Randomized, Double-blind, Phase 3 Study of Tucatinib or Placebo in Combination With Ado-trastuzumab Emtansine (T-DM1) for Subjects With Unresectable Locally-advanced or Metastatic HER2+ Breast Cancer (HER2CLIMB-02)
Phase: PHASE3
Conditions: HER2-positive Breast Cancer
Sponsor: Seagen, a wholly owned subsidiary of Pfizer

 
Protocol Number: 
SGNTUC-016 
Version: 
Amendment 4; 08-Nov-2023 
Protocol Title: 
Randomized, double-blind, phase 3 study of tucatinib or 
placebo in combination with ado-trastuzumab emtansine 
(T-DM1) for subjects with unresectable locally-advanced or 
metastatic HER2+ breast cancer 
(HER2CLIMB-02) 
Investigational Product: 
Tucatinib  
Brief Title: 
A study of tucatinib vs. placebo in combination with 
ado-trastuzumab emtansine (T-DM1) for subjects with 
advanced or metastatic HER2+ breast cancer 
Indication: 
Unresectable Locally-Advanced or Metastatic HER2+ Breast 
Cancer 
Phase: 
3 
IND Number: 
119421 
EudraCT Number 
2019-005017-39 
EU CT Number 
2023-506418-30 
Sponsor: 
Seagen Inc. 
21823 30th Drive SE 
Bothell, WA 98021, USA 
Medical Monitor: 
 
Seagen Inc. 
Tel: 
 
E-mail: 
 
SAE Email or Fax: 
See email or fax number specified on the SAE report form. 
 
 
 
This document contains information proprietary to Seagen Inc. The information is being provided to you for the 
purpose of conducting a clinical trial for Seagen Inc. You may disclose the contents of this document to study 
personnel under your supervision and to your Institutional Review Board (IRB) or Ethics Committee (EC) for the 
same purpose. You may not disclose the contents of this document to any other party, unless government regulations 
or laws require such disclosure, without prior written permission from Seagen Inc. Any supplemental information 
that may be added to this document is proprietary to Seagen Inc. and should be handled using the disclosure 
procedure described above

Study SGNTUC-016 
Clinical Protocol 
Amendment 4, 08-Nov-2023 
Tucatinib 
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PROTOCOL SYNOPSIS 
Protocol Number 
SGNTUC-016 
Version 
Amendment 4; 08-Nov-2023 
Phase 
3 
Product Name 
Tucatinib 
Sponsor 
Seagen Inc. 
21823 30th Drive SE 
Bothell, WA 98021, USA 
Protocol Title 
 
Randomized, double-blind, phase 3 study of tucatinib or placebo in combination with ado-trastuzumab emtansine 
(T-DM1) for subjects with unresectable locally-advanced or metastatic HER2+ breast cancer (HER2CLIMB-02) 
Study Objectives 
Primary 
● Compare progression-free survival (PFS) by investigator assessment per Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1 between treatment arms 
Key Secondary 
● Compare overall survival (OS) between treatment arms 
● Compare PFS by investigator assessment per RECIST v1.1 in subjects with brain metastases at baseline (PFS.BM 
per investigator) between treatment arms 
● Compare the objective response rate (ORR) by investigator assessment per RECIST v1.1 between treatment arms 
● Compare overall survival in subjects with brain metastases at baseline (OS.BM) between treatment arms 
Other Secondary 
● Evaluate PFS by blinded independent central review (BICR) per RECIST v1.1 between treatment arms 
● Evaluate PFS by BICR per RECIST v1.1 in subjects with brain metastases at baseline (PFS.BM per BICR) 
between treatment arms 
● Evaluate the ORR by BICR per RECIST v1.1 between treatment arms 
● Evaluate the duration of response (DOR) by investigator assessment per RECIST v1.1 between treatment arms 
● Evaluate the DOR by BICR per RECIST v1.1 between treatment arms 
● Evaluate the clinical benefit rate (CBR; stable disease [SD] or non-complete response [CR]/non-progressive 
disease [PD] for ≥6 months or best response of CR or partial response [PR]) by investigator assessment per 
RECIST v1.1 between treatment arms  
● Evaluate the CBR by BICR per RECIST v1.1 between treatment arms 
● Evaluate the safety of tucatinib in combination with T-DM1 
Exploratory 
● Evaluate the pharmacokinetics of tucatinib and DM1 following administration of tucatinib and T-DM1 in 
combination 
● Evaluate on-trial healthcare resource utilization (HCRU) between treatment arms 
● Evaluate patient-reported outcomes (PROs) and health-related quality of life (QoL) between treatment arms 

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Study Population 
Eligible subjects are at least 18 years of age or at least the age of majority in the geographic location and have 
unresectable locally-advanced or metastatic (LA/M) human epidermal growth factor receptor 2 positive (HER2+) 
breast cancer with a life expectancy of at least 6 months. Subjects must have histologically confirmed HER2+ breast 
carcinoma and had prior treatment with a taxane and trastuzumab in any setting (separately or in combination), and 
must have progressed or have been intolerant of the last systemic therapy (see Appendix L  for France-specific 
requirements).  
Hormone receptor status must also be known prior to randomization. Subjects must have an Eastern Cooperative 
Oncology Group (ECOG) performance status of ≤1, adequate cardiac function, and adequate renal, hepatic, and 
hematologic function at baseline. Prior treatment with tucatinib, T-DM1, afatinib, trastuzumab deruxtecan (T-Dxd; 
DS-8201a), or any other investigational anti-HER2 or anti-epidermal growth factor receptor agent or HER2 tyrosine 
kinase inhibitor agent is not permitted. Lapatinib or neratinib are prohibited if received within 12 months of starting 
study treatment (except in cases where they were given for ≤21 days and were discontinued for reasons other than 
disease progression or severe toxicity). Prior treatment with pyrotinib for recurrent or metastatic breast cancer 
(mBC) is not permitted (except in cases where pyrotinib was given for ≤21 days and was discontinued for reasons 
other than disease progression or severe toxicity). Prior pertuzumab therapy is allowed, but not required. Subjects 
must be >3 weeks post-treatment from any prior systemic anticancer therapy (including hormonal therapy), 
noncentral nervous system radiotherapy (palliative or therapeutic), or participation in another interventional clinical 
trial. 
Subjects with untreated brain metastases on screening brain magnetic resonance imaging (MRI) are eligible if 
immediate local therapy is not required. Subjects with brain metastases previously treated with local therapy are 
eligible if the brain metastases are stable since treatment; or, if there has been progression since the prior local 
central nervous system (CNS) therapy, immediate retreatment with local therapy is not required. If treatment for 
newly identified lesions or previously treated and progressing lesions is initiated, subjects may still be eligible if 
other sites of evaluable disease are present and treatment is completed prior to the first dose of study treatment as 
follows: stereotactic radiosurgery is completed ≥7 days prior, whole brain radiation therapy is completed ≥14 days 
prior, or time since surgical resection is ≥28 days. Ongoing use of systemic corticosteroids at a total daily dose of 
>2 mg of dexamethasone (or equivalent) for symptomatic control is not permitted. Subjects with poorly controlled 
generalized or complex partial seizures, or manifest neurologic progression due to brain metastases notwithstanding 
CNS-directed therapy are not permitted. 
Number of Planned Subjects 
Approximately 460 subjects (approximately 230 subjects per treatment arm) will be randomized in the global 
portion of this study. After enrollment of the global portion of the study is completed, the study may remain open to 
enrollment in China alone until approximately 105 (up to 110) subjects in China (including those randomized in the 
global portion and China portion) have been randomized.  
Study Design 
This is a randomized, double-blind, placebo-controlled, international, multicenter, phase 3 study designed to 
evaluate the efficacy and safety of tucatinib in combination with T-DM1 in subjects with unresectable LA/M 
HER2+ breast cancer who have had prior treatment with a taxane and trastuzumab in any setting. Baseline disease 
assessments include measurement of all known sites of unresectable locally-advanced/metastatic disease through 
radiographic imaging. Assessment for brain metastases is performed with contrast MRI of the brain for all subjects, 
regardless of prior history of brain metastases. Subjects will be randomized in a 1:1 manner to receive 21-day cycles 
of either tucatinib or placebo in combination with T-DM1. Randomization will be stratified by line of treatment for 
metastatic disease, hormone receptor status, presence or history of brain metastases, and ECOG performance status. 
While on study treatment, subjects will be assessed for progression every 6 weeks for the first 24 weeks, and every 
9 weeks thereafter, irrespective of dose holds or interruptions. After completion of study treatment and after 
occurrence of disease progression, subjects in both arms of the study will continue to be followed for survival until 
study closure or withdrawal of consent. 

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An independent data monitoring committee will periodically review relevant aggregate safety data (blinded and 
unblinded) and will make recommendations to the sponsor. Safety will also be monitored in an ongoing, blinded 
basis by the sponsor throughout the study.  
Investigational Product, Dose, and Mode of Administration 
Subjects will be randomized in a 1:1 manner to receive study treatment on a 21-day cycle, either: 
● Control arm: Placebo given orally twice a day (PO BID); T-DM1 3.6 mg/kg given intravenously (IV) every 
21 days 
● Experimental arm: Tucatinib 300 mg PO BID; T-DM1 3.6 mg/kg IV every 21 days 
Duration of Treatment 
Study treatment will continue until unacceptable toxicity, disease progression, withdrawal of consent, or study 
closure. In the absence of clear evidence of radiographic progression, development of CNS symptoms, or 
radiographic changes thought to pose potential immediate risk to the subject, all efforts should be made to continue 
treatment until unequivocal evidence of radiologic progression occurs. No crossover from placebo to tucatinib will 
be allowed. Subjects assessed as having isolated progression in the brain per RECIST v1.1 may be eligible to 
continue on study treatment for clinical benefit after undergoing local therapy to CNS disease, with approval from 
the medical monitor. 
Efficacy Assessments 
Disease response per RECIST v1.1 (Eisenhauer 2009) will be assessed by both investigator assessment and BICR. 
Response assessments will include measurement of all known sites of unresectable LA/M disease (including at a 
minimum the chest, abdomen, and pelvis), preferably by high quality spiral contrast computed tomography (CT), at 
baseline, every 6 weeks for the first 24 weeks, and every 9 weeks thereafter, irrespective of dose interruptions. 
Positron emission tomography/CT (if high quality CT scan included), and/or MRI scan may also be done as 
appropriate, as well as additional imaging of any other known sites of disease (eg, skin lesion photography for skin 
lesions, nuclear bone scan imaging for bone lesions). 
Contrast MRI of the brain will be required on this same schedule only in those subjects with prior history of brain 
metastases or brain metastases found at screening. Additional contrast MRIs of the brain may also be performed in 
subjects without known brain metastases if there is clinical suspicion of new brain lesions. 
Treatment decisions will be made based upon local assessment of radiologic scans. Response assessments for each 
subject will continue until a PFS event per RECIST v1.1 by investigator assessment has been documented. 
Follow-up for survival will continue until study closure or withdrawal of consent. 
Pharmacokinetic Assessments 
Pharmacokinetic (PK) assessments will be performed from Cycle 3 to Cycle 6 in all subjects to assess the steady 
state pharmacokinetics of tucatinib and DM1. In the US only, approximately 50 subjects (25 from each treatment 
arm) will participate in a PK substudy with additional PK sampling on Days 1, 2, 3, and 5 in Cycle 2 to assess any 
effects of tucatinib on the pharmacokinetics of DM1. 
Other Assessments – PROs and Health Care Resource Utilization 
PROs will be assessed at protocol-specified time points using standardized assessment tools. These PRO instruments 
include the European Quality of Life 5-Dimension 3-Level (EQ-5D-3L) instrument, 2 questions to capture global 
health status/quality of life from the European Organization for Research and Treatment of Cancer quality-of-life 
questionnaire (EORTC QLQ IL6), the National Cancer Institute's Patient-Reported Outcomes version of the 
Common Terminology Criteria for Adverse Events (NCI PRO-CTCAE) questionnaire customized to focus on 
adverse events (AEs) or symptoms of interest, and 1 question from the Functional Assessment of Cancer Therapy – 
Breast (FACT-B GP5) questionnaire to capture the patients’ perceptions of side effects. In addition, a summary of 
health care resource utilization (HCRU) will be presented.  

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Safety Assessments 
Safety assessments will include surveillance and recording of AEs, physical examination findings, and laboratory 
tests. Assessment of cardiac ejection fraction will be performed by multigated acquisition scan or echocardiogram. 
Statistical Methods 
Stratification 
Stratification factors will include line of treatment for metastatic disease (1st line metastatic versus other), hormone 
receptor status (positive/negative), presence or history of treated or untreated brain metastases (yes/no), and ECOG 
performance status (0 versus 1). Stratification for presence of brain metastases will be based upon medical history 
and investigator assessment of screening contrast brain MRI. Only subjects with parenchymal lesions are considered 
as having brain metastases at baseline for purposes of stratification. 
Sample Size Considerations 
This study is designed to detect a tucatinib treatment effect of at least a 30% reduction in risk of PFS events (hazard 
ratio [HR] of 0.70; median PFS from 6 months in the control arm to 8.57 months in the experimental arm). 
A total of 331 PFS events will provide 90% power to detect a HR of 0.70 at a 2-sided significance level of 0.05 
using a log-rank test. Approximately 460 subjects will be randomized in a 1:1 ratio to either the experimental arm or 
the control arm to observe 331 PFS events in approximately 30 months after the first subject is randomized, 
assuming 24 months of subject accrual, and a 5% annual dropout rate. 
It is planned that follow-up for OS will continue after the primary analysis of PFS. The final OS analysis will be 
performed when approximately 253 OS events have occurred. With 253 events, it will provide 80% power to detect 
a HR of 0.70 in OS at a 2-sided significance level of 0.05 using a log-rank test. The final analysis of OS is estimated 
to take place approximately 30 months after the primary analysis of PFS per investigator assuming that OS for the 
control arm follows an exponential distribution with a median of 29 months. 
Follow-up of PFS.BM per investigator will continue after the primary analysis of PFS until the second interim 
analysis of OS. It is anticipated that approximately 175 PFS.BM events would have occurred, which will provide 
65% power to detect a HR of 0.7 in PFS.BM at a 2-sided significance level of 0.05 using a log-rank test.  
To evaluate the consistency of efficacy and safety in a China subpopulation compared with the global population, 
after completion of enrollment in the global portion, subjects in China may continue to be randomized in a 1:1 ratio 
to either the experimental arm or the control arm until the planned sample size of approximately 105 (up to 110) 
subjects in China including those randomized in the global portion and China portion is reached. Subjects in China 
randomized after completion of enrollment in the global portion will not be included in the analysis of the global 
portion. After the completion of the global portion, the study may remain open to complete the China portion as an 
extension of the study.  
Analysis Methods 
For the primary endpoint of PFS per investigator assessment, the 2 treatment groups will be compared using a 
2-sided stratified log-rank test. Estimation of the HR will be based upon the stratified Cox regression model. PFS 
will also be summarized using the Kaplan-Meier method. All randomized subjects will be included in the primary 
analysis of PFS. Kaplan-Meier methodology will be used to estimate the PFS time curves, including the median. 
Similar methods will be used for the key and other secondary time-to-event endpoints and other exploratory 
time-to-event endpoints. No interim analyses will be performed for the primary endpoint.  
If PFS per investigator is statistically significant, then there will be 3 analyses of the key secondary endpoint of OS. 
The first OS interim analysis (OS IA1) will be conducted at the time of analysis of the primary endpoint when 
approximately 331 PFS events per investigator assessment have occurred. The second OS interim analysis (OS IA2) 
will be conducted when approximately 202 (80%) OS events have occurred. The final OS analysis (OS FA) is 
planned when approximately 253 OS events have occurred.  
If both PFS and OS (OS IA1, OS IA2, or OS FA) results are statistically significant, then there will be 2 analyses of 
the key secondary endpoint of PFS.BM by investigator assessment per RECIST v1.1. The first PFS.BM analysis 

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will use the PFS.BM data at the time of analysis of the primary endpoint when approximately 331 PFS events per 
investigator assessment have occurred. The final PFS.BM analysis will use the PFS.BM data at the time of OS IA2.  
If the results of PFS, OS, and PFS.BM are all statistically significant, a formal statistical test of ORR will be 
performed.  
If the results of PFS per investigator, OS, PFS.BM per investigator and ORR per investigator are all statistically 
significant, then OS in subjects with brain metastases at baseline (OS.BM) will be formally tested. Hierarchical 
Testing Strategy 
 
 
 

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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS .............................................................................................................................................. 2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................................................................. 12 
1. 
INTRODUCTION ................................................................................................................................ 15 
1.1. 
HER2+ Breast Cancer ........................................................................................................................... 15 
1.2. 
Use and Sequencing of T-DM1 in the Metastatic Setting ..................................................................... 16 
1.3. 
Brain Metastases ................................................................................................................................... 17 
1.4. 
Tucatinib ............................................................................................................................................... 18 
1.4.1. 
Rationale for Tucatinib in Combination with T-DM1 ......................................................... 19 
1.4.2. 
Tucatinib + T-DM1 Nonclinical Experience ....................................................................... 19 
1.4.3. 
Tucatinib + T-DM1 Clinical Experience ............................................................................. 20 
1.4.4. 
Rationale for Study .............................................................................................................. 21 
2. 
OBJECTIVES AND ENDPOINTS ...................................................................................................... 23 
3. 
INVESTIGATIONAL PLAN ............................................................................................................... 25 
3.1. 
Summary of Study Design .................................................................................................................... 25 
3.1.1. 
Independent Data Monitoring Committee ........................................................................... 27 
3.1.2. 
Stopping Criteria.................................................................................................................. 27 
3.1.3. 
End of Study ........................................................................................................................ 27 
3.2. 
Discussion and Rationale for Study Design .......................................................................................... 28 
3.2.1. 
Method of Assigning Subjects to Treatment Groups ........................................................... 28 
3.2.2. 
Rationale for Selection of Doses ......................................................................................... 29 
3.2.3. 
Blinding and Unblinding ..................................................................................................... 29 
3.2.3.1. 
Unblinding for Safety Monitoring ............................................................................ 29 
4. 
STUDY POPULATION ....................................................................................................................... 30 
4.1. 
Inclusion Criteria .................................................................................................................................. 30 
4.2. 
Exclusion Criteria ................................................................................................................................. 32 
4.3. 
Childbearing Potential .......................................................................................................................... 34 
4.4. 
Removal of Subjects From Therapy or Assessment ............................................................................. 34 
4.4.1. 
Discontinuation of Study Treatment .................................................................................... 35 
4.4.1.1. 
Continuation on Study Treatment After CNS-Only Progression ............................. 35 
4.4.2. 
Subject Withdrawal From Study ......................................................................................... 36 
5. 
TREATMENTS .................................................................................................................................... 37 
5.1. 
Treatments Administered ...................................................................................................................... 37 
5.1.1. 
Investigational Study Drug (Tucatinib or Placebo) ............................................................. 37 
5.1.1.1. 
Description ............................................................................................................... 37 
5.1.1.2. 
Method of Procurement ............................................................................................ 37 
5.1.1.3. 
Dose and Administration .......................................................................................... 37 
5.1.1.4. 
Overdose .................................................................................................................. 38 
5.1.1.5. 
Storage and Handling ............................................................................................... 38 
5.1.1.6. 
Packaging and Labeling ........................................................................................... 38 
5.1.1.7. 
Study Drug Accountability....................................................................................... 38 
5.1.2. 
T-DM1 ................................................................................................................................. 39 
5.1.2.1. 
Description ............................................................................................................... 39 
5.1.2.2. 
Method of Procurement ............................................................................................ 39 
5.1.2.3. 
Dose, Preparation, and Administration .................................................................... 39 
5.1.2.4. 
Overdose .................................................................................................................. 39 
5.1.2.5. 
Storage and Handling ............................................................................................... 39 
5.2. 
Dose Modifications ............................................................................................................................... 39 
5.2.1. 
Tucatinib or Placebo Dose Reductions ................................................................................ 40 
5.2.2. 
T-DM1 Dose Reductions ..................................................................................................... 41 
5.2.3. 
Dose Modifications for Adverse Events .............................................................................. 41 
5.2.3.1. 
General Guidelines ................................................................................................... 41 

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5.2.3.2. 
Hepatotoxicity .......................................................................................................... 43 
5.2.3.3. 
Nodular Regenerative Hyperplasia .......................................................................... 43 
5.2.3.4. 
Thrombocytopenia ................................................................................................... 43 
5.2.3.5. 
Left Ventricular Dysfunction ................................................................................... 44 
5.2.3.6. 
Pulmonary Toxicity .................................................................................................. 44 
5.3. 
Concomitant Therapy ........................................................................................................................... 44 
5.3.1. 
Required Concomitant Therapy ........................................................................................... 45 
5.3.2. 
Permitted Concomitant Therapy .......................................................................................... 45 
5.3.3. 
Prohibited Concomitant Therapy ......................................................................................... 45 
5.4. 
Treatment Compliance .......................................................................................................................... 46 
6. 
STUDY ACTIVITIES .......................................................................................................................... 47 
6.1. 
Schedule of Events ............................................................................................................................... 47 
6.2. 
Screening Period ................................................................................................................................... 47 
6.2.1. 
HER2 Testing (Up to 1 Year Before the Screening Visit) ................................................... 47 
6.2.2. 
Screening Visit (Day −28 to Day 1) .................................................................................... 47 
6.2.3. 
Baseline Visit (Day −7 to Day 1) ........................................................................................ 48 
6.3. 
Randomization (Day −5 to Day 1) ........................................................................................................ 49 
6.4. 
Treatment Period (21-day cycles) ......................................................................................................... 49 
6.4.1. 
Cycle 1 Day 1 ...................................................................................................................... 49 
6.4.2. 
Cycle 1 Day 12 (±3 days) .................................................................................................... 49 
6.4.3. 
Cycle 2 Day 1, and Day 1 of All Subsequent Cycles (−1 to +3 days) ................................. 50 
6.4.4. 
Cycle 2 Day 1, 2, 3, and 5 (PK Substudy Subjects Only) .................................................... 51 
6.4.5. 
Cycle 2 Day 12 (±3 days) .................................................................................................... 51 
6.4.6. 
Every 6 Weeks (−7 days) as Determined by Cycle 1 Day 1, through Week 24, 
then Every 9 Weeks (−7 days) Through End of Treatment ................................................. 51 
6.4.7. 
Every 12 Weeks as Determined by Screening Exam (−7 days) .......................................... 52 
6.5. 
End of Treatment Visit (30 to 37 days after last dose of study treatment) ............................................ 52 
6.6. 
Long-Term Follow-up .......................................................................................................................... 53 
6.7. 
Subject End of Study/End of Follow-up ............................................................................................... 55 
7. 
STUDY ASSESSMENTS .................................................................................................................... 56 
7.1. 
Screening/Baseline Assessments .......................................................................................................... 56 
7.1.1. 
Confirmation of HER2 Expression for Study Eligibility ..................................................... 56 
7.1.2. 
Treatment for Brain Metastases Prior to Study Entry .......................................................... 57 
7.2. 
Response/Efficacy Assessments ........................................................................................................... 57 
7.2.1. 
Evaluation of Brain Metastases ........................................................................................... 58 
7.2.2. 
Isolated Progression in the Brain ......................................................................................... 59 
7.3. 
Pharmacokinetic Assessments .............................................................................................................. 59 
7.4. 
Biospecimen Repository ....................................................................................................................... 60 
7.5. 
Healthcare Resource Utilization Data Collection ................................................................................. 61 
7.6. 
Patient-Reported Outcomes .................................................................................................................. 61 
7.6.1. 
EQ-5D-3L – Utility Measurement ....................................................................................... 61 
7.6.2. 
EORTC QLQ IL6 ................................................................................................................ 61 
7.6.3. 
FACT-B ............................................................................................................................... 62 
7.6.4. 
NCI PRO-CTCAE ............................................................................................................... 62 
7.7. 
Safety Assessments ............................................................................................................................... 62 
7.7.1. 
Adverse Events .................................................................................................................... 62 
7.7.1.1. 
Definitions ................................................................................................................ 62 
7.7.1.2. 
Procedures for Eliciting and Recording Adverse Events ......................................... 64 
7.7.1.3. 
Reporting Periods for Adverse Events and Serious Adverse Events ....................... 66 
7.7.1.4. 
Serious Adverse Events Require Immediate Reporting ........................................... 66 
7.7.1.5. 
Sponsor Safety Reporting to Regulatory Authorities ............................................... 66 
7.7.1.6. 
Adverse Events of Special Interest ........................................................................... 67 
7.7.2. 
Physical Examination .......................................................................................................... 68 
7.7.3. 
Vital Signs ........................................................................................................................... 68 
7.7.4. 
Clinical Laboratory Tests .................................................................................................... 68 

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7.7.5. 
Pregnancy Testing ............................................................................................................... 68 
7.7.6. 
Cardiac Function.................................................................................................................. 69 
7.7.6.1. 
MUGA or ECHO ..................................................................................................... 69 
7.7.6.2. 
Electrocardiogram .................................................................................................... 69 
7.8. 
Appropriateness of Measurements ........................................................................................................ 69 
8. 
DATA QUALITY CONTROL AND QUALITY ASSURANCE ........................................................ 70 
8.1. 
Site Training and Monitoring Procedures ............................................................................................. 70 
8.2. 
Data Management Procedures .............................................................................................................. 70 
8.3. 
Access to Source Data .......................................................................................................................... 71 
8.4. 
Accuracy and Reliability of Data .......................................................................................................... 71 
8.5. 
Quality Assurance Procedures .............................................................................................................. 71 
8.6. 
Data Handling and Record Keeping ..................................................................................................... 71 
8.6.1. 
Data Handling ...................................................................................................................... 71 
8.6.2. 
Investigator Record Retention ............................................................................................. 71 
9. 
DATA ANALYSIS METHODS .......................................................................................................... 73 
9.1. 
Determination of Sample Size .............................................................................................................. 73 
9.2. 
Study Endpoint Definitions .................................................................................................................. 73 
9.2.1. 
Primary Endpoint: PFS per Investigator Assessment .......................................................... 73 
9.2.2. 
Key Secondary Endpoints.................................................................................................... 74 
9.2.2.1. 
Overall Survival ....................................................................................................... 74 
9.2.2.2. 
PFS per Investigator Assessment in Subjects With Brain Metastases at Baseline 
(PFS.BM per Investigator) ....................................................................................... 74 
9.2.2.3. 
Objective Response Rate by Investigator Assessment ............................................. 74 
9.2.2.4. 
OS in Subjects with Brain Metastases at Baseline (OS.BM) ................................... 74 
9.2.3. 
Other Secondary Endpoints ................................................................................................. 74 
9.2.3.1. 
PFS per BICR ........................................................................................................... 74 
9.2.3.2. 
PFS per BICR in Subjects With Brain Metastases at Baseline (PFS.BM per BICR)
.................................................................................................................................. 75 
9.2.3.3. 
Objective Response Rate by BICR .......................................................................... 75 
9.2.3.4. 
Duration of Response ............................................................................................... 75 
9.2.3.5. 
Clinical Benefit Rate ................................................................................................ 75 
9.2.4. 
Exploratory Endpoints ......................................................................................................... 75 
9.2.4.1. 
PK Analysis .............................................................................................................. 75 
9.2.4.2. 
Healthcare Resource Utilization ............................................................................... 75 
9.2.4.3. 
Patient-Reported Outcomes ...................................................................................... 75 
9.3. 
Statistical and Analytical Plans ............................................................................................................. 75 
9.3.1. 
General Considerations ........................................................................................................ 76 
9.3.1.1. 
Randomization and Blinding .................................................................................... 76 
9.3.1.2. 
Adjustments for Covariates ...................................................................................... 76 
9.3.1.3. 
Handling of Dropouts and Missing Data .................................................................. 76 
9.3.1.4. 
Multicenter Studies .................................................................................................. 76 
9.3.1.5. 
Multiple Comparisons and Multiplicity ................................................................... 76 
9.3.1.6. 
Analysis Sets ............................................................................................................ 77 
9.3.1.7. 
Examination of Subgroups ....................................................................................... 78 
9.3.1.8. 
Timing of Analyses .................................................................................................. 78 
9.3.2. 
Subject Disposition .............................................................................................................. 78 
9.3.3. 
Subject Characteristics ........................................................................................................ 79 
9.3.4. 
Treatment Compliance ........................................................................................................ 79 
9.3.5. 
Efficacy Analyses ................................................................................................................ 79 
9.3.5.1. 
Primary Efficacy Analyses ....................................................................................... 79 
9.3.5.2. 
Secondary Efficacy Analyses ................................................................................... 79 
9.3.6. 
Pharmacokinetic Analyses ................................................................................................... 80 
9.3.7. 
Health Outcomes Analyses .................................................................................................. 80 
9.3.8. 
Safety Analyses ................................................................................................................... 80 
9.3.8.1. 
Extent of Exposure ................................................................................................... 81 

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9.3.8.2. 
Adverse Events......................................................................................................... 81 
9.3.8.3. 
Deaths and Serious Adverse Events ......................................................................... 81 
9.3.8.4. 
Clinical Laboratory Results ...................................................................................... 81 
9.3.8.5. 
Vital Signs, Physical Examination Findings, and ECOG Performance Status ......... 81 
9.3.8.6. 
Cardiac Ejection Fraction ......................................................................................... 82 
9.3.9. 
Interim Analyses .................................................................................................................. 82 
10. 
INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY 
CONSIDERATIONS ............................................................................................................................ 83 
10.1. 
Informed Consent ................................................................................................................................. 83 
10.2. 
Ethical Review ...................................................................................................................................... 83 
10.3. 
Regulatory Considerations .................................................................................................................... 83 
10.3.1. 
Investigator Information ...................................................................................................... 84 
10.3.2. 
Protocol Amendments and Study Termination .................................................................... 84 
10.4. 
Study Documentation, Privacy, and Records Retention ....................................................................... 84 
10.5. 
Clinical Trial Agreement ...................................................................................................................... 84 
11. 
REFERENCES ..................................................................................................................................... 85 
APPENDIX A. 
SCHEDULE OF EVENTS .................................................................................................. 90 
APPENDIX B. 
PERFORMANCE STATUS SCALES CONVERSION ..................................................... 93 
APPENDIX C. 
CYP3A4 INHIBITORS/INDUCERS AND THEIR ELIMINATION HALF-LIVES ......... 94 
APPENDIX D. 
CYP2C8 INHIBITORS/INDUCERS AND THEIR ELIMINATION HALF-LIVES ......... 96 
APPENDIX E. 
CLINICAL SUBSTRATES FOR CYP3A-MEDIATED METABOLISM ......................... 97 
APPENDIX F. 
RECIST VERSION 1.1 ....................................................................................................... 98 
APPENDIX G. 
EQ-5D-3L ............................................................................................................................ 99 
APPENDIX H. 
EORTC QLQ IL6 .............................................................................................................. 102 
APPENDIX I. 
FACT-B GP5 ..................................................................................................................... 103 
APPENDIX J. 
NCI PRO-CTCAE ............................................................................................................. 104 
APPENDIX K. 
GUIDANCE ON CONTRACEPTION ............................................................................. 108 
APPENDIX L. 
FRANCE SPECIFIC REQUIREMENTS .......................................................................... 110 
APPENDIX M. 
INVESTIGATOR SIGNATURE PAGE ........................................................................... 111 
APPENDIX N. 
DOCUMENT HISTORY .................................................................................................. 112 
SUMMARY OF CHANGES IN AMENDMENT 1.1 ............................................................................................... 113 
SUMMARY OF CHANGES IN AMENDMENT 2 .................................................................................................. 114 
SUMMARY OF CHANGES IN AMENDMENT 3 .................................................................................................. 119 
SUMMARY OF CHANGES IN AMENDMENT 4 .................................................................................................. 127 
 
LIST OF IN-TEXT TABLES 
Table 1:  
Objectives and corresponding endpoints .............................................................................................. 23 
Table 2: 
Tucatinib/placebo: Recommended dose reduction schedule for adverse events* ................................. 40 
Table 3: 
T-DM1: Recommended dose reduction schedule for adverse events ................................................... 41 
Table 4: 
Dose modifications for clinical adverse events related to either tucatinib/placebo or T-DM1 ............. 42 

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Table 5: 
Dose modification guidelines for liver function abnormalities (regardless of relationship to 
tucatinib/placebo or T-DM1) ................................................................................................................ 43 
Table 6: 
Dose modification guidelines for thrombocytopenia ............................................................................ 43 
Table 7: 
Dose modification guidelines for left ventricular dysfunction.............................................................. 44 
Table 8: 
Pharmacokinetic sampling – all subjects .............................................................................................. 60 
Table 9: 
Pharmacokinetic sampling – Pharmacokinetics substudy (US only) subjects ...................................... 60 
 
LIST OF IN-TEXT FIGURES 
Figure 1: 
Combination of tucatinib and T-DM1 in HER2+ breast cell line-derived xenograft model ................. 20 
Figure 2: 
Combination of tucatinib and T-DM1 in HER2+ patient-derived breast cancer model ....................... 20 
Figure 3: 
Study schema ........................................................................................................................................ 26 
Figure 4: 
Pharmacokinetics substudy (US only), Cycle 2 only ............................................................................ 27 
Figure 5: 
Hierarchical Testing Strategy ............................................................................................................... 78 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC  
area under the concentration-time curve 
β-hCG 
beta human chorionic gonadotropin 
BICR 
blinded independent central review 
BID 
twice per day 
CBC 
complete blood count 
CBR 
clinical benefit rate 
CHF 
congestive heart failure 
CI 
confidence interval 
CNS 
central nervous system 
CR 
complete response 
CRF 
case report form 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DFS 
disease-free survival 
DILI 
drug-induced liver injury 
DOR 
duration of response 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EGFR 
epidermal growth factor receptor 
EORTC 
European Organization for Research and Treatment of Cancer 
EORTC QLQ 
European Organization for Research and Treatment of Cancer Quality-of-Life 
Questionnaire 
EOT 
end of treatment 
EQ-5D-3L 
European Quality of Life 5-Dimension 3-Level 
EQ-VAS 
European Qualify of Life Visual Analogue Scales 
EuroQoL 
European Quality of Life 

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FACT-B 
Functional Assessment of Cancer Therapy – Breast  
FACT-B GP5 
Functional Assessment of Cancer Therapy – Breast, Item GP5 
FDA 
Food and Drug Administration 
FISH 
fluorescence in situ hybridization 
FOCBP 
females of childbearing potential 
GFR 
glomerular filtration rate 
HCRU 
healthcare resource utilization 
HER2 
human epidermal growth factor receptor 2 
HER2+ 
human epidermal growth factor receptor 2 positive 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
ICH 
International Council for Harmonisation 
IDMC 
independent data monitoring committee 
IEC 
independent ethics committee 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IRB 
institutional review board 
ITT 
intent-to-treat 
IV 
intravenous 
LA/M 
locally-advanced or metastatic 
LFT 
liver function test 
LVEF 
left ventricular ejection fraction 
mBC 
metastatic breast cancer 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum-tolerated dose 
MUGA 
multigated acquisition  
NCI 
National Cancer Institute 
NCI PRO-CTCAE 
National Cancer Institute’s Patient-Reported Outcomes version of the Common 
Terminology Criteria for Adverse Events 
ORR 
objective response rate 
OS 
overall survival 
OS FA 
final analysis of overall survival 
OS IA1 
overall survival interim analysis 1 
OS IA2 
overall survival interim analysis 2 
PCR 
polymerase chain reaction 

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PD 
progressive disease 
PDX 
patient-derived 
PET 
positron emission tomography 
PFS 
progression-free survival 
PFS.BM 
progression-free survival in subjects with brain metastasis at baseline 
P-gp 
P-glycoprotein 
PH 
proportional-hazards 
PI3K 
phosphatidylinositol 3-kinase 
PK 
pharmacokinetic 
PO BID 
orally twice per day 
PR 
partial response 
PRO 
patient-reported outcome 
PTT 
partial thromboplastin time 
QoL 
quality of life 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
Scr 
serum creatine 
SD 
stable disease 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SRS 
stereotactic radiosurgery 
SUSAR 
suspected unexpected serious adverse reaction 
T-DM1 
ado-trastuzumab emtansine 
TEAE 
treatment-emergent adverse event 
TKI 
tyrosine kinase inhibitor 
ULN 
upper limit of normal 
WBRT 
whole-brain radiation therapy 

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1. 
INTRODUCTION 
1.1. 
HER2+ Breast Cancer 
Breast cancer is the most common form of cancer in women worldwide, and the second leading 
cause of cancer-related death in the United States (Ferlay 2013; Siegel 2018). In 2018, the 
estimated number of men and women who were newly diagnosed with breast cancer in the 
United States was 268,670 and there were 40,920 deaths overall due to the disease (Siegel 2018). 
Approximately 15%–20% of breast cancers overexpress the human epidermal growth factor 
receptor 2 (HER2) (Owens 2004; Giordano 2014; Howlader 2014; American Cancer Society 
(ACS) 2018). HER2 is a transmembrane tyrosine kinase receptor that mediates cell growth, 
differentiation, and survival. Tumors that overexpress HER2 are more aggressive and historically 
have been associated with poorer overall survival (OS) compared to HER2 negative cancers 
(Slamon 1987). 
The introduction of HER2-targeted therapy using either antibody-based therapies or small 
molecule tyrosine kinase inhibitors (TKI) has led to significant and ongoing improvements in 
disease-free survival (DFS), progression-free survival (PFS), and OS in both the 
neoadjuvant/adjuvant and metastatic settings (Slamon 2001; Geyer 2006; Baselga 2012b; Verma 
2012). Trastuzumab, a humanized anti-HER2 antibody that binds to the HER2 extracellular 
domain, was the first anti-HER2 agent approved by the Food and Drug Administration (FDA) 
for use in the treatment of HER2-positive (HER2+) breast cancer, and remains the backbone of 
treatment in the neoadjuvant, adjuvant, and metastatic settings, usually in combination with a 
taxane (Slamon 2001; Vogel 2002). 
The development of trastuzumab has been followed by the approval of multiple anti-HER2 
agents for the management of HER2+ breast cancer including: 
• Pertuzumab, a monoclonal antibody that binds to the HER2 receptor at a site different 
from trastuzumab, was approved in combination with trastuzumab and docetaxel as 
first-line therapy for patients with metastatic disease (Swain 2015), and for the 
neoadjuvant treatment of patients with early-stage breast cancer (either greater than 
2 cm in diameter or node positive) (Gianni 2016) (PERJETA® Prescribing 
Information, Genentech, Inc., December 2018). More recently, it was approved for 
the adjuvant treatment of patients with HER2+ early breast cancer at high risk of 
recurrence (von Minckwitz 2017). 
• Ado-trastuzumab emtansine (T-DM1), an antibody-drug conjugate composed of 
trastuzumab, a thioether linker, and a derivative of the antimitotic agent maytansine, 
was approved for the treatment of patients with HER2+ metastatic breast cancer 
(mBC) who previously received trastuzumab and a taxane (prior therapy for 
metastatic disease, or development of recurrence during or within 6 months of 
completing adjuvant therapy) (Verma 2012) (KADCYLA® Prescribing Information, 
Genentech, Inc., December 2018). More recently, T-DM1 showed superior efficacy 
relative to trastuzumab in the adjuvant therapy management of subjects who had less 
than a pathological complete remission to neoadjuvant trastuzumab-based therapy in 
the KATHERINE trial (von Minckwitz 2019). 

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• Two TKIs, lapatinib and neratinib, have been approved. Lapatinib targets both the 
HER2 receptor and the epidermal growth factor receptor (EGFR) and was approved 
in combination with capecitabine in patients with metastatic disease who have 
progressed following prior trastuzumab, anthracycline, and taxane therapy (Geyer 
2006) (TYKERB® Prescribing Information, Novartis Pharmaceuticals Corp., 
December 2018). Lapatinib has also been approved in combination with letrozole in 
postmenopausal patients with hormone receptor positive metastatic disease 
(Schwartzberg 2010). Neratinib, a pan-Erb inhibitor, was approved for the extended 
adjuvant treatment of patients with high-risk early-stage HER2+ breast cancer, to 
follow adjuvant trastuzumab-based therapy (Chan 2016). Lapatinib and neratinib 
have been associated with toxicities including diarrhea and rash that are likely 
associated with EGFR inhibition. For example, over 40% of subjects in the neratinib 
adjuvant ExteNET study experienced Grade ≥3 diarrhea, and antidiarrheal 
prophylaxis is now recommended with neratinib use (NERLYNX® Prescribing 
Information, Puma Biotechnology, Inc., June 2018). Therefore, more selective small 
molecule inhibitors of HER2 that could be combined with other anti-HER2 therapies 
to improve clinical outcomes are needed. 
HER2-targeted therapies for the management of metastatic HER2+ breast cancer have led to 
meaningful prolongation in the median survival of these subjects; however, essentially all 
subjects in the metastatic setting ultimately progress (Verma 2012; Swain 2015). There have also 
been significant improvements in the outcomes for early-stage HER2+ breast cancer, but despite 
these improvements, up to a quarter of all subjects treated with anti-HER2 therapy in the 
adjuvant setting relapse (Gianni 2012; Chan 2016; von Minckwitz 2017). In addition, treatment 
and prevention of brain metastases continue to be a significant unmet need for subjects with 
HER2+ breast cancer, with up to 50% of subjects with metastatic disease eventually developing 
brain metastases (Clayton 2004; Goldhirsch 2013; Pestalozzi 2013). 
1.2. 
Use and Sequencing of T-DM1 in the Metastatic Setting 
As noted above, T-DM1 is approved for the treatment of HER2+ mBC. The sequencing of 
therapy may differ, however, depending on whether a subject has de novo versus relapsed 
HER2+ mBC. 
The current preferred standard of care for patients with de novo HER2+ metastatic disease 
consists of treatment with pertuzumab plus trastuzumab and a taxane as first-line treatment based 
on results of the CLEOPATRA trial, followed by T-DXd (Enhertu®) in second-line based on 
results from the randomized, open-label DESTINY-Breast03 trial. T-DM1 remains a treatment 
option in this setting and in later treatment lines for patients who did not receive T-DM1 in the 
second-line setting (Giordano 2014). In 2013, T-DM1 was approved by the FDA as a second-line 
therapy based upon prolongation of PFS and OS in metastatic subjects previously treated with 
trastuzumab and taxane in the metastatic setting, or who relapsed within 6 months of completion 
of adjuvant therapy, based on the results of the EMILIA trial. Among 991 randomly assigned 
subjects, median PFS was 9.6 months with T-DM1 versus 6.4 months with lapatinib + 
capecitabine (HR=0.65; 95% CI: 0.55, 0.77; P<0.001), and median OS of 30.9 months versus 
25.1 months (HR=0.68), respectively (Verma 2012). 

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The sequencing of therapies may differ for patients who relapse after treatment for early-stage 
disease with the approval of pertuzumab in both the neoadjuvant and adjuvant settings. Patients 
diagnosed with metastatic disease after relapsing from early-stage disease often have already 
been treated with pertuzumab, a clinical scenario which did not exist at the time of the EMILIA 
trial. The best treatment approach for these patients is not clear, as there are not sufficient data to 
support re-treatment with pertuzumab in this setting.  
Another uncertainty, introduced by contemporaneous development of pertuzumab and T-DM1, is 
that efficacy of T-DM1 in the metastatic setting after treatment with pertuzumab-based regimens 
is not well known. Because pertuzumab was not yet available, the EMILIA pivotal trial did not 
include subjects previously treated with pertuzumab, so it may not reflect the current patient 
population in this setting. The TH3RESA trial of T-DM1 in the third-line or later setting 
demonstrated a median PFS of 6.2 months (95% CI: 5.59, 6.87) with T-DM1 treatment (Krop 
2014), while the earlier line EMILIA trial had demonstrated PFS of 9.6 months (HR=0.65; 95% 
CI: 0.55, 0.77; P<0.001) (Verma 2012). However, more recent data from the post-pertuzumab 
era in subjects treated with T-DM1 after pertuzumab have reported time on treatment and PFS in 
the range of 4–5.3 months (Dzimitrowicz 2016; Fabi 2017; Tiwari 2018), suggesting that T-DM1 
efficacy after pertuzumab may be less than the original efficacy reported in the EMILIA trial. 
Notwithstanding some of the above uncertainties regarding current T-DM1 efficacy, it is a 
standard of care therapy and can be further improved upon. 
1.3. 
Brain Metastases 
Over the last 2 decades, advances in the development of cancer therapies for HER2+ mBC have 
resulted in better control of systemic disease. Because of this significant improvement, subjects 
live longer (as demonstrated by increases in PFS and OS) and more subjects develop brain 
metastases. Clinical trials suggest that there is an increased risk of first relapse occurring in the 
central nervous system (CNS) in subjects who have received trastuzumab-based adjuvant therapy 
(Clayton 2004; Olson 2013a; Olson 2013b), and up to 50% of HER2+ subjects with metastatic 
disease will develop CNS metastases at some point during the course of the disease (Clayton 
2004; Goldhirsch 2013; Pestalozzi 2013). The increasing prevalence of CNS metastases in 
subjects with HER2+ breast cancer may be due to several factors (Lin 2004). First, HER2+ 
breast cancer appears to display a special tropism for the CNS tissue. Second, with better control 
of non-CNS disease, subjects may be living longer allowing CNS metastases to progress and 
become clinically significant. Finally, the CNS may represent a sanctuary site for HER2+ 
disease, as large molecules such as trastuzumab and pertuzumab do not penetrate the blood-brain 
barrier to any meaningful extent at their approved doses. Evidence suggests that drug blood-brain 
barrier permeability is most likely a function of not only P-glycoprotein (P-gp) expression but 
also the interplay of molecule size, charge, lipophilicity, tumor neovasculature anatomy, and 
plasma protein binding (Gerstner 2007). Therefore, HER2-targeted therapies that better distribute 
into the brain are needed. 
Treatment for brain metastases usually includes either surgical resection, radiosurgery, and/or 
whole brain radiotherapy in addition to continuation of systemic anti-HER2 therapy. 
Unfortunately, these treatments often result in significant neurologic toxicities, which may 
impair quality of life (QoL). Stereotactic radiosurgery (SRS) has been increasingly used to avoid 
the neurologic toxicities of whole-brain radiotherapy, but the trade-off for this decrease in 
toxicity has been inferior control of distant brain relapse outside of the radiation fields (Chang 

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2009; Brown 2016; Kaidar-Person 2016). Subjects with brain metastases have historically been 
excluded from clinical trials. 
Breast cancer subjects with HER2+ brain metastases have a worse prognosis relative to those 
without CNS disease. In population-based registries of HER2+ mBC subjects enrolled at 
diagnosis, evidence of brain metastases led to a shortened survival relative to subjects without 
brain metastases (Brufsky 2011). Among the 377 subjects with brain metastases, median OS 
from the date of initial mBC diagnosis was 26.3 months (range: 1.0 to 60.9 months) compared to 
44.6 months (range: 0.5 to 59.7 months) in the 635 subjects who did not have CNS metastases 
(Brufsky 2011). 
As with many systemic therapies, T-DM1 may also be less efficacious in patients with brain 
metastases. While subjects with active brain metastases were excluded from the EMILIA and 
TH3RESA T-DM1 trials, subjects with stable treated brain metastases were included. In the 
EMILIA trial, subjects with brain metastases treated with T-DM1 had no significant 
improvement in PFS compared to the control arm (5.9 months versus 5.7 months; HR=1.00; 95% 
CI: 0.54, 1.84; P=1.000) and the PFS.BM of 5.9 months compared unfavorably to the median 
PFS of 9.6 months in the trial overall, although there was an improvement in OS (Krop 2015). In 
the third-line+ TH3RESA trial, subjects with stable treated brain metastases had similar median 
PFS but shorter median OS compared to subjects without [PFS: 5.8 months versus 6.2 months 
(Krop 2015); OS: 17.3 months versus 23.7 months (Krop 2017)]. Most recently, data from the 
KATHERINE trial demonstrated that adjuvant treatment with T-DM1 for high-risk subjects 
yielded a significant improvement in DFS, but failed to have any significant impact on the 
development of brain metastases (von Minckwitz 2019). Therefore, development of treatments 
for this patient population remains an important unmet medical need, and addressing this need 
will require including these subjects in clinical trials. 
1.4. 
Tucatinib 
Tucatinib (ONT-380) is an orally-available, reversible HER2 small molecule TKI. Two key 
features of tucatinib are its potency and selectivity for HER2 compared to the closely-related 
kinase EGFR. Tucatinib is approximately 6-fold more potent in its inhibition of HER2 compared 
to lapatinib, the only currently approved HER2 TKI for patients with metastatic disease. In 
addition, tucatinib is highly selective for HER2 compared to EGFR. With a 500-fold increase in 
potency for HER2 inhibition compared to EGFR, it has the potential to inhibit HER2 signaling 
while avoiding known EGFR-related side effects (eg, severe skin rash and gastrointestinal 
toxicity). This unique feature also differentiates tucatinib from other HER2 inhibitors, including 
both neratinib and lapatinib, which inhibit HER2 and EGFR with similar potency and are 
associated with side effects related to EGFR inhibition. 
Tucatinib is being developed as a novel treatment for patients with HER2+ mBC, including 
patients with brain metastases. The pivotal trial HER2CLIMB demonstrated that in subjects with 
HER2+ locally advanced or metastatic breast cancer who had previously received trastuzumab, 
pertuzumab, and T-DM1, the addition of tucatinib to trastuzumab and capecitabine significantly 
improved PFS and OS, in the overall study population and in subjects with brain metastases at 
baseline (Lin 2020; Murthy 2020). Tucatinib is currently approved in combination with 
trastuzumab and capecitabine to treat patients with HER2+ breast cancer in over 45 countries.  

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A complete summary of the nonclinical and clinical data for tucatinib is provided in the 
investigator’s brochure. 
1.4.1. 
Rationale for Tucatinib in Combination with T-DM1 
Treatment failures in HER2+ breast cancer may result from primary or acquired resistance to 
HER2 blockade (Lu 2001; Nahta 2006; Scaltriti 2007; Pohlmann 2009). There is evidence that 
dual targeting of HER2, either through combination of 2 different HER2-targeted antibodies or 
through use of an antibody-based therapy and a TKI, can lead to further improvements in 
efficacy in metastatic disease (Baselga 2012a; Baselga 2012b). In particular, combination of a 
small molecule TKI with an antibody-based therapy may be effective, as it may help overcome 
resistance to antibody-mediated inhibition through an alternative mechanism of receptor 
inhibition. For example, lapatinib has been shown to have increased activity in combination with 
trastuzumab compared to lapatinib alone, even when given to subjects who have previously 
progressed on prior trastuzumab-based therapy (Blackwell 2010; Blackwell 2012). 
T-DM1 treatment results in the targeted delivery of the potent antimitotic DM1 to HER2+ tumor 
cells, which binds to tubulin and causes mitotic arrest and cell death (Lewis Phillips 2008). 
Combining tucatinib with T-DM1 may potentially improve upon the efficacy of T-DM1 through 
increased inhibition of HER2 signal transduction, including blockade of both the -Erk-/MEK and 
phosphatidylinositol 3-kinase (PI3K)/AKT pathways. Inhibition of pro-survival signaling 
mediated by the PI3K/AKT pathway, together with DM1 toxin delivery, may result in increased 
cell death, potentially overcoming or delaying the development of resistance. 
1.4.2. 
Tucatinib + T-DM1 Nonclinical Experience 
Nonclinical data show the combination of tucatinib with T-DM1 results in improved antitumor 
activity in HER2+ breast cancer models. In HER2+ tumor-derived cell lines, tucatinib in 
combination with T-DM1 can result in additive or synergistic activity (data not shown). In 
addition, the combination of tucatinib and T-DM1 was more effective than either drug 
individually in the BT-474 cell line-derived xenograft model (Figure 1) and in 2 HER2+ 
patient-derived (PDX) breast cancer models (Figure 2). Each of the HER2+ PDX models are 
estrogen receptor/progesterone receptor negative, immunohistochemistry 3+ for HER2, and 
contain genomic amplification of the HER2 gene. 

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Figure 1: 
Combination of tucatinib and T-DM1 in HER2+ breast cell line-derived xenograft 
model 
 
Mice bearing BT-474 subcutaneous xenografts were treated by oral gavage with tucatinib, intravenous (IV) T-DM1 
or control IgG1-DM1, or a combination of tucatinib with both drugs, at the dose levels and schedules as indicated. 
Figure 2: 
Combination of tucatinib and T-DM1 in HER2+ patient-derived breast cancer model 
 
Mice bearing HER2+ subcutaneous xenografts were treated by oral gavage with tucatinib, IV T-DM1 or control 
IgG1-DM1, or a combination of tucatinib with both drugs, at the dose levels and schedules as indicated. 
In the T-DM1 resistant PDX models, tucatinib inhibited tumor growth and the combination of 
tucatinib with T-DM1 produced increased tumor control when compared with either drug alone 
in the cell line derived BT-474 model, and in both PDX models. 
1.4.3. 
Tucatinib + T-DM1 Clinical Experience 
One clinical trial has been conducted to evaluate the safety, tolerability, and preliminary clinical 
activity of tucatinib in combination with T-DM1. Study ONT-380-004 is a phase 1b, open-label, 
multicenter, 3+3 dose-escalation study in subjects with HER2+ mBC, designed to identify the 
maximum-tolerated dose (MTD) or recommended phase 2 dose of tucatinib in combination with 

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T-DM1. Subjects had a history of prior therapy with trastuzumab and a taxane, separately or in 
combination; for subjects in the dose-escalation and MTD-expansion cohorts, prior therapy with 
trastuzumab and a taxane must have been for metastatic disease. For subjects in the CNS 
disease-expansion cohorts, trastuzumab and taxane (together or separately) might have been 
given at any time prior to study enrollment as part of neoadjuvant therapy, adjuvant therapy, or 
therapy for metastatic disease. 
Fifty-seven T-DM1-naive subjects were treated (Borges 2018). The tucatinib MTD was 
determined to be 300 mg administered orally twice per day (PO BID) in combination with the 
approved dose of T-DM1 (3.6 mg/kg every 21 days). Among the 50 subjects treated at the MTD, 
the most common adverse events (AEs) occurring in ≥40% of subjects were nausea, diarrhea, 
fatigue, epistaxis, headache, vomiting, constipation, and decreased appetite; the majority of AEs 
were Grade 1 or 2. In these 50 subjects, the median PFS was 8.2 months (95% CI: 4.8, 10.3); the 
clinical benefit rate (CBR; subjects with best response of complete response [CR] or partial 
response [PR], or stable disease [SD] for >6 months) among 48 evaluable subjects was 58% 
(28 subjects). Thirty-four of 50 subjects (68%) treated with the MTD had measurable disease and 
were evaluable for response with an objective response rate (ORR) of 47% (1 subject with CR, 
15 subjects with PR, 14 subjects with SD, and 4 subjects with progressive disease [PD]). Among 
the subjects whose disease responded to treatment, the median duration of response (DOR) was 
6.9 months (95% CI: 2.8, 19.8). Thirty of 50 subjects (60%) treated at the MTD had brain 
metastases at study entry. Of these, 21 of 30 subjects (70%) had either untreated or previously 
treated and progressive brain metastases. Median PFS among subjects with brain metastases was 
6.7 months (95% CI: 4.1, 10.2). 
 
 
 
 
 (Seagen internal data). The combination of 
tucatinib with T-DM1 was found to have a tolerable safety profile, with evidence of clinical 
activity, including in subjects with brain metastases. 
1.4.4. 
Rationale for Study 
The development and approval of multiple targeted agents for HER2+ breast cancer over the last 
20 years has led to improvements in response rates, PFS, and OS. However, in most cases, 
subjects with mBC progress on currently available therapy and cannot be cured. The intent of 
this phase 3, randomized trial is to assess whether the addition of tucatinib to T-DM1 can not 
only improve the efficacy observed with T-DM1 as second-line therapy in subjects with HER2+ 
mBC that failed trastuzumab and taxane, but also whether the combination can be effective 
against CNS metastases in HER2+ breast cancer (an area of continued medical need). 
Given tucatinib’s selectivity for HER2 over EGFR, it has the potential to provide dual HER2 
inhibition by combining with other oral anti-HER2 agents with fewer significant EGFR-related 
toxicities such as severe diarrhea. The combination of tucatinib and T-DM1 was found to be well 
tolerated and showed clinical activity in the ONT-380-004 study. ONT-380-004 included a 
meaningful number of subjects with brain metastases, and preliminary data suggests activity, 
including intracranial responses and a similar median PFS in subjects with brain metastases 
compared to those without (Borges 2018; Murthy 2018). A systemic therapy such as tucatinib 
that effectively treats existing brain metastases could control neurologic symptoms of brain 

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metastases and potentially delay the need for radiotherapy or surgical resection, thus avoiding the 
sequelae associated with progressive brain metastases and their local treatment. Furthermore, a 
systemic treatment effective against micrometastases could potentially prevent or delay the 
eventual development of clinically evident brain metastases. Based on nonclinical data 
demonstrating improved antitumor activity of tucatinib in combination with T-DM1, as well as 
the experience on the phase 1b ONT-380-004 trial, the addition of tucatinib to T-DM1 could 
potentially further improve the efficacy of T-DM1 and the standard-of-care management, 
including in subjects with brain metastases. 

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2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy and safety of tucatinib versus placebo in combination with 
T-DM1 in subjects with unresectable locally-advanced or metastatic (LA/M) HER2+ breast 
cancer. Specific objectives and corresponding endpoints for the study are summarized below 
(Table 1). 
Table 1:  
Objectives and corresponding endpoints 
Objective 
Corresponding Endpoint 
Primary  
 
● Compare PFS by investigator assessment per RECIST v1.1 
between treatment arms  
● PFS per RECIST v1.1, as determined by 
investigator assessment 
Key Secondary  
 
● Compare OS between treatment arms  
● OS 
● Compare PFS by investigator assessment per RECIST v1.1 in 
subjects with brain metastases at baseline (PFS.BM per 
investigator) between treatment arms 
● PFS.BM per RECIST v1.1, as determined by 
investigator assessment 
● Compare the ORR by investigator assessment per 
RECIST v1.1 between treatment arms 
● ORR per RECIST v1.1, by investigator 
assessment 
● Compare overall survival in subjects with brain metastases at 
baseline (OS.BM) between treatment arms 
● OS.BM 
Other Secondary  
 
● Evaluate PFS by blinded independent central review (BICR) 
per RECIST v1.1 between treatment arms 
● PFS per RECIST v1.1, as determined by BICR 
● Evaluate PFS by BICR per RECIST v1.1 in subjects with 
brain metastases at baseline (PFS.BM by BICR) between 
treatment arms 
● PFS.BM per RECIST v1.1, by BICR  
● Evaluate the ORR by BICR per RECIST v1.1 between 
treatment arms  
● ORR per RECIST v1.1, by BICR  
● Evaluate the DOR by investigator assessment per 
RECIST v1.1 between treatment arms 
● DOR per RECIST v1.1, by investigator 
assessment 
● Evaluate the DOR by BICR per RECIST v1.1 between 
treatment arms 
● DOR per RECIST v1.1, by BICR  
● Evaluate the CBR (SD or non-CR or non-progressive disease 
[PD] for ≥6 months or best response of CR or PR) by 
investigator assessment per RECIST v1.1 between treatment 
arms  
● CBR per RECIST v1.1, by investigator 
assessment 
● Evaluate the CBR by BICR per RECIST v1.1 between 
treatment arms  
● CBR per RECIST v1.1, by BICR 
● Evaluate the safety of tucatinib in combination with T-DM1 
● Incidence of AEs 
Exploratory  
 

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Objective 
Corresponding Endpoint 
● Evaluate the pharmacokinetics of tucatinib and DM1 
following administration of tucatinib and T-DM1 in 
combination 
● Pharmacokinetic (PK) parameters for tucatinib 
and DM1  
● Evaluate on-trial healthcare resource utilization (HCRU) 
between treatment arms 
● HCRU based on the number of medical care 
encounters and other procedures of interest 
● Evaluate patient-reported outcomes (PROs) and health-related 
QoL between treatment arms  
● QoL measured by the European Quality of 
Life 5-Dimension 3-Level (EQ-5D-3L), 
European Organization for Research and 
Treatment of Cancer Quality-of-Life 
Questionnaire (EORTC QLQ IL6), National 
Cancer Institute’s Patient-Reported Outcomes 
version of the Common Terminology Criteria 
for Adverse Events (NCI PRO-CTCAE), and 
Functional Assessment of Cancer 
Therapy – Breast (FACT-B GP5) 

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3. 
INVESTIGATIONAL PLAN 
3.1. 
Summary of Study Design 
This is a randomized, double-blind, placebo-controlled, international, multicenter, phase 3 study 
designed to evaluate the efficacy and safety of tucatinib in combination with T-DM1 in subjects 
with unresectable LA/M HER2+ breast cancer who have had prior treatment with a taxane and 
trastuzumab in any setting. Subjects will be randomized in a 1:1 manner to receive 21-day cycles 
of treatment in 1 of the following 2 treatment groups: 
• Control arm: Placebo given PO BID; T-DM1 3.6 mg/kg given intravenously (IV) 
every 21 days 
• Experimental arm: Tucatinib 300 mg PO BID; T-DM1 3.6 mg/kg IV every 21 days 
Tucatinib or placebo will be dispensed to subjects in a double-blinded manner. Protocol-defined 
visits and cycle numbering will be determined by T-DM1 dosing date, allowing for dose holds or 
delays with T-DM1. Study treatment will continue until unacceptable toxicity, disease 
progression, withdrawal of consent, or study closure. 
Disease response and progression will be assessed using RECIST v1.1. While on study 
treatment, radiographic disease evaluations will be performed every 6 weeks for the first 
24 weeks, and every 9 weeks thereafter, irrespective of dose holds or interruptions. In the 
absence of clear evidence of radiographic progression, development of CNS symptoms, or 
radiographic changes thought to pose potential immediate risk to the subject, all efforts should be 
made to continue treatment until unequivocal evidence of radiologic progression occurs. Subjects 
assessed as having isolated progression in the brain per RECIST v1.1 may be eligible to continue 
on study treatment for clinical benefit after undergoing local therapy for CNS disease, with 
approval from the medical monitor (see Section 4.4.1.1). 
After completion of study treatment and after occurrence of disease progression, subjects in both 
arms of the study will continue to be followed for survival until study closure or withdrawal of 
consent. 
Safety will be monitored on a blinded basis by the sponsor throughout the study. An independent 
data monitoring committee (IDMC) will regularly review all relevant aggregate safety data 
(blinded and unblinded). 
Approximately 460 subjects (approximately 230 subjects per treatment arm) will be randomized 
in this study. A study schema is provided in Figure 3. See Appendix A for a schedule of 
evaluations.  
China Portion of the Study 
After completion of enrollment in the global portion, subjects in China may continue to be 
randomized in a 1:1 ratio to either the experimental arm or the control arm until the planned 
sample size of approximately 105 (up to 110) subjects in China is reached. After the completion 
of the global portion, the study may remain open to complete the China portion as an extension 
of the study.  

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Figure 3: 
Study schema 
 
a Includes measurement of all known sites of unresectable LA/M disease through radiographic imaging. Assessment 
for brain metastases is performed with contrast magnetic resonance imaging (MRI) of the brain for all subjects, 
regardless of prior history of brain metastases. 
b Response assessments are performed every 6 weeks for the first 24 weeks, and then every 9 weeks thereafter, 
irrespective of dose holds or interruptions. Contrast brain MRI is required on this same schedule only in those 
subjects with known brain metastases. 
c For subjects who discontinue study treatment for any reason prior to documented disease progression by 
investigator assessment (per RECIST v1.1), response assessments are performed every 9 weeks until disease 
progression, death, withdrawal of consent, or study closure. Contrast brain MRI is required on this same schedule 
only in those subjects with known brain metastases. 
d After documented progression (per RECIST v1.1) or clinical progression by investigator assessment, continued 
follow-up for survival is performed every 90 days until death, withdrawal of consent, lost to follow up, or study 
closure, whichever comes first (Refer to Section 6.6 for more details).  
In the US only, a pharmacokinetics substudy will assess the effects of tucatinib on the 
pharmacokinetics of DM1. With additional consent, approximately 50 subjects (enrollment will 
continue until at least 25 subjects from each treatment arm have completed the substudy) will 
participate in a pharmacokinetics substudy in which additional PK assessments on Days 1, 2, 3, 
and 5 in Cycle 2 are performed (Figure 4; Table 9; Section 7.3).  

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Figure 4: 
Pharmacokinetics substudy (US only), Cycle 2 only 
 
3.1.1. 
Independent Data Monitoring Committee 
The IDMC will be responsible for monitoring the safety of subjects in the study at regular 
intervals. The IDMC will look at blinded and unblinded data including deaths, discontinuations, 
dose reductions, AEs, and serious adverse events (SAEs) on a regular basis. The IDMC will 
make recommendations to the sponsor regarding the conduct of the study, including study 
continuation as planned or with protocol amendment, or early discontinuation of the study for 
excessive toxicity. A separate IDMC Charter will outline the committee’s composition, 
members’ roles and responsibilities, and describe IDMC procedures. The sponsor will provide a 
copy of each IDMC recommendation to the investigators. 
3.1.2. 
Stopping Criteria 
Reasons for prematurely terminating the study may include but are not limited to the following: 
• The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to subjects, either through a safety review by the sponsor or an independent 
safety assessment by the IDMC. 
• Subject enrollment is unsatisfactory. 
3.1.3. 
End of Study 
The study ends once the number of events required for analysis of endpoints (see Section 9.2) 
has been reached (estimated 5 years after first subject enrolled) or when the last subject 
completes the last visit, or last contact, discontinues from the study, or is lost to follow-up, 
whichever occurs first. In addition, the sponsor may terminate the study at any time (see Section 
10.3.2). 

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3.2. 
Discussion and Rationale for Study Design 
Despite advances in treatment, unresectable LA/M HER2+ breast cancer is incurable. The 
primary goals of treatment remain to extend life and palliate symptoms while preserving QoL. 
As demonstrated by the phase 1 clinical experience, tucatinib has shown activity and a 
manageable safety profile in heavily pretreated subjects with unresectable LA/M HER2+ breast 
cancer, including those with brain metastases (Moulder 2017; Borges 2018; Hamilton 2018; 
Murthy 2018). All subjects enrolled in this study will receive either tucatinib or placebo in 
combination with T-DM1, a recommended standard of care regimen for treatment of patients 
with HER2+ mBC who have progressed after prior treatment with trastuzumab and a taxane. 
Treatment with T-DM1 has been shown to prolong both PFS and OS in this population when 
compared to capecitabine and lapatinib (Verma 2012). 
Patients with brain metastases from HER2+ breast cancer represent an important unmet medical 
need, and these patients are frequently excluded from clinical trials. This trial screens all subjects 
at baseline to determine if occult brain metastases are present, and subjects with brain metastases 
are included in the trial provided they do not require immediate local therapy and with medical 
monitor approval. The inclusion of this subject population is supported by data from 
ONT-380-004, the phase 1b study of tucatinib + T-DM1, in which a majority of subjects had 
brain metastases (Murthy 2018). Subjects with brain metastases in this trial had similar safety 
and efficacy outcomes compared to subjects without, and the activity of this combination will be 
further evaluated in this trial. Subjects randomized to placebo will be treated with T-DM1, which 
has been described in multiple smaller series to also show early evidence of activity in subjects 
with brain metastases (Krop 2015; Jacot 2016; Krop 2017). 
The randomized, blinded trial design and the selection of PFS as the primary endpoint are based 
on the considerations outlined in the FDA Guidance for Industry “Clinical Trial Endpoints for 
the Approval of Cancer Drugs and Biologics” and the European Medicines Agency (EMA; 
“Guideline on the Evaluation of Anticancer Medicinal Products in Man”, EMA/CPMP/ 205/95 
Rev.5) for approval of anticancer drugs. Defined as the time from randomization until objective 
tumor progression or death, PFS is a direct reflection of tumor growth and can be assessed before 
determination of a survival benefit. Furthermore, because PFS includes death from any cause, it 
may be a correlate to OS, a secondary endpoint of this study. An additional advantage of PFS is 
that its determination is not confounded by subsequent therapy. Standardized criteria (RECIST 
v1.1) will be employed to evaluate progression. To ensure consistent unbiased application of 
these criteria, all imaging studies performed to confirm disease status and to assess progression 
during the study will be submitted to an independent third-party imaging core laboratory for 
blinded review, and all subjects will have evaluations for progression performed on the same 
schedule. 
3.2.1. 
Method of Assigning Subjects to Treatment Groups 
Following informed consent and screening assessments, subjects will be randomly assigned to 
study treatment in a 1:1 ratio. Randomization will be performed centrally using a system that will 
assign a unique subject randomization number but will not specify the actual treatment 
assignment. Randomization procedures are detailed in the study manual. 

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Randomization will be stratified by: 
• Line of treatment for metastatic disease: 1st line metastatic versus other 
• Hormone receptor status: negative versus positive 
• Presence or history of treated or untreated brain metastases: yes versus no 
• Eastern Cooperative Oncology Group (ECOG) performance status: 0 versus 1 
3.2.2. 
Rationale for Selection of Doses 
In Study ONT-380-004, the phase 1b study of tucatinib administered in combination with 
T-DM1, the recommended phase 2 dose was defined as 300 mg PO BID. T-DM1 will be given at 
the full dose of 3.6 mg/kg IV every 21 days as approved for single-agent use. 
3.2.3. 
Blinding and Unblinding 
Maintaining the blind of the study is crucial for achieving the study objectives. Unblinding an 
individual subject treatment assignment may only occur when one of the following 
circumstances is applicable: 
1. At the time of study closure, the study treatment assignment will be provided to the 
investigator. 
2. Unblinding a subject’s treatment assignment prior to study closure must be limited to 
safety emergency circumstances only where knowledge of the treatment assignment 
would affect decisions regarding the immediate clinical management of the subject. In 
the event of such an emergency circumstance, the investigator will assume full 
responsibility for unblinding the study treatment and a formal unblinding procedure, 
carried out by a third-party organization, will be followed to allow the investigator to 
immediately access a subject’s treatment assignment (see study manual). Information on 
study treatment assignment must not be distributed to any other personnel involved in the 
clinical trial. In the event of any emergency unblinding, the sponsor is to be notified 
within 24 hours of the occurrence. 
Details regarding unblinding procedures are described in the study manual. 
3.2.3.1. 
Unblinding for Safety Monitoring 
Safety data is monitored by an IDMC. Unblinding of aggregate safety data for ongoing safety 
monitoring and risk/benefit assessment by the IDMC will be performed through an independent 
data coordinating center to ensure the integrity of the study. 
Suspected unexpected serious adverse reactions (SUSARs) will be unblinded in accordance with 
local regulatory reporting requirements. Prespecified personnel from the sponsor’s Global Safety 
and Risk Management will unblind the identity of study medication for any unexpected (as per 
the investigator’s brochure) SAEs that are considered to be related to the blinded study drug 
(tucatinib or placebo). 

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4. 
STUDY POPULATION 
Subjects must meet all of the enrollment criteria to be eligible for this study. Eligibility criteria 
may not be waived by the investigator and are subject to review in the event of a good clinical 
practice audit and/or health regulatory authority inspection. 
4.1. 
Inclusion Criteria 
1. Histologically confirmed HER2+ breast carcinoma, as determined by sponsor-designated 
central laboratory testing on tumor tissue submitted prior to randomization (see 
Section 7.1.1) from either: 
a. Archival tissue (most recent tumor tissue sample preferred) 
b. If archival tissue is not available, then a newly-obtained baseline biopsy of an 
accessible tumor lesion that has not been previously irradiated is required 
2. History of prior treatment with a taxane and trastuzumab in any setting, separately or in 
combination. Prior pertuzumab therapy is allowed, but not required (see Appendix L for 
France-specific requirements) 
3. Have progression of unresectable LA/M breast cancer after last systemic therapy (as 
confirmed by investigator), or be intolerant of last systemic therapy.  
4. Measurable or nonmeasurable disease assessable by RECIST v1.1 (Appendix F)  
5. Hormone receptor (estrogen receptor/progesterone receptor) status must be known prior 
to randomization 
6. Age ≥18 years at time of consent or ≥ the age of majority in the geographic location  
7. ECOG performance status score of 0 or 1 (see Appendix B) for conversion of 
performance status using Karnofsky scale, if applicable) 
8. Life expectancy ≥6 months, in the opinion of the investigator 
9. Adequate hepatic function as defined by the following: 
a. Total bilirubin ≤1.5 × upper limit of normal (ULN), except for subjects with known 
Gilbert’s disease, who may enroll if the conjugated bilirubin is ≤1.5 × ULN 
b. Transaminases (aspartate aminotransferase/serum glutamic oxaloacetic transaminase 
[AST/SGOT] and alanine aminotransferase/serum glutamic pyruvic transaminase 
[ALT/SGPT]) ≤2.5 × ULN (≤5 × ULN if liver metastases are present) 
10. Adequate baseline hematologic parameters as defined by: 
a Absolute neutrophil count ≥1.0 × 103/µL 
b Platelet count ≥100 × 103/µL 
c Hemoglobin ≥9 g/dL 
d In subjects transfused before study entry, transfusion must be ≥14 days prior to start 
of therapy to establish adequate hematologic parameters independent from 
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11. Estimated glomerular filtration rate (GFR) ≥50 mL/min/1.73 m2 using the Modification 
of Diet in Renal Disease (MDRD) study equation (see Section 7.7.4)  
12. International normalized ratio (INR) and partial thromboplastin time (PTT)/activated 
partial thromboplastin time (aPTT) ≤1.5 × ULN, unless on medication known to alter 
INR and PTT/aPTT  
13. Left ventricular ejection fraction (LVEF) ≥50% as assessed by echocardiogram (ECHO) 
or multigated acquisition (MUGA) scan documented within 4 weeks prior to first dose of 
study treatment (see Section 6.2.2 for exceptions) 
14. For subjects of childbearing potential, as defined in Section 4.3, the following 
stipulations apply: 
a Must have a negative serum or urine pregnancy test (minimum sensitivity of 
25 mIU/mL or equivalent units of beta human chorionic gonadotropin [β-hCG]) result 
within 7 days prior to the first dose of study treatment. A subject with a false positive 
result and documented verification that the subject is not pregnant is eligible for 
participation. 
b Must agree not to try to become pregnant during the study and for at least 7 months 
after the final dose of study drug administration 
c Must agree not to breastfeed or donate ova, starting at time of informed consent and 
continuing through 7 months after the final dose of study drug administration 
d If sexually active in a way that could lead to pregnancy, must consistently use 
2 highly effective methods of birth control (as defined in Appendix K) starting at the 
time of informed consent and continuing throughout the study and for at least 
7 months after the final dose of study drug administration  
15. For subjects who can father children, the following stipulations apply: 
a. Must agree not to donate sperm starting at time of informed consent and continuing 
throughout the study period and for at least 7 months after the final study drug 
administration 
b. If sexually active with a person of childbearing potential in a way that could lead to 
pregnancy, must consistently use 2 highly effective methods of birth control (as 
defined in Appendix K ) starting at time of informed consent and continuing 
throughout the study and for at least 7 months after the final dose of study drug 
administration 
c. If sexually active with a person who is pregnant or breastfeeding, must consistently 
use 1 of 2 highly effective methods of birth control (as defined in Appendix K) 
starting at time of informed consent and continuing throughout the study and for at 
least 7 months after the final dose of study drug administration 
16. The subject must provide written informed consent 
17. Subject must be willing and able to comply with study procedures 
18. CNS Inclusion – Based on screening contrast brain magnetic resonance imaging (MRI), 
subjects must have at least one of the following: 

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a. No evidence of brain metastases 
b. Untreated brain metastases not needing immediate local therapy. For subjects with 
untreated CNS lesions >2.0 cm in diameter on screening contrast brain MRI, approval 
from the medical monitor is required prior to enrollment. 
c. Previously treated brain metastases 
i. Brain metastases previously treated with local therapy may either be stable since 
treatment or may have progressed since prior local CNS therapy, provided that 
there is no clinical indication for immediate re-treatment with local therapy in the 
opinion of the investigator. 
ii. Subjects treated with CNS local therapy for newly identified lesions or 
previously treated and progressing lesions found on contrast brain MRI 
performed during screening for this study may be eligible to enroll if all of the 
following criteria are met: 
o Time since SRS is ≥7 days prior to first dose of study treatment, time since 
whole-brain radiation therapy (WBRT) is ≥14 days prior to first dose of 
study treatment, or time since surgical resection is ≥28 days 
o Other sites of evaluable disease are present 
iii. Relevant records of any CNS treatment must be available to allow for 
classification of target and nontarget lesions 
4.2. 
Exclusion Criteria 
1. Prior treatment with tucatinib, afatinib, trastuzumab deruxtecan (DS-8201a), or any other 
investigational anti-HER2, anti-EGFR, or HER2 TKI agent. Prior treatment with 
lapatinib or neratinib within 12 months of starting study treatment (except in cases where 
they were given for ≤21 days and discontinued for reasons other than disease progression 
or severe toxicity). Prior treatment with pyrotinib for recurrent or mBC (except in cases 
where pyrotinib was given for ≤21 days and discontinued for reasons other than disease 
progression or severe toxicity) 
2. Prior treatment with T-DM1 in any treatment setting 
3. History of allergic reactions to trastuzumab or compounds chemically or biologically 
similar to tucatinib, except for Grade 1 or 2 infusion-related reactions to trastuzumab that 
were successfully managed, or known allergy to any of the excipients in the study drugs 
4. Treatment with any systemic anticancer therapy (including hormonal therapy), non-CNS 
radiation (palliative or therapeutic), experimental agent or participation in another 
interventional clinical trial ≤3 weeks prior to first dose of study treatment. An exception 
for the washout of hormonal therapies is gonadotropin releasing hormone agonists used 
for ovarian suppression in premenopausal women, which are permitted concomitant 
medications 
5. Any toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1, with the 
following exceptions: 

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• Alopecia 
• Neuropathy, which must have resolved to ≤ Grade 2  
• Congestive heart failure (CHF), which must have been ≤ Grade 1 in severity at the 
time of occurrence, and must have resolved completely 
6. Clinically significant cardiopulmonary disease such as: 
• Ventricular arrhythmia requiring therapy 
• Symptomatic hypertension or uncontrolled asymptomatic hypertension as determined 
by the investigator 
• Any history of symptomatic CHF, symptomatic left ventricular systolic dysfunction, 
or symptomatic decrease in ejection fraction 
• For France and Italy only: Any history of interstitial lung disease or pneumonitis 
• Severe dyspnea at rest (Common Terminology Criteria for Adverse Events [CTCAE] 
Grade 3 or above) due to complications of advanced malignancy or hypoxia requiring 
supplementary oxygen therapy 
• ≥ Grade 2 QTc prolongation on screening electrocardiogram (ECG) 
7. Known myocardial infarction or unstable angina within 6 months prior to first dose of 
study treatment 
8. Known carrier of Hepatitis B or Hepatitis C or has other known chronic liver disease 
• For Italy: Positive for Hepatitis B by surface antigen expression, positive for Hepatitis 
C infection, or the presence of known chronic liver disease. Subjects who have been 
treated for Hepatitis C infection are permitted if they have documented sustained 
virologic response of 12 weeks. The latest local guidelines should be followed 
regarding the testing of Hepatitis B DNA levels by polymerase chain reaction (PCR). 
Subjects with Hepatitis B DNA levels by PCR that require nucleoside analogue 
therapy are not eligible for the trial.  
9. Subjects known to be positive for human immunodeficiency virus (HIV) if they meet any 
of the following criteria: 
• CD4+ T-cell count of <350 cells/μL 
• Detectable HIV viral load 
• History of an opportunistic infection within the past 12 months 
• On stable antiretroviral therapy for <4 weeks 
10. Subjects who are pregnant, breastfeeding, or planning to become pregnant from time of 
informed consent until 7 months following the last dose of study drug 
11. Unable to swallow pills or has significant gastrointestinal disease which would preclude 
the adequate oral absorption of medications 
12. Use of a strong cytochrome P450 (CYP) 3A4 or CYP2C8 inhibitor within 1 week, or use 
of a strong CYP3A4 or CYP2C8 inducer within 5 days prior to the first dose of study 

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treatment (see Appendix C and Appendix D). CYP3A4 or CYP2C8 inducers and 
inhibitors are also prohibited as concomitant medications within 1 week of 
discontinuation of tucatinib treatment. Use of sensitive CYP3A substrates (Appendix E) 
should be avoided 1 week before enrollment and during study treatment.  
13. Unable to undergo contrast MRI of the brain 
14. Other medical, social, or psychosocial factors that, in the opinion of the investigator, 
could impact safety or compliance with study procedures 
15. Systemic therapy for another malignancy within 2 years of the start of study treatment  
16. CNS Exclusion – Based on screening brain MRI, subjects must not have any of the 
following: 
a. Any untreated brain lesions >2.0 cm in size, unless approved by the medical monitor 
b. Ongoing use of systemic corticosteroids for control of symptoms of brain metastases 
at a total daily dose of >2 mg of dexamethasone (or equivalent). However, subjects on 
a chronic stable dose of ≤2 mg total daily of dexamethasone (or equivalent) may be 
eligible with approval of the medical monitor. 
c. Any brain lesion thought to require immediate local therapy, including (but not 
limited to) a lesion in an anatomic site where increase in size or possible 
treatment-related edema may pose risk to the subject (eg, brain stem lesions). 
Subjects who undergo local treatment for such lesions identified by screening contrast 
brain MRI may still be eligible for the study based on criteria described under CNS 
Inclusion 18c (ii). 
d. Known or concurrent leptomeningeal disease as documented by the investigator 
e. Poorly controlled (>1/week) generalized or complex partial seizures, or manifest 
neurologic progression due to brain metastases notwithstanding CNS-directed therapy 
4.3. 
Childbearing Potential 
A person of childbearing potential is anyone born female, who has experienced menarche, and 
who has not undergone surgical sterilization (eg, hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy) or has not completed menopause. Menopause is defined clinically as 12 months 
of amenorrhea in a person over age 45 in the absence of other biological, physiological, or 
pharmacological causes. 
A person who can father children is anyone born male, who has testes, and who has not 
undergone surgical sterilization (eg, vasectomy followed by a clinical test proving that the 
procedure was effective). 
4.4. 
Removal of Subjects From Therapy or Assessment 
Seagen or their designee must be notified if a subject is withdrawn from study treatment or from 
the study. The reason(s) for withdrawal must be documented in the subject’s medical records and 
case report form (CRF).  

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4.4.1. 
Discontinuation of Study Treatment 
A subject’s study treatment may be discontinued for any of the following reasons: 
• AE 
• PD (per RECIST v1.1), as assessed by the investigator 
• Second disease progression after isolated progression in brain (see Section 4.4.1.1 
regarding initial CNS-only progression) 
• Investigator decision due to clinical progression 
• Pregnancy or begins breastfeeding while on trial 
• Investigator decision (other) 
• Subject decision, non-AE 
• Study termination by sponsor 
• Other, non-AE 
In the absence of clear evidence of disease progression (per RECIST v1.1), or development of 
CNS symptoms or radiographic changes thought to pose potential immediate risk to subject, all 
efforts should be made to continue treatment until unequivocal evidence of radiologic 
progression occurs (Section 7.2), as defined in RECIST v1.1. If study treatment is discontinued 
for reasons other than unequivocal disease progression (per RECIST v1.1) or death, subjects will 
continue in long-term follow-up until criteria for subject withdrawal from the study are met 
(Section 4.4.2). Every effort should be made to collect scans and clinical data until disease 
progression, in order to document a PFS event date. Following disease progression, subjects will 
continue in long-term follow-up for survival. 
Subjects who withdraw consent from the interventional portion of the study should specify 
whether to allow continued follow-up and further data collection subsequent to their withdrawal 
of consent, including (but not limited to) follow-up through medical records, public records, or 
other public platform. Every attempt should be made to follow the subject until progression, 
death, or administrative study closure.  
In the absence of progression, subjects who discontinue T-DM1 due to a T-DM1-related toxicity 
may continue receiving tucatinib/placebo alone. Subjects who discontinue tucatinib/placebo may 
continue to receive T-DM1 alone, provided progression has not occurred. 
4.4.1.1. 
Continuation on Study Treatment After CNS-Only Progression 
If a subject is found to have isolated progression in the CNS per RECIST v1.1 (including either 
parenchymal brain or dural metastases but not skull-based or leptomeningeal metastases) and 
does not have progression of disease outside the CNS, the subject may be eligible to continue on 
study treatment after completion of local treatment (radiotherapy or surgery) of any progressive 
brain/dural metastases to allow for clinical benefit. Local treatment must be completed prior to 
the subject’s next response assessment timepoint. Subjects may continue on study treatment for 
clinical benefit after this PFS event in the brain, however, requires discussion with and 
documented approval from the study medical monitor and subjects may continue until either 
systemic progression or a second isolated CNS progression. The subject will remain on the same 

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treatment arm assigned initially, and may continue on study provided the following criteria are 
met and the subject continues to receive clinical benefit: 
• The subject is not experiencing any worsening of cancer-related symptoms or signs 
indicating clinically significant progression of disease. Subjects who are clinically 
deteriorating (eg, have a decline in ECOG or Karnofsky performance status, 
symptomatic rapid disease progression requiring urgent medical intervention) and 
unlikely to receive further benefit from continued treatment should discontinue study 
treatment 
• The subject is tolerating study drug 
• Review and concurrence by the medical monitor 
• Subject has no evidence of unequivocal systemic progression 
• Subject has not had a previous isolated CNS progression while on study 
• Subject will be reconsented prior to continuing treatment on study 
Study treatment may be held up to 6 weeks to allow local CNS therapy. Longer holds must be 
discussed and approved by the medical monitor. Interruption and re-initiation of study treatment 
is described in Section 5.2. 
4.4.2. 
Subject Withdrawal From Study 
Any subject may be discontinued from the study for any of the following reasons: 
• Subject withdrawal of consent 
• Study termination by sponsor 
• Lost to follow-up 
• Death 
 

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5. 
TREATMENTS 
5.1. 
Treatments Administered 
Subjects will be randomized in a 1:1 manner to receive 1 of the following study treatments, 
either: 
• Control arm: Placebo tablets PO BID, and T-DM1 3.6 mg/kg IV every 21 days, or 
• Experimental arm: Tucatinib 300 mg PO BID, and T-DM1 3.6 mg/kg IV every 
21 days 
5.1.1. 
Investigational Study Drug (Tucatinib or Placebo)  
Tucatinib, the investigational agent under study in this protocol, is a kinase inhibitor that 
selectively inhibits HER2, and displays limited activity against the related kinase EGFR. 
Tucatinib and placebo are supplied as yellow oval (150 mg) or round (50 mg) capsule-shaped 
tablets for oral administration. Investigational study drug (tucatinib or placebo) will be supplied 
in a blinded manner. No treatment crossover from placebo to tucatinib will be allowed.  
Detailed information describing the preparation, administration, and storage of the 
investigational study drug (tucatinib or placebo) is located in the pharmacy instructions. 
5.1.1.1. 
Description 
Tucatinib drug product is supplied as both a coated yellow oval-shaped tablet in a 150 mg dosage 
strength and a coated yellow round convex tablet in a 50 mg dosage strength. The tablets are 
manufactured from a drug product intermediate amorphous dispersion of tucatinib in 
polyvinylpyrrolidone-vinyl acetate copolymer, which is then combined with the pharmaceutical 
excipients (microcrystalline cellulose, sodium chloride, potassium chloride, sodium bicarbonate, 
silicon dioxide, crospovidone, and magnesium stearate), and compressed into tablets. 
Tucatinib matching placebo tablets are formulated with common pharmaceutical excipients, but 
they do not contain the active ingredient. They are coated to be identical in appearance to active 
tablets and are supplied in the same format to maintain blinding. 
5.1.1.2. 
Method of Procurement 
The investigational study drug (tucatinib or placebo) will be provided by the sponsor. 
5.1.1.3. 
Dose and Administration 
The investigational study drug (tucatinib or placebo) will be administered PO BID and may be 
taken with or without food. Dose modifications of tucatinib or placebo are described in Section 
5.2. Subjects will be instructed by the pharmacist or investigator as to the specific number of 
tablets required for each dose. At each visit during study treatment, subjects will be supplied 
with the appropriate number of tablets for the number of doses to be taken prior to the next 
scheduled visit.  
Subjects will be instructed to take tucatinib/placebo tablets twice each day (once in the morning, 
and once in the evening) approximately 8-12 hours between doses in the same calendar day. It is 
recommended that if a subject misses a scheduled dose of tucatinib and less than 6 hours have 

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passed since the scheduled dosing time, the dose should be immediately taken. It is 
recommended that if more than 6 hours have passed since the scheduled dosing time, the subject 
should not take the missed dose but should wait and take the next regularly scheduled dose. 
Tablets may be taken with or without food. Tablets must be swallowed whole and may not be 
crushed, chewed, or dissolved in liquid. On the day of dosing, the individual unit dose of the 
tucatinib tablet may be exposed to ambient temperature for up to 6 hours prior to dose. 
Complete dosing instructions will be provided to the pharmacist prior to the initiation of the 
study. Complete dosing instructions will also be provided to study subjects and will include the 
minimum times between doses, dosing in relation to meals, and instructions for missed doses. 
Subject compliance with investigational study drug dosing instructions will be assessed with the 
use of subject diaries and study drug accountability. 
5.1.1.4. 
Overdose 
In the event of an overdose of investigational study drug (tucatinib or placebo), defined as any 
dose greater than the prescribed dose, study personnel should: 
• Care for and medically stabilize the subject until there is no immediate risk of 
complications or death, if applicable. There is currently no known antidote for an 
overdose of tucatinib. 
• Notify the medical monitor as soon as they become aware of the overdose, to discuss 
details of the overdose (eg, exact amount of tucatinib or placebo administered, subject 
weight) and AEs, if any. 
5.1.1.5. 
Storage and Handling 
Tablets of tucatinib and placebo are packaged in round, high-density polyethylene bottles 
containing a desiccant, with an induction sealed liner and child-resistant plastic closure cap. For 
storage information, refer to the tucatinib Pharmacy Instructions. 
The tablets are coated with a nonhazardous film to prevent any exposure to the active 
pharmaceutical ingredient during routine handling. Avoid breaking or crushing tablets. In the 
event the tablets are broken or crushed, wash hands and exposed skin thoroughly with soap and 
water.  
Refer to the pharmacy instructions for more information. 
5.1.1.6. 
Packaging and Labeling 
Each bottle of investigational study drug will be labeled in compliance with applicable 
regulatory requirements. 
5.1.1.7. 
Study Drug Accountability 
Tucatinib or placebo used during the course of the study should be handled according to the 
pharmacy instructions. Tucatinib and placebo are to be tracked and documented from the time of 
receipt at the site, through subject dosing, and until the sponsor approves of the final return or 
destruction. All supplies, including partially used or empty bottles, should be tracked. 

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The sponsor or designee will conduct drug accountability monitoring during the course of the 
study. All used and unused bottles of tucatinib or placebo should be handled according to the 
sponsor’s instructions. 
5.1.2. 
T-DM1 
5.1.2.1. 
Description 
T-DM1 (KADCYLA®) is a HER2-targeted antibody and microtubule inhibitor conjugate, which 
is indicated, as a single agent, for the treatment of patients with HER2+ mBC who have 
previously received trastuzumab and a taxane, either separately or in combination. 
5.1.2.2. 
Method of Procurement 
T-DM1 is commercially available and details regarding sourcing of T-DM1 may vary by site 
and/or region as outlined in other documents such as clinical trial agreements. 
5.1.2.3. 
Dose, Preparation, and Administration 
T-DM1 3.6 mg/kg IV will be administered on Day 1 of each 21-day cycle. T-DM1 should be 
prepared and administered per instructions in the KADCYLA package insert. T-DM1 will be 
administered intravenously per institutional guidelines, under the direction of the investigator. 
Protocol-defined visits and cycle numbering will be determined by T-DM1 dosing date, allowing 
for dose holds or delays with T-DM1. Dose modifications of T-DM1 are described in 
Section 5.2. 
5.1.2.4. 
Overdose 
For this trial, an overdose will be defined as any dose greater than the prescribed dose of T-DM1. 
In the event of an overdose, study personnel should: 
• Care for and medically stabilize the subject until there is no immediate risk of 
complications or death, if applicable. There is currently no known antidote for an 
overdose of T-DM1. 
• Notify the medical monitor as soon as they become aware of the overdose, to discuss 
details of the overdose (eg, exact amount of T-DM1 administered, subject weight) 
and AEs, if any. 
5.1.2.5. 
Storage and Handling 
T-DM1 should be stored according to the package insert. 
5.2. 
Dose Modifications 
Investigational study drug (tucatinib or placebo) and T-DM1 dose-reduction recommendations 
are described in Table 2 and Table 3, respectively. Guidelines for dose modification 
recommendations (including dose holds, dose reduction, or discontinuation of drug) in response 
to potential AEs are described in the tables in Section 5.2.3. Dose reductions or treatment 
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by the investigator if it is deemed in the best interest of subject safety. Whenever possible, these 
decisions should first be discussed with the study medical monitor. 
All AEs and clinically significant laboratory abnormalities should be assessed by the investigator 
for relationship to tucatinib/placebo and T-DM1. An AE may be considered related to 
tucatinib/placebo alone, T-DM1 alone, to both drugs, or to neither. In the event that the 
relationship is unclear, discussion should be held with the study medical monitor, to discuss 
which study drug(s) should be held and/or modified. 
Doses held for toxicity will not be replaced. Investigational study drug (tucatinib or placebo) or 
T-DM1 should be discontinued if a delay greater than 6 weeks is required due to 
treatment-related toxicity, unless a longer delay is approved by the study medical monitor. 
In the event of isolated progression in the CNS, study treatment may be held up to 6 weeks to 
allow local CNS therapy. Tucatinib/placebo and T-DM1 are to be held 1 week prior to planned 
CNS-directed therapy. The potential for radiosensitization with tucatinib and T-DM1 is 
unknown. Study treatment may be reinitiated ≥7 days after completion of SRS, ≥14 days after 
WBRT, and ≥28 days after surgical resection. Plans for holding and reinitiating study drugs 
before and after local therapy will require discussion with, and documented approval from, the 
medical monitor. 
Protocol-defined visits and cycle numbering will be determined by T-DM1 dosing, allowing for 
dose holds or delays with T-DM1. In the event T-DM1 is discontinued but study treatment with 
tucatinib/placebo continues, protocol-defined visits and cycle numbering will proceed using a 
21-day cycle regardless of dose holds or delays for tucatinib/placebo. 
5.2.1. 
 Tucatinib or Placebo Dose Reductions 
Up to 3 dose reductions of tucatinib/placebo are allowed. In the case of recurrent toxicity after 
3 dose reductions, treatment with tucatinib/placebo should be discontinued. Dose reductions of 
larger intervals than those described in Table 2 may be made at the discretion of the investigator, 
but dose reductions to below 150 mg BID are not allowed. Subjects who would require a dose 
reduction to below 150 mg BID should discontinue treatment with tucatinib/placebo. 
Tucatinib/placebo dose should not be re-escalated after a dose reduction is made. 
Table 2: 
Tucatinib/placebo: Recommended dose reduction schedule for adverse events* 
Dose Reduction Schedule 
Tucatinib/Placebo Dose Level 
Starting dose 
300 mg PO BID 
1st dose reduction 
250 mg PO BID 
2nd dose reduction 
200 mg PO BID 
3rd dose reduction 
150 mg PO BID 
Requirement for further dose reduction 
Discontinue treatment 
* Dose reductions of greater intervals than those recommended in this table (ie, more than 50 mg per dose reduction) 
may be made if considered clinically appropriate by the investigator and approved by the medical monitor. 
However, tucatinib/placebo may not be dose reduced below 150 mg BID. 

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5.2.2. 
T-DM1 Dose Reductions 
Up to 2 dose reductions of T-DM1 will be allowed (Table 3). In the case of recurrent toxicity 
after 2 dose reductions, treatment with T-DM1 should be discontinued. 
T-DM1 dose should not be re-escalated after a dose reduction is made. 
Table 3: 
T-DM1: Recommended dose reduction schedule for adverse events 
Dose Reduction Schedule 
T-DM1 Dose Level 
Starting dose 
3.6 mg/kg 
1st dose reduction 
3 mg/kg 
2nd dose reduction 
2.4 mg/kg 
Requirement for further dose reduction 
Discontinue treatment 
5.2.3. 
Dose Modifications for Adverse Events 
5.2.3.1. 
General Guidelines 
General dose modification guidelines for investigational study drug (tucatinib or placebo) and 
T-DM1 are provided in Table 4 for clinical AEs. 
Separate dose modification guidelines are provided for AEs of hepatotoxicity (Table 5), nodular 
regenerative hyperplasia (Section 5.2.3.3), thrombocytopenia (Table 6), left ventricular 
dysfunction (Table 7), and pulmonary toxicity (Section 5.2.3.6). 

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Table 4: 
Dose modifications for clinical adverse events related to either tucatinib/placebo or 
T-DM1 
 
Tucatinib/Placebo 
T-DM1 
Clinical Adverse Event 
Related to tucatinib/placebo 
Related to T-DM1 
All ≥ Grade 3 AEs 
except the following: Grade 3 
fatigue lasting ≤3 days; alopeciaa; 
nausea; vomiting; diarrhea; rash; 
correctable electrolyte 
abnormalities 
Hold until severity ≤ Grade 1 or 
pretreatment level. 
Restart at next lowest dose level. 
Do not administer until severity 
≤ Grade 1 or pretreatment level. 
Reduce to next lowest dose level. 
Note: Dose reduction is not 
required for hematologic 
abnormalities (other than 
thrombocytopeniab) that recover to 
≤ Grade 1 prior to dosing. 
Grade 3 nausea, vomiting, or 
diarrhea WITHOUT maximal use 
of antiemetics or antidiarrheals 
Hold until severity ≤ Grade 1 or 
pretreatment level. 
Initiate appropriate therapy. 
Restart without dose reduction. 
Do not administer until severity 
≤ Grade 1 or pretreatment level. 
Initiate appropriate therapy. 
Optional dose reduction to next 
lowest dose level. 
Grade 3 nausea, vomiting, or 
diarrhea WITH maximal use of 
antiemetics or antidiarrheals 
Hold until severity ≤ Grade 1 or 
pretreatment level. 
Restart at next lowest dose level. 
Do not administer until severity 
≤ Grade 1 or pretreatment level. 
Optional dose reduction to next 
lowest dose level. 
Grade 4 nausea, vomiting, or 
diarrhea regardless of use of 
anti-emetics or antidiarrheals 
Do not administer until severity 
≤ Grade 1. 
Reduce to next lowest dose level. 
Do not administer until severity  
≤ Grade 1. 
Reduce to next lowest dose level. 
Grade 1 or 2 diarrhea with 
complicating featuresc 
Hold until severity ≤ Grade 1 or 
pretreatment level. 
Restart at next lowest dose level. 
Do not administer until severity 
≤ Grade 1 or pretreatment level. 
Optional dose reduction to next 
lowest dose level. 
Grade 3 rash WITHOUT maximal 
use of topical corticosteroids or 
anti-infectives 
Hold until severity ≤ Grade 1 or 
pretreatment level. 
Initiate appropriate therapy. 
Restart without dose reduction. 
Do not administer until severity 
≤ Grade 1 or pretreatment level. 
Initiate appropriate therapy. 
Optional dose reduction to next 
lowest dose level. 
Grade 3 rash WITH maximal use of 
topical corticosteroids or 
anti-infectives 
Hold until severity ≤ Grade 1 or 
pretreatment level. 
Restart at next lowest dose level. 
Do not administer until severity 
≤ Grade 1 or pretreatment level. 
Optional dose reduction to next 
lowest dose level. 
Grade 4 rash regardless of use of 
topical corticosteroids or 
anti-infectives 
Hold until severity ≤ Grade 1 or 
pretreatment level. 
Restart at next lowest dose level. 
Do not administer until severity 
≤ Grade 1 or pretreatment level. 
Restart at next lowest dose level. 
a No dose modifications are required for alopecia 
b Refer to Table 6 for thrombocytopenia dose reduction requirements 
c Moderate to severe abdominal cramping, nausea, or vomiting ≥ National Cancer Institute’s (NCI) CTCAE 
Grade 2, decreased performance status, fever, sepsis, neutropenia, frank bleeding, or dehydration 

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5.2.3.2. 
Hepatotoxicity 
Dose modification may be required in the case of liver function abnormalities, regardless of 
relationship to study drug (Table 5). 
For subjects with documented Gilbert’s disease, contact the medical monitor for guidance 
regarding dose modifications. 
Table 5: 
Dose modification guidelines for liver function abnormalities (regardless of 
relationship to tucatinib/placebo or T-DM1) 
 
Tucatinib/Placebo 
T-DM1 
Grade 2 elevation of ALT and/or 
AST of >3.0 to ≤5 × ULN 
Dose modification not required 
Dose modification not required 
Grade 3 elevation of ALT and/or 
AST (>5–20 × ULN) 
Hold until severity ≤ Grade 1. 
Restart at next lowest dose level. 
Hold until severity ≤ Grade 1. 
Restart at next lowest dose level. 
Grade 4 elevation of ALT and/or 
AST (>20 × ULN) 
Discontinue drug 
Discontinue drug 
Elevation of ALT and/or AST 
 >3 × ULN 
AND 
Bilirubin >2 × ULN 
Discontinue drug 
Discontinue drug 
Grade 2 elevation of bilirubin  
(>1.5–3 × ULN)  
Hold until severity ≤ Grade 1. 
Restart at same dose level. 
Hold until severity ≤ Grade 1. 
Restart at same dose level. 
Grade 3 elevation of bilirubin 
(>3 to ≤10 × ULN) 
Hold until severity ≤ Grade 1. 
Restart at next lowest dose level. 
Hold until severity ≤ Grade 1. 
Restart at next lowest dose level. 
Grade 4 elevation of bilirubin  
(>10 × ULN) 
Discontinue drug 
Discontinue drug 
5.2.3.3. 
Nodular Regenerative Hyperplasia 
Investigational study drug (tucatinib or placebo) and T-DM1 should be discontinued 
permanently in subjects diagnosed with nodular regenerative hyperplasia, regardless of 
relationship to study drug. 
5.2.3.4. 
Thrombocytopenia 
T-DM1 dose modification are required for thrombocytopenia, regardless of relationship to 
T-DM1 (Table 6). Dose modification of investigational study drug (tucatinib or placebo) is not 
required for thrombocytopenia. 
Table 6: 
Dose modification guidelines for thrombocytopenia 
 
Tucatinib/Placebo 
T-DM1 
Grade 3 thrombocytopenia  
Platelet count 25,000/mm3 to 
<50,000/mm3 
Dose modification not required 
Hold until platelet count recovers to 
≤ Grade 1 (≥75,000/mm3), and then 
restart at same dose level 

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Grade 4 thrombocytopenia 
Platelet count <25,000/mm3 
Dose modification not required 
Hold until platelet count recovers to 
≤ Grade 1 (≥75,000/mm3), and then 
reduce one dose level 
5.2.3.5. 
Left Ventricular Dysfunction 
Investigational study drug (tucatinib or placebo) and T-DM1 dose modification guidelines for 
left ventricular dysfunction, regardless of relationship to study drug, are provided in Table 7. 
Table 7: 
Dose modification guidelines for left ventricular dysfunction 
Symptomatic CHF 
LVEF <40% 
LVEF 40% to ≤45% 
and decrease is 
≥10% points from 
baseline 
LVEF 40% to ≤45% 
and decrease is 
<10% points from 
baseline 
LVEF >45% 
Discontinue 
T-DM1 and 
tucatinib/placebo 
Do not administer  
T-DM1 or 
tucatinib/placebo. 
Repeat LVEF 
assessment within 
3 weeks. 
If LVEF <40% is 
confirmed, 
discontinue T-DM1 
and 
tucatinib/placebo. 
Do not administer  
T-DM1 or 
tucatinib/placebo. 
Repeat LVEF 
assessment within 
3 weeks. 
If the LVEF has not 
recovered to within 
10% points from 
baseline, discontinue 
T-DM1 and 
tucatinib/placebo. 
Continue treatment 
with T-DM1 and 
tucatinib/placebo. 
Repeat LVEF 
assessment within 
3 weeks. 
Continue treatment 
with T-DM1 and 
tucatinib/placebo. 
5.2.3.6. 
Pulmonary Toxicity 
T-DM1 should be permanently discontinued in subjects diagnosed with interstitial lung disease 
or pneumonitis, regardless of relationship to T-DM1. 
5.3. 
Concomitant Therapy 
All concomitant medications, blood products, and radiotherapy administered will be recorded 
from Day 1 (predose) through the safety reporting period. Any concomitant medication given for 
a study protocol-related AE should be recorded from the time of informed consent through the 
safety reporting period. 
Any planned non-CNS surgery (major or minor) not directly related to cancer that occurs on 
study requires prior consultation with the sponsor medical monitor. In France and Italy, subjects 
are required to suspend study treatment 3 to 7 days prior to surgery and, depending on the nature 
of the surgery, resume study treatment 3 to 21 days postoperatively. The medical monitor must 
be contacted prior to subjects resuming treatment. It is not necessary for both study treatments to 
resume simultaneously post procedure. Refer to Section 4.4.1 for additional guidance regarding 
dose modifications when resuming treatment and for CNS surgery. For emergency surgeries, 
contact the medical monitor as soon as feasible to discuss resumption of study treatment 
postoperatively.  

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5.3.1. 
Required Concomitant Therapy 
There are no required concomitant therapies. For subjects with CNS metastases, prophylactic 
pretreatment systemic corticosteroids may be administered at the discretion of the investigator. 
5.3.2. 
Permitted Concomitant Therapy 
Subjects may continue to use any ongoing medications not prohibited by the inclusion/exclusion 
criteria. However, efforts should be made to maintain stable doses of concomitant medications 
during the course of study treatment. 
Supportive treatments will be given according to label instructions as medically indicated. 
Concomitant medications can be administered at the investigator’s discretion to conform to 
standard practice during the treatment period.  
• Routine prophylaxis with vaccines (without live virus) are permitted during the study 
• If surgery or localized radiation become indicated (either for palliation or 
down-staging of previously nonresectable tumor), these concomitant procedures are 
permitted for nontarget, non-CNS lesions only in situations where other disease 
remains assessable by RECIST v1.1 (Appendix F). These interventions should be 
avoided if clinically feasible until after the second response assessment. The medical 
monitor must be consulted prior to the intervention occurring. 
• Corticosteroids 
o Subjects requiring systemic corticosteroids for control of brain metastases at a 
dose of >2 mg of dexamethasone (or equivalent) on the first day of study 
treatment are not eligible to begin study treatment, and should not be 
randomized until doses ≤2 mg can be achieved 
o After initiation of study treatment, corticosteroids may be initiated for control 
of CNS symptoms only after consultation and approval of the medical monitor 
o For subjects with CNS metastases, prophylactic pretreatment systemic 
corticosteroids may be administered at the discretion of the investigator 
o Premedication with corticosteroids solely for contrast used in scans or MRI 
can be used without prior medical approval 
o Subjects requiring systemic steroids for control of other comorbidities (eg, 
asthma or auto-immune diseases) may be eligible after consultation and 
approval of the medical monitor 
• Transfusion support with blood products is permitted. (However, note that no 
transfusions are permitted from <14 days prior to starting study treatment until the 
initiation of study treatment in order to establish adequate hematologic parameters for 
study eligibility independent of transfusion support) 
5.3.3. 
Prohibited Concomitant Therapy 
The following therapies are prohibited during the study (unless otherwise noted): 
• Investigational drugs and devices 

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• Anticancer therapy, including but not limited to chemotherapy or hormonal therapy 
• Radiation therapy, except for palliative radiotherapy at focal sites, which may be 
given after consultation with the medical monitor, provided that there remain other 
sites of measurable disease accessible by RECIST v1.1 (see Section 5.3.2) 
• Strong inhibitors or inducers of CYP3A4 are prohibited as concomitant medications 
during study treatment and within 1 week of discontinuation of study treatment (see 
Appendix C) 
• Strong inhibitors or inducers of CYP2C8 are prohibited as concomitant medications 
during study treatment and within 1 week of discontinuation of tucatinib/placebo 
treatment (see Appendix D) 
The following therapies should be used with caution during the study 
• Subjects on anticoagulant treatment should be closely monitored during study 
treatment 
• Sensitive substrates of CYP3A (Appendix E); tucatinib exhibits inhibition of human 
CYP3A enzymes, and therefore has the potential to interact with other medications 
that are substrates of CYP3A. Therefore, concomitant use of tucatinib with sensitive 
CYP3A substrates should be avoided. Consider using an alternate medication which 
is not a sensitive CYP3A substrate. If unavoidable, consider dose reduction of 
CYP3A substrates with narrow therapeutic indices and/or increased monitoring for 
potential adverse reactions as described in the medication’s prescribing information 
• Concomitant use of tucatinib with digoxin, a P-gp substrate, increases digoxin 
concentrations, which may increase the risk for digoxin related adverse reactions. 
Concomitant use of tucatinib with digoxin or P-gp substrates with a narrow 
therapeutic index (such as, but not limited to, dabigatran, fexofenadine, and 
cyclosporine) should be used with caution. Refer to the prescribing information of 
digoxin or other P-gp substrates for dosage adjustment recommendations due to drug 
interactions. 
5.4. 
Treatment Compliance 
Study drug administration will be documented in source documents and the CRF. 
Study-drug compliance will be assessed on a subject-by-subject basis using subject diaries. The 
pharmacist or designee will record the number of investigational study drug (tucatinib or 
placebo) tablets dispensed to each individual subject, and the number of tablets returned to the 
clinic. 
Data regarding the administration and dose of T-DM1 will also be collected by the site after each 
cycle. Dose modifications and interruptions of any study drug will be documented in the source 
documents and the CRF. 

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6. 
STUDY ACTIVITIES 
6.1. 
Schedule of Events 
AEs and concomitant medications will be recorded from Day 1(predose) through the safety 
reporting period (see Section 7.7.1.3). Any study protocol-related AE, as well as any 
concomitant medications given for treatment of the AE, should be recorded from the time of 
informed consent. 
Study assessments will continue regardless of any dose holds or delays. 
A schedule of events is provided in Appendix A. Study activities are listed by visit in this section 
and descriptions of all study assessments are presented in Section 7. 
6.2. 
Screening Period 
6.2.1. 
HER2 Testing (Up to 1 Year Before the Screening Visit)  
Subjects may consent to submit an archival tumor specimen for central assessment to complete 
HER2 expression testing up to one year before the screening visit. Subjects must be informed 
that HER2 testing consent is not informed consent for the study and participation in HER2 
testing does not guarantee study eligibility. 
• HER2 expression testing consent 
• Submission of archival tumor specimen for central assessment to confirm HER2 
expression meets eligibility requirements (see Section 7.1.1) 
• Confirmatory central HER2 testing, with archival tissue showing HER2-positivity by 
in situ hybridization (ISH). In China, refer to the laboratory manual for details 
regarding HER2 testing.  
6.2.2. 
Screening Visit (Day −28 to Day 1)  
• Informed consent 
• Study eligibility per inclusion/exclusion criteria 
• Medical history (see Section 7.1) 
• For Italy only: Hepatitis B and C testing (See Section 7.7.4) 
• Collection of concomitant medication information 
• Confirm HER2+ status  
o Confirmation from an archival tumor specimen for central assessment to confirm 
HER2 expression (see Section 7.1.1 for eligibility requirements). 
o If archival tissue that meets requirements is not available, a fresh tumor biopsy 
must be obtained and submitted for central assessment for HER2 testing 
• Hormone receptor status must be known prior to randomization (hormone receptor 
positive: estrogen receptor positive and/or progesterone receptor positive; hormone 

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receptor negative: both estrogen receptor negative and progesterone receptor 
negative) 
• ECG (see Section 7.7.6.2, must be collected prior to first dose of any study treatment) 
• ECHO, or MUGA scan to include at a minimum LVEF (see Section 7.7.6.1); the 
testing modality chosen in screening should be used for subsequent cardiac 
assessments to allow comparison 
• High-quality spiral contrast computed tomography (CT; preferred); positron emission 
tomography (PET)/CT (if high quality CT scan is included), and/or nonbrain MRI 
scan may be done as appropriate (see Section 7.2). At a minimum, scans must include 
chest, abdomen, and pelvis. Additional appropriate imaging of any other known sites 
of disease (eg, skin lesion photography for skin lesions, bone imaging for bone 
lesions) should also be performed at the investigator’s discretion. 
• Contrast MRI scan of the brain for all subjects for assessment of brain tumor burden 
(see Section 7.2.1) 
o For subjects with brain metastases discovered during screening or a history of 
brain metastases, confirm that relevant MRI brain reports and CNS treatment 
records can be obtained 
* For subjects with unsuspected brain metastases discovered at screening and who go on to 
receive immediate local therapy to the CNS or who require a fresh tumor biopsy for HER2 
confirmation, the screening process may be delayed beyond the 28-day screening window. 
Certain screening evaluations may not need to be repeated outside the 28-day screening window 
with medical monitor approval. This includes the following: informed consent and 
ECHO/MUGA. All other safety laboratories and assessments will need to be repeated per the 
schedule of events for these subjects. If local CNS therapy involves radiation treatment, do not 
repeat the contrast MRI of the brain prior to starting study treatment. If local CNS therapy 
involves surgical resection, a postoperative contrast MRI of the brain is required prior to starting 
study treatment. 
6.2.3. 
Baseline Visit (Day −7 to Day 1)  
• Physical examination (see Section 7.7.2), including height and weight 
• Vital signs (blood pressure, heart rate, temperature, and respiration rate) 
• ECOG performance status (Appendix B) 
• Blood samples for laboratory testing (as listed in Section 7.7.4) 
o Chemistry 
o Liver function tests (LFTs) 
o Complete blood count (CBC) with differential 
o Coagulation panel  
• For persons of childbearing potential, serum or urine pregnancy test (see 
Section 7.7.5) within 7 days of first study treatment 

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• Review HER2+ status and laboratory results, and confirm eligibility prior to 
randomization 
6.3. 
Randomization (Day −5 to Day 1)  
• Occurs after eligibility per inclusion/exclusion criteria is confirmed. Randomization 
MUST occur on or before Cycle 1 Day 1, such that dosing commences within 5 days 
after randomization. 
6.4. 
Treatment Period (21-day cycles)  
6.4.1. 
Cycle 1 Day 1 
• Physical examination, including weight* 
• Vital signs (blood pressure, heart rate, temperature, and respiration rate) 
• ECOG performance status* 
• Predose blood samples for laboratory testing. Review results to confirm eligibility 
prior to first dose of study treatment: 
o Chemistry * 
o LFTs* 
o CBC with differential* 
• QoL questionnaires* (Section 7.6; to be completed prior to evaluation by study 
personnel [physical examination, review of AEs] and administration of study 
treatment): 
o EQ-5D-3L 
o EORTC QLQ IL6 
o FACT-B GP5 
o NCI PRO-CTCAE 
• Dispense tucatinib or placebo and administer the first dose of tucatinib/placebo and 
provide dosing diary to subject. (Subject will self-administer the remainder of doses 
during the treatment cycle and document in the diary) ‡ 
• Administer T-DM1 at 3.6 mg/kg IV ‡ 
* Predose assessments do not need to be repeated if performed within 1 day prior to Cycle 1, 
Day 1. 
‡ Study drugs may be administered in any order and can be given simultaneously. 
6.4.2. 
Cycle 1 Day 12 (±3 days)  
• Physical examination, including weight 
• Vital signs (blood pressure, heart rate, temperature, and respiration rate) 

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• ECOG performance status 
• EORTC QLQ IL6  
• NCI PRO-CTCAE 
• FACT-B GP5  
• Review subject diary for tucatinib/placebo drug compliance 
• Blood samples for laboratory testing 
o Chemistry 
o LFTs 
o CBC with differential 
• Provide tucatinib/placebo day-of dosing instructions for the Cycle 2 Day 1 visit, so 
that the visit’s predose blood sample can be collected within the required time 
window (ie, 2 hours prior to tucatinib/placebo) 
6.4.3. 
Cycle 2 Day 1, and Day 1 of All Subsequent Cycles (−1 to +3 days)  
• QoL questionnaires (to be completed prior to evaluation by study personnel [physical 
examination, review of AEs] and administration of study treatment)*: 
o EQ-5D-3L 
o EORTC QLQ IL6 
o FACT-B GP5 
o NCI PRO-CTCAE 
• Review HCRU during the previous treatment cycle (see Section 7.5)* 
• Physical examination, including weight*  
• Vital signs (blood pressure, heart rate, temperature, and respiration rate) 
• ECOG performance status* 
* Predose assessments do not need to be repeated if performed within 1 day prior to Day 1. 
Blood sample collections: 
• All cycles: Predose blood samples for laboratory testing. Must be performed within 
1 day prior to Day 1 of the treatment cycle. Review results prior to the administration 
of study treatment to confirm continued study treatment and allow for potential dose 
adjustments: 
o Chemistry 
o LFTs 
o CBC with differential 
o For persons of child-bearing potential only: predose serum or urine pregnancy 
test (see Section 7.7.5) within 7 days prior to Day 1 of the treatment cycle. 

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• Cycles 3–6 only: Predose blood sample (up to 2 hours prior to dosing with 
tucatinib/placebo) and end of infusion (up to 15 minutes after end of T-DM1 
infusion) for PK analysis  
• Cycle 3 only:  
o Postdose blood sample (1–4 hours postdose) for PK analysis following 
administration of tucatinib/placebo 
Study treatment administration: 
• Review subject diary for tucatinib/placebo drug compliance from previous cycle and 
dispense tucatinib/placebo for next cycle  
• Administer the first dose of tucatinib/placebo for the current cycle. (Subject will 
self-administer the evening dose, unless the cycle began in the afternoon.) ‡ 
• Administer T-DM1 given intravenously ‡ 
• Cycles 3–5 only: Provide tucatinib/placebo day-of dosing instructions for the next 
cycle’s Day 1 visit, so that the visit’s predose blood sample can be collected within 
the required time window (ie, 2 hours prior to tucatinib/placebo) and ensure subject 
withholds AM tucatinib dose on Day 1 of next cycle 
‡ Study drugs may be administered in any order and can be given simultaneously. 
6.4.4. 
Cycle 2 Day 1, 2, 3, and 5 (PK Substudy Subjects Only)  
• Blood samples for PK analysis of tucatinib and DM1 on Cycle 2 Day 1 predose (up to 
2 hours predose), after end of T-DM1 infusion (up to 15 minutes after end of 
infusion) on Cycle 2 Day 1, and 24 (± 4 hours), 48 (±4 hours) and 96 (±6 hours) 
hours after end of infusion on Cycle 2 Day 2, Cycle 2 Day 3, and Cycle 2 Day 5, 
respectively 
6.4.5. 
Cycle 2 Day 12 (±3 days)  
• Blood sample for LFTs (total bilirubin, AST, ALT, and alkaline phosphatase [ALP]) 
• Review subject diary for tucatinib/placebo drug compliance 
• Provide tucatinib/placebo day-of dosing instructions for the Cycle 3 Day 1 visit, so 
that the visit’s predose blood sample can be collected within the required time 
window (ie, 2 hours prior to tucatinib/placebo) 
• EORTC QLQ IL6 
• FACT-B GP5  
• NCI PRO-CTCAE 
6.4.6. 
Every 6 Weeks (−7 days) as Determined by Cycle 1 Day 1, through 
Week 24, then Every 9 Weeks (−7 days) Through End of Treatment 
• High-quality spiral contrast CT (preferred); PET/CT (if high quality CT scan is 
included), and/or nonbrain MRI scan may be done as appropriate (see Section 7.2). 

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The same imaging modalities used in Screening/Baseline should be repeated, unless 
otherwise clinically indicated. 
• Contrast MRI of the brain (only in subjects with brain metastases at baseline, as 
defined in Section 7.2.1) and assessment of CNS lesions (brain and/or dura) 
• If cycles are delayed for any reason, continue with initial scan schedule as determined 
by the date of Cycle 1 Day 1 visit. 
• If an interim unscheduled assessment is performed, scans should continue to be done 
on schedule, with scheduling determined by the date of Cycle 1 Day 1. In cases of 
medical contraindication for repeat scans, contact the medical monitor to discuss as, 
in some instances, assessments done at an unscheduled timepoint may not need to be 
repeated if medically contraindicated as approved by the medical monitor. 
6.4.7. 
Every 12 Weeks as Determined by Screening Exam (−7 days)  
• ECHO or MUGA, using the same cardiac testing modality performed in 
Screening/Baseline 
• If there is an interim assessment, subsequent cardiac ECHO or MUGA should be 
performed every 12 weeks as determined by the date of the most recent interim 
assessment 
6.5. 
End of Treatment Visit (30 to 37 days after last dose of study treatment)  
The time of End of Treatment (EOT) visit may be longer than 37 days, but in no case should it 
be <30 days. However, EOT evaluations must be performed before initiation of a new therapy. If 
EOT visit evaluations are completed before 30 days after the last dose of study treatment, the 
subject will be contacted 30 to 37 days following the last dose of study treatment to assess for 
AEs.  
• QoL questionnaires (to be completed prior to evaluation by study personnel [physical 
examination, review of AEs]): 
o EQ-5D-3L 
o EORTC QLQ IL6 
o FACT-B GP5 
o NCI PRO-CTCAE 
• Review HCRU since the last study visit 
• Physical examination, including weight 
• Vital signs (blood pressure, heart rate, temperature, and respiration rate) 
• ECG 
• ECOG performance status 
• Blood samples for laboratory testing 
o Chemistry 

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o LFTs 
o CBC with differential 
o Coagulation panel 
o For females of childbearing potential (FOCBP) only (if not done within the 
last 30 days): serum or urine pregnancy test (see Section 7.7.5) 
• Only in subjects who discontinue study treatment for reasons other than radiographic 
disease progression: high-quality spiral contrast CT (preferred); PET/CT (if high 
quality CT scan included), and/or nonbrain MRI scan may be done as appropriate. 
The same imaging modalities used in Screening/Baseline should be repeated, unless 
otherwise clinically indicated. Not required if imaging was performed within 30 days 
of discontinuing study treatment. 
• Contrast MRI of the brain for all subjects and assessment of CNS lesions. Not 
required if brain MRI was performed within 30 days of discontinuing study treatment, 
or if progression in the brain has already been documented while on study. 
• ECHO or MUGA, using the same cardiac testing modality performed in 
Screening/Baseline. Not required if ECHO/MUGA was done within the previous 
12 weeks (excluding the Screening/Baseline assessment). 
• Review subject diary for tucatinib/placebo drug compliance from last cycle of study 
treatment. 
• For persons of childbearing potential: Remind subject that monthly pregnancy tests 
should be performed for 7 months after the last dose of study treatment. Testing may 
be performed at home. If performed at home, site staff will contact the subject 
monthly to confirm testing was performed and obtain pregnancy test results. 
6.6. 
Long-Term Follow-up 
Subjects who discontinue study treatment will remain on study for follow-up until withdrawal 
from the study. A subject may discontinue study treatment without withdrawing from the study 
(Section 4.4.1). If a subject discontinues study treatment, every attempt should be made to follow 
the subject until progression, death, or administrative study closure. 
For subjects who discontinue study treatment for any reason prior to documented disease 
progression per RECIST v1.1, the following assessments must be obtained every 9 weeks 
(±1 week) starting from the date of the last imaging scan, until investigator-assessed disease 
progression (per RECIST v1.1), death, withdrawal of consent, or study closure, in order to 
document a PFS event date: 
• High-quality spiral contrast CT (preferred); PET/CT (if high quality CT scan is 
included), and/or nonbrain MRI scan as appropriate. The same imaging modalities 
used in Screening/Baseline should be repeated, unless otherwise clinically indicated. 
• Contrast MRI of the brain (only in subjects with brain metastases at baseline, as 
defined in Section 7.2.1) and assessment of CNS lesions (brain and/or dura) 

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• QoL questionnaires (to be completed prior to any study assessments or evaluation by 
study personnel): 
o EQ-5D-3L 
o EORTC QLQ IL6 
• For persons of childbearing potential (for 7 months after the last dose of study 
treatment; see Section 7.7.5): 
o Confirm with the subject that monthly pregnancy tests have been performed 
and review results 
o Remind subject that monthly pregnancy tests should be performed for 
7 months after the last dose of study treatment 
Subsequent long-term follow-up scan windows are based on the most recent scan completed. 
Once a subject experiences PD (per RECIST v1.1) or clinical progression as assessed by the 
investigator, subjects will continue in long-term survival follow-up. The following information 
must be collected starting 90 days (±7 days) from the date of the last imaging scan or 90 days 
from the last study visit, whichever is later, and continuing every 90 days (±7 days) until death, 
withdrawal of consent, lost to follow up, or study closure.  
• Subject contact or in-person assessment of OS and/or disease recurrence, as well as 
collection of information regarding any additional anticancer therapies administered 
after completion of study treatment. Review of medical records, public records, or 
other public platforms may be used to obtain this information if reasonable efforts to 
contact the subject are unsuccessful. For subjects who are lost to follow up or 
withdraw consent from study participation, data for OS will be collected from public 
records if allowed per local regulations.  
• Administer QoL questionnaires (can be administered by phone once the patient has 
experienced a progression event as determined by RECIST v1.1) 
o EQ-5D-3L 
o EORTC QLQ IL6 
• For persons of childbearing potential (for 7 months after the last dose of study 
treatment; see Section 7.7.5): 
o Confirm with the subject that monthly pregnancy tests have been performed 
and have been negative 
o Remind subject that monthly pregnancy tests should be performed for 
7 months after the last dose of study treatment 
• More frequent long-term follow-up may be conducted as needed for OS event 
tracking (eg, for subjects with clinical progression, OS event tracking may be 
conducted at the same time radiographic scans and PFS event tracking will be 
performed every 9 weeks, until PD per RECIST v1.1 is confirmed, at which time PFS 
tracking ends and OS event tracking may be performed starting 90 days [±7 days] 
from the date of the last imaging scan ) 

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6.7. 
Subject End of Study/End of Follow-up 
The date the subject met criteria for study discontinuation and the reason for study 
discontinuation will be recorded. 

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7. 
STUDY ASSESSMENTS 
7.1. 
Screening/Baseline Assessments 
Screening/Baseline assessments will be conducted to establish study baseline status and 
determine study eligibility. Only subjects who meet all inclusion and exclusion criteria specified 
in Sections 4.1 and 4.2 will be enrolled in this study. 
Tumor tissue must be submitted to the sponsor-designated central laboratory for confirmatory 
HER2 testing to determine subject eligibility; confirmatory HER2 testing may be performed on 
archival tissue or a newly-obtained baseline biopsy of an accessible tumor lesion that has not 
been previously irradiated (see Section 7.1.1). 
Subject medical history includes a thorough review of significant past medical history, current 
conditions, any treatment for prior malignancies and response to prior treatment, and any 
concomitant medications. 
All measurable and evaluable lesions will be assessed and documented at Screening/Baseline 
(see Section 7.2). A contrast MRI of the brain is performed to evaluate for the presence of brain 
metastases (see Section 7.2.1). Subjects with brain metastases at study entry may be eligible for 
study participation if they meet the inclusion/exclusion criteria and the conditions described in 
Section 7.1.2. 
A physical examination including height and weight (Section 7.7.2), vital signs (Section 7.7.3), 
ECOG performance status (Appendix B), clinical laboratory testing (Section 7.7.4), and 
pregnancy testing (Section 7.7.5) will be done at Screening/Baseline. 
7.1.1. 
Confirmation of HER2 Expression for Study Eligibility 
Archival or freshly-obtained tumor tissue (most recent tumor tissue sample requested) must be 
submitted to the sponsor-designated central laboratory for confirmatory HER2 testing prior to 
randomization. The central laboratory will require sufficient tumor tissue to generate unstained, 
positively-charged slides for HER2 expression testing. Archived tumor samples must be 
formalin-fixed and paraffin-embedded. If archival tissue that meets sample requirements is not 
available, fresh tissue from a tumor site (metastatic site preferred as applicable) suitable for 
biopsy must be obtained and submitted for confirmatory HER2 testing. 
HER2 expression will be analyzed using ISH (DAKO IQFISH pharmDx), and positivity will be 
assessed according to the package insert for HER2 interpretation. In China, refer to the 
laboratory manual for details regarding HER2 testing. 
A tumor suitable for biopsy should be accessible, not previously irradiated, and without 
contraindication to biopsy, in the opinion of the investigator. Tissue samples obtained through 
resection, excision, punch (skin lesions only), or core needle from a tumor site are suitable for 
testing. Fine needle aspiration, brushing, cell pellets from pleural effusion, forceps, and lavage 
samples are not acceptable. Tumor tissue should be of good quality based on total and viable 
tumor content; eg, samples should contain tumor cells that preserve cellular context and tissue 
architecture, regardless of the needle gauge used to collect the sample or the retrieval method.  
See the central laboratory manual for more details. 

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7.1.2. 
Treatment for Brain Metastases Prior to Study Entry 
Subjects with brain metastases at study entry may be eligible for study participation if they meet 
the eligibility criteria described in Sections 4.1 and 4.2. In order to minimize the risk of 
symptomatic cerebral edema in subjects with brain metastases in this study, subjects with 
high-risk metastases, including those requiring immediate local therapy, those with rapidly 
progressing lesions, those requiring corticosteroids at the start of the study (>2 mg of 
dexamethasone or equivalent per day) for control of CNS symptoms, and those with larger 
untreated lesions are excluded from the trial. However, if these subjects are amenable to 
immediate CNS-directed therapy with either surgery or radiation, they may undergo local 
therapy and then be eligible for the trial. Under select circumstances subjects may receive 
corticosteroid therapy for acute management of symptomatic local edema, as long as contrast 
brain MRI does not show clear evidence of CNS progression and requires approval from the 
study medical monitor.  
Immediate local therapy to the CNS may delay the screening process beyond the 28-day 
screening window, in which case the requirement for a repeat contrast MRI after completion of 
local therapy and prior to starting study treatment is as follows:  
• For subjects who receive brain radiotherapy during the screening period, the original 
baseline contrast brain MRI will serve as the baseline for comparison for further 
response assessments. 
• For subjects who undergo surgical resection of brain metastases during the screening 
period, a postoperative contrast brain MRI will be performed and will serve as the 
baseline for comparison for further response assessments. 
For subjects with brain metastases discovered during screening or a history of brain metastases, 
relevant MRI brain reports and CNS treatment records should be obtained and available for CRF 
source verification.  
7.2. 
Response/Efficacy Assessments 
Radiographic scans and additional imaging assessments (if applicable) will be performed at 
protocol-specified time points outlined in Section 6 and Appendix A, or if disease progression is 
suspected. Clinical response of PD, SD, PR, or CR will be determined at each assessment 
according to RECIST v1.1 (Eisenhauer 2009), by the investigator and by BICR. Clinical 
management decisions will be based on local investigator assessment to ensure that treatment 
decisions are made in a timely manner; results of centralized review will not be available to 
investigators for clinical decision making.  
All known sites of LA/M unresectable disease should be assessed by radiographic imaging at 
Screening/Baseline to document sites of extracranial disease and tumor burden and chosen as 
either target or nontarget lesions. Imaging, preferably by high quality spiral contrast CT scan 
(with oral and/or IV contrast), should include the chest, abdomen, and pelvis, at a minimum; 
PET/CT (if high quality CT scan is included) and/or MRI scan may also be done as appropriate. 
If a CT scan with contrast is contraindicated (ie, in subjects with contrast allergy or impaired 
renal clearance), a noncontrast CT scan of the chest may be performed instead, with MRI scans 
of the abdomen and pelvis. At the investigator’s discretion, other appropriate imaging (eg, skin 
lesion photography for skin lesions, nuclear bone scan imaging for bone lesions) should be used 

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to assess additional known sites of  disease. The same imaging modalities employed in 
Screening/Baseline should be used for all subsequent response assessments during study 
treatment and in the follow-up period, unless otherwise clinically indicated. If any other 
radiographic or assessment exam, including pathology from any on-study biopsies or procedures, 
is conducted per standard of care, the assessment information will be collected in the CRF. All 
imaging will be collected for retrospective BICR. 
In the event of equivocal progression, for example a new lesion which is small in size (defined as 
an equivocal new lesion) and no imminent threat to subject safety, all efforts should be made to 
continue the subject until unequivocal radiologic progression or clinical progression is 
documented. Demonstration of an unequivocal new lesion constitutes disease progression 
(Appendix F). 
Subjects’ clinical data must be available for CRF source verification. Copies of tumor images 
must be made available for review by the sponsor (or its designee) upon request. All imaging 
will be submitted or uploaded for retrospective BICR as soon as reasonably possible (eg, within 
approximately 2 weeks) following the date of assessment. Refer to the study manual for 
instructions on collecting and submitting tumor imaging studies to the third-party imaging core 
laboratory for BICR. 
7.2.1. 
Evaluation of Brain Metastases 
Brain MRI imaging will be performed locally and collected prospectively for centralized 
independent review. However, treatment decisions will be made on the basis of local review of 
radiologic imaging.  
Contrast MRI scan of the brain will be performed for all subjects at Screening/Baseline to assess 
tumor burden in the brain and/or dura and identify subjects with brain metastases at baseline. CT 
of the brain will not be allowed, and subjects with known contraindications to undergoing 
contrast MRI imaging will be excluded from the study. Subjects are considered to have brain 
metastases at baseline with any of the following: 
• Any history of brain metastases 
• Any brain metastases at baseline  
• Brain lesions of equivocal significance at baseline 
Only subjects with documented brain metastases at baseline, as defined above, will continue to 
have follow-up contrast MRIs of the brain on the same schedule as non-CNS response 
assessments (Section 6.4.6 and Appendix A). Contrast MRIs of the brain may also be performed 
in subjects without known brain metastases if there is clinical suspicion of new brain lesions. All 
subjects will have an additional contrast MRI of the brain at the EOT visit, unless one has been 
performed within 30 days of discontinuing study treatment or the reason for going off treatment 
was progression in the brain. 
In subjects with baseline brain lesions, all brain lesions should be included in the baseline 
RECIST lesion selection as either a target or nontarget lesion. When unsuspected brain 
metastases are discovered at screening and immediate CNS-directed therapy is administered, 
treated lesions should not be selected as target lesions but as nontarget lesions for the purpose of 
disease assessment by RECIST v1.1.  

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Copies of brain imaging must be made available for review by the sponsor (or its designee) upon 
request. Copies of all brain imaging will be submitted or uploaded for retrospective BICR as 
soon as reasonably possible (eg, within approximately 2 weeks) following the date of 
assessment. Refer to the study manual for instructions on collecting and submitting brain 
imaging studies to the third-party imaging core laboratory for BICR. 
7.2.2. 
Isolated Progression in the Brain 
In subjects with isolated progression in the brain per RECIST v1.1 (including either parenchymal 
brain or dural metastases but not skull-based or leptomeningeal metastases) and do not have 
progression of disease outside the CNS, subjects may be eligible to continue on study treatment 
after completion of local treatment (radiotherapy or surgery) to the brain/dural metastases to 
allow for clinical benefit with medical monitor approval. This approach approximates standard 
clinical practice in this clinical scenario.  
Because the primary endpoint of the study is PFS, every effort should be made to avoid radiation 
or surgery to target lesions in the brain in the absence of PD by RECIST v1.1 unless clinically 
necessary in the opinion of the investigator. Target lesions, once treated with local CNS therapy, 
cannot be adequately assessed for subsequent response to systemic therapy. Because of this, if a 
subject continues on assigned study therapy after local CNS treatment to a target lesion, special 
consideration must be given for evaluation of the treated target lesion and the impact on the 
overall RECIST v1.1 assessment. 
Following CNS-directed therapy for isolated CNS disease progression, RECIST v1.1 criteria 
would continue to measure CNS target lesions(s) if previously identified and used in the overall 
estimation of the sum of diameters measuring total disease burden. However, following 
treatment, measurement of the treated CNS target lesion(s) would use the immediate pre-CNS 
treatment measurement. If a subsequent decrease in the size of a treated CNS lesion 
posttreatment is seen, the immediate pre-CNS treatment longest diameter would be used for 
RECIST measurement. Should a treated CNS lesion enlarge following CNS-directed therapy that 
was identified as a target lesion, the new and larger longest diameter is to be used for RECIST 
measurement. 
Additionally, treatment changes which may mimic progression will be taken into account, and 
subjects with possible “pseudo-progression” should continue on study until unequivocal 
evidence of radiographic or clinical progression is present. In the absence of clear evidence of 
PD (per RECIST v1.1), development of CNS symptoms or radiographic changes thought to pose 
potential immediate risk to subject, all efforts should be made to continue treatment until 
unequivocal evidence of radiologic progression occurs, as defined in RECIST v1.1. 
After discontinuing study treatment, subjects may receive further care as determined by their 
physician. 
7.3. 
Pharmacokinetic Assessments 
In all subjects, measurements from Cycle 3 to Cycle 6 will be obtained to assess the steady-state 
pharmacokinetics of tucatinib and DM1 (Table 8). Additional blood samples will be collected 
and processed for exploratory PK assessment. 

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Additionally, approximately 50 subjects (US only; enrollment will continue until at least 
25 subjects from each treatment arm have completed the substudy) will participate in a PK 
substudy with additional PK sampling on Days 1, 2, 3, and 5 in Cycle 2 to assess tucatinib and 
DM1 plasma concentrations (Table 9). Additional blood samples will be collected and processed 
for exploratory PK assessment. 
A liquid chromatography/tandem mass spectrometry assay will be used to assess plasma 
concentrations of tucatinib and DM1. Other assays may be performed if further characterization 
is required on the exploratory PK sample. Additional PK data analyses, including population 
pharmacokinetics and exploratory exposure-response analyses may be conducted; such analyses 
will be described in a separate analysis plan. 
Trough (predose) PK samples should continue to be collected on schedule regardless of dose 
holds or interruptions of tucatinib/placebo on Day 1 of Cycles 3–6. The Cycle 3 Day 1 postdose 
sample should not be collected during dose hold or interruptions of tucatinib/placebo. 
Table 8: 
Pharmacokinetic sampling – all subjects 
Cycle 
Day 
Timepoint 
Tucatinib/Placebo Exploratory PK 
DM1 
3 
1 
0 hour (−2 hours) prior to administration of 
tucatinib/placebo 
X 
X 
X 
End of T-DM1 infusion (+15 minutes)  
 
X 
X 
1–4 hours following administration of 
tucatinib/placebo 
X 
4–6 
1 
0 hour (−2 hours) prior to administration of 
tucatinib/placebo 
X 
X 
X 
End of T-DM1 infusion (+15 minutes) 
 
X 
X 
Table 9: 
Pharmacokinetic sampling – Pharmacokinetics substudy (US only) subjects 
Cycle 
Day 
Timepoint 
Tucatinib/ 
Placebo 
Exploratory PK 
DM1 
2 
1 
0 hour (−2 hour) prior to T-DM1 
administration 
X 
X 
X 
End of T-DM1 infusion (+15 minutes) 
X 
X 
X 
2 
2 
24 hours post-end of T-DM1 infusion  
(±4 hours) 
X 
X 
X 
2 
3 
48 hours post-end of T-DM1 infusion  
(±4 hours) 
X 
X 
X 
2 
5 
96 hours post-end of T-DM1 infusion  
(±6 hours) 
X 
X 
X 
7.4. 
Biospecimen Repository 
In the US only, for subjects who provide additional consent, remaining de-identified unused 
blood and/or tissue will be retained by Seagen and used for future research, including but not 
limited to the evaluation of targets for novel therapeutic agents, the biology of sensitivity and 
resistance mechanisms to targeted therapeutics, and the identification of pharmacodynamic 

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biomarkers of potential targeted therapeutics. Blood and tissue samples donated for future 
research will be retained for a period of up to 25 years. If additional consent is not provided, any 
remaining biological samples will be destroyed after the study has been completed and all 
applicable regulatory obligations have been met. 
7.5. 
Healthcare Resource Utilization Data Collection 
All healthcare encounters related to the subject’s breast cancer, cancer treatment, or 
cancer-related assessments will be collected for all subjects until the EOT visit. HCRU data 
include, but are not limited to, procedures that occur on study, such as length of stay, 
hospitalizations, emergency department visits, planned/unplanned provider visits, medication 
use, radiology, and other treatments and procedures. See Appendix A and Section 6 for timing of 
HCRU data collection, and see the study manual for detailed guidance. 
7.6. 
Patient-Reported Outcomes 
QoL questionnaires will be administered as specified in Appendix A and Section 6. The 
objective is to compare improvements, deteriorations, and stabilization in health-related QoL 
between treatment arms. During study treatment, these questionnaires must be completed prior to 
evaluation by study personnel (physical examination, review of AEs) and administration of study 
treatment on treatment days. Questionnaires may be collected by phone once a subject 
experiences disease progression (per RECIST v.1.1) by investigator assessment and is in 
long-term survival follow-up. 
7.6.1. 
EQ-5D-3L – Utility Measurement 
The EQ-5D-3L is a standardized instrument developed by the European Quality of Life 
(EuroQol) Group for use as a generic, preference-based measure of health-related QoL outcomes 
that can be used in a wide range of health conditions and treatments (van Agt 1994). The 
EQ-5D-3L consists of a descriptive system questionnaire and the EuroQoL visual analog scale 
(EQ-VAS; Appendix G).  
The descriptive system questionnaire assesses 5 dimensions of health, including mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension comprises 3 
levels: no problems, some problems, and extreme problems. The scores on these 5 dimensions 
can be presented as a health profile or can be converted to a single summary index number 
(utility) reflecting preference compared to other health profiles. The recall time frame for the 
descriptive system is the day in which the questionnaire is administered. The EQ-VAS records 
the subject’s self-rated health status on a vertical visual analogue scale ranging from 0 (worst 
imaginable health state) to 100 (best imaginable health state) and can be used as a quantitative 
measure of health outcome that reflects the subject’s own judgment.  
7.6.2. 
EORTC QLQ IL6 
The EORTC QLQ was developed to measure aspects of health-related QoL pertinent to subjects 
with a broad range of cancers who are participating in international clinical trials (Aaronson 
1993; Bjordal 1994; Sneeuw 1998). The core instrument, the QLQ-C30 (Version 3.0), is a 
30-item questionnaire consisting of the following: 
• 5 functional domains (physical, role, cognitive, emotional, social) 

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• 3 symptom scales (fatigue, pain, nausea and vomiting) 
• Single items for symptoms (shortness of breath, loss of appetite, sleep disturbance, 
constipation, diarrhea) and financial impact of the disease 
• 2 global items (health, overall QoL) 
The questionnaire has been streamlined based on a patient-centric approach to minimize the 
number of questions being asked as part of the patient-reported outcome (PRO) data collection, 
therefore only Questions 29 and 30 of the questionnaire, which make up the ‘global health 
status/QoL’ scale of the QLQ-C30, will be used for this study (Appendix H). The EORTC refers 
to this set of questions as the EORTC QLQ IL6. 
7.6.3. 
FACT-B 
The FACT-B is a self-report instrument designed to measure multidimensional QoL in patients 
with breast cancer (Brady 1997). It is reliable, relates to similar measures in an expected pattern, 
and performs as predicted in relation to change in clinical status over time. To minimize the 
number of questions to reduce patient burden, only Question 5 (ie, GP5) regarding patient’s 
perception of bother due to treatment side effects will be used (Appendix I). Responses to this 
question will be collected while subjects are receiving study treatment and until the EOT visit. 
7.6.4. 
NCI PRO-CTCAE 
The NCI PRO-CTCAE is a validated PRO measurement system developed to characterize the 
frequency, severity, and interference of 78 symptomatic treatment toxicities (Smith 2016). These 
include symptomatic toxicities such as pain, fatigue, nausea, and cutaneous side effects such as 
rash and hand-foot syndrome, all toxicities that can be meaningfully reported from the patient 
perspective. The NCI PRO-CTCAE allows for customization; thus, symptomatic toxicities of 
interest (17 items) in both the control and experimental arms will be collected as part of the PRO 
data collection (Appendix J). 
7.7. 
Safety Assessments 
The assessment of safety during the course of this study will consist of the surveillance and 
recording of AEs including SAEs, recording of concomitant medication, and measurements of 
protocol-specified physical examination findings and laboratory tests. 
Safety will be monitored over the course of the study by an IDMC as described in Section 3.1.1. 
7.7.1. 
Adverse Events 
7.7.1.1. 
Definitions 
Adverse Event 
According to the International Council for Harmonisation (ICH) E2A guideline Definitions and 
Standards for Expedited Reporting, and 21 CFR 312.32, Investigational New Drug (IND) Safety 
Reporting, an AE is any untoward medical occurrence in a subject or clinical investigational 
subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. 

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The following information should be considered when determining whether or not to record a 
test result, medical condition, or other incident on the Adverse Events CRF: 
• From the time of informed consent through the day prior to study Day 1, only study 
protocol-related AEs should be recorded. A protocol-related AE is defined as an 
untoward medical event occurring as a result of a protocol mandated procedure. 
• All medical conditions present or ongoing predose on study Day 1 that increase in 
CTCAE grade should be recorded. 
• All AEs (regardless of relationship to study treatment) should be recorded from study 
Day 1 (predose) through the end of the safety reporting period (see Section 7.7.1.3). 
Complications that occur in association with any procedure (eg, biopsy) should be 
recorded as AEs whether or not the procedure was protocol mandated. 
• Changes in medical conditions and AEs, including changes in severity, frequency, or 
character, during the safety reporting period should be recorded. 
• In general, an abnormal laboratory value should not be recorded as an AE unless it is 
associated with clinical signs or symptoms, requires an intervention, results in an 
SAE, or results in study termination or interruption/discontinuation of study 
treatment. When recording an AE resulting from a laboratory abnormality, the 
resulting medical condition rather than the abnormality itself should be recorded (eg, 
record “anemia” rather than “low hemoglobin”). 
Serious Adverse Events 
An AE should be classified as an SAE if it meets one of the following criteria: 
Fatal: 
AE resulted in death 
Life threatening: 
The AEs placed the subject at immediate risk of death. This classification does not 
apply to an AE that hypothetically might cause death if it were more severe. 
Hospitalization: 
The AE resulted in hospitalization or prolonged an existing inpatient hospitalization. 
Hospitalizations for elective medical or surgical procedures or treatments planned 
before the signing of informed consent in the study or routine check-ups are not SAEs 
by this criterion. Admission to a palliative unit or hospice care facility is not 
considered to be a hospitalization. Hospitalizations or prolonged hospitalizations for 
scheduled therapy of the underlying cancer or study target disease need not be 
captured as SAEs. 
Disabling/ 
incapacitating: 
An AE that resulted in a persistent or significant incapacity or substantial disruption 
of the subject’s ability to conduct normal life functions. 
Congenital anomaly or 
birth defect: 
An adverse outcome in a child or fetus of a subject exposed to the molecule or study 
treatment regimen before conception or during pregnancy. 
Medically significant: 
The AE did not meet any of the above criteria, but could have jeopardized the subject 
and might have required medical or surgical intervention to prevent one of the 
outcomes listed above or involves suspected transmission through a medicinal product 
of an infectious agent. Potential drug-induced liver injury (DILI) also is considered a 
medically significant event (see Section 7.7.1.6 for the definition of potential DILI) 

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Adverse Event Severity 
AE severity should be graded using the NCI CTCAE, Version 4.03. These criteria are provided 
in the study manual. 
AE severity and seriousness are assessed independently. ‘Severity’ characterizes the intensity of 
an AE. ‘Serious’ is a regulatory definition and serves as a guide to the sponsor for defining 
regulatory reporting obligations (see definition for Serious Adverse Events, above). 
Relationship of the Adverse Event to Study Treatment 
The relationship of each AE to each study treatment (tucatinib or placebo, T-DM1) should be 
evaluated by the investigator using the following criteria: 
Related: 
There is evidence to suggest a causal relationship between the drug and the AE, such as: 
● A single occurrence of an event that is uncommon and known to be strongly associated with 
drug exposure (eg, angioedema, hepatic injury, Stevens-Johnson Syndrome) 
● One or more occurrences of an event that is not commonly associated with drug exposure, but 
is otherwise uncommon in the population exposed to the drug (eg, tendon rupture) 
Unrelated: 
Another cause of the AE is more plausible (eg, due to underlying disease or occurs commonly in 
the study population), or a temporal sequence cannot be established with the onset of the AE and 
administration of the study treatment, or a causal relationship is considered biologically 
implausible 
7.7.1.2. 
Procedures for Eliciting and Recording Adverse Events 
Investigator and study personnel will report all AEs and SAEs whether elicited during subject 
questioning, discovered during physical examination, laboratory testing and/or other means by 
recording them on the CRF and/or SAE form, as appropriate. 
Eliciting Adverse Events 
An open-ended or nondirected method of questioning should be used at each study visit to elicit 
the reporting of AEs. 
Recording Adverse Events 
The following information should be recorded on the Adverse Events and Pre-existing 
Conditions CRF: 
• Description including onset and resolution dates 
• Whether it met SAE criteria 
• Severity 
• Relationship to study treatment or other causality 
• Outcome 
Diagnosis Versus Signs or Symptoms 
In general, the use of a unifying diagnosis is preferred to the listing out of individual symptoms. 
Grouping of symptoms into a diagnosis should only be done if each component sign and/or 

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symptom is a medically confirmed component of a diagnosis as evidenced by standard medical 
textbooks. If any aspect of a sign or symptom does not fit into a classic pattern of the diagnosis, 
report the individual symptom as a separate AE. 
Important exceptions for this study are adverse reactions associated with the infusion of study 
drug. Record each sign or symptom as an individual AE in addition to the infusion-related 
reaction term. If multiple signs or symptoms occur with a given infusion-related event, each sign 
or symptom should be recorded separately with its level of severity. 
Recording Serious Adverse Events 
For SAEs, record the event(s) on both the CRF and the SAE form. 
The following should be considered when recording SAEs: 
• Death is an outcome of an event. The event that resulted in the death should be 
recorded and reported on both an SAE form and CRF. 
• For hospitalizations, surgical or diagnostic procedures, the illness leading to the 
surgical or diagnostic procedure should be recorded as the SAE, not the procedure 
itself. The procedure should be captured in the narrative as part of the action taken in 
response to the illness. 
Progression of the Underlying Malignancy 
Since progression of underlying malignancy is being assessed as an efficacy variable, it should 
not be reported as an AE or SAE. The terms “Disease Progression”, “Progression of Disease”, or 
“Malignant disease progression” and other similar terms should not be used to describe an AE or 
SAE. Symptomatic clinical deterioration due to disease progression as determined by the 
investigator will not be reported as an AE or SAE. However, clinical symptoms of progression 
may be reported as AEs or SAEs if the symptom cannot be determined as exclusively due to 
progression of the underlying malignancy or does not fit the expected pattern of progression for 
the disease under study. In addition, complications from progression of the underlying 
malignancy should be reported as AEs or SAEs. The events described above are the only 
protocol-defined events which do not need immediate reporting from the investigator to the 
sponsor for this study. 
Pregnancy 
Notification to Drug Safety 
Complete a Pregnancy Report Form for all pregnancies that occur from the time of first study 
drug dose until 7 months after the last dose of study drug(s), including any pregnancies that 
occur in the partner of a male study subject. Only report pregnancies that occur in a male 
subject’s partner if the estimated date of conception is after the male subject’s first study drug 
dose. Email or fax to the sponsor’s Drug Safety Department within 24 hours of becoming aware 
of a pregnancy. All pregnancies will be monitored for the full duration; all perinatal and neonatal 
outcomes should be reported. Infants should be followed for a minimum of 8 weeks. 

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Collection of data on the CRF 
All pregnancies (as described above) that occur within 30 days of the last dose of study drug(s), 
will also be recorded on the Adverse Events and Pre-existing Conditions CRF. 
Abortion, whether accidental, therapeutic, or spontaneous, should be reported as an SAE. 
Congenital anomalies or birth defects, as defined by the ‘serious’ criterion above (see definitions 
Section 7.7.1.1) should be reported as SAEs. 
7.7.1.3. 
Reporting Periods for Adverse Events and Serious Adverse Events 
The safety reporting period for all AEs and SAEs is from study Day 1 (predose) through the 
EOT Visit or 30 days after the last study treatment (tucatinib or placebo, T-DM1), whichever is 
later. However, all study protocol-related AEs are to be recorded from the time of study 
informed consent. All SAEs that occur after the safety reporting period and are considered study 
treatment-related in the opinion of the investigator should also be reported to the sponsor. 
SAEs will be followed until significant changes return to baseline, the event stabilizes 
(recovering/resolving) or is no longer considered clinically significant by the investigator, or the 
subject dies or withdraws consent. All nonserious AEs will be followed through the safety 
reporting period. Certain nonserious AEs of interest may be followed until resolution, return to 
baseline, or study closure. 
7.7.1.4. 
Serious Adverse Events Require Immediate Reporting 
Within 24 hours of observing or learning of an SAE, investigators are to report the event to the 
sponsor, regardless of the relationship of the event to the study treatment regimen. 
For initial SAE reports, available case details are to be recorded on an SAE form. At a minimum, 
the following should be included: 
• Subject number 
• Date of event onset 
• Description of the event 
• Study treatment, if known 
The completed SAE form and SAE Fax Cover Sheet are to be emailed or faxed to the sponsor’s 
Drug Safety Department within 24 hours (see email address or fax number specified on the SAE 
report form). 
Relevant follow-up information is to be submitted to the sponsor as soon as it becomes available. 
7.7.1.5. 
Sponsor Safety Reporting to Regulatory Authorities 
Investigators are required to report all SAEs, including anticipated SAEs, to the sponsor (see 
Section 7.7.1.4). 
The sponsor will report all SAEs, including SUSARs, to regulatory authorities as required per 
local legislation or regulatory reporting requirements. In the United States, endpoints that assess 
disease-related mortality or major morbidity, as well as other SAEs that are not study endpoints 
but are known consequences of the underlying disease or condition that are anticipated to occur 

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in the study population, should not be reported to the FDA as individual IND safety reports per 
the final rule amending the IND safety reporting requirements under 21 CFR 312.32 and the 
FDA’s guidance Safety Assessment for IND Safety Reporting Guidance for Industry (draft 
guidance December 2015). 
In this study, the SAEs that do not require individual IND safety reports to the FDA are 
progression of the underlying cancer. These anticipated SAEs will be reviewed periodically by 
an IDMC and the Seagen Drug Safety Department. If upon review, an SAE is occurring at a 
higher rate than that which would be expected for the study drug treatment arm, then an IND 
safety report for the SAE will be submitted to the FDA. 
7.7.1.6. 
Adverse Events of Special Interest 
An AE of special interest (AESI) can be any serious or nonserious AE that is of scientific or 
medical concern as defined by the sponsor and specific to the program, for which ongoing 
monitoring and rapid communication to the sponsor may be appropriate.  
The AESIs will need to be reported to the sponsor irrespective of regulatory seriousness criteria 
or causality within 24 hours (Section 7.7.1.4). 
Potential drug-induced liver injury 
The following 2 types of LFT elevations are considered AESIs: 
• AST or ALT elevations that are >3 × ULN with concurrent elevation (within 21 days 
of AST and/or ALT elevations) of total bilirubin >2 × ULN, except in subjects with 
documented Gilbert’s syndrome  
• Grade 4 AST, ALT, or bilirubin elevations  
Measurement of direct and indirect bilirubin should be considered in cases of hyperbilirubinemia 
to assist in determination of its etiology. The sponsor will subsequently determine whether the 
elevations are associated with other possible causes of aminotransferase elevation and 
hyperbilirubinemia, such as viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic. 
Asymptomatic left ventricular systolic dysfunction 
In general, asymptomatic declines in LVEF should not be reported as AEs since LVEF data are 
collected separately in the electronic CRF (eCRF). However, an asymptomatic decline in LVEF 
leading to a change in study treatment or discontinuation of study treatment is considered an 
event of special interest and an SAE, and must be reported to the sponsor.  
Cerebral Edema 
Any event of cerebral edema not clearly attributable to progression of disease should be reported 
as an AESI. 

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7.7.2. 
Physical Examination 
Physical examinations should include assessments of the following body parts/systems: 
abdomen, extremities, head, heart, lungs, neck, and neurological. Measurements of height 
obtained within the prior 12 months may be utilized. 
7.7.3. 
Vital Signs 
Vital sign measurements are to include heart rate, systolic and diastolic blood pressure, 
temperature, and respiration rate. Vital signs should be measured after the subject has been 
sitting/resting. 
7.7.4. 
Clinical Laboratory Tests 
The following laboratory assessments will be performed by the local laboratory to evaluate 
safety at scheduled timepoints (see Appendix A) and make clinical decisions during the course of 
the study: 
• The chemistry panel is to include the following tests: blood urea nitrogen or urea, 
creatinine, glucose, lactate dehydrogenase, potassium, and sodium.  
• LFTs include ALT/SGPT, AST/SGOT, ALP, and total bilirubin (and direct bilirubin 
when total bilirubin is >ULN) 
• The CBC with differential is to include the following tests: CBC with differential that 
includes hemoglobin, hematocrit, platelet count, and white blood cell count with 
5-part differential (basophils, eosinophils, lymphocytes, monocytes, and neutrophils) 
• The coagulation panel is to include the following tests: INR, prothrombin time, and 
PTT/aPTT 
• The estimated GFR should be calculated using the MDRD equation, with serum 
creatinine (Scr) reported in mg/dL 
GFR (mL/min/1.73 m2) = 175 × (Scr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if 
African American) 
• A serum or urine β-hCG pregnancy test (minimum sensitivity of 25 mIU/mL or 
equivalent units) for subjects of childbearing potential (see Section 7.7.5) 
• For Italy only: Blood samples for Hepatitis B surface antigen (HBsAg), antibodies to 
Hepatitis B surface antigen (anti-HBs), antibodies to Hepatitis B core antigen (anti-
HBc), Hepatitis B DNA levels by PCR (as applicable; refer to latest local guidelines 
for the management of Hepatitis B virus infection), and antibodies to Hepatitis C 
(anti-HCV). If positive, contact medical monitor.  
7.7.5. 
Pregnancy Testing 
For subjects of childbearing potential, a serum or urine β-hCG pregnancy test (minimum 
sensitivity of 25 mIU/mL or equivalent units) will be performed at baseline, within 7 days prior 
to Day 1 of each treatment cycle, and at the EOT Visit. A negative pregnancy result is required 
before the subject may receive study treatment. 

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Subjects with false positive results and documented verification that the subject is not pregnant 
are eligible for study participation. Similarly, subjects with false positive results that develop 
during study treatment are allowed to continue treatment with documented verification that the 
subject is not pregnant. 
After the last dose of study treatment, pregnancy tests will be performed once a month for 
7 months. Subjects may do monthly home pregnancy tests and report interim results at long-term 
follow-up visits. Pregnancy tests may also be repeated as requested per institutional review 
board/independent ethics committee (IRB/IEC) or if required by local regulations. 
7.7.6. 
Cardiac Function 
7.7.6.1. 
MUGA or ECHO 
Assessment of cardiac ejection fraction will be performed by MUGA or ECHO at screening and 
at least once every 12 weeks thereafter until study discontinuation, and at EOT (unless done 
within 12 weeks prior to the EOT Visit, excluding screening/baseline assessment). If there is an 
interim assessment, subsequent cardiac ECHO or MUGA should be performed every 12 weeks 
as determined by the date of the most recent interim assessment. The modality chosen in 
screening should be used for all subsequent cardiac assessments throughout the study for 
comparison. 
7.7.6.2. 
Electrocardiogram 
An ECG will be performed during screening (must be collected prior to first dose of any study 
treatment). To correct for heart rate, QT intervals should be calculated using the Fridericia 
formula (QTcF).  
7.8. 
Appropriateness of Measurements 
Response will be assessed according to RECIST v1.1 (Eisenhauer 2009), which are standardized 
criteria for evaluating response in solid tumors. The schedule for tumor imaging is consistent 
with general oncological practice and appropriately balances measurement of tumor control with 
the expense and subject inconvenience associated with CT and PET scanning. 
The safety measures that will be used in this trial are considered standard procedures for 
evaluating the potential adverse effects of study medications. AEs and clinical laboratory data 
will be graded using standardized criteria for oncology (NCI CTCAE v4.03). 
The PRO instruments included in this study (EORTC QLQ IL6, EQ-5D-3L, and FACT-B GP5) 
are validated questionnaires that have been incorporated into previous clinical trials to assess 
global health status and quality of life as well as perception of side effects, respectively. 

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8. 
DATA QUALITY CONTROL AND QUALITY ASSURANCE 
8.1. 
Site Training and Monitoring Procedures 
A study manual with instructions for study compliance and CRF completion will be provided. 
Prior to the enrollment of subjects at the site, Seagen or its designated clinical and medical 
personnel will review the following items with the investigator and clinic staff: 
• The protocol, study objectives, eligibility requirements, study procedures, registration 
and withdrawal processes 
• Current investigator’s brochure/package insert 
• Recording and reporting AEs and SAEs 
• Enrollment goals and study timelines 
• The CRF completion process and source documentation requirements 
• Monitoring requirements 
• IRB/IEC review and approval process 
• Informed consent process 
• Good clinical practice guidelines and related regulatory documentation requirements 
• Key study team roles and responsibilities 
• Investigational product storage, accountability, labeling, dispensing, and record 
keeping 
• Subject coding and randomization  
• Study samples/specimen collection, handling, and shipping 
• Protocol compliance 
• Clinical study record keeping, document retention, and administrative requirements 
Monitoring visits will occur periodically, with frequency dependent on the rate of enrollment and 
workload at each site. During monitoring visits, the Seagen representative will typically review 
regulatory documentation, CRFs, source documentation, and investigational product storage, 
preparation, and accountability. The CRFs will be reviewed for completeness, adherence to the 
provided guidelines, and accuracy compared to the source documents. The investigators must 
ensure that the monitor is allowed to inspect all source documents pertinent to study subjects, 
and must cooperate with the monitor to ensure that any problems noted in the course of the trial 
are resolved. The investigator must maintain a comprehensive and centralized filing system of all 
study-related documentation that is suitable for inspection by Seagen or its designated monitors 
and by quality assurance auditors, or representatives of regulatory authorities. 
8.2. 
Data Management Procedures 
Seagen will provide CRF completion guidelines for eCRF data entry. Study specific data 
management procedures will be maintained in the data management plan. Queries resulting from 
edit checks and/or data verification procedures will be posted electronically in the eCRF. 

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8.3. 
Access to Source Data 
The investigator will permit the sponsor’s representatives to monitor the study as frequently as 
the sponsor deems necessary to determine that protocol adherence and data recording are 
satisfactory. Appropriate measures to protect subject confidentiality are to be employed during 
monitoring. The CRFs and related source documents will typically be reviewed in detail by the 
monitor at each site visit. Original source documents or certified copies are needed for review. 
This review includes inspection of data acquired as a requirement for participation in this study 
and other medical records as required to confirm that the information contained in the CRFs, 
such as disease assessments, AEs, and concomitant medications, is complete and correct. Other 
study records, such as correspondence with the sponsor and the IRB/IEC and screening and drug 
accountability logs will also be inspected. All source data and study records must also be 
available for inspection by representatives of regulatory authorities and the IRB/IEC. 
8.4. 
Accuracy and Reliability of Data 
Steps to be taken to assure the accuracy and reliability of data include: 
• The selection of qualified investigators and appropriate study centers. 
• Review of protocol procedures with the investigators and associated personnel prior 
to the study. 
• Periodic monitoring visits by the designated monitor(s). 
• CRFs will be reviewed for accuracy and completeness during monitoring visits to the 
study centers and/or by centralized monitoring. Any discrepancies will be resolved 
with the investigator or designees as appropriate. 
8.5. 
Quality Assurance Procedures 
The Research and Development Quality group or its designee may conduct audits at the clinical 
site or other study-related facilities and organizations. Audit reports will be retained by the 
Research and Development Quality group of Seagen as part of the written record. 
8.6. 
Data Handling and Record Keeping 
8.6.1. 
Data Handling 
It is the investigator’s responsibility to ensure the accuracy, completeness, legibility, and 
timeliness of the data reported to the sponsor in the CRFs and in all required reports. Data 
reported on the CRF that is derived from source documents should be consistent with the source 
documents or the discrepancies should be explained. 
Any change or correction to a CRF will be maintained in an audit trail within the electronic data 
capture system. Data changes may only be made by those individuals so authorized. The 
investigator should retain records of the changes and corrections, written and/or electronic. 
8.6.2. 
Investigator Record Retention 
The investigator shall retain study drug disposition records and all source documentation (such 
as original ECG tracings, laboratory reports, inpatient or office patient records) for the maximum 

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period required by the country and institution in which the study will be conducted, or for the 
period specified by Seagen, whichever is longer. The investigator must contact Seagen prior to 
destroying any records associated with the study. If the investigator withdraws from the study 
(due to relocation, retirement, etc.), the records shall be transferred to a mutually agreed-upon 
designee, such as another investigator or IRB/IEC. Notice of such transfer will be provided in 
writing to Seagen. 

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9. 
DATA ANALYSIS METHODS 
9.1. 
Determination of Sample Size 
This study is designed to detect a tucatinib treatment effect of at least a 30% reduction in risk of 
PFS events (HR 0.70; median PFS from 6 months in the control arm to 8.57 months in the 
experimental arm). 
A total of 331 PFS events will provide 90% power to detect a HR of 0.70 at a 2-sided 
significance level of 0.05 using a log-rank test. Approximately 460 subjects will be randomized 
in a 1:1 ratio to either the experimental arm or the control arm to observe 331 PFS events in 
approximately 30 months after the first subject is randomized, assuming 24 months of subject 
accrual, and a 5% annual dropout rate. 
If the final analysis of the primary endpoint is statistically significant, a formal statistical test of 
OS is planned at the same time. It is also planned that follow-up for OS will continue after the 
primary analysis of PFS. The final OS analysis will be performed when approximately 253 OS 
events have occurred. With 253 events, it will provide 80% power to detect a HR of 0.70 in OS 
at a 2-sided significance level of 0.05 using a log-rank test. The final analysis of OS is estimated 
to take place approximately 30 months after the primary analysis of PFS, assuming that the OS 
for the control follows an exponential distribution with a median of 29 months. 
If both PFS and OS results are statistically significant, a formal statistical test of PFS.BM is 
planned. Follow-up of PFS.BM will continue after the primary analysis of PFS. It is anticipated 
that approximately 175 PFS.BM events would have occurred, which will provide 65% power to 
detect a HR of 0.7 in PFS.BM at a 2-sided significance level of 0.05 using a log-rank test, 
assuming that PFS.BM for the control arm follows an exponential distribution with a median of 
5.7 months.  
China Portion of the Study 
To evaluate the consistency of efficacy and safety in a China subpopulation compared with the 
global population, after completion of enrollment in the global portion, subjects in China may 
continue to be randomized in a 1:1 ratio to either the experimental arm or the control arm until 
the planned sample size of approximately 105 (up to 110) subjects in China is reached. Subjects 
in China randomized after completion of enrollment in the global portion will not be included in 
the analysis of the global portion. After the completion of the global portion, the study may 
remain open to complete the China portion as an extension of the study. The details will be 
provided in the statistical analysis plan (SAP). 
9.2. 
Study Endpoint Definitions 
9.2.1. 
Primary Endpoint: PFS per Investigator Assessment 
PFS per investigator is defined as the time from the date of randomization to the investigator 
assessment of disease progression according to RECIST v1.1 or death from any cause, 
whichever occurs first. For subjects who continue on study treatment after isolated CNS 
progression per RECIST v1.1, PFS per investigator will be calculated from the date of 
randomization to the first (or earliest) investigator assessment of disease progression. Subjects 

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without documentation of PD, or death at the time of analysis, will be censored at the date of the 
last tumor assessment with an overall response of CR, PR, SD or non-CR/non-PD. 
If there is no radiographic postbaseline tumor assessment, PFS will be censored at the date of 
randomization. 
Detailed methodology, including handling rules for missing assessments and censoring 
approaches for the analysis of PFS, is provided in the SAP. 
9.2.2. 
Key Secondary Endpoints 
9.2.2.1. 
Overall Survival 
OS is defined as the time from randomization to death due to any cause. 
For a subject who is not known to have died by the end of study follow-up, observation of OS is 
censored on the date the subject was last known to be alive (ie, the date of last contact). Subjects 
lacking data beyond the day of randomization will have their survival time censored on the date 
of randomization (ie, OS duration of 1 day). 
9.2.2.2. 
PFS per Investigator Assessment in Subjects With Brain Metastases at 
Baseline (PFS.BM per Investigator) 
PFS.BM is defined in the same manner as the primary endpoint of PFS per investigator 
assessment. For this endpoint, PFS per investigator assessment will be analyzed in subjects with 
brain metastases at baseline. 
9.2.2.3. 
Objective Response Rate by Investigator Assessment 
ORR is defined as the proportion of subjects with confirmed CR or PR according to 
RECIST v1.1. Subjects whose disease response cannot be assessed will be considered as 
nonresponders for calculating the ORR. ORR by investigator assessment is based on investigator 
response assessments. 
9.2.2.4. 
OS in Subjects with Brain Metastases at Baseline (OS.BM) 
OS.BM is defined in the same manner as the key secondary endpoint of OS. For this endpoint, 
OS will be analyzed in subjects with brain metastases at baseline. 
9.2.3. 
Other Secondary Endpoints 
9.2.3.1. 
PFS per BICR 
PFS per BICR is defined as the time from the date of randomization to the centrally-reviewed 
documented disease progression according to RECIST v1.1 or death from any cause, whichever 
occurs first. Subjects without documentation of PD or death at the time of analysis, will be 
censored at the date of last radiographic disease assessment with an overall response of CR, PR, 
SD or non-CR/non-PD. 

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9.2.3.2. 
PFS per BICR in Subjects With Brain Metastases at Baseline (PFS.BM 
per BICR) 
PFS.BM per BICR is defined in the same manner as the primary endpoint of PFS per 
investigator assessment. For this endpoint, PFS per BICR will be analyzed in the subset of 
subjects with brain metastases at baseline per the CRF. 
9.2.3.3. 
Objective Response Rate by BICR 
ORR is defined as the proportion of subjects with CR or PR according to RECIST v1.1. Subjects 
whose disease response cannot be assessed will be considered as nonresponders for calculating 
the ORR. ORR per BICR is based on BICR response assessments. 
9.2.3.4. 
Duration of Response 
DOR is defined as the time from first documentation of objective response (CR or PR that is 
subsequently confirmed) to the first documentation of disease progression per RECIST v1.1 or 
death from any cause, whichever occurs earlier. Only subjects with an objective response will be 
included in the analysis of DOR. DOR per investigator is based on investigator response 
assessments and DOR per BICR is based on BICR response assessments. 
9.2.3.5. 
Clinical Benefit Rate 
CBR is defined as the proportion of subjects with SD or non-CR or non-PD for ≥6 months or 
best response of CR or PR according to RECIST v1.1. CBR per investigator is based on 
investigator response assessments and CBR per BICR is based on BICR response assessments. 
9.2.4. 
Exploratory Endpoints 
9.2.4.1. 
PK Analysis 
The pharmacokinetics of tucatinib and DM1 will be evaluated.  
9.2.4.2. 
Healthcare Resource Utilization 
HCRU data include healthcare encounters related to the subject’s breast cancer, cancer treatment, 
or cancer-related assessments.  
9.2.4.3. 
Patient-Reported Outcomes 
Changes in PROs will be assessed using the EQ-5D-3L, EORTC QLQ IL6, NCI PRO-CTCAE, 
and FACT-B GP5. 
9.3. 
Statistical and Analytical Plans 
The statistical methods are outlined below; additional analysis details of the global portion and 
China population will be provided in the SAP. The SAP will be finalized prior to study 
unblinding. Exploratory analyses of the data not described in the following subsections may be 
conducted as deemed appropriate. Deviations from the statistical analyses outlined in this 
protocol will be indicated in the SAP; any further modifications will be noted in the final clinical 
study report. 

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9.3.1. 
General Considerations 
In general, summary tabulations will be presented by treatment arm and will display the number 
of observations, mean, standard deviation, median, minimum, and maximum for continuous 
variables, and the number and percent per category for categorical data. The Kaplan-Meier 
survival curves and 25th, 50th (median), and 75th percentiles will be provided along with their 
2-sided 95% CIs for time-to-event data. 
9.3.1.1. 
Randomization and Blinding 
This is a randomized, double-blind, placebo-controlled, international, multicenter, phase 3 study. 
Subjects will be randomized in a 1:1 manner to receive either tucatinib or placebo in 
combination with T-DM1. Randomization will be stratified by line of treatment for metastatic 
disease, hormone receptor status, presence or history of brain metastases, and ECOG 
performance status. 
Randomization will be performed centrally using a system that will assign a unique subject 
randomization number but will not specify the actual treatment assignment. Randomization 
procedures are detailed in the study manual. 
The blinding plan for the safety and efficacy data will be specified in the SAP. 
9.3.1.2. 
Adjustments for Covariates 
Stratified analyses will include adjustment for the stratification factors as recorded at 
randomization (described in Section 9.3.1.1). Please note, if the sample size of one strata by a 
stratification factor is too small, the statistical analysis will not include this randomization 
stratification factor in the statistical analysis, such as stratified log-rank test and stratified Cox 
regression model. This minimum sample size requirement will be specified in the SAP. 
Covariates may be considered for adjustment in exploratory analyses. Only subjects with 
parenchymal lesions are considered as having brain metastases at baseline for purposes of 
stratification. 
9.3.1.3. 
Handling of Dropouts and Missing Data 
With the exception of time-to-event endpoints, no imputation will be conducted for missing data 
unless otherwise specified in the SAP.  
9.3.1.4. 
Multicenter Studies 
This study will be conducted at multiple study centers, however it is not anticipated that any 
center will accrue enough subjects to warrant an analysis by center. 
9.3.1.5. 
Multiple Comparisons and Multiplicity 
To maintain strong control of the family-wise type I error rate at 0.05, a fixed sequential testing 
procedure will be used to test the primary endpoint of PFS per investigator assessment and the 
key secondary endpoints of OS, PFS.BM per investigator assessment, and ORR per investigator.  
If the PFS per investigator assessment is positive at the 2-sided 0.05 level, OS will be tested 3 
times with an overall 2-sided alpha of 0.05. The first analysis of OS (OS interim analysis 1 
[OS IA1]) will be performed at the same time as the primary PFS analysis when approximately 

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331 PFS events per investigator assessment are observed. The second OS interim analysis (OS 
IA2) is planned when approximately 202 (80% information fraction) OS events have been 
observed. The final analysis of OS (OS FA) will occur when approximately 253 OS events are 
observed from the study. The Lan-DeMets O’Brien-Fleming approximation spending function 
(Chen 2014) will be used for the calculation of the alpha level at each test of OS based on the 
actual number of OS events observed at the time of each analysis.  
If both PFS and OS (OS IA1, OS IA2, or OS FA) results are statistically significant, then 
PFS.BM by investigator assessment per RECIST v1.1 will be tested twice with an overall 
2-sided alpha of 0.05. The first PFS.BM analysis will use the PFS.BM data at the time of the 
primary endpoint analysis when approximately 331 PFS events per investigator assessment have 
occurred and the p-value will be compared with a nominal 2-sided alpha of 0.0001 
(Haybittle-Peto approach). The final PFS.BM analysis will use the PFS.BM data at the time of 
OS IA2, and the p-value will be compared with a 2-sided alpha of 0.05.  
If the results of PFS, OS, and PFS.BM are all statistically significant, the ORR per investigator 
assessment will be formally tested between 2 arms at the 2-sided significance level of 0.05. 
Specifically, ORR will be tested once with the same data as used at the PFS analysis.  
If the results of PFS per investigator, OS, PFS.BM per investigator, and ORR per investigator are 
all statistically significant, then OS in subjects with brain metastases at baseline (OS.BM) will be 
formally tested between treatment arms at the 2-sided significance level of 0.05 (Figure 5). It is 
anticipated that approximately 134 OS.BM events would have occurred at the time of final OS 
analysis, which will provide 83% power to detect a HR of 0.6 in OS.BM at a 2-sided significance 
level of 0.05 using a log-rank test assuming OS.BM for the control arm follows an exponential 
distribution with a median of 26 months.  
Detailed rejection boundaries of P-values will be specified in the SAP. 
Baseline values used in all statistical analyses will be the most recent nonmissing measurement 
prior to the first dose of study treatment unless otherwise specified in the analysis plan. 
9.3.1.6. 
Analysis Sets 
The intent-to-treat (ITT) analysis set will include all randomized subjects. Subjects will be 
included in the treatment group assigned at randomization regardless of the actual treatment 
received. The primary analysis of the efficacy endpoints will be based on the ITT analysis set. 
The safety analysis set will include all randomized subjects who receive at least one dose of 
tucatinib or placebo, or T-DM1. Treatment groups will be determined using the actual treatment 
received, regardless of the randomization treatment assignment. 
China Portion of the Study 
Subjects in China who are randomized in the China portion will not be included in the analysis 
population for the global portion. The China ITT population, including all subjects in China 
randomized in both the global portion and the China portion will be analyzed in the 
China-specific efficacy analyses. The China safety analysis set, including all randomized 
subjects in China (both the global portion and the China portion) who receive at least one dose of 
tucatinib or placebo, or T-DM1 will be analyzed in the China-specific safety analyses.  

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Any additional analysis sets will be included in the SAP. 
9.3.1.7. 
Examination of Subgroups 
As exploratory analyses, subgroup analyses may be conducted for selected endpoints. Detailed 
methodology will be provided in the SAP. 
9.3.1.8. 
Timing of Analyses 
There is only one formal analysis of the primary endpoint, PFS per investigator assessment, 
which will occur after approximately 331 PFS events in the ITT analysis set have occurred. The 
analysis cutoff date for this analysis will be determined once approximately 331 PFS events per 
investigator assessment have been observed. This is estimated to be approximately 30 months 
after randomization of the first subject. 
The key secondary endpoint of OS will be analyzed 3 times. OS IA1 will be performed at the 
same time as the primary analysis of PFS per investigator assessment. OS IA2 is planned when 
approximately 202 (80%) OS events have occurred, which is estimated to be approximately 
46 months after randomization of the first subject. The final analysis of OS will occur when 
approximately 253 OS events have occurred. The final OS analysis is estimated to occur 
60 months after randomization of the first subject.  
PFS.BM will be analyzed twice. The first analysis will be performed using the PFS.BM data at 
the same time as the primary analysis of PFS per investigator assessment. The final PFS.BM 
analysis will be conducted using the PFS.BM data at the time of OS IA2. If the OS result is not 
statistically significant at the second analysis but statistically significant at the final OS analysis, 
then PFS.BM will be formally tested again along with the OS final analysis. 
ORR by investigator assessment will be formally tested if the results of the PFS, OS, and 
PFS.BM analyses are all statistically significant, using the data at time of the primary analysis of 
PFS.  
If the results of PFS per investigator, OS, PFS.BM per investigator and ORR per investigator are 
all statistically significant, then OS in subjects with brain metastases at baseline (OS.BM) will be 
formally tested.  
The hierarchical testing strategy is represented in Figure 5.  
Figure 5: 
Hierarchical Testing Strategy 
 
9.3.2. 
Subject Disposition 
An accounting of study subjects by disposition will be tabulated and the number of subjects in 
each analysis set will be summarized. Subjects who discontinue study treatment and subjects 
who withdraw from the study will be summarized with reason for discontinuation or withdrawal. 

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9.3.3. 
Subject Characteristics 
The following baseline characteristics will be summarized by treatment group 
• Subject demographics 
• Disease history 
• Prior disease-related therapies; and 
• Baseline disease characteristics 
Concomitant medications, separately for medications taken prior to enrollment and while on 
study, will be listed and summarized by treatment group. 
Details will be provided in the SAP. 
9.3.4. 
Treatment Compliance 
Treatment compliance (percent of actual to planned dosing) for tucatinib/placebo will be 
summarized by treatment group. 
9.3.5. 
Efficacy Analyses 
9.3.5.1. 
Primary Efficacy Analyses 
The stratified log-rank test will be used in the primary evaluation of PFS differences between the 
treatment arms in the ITT analysis set using a 2-sided significance level of 0.05. A stratified Cox 
proportional-hazards (PH) model will be used to estimate the HR and its 95% CI. Both stratified 
log-rank and Cox PH models will take into account the stratification factors for randomization. 
Please note, if the sample size of one stratum from a stratification factor is too small, statistical 
analysis may not include this stratification factor. The minimum sample size for a stratum to be 
included in the statistical model will be specified in the SAP. 
All events entered in the database at the time of analysis will be included in the analysis of PFS 
per investigator, even if there are more than the prespecified number of events. 
Kaplan-Meier curves depicting PFS in the 2 treatment arms will be generated. Additionally, 
median PFS and the 2-sided 95% CIs for the median will be reported using the complementary 
log-log transformation method (Collett 1994). Detailed methodology is provided in the SAP. 
9.3.5.2. 
Secondary Efficacy Analyses 
OS will be analyzed using similar methods used for the primary endpoint. The stratified log-rank 
test will be used to evaluate the OS differences between the treatment arms. A stratified Cox PH 
model will be used to estimate the HR and its 95% CI. Both stratified log-rank and Cox PH 
models will take into account the stratification factors for randomization. Please note, if the 
sample size of one strata by a stratification factor is too small, statistical analysis may not include 
this stratification factor. The minimum sample size for a strata to be included in the statistical 
model will be specified in the SAP. 
Kaplan-Meier methodology and Kaplan-Meier plots will be provided by treatment group using 
the ITT analysis set. The median OS and its 2-sided 95% CI using the complementary log-log 
transformation method (Collett 1994) will be calculated by treatment group. 

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Secondary endpoints of PFS.BM and PFS by BICR will be analyzed using same method used for 
the primary endpoint. 
Response Rates – Objective Response Rate and Clinical Benefit Rate 
Data summaries for ORR will be provided for the response evaluable set (subjects in ITT with 
measurable disease at baseline). The 95% CI of ORR will be estimated for each treatment group. 
Additionally, comparison of ORR between treatment groups will be conducted using 2-sided 
Cochran-Mantel-Haenszel test controlling for the study stratification factors. 
A similar approach will be used for the CBR analysis, but the analysis for CBR will be applied to 
the ITT analysis set. 
Duration of Response 
Only subjects with a confirmed response will be included in the analysis of DOR. DOR is 
defined as the time from first documented objective response (CR or PR that is subsequently 
confirmed) to documented disease progression per RECIST v1.1 or death from any cause, 
whichever occurs first. DOR will be graphically described using Kaplan-Meier methodology. 
The median DOR and its 95% CI will be provided for the 2 treatment arms. 
9.3.6. 
Pharmacokinetic Analyses 
Individual (subject) plasma tucatinib and DM1 concentrations at each sampling time will be 
listed; corresponding summary statistics at each sampling time will also be calculated. 
For subjects in the PK substudy (US only), summary statistics comparing the concentration time 
profiles of DM1 will be calculated. 
Additional exploratory PK analyses may be conducted. 
Exploratory analyses investigating the relationship between tucatinib and/or DM1 exposure and 
efficacy and safety endpoints may be conducted. 
9.3.7. 
Health Outcomes Analyses 
PRO assessments based on the EQ-5D-3L, EORTC QLQ IL6, NCI PRO-CTCAE, FACT-B GP5, 
and HCRU data will be summarized using descriptive statistics by treatment group. 
PRO assessments will be analyzed to determine if treatment affects PRO scores. All subscales 
and individual item scores will be tabulated. Descriptive summaries of observed data at each 
scheduled assessment timepoint may be presented. Additional statistical modeling for PRO and 
HCRU measures may be performed separately in post hoc analyses. 
9.3.8. 
Safety Analyses 
Safety is assessed through summaries of AEs, changes in laboratory test results, changes in vital 
signs, physical examination findings, changes in ECOG performance status, and changes in 
cardiac ejection fraction results. AEs will be classified by system organ class and preferred term 
using the Medical Dictionary for Regulatory Activities (MedDRA); AE severities will be 
classified using the CTCAE criteria. 

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9.3.8.1. 
Extent of Exposure 
Duration of treatment, number of cycles, total dose and dose intensity will be summarized by 
treatment arm using the safety analysis set. Dose modifications will also be summarized. 
Details will be provided in the SAP. 
9.3.8.2. 
Adverse Events 
An overview of AEs will provide a tabulation of the incidence of all treatment-emergent AEs 
(TEAEs), treatment-related TEAEs, Grade 3 and higher TEAEs, treatment-emergent SAEs, 
treatment-related treatment-emergent SAEs, deaths, and AEs leading to study treatment 
discontinuation. AEs will be defined as treatment emergent if they are newly occurring or 
worsen following study treatment. 
AEs will be listed and summarized by MedDRA preferred term, severity, and relationship to 
study drug. In the event of multiple occurrences of the same AE with the same preferred term in 
1 subject, the AE will be counted once as the occurrence. The incidence of AEs will be tabulated 
by preferred term and treatment group. AEs leading to premature discontinuation of study drug 
will be summarized and listed in the same manner. 
All collected AE data will be listed by treatment group, study site, subject number, and cycle. 
Separately, all SAEs and AESIs (eg, any DILI, asymptomatic left ventricular systolic 
dysfunction, and/or cerebral edema) will be analogously listed. 
A separate listing of all on-study deaths will be presented. 
9.3.8.3. 
Deaths and Serious Adverse Events 
SAEs will be listed and summarized in the same manner as all AEs. Events with a fatal outcome 
will be listed. 
9.3.8.4. 
Clinical Laboratory Results 
For laboratory results, summary statistics for actual values and for change from baseline may be 
tabulated as appropriate by scheduled visit. Laboratory values will be listed with grade per NCI 
CTCAE v4.03 and flagged when values are outside the normal reference range. 
Changes from baseline in laboratory values (hematology, coagulation, chemistry, and liver 
function) will be summarized by treatment group and scheduled visit. Laboratory shift tables will 
also be provided by treatment group and scheduled visit. Abnormal values (relative to respective 
normal ranges) will be flagged in listings. 
Additional analytical methods for a more thorough investigation of LFTs (including 
temporal/simultaneous summaries and figures) will be specified in the SAP. 
9.3.8.5. 
Vital Signs, Physical Examination Findings, and ECOG Performance 
Status 
The frequency and percentage of subjects with postbaseline clinically significant vital signs will 
be summarized. Abnormal physical examination findings may be collected as AEs. ECOG 
performance status shift tables will likewise be provided by treatment group and scheduled visit. 

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9.3.8.6. 
Cardiac Ejection Fraction 
Cardiac ejection fraction data will be summarized by treatment group by baseline and 
postbaseline assessment. Corresponding shift tables will also be provided by treatment group and 
baseline and postbaseline assessment. 
9.3.9. 
Interim Analyses 
No formal interim analyses are planned for the primary endpoint.  
The key secondary endpoint of OS will be analyzed 3 times. OS IA1 is at the time of analysis of 
primary endpoint when approximately 331 PFS events per investigator assessment have 
occurred. OS IA2 is planned when approximately 202 (80%) OS events have occurred. OS FA 
will be performed when approximately 253 OS events have occurred. The Lan-DeMets 
O'Brien-Fleming approximation spending function (Chen 2014) will be used for calculation of 
the alpha level at each test of OS based on the actual number of OS events observed at the 
interim.  
If the PFS and OS (OS IA1, OS IA2 or OS FA) results are statistically significant, a formal 
statistical test of the PFS.BM analysis will be performed twice. The first PFS.BM analysis will 
use the PFS.BM data at the time of analysis of the primary endpoint when approximately 331 
PFS events per investigator assessment have occurred, and the p-value will be compared with a 
nominal 2-sided alpha of 0.0001. The final PFS.BM analysis will use the PFS.BM data at the 
time of OS IA2, and the p-value will be compared with a 2-sided alpha of 0.05.  
If the results of the PFS, OS, and PFS.BM analyses are all statistically significant, a formal test 
of ORR per investigator assessment will be performed.  
If the results of PFS per investigator, OS, PFS.BM per investigator, and ORR per investigator are 
all statistically significant, then OS in subjects with brain metastases at baseline (OS.BM) will be 
formally tested between treatment arms at the 2-sided significance level of 0.05 (Figure 5). It is 
anticipated that approximately 134 OS.BM events would have occurred at the time of final OS 
analysis.  
Detailed rejection boundaries of P-values will be specified in the SAP. 

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10. 
INFORMED CONSENT, ETHICAL REVIEW, AND REGULATORY 
CONSIDERATIONS 
This study will be conducted in accordance with the Note for Guidance on Good Clinical 
Practice (ICH Harmonised Tripartite Guideline E6 (R2); FDA CFR [21 CFR § 50, 56, 312]), 
Declaration of Helsinki (Brazil 2013), and all applicable regulatory requirements. 
10.1. 
Informed Consent 
The investigator is responsible for presenting the risks and benefits of study participation to the 
subject in simple terms using the IRB/IEC approved informed consent document and for 
ensuring subjects are reconsented when the informed consent document is updated during the 
study, if required. The investigator will ensure that written informed consent is obtained from 
each subject by obtaining the signature and date on the informed consent document prior to the 
performance of protocol evaluations or procedures. 
10.2. 
Ethical Review 
The investigator will provide the sponsor or its designee with documentation of the IRB/IEC 
approval of the protocol and the informed consent document before the study may begin at the 
investigative site(s). The name and address of the reviewing ethics committee are provided in the 
investigator file. 
The investigator will supply the following to the investigative site’s IRB/IEC: 
• Protocol and amendments 
• Informed consent document and updates 
• Clinical investigator’s brochure and updates 
• Relevant curricula vitae, if required 
• Required safety and SAE reports 
• Any additional submissions required by the site’s IRB/IEC 
The investigator must provide the following documentation to the sponsor or its designee: 
• The IRB/IEC periodic (eg, quarterly, annual) re-approval of the protocol. 
• The IRB/IEC approvals of any amendments to the protocol or revisions to the 
informed consent document. 
• The IRB/IEC receipt of safety and SAE reports, as appropriate. 
10.3. 
Regulatory Considerations 
This study will be conducted in accordance with the protocol and ethical principles stated in the 
applicable guidelines on good clinical practice, and all applicable local and/or regional laws, 
rules, and regulations. 

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10.3.1. 
Investigator Information 
The contact information and qualifications of the principal investigator and subinvestigators and 
name and address of the research facilities are included in the investigator file. 
10.3.2. 
Protocol Amendments and Study Termination 
Protocol amendments will be submitted to the IRB/IEC prior to implementing. The investigator 
is responsible for enrolling subjects who have met protocol eligibility criteria. Protocol 
deviations must be reported to the sponsor and the local IRB/IEC in accordance with IRB/IEC 
policies. 
The sponsor may terminate the study at any time. The IRB/IEC must be advised in writing of 
study completion or early termination. 
10.4. 
Study Documentation, Privacy, and Records Retention 
To protect the safety of subjects in the study and to ensure accurate, complete, and reliable data, 
the investigator will keep records of laboratory tests, clinical notes, and subject medical records 
in the subject files as original source documents for the study. If requested, the investigator will 
provide the sponsor, its licensees and collaborators, applicable regulatory agencies, and 
applicable IRB/IEC with direct access to original source documents or certified copies. 
Records containing subject medical information must be handled in accordance with local and 
national laws, rules, and regulations and consistent with the terms of the subject authorization 
contained in the informed consent document for the study (the Authorization). Care should be 
taken to ensure that such records are not shared with any person or for any purpose not 
contemplated by the Authorization. Furthermore, CRFs and other documents to be transferred to 
the sponsor should be completed in strict accordance with the instructions provided by the 
sponsor, including the instructions regarding the coding of subject identities. 
In compliance with local and/or regional regulations, this trial may be registered and trial results 
may be posted on public registries, such as ClinicalTrials.gov. 
10.5. 
Clinical Trial Agreement 
Payments by the sponsor to investigators and institutions conducting the trial, requirements for 
investigators’ insurance, the publication policy for clinical trial data, and other requirements are 
specified in the clinical trial agreement. 

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11. 
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Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for HER2-positive early 
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Baselga J, Cortes J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic 
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Blackwell KL, Burstein HJ, Storniolo AM, et al. Randomized study of lapatinib alone or in 
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Blackwell KL, Burstein HJ, Storniolo AM, et al. Overall survival benefit with lapatinib in 
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Borges VF, Ferrario C, Aucoin N, et al. Tucatinib combined with ado-trastuzumab emtansine in 
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Brown PD, Jaeckle K, Ballman KV, et al. Effect of radiosurgery alone vs radiosurgery with 
whole brain radiation therapy on cognitive function in patients with 1 to 3 brain 
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Brufsky AM, Mayer M, Rugo HS, et al. Central nervous system metastases in patients with 
HER2-positive metastatic breast cancer: incidence, treatment, and survival in patients 
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Chan A, Delaloge S, Holmes FA, et al. Neratinib after trastuzumab-based adjuvant therapy in 
patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, 
double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016;17(3):367-77. 
 
Chang EL, Wefel JS, Hess KR, et al. Neurocognition in patients with brain metastases treated 
with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled 
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Chen LM, Ibrahim JG, Chu H. Flexible stopping boundaries when changing primary endpoints 
after unblinded interim analyses. J Biopharm Stat. 2014;24(4):817-33. 
 
Clayton AJ, Danson S, Jolly S, et al. Incidence of cerebral metastases in patients treated with 
trastuzumab for metastatic breast cancer. Br J Cancer. 2004;91(4):639-43. 
 
Collett D. Interval-censored survival data. Modelling survival data in medical research. London, 
Chapman & Hall. 1994:237-51. 
 
Dzimitrowicz H, Berger M, Vargo C, et al. T-DM1 activity in metastatic human epidermal 
growth factor receptor 2-positive breast cancers that received prior therapy with 
trastuzumab and pertuzumab. J Clin Oncol. 2016;34(29):3511-7. 
 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-47. 
 
Fabi A, Giannarelli D, Moscetti L, et al. Ado-trastuzumab emtansine (T-DM1) in HER2+ 
advanced breast cancer patients: does pretreatment with pertuzumab matter? Future 
Oncol. 2017;13(30):2791-7. 
 
Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, Cancer incidence and 
mortality worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International 
Agency for Research on Cancer; 2013. Accessed Sep 09, 2018. http://globocan.iarc.fr. 
2013. 
 
Gerstner ER, Fine RL. Increased permeability of the blood-brain barrier to chemotherapy in 
metastatic brain tumors: establishing a treatment paradigm. J Clin Oncol. 
2007;25(16):2306-12. 
 
Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced 
breast cancer. N Engl J Med. 2006;355(26):2733-43. 
 
Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and 
trastuzumab in women with locally advanced, inflammatory, or early HER2-positive 
breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet 
Oncol. 2012;13(1):25-32. 
 
Gianni L, Pienkowski T, Im YH, et al. 5-year analysis of neoadjuvant pertuzumab and 
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positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. 
Lancet Oncol. 2016;17(6):791-800. 
 
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epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical 
Oncology clinical practice guideline. J Clin Oncol. 2014;32(19):2078-99. 
 
Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, et al. 2 years versus 1 year of adjuvant 
trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised 
controlled trial. Lancet. 2013;382(9897):1021-8. 
 
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University of Washington Metabolism and Transport Drug Interaction Database. Hum 
Genomics. 2010;5(1):61-72. 
 
Hamilton E, Murthy R, Ferrario C, et al. Prolonged progression-free survival (PFS) in advanced 
HER2+ metastatic breast cancer with or without brain metastases: a pooled analysis of 
tucatinib phase 1b studies. Cancer Res. 2018;78(Suppl 4):Abstract P5-20-01. 
 
Howlader N, Altekruse SF, Li CI, et al. US incidence of breast cancer subtypes defined by joint 
hormone receptor and HER2 status. J Natl Cancer Inst. 2014;106(5):dju055. 
 
Jacot W, Pons E, Frenel JS, et al. Efficacy and safety of trastuzumab emtansine (T-DM1) in 
patients with HER2-positive breast cancer with brain metastases. Breast Cancer Res 
Treat. 2016;157(2):307-18. 
 
Kaidar-Person O, Anders CK, Zagar TM. Whole brain radiotherapy for brain metastases: is the 
debate over? JAMA. 2016;316(4):393-5. 
 
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randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15(7):689-99. 
 
Krop IE, Kim SB, Martin AG, et al. Trastuzumab emtansine versus treatment of physician's 
choice in patients with previously treated HER2-positive metastatic breast cancer 
(TH3RESA): final overall survival results from a randomised open-label phase 3 trial. 
Lancet Oncol. 2017;18(6):743-54. 
 
Krop IE, Lin NU, Blackwell K, et al. Trastuzumab emtansine (T-DM1) versus lapatinib plus 
capecitabine in patients with HER2-positive metastatic breast cancer and central nervous 
system metastases: a retrospective, exploratory analysis in EMILIA. Ann Oncol. 
2015;26(1):113-9. 
 

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Lewis Phillips GD, Li G, Dugger DL, et al. Targeting HER2-positive breast cancer with 
trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 2008;68(22):9280-
90. 
 
Lin NU, Bellon JR, Winer EP. CNS metastases in breast cancer. J Clin Oncol. 
2004;22(17):3608-17. 
 
Lin NU, Murthy RK, Anders CK, et al. Tucatinib versus placebo added to trastuzumab and 
capecitabine for patients with previously treated HER2+ metastatic breast cancer with 
brain metastases (HER2CLIMB). J Clin Oncol. 2020;38(15 Suppl):Abstract 1005. 
 
Lu Y, Zi X, Zhao Y, Mascarenhas D, Pollak M. Insulin-like growth factor-I receptor signaling 
and resistance to trastuzumab (Herceptin). J Natl Cancer Inst. 2001;93(24):1852-7. 
 
Moulder S, Hamilton E, Ferrario C, et al. Progression-free survival (PFS) and site of first 
progression in HER2+ metastatic breast cancer (MBC) patients (pts) with (w) or without 
(w/o) brain metastases: a pooled analysis of tucatinib phase I studies. Ann Oncol. 
2017;28(Suppl 5):85. 
 
Murthy R, Borges VF, Conlin A, et al. Tucatinib with capecitabine and trastuzumab in advanced 
HER2-positive metastatic breast cancer with and without brain metastases: a non-
randomised, open-label, phase 1b study. Lancet Oncol. 2018;19(7):880-8. 
 
Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive 
metastatic breast cancer. N Engl J Med. 2020;382(7):597-609. 
 
Nahta R, Esteva FJ. HER2 therapy: molecular mechanisms of trastuzumab resistance. Breast 
Cancer Res. 2006;8(6):215. 
 
Olson EM, Abdel-Rasoul M, Maly J, et al. Incidence and risk of central nervous system 
metastases as site of first recurrence in patients with HER2-positive breast cancer treated 
with adjuvant trastuzumab. Ann Oncol. 2013a;24(6):1526-33. 
 
Olson EM, Najita JS, Sohl J, et al. Clinical outcomes and treatment practice patterns of patients 
with HER2-positive metastatic breast cancer in the post-trastuzumab era. Breast. 
2013b;22(4):525-31. 
 
Owens MA, Horten BC, Da Silva MM. HER2 amplification ratios by fluorescence in situ 
hybridization and correlation with immunohistochemistry in a cohort of 6556 breast 
cancer tissues. Clin Breast Cancer. 2004;5(1):63-9. 
 
Pestalozzi BC, Holmes E, de Azambuja E, et al. CNS relapses in patients with HER2-positive 
early breast cancer who have and have not received adjuvant trastuzumab: a retrospective 
substudy of the HERA trial (BIG 1-01). Lancet Oncol. 2013;14(3):244-8. 
 
Pohlmann PR, Mayer IA, Mernaugh R. Resistance to trastuzumab in breast cancer. Clin Cancer 
Res. 2009;15(24):7479-91. 
 

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Scaltriti M, Rojo F, Ocana A, et al. Expression of p95HER2, a truncated form of the HER2 
receptor, and response to anti-HER2 therapies in breast cancer. J Natl Cancer Inst. 
2007;99(8):628-38. 
 
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HER-2+ hormone receptor-positive metastatic breast cancer. Oncologist. 2010;15(2):122-
9. 
 
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7-30. 
 
Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival 
with amplification of the HER-2/neu oncogene. Science. 1987;235(4785):177-82. 
 
Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody 
against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 
2001;344(11):783-92. 
 
Smith AW, Mitchell SA, De Aguiar CK, et al. News from the NIH: person-centered outcomes 
measurement: NIH-supported measurement systems to evaluate self-assessed health, 
functional performance, and symptomatic toxicity. Transl Behav Med. 2016;6(3):470-4. 
 
Sneeuw KC, Aaronson NK, Sprangers MA, et al. Comparison of patient and proxy EORTC 
QLQ-C30 ratings in assessing the quality of life of cancer patients. J Clin Epidemiol. 
1998;51(7):617-31. 
 
Swain SM, Baselga J, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive 
metastatic breast cancer. N Engl J Med. 2015;372(8):724-34. 
 
Tiwari SR, Sussman T, Kota K, et al. T-DM1 activity in metastatic HER2-positive breast cancer 
patients who have received prior trastuzumab and pertuzumab: NSABP B-005. Cancer 
Res. 2018;78(Suppl 4):Abstract P5-21-26. 
 
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valuations collected with the EuroQol questionnaire. Soc Sci Med. 1994;39(11):1537-44. 
 
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cancer. N Engl J Med. 2012;367(19):1783-91. 
 
Vogel CL, Cobleigh MA, Tripathy D, et al. Efficacy and safety of trastuzumab as a single agent 
in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol. 
2002;20(3):719-26. 
 
von Minckwitz G, Huang CS, Mano MS, et al. Trastuzumab emtansine for residual invasive 
HER2-positive breast cancer. N Engl J Med. 2019;380(7):617-28. 
 
von Minckwitz G, Procter M, de Azambuja E, et al. Adjuvant pertuzumab and trastuzumab in 
early HER2-positive breast cancer. N Engl J Med. 2017;377(2):122-31. 
 

 
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APPENDIX A. 
SCHEDULE OF EVENTS 
 
Day 
PrescreeningH 
Screening/ 
Baseline 
Randomization 
Cycle 1 
Subsequent  
21-Day 
Cycles 
Response Assessments 
ECHO/ 
MUGA 
EOT 
Follow-up 
Survival 
Status 
Up to 1 year 
before 
Screening 
Visit 
D −28 
to 1 
D −7 
to 1 
Within 5D of 
1st dose 
D1 
D12 
D1 
D12A 
Every 
6 weeks, 
through 
Week 24B 
Every 
9 weeks, 
beginning 
Week 24B 
Every  
12 weeksC 
Within  
30–37D 
after last 
doseD 
Every  
9 weeks 
until 
progression
E 
After 
progressi
on, 
every  
90 daysF 
Visit Window 
 
 
 
 
 
±3d 
−1 to 
+3d 
±3d 
−7d 
−7d 
−7d 
 
±1 week 
±7d 
HER2 
Expression 
Testing 
HER2 testing consent 
X 
 
 
Eligibility documentation submitted to sponsor prior to randomization 
 
 
 
 
 
 
 
 
 
 
Submit tumor sample for 
HER2 testing 
(Section 7.1.1) 
XG 
XG, H 
 
 
 
 
 
 
 
 
 
 
 
Screening/ 
Baseline 
Assessments 
Study informed consent 
 
XH 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
 
 
X 
XI 
X 
XI 
 
 
 
 
X 
 
 
Height 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
 
 
X 
XI 
X 
XI 
 
 
 
 
X 
 
 
Vital signsL 
 
 
X 
X 
X 
X 
 
 
 
 
X 
 
 
Safety 
Assessments 
ECOG performance status 
 
 
X 
XI 
X 
XI 
 
 
 
 
X 
 
 
ECHO or MUGAJ 
 
X 
 
 
 
 
 
 
 
X 
XK 
 
 
ECG 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
CBC with differential 
 
 
X 
XI 
X 
XM 
 
 
 
 
X 
 
 
Chemistry 
 
 
X 
XI 
X 
XM 
 
 
 
 
X 
 
 
Liver function tests 
 
 
X 
XI 
X 
XM 
X 
 
 
 
X 
 
 
Coagulation panel  
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Pregnancy test (FOCBP)N 
 
 
X 
 
 
X 
 
 
 
 
XO 
XO 
XO 
Italy only: Hepatitis B and 
C screeningX  
 
Xx 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
and AEs 
 
Collect any related to study 
protocol proceduresP 
Collect from Day 1 (predose) through 30 days post last dose or through EOT visit, 
whichever is later 
 
 

 
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Day 
PrescreeningH 
Screening/ 
Baseline 
Randomization 
Cycle 1 
Subsequent  
21-Day 
Cycles 
Response Assessments 
ECHO/ 
MUGA 
EOT 
Follow-up 
Survival 
Status 
Up to 1 year 
before 
Screening 
Visit 
D −28 
to 1 
D −7 
to 1 
Within 5D of 
1st dose 
D1 
D12 
D1 
D12A 
Every 
6 weeks, 
through 
Week 24B 
Every 
9 weeks, 
beginning 
Week 24B 
Every  
12 weeksC 
Within  
30–37D 
after last 
doseD 
Every  
9 weeks 
until 
progression
E 
After 
progressi
on, 
every  
90 daysF 
Visit Window 
 
 
 
 
 
±3d 
−1 to 
+3d 
±3d 
−7d 
−7d 
−7d 
 
±1 week 
±7d 
Treatment 
Dispense 
tucatinib/placebo 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
Administer T-DM1 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
Review subject diary 
 
 
 
 
X 
X 
X 
 
 
 
X 
 
 
Provide dosing 
instructions for next 
visit’s day-of dose 
 
 
 
 
X 
XQ 
X 
 
 
 
 
 
 
PRO/QoL 
EQ-5D-3LR 
 
 
 
X 
 
X 
 
 
 
 
X 
X 
X 
EORTC QLQ IL6R 
 
 
 
X 
X 
X 
X 
 
 
 
X 
X 
X 
NCI PRO-CTCAE R 
 
 
 
X 
X 
X 
X 
 
 
 
X 
 
 
FACT-B GP5R 
 
 
 
 
X 
X 
X 
X 
 
 
 
X 
 
 
HCRU 
Healthcare resource 
utilization 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
PK 
Blood samples for PKS 
 
 
 
 
See Section 7.3 
Response 
Assessments 
CT (chest, abdomen, 
pelvis)J 
 
X 
 
 
 
 
 
 
X 
X 
 
XT 
XT 
 
Additional imaging of 
other known sites of 
disease, as appropriateJ 
 
X 
 
 
 
 
 
 
X 
X 
 
XT 
XT 
 
Brain MRI 
 
XU 
 
 
 
 
 
 
XV 
XV 
 
XW 
XT, V 
 
A Cycle 2 only. 
B Scheduling determined by date of Cycle 1 Day 1 visit. 
C Scheduling determined by date of Screening ECHO/MUGA. However, if there is an interim assessment, 
subsequent ECHO/MUGAs should be performed every 12 weeks as determined by the date of the most 
recent interim assessment. See Section 7.7.6.1. 
D If EOT evaluations are completed before 30 days following the last study treatment, conduct a phone 
screen 30-37 days following the subject’s last study treatment to ensure that no changes in AE profile have 
occurred. 
E Scheduling determined by date of the last imaging scan. See Section 6.6. 
 
M Predose laboratory testing must be done within 1 day prior to study visit. Confirm laboratory results prior 
to continuing study treatment dosing. 
N FOCBP only: can be performed within 7 days prior to study treatment dosing on Day 1 of cycle. Confirm 
negative pregnancy test prior to continuing study treatment dosing. 
O FOCBP only: monthly pregnancy tests should be performed for 7 months after the last dose of study 
treatment. Subject will be asked to confirm that monthly pregnancy tests have been performed and have 
been negative. 
P From time of study informed consent.  
Q Cycles 3–5 only. 
 

 
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F Scheduled 90 days (±7 days) from the date of the last imaging scan or 90 days from the last study visit, 
whichever is later and continuing every 90 days (±7 days) until death, withdrawal of consent, lost to 
follow up, or study closure. May be an in-person assessment, contact by telephone, review of medical 
records, or review of publicly available information if allowed per local regulations (if reasonable efforts 
to contact the subject are unsuccessful). See Section 6.6 
G Archival tissue specimen may be submitted up to 1 year prior to Screening visit. If archival tissue is 
unavailable, a fresh tumor biopsy must be obtained (Section 6.2.2). 
H All subjects must sign informed consent for the study before Screening/Baseline procedures are 
conducted, including obtaining a fresh tumor biopsy for those subjects who require one to be performed 
for HER2 confirmation. The HER2 testing prescreening consent is not informed consent for the study. 
Subjects who remain in prescreening for >1 year must resign the prescreening consent.  
I Assessment does not need to be repeated, if already done within 1 day of study visit (eg, as part of 
Screening/Baseline visit). Confirm laboratory results prior to initiating study treatment dosing. 
J Use the same assessment modality throughout the study.  
K Perform ECHO/MUGA if not done within the previous 12 weeks (excluding the Screening/Baseline 
assessment). 
L Assessment to be done predose on days when study drug(s) are administered. 
R Subject should complete questionnaires prior to evaluation by study personnel (physical examination, 
review of AEs) and administration of study treatment on treatment days (ie, within 1 day prior to study 
treatment). Questionnaires may be completed by phone after a subject experiences disease progression 
(per RECIST v1.1) and is in long-term survival follow-up. See Section 7.6. 
S See Table 8 and Table 9 for predose and postdose PK sample collection details. 
T Only in subjects who discontinue study treatment for reasons other than radiographic disease progression. 
Response assessments at the EOT visit are not required if performed within 30 days of discontinuing study 
treatment. 
U For subjects with brain metastases discovered during screening or a history of brain metastases, confirm 
that relevant MRI brain reports and CNS treatment records can be obtained. 
V Required only for subjects with brain metastases at baseline, as defined in Section 7.2.1. 
W Contrast MRI of the brain required for all subjects. Not required if brain MRI was performed within 
30 days of discontinuing study treatment, or if progression in the brain has already been documented while 
on study. 
X For sites in Italy only: Blood samples for Hepatitis B surface antigen (HBsAg), antibodies to Hepatitis B 
surface antigen (anti-HBs), antibodies to Hepatitis B core antigen (anti-HBc), Hepatitis B DNA levels by 
PCR (as applicable; refer to latest local guidelines for the management of Hepatitis B virus infection), and 
antibodies to Hepatitis C (anti-HCV). If positive, contact medical monitor.  
 

 
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APPENDIX B. 
PERFORMANCE STATUS SCALES CONVERSION 
Karnofsky 
 
ECOG 
Percent 
Description 
 
Score 
Description 
100 
Normal, no complaints, no evidence of 
disease. 
 
0 
Normal activity. Fully active, able to 
carry on all pre-disease performance 
without restriction. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
 
1 
Symptoms, but ambulatory. Restricted 
in physically strenuous activity, but 
ambulatory and able to carry out work 
of a light or sedentary nature (eg, light 
housework, office work). 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
 
2 
In bed <50% of the time. Ambulatory 
and capable of all self-care, but unable 
to carry out any work activities. Up and 
about more than 50% of waking hours. 
50 
Requires considerable assistance and 
frequent medical care. 
 
40 
Disabled, requires special care and 
assistance. 
 
3 
In bed >50% of the time. Capable of 
only limited self-care, confined to bed 
or chair more than 50% of waking 
hours. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
 
4 
100% bedridden. Completely disabled. 
Cannot carry on any self-care. Totally 
confined to bed or chair. 
10 
Moribund, fatal processes progressing 
rapidly. 
 
0 
Dead 
 
5 
Dead 
 

 
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APPENDIX C. 
CYP3A4 INHIBITORS/INDUCERS AND THEIR ELIMINATION 
HALF-LIVES 
CYP3A4 inhibitors and inducers include but are not limited to the following. There could also be 
additional new drugs and marketed drugs that could be identified as inhibitors/inducers with 
continued research. 
Druga, b, c 
Elimination Half-lifed  
(hours) 
Strong Inhibitors 
Macrolide Antibiotics 
 
Clarithromycin 
3–7 hours 
Troleandomycin 
2 hours 
Azole Antifungals 
 
Itraconazole 
16-28 hours (single dose), 34–42 hours (repeat dose) 
Ketoconazole (systemic) 
2–8 hours 
Voriconazole 
Dose dependent 
Posaconazole 
27–35 hours 
Antivirals 
 
Boceprevir 
3–4 hours 
Indinavir 
1–2 hours 
Nelfinavir 
3–5 hours 
Ritonavir 
3–5 hours 
Telaprevir 
9–11 hours 
Other 
 
Nefazodone 
2–4 hours 
Diltiazem 
3–4 hours 
White grapefruit juice 
~ 4–5 hourse 
Strong Inducers 
Barbiturates 
Variable 
Carbamazepine 
25–65 hours (single dose), 12–17 hours (repeat dose) 
Phenytoin 
7–42 hours 
Rifampin 
3–4 hours (single dose), 2–3 hours (repeat dose) 
St. John’s Wort 
9–43 hoursf 
Note: Any additional CYP3A4 inhibitors/inducers that are identified or become commercially available while the 
clinical trial is ongoing are also prohibited. 
a FDA. “Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers” 
(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm
093664.htm#potency) 

 
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b EMA. “Guideline on the investigation of drug interactions” 
(http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/07/WC500129606.pdf) 
c Strong CYP3A inhibitors are defined as those drugs that increase the area under the concentration-time curve 
(AUC) of oral midazolam or other CYP3A substrates ≥5-fold.  
d Drug package insert 
e (Bailey 1998) 
f (Kerb 1996) 

 
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APPENDIX D. 
CYP2C8 INHIBITORS/INDUCERS AND THEIR ELIMINATION 
HALF-LIVES 
CYP2C8 inhibitors and inducers include but are not limited to the following. There could also be 
additional new drugs and marketed drugs that could be identified as inhibitors/inducers with 
continued research. 
Druga, b 
Elimination Half-lifec 
(hours) 
Strong Inhibitors 
 
 
Gemfibrozil 
1–2 hours 
Moderate Inhibitors 
 
Clopidogrel 
6 hours 
Strong Inducer 
Rifampin 
3–5 hours 
Note: Any additional CYP2C8 inhibitors/inducers that are identified or become commercially available while the 
clinical trial is ongoing are also prohibited. 
a FDA. “Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers” 
(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm
093664.htm#potency) 
b EMA. “Guideline on the investigation of drug interactions” 
(http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/07/WC500129606.pdf)  
c Drug package insert 

 
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APPENDIX E. 
CLINICAL SUBSTRATES FOR CYP3A-MEDIATED METABOLISM 
The following table provides examples of clinical substrates for CYP3A-mediated metabolism 
and is not intended to be an exhaustive list. 
Sensitive 
(AUC increase ≥5-fold with strong index inhibitor) 
Moderate Sensitive 
(AUC increase 2- to 5-fold with strong index 
inhibitor) 
alfentanil, avanafil, buspirone, conivaptan, 
darifenacin, darunavira, ebastine, everolimus, 
ibrutinib, lomitapide, lovastatinb, midazolam, 
naloxegol, nisoldipine, saquinavira, simvastatinb, 
sirolimus, tacrolimus, tipranavira, triazolam, 
vardenafil 
alprazolam, aprepitant, atorvastatinc, colchicine, 
eliglustatd, pimozide, rilpivirine, rivaroxaban, 
tadalafil 
budesonide, dasatinib, dronedarone, eletriptan, 
eplerenone, felodipine, indinavira, lurasidone, 
maraviroc, quetiapine, sildenafil, ticagrelor, 
tolvaptan 
Note: Sensitive substrates are drugs that demonstrate an increase in area under the concentration-time curve (AUC) 
of ≥5-fold with strong index inhibitors of a given metabolic pathway in clinical drug-drug interaction (DDI) 
studies. Moderate sensitive substrates are drugs that demonstrate an increase in AUC of ≥2- to <5-fold with strong 
index inhibitors of a given metabolic pathway in clinical DDI studies. Sensitive substrates of CYP3A with 
≥10-fold increase in AUC by co-administration of strong index inhibitors are shown above the dashed line. Other 
elimination pathways may also contribute to the elimination of the substrates listed in the table above and should 
be considered when assessing the drug interaction potential. 
a Usually administered to patients in combination with ritonavir, a strong CYP3A inhibitor. 
b Acid form is an organic anion transporting polypeptide 1B1 (OATP1B1) substrate. 
c Listed based on pharmacogenetic studies. 
d Sensitive substrate of CYP2D6 and moderate sensitive substrate of CYP3A. 
DDI data were collected based on a search of the University of Washington Metabolism and 
Transport Drug Interaction Database (Hachad 2010). 
Source: 
(https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteract
ionsLabeling/ucm093664.htm#table3-1) 

 
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APPENDIX F. 
RECIST VERSION 1.1 
Response Evaluation Criteria in Solid Tumors 
Term 
Definition 
Complete response (CR) 
Disappearance of all target lesions. Any pathological lymph nodes must have 
reduction in short axis to <10 mm. 
Partial response (PR) 
A ≥30% decrease in the sum of diameters of target lesions, taking as reference the 
baseline sum diameters. 
Progressive disease (PD) 
At least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. The appearance of one or more 
new lesions is also considered progression. 
Stable disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum diameters while on study. 
Measurable lesion 
Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of 10 mm by CT 
scan (CT slice thickness no greater than 5 mm). 
From RECIST v1.1 (Eisenhauer 2009)

 
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APPENDIX H. 
EORTC QLQ IL6 

 
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APPENDIX J. 
NCI PRO-CTCAE 

 
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APPENDIX K. 
GUIDANCE ON CONTRACEPTION 
For the purposes of this guidance, complete abstinence, if consistent with the subject’s preferred 
lifestyle, is an acceptable form of contraception. Complete abstinence is defined as abstinence 
starting from the time of informed consent and continuing throughout the study and until the end 
of systemic exposure (at least 7 months after the final dose of study drug; see Section 4.3). 
Acceptable methods for highly effective birth control (preventing conception) 
Subjects who are of childbearing potentiala or whose partners are of childbearing potentiala 
and who are sexually active in a way that could lead to pregnancy may choose any TWO 
of the following methods (please see acceptable combinations below): 
• Hormonal methods of contraception (excluding progestin-only pills; method 
must be associated with inhibition of ovulation), unless contraindicated 
• Intrauterine device with failure rate <1% 
• Tubal ligation 
• Vasectomy (at least 90 days from the date of surgery with a semen analysis 
documenting azoospermia) 
• Barrier method (male or female condom with or without spermicide, cervical 
cap with or without spermicide, diaphragm with or without spermicide)b 
a A person of childbearing potential is defined as anyone born female who has experienced menarche and 
who has not undergone surgical sterilization (eg, hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy) or has not completed menopause. Menopause is defined clinically as 12 months of 
amenorrhea in a person born female over age 45 in the absence of other biological, physiological, or 
pharmacological causes. 
b A barrier method should only be used with a highly effective birth control method that is not a barrier 
method. Barrier methods alone, including a double-barrier method, are not considered highly effective 
contraceptive measures (see unacceptable methods of contraception). 
Acceptable combinations of contraceptive methods:  
• Hormonal method and vasectomy 
• Hormonal method and barrier method 
• Intrauterine device and vasectomy 
• Intrauterine device and barrier method 
• Tubal ligation and vasectomy 
• Tubal ligation and barrier method 
Acceptable methods for preventing secondary exposure to seminal fluid 
Subjects born male and who are sexually active with a pregnant person must use a male condom 
(even if the subject has had a vasectomy).  

 
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Subjects born male and who are sexually active with a breastfeeding person must use a male 
condom (even if the subject has had a vasectomy). In addition, it is recommended that the 
breastfeeding partner use a highly effective female contraceptive method as listed in the section 
titled “Acceptable combinations of contraceptive methods”. 
Unacceptable methods of contraception 
• Periodic abstinence 
• Spermicide only  
• No method 
• Progestin-only pills 
• Withdrawal 
• Concomitant use of female and male condoms 
• Rhythm 
• Barrier methods alone, including double-barrier methods 

 
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APPENDIX L. 
FRANCE SPECIFIC REQUIREMENTS 
In France, the Study Population section of the synopsis should include:  
Subjects must have histologically confirmed HER2+ breast carcinoma and had 
progression after prior treatment with a taxane, trastuzumab, and pertuzumab for 
advanced/metastatic HER2+ breast cancer. Subjects with recurrence during or within 6 
months of completing adjuvant treatment are also eligible with a history of prior 
treatment with a taxane or trastuzumab. Subjects who received T-DM1 in the adjuvant 
setting and relapsed during or within 6 months of completing adjuvant treatment are not 
allowed. 
In France, inclusion criterion #2 should read as follows:  
Subjects must have documented disease progression after prior treatment with a taxane, 
trastuzumab, and pertuzumab for advanced/metastatic HER2+ breast cancer. Subjects 
with recurrence during or within 6 months of completing adjuvant treatment are also 
eligible with a history of prior treatment with a taxane and trastuzumab. Note: Subjects 
who received T-DM1 in the adjuvant setting and relapsed during or within 6 months of 
completing adjuvant treatment are not allowed. 
In France, an additional section is included as follows: 
Section 4.4.3 Commitment to Continue Providing Tucatinib  
The Sponsor commits to continue providing tucatinib in accordance with local regulations 
to subjects who are continuing to demonstrate clinical benefit while receiving tucatinib 
upon study closure. 

 
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APPENDIX M. 
INVESTIGATOR SIGNATURE PAGE 
Investigator Statement and Signature 
I have read the attached protocol entitled “Randomized, double-blind, phase 3 study of tucatinib 
or placebo in combination with ado-trastuzumab emtansine (T-DM1) for subjects with 
unresectable locally-advanced or metastatic HER2+ breast cancer.” (HER2CLIMB-02) 
I understand and agree to the provisions of the protocol, and I accept the responsibilities listed 
above in my role as principal investigator for the study. 
 
 
 
Investigator Signature 
 
Date 
 
 
 
 
 
 
Investigator Name, Printed 
 
 

 
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APPENDIX N. 
DOCUMENT HISTORY 
Version 
Date 
Original 
24-Apr-2019 
Amendment 1 
13-Aug-2019 
Amendment 1.1 
20-Dec-2019 
Amendment 2 
07-Apr-2021 
Amendment 3 
01-Mar-2022 
Amendment 4 
08-Nov-2023 
 

 
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SUMMARY OF CHANGES IN AMENDMENT 1.1 
Section(s) 
Change 
Rationale 
Cover page 
EudraCT number was added. 
Documents the assigned study identifier in the 
European Union. Update was made to enable 
clinical trial applications in Europe. 
Synopsis 
Included the Secondary Endpoint - Evaluate the duration of 
response (DOR) by BICR per RECIST v1.1 between treatment 
arms 
To be consistent with the body of the protocol. 
Section 5.2 
The minimum time allowed between whole-brain radiotherapy 
and the initiation of study treatment was changed from ≥21 days 
to ≥14 days 
Correction 

 
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SUMMARY OF CHANGES IN AMENDMENT 2 
Section(s) 
Change 
Rationale 
Sections 2 (Table 1), 6.4.1, 6.4.3, 
6.5, 7.4, 9.2.4.2, 9.3.7, Appendix A, 
and Synopsis 
Removed language regarding biomarkers as an exploratory 
endpoint and blood sample collection for biomarker analysis.  
Sections 7.4, 9.2.4.2 and 9.3.7 have been removed and the 
subsequent sections have been renumbered. 
Exploratory biomarker analysis is no longer 
included in this study. 
Section 3.2.3 
 
Updated text in criterion #2: Information on study treatment 
assignment should must not be distributed to any other personnel 
involved in the clinical trial. In the event of any emergency 
unblinding, the sponsor is to be notified within 24 hours of the 
occurrence. 
Update 
Section 3.2.3.1 
 
Changed text from “sponsor safety” to “sponsor Global Safety 
and Risk Management” 
Update 
Section 4.1 
Updated text in inclusion criterion 1 by removing the word 
“metastatic” 
Changed criterion 6 from “Age ≥18 years at time of consent” to 
“Age ≥18 years at time of consent or ≥ the age of majority in the 
geographic location”  
Changed absolute neutrophil count from ≥1.5 × 103/µL to 
≥1.0 × 103/µL  
Correction 
Provide clarification on age requirements 
Update absolute neutrophil count safe for subjects 
to enroll on study 
 
To align with CTCAE v4.03 criteria for Grade 1 
ALT/AST elevation 
Sections 4.1 and 10.1 
Removal of language allowing a legally acceptable representative 
to provide consent on behalf of the subject. 
Updated contraception language for effective birth control 
methods in inclusion criteria 14d, 15b, and 15c and added 
Appendix K.  
To disallow informed consent from a legally 
acceptable representative. 
Update, clarification, and addition 
Section 4.1  
Inclusion criterion 18: Added “or previously treated and 
progressing lesions found”  
Update 
Section 4.2 
Exclusion criterion 12: Shortened window for avoiding sensitive 
CYP3A substrates from 2 to 1 week. 
Update  
Section 4.2 
Exclusion criterion 1: Changed to exclude use of pryotinib  
Update 
Section 4.2 
Clarified that left ventricular systolic dysfunction or decrease in 
ejection fraction to indicate that histories must be symptomatic. 
Provided clarification of criterion 

 
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Section(s) 
Change 
Rationale 
Section 4.2 
Exclusion criterion 9: Updated text to clarify HIV-positive 
exclusion criteria 
Clarification 
Section 5.3 
Added guidance regarding planned surgery.  
Clarification 
Section 5.3.2 
Added routine prophylaxis with vaccines. 
Clarification 
Section 5.4 
Removed “at the end of each cycle”. 
Clarification 
Section 6.2.1 
Added requirement that subject must be reconsented if they 
remain in prescreening for more than 1 year. Added “In China, 
refer to the lab manual for details regarding HER2 testing.” 
Clarification 
Section 6.2.2 
Updated text to the following: “All other safety labs and 
assessments will need to be repeated per the schedule of events if 
outside the 28 day window for these subjects.”  
Correction 
Section 6.2.3, etc. 
Changed references from “serum chemistry” for laboratory 
testing to “chemistry” 
Update 
Section 6.4.1 
Removed ECG 
Update 
Section 6.4.2 
Added “blood pressure, heart rate, temperature, and respiration 
rate” after vital signs 
Clarification 
Section 6.4.3 
Updated text: Administer the first cycle morning dose of 
tucatinib/placebo. (Subject will self-administer the evening dose, 
unless the cycle began in the afternoon) 
Clarification 
Section 6.4.5 
Added ALP to blood samples for LFTs 
Update 
Section 6.5 
Added the following text: The time of End of Treatment (EOT) 
visit may be longer than 37 days, but in no case should it be 
<30 days. However, EOT evaluations must be performed before 
initiation of a new therapy. 
Clarification 
Section 6.6 
Added “Subsequent long-term follow-up scan windows are based 
on the most recent scan completed”. 
Clarification 
Sections Synopsis, 3.1, 7.1, 9.1, 9.3, 
9.3.1.6 
Revised to include language about China portion. 
Update 

 
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Section(s) 
Change 
Rationale 
Section 7.1.1 
Removed requirement of 5 unstained charged slides for HER2 
expression testing from the protocol. It will instead be specified 
in the lab manual. 
Removed requirement of “a minimum of 100 tumor cells” from 
the protocol. It will instead be specified in the lab manual.  
Update 
Section 7.1.2 
Deleted “All such instances, with the exception of immediate 
local therapy to the CNS”. 
Clarification 
Section 7.2 
Added “and chosen as either target or non-target lesions”. 
Clarification 
Section 7.2.1 
Updated text:  
In subjects with baseline brain lesions, at least one all brain 
lesions should be included in the baseline RECIST lesion 
selection as either a target or non-target lesion. As an exception, 
however, When unsuspected brain metastases are discovered at 
screening and immediate CNS-directed therapy is administered, 
treated lesions should not be selected as target lesions but as 
non-target lesions for the purpose of disease assessment by 
RECIST v1.1.  
To provide clarification and align with Response 
Assessment Manual v02 
Section 7.8.1.1 (renumbered to 
7.7.1.1) 
Changed from “Adverse Events and Pre-existing Conditions 
CRF” to “Adverse Events CRF”. 
Clarification 

 
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Section(s) 
Change 
Rationale 
Section 7.8.1.2 (renumbered to 
7.7.1.2) 
Updated subsection for Diagnosis vs. Signs or Symptoms: 
If applicable: Important exceptions for this study are adverse 
reactions associated with the infusion of study drug. For 
infusion related reactions, do not use the NCI CTCAE terms of 
‘cytokine release syndrome,’ ‘acute infusion reaction,’ or 
‘allergic or hypersensitivity reaction.’ Instead, record each sign 
or symptom as an individual AE. If multiple signs or symptoms 
occur with a given infusion related event, each sign or symptom 
should be recorded separately with its level of severity. Record 
each sign or symptom as an individual AE in addition to the 
infusion-related reaction term. If multiple signs or symptoms 
occur with a given infusion-related event, each sign or symptom 
should be recorded separately with its level of severity. 
Added language to Progression of the Underlying Malignancy 
subsection:  
The events described above are the only protocol-defined events 
which do not need immediate reporting from the investigator to 
the sponsor for this study. 
Clarification 
Section 7.8.1.5 (renumbered to 
7.7.1.5) 
Added language to include reporting of SUSARs 
Addition of SAE type for reporting to regulatory 
authorities 
Section 7.8.4 (renumbered to 7.7.4) 
Updated list of tests to be included in the chemistry panel, CBC 
with differential, and coagulation panel 
Update 
Section 9 
Table 10 removed 
Redundant information 
Section 9.2.4.1 
Language replaced as follows: 
The PK of tucatinib and T-DM1 will be evaluated. Peripheral 
blood will be collected from subjects per Section 7.3. 
Exploratory, predictive, and prognostic biomarkers associated 
with response, resistance, or safety observations will be 
monitored before and during treatment with tucatinib. Correlative 
studies will be conducted to gain a better understanding of target 
response relationship, predictive biomarkers, MOA, and 
resistance mechanisms. 
Update 
Section 9.3.1 
Revised for clarity 
Administrative change 
Section 9.3.1.5 
Revised description of multiple comparisons and multiplicity 
Update 

 
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Section(s) 
Change 
Rationale 
Throughout protocol 
Minor grammatical corrections, cross-reference updates, section 
renumbering, formatting, and sponsor name change 
Administrative changes 

 
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SUMMARY OF CHANGES IN AMENDMENT 3 
Section(s) 
Change 
Rationale 
Title page 
Updated name and contact information for the study’s medical 
monitor. 
Update due to change in study medical monitors 
Synopsis 
Modified text:  
Subjects must be >3 weeks post-treatment from any prior 
systemic anticancer therapy (including hormonal therapy), 
noncentral nervous system radiotherapy (palliative or 
therapeutic), or participation in another interventional clinical 
trial. 
Modified text: 
If treatment for newly identified lesions or previously treated or 
and progressing lesions is initiated, subjects may still be 
eligible…” 
Added text: 
Baseline disease assessments include measurement of all known 
sites of unresectable locally-advanced/metastatic disease through 
radiographic imaging. Assessment for brain metastases is 
performed with contrast MRI of the brain for all subjects, 
regardless of prior history of brain metastases. 
Modified text: 
These PRO instruments include the European Quality of Life 
5-Dimension 3-Level (EQ-5D-3L) instrument, 2 questions to 
capture global health status/quality of life from the European 
Organization for Research and Treatment of Cancer (EORTC) 
quality-of-life questionnaire (EORTC QLQ C30 IL6), the 
National Cancer Institute's Patient-Reported Outcomes version of 
the Common Terminology Criteria for Adverse Events (NCI 
PRO-CTCAE) questionnaire customized to focus on adverse 
events (AEs) or symptoms of interest, and 1 question from the 
Functional Assessment of Cancer Therapy – Breast 
(FACTBFACT-B GP5) questionnaire to capture the patients’ 
perceptions of side effects. 
Added text:  
In addition, a summary of health care resource utilization 
(HCRU) will be presented. 
Clarification 
 
 
 
 
 
Correction for consistency with Section 4.1, 
Criterion 18.c.ii 
 
 
 
Clarification that contrast MRI of the brain is 
required as a baseline assessment for all subjects in 
the study  
 
 
 
 
 
Clarification that the study uses the 
EORTC QLQ IL6 and FACT-B GP5 rather than 
the respective full scales.  
 
 
 
 
 
 
 
 
 
 

 
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Section(s) 
Change 
Rationale 
 
 
 
Update to indicate that health care resource 
utilization will be assessed. 
Section 2, Synopsis 
The following endpoint was revised and reclassified from ‘other 
secondary endpoint’ to a ‘key secondary endpoint’: 
EvaluateCompare progression-free survival (PFS) by investigator 
assessment per RECIST v1.1 in subjects with brain metastases at 
baseline between treatment arms.  
Update to include PFS by investigator assessment 
per RECIST v1.1 in subjects with brain metastases 
at baseline as an alpha-controlled endpoint.  
Section 3.1 (Figure 3), Section 6.6 
Modified text to clarify that the description of one of the 
assessment schedules applies to subjects who discontinue 
treatment for any reason prior to documented disease 
progression.  
Clarification because many investigative sites have 
asked about imaging requirements after end of 
treatment. Clarifying the text in the amendment 
may simplify site communications and ensure that 
all required imaging is obtained. 
Section 3.2.3 
Modified Items #2:  
Unblinding a subject’s treatment assignment prior to study 
closure must be limited to safety emergency circumstances only 
where knowledge of the treatment assignment would affect 
decisions regarding the immediate clinical management of the 
subject. In the event of such an emergency circumstance, the 
investigator will assume full responsibility for unblinding the 
study treatment and a formal unblinding procedure, carried out 
by a third-party organization, will be followed to allow the 
investigator to immediately access a subject’s treatment 
assignment (see study manual). Information on study treatment 
assignment must not be distributed to any other personnel 
involved in the clinical trial. In the event of any emergency 
unblinding, the sponsor is to be notified within 24 hours of the 
occurrence. 
Clarification 
Section 4.2 
Modified Item #4:  
Treatment with any systemic anticancer therapy (including 
hormonal therapy), non-CNS radiation (palliative or therapeutic), 
experimental agent or participation in another interventional 
clinical trial ≤3 weeks prior to first dose of study treatment. An 
exception for the washout of hormonal therapies is gonadotropin 
Clarification 

 
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Section(s) 
Change 
Rationale 
releasing hormone agonists used for ovarian suppression in 
premenopausal women, which are permitted concomitant 
medications. 
Section 5.2.3.1, Table 4 
Modified text:  
● Clinical Adverse Event column: All ≥ Grade 3 AEs other than 
except the following: Grade 3 fatigue lasting ≤3 days; 
alopeciaa; nausea; vomiting; diarrhea; rash; correctable 
electrolyte abnormalities 
● T-DMI column: Do not administer until severity 
≤ Grade 1 or pretreatment level. Reduce to next lowest dose 
level. Note: Dose reduction is not required for hematologic 
abnormalities (other than thrombocytopeniab) that recover to 
≤ Grade 1 prior to dosing. 
Footnote b: Refer to Table 6 for thrombocytopenia dose 
reduction requirements 
 
Clarification of which adverse events are not 
included in the category of all ≥ Grade 3 adverse 
events that require dose modification 
 
 
Update to address dose modifications in the event 
of hematologic laboratory abnormalities 
Section 6.4.3 
Added text:  
* Predose assessments do not need to be repeated if performed 
within 1 day prior to Day 1. 
Clarification 
Section 6.6 
Added text:  
More frequent long-term follow-up may be conducted as needed 
for OS event tracking (eg, for subjects with clinical progression, 
OS event tracking may be conducted at the same time 
radiographic scans and PFS event tracking will be performed 
every 9 weeks, until PD per RECIST 1.1 is confirmed, at which 
time PFS tracking ends and OS event tracking may be performed 
starting 90 days [±7 days] from the date of the last imaging scan) 
Clarification with an example of when more 
frequent long-term follow-up may be conducted as 
needed for OS event tracking 
 
Section 7.6.1 
Added a reference to Appendix G  
Clarification 
Section 7.6.2 
Modified text: 
The questionnaire has been streamlined based on a patient-centric 
approach to minimize the number of questions being asked as 
part of the patient-reported outcome (PRO) data collection, 
therefore only Questions 29 and 30 of the questionnaire which 
make up the ‘global health status/QoL’ scale of the QLQ-C30 
will be used for this study (Appendix H). The EORTC refers to 
Clarification that Questions 29 and 30 of the 
EORTC QLQ-C30 make up the ‘global health 
status/QoL’ scale of this measure and is referred to 
as the EORTC QLQ IL6.  
 
 
 

 
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Section(s) 
Change 
Rationale 
the combination of questions used in this study set of questions as 
the EORTC QLQ IL6. 
Added a reference to Appendix H. 
 
 
Clarification 
Section 7.6.3 
Modified text: 
The FACT B was created with an emphasis on patients' values 
and brevity. It is written at the sixth grade reading level, takes 
approximately 10 minutes to complete, and is available in nine 
languages. Its psychometric properties, brevity, and relevance to 
patients' values make its suitable for use in both research and 
clinical settings. The FACT B will be collected while subjects 
are receiving study treatment and until the EOT visit; the 
instrument has been customized to minimize the number of 
questions be asked as part of the PRO data collection, therefore 
only question 5 will be used (). The Functional Assessment of 
Chronic Illness Therapy (FACIT) organization referred to the 
combination of questions used in this study as the GP5.To 
minimize the number of questions to reduce patient burden, only 
Question 5 (ie, GP5) regarding patient’s perception of bother due 
to treatment side effects will be used (Appendix I). Responses to 
this question will be collected while subjects are receiving study 
treatment and until the EOT visit. 
Added a reference to Appendix I 
Update to focus on the FACT-B GP5 rather than 
the FACT-B overall because the study uses only 
the FACT-B for subject assessment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clarification 
Section 7.6.4 
Modified text: 
The NCI Patient Reported Outcomes Common Terminology 
Criteria for Adverse Events (PRO-CTCAE) is a new 
patient reported outcome (validated PRO) measurement system 
developed to characterize the frequency, severity, and 
interference of 78 symptomatic treatment toxicities (Smith 2016). 
These include symptomatic toxicities such as pain, fatigue, 
nausea, and cutaneous side effects such as rash and hand-foot 
syndrome, all toxicities that can be meaningfully reported from 
the patient perspective. The NCI PRO-CTCAE allows for 
customization; thus, symptomatic toxicities of interest (17 items) 
in both the control and experimental arms will be collected as 
part of the PRO data collection (Appendix J). The PRO CTCAE 
measurement system consists of an item library of adverse 
symptoms, and a prototype electronic platform with a variety of 
Reduced length of text to focus on the purpose of 
implementing the NCI PRO-CTCAE in this study 
rather than on the measure’s background 
information.  
 
 
 
 
 
 
 
 
 
 
 

 
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Section(s) 
Change 
Rationale 
features designed to promote integration of the PRO CTCAE 
measurement system into clinical trials workflow. The system 
allows for data collection via the web, a hand held computer, or 
an interactive voice response system, and includes features that 
allow for customized PRO CTCAE questionnaires, tailoring the 
schedule for data collection, as well as patient reminders and 
clinician alerts for severe symptoms. Development and validation 
of PRO CTCAE were consistent with well established 
measurement principles as well as guidelines for PROs 
instrument development proposed by the FDA and EMA. The 
development process included patients with cancer as well as 
professionals from the US and Europe with expertise in 
oncology, instrument development, clinical research and the 
regulatory aspects of cancer therapy development. The 
NCI PRO CTCAE will be customized to focus on symptomatic 
toxicities of interest in both the control and experimental arms. 
Added a reference to Appendix J 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clarification 
Section 7.7.1.2 
Modified text:  
Email or fax to the sponsor’s Drug Safety Department within 
4824 hours of becoming aware of a pregnancy.  
Correction 
Section 7.8 
Modified text: 
The QLQ C30 (Version 3.0) is a validated questionnaire 
developed by thePROs included in this study (EORTC to assess 
the QoL of cancer subjects . TheQLQ IL6, EQ-5D-3L is a 
validated instrument for use as a measure of health related QoL. 
The , and FACT-B is a sound instrumentGP5) are validated 
questionnaires that can be used to measure symptoms in subjects 
with breast cancer. These PROs have been incorporated into 
previous clinical trials that seek to quantify the QoL in subjectsto 
assess global health status and quality of life as well as 
perception of side effects, respectively. 
Simplified text for clarification 
Section 9.1, Synopsis 
Revised the final analysis of OS to take place approximately 
30 months instead of 29 months after the primary analysis of 
PFS.  
Added text to describe the analyses related to PFS in subjects 
with brain metastases at baseline. 
Update to accommodate one additional OS interim 
analysis 
 
Update 

 
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Section(s) 
Change 
Rationale 
Section 9.1, Section 9.3.1.5, Section 
9.3.1.8, Section 9.3.9, Synopsis 
Increased the number of overall survival (OS) events required for 
the final OS analysis from 248 to 253  
Update to accommodate one additional interim 
analysis of OS 
Section 9.2.2.2 (new section), 
Section9.2.3.2 
Reclassified the analysis related to the endpoint of PFS by 
investigator assessment per RECIST v1.1 in subjects with brain 
metastases at baseline between treatment arms from other 
secondary endpoint to a key secondary endpoint. 
Update 
Section 9.2.4.1 
Modified text: 
The pharmacokinetics of tucatinib and T DM1 will be evaluated. 
Correction 
Section 9.2.4.3, Synopsis 
Replaced the words ‘Quality of Life’ and ‘health-related quality 
of life’ with ‘Patient-Reported Outcomes’ when referring to the 
PRO measures overall that are implemented in this study. 
Correction 
Section 9.3.1.5, Section9.3.1.8, 
Section 9.3.9, Synopsis 
Updated text to reflect that an additional OS analysis (key 
secondary endpoint) is planned when approximately 202 (80%) 
OS events have been observed.  
Updated text to state that a formal statistical test of objective 
response rate (ORR) will only be performed if the results of the 
PFS, OS, and PFS.BM analyses are all statistically significant. 
Update to accommodate one additional interim 
analysis of OS 
 
Update 
Section 9.3.1.5, Section 9.3.9, 
Synopsis 
Added text to describe 2 possible analyses of the key secondary 
endpoint of PFS by investigator assessment per RECIST v1.1 in 
subjects with brain metastases at baseline if both PFS and OS 
(OS IA1, OS IA2, or OS FA) results are statistically significant. 
Update 
Section 9.3.1.8 
Modified text related to the timing of analyses relative to the 
randomization of the first subject. 
Added text to describe the timing of the analyses of PFS by 
investigator assessment per RECIST v1.1 in subjects with brain 
metastases at baseline 
Update to accommodate one additional OS interim 
analysis 
Update 
Section 9.3.7 
Modified text: 
PRO assessments will be analyzed to determine if treatment 
affects PRO scores. PRO scores will be analyzed using 
longitudinal models. All subscales and individual item scores will 
be tabulated. Descriptive summaries of observed data at each 
scheduled assessment timepoint may be presented. Time to 
deterioration will be assessed in specific pre specified single 
items from either the EORTC QLQ C30 or FACT B.  
Removed statements related to PRO scores being 
analyzed using longitudinal models and 
assessment of time to deterioration. As time to 
deterioration may be difficult to interpret for 
regulatory purposes, it will be reserved as ad-hoc 
analysis. Additional detail of the PRO analyses 
will be included in the supplemental SAP for the 
prespecification. 

 
Study SGNTUC-016 
Clinical Protocol 
Amendment 4, 08-Nov-2023 
Tucatinib 
Seagen Inc. – Confidential 
Page 125 of 129 
Section(s) 
Change 
Rationale 
Appendix A 
Added an ‘X’ for assessment HRCU at the ‘End of Treatment 
(EOT)’ visit.  
Added Footnote I to the following assessments at Day 1 in the 
‘Subsequent 21-Day Cycles’ column: physical examination, 
weight, and ECOG performance status.  
Modified text under Footnote M: 
Predose laboratory testing can must be done within 1 day prior to 
study visit. Confirm laboratory results prior to continuing study 
treatment dosing. 
Added text under Footnote R: 
Subject should complete questionnaires prior to evaluation by 
study personnel (physical examination, review of AEs) and 
administration of study treatment on treatment days (ie, within 
1 day prior to study treatment). 
Correction to be consistent with text in Section 
6.5. 
Update to indicate that these assessments do not 
need to be repeated, if already done within 1 day 
of study visit  
Correction to be consistent with text in Section 
6.4.3 
 
 
Clarification 
Appendix C 
Modified text: 
PosoconazolePosaconazole 
Added text: 
Antivirals 
 
Boceprevir 
3–4 hours 
Indinavir 
1–2 hours 
Nelfinavir 
3–5 hours 
Ritonavir 
3–5 hours 
Telaprevir 
9–11 hours 
Removed text (Footnote c): 
Strong CYP3A inhibitors are defined as those drugs that increase 
the area under the concentration-time curve (AUC) of oral 
midazolam or other CYP3A substrates ≥ 5-fold. Ritonavir, 
indinavir, nelfinavir, atazanavir, and saquinavir are also strong 
CYP3A3 inhibitors, but would not be used in this study as 
subjects with known human immunodeficiency virus are 
excluded. 
Spelling correction 
 
Added antiviral drugs under the category of 
‘Strong Inhibitors’ 
 
 
 
 
 
Modified footnote c because the study allows now 
enrollment of patients who were diagnosed as HIV 
positive. 
Appendix K 
Added text: 
Acceptable methods for preventing secondary exposure to 
seminal fluid 
Update to describe acceptable methods for 
preventing secondary exposure to seminal fluid 
and unacceptable methods of contraception 

 
Study SGNTUC-016 
Clinical Protocol 
Amendment 4, 08-Nov-2023 
Tucatinib 
Seagen Inc. – Confidential 
Page 126 of 129 
Section(s) 
Change 
Rationale 
Subjects born male and who are sexually active with a pregnant 
person must use a male condom (even if the subject has had a 
vasectomy).  
Subjects born male and who are sexually active with a 
breastfeeding person must use a male condom (even if the subject 
has had a vasectomy). In addition, it is recommended that the 
breastfeeding partner use a highly effective female contraceptive 
method as listed in the section titled “Acceptable combinations of 
contraceptive methods”. 
Unacceptable methods of contraception 
• Periodic abstinence 
• Spermicide only 
• No method 
• Progestin-only pills 
• Withdrawal 
• Concomitant use of female and male condoms 
• Rhythm 
• Barrier methods alone, including double-barrier methods 
 
Throughout protocol 
Changed the name of the patient-reported outcome measure 
‘EORTC IL6’ to ‘EORTC QLQ IL6’ when referring only to 2 
items on global health status and quality of life. 
Changed the name of the patient-reported outcome measure 
‘FACT-B’ to ‘FACT-B GP5’ when referring only to Item GP5 of 
the measure. 
Minor grammatical and spelling corrections, and formatting 
Correction 
 
 
Correction 
 
Administrative changes 
 
 
 

 
Study SGNTUC-016 
Clinical Protocol 
Amendment 4, 08-Nov-2023 
Tucatinib 
Seagen Inc. – Confidential 
Page 127 of 129 
SUMMARY OF CHANGES IN AMENDMENT 4  
Section(s) 
Change 
Rationale 
Cover page 
EU clinical trial (CT) number 2023-506418-30 added 
EU CT number was available 
Synopsis, Key Secondary 
Endpoints, Section 2 , 
Section 9.2.2.4 
Added text to include key secondary endpoint “compare overall 
survival in subjects with brain metastases at baseline (OS.BM) 
between treatment arms” 
Update for consistency with existing statistical 
analysis plan (SAP). 
Synopsis, Study Population 
Adjusted text to specify subjects must have histologically 
confirmed HER2+ breast carcinoma (previously the word ‘breast’ 
was not present). 
Addition of inadvertently omitted word  
Synopsis, Study Population, 
Section 4.1 inclusion criterion 2 
Added parenthetical reference to Appendix L which specifies 
eligible study population in France 
Direct to Appendix L for France specific language 
related to eligible study population 
Synopsis, Sample Size 
Considerations 
Adjusted wording about final OS analysis to be consistent with 
wording in Section 9.1 
Consistency across the document. 
Synopsis, Analysis Methods, 
Section 9.3.1.8 
 
Added text about hierarchical testing and graphic to illustrate 
hierarchical testing strategy 
More clearly present hierarchical testing strategy 
given multiple endpoints and analyses planned. 
Section 1.2 , Section 1.3, 
Section 1.4  
Updated text to be consistent with current standard of care 
Update to reflect current standard of care 
Section 3.1 , Figure 3 
Updated footnote d to be consistent with updates made to Section 
6.6. 
Consistency across the document. 
Section 4.2  
Added bullet to exclusion criterion (EC) 6 as follows: 
“For France and Italy only: Any history of interstitial lung 
disease or pneumonitis.” 
Added information to EC 8 to clarify Hepatitis B, Hepatitis C, 
and other known chronic liver disease exclusion criteria for 
subjects in Italy. 
France and Italy specific language being 
consolidated in this global amendment  
 
Italy specific language being consolidated in this 
global amendment 
Section 5.1.1.5  
Updated storage information to refer to the tucatinib pharmacy 
instructions. 
Provide source of most up to date storage 
information 
Section 5.3  
For France and Italy, added guidance about subjects being 
required to suspend treatment prior to surgery and when 
treatment can resume postoperatively in France and Italy. 
France and Italy specific language being 
consolidated in this global amendment  
Section 6.2.1  
Changed FISH to ISH.  
Make ISH method more general.  

 
Study SGNTUC-016 
Clinical Protocol 
Amendment 4, 08-Nov-2023 
Tucatinib 
Seagen Inc. – Confidential 
Page 128 of 129 
Section(s) 
Change 
Rationale 
Section 6.2.2  
Added bullet for Hepatitis B and C testing in Italy 
Italy specific language being consolidated in this 
global amendment 
Section 6.6, Appendix A Footnote F 
Updated language to more clearly indicate after the last imaging 
scan is completed, the follow up visits much be scheduled every 
90 days ± 7 days from the date of the last imaging scan or 90 
days from the last study visit, whichever is later, and continuing 
every 90 days (±7 days) until death, withdrawal of consent, lost 
to follow up, or study closure. Added text to indicate data for OS 
will be collected from public records if allowed per local 
regulations. 
 
Updated Footnote F in Appendix A to align with the changes to 
text in Section 6.6. 
Clarification about collection of follow up 
information after last imaging scan is completed 
and to indicate public records may be used as 
allowed per local regulations 
 
Addition of medical record review as a method of 
assessing survival status 
Section 7.1.1 
Adjusted language as follows: 
• “(most recent tumor tissue sample preferred requested)” … 
• 
“The central laboratory will require sufficient tumor tissue 
to generate unstained, positively-charged slides for HER2 
expression testing.” 
• 
“HER2 expression will be analyzed using FISH (DAKO 
IQFISH pharmDx)…" 
Clarification of requirements for HER2 expression 
confirmation and consistency across document. 
Section 7.2 
Removed specification of measurable disease for imaging: 
“At the investigator’s discretion, other appropriate imaging (eg, 
skin lesion photography for skin lesions, nuclear bone scan 
imaging for bone lesions) should be used to assess known sites of 
measurable disease” 
Clarification to clearly indicate these would be 
non-target lesions and not allowed as target lesions  
Section 7.6.2 
Adjusted PRO measurement tool title to “EORTC QLC IL6” 
instead of “EORTC QLQ-C30”. 
Clarification to be consistent across document and 
with protocol text description of PRO 
measurement tool  being used 
Section 7.7.4 
Updated clinical laboratory tests serum chemistry section to: 
“The chemistry panel is to include the following tests: blood urea 
nitrogen or urea,….” 
 
Clarification that either blood urea nitrogen or urea 
are acceptable. 
 
 

 
Study SGNTUC-016 
Clinical Protocol 
Amendment 4, 08-Nov-2023 
Tucatinib 
Seagen Inc. – Confidential 
Page 129 of 129 
Section(s) 
Change 
Rationale 
Added bullet about blood samples for Hepatitis B and C related 
testing specific to Italy. 
Italy specific language being consolidated in this 
global amendment 
Synopsis, Analysis Methods, 
Section 9.3.1.5, Section 9.3.1.8, 
Section 9.3.9 
Updated text to include OS.BM statistical analysis details 
Update for consistency with existing statistical 
analysis plan (SAP). 
Section 9.3.1.5, 
Section 9.3.9 
Updated 2-sided alpha value from 0.0499 to 0.05 
Update to alpha spend in statistical approach 
Appendix A 
Added safety assessment to table for Hepatitis B and C screening 
in Italy and added footnote X about requirement for Hepatitis B 
and C screening as a Safety Assessment in Italy. 
Italy specific assessment being consolidated in this 
global amendment 
Appendix D 
Updated to indicate that clopidogrel is a moderate CYP2C8 
inhibitor (previously listed as strong CYP2C8 inhibitor) 
Update based on most relevant classifications of 
CYP2C8 inhibitors 
Appendix K 
Added parenthetical phrase “see unacceptable methods of 
contraception” 
Added reference to unacceptable methods of 
contraception 
Appendix L (new Appendix) 
Added appendix with France-specific protocol requirements. As 
a result, subsequent appendix alphabetized titles have been 
shifted by 1 letter.  
France specific language being consolidated in this 
global amendment 
Throughout protocol 
Minor grammatical corrections, cross-reference updates, section 
formatting, addition of abbreviations to minimize wordiness, etc. 
Administrative updates