin or Carboplatin
Chemotherapy
Dose/Route
Infusion
Vinorelbine plus 
Cisplatin
25 mg/m2 IV
75 mg/m2 IV
Over 610 minutes on Days 1 and 8 Q21D
Over 68 hours on Day 1 Q21D
Vinorelbine plus 
Carboplatin a
25 mg/m2 IV
AUC 5 IV
Over 610 minutes on Days 1 and 8 Q21D
Over approximately 3060 minutes on Day 1 Q21D
AUCarea under concentration-time curve; Q21Devery 21 days.
a Only in case of intolerability, cisplatin can be replaced by carboplatin.
The vinorelbine injection must be diluted prior to infusion in an IV bag.  The following 
solutions may be used for dilution of vinorelbine in IV bag:  5% dextrose injection, 0.9% 
sodium chloride, 0.45% sodium chloride, 5% dextrose and 0.45% sodium chloride, 
Ringer's Injection, or Lactated Ringer's Injection. The administration of vinorelbine 
should be done in accordance with local practice and prescribing information.
It is very important that the IV needle or catheter is properly positioned before 
vinorelbine is injected. Leakage into surrounding tissue during IV administration of 
vinorelbine may cause considerable irritation, local tissue necrosis, and/or 
thrombophlebitis. If extravasation occurs, the injection should be discontinued 
immediately, and any remaining portion of the dose should then be introduced into 
another vein. Because there are no established guidelines for the treatment of 
extravasation injuries with vinorelbine, institutional guidelines may be used.
A prophylactic bowel regimen should be instituted to mitigate potential constipation, 
bowel obstruction, and/or paralytic ileus, considering adequate dietary fiber intake, 
hydration, and routine use of stool softeners.
Guidelines for dose modification and treatment interruption or discontinuation are 
provided in Section 5.1.8 for vinorelbine, Section 5.1.11 for cisplatin, and Section 5.1.12
for carboplatin.
Cisplatin plus Gemcitabine
Table 5 lists the doses and the suggested infusion times for gemcitabine plus 
platinum-based treatments at Cycle 1. Doses for subsequent cycles can be modified in 
case of toxicities. Chemotherapy infusion times may be adapted in accordance with 
local standard of care.

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Table 5
Doses and Suggested Infusion Times for Administration of 
Gemcitabine in Combination with Cisplatin or Carboplatin
Chemotherapy
Dose/Route
Infusion
Gemcitabine plus 
Cisplatin
1250 mg/m2 IV
75 mg/m2 IV
Over 30 minutes on Days 1 and 8 Q21D
Over 68 hours on Day 1 Q21D
Gemcitabine plus 
Carboplatin a
1000 mg/m2 IV 
AUC 5 IV
Over 30 minutes on Days 1 and 8 Q21D
Over approximately 30–60 minutes on Day 1 Q21D
AUCarea under the concentrationtime curve; Q21D every 21 days.
a Only in case of intolerability, cisplatin can be replaced by carboplatin.
The gemcitabine injection must be diluted prior to infusion. The recommended diluent 
for reconstitution of gemcitabine is 0.9% sodium chloride injection without preservatives.
The administration of gemcitabine should be done in accordance with local practice and 
the prescribing information; sites should follow their institutional standard of care for 
determining the gemcitabine dose for obese patients and for dose adjustment in the 
event of patient weight changes.
Renal and hepatic function must be monitored prior to initiation of therapy and 
periodically thereafter.
Guidelines for dose modification and treatment interruption or discontinuation are 
provided in Section 5.1.9 for gemcitabine, Section 5.1.11 for cisplatin, and 
Section 5.1.12 for carboplatin.
Cisplatin plus Pemetrexed
Table 6 lists the doses and the suggested infusion times for pemetrexed plus 
platinum-based treatments at Cycle 1. Doses for subsequent cycles can be modified in 
case of toxicities. Chemotherapy infusion times may be adapted in accordance with 
local standard of care.
Table 6
Doses and Suggested Infusion Times for Administration of 
Pemetrexed in Combination with Cisplatin or Carboplatin
Treatment
Dose/Route
Infusion
Pemetrexed
500 mg/m2 IV
Over ~10 minutes on Day 1 Q21D
Cisplatin
75 mg/m²
Over 68 hours on Day 1 Q21D
Carboplatin a
AUC 5 or 6 IV a
Over ~3060 minutes on Day 1 Q21D
AUCarea under the concentration-time curve; Q21D every 21 days.
a Only in case of intolerability, cisplatin can be replaced by carboplatin.

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Patients should receive steroid, folic acid, and vitamin B12 premedication for 
pemetrexed to reduce the severity of skin, hematologic, and GI toxicity. The choice of 
steroid and timing of premedication can be administered according to the local standard 
of care and prescribing information (see Table 7).
Table 7 lists the suggested premedication for the pemetrexed plus platinum-based 
chemotherapy.
Table 7
Premedication for Pemetrexed Plus Platinum-Based 
Chemotherapy
Premedication
Dose/Route
Treatment
Folic acid
3501000 g PO
Once daily beginning 57 days before Cycle 1, 
Day 1, and continuing until 21 days after 
discontinuation of pemetrexed or as per local
standard of care
Vitamin B12
1000 g IM
Q9W (i.e., every 3 cycles) beginning in the week 
prior to first dose of pemetrexed and continuing 
until 21 days after discontinuation of pemetrexed 
or as per local standard of care.  Subsequent 
vitamin B12 injections may be given the same day 
as treatment with pemetrexed.
Dexamethasone 
(or equivalent to 
4 mg 
dexamethasone)
4 mg PO
Twice daily the day prior to, the day of, and the day 
after each infusion of pemetrexed or as per local 
standard of care
IM intramuscular; PO by mouth; Q9W every 9 weeks.
Note:  Prophylactic anti-emetics per local practice.
Patients with mild-to-moderate renal insufficiency (CrCl 4579 mL/min) should avoid 
taking nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and 
acetylsalicylic acid (1.3 g daily) for:

At least 2 days prior to pemetrexed administration if the NSAID has a short 
elimination half-life

At least 5 days if the NSAID has a long elimination half-life

On the day of pemetrexed administration

At least 2 days following pemetrexed administration
Patients should be monitored more frequently for myelosuppression, renal toxicity, and 
GI toxicity if concomitant administration of ibuprofen cannot be avoided.
At the start of each cycle, the ANC must be 1500/L, the platelet count must be 
100,000/mm3, and the CrCl must be 45 mL/min (or CrCl must be 60 mL/min when 
pemetrexed is given together with cisplatin).

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The effect of third space fluid, such as pleural effusion or ascites, on pemetrexed is not 
fully defined.  Thus, drainage of third space fluid collection prior to pemetrexed treatment 
should be considered but may not be necessary.
Guidelines for dose modification and treatment interruption or discontinuation are 
provided in Section 5.1.10 for pemetrexed, Section 5.1.11 for cisplatin, and 
Section 5.1.12 for carboplatin.
General Guidance for Cisplatin and Carboplatin Administration
Cisplatin:  Cisplatin should be administered by IV infusion approximately 30 minutes 
after completion of the vinorelbine, gemcitabine, or pemetrexed infusion at a dose of 
75 mg/m² over 68 hours (see Table 4, Table 5, and Table 6, respectively). 
Patients must receive adequate anti-emetic treatment and appropriate hydration prior to 
and/or after receiving cisplatin.  Hydration is necessary to cause sufficient diuresis 
during and after treatment with cisplatin.  Refer to local clinical practice guidelines for 
further details.
Prior to initiating therapy and prior to each subsequent cycle, safety laboratory tests 
(in particular serum creatinine, BUN, CrCl, magnesium, sodium, potassium, and calcium) 
should be assessed, and audiometric testing should be performed as per local clinical 
practice.
Peripheral blood counts and liver function should be monitored periodically, and 
neurologic examination should be performed regularly as per local clinical practice.
Carboplatin:  Carboplatin should be administered by IV infusion at a dose of area under 
the concentration-time curve (AUC) 5 when given in combination with vinorelbine
(see Table 4) or gemcitabine (see Table 5) or at a dose of AUC 5 or 6 when given in 
combination with pemetrexed (see Table 6), or after completion of the pemetrexed,
gemcitabine, or vinorelbine infusion, with standard anti-emetics per local practice 
guidelines.
The carboplatin dose will be calculated using the Calvert formula (Calvert et al. 1989):
Total dose (mg)(target AUC)(glomerular filtration rate [GFR]25)
The GFR used in the Calvert formula to calculate AUC-based dosing should not exceed 
125 mL/min. For the purposes of this protocol, the GFR is considered to be equivalent 
to the CrCl. The CrCl is calculated by institutional guidelines or by the method of 
Cockcroft and Gault (1976) using the following formula:

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Where: CrClcreatinine clearance in mL/min
agepatient's age in years
wt patient's weight in kg
Scrserum creatinine in mg/dL
NOTE: For patients with an abnormally low serum creatinine level, estimate GFR using 
a minimum creatinine level of 0.8 mg/dL or cap the estimated GFR at 125 mL/min.
If a patient's GFR is estimated on the basis of serum creatinine measurements by the 
isotope dilution mass spectroscopy method, the FDA recommends that physicians 
consider capping the dose of carboplatin for desired exposure (AUC) to avoid potential 
toxicity caused by overdosing. On the basis of the Calvert formula described in the 
carboplatin label, the maximum doses can be calculated as follows:
Maximum carboplatin dose (mg)target AUC (mgmin/mL)(GFR25 mL/min)
The maximum dose is based on a GFR estimate that is capped at 150 mL/min for 
patients with normal renal function. No higher estimated GFR values should be used.
For a target AUC6, the maximum dose is 6150900 mg.
For a target AUC5, the maximum dose is 5150750 mg.
For a target AUC4, the maximum dose is 4150600 mg.
Refer to the FDA's communication regarding carboplatin dosing for more details at the 
following Web site:
https://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cde
r/ ucm228974.htm
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (alectinib and all chemotherapy drugs) will 
be provided by the Sponsor where required by local health authority regulations. 
The study site will acknowledge receipt of IMPs supplied by the Sponsor using IxRS to 
confirm the shipment condition and content.  Any damaged shipments will be replaced.
Investigational medicinal products will either be disposed of at the study site according to 
the study site’s institutional standard operating procedure or be returned to the Sponsor 
(if supplied by the Sponsor) with the appropriate documentation.  The site's method of 
destroying Sponsor-supplied IMPs must be agreed to by the Sponsor.  The site must 
obtain written authorization from the Sponsor before any Sponsor-supplied IMP is 
destroyed, and IMP destruction must be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.

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4.3.4
Continued Access to Alectinib
Currently, the Sponsor does not have any plans to provide the Roche IMP (alectinib) or 
any other study treatments or interventions to patients who have completed the study.  
The Sponsor may evaluate whether to continue providing alectinib in accordance with 
the Roche Global Policy on Continued Access to Investigational Medicinal Product, 
available at the following Web site:
https://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY AND PROHIBITED FOOD
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment from 14 days 
prior to initiation of study drug to the study drug discontinuation visit.  All such 
medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF.
Premedication with antihistamines, anti-pyretics, and/or analgesics may be administered 
at the discretion of the investigator.
In general, investigators should manage a patient’s care with supportive therapies as 
clinically indicated, per local standard practice.  Patients who experience 
infusion-associated symptoms may be treated symptomatically with acetaminophen, 
ibuprofen, diphenhydramine, and/or H2-receptor antagonists (e.g., famotidine, 
cimetidine), or equivalent medications per local standard practice.  
Serious infusion-associated events manifested by dyspnea, hypotension, wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should 
be managed with supportive therapies as clinically indicated (e.g., supplemental oxygen 
and 2-adrenergic agonists).
All therapy and/or medication administered to manage adverse events should be 
recorded on the Concomitant Medications eCRF.
4.4.1
Cautionary Therapy
4.4.1.1
Alectinib
Caution should be exercised when the following are co-administered with alectinib:

For medications that are substrates of P-glycoprotein (P-gp) transporter or breast 
cancer resistance protein transporter, the investigator should carefully assess the 
risks against benefits when considering concomitant use of alectinib.  Alectinib has 
been shown to have potential for inhibition of these transporters.  Substrates with a 
narrow therapeutic index (e.g., methotrexate, digoxin) should be avoided.  
If co-administration cannot be avoided, it is recommended that drug levels and/or 
signs for toxicity are carefully monitored (see Appendix 5).

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4.4.1.2
Protocol-Defined Platinum-Based Chemotherapy Regimens
Plasma levels of anti-convulsant agents may become subtherapeutic during cisplatin 
therapy. Caution should be exercised when are co-administered with cisplatin. For full 
details, refer to the current versions of the local product labels.
4.4.1.3
Medications Given with Precaution due to Effects Related to 
CYP450 Enzymes
Vinorelbine is metabolized by CYP3A4. Exercise caution in patients concurrently taking 
drugs known to inhibit drug metabolism by hepatic CYP450 isoenzymes in the CYP3A 
subfamily. Concurrent administration of vinorelbine with an inhibitor of this metabolic 
pathway may cause an earlier onset and/or an increased severity of adverse reactions.
Therefore, the medications listed below should be avoided.  If use of one of these 
medications is necessary, the risks and benefits should be discussed with the 
Medical Monitor prior to concomitant administration with vinorelbine.

CYP3A4 inhibitors, including, but not limited to, boceprevir, cobicistat conivaptan, 
danoprevir and ritonavir, elvitegravir and ritonavir, grapefruit juice, indinavir and 
ritonavir, itraconazole, ketoconazole, lopinavir and ritonavir, paritaprevir and 
ritonavir and (ombitasvir and/or dasabuvir) posaconazole, ritonavir saquinavir and 
ritonavir, telaprevir, tipranavir and ritonavir, troleandomycin, voriconazole
aprepitant, cimetidine, ciprofloxacin, clotrimazole, crizotinib, cyclosporine, 
dronedarone(h), erythromycin, fluconazole fluvoxamine imatinib, tofisopam, 
verapamil
The above lists of medications are not necessarily comprehensive.  The investigator 
should consult the prescribing information when determining whether a concomitant
medication can be safely administered with study treatment.  In addition, the investigator 
should contact the Medical Monitor if questions arise regarding medications not listed 
above.
4.4.2
Prohibited Therapy
4.4.2.1
For Patients Receiving Either Alectinib or Protocol-Defined
Chemotherapy Regimens
Use of the following therapies (e.g., prescription drugs, over-the-counter drugs, herbal or 
homeopathic remedies, nutritional supplements) is prohibited during the study and for at 
least 14 days prior to initiation of study treatment, unless otherwise specified below.  
Exceptions to restrictions of the concomitant therapies listed below (e.g., prescription 
drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) 
may be made if the rationale is discussed and documented between the investigator and 
the Sponsor's Clinical Pharmacologist.

Systemic immunosuppressive drugs, cytotoxic or chemotherapeutic agents 
(other than study drug treatment).  Probenecid is prohibited for patients receiving 
pemetrexed chemotherapy.

Systemic anti-cancer therapy

Additional investigational drug (except for during the follow-up period)

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
Radiotherapy/radionuclide therapy

For patients receiving pemetrexed:
–
Use of NSAIDs such as ibuprofen and acetylsalicylic acid should be avoided, in 
accordance with Section 4.3.2.2.
For full details regarding prohibited therapies during chemotherapy treatment, refer to 
the current version of the local product label.
4.4.2.2
For Japan Only:  Patients Receiving Alectinib
For Japanese patients participating in the serial/intensive PK sample collection only, use 
of potent inducers of CYP3A (e.g., rifampin, rifabutin, phenobarbital, phenytoin, 
carbamazepine, and St. John's wort [Hypericum perforatum]) and or potent inhibitors of 
CYP3A (e.g., ketoconazole) within 2 weeks or 5 half-lives (whichever is longer) should 
be avoided before the first dose of study drug treatment and while on treatment with 
alectinib up to Week 3 (see Appendix 5).  This is included to minimize the impact of 
extrinsic factors such as CYP3A inducers/inhibitors, which could confound PK 
assessments of the individual analytes, alectinib, or its active metabolite, M4.
The above list of medications is not necessarily comprehensive.  Thus, the investigator 
should consult the prescribing information for any concomitant medication, as well as the 
Internet references provided below, when determining whether a certain medication
strongly inhibits or induces CYP3A.  In addition, the investigator should contact the 
Medical Monitor if questions arise regarding medications not listed above.
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM292362.pdf
https://medicine.iupui.edu/clinpharm/ddis/table.aspx (for CYP450 drug interactions)
4.4.3
Prohibited Food
Use of the following foods is prohibited as described below for patients receiving 
alectinib:

For Japanese patients participating in the serial/intensive PK sample collection:
use of grapefruit or grapefruit juice for at least 14 days prior to the initiation of the 
study and while on alectinib treatment up to Week 3 due to its potent CYP3A 
inhibitory effect
Use of the following foods is prohibited as described below for patients receiving 
vinorelbine:

Use of grapefruit or grapefruit juice for at least 14 days prior to the initiation of the 
study and while on platinum-based chemotherapy regimens with vinorelbine
treatment due to its potent CYP3A inhibitory effect

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4.5
STUDY ASSESSMENTS
The schedules of activities to be performed during the study are provided in Appendix 1
and Appendix 2.  All activities must be performed and documented for each patient.
At applicable sites, certain study assessments may be performed by a 
mobile nursing (MN) professional at the patient's home or another suitable location to 
improve access and convenience for patients participating in the study.  The Sponsor 
will select a vendor that will be responsible for providing MN services for participating 
sites (the MN vendor).  The MN vendor is responsible for ensuring that all 
MN professionals are licensed, qualified, and in good standing, as per applicable 
regulations, and that appropriate background checks have been performed.  If the 
investigator at a participating site determines that MN services are appropriate for a 
patient and the patient gives written informed consent to participate in MN visits, the 
MN network will communicate with the patient and the patient's site. Once the patient 
completes the onsite visit for Week 1, MN visits could be scheduled on specified visit 
days, to allow relevant assessments to be performed by the MN professional. The MN 
may contact the investigators during the home visit if required. Further details will be 
provided in the MN and Site guidance package.  These assessments may include
ECOG Performance Status, biospecimen collection (biomarkers, chemistry, coagulation, 
hematology, PK, pregnancy test, urinalysis, as applicable), vital signs, weight, limited 
symptom-directed physical assessment requested by the Principal Investigator, 
assistance/supervision with completion of PROs (SF-36v2; EQ-5D-5L), ECG, and 
assessing changes in signs/symptoms and concomitant medications, etc.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  
Informed Consent Forms for enrolled patients and for patients who are not subsequently 
enrolled will be maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
4.5.2
Medical History, Concomitant Medication, and Demographic 
Data
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies, radiotherapy and surgery, size of the resected tumor
and date the patient underwent surgery for complete resection), female reproductive 
status, and tobacco use history, will be recorded at baseline.  In addition, all medications 
(e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic 
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study treatment will be recorded.  At the time of each follow-up physical examination, an 
interval medical history should be obtained and any changes in medications and 
allergies should be recorded.
Demographic data will include age, sex, and self-reported race/ethnicity.
Details of any COVID-19 vaccination received before study enrollment should be 
captured in the medical history section, at screening, whereas details regarding the 
COVID-19 vaccine received during the study should be recorded in the concomitant 
medication section.
4.5.3
Physical Examinations
A complete physical examination performed at screening should include an evaluation of 
the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, 
musculoskeletal, respiratory, GI, genitourinary, and neurologic systems.  
Any abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions eCRF.
Limited, symptom-directed physical examinations should be performed at specified 
post-baseline visits and as clinically indicated.  Changes from baseline abnormalities 
should be recorded in patient notes.  New or worsened clinically significant abnormalities 
should be recorded as adverse events on the Adverse Event eCRF.
4.5.4
Vital Signs
Vital signs will include measurements of temperature, weight, respiratory rate, pulse 
rate, and systolic and diastolic blood pressure while the patient is in a seated position.
4.5.5
Eastern Cooperative Oncology Group Performance Status
Performance status will be measured using the ECOG Performance Status Scale 
(see Appendix 6). It is recommended, where possible, that a patient’s performance 
status be assessed by the same person throughout the study.
4.5.6
Disease Assessments
Patients must be disease-free at baseline and reassessed at each subsequent tumor 
evaluation once randomized into the study. The disease recurrence will be assessed by 
the investigator using an integrated assessment of radiographic data, biopsy sample 
results (if clinically feasible), and clinical status. Disease assessments are to be 
performed at the timepoints specified below and in Appendix 1 and Appendix 2.
During the treatment period, the disease assessment schedule should be kept, 
regardless of drug delays or interruptions.
Positive efficacy results at an interim analysis, as described in Section 6.8, will not 
influence the conduct and timing of disease assessments during the study.

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Screening assessments will include:

CT scan (with oral/IV contrast unless contraindicated) of the chest and abdomen 
(including liver and adrenal glands)

Magnetic resonance imaging (MRI) of the brain to rule out CNS metastasis. If MRI 
is not available, CT scans (with oral/IV contrast unless contraindicated) can be 
performed instead.

Patients with metastatic disease are to be excluded from this study. Patients who 
have clinical signs, symptoms, biochemical abnormalities (including, but not limited 
to, ALP, LDH, etc.), or radiological imaging that could be suggestive of bone 
metastases at baseline, must undergo further investigation to exclude the 
presence of bone metastases at study entry.  Additional appropriate imaging 
techniques include but are not limited to PET imaging and isotope bone scans.

CT/MRI scans (with oral/IV contrast unless contraindicated) of the pelvis and neck 
should be included if clinically indicated

The radiological assessments performed as per standard of care prior to obtaining 
informed consent and within 28 days before randomization do not have to be 
repeated at screening
If a CT scan with contrast is medically contraindicated, a noncontrast-enhanced chest 
CT scan is acceptable. If contrast-enhanced MRI is contraindicated, then 
noncontrast-enhanced MRI will suffice.
Subsequent disease assessments will include CT scans (with oral/IV contrast unless 
contraindicated) of the chest, CT/MRI scan of abdomen (including liver and adrenal
glands) and brain, every 12 weeks (7 days) for the first 2 years, every 24 weeks
(14 days) during years 35, and annually thereafter (28 days) until disease 
recurrence, death, loss to follow-up, consent withdrawal, or study termination by the 
Sponsor, whichever occurs first. Computed tomography/MRI scans of the pelvis and 
neck, and isotope bone scans (where imaging of the bone is medically appropriate)
should be included if clinically indicated.
Brain imaging should be performed preferably using MRI, with the following image 
acquisition requirements.
Minimum sequences required:

Pre-contrast T1, T2/FLAIR

Post-contrast T1, with 2 orthogonal planes (or a volume acquisition) recommended
Recommended slice thickness 5 mm with no gap.
The same radiographic procedure used to assess disease sites at screening should be 
used throughout the study (e.g., the same contrast protocol for CT scans). Assessments 
should be performed by the same evaluator if possible to ensure internal consistency 

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across visits. At the investigator’s discretion, radiographic scans may be repeated at 
any time if disease recurrence or a new primary NSCLC is suspected.
For patients in both arms, a tumor sample should be obtained at the time of first 
radiographic confirmation of disease recurrence or confirmation of a new primary 
NSCLC unless not clinically feasible (within 30 days of disease recurrence or prior to 
start of the next anti-cancer therapy, whichever is sooner). Results of histological 
confirmation will be captured in the eCRF.
Radiographic images will be submitted to an IRF for a quality and completeness check, 
and for temporary storage prior to transfer to the Sponsor for long-term retention and 
potential independent reading.
4.5.7
Laboratory, Biomarker, and Other Biological Samples
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis:

Hematology: hemoglobin, hematocrit, platelet count, RBC count, WBC count, 
absolute count (neutrophils, eosinophils, lymphocytes, monocytes, basophils, 
other cells)
For patients randomized to the alectinib arm, reticulocytes and haptoglobin 
should be tested at baseline and a peripheral blood smear should be 
performed.  In case of Grade2 anemia as per NCI CTCAE v5.0 
(hemoglobin10 g/dL), hemoglobin, RBC count, reticulocytes, and haptoglobin 
should be tested.  In addition, a peripheral blood smear and a direct Coombs 
test (direct anti-globulin test [DAT]) should be performed.  This laboratory 
work-up should be conducted at each new occurrence of anemia of Grade2 in 
patients receiving alectinib.

Coagulation: PT (or INR), and aPTT (or PTT)

Serum chemistry: sodium, potassium, chloride, bicarbonate (optional), fasting 
glucose, BUN or urea, creatinine and CrCl (calculated according to the method of 
Cockcroft and Gault [1976]), CPK, gamma-glutamyl transferase (GGT), calcium,
total and direct bilirubin, total protein, albumin, ALT, AST, ALP, phosphorus,
magnesium, thyroid-stimulating hormone, and uric acid
For patients randomized to the alectinib arm, LDH should be tested at baseline.  
In case of Grade2 anemia as per NCI CTCAE v5.0 (hemoglobin10 g/dL), 
ALT, total and direct bilirubin and LDH should be tested.  This laboratory 
workup should be conducted at each new occurrence of anemia of Grade 2 or 
higher in patients receiving alectinib.

Urinalysis, including dipstick (pH, specific gravity, glucose, protein, ketones, blood)

Pregnancy test
All women who are not postmenopausal (12 months of nontherapy-induced 
amenorrhea) or surgically sterile will have a serum pregnancy test at screening, 
within 3 days of dosing. Urine pregnancy tests will be performed at all safety 

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visits during the course of the study. If a urine pregnancy test is positive, it 
must be confirmed by a serum pregnancy test.
The following samples will be sent to one or several central laboratories or to the 
Sponsor or a designee for analysis:

Samples for PK analysis (see Section 4.5.7.1)

Pretreatment tumor tissue sample obtained at screening for determination of ALK 
status for patient eligibility (see Section 4.5.7.2)

Tumor tissue sample obtained at the time of recurrence, if deemed clinically 
feasible, for exploratory research on biomarkers (see Section 4.5.7.2)

Plasma samples for exploratory research on biomarkers (see Section 4.5.7.2)
Biomarker plasma and tissue sampling will be in accordance with the Institutional 
Review Board (IRB)/Ethics Committee (EC)-approved Informed Consent Form and 
applicable laws (e.g., health authority requirements).
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (Section 4.5.10), biological samples will be destroyed 
when the final Clinical Study Report has been completed, with the following exceptions:

Tumor and plasma samples collected for biomarker research will be destroyed no 
later than 5 years after the final Clinical Study Report has been completed.

For enrolled patients, remaining tissue blocks [pretreatment and at recurrence] will 
be returned to the site upon request or 18 months after final closure of the study 
database, whichever occurs first.  For patients who are not enrolled, remaining 
pretreatment tissue blocks will be returned to the site no later than 6 months after 
eligibility determination.  Slides will not be returned.
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data.
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4.
4.5.7.1
Samples for Pharmacokinetic Assessments
Pharmacokinetic samples will be collected in all patients receiving alectinib treatment, as 
indicated in Appendix 1 and Appendix 2, and sent to a Sponsor-designated central 
laboratory for the analysis of alectinib and its major metabolite(s). All trough/pre-dose 

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PK samples should be collected within 2 hours before the morning doses of study 
medications.
Plasma concentrations for alectinib and its metabolite(s), if applicable, will be measured 
by specific and validated liquid chromatography tandem-mass spectrometry methods.  
For each sample, approximately 2 mL of venous blood will be collected for alectinib PK 
analysis at the timepoints specified in the PK schedule in Appendix 3.  Patients who 
permanently discontinue alectinib will also discontinue from all PK sampling and 
assessments.
For Japanese patients on alectinib treatment participating in serial/intensive PK sample 
collection (approximately the first 6 patients who consented to participate to the 
serial/intensive PK sample collection), additional PK samples will be collected at the 
timepoints specified in Appendix 3.  Serial/intensive PK is for the alectinib arm and only
applies to Japanese patients.
On the basis of continuous analysis of the data in this study and other studies, any 
sample type collection may be stopped at any time if the data from the samples collected 
do not produce useful information or at the discretion of the Sponsor.
4.5.7.2
Samples for Biomarker Assessments
Exploratory biomarker research may include, but will not be limited to, the analysis of 
DNA from tumor tissue and of circulating tumor DNA, and genes (e.g., ALK, KRAS, 
EGFR) and gene signatures associated with tumor biology and may involve analysis of 
somatic mutations, rearrangements, and genomic profiling through use of 
next-generation sequencing (NGS) of a comprehensive panel of oncogenes.  
Next-generation sequencing methods will not include whole-genome sequencing (WGS)
or whole-exome sequencing (WES).
Next-generation sequencing may be performed by Foundation Medicine.  If performed 
by Foundation Medicine, the investigator may obtain results from these analyses by 
requesting an NGS report directly from Foundation Medicine.  If allowed by local laws, 
the investigator may share and discuss the results with the patient, unless the patient 
chooses otherwise.  The NGS report is generated for research purposes and is not 
provided for the purpose of guiding future treatment decisions.  Results may not be 
available for samples that do not meet criteria for testing.
Pretreatment Tumor Tissue Samples
For ALK-positive patient samples tested locally, mandatory pretreatment tumor samples 
will be collected to centrally examine ALK status by Ventana IHC for retrospective 
confirmation.

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For sites where local ALK testing with an FDA-approved and CE-marked ALK test is not 
feasible, tumor samples can be tested centrally with the Ventana ALK IHC assay to 
determine ALK status for enrollment.
Tumor blocks (formalin-fixed, preferred 10% neutral-buffered formalin) are the preferred 
source, but if blocks are not available, unstained slides (minimum of 5 slides for ALK IHC 
test and 510 slides for biomarker analysis, cut less than 3 months before screening) 
are also accepted. Remaining tumor blocks will be returned to the sites; slides will not 
be returned. Central ALK testing to confirm or to determine patient ALK status will be
performed at a Sponsor-designated central laboratory. In addition, other ALK assays 
may be used for testing patient samples to establish performance characteristics of 
these assays for diagnostic development. Testing may be performed on all enrolled 
patients. These additional testing data will have no impact on eligibility, and testing will 
be performed only after eligibility is established for each patient. In addition, local ALK 
test information, baseline demographic, and disease-related characteristic data for all 
screened patients may be collected.  Pretreatment tumor samples will be used for 
targeted tumor sequencing if in accordance with local laws and regulations.
Tumor Tissue Samples at Time of Recurrence
Patients from both treatment arms will undergo a mandatory tumor biopsy sample
collection, unless not clinically feasible as assessed and documented by investigators, at
the first evidence of radiographic disease recurrence. These data will be used to explore
whether the radiographic findings are consistent with the presence of tumor. Biopsies to 
confirm recurrence should be performed within 30 days of radiographic detection of 
disease recurrence or prior to the next anti-cancer therapy, whichever is sooner, unless 
not clinically feasible.
Acceptable samples include:

Core-needle biopsies for deep tumor tissue; at least 3 cores, embedded into a 
single paraffin block, should be submitted for evaluation

Excisional, incisional, punch, or forceps biopsy specimens for cutaneous, 
subcutaneous, or mucosal lesions

Tumor tissue resection
Histological confirmation of recurrence or the new primary NSCLC will be performed at 
study site's local laboratory according to local general practice.
Following local histological confirmation of recurrence or the new primary NSCLC, 
formalin-fixed blocks (preferred; or if block is not available, a minimum of 510 unstained 
slides) should be sent to the Sponsor-designated central laboratory.  These samples will 
be used for targeted sequencing with a panel of cancer genes, including ALK, to explore
and elucidate molecular mechanisms of resistance to ALK inhibitors.

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Biomarker Plasma Samples
Mandatory plasma samples will be collected for the isolation of circulating tumor nucleic 
acids in order to detect early tumor recurrence and also to determine ALK
rearrangements and mutation status in ALK and other escape genes (e.g., EGFR, 
KRAS) by targeted sequencing. It will require 20 mL of blood (2 tubes of 10 mL each) to 
be collected at baseline, at recurring scheduled visits during treatment (see Appendix 4
for detailed information), and at disease recurrence.
4.5.8
Electrocardiograms
Single ECG recordings will be obtained at specified timepoints, as outlined in the 
schedules of activities (see Appendix 1 and Appendix 2), and may be obtained at 
unscheduled timepoints as indicated.
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements. 
Lead placement should be as consistent as possible.  Electrocardiogram recordings 
must be performed after the patient has been resting in a supine position for at least 
10 minutes.  All ECGs are to be obtained prior to other procedures scheduled at that 
same time (e.g., vital sign measurements, blood draws) and should not be obtained 
within 3 hours after any meal.  Circumstances that may induce changes in heart rate, 
including environmental distractions (e.g., television, radio, conversation) should be 
avoided during the pre-ECG resting period and during ECG recording.
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  Digital recordings will be stored at the site.  The following should be 
recorded in the appropriate eCRF:  heart rate, RR interval, QRS interval, PR duration, 
uncorrected QT interval, and QT interval corrected with use of Fridericia’s formula
(QTcF) based on the machine readings of the individual ECG tracings. In the event that 
the ECG machine does not directly provide results for RR and/or QTcF, these 
parameters can be derived using the formulae provided in Appendix 7.  Any morphologic 
waveform changes or other ECG abnormalities must be documented on the eCRF.  If 
considered appropriate by the Sponsor, ECGs may be analyzed retrospectively at a 
central laboratory.
If at a particular postdose timepoint the mean QTcF is 500 ms and/or 60 ms longer
than the baseline value, another ECG must be recorded, ideally within the next 
5 minutes, and ECG monitoring should continue until QTcF has stabilized on 
2 successive ECGs. Standard-of care treatment may be instituted per the discretion of 
the investigator. The investigator should also evaluate the patient for potential 
concurrent risk factors (e.g., electrolyte abnormalities, co-medications known to prolong 
the QT interval, severe bradycardia).

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If any ECG abnormality is associated with an adverse event, it must be recorded and
managed as described in Section 5.1.7.
4.5.9
Patient-Reported Outcomes
Patient-reported outcome questionnaires, namely the SF-36v2 and EQ-5D-5L, will be 
collected on paper at the investigational sites to more fully characterize the clinical 
profile of the study drugs. The questionnaires will be translated as required in the local 
language. Patient-reported outcome questionnaires scheduled for administration during 
a clinic visit are required to be completed by the patient at the investigational site at the 
start of the clinic visit before discussion of the patient’s health state, laboratory results, or 
health record; before administration of study treatment; and/or prior to any other study 
assessment(s) that could bias patients' responses to ensure that the validity of the 
instrument is not compromised and that data quality meets regulatory requirements.
The PRO questionnaires will be collected at baseline, every 3 weeks through Week 12; 
and every 12 weeks thereafter until recurrence of disease, withdrawal of consent, death, 
or Week 96, whichever occurs first.  Patient-reported outcome will also be collected at 
the safety follow-up visit.
Patients whose native language is not available on the PRO instrument or who are 
deemed by the investigator incapable of completing their PRO assessment after 
undergoing appropriate training are exempted from completing all PRO assessments.
4.5.9.1
SF-36v2
The SF-36v2 is a generic health-status measure with 36 items comprising 2 health 
component summary scores (i.e., physical component summary [PCS] and mental 
component summary [MCS]) as well as 8 health domain scores (i.e., physical 
functioning, role-physical, bodily pain, general health, vitality, social functioning, 
role-emotional, and mental health; Ware and Sherbourne 1992; Ware et al. 2007;
Ware et al. 2008; see Appendix 8).
4.5.9.2
EQ-5D-5L
The EQ-5D-5L is a generic preference-based health utility measure with questions about 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression that is used 
to build a composite of the patient's health status (EuroQol Group 1990; Brooks 1996; 
Herdman et al. 2011; Janssen et al. 2013; see Appendix 9).  An additional visual 
analogue scale is also used to measure health status, separately from the composite 
score.
4.5.10
Optional Samples for Research Biosample Repository
4.5.10.1
Overview of the Research Biosample Repository
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection, 
storage, and analysis of RBR specimens will facilitate the rational design of new 

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pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future.
Remains of tissue and plasma samples for study-related or nonstudy-related 
procedures that are performed or collected during the study will be collected for RBR 
from patients who give specific consent to participate in this optional research.  
Research Biosample Repository specimens will be used to achieve the following 
objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug 
absorption and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.10.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection and submission of biological samples to the RBR is contingent upon the 
review and approval of the exploratory research and the RBR portion of the 
Informed Consent Form by each site's IRB/EC and, if applicable, an appropriate 
regulatory body.  If a site has not been granted approval for RBR sampling, this section 
of the protocol (Section 4.5.10) will not be applicable at that site.
4.5.10.3
Sample Collection
No samples will be taken for RBR purposes only. However, any remaining tissue and 
plasma samples for study-related or nonstudy-related procedures that are performed or 
collected during the study may also be collected for RBR purposes. For all samples, 
date of consent should be recorded on the associated RBR page of the eCRF. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to ALK-positive NSCLC:

Biomarker plasma samples collected according to Appendix 4

Pretreatment tumor tissue samples collected at screening

Tumor samples from site of recurrence collected at time of recurrence
The above samples may be sent to one or more laboratories for analysis of germline or
somatic mutations via WGS, WES, NGS, or other genomic analysis methods.
Genomics is increasingly informing researchers' understanding of disease pathobiology.  
Whole-genome sequencing and WES provide a comprehensive characterization of the 

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genome and exome, respectively, and, along with clinical data collected in this study, 
may increase the opportunity for developing new therapeutic approaches.  Data will be 
analyzed in the context of this study but will also be explored in aggregate with data from 
other studies.  The availability of a larger dataset will assist in identification of important 
pathways, guiding the development of new targeted agents.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Research Biosample Repository specimens are to be stored until they are no longer 
needed or until they are exhausted.  However, the RBR storage period will be in 
accordance with the IRB/EC-approved Informed Consent Form and applicable laws 
(e.g., health authority requirements).
4.5.10.4
Confidentiality
Specimens and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RBR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law.
Given the complexity and exploratory nature of the analyses of RBR specimens, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study -data publication.
Data generated from RBR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise.
4.5.10.5
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR specimens.  
Patients who decline to participate will not provide a separate signature.

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The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF.
In the event of an RBR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RBR research.
4.5.10.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR specimens have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining samples 
will be handled as described in the signed Informed Consent Form and, when 
applicable, will be destroyed or will no longer be linked to the patient.  However, if RBR 
specimens have been tested prior to withdrawal of consent, results from those tests will
remain as part of the overall research data.  If a patient wishes to withdraw consent to 
the testing of his or her specimens, the investigator must inform the Medical Monitor in 
writing of the patient's wishes through use of the appropriate RBR Subject Withdrawal 
Form and, if the trial is ongoing, must enter the date of withdrawal on the RBR Research 
Sample Withdrawal of Informed Consent eCRF.  The patient will be provided with 
instructions on how to withdraw consent after the trial is closed.  A patient's withdrawal 
from Study BO40336 does not, by itself, constitute withdrawal of specimens from the 
RBR.  Likewise, a patient's withdrawal from the RBR does not constitute withdrawal from 
Study BO40336.
4.5.10.7
Monitoring and Oversight
Research Biosample Repository specimens will be tracked in a manner consistent with 
Good Clinical Practice by a quality-controlled, auditable, and appropriately validated 
laboratory information management system, to ensure compliance with data 
confidentiality as well as adherence to authorized use of specimens as specified in this 
protocol and in the Informed Consent Form.  Sponsor monitors and auditors will have 
direct access to appropriate parts of records relating to patient participation in the RBR 
for the purposes of verifying the data provided to the Sponsor.  The site will permit 
monitoring, audits, IRB/EC review, and health authority inspections by providing direct 
access to source data and documents related to the RBR samples.
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment if they experience any of the 
following:

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues to receive study treatment

Investigator or Sponsor determines it is in the best interest of the patient

Pregnancy

Inability to tolerate study medication on the basis of the investigator judgment

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See guidelines for managing adverse events and for comprehensive guidance on 
study-drug discontinuation in Section 5.1.7.
Patients who discontinue study drug prematurely will be asked to return to the clinic for 
safety assessments at a safety follow-up visit, which occurs 28 days after the last dose 
of alectinib or 28 days after the end of the last cycle of chemotherapy (7 weeks after 
Day 1 of the last cycle).  Disease assessments must continue until recurrence as per the 
schedule of activities (see Appendix 1 and Appendix 2).
Patients who discontinue treatment prior to completion of the protocol-defined treatment 
period will remain in the study and should continue to be followed for disease 
assessments until recurrence, and for OS, provided they have not withdrawn consent for 
the study.
If patients stop scheduled assessments after study drug discontinuation, they will be 
contacted via phone calls regularly, as long as the patient hasn’t withdrawn from the 
study, for disease recurrence status if no recurrence occurs, for survival status, and for
any new anti-cancer therapy(ies) until death, withdrawal from the study, or the Sponsor 
terminates the study.
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced.
4.6.2
Patient Discontinuation from Study
Patients will return to the clinic for a study completion visit at the time of consent 
withdrawal or study closure.
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent

Study termination or site closure
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF. Patients will not be followed for any reason after consent for the 
study has been withdrawn; however, if patient withdraws from the study, site may use a 
public information source (e.g., county records) to obtain information about survival 
status. If a patient requests to be withdrawn from the study, this request must be 
documented in the source documents and signed by the investigator.  Patients who 
withdraw from the study will not be replaced.

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After study completion visit, no further information will be collected.
4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients

Patient enrollment is unsatisfactory
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.
4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council on Harmonisation of Technical 
Requirements for Registration of pharmaceuticals for Human Use (ICH) guideline 
for Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations 
have been fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
The safety plan for patients receiving alectinib in this study is based on clinical 
experience and results from completed and ongoing studies in the metastatic setting as 
well as postmarketing experience. For the comparator arm, warnings and precautions 
are based on product labels for the respective regimens.  The anticipated safety risks for
alectinib and comparator treatments are outlined below.  For a complete summary of 
safety information, please refer to the Alectinib Investigator's Brochure and the current 
version of the local product labels for the comparator arm treatments.
An external iDMC will review the safety data collected during the conduct of the study 
and perform periodic review. Further details will be outlined in the iDMC Charter.
All summaries and analyses by treatment arm for the iDMC's review will be prepared by 
an external independent data coordinating center. Members of the iDMC will be external 
to the Sponsor and will follow a charter that outlines their roles and responsibilities. 
Any outcomes of these reviews that affect study conduct will be communicated in a 
timely manner to the investigators for notification of the IRB/EC. A detailed plan will be 
included in the iDMC Charter.

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Several measures will be taken to ensure the safety of patients participating in this 
study.  Eligibility criteria have been designed to exclude patients at higher risk for 
toxicities.  Patients will undergo safety monitoring during the study, including 
assessment of the nature, frequency, and severity of adverse events.  In addition, 
guidelines for managing adverse events, including criteria for dosage modification and 
treatment interruption or discontinuation, are provided below.
5.1.1
Risks Associated with Alectinib
Events described in Section 5.1.1 will be closely monitored and represent selected 
adverse events for this study.
A more detailed safety profile of alectinib is provided in the Alectinib 
Investigator's Brochure.
5.1.1.1
Interstitial Lung Disease
Tyrosine kinase inhibitors, including ALK inhibitors crizotinib and ceritinib, have been 
associated with the occurrence of treatment-related interstitial lung disease 
(ILD)/pneumonitis (including fatalities). Signs and symptoms may include dyspnea, 
cough, fatigue, and pulmonary infiltrates.
Guidelines for management and follow-up of patients who develop ILD or pneumonitis 
are provided in Table 8.
5.1.1.2
Hepatotoxicity
Hepatobiliary findings were observed in both the rat and monkey 4- and 13-week toxicity
studies with alectinib, and findings in the 13-week studies were similar to those of the
4-week studies. The findings were at or close to clinically relevant exposures.
Hepatobiliary effects included increased hepatic ALP, direct bilirubin, GGT and liver
weight, vacuolation/degeneration/necrosis of bile duct epithelium, inflammatory cell
infiltration in Glisson's sheath, enlargement/focal necrosis of hepatocytes, and
enlargement of Kupffer cells.
Abnormal hepatobiliary laboratory test values, such as increased ALT, AST, or bilirubin
levels, have been observed after alectinib administration. Aspartate aminotransferase, 
ALT, and total bilirubin levels temporarily increased in the initial stages of treatment and 
then improved. In patients with Grades 34 AST/ALT elevations, documented 
drug-induced liver injury by liver biopsy was reported with uncommon frequency in 
alectinib pivotal clinical trials. Concurrent elevations in ALT or AST 3ULN and total 
bilirubin 2ULN, with normal ALP, occurred with uncommon frequency in patients 
treated in alectinib clinical trials.
In patients treated with other tyrosine kinase ALK inhibitor drugs, abnormal liver function
tests and drug-induced hepatotoxicity, including cases with fatal outcome, have been
reported.

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Guidelines for management and follow-up of patients who develop hepatotoxicity are 
provided in Table 8.
5.1.1.3
Anemia
Hematologic findings were observed in both the rat and cynomolgus monkey 4- and 
13-week toxicity studies with alectinib. The findings were at or close to clinically relevant 
exposures. Changes in RBC morphology (e.g., poikilocytosis, red cell fragmentation)
and in other erythroid parameters (e.g., reticulocyte count, hemoglobin, hematocrit, 
mean corpuscular volume) were seen with alectinib in these studies. However, the 
changes on the erythroid system were considered to be of little toxicological significance 
because they were slight (0.94- to 1.3-fold vs. baseline), considered reversible, and did 
not exacerbate with prolonged treatment with alectinib.
Cases of anemia, including hemolytic anemia, have been reported in patients treated 
with alectinib; the majority of the events were Grades 1 and 2.
To further enhance the understanding of hemolytic anemia in patients treated with 
alectinib, specific laboratory parameters for hemolytic anemia (blood smear, 
reticulocytes, haptoglobin, and LDH) will be tested at baseline for patients randomized to 
the alectinib arm.  In case of Grade2 anemia as per NCI CTCAE v5.0 
(hemoglobin10 g/dL), laboratory tests including hemoglobin, RBC count, reticulocytes, 
haptoglobin, ALT, LDH, total and direct bilirubin, peripheral blood smear, and a direct 
Coombs test (DAT) should be performed.
Guidelines for management and follow-up of patients who develop anemia (including
hemolytic anemia) are provided in Table 8.
5.1.1.4
Gastrointestinal Disorders
Gastrointestinal disorders such as nausea, vomiting, constipation, diarrhea, and 
stomatitis have been reported with alectinib. Similar GI disorders have been observed 
with other TKIs, including ALK inhibitors crizotinib and ceritinib.
Sodium dodecyl sulfate is a surfactant excipient in the clinical formulation at a 
concentration of 50% (weight per weight SLS to active pharmaceutical ingredient). 
This excipient is a known GI irritant and may be associated with GI adverse events, 
including nausea, vomiting, diarrhea, and abdominal pain. Of note, GI tract toxicity as
the safety determinant of SLS is not because of systemic toxicity but a consequence of
local irritation to the GI tract.  In general, when mixed with diet, higher levels of 
SLSa known GI tract mucosal irritantare tolerated versus gavage administrations.
Guidelines for management and follow-up of patients who develop GI disorders are 
provided in Table 8.

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5.1.1.5
Skin Disorders
Results of an in vitro phototoxicity study indicated that alectinib may have phototoxic
potential. Skin rash has been reported with majority of TKIs including those targeting the 
ALK receptor (Hartmann et al. 2009).
Cases of skin rash and photosensitivity have been reported with alectinib and were
generally Grades 1 and 2.
Guidelines for management and follow-up of patients who develop skin disorders are 
provided in Table 8.
5.1.1.6
Vision Disorders
In the rat quantitative whole-body autoradiography study, tissue radioactivity
disappeared over time, following a time course comparable with that of plasma
radioactivity, except for melanin-containing tissues such as uveal tract of eyes, which
had much higher and more sustained exposure in pigmented rats. This is consistent
with what is commonly observed for lipophilic basic drugs.
Vision disorders, including diplopia, photopsia, blurred vision, visual impairment, and
vitreous floaters, have been reported with several TKIs, including ALK inhibitors
(crizotinib; Shaw et al. 2013).
Vision disorders, such as blurred vision, visual impairment, vitreous floaters, reduced 
visual acuity, asthenopia, and diplopia, have been reported with alectinib and were 
generally Grades 1 and 2.
Guidelines for management and follow-up of patients who develop vision disorders are 
provided in Table 8.
5.1.1.7
Edema
Most TKIs, including ALK inhibitor crizotinib, have been associated with edema. 
Events of edema (mainly peripheral edema) have been reported with alectinib, mostly 
Grades 1 and 2.
Guidelines for management and follow-up of patients who develop edema are provided 
in Table 8.
5.1.1.8
Bradycardia
In the cynomolgus monkey telemetry study, there were no effects on the ECG, any of 
the other cardiovascular parameters, or body temperature at doses of up to 15 mg/kg 
(mean maximum observed concentration [Cmax]: 279 ng/mL).
In a preliminary nonGood Laboratory Practice telemetry study in conscious cynomolgus
monkeys, there were no effects on ECG or heart rate.

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Events of bradycardia have been reported with alectinib. Data based on ECG and pulse 
measurements from the ongoing alectinib clinical trials show a decrease in heart rate 
during alectinib treatment, which is mainly asymptomatic. In patients treated with other 
ALK inhibitors (crizotinib and ceritinib), bradycardia adverse events, as well as 
decreases in heart rate based on ECG and pulse measurements, have also been 
reported (Xalkori U.S. Package Insert; Zykadia™U.S. Package Insert).
In case of bradycardia, concomitant medications must be evaluated to identify those that
are known to cause bradycardia, as well as anti-hypertensive medications; and
discontinuation or dose reduction of these concomitant medications must be considered.
In case of bradycardia adverse event related to alectinib, refer to adverse event
grade-dependent rules for dose modification outlined in the first section of Table 8.
5.1.1.9
Abnormal Renal Function (Serum Creatinine Increased, 
Acute Kidney Injury)
In the 2-week, nonclinical primate study at 60 mg/kg alectinib, an increase in creatinine 
was observed but no changes were observed in histopathology. In all other nonclinical
primate studies, no changes in creatinine were observed.
Serum creatinine increases have been reported with alectinib treatment with common 
frequency. Acute kidney injury, including fatal outcome, has been observed with 
uncommon frequency in patients treated in alectinib clinical trials.
Serum creatinine increases and/or decreases in GFR, renal failure, and/or renal 
impairment have been reported for other ALK inhibitors (crizotinib, ceritinib).
Guidelines for management and follow-up of patients who develop abnormal renal 
function are provided in Table 8.
5.1.1.10
Severe Myalgia and CPK Elevations
Postmarketing experience with some TKIs includes reports of myopathy and
rhabdomyolysis (Hohenegger 2012).
Blood CPK increases, generally Grades 1 and 2, and muscular adverse events have 
been reported with alectinib treatment. Grade 3 myalgia and CPK elevations have been 
reported with alectinib treatment and were reversible upon dose reduction and 
interruption.
Guidelines for management and follow-up of patients who develop severe myalgia and 
CPK elevations are provided in Table 8.

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5.1.1.11
Dysgeusia
Events of dysgeusia have been reported in clinical trials with alectinib and were 
generally of Grades 1 and 2 severity. All patients who experienced dysgeusia continued 
alectinib treatment without any modification.
In patients treated with other ALK inhibitors, such as crizotinib and ceritinib, dysgeusia 
has been reported.
In case of dysgeusia adverse event related to alectinib, refer to adverse event
grade-dependent rules for dose modification outlined in the first section of Table 8.
5.1.1.12
Alkaline Phosphatase Increase
Cases of increased blood ALP have been observed after alectinib administration.
The majority of the cases were of Grades 1 and 2 severity.
In patients treated with other ALK inhibitors, increased blood ALP has been reported.
In case of ALP increase adverse event related to alectinib, refer to adverse event
grade-dependent rules for dose modification outlined in the first section of Table 8.
5.1.2
Risks Associated with Vinorelbine
For full details regarding risks, warnings, and precautions relating to vinorelbine 
treatment, refer to the current version of the local product label. Management of patients 
who experience adverse events related to vinorelbine is outlined in Section 5.1.8.
The most common adverse reactions (incidence 20%) of vinorelbine are neutropenia, 
anemia, liver enzyme elevation, nausea, vomiting, asthenia, constipation, injection-site 
reaction, and peripheral neuropathy.
5.1.2.1
Myelosuppression
Severe myelosuppression resulting in serious infection, septic shock, and death may 
occur. Myelosuppression manifested by neutropenia, anemia, and thrombocytopenia 
occur with vinorelbine as a single agent and in combination with cisplatin. 
Neutropenia is the major dose-limiting toxicity (DLT).  Neutropenia nadirs occur between 
7 and 10 days after dosing, with neutropenia count recovery usually occurring within the 
following 714 days.
5.1.2.2
Hepatotoxicity
Drug-induced liver injury manifested by elevations of AST and bilirubin can occur in 
patients receiving vinorelbine alone or in combination with cytotoxic agents.
5.1.2.3
Severe Constipation and Bowel Obstruction
Severe constipation and bowel obstruction, including necrosis and perforation, can 
occur. A prophylactic bowel regimen should be instituted to mitigate potential 
constipation, bowel obstruction, and/or paralytic ileus, considering adequate dietary fiber 

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intake, hydration, and routine use of stool softeners.  Patients should be monitored for 
abdominal pain and severe constipation.
5.1.2.4
Extravasation and Tissue Injury
Extravasation can result in severe tissue injury, necrosis, and/or thrombophlebitis. 
If signs or symptoms of extravasation occur, administration of vinorelbine should be 
immediately stopped and the recommended management procedures instituted.
5.1.2.5
Neurologic Toxicity
Severe sensory and motor neuropathies, including severe neuropathies, can occur in 
patients receiving vinorelbine. Patients should be monitored for new or worsening signs 
and symptoms of neuropathy, such as paresthesia, hyperesthesia, hyporeflexia, and 
muscle weakness, while receiving vinorelbine.
5.1.2.6
Pulmonary Toxicity and Respiratory Failure
Pulmonary toxicity, including severe acute bronchospasm, interstitial pneumonitis, acute 
respiratory distress syndrome (ARDS), and respiratory failure, can occur, including 
fatalities. The mean time to onset of interstitial pneumonitis and ARDS after vinorelbine 
administration was 1 week (range: 38 days).  Patients should be monitored for 
respiratory disorders (dyspnea and bronchospasm).
5.1.2.7
Embryo-Fetal Toxicity
Vinorelbine can cause fetal harm when administered to a pregnant woman.  Refer to the 
current version of the local label for detailed guidance on contraception as well as details 
of impact on fertility.
5.1.3
Risks Associated with Gemcitabine
For full details regarding risks, warnings, and precautions relating to gemcitabine 
treatment, refer to the current version of the local product label.  Management of patients 
who experience adverse events related to gemcitabine is outlined in Section 5.1.9.
The most common (20%) adverse reactions for the single-agent treatment are 
nausea/vomiting, anemia, hepatic transaminitis, neutropenia, increased ALP, proteinuria, 
fever, hematuria, rash, thrombocytopenia, dyspnea, and peripheral edema.
5.1.3.1
Schedule-Dependent Toxicity
Gemcitabine infusion times that are longer than 60 minutes or gemcitabine 
administration that occurs more frequently than once a week have been shown to 
increase toxicity (occurrence of clinically significant hypotension, severe flu-like 
symptoms, myelosuppression, and asthenia). The half-life of gemcitabine is influenced 
by the length of the infusion.
Pulmonary toxicity has been reported with the use of gemcitabine.  Myelosuppression 
manifested by neutropenia, thrombocytopenia, and anemia has been reported with 
gemcitabine as a single agent or in combination with other cytotoxic drugs.  

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Hemolytic-uremic syndrome (HUS) and/or renal failure have been reported following 1 or 
more doses of gemcitabine.  Renal failure leading to death or requiring dialysis, despite 
discontinuation of therapy, has been rarely reported.  Serious hepatotoxicity, including 
liver failure and death, has been reported very rarely in patients receiving gemcitabine 
alone or in combination with other potentially hepatotoxic drugs.  Patients will be 
monitored for gemcitabine-related adverse events.
5.1.3.2
Myelosuppression
Myelosuppression manifested by neutropenia, thrombocytopenia, and anemia occurs 
with gemcitabine as a single agent, and the risks are increased when combined with 
other cytotoxic drugs.  Monitor for myelosuppression prior to each cycle.
5.1.3.3
Pulmonary Toxicity and Respiratory Failure
Pulmonary toxicity, including interstitial pneumonitis, pulmonary fibrosis, pulmonary 
edema, and ARDS, has been reported. In some cases, these pulmonary events can 
lead to fatal respiratory failure despite discontinuation of therapy. The onset of 
pulmonary symptoms may occur up to 2 weeks after the last dose of gemcitabine.
5.1.3.4
Hemolytic-Uremic Syndrome
Hemolytic-uremic syndrome, including fatalities from renal failure or the requirement for 
dialysis, can occur in patients treated with gemcitabine. Renal function should be 
assessed prior to initiation of gemcitabine, and assessment should be repeated 
periodically during treatment. Consider the diagnosis of HUS in patients who develop
anemia with evidence of microangiopathic hemolysis, elevation of bilirubin or LDH, or 
reticulocytosis; severe thrombocytopenia; or evidence of renal failure (elevation of serum 
creatinine or BUN).  Renal failure may not be reversible even with discontinuation of 
therapy.
5.1.3.5
Hepatic Toxicity
Drug-induced liver injury, including liver failure and death, has been reported in patients 
receiving gemcitabine alone or in combination with other potentially hepatotoxic drugs.  
Administration in patients with concurrent liver metastases or a preexisting medical 
history or hepatitis, alcoholism, or liver cirrhosis can lead to exacerbation of the 
underlying hepatic insufficiency. Assess hepatic function prior to initiation of 
gemcitabine treatment and periodically during treatment.
5.1.3.6
Embryo-Fetal Toxicity
Gemcitabine can cause fetal harm when administered to a pregnant woman, based on 
its mechanism of action.  Refer to the current version of local label for detailed guidance 
on contraception as well as details of impact on fertility.

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5.1.3.7
Exacerbation of Radiation Therapy Toxicity
Gemcitabine is not indicated for use in combination with radiation therapy.  Severe and 
life-threatening toxicity may occur when gemcitabine is administered during or within 
7 days of radiation therapy.
5.1.3.8
Capillary Leak Syndrome
Capillary leak syndrome with severe consequences has been reported in patients 
receiving gemcitabine as a single agent or in combination with other chemotherapeutic 
agents.
5.1.3.9
Posterior Reversible Encephalopathy Syndrome
Posterior reversible encephalopathy syndrome (PRES) has been reported in patients 
receiving gemcitabine as a single agent or in combination with other chemotherapeutic 
agents. Posterior reversible encephalopathy syndrome can present with headache, 
seizure, lethargy, hypertension, confusion, blindness, and other visual and neurologic 
disturbances. Diagnosis of PRES should be confirmed with MRI.
5.1.4
Risks Associated with Pemetrexed
For full details regarding risks, warnings, and precautions relating to pemetrexed 
treatment, refer to the current version of the local product label. Management of patients 
who experience adverse events related to pemetrexed is outlined in Section 5.1.10.
The most commonly reported undesirable adverse effects related to pemetrexed, 
whether used as monotherapy or in combination, are anorexia, nausea, vomiting, 
diarrhea, constipation, stomatitis, pharyngitis, mucositis, neutropenia, anemia, 
leukopenia, and thrombocytopenia.
5.1.4.1
Myelosuppression
Pemetrexed can cause severe bone marrow suppression resulting in cytopenia and an 
increased risk of infection, and may result in a requirement for transfusions. 
Myelosuppression is usually the DLT.
Less toxicity and reduction in Grade 3/4 hematological and non-hematological toxicities,
such as neutropenia, febrile neutropenia, and infection with Grade 3/4 neutropenia, were 
reported when pretreatment with folic acid and vitamin B12 was administered. 
Therefore, all patients treated with pemetrexed must be instructed to take folic acid and 
vitamin B12 as a prophylactic measure to reduce treatment-related toxicity
(see Section 4.3.2.2).
5.1.4.2
Renal Failure
Pemetrexed can cause severe, and sometimes fatal, renal failure. Do not administer 
when CrCl is 45 mL/min.
Due to the GI toxicity of pemetrexed given in combination with cisplatin, severe 
dehydration has been observed. Therefore, patients should receive adequate 

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anti-emetic treatment and appropriate hydration prior to and/or after receiving treatment
(see Section 4.3.2.2).
5.1.4.3
Bullous and Exfoliative Skin Toxicity
Serious and sometimes fatal, bullous, blistering, and exfoliative skin toxicity, including 
cases suggestive of Stevens-Johnson syndrome/toxic epidermal necrolysis, can occur 
with pemetrexed. Skin reactions, such as rash, desquamation, alopecia, and pruritus, 
have been reported in pemetrexed-treated patients not pretreated with a corticosteroid.
5.1.4.4
Interstitial Pneumonitis
Serious interstitial pneumonitis, including fatal cases, can occur with pemetrexed
treatment.
5.1.4.5
Radiation Recall
Radiation recall can occur in patients who received radiation weeks to years previously. 
Monitor patients for inflammation or blistering in areas of previous radiation treatment.
5.1.4.6
Cardiovascular Events
Serious cardiovascular events, including myocardial infarction and cerebrovascular 
events, have been uncommonly reported during clinical studies with pemetrexed, usually 
when given in combination with another cytotoxic agent. Most of the patients in whom 
these events have been observed had preexisting cardiovascular risk factors.
5.1.4.7
Immunosuppression
An immunosuppressed status is common in cancer patients. As a result, concomitant 
use of live, attenuated vaccines (except yellow fever, which is contraindicated) is not
recommended.
5.1.4.8
Embryo-Fetal Toxicity
Based on findings from nonclinical studies and its mechanism of action, pemetrexed can 
cause fetal harm when administered to a pregnant woman. Refer to the current version 
of local label for detailed guidance on contraception as well as details of impact on 
fertility.
5.1.5
Risks Associated with Cisplatin
For full details regarding risks, warnings, and precautions relating to cisplatin treatment, 
refer to the current version of the local product label. Management of patients who 
experience adverse events related to cisplatin is outlined in Section 5.1.11.
Cumulative renal toxicity associated with cisplatin is severe. Other major dose-related 
toxicities are myelosuppression, nausea, and vomiting. Ototoxicity, which may be more 
pronounced in children and is manifested by tinnitus and/or loss of high-frequency 
hearing and occasionally deafness, is significant.  Anaphylactic-like reactions to cisplatin 
have been reported. Facial edema, bronchoconstriction, tachycardia, and hypotension 

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may occur within minutes of cisplatin administration. Epinephrine, corticosteroids, and 
antihistamines have been effectively employed to alleviate symptoms.
5.1.5.1
Nephrotoxicity
Cisplatin causes severe cumulative nephrotoxicity.  Dose-related and cumulative renal 
insufficiency, including acute renal failure, is the major DLT of cisplatin. Renal toxicity is 
first noted during the second week after a dose and is manifested by elevations in BUN 
and creatinine, serum uric acid, and/or a decrease in CrCl. Renal toxicity becomes more 
prolonged and severe with repeated courses of the drug.  Elderly patients may be more 
susceptible to nephrotoxicity.  Impairment of renal function has been associated with 
renal tubular damage.
The administration of cisplatin using a 6- to 8-hour infusion with IV hydration and 
mannitol has been used to reduce nephrotoxicity.  However, renal toxicity still can occur 
after utilization of these procedures. A urine output of 100 mL/hour or greater will tend to 
minimize cisplatin nephrotoxicity. This can be accomplished by pre-hydration with 2 L of 
an appropriate IV solution, and similar post-cisplatin hydration (recommended 
2500 mL/m2/24 hours).
5.1.5.2
Ototoxicity
Ototoxicity has been observed in patients treated with a single dose of cisplatin 
50 mg/m2 and is manifested by tinnitus and/or hearing loss in the high-frequency range 
(40008000 Hz).  Decreased ability to hear normal conversational tones may occur. 
Deafness after the initial dose of cisplatin has been reported.  Hearing loss can be 
unilateral or bilateral and tends to become more frequent and severe with repeated 
cisplatin doses.  It is unclear whether cisplatin-induced ototoxicity is reversible. 
Vestibular toxicity has also been reported.  Ototoxic effects may be related to the Cmax of 
cisplatin.  Ototoxicity can occur during treatment or be delayed. Audiometric monitoring 
should be performed according to the local prescribing information. The risk of 
ototoxicity may be increased by prior or simultaneous cranial irradiation, and it may be 
more severe in patients being treated with other ototoxic drugs (e.g., aminoglycosides 
and vancomycin) and in patients with renal impairment.  Genetic factors (e.g., variants in 
the thiopurine S-methyltransferase gene) may contribute to cisplatin-induced ototoxicity,
although this association has not been consistent across populations and study designs.
5.1.5.3
Hematologic Toxicities
Myelosuppression can occur in patients treated with cisplatin. The nadirs in circulating 
platelets and leukocytes occur between Days 1823 (range: 7.545 days), with most 
patients recovering by Day 39 (range: 1362 days). Leukopenia and thrombocytopenia 
are more pronounced at higher doses (50 mg/m2).  Anemia (decrease of 
2 g hemoglobin/100 mL) occurs at approximately the same frequency and with the same 
timing as leukopenia and thrombocytopenia. Fever and infection have also been 
reported in patients with neutropenia. Potential fatalities due to infection (secondary to 

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myelosuppression) have been reported. Elderly patients may be more susceptible to 
myelosuppression.
In addition to anemia secondary to myelosuppression, a Coombs-positive hemolytic 
anemia has been reported. In the presence of cisplatin hemolytic anemia, a further 
course of treatment may be accompanied by increased hemolysis, and this risk should 
be weighed by the treating physician.
5.1.5.4
Gastrointestinal Toxicities
Marked nausea and vomiting occur in almost all patients treated with cisplatin and may 
be so severe that the drug must be discontinued. Nausea and vomiting may begin 
within 14 hours after treatment and last up to 24 hours. Various degrees of vomiting, 
nausea, and/or anorexia may persist for up to 1 week after treatment. Delayed nausea 
and vomiting (begins or persists 24 hours or more after chemotherapy) has occurred in 
patients attaining complete emetic control on the day of cisplatin therapy.  Diarrhea has 
also been reported.
5.1.5.5
Vascular Toxicities
Vascular toxicities coincident with the use of cisplatin in combination with other 
anti-neoplastic agents have been reported. The events are clinically heterogeneous and 
may include myocardial infarction, cerebrovascular accident, thrombotic 
microangiopathy (HUS), or cerebral arteritis. Various mechanisms have been proposed 
for these vascular complications.  There are also reports of Raynaud phenomenon 
occurring in patients treated with the combination of bleomycin and vinblastine with or 
without cisplatin.  It has been suggested that hypomagnesemia developing coincident 
with the use of cisplatin may be an added, although not essential, factor associated with 
this event. However, it is currently unknown if the cause of Raynaud phenomenon in 
these cases is the disease, underlying vascular compromise, bleomycin, vinblastine, 
hypomagnesemia, or a combination of any of these factors.
5.1.5.6
Serum Electrolyte Disturbances
Hypomagnesemia, hypocalcemia, hyponatremia, hypokalemia, and hypophosphatemia 
have been reported to occur in patients treated with cisplatin and are probably related to 
renal tubular damage. Tetany has been reported in those patients with hypocalcemia 
and hypomagnesemia.  Generally, normal serum electrolyte levels are restored by 
administering supplemental electrolytes and discontinuing cisplatin.  Inappropriate 
anti-diuretic hormone syndrome has also been reported.
5.1.5.7
Hyperuricemia
Hyperuricemia has been reported to occur at approximately the same frequency as the 
increases in BUN and serum creatinine. It is more pronounced after doses greater than 
50 mg/m2, and peak levels of uric acid generally occur between 35 days after the dose. 
Allopurinol therapy for hyperuricemia effectively reduces uric acid levels.

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5.1.5.8
Neurotoxicity
Neurotoxicity, usually characterized by peripheral neuropathies, has been reported. 
The neuropathies usually occur after prolonged therapy (47 months); however,
neurologic symptoms have been reported to occur after a single dose. 
Although symptoms and signs of cisplatin neuropathy usually develop during treatment, 
symptoms of neuropathy may begin 38 weeks after the last dose of cisplatin. 
Cisplatin therapy should be discontinued when the symptoms are first observed.  
The neuropathy, however, may progress further even after stopping treatment. 
Preliminary evidence suggests peripheral neuropathy may be irreversible in some 
patients. Elderly patients may be more susceptible to peripheral neuropathy.
Lhermitte sign, dorsal column myelopathy, and autonomic neuropathy have also been 
reported. Loss of taste, seizures, leukoencephalopathy, and reversible posterior 
leukoencephalopathy syndrome have also been reported.  Muscle cramps, defined as 
localized, painful, involuntary skeletal muscle contractions of sudden onset and short 
duration, have been reported and were usually associated in patients receiving a 
relatively high cumulative dose of cisplatin and with a relatively advanced symptomatic 
stage of peripheral neuropathy.
5.1.5.9
Ocular Toxicity
Optic neuritis, papilledema, and cerebral blindness have been reported in patients 
receiving standard recommended doses of cisplatin.  Improvement and/or total recovery 
usually occurs after discontinuing cisplatin. Steroids with or without mannitol have been 
used; however, efficacy has not been established.
Blurred vision and altered color perception have been reported after the use of regimens 
with higher doses of cisplatin or greater dose frequencies than recommended in the 
package insert. The altered color perception manifests as a loss of color discrimination, 
particularly in the blue-yellow axis. The only finding on funduscopic examination is 
irregular retinal pigmentation of the macular area.
5.1.5.10
Anaphylactic-Like Reactions
Anaphylactic-like reactions have been reported in patients previously exposed to 
cisplatin. The reactions consist of facial edema, wheezing, tachycardia, and 
hypotension within a few minutes of drug administration.  Reactions may be controlled 
by IV epinephrine with corticosteroids and/or antihistamines as indicated. 
Patients receiving cisplatin should be observed carefully for possible anaphylactic-like 
reactions, and supportive equipment and medication should be available to treat such a 
complication.
5.1.5.11
Hepatotoxicity
Transient elevations of liver enzymes, especially AST, as well as bilirubin, have been 
reported to be associated with cisplatin administration at the recommended doses.

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5.1.5.12
Other Events
Cardiac abnormalities, hiccups, elevated serum amylase, rash, alopecia, malaise, 
asthenia, and dehydration have been reported.  Local soft tissue toxicity has been 
reported following extravasation of cisplatin. Severity of the local tissue toxicity appears 
to be related to the concentration of the cisplatin solution.  Infusion of solutions with a 
cisplatin concentration greater than 0.5 mg/mL may result in tissue cellulitis, fibrosis, 
necrosis, pain, edema, and erythema.
5.1.5.13
Embryo-Fetal Toxicity
Cisplatin can cause fetal harm when administered to a pregnant woman.  Refer to the 
current version of local label for detailed guidance on contraception as well as details of 
impact on fertility.
5.1.5.14
Carcinogenic Potential
In humans, in rare cases the appearance of acute leukemia has coincided with use of 
cisplatin, which was in general associated with other leukemogenic agents.  Cisplatin is 
a bacterial mutagen and causes chromosome aberrations in cultures on animal cells. 
Carcinogenicity is possible but has not been demonstrated. Cisplatin is teratogenic and 
embryotoxic in mice.
5.1.6
Risks Associated with Carboplatin
For full details regarding risks, warnings, and precautions relating to carboplatin 
treatment, refer to the current version of the local product label. Management of patients 
who experience adverse events related to carboplatin is outlined in Section 5.1.12 .
Carboplatin is known to cause bone marrow suppression including myelosuppression, 
anemia, and thrombocytopenia. Carboplatin-based chemotherapy is considered to be 
moderately emetogenic. Patients will be monitored for carboplatin-related adverse 
events.
5.1.6.1
Hematologic Toxicities
Bone marrow suppression (leukopenia, neutropenia, and thrombocytopenia) is 
dosedependent and is also the DLT. Peripheral blood counts should be frequently 
monitored during treatment with carboplatin and, when appropriate, until recovery is 
achieved. Median nadir occurs at Day 21 in patients receiving single-agent carboplatin. 
In general, single intermittent courses of carboplatin should not be repeated until 
leukocyte, neutrophil, and platelet counts have recovered.  The hematologic effects, 
although usually reversible, can result in infectious or hemorrhagic complications, 
including drug-related deaths. Fever has also been reported in patients with 
neutropenia.
Anemia with hemoglobin less than 11 g/dL has been observed with carboplatin 
treatment. Since anemia is cumulative, transfusions may be needed during treatment 
with carboplatin, particularly in patients receiving prolonged therapy. Bone marrow 

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suppression is increased in patients who have received prior therapy, especially 
regimens including cisplatin.
Marrow suppression is also increased in patients with impaired kidney function. 
Initial carboplatin dosages in these patients should be appropriately reduced, and blood 
counts should be carefully monitored between courses. The use of carboplatin in 
combination with other bone marrow suppressing therapies must be carefully managed 
with respect to dosage and timing in order to minimize additive effects.
5.1.6.2
Nephrotoxicity
Development of abnormal renal function test results is uncommon.  Most of the reported 
abnormalities have been mild, and about one-half of them were reversible. Even though 
carboplatin has limited nephrotoxic potential, concomitant treatment with 
aminoglycosides has resulted in increased renal and/or audiologic toxicity, and caution 
must be exercised when a patient receives both drugs.
Creatinine clearance has proven to be the most sensitive measure of kidney function in 
patients receiving carboplatin, and it appears to be the most useful test for correlating 
drug clearance and bone marrow suppression.
5.1.6.3
Ototoxicity
Clinically significant hearing loss has been reported to occur in pediatric patients when 
carboplatin was administered at higher than recommended doses in combination with 
other ototoxic agents.
5.1.6.4
Gastrointestinal Toxicities
Carboplatin can induce emesis, which can be more severe in patients previously 
receiving emetogenic therapy. The incidence and intensity of emesis have been 
reduced by using premedication with anti-emetics. Both nausea and vomiting usually 
cease within 24 hours of treatment and are often responsive to anti-emetic measures. 
Although no conclusive efficacy data exist with the following schedules of carboplatin, 
lengthening the duration of single IV administration to 24 hours or dividing the total dose 
over 5 consecutive daily pulse doses has resulted in reduced emesis. Other GI effects 
observed frequently are pain, diarrhea, and constipation.
5.1.6.5
Neurotoxicity
Peripheral neuropathies have been observed in patients receiving carboplatin, with mild 
paresthesias occurring most frequently. Although peripheral neurotoxicity is infrequent, 
its incidence is increased in patients older than 65 years and in patients previously 
treated with cisplatin. Preexisting cisplatin-induced neurotoxicity does not worsen in 
about 70% of the patients receiving carboplatin as secondary treatment.

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5.1.6.6
Ocular Toxicity
Loss of vision, which can be complete for light and colors, has been reported after the 
use of carboplatin with doses higher than those recommended.  Vision appears to 
recover totally or to a significant extent within weeks of stopping these high doses.
5.1.6.7
Allergic Reactions
As in the case of other platinum-coordination compounds, allergic reactions to 
carboplatin have been reported (rash, urticaria, erythema, pruritus, and rarely 
bronchospasm and hypotension). These may occur within minutes of administration and 
should be managed with appropriate supportive therapy. There is increased risk of 
allergic reactions including anaphylaxis in patients previously exposed to platinum 
therapy.
5.1.6.8
Hepatotoxicity
Abnormal liver function tests (total bilirubin, AST, ALP) have been reported.
These abnormalities have generally been mild and reversible in about one-half of the 
cases.  In a limited series of patients receiving very high dosages of carboplatin and 
autologous bone marrow transplantation, severe abnormalities of liver function tests 
were reported. High dosages of carboplatin (more than 4 times the recommended dose) 
have resulted in severe abnormalities of liver function tests.
5.1.6.9
Embryo-Fetal Toxicity
Carboplatin may cause fetal harm when administered to a pregnant woman.  Refer to 
the current version of local label for detailed guidance on contraception as well as details 
of impact on fertility.
5.1.6.10
Other Toxicities
Changes in electrolyte serum values have been reported for sodium, potassium, 
calcium, and magnesium; these electrolyte abnormalities were rarely associated with 
symptoms.  Injection-site reactions, including redness, swelling, and pain, have been 
reported; necrosis associated with extravasation has also been reported.  Pain and 
asthenia were the most frequently reported miscellaneous adverse effects; their 
relationship to the tumor and to anemia was likely. Alopecia was reported.  
Cardiovascular, respiratory, genitourinary, and mucosal side effects have occurred, 
including fatalities that did not appear to be related to chemotherapy.  Cancer-associated 
HUS has been reported rarely. Malaise, anorexia, hypertension, dehydration, and 
stomatitis have been reported.

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5.1.7
Management of Patients who Experience Adverse Events with 
Alectinib
5.1.7.1
Dose Modifications
The dose of alectinib can be reduced in steps of 150 mg up to 2 times for management 
of drug-related toxicities (i.e., from 600 mg BID to 450 mg BID and then from 450 mg 
BID to 300 mg BID).
Dose Reduction Schedule
Dose Level
Dose
600 mg twice daily
First dose reduction
450 mg twice daily
Second dose reduction
300 mg twice daily
If further dose reduction is indicated after 2 dose-reductions, the patient must 
discontinue alectinib. Administration of a dose below 300 mg BID is not allowed.  
Dose modification may occur per Table 8 guidelines.
5.1.7.2
Treatment Interruption
Alectinib treatment may be temporarily suspended in patients who experience toxicity 
considered to be related to study drug as per guidance in Table 8.
If alectinib has been withheld for 21 days because of toxicity, the patient should be 
discontinued from alectinib.  Alectinib treatment may be suspended for reasons other 
than toxicity (e.g., surgical procedures) at the investigator’s discretion. The Medical 
Monitor should be informed and may be consulted, to determine the acceptable length of 
treatment interruption.
5.1.7.3
Management Guidelines
Guidelines for management of specific adverse events with alectinib are outlined in 
Table 8.

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Table 8
Guidelines for Management of Risks, Adverse Events, and 
Selected Laboratory Abnormalities with Alectinib
Event
Action to Be Taken
All AEs related a to 
alectinib 
(unless otherwise 
specified in this 
table)

Hepatotoxicity AEs 
(irrespective of 
relatedness)
Grade 4:
Temporarily interrupt alectinib for a maximum of 21 days after which the 
drug must be permanently withdrawn. If improvement to Grade1 or 
baseline does not occur within 3 weeks, permanently discontinue 
alectinib.
First episode:  If improvement to Grade1 within 21 days, decrease the 
current dose of alectinib by 150 mg (1 capsule) BID.
Second episode:  If improvement to Grade1 within 21 days, decrease 
the current dose of alectinib by another 150 mg (1 capsule) BID.
Third episode:  Permanently discontinue alectinib.
Please note that dose should not be reduced below 300 mg BID.
Grade 3:
Temporarily interrupt alectinib for a maximum of 21 days after which 
drug must be permanently withdrawn.
First episode:  If improvement to Grade1 occurs within 10 days,
alectinib may be restarted at the original dose or dose reduced by 
150 mg (1 capsule) as per investigator discretion.  If improvement to 
Grade1 or baseline occurs after 10 days but within 21 days, the 
alectinib dose must be decreased by 150 mg (1 capsule BID).
Second episode:  If improvement to Grade1 occurs within 21 days, 
decrease the current dose of alectinib by 150 mg (1 capsule) BID.
Third episode: Permanently discontinue alectinib.
Grade 2:
To be managed at the investigator’s discretion.  Please note that 
alectinib cannot be interrupted for more than 21 days and cannot be 
dose reduced below 300 mg BID.
Grade 1:  No action required.
Interstitial lung 
disease/
pneumonitis
Patients should be monitored for pulmonary symptoms indicative of 
interstitial lung disease/pneumonitis.
Regardless of relatedness to alectinib, study drug should be 
permanently discontinued in patients diagnosed with interstitial lung 
disease/pneumonitis of any grade.
Hepatotoxicity
Liver test laboratory abnormalities are to be reported as AEs only if 
fulfilling the criteria listed in Section 5.3.5.5 and Section 5.3.5.7.
At any time during the study treatment, if symptoms compatible with liver 
injury are observed, liver enzymes should be measured as soon as 
possible.

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Table 8
Guidelines for Management of Risks, Adverse Events, and 
Selected Laboratory Abnormalities with Alectinib (cont.)
Event
Action to Be Taken
Hepatotoxicity (cont.) Regardless of relatedness to alectinib, the grade-dependent rules for 
dose interruptions and dose modification outlined in the first section 
of this table must be followed.
In addition, study drug treatment has to be permanently discontinued if 
any of the following occurs:
First observation of ALT or AST 8ULN
ALT or AST 5ULN for more than 2 weeks
First observation of ALT or AST 3ULN and total bilirubin2ULN
First observation of ALT or AST 3ULN and the appearance of 
jaundice or signs of hepatic dysfunction or other symptoms (such as 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash, or eosinophilia [5%])
Following study drug discontinuation, weekly monitoring of laboratory 
values should continue until the abnormal values have normalized to 
pretreatment levels and/or an adequate explanation of the abnormal 
value is found
Resumption of study drug is not allowed in patients discontinuing 
because of any of the above criteria
Gastrointestinal tract 
AEs
(e.g., nausea, 
vomiting, diarrhea, 
stomatitis)
The events are expected to be minimized by taking the study drug with a 
meal.  If GI events occur, appropriate measures should be taken in 
accordance with local clinical practice guidelines.
In case of AEs related to alectinib, follow the grade-dependent rules 
for dose interruption and modification outlined in the first section of 
this table.
Skin disorder AEs 
(e.g., phototoxicity, 
rash)
Patients should be advised to avoid prolonged sun exposure while taking 
alectinib and for at least 7 days after study drug discontinuation.  Patients 
should also be advised to use a broad-spectrum sunscreen and lip balm 
of at least SPF 50 to help protect against potential sunburn during this 
period.
In case of AEs related to alectinib, follow the grade-dependent rules 
for dose interruption and modification outlined in the first section of 
this table.
Vision disorders
Investigators should consider referring the patients for an ophthalmologic 
evaluation according to local clinical practice guidelines if vision disorders 
persist or worsen in severity and to advise patients to exercise caution 
when driving or operating machinery due to the risk of developing a vision 
disorder.
In case of AEs related to alectinib, follow the grade-dependent rules 
for dose interruption and modification outlined in the first section of 
this table.

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Table 8
Guidelines for Management of Risks, Adverse Events, and 
Selected Laboratory Abnormalities with Alectinib (cont.)
Event
Action to Be Taken
Edema
Physical examinations will be performed routinely in clinical trials.  In case 
edema events occur, appropriate measures should be taken in 
accordance with local clinical practice guidelines.
In case of AEs related to alectinib, follow the grade-dependent rules 
for dose interruption and modification outlined in the first section of 
this table.
Abnormal renal 
function AEs
Kidney function laboratory abnormalities are to be reported as AEs if they 
fulfill the criteria listed in Section 5.3.5.5.
If at any time during the study treatment serum creatinine increases by 
2over the baseline visit value, the patient has to be carefully 
monitored.  All underlying factors that may have acutely impacted serum 
creatinine levels need to be evaluated and corrected (e.g., dehydration, 
recent exposure to contrast media, increased amount of cooked meat in 
diet, concomitant medications affecting renal function as appropriate, 
etc.).
Any serum creatinine value that is increased by 2over the baseline 
visit-value requires repeat testing.
For Grade 1 and Grade 2 AEs related to alectinib, follow the 
grade-dependent rules for dose interruption and modification 
outlines in the first section of this table.
For Grade 3 AEs related to alectinib, temporarily interrupt alectinib 
until serum creatinine recovers to Grade 1 or baseline, then 
resume at reduced dose.
For Grade 4 AEs related to alectinib, permanently discontinue 
study drug.
Severe myalgia and 
CPK elevations 
CPK laboratory abnormalities are to be reported as AEs if they fulfill the 
criteria listed in Section 5.3.5.5.
Myopathy should be considered in any patient with diffuse myalgia, 
muscle tenderness or weakness, and/or marked elevations of CPK levels.  
Patients should promptly report unexplained muscle pain, tenderness, or 
weakness, particularly if accompanied by malaise or fever.  Creatinine 
phosphokinase levels should be monitored in patients reporting these 
symptoms.
In case of AEs related to alectinib, follow the grade-dependent rules 
for dose interruption and modification outlined in the first section of 
this table.

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Table 8
Guidelines for Management of Risks, Adverse Events, and 
Selected Laboratory Abnormalities with Alectinib (cont.)
Event
Action to Be Taken
Anemia
(including hemolytic 
anemia)
Grade 2 anemia (regardless of clinical relevance):
At the time of assessing hemoglobin level for routine monitoring of 
Grade2 anemia, RBC count, reticulocytes, haptoglobin, ALT, LDH, and 
total and direct bilirubin should also be tested.  In addition, peripheral 
blood smear and a direct Coombs test should be performed.  
This laboratory workup is to be conducted at each new occurrence of 
anemia of Grade2 in patients receiving alectinib.
If hemolytic anemia is suspected, withhold alectinib. If hemolytic 
anemia is confirmed, resume alectinib at a reduced dose (refer to the 
general dose modification table in Section 5.1.7.1) upon resolution 
with improvement of hemoglobin to Grade ≤ 1 or baseline, or 
permanently discontinue alectinib.
In case of anemia of non-hemolytic mechanism, assessed as related 
to alectinib, follow the grade-dependent rules for dose interruption 
and modification outlined in the first section of this table.
Bradycardia b
Grade 2 or Grade 3 

Temporarily withhold for a maximum of 21 days (after which the 
drug must be permanently withdrawn) until recovery to Grade 
1 (asymptomatic) bradycardia or to a heart rate of 60 bpm. 
Evaluate concomitant medicinal products known to cause 
bradycardia, as well as anti-hypertensive medicinal products. 

If a contributing concomitant medicinal product is identified 
and discontinued, or its dose is adjusted, resume at previous 
dose upon recovery toGrade 1 (asymptomatic) bradycardia, or 
to a heart rate of 60 bpm. 
If no contributing concomitant medicinal product is identified, or if 
contributing concomitant medicinal products are not discontinued or 
dose modified, resume at reduced dose upon recovery to Grade 1 
(asymptomatic) bradycardia or to a heart rate of 60 bpm. 
Grade 4 

Permanently discontinue if no contributing concomitant 
medicinal product is identified. 

If a contributing concomitant medicinal product is identified 
and discontinued, or its dose is adjusted, resume at reduced 
dose upon recovery to Grade 1 (asymptomatic) bradycardia or 
to a heart rate of 60 bpm within 21 days, with frequent 
monitoring as clinically indicated.
Permanently discontinue in case of recurrence.

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Table 8
Guidelines for Management of Risks, Adverse Events, and 
Selected Laboratory Abnormalities with Alectinib (cont.)
Event
Action to Be Taken
AEadverse event; BIDtwice a day; GIgastrointestinal; ULNupper limit of normal.
Note:  Diarrhea, nausea, and vomiting should be handled with best supportive care first before 
considering dose modification.  Preexisting pleural effusion will not be considered as an adverse 
event.
a Please refer to Section 5.3.4 to determine whether event should be assessed as related or 
unrelated.
b Heart rate less than 60 bpm.
5.1.8
Management of Patients who Experience Adverse Events with
Vinorelbine
For full details regarding warnings, precautions, and dose modifications/delays relating
to vinorelbine treatment, refer to the current version of the local product label.  
Please refer also to any additional dose recommendations required for cisplatin 
(Section 5.1.11) or carboplatin (Section 5.1.12), depending on the treatment combination 
used.
Patients should be monitored for abdominal pain and severe constipation, for new or 
worsening signs and symptoms of neuropathy such as paresthesia, hyperesthesia, 
hyporeflexia, and muscle weakness, as well as for respiratory disorders (dyspnea and 
bronchospasm).
5.1.9
Management of Patients who Experience Adverse Events with
Gemcitabine
For full details regarding warnings, precautions, and dose modifications/delays relating 
to gemcitabine treatment, refer to the current version of the local product label.
Please refer also to any additional dose recommendations required for cisplatin 
(Section 5.1.11) or carboplatin (Section 5.1.12), depending on the treatment combination 
used.
Investigators should be vigilant and alert to early and overt signs of myelosuppression, 
infection, or febrile neutropenia so that these complications can be promptly and 
appropriately managed. Patients should be made aware of these signs and encouraged 
to seek medical attention at the earliest opportunity.
5.1.10
Management of Patients who Experience Adverse Events with
Pemetrexed
For full details regarding dose modifications relating to pemetrexed treatment, refer to 
the current version of the local product label. Please refer also to any additional dose 
recommendations required for cisplatin (Section 5.1.11) or carboplatin (Section 5.1.12), 

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depending on the treatment combination used. The dose modification guidelines are 
applicable for pemetrexed used in combination with cisplatin or carboplatin.
Investigators should be vigilant and alert to early and overt signs of myelosuppression, 
infection, or febrile neutropenia so that these complications can be promptly and 
appropriately managed. Patients should be made aware of these signs and encouraged 
to seek medical attention at the earliest opportunity.
5.1.10.1
Non-Hematologic Toxicity
At the start of each cycle, the CrCl must be 45 mL/min. For enrollment and dosing 
decisions, CrCl will be estimated using the standard Cockcroft and Gault formula 
(or GFR measured Tc99m-DPTA serum clearance model).  The method of CrCl 
assessment used at baseline should be used throughout the study.
5.1.11
Management of Patients who Experience Adverse Events with
Cisplatin
For full details regarding dose modifications relating to cisplatin treatment, refer to the 
current version of the local product label. Please refer also to any additional dose 
recommendations required for vinorelbine (Section 5.1.8), gemcitabine (Section 5.1.9),
or pemetrexed (Section 5.1.10), depending on the treatment combination used.
5.1.12
Management of Patients who Experience Adverse Events with
Carboplatin
For full details regarding warnings and precaution relating to carboplatin treatment, refer 
to the current version of the local product label. Please refer also to any additional dose 
recommendations required for vinorelbine (Section 5.1.8), gemcitabine (Section 5.1.9, or 
pemetrexed (Section 5.1.10), depending on the treatment combination used.
5.1.12.1
Hematologic Toxicities
Patients with CrCl values below 60 mL/min are at increased risk of severe bone marrow 
suppression.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in
Section 5.4.

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5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition; see Sections 5.3.5.9
and 5.3.5.10 for more information)

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that 
is associated with symptoms or leads to a change in study treatment or 
concomitant treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including 
those that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life-threatening (i.e., the adverse event, in the view of the investigator, places 
the patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.11)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed 
to study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize 
the patient or may require medical/surgical intervention to prevent one of the 
outcomes listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 

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see Section 5.3.3); the event itself may be of relatively minor medical significance 
(such as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; 
see Section 5.4.2 for reporting instructions).  Adverse events of special interest for this 
study are as follows:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.3.5.7)

Suspected transmission of an infectious agent by the study drug, as defined below
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity 
(see Section 5.3.3), and causality (see Section 5.3.4). 
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  
All adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 

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procedures or discontinuation of medications) should be reported (see Section 5.4.2 for 
instructions for reporting serious adverse events).
After initiation of study drug, all adverse events will be reported during treatment and 
until 28 days after last dose of alectinib or 28 days after end of last cycle of 
chemotherapy (7 weeks after day one of last cycle).
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?"
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity.  Table 9 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.

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Table 9
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no"
accordingly.  The following guidance should be taken into consideration (see also
Table 10):

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event

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Table 10 Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon rechallenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below. 
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only 1 adverse event term should be recorded in the event field on the 
Adverse Event eCRF.
5.3.5.1
Infusion-Related Reactions
Adverse events that occur during or within 24 hours after study drug administration and 
are judged to be related to study drug infusion should be captured as a diagnosis 
(e.g., "infusion-related reaction") on the Adverse Event eCRF.  If possible, avoid 
ambiguous terms such as "systemic reaction."  Associated signs and symptoms should 
be recorded on the dedicated Infusion-Related Reaction eCRF.  If a patient experiences 
both a local and systemic reaction to the same dose of study drug, each reaction should 
be recorded separately on the Adverse Event eCRF, with signs and symptoms also 
recorded separately on the dedicated Infusion-Related Reaction eCRF.
5.3.5.2
Diagnosis versus Signs and Symptoms
For adverse events other than infusion-related reactions (see Section 5.3.5.1), a
diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the 
Adverse Event eCRF.  If a diagnosis is subsequently established, all previously reported 

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adverse events based on signs and symptoms should be nullified and replaced by one 
adverse event report based on the single diagnosis, with a starting date that 
corresponds to the starting date of the first symptom of the eventual diagnosis.
5.3.5.3
Adverse Events that are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy 
adult, only vomiting should be reported on the eCRF

If vomiting results in severe dehydration, both events should be reported 
separately on the eCRF

If a severe GI hemorrhage leads to renal failure, both events should be reported 
separately on the eCRF

If dizziness leads to a fall and consequent fracture, all 3 events should be reported 
separately on the eCRF

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.4
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the 
Adverse Event eCRF.  If the event becomes serious, it should be reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning that the event became 
serious; see Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should 
be updated by changing the event from "non-serious" to "serious," providing the date 
that the event became serious, and completing all data fields related to serious adverse 
events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.

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5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for 
hypokalemia) or a change in concomitant therapy

Is clinically significant in the investigator’s judgment
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events.
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment

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It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury
(as defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3ULN in combination with total bilirubin 
2ULN

Treatment-emergent ALT or AST 3ULN in combination with clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see Section 5.4.2).
5.3.5.8
Deaths
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified adverse event reporting period (see Section 5.3.1) that are attributed 
by the investigator solely to recurrence of NSCLC should be recorded on the 
Death Attributed to Disease Recurrence eCRF.  All other deaths that occur during the 
adverse event reporting period, regardless of relationship to study drug, must be 
recorded on the Adverse Event eCRF and immediately reported to the Sponsor 
(see Section 5.4.2). An iDMC will monitor the frequency of deaths from all causes.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only 1 such event should be reported.  
If the cause of death is unknown and cannot be ascertained at the time of reporting, 
"unexplained death" should be recorded on the Adverse Event eCRF.  If the cause of 
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replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  
When recording such events on the Adverse Event eCRF, it is important to convey the 
concept that the preexisting condition has changed by including applicable descriptors
(e.g., "more frequent headaches").
5.3.5.10
Lack of Efficacy or Recurrence of NSCLC
Events that are clearly consistent with the expected pattern of disease recurrence should 
not be recorded as adverse events.  These data will be captured as efficacy assessment 
data only. The expected pattern of disease recurrence will be based on determination 
by the investigator after an integrated assessment of radiographic data, biopsy sample 
results (if available), and clinical status. Every effort should be made to document 
disease recurrence with use of radiographic data, confirmed by biopsy sample results as 
per protocol.  If there is any uncertainty as to whether an event is due to disease 
recurrence, it should be reported as an adverse event.
Recurrence of disease should not be recorded as an adverse event or serious adverse 
event, since recurrence of disease will be captured as an efficacy endpoint. However in 
situations in which there is no confirmation, the underlying symptoms should be captured 
as adverse events and assessed accordingly for seriousness, severity, and causality 
until a diagnosis or cause for such events is established or until confirmation of NSCLC 
recurrence. If the symptoms are later confirmed to be due to recurrence of disease, then 
symptoms reported as adverse events should be retracted. Data for disease recurrence 
will be captured as efficacy assessment data only.
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital)
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.

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An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study drug administration 
or insertion of access device for study drug administration)

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease.
The patient has not experienced an adverse event.

Hospitalization due solely to recurrence of NSCLC
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.12
Cases of Overdose, Medication Error, Drug Abuse, or 
Drug Misuse
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse
(hereafter collectively referred to as "special situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is 
higher than the assigned dose

Intentional overdose:  intentional administration of a drug in a quantity that is 
higher than the assigned dose

Medication error:  accidental deviation in the administration of a drug
In some cases, a medication error may be intercepted prior to administration of 
the drug.

Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm

Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse
In cases where drug is to be self-administered by the patient, drug misuse 
could involve the drug being administered to someone other than the patient.
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately 

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(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).  For alectinib 
or any protocol chemotherapy regimen, adverse events associated with special 
situations should be recorded as described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the 
"Accidental overdose" and "Medication error" boxes.

Intentional overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" box.  If drug abuse is suspected, check the "Drug abuse" 
box.  If drug abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.

Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug abuse" box.

Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Intentional overdose" and "Drug abuse" boxes.

Drug misuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug misuse" box.

Drug misuse that qualifies as an overdose:  Enter the adverse event term. 
Check the "Intentional overdose" and "Drug misuse" boxes.
In addition, all special situations associated with alectinib and any protocol 
chemotherapy regimen, regardless of whether they result in an adverse event, should be 
recorded on the Adverse Event eCRF as described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Intentional overdose:  Enter the drug name and "intentional overdose" as the event 
term.  Check the "Intentional overdose" box.  If drug abuse is suspected, check the 
"Drug abuse" box.  If drug abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and 
"accidental overdose" as the event term.  Check the "Accidental overdose" and 
"Medication error" boxes.  Enter a description of the error in the additional case 
details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.

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
Drug abuse that does not qualify as an overdose:  Enter the drug name and 
"drug abuse" as the event term.  Check the "Drug abuse" box.

Drug abuse that qualifies as an overdose:  Enter the drug name and 
"intentional overdose" as the event term.  Check the "Intentional overdose" and 
"Drug abuse" boxes.

Drug misuse that does not qualify as an overdose:  Enter the drug name and 
"drug misuse" as the event term.  Check the "Drug misuse" box.

Drug misuse that qualifies as an overdose:  Enter the drug name and 
"intentional overdose" as the event term.  Check the "Intentional overdose" and 
"Drug misuse" boxes.

Drug administered to someone other than the patient:  Enter the drug name and 
"patient supplied drug to third party" as the event term.  Check the "Drug misuse" 
box.
As an example, an accidental overdose that resulted in a headache would require 
2 entries on the Adverse Event eCRF, 1 entry to report the accidental overdose and 
1 entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries.
5.3.5.13
Patient-Reported Outcome Data
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data.  Investigators and site staff are not 
expected to review the PRO data for adverse events.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

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
Significant new diagnostic test results

Change in causality based on new information

Change in the event's outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information for All Sites
Medical Monitor/Roche Medical Responsible:
, M.D.
Mobile Telephone No.:
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche 
Medical Responsible (listed above and/or on the Roche Medical Emergency List), and 
track all calls.  The Emergency Medical Call Center Help Desk will be available 24 hours 
per day, 7 days per week.  Toll-free numbers for the Help Desk, as well as 
Medical Monitor and Medical Responsible contact information, will be distributed to all 
investigators.
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events that Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention or procedures 
permitted by the protocol, should be reported.  The paper Clinical Trial Adverse 
Event/Special Situations Form provided to investigators should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the event), either by faxing or by scanning and emailing the form using the 
fax number or e-mail address provided to investigators.
5.4.2.2
Events that Occur after Study Drug Initiation
After initiation of study drug, all adverse events (serious and non-serious adverse events 
and adverse events of special interest) will be reported until the safety follow-up visit
(28 days after last dose of alectinib or 28 days after the end of last cycle of 
chemotherapy [7 weeks after day one of last cycle]).  Investigators should record all 
case details that can be gathered immediately (i.e., within 24 hours after learning of the 
event) on the Adverse Event eCRF and submit the report via the electronic data capture 
(EDC) system.  A report will be generated and sent to Roche Safety Risk Management 
by the EDC system.

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In the event that the EDC system is unavailable, the paper Clinical Trial Adverse 
Event/Special Situations Form provided to investigators should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the event), either by faxing or by scanning and emailing the form using the 
fax number or e-mail address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.
Instructions for reporting serious adverse events that occur outside the defined reporting 
period treatment are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 90 days after the last 
dose of alectinib or according to local label for chemotherapy.  A paper Clinical Trial 
Pregnancy Reporting Form should be completed and submitted to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form using the fax number or e-mail
address provided to investigators.  Pregnancy should not be recorded on the 
Adverse Event eCRF.  The investigator should discontinue study drug and counsel the 
patient, discussing the risks of the pregnancy and the possible effects on the fetus.  
Monitoring of the patient should continue until conclusion of the pregnancy.  Any serious 
adverse events associated with the pregnancy (e.g., an event in the fetus, an event in 
the mother during or after the pregnancy, or a congenital anomaly/birth defect in the 
child) should be reported on the Adverse Event eCRF.  In addition, the investigator will 
submit a Clinical Trial Pregnancy Reporting Form when updated information on the 
course and outcome of the pregnancy becomes available.
5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
90 days after the last dose of alectinib or according to local label for chemotherapy.  
A paper Clinical Trial Pregnancy Reporting Form should be completed and submitted to 
the Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
pregnancy), either by faxing or by scanning and emailing the form using the fax number
or e-mail address provided to investigators.  Attempts should be made to collect and 
report details of the course and outcome of any pregnancy in the partner of a male 
patient exposed to study drug.  When permitted by the site, the pregnant partner would
need to sign an Authorization for Use and Disclosure of Pregnancy Health Information to 
allow for follow-up on her pregnancy.  If the authorization has been signed, the 
investigator should submit a Clinical Trial Pregnancy Reporting Form when updated 
information on the course and outcome of the pregnancy becomes available.  
An investigator who is contacted by the male patient or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus, to 

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support an informed decision in cooperation with the treating physician and/or 
obstetrician.
5.4.3.3
Abortions
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryo-fetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).
A therapeutic or elective abortion performed for reasons other than an underlying 
maternal or embryo-fetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; 
see Section 5.4.2).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
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to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
After the end of the adverse event reporting period (defined as 28 days after last dose of 
alectinib or 28 days after end of last cycle of chemotherapy [7 weeks after Day 1 of the
last cycle], see Section 5.3.1), all deaths, regardless of cause, should be captured on the
Death during Disease Follow-Up eCRF. All deaths, regardless of cause, occurring after 
disease recurrence, should be reported through use of the Long-Term Survival 
Follow-Up eCRF.
In addition, if the investigator becomes aware of a serious adverse event that is believed 
to be related to prior exposure to study drug, the event should be reported through use 
of the Adverse Event eCRF.  However, if the EDC system is not available, the 
investigator should report these events directly to the Sponsor or its designee, either by 
faxing or by scanning and emailing the paper Clinical Trial Adverse Event/Special 
Situations Form using the fax number or e-mail address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents:

Alectinib Investigator's Brochure

USPI for vinorelbine and gemcitabine

EU-SmPC for pemetrexed

UK-SmPC for cisplatin and carboplatin
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.

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6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
The primary and secondary efficacy analyses will be performed for all randomized 
patients (ITT population) and for the Stage IIIIIa subpopulation.  The same analysis 
methods will be applied for both the ITT population and the Stage IIIIIa subpopulation.
Safety analyses will be performed on all randomized patients who received at least 
1 dose of study medication.
6.1
DETERMINATION OF SAMPLE SIZE
Approximately 255 patients are expected to be randomized into the study. 
As mentioned in Section 3.3.3, the number of Stage Ib patients will be capped at 25% to 
ensure that at least 75% of all randomized patients will have Stage IIIIIa disease. 
The resulting ITT population of all patients randomized will include a minimum of
191 patients in the Stage IIIIIa subpopulation.
Recruitment is assumed to happen at a rate of 0.034 patients per site per month, with a 
total of approximately 200 sites. Detailed recruitment is as follows:

Months 12: 1 patient per month

Month 3: 2 patients per month

Month 4: 3 patients per month

Months 56: 4 patients per month

Months 79: 5 patients per month

Months 1012: 7 patients per month

Month 13 onwards: 8 patients per month
Based on these assumptions, enrollment will take approximately 38 months to complete.
The sample size and the number of events required to demonstrate efficacy with regard
to the primary efficacy endpoint DFS at the primary analysis are based on the following
assumptions:

Overall 2-sided significance level of 0.05 in the Stage IIIIIa subpopulation and the 
ITT population

80% power to detect an HR0.55, corresponding to an improvement in median 
DFS from 3055 months for patients receiving alectinib compared with
chemotherapy in the Stage IIIIIa subpopulation

80% power to detect an HR0.58 corresponding to an improvement in median 
DFS from 3662 months for patients receiving alectinib compared with
chemotherapy in the ITT population

One interim analysis for DFS when approximately 67% of the total DFS events 
have occurred, with use of the Lan-DeMets approximation to the O'Brien-Fleming 
boundaries (see Section 6.9.1)

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Based on these assumptions, the primary DFS analysis will be conducted after 
approximately 89 DFS events in the Stage IIIIIa subpopulation have been observed.  
This is predicted to occur approximately 60 months (5 years) after the first patient is 
randomized.
The focus of this clinical trial is hypothesis testing, testing superiority of alectinib 
compared with chemotherapy with respect to DFS.  To control the overall level of 
significance at a 2-sided error rate of 0.05, comparisons with respect to DFS between 
the alectinib and chemotherapy arms within the Stage IIIIIa subpopulation and the 
ITT population will be conducted hierarchically as follows:

Disease-free survival (DFS) in the Stage IIIIIa subpopulation will be first tested at 
an overall 2-sided -level of 0.05. If the 2-sided p-value corresponding to the 
stratified log-rank test is less than 0.0464 at the primary analysis (in order to adjust 
for 1 interim analysis for efficacy, as specified in Section 6.9.1), the null hypothesis 
will be rejected, and it will be concluded that alectinib prolongs duration of DFS 
relative to chemotherapy in the Stage IIIIIa subpopulation. Stopping boundaries 
will be adjusted depending on the actual number of DFS events.

If alectinib significantly prolongs DFS in the Stage IIIIIa subpopulation, then DFS 
in the ITT population will be tested at an overall 2-sided -level of 0.05. If the 
2-sided p-value corresponding to the stratified log-rank test is less than 0.0463 at 
the primary analysis (in order to adjust for 1 interim analysis for efficacy, as 
specified in Section 6.9.1), the null hypothesis will be rejected, and it will be 
concluded that alectinib prolongs duration of DFS relative to chemotherapy in the 
ITT population.  Stopping boundaries will be adjusted depending on the actual 
number of DFS events.
If alectinib has no significant effect on DFS in the Stage IIIIIa subpopulation, then DFS 
in the ITT population will not be tested.
6.2
SUMMARIES OF CONDUCT OF STUDY
Study enrollment, study treatment administration, reasons for discontinuation from study 
treatment, and reasons for study termination will be summarized by treatment arm for 
the Stage IIIIIa subpopulation and the ITT population. Major protocol deviations, 
including major deviations of inclusion/exclusion criteria, will be reported and 
summarized by treatment arm for the Stage IIIIIa subpopulation and ITT population.
6.3
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic characteristics, such as age, sex, race/ethnicity, and baseline disease 
characteristics (e.g., ECOG Performance Status), will be summarized by treatment arm 
for the Stage IIIIIa subpopulation and the ITT population. Descriptive statistics 
(mean, median, standard deviation, and range) will be presented for continuous data, 
and frequencies and percentages will be presented for categorical data.

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Baseline measurements are the last available data obtained prior to the patient receiving 
the first dose of alectinib or starting the first cycle of chemotherapy in the randomized 
phase.
6.4
EFFICACY ANALYSES
The primary and secondary efficacy analyses will be performed for the Stage IIIIIa
subpopulation followed by the ITT population, which is defined as all randomized 
patients. Patients will be analyzed in the treatment group to which they were 
randomized.
6.4.1
Primary Efficacy Endpoint
The primary efficacy objective for this study is to evaluate the efficacy of alectinib 
compared with platinum-based chemotherapy on the basis of DFS. Disease-free 
survival is defined as the time from randomization to the first documented recurrence of 
disease or new primary NSCLCas determined by the investigator through use of an 
integrated assessment of radiographic data, biopsy sample results (if clinically feasible), 
and clinical statusor death from any cause, whichever occurs first.
Patients who are not reported as experiencing disease recurrence, a new primary 
NSCLC, or death will be censored at the date of the last disease assessment. If no 
post-baseline data are available, patients will be censored at the date of randomization.
To control the overall level of significance at a 2-sided error rate of 0.05, comparisons 
with respect to DFS between the alectinib and chemotherapy arms within the 
Stage IIIIIa subpopulation and the ITT population will be conducted hierarchically as 
described in Section 6.1.
The null (H0) and alternative (HA) hypotheses regarding DFS in each population 
(the Stage IIIIIa subpopulation and the ITT population) can be phrased in terms of the 
DFS survival distribution function (SDF) in the alectinib arm and SDF in the control arm, 
respectively:
H0: SDF (alectinib)SDF (chemotherapy)
versus
HA: SDF (alectinib) ≠ SDF (chemotherapy)
The HR in the Stage IIIIIa subpopulation will be estimated with use of a stratified 
Cox regression model with race as stratification factor, including 95% CIs. For the 
ITT population, all stratification factors specified for randomization will be used for the 
stratified Cox regression model. Strata with less than 20 patients will be pooled for 
analysis in the stratified Cox regression model. The unstratified HR will also be 
presented. Kaplan-Meier methodology will be used to estimate the median DFS for
each treatment arm, and the Kaplan-Meier curve will be constructed to provide a visual
description of the difference between the treatment and control arms.  

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Brookmeyer-Crowley methodology will be used to construct the 95% CI for the median 
DFS for each treatment arm.
In addition, the impact of loss to follow-up on DFS will be assessed depending on the 
number of patients who are lost to follow-up.  If more than 5% of patients are lost to 
follow-up for DFS in either treatment arm, a sensitivity analysis ("worst-case" analysis) 
will be performed in which patients who are lost to follow-up will be considered to have 
recurrent disease at the date of the last disease assessment.
6.4.2
Secondary Efficacy Endpoints
Overall survival is defined as the time from the date of randomization to death due to any 
cause. Data for patients who are not reported as having died at the date of analysis will 
be censored at the date when they were last known to be alive. If no post-baseline data 
are available, OS will be censored at the date of randomization plus 1 day.
The methodology (as described in Section 6.4.1) used for DFS will be applied for OS.
Overall survival will be analyzed at the time of the DFS analyses and at the time of the 
final survival follow-up analysis, which will be conducted at approximately 5 years 
after the last patient is enrolled.
6.4.3
Exploratory Efficacy Endpoints
Analyses at landmark timepoints of 3, 4, and 5 years within the Stage IIIIIa
subpopulation and the ITT population will be performed for DFS. Rates will be estimated 
using Kaplan-Meier methodology for each treatment arm, with 95% CIs calculated using 
Greenwood's formula.
The effects of demographics (e.g., age, sex, and race/ethnicity) and baseline prognostic 
characteristics (e.g., disease stage, smoking history, and ECOG Performance Status) on 
duration of DFS will be examined by subgroup analyses. Summaries of DFS, including 
unstratified HRs estimated from Cox proportional hazards models and Kaplan-Meier 
estimates of median survival time will be produced separately for each level of the 
categorical variables.
Disease-free survival as an endpoint does not distinguish between the location of the 
first documented recurrence of disease or new primary NSCLC. Descriptive statistics 
(i.e., frequencies and percentages) will be used to explore the first site of recurrence of 
disease or new primary NSCLC.
6.5
SAFETY ANALYSES
Safety analyses will be performed on the safety evaluable population, defined as all 
randomized patients who were enrolled during the global enrollment phase and received 
any amount of study drug, with patients grouped according to treatment received.
All patients who receive any dose of alectinib will be included in the alectinib treatment 
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Drug exposure will be summarized to include treatment duration, number of doses, and 
dose intensity.
Verbatim description of adverse events will be mapped to thesaurus terms and graded 
according to NCI CTCAE v5.0. All adverse events that occur during or after the first 
study drug dose will be summarized using descriptive statistics (i.e., frequencies and 
percentages) by treatment arm and NCI CTCAE grade. In addition, serious adverse 
events, severe adverse events (Grade 3), adverse events of special interest, and 
adverse events leading to study drug discontinuation or interruption will be summarized 
accordingly. Multiple occurrences of the same event will be counted once at the 
maximum severity. Adverse events will be described in individual listings and by body 
system, as well as by severity. In tables showing the overall incidence of adverse 
events, patients who experienced the same event on more than one occasion are 
counted only once in the calculation of the event frequency.
Summaries of treatment-related serious adverse events, adverse events of special 
interest, and all listings of adverse events will include all events that occur during or after 
the first study drug treatment. Safety summaries of all other adverse events will include 
treatment-emergent adverse events with onset up to 28 days after the last dose of 
alectinib or up to 28 days after the end of last cycle of chemotherapy (7 weeks after
Day 1 of the last cycle), or until patients receive another anti-cancer therapy, whichever 
comes first.
Laboratory data with values outside the normal ranges will be identified.  In addition, 
selected laboratory data will be summarized in shift tables. Changes in vital signs and 
ECGs will be summarized by treatment arm.  Deaths reported during the study treatment 
period and those reported during the follow-up period after treatment 
completion/discontinuation will be summarized by treatment arm.
Subgroup analyses will be performed to evaluate the safety profile within subgroups of 
patients, including by sex, age (65 years vs. 65 years), race (non-Asian vs. Asian),
and for the subpopulation of patients with Stage IIIIIa NSCLC. Furthermore, safety 
analyses will also be performed within the subgroups of patients by disease stage 
(Stage Ib vs. II vs. IIIa).
An external iDMC will evaluate safety data on an ongoing basis.  All summaries and 
analyses by treatment arm for the iDMC's review will be prepared by an external
independent data coordinating center. Members of the iDMC will be external to the 
Sponsor and will follow a charter that outlines their roles and responsibilities. 
Any outcomes of these reviews that affect study conduct will be communicated in a 
timely manner to the investigators for notification of the IRB/EC. A detailed plan will be 
included in the iDMC Charter.

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6.6
PHARMACOKINETIC ANALYSES
The serial/intensive PK analysis population (if Japan will participate in the study) will 
consist of the subset of Japanese patients who underwent serial/intensive PK sampling
with sufficient data to enable estimation of key parameters (e.g., AUC, time to Cmax [tmax], 
Cmax, and half-life).
The sparse PK-evaluable population will consist of all patients who had at least 
1 post-baseline quantifiable PK sample available.
Standard non-compartmental analysis may be conducted for PK data collected from 
patients participating in serial/intensive PK collections for relevant analytes, as data 
allow, as appropriate, and if needed.  Pharmacokinetic parameters including, but not 
limited, to AUC, Cmax, and tmax will be calculated on the basis of the available data as 
appropriate and where data allow.
Additional PK parameters may be calculated as deemed appropriate.
Individual and mean plasma concentrations at each sampling timepoint and/or PK 
parameters for alectinib and metabolite(s) will be listed, as appropriate.
Summary statistics (e.g., means, standard deviation, % coefficient of variation, 
geometric means, medians, and ranges) for plasma concentrations and/or PK 
parameters for alectinib and metabolite(s) will be presented by treatment and nominal 
collection times (plasma concentrations only), as appropriate.  Additional plots or 
summary statistics may be constructed or calculated, as appropriate.
Results of PK and/or any PK/pharmacodynamic analyses may be reported outside the 
Clinical Study Report.
Nonlinear mixed-effects modeling (with software NONMEM; Beal et al. 1999) will be 
used to analyze the sparse and/or serial/intensive plasma concentrationtime data for 
alectinib.  The PK data from this study may be pooled with data from other studies.  
Population and individual PK parameters will be estimated, and the influence of various 
covariates (such as age, sex, and body weight) on these parameters will be investigated.
Exploratory analyses will be conducted to investigate the relationship between alectinib 
PK exposure and efficacy/safety parameters.
Details of the mixed-effects modeling and exploratory analyses will be reported in a 
document separate from the Clinical Study Report.
6.7
EXPLORATORY BIOMARKER ANALYSIS
Anaplastic lymphoma kinase tumor tissue and plasma assays (e.g., next-generation 
targeted sequencing, PCR) will be used as exploratory assays for all enrolled 
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resistance mechanisms to alectinib and the relevance of ALK rearrangement variant or 
fusion partner.  Minimal residual disease after surgery, early recurrence, and changes in 
the mutational profile of the tumor by monitoring circulating tumor nucleic acids in 
plasma during treatment or at recurrence compared with baseline will be explored. 
Tumor mutations, tumor mutation allele frequencies, and circulating tumor nucleic acid 
amounts may be correlated with clinical efficacy. Efficacy analysis of different ALK 
tumor and ALK plasma subpopulations maybe performed.
Results from the exploratory biomarker analyses from baseline and recurrence tumor 
samples and from plasma samples at baseline, on treatment, and post-recurrence will 
be communicated outside the main Clinical Study Report.
6.8
EXPLORATORY PATIENT-REPORTED OUTCOME ANALYSES
The SF-36v2 and EQ-5D-5L will be scored per authors' guidelines.  Completion and 
compliance rates will be summarized by number and proportion of patients among those 
expected to complete each questionnaire at each timepoint by treatment arm. 
Reasons for non-completion will be summarized at each timepoint by treatment arm.
In the ITT population, summary statistics (mean, standard deviation, median, 25th and 
75th percentiles, and range) and the mean changes from baseline will be reported for 
the PCS score, MCS score, and each health domain from the SF-36v2 by visit and by 
treatment arm.
A single summary index from the EQ-5D-5L health states will be used in this study for 
economic modeling. 
Furthermore, PRO analyses will also be performed in the subpopulation of patients with 
Stage II-IIIa NSCLC.
These results may not be reported in the Clinical Study Report.
6.9
INTERIM ANALYSIS
6.9.1
Planned Interim Analysis
There is 1 interim analysis for efficacy planned in the study for DFS.  The interim 
analysis will be conducted after approximately 67% of events have been observed in the 
Stage IIIIIa subpopulation. Based on the assumptions described in Section 6.1, this 
relates to approximately 59 DFS events for the Stage IIIIIa subpopulation.  This is 
predicted to occur approximately 44 months after the first patient is randomized 
(i.e., approximately 16 months before the primary analysis), although the exact timing of 
this analysis will depend on the actual number of DFS events in the Stage IIIIIa
subpopulation, but irrespective of the number of DFS events observed in the 
ITT population.

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To control the type I error, the stopping boundaries for the DFS interim and primary 
analyses are to be computed with use of the Lan-DeMets approximation to the 
O'Brien-Fleming boundaries.  In the Stage IIIIIa subpopulation, the stopping boundary 
for early rejection of the null hypothesis for an overall 2-sided 5% significance level is 
HR0.52 (p0.0118).  In the ITT population, the stopping boundary for early rejection of 
the null hypothesis for an overall 2-sided 5% significance level is HR0.55 (p0.0121).  
If less than 67% of DFS events in the ITT population have been observed at the time of 
reaching the required number of events for the interim analysis in the Stage IIIIIa
subpopulation, the stopping boundaries will be adjusted depending on the actual number 
of DFS events observed in the ITT population.  However, the ITT interim analysis would 
only take place in the case of early rejection of the null hypothesis in the Stage IIIIIa
subpopulation.
An external iDMC will evaluate safety data on an ongoing basis and review the data from 
the interim analysis.  All summaries and analyses by treatment arm for the iDMC's 
review will be prepared by an external independent data coordinating center. 
Members of the iDMC will be external to the Sponsor and will follow a charter that 
outlines their roles and responsibilities. Any outcomes of these reviews that affect study 
conduct will be communicated in a timely manner to the investigators for notification to 
the IRB/EC. A detailed plan will be included in the iDMC Charter.
Positive efficacy results at the interim analysis will not change the conduct of the study 
and timing of disease assessments, as described in Section 4.5.6.
6.9.2
Optional Interim Analysis
To adapt to information that may emerge during the course of this study, the Sponsor 
may choose to conduct one additional interim efficacy analysis. Below are the 
specifications in place to ensure the study continues to meet the highest standards of 
integrity when an optional interim analysis is executed.
The interim analysis will be conducted by an external statistical group and reviewed by 
the iDMC.  Interactions between the iDMC and Sponsor will be carried out as specified 
in the iDMC Charter.
The decision to conduct the optional interim analysis, along with the rationale, timing, 
and statistical details for the analysis, will be documented in the Statistical Analysis Plan 
(SAP), and the SAP will be submitted to relevant health authorities at least 2 months 
prior to the conduct of the interim analysis.  The iDMC Charter will be updated to 
document potential recommendations the iDMC can make to the Sponsor as a result of 
the analysis (e.g., stop the study for positive efficacy, stop the study for futility), and the 
iDMC Charter will also be made available to relevant health authorities.
If there is a potential for the study to be stopped for positive efficacy, as a result of the 
interim analysis, the type I error rate will be controlled to ensure statistical validity is 

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maintained.  Specifically, the Lan-DeMets -spending function that approximates the 
O'Brien-Fleming boundary will be applied to determine the critical value for stopping for 
positive efficacy at the interim analysis (DeMets and Lan 1994).  Additional criteria for 
recommending that the study to be stopped for positive efficacy may be added to the 
iDMC Charter. If the study continues beyond the interim analysis, the critical value at 
the primary DFS analysis would be adjusted accordingly to maintain the 
protocol-specified overall type I error rate, per standard Lan-DeMets methodology.
Positive efficacy results at an optional interim analysis will not change the conduct of the 
study and timing of disease assessments, as described in Section 4.5.6.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data and other 
electronic data will be sent directly to the Sponsor, using the Sponsor's standard 
procedures to handle and process the electronic transfer of these data.
Electronic Case Report Forms and correction documentation will be maintained in the 
EDC system's audit trail.  System backups for data stored by the Sponsor and records 
retention for the study data will be consistent with the Sponsor’s standard procedures.
Patient-reported outcome data will be collected on paper questionnaires.  The data from 
the questionnaires will be entered into the EDC system by site staff.
7.2
ELECTRONIC CASE REPORT FORMS
Electronic Case Report Forms are to be completed through use of a Sponsor-designated 
EDC system.  Sites will receive training and have access to a manual for appropriate 
eCRF completion.  Electronic Case Report Forms will be submitted electronically to the 
Sponsor and should be handled in accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  Electronic Case Report 
Forms should be reviewed and electronically signed and dated by the investigator or a 
designee.

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At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents.
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  
An acceptable computerized data collection system allows preservation of the original 
entry of data.  If original data are modified, the system should maintain a viewable audit 
trail that shows the original data as well as the reason for the change, name of the 
person making the change, and date of the change.

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7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, paper PRO data, Informed Consent Forms, laboratory test 
results, and medication inventory records, must be retained by the Principal Investigator 
for at least 15 years after completion or discontinuation of the study or for the length of 
time required by relevant national or local health authorities, whichever is longer.  After 
that period of time, the documents may be destroyed, subject to local regulations.
No records may be disposed of without the written approval of the Sponsor.  
Written notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
Radiographic images will be submitted to an IRF for a quality and completeness check, 
and for temporary storage prior to transfer to the Sponsor for the long-term retention
for potential independent reading.
Roche will retain study data for 25 years after the initial study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for 
Good Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a 
U.S. Investigational New Drug (IND) Application will comply with FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the EU Clinical Trial Directive (2001/20/EC).
Biomarker plasma and tissue sampling will be conducted in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Pregnant Partner Authorization Form or Mobile Nursing
Informed Consent Form, if applicable) will be provided to each site.  If applicable, it will 
be provided in a certified translation of the local language.  The Sponsor or its designee 
must review and approve any proposed deviations from the Sponsor's sample 
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(collectively, the "Consent Forms") before IRB/EC submission.  The final 
IRB/ECapproved Consent Forms must be provided to the Sponsor for health authority 
submission purposes according to local requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the 
U.S. Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site 
utilizes a separate Authorization Form for patient authorization for use and disclosure of 
personal health information under the HIPAA regulations, the review, approval, 
and other processes outlined above apply except that IRB review and approval may not 
be required per study site policies.

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8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the 
Principal Investigator and reviewed and approved by the IRB/EC before the study is 
initiated.  In addition, any patient recruitment materials must be approved by the IRB/EC.
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments (see 
Section 9.7).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file.
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Roche policy on study data publication 
(see Section 9.6).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.

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8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2).
9.
STUDY DOCUMENTATION, MONITORING, AND
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
MANAGEMENT OF STUDY QUALITY
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity during 
Q4 2019.  The Sponsor will identify potential risks associated with critical trial processes 
and data and will implement plans for evaluating and controlling these risks.  
Risk evaluation and control will include the selection of risk-based parameters 
(e.g., adverse event rate, protocol deviation rate) and the establishment of quality 
tolerance limits for these parameters. Detection of deviations from quality tolerance 
limits will trigger an evaluation to determine if action is needed.  Details on the 
establishment and monitoring of quality tolerance limits will be provided in a 
Quality Tolerance Limit Management Plan.

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9.4
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.5
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring.
Where required, specific-site management activities may be delegated to a contract 
research organization.
Approximately 200 sites globally will participate to enroll approximately 255 patients.  
Randomization will occur through an IxRS. 
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker and PK analyses), as specified in Section 4.5.  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected.
If testing for the study inclusion criteria of ALK-positive NSCLC cannot be performed 
locally, central testing will be offered. This will be performed at Sponsor's designated 
central laboratories and assessed by a Ventana IHC test.
Steering Committee is established to provide the study Sponsor with recommendations
related to any aspect of the trial, specifically study design, data interpretation,
exploratory analyses, or alternate changes to the trial that may assist in patient accrual,
data collection, analysis, and interpretation of the study results. The Sponsor is
ultimately responsible for all decisions regarding the study.
An iDMC will be employed monitor the progress of the study and ensure that the safety 
of patients enrolled in the study is not compromised. Details of the composition, roles, 
and responsibilities, and processes of the iDMC are documented in a separate iDMC
Charter. The iDMC will review safety data and can make recommendations to the
Sponsor to stop or amend the study on the basis of safety findings. The frequency of
these reviews as well as the data to be reviewed will be agreed with the iDMC and
outlined in the separate iDMC Charter. No stopping for early proof of efficacy will result
from any of these regular safety reviews. iDMC review meetings will be held in a blinded
manner to the Sponsor.
An Independent Review Facility (IRF) will collect, store, and potentially review 
imaging data. It may perform a blinded independent central review (BICR) of images 
and other clinical data as needed.  In the event that such review is undertaken, BICR 
membership and procedures will be detailed in a separate BICR charter.

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9.6
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals. The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.7
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 

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eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).

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10.
REFERENCES
[ACS] American Cancer Society. Nonsmall-cell lung cancer survival rates, by stage 
[resource on the Internet]. 2016 [cited 14 November 2017]. Available from: 
https://www.cancer.org/cancer/non-small-cell-lung-cancer/detection-diagnosis-
staging/survival-rates.html.
Beal SL, Boeckmann AJ, Sheiner LB. NONMEM Project Group. NONMEM users guides. 
Version 5 ed. San Francisco, CA: University of California at San Francisco. 1999.
Blackhall FH, Peters S, Bubendorf L, et al. Prevalence and clinical outcomes for patients 
with ALK-positive resected stage I to III adenocarcinoma: results from the 
European Thoracic Oncology Platform Lungscape Project. J Clin Oncol 
2014;32:27807.
Brooks R. EuroQol: the current state of play. Health Policy 1996;37:5372.
Brunelli A, Socci L, Regai M, et al. Quality of life before and after major lung resection for 
lung cancer: a prospective follow-up analysis. Ann Thorac Surg 2007;84:4106.
Calvert AH, Newell DR, Gumbrell LA, et al. Carboplatin dosage: prospective evaluation 
of a simple formula based on renal function. J Clin Oncol 1989;7:174856.
Cancer Research UK. Lung cancer incidence statistics [resource on the Internet]. Last 
reviewed February 2017 [cited 15 November 2017]. Available from: 
http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-
cancer-type/lung-cancer/incidence#ref-5.
Choi YL, Soda M. Yamashita Y, et al. EML4-ALK mutations in lung cancer that confer 
resistance to ALK inhibitors. N Engl J Med 2010;363:17349.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron 1976;16:3141.
Decision Resources Group. Non-small-cell lung cancer [resource on the Internet]. 2014 
[cited 12 December 2017]. Available from: 
https://decisionresourcesgroup.com/report/246121-biopharma-non-small-cell-lung-
cancer-2014/.
DeMets DL, Lan KK. Interim analysis: the alpha spending function approach. Stat Med 
1994;13:134152.
Detterbeck FC, Boffa DJ, Tanoue LT. The new lung cancer staging system. 
Chest 2009;136:26071.
Doebele RC, Pilling AB, Aisner DL, et al. Mechanisms of resistance to crizotinib in 
patients with ALK gene rearranged non-small cell lung cancer. Cin Cancer Res 
2012;18:147282.
EuroQol Group. EuroQol: a new facility for the measurement of health-related quality of 
life. Health Policy 1990;16:199208.

Alectinib—F. Hoffmann-La Roche Ltd
135/Protocol BO40336, Version 7
Forshew T, Mertaza M, Parkinson C, et al. Noninvasive identification and monitoring of 
cancer mutations by targeted deep sequencing of plasma DNA. Sci Transl Med 
2012;4:136ra68.
Gadgeel SM, Gandhi L, Riely GJ, et al. Safety and activity of alectinib against systemic 
disease and brain metastases in patients with crizoitinib-resistant ALK-rearranged 
non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a 
phase 1/2 study. Lancet Oncol 2014;15:111928.
GLOBOCAN. Lung Cancer: estimatedincidence, mortality, and prevalence worldwide in 
2012.  2012. Accessed December 2017. Available at: 
http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx?cancer=lung
Goss GD, O'Callaghan C, Lorimer I, et al. Gefitinib versus placebo in completely 
resected non-small-cell lung cancer: results of the NCIC CTG BR19 study. J Clin 
Oncol 2013;31:33206.
Hartmann JT, Haap M, Kopp HG, et al. Tyrosine kinase inhibitorsa review on 
pharmacology, metabolism and side effects. Curr Drug Metab 2009;10:47081.
Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new 
five-level version of EQ-5D (EQ-5D-5L). Qual Life Res 2011;20:172736.
Hohenegger M. Drug induced rhabdomyolysis. Curr Opin Pharmacol 2012;12:3359.
Hsu JC, Jaminion F, Guerini E, et al. Population pharmacokinetics (popPK) and 
exposure-response (ER) analyses bridge J-ALEX to the global population with an 
alectinib (ALC) 600 mg BID dosing regimen [abstract]. J Clin Oncol 2017;35(Suppl 
15):e20616.
Janssen MF, Pickard AS, Golicki D, et al. Measurement properties of the EQ-5D-5L 
compared to the EQ-5D-3L across eight patient groups: a multi-country study. 
Qual Life Res 2013;22:171727.
Katayama R. Khan TM, Benes C, et al. Therapeutic strategies to overcome crizotinib 
resistance in non-small cell lung cancers harboring the fusion oncogene 
EML4-ALK. Proc Natl Acad Sci U S A 2011;108:753540.
Kelly K, Altorki NK, Eberhardt WE, et al. Adjuvant erlotinib versus placebo in patients 
with stage IB-IIIA non-small-cell lung cancer (RADIANT): a randomized, 
double-blind, phase III trial. J Clin Oncol 2015;33:400714.
Kim S, Kim TM, Kim DW, et al. Heterogeneity of genetic changes associated with 
acquired crizotinib resistance in ALK-rearranged lung cancer. J Thorac Oncol 
2013;8:41522.
Kris MG, Gaspar LE, Chaft JE, et al. Adjuvant systemic therapy and adjuvant radiation 
therapy for Stage I to IIIA completely resected non-small-cell lung cancers: 
American Society of Clinical Oncology/Cancer Care Ontario Clinical Practice 
Guideline Update. J Clin Oncol 2017;35:296074.

Alectinib—F. Hoffmann-La Roche Ltd
136/Protocol BO40336, Version 7
Lin JJ, Riely GJ, Shaw AT. Targeting ALK: precision medicine takes on drug resistance. 
Cancer Discov 2017;7:13755.
Myrdal G, Gustafsson G, Lambe M, et al. Outcome after lung cancer surgery. Factors 
predicting early mortality and major morbidity. Eur J Cardiothorac Surg 
2001;20:6949.
[NCCN] National Comprehensive Cancer Network. NCCN clinical practice guidelines in 
oncology: nonsmall-cell lung cancer, version 8 [resource on the Internet]. 2017 
[cited 20 August 2017]. Available from: 
https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf.
Nishio M, Kim DW, Wu YL, et al. Crizotinib versus chemotherapy in Asian patients with 
advanced ALK-positive nonsmall cell lung cancer. Cancer Res Treat 2017; 
doi: 10.4143/crt.2017.280 [ePub ahead of print].
Novello S, Mazieres J, Oh I, et al. Primary results from the phase III ALUR study of 
alectinib vs. chemotherapy in previously treated ALKnonsmall-cell lung cancer
(NSCLC). Ann Oncol 2017;28(Suppl 5):v60549.
Ostroff JS, Krebs P, Coups EJ, et al. Health-related quality of life among early-stage, 
non-small cell, lung cancer survivors. Lung Cancer 2011;71:1038.
Ou SH, Ahn JS, DePetris L, et al. Alectinib in crizotinib-refractory ALK-rearranged 
nonsmall-cell lung cancer: a Phase II global study J Clin Oncol 2016;34:6618.
Ou SH, Bartlett CH, Mino-Kenudson M, et al. Crizotinib for the treatment of ALK-
rearranged non-small cell lung cancer: a success story to usher in the second 
decade of molecular targeted therapy in oncology. Oncologist 2012;17:135175.
Paik JH, Choi CM, Kim H, et al. Clinicopathologic implication of ALK rearrangement in 
surgically resected lung cancer: a proposal of diagnostic algorithm for ALK-
rearranged adenocarcinoma. Lung Cancer 2012;76:4039.
Patel SH, Ma Y, Wernicke AG, et al. Evience supporting contemporary post-operative 
radiation therapy (PORT) using linear accelerators in N2 lung cancer. Lung 
Cancer 2014;84:15660.
Peters S, Camidge DR, Shaw AT et al. Alectinib versus crizotinab in untreated 
ALK-positive nonsmall-cell lung cancer. N Engl J Med 2017;377:82938.
Pignon JP, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatin evaluation: a pooled 
analysis by the LACE Collaborative Group. J Clin Oncol 2008;26:35529.
Ponn RB, Lo Cicero J III, Daly BDT. Surgical treatment of nonsmall cell lung cancer. 
In: Shields TW, Lo Cicero III J, Ponn R, et al., editors. General Thoracic Surgery 
(6th edition). Philadelphia: Lippincott Williams & Wilkins, 2005:154887. 
Postmus PE, Kerr KM, Oudkerk M, et al. Early and locally advanced non-small-cell lung 
cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment and 
follow-up. Ann of Oncol 2017;28(Suppl 4):iv121.

Alectinib—F. Hoffmann-La Roche Ltd
137/Protocol BO40336, Version 7
RadiologyInfo.org. Lung cancer treatment [resource on the Internet]. 2017 
[updated 1 February 2017; cited 14 April 2018]. Available from: 
https://www.radiologyinfo.org/en/info.cfm?pg=lung-cancer-therapy.
Ravdin PM, Davis G. Prognosis of patients with resected non-small cell lung cancer: 
impact of clinical and pathologic variables. Lung Cancer 2006;52:20712.
Sahu A, Prabhash K, Noronha V, et al. Crizotonib: a comprehensive review. South Asian 
J Cancer 2013;2:917.
Saynak M, Higginson DS, Morris DE, et al. Current status of postoperative radiation for 
non–small-cell lung cancer. Semin Radiat Oncol 2010;20:192200.
Shaw AT, Gandhi L, Gadgeel S, et al. Alectinib in ALK-positive, crizotinib-resistant, 
nonsmall cell lung cancer: a single-group, multicentre, Phase 2 trial. Lancel Oncol 
2016;17:23442.
Shaw AT, Kim D-W, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced 
ALK-positive lung cancer. N Engl J Med 2013;368:238594.
Solomon BJ, Mok T, Kim D-W, et al. First-line crizotinib versus chemotherapy in 
ALK-positive lung cancer. N Engl J Med 2014;371:216777.
Strauss GM, Herndon JE 2nd, Maddaus MA, et al. Adjuvant paclitaxel plus carboplatin 
compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 
with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and 
North Central Cancer Treatment Group Study Groups. J Clin Oncol 
2008;26:504351.
Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). 
Conceptual framework and item selection. Med Care 1992;30:47383 (abstract)
Ware J, Kosinski M, Bjorner J, et al. User's Manual for the SF-36v2Health Survey. 
Lincoln (RI): QualityMetric Incorporated; 2007:151185.
Ware JE Jr., Kosinski M, Bjorner JB, et al. SF-36v2 health survey: administration guide 
for clinical trial investigators. Lincoln, Rhode Island: QualityMetric, Incorporated, 
2008.
WHO. Cancer fact sheet [resource on the Internet]. 2017 [cited December 2017]. 
Available from: http://www.who.int/mediacentre/factsheets/fs297/en/.
Wu YL, Tsuboi M, He J, et al. Osimertinib in resected EGFR-mutated non–small-cell 
lung cancer. N Engl J Med 2020;383:171123
Wu YL, Zhong W, Wang Q, et al. Gefitinib (G) versus vinorelbinecisplatin (VP) as 
adjuvant treatment in stage IIIIIA (N1N2) nonsmall-cell lung cancer (NSCLC) 
with EGFR-activating mutation (ADJUVANT): a randomized, Phase III trial 
(CTONG 1104) [abstract]. J Clin Oncol 2017;35(Suppl 15):8500.

Alectinib—F. Hoffmann-La Roche Ltd
138/Protocol BO40336, Version 7
Xalkori® (crizotinib, capsules for oral use). U.S. Package Insert, Pfizer. February 2012 
[cited December 2017]. Available from:  
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202570s002lbl.pdf.
Yoshida T, Oya Y, Tanaka K, et al. Differential crizotinib response duration among ALK 
fusion variants in ALK-positive non-small-cell lung cancer. J Clin Oncol 
2016;34:33839.
Zykadia® (certinib, capsules for oral use). U.S. Package Insert, Novartis Pharmaceuticals 
Corporation. November 2017 [cited December 2017]. Available from: 
https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/zyka
dia.pdf.
.

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Appendix 1 Schedule of Activities: Alectinib Arm
Assessment
Screening
Treatment Period
Safety 
FU
Visit b
Disease 
Recurrence 
Visit c
Long-Term 
Follow-Up d
Day 28 
to 1 
Day 3 
to 1
Weeks 112 a
Weeks 1348 Weeks 4996
Baseline
Q3W 
(3 Days)
Q6W
(3 Days)
Q12W
(5 Days)
Informed consent e
x
Demographic data
x
Medical history, baseline conditions
x
ECOG Performance Status
x
x
x
x
x
x
Vital signs f
x
x
x
x
x
x
Weight
x
x
x
x
x
x
Height
x
Complete physical examination g
x
x
Limited physical examination h
x
x
x
x
ECG
x i
x
At Weeks 3, 24, and 60
x
Additional mandatory safety 
assessments
Every 2 weeks for the 
first 12 weeks a
Hematology j, k
x i
x 
x
x
x
x
Coagulation j
x i
x 
x
x
x
x
Chemistry l, k
x i
x
x
x
x
x
Pregnancy test m
x
To be repeated at all scheduled safety visits and as clinically indicated
Urinalysis, dipstick
x
x
x
x
x
x
Alectinib dispensing n
x
Every 3 weeks until Week 12 and every 
12 weeks thereafter

Appendix 1 Schedule of Activities:  Alectinib Arm (cont.)
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Assessment
Screening
Treatment Period
Safety 
FU
Visit b
Disease 
Recurrence 
Visit c
Long-Term 
Follow-Up d
Day 28 
to 1 
Day 3 
to 1
Weeks 112 a
Weeks 1348 Weeks 4996
Baseline
Q3W 
(3 Days)
Q6W
(3 Days)
Q12W
(5 Days)
Disease assessment
(including MRI of the brain) o
x p
x
Every 12 weeks for the first 2 years, every 
24 weeks during Years 3 to 5 and 
annually thereafter until recurrence
Plasma PK sample (2 mL) q
See Appendix 3
Plasma sample for biomarker analysis r
See Appendix 4
Tumor tissue sample for biomarker 
analysis s
See Appendix 4
Mandatory biopsy from site of 
recurrence t
x t
Concomitant medications u
x u
x
x
x
x
x
Adverse events v
x v
x
x
x
x
x
Subsequent therapy and SFU d
x
Patient-Reported Outcome w
xx
x
x w
x w
x
ALK anaplastic lymphoma kinase; BID twice a day; COVID-19 coronavirus disease 2019; CT computed tomography; ECOG Eastern 
Cooperative Oncology Group; eCRF electronic Case Report Form; FU follow-up; GGT gamma-glutamyl transferase; IRF Independent Review 
Facility; MRI magnetic resonance imaging; NCI CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events; 
NSCLC non-small-cell lung cancer; PET positron emission tomography; PK pharmacokinetic; PRO patient-reported outcome; 
Q3W every 3 weeks; Q6W every 6 weeks; Q12W every 12 weeks; RBR Research Biosample Repository; SFU survival follow-up.
Notes:  The screening period is within 28 days prior to randomization.  Baseline (Week 1) occurs when the first dose is administered.  The first dose 
should be administered as soon as possible after randomization and no later than 7 days after randomization.  All assessments should be performed 
within 3 days of the scheduled visit, unless otherwise specified.  On treatment days, all assessments should be performed prior to dosing, unless 
otherwise specified.  For patients at participating sites who have provided written informed consent to participate in the mobile nursing visits, 
assessments normally performed by a nurse at the sites may be performed by a trained nursing professional at the patient’s home or another suitable 
location, for visits after Week 1.

Appendix 1 Schedule of Activities:  Alectinib Arm (cont.)
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a Additional mandatory safety assessments include CPK at Weeks 2 and 4 and ALT, AST, ALP, and total and direct bilirubin at Weeks 2, 4, 8, 
and 10.
b The safety follow-up visit will take place 28 (3) days after last dose of alectinib.
c The disease recurrence visit should be scheduled within 30 days after diagnosis of recurrence for a mandatory biopsy.
d Required follow-up information (e.g., survival status and information on further cancer therapies and procedures [radiotherapy, surgery]) will be 
collected after the first documented disease recurrence or new primary NSCLC, via telephone calls or clinic visits every 6 months (14 days) 
until death, loss to follow-up, or study termination by the Sponsor.
e Informed consent must be documented before any study-specific screening procedure is performed and may be obtained more than 28 days 
before initiation of study treatment.
f
Includes respiratory rate, pulse rate, temperature, and systolic and diastolic blood pressure while the patient is in a seated position.  
Record abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or 
worsened clinically significant abnormalities on the Adverse Event eCRF.
g Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurologic systems.  Record abnormalities observed at baseline on the General Medical History and 
Baseline Conditions eCRF.  At subsequent visits, record new or worsened clinically significant abnormalities on the Adverse Event eCRF.
h Perform a limited, symptom-directed examination at specified timepoints and as clinically indicated.  Record new or worsened clinically 
significant abnormalities on the Adverse Event eCRF.
i
Results of laboratory tests and ECG performed within 3 days of first dose can be used as baseline assessments.
j
Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and absolute count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells). Peripheral blood smear, reticulocytes, and haptoglobin should be tested at baseline and in case of 
Grade 2 or higher anemia as per NCI CTCAE v5.0 (hemoglobin 10 g/dL).  Coagulation includes PT (or INR) and aPTT (or PTT).
k In case of Grade 2 or higher anemia as per NCI CTCAE v5.0 (hemoglobin10 g/dL), laboratory tests including hemoglobin, RBC count, 
reticulocytes, haptoglobin, ALT, LDH, total and direct bilirubin, peripheral blood smear, and a direct Coombs test (DAT) should be performed.  
This laboratory workup is to be conducted at each new occurrence of anemia at Grade 2 or higher.
l
Chemistry panel (serum or plasma) includes sodium, potassium, chloride, bicarbonate (optional), fasting glucose, BUN or urea, creatinine, 
creatinine clearance (calculated according to the method of Cockcroft and Gault), GGT, total protein, albumin, phosphorus, magnesium, 
calcium, total and direct bilirubin, ALP, CPK, ALT, AST, uric acid, and thyroid-stimulating hormone.  Lactate dehydrogenase should be tested at 
baseline and in case of Grade 2 or higher anemia as per NCI CTCAE v5.0 (hemoglobin10 g/dL).
m For all women of childbearing potential, a negative serum pregnancy test result must be available prior to randomization (maximum of 3 days) 
and within 10 days of the first dose of alectinib. The first dose of alectinib must be administered within 7 days from randomization. Urine 

Appendix 1 Schedule of Activities:  Alectinib Arm (cont.)
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pregnancy tests should be performed at scheduled safety visits throughout the study.  If a urine pregnancy test is positive, it must be confirmed 
by a serum pregnancy test.
n Alectinib will be administered BID until completion of the 24-month treatment period, recurrence of disease, unacceptable toxicity, withdrawal of 
consent, or death, whichever occurs first. Alectinib will be dispensed on Week 96 for an additional 8 weeks of treatment in order to complete the 
24-month treatment period (until Week 104).
o Screening disease assessments consist, at minimum, of a CT scan of chest, CT/MRI scan of abdomen (including liver and adrenal glands), as 
well as an MRI of the brain (a CT scan may be used if MRI is not feasible).  Patients who have clinical signs, symptoms, biochemical 
abnormalities (including, but not limited to, ALP, LDH, etc), or radiological imaging that could be suggestive of bone metastases at baseline, 
must undergo further investigation to exclude the presence of bone metastases at study entry.  Subsequent assessments consist, at minimum,
of a CT of the chest, CT/MRI scan of abdomen (including liver and adrenal glands) and brain. In case of suspicion of disease recurrence based 
on clinical or laboratory findings, a disease assessment should be performed as soon as possible before the next scheduled evaluation. If 
disease assessments continue after the treatment period, visit windows are as described in Section 4.5.6. Images will be submitted and stored 
at an IRF.
p A screening disease assessment done within 28 days of randomization will be counted as the baseline assessment.
q Predose PK (2 mL) sampling for all patients on alectinib treatment will be performed at baseline, every 3 weeks until Week 12, and 
every 12 weeks thereafter until recurrence of disease, unacceptable toxicity, withdrawal of consent, death, or Week 96, whichever occurs first.  
The predose PK samples should be taken immediately (within 2 hours) before intake of study medication at specified study visits.  Remind the 
patient not to take the daily dose at home on the day of the scheduled study visit. For Japan sites only (if Japan will participate in the study), a 
subset of Japanese patients on alectinib treatment (approximately the first 6 patients) participating in serial/intensive PK sample collection, 
additional PK samples will be collected at Week 3 predose (within 2 hours before intake of study medication), 0.5, 1, 2, 4, 6, 8, 10, and 12 hours 
(optional) postdose. See Appendix 3 for a detailed schedule.
r
Residual plasma samples can be used for the RBR if the patient has provided written informed consent to participate.  See Appendix 4 for a 
detailed schedule.
s Mandatory tumor sample obtained at study entry and taken at disease recurrence (if clinically feasible) for biomarker analysis 
(confirmatory central ALK testing [at baseline only] and ALK rearrangements/mutations and other genes and gene mutations involved in 
resistance).  Residual tissue samples can be used for the RBR if the patient has provided written informed consent to participate.
t
Mandatory biopsy (if clinically feasible) for confirmation of diagnosis of recurrence within 30 days from the time of recurrence.  A tumor tissue for 
biomarker analysis will be obtained from the mandatory biopsy at recurrence.
u Concomitant medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) 
used by a patient in addition to protocol-mandated treatment from 14 days prior to initiation of study drug until safety follow-up visit. Details of 
regarding the COVID-19 vaccine received should be recorded in the concomitant medication section. 

Appendix 1 Schedule of Activities:  Alectinib Arm (cont.)
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v After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until the safety follow-up visit at 28 days after 
last dose of alectinib. After the adverse event reporting period, all deaths, regardless of cause, should be reported.  In addition, the Sponsor 
should be notified if the investigator becomes aware of any serious adverse event that is believed to be related to prior study drug treatment.
The investigator should follow each adverse event until the event has resolved to baseline grade or better, the event is assessed as stable by 
the investigator, the patient is lost to follow-up, or the patient withdraws consent.  Every effort should be made to follow all serious adverse 
events considered to be related to study drug or trial-related procedures until a final outcome can be reported.
w The PRO questionnaires (SF-36v2and EQ-5D-5L) will be completed by patients at the investigational site within the window (3 days) 
specified for the clinic visit prior to any assessment at: baseline, every 3 weeks through Week 12, and every 12 weeks thereafter until 
recurrence of disease, withdrawal of consent, death, or Week 96, whichever occurs first. Patient-reported outcome will also be collected at the 
safety follow-up visit.
x Patient-reported outcome at baseline can be performed within -3 days of the first dose if not possible during the baseline (Week 1) visit. 
Patient-reported outcome must be collected at the clinic visit prior to any visit assessments.

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Appendix 2 Schedule of Activities: Patients Randomized to Chemotherapy
Assessments
Screening
Treatment Period
Safety 
FU
Visit c
Disease 
Recurrence 
Visit d
Long-Term 
Follow-Up e
Day 28 to 1
Day 3 to 1
Weeks 112 a
Baseline
Q3W (3 Days)
Informed consent f
x
Demographic data
x
Medical history and baseline 
x
ECOG Performance Status
x
x
x
x
Vital signs g
x
x
x
x
Weight
x
x
x
x
Height
x
Complete physical examination h
x
x
Limited physical examination i
x
x
ECG
x u
x
At Week 3
x
Hematology j
x u
x
x
x
Coagulation j
x u
x
x
x
Chemistry k
x u
x
x
x
Pregnancy test l
x
To be repeated
at all scheduled 
safety visits and 
as clinically 
indicated
Urinalysis, dipstick
x
x
x
x
Chemotherapy administration b
x
x

Appendix 2 Schedule of Activities: Patients Randomized to Chemotherapy (cont.)
Alectinib—F. Hoffmann-La Roche Ltd
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Assessments
Screening
Treatment Period
Safety 
FU
Visit c
Disease 
Recurrence 
Visit d
Long-Term 
Follow-Up e
Day 28 to 1
Day 3 to 1
Weeks 112 a
Baseline
Q3W (3 Days)
Disease assessment
(including MRI of the brain) m
x n
x
Every 12 weeks 
for the first 
2 years, every 
24 weeks during 
Years 35 and 
annually 
thereafter until 
recurrence
Plasma sample for biomarker
analysis o
See 
Appendix 4
Tumor tissue sample for biomarker 
analysis p
See 
Appendix 4
Mandatory biopsy from site of 
recurrence q
x q
Concomitant medications r
x
x
x
x
Adverse events s
x
x
x
x
Subsequent treatment and SFU e
x
PROs t
x v
x
x
ALKanaplastic lymphoma kinase; COVID-19 coronavirus disease 2019; CT computed tomography; ECOG Eastern Cooperative Oncology 
Group; eCRFelectronic Case Report Form; FUfollow-up; GGT gamma-glutamyl transferase; IRF Independent Review Facility; 
MRImagnetic resonance imaging; NSCLC non-small-cell lung cancer; PET positron emission tomography; PROpatient-reported outcome; 
Q3W every 3 weeks; RBR Research Biosample Repository; SFUsurvival follow-up.

Appendix 2 Schedule of Activities: Patients Randomized to Chemotherapy (cont.)
Alectinib—F. Hoffmann-La Roche Ltd
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Notes:  The screening period is within 28 days prior to randomization. Baseline (Week 1) occurs when the first dose of platinum-based 
chemotherapy is administered.  The first dose should be administered as soon as possible after randomization and no later than 7 days after
randomization. All assessments should be performed within 3 days of the scheduled visit, unless otherwise specified.  On treatment days, all 
assessments should be performed prior to dosing, unless otherwise specified. For patients at participating sites who have provided written 
informed consent to participate in the mobile nursing visits, assessments normally performed by a nurse at the sites may be performed by a trained 
nursing professional at the patient’s home or another suitable location, for visits after Week 1.
a Additional mandatory phone calls at Weeks 2, 4, 8, and 10 need to be conducted for safety monitoring.
b Platinum-based chemotherapies will be administered until the completion of the treatment period (4 cycles), recurrence of disease, unacceptable 
toxicity, withdrawal of consent, or death, whichever occurs first.
c The safety follow-up visit will take place 28 days after the end of the last cycle of chemotherapy (7 weeks after Day 1 of the last cycle3 days).
d The disease recurrence visit should be scheduled within 30 days after a diagnosis of recurrence for mandatory biopsy.
e Required follow-up information (e.g., survival status and information on further cancer therapies and procedures [radiotherapy, surgery] will be 
collected after the first documented disease recurrence or new primary NSCLC, via telephone calls and/or clinic visits every 6 months
(14 days) until death, loss to follow-up, or study termination by the Sponsor.
f
Informed consent must be documented before any study-specific screening procedure is performed and may be obtained more than 28 days 
before initiation of study treatment.
g Includes respiratory rate, pulse rate, temperature, and systolic and diastolic blood pressure while the patient is in a seated position.  
Record abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or 
worsened clinically significant abnormalities on the Adverse Event eCRF.
h Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurologic systems.  Record abnormalities observed at baseline on the General Medical History and Baseline 
Conditions eCRF.  At subsequent visits, record new or worsened clinically significant abnormalities on the Adverse Event eCRF.
i
Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated.  Record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF.
j
Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, absolute count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, other cells). Coagulation includes PT (or INR) and aPTT (or PTT).
k Chemistry panel (serum or plasma) includes sodium, potassium, chloride, bicarbonate (optional), fasting glucose, BUN or urea, creatinine, 
creatinine clearance (calculated according to the method of Cockcroft and Gault), GGT, total protein, albumin, phosphorus, magnesium, calcium, 
total and direct bilirubin, ALP, CPK, ALT, AST, uric acid, and thyroid-stimulating hormone.
l
For all women of childbearing potential, a negative serum pregnancy test result must be available prior to randomization (maximum of 3 days) 
and within 10 days of the first dose of chemotherapy. The first dose of chemotherapy must be administered within 7 days from randomization.  
Urine pregnancy tests should be performed at all safety visits throughout the study. If a urine pregnancy test is positive, it must be confirmed by 
a serum pregnancy test.

Appendix 2 Schedule of Activities: Patients Randomized to Chemotherapy (cont.)
Alectinib—F. Hoffmann-La Roche Ltd
147/Protocol BO40336, Version 7
m Screening disease assessments consist, at minimum, of a CT scan of chest, CT/MRI scan of abdomen (including liver and adrenal glands), as 
well as an MRI of the brain (CT scan may be used if MRI is not feasible).  Patients who have clinical signs, symptoms, biochemical abnormalities 
(including but not limited to ALP, LDH, etc), or radiological imaging that could be suggestive of bone metastases at baseline, must undergo 
further investigation to exclude the presence of bone metastases at study entry.  Subsequent assessments consist, at minimum, of a CT of the 
chest, CT/MRI scan of abdomen (including liver and adrenal glands) and brain.  In case of suspicion of recurrence of disease based on clinical or 
laboratory findings, a disease assessment should be performed as soon as possible before the next scheduled evaluation. If disease 
assessments continue after the treatment period, visit windows are as described in Section 4.5.6.  Images will be submitted and stored at an 
IRF.
n A screening disease assessment done within 28 days of randomization will be counted as the baseline assessment.
o Residual plasma samples can be used for RBR if patient has provided written informed consent to participate.  See Appendix 4 for a detailed 
schedule.
p Mandatory tumor sample obtained at study entry and taken at disease recurrence (if clinically feasible) for biomarker analysis 
(confirmatory central ALK testing [at baseline only] and ALK rearrangements/mutations and other genes and gene mutations involved in 
resistance).  Residual tissue samples can be used for the RBR if the patient has provided written informed consent to participate.
q Mandatory biopsy (if clinically feasible) for confirmation of a diagnosis of recurrence within 30 days from time of recurrence.  Tumor tissue for 
biomarker analysis will be obtained from the mandatory biopsy at recurrence.
r
Concomitant medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) 
used by a patient in addition to protocol-mandated treatment from 14 days prior to initiation of study drug until safety follow-up visit. Details of 
regarding the COVID-19 vaccine received should be recorded in the concomitant medication section.
s After informed consent has been obtained, but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported. After initiation of study drug, all adverse events will be reported until the safety follow-up visit at 28 days after 
the end of the last cycle of chemotherapy (7 weeks after Day 1 of the last cycle).  After the adverse event reporting period, all deaths, regardless 
of cause, should be reported.  In addition, the Sponsor should be notified if the investigator becomes aware of any serious adverse event that is 
believed to be related to prior study drug treatment. The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to follow-up, or the patient withdraws consent.  Every effort 
should be made to follow all serious adverse events considered to be related to study drug or trial-related procedures until a final outcome can 
be reported.
t
The PRO questionnaires (SF-36v2and EQ-5D-5L) will be completed by patients at the investigational site within the window (3 days) specified 
for the clinic visit prior to any assessment at: baseline, every 3 weeks through Week 12, and every 12 weeks thereafter until recurrence of 
disease, withdrawal of consent, death, or Week 96, whichever occurs first.  PROs will also be collected at the safety follow-up visit.
u Results of laboratory tests and ECG performed within 3 days of first dose can be used as baseline assessments.
v Patient-reported outcome baseline questionnaires can be performed within 3 days of the first dose if not possible during the baseline (Week 1) 
visit. Patient-reported outcome must be collected at the clinic visit prior to any visit assessments.

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Appendix 3 Schedule of Pharmacokinetic Assessments for Patients Randomized to Alectinib
Visit
Timepoint
Sample Type
Baseline
Predose (within 2 hours before first administration of alectinib)
Plasma
Weeks 3, 6, 9, 12, 24, 36, 
48, 60, 72, 84, and 96
Predose (within 2 hours before intake of alectinib)
Plasma
Week 3 a
Predose (within 2 hours before intake of alectinib), 0.5, 1, 2, 4, 6, 8, 10, and 12 (optional) hours
Plasma
PKpharmacokinetic.
a Japan only (if Japan participates in the study): Japanese patients participating in the serial/intensive PK sample collection only.

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Appendix 4 Schedule of Biomarker Samples
Visit
Timepoint
Sample Type
Biomarkers
Baseline
At visit
Plasma
ALK rearrangements/mutations and other genes and 
gene mutations involved in resistance and 
circulating tumor nucleic acids for MRD and early 
recurrence
From prior sampling
Tumor tissue
Confirmatory central ALK testing, ALK
rearrangements/mutations and other genes and 
gene mutations involved in resistance 
Scheduled visits until 
recurrence
Every 3 weeks until Week 12, every 12 weeks 
between Weeks 1396, every 24 weeks during
Years 35, and annually thereafter until disease 
recurrence
Plasma
ALK rearrangements/mutations and other genes and 
gene mutations involved in resistance and 
circulating tumor nucleic acids for MRD and early 
recurrence
At disease recurrence 
visit
At disease recurrence
Plasma
ALK rearrangements/mutations and other genes and 
gene mutations involved in resistance and 
circulating tumor nucleic acids for MRD and early 
recurrence
Tumor tissue a
ALK rearrangements/mutations and other genes and 
gene mutations involved in resistance
ALKanaplastic lymphoma kinase; MRDminimal residual disease.
a A tumor tissue for biomarker analysis will be obtained from the biopsy collected at recurrence.

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Appendix 5 List of Substrates, Inhibitors, and Inducers of 
Drug-Metabolizing Enzymes and Transporters
This representative list is not intended to be an exhaustive list.  Each patient’s 
concomitant medications should be carefully considered by the investigator with regard 
to the risk-benefit for the particular patient and appropriate monitoring, including any 
concomitant medication, dose adjustment, or therapeutic alternatives, which should be 
determined by the investigator caring for the patient.
CYP3A Potent Inducers
CYP3A Potent Inhibitors
avasimibe, barbiturates, carbamazepine, 
efavirenz, ethosuximide, garlic supplements, 
modafinil, nevirapine, oxcarbazepine, 
phenobarbital, phenytoin, pioglitazone, 
primidone, rifabutin, rifampin, rifapentine, 
St. John’s wort, troglitazone
aprepitant, atazanavir, boceprevir, 
ciprofloxacin, clarithromycin, conivaptan, 
diltiazem, erythromycin, fluconazole, 
grapefruit juice, indinavir, itraconazole, 
ketoconazole, lopinavir, mibefradil, 
nefazodone, nelfinavir, posaconazole, 
ritonavir, saquinavir, telaprevir, telithromycin, 
troleandomycin, verapamil, voriconazole
P-gp Substrates
aliskiren, ambrisentan, colchicine, dabigatran, digoxin, everolimus, fexofenadine, imatinib, 
lapatinib, maraviroc, nilotinib, posaconazole, pravastatin, ranolazine, saxagliptin, sirolimus, 
sitagliptin, talinolol, tolvaptan, topotecan
Source:  Levien and Baker 2003; Zhang 2010.
This information in this appendix is adapted from Levien and Baker 2003, Zhang 2010, 
and the FDA’s Guidance on DrugDrug Interactions.
Also see:

https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/
DrugInteractionsLabeling/ucm080499.htm

https://medicine.iupui.edu/clinpharm/ddis/table.aspx
REFERENCES
Levien TL, Baker DE. Cytochrome P450 drug interactions. Therapeutic Research Center 
Pharmacist’s Letter/Prescriber’s Letter [resource on the internet]. 2003 
[cited November 2017]. Available from: https://www.pharmacistletter.com.
Zhang L. Transporter mediated drugdrug interactions (DDIs). FDA. 
Clinical Pharmacology Advisory Committee Meeting Topic 4: Transporter-Mediated 
DrugDrug Interactions. Atlanta, GA: 17 March 2010.

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Appendix 6 Eastern Cooperative Oncology Group Performance 
Status Scale
Grade
ECOG Performance Status
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities; up and about more than 50% of waking hours
3
Capable of only limited self-care; confined to bed or chair more than 50% of 
waking hours
4
Completely disabled; cannot carry on any self-care; totally confined to bed or 
chair
5
Dead

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Appendix 7 Formulae for the Calculation of QTcF and RR
QTcFFridericia’s correction for QTc measurement (if not provided directly by the ECG 
machine):
RR Interval Formula (if not provided directly by the ECG machine):
RR (ms)60000/heart rate (bpm)

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Appendix 8 SF-36v2Health Survey
Do not reproduce or distribute:  The Sponsor will provide sites with all instruments to 
be completed in this study.

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Appendix 8 SF-36v2Health Survey (cont.)

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Appendix 8 SF-36v2Health Survey (cont.)

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Appendix 8 SF-36v2Health Survey (cont.)

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Appendix 8 SF-36v2Health Survey (cont.)

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Appendix 8 SF-36v2Health Survey (cont.)

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Appendix 9 EuroQol 5-Dimension, 5-Level Questionnaire
Do not reproduce or distribute:  The Sponsor will provide sites with all instruments to 
be completed in this study.

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Appendix 9 EuroQol 5-Dimension, 5-Level Questionnaire (cont.)

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Appendix 9 EuroQol 5-Dimension, 5-Level Questionnaire (cont.)