Clinical trial NCT05493501
Conditions: NSCLC
Sponsor: EQRx International, Inc.
Start date: 2022-12-14; Completion date: 2023-08-31
Enrollment: 8 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Aumolertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that targets EGFR mutations. The reason for this study is to learn whether adding chemotherapy to a new investigational drug called aumolertinib helps to slow or stop cancer growth in people with EGFR mutation-positive, locally advanced or metastatic non-small cell lung cancer (NSCLC). The study will compare this new combination of drugs to osimertinib, given alone. Aumolertinib given alone will also be used in the study, and it will be looked at in comparison with osimertinib given alone.

This is a randomized, open-label study with 3 different groups that are listed below. "Randomized" means the study treatment participants take will be chosen by chance (decided at random by a computer). "Open-label" means that the participant, the study doctor, and the Sponsor will know which study treatment each participant is receiving.

Participants will be randomly assigned to one of the following 3 treatment groups:

* Group 1: Treatment with aumolertinib alone, taken orally (by mouth) as a pill once a day. Around 100 participants will be randomly assigned to this group.
* Group 2: Treatment with aumolertinib taken orally as a pill once a day, in combination with chemotherapy given intravenously (IV; through a needle placed in a vein) on the schedule provided by the study doctor. Around 200 participants will be randomly assigned to this group.
* Group 3: Treatment with osimertinib alone, taken orally as a pill once a day. Around 200 participants will be randomly assigned to this group.

Because there will be twice as many participants in Group 2 and Group 3 as in Group 1, the chance of a participant being randomly assigned to either of those groups is twice as likely as being assigned to Group 1.

Participants can continue to receive study treatment as long as they have not withdrawn consent, as long as they choose to continue to receive study treatment and are judged by their doctor to continue to receive clinical benefit from receiving the study treatment, and as long as no other study treatment and/or study discontinuation criteria are met .

Detailed description:

Arms: arm 1: None arm 2: For adenocarcinoma, either:

* Aumolertinib + cisplatin with pemetrexed, or
* Aumolertinib + carboplatin with pemetrexed

For squamous cell carcinoma, one of the following:

* Aumolertinib + cisplatin or carboplatin with paclitaxel;
* Aumolertinib + cisplatin or carboplatin with albumin-bound paclitaxel; or
* Aumolertinib + cisplatin or carboplatin with gemcitabine arm 3: None
Interventions: intervention 1: Aumolertinib monotherapy intervention 2: Osimertinib monotherapy intervention 3: Pemetrexed intervention 4: Cisplatin intervention 5: Carboplatin intervention 6: Paclitaxel intervention 7: Nab paclitaxel intervention 8: Gemcitabine
Intervention descriptions: intervention 1: Administered orally, once daily as two 55-mg tablets for a total dose of 110 mg. intervention 2: 80 mg tablet administered orally, once daily intervention 3: Administered by IV Infusion per prescribing information. Maybe be continued as maintenance therapy intervention 4: Administered by IV Infusion given over 4 fixed cycles (q3wk × 4 cycles) per prescribing information. intervention 5: Administered by IV Infusion given over 4 fixed cycles (q3wk × 4 cycles) per prescribing information. intervention 6: Administered by IV Infusion given over 4 -6 fixed cycles per prescribing information. intervention 7: Administered by IV Infusion given over 4 fixed cycles per prescribing information. intervention 8: Administered by IV Infusion over 4 fixed cycles per prescribing information.

Protocol documents:
Prot_000.pdf: 
EQRx International, Inc. 
Protocol Amendment 5 (v6.0) 
EQ143-301 
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Confidential and Proprietary 
 
 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
Protocol Title: A Randomized, Three-Arm, Open-Label Phase 3b Clinical Trial of 
Aumolertinib, versus Aumolertinib with Chemotherapy, versus Osimertinib for Patients 
with Metastatic NSCLC and an EGFR Mutation (TREBLE) 
Protocol Number: EQ143-301 
Compound: aumolertinib (EQ143) 
Brief Title: Aumolertinib with Chemotherapy or Alone Compared with Osimertinib in Patients 
with Epidermal Growth Factor Receptor-Mutant Non-Small Cell Lung Cancer 
Study Phase: Phase 3b 
Sponsor Name: EQRx International, Inc. 
Legal Registered Address: 
50 Hampshire Street 
Cambridge, MA 02139 USA 
Regulatory Agency Identifier Number(s): 
US: 
 
CTIS: 
 
EU: 
 
NCT Number: NCT05493501 
Protocol Version and Date: Version 6.0 (Amendment 5), 19 May 2023 
 
 
 
Confidentiality Statement 
This document contains confidential information, which should not be copied, 
referred to, released, or published without written approval from EQRx 
International, Inc. Background information provided in this protocol is subject to 
change and revision. 


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SPONSOR SIGNATORY 
As representative of the Sponsor, EQRx International, Inc., I confirm that this study protocol was 
subjected to critical review. The information contained herein is consistent with current 
knowledge of the risks and benefits of the investigational product, as well as with the moral, 
ethical, and scientific principles governing clinical research as set out in the relevant law and any 
amendments thereof and in the International Council for Harmonisation (ICH) guidelines on 
Good Clinical Practice (GCP). 
I confirm that the following protocol has been agreed to and accepted. The Sponsor will collect 
the signed Investigator’s Agreement page of the protocol, in which each Investigator agrees to 
conduct the trial in compliance with the approved protocol and adhere to the principles outlined 
in the current ICH GCP Guidelines and any subsequent amendments thereof; the Sponsor’s (and 
any other relevant) standard operating procedures; and all applicable regulatory requirements in 
the countries where the study is conducted and any subsequent amendments thereof. 
I also confirm that the Sponsor will make the findings of the trial publicly available through 
publication or other dissemination tools without any unnecessary delay, and that an honest, 
accurate, and transparent account of the trial will be given; and that any discrepancies and 
serious breaches of GCP from the trial as planned in this protocol will be explained. 
 
5/21/2023 
 
 
 
 
 
 
Date 
 
 
 
DOCUMENT HISTORY 
Document 
Date 
Amendment 5 (v6.0) 
19 May 2023 
Amendment 4 (v5.0) 
10 April 2023 
Amendment 3 (v4.0) 
13 December 2022 
Amendment 2 (v3.0) 
01 July 2022 
Amendment 1 (v2.0) 
22 June 2022 
Original Protocol (v1.0) 
09 February 2022 


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INVESTIGATOR’S AGREEMENT 
Protocol Title: 
A Randomized, Three-Arm, Open-Label Phase 3b Clinical Trial of 
Aumolertinib, versus Aumolertinib with Chemotherapy, versus Osimertinib 
for Patients with Metastatic NSCLC and an EGFR Mutation (TREBLE) 
All documentation for this study that is supplied to me and has not previously been published 
will be kept in the strictest confidence. Documentation includes, but is not limited to, the study 
protocol, Investigator’s Brochure(s), electronic case report forms, and other scientific data. 
The study will not commence without the approvals and/or registrations as required in the 
countries where the study is conducted. No changes will be made to the study protocol without 
the prior written approval of the Sponsor, Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC), and all other applicable approvals as required in the countries where the study 
is conducted, except where necessary to avert an immediate hazard to the study participants. 
I have read the protocol and agree that the study will be conducted in compliance with the 
protocol and in accordance with the principles outlined in the current ICH GCP Guidelines and 
any subsequent amendments thereof; the Medicines for Human Use (Clinical Trials) Regulations 
2004 (SI 2004/1031), amended regulations (SI 2006/1928), and any subsequent amendments 
thereof; the current Guideline for GCP E6 (R2) (European Medicines Agency/Committee for 
Medicinal Products for Human Use/ICH/135/1995) and any subsequent amendments thereof; the 
current clinical trial regulations in the countries where the study is conducted and any subsequent 
amendments thereof; the Sponsor’s (and any other relevant) requirements; and all applicable 
regulatory requirements in the countries where the study is conducted and any subsequent 
amendments thereof. The conduct of the study will be in accordance with the Integrated 
Addendum to ICH E6 (R1): Guideline for GCP ICH E6 (R2) and any subsequent 
amendments thereof. 
I acknowledge that I am responsible for the overall study conduct. I agree to personally conduct 
or supervise the described clinical study. I agree to ensure that all associates, colleagues, and 
employees assisting in the conduct of the study at my site are informed about their obligations. 
Mechanisms are in place to ensure that site staff receive the appropriate information throughout 
the study. 
 
 
 
Investigational Site 
 
 
 
Printed Name of Investigator 
 
 
 
Signature of Investigator 
 
 
 
Date 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
 
DOCUMENT HISTORY 
Document Version 
Date 
Version 6.0 (Amendment 5) 
19 May 2023 
Version 5.0 (Amendment 4) 
10 April 2023 
Version 4.0 (Amendment 3) 
13 December 2022 
Version 3.0 (Amendment 2) 
01 July 2022 
Version 2.0 (Amendment 1) 
22 June 2022 
Version 1.0 (Original Protocol) 
09 February 2022 
Version 6.0 (Amendment 5): 19 May 2023 
Version 6.0 (Amendment 5) of this Phase 3b study protocol is considered to be a nonsubstantial 
protocol amendment because it does not impact participant safety, the design and conduct of the 
study, or the study data analysis. 
Overall Rationale for the Protocol Amendment 
As detailed in the Summary of Changes table below, the main overall rationale for updating to 
protocol Version 6.0 (Amendment 5) is to clarify ambiguity in Exclusion Criterion #6 and 
remove an incorrect reference to rescue medication (which is not applicable to this study). 


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Section #(s), Title(s) 
Description of Change 
Brief Rationale 


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Cover Page 
• 
The study Clinical Trials Information System (CTIS) number 
has been added to the protocol cover page. 
• 
To comply with applicable European Union 
regulatory guidance 


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5.2, Exclusion Criteria 
• 
Exclusion Criterion #6 has been modified as follows: 
Has received prior systemic treatment for metastatic NSCLC. 
Notes: 
o 
Prior chemotherapy is permitted, provided that it was 
used for treatment of locoregional NSCLC as a 
component of curative intent therapy and 
administration was completed more than 
6 months prior to Screening. 
o 
Participants with a history of radiotherapy for Stage 
III NSCLC may be eligible (with a required washout 
period of ≥ 2 weeks before Screening, as detailed in 
Inclusion Criterion #9 above); however: 
 
Lesions that received radiotherapy are not 
included in the calculation of RECIST v1.1. 
 
Radiation in the metastatic setting, for any 
reason, is not permitted. 
 
Concurrent radiotherapy is not permitted. 
 
Prior EGFR-TKI therapy is not permitted. 
• 
To remove ambiguity concerning the permissible 
participant population for the study 


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6.7.1, Rescue Medication (now 
deleted) 
• 
This section of the protocol has been removed. 
• 
To correct an administrative error in previous 
versions of the protocol; no rescue medication is 
provided for/applicable to this study. 


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5.1, Inclusion Criteria 
10.4, Appendix 4: Hy’s Law 
Definition, Reporting, and 
Observation Requirements 
• 
References to direct bilirubin have been removed from 
Inclusion Criterion #6 and the Hy’s Law Definition, Reporting, 
and Observation Requirements appendix. 
• 
To indicate that total bilirubin alone (not total 
bilirubin in combination with direct bilirubin) is to be 
used when determining adequate hepatic function 
during Screening and when evaluating cases 
indicative of possible hepatocellular injury (Hy’s 
Law). 


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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................................... 1 
SPONSOR SIGNATORY ................................................................................................................ 2 
INVESTIGATOR’S AGREEMENT ............................................................................................... 3 
PROTOCOL AMENDMENT SUMMARY OF CHANGES .......................................................... 4 
TABLE OF CONTENTS ............................................................................................................... 10 
LIST OF TABLES ......................................................................................................................... 15 
LIST OF FIGURES ........................................................................................................................ 15 
1. 
PROTOCOL SUMMARY .......................................................................................... 16 
1.1. 
Synopsis ...................................................................................................................... 16 
1.2. 
Schema ........................................................................................................................ 21 
1.3. 
Schedules of Activities (SoAs) ................................................................................... 22 
2. 
INTRODUCTION ...................................................................................................... 42 
2.1. 
Study Rationale ........................................................................................................... 42 
2.2. 
Background ................................................................................................................. 43 
2.3. 
Benefit/Risk Assessment ............................................................................................. 44 
2.3.1. 
Benefit Assessment ..................................................................................................... 44 
2.3.2. 
Risk Assessment ......................................................................................................... 44 
2.3.3. 
Overall Benefit/Risk Conclusion ................................................................................ 45 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................ 46 
4. 
STUDY DESIGN ........................................................................................................ 48 
4.1. 
Overall Design ............................................................................................................ 48 
4.2. 
Scientific Rationale for Study Design ......................................................................... 50 
4.2.1. 
Scientific Rationale for Evaluation of Tumor Growth Rate ....................................... 50 
4.3. 
Rationale for Dose Selection ....................................................................................... 50 
4.4. 
End of Study ............................................................................................................... 51 
5. 
STUDY POPULATION ............................................................................................. 52 
5.1. 
Inclusion Criteria ......................................................................................................... 52 
5.2. 
Exclusion Criteria ....................................................................................................... 54 
5.3. 
Lifestyle Considerations .............................................................................................. 56 
5.3.1. 
Meals and Dietary Restrictions ................................................................................... 56 
5.3.2. 
Activity ....................................................................................................................... 56 


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5.4. 
Screen Failures ............................................................................................................56 
5.4.1. 
Screening and Enrollment Log and Participant Identification Numbers ....................57 
6. 
STUDY INTERVENTIONS AND CONCOMITANT THERAPY ...........................58 
6.1. 
Study Interventions Administered ...............................................................................58 
6.2. 
Preparation, Handling, Storage, and Accountability ...................................................59 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................59 
6.4. 
Study Intervention Compliance...................................................................................59 
6.5. 
Dose Modification .......................................................................................................60 
6.5.1. 
General Principles of Aumolertinib Dose Adjustment Related to Selected 
AEs ..............................................................................................................................60 
6.5.2. 
Dose Adjustments to Osimertinib or Chemotherapy Regimens .................................62 
6.5.2.1. 
Recommendations for Discontinuing Osimertinib or Chemotherapy .........................63 
6.6. 
Treatment of Overdose ................................................................................................64 
6.7. 
Prior and Concomitant Therapy/Procedures ...............................................................64 
7. 
DISCONTINUATION FROM STUDY TREATMENT AND FROM THE 
OVERALL STUDY....................................................................................................66 
7.1. 
Permanent Discontinuation of a Participant from Study Treatment ...........................66 
7.1.1. 
Liver Chemistry Stopping Criteria ..............................................................................68 
7.1.2. 
Cardiac Stopping Criteria ............................................................................................68 
7.1.3. 
Temporary Discontinuation of a Participant from Study Treatment ...........................68 
7.1.4. 
Re-challenge Therapy .................................................................................................68 
7.2. 
Permanent Discontinuation/Withdrawal of a Participant from the Study ...................68 
7.2.1. 
Criteria for Permanent Participant Discontinuation/Withdrawal from the 
Study ...........................................................................................................................69 
7.3. 
Lost to Follow-up ........................................................................................................70 
7.4. 
Criteria for Potential Stoppage (Permanent Discontinuation) of the Study ................70 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................72 
8.1. 
Efficacy Assessments ..................................................................................................73 
8.1.1. 
Antitumor Activity Assessments.................................................................................73 
8.1.2. 
Tumor Imaging Assessments ......................................................................................73 
8.1.2.1. 
Computed Tomography Scans of the Chest and Abdomen/Pelvis with 
Contrast .......................................................................................................................73 
8.1.2.2. 
Positron Emission Tomography/Computed Tomography Scans ................................73 
8.1.2.3. 
Anatomic Coverage.....................................................................................................73 


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8.1.2.4. 
IV Contrast Administration ......................................................................................... 74 
8.1.2.5. 
Slice Thickness and Reconstruction Interval .............................................................. 74 
8.1.2.6. 
Sites and Schedule of Tumor Assessments ................................................................. 75 
8.1.2.7. 
Brain Imaging ............................................................................................................. 75 
8.1.3. 
ECOG Performance Status.......................................................................................... 75 
8.1.4. 
Post-treatment Circulating Tumor DNA Clearance .................................................... 76 
8.1.5. 
Companion Diagnostic Testing ................................................................................... 76 
8.2. 
Safety Monitoring ....................................................................................................... 77 
8.3. 
Safety Assessments ..................................................................................................... 77 
8.3.1. 
Physical Examinations ................................................................................................ 77 
8.3.1.1. 
Full and Symptom-directed Physical Exams .............................................................. 77 
8.3.1.2. 
Body Weight and Height ............................................................................................ 77 
8.3.2. 
Vital Signs ................................................................................................................... 78 
8.3.3. 
Electrocardiograms ...................................................................................................... 78 
8.3.4. 
Clinical Safety Laboratory Tests ................................................................................. 79 
8.3.5. 
Pregnancy Testing ....................................................................................................... 79 
8.4. 
AEs, SAEs, and Other Safety Reporting ..................................................................... 79 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information ....................... 80 
8.4.2. 
Method of Detecting AEs and SAEs ........................................................................... 81 
8.4.3. 
Follow-up of AEs and SAEs ....................................................................................... 81 
8.4.4. 
Regulatory Reporting Requirements for SAEs ........................................................... 81 
8.4.5. 
Pregnancy .................................................................................................................... 81 
8.4.6. 
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs ............................................................................................................... 82 
8.5. 
Pharmacokinetic Assessments (Aumolertinib and Aumolertinib with 
Chemotherapy Arms Only) ......................................................................................... 83 
8.6. 
Patient-reported Outcomes and Quality of Life Assessments ..................................... 83 
8.7. 
Blood Volume ............................................................................................................. 83 
8.8. 
Biomarkers and Immunogenicity Assessments ........................................................... 84 
8.9. 
Medical Resource Utilization and Health Economics ................................................ 84 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 85 
9.1. 
General Considerations ............................................................................................... 85 
9.1.1. 
Statistical Hypotheses ................................................................................................. 85 


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9.1.2. 
Determination of Sample Size ....................................................................................85 
9.1.3. 
Interim Analysis ..........................................................................................................86 
9.2. 
Definition of Statistical Analysis Sets.........................................................................86 
9.2.1. 
Full Analysis Set .........................................................................................................86 
9.2.2. 
Safety Analysis Set .....................................................................................................86 
9.2.3. 
Pharmacokinetic Analysis Set .....................................................................................86 
9.3. 
Definitions for Efficacy Endpoints .............................................................................86 
9.4. 
Statistical Analyses .....................................................................................................87 
9.4.1. 
Participant Disposition ................................................................................................87 
9.4.2. 
Demographics and Baseline Disease Characteristics ..................................................87 
9.4.3. 
Efficacy Analyses .......................................................................................................88 
9.4.3.1. 
Primary Endpoint Analysis .........................................................................................88 
9.4.3.2. 
Key Secondary Endpoint Analysis .............................................................................88 
9.4.3.3. 
Other Secondary Endpoint Analyses ..........................................................................88 
9.4.3.4. 
Exploratory Endpoint Analyses ..................................................................................89 
9.4.4. 
Safety Analyses ...........................................................................................................90 
9.4.4.1. 
Exposure .....................................................................................................................90 
9.4.4.2. 
AEs ..............................................................................................................................90 
9.4.4.3. 
Physical Exam Findings ..............................................................................................90 
9.4.4.4. 
Vital Signs ...................................................................................................................90 
9.4.4.5. 
Electrocardiograms ......................................................................................................90 
9.4.4.6. 
Clinical Laboratory Tests ............................................................................................91 
9.4.5. 
Patient-reported Outcomes and Quality of Life Analyses ..........................................91 
9.4.6. 
Pharmacokinetic Analyses ..........................................................................................91 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................92 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations .....................92 
10.1.1. 
Regulatory and Ethical Considerations .......................................................................92 
10.1.2. 
Financial Disclosure ....................................................................................................93 
10.1.3. 
Informed Consent Process ..........................................................................................93 
10.1.4. 
Data Protection ............................................................................................................93 
10.1.5. 
Committees Structure ..................................................................................................94 
10.1.5.1. 
Committee for Blinded Independent Central Review .................................................94 


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10.1.6. 
Dissemination of Clinical Study Data ......................................................................... 94 
10.1.7. 
Data Quality Assurance .............................................................................................. 94 
10.1.7.1. 
Study Monitoring ........................................................................................................ 94 
10.1.7.2. 
Audits and Inspections ................................................................................................ 94 
10.1.7.3. 
Quality Control and Quality Assurance ...................................................................... 95 
10.1.8. 
Source Documents ...................................................................................................... 96 
10.1.8.1. 
Records Retention ....................................................................................................... 96 
10.1.9. 
Study and Site Start and Closure ................................................................................. 97 
10.1.9.1. 
First Act of Recruitment .............................................................................................. 97 
10.1.9.2. 
Study Termination ....................................................................................................... 97 
10.1.9.3. 
Site Termination .......................................................................................................... 97 
10.1.10. 
Publication Policy ....................................................................................................... 98 
10.1.11. 
Protocol Approval and Amendments .......................................................................... 98 
10.1.12. 
Liability and Insurance ................................................................................................ 98 
10.1.13. 
Access to Source Data ................................................................................................. 99 
10.2. 
Appendix 2: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ...................................................................... 100 
10.2.1. 
Definition of an AE ................................................................................................... 100 
10.2.2. 
Definition of an SAE ................................................................................................. 101 
10.2.3. 
Recording and Follow-up of AEs and SAEs ............................................................ 102 
10.2.4. 
Reporting of SAEs .................................................................................................... 104 
10.2.4.1. 
SAE Contact Details ................................................................................................. 106 
10.3. 
Appendix 3: Contraceptive and Barrier Guidance .................................................... 107 
10.3.1. 
Definitions ................................................................................................................. 107 
10.3.2. 
Contraception Guidance ............................................................................................ 108 
10.4. 
Appendix 4: Hy’s Law Definition, Reporting, and Observation 
Requirements............................................................................................................. 110 
10.5. 
Appendix 5: Prohibited Concomitant Medications ................................................... 112 
10.6. 
Appendix 6: Tumor Identification, Response, and Progression per RECIST 
v1.1 ............................................................................................................................ 113 
10.6.1. 
Definitions of Tumor Response and Disease Progression per RECIST v1.1 ........... 113 
10.6.1.1. 
Evaluation of Target Lesion Response ..................................................................... 113 
10.6.1.2. 
Evaluation of Nontarget Lesions............................................................................... 114 


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10.6.1.3. 
Evaluation of Overall Response ................................................................................114 
10.7. 
Appendix 7: Definitions of Response and Progression for Brain Metastases 
per RANO Criteria ....................................................................................................115 
10.8. 
Appendix 8: Clinical Safety Laboratory Tests ..........................................................116 
10.8.1. 
Hematology ...............................................................................................................116 
10.8.2. 
Serum Chemistry.......................................................................................................116 
10.8.3. 
Urinalysis ..................................................................................................................117 
10.8.4. 
Coagulation ...............................................................................................................117 
10.9. 
Appendix 9: Pre-Screening EGFR Mutation Testing for Prospective Study 
Participants (as applicable) .......................................................................................118 
10.10. 
Appendix 10: Patient-Reported Outcomes Questionnaire ........................................119 
10.11. 
Appendix 11: Abbreviations and Definitions of Terms ............................................125 
11. 
REFERENCES..........................................................................................................130 
 
LIST OF TABLES 
Table 1: 
Aumolertinib Monotherapy Arm – SoA (EQ143-301 [TREBLE]) ............................23 
Table 2: 
Aumolertinib with Chemotherapy Arm – SoA (EQ143-301 [TREBLE]) ..................30 
Table 3: 
Osimertinib Monotherapy Arm – SoA (EQ143-301 [TREBLE]) ...............................36 
Table 4: 
Study Treatment Arms ................................................................................................58 
Table 5: 
Specifications for Aumolertinib Dose Reduction .......................................................60 
Table 6: 
Dose Adjustment Principles of Aumolertinib Tablets when Selected AEs 
Considered Treatment-related by the Investigator Occur ...........................................61 
Table 7: 
Eastern Cooperative Oncology Group Performance Status ........................................76 
Table 8: 
Examples of Prohibited Concomitant Agents Because of the Potential for 
Pharmacokinetic Drug-Drug Interaction with Aumolertiniba ................................................... 112 
Table 9: 
Evaluation of Overall Response per RECIST v1.1 at Each Time Point ...................114 
Table 10: 
Evaluation of Response and Progression for Brain Metastases per RANO 
Criteria ......................................................................................................................115 
LIST OF FIGURES 
Figure 1: 
Study Schema (EQ143-301 [TREBLE]) .....................................................................21 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Randomized, Three-Arm, Open-Label Phase 3b Clinical Trial of 
Aumolertinib, versus Aumolertinib with Chemotherapy, versus Osimertinib for 
Patients with Metastatic NSCLC and an EGFR Mutation (TREBLE) 
Protocol Number: EQ143-301 
Protocol Version: 6.0 (Amendment 5) 
Compound: aumolertinib (EQ143) 
Brief Title: Aumolertinib with Chemotherapy or Alone Compared with Osimertinib in Patients 
with Epidermal Growth Factor Receptor-Mutant Non-Small Cell Lung Cancer 
Rationale: Whether the addition of chemotherapy to a third-generation epidermal growth 
factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), such as aumolertinib, improves 
progression-free survival (PFS) in patients with metastatic EGFR-mutated non-small cell lung 
cancer (NSCLC) is unknown. In particular, the efficacy, safety, and tolerability of this approach 
compared with that of EGFR-TKI monotherapy in patients with an Eastern Cooperative 
Oncology Group (ECOG) performance status (PS) of 2 has not been studied prospectively. 
Objectives and Endpoints: 
 
Objectives 
Endpoints 
Primary 
• 
To assess the efficacy of 
aumolertinib in combination 
with chemotherapy compared 
with osimertinib monotherapy 
• 
PFS, as assessed by blinded independent central 
review (BICR) per RECIST v1.1 
Key Secondary 
• 
To further assess the efficacy of 
aumolertinib in combination 
with chemotherapy compared 
with osimertinib monotherapy 
• 
OS 
Other Secondary 
• 
To assess other efficacy 
measures of aumolertinib in 
combination with 
chemotherapy compared with 
osimertinib monotherapy 
• 
TGR, ORR, DCR, DepOR, and DoR, each assessed 
by BICR per RECIST v1.1 
• 
PFS, TGR, ORR, DCR, DepOR, and DoR, each 
assessed by the Investigator per RECIST v1.1 
• 
ctDNA clearance 


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Objectives 
Endpoints 
• 
To assess the efficacy of 
aumolertinib monotherapy 
compared with osimertinib 
monotherapy 
• 
PFS, TGR, ORR, DCR, DepOR, and DoR, each 
assessed by BICR per RECIST v1.1 
• 
PFS, TGR, ORR, DCR, DepOR, and DoR, each 
assessed by the Investigator per RECIST v1.1 
• 
OS 
• 
ctDNA clearance 
• 
To assess safety, including 
toxicities mediated by EGFR 
WT inhibition, in the study 
treatment arms 
• 
TEAEs, vital signs, ECGs, and laboratory test 
results (including chemistry, hematology, and 
urinalysis) by treatment arm 
• 
To evaluate selected PROs and 
QoL, including toxicities 
mediated by EGFR WT 
inhibition, in the study 
population 
• 
NCI PRO-CTCAE questionnaire 
• 
To characterize the PK profile 
of aumolertinib alone and in 
combination with 
chemotherapy 
• 
Aumolertinib concentration for population 
PK analysis 
Exploratory 
• 
To characterize mechanisms of 
acquired resistance in the 
treatment population 
• 
Exploratory biomarker analysis of plasma samples 
banked for the purpose of characterizing resistance 
mechanisms in participants treated with 
aumolertinib in combination with chemotherapy, 
aumolertinib monotherapy, and osimertinib 
monotherapy 
• 
To evaluate CNS efficacy for 
participants in the study 
treatment arms with measurable 
CNS lesions at baseline 
• 
Description of CNS efficacy as measured by PFS; 
OS; and ORR, DCR, DepOR, and DoR (each 
assessed by the Investigator per Response 
Assessment in Neuro-Oncology [RANO] criteria) 
• 
To evaluate additional efficacy 
measures in the study treatment 
arms 
• 
PFS2, as applicable 
• 
TFST and TSST, as applicable 
• 
To evaluate the correlation 
between TGR and ctDNA 
clearance with PFS and OS in 
the study treatment arms 
• 
TGR, ctDNA, PFS assessed by the Investigator per 
RECIST v1.1, and OS 
• 
To evaluate the exposure- 
response relationship of 
aumolertinib alone and in 
combination with 
chemotherapy 
• 
Exposure-response analysis of safety and efficacy 
endpoints 


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Overall Design: 
EQ143-301 (TREBLE) is a Phase 3b, multicenter, randomized, 3-arm, open-label study of 
aumolertinib + chemotherapy combination therapy compared with osimertinib monotherapy, and 
aumolertinib monotherapy described in comparison with osimertinib monotherapy. 
Approximately 200 study sites in multiple regions are currently planned to participate. 
The primary study endpoint is efficacy by PFS (as assessed by BICR per RECIST v1.1). PFS is 
defined as the time from date of participant randomization to either the first date of disease 
progression (per RECIST v1.1) or the date of death by any cause, whichever occurs first. 
Brief Summary: 
The purpose of this study is to evaluate the efficacy and safety of aumolertinib alone, 
aumolertinib with chemotherapy, and osimertinib alone (active comparator) in systemic 
treatment-naïve participants who have metastatic EGFR-mutant NSCLC and an ECOG PS of 
0, 1, or 2. 
Additional study details include the following: 
• The study duration will be 5 years or more. 
• A cycle of treatment is defined as 21 days for all arms. 
− Cycles 2 onward have a window of 2 days prior to, or 7 days following, the cycle 
due date. 
• Participants can continue to receive study treatment as long as they have not withdrawn 
consent and are judged by the Investigator to continue to receive clinical benefit, in the 
absence of meeting other treatment and/or study discontinuation criteria. 
Number of Participants: 
Approximately 500 participants will be randomized in a 2:2:1 ratio (by the stratified permuted 
block randomization method) and enrolled into one of 3 study treatment arms: aumolertinib + 
chemotherapy combination therapy, osimertinib monotherapy, or aumolertinib monotherapy, 
respectively. 
Note: “Enrolled” in the context of the clinical study means the agreement of a participant to 
participate in the study following completion of the informed consent process. Potential 
participants who are screened for the purpose of determining study eligibility, but are not 
randomized to study treatment (ie, are not eligible for study participation), are not considered 
enrolled. 


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Intervention Groups and Duration: 
Approximately 500 study participants will be randomized in a 2:2:1 ratio (by stratified permuted 
block randomization method) and enrolled into one of 3 study treatment arms: 
1. Aumolertinib with chemotherapy (platinum-based doublet), as follows (approximately 
200 participants): 
• For adenocarcinoma, either: 
− Aumolertinib + cisplatin with pemetrexed, or 
− Aumolertinib + carboplatin with pemetrexed 
• For squamous cell carcinoma, one of the following: 
− Aumolertinib + cisplatin or carboplatin with paclitaxel; 
− Aumolertinib + cisplatin or carboplatin with albumin-bound paclitaxel; or 
− Aumolertinib + cisplatin or carboplatin with gemcitabine 
2. Osimertinib alone (approximately 200 participants) 
3. Aumolertinib alone (approximately 100 participants) 
All participants will be stratified by the following factors: 
• EGFR mutation (ex19del versus L858R) 
• ECOG PS (0 versus 1/2) 
• Race (White versus Asian versus Other Races Combined) 
Aumolertinib will be administered as two 55-mg tablets for a total dose of 110 mg once daily. 
Each aumolertinib tablet contains EQ143 drug substance, microcrystalline cellulose (KG802), 
anhydrous lactose (21AN), sodium carboxymethyl starch (type A), sodium stearyl fumarate, and 
magnesium stearate (MF-2-V). Based on current available data, aumolertinib may be taken with 
or without food. 
Osimertinib will be administered as a single 80-mg tablet once daily. 
While selected participants with a percutaneous endoscopic gastrostomy (PEG) tube may be 
eligible for this study at Investigator discretion, aumolertinib and osimertinib tablets are not to be 
crushed or otherwise damaged. 
Participants randomized to receive aumolertinib with chemotherapy will receive up to 4 cycles of 
a platinum-based doublet, along with once-daily aumolertinib at 110 mg. 
Thereafter, at the Investigator’s discretion as based on assessment of continued clinical benefit, 
the participant may go on to receive maintenance pemetrexed with once-daily aumolertinib for 
the remainder of their time on study treatment—provided that they do not meet any of the study 
treatment discontinuation and/or overall study discontinuation criteria. 
As specified in the SoAs (Section 1.3), participants will continue on study treatment until disease 
progression (with certain exceptions, as noted immediately below), withdrawal of consent, 
Investigator decision, or other reasons as detailed in Section 7.2. 


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Note: Based upon Investigator judgment, selected participants who experience confirmed 
disease progression (per RECIST v1.1) may be permitted to continue post-progression study 
treatment upon discussion with and approval by the Sponsor. These participants, who will be 
required to sign a separate ICF, must meet both of the following criteria to continue their 
assigned study treatment after progression: 
• No decline in ECOG PS attributable to underlying disease. 
• Absence of symptomatic rapid disease progression requiring urgent medical 
intervention (eg, symptomatic pleural effusion, spinal cord compression). 
Committee for Blinded Independent Central Review: 
A central blinded Independent Review Committee will be used for the primary study endpoint of 
BICR-assessed PFS (per RECIST v1.1). BICR will also be used to evaluate images collected 
during the study for assessment of the secondary tumor-based efficacy endpoints. 
A separate charter will define the procedures used by this committee for the purposes of BICR. 


21 
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1.2. 
Schema 
Figure 1: 
Study Schema (EQ143-301 [TREBLE]) 
 
 
 
del = deletion; EGFR = epidermal growth factor receptor; ECOG PS = Eastern Cooperative Oncology Group performance status. 


22 
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1.3. 
Schedules of Activities (SoAs) 
The study SoAs are presented by treatment arm, as follows: the aumolertinib monotherapy arm 
in Table 1; the aumolertinib with chemotherapy arm in Table 2; and the osimertinib 
monotherapy arm in Table 3. 


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Table 1: 
Aumolertinib Monotherapy Arm – SoA (EQ143-301 [TREBLE]) 
 
Study Period: 
Screeninga 
Study Treatmenta, h 
(all treatment cycles = 21 days; 
from C2 onward, window of -2/+7 daysb) 
Study 
Treatment 
D/Ca 
Safety 
Follow-up 
k, n 
Survival 
Follow- 
upl 
Time Point(s): 
D -28 to 
D -1 
D -7 to 
D -1 
C1 
D1 
C2b 
D1 
C3b 
D1 
C4b 
D1 
C5b 
D1 
C6b 
D1 
C7+b 
D1 
(non- 
dosing 
activities 
are 
q12wk) 
At any 
point 
Post- 
treatment 
D/C 
Post- 
treat- 
ment 
D/C 
Frequency: 
Once 
Once 
Once 
Visit Window for all 
non-dosing activities: 
± 2 days 
+ 7 days 
-- 
General Screening Procedures 
Study Informed Consent 
X 
IRT Screening (after ICF 
Signature) 
X 
Participant History & Study Eligibility Review 
Demographics/Baseline 
Characteristics 
X 
Inclusion/Exclusion 
Criteria 
X 
Medical History & Current 
Medical Conditions 
X 
Prior & Concomitant 
Medications/Procedures 
Review 
X 
X 
X 
X 
X 
X 
X 
X 
Smoking Status 
X 
SARS-CoV-2 
Vaccination, Symptom, 
& Testing Reviewj 
X 
Diagnosis & Extent of 
Cancer 
X 
Prior Anticancer Therapy 
X 
IRT – Randomization 
X 


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Study Period: 
Screeninga 
Study Treatmenta, h 
(all treatment cycles = 21 days; 
from C2 onward, window of -2/+7 daysb) 
Study 
Treatment 
D/Ca 
Safety 
Follow-up 
k, n 
Survival 
Follow- 
upl 
Time Point(s): 
D -28 to 
D -1 
D -7 to 
D -1 
C1 
D1 
C2b 
D1 
C3b 
D1 
C4b 
D1 
C5b 
D1 
C6b 
D1 
C7+b 
D1 
(non- 
dosing 
activities 
are 
q12wk) 
At any 
point 
Post- 
treatment 
D/C 
Post- 
treat- 
ment 
D/C 
Frequency: 
Once 
Once 
Once 
Visit Window for all 
non-dosing activities: 
± 2 days 
+ 7 days 
-- 
IRT – Study Drug 
Dispensation (Participant 
Dispensation) 
X 
X 
X 
X 
X 
X 
X 
ECOG PS & Physical Examinations 
Physical Exam 
X 
Xc 
X 
X 
X 
X 
X 
X 
ECOG PS 
X 
Xc 
X 
X 
X 
X 
X 
X 
Height 
X 
Body Weight 
X 
Xc 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
Xc 
X 
X 
X 
X 
X 
X 
Laboratory Assessments*,o 
EGFR Mutation Testingp 
X 
(pre-screening)p 
X 
Hematology: ANCo, Hgb, 
WBC, & PLAT 
X 
Xc 
X 
X 
X 
X 
X 
X 
Hematology: all other labs 
listed in Section 10.8.1 
As clinically indicated 
Serum Chemistry: ALT, 
ALP, AST, TBIL + IBILI, 
CPK, calculated CLCro, 
CREATo, & GLUo 
X 
Xc 
X 
X 
X 
X 
X 
X 
Serum Chemistry: all 
other labs listed in 
Section 10.8.2 
As clinically indicated 
Coagulation: PT/INR 
X 
As clinically indicated 


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Study Period: 
Screeninga 
Study Treatmenta, h 
(all treatment cycles = 21 days; 
from C2 onward, window of -2/+7 daysb) 
Study 
Treatment 
D/Ca 
Safety 
Follow-up 
k, n 
Survival 
Follow- 
upl 
Time Point(s): 
D -28 to 
D -1 
D -7 to 
D -1 
C1 
D1 
C2b 
D1 
C3b 
D1 
C4b 
D1 
C5b 
D1 
C6b 
D1 
C7+b 
D1 
(non- 
dosing 
activities 
are 
q12wk) 
At any 
point 
Post- 
treatment 
D/C 
Post- 
treat- 
ment 
D/C 
Frequency: 
Once 
Once 
Once 
Visit Window for all 
non-dosing activities: 
± 2 days 
+ 7 days 
-- 
Urinalysis: dipstick 
parameters (refer to 
Section 10.8.3) 
As clinically indicated 
Pregnancy Test (all female 
participants of 
childbearing potential)d 
X 
(≤ 48 h 
pre-first 
dose) 
Pregnancy Test (only 
female participants of 
childbearing potential 
who are not on 
contraceptiond) 
X 
X 
X 
X 
X 
X 
X 
Blood Sample Collection 
for ctDNA Analysism 
Xm 
X 
X 
At disease progression (as appl.) 
Cardiac Assessments 
ECGe 
X 
Xc 
X 
ECHO or MUGA (LVEF)g 
X 
Xc 
Xg 
Pharmacokinetic Assessments 
PK Blood Sample 
Collectionf 
X 
X 
X 
X 
X 


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Study Period: 
Screeninga 
Study Treatmenta, h 
(all treatment cycles = 21 days; 
from C2 onward, window of -2/+7 daysb) 
Study 
Treatment 
D/Ca 
Safety 
Follow-up 
k, n 
Survival 
Follow- 
upl 
Time Point(s): 
D -28 to 
D -1 
D -7 to 
D -1 
C1 
D1 
C2b 
D1 
C3b 
D1 
C4b 
D1 
C5b 
D1 
C6b 
D1 
C7+b 
D1 
(non- 
dosing 
activities 
are 
q12wk) 
At any 
point 
Post- 
treatment 
D/C 
Post- 
treat- 
ment 
D/C 
Frequency: 
Once 
Once 
Once 
Visit Window for all 
non-dosing activities: 
± 2 days 
+ 7 days 
-- 
Other Safety Assessments 
AE/SAE Collection 
Continuous 
Refer to 
footnote 
“k” 
Refer to 
footnote 
“l” 
SARS-CoV-2 Testing (per 
institutional standards & 
local/country regulations)j 
As appl. 
Tumor Assessments 
CT of Chest & 
Abdomen/Pelvis with 
Contrast (or PET/CT, at 
Inv. discretion)h 
X 
q6wk (± 3 days) for first 3 post-baseline assessments, then q12wkh 
Brain Imaging for 
Participants with Baseline 
Brain Metastasesi 
X 
q6wk (± 3 days) for first 3 post-baseline assessments, then q12wkh 
Brain Imaging for 
Participants without 
Baseline Brain Metastases 
X 
If clinically indicated (as appl.)h,i 
Archival Tissue Collection 
for CDx Testingq (only if 
available; not required) 
X 
Patient-Reported Outcomes & Quality of Life Assessments 
PRO/QoL Assessment 
(NCI PRO-CTCAE) 
qwk 
qwk 
qwk 
qwk 
X 
X 
q6wk 
X 
IRT – Discontinuation 
X 
Follow-up Assessments (Post-Discontinuation of Study Treatment) 


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Study Period: 
Screeninga 
Study Treatmenta, h 
(all treatment cycles = 21 days; 
from C2 onward, window of -2/+7 daysb) 
Study 
Treatment 
D/Ca 
Safety 
Follow-up 
k, n 
Survival 
Follow- 
upl 
Time Point(s): 
D -28 to 
D -1 
D -7 to 
D -1 
C1 
D1 
C2b 
D1 
C3b 
D1 
C4b 
D1 
C5b 
D1 
C6b 
D1 
C7+b 
D1 
(non- 
dosing 
activities 
are 
q12wk) 
At any 
point 
Post- 
treatment 
D/C 
Post- 
treat- 
ment 
D/C 
Frequency: 
Once 
Once 
Once 
Visit Window for all 
non-dosing activities: 
± 2 days 
+ 7 days 
-- 
Review of Any Anticancer 
Therapies since Study 
Treatment D/C (as appl.) 
X 
AE/SAE Collectionk 
X 
Treatment-Related SAE 
Collectionl 
X 
Survival Statusl 
X 
* Laboratory assessments are to be conducted predose, and processed by local laboratory, unless otherwise specified in the protocol. Clinical safety labs for screening and enrollment 
purposes will be processed using a licensed laboratory/laboratory with applicable local accreditation. 
a 
The Investigator is to make every effort to obtain assessments at each time point, including if a participant discontinues from the study. In the context of SARS-CoV-2 or other 
pandemics, natural disasters, or major disruptions, provisions may be made to accommodate participants who are unable to attend onsite study visits for scheduled assessments and 
dispensation of study intervention. 
b 
Each treatment cycle is 21 days. For Cycles 2 onward, there is a window of -2 days or +7 days from the due date for that cycle. 
c 
If C1D1 and Screening are within 7 days of each other, then this assessment does not need to be repeated on C1D1. 
d 
Serum or urine Screening pregnancy test is required for all female participants of childbearing potential; this test must be completed within 48 hours before the participant’s first dose of 
any study intervention. 
• 
Female participants of childbearing potential who are not on contraception (and therefore must agree be abstinent to comply with the study requirements; refer to 
Section 10.3.2) are to have serum or urine pregnancy testing performed during each dosing visit, prior to dosing with any study intervention. 
• 
Additional serum or urine pregnancy testing may be performed at any other time point at Investigator discretion. 
e 
ECG schedule (prior to PK sampling): C1D1 – predose (within 30 minutes before dosing) and 2 hours to 6 hours (± 30 minutes) postdose; C4D1 – within 30 minutes before dosing and 
2 hours to 6 hours (± 30 minutes) postdose. ECG may also be performed at any other time point as clinically indicated. 
f 
PK blood sampling schedule for the aumolertinib monotherapy arm (during participant clinic visits for clinical assessment): PK samples should be collected prior to the study drug dose 
(within 30 minutes before dosing) on C2D1, C3D1, C4D1, and C5D1. PK samples should be collected post-study drug dose (between 2 hours and 8 hours [± 30 minutes] after dosing) 
on C1D1 and C2D1. 
g 
Whenever possible, the same imaging modality (ECHO or MUGA) should be used across all LVEF collections for the individual participant. Screening imaging results must be 
provided prior to the first dose on C1D1 (ie, baseline). 


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h 
Note that all tumor imaging assessments, including brain imaging assessments (refer to footnote “i”), are to be performed at the scheduled interval of q6wk (± 3 days) for the first 
3 post-baseline assessments (with “baseline” defined as the participant’s most recent scan performed prior to the first dose of any study intervention and within 28 days before C1D1), 
then q12wk thereafter, regardless of whether the participant’s treatment cycle is delayed. 
• 
For all participants, CT scans of the chest and abdomen/pelvis with contrast (or PET/CT, at Investigator discretion) are to be collected at baseline. 
• 
The same imaging modality should be used across all tumor assessment scan collections for the individual participant. 
• 
Whenever possible, any participant who discontinues from study treatment for a reason other than disease progression should have CT with contrast (or PET/CT, as 
applicable) performed if they have not undergone a scan within the prior 4 weeks. 
i 
Brain imaging in this study is to be performed as clinically indicated. General guidance, which may be modified for an individual participant at Investigator discretion, is 
as follows: 
• 
For participants with baseline brain metastases: In general, brain imaging every 3 months is recommended per RANO criteria (Chukwueke 2019). 
− 
For participant and Investigator/site convenience in this study, RANO-based assessments are scheduled to occur in parallel with RECIST v1.1-based assessments (q6wk 
[± 3 days] for the first 3 post-baseline assessments and q12wk thereafter). 
− 
All brain imaging assessments are to be performed at the scheduled interval, regardless of whether the participant’s treatment cycle is delayed. 
− 
MRI is the preferred modality for brain imaging; CT may be used if MRI is medically contraindicated. Whenever possible, the same modality should be used across all 
brain imaging collections for the individual participant. 
• 
For participants without baseline brain metastases: No prescheduled follow-up brain imaging is required. 
j 
There are no protocol-specified testing requirements for SARS-CoV-2 in this study. SARS-CoV-2 requirements are instead determined by institutional standards (and local/country 
regulations, as applicable) and Investigator judgment. 
• 
At Investigator discretion, any participant who tests positive and/or is symptomatic for SARS-CoV-2 during Screening may either be excluded from the study or delay 
enrollment until active infection has been excluded per institutional standards. 
• 
During the study, any SARS-CoV-2 testing is to be performed as clinically indicated for the individual participant. The Investigator must document the results of all tests 
performed. Any confirmed infection is to be recorded as an AE or, in the event that clinical manifestation warrants such, recorded and handled as an SAE as detailed in 
Section 10.2.4. 
k 
All participants who discontinue study treatment, but do not withdraw overall consent, will remain in the study for safety follow-up. Safety follow-up will begin at the time of the 
participant’s discontinuation from study treatment and continue through 28 days after their last dose of any study intervention, or until the start of a new anticancer therapy (whichever 
occurs first). 
• 
AEs and SAEs are recorded from time of informed consent throughout the safety follow-up period. All AEs and SAEs occurring during this period are to be reported and 
handled as detailed in Section 10.2.4. 
• 
The Safety Follow-up Visit can be conducted virtually. 
l 
For all participants who have discontinued study treatment, but have not withdrawn overall consent, survival follow-up is to be performed approximately every 12 weeks after their last 
dose of any study intervention until the participant’s death or the end of the overall study (whichever occurs first). 
• 
At approximately q12wk intervals, good effort (defined as at least 3 attempts) should be made by the Investigator or designee to follow up with the participant or caregiver, 
either by telephone or secure electronic communication. 
• 
The Investigator or designee should obtain any available information on known aspects of the participant’s status, including survival status and (as applicable) any subsequent 
initiation of anticancer therapy and any SAEs considered treatment-related by the Investigator. 
m 
Blood samples for ctDNA analysis are to be collected predose (within 30 minutes before dosing) on Day 1. However, in the event that the Day 1 sample is obtained after dosing, that 
sample should not be discarded, but instead included for analysis with appropriate annotation as to sample time relative to time of active treatment administration. All other samples for 
ctDNA analysis may be collected before, during, or after dosing. All ctDNA samples will be processed by central laboratory. 


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n 
For participants who discontinue study treatment without experiencing disease progression, but do not withdraw overall consent, tumor assessments will continue until confirmed 
progression (per RECIST v1.1); initiation of subsequent anticancer therapy; or withdrawal from the study. 
o 
For participants in the aumolertinib monotherapy arm, ANC, calculated CLCr, and CREAT are required at Screening only, and then only as clinically indicated. GLU is to be collected 
in the fasted state at Screening and non-fasted at all other time points. 
p 
For screening and enrollment purposes, all participants are to have undergone EGFR mutation testing (of blood or tissue) performed by clinically validated assay, using a licensed 
laboratory/laboratory with applicable local accreditation. 
• 
If available, existing EGFR mutation test results may be used to confirm participant eligibility, provided that they were obtained within ≤ 3 months prior to study entry. 
• 
The Investigator may recommend that prospective participants for whom EGFR mutation testing is not covered or reimbursed by standard of care undergo pre-screening 
confirmatory testing. Any such individual will be required to sign a Pre‑ Screening ICF allowing blood or tissue sample collection for local EGFR mutation testing prior to 
the 28-day study Screening window. Refer to Appendix 9 (Section 10.9) for details. 
• 
For all participants in the study, blood will also be collected at C1D1 for central retrospective testing. 
q 
If archival tumor tissue (FFPE or unstained slides) is available (regardless of when it was obtained), it should also be collected (with participant’s consent) for central retrospective 
testing; however, this is not mandatory. 
AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; ANC = absolute neutrophil count; appl. = applicable; approx. = approximately; AST = aspartate 
aminotransferase; C = study Cycle; CDx = companion diagnostic; CLCr = creatinine clearance; CPK = creatine phosphokinase; CREAT = creatinine; CT = computed tomography; CTCAE = 
Common Terminology Criteria for Adverse Events; ctDNA = circulating tumor deoxyribonucleic acid; D = study Day; D/C = discontinuation; ECG = electrocardiogram; ECHO = 
echocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance status; EGFR = epidermal growth factor receptor; FFPE = formalin-fixed paraffin-embedded; GLU = 
glucose; h = hours; Hgb = hemoglobin; IBILI = indirect bilirubin; ICF = informed consent form; INR = International Normalized Ratio; Inv. = Investigator; IRT = interactive response 
technology; LVEF = left ventricular ejection fraction; MRI = magnetic resonance imaging; MUGA = multigated acquisition; NCI = National Cancer Institute; PET = positron emission 
tomography; PK = pharmacokinetic(s); PLAT = platelets; PRO = patient-reported outcome; PT = prothrombin time; QoL = quality of life; qwk = once weekly; q6wk = once every 6 weeks; 
q12wk = once every 12 weeks; RANO = Response Assessment in Neuro-Oncology; RECIST = Response Evaluation Criteria for Solid Tumors; SAE = serious adverse event; SARS-CoV-2 
= severe acute respiratory syndrome coronavirus 2; TBIL = total bilirubin; WBC = white blood cell. 


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Table 2: 
Aumolertinib with Chemotherapy Arm – SoA (EQ143-301 [TREBLE]) 
 
Study Period: 
Screeninga 
Study Treatment**, a, h 
(all treatment cycles = 21 days; 
from C2 onward, window of -2/+7 daysb) 
Study 
Treatment 
D/Ca 
Safety 
Follow-upk, n 
Survival 
Follow-upl 
Time Point(s): 
D -28 to 
D -1 
D -7 to 
D -1 
C1 
D1 
C2b 
D1 
C3b 
D1 
C4b 
D1 
C5b 
D1 
C6b 
D1 
C7+b D1 
(non-dosing 
activities 
are q12wk) 
At any point 
Post-treatment 
D/C 
Post- 
treatment 
D/C 
Frequency: 
Once 
Once 
Once 
Visit Window for all non-dosing 
activities: 
± 2 days 
+ 7 days 
-- 
General Screening Procedures 
Study Informed Consent 
X 
IRT Screening (after ICF Signature) 
X 
Participant History & Study Eligibility Review 
Demographics/Baseline Characteristics 
X 
Inclusion/Exclusion Criteria 
X 
Medical History & Current Medical 
Conditions 
X 
Prior & Concomitant Medications/ 
Procedures Review 
X 
X 
X 
X 
X 
X 
X 
X 
Smoking Status 
X 
SARS-CoV-2 Vaccination, Symptom, & 
Testing Reviewj 
X 
Diagnosis & Extent of Cancer 
X 
Prior Anticancer Therapy 
X 
IRT – Randomization 
X 
IRT – Study Drug** Dispensation 
(Participant Dispensation) 
X 
X 
X 
X 
X 
X 
X 


EQRx International, Inc. 
Protocol Amendment 5 (v6.0) 
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Study Period: 
Screeninga 
Study Treatment**, a, h 
(all treatment cycles = 21 days; 
from C2 onward, window of -2/+7 daysb) 
Study 
Treatment 
D/Ca 
Safety 
Follow-upk, n 
Survival 
Follow-upl 
Time Point(s): 
D -28 to 
D -1 
D -7 to 
D -1 
C1 
D1 
C2b 
D1 
C3b 
D1 
C4b 
D1 
C5b 
D1 
C6b 
D1 
C7+b D1 
(non-dosing 
activities 
are q12wk) 
At any point 
Post-treatment 
D/C 
Post- 
treatment 
D/C 
Frequency: 
Once 
Once 
Once 
Visit Window for all non-dosing 
activities: 
± 2 days 
+ 7 days 
-- 
ECOG PS & Physical Examinations 
Physical Exam 
X 
Xc 
X 
X 
X 
X 
X 
X 
ECOG PS 
X 
Xc 
X 
X 
X 
X 
X 
X 
Height 
X 
Body Weight 
X 
Xc 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
Xc 
X 
X 
X 
X 
X 
X 
Laboratory Assessments*,o 
EGFR Mutation Testingq 
X (pre- 
screening)q 
X 
Hematology: ANC, Hgb, WBC, & PLAT 
X 
Xc 
X 
X 
X 
X 
X 
X 
Hematology: all other labs listed in 
Section 10.8.1 
As clinically indicated 
Serum Chemistry: ALT, ALP, AST, 
TBIL + IBILI, CPK, calculated CLCrp, 
CREAT, & GLUp 
X 
Xc 
X 
X 
X 
X 
X 
X 
Serum Chemistry: all other labs listed in 
Section 10.8.2 
As clinically indicated 
Coagulation: PT/INR 
X 
As clinically indicated 
Urinalysis: dipstick parameters (refer to 
Section 10.8.3) 
As clinically indicated 
Pregnancy Test (all female participants 
of childbearing potential)d 
X 
(≤ 48 h 
pre- 
first 
dose) 
Pregnancy Test (only female participants 
of childbearing potential who are not on 
contraception)d 
X 
X 
X 
X 
X 
X 
X 


EQRx International, Inc. 
Protocol Amendment 5 (v6.0) 
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Study Period: 
Screeninga 
Study Treatment**, a, h 
(all treatment cycles = 21 days; 
from C2 onward, window of -2/+7 daysb) 
Study 
Treatment 
D/Ca 
Safety 
Follow-upk, n 
Survival 
Follow-upl 
Time Point(s): 
D -28 to 
D -1 
D -7 to 
D -1 
C1 
D1 
C2b 
D1 
C3b 
D1 
C4b 
D1 
C5b 
D1 
C6b 
D1 
C7+b D1 
(non-dosing 
activities 
are q12wk) 
At any point 
Post-treatment 
D/C 
Post- 
treatment 
D/C 
Frequency: 
Once 
Once 
Once 
Visit Window for all non-dosing 
activities: 
± 2 days 
+ 7 days 
-- 
Blood Sample Collection for ctDNA 
Analysism 
Xm 
X 
X 
At disease progression (as appl.) 
Cardiac Assessments 
ECGe 
X 
Xc 
X 
ECHO or MUGA (LVEF)g 
X 
Xc 
Xg 
Pharmacokinetic Assessments 
PK Blood Sample Collectionf 
X 
X 
X 
X 
X 
Other Safety Assessments 
AE/SAE Collection 
Continuous 
Refer to 
footnote “k” 
Refer to 
footnote “l” 
SARS-CoV-2 Testing (per institutional 
standards & local/country regulations)j 
As appl. 
Tumor Assessments 
CT of Chest & Abdomen/Pelvis with 
Contrast (or PET/CT, at Inv. discretion)h 
X 
q6wk (± 3 days) for first 3 post-baseline assessments, then q12wkh 
Brain Imaging for Participants with 
Baseline Brain Metastasesi 
X 
q6wk (± 3 days) for first 3 post-baseline assessments, then q12wkh 
Brain Imaging for Participants without 
Baseline Brain Metastases 
X 
If clinically indicated (as appl.)h,i 
Archival Tissue Collection for CDx 
Testingr (only if available; not 
required) 
X 
Patient-Reported Outcomes & Quality of Life Assessments 
PRO/QoL Assessment (NCI 
PRO-CTCAE) 
qwk 
qwk 
qwk 
qwk 
X 
X 
q6wk 
X 
IRT – Discontinuation 
X 
Follow-up Assessments (Post-Discontinuation of Study Treatment) 


EQRx International, Inc. 
Protocol Amendment 5 (v6.0) 
EQ143-301 
33 
Confidential and Proprietary 
 
 
 
Study Period: 
Screeninga 
Study Treatment**, a, h 
(all treatment cycles = 21 days; 
from C2 onward, window of -2/+7 daysb) 
Study 
Treatment 
D/Ca 
Safety 
Follow-upk, n 
Survival 
Follow-upl 
Time Point(s): 
D -28 to 
D -1 
D -7 to 
D -1 
C1 
D1 
C2b 
D1 
C3b 
D1 
C4b 
D1 
C5b 
D1 
C6b 
D1 
C7+b D1 
(non-dosing 
activities 
are q12wk) 
At any point 
Post-treatment 
D/C 
Post- 
treatment 
D/C 
Frequency: 
Once 
Once 
Once 
Visit Window for all non-dosing 
activities: 
± 2 days 
+ 7 days 
-- 
Review of Any Anticancer Therapies 
since Study Treatment D/C (as appl.) 
X 
AE/SAE Collectionk 
X 
Treatment-Related SAE Collectionl 
X 
Survival Statusl 
X 
* Laboratory assessments are to be conducted predose, and processed by local laboratory, unless otherwise specified in the protocol. Clinical safety labs for screening and enrollment 
purposes will be processed using a licensed laboratory/laboratory with applicable local accreditation. 
** Participants in the aumolertinib with chemotherapy arm will receive up to 4 cycles of a platinum-based doublet along with once-daily aumolertinib at 110 mg QD. Thereafter, at the 
Investigator’s discretion (based on assessment of continued clinical benefit), the participant may go on to receive maintenance pemetrexed with QD aumolertinib for the remainder of their 
study treatment—provided that they do not meet study treatment and/or overall study discontinuation criteria. No delay in aumolertinib dosing is necessitated by a delay in chemotherapy 
dosing (refer to Section 6.5.2). 
a 
The Investigator is to make every effort to obtain assessments at each time point, including if a participant discontinues from the study. In the context of SARS-CoV-2 or other 
pandemics, natural disasters, or major disruptions, provisions may be made to accommodate participants who are unable to attend onsite study visits for scheduled assessments and 
dispensation of study intervention. 
b 
Each treatment cycle is 21 days. For Cycles 2 onward, there is a window of -2 days or +7 days from the due date for that cycle. 
c 
If C1D1 and Screening are within 7 days of each other, then this assessment does not need to be repeated on C1D1. 
d 
Serum or urine Screening pregnancy test is required for all female participants of childbearing potential; this test must be completed within 48 hours before the participant’s first dose of 
any study intervention. 
• 
Female participants of childbearing potential who are not on contraception (and therefore must agree be abstinent to comply with the study requirements; refer to 
Section 10.3.2) are to have serum or urine pregnancy testing performed during each dosing visit, prior to dosing with any study intervention. 
• 
Additional serum or urine pregnancy testing may be performed at any other time point at Investigator discretion. 
e 
ECG schedule (prior to PK sampling): C1D1 – predose (within 30 minutes before dosing) and 2 hours to 6 hours (± 30 minutes) postdose; C4D1 – within 30 minutes before 
dosing and 2 hours to 6 hours (± 30 minutes) postdose. ECG may also be performed at any other time point as clinically indicated. 
f 
PK blood sampling schedule for the aumolertinib with chemotherapy arm (during participant clinic visits for clinical assessment): PK samples should be collected prior to the study drug 
dose (within 30 minutes before dosing) on C2D1, C3D1, C4D1, and C5D1. PK samples should be collected post-study drug dose (between 2 hours and 8 hours [± 30 minutes] after 
dosing) on C1D1 and C2D1. 
g 
Whenever possible, the same imaging modality (ECHO or MUGA) should be used across all LVEF collections for the individual participant. Screening imaging results must beprovided 
prior to the first dose on C1D1 (ie, baseline). 


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Protocol Amendment 5 (v6.0) 
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Confidential and Proprietary 
 
 
h 
Note that all tumor imaging assessments, including brain imaging assessments (refer to footnote “i”), are to be performed at the scheduled interval of q6wk (± 3 days) for the first 
3 post-baseline assessments (with “baseline” defined as the participant’s most recent scan performed prior to the first dose of any study intervention and within 28 days before C1D1), 
then q12wk thereafter, regardless of whether the participant’s treatment cycle is delayed. 
• 
For all participants, CT scans of the chest and abdomen/pelvis with contrast (or PET/CT, at Investigator discretion) are to be collected at baseline. 
• 
The same imaging modality should be used across all tumor assessment scan collections for the individual participant. 
• 
Whenever possible, any participant who discontinues from study treatment for a reason other than disease progression should have a CT with contrast (or PET/CT, as 
applicable) performed if they have not undergone a scan within the prior 4 weeks. 
i 
Brain imaging in this study is to be performed as clinically indicated. General guidance, which may be modified for an individual participant at Investigator discretion, is as follows: 
• 
For participants with baseline brain metastases: In general, brain imaging every 3 months is recommended per RANO criteria (Chukwueke 2019). 
− 
For participant and Investigator/site convenience in this study, RANO-based assessments are scheduled to occur in parallel with RECIST v1.1-based assessments (q6wk 
[± 3 days] for the first 3 post-baseline assessments and q12wk thereafter). 
− 
All brain imaging assessments are to be performed at the scheduled interval, regardless of whether the participant’s treatment cycle is delayed. 
− 
MRI is the preferred modality for brain imaging; CT may be used if MRI is medically contraindicated. Whenever possible, the same modality should be used across all 
brain imaging collections for the individual participant. 
• 
For participants without baseline brain metastases: No prescheduled follow-up brain imaging is required. 
j 
There are no protocol-specified testing requirements for SARS-CoV-2 in this study. SARS-CoV-2 requirements are instead determined by institutional standards (and local/country 
regulations, as applicable) and Investigator judgment. 
• 
At Investigator discretion, any participant who tests positive and/or is symptomatic for SARS-CoV-2 during Screening may either be excluded from the study or delay 
enrollment until active infection has been excluded per institutional standards. 
• 
During the study, any SARS-CoV-2 testing is to be performed as clinically indicated for the individual participant. The Investigator must document the results of all tests 
performed. Any confirmed infection is to be recorded as an AE or, in the event that clinical manifestation warrants such, recorded and handled as an SAE as detailed in 
Section 10.2.4. 
k 
All participants who discontinue study treatment, but do not withdraw overall consent, will remain in the study for safety follow-up. Safety follow-up will begin at the time of the 
participant’s discontinuation from study treatment and continue through 28 days after their last dose of any study intervention, or until the start of a new anticancer therapy (whichever 
occurs first). 
• 
AEs and SAEs are recorded from time of informed consent throughout the safety follow-up period. All AEs and SAEs occurring during this period are to be reported and 
handled as detailed in Section 10.2.4. 
• 
The Safety Follow-up Visit can be conducted virtually. 
l 
For all participants who have discontinued study treatment, but have not withdrawn overall consent, survival follow-up is to be performed approximately every 12 weeks after their last 
dose of any study intervention, until the participant’s death or the end of the overall study (whichever occurs first). 
• 
At approximately q12wk intervals, good effort (defined as at least 3 attempts) should be made by the Investigator or designee to follow up with the participant or caregiver, 
either by telephone or secure electronic communication. 
• 
The Investigator or designee should obtain any available information on known aspects of the participant’s status, including survival status and (as applicable) any subsequent 
initiation of anticancer therapy and any SAEs considered treatment-related by the Investigator. 
m 
Blood samples for ctDNA analysis are to be collected predose (within 30 minutes before dosing) on Day 1. However, in the event that the Day 1 sample is obtained after dosing, that 
sample should not be discarded, but instead included for analysis with appropriate annotation as to sample time relative to time of active treatment administration. All other samples for 
ctDNA analysis may be collected before, during, or after dosing. All ctDNA samples will be processed by central laboratory. 
n 
For participants who discontinue study treatment without experiencing disease progression, but do not withdraw overall consent, tumor assessments will continue until confirmed 
progression (per RECIST v1.1); the initiation of subsequent anticancer therapy; or withdrawal from the study. 


EQRx International, Inc. 
Protocol Amendment 5 (v6.0) 
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Confidential and Proprietary 
 
 
o 
For participants in the aumolertinib with chemotherapy arm only, safety laboratory test results are to be obtained and reviewed by the Investigator prior to study drug dosing for as long 
as the participant is receiving non-maintenance chemotherapy. 
p 
For participants in the aumolertinib with chemotherapy arm, calculated CLCr is required at Screening only, and then only as clinically indicated. GLU is to be collected in the fasted 
state at Screening and non-fasted at all other time points. 
q 
For screening and enrollment purposes, all participants are to have undergone EGFR mutation testing (of blood or tissue) performed by clinically validated assay, using a licensed 
laboratory/laboratory with applicable local accreditation. 
• 
If available, existing EGFR mutation test results may be used to confirm participant eligibility, provided that they were obtained within ≤ 3 months prior to study entry. 
• 
The Investigator may recommend that prospective participants for whom EGFR mutation testing is not covered or reimbursed by standard of care undergo pre-screening 
confirmatory testing. Any such individual will be required to sign a Pre‑ Screening ICF allowing blood or tissue sample collection for local EGFR mutation testing prior to 
the 28-day study Screening window. Refer to Appendix 9 (Section 10.9) for details. 
• 
For all participants in the study, blood will also be collected at C1D1 for central retrospective testing. 
r 
If archival tumor tissue (FFPE or unstained slides) is available (regardless of when it was obtained), it should also be collected (with participant’s consent) for central retrospective 
testing; however, this is not mandatory. 
AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; ANC = absolute neutrophil count; approx. = approximately; AST = aspartate aminotransferase; 
C = study Cycle; CDx = companion diagnostic; CLCr = creatinine clearance; CPK = creatine phosphokinase; CREAT = creatinine; CT = computed tomography; CTCAE = Common 
Terminology Criteria for Adverse Events; ctDNA = circulating tumor deoxyribonucleic acid; D = study Day; D/C = discontinuation; ECG = electrocardiogram; ECHO = echocardiogram; 
ECOG PS = Eastern Cooperative Oncology Group performance status; EGFR = epidermal growth factor receptor; FFPE = formalin-fixed paraffin-embedded; GLU = glucose; Hgb = 
hemoglobin; IBILI = indirect bilirubin; ICF = informed consent form; INR = International Normalized Ratio; Inv. = Investigator; IRT = interactive response technology; LVEF = left 
ventricular ejection fraction; MRI = magnetic resonance imaging; MUGA = multigated acquisition; NCI = National Cancer Institute; PET = positron emission tomography; PK = 
pharmacokinetic(s); PLAT = platelets; PRO = patient-reported outcome; PT = prothrombin time; QD = once daily; QoL = quality of life; qwk = once weekly; q6wk = once every 6 weeks; 
q12wk = once every 12 weeks; RANO = Response Assessment in Neuro-Oncology; RECIST = Response Evaluation Criteria for Solid Tumors; SAE = serious adverse event; SARS-CoV-2 
= severe acute respiratory syndrome coronavirus 2; TBIL = total bilirubin; WBC = white blood cell. 


EQRx International, Inc. 
Protocol Amendment 5 (v6.0) 
EQ143-301 
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Confidential and Proprietary 
 
 
Table 3: 
Osimertinib Monotherapy Arm – SoA (EQ143-301 [TREBLE]) 
 
Study Period: 
Screeninga 
Study Treatmenta, g 
(all treatment cycles = 21 days; 
from C2 onward, window of -2/+7 daysb) 
Study 
Treatment 
D/Ca 
Safety 
Follow-upj, m 
Survival 
Follow-upk 
Time Point(s): 
D -28 to 
D -1 
D -7 to 
D -1 
C1 
D1 
C2b 
D1 
C3b 
D1 
C4b 
D1 
C5b 
D1 
C6b 
D1 
C7+b D1 
(non-dosing 
activities 
are q12wk) 
At any point 
Post-treatment 
D/C 
Post- 
treatment 
D/C 
Frequency: 
Once 
Once 
Once 
Visit Window for all 
non-dosing activities: 
± 2 days 
+ 7 days 
-- 
General Screening Procedures 
Study Informed Consent 
X 
IRT Screening (after ICF 
Signature) 
X 
Participant History & Study Eligibility Review 
Demographics/Baseline 
Characteristics 
X 
Inclusion/Exclusion Criteria 
X 
Medical History & Current 
Medical Conditions 
X 
Prior & Concomitant Medications/ 
Procedures Review 
X 
X 
X 
X 
X 
X 
X 
X 
Smoking Status 
X 
SARS-CoV-2 Vaccination, 
Symptom, & Testing Reviewi 
X 
Diagnosis & Extent of Cancer 
X 
Prior Anticancer Therapy 
X 
IRT – Randomization 
X 
IRT – Study Drug Dispensation 
(Participant Dispensation) 
X 
X 
X 
X 
X 
X 
X 


EQRx International, Inc. 
Protocol Amendment 5 (v6.0) 
EQ143-301 
37 
Confidential and Proprietary 
 
 
 
Study Period: 
Screeninga 
Study Treatmenta, g 
(all treatment cycles = 21 days; 
from C2 onward, window of -2/+7 daysb) 
Study 
Treatment 
D/Ca 
Safety 
Follow-upj, m 
Survival 
Follow-upk 
Time Point(s): 
D -28 to 
D -1 
D -7 to 
D -1 
C1 
D1 
C2b 
D1 
C3b 
D1 
C4b 
D1 
C5b 
D1 
C6b 
D1 
C7+b D1 
(non-dosing 
activities 
are q12wk) 
At any point 
Post-treatment 
D/C 
Post- 
treatment 
D/C 
Frequency: 
Once 
Once 
Once 
Visit Window for all 
non-dosing activities: 
± 2 days 
+ 7 days 
-- 
ECOG PS & Physical Examinations 
Physical Exam 
X 
Xc 
X 
X 
X 
X 
X 
X 
ECOG PS 
X 
Xc 
X 
X 
X 
X 
X 
X 
Height 
X 
Body Weight 
X 
Xc 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
Xc 
X 
X 
X 
X 
X 
X 
Laboratory Assessments*, m 
EGFR Mutation Testingo 
X (pre- 
screening)o 
X 
Hematology: ANCn, Hgb, WBC, 
& PLAT 
X 
Xc 
X 
X 
X 
X 
X 
X 
Hematology: all other labs listed in 
Section 10.8.1 
As clinically indicated 
Serum Chemistry: ALT, ALP, 
AST, TBIL + IBILI, CPK, 
calculated CLCrn, CREATn, 
& GLUn 
X 
Xc 
X 
X 
X 
X 
X 
X 
Serum Chemistry: all other labs 
listed in Section 10.8.2 
As clinically indicated 
Coagulation: PT/INR 
X 
As clinically indicated 
Urinalysis: dipstick parameters 
(refer to Section 10.8.3) 
As clinically indicated 
Pregnancy Test (all female 
participants of childbearing 
potential)d 
X 
(≤ 48 h 
pre- 
first dose) 
As clinically indicated 


EQRx International, Inc. 
Protocol Amendment 5 (v6.0) 
EQ143-301 
38 
Confidential and Proprietary 
 
 
 
Study Period: 
Screeninga 
Study Treatmenta, g 
(all treatment cycles = 21 days; 
from C2 onward, window of -2/+7 daysb) 
Study 
Treatment 
D/Ca 
Safety 
Follow-upj, m 
Survival 
Follow-upk 
Time Point(s): 
D -28 to 
D -1 
D -7 to 
D -1 
C1 
D1 
C2b 
D1 
C3b 
D1 
C4b 
D1 
C5b 
D1 
C6b 
D1 
C7+b D1 
(non-dosing 
activities 
are q12wk) 
At any point 
Post-treatment 
D/C 
Post- 
treatment 
D/C 
Frequency: 
Once 
Once 
Once 
Visit Window for all 
non-dosing activities: 
± 2 days 
+ 7 days 
-- 
Pregnancy Test (only female 
participants of childbearing 
potential who are not on 
contraception)d 
X 
X 
X 
X 
X 
X 
X 
Blood Sample Collection for 
ctDNA Analysisl 
Xm 
X 
X 
At disease progression (as appl.) 
Cardiac Assessments 
ECGe 
X 
Xc 
X 
ECHO or MUGA (LVEF)f 
X 
Xc 
Xg 
Other Safety Assessments 
AE/SAE Collection 
Continuous 
Refer to 
footnote “j” 
Refer to 
footnote “k” 
SARS-CoV-2 Testing (per 
institutional standards & 
local/country regulations)i 
As appl. 
Tumor Assessments 
CT of Chest & Abdomen/Pelvis 
with Contrast (or PET/CT, at Inv. 
discretion)g 
X 
q6wk (± 3 days) for first 3 post-baseline assessments, then q12wkg 
Brain Imaging for Participants with 
Baseline Brain Metastasesh 
X 
q6wk (± 3 days) for first 3 post-baseline assessments, then q12wkg 
Brain Imaging for Participants 
without Baseline Brain Metastases 
X 
If clinically indicated (as appl.)g 
Archival Tissue Collection for CDx 
Testingp (only if available; not 
required) 
X 


EQRx International, Inc. 
Protocol Amendment 5 (v6.0) 
EQ143-301 
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Confidential and Proprietary 
 
 
 
Study Period: 
Screeninga 
Study Treatmenta, g 
(all treatment cycles = 21 days; 
from C2 onward, window of -2/+7 daysb) 
Study 
Treatment 
D/Ca 
Safety 
Follow-upj, m 
Survival 
Follow-upk 
Time Point(s): 
D -28 to 
D -1 
D -7 to 
D -1 
C1 
D1 
C2b 
D1 
C3b 
D1 
C4b 
D1 
C5b 
D1 
C6b 
D1 
C7+b D1 
(non-dosing 
activities 
are q12wk) 
At any point 
Post-treatment 
D/C 
Post- 
treatment 
D/C 
Frequency: 
Once 
Once 
Once 
Visit Window for all 
non-dosing activities: 
± 2 days 
+ 7 days 
-- 
Patient-Reported Outcomes & Quality of Life Assessments 
PRO/QoL Assessment (NCI 
PRO-CTCAE) 
qwk 
qwk 
qwk 
qwk 
X 
X 
q6wk 
X 
IRT – Discontinuation 
X 
Follow-up Assessments (Post-Discontinuation of Study Treatment) 
Review of Any Anticancer 
Therapies since Study Treatment 
D/C 
X 
AE/SAE Collectionj 
X 
Treatment-Related SAE Collectionk 
X 
Survival Statusk 
X 
* Laboratory assessments are to be conducted predose. All labs will be processed by local laboratory unless otherwise specified in the protocol. Clinical safety labs for screening and 
enrollment purposes will be processed using a licensed laboratory/laboratory with applicable local accreditation. 
a 
The Investigator is to make every effort to obtain assessments at each time point, including if a participant discontinues from the study. In the context of SARS-CoV-2 or other 
pandemics, natural disasters, or major disruptions, provisions may be made to accommodate participants who are unable to attend onsite study visits for scheduled assessments and 
dispensation of study intervention. 
b 
Each treatment cycle is 21 days. For Cycles 2 onward, there is a window of -2 days or +7 days from the due date for that cycle. 
c 
If C1D1 and Screening are within 7 days of each other, then this assessment does not need to be repeated on C1D1. 
d 
Serum or urine Screening pregnancy test is required for all female participants of childbearing potential; this test must be completed within 48 hours before the participant’s first dose of 
any study intervention. 
• 
Female participants of childbearing potential who are not on contraception (and therefore must agree be abstinent to comply with the study requirements; refer to 
Section 10.3.2) are to have serum or urine pregnancy testing performed during each dosing visit, prior to dosing with any study intervention. 
• 
Additional serum or urine pregnancy testing may be performed at any other time point at Investigator discretion. 
e 
 ECG schedule: C1D1 – predose (within 30 minutes before dosing) and 2 hours to 6 hours (± 30 minutes) postdose; C4D1 – within 30 minutes before dosing and 2 hours to 6 hours 
(± 30 minutes) postdose. ECG may also be performed at any other time point as clinically indicated. 
f 
Whenever possible, the same imaging modality (ECHO or MUGA) should be used across all LVEF collections for the individual participant. Screening imaging results must be 
provided prior to the first dose on C1D1 (ie, baseline). 


EQRx International, Inc. 
Protocol Amendment 5 (v6.0) 
EQ143-301 
40 
Confidential and Proprietary 
 
 
g 
Note that all tumor imaging assessments, including brain imaging assessments (refer to footnote “h”), are to be performed at the scheduled interval of q6wk (± 3 days) for the first 
3 post-baseline visits (with “baseline” defined as the participant’s most recent scan performed prior to the first dose of any study intervention and within 28 days before C1D1), then 
q12wk thereafter, regardless of whether the participant’s treatment cycle is delayed. 
• 
For all participants, CT scans of the chest and abdomen/pelvis with contrast (or PET/CT, at Investigator discretion) are to be collected at baseline. 
• 
The same imaging modality should be used across all tumor assessment scan collections for the individual participant. 
• 
Whenever possible, any participant who discontinues from study treatment for a reason other than disease progression should have a CT with contrast (or PET/CT, as 
applicable) performed if they have not undergone a scan within the prior 4 weeks. 
h 
Brain imaging in this study is to be performed as clinically indicated. General guidance, which may be modified for an individual participant at Investigator discretion, is 
as follows: 
• 
For participants with baseline brain metastases: In general, brain imaging every 3 months is recommended per RANO criteria (Chukwueke 2019). 
− 
For participant and Investigator/site convenience in this study, RANO-based assessments are scheduled to occur in parallel with RECIST v1.1-based assessments (every 
6 weeks ± 3 days for the first 3 post-baseline assessments and then every 12 weeks thereafter). 
− 
All brain imaging assessments are to be performed at the scheduled interval, regardless of whether the participant’s treatment cycle is delayed. 
− 
MRI is the preferred modality for brain imaging; CT may be used if MRI is medically contraindicated. Whenever possible, the same modality should be used across all 
brain imaging collections for the individual participant. 
• 
For participants without baseline brain metastases: No prescheduled follow-up brain imaging is required. 
i 
There are no protocol-specified testing requirements for SARS-CoV-2 in this study. SARS-CoV-2 requirements are instead determined by institutional standards (and local/country 
regulations, as applicable) and Investigator judgment. 
• 
At Investigator discretion, any participant who tests positive and/or is symptomatic for SARS-CoV-2 during Screening may either be excluded from the study or delay 
enrollment until active infection has been excluded per institutional standards. 
• 
During the study, any SARS-CoV-2 testing is to be performed as clinically indicated for the individual participant. The Investigator must document the results of all tests 
performed. Any confirmed infection is to be recorded as an AE or, in the event that clinical manifestation warrants such, recorded and handled as an SAE as detailed in 
Section 10.2.4. 
j 
All participants who discontinue study treatment, but do not withdraw overall consent, will remain in the study for safety follow-up. Safety follow-up will begin at the time of the 
participant’s discontinuation from study treatment and continue through 28 days after their last dose of any study intervention or until the start of a new anticancer therapy (whichever 
occurs first). 
• 
AEs and SAEs are recorded from time of informed consent throughout the safety follow-up period. All AEs and SAEs occurring during this period are to be reported and 
handled as detailed in Section 10.2.4. 
• 
The Safety Follow-up Visit can be conducted virtually. 
k 
For all participants who have discontinued study treatment, but have not withdrawn overall consent, survival follow-up is to be performed approximately every 12 weeks after their last 
dose of any study intervention until the participant’s death or the end of the overall study (whichever occurs first). 
• 
At approximately q12wk intervals, good effort (defined as at least 3 attempts) should be made by the Investigator or designee to follow up with the participant or caregiver, 
either by telephone or secure electronic communication. 
• 
The Investigator or designee should obtain any available information on known aspects of the participant’s status, including survival status and (as applicable) any subsequent 
initiation of anticancer therapy and any SAEs considered treatment-related by the Investigator. 
l 
Blood samples for ctDNA analysis are to be collected predose (within 30 minutes before dosing) on Day 1. However, in the event that the Day 1 sample is obtained after dosing, that 
sample should not be discarded, but instead included for analysis with appropriate annotation as to sample time relative to time of active treatment administration. All other samples for 
ctDNA analysis may be collected before, during, or after dosing. All ctDNA samples will be processed by central laboratory. 


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m 
For participants who discontinue study treatment without experiencing disease progression, but do not withdraw overall consent, tumor assessments will continue until confirmed 
progression (per RECIST v1.1); the initiation of subsequent anticancer therapy; or withdrawal from the study. 
n 
For participants in the osimertinib monotherapy arm, ANC, calculated CLCr, and CREAT are required at Screening only, and then only as clinically indicated. GLU is to be collected in 
the fasted state at Screening and non-fasted at all other time points. 
o 
For screening and enrollment purposes, all participants are to have undergone EGFR mutation testing (of blood or tissue) performed by clinically validated assay, using a licensed 
laboratory/laboratory with applicable local accreditation. 
• 
If available, existing EGFR mutation test results may be used to confirm participant eligibility, provided that they were obtained within ≤ 3 months prior to study entry. 
• 
The Investigator may recommend that prospective participants for whom EGFR mutation testing is not covered or reimbursed by standard of care undergo 
pre-screening confirmatory testing. Any such individual will be required to sign a Pre‑ Screening ICF allowing blood or tissue sample collection for local EGFR mutation 
testing prior to the 28-day study Screening window. Refer to Appendix 9 (Section 10.9) for details. 
• 
For all participants in the study, blood is also to be collected at C1D1 for central retrospective testing. 
p 
If archival tumor tissue (FFPE or unstained slides) is available (regardless of when it was obtained), it should also be collected (with participant’s consent) for central retrospective 
testing; however, this is not mandatory. 
AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; ANC = absolute neutrophil count; approx. = approximately; AST = aspartate aminotransferase; C = study 
Cycle; CDx = companion diagnostic; CLCr = creatinine clearance; CPK = creatine phosphokinase; CREAT = creatinine; CT = computed tomography; CTCAE = Common Terminology 
Criteria for Adverse Events; ctDNA = circulating tumor deoxyribonucleic acid; D = study Day; D/C = discontinuation; ECG = electrocardiogram; ECHO = echocardiogram; ECOG PS = 
Eastern Cooperative Oncology Group performance status; EGFR = epidermal growth factor receptor; FFPE = formalin-fixed paraffin-embedded; GLU = glucose; Hgb = hemoglobin; IBILI 
= indirect bilirubin; ICF = informed consent form; INR = International Normalized Ratio; Inv. = Investigator; IRT = interactive response technology; LVEF = left ventricular ejection 
fraction; MRI = magnetic resonance imaging; MUGA = multigated acquisition; NCI = National Cancer Institute; PET = positron emission tomography; PLAT = platelets; PRO = patient- 
reported outcome; PT = prothrombin time; QoL = quality of life; qwk = once weekly; q6wk = once every 6 weeks; q12wk = once every 12 weeks; RANO = Response Assessment in Neuro- 
Oncology; RECIST = Response Evaluation Criteria for Solid Tumors; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; TBIL = total bilirubin; 
WBC = white blood cell. 


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2. 
INTRODUCTION 
Aumolertinib (also known as EQ143, HS-10296, HSE-10296, almonertinib, or Ameile™ in 
China) is a novel, irreversible, small-molecule third generation EGFR inhibitor that is in clinical 
development for the treatment of patients with EGFR-mutant metastatic NSCLC. It was 
approved in China in 2020 for the treatment of adult patients with locally advanced EGFR 
T790M mutation-positive or metastatic NSCLC who have progressed during or after EGFR-TKI 
therapy. In 2021, the China National Medical Products Administration (NMPA) also approved 
aumolertinib for the treatment of patients with EGFR exon 19 del or L858R-mutant NSCLC in the 
first-line setting. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.1. 
Study Rationale 
The primary purpose of the EQ143-301 (TREBLE) study is to investigate whether the addition 
of chemotherapy to the third-generation EGFR-TKI aumolertinib improves PFS, as compared 
with osimertinib monotherapy, in patients with metastatic EGFR-mutated NSCLC. 
Overall, the study is designed to: 
• Combine key elements of a prospective randomized trial comparing aumolertinib + 
chemotherapy combination therapy with osimertinib monotherapy, and describing 
aumolertinib monotherapy in comparison to osimertinib monotherapy 


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• Compare efficacy and safety measures of aumolertinib and osimertinib within a 
diverse and inclusive patient population 
• Evaluate EGFR WT-mediated toxicity in participants receiving aumolertinib 
monotherapy, aumolertinib with chemotherapy, or osimertinib monotherapy 
• Assess TGR and the clearance of ctDNA with aumolertinib monotherapy, 
aumolertinib with chemotherapy, and osimertinib monotherapy 
• Characterize the PK of aumolertinib in the first-line advanced/metastatic 
EGFR-mutant setting 
2.2. 
Background 
Lung cancer accounts for approximately 11% of all cancers diagnosed globally (Globocan 2020), 
and NSCLC is the most common type of lung cancer, accounting for approximately 85% of all 
lung cancer cases. The prognosis remains poor, especially in patients with advanced NSCLC, 
for whom the median overall survival is only 1 year and the 5-year survival rate is 3.5% 
(Zhang 2016). 
EGFR is a transmembrane protein with an external ligand-binding receptor domain and an 
intracellular tyrosine kinase domain. EGFR-TKIs have proven to be effective treatments for 
advanced EGFR-mutated NSCLC. Therefore, clinical guidelines recommend that patients with 
advanced NSCLC with EGFR-sensitizing mutations receive first-line treatment with TKIs 
(Cohen 2004, Cohen 2005). 
However, most patients develop acquired resistance to first-generation EGFR-targeting TKIs, and 
disease progression typically occurs after 9 to 14 months of treatment (Maemondo 2010). On 
disease progression, a “gatekeeper” mutation, T790M, within EGFR is detected in tumor cells or 
ctDNA from more than 50% of patients and is the most common mechanism of acquired 
resistance (Kobayashi 2005). 
Second-generation irreversible EGFR-TKIs are effective in EGFR-mutant NSCLC, but do not 
inhibit T790M at clinically achievable concentrations due to dose-limiting toxicity. Thus, there 
remains a significant unmet medical need for the development of third-generation EGFR 
inhibitors that can more selectively target the EGFR T790M mutation, sparing WT EGFR. This 
has led to the development of third-generation EGFR-TKIs, such as osimertinib and 
aumolertinib. 
Osimertinib is a US Food and Drug Administration (FDA)-approved TKI that is standard of care 
for patients with advanced/metastatic NSCLC and an EGFR-sensitizing mutation in the US. 
Initially developed by Hansoh Pharmaceuticals as HS-10296, aumolertinib is a novel, 
irreversible, small-molecule, third-generation EGFR inhibitor. In nonclinical studies, 
aumolertinib displayed potent inhibition of EGFR T790M and notably less inhibitory activity on 
the WT EGFR than other TKIs. 
In March 2020, aumolertinib was approved for use in China for the treatment of adult patients 
with locally advanced or metastatic NSCLC who have experienced disease progression during or 
after treatment with EGFR-TKIs in the past and have tested positive for the presence of the 
confirmed EGFR T790M mutation. 


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In December 2021, aumolertinib was subsequently approved in China for the treatment of patients 
with EGFR exon 19 del or L858R-mutant NSCLC in the first-line setting. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.3. 
Benefit/Risk Assessment 
2.3.1. 
Benefit Assessment 
Aumolertinib can selectively inhibit EGFR-sensitizing mutations and T790M drug-resistance 
mutations. Additionally, aumolertinib has relatively little inhibitory activity on WT EGFR. 
Based on these characteristics, aumolertinib given in combination with chemotherapy or alone 
may enhance PFS and tolerability for patients with NSCLC. 
2.3.2. 
Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs for aumolertinib—including risk management of the same—can be found in the 
summary of safety provided in the current aumolertinib IB. 
Overall, the safety profile of aumolertinib is generally consistent with that of other EGFR-TKIs. 


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Well-known risks associated with EGFR-TKIs which have been observed during clinical trials 
with aumolertinib, including in the data from the 2 pivotal clinical studies in NSCLC 
(HS-10296-12-01 and HS-10296-03-01) and from clinical pharmacology studies, are as follows: 
• Hepatoxicity: Hepatotoxicity was frequently reported in participants with advanced 
NSCLC treated with 110 mg of aumolertinib in clinical trials. However, this mostly 
occurred as Grade 1 or 2 elevations in AST, ALT, and other liver function tests. Fatal 
hepatotoxicity has not been described for aumolertinib. 
• Elevated blood CPK: Overall, elevations in blood CPK—a recognized risk with 
EGFR-TKIs—were commonly reported AEs in clinical trials with aumolertinib; 
however, rhabdomyolysis has not been reported. The frequencies of musculoskeletal 
pain, myalgia, muscular weakness, and myositis were generally low. 
• Interstitial lung disease: ILD, including fatal events, has been reported in participants 
with NSCLC treated with aumolertinib 110 mg in clinical trials. 
• Cardiac failure: Cardiac failure, including fatal events and events of decreased ejection 
fraction, has been reported in aumolertinib clinical trials. 
• QTc prolongation: QTc prolongation has been reported in aumolertinib clinical trials. 
Events have been primarily low-grade in severity, and no events of Torsades de Pointes 
have been reported. 
• Ocular toxicity: Ocular AEs, including dry eye, eye pain, blurred vision, and 
conjunctivitis, have been reported in aumolertinib clinical trials. Events have been 
primarily low-grade in severity. 
At present, there are no data on the use of aumolertinib in pregnant female participants, and the 
possible safety risks to the fetus are currently unknown. Based on its mechanism of action, the 
use of aumolertinib in pregnant female participants may cause harm to the fetus. It is also 
unknown whether aumolertinib and/or its metabolites are excreted in human milk. A risk to 
newborns/infants cannot be excluded. There are no clinical data for the effect of aumolertinib on 
human fertility. 
In consideration of the above, female participants of childbearing potential should avoid 
conceiving while taking aumolertinib. Female and male participants should use highly effective 
contraceptive measures (as detailed in Section 10.3) during heterosexual intercourse throughout 
the study and for 12 weeks after completing study treatment. 
For information on risks associated with the other study interventions, refer to the current 
prescribing information for osimertinib, pemetrexed, cisplatin, carboplatin, paclitaxel, 
albumin-bound paclitaxel, or gemcitabine, as applicable. 
2.3.3. 
Overall Benefit/Risk Conclusion 
Taking into account the measures taken to minimize risk to participants in this study, the 
potential and identified risks in association with aumolertinib are justified by the anticipated 
benefits that may be afforded to patients with NSCLC. 


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3. 
OBJECTIVES AND ENDPOINTS 
 
Objectives 
Endpoints 
Primary 
• 
To assess the efficacy of aumolertinib 
in combination with chemotherapy 
compared with osimertinib 
monotherapy 
• 
PFS, as assessed by blinded independent 
central review (BICR) per RECIST v1.1 
Key Secondary 
• 
To further assess the efficacy of 
aumolertinib in combination with 
chemotherapy compared with 
osimertinib monotherapy 
• 
OS 
Other Secondary 
• 
To assess other efficacy measures of 
aumolertinib in combination with 
chemotherapy compared with 
osimertinib monotherapy 
• 
TGR, ORR, DCR, DepOR, and DoR, each 
assessed by BICR per RECIST v1.1 
• 
PFS, TGR, ORR, DCR, DepOR, and DoR, 
each assessed by the Investigator per 
RECIST v1.1 
• 
ctDNA clearance 
• 
To assess the efficacy of aumolertinib 
monotherapy compared with 
osimertinib monotherapy 
• 
PFS, TGR, ORR, DCR, DepOR, and DoR, 
each assessed by BICR per RECIST v1.1 
• 
PFS, TGR, ORR, DCR, DepOR, and DoR, 
each assessed by Investigator per 
RECIST v1.1 
• 
OS 
• 
ctDNA clearance 
• 
To assess safety, including toxicities 
mediated by EGFR WT inhibition, in 
the study treatment arms 
• 
TEAEs, vital signs, ECGs, and laboratory 
test results (including chemistry, 
hematology, and urinalysis) by treatment 
arm 
• 
To evaluate selected PROs and QoL, 
including toxicities mediated by EGFR 
WT inhibition, in the study population 
• 
NCI PRO-CTCAE questionnaire 
• 
To characterize the PK profile of 
aumolertinib alone and in combination 
with chemotherapy 
• 
Aumolertinib concentration for population 
PK analysis 


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Objectives 
Endpoints 
Exploratory 
• 
To characterize mechanisms of 
acquired resistance in the treatment 
population 
• 
Exploratory biomarker analysis of plasma 
samples banked for the purpose of 
characterizing resistance mechanisms in 
participants treated with aumolertinib in 
combination with chemotherapy, 
aumolertinib monotherapy, and osimertinib 
monotherapy 
• 
To evaluate CNS efficacy for 
participants in the study treatment arms 
with measurable CNS lesions at 
baseline 
• 
Description of CNS efficacy as measured by 
PFS; OS; and ORR, DCR, DepOR, and DoR 
(each assessed by the Investigator per 
RANO criteria) 
• 
To evaluate additional efficacy 
measures in the study treatment arms 
• 
PFS2, as applicable 
• 
TFST and TSST, as applicable 
• 
To evaluate the correlation between 
TGR and ctDNA clearance with PFS 
and OS in the study treatment arms 
• 
 TGR, ctDNA, PFS assessed by the 
Investigator per RECIST v1.1, and OS 
• 
To evaluate the exposure-response 
relationship of aumolertinib alone and 
in combination with chemotherapy 
• 
Exposure-response analysis of safety and 
efficacy endpoints 


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4. 
STUDY DESIGN 
4.1. 
Overall Design 
EQ143-301 (TREBLE) is a Phase 3b multicenter, randomized, 3-arm, open-label study to 
evaluate aumolertinib + chemotherapy combination therapy compared with osimertinib 
monotherapy, and to describe aumolertinib monotherapy in comparison with osimertinib 
monotherapy. The intended study population is systemic treatment-naïve participants with 
metastatic EGFR-mutant NSCLC. Approximately 200 study sites in multiple regions are 
currently planned to participate. 
The primary study endpoint is efficacy of aumolertinib in combination with chemotherapy 
compared with osimertinib monotherapy, as measured by PFS (assessed by BICR per RECIST 
v1.1). PFS is defined as the time from date of participant randomization to either the first date of 
disease progression (per RECIST v1.1) or the date of death by any cause, whichever occurs first. 
Approximately 500 study participants will be randomized in a 2:2:1 ratio (by the stratified 
permuted block randomization method) into one of the following 3 treatment arms, respectively: 
4. Aumolertinib with chemotherapy (platinum-based doublet), as follows (approximately 
200 participants): 
• For adenocarcinoma, either: 
− Aumolertinib + cisplatin with pemetrexed, or 
− Aumolertinib + carboplatin with pemetrexed 
• For squamous cell carcinoma, one of the following: 
− Aumolertinib + cisplatin or carboplatin with paclitaxel; 
− Aumolertinib + cisplatin or carboplatin with albumin-bound paclitaxel; or 
− Aumolertinib + cisplatin or carboplatin with gemcitabine 
5. Osimertinib alone (approximately 200 participants) 
6. Aumolertinib alone (approximately 100 participants) 
All participants will be stratified by the following factors: 
• EGFR mutation (ex19del versus L858R) 
• ECOG PS (0 versus 1/2) 
• Race (White versus Asian versus Other Races Combined) 
A cycle of treatment is defined as 21 days for all 3 treatment arms; Cycles 2 onward have a 
window of 2 days prior to, or 7 days following, the cycle due date. 


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Note: All tumor imaging assessments are to be performed at the scheduled interval of every 
6 weeks (± 3 days) for the first 3 post-baseline assessments (with “baseline” defined as the 
participant’s most recent scan performed prior to the first dose of any study intervention 
and within 28 days before Day 1 of Cycle 1), then every 12 weeks (refer to the applicable SoA 
[Section 1.3]). This schedule is to be maintained regardless of any delays in the participant’s 
treatment. 
Aumolertinib will be administered in the study as two 55-mg tablets for a total dose of 110 mg 
once daily. Each aumolertinib tablet contains EQ143 drug substance, microcrystalline cellulose 
(KG802), anhydrous lactose (21AN), sodium carboxymethyl starch (type A), sodium stearyl 
fumarate, and magnesium stearate (MF-2-V). 
Participants randomized to receive aumolertinib with chemotherapy will receive up to 4 cycles of 
a platinum-based doublet along with once-daily aumolertinib at 110 mg once daily. Thereafter, at 
the Investigator’s discretion—based on assessment of continued clinical benefit for the 
individual—the participant may go on to receive maintenance pemetrexed with once-daily 
aumolertinib for the remainder of their study treatment, provided that they do not meet study 
treatment discontinuation and/or overall study discontinuation criteria. 
Osimertinib will be administered in the study as a single 80-mg tablet once daily. 
Based on available data, aumolertinib may be taken with or without food. While participants 
with a PEG tube may be eligible for this study at Investigator discretion, aumolertinib and 
osimertinib tablets are not to be crushed or otherwise damaged. 
As specified in the applicable SoA (Section 1.3), participants will continue on study treatment 
until disease progression (with certain exceptions, as noted below), withdrawal of consent, 
Investigator decision, or other reasons as detailed in Section 7.2. 
• Note: Selected participants who experience confirmed disease progression (per 
RECIST v1.1) may—at the discretion of the Principal Investigator—be permitted to 
continue on therapy upon discussion with the Sponsor. These participants must meet 
both of the criteria listed in Section 7.1 to continue on their assigned study treatment 
after progression, and will be required to sign a separate ICF. 
Refer to the SoAs in Section 1.3 for the list of study assessments and corresponding time points 
presented by treatment arm. Safety assessments conducted in all treatment arms will include 
monitoring of AEs/SAEs, vital signs, physical examination findings, ECGs, and laboratory test 
results (including hematology, serum chemistry, urinalysis, and coagulation). 
Participants who discontinue study treatment but do not withdraw overall consent will remain in 
the study for safety and survival follow-up, as detailed in the applicable SoA (Section 1.3). 
Pharmacokinetic (PK) plasma samples will be collected from all participants in the aumolertinib 
and aumolertinib with chemotherapy treatment arms (not the osimertinib arm), as indicated in the 
applicable SoAs (Table 1 and Table 2, respectively). These PK samples will be analyzed for the 
concentrations of aumolertinib and its major metabolite, HAS-719, using a validated 
bioanalytical method. A population PK assessment will be performed, using nonlinear 
mixed-effect models. 


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4.2. 
Scientific Rationale for Study Design 
The primary purpose of the EQ143-301 (TREBLE) study is to investigate whether the addition 
of chemotherapy to the third-generation EGFR-TKI aumolertinib improves PFS in patients with 
metastatic EGFR-mutated NSCLC. The rationale for dose selection is further detailed in 
Section 4.3. 
4.2.1. 
Scientific Rationale for Evaluation of Tumor Growth Rate 
TGR, which is derived from radiologic tumor measurements in clinical trials, has been found to 
correlate with PFS and OS in a number of malignancies. The rate of tumor growth—referred to 
as “g” (defined as the constant exponential rate of tumor growth)—is another surrogate for PFS 
that has been investigated in the setting of NSCLC, including in several FDA-authored studies. 
Gong 2020 observed that “g” was inversely correlated with survival in 5532 cases of advanced 
NSCLC, with this finding consistent across lines and types of therapy. More specifically, growth 
rate after nadir of tumor volume is reached on treatment is correlated with survival for 
EGFR-mutant NSCLC (Nishino 2021). 
The aforementioned findings demonstrate key advantages associated with utilizing TGR as an 
analysis of efficacy in NSCLC: unlike PFS, which uses data captured in discrete intervals of 
time, estimates of the rates of tumor growth yield data along a continuum—an output that might 
be preferential to the participant as an earlier indicator of response. 
A detailed TGR analysis plan (Section 9.4.3.3.4) will be included in the study SAP. 
4.3. 
Rationale for Dose Selection 
In this study, eligible participants will be randomized 2:2:1 to receive aumolertinib 110 mg 
once daily in combination with chemotherapy (platinum-based doublet); osimertinib 80 mg 
once daily as monotherapy; or aumolertinib 110 mg once daily as monotherapy, respectively. 
Aumolertinib at the 110 mg once-daily dose was approved by the China NMPA in March 2020 
for the treatment of patients with EGFR T790M mutation-positive NSCLC who have progressed 
during or following treatment with other EGFR-TKIs. In December 2021, the NMPA also 
approved aumolertinib for the treatment of patients with EGFR exon 19 del or L858R-mutant 
NSCLC in the first-line setting. 
The 110 mg once-daily dose of aumolertinib chosen for evaluation in this study is supported by a 
combination of safety and efficacy data across the Phase 1, Phase 2, and Phase 3 studies in the 
aumolertinib clinical development program. 
Safety data collected across the Phase 1/2 clinical study in participants with NSCLC 
(Study HS-10296-12-01, conducted in China) showed a dose-dependent increase in the incidence 
of ≥ Grade 3 AEs and SAEs. This increase was observed across the dose range evaluated (55 mg 
to 260 mg). However, the overall frequency of ≥ Grade 3 AEs was low in both the 55-mg and 
110-mg dose groups. Aumolertinib administered at a dose of 110 mg once daily was found to be 
safe and well tolerated, with a safety profile consistent with its mechanism of action. 
In the pivotal Phase 2 dose-extension portion of Study HS-10296-12-01, aumolertinib at a dose 
of 110 mg once daily achieved a high level of efficacy. 


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Based on the August 2021 data cut, as assessed by Investigator, ORR was 61.9% and the DCR 
was 91.8%, while median PFS and median DoR were 12.4 months and 13.8 months, 
respectively. 
In the pivotal Phase 3 study in participants with NSCLC (Study HS-10296-03-01, conducted in 
China), aumolertinib at 110 mg once daily was shown to significantly prolong PFS (median of 
19.8 months) and DoR (median of 19.2 months) as assessed by Investigator, compared with 
gefitinib (median of 9.7 months and 8.3 months for PFS and DoR, respectively). 
Aumolertinib was also associated with fewer side effects than gefitinib in the first-line treatment 
of patients with advanced EGFR-mutated NSCLC (Lu 2021). 
Overall, the 110 mg once-daily dosing regimen for aumolertinib has been proposed based on 
robust clinical experience (safety and efficacy) in Phase 1 through Phase 3 studies conducted in 
participants who have NSCLC. 
The dosing regimens for the other study interventions (ie, osimertinib and chemotherapy) are per 
current standard of care. 
Dose Modifications Upon Adverse Reactions 
Aumolertinib dosing interruption and/or dose reduction may be required based on individual 
safety and tolerability. If dose reduction is necessary, then the participant’s aumolertinib dose 
should be reduced to 55 mg once daily. Dose reduction guidelines for aumolertinib adverse 
reactions are provided in Section 6.5. 
Any dose modifications for the other study interventions are to occur in accordance with the 
current local label for osimertinib, pemetrexed, cisplatin, carboplatin, paclitaxel, albumin-bound 
paclitaxel, or gemcitabine, as applicable, and with institutional standard of care. 
4.4. 
End of Study 
The end of the overall study will be reached when all participants have ended their participation 
in the study. 
Additionally, the study may be placed on hold or terminated in any of the following 
circumstances: 
• Overall, country-/region-specific, or site-specific study hold or termination by the 
Sponsor at any time, for any reason 
• Study hold or termination in a specific country/region by the relevant 
Health Authority 
• Study-site closure initiated by the IRB/IEC, or by the Principal Investigator as 
detailed in Section 10.1.9.3 
Refer to Section 7.4 for additional information. 
The Sponsor will notify the Investigators in the event of any study hold or termination, or in the 
event of overall study completion (defined as completion of the last study visit of the last 
participant in the study). 


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5. 
STUDY POPULATION 
The EQ143-301 (TREBLE) study population will consist of participants who have not received 
systemic therapy for recurrent or metastatic EGFR-mutant NSCLC and have an ECOG PS of 0, 
1, or 2. All participants must be able to provide signed informed consent, and must meet all of 
the other study inclusion criteria and none of the study exclusion criteria. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in this study only if all of the following criteria apply: 
1. Is capable of giving signed informed consent, as described in Section 10.1.3, which 
includes compliance with the requirements and restrictions listed in the informed consent 
form (ICF) and in the protocol. 
2. Is at least 18 years of age (or the legal age of consent in the jurisdiction in which the 
study is taking place) and capable of complying with the study procedures. 
3. Has pathologically confirmed NSCLC that is Stage IIIB or Stage IIIC (for selected 
participants who are not candidates for curative approaches per the treating Investigator); 
metastatic (Stage IVA or IVB); or recurrent, and which is not amenable to curative intent 
therapy. 
• Note: 
− Participants with brain metastases may be eligible if they are minimally 
symptomatic or asymptomatic (as judged by their treating physician); have a 
minimum life expectancy of 12 weeks; and are either not on any steroids or on a 
stable or tapering dose of steroids. 
4. Tumor harbors one of the 2 common EGFR mutations known to be associated with 
EGFR-TKI sensitivity—ex19del or L858R—either alone or in combination with other 
EGFR mutations (eg, G719X, exon 20 insertions, S7681, L861Q). 
• Notes: 
− For screening and enrollment purposes, EGFR mutation status testing (of 
collected blood or tissue) is to have been performed by clinically validated assay, 
using a licensed laboratory/laboratory with applicable local accreditation (refer to 
Section 8.1.5). If available, existing EGFR mutation test results may be used to 
confirm eligibility, provided that they were obtained within ≤ 3 months prior to 
study entry. 
− If available, archival tissue may be collected (with participant’s consent) at 
Screening for central retrospective testing (this is optional; refer to Section 8.1.5). 
There is no specific prior interval during which the archival tissue must have been 
obtained. 
− All participants will also have a blood sample for central retrospective EGFR 
mutation testing collected predose on Day 1 of treatment Cycle 1. 


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5. Has ECOG PS of 0, 1, or 2 at the time of enrollment. 
6. Has adequate organ function, as defined by all of the following: 
• AST and ALT ≤ 3 × ULN 
• TBIL ≤ 1.5 × ULN in participants with well-documented absence of Gilbert’s 
Syndrome 
• Calculated CLcr ≥ 45 mL/min, as estimated by Cockroft-Gault equation 
• ANC ≥ 1000 cells/mm3 
• Hgb ≥ 8.0 g/dL 
• International Normalized Ratio (INR) ≤ 1.5, unless the participant is receiving 
chronic anticoagulation therapy as noted below. 
− Note: Therapeutic INR is higher in individuals on chronic anticoagulation 
treatment. Any such participant whose INR exceeds 1.5 may be considered 
eligible per Investigator judgment if otherwise meeting the study entry criteria. 
• PLAT ≥ 100,000/mm3 
7. Has QTc interval of ≤ 470 ms. 
8. Must meet all of the applicable requirements for pregnancy and contraception, as follows: 
a. If female: 
• Is a participant of childbearing potential (as defined in Section 10.3.1) who: 
− Has a negative serum or urine pregnancy test result within 48 hours prior to 
initiation of study drug dosing; 
− Is not breastfeeding; 
− Agrees to use highly effective contraceptive measures (as defined in 
Section 10.3.2) during heterosexual intercourse, or—if not using 
contraception—to remain abstinent (refer to Section 10.3.2) and undergo 
pregnancy testing predose during each dosing visit, while receiving study 
treatment (all 3 arms) through 12 weeks following the completion of study 
treatment; and 
− Agrees not to donate ova for the same time period; 
or 
• Is a participant who is confirmed by the Investigator to be of non-childbearing 
potential or medically postmenopausal per one or more of the following 
parameters: 
− Age, in addition to any of the other parameters listed here; 
− Menses status (ie, absence of menses for ≥ 1 year); or 


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− Surgical status (ie, prior hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy, or bilateral tubal ligation/occlusion); or 
− FSH level. 
b. If male: 
• Agrees to use a highly effective method of contraception (eg, male condom in 
addition to hormonal contraception; refer to Section 10.3) during heterosexual 
intercourse while receiving study treatment (all 3 arms) through 12 weeks following 
the completion of study treatment; and 
• Agrees to refrain from donating sperm for the same time period. 
Notes: 
• For all study participants, contraceptive use must be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies. 
Refer to Section 10.3 for additional guidance. 
• All participants must follow the contraception duration requirements for the drugs 
they receive, in accordance with the current local label for each drug. 
9. Must adhere to the following washout period requirements for all protocol-permitted 
prior anticancer therapies (all periods are in relation to Screening): 
• Major surgery: 4 weeks 
• Chemotherapy: 6 months 
• All other permitted therapies, including permitted radiotherapy (refer to Exclusion 
Criterion #6 below): 2 weeks 
5.2. 
Exclusion Criteria 
Participants are excluded from this study if any of the following criteria apply: 
Medical Conditions 
1. Has refractory nausea and vomiting; chronic gastrointestinal disease(s); inability to 
swallow the formulated product (or for selected participants, to receive it by PEG tube as 
noted below); or a history of previous significant bowel resection—any of which would 
preclude adequate absorption of aumolertinib or osimertinib. 
• Note: At the discretion of the Investigator, selected participants with a PEG tube may 
be eligible for this study. For any such participant, the PEG must allow for the 
safe and adequate administration of tablets (ie, without crushing or otherwise 
damaging them). 
2. Has evidence, and/or a past medical history, of interstitial lung disease; drug-induced 
interstitial lung disease; radiation pneumonitis that required steroid treatment; or 
clinically active interstitial lung disease. 


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3. Has evidence of any active bacterial infection, fungal infection, or viral infection 
(including SARS-CoV-2, as detailed below) which would preclude safe enrollment, as 
assessed by the treating Investigator. 
• Note: There are no protocol-specified testing requirements for SARS-CoV-2 in this 
study. SARS-CoV-2 requirements are instead determined by institutional standards 
(and local/country regulations, as applicable) and Investigator judgment. 
− At Investigator discretion, any participant who tests positive and/or is 
symptomatic for SARS-CoV-2 during Screening may either be excluded from the 
study or delay enrollment until active infection has been excluded per institutional 
standards. 
− During the study, any SARS-CoV-2 testing is to be performed as clinically 
indicated for the individual participant. The Investigator must document the 
results of all tests performed. Any confirmed infection is to be recorded as an AE 
or, in the event that clinical manifestation warrants such, recorded and handled as 
an SAE as detailed in Section 10.2.4. 
4. Has, or shows evidence of, any other active infection; significant medical illness; serious 
underlying medical condition; abnormal laboratory finding; or psychiatric illness/social 
situation that might, in the Investigator’s judgment, prevent the participant from receiving 
study treatment or being followed in this study, or which otherwise renders the 
participant inappropriate for the study, as judged by the Investigator. 
5. Hypersensitivity or allergy to aumolertinib or osimertinib or their excipients. 
Prior/Concomitant Therapy 
6. Has received prior systemic treatment for metastatic NSCLC. 
• Notes: 
− Prior chemotherapy is permitted, provided that it was used for treatment of 
locoregional NSCLC as a component of curative intent therapy and 
administration was completed more than 6 months prior to Screening. 
− Participants with a history of radiotherapy may be eligible (with a required 
washout period of ≥ 2 weeks before Screening, as detailed in Inclusion Criterion 
#9 above); however: 
 Concurrent radiotherapy is not permitted. 
− Prior EGFR-TKI therapy is not permitted. 
7. For participants in the aumolertinib monotherapy and aumolertinib with 
chemotherapy arms: Use of any prohibited concomitant medications, as outlined in 
Section 6.7 and Section 10.5; this includes use of any strong CYP3A4 inhibitors/inducers 
within approximately 14 days (or 5 half-lives) before Day 1 and use of any grapefruit or 
grapefruit-containing products within 72 hours before Day 1 through the participant’s 
final study visit. 


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• Note for participants in the osimertinib monotherapy and aumolertinib with 
chemotherapy arms: Guidance concerning prohibited concomitant medications is to 
be followed per the current prescribing information for osimertinib, pemetrexed, 
cisplatin, carboplatin, paclitaxel, albumin-bound paclitaxel, or gemcitabine, as 
applicable; institutional standard of care; and (as applicable) local regulations. 
Diagnostic Assessments 
8. Is a candidate for curative intent therapy for the NSCLC diagnosis. 
9. Tumor has mixed small-cell and non-small cell pathology. 
10. Has a history of prolonged QT syndrome or Torsades de Pointes. 
11. Meets any of the following cardiac criteria: 
• Has any clinically important abnormalities in rhythm, conduction, or morphology of 
resting ECG, including evidence of QT prolongation. 
• Has any factor, including any current medication(s), known to increase the risk of 
QTc prolongation or the risk of arrhythmic events. 
− Note: Bundle branch block (BBB) is a correction factor for QTc prolongation. 
Thus, QTc is corrected based on the institutional criteria in the presence of BBB. 
5.3. 
Lifestyle Considerations 
To reduce the probability or severity of skin reactions, protection from sunlight is recommended 
from the start of treatment with aumolertinib until 3 to 4 weeks after discontinuation of 
aumolertinib treatment. 
5.3.1. 
Meals and Dietary Restrictions 
Consumption of grapefruit or grapefruit-containing products is prohibited from 72 hours before 
Day 1 through the participant’s final study visit. 
5.3.2. 
Activity 
Participants are to abstain from strenuous exercise for 4 hours before each blood collection 
performed for the study clinical laboratory tests. 
5.4. 
Screen Failures 
A screen failure occurs when a participant who consents to enroll in the clinical study is not 
subsequently randomized. A minimal set of screen-failure information is required to ensure 
transparent reporting of screen-failure participants in order to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements, and to respond to queries from 
regulatory authorities. Minimal information for this study will include informed consent date, 
demography, screen failure details, eligibility criteria, and any SAE(s). 
Individuals who do not meet the criteria for participation in this study within 28 days (screen 
failures) are not enrolled. Previously screened participants may undergo one (1) additional 
re-screening for screen failure purposes and to confirm eligibility for study participation. The 
Investigator should confirm any such re-screening with the Sponsor. 


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Any re-screened participants should be assigned a different participant number. 
• Note: The Investigator may recommend that prospective study participants for whom 
EGFR mutation testing is not covered or reimbursed by standard of care undergo such 
testing for confirmatory purposes pre-screening (refer to Appendix 9 [Section 10.9]). 
− Any such individual will be required to sign the separate Pre-Screening Informed 
Consent Form to allow this testing. 
− After signing the form, the participant will proceed to full screening if the test 
results confirm that a required EGFR mutation is present and the participant 
agrees to join the study by signing the main study Informed Consent Form. 
− Without a confirmed EGFR mutation, prospective participants will not be eligible 
to participate in the study and will not be considered screen failures. 
5.4.1. 
Screening and Enrollment Log and Participant Identification Numbers 
Each participant’s enrollment in the study will be recorded in the screening and enrollment log. 
Upon provision of signed informed consent, each participant will receive a unique participant 
identification number. This number is assigned by the IRT system. Participant numbers will not 
be re-used for different participants. 


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6. 
STUDY INTERVENTIONS AND CONCOMITANT THERAPY 
Study intervention is defined as any investigational intervention(s), marketed product(s), or 
placebo intended to be administered to a study participant according to the study protocol. 
6.1. 
Study Interventions Administered 
Aumolertinib (as two 55-mg tablets) is to be administered once daily, and may be administered 
with or without food. (Of note, glucose is to be obtained in the fasted state for the Screening 
serum chemistry lab collection [refer to the applicable SoA in Section 1.3], but non-fasted at all 
other time points.) Each participant should be given instructions to maintain approximately the 
same daily time of aumolertinib administration to ensure a similar interval between doses. 
Osimertinib (as single 80-mg tablet) is to be administered once daily in accordance with the 
current osimertinib prescribing information and institutional standard of care. 
Administration of the other study interventions is to occur in accordance with the current 
prescribing information for pemetrexed, cisplatin, carboplatin, paclitaxel, albumin-bound 
paclitaxel, or gemcitabine, as applicable, and with institutional standard of care. 
Table 4:  Study Treatment Arms 
 
Arm Title: 
Aumolertinib 
monotherapy arm 
Aumolertinib with chemotherapy 
(combination) arm, consisting of either: 
For adenocarcinoma: 
aumolertinib + either cisplatin or carboplatin, 
along with pemetrexed 
OR 
For squamous cell carcinoma: 
aumolertinib + either cisplatin or carboplatin, 
along with one of the following: paclitaxel, 
albumin-bound paclitaxel, or gemcitabinea 
Osimertinib 
monotherapy arm 
Arm Type: 
Investigational 
Investigational 
Active comparator 
Arm 
Description: 
Not applicable 
Participants randomized to receive aumolertinib 
with chemotherapy will receive up to 4 cycles of 
a platinum-based doublet along with once-daily 
aumolertinib administered at 110 mg. 
Thereafter, at the Investigator’s discretion, 
participants may go on to receive maintenance 
pemetrexed along with once-daily aumolertinib,b 
Not applicable 
Associated 
Intervention 
Label: 
Two 55-mg tablets 
taken orally, QD 
Two 55-mg tablets taken orally, QD 
Single 80-mg tablet 
taken orally, QD 
a  Paclitaxel is to be given over 4 to 6 (fixed) cycles of treatment; this is the only study chemotherapy drug that may be 
administered for up to 6 cycles. Carboplatin/carboplatin-containing chemotherapy is to be given over 4 fixed cycles (q3wk 
× 4 cycles). 
b  If the Investigator considers it to be of continued clinical benefit for the individual participant, pemetrexed will be given as 
maintenance therapy for the remainder of the participant’s time on study treatment—provided the participant does not meet 
any of the study treatment discontinuation and/or overall study discontinuation criteria. 
q3wk = once every 3 weeks; QD = once daily. 


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6.2. 
Preparation, Handling, Storage, and Accountability 
The Investigator or designee must confirm that appropriate temperature conditions have been 
maintained during transit for all study intervention received, and that any discrepancies are 
reported and resolved before use of the study intervention. 
Only participants enrolled in the study may receive study intervention, and only authorized site 
staff may supply or administer study intervention. 
All study intervention must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions, with access 
limited to the Investigator and authorized site staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study interventions will be 
provided in the pharmacy manual. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
 
Type of Study 
Measures 
Open-label, using permuted 
block central randomization 
via IVRS/IWRS 
This is an open-label study; however, the specific intervention to be 
taken by a participant will be assigned using an IVRS/IWRS and 
integrated into the EDC on the proper case report form. The site will 
contact the IVRS/IWRS prior to the start of study intervention 
administration for each participant. 
Potential bias will be reduced by permuted block randomization. Site 
is not a stratification factor for this study. 
EDC = electronic data capture; IVRS = interactive voice response system; IWRS = interactive 
Web response system. 
6.4. 
Study Intervention Compliance 
When participants are dosed at the study site, they will receive study intervention directly from 
the Investigator or designee under medical supervision. The date and time of each dose of study 
intervention administered in the clinic will be recorded in the source documents. The dose of 
study intervention and study participant identification will be confirmed at the time of dosing by 
a member of the study site staff other than the person administering the study intervention. For 
orally administered study intervention, study site staff will examine each participant’s mouth to 
ensure that the study intervention was ingested. 
When participants orally self-administer study intervention(s) at home, compliance with the 
study intervention will be assessed at each visit. Compliance with orally administered study 
intervention will be assessed by counting returned tablets during the site visits and documented 
in the source documents and relevant form. Any deviation(s) from the prescribed dosage regimen 
should be recorded. 


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The Investigator should consult with the Sponsor regarding any suspected treatment 
compliance issues in the study. 
A record of the quantity of all study interventions dispensed to and administered by each 
participant must be maintained and reconciled with study intervention and compliance records. 
Intervention start and stop dates, including dates for intervention delays and/or dose reductions, 
will also be recorded. 
6.5. 
Dose Modification 
Any toxicity observed with aumolertinib could be managed by dose reductions of that study 
intervention, as specified in Table 5. If the aumolertinib dose has been reduced to the minimum, 
but the participant is still unable to tolerate the drug, termination of treatment is recommended. 
Dose reduction of any of the other study interventions is to be performed in accordance with the 
current local label for osimertinib, pemetrexed, cisplatin, carboplatin, paclitaxel, albumin-bound 
paclitaxel, or gemcitabine, as applicable, and with institutional standard of care. 
For participants in the aumolertinib with chemotherapy arm who have any of the component 
agents held or discontinued due to safety/toxicity concerns, treatment with the other agent(s)— 
whether aumolertinib or chemotherapy—may be continued at the discretion of the Investigator. 
Participants who have one chemotherapy agent discontinued may continue on the other agent, as 
well as aumolertinib, per Investigator discretion. 
Table 5: Specifications for Aumolertinib Dose Reduction 
 
Initial Treatment 
First Dose Reduction Treatment 
Dose: 
110 mg/day aumolertinib 
55 mg/day aumolertinib 
Drug: 
Aumolertinib active, 55 mg, 2 tablets Aumolertinib active, 55 mg, 1 tablet 
Frequency, Method of 
Administration: 
QD, PO 
QD, PO 
PO = orally; QD = once daily. 
6.5.1. 
General Principles of Aumolertinib Dose Adjustment Related to Selected AEs 
Refer to Section 2.3.1 and to the current aumolertinib IB for information regarding risks that may 
be associated with aumolertinib. 
If a participant experiences a) an AE that is, as judged by the Investigator, NCI CTCAE Grade 3 
or higher in severity; and/or b) an AE of any grade that is considered unacceptable by the 
Investigator—and the Investigator assesses the event(s) as treatment-related—dosing will be 
withheld and supportive care will be given in accordance with local practice/guidelines, as 
needed. 
• Note: “Treatment-related” here can be explained as definitely related, probably related, 
or possibly related to study treatment per Investigator assessment, but excluding unlikely 
related and not related. 
Aumolertinib dose adjustment guidelines are specified in Table 6. These guidelines apply to 
participants in the aumolertinib monotherapy arm and the aumolertinib with chemotherapy arm. 


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Table 6: 
Dose Adjustment Principles of Aumolertinib Tablets when Selected AEs 
Considered Treatment-related by the Investigator Occur 
 
Type 
AEs Considered Related to Study 
Treatment with Aumolertinib 
Dose Adjustmenta 
All 
Any treatment-related AE of ≥ Grade 3 
severity not addressed elsewhere in this 
table 
Unless otherwise instructed within this table: 
Hold study treatment for up to 3 weeks; 
• 
If the AE improves to ≤ Grade 2, 
resume treatment. 
− 
Resume treatment at 110 mg for 
the first occurrence. 
− 
Resume treatment at 55 mg for 
the second occurrence. 
• 
If the AE has not improved to 
≤ Grade 2 after 3 weeks, permanently 
discontinue aumolertinib. 
Heart 
At least 2 independent ECG examinations 
have found that the QTc interval is greater 
than 500 ms. 
Hold study treatment for up to 3 weeks; 
• 
If the baselineb value is > 470 ms, and 
the QTc interval is improved to 
baseline within 3 weeks, resume 
treatment at 55 mg. 
• 
If the baseline value is ≤ 470 ms, and 
the QTc interval is improved to 
≤ 470 ms within 3 weeks: 
− 
Resume treatment at 110 mg for 
the first occurrence. 
− 
Resume treatment at 55 mg for 
the second occurrence. 
If the QTc interval remains > 500 ms after study 
treatment has been held for 3 weeks, permanently 
discontinue aumolertinib. 
QTc prolongation combined with any of 
the following: 
• 
Torsades de Pointes 
• 
polymorphic ventricular 
tachycardia 
• 
signs or symptoms of 
serious arrhythmia 
Permanently discontinue aumolertinib. 
Absolute decrease from baseline in 
asymptomatic LVEF > 10% and 
associated absolute value < 50% 
Hold study treatment for up to 3 weeks; 
If improved to baseline LVEF within 3 weeks: 
• 
Resume treatment at 110 mg for the 
first occurrence. 
• 
Resume treatment at 55 mg for the 
second occurrence. 
Symptomatic congestive heart failure 
Permanently discontinue aumolertinib. 


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Type 
AEs Considered Related to Study 
Treatment with Aumolertinib 
Dose Adjustmenta 
Liver 
dysfunction 
Abnormal liver function as described in 
Section 10.4 
Hold study treatment for up to 3 weeks; 
If ALT and/or AST improve(s) to ≤ Grade 1 and 
TBIL improves to ≤ Grade 1 within 3 weeks: 
• 
Resume treatment at 110 mg for the 
first occurrence. 
• 
Resume treatment at 55 mg for the 
second occurrence. 
Permanently discontinue aumolertinib if: 
• 
ALT and/or AST > 8 × ULN any one 
time; 
or 
• 
ALT and/or AST > 5 × ULN for more 
than 2 weeks; 
or 
• 
ALT and/or AST > 3 × ULN and 
TBIL > 2 × ULN. 
Cornea 
Corneal ulcer 
Permanently discontinue aumolertinib. 
Permanent discontinuation of aumolertinib should be considered if, at any time, the participant is unable 
to tolerate 55 mg (≥ Grade 3 adverse reactions). 
Note: All grades described in this table refer to severity grading using NCI CTCAE version 5.0. 
a The recommendations herein are general guidance principles. The final course of action can be modified by the 
Investigator in concert with the Medical Monitor. 
b The Screening QTc interval in this study is considered the baseline QTc interval. 
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; ECG = electrocardiogram; 
LVEF = left ventricular ejection fraction; NCI CTCAE = National Cancer Institute Common Terminology Criteria 
for Adverse Events; QTc = corrected QT interval; TBIL = total bilirubin; ULN = upper limit of normal. 
6.5.2. 
Dose Adjustments to Osimertinib or Chemotherapy Regimens 
The doses of osimertinib and the protocol-permitted chemotherapy regimens in this study are 
permitted to be adjusted in response to AEs considered treatment-related by the Investigator. 
Any such dose adjustments are to be performed in accordance with the current local label for 
osimertinib, pemetrexed, cisplatin, carboplatin, paclitaxel, albumin-bound paclitaxel, or 
gemcitabine (as applicable), and with institutional standard of care. 
If an AE is considered by the Investigator to be related to treatment with only one study 
intervention, dose adjustment only applies to that study intervention. 
As noted previously, participants in the aumolertinib with chemotherapy arm who have had any 
of the component agents held or discontinued due to safety/toxicity concerns may continue on 
the other agents (aumolertinib or chemotherapy) at the discretion of the Investigator. Participants 
who have one chemotherapy agent discontinued may continue on the other agent, as well as 
aumolertinib, per Investigator discretion, and no delay in aumolertinib dosing is necessitated by a 
delay in chemotherapy drug dosing. 


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The Investigator should reach a consensus with the Medical Monitor on the appropriate next 
steps for any participant who undergoes an osimertinib or chemotherapy dose adjustment. 
The time window of each dose of chemotherapy is calculated from the date of the last dose. 
Before each chemotherapy cycle of a protocol-permitted chemotherapy regimen, the treating 
Investigator should follow institutional guidelines and best clinical practice in interpreting the 
required laboratory data, and then deciding on the dosing and timing of chemotherapy 
administration. 
For some participants, the Investigator may decide, due to benefit/risk considerations, to 
administer chemotherapy after a delay of more than 1 week. Whenever possible, the Investigator 
should review the applicable circumstances with the Medical Monitor before administering 
chemotherapy to such participants. 
If the above criteria for starting chemotherapy are not met, or if the delay in chemotherapy 
administration exceeds 21 days, the Investigator should reach a consensus with the Medical 
Monitor on the appropriate next steps for the individual participant. 
Overlapping Toxicities of Aumolertinib and Chemotherapy 
Concomitant administration of aumolertinib with potent inhibitors of CYP3A4 enzymes may 
increase blood CPK, as discussed in the current aumolertinib IB and in the Hansoh package 
insert for aumolertinib mesylate tablets. This potential toxicity has been addressed in the 
EQ143-301 (TREBLE) study by the exclusion criteria (Section 5.2) which prohibit the 
participation of individuals who have used strong CYP3A4 inhibitors within approximately 
14 days before Day 1 of the trial. 
Potential risks of aumolertinib that overlap with the known risks of chemotherapy in this study 
include gastrointestinal toxicity (including diarrhea, nausea, and vomiting); skin disorders 
(such as rash); respiratory disorders (such as interstitial lung disease); myelosuppression; 
ocular disorders; and hepatic disorders. Refer to the current aumolertinib IB for all available 
safety data. 
In the case of overlapping toxicity, the Investigator should use clinical judgment when 
attributing a toxicity to one or more of the study interventions and consider following the more 
conservative approach. 
6.5.2.1. 
Recommendations for Discontinuing Osimertinib or Chemotherapy 
Some participants in this study may require discontinuation of osimertinib or a 
protocol-permitted chemotherapy regimen (eg, for toxicities considered treatment-related by the 
Investigator). Any such discontinuation is to be performed in accordance with the current 
prescribing information for osimertinib, pemetrexed, cisplatin, carboplatin, paclitaxel, 
albumin-bound paclitaxel, or gemcitabine (as applicable), and with institutional standard of care. 
The Investigator should reach a consensus with the Medical Monitor on the appropriate 
next steps for any participant who discontinues osimertinib or a protocol-permitted 
chemotherapy regimen. 


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6.6. 
Treatment of Overdose 
In the context of a clinical study, an overdose is any dose which exceeds the daily dose that is 
defined in the clinical study protocol. Thus, for this study, any dose of aumolertinib greater than 
110 mg within a 24-hour time period will be considered an overdose. Symptoms of aumolertinib 
overdose are not established, and there is no specific treatment for such an overdose. 
Overdoses of any of the other study interventions should be determined by the current 
prescribing information for osimertinib, pemetrexed, cisplatin, carboplatin, paclitaxel, 
albumin-bound paclitaxel, or gemcitabine (as applicable), and by institutional standard 
of care. 
In the event of any overdose of any study intervention in this trial, the Investigator should 
take the following steps: 
• Contact the Medical Monitor immediately (within no more than 24 hours of 
awareness). The designated Sponsor representative will work with the Investigator to 
ensure that all relevant information is provided to the Sponsor or designee. 
• Document the quantity of the excess dose, as well as the duration of the overdose. 
• Withhold the study intervention and closely monitor the participant for any 
AEs/SAEs and/or laboratory abnormalities. 
− Note: For overdoses associated with an AE/SAE, the standard reporting timelines 
apply as detailed in Section 10.2. 
• Obtain a plasma sample for PK analysis as soon as possible. 
• Follow general supportive measures and treat symptomatically. 
Overdoses of any study intervention other than aumolertinib should be treated in accordance 
with the current prescribing information for osimertinib, pemetrexed, cisplatin, carboplatin, 
paclitaxel, albumin-bound paclitaxel, or gemcitabine, as applicable, and with institutional 
standard of care. 
6.7. 
Prior and Concomitant Therapy/Procedures 
The Investigator or qualified designee will review participants’ prior medication use, including 
prescription medications and over-the-counter preparations, and record prior medications taken 
by the participant within 28 days prior to the first day of Screening. 
Concomitant therapy is defined as any medication (other than study intervention) that was used 
at least once after the administration of study intervention. 
• If a clear determination cannot be made (partial medication end dates), the medication 
will be classified as concomitant. 
• Any vaccine administration that occurs during the study will recorded as a 
concomitant medication. 


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• Any SARS-CoV-2 testing during the study will be performed if clinically indicated 
per the Investigator, in accordance with institutional standards (and, if applicable, 
local/country regulations), and will be recorded as a laboratory procedure as detailed 
in the applicable SoA (Section 1.3). Any positive result is to be recorded and handled 
as an AE (or, if clinical manifestation warrants such, as an SAE) in accordance with 
Section 10.2. 
• Any treatment known to prolong the QTc interval will not be allowed. 
• Participants must refrain from using any prohibited concomitant medications, as 
outlined in Section 10.5. 
• If a clear determination cannot be made (partial medication end dates), the medication 
will be classified as concomitant. 
• The Investigator or qualified designee will record any medication(s) taken by the 
participant, and any procedure(s) performed (as applicable), during the participant’s 
time on study through the last study visit. Documentation will include information 
regarding start and stop dates, dose(s), and reasons for the medication use. 
• All participants must adhere to the following washout period requirements for 
protocol-permitted prior anticancer therapies (refer to Section 5.1 and Section 5.2): 
− Major surgery: 4 weeks before Screening 
− Chemotherapy: 6 months before Screening 
− All other permitted therapies, including permitted radiotherapy (refer to Exclusion 
Criterion #6 in Section 5.2): 2 weeks before Screening 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 


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7. 
DISCONTINUATION FROM STUDY TREATMENT AND FROM 
THE OVERALL STUDY 
Discontinuation of specific study sites is handled as part of the appendix on governance (refer to 
Section 10.1.9.3). 
Refer to Section 7.4 for criteria that may potentially result in the Sponsor reviewing the 
evaluable data and considering whether study stoppage (permanent discontinuation) may be 
appropriate. 
7.1. 
Permanent Discontinuation of a Participant from Study Treatment 
It may be necessary for a participant to permanently discontinue from study treatment (all 
3 arms). Should such permanent discontinuation of study treatment occur, the participant will 
remain in the study for safety and survival follow-up, provided that overall consent has not been 
withdrawn. Refer to the applicable SoA (Section 1.3) for data to be collected at the time of the 
participant’s discontinuation from study treatment and during subsequent follow-up. 
A participant’s study treatment will be permanently discontinued if any of the following 
occurs during the study: 
• The participant experiences disease progression as assessed by the Principal 
Investigator or sub-Investigator and agreed to by the Sponsor Medical Monitor 
following consultation, except in the following scenario: 
− If it is the medical opinion of the Investigator that continuation of assigned 
study treatment would provide clinical benefit to a participant whose disease 
progression is confirmed, that participant may continue therapy upon 
discussion with the Sponsor, provided that both of the following criteria are met. 
Any such participant will also be required to sign a separate ICF: 
 No decline in ECOG PS attributable to underlying disease. 
 Absence of symptomatic rapid disease progression requiring urgent 
medical intervention (eg, symptomatic pleural effusion, spinal cord 
compression). 
− For all participants, all tumor imaging assessments—including brain imaging 
assessments, if applicable—are to continue at the scheduled interval of every 
6 weeks (± 3 days) for the first 3 post-baseline assessments (with “baseline” 
defined as the participant’s most recent scan performed prior to the first dose of 
any study intervention and within 28 days before Day 1 of Cycle 1), then every 
12 weeks (refer to the applicable SoA [Section 1.3]), regardless of any treatment 
delays. 
• The participant suffers an AE which, in the judgment of the Investigator, Sponsor, or 
Medical Monitor, presents an unacceptable risk to the participant. 
• General or specific changes in the participant’s condition (eg, a significant 
intercurrent illness or complication) which, in the judgment of the Investigator, 
renders further administration of study intervention unacceptable for the participant. 


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• The participant has either of the following: 
− Liver toxicity, as noted in Section 7.1.1 and defined in Section 10.4; or 
− Appearance of a corneal ulcer. 
• Occurrence of pregnancy in a female study participant or female partner of a male 
study participant (as applicable). 
• Significant noncompliance of the participant with protocol requirements. 
• The Sponsor, or legal representative of the Sponsor, requests the participant to 
withdraw. 
• The participant is lost to follow-up (must have at least 3 documented attempts to 
contact the participant; refer to Section 7.3). 
• The participant exhibits any evidence of drug abuse in the opinion of the Investigator. 
• Permanent study treatment discontinuation is judged by the Investigator to be in the 
best interest of the participant. 
• The participant withdraws consent for the study. 
• The Sponsor makes the decision to terminate the site or study. 
In the event of a participant discontinuing from study treatment without withdrawing overall 
consent, that participant should be strongly encouraged to complete all protocol-scheduled 
assessments—including safety and survival follow-up—as detailed in the applicable SoA 
(Section 1.3). 
Whenever possible, any participant who discontinues from study treatment for a reason other 
than progression of disease should have a CT scan of the chest and abdomen/pelvis with contrast 
(or a PET/CT scan, if that is the imaging modality used for the individual participant per 
Investigator discretion) performed, provided that they have not undergone a scan within the prior 
4 weeks. 
The Investigator will document the reason for each participant’s discontinuation from study 
treatment on the applicable eCRF page. 
When a participant’s study treatment discontinuation is due to either an SAE or a Grade 3 or 4 
toxicity (regardless of seriousness) that is considered treatment-related by the Investigator, the 
Investigator should follow the event until resolution, stabilization, or it is deemed that further 
recovery is unlikely. Data on all such events should be collected in the AE section of the eCRF. 
In the event that a participant discontinues from study treatment due to an AE (or SAE, as 
applicable), the Investigator should notify the Medical Monitor or Pharmacovigilance 
representative by email within 24 hours of treatment discontinuation. All SAEs in the study are 
to be recorded and handled as detailed in Section 10.2.4. 
In the event of a pregnancy (of a female study participant or female partner of a male study 
participant) during the study, the Investigator is to record pregnancy information on the 
Pregnancy Reporting and Outcome Form and submit the completed form to the Sponsor within 
24 hours as detailed in Section 8.4.5. 


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7.1.1. 
Liver Chemistry Stopping Criteria 
Discontinuation of study treatment in response to abnormal liver test results is required by the 
Investigator a) when a participant meets one of the conditions outlined in Section 10.4, or b) in 
the presence of abnormal liver chemistries not meeting protocol-specified stopping rules, if the 
Investigator believes that this is in the best interest of the participant. 
7.1.2. 
Cardiac Stopping Criteria 
If a clinically significant cardiac finding is identified after study enrollment—eg, any Grade 4 
cardiac AE or any Grade 3 QTc prolongation event that is not resolved within 3 weeks (refer to 
Table 6)—the Investigator or qualified designee will determine if the participant can continue on 
study treatment or must be permanently discontinued from treatment. 
The review of the ECG printed at the time of collection must be documented. Any new clinically 
relevant finding should be reported as an AE per Section 10.2.3. 
7.1.3. 
Temporary Discontinuation of a Participant from Study Treatment 
A participant may temporarily discontinue from study treatment with any study intervention for a 
duration of up to 3 weeks, for any reason. However, any such temporary discontinuation must be 
reported to the Medical Monitor, and the participant’s study assessments must continue as 
specified in the applicable SoA (Section 1.3). 
If treatment with any study intervention is temporarily discontinued for any participant, it may be 
re-started within the aforementioned 3-week period at the discretion of the Investigator with 
notice to the Medical Monitor. 
Beyond a duration of 3 weeks, the participant may not re-start study treatment and will be 
permanently removed from the study. 
7.1.4. 
Re-challenge Therapy 
Re-challenge (re-introduction) may be initiated with any study intervention in participants whose 
temporary discontinuation of study treatment has occurred within ≤ 3 weeks—provided that, in 
the opinion of the Investigator, the benefits of continuing the participant’s study treatment 
outweigh the risks. 
If treatment with any study intervention has been discontinued due to toxicity, the Investigator 
must confirm the toxicity is resolving (to at least ≤ Grade 2 severity) before attempting 
re-challenge. 
If treatment with any study intervention has been discontinued for any other reason, that reason 
must be provided to the Medical Monitor. 
7.2. 
Permanent Discontinuation/Withdrawal of a Participant from 
the Study 
Participants may permanently discontinue/withdraw from the study at any time at their own 
request or may be permanently discontinued/withdrawn at any time at the discretion of the 
Investigator for safety, behavioral, or compliance reasons. Any such participant will be 
permanently discontinued from study treatment and from the overall study at that time. 


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If a participant withdraws consent for disclosure of their future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent, subject to any 
limitations under applicable data privacy and data protection laws. 
If a participant permanently discontinues/withdraws from the study, they may request destruction 
of any samples taken and not tested, and the Investigator must document this in the site study 
records. 
Refer to the applicable SoA (Section 1.3) for details of the data to be collected at the time of 
study discontinuation. 
7.2.1. 
Criteria for Permanent Participant Discontinuation/Withdrawal from the Study 
All participants should be encouraged to complete all study evaluations. However, participants 
may withdraw overall consent for participation in this study at any time without penalty or loss 
of benefits to which they are otherwise entitled. 
Every reasonable effort should be made to determine the reason a participant withdraws study 
consent, and this information should be recorded on the appropriate page(s) of the eCRF. 
Where participants discontinue study treatment prematurely without withdrawing overall 
consent, reasonable efforts should be made to perform all protocol-specified assessments in order 
to avoid losing outcome data that is necessary for the evaluation of safety. 
Participants may withdraw from the study at their own discretion (or be withdrawn at the 
discretion of the Investigator) for any reason, at any time. 
The reasons participants may be withdrawn from the study may include, but are not limited to, 
the following: 
• Occurrence of an AE that in the opinion of the Investigator, warrants the participant’s 
permanent withdrawal from the study. 
− In the event of permanent withdrawal due to the occurrence of a nonserious AE, 
the study site should notify the Sponsor or Sponsor’s representative as soon as 
possible. 
− In the event of permanent withdrawal due to the occurrence of an SAE, the 
Medical Monitor or representative must be notified within 24 hours as specified in 
Section 10.2.4. 
• Significant noncompliance, defined as refusal or inability to adhere to the prescribed 
dosing and follow-up regimen. 
• Request of the participant, Investigator, or study Sponsor. 
• Participant withdraws informed consent. 
• Participant is lost to follow-up (must have at least 2 documented attempts to contact 
the participant; refer to Section 7.3). 
• Death. 
All data and laboratory samples collected prior to the date on which the participant’s consent is 
withdrawn will remain in the clinical database and at the laboratory vendor. 


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7.3. 
Lost to Follow-up 
Participants will be considered lost to follow-up if they repeatedly fail to return for scheduled 
study visits and are unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the site for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible (and within the visit window, where one is defined in the applicable 
SoA [Section 1.3]); counsel the participant on the importance of maintaining the 
assigned visit schedule; and ascertain whether the participant wishes to, and/or 
should, continue in the study. 
• In cases in which the participant is deemed lost to follow-up, the Investigator or 
designee must make every effort to regain contact with the participant—where 
possible, 2 telephone calls and, if necessary, a certified letter to the participant’s last 
known mailing address, or local equivalent methods—and to regain any remaining 
study intervention from the participant. The Investigator should be making every 
effort to collect any unused medication, and these contact attempts should be 
documented in the participant’s medical record. 
• Should the participant, and/or caregiver authorized to serve as a contact for the 
participant (as applicable), continue to be unreachable, that participant will be 
considered to have withdrawn from the study. 
• For all participants enrolled in the study, site personnel or an independent third party 
will attempt to collect the vital status of the participant within legal and ethical 
boundaries. Public sources may be searched for vital status information. If a 
participant’s vital status is determined as deceased, this will be documented, and the 
participant will not be considered lost to follow-up. Sponsor personnel will not be 
involved in any attempts to collect vital status information. 
A participant will be considered lost to follow-up after 3 months of documented unsuccessful 
contact attempts. 
7.4. 
Criteria for Potential Stoppage (Permanent Discontinuation) of 
the Study 
The Sponsor will review the evaluable data—including any emerging safety signals attributed to 
the study drug—and will consider whether the permanent stoppage (discontinuation) of the study 
may potentially be appropriate. 
As noted in Section 4.4, stoppage (permanent discontinuation) of the study may also occur in any 
of the following circumstances: 
• Overall, country-/region-specific, or site-specific stoppage by the Sponsor at any 
time, for any reason 
• Stoppage in a specific country or region by the relevant Health Authority 


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• Stoppage at a specific site by the relevant IRB/IEC or by the Principal Investigator 
(refer to the relevant portion of the appendix on governance [Section 10.1.9.3]) 


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their associated timing are summarized in the SoAs for each treatment arm 
(Section 1.3). 
Protocol waivers or exemptions are not permitted. 
Additional Information 
• Immediate safety concerns should be discussed with the Medical Monitor 
immediately upon occurrence or awareness to determine the appropriate course of 
action for the individual participant. 
• Adherence to the study design requirements, including those specified in the SoAs 
(Section 1.3), is essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
• Procedures conducted as part of the individual participant’s routine clinical 
management (eg, blood count) and obtained before the provision of signed informed 
consent may be utilized for screening or baseline purposes, provided that the 
procedures met the protocol-specified criteria and were performed within the 
timeframe defined in the applicable SoA (Section 1.3). 
• Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples. 
• The maximum amount of blood collected from each participant over the duration of 
the study, including any extra (ie, repeat or unscheduled) assessments that may be 
required, is not expected to exceed 300 mL. Refer to Section 8.7 for details. 
Medical History 
For all participants, a medical history will be obtained by the Investigator or qualified designee. 
The medical history will collect all medical and surgical conditions which the Investigator 
considers to be clinically significant and relevant for the individual participant. 
Details regarding the disease for which the participant has enrolled in this study will be recorded 
separately and not listed as medical history. 
Calibration of Equipment 
The Investigator (or qualified designee) is responsible for ensuring that any device or instrument 
used for a clinical evaluation/test during the study that provides information about eligibility 
criteria, and/or safety or efficacy parameters, is suitably calibrated and/or maintained to ensure 
that the data obtained are reliable and/or reproducible. Equipment calibration documentation is to 
be retained at the study site and available for inspection. 


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8.1. 
Efficacy Assessments 
Planned time points for all study efficacy assessments are presented (by treatment arm) in the 
SoAs (Section 1.3). 
8.1.1. 
Antitumor Activity Assessments 
RECIST v1.1 guidelines (Eisenhauer 2009) will be used for all tumor assessments in the study, 
as detailed in Section 10.6. 
In addition, assessments of brain metastases will follow RANO criteria as detailed in 
Section 10.7. 
8.1.2. 
Tumor Imaging Assessments 
8.1.2.1. 
Computed Tomography Scans of the Chest and Abdomen/Pelvis with Contrast 
CT scan of the chest and abdomen/pelvis (covering the liver and adrenal glands) with contrast is 
the preferred imaging modality for the study. (PET/CT may be used for an individual participant 
at Investigator discretion; refer to Section 8.1.2.2.) 
Scans should be contiguous throughout the anatomic region of interest. 
The most critical CT image acquisition parameters for optimal tumor evaluation using 
RECIST v1.1 (refer to Section 10.6) are anatomic coverage, contrast administration, slice 
thickness, and reconstruction interval. 
8.1.2.2. 
Positron Emission Tomography/Computed Tomography Scans 
As noted above in Section 8.1.2.1, CT with contrast is the preferred imaging modality for use in 
the study; however, PET/CT may instead be used for an individual participant at the discretion of 
the Investigator. The same imaging modality (CT with contrast or PET/CT) should be used 
across all tumor assessment scan collections for the individual participant. 
Bone lesions that are identified on any PET/CT scan performed at baseline and are confirmed by 
CT or X-ray should be recorded as nontarget lesions and followed by the same method as per the 
baseline assessment. 
PET/CT scans may be used as a method of assessment to identify the presence of new bone 
lesions during follow-up. 
New lesions will be recorded where a positive hot spot that was not present on the baseline scan 
assessment is identified on a PET/CT scan performed at any time during the study. The 
Investigator should consider the positive hot spot to be a significant new site of malignant 
diseases and to represent true disease progression in order to record the new lesion. 
Confirmation by CT and X-ray is recommended where PET/CT scan findings are equivocal. 
8.1.2.3. 
Anatomic Coverage 
Optimal anatomic coverage for most solid tumors is the chest, abdomen, and pelvis. 
Coverage should encompass all areas of known predilection for metastases in the disease under 
evaluation and should additionally investigate areas that may be involved based on signs and 
symptoms of individual participants. 


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Because a lesion later identified in a body part not scanned at baseline would be considered as a 
new lesion representing disease progression, careful consideration should be given to the extent 
of imaging coverage at baseline and at subsequent follow-up time points. This will enable better 
consistency of not only tumor measurements, but also identification of new disease. 
8.1.2.4. 
IV Contrast Administration 
Optimal visualization and measurement of metastases in solid tumors requires consistent 
administration (dose and rate) of IV contrast as well as timing of scanning. Typically, most 
abdominal imaging is performed during the portal venous phase and (optimally) about the same 
time frame after injection on each examination. 
An adequate volume of a suitable contrast agent should be given so that the metastases are 
demonstrated to best effect and a consistent method is used on subsequent examinations for any 
given participant. It is very important that the same technique be used at baseline and on 
follow-up examinations. 
For participants who develop contraindications to contrast after baseline contrast CT is done, the 
decision as to whether non-contrast CT or MRI (enhanced or non-enhanced) should be 
performed should also be based on the tumor type and anatomic location of the disease and 
should be optimized to allow for comparison to prior studies, if possible. 
Each case should be discussed with the radiologist to determine if substitution of the other 
approaches is possible and, if not, the participant should be considered not evaluable from that 
point forward. 
Care must be taken in the measurement of target lesions on a different modality and the 
interpretation of nontarget disease or new lesions because the same lesion may appear to have a 
different size using a new modality. Oral contrast is recommended to help visualize and 
differentiate structures in the abdomen. 
If iodinated contrast is medically contraindicated at baseline or at any time during the study, the 
recommended approach is chest CT without contrast and PET/CT of the abdomen and pelvis. 
If PET/CT is not available, CT without IV contrast is the choice for one of the chest, abdomen, 
and pelvis collections. 
For assessment of brain lesions, MRI is the preferred method; CT may be used if MRI is 
medically contraindicated. Refer to Section 8.1.2.7 for details. 
8.1.2.5. 
Slice Thickness and Reconstruction Interval 
It is recommended that CT scans be performed at 5-mm contiguous slice thickness or less; this 
guideline presumes a minimum 5-mm thickness in recommendations for measurable lesion 
definition. Occasionally, institutions may perform medically acceptable scans at slice thicknesses 
greater than 5 mm. If this occurs, the minimum size of measurable lesions at baseline should be 
twice the slice thickness of the baseline scans. 
All CT window settings should be included, particularly in the thorax, where the lung and 
soft-tissue windows should be considered. 
The target lesions are measured by use of the same window settings for repeated examinations 
throughout the study. 


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All images from each examination should be included and not “selected” images of the apparent 
lesion. 
8.1.2.6. 
Sites and Schedule of Tumor Assessments 
If a participant is found to have brain lesions, or metastatic lesions in other sites, on baseline 
imaging, tumor assessments must be performed on the corresponding site(s) during each 
subsequent follow-up. 
All tumor assessments are to be performed per RECIST v1.1 (refer to Section 10.6). 
Additionally, all brain metastases are to be assessed per RANO criteria (refer to Section 10.7). 
For participant and Investigator/site convenience in this study, tumor assessments are scheduled 
to occur in parallel every 6 weeks ± 3 days for the first 3 post-baseline assessments (with 
“baseline” defined as the participant’s most recent scan performed prior to the first dose of any 
study intervention and within 28 days before Day 1 of Cycle 1), and then every 12 weeks 
thereafter. Scans will be reviewed centrally. 
Sites with no metastasis at baseline (for example, no brain or bone metastases) need not be 
evaluated during subsequent follow-ups, per Investigator discretion. 
Additional imaging examinations are to be performed at Investigator discretion, as clinically 
indicated (i.e, based on individual participant signs and/or symptoms). 
Whenever possible, any participant who discontinues from study treatment for a reason other 
than disease progression should have a CT with contrast (or PET/CT, if that has been the 
participant’s imaging modality throughout the study per Investigator discretion) performed if 
they have not undergone a scan within the prior 4 weeks. 
Note that all tumor imaging assessments are to be performed at the scheduled interval of 
every 6 weeks (± 3 days) for the first 3 post-baseline assessments and then every 12 weeks, 
regardless of whether the participant’s treatment cycle is delayed. 
8.1.2.7. 
Brain Imaging 
Brain imaging is to be performed as indicated in the applicable SoA (Section 1.3). As with all 
other tumor imaging assessments in the study, brain imaging assessments are to be performed at 
the scheduled interval regardless of any treatment delays. 
CT and MRI are generally considered to be the best currently available and reproducible 
methods to measure target lesions selected for response assessment, and to assess nontarget 
lesions and identify new lesions. 
For assessment of brain lesions, MRI is the preferred method; CT scans may be used if MRI is 
medically contraindicated. 
As noted in the applicable SoA (Section 1.3), baseline brain imaging must be performed within 
28 days before the start of study treatment. Ideally, these scans should be performed as close in 
time as possible to the start of study treatment. Additional imaging examinations can be 
performed based on individual participant signs and/or symptoms. 
8.1.3. 
ECOG Performance Status 
The assessment of ECOG PS will be performed following the grading described in Table 7. 


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Table 7: 
Eastern Cooperative Oncology Group Performance Status 
 
PS 
ECOG Definition 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light housework, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities; up and 
about more than 50% of waking hours. 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair. 
5 
Dead. 
ECOG = Eastern Cooperative Oncology Group; PS = performance status. 
Source: Oken 1982 
8.1.4. 
Post-treatment Circulating Tumor DNA Clearance 
Post-baseline ctDNA will be assessed via validated assay, using blood samples of approximately 
20 mL each. These samples will be collected as per the applicable SoA (Section 1.3), including 
at the time of disease progression (as applicable). ctDNA samples will then be sent to the central 
laboratory for processing. 
8.1.5. 
Companion Diagnostic Testing 
Confirmed presence of a required EGFR mutation is a requirement for all participants in the 
EQ143-301 (TREBLE) study. For screening and enrollment purposes, results of a clinically 
validated assay—using a licensed laboratory/laboratory with applicable local accreditation—will 
be acceptable to confirm the presence of such a mutation in the blood or tissue. If available, 
existing EGFR mutation test results may be used to confirm participant eligibility, provided that 
they were obtained within ≤ 3 months prior to study entry. 
• If recommended by the Investigator, prospective study participants for whom EGFR 
mutation testing is not covered or reimbursed by standard of care may undergo 
confirmatory testing pre-screening. 
− Any such prospective participant will be required to sign a separate Pre-Screening 
ICF, as detailed in Appendix 9 (Section 10.9). This ICF will allow blood or tissue 
sample collection to be performed for local EGFR mutation testing prior to the 
28-day study Screening window. 
All participants in the study will also have a blood sample for central retrospective testing 
collected predose on Day 1 of treatment Cycle 1. 
If archival tumor tissue (FFPE or unstained slides) is available (regardless of when it was 
obtained), and the participant agrees to provide this tissue by completing the applicable section 
of the main study ICF, it will also be collected during Screening; however, this is not mandatory. 


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8.2. 
Safety Monitoring 
Phase 1 and 2 clinical studies have shown that aumolertinib monotherapy is well tolerated at an 
oral dose of 110 mg daily, with no unexpected toxicity events. In addition, a Phase 3 
randomized, controlled, open-label, multicenter study is currently ongoing to compare the 
efficacy and safety of aumolertinib monotherapy versus aumolertinib in combination with 
platinum-containing doublet chemotherapy; no unexpected safety findings have been reported. 
Safety monitoring in the EQ143-301 (TREBLE) study will be conducted from the time 
participant signed informed consent is provided through the time points indicated in the 
applicable SoA (Section 1.3). Routine safety evaluations will include monitoring of AEs/SAEs, 
vital sign measurements, physical examinations, 12-lead ECGs, and clinical laboratory 
assessments (including hematology, serum chemistry, urinalysis, and coagulation, which are to 
be collected by local laboratory as detailed in Section 8.3.4). 
Additional safety evaluations will be performed at the discretion of the Investigator with the 
oversight of the Medical Monitor. 
8.3. 
Safety Assessments 
Planned time points for all safety assessments are provided in the applicable SoA (Section 1.3). 
The toxicity of all study interventions will be assessed by the Investigator per NCI CTCAE 
version 5.0. 
8.3.1. 
Physical Examinations 
8.3.1.1. 
Full and Symptom-directed Physical Exams 
Full physical examination evaluations at Screening should include general appearance; skin; 
neck; eyes; ears; nose; throat; lungs; heart; abdomen; back; lymph nodes; extremities; and 
neurological examinations. Subsequent physical examinations will be performed as per the 
applicable SoA (Section 1.3). At Investigator discretion, these subsequent exams can be either 
full or abbreviated (ie, symptom-directed to include body systems as the Investigator considers 
medically appropriate). 
Information about each physical examination must be present in the source documentation at the 
study site. 
Findings on physical examination that a) were present at the time of the participant providing 
signed informed consent and b) are considered clinically significant by the Investigator are to be 
recorded (under “Physical Examination”) as medical history in the eCRF. 
Findings on physical examination that occur after the participant has provided signed informed 
consent, and which are considered clinically significant by the Investigator and meet the 
definition of an AE (or SAE) as detailed in Section 10.2, must be recorded as an AE (or SAE) in 
the eCRF. All SAEs must be reported as detailed in Section 10.2.4. 
8.3.1.2. 
Body Weight and Height 
Body weight (in kg) will be measured by study site staff under the following conditions: 
participant in light clothing and without shoes, after having emptied his/her bladder. 


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The participant’s height (in cm) will be measured (without shoes) at Screening only, in order to 
calculate the body mass index. 
8.3.2. 
Vital Signs 
Vital signs collected during the study will include body temperature, systolic and diastolic blood 
pressure, pulse rate (after 5 minutes resting), and respiration rate. Vital signs will be measured at 
the time points specified in the applicable SoA (Section 1.3) with participants resting for at least 
5 minutes in a supine position. 
When the time of vital sign measurement coincides with a blood draw, the vital signs will be 
taken before the scheduled blood draw where possible, ensuring that the blood draw is within the 
window specified in the protocol (refer to the applicable SoA [Section 1.3]). 
In the event of an abnormality that is considered clinically significant by the Investigator, and/or 
meets the definition of an AE (or SAE) as detailed in Section 10.2, vital sign assessments will be 
repeated at Investigator discretion. All repeat vital sign values should be entered on an 
unscheduled eCRF page. 
8.3.3. 
Electrocardiograms 
A standard 12-lead ECG will be taken at the time points specified in the applicable SoA 
(Section 1.3). Additional ECGs may be performed at any other time point as clinically indicated 
per Investigator discretion. 
ECGs will be performed prior to vital signs collection, with participants in a supine position. 
Participants should remain in this position for at least 5 minutes before the ECG reading is taken. 
The following ECG parameters should be evaluated by the Investigator: 
• Heart rate 
• QT interval 
• PR interval 
• QRS interval 
• RR interval 
• ST segment 
• QTcF 
All ECG tracings will be reviewed by the Investigator or designee. 
If the QTcF exceeds 480 ms in a male participant or 500 ms in a female participant, or the QRS 
interval exceeds 120 ms in any participant, the ECG should be repeated in triplicate. If a repeat 
of an ECG is necessary for any other reason considered clinically significant by the Investigator, 
the repeat is not required in triplicate. 
When the time of ECG monitoring coincides with a blood draw, the ECG will be taken before 
the scheduled blood draw while ensuring that the blood draw is within the window specified in 
this protocol (refer to the applicable SoA [Section 1.3]). 


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8.3.4. 
Clinical Safety Laboratory Tests 
Refer to Section 10.8 for details of the specific clinical safety laboratory tests (including 
hematology, serum chemistry, urinalysis, and coagulation) that are to be collected during 
the study. 
Clinical safety laboratory tests will be performed at the time points specified in the applicable 
SoA (Section 1.3) and will be analyzed by local laboratory. Only selected safety labs will be 
collected at scheduled time points; the others will be collected, per Investigator discretion, only 
as clinically indicated for safety monitoring purposes. 
• For participants in the aumolertinib with chemotherapy arm, safety laboratory test 
results should be obtained and reviewed by the Investigator prior to study drug 
dosing. 
• For participants in the aumolertinib monotherapy and osimertinib monotherapy arms, 
safety lab assessments should be performed pre-study drug dosing if any such 
assessment(s) may impact treatment decisions for the individual participant in the 
judgment of the Investigator. 
Additional safety laboratory tests may be performed at other times if deemed necessary (per 
Investigator discretion), based on the participant’s clinical condition. 
Findings from safety laboratory assessments performed after the participant has provided signed 
informed consent that are considered clinically significant by the Investigator, and which meet 
the definition of an AE (or SAE) as detailed in Section 10.2, must be recorded as an AE (or 
SAE) in the eCRF. All SAEs must be reported as detailed in Section 10.2.4. 
8.3.5. 
Pregnancy Testing 
For all female participants of childbearing potential, a serum or urine pregnancy test will be 
performed at Screening as per the applicable SoA (Section 1.3). 
Additionally, all female participants of childbearing potential who are not using contraception 
(and therefore must agree to be abstinent to comply with the study requirements; refer to 
Section 10.3.2) will have a serum or urine pregnancy test performed during each dosing visit, 
prior to dosing with any study intervention. 
Additional serum or urine pregnancy tests may be performed to establish the absence of 
pregnancy at any other time during the study, if determined to be medically necessary by the 
Investigator or required by local regulations. 
8.4. 
AEs, SAEs, and Other Safety Reporting 
The definitions of AEs and SAEs are provided in Section 10.2. 
Adverse events will be reported by the participant or, when appropriate, by a caregiver or 
surrogate. 
All AEs (including SAEs) occurring during the study will be reported in the eCRF, regardless of 
whether or not attributed to study intervention and whether or not observed by the Investigator or 
the participant. In any circumstance, every effort should be made to document participant 
outcome if at all possible. 


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As detailed in Section 10.2.4, all SAEs occurring during the study must be reported via email to 
BOTH 
 and 
 using SAE Form, along with any 
other supporting information, and must be recorded in the AE section of the eCRF. The outcome 
of any ongoing SAEs should be documented, if possible. 
For participant deaths, the working diagnosis or cause of each death—as stated on a death 
certificate, available autopsy report(s), and/or relevant medical report(s)—should be sent 
promptly to both the Sponsor and the Parexel Pharmacovigilance Group. 
Definite progression of the disease under study, including signs and symptoms of progression as 
assessed by the Investigator, should not be reported as an AE or SAE. 
• Note: Death unequivocally due to disease progression, as agreed by both the 
Investigator and the Medical Monitor, should be documented in the eCRF but should 
not be reported as an SAE. 
The Investigator and any qualified designee(s) are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and should make every effort to 
document participant outcome if at all possible. 
The methods of recording, evaluating, and assessing the causality of AEs and SAEs, and the 
procedures for completing and transmitting SAE reports, are detailed in Section 10.2. 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information 
In this study, AEs will be reported for all participants from the time of providing signed 
informed consent through the completion of the participant’s final follow-up visit. SAEs will be 
reported for all participants (enrolled and not enrolled) from the time of obtaining signed 
informed consent. 
Medical occurrences that begin before obtaining signed informed consent will be recorded as 
medical history/current medical conditions, not as AEs. 
AEs that are ongoing at the final follow-up visit will be marked as “Not Recovered/Not 
Resolved” on the AE eCRF page. 
All SAEs will be recorded using the SAE Form, along with any other supporting information, 
and will be recorded in the AE section of the eCRF and reported via email to BOTH 
 and 
 within 24 hours of awareness as described 
in Section 10.2.4. 
The Investigator will submit any updated SAE data to BOTH the Sponsor and the Parexel 
Pharmacovigilance Group within 24 hours of discovery or notification of the event, as detailed in 
Section 10.2.4. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the participant’s study participation; however, in any circumstance, every effort should be made 
to document the outcome of the event if possible. 
If the Investigator learns of any SAE, including a death, at any time after a participant has been 
discharged from the study—and if the Investigator considers the event to be reasonably related to 
treatment with any study intervention, or to study participation—the Investigator must notify 
the Sponsor promptly (within no more than 24 hours of awareness). 


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8.4.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant, or the assigned caretaker (with the participant’s 
written approval), is the preferred method to inquire about AE occurrences. 
Any post-baseline findings in the study that are considered clinically significant by the 
Investigator and meet the definition of an AE (or SAE, as applicable) must be recorded as AEs 
(or SAEs). All SAEs must also be reported as detailed in Section 10.2.4. 
8.4.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, 
the event is otherwise explained, or the participant is lost to follow-up (as defined in 
Section 7.3). Further information on follow-up procedures is provided in Section 10.2. 
Participants who discontinue from study treatment but do not withdraw overall consent will 
remain in the study for safety and survival follow-up, as detailed in the applicable SoA 
(Section 1.3). 
8.4.4. 
Regulatory Reporting Requirements for SAEs 
Prompt notification of an SAE (within 24 hours of awareness; refer to Section 10.2.4 for full 
details of SAE recording and handling) by the Investigator to BOTH the Sponsor and the Parexel 
Pharmacovigilance Group is essential. This is required so that legal obligations and ethical 
responsibilities toward the safety of participants, and the safety of a study intervention that is 
under clinical investigation, are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority/agencies, IRBs/IECs or such other entity as required, and Investigators. 
An Investigator who receives an Investigator safety report describing an SAE, or other specific 
safety information (eg, summary or listing of SAEs), from the Sponsor will review and then file 
it along with the IB/package insert and will notify the IRB/IEC if appropriate according to local 
requirements. 
Investigator safety reports must be prepared for SUSARs (refer to Section 10.2.4) according to 
local regulatory requirements and Sponsor policy and forwarded to Investigators as necessary. 
The Investigator will be responsible for safety reporting to local IRBs/IECs, or such other entity 
as required, in accordance with applicable local laws and regulations. 
8.4.5. 
Pregnancy 
Details of any pregnancy in a female participant and (if applicable) any female partner of a male 
participant will be collected after the participant’s exposure to the investigational product, and 
will be followed (to term) to determine the outcome. 
If any such pregnancy is reported in this study, the Investigator will record pregnancy 
information on the Pregnancy Reporting and Outcome Form. 


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The completed form is then to be submitted to the Sponsor within 24 hours of learning of the 
pregnancy. 
For pregnant female partners of male participants, the necessary signed informed consent must 
be obtained by the partner signing the separate Pregnant Partner ICF. 
While pregnancy itself is not considered to be an AE (or SAE), any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE, 
as applicable. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and will be reported as such per 
Section 10.2.4. 
The pregnant female participant, or pregnant female partner of a male participant (after obtaining 
the necessary informed consent from the latter), will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the pregnant 
participant/pregnant partner and (if applicable) the neonate, and this information will be 
forwarded to the Sponsor. 
Any post-study pregnancy-related SAE that is considered by the Investigator to be reasonably 
related to treatment with any study intervention will be reported to the Sponsor as described in 
Section 10.2.4. While the Investigator is not obligated to actively seek this information from 
former study participants/pregnant partners of former study participants, the Investigator may 
learn of an SAE through spontaneous reporting. 
Any female participant who becomes pregnant while participating in the study will discontinue 
study intervention or be withdrawn from the study. 
8.4.6. 
Disease-related Events and/or Disease-related Outcomes Not Qualifying as AEs 
or SAEs 
Definite progression of the disease under study, including signs and symptoms of clinical 
progression as assessed by the Investigator, should not be reported as an AE or SAE—unless the 
signs and symptoms are more severe than expected for the participant’s condition. 
Death unequivocally due to disease progression, as agreed by both the Investigator and the 
Medical Monitor, should be documented in the eCRF but not reported as an SAE. 
The Investigator and any qualified designee(s) are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE (refer to Section 10.2), and should 
make every effort to document the outcome of the event, if possible. 
The methods of recording, evaluating, and assessing the causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.2. 
For overdoses (Section 6.6) that are associated with an AE or SAE, the standard reporting 
timelines apply as detailed in Section 10.2.3. 


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8.5. 
Pharmacokinetic Assessments (Aumolertinib and Aumolertinib with 
Chemotherapy Arms Only) 
Blood samples of approximately 4 mL each are to be collected from all participants in the 
aumolertinib arm and the aumolertinib with chemotherapy arm (not the osimertinib arm) for PK 
analyses. Refer to the SoAs in Table 1 and Table 2, respectively. 
Specifically, the PK samples collected will be analyzed for measurement of plasma 
concentrations of aumolertinib and its metabolite HAS-719 (and other metabolites, if applicable), 
using a validated bioanalytical method in compliance with all applicable regulatory 
requirements. 
The actual date and time (24-hour clock time) of each sample collection will be recorded in the 
source documents and in the eCRF. 
Details of PK sample collection, processing, and shipment will be provided in the laboratory 
manual. 
8.6. 
Patient-reported Outcomes and Quality of Life Assessments 
Patient-reported outcomes and QoL will be assessed for all participants, as indicated in the 
applicable SoA (Section 1.3), via NCI PRO-CTCAE® questionnaire (Appendix 10). In 
accordance with the official PRO-CTCAE Terms of Use (NCI 2022), the instrument is intended 
for use to capture symptomatic adverse events by patient self-report in study participants 
≥ 7 years of age; therefore, in this study, only the participants themselves are permitted to 
complete the questionnaire. 
Any relevant AEs/SAEs will be summarized by the same approach as described in Section 8.4. 
The questionnaire will be provided in either paper or electronic format and should be completed 
by the participant using a recall period of the previous 7 days. All data generated by study 
participants will be captured on a paper device or in an electronic PRO device or online portal. 
Whenever possible, the NCI PRO-CTCAE questionnaire should be completed before other study 
procedures are performed. If the participant is unable to complete the questionnaire when 
scheduled, the reason for not completing the questionnaire should be documented. 
8.7. 
Blood Volume 
• For safety laboratory assessments, average total blood volume collection per 
participant is up to approximately 120 mL (across all study participants, an estimated 
collection of approximately 20 mL per sample and average of 6 samples collected per 
participant; depending on their duration of study participation, some participants will 
have fewer or more samples collected). 
• For ctDNA assessments, total blood volume collection per participant is 
approximately 80 mL (approximately 20 mL per sample and 4 samples per 
participant). 


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• For PK assessments in participants in the aumolertinib arm and aumolertinib with 
chemotherapy arm—ie, not the osimertinib arm—total blood volume collection per 
participant is up to approximately 24 mL (approximately 4 mL per sample and 
6 samples per participant). 
Thus, the total blood volume collection per participant is anticipated to be up to approximately 
225 mL for scheduled assessments and up to 300 mL when accounting for any potential extra 
(ie, repeat or unscheduled) assessments. 
8.8. 
Biomarkers and Immunogenicity Assessments 
There are no immunogenicity assessments in this study. 
All study participants will be required to provide urine and blood (plasma) samples, including 
plasma samples for ctDNA analysis, at the time points specified in the applicable SoA (Section 
1.3). Participants will also have imaging assessments performed as specified in the applicable 
SoA. 
In addition, participants may consent to provide archival tumor tissue (FFPE or unstained slides) 
for CDx testing (refer to Section 8.1.5) if such tissue is available (regardless of when it was 
obtained); however, this is optional and not a study requirement. 
The samples collected in the study will be used only for scientific research. Each sample will be 
labeled with a code so that the laboratory personnel testing the samples will not know the 
participant’s identity. 
With participants’ additional consent, the samples collected in the study may be used for further 
future research by the Sponsor—or by other researchers, such as those at universities or other 
companies—provided that participants’ confidentiality is maintained. The aim of conducting 
such further future research is to contribute to the understanding of EGFR-mutant NSCLC or 
other diseases, and/or the development of related or new treatments or research methods. 
Unless a longer time limitation is required by local regulations or ethical requirements, the 
Sponsor may store the collected plasma and urine samples until all study research objectives 
have been met or valid study results have been obtained. With participants’ additional consent, 
the Sponsor may store the collected imaging and tissue samples at a central repository for up to 
25 years after the end of the study (as defined in Section 4.4), in order to achieve further future 
research objectives. 
If participants do not provide their additional consent for further future research use, any of their 
samples that remain will be destroyed after the protocol-specified study objectives have been met 
and all regulatory obligations have been fulfilled. 
All samples collected from study participants will be transported, stored, accessed, and processed 
in accordance with applicable regulatory requirements and laws. 
8.9. 
Medical Resource Utilization and Health Economics 
Medical resource utilization and health economics parameters are not evaluated in this study. 


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9. 
STATISTICAL CONSIDERATIONS 
The study SAP will be finalized prior to database lock. The SAP will include a more technical 
and detailed description of the statistical analyses described in this section of the protocol, which 
is a summary of the planned statistical analyses of the most important endpoints. 
9.1. 
General Considerations 
Summary statistics for continuous variables will include, at the very least, n; median; mean; 
standard deviation; minimum; and maximum. For categorical variables, frequencies and 
percentages will be presented. For time-to-event variables, the Kaplan-Meier method will be 
used for descriptive summaries. Graphical displays will be provided as appropriate. 
The primary analysis will be performed when approximately 251 PFS events have occurred in 
the aumolertinib with chemotherapy and osimertinib monotherapy treatment arms, as based on 
BICR assessment. 
9.1.1. 
Statistical Hypotheses 
The hypotheses for the primary study endpoint of BICR-assessed PFS are as follows: 
• H0: Saumo chemo (t) = Sosi (t) 
• HA: Saumo chemo (t) > Sosi (t), 
where Saumo chemo (t) is the function of PFS for the aumolertinib with chemotherapy arm and 
Sosi (t) is the PFS for the osimertinib monotherapy arm. 
9.1.2. 
Determination of Sample Size 
Assuming a randomization ratio of 1:1 for aumolertinib with chemotherapy:osimertinib 
monotherapy, a true HR of 0.7 (median PFS improves from 19 months to 27.1 months), and an 
exponential distribution for PFS, 251 PFS events will provide 80% power at a 2-sided Type I 
error of 0.05. If the result of the primary endpoint analysis is statistically significant, a sequential 
testing method will be used to test the key secondary endpoint of OS to control the overall Type I 
error for the study at 2-sided 0.05. Assuming a true HR of 0.70 (ie, median OS improves from 38.6 
months to 55.1 months) and an exponential distribution for OS, 200 OS events will provide 71.1% 
power at a 2-sided Type I error of 0.05. 
Approximately 400 participants in total will be enrolled in the aumolertinib with chemotherapy 
and osimertinib monotherapy arms (200 per arm) to reach 251 PFS events. The sample size of 
100 participants in the aumolertinib monotherapy arm will allow the precision of estimating an 
incidence rate for toxicity—in terms of TEAEs, ≥ Grade 3 TEAEs, SAEs, and AEs of clinical 
interest—to be within ± 10.3% (eg, incidence rate, 50%; Clopper-Pearson 95% CI, 39.8%, 
60.2%). Therefore, approximately 500 total participants are planned to be randomized in the 
study in a 2:2:1 ratio to receive aumolertinib in combination with chemotherapy, osimertinib 
monotherapy, or aumolertinib monotherapy, respectively. 
Cytel East® version 6.5 was used for the sample size calculations. 


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9.1.3. 
Interim Analysis 
Two interim analyses are planned, as follows: 
• The first interim analysis will be performed approximately 12 weeks after enrollment 
is completed. 
• The second interim analysis will be performed upon occurrence of 70% of the 
projected PFS events. 
The interim analyses will include PFS and the other endpoints listed below: 
• ORR and DCR 
• ctDNA clearance 
• TGR 
• AEs 
The Lan DeMets approach, which approximates the O’Brien-Fleming spending function, will be 
used to maintain an overall 2-sided 0.05 Type I error for the primary PFS comparison. 
The key secondary endpoint of OS (aumolertinib + chemotherapy combination therapy 
compared with osimertinib monotherapy) will be tested sequentially at a 2-sided 0.05 Type I 
error if the result of the primary endpoint analysis (PFS) is statistically significant. Formal 
interim OS analyses will be conducted at the time of the primary PFS analysis if the PFS analysis 
is positive (at one of the interim analyses, or at the final PFS analysis) and at all subsequent 
planned analysis points. Type I error for OS will also be controlled using Lan-DeMets method 
with O’Brien-Fleming boundary. 
9.2. 
Definition of Statistical Analysis Sets 
9.2.1. 
Full Analysis Set 
The Full Analysis Set (FAS) will include all randomized participants. Participants will be 
analyzed in the treatment arm to which they were randomized, and strata (with stratification by 
EGFR mutation, ECOG PS, and race) will be assigned at the time of randomization. 
9.2.2. 
Safety Analysis Set 
The Safety Analysis Set (SAS) will include all participants who received at least one dose of 
study intervention. Safety data will be summarized based on the actual treatment received. 
9.2.3. 
Pharmacokinetic Analysis Set 
The PK Analysis Set will include all participants in the Safety Analysis Set who received at least 
one dose of aumolertinib and have at least one non-missing data collection for aumolertinib 
and/or its metabolite HAS-719. 
Participants with protocol violations will be assessed on an individual basis for inclusion in the 
PK Analysis Set. 
9.3. 
Definitions for Efficacy Endpoints 
The following definitions apply to the primary, secondary, and exploratory efficacy endpoints: 


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• PFS: Defined as the time from date of participant randomization to either the first 
date of disease progression (as assessed per RECIST v1.1) or the date of death by any 
cause, whichever occurs first. 
• OS: Defined as the time from randomization until the date of death due to any cause. 
• ORR: Defined as the proportion of participants who achieve a CR or PR at any time 
before PD or initiating a subsequent anticancer therapy. 
• DCR: Defined as the proportion of participants who have a best overall response of 
CR or PR or SD. 
• DoR: Defined as the time from the date of first response (CR or PR) until the date of 
PD or death due to any cause, whichever occurs first. 
• DepOR: Defined as the relative change in target lesion tumor size (calculated as the 
sum of the longest diameters of the target lesions, in the absence of new lesions or 
progression of nontarget lesions) as compared to baseline. 
• ctDNA clearance at 6 weeks: Defined as when a detectable EGFR mutation in 
ctDNA at baseline becomes undetectable or drops below a predetermined threshold at 
6 weeks. Rate of ctDNA clearance is defined as: 
100 × Number of Participants who are ctDNA−negative at 6 weeks 
Number of Participants who are ctDNA−positive at baseline 
• TGR: Defined as the constant exponential growth rate estimated using the sum of 
longest diameters based on radiological tumor assessment per RECIST v1.1. 
• PFS2: Defined as the time from randomization until the date of the first progression 
event subsequent to that used in the primary analysis of PFS, or death due to any 
reason, whichever occurs first. 
• TFST: Defined as the time from randomization to the start date of the first anticancer 
therapy subsequent to the discontinuation of the study intervention, or death due to 
any reason, whichever occurs first. 
• TSST: Defined as the time from randomization to the start date of the second 
subsequent anticancer therapy after the discontinuation of the study intervention, or 
death due to any reason, whichever occurs first. 
9.4. 
Statistical Analyses 
9.4.1. 
Participant Disposition 
All participants’ enrollment, randomization, and treatment start/ending dates, as well as reasons 
for discontinuation from study treatment (randomized population) and reasons for 
discontinuation from study (randomized population), will be listed. Reasons for discontinuation 
from study treatment and from the overall study will also be summarized. 
9.4.2. 
Demographics and Baseline Disease Characteristics 
Participants’ demographics and baseline disease characteristics will be listed and summarized. 
Participants’ medical history and prior medications/procedures will be listed. 


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9.4.3. 
Efficacy Analyses 
All efficacy analyses will be performed on the FAS population, based on the treatment arm 
assigned in the randomization. 
Response assessment (per RECIST v1.1) will be based on BICR for the primary endpoint, and 
on both BICR and Investigator assessment for the secondary tumor-based efficacy endpoints. 
9.4.3.1. 
Primary Endpoint Analysis 
The primary endpoint of PFS as determined by BICR (per RECIST v1.1) will be analyzed when 
251 PFS events are reached in the aumolertinib with chemotherapy and osimertinib monotherapy 
treatment arms. The primary analysis of PFS will be based on BICR assessment and will use the 
stratified log-rank test to compare aumolertinib with chemotherapy combination therapy with 
osimertinib monotherapy (2-sided 0.05 level). 
The median event time will be evaluated with a 95% CI for each treatment arm, using the 
Kaplan-Meier method. HRs with a 95% CI will be estimated by a stratified Cox proportional 
hazard model, using the Breslow method of tie handling, with treatment as the factor. The strata 
will be the same stratification factors (EGFR mutation, ECOG PS, and race) used in the 
randomization. 
9.4.3.2. 
Key Secondary Endpoint Analysis 
The final OS analysis will be performed when 200 OS events are reached in the aumolertinib 
with chemotherapy and osimertinib monotherapy treatment arms. The OS comparison of 
aumolertinib + chemotherapy combination therapy with osimertinib monotherapy will be tested 
sequentially at a 2-sided 0.05 Type I error if the result of the primary endpoint analysis (PFS) is 
statistically significant. The OS comparison will use the same methods as used for the primary 
PFS analyses. 
9.4.3.3. 
Other Secondary Endpoint Analyses 
The other secondary endpoints will be analyzed by the following comparisons: 
• aumolertinib + chemotherapy combination therapy compared with osimertinib 
monotherapy 
• aumolertinib monotherapy compared with osimertinib monotherapy 
Secondary tumor-based efficacy endpoints will include both BICR and Investigator assessments 
performed per RECIST v1.1. 
Statistical comparison will be at nominal significance level of 0.05 based on 2-sided tests. 
9.4.3.3.1. Secondary Binary Endpoints 
Secondary binary endpoints, including ORR, DCR, and the rate of ctDNA clearance at 6 weeks, 
will be analyzed using the CMH test stratified by the randomization stratification factors. The 
CMH estimate of the odds ratio with a 95% CI will be reported. 


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A 2-sided p-value will be provided to compare aumolertinib + chemotherapy combination 
therapy with osimertinib monotherapy, and aumolertinib monotherapy with osimertinib 
monotherapy. For each arm, the point estimate for ORR, DCR, and the rate of ctDNA clearance 
at 6 weeks with its exact 95% CI will be provided. 
9.4.3.3.2. Secondary Time-to-Event Endpoints 
Other time-to-event secondary endpoints, including PFS, DoR and OS, will be analyzed using 
the stratified log-rank test and the stratified Cox proportional hazard model, as described above 
for the primary endpoint analysis. 
Specifically, these secondary endpoint analyses will be performed to compare aumolertinib + 
chemotherapy combination therapy with osimertinib monotherapy, and aumolertinib 
monotherapy with osimertinib monotherapy. The median event time will be evaluated with a 
95% CI using the Kaplan-Meier method. 
9.4.3.3.3. Analysis of DepOR 
DepOR will be analyzed among participants with measurable lesions at baseline. Absolute and 
percentage change from baseline in target lesion tumor size (calculated as the sum of the longest 
diameters of target lesions) will be summarized using descriptive statistics at each visit for all 3 
treatment arms. The best DepOR values will be calculated from assessments before disease 
progression or before starting subsequent anticancer treatment. 
9.4.3.3.4. Analysis of TGR 
TGR will be analyzed based on the sum of longest diameters over time, using the R package 
tumgr (Wilkerson 2016), which is based on the regression-growth models proposed by 
Stein, et al (Stein 2011). 
Participants who have measurable disease at baseline and at least 1 post-baseline tumor 
assessment will be included in the TGR analyses. The estimated participants’ TGRs will be 
summarized by treatment arm. Boxplots of the TGRs will be generated side-by-side to visualize 
TGRs for each arm. For all 3 arms, the estimated median TGR value with its 95% Wilcoxon CI 
will be reported. 
A detailed TGR analysis plan will be included in the study SAP. 
9.4.3.4. 
Exploratory Endpoint Analyses 
9.4.3.4.1. Description of CNS Efficacy 
CNS efficacy will be assessed on a subset of the FAS population, to include all participants in all 
3 treatment arms who have been identified as having at least 1 measurable brain lesion at 
baseline based on Investigator assessment. 
CNS efficacy endpoints will include PFS, OS, DoR, ORR, DCR, and DepOR, each based on 
Investigator assessment of CNS scans. 
For time-to-event CNS endpoints, including PFS, OS, and DoR, the median event time will be 
evaluated with a 95% CI for each treatment arm using the Kaplan-Meier method. 
For binary CNS endpoints, including ORR and DCR, the point estimate of the rate with its exact 
95% CI will be calculated for each arm. 


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DepOR will be analyzed using the same method as for the secondary endpoint of DepOR. 
9.4.3.4.2. Analysis of PFS2, TFST, and TSST 
Time-to-event endpoints of PFS2, TFST, and TSST will be analyzed for all 3 treatment arms. 
The median event time will be evaluated with a 95% CI for each treatment arm using the 
Kaplan-Meier method. 
9.4.4. 
Safety Analyses 
Safety analyses will be performed on the SAS and will be presented by the actual treatment arm. 
Details of the safety analyses will be described in the SAP. 
9.4.4.1. 
Exposure 
Exposure parameters (including cumulative total actual dose, total/actual exposure time, actual 
dose intensity, relative dose intensity, and compliance) of each study intervention will be 
summarized using descriptive statistics. 
9.4.4.2. 
AEs 
Adverse events coded by MedDRA and graded per NCI CTCAE version 5.0 will be presented in 
tables and listings, using MedDRA system organ class and preferred term. 
The incidence rate of TEAEs will be presented in summary tables. TEAEs are defined as AEs 
that start on or after the first dose of any study intervention, through 28 days after the last dose of 
any study intervention. Any events that start after 28 days after the last dose of any study 
intervention, or after a participant receives a subsequent anticancer therapy, will be included in 
the data listing but will not be considered as a TEAE. 
Statistical analysis of AEs will utilize the Investigator-assessed relationship between study 
intervention and the occurrence of each AE, as detailed in Section 10.2.1. 
In the event that a participant has repeat episodes of the same AE, the event with the highest 
severity and/or strongest causal relationship to treatment will be used for the purpose of 
statistical tabulations. 
9.4.4.3. 
Physical Exam Findings 
For physical exams (full and symptom-directed), findings considered clinically significant by the 
Investigator that were present before the participant provided signed informed consent will be 
reported as medical history; findings considered clinically significant by the Investigator that 
occurred after the provision of signed informed consent, and which meet the definition of an AE 
(or SAE, as applicable) as detailed in Section 10.2, will be reported as AEs/SAEs. 
9.4.4.4. 
Vital Signs 
For each treatment arm, the actual value and the change from baseline to each parameter on 
study evaluation will be summarized for vital signs including body temperature, systolic and 
diastolic blood pressures, pulse rate (after 5 minutes resting), and respiration rate. 
9.4.4.5. 
Electrocardiograms 
ECG results will be summarized descriptively. Actual values and changes from baseline will be 
reported for each study visit. 


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9.4.4.6. 
Clinical Laboratory Tests 
For each treatment arm, the actual value and the change from baseline to each parameter on 
study evaluation will be summarized for selected clinical laboratory tests. 
The severity of selected laboratory tests will be evaluated by NCI CTCAE version 5.0 criteria if 
the tests have a corresponding CTCAE classification. 
9.4.5. 
Patient-reported Outcomes and Quality of Life Analyses 
PROs and QoL will be assessed via item subset of NCI PRO-CTCAE questions. A descriptive 
summary over time will be provided. 
9.4.6. 
Pharmacokinetic Analyses 
Plasma concentrations of aumolertinib and its metabolite (HAS-719) will be listed and 
summarized using descriptive statistics (eg, sample size, arithmetic mean, geometric mean, 
% coefficient of variation, standard deviation, median, minimum, and maximum). 
Details of population PK modeling, including data processing and statistical methodologies, will 
be provided in a separate pharmacometrics analysis plan. Data from this study may be combined 
with data from other aumolertinib studies for the population PK analysis. 
Additional analyses such as exposure-response analysis to evaluate the relationship between 
aumolertinib exposure and efficacy/safety endpoints in this study may be performed if the data 
allows for this analysis to be completed. 
Results of the population PK and exposure-response analyses may be summarized in a separate 
report, rather than in the clinical study report. 


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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines applicable to the 
countries where the study is conducted 
• Applicable ICH GCP Guidelines 
• Applicable laws and regulations 
• The protocol, protocol amendments, ICF, IB, and other relevant documents must be 
submitted to the IRB/IEC by the Investigator and reviewed and approved by the 
IRB/IEC before the study is initiated. 
• The decision of whether a formal protocol amendment is needed to accommodate 
administrative changes (ie, those not affecting the participant benefit/risk ratio) will 
be made in accordance with current ICH GCP Guidelines and all other applicable 
guidelines in the countries where the study is conducted. Administrative changes may 
be conveyed to study Investigators and sites via a protocol clarification letter 
compliant with ICH GCP and all other applicable guidelines. 
• Protocols and any substantial amendments to the protocol will require approval from 
the Health Authority/ies and the IRB/IEC (for site initiation/implementation) prior to 
initiation of the protocol or overall implementation of changes made to the study 
design, except for changes necessary to eliminate an immediate hazard to study 
participants. 
• The Investigator will be responsible for overall conduct of the study at the site, and 
adherence to requirements of 21 Code of Federal Regulations (CFR; US); ICH GCP 
Guidelines; the IRB/IEC; European Regulation 536/2014 for clinical studies (if 
applicable) and any subsequent amendments thereof; and all other applicable local 
regulations. 
• The Investigator or designee will be responsible for the following: 
− Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
− Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
the procedures of the IRB/IEC, in accordance with the study safety reporting rules 
(refer to Section 10.2) 


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10.1.2. 
Financial Disclosure 
Investigators and sub-Investigators will provide the Sponsor with accurate financial information 
in accordance with all applicable local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate regulatory authorities 
and IRB/IEC. Investigators are responsible for providing information on financial interests 
during the course of the study and for 1 year after completion of the study. 
10.1.3. 
Informed Consent Process 
The Investigator or his/her representative will explain the nature of the study, including the risks 
and benefits, to the participant in simple layperson’s terms and answer all questions regarding 
the study. 
Participants must be informed that their participation is voluntary. Participants will be required to 
sign a statement of informed consent (ie, ICF) that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, privacy and data protection requirements, where applicable, and the 
requirements of the study center and IRB/IEC. 
The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
Participants must be re-consented to the most current version(s) of the ICF(s) during their 
participation in the study. 
A copy of the signed ICF(s) must be provided to the participant and the site must document the 
provision of the signed copy to each participant or representative. The signed copy of the ICF 
should be filed with the participant’s case history. 
Prospective participants who are re-screened are required to sign another ICF if the re-screening 
occurs more than 28 days after the initial Screening. No more than one re-screening may occur 
for any individual. 
If a protocol amendment is required, the ICF may need to be revised to reflect the changes to the 
protocol. If the ICF is revised, it must be reviewed and approved by the appropriate IRB/IEC. 
Original signed ICFs will be maintained at the site and be made available for inspection, as 
appropriate. 
10.1.4. 
Data Protection 
Participants will be assigned a unique pseudonymized participant number by the Sponsor or 
designee. Any participant records or datasets that are transferred to the Sponsor or designee will 
contain the pseudonymized identifier only; participant names or any information which would 
make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used and 
disclosed by the Sponsor or designee in accordance with local data protection law, the ICF, and 
any additional consents obtained from the participant. 
The level of disclosure must also be explained to the participant who will be required to give 
consent for their data to be used as described in the ICF. 


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The ICF must notify the participant that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor or designee, 
by appropriate members of the IRB/IEC, and by inspectors from regulatory authorities. 
10.1.5. 
Committees Structure 
10.1.5.1. Committee for Blinded Independent Central Review 
A central, blinded Independent Review Committee will evaluate all images collected during the 
study for the primary endpoint of BICR-assessed PFS. BICR will also be used to assess the 
secondary tumor-based efficacy endpoints in the study. 
A central imaging vendor will be used to collect and assess images for determination of the 
primary and relevant secondary study endpoints, and for management of participant treatment. 
A separate charter will define the procedures used by this committee for the purposes of BICR. 
10.1.6. 
Dissemination of Clinical Study Data 
A summary of the results of the clinical study, together with a summary that is understandable to 
a layperson, will be provided after the global end (or early termination) of the study in all 
countries concerned to ensure full availability of all clinical data under this protocol, within 
12 months. 
10.1.7. 
Data Quality Assurance 
Quality tolerance limits (QTLs) for this study will be predefined in the electronic trial master file 
(eTMF) to identify systematic issues that can impact participant safety and/or reliability of study 
results. These predefined parameters will be monitored during the study, and important 
deviations from the QTLs and remedial actions taken will be summarized in the clinical study 
report. 
10.1.7.1. Study Monitoring 
Qualified representatives of the Sponsor or Sponsor designees (study monitors) will monitor the 
study according to a predetermined monitoring plan. The Investigator must permit the study 
monitors to periodically review all eCRFs and source documents supporting the participation of 
each participant in the study. The eCRFs and other documentation supporting the study must be 
kept up to date by the Investigator and the staff at the study site. 
These study materials must be available for review by the study monitor, and/or other qualified 
representatives of the Sponsor, at each monitoring visit (onsite or remote) and must be provided 
in a way such that the participant’s confidentiality is maintained in accordance with local 
institution, state, country, and federal requirements. 
10.1.7.2. Audits and Inspections 
At some point during or after the study, an audit may be performed by appropriately qualified 
personnel from the Sponsor’s Quality Assurance group or their authorized representative. 
During any such audit, the Investigator agrees to give the auditor direct access to all relevant 
documents supporting the eCRFs and other study-related documents, and to discuss any findings 
with the auditor. 


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Additionally, a representative from a regulatory agency may visit the Investigator at any point 
during or after the study to conduct an inspection of the study and the site. 
In the event of any such inspection, the Investigator agrees to give the inspector direct access to 
all relevant documents and to discuss any findings with the inspector. 
10.1.7.3. Quality Control and Quality Assurance 
eCRFs must be completed for each participant enrolled. Each completed eCRF, as well as 
records for all participants who are screen failures or discontinue the study, will require a 
signature by the Principal Investigator at the study site. 
If a participant withdraws from the study, the reason must be noted on the eCRF, and if a 
participant is withdrawn from the study because of a treatment-limiting AE, thorough efforts 
should be made to clearly document the outcome. The Investigator should ensure the accuracy, 
completeness, legibility, and timeliness of the data reported to the Sponsor in the eCRFs and in 
all required reports. 
Accurate and reliable data collection will be assured by verification and cross-check activities 
(eg, the study monitor checking representative eCRFs against the Investigator’s records [source 
document verification]) and maintenance of a drug-dispensing log by the Investigator. A 
comprehensive validation check program will be used to verify data and discrepancy reports will 
be generated accordingly for resolution by the Investigator. 
Review of eCRFs, and validation/edit checks to identify and resolve discrepancies, will be 
performed throughout the study. Investigator signatures will be collected upon completion of 
eCRF review. eCRFs are not considered a study data source but are used to record participant 
data relating to the study unless such data are transmitted to the Sponsor or designee 
electronically (eg, PK data, biomarker data). 
The Investigator is responsible for verifying that data entries are accurate and correct by 
electronically signing the eCRF. Guidance on completion of eCRFs will be provided in a 
separate technical document. 
The Investigator must permit study audits and inspections according to Sponsor, IRB/IEC, and 
regulatory requirements and must provide direct access to source data documents. 
Monitoring details describing strategies, including definition of study critical data items and 
processes (eg, risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities and 
requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or onsite monitoring) are provided in the monitoring plan. 
The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
The Sponsor assumes accountability for actions delegated to other individuals (eg, contract 
research organizations). 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 2 years after study completion unless local regulations or 
institutional policies require a longer retention period. 


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No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written notification 
to the Sponsor. 
All data generated by the study site personnel will be captured electronically in Veeva Vault 
Electronic Data Capture, a 21 CFR Part 11-compliant system. 
All data generated by the participants in the study will be captured via a paper or electronic PRO 
device that is 21 CFR Part 11-compliant. These devices will be considered a study data source. 
10.1.8. 
Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
Data reported in the CRF that are transcribed from source documents must be consistent with the 
source documents or the discrepancies must be explained. 
The Investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
Study monitors will perform ongoing targeted data verification and ongoing review of participant 
source records to confirm that data entered into the CRF by authorized site personnel are 
accurate, complete, and verifiable from source documents; that the safety and rights of 
participants are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
10.1.8.1. Records Retention 
After closure of the study, the Investigator will maintain copies of all study records 
(ie, Investigator files and participant files) in a secure location. 
The Investigator’s study file will contain the protocol, protocol amendments, eCRF and query 
forms, IRB/IEC approval with correspondence, drug records, staff curriculum vitae and 
authorization forms, and other appropriate documents and correspondence. 
Participant clinical source documents may include (but are not limited to) participant hospital 
records, physician’s and nurse’s notes, original laboratory reports, ECGs, X-rays, signed ICFs, 
consultant letters, and participant screening and enrollment logs. 
These documents must be kept on file by the Investigator for a period of 2 years following the 
date the marketing application is approved for the drug indication for which it is being 
investigated, or as otherwise specified by local regulations. 
If no application is to be filed or if the application is not approved for such indication, all records 
pertaining to the conduct of the clinical study must be adequately maintained until 2 years after 
the investigation is discontinued and the regulatory authorities are notified, or as otherwise 
specified by local regulations. After that period of time, the documents may be destroyed, subject 
to local regulations upon approval of the Sponsor. 


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The Investigator must not destroy any records associated with the study without receiving 
approval from the Sponsor. 
The Investigator must notify the Sponsor in the event of accidental loss or destruction of any 
study records and should notify the Sponsor of any reassignment of study records to another 
party or move to another location. 
10.1.9. 
Study and Site Start and Closure 
10.1.9.1. First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first site open and will be the study start date. 
10.1.9.2. Study Termination 
The entire study may be terminated in the event of any of the following: 
• Occurrence of AEs unknown to date with respect of their nature, severity, and 
duration, or the unexpected incidence of known AEs 
• Medical or ethical reasons affecting the continued performance of the study 
• Difficulties in the recruitment of participants 
• Cancellation of the drug development program 
• Sponsor decision for any other reason, as detailed in Section 4.4 
The Sponsor reserves the right to terminate the study at any time. If the study is terminated by 
the Sponsor, participants will not be provided further study intervention or concomitant 
medication. 
10.1.9.3. Site Termination 
The Sponsor or designee reserves the right to close any study site(s) or terminate the study at 
site(s) at any time for any reason at the sole discretion of the Sponsor. 
The Principal Investigator may initiate study-site closure at any time and shall notify the Sponsor 
in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include, but are 
not limited to the following: 
For study termination at a site: 
• Discontinuation of further study intervention development 
For site termination: 
• Failure of the Investigator to comply with the protocol; the requirements of the 
IRB/IEC or local Health Authorities; the Sponsor’s procedures; or GCP Guidelines 
• Inadequate or no recruitment of participants by the Investigator 
• Total number of participants included earlier than expected 


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In the event of premature termination or suspension, the Sponsor shall promptly inform the 
Investigators, the IRBs/IECs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. 
The Investigator shall promptly inform each participant and should assure appropriate participant 
therapy and/or follow-up. 
10.1.10. 
Publication Policy 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. 
This allows the Sponsor to protect proprietary information and to provide comments. 
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
Coordinating Investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
10.1.11. 
Protocol Approval and Amendments 
Before the start of the study, the study protocol and/or other relevant documents will be approved 
by the IRB/IEC /Competent Authorities, in accordance with local legal requirements. The 
Sponsor must ensure that all ethical and legal requirements have been met before the first 
participant is enrolled in the study. 
This protocol is to be followed exactly. To alter the protocol, amendments must be written, 
receive approval from the appropriate personnel, and receive approval from the IRB/IEC 
/Competent Authorities prior to implementation (if appropriate). 
In the US: Following approval, the protocol amendment(s) will be submitted to the IND under 
which the study is being conducted. 
The decision of whether a formal protocol amendment is needed to accommodate administrative 
changes (i.e, those not affecting the participant benefit/risk ratio) will be made in accordance 
with current ICH GCP Guidelines and all other applicable guidelines in the countries where the 
study is conducted. Administrative changes may be conveyed to study Investigators and sites via 
a protocol clarification letter compliant with ICH GCP and all other applicable guidelines. 
All protocol amendments will be distributed to all protocol recipients, with appropriate 
instructions. 
10.1.12. 
Liability and Insurance 
The Sponsor will take out third-party liability insurance cover in accordance with all legal 
requirements. The civil liability of the Investigator, the persons instructed by the Investigator and 
the hospital, practice, or institute in which they are employed, and the liability of the Sponsor 
with respect to financial loss due to personal injury and other damage that may arise as a result of 
the carrying out of this study are governed by the applicable law. 


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The Sponsor will arrange for participants taking part in this study to be insured against financial 
loss due to personal injury caused by the pharmaceutical products being tested or by medical 
steps taken in the course of the study. 
10.1.13. 
Access to Source Data 
During the study, a monitor will make remote or onsite visits to review protocol compliance, 
compare eCRF entries and individual participant’s medical records, assess drug accountability, 
and ensure that the study is being conducted according to pertinent regulatory requirements. 
eCRF entries will be verified with source documentation. The review of medical records will be 
performed in a manner to ensure that participant confidentiality is maintained. 
Checking of the eCRF entries for completeness and clarity, and cross-checking with source 
documents, will be required to monitor the progress of the study. Moreover, regulatory 
authorities of certain countries, IRBs/IECs, and/or the Sponsor’s Clinical Quality Assurance 
Group may wish to carry out such source data checks and/or onsite audit inspections. 
Direct access to source data will be required for these inspections and audits; they will be carried 
out giving due consideration to data protection and medical confidentiality. The Investigator 
assures the Sponsor, and any contract research organization or other individual or entity working 
on the Sponsor’s behalf, if involved in monitoring/data management, of the necessary support at 
all times. 


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10.2. 
Appendix 2: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.2.1. 
Definition of an AE 
 
AE Definition 
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with 
the use of study intervention, whether or not considered related to the study intervention. 
• 
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
Events Meeting the AE Definition: 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the Investigator (i.e, not related to progression of underlying 
disease) 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency or intensity of the condition 
• 
New condition detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study 
• 
Signs, symptoms, or the clinical sequelae of a suspected intervention-intervention 
interaction 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose, per se, will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae. 
Events NOT Meeting the AE Definition: 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
• 
Medical or surgical procedure (e.g, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social or convenience 
admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 


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10.2.2. 
Definition of an SAE 
 
An SAE is an AE that meets one of the following criteria: 
1. Results in death. 
2. Is life-threatening. 
The term “life-threatening” in the definition of “serious” refers to an event in which the participant was 
at risk of death at the time of the event. It does not refer to an event which hypothetically might have 
caused death if it were more severe. 
3. Requires inpatient hospitalization or prolongation of existing hospitalization. 
In general, hospitalization signifies that the participant has been admitted (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalization are AEs. If a complication prolongs hospitalization or 
fulfills any other serious criteria, the event is serious. 
When in doubt as to whether hospitalization occurred or was necessary, the AE should be considered 
serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is 
not considered an AE. 
4. Results in persistent or significant disability/incapacity. 
The term “disability” means a substantial disruption of a person’s ability to conduct normal life 
functions. 
This definition is not intended to include experiences of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (eg, sprained 
ankle) that may interfere with or prevent everyday life functions but do not constitute a substantial 
disruption. 
5. Is a congenital anomaly/birth defect. 
6. Other situations: 
• 
Medical or scientific judgment should be exercised by the Investigator in deciding whether 
SAE reporting is appropriate in other situations such as significant medical events that may 
jeopardize the participant or may require medical or surgical intervention to prevent one of 
the other outcomes listed in the above definition. These events should usually be 
considered serious. 
• 
Examples of such events include invasive or malignant cancers, intensive treatment for 
allergic bronchospasm, blood dyscrasias, convulsions or development of drug dependency 
or drug abuse. 


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10.2.3. 
Recording and Follow-up of AEs and SAEs 
 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• 
The Investigator will then record all relevant AE/SAE information using the AE section of 
the CRF and, for SAEs, the SAE Form (refer to Section 10.2.4). 
• 
It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to EQRx International, Inc. and Parexel Pharmacovigilance Group in lieu of 
completion of the SAE Form. 
• 
There may be instances when copies of medical records for certain cases are requested by 
both EQRx International, Inc. and Parexel Pharmacovigilance Group. In this case, all 
participant identifiers, with the exception of the participant number, will be blinded on the 
copies of the medical records before submission to EQRx International, Inc. and Parexel 
Pharmacovigilance Group. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
 
 
Assessment of Intensity 
The intensity of AEs should be documented using NCI CTCAE version 5.0. 
For events not listed in the NCI CTCAE version 5.0, the intensity of AEs should be classified 
according to the following categories: 
• 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL; instrumental ADL refers to 
preparing meals, shopping for groceries or clothes, using the telephone, managing money, 
etc.) 
• 
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL (Self-care ADL refers to bathing, dressing and undressing, feeding self, using the 
toilet, taking medications, and not bedridden.) 
• 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
• 
Grade 5: Death related to AE. 
An event is defined as “serious” when it meets at least one of the predefined outcomes as described in 
the definition of an SAE, not when it is rated as severe. 


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Assessment of Causality 
The Investigator will assess the relationship between study intervention and the occurrence of each AE. 
The Investigator’s assessment of the relationship of each AE to study intervention will be recorded in 
the source documents and the eCRF. Alternative causes, such as medical history, concomitant therapy, 
other risk factors, and the temporal relationship of the event to study intervention should be considered 
and investigated, if appropriate. 
The following definitions are general guidelines to help assign grade of attribution: 
• 
Not related: The event is clearly related to other factors such as the participant’s 
environment or clinical state, therapeutic interventions or concomitant drugs administered 
to the participant. This is especially so when an event occurs prior to the commencement of 
treatment with the study intervention. 
• 
Unlikely related: The temporal association, participant history, and/or circumstances are 
such that study intervention is not likely to have had an association with the observed 
event. Other conditions, including concurrent illness, progression, or expression of the 
disease state, or reaction to a concomitant drug administered appear to explain the event. 
• 
Possibly related: The event follows a reasonable temporal sequence from the time of 
study intervention administration or follows a known response to the study intervention but 
could have been produced by other factors such as the participant’s clinical state, other 
therapeutic interventions, or concomitant drugs administered to the participant. 
• 
Probably related: The event follows a reasonable temporal sequence from the time of 
study intervention administration and follows a known response to the study intervention 
and cannot be reasonably explained by other factors such as the participant’s clinical state, 
other therapeutic interventions, or concomitant drugs administered to the participant. 
• 
Definitely related: The event follows a reasonable temporal sequence from the time of 
study intervention administration or control abates upon discontinuation or cannot be 
explained by known characteristics of the participant’s clinical state. 


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Follow-up of AEs and SAEs 
The Investigator is obligated to perform or arrange for the conduct of supplemental measurements or 
evaluations as medically indicated or as requested by the Sponsor to elucidate the nature or causality of 
the AE or SAE as fully as possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
If a participant dies during participation in the study or during a recognized follow-up period, the 
Investigator will provide BOTH EQRx International, Inc. and Parexel Pharmacovigilance Group with 
a copy of any available postmortem findings, including histopathology. 
New or updated information will be recorded in the originally completed form. 
The Investigator will submit any updated SAE data via email to BOTH 
 and 
 within 24 hours of receipt of the information. 
10.2.4. 
Reporting of SAEs 
 
SAE Reporting via Email 
The Investigator must report any SAE via email to BOTH 
 and 
 within 24 hours of becoming aware of the event. 
The Investigator and the Sponsor (or Sponsor’s designated agent) will review each SAE report, and the 
Sponsor/Sponsor’s designated agent will evaluate the seriousness and the causal relationship of the 
event to study intervention. In addition, the Sponsor (or Sponsor’s designated agent) will evaluate the 
expectedness according to the Reference Safety Information (Investigator’s Brochure or Summary of 
Product Characteristics). 
Based on the Investigator and Sponsor’s assessment of the event, a decision will be made concerning 
the need for further action. 
After the study is completed at a given site, the electronic data collection tool will be deactivated to 
prevent the entry of new data or changes to existing data. 
If a site receives a report of a new SAE from a study participant, or receives updated data on a 
previously reported SAE after the EDC system has been deactivated, then the site can report this 
information on the paper SAE Form (refer to Section 10.2.4) or by telephone. 
Contacts for SAE reporting (as detailed in Section 10.2.4.1) can also be found in the Investigator site 
file. 
 
 
SAE Reporting via the SAE Form 
Email transmission of the SAE Form is the preferred method to transmit this information. 
In rare circumstances, and in the absence of email equipment, notification by telephone is acceptable. 
Initial notification via telephone does not replace the need for the Investigator to complete and sign the 
SAE Form within the designated reporting timeframes. 
Contacts for SAE reporting (as detailed in Section 10.2.4.1) can also be found in the Investigator site 
file. 


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Serious Unexpected Serious Adverse Reactions (SUSARs) 
Any AE that is serious, associated with the use of the study intervention, and unexpected—and which 
has a reasonable suspected causal relationship to the study intervention—is considered a SUSAR and 
has additional reporting requirements, as described below. 
• 
An unexpected AE is an event or reaction that is not listed in the IB, or not listed at the 
specificity or severity that has been observed; for which the nature and severity is not 
consistent with the information about the medicinal product in question as set out in the 
reference safety information; or, if an IB is not required or available, is not consistent with the 
risk information described in the General Investigational Plan, or elsewhere in the relevant 
current Investigational New Drug application. 
• 
A reasonable suspected causal relationship means that there is a reasonable possibility that the 
study intervention caused the AE—i.e, evidence to suggest a causal relationship. 
• 
If the SUSAR is fatal or life-threatening, associated with study intervention, and unexpected, 
regulatory authorities and IRBs/IECs will be notified as soon as possible, and in any event 
within 7 calendar days after the Sponsor first learns of the event, or such earlier time period as 
required under national law. 
− Additional follow-up information for fatal or life-threatening SUSARs (e.g, cause of death, 
autopsy report, hospital report) should be reported within an additional 8 days (15 days 
total). 
• 
If the SUSAR is not fatal or life-threatening—but is otherwise serious, associated with study 
intervention, and unexpected—regulatory authorities and IRBs/IECs will be notified as soon as 
possible, and in any event within 15 calendar days after the Sponsor first learns of the event, or 
such earlier time period as required under national law. 
• 
Additional follow-up information for non-fatal/non-life-threatening SUSARs (e.g, hospital 
report) should be reported within 15 days total. 
• 
The Sponsor will notify the Investigators in a timely fashion of relevant information about 
SUSARs that could adversely affect the safety of study participants. Follow-up information 
may be submitted if necessary. 
• 
The Sponsor will also provide annual safety updates to the regulatory authorities and 
IRBs/IECs responsible for the study. These updates will include information on SUSARs and 
other relevant safety findings. 


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10.2.4.1. SAE Contact Details 
 
SERIOUS ADVERSE EVENT REPORTING INSTRUCTIONS 
Parexel International Corporation 
Parexel Safety Services 
Telephone Number: +1-781-434-5010 
Parexel International Email: 
 
EQRx Safety Email: 
. 
Email the SAE Form and any supporting documentation to BOTH 
 AND 
 within 24 hours of becoming aware of the event. 
Following receipt of the SAE Form, Parexel will provide a confirmation of receipt, which should be 
filed with the safety report. If you do not receive a confirmation of receipt within 3 working days, 
please re-submit the SAE report. 
In the event that email is down, a Parexel Safety Contact may be reached through Parexel’s voice 
mailbox at +1 781-434-5010 to report the SAE. Please leave the following information in your voice 
mail message: 
• 
Your name 
• 
The telephone number where you can be reached 
• 
The study protocol number and title 
• 
The study intervention name 
• 
The Principal Investigator’s name 
• 
The name of the Sponsoring pharmaceutical company 


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10.3. 
Appendix 3: Contraceptive and Barrier Guidance 
10.3.1. 
Definitions 
Female Participants of Childbearing Potential 
• Female participants in the following categories are considered to be of childbearing 
potential (fertile): 
− 
Following menarche. 
− 
From the time of menarche until becoming postmenopausal, unless permanently 
sterile (see below). 
Postmenopausal and Permanent Sterilization 
• A postmenopausal state is defined as no menses for ≥ 1 year without an alternative 
medical cause. 
− 
At Investigator discretion, a high FSH level in the postmenopausal range may be 
used to confirm a medically postmenopausal state in female participants who are 
not using hormonal contraception or hormonal replacement therapy (HRT). 
However, in the absence of 1 year of amenorrhea, confirmation with more than 
1 FSH measurement is required. 
− 
Female participants who are on HRT and whose postmenopausal status is in doubt 
will be required to use one of the non-estrogen hormonal, highly effective 
contraception methods (refer to Section 10.3.2) if they wish to continue their HRT 
during the study. Otherwise, they must discontinue HRT to allow confirmation of 
their postmenopausal status before study enrollment. 
• Permanent sterilization methods (for the purpose of confirming non-childbearing 
potential status in this study, at Investigator discretion) include the following: 
− 
Documented hysterectomy 
− 
Documented bilateral salpingectomy 
− 
Documented bilateral oophorectomy 
− 
Documented bilateral tubal ligation/occlusion 
For individuals with permanent infertility due to an alternate medical cause other than the above 
(eg, Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), Investigator discretion 
should be applied to determining study entry. 
Notes: 
• Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
• If fertility status is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual 
cycle cannot be confirmed before first dose of any study intervention, additional 
evaluation should be considered. 


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10.3.2. 
Contraception Guidance 
 
Contraceptivesa Allowed During the Study Include the Following: 
Highly Effective Methodsb that Have Low User-Dependency 
Failure rate of < 1% per year when used consistently and correctly. 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationc 
Intrauterine device 
Intrauterine hormone-releasing systemc 
Bilateral tubal occlusion 
Azoospermic male partner (vasectomized or due to a medical cause) 
• 
Azoospermia is a highly effective contraceptive method provided that the partner is the 
sole heterosexual partner of the female participant of childbearing potential (as defined in 
Section 10.3.1) and the absence of sperm has been confirmed. If not, an additional highly 
effective method of contraception should be used. 
• 
Spermatogenesis cycle is approximately 90 days. 
− Note: Documentation of azoospermia for a male participant can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview. 
Highly Effective Methodsb that are User-Dependent 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition 
of ovulation: 
• 
oral 
• 
intravaginal 
• 
transdermal 
• 
injectable 
Progestogen-only hormone contraception associated with inhibition of ovulation: 
• 
oral 
• 
injectable 
Sexual abstinence 
• 
Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
intervention. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant. 
a Contraceptive use by male and female participants in all treatment arms should be consistent with local regulations 
regarding the use of contraceptive methods for those participating in clinical studies. Refer to the Clinical Trial 
Facilitation Group (CTFG) guidelines for additional information. 
• 
All participants must follow the contraception duration requirements for the drugs they receive, in 
accordance with the current local label for each drug. 
b Failure rate of < 1 % per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
c Male condoms must be used in addition to hormonal contraception. If locally required, in accordance with CTFG 
guidelines, acceptable contraceptive methods are limited to those which inhibit ovulation as the primary mode of 
action. 


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Notes: 
• 
Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method are not acceptable methods of contraception for this 
study. 
• 
Male condom and female condom should not be used together (due to risk of failure from friction). 


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10.4. 
Appendix 4: Hy’s Law Definition, Reporting, and Observation 
Requirements 
Hy’s Law cases may be indicative of drug-induced hepatocellular injury. 
The following events may indicate hepatocellular injury (Hy’s Law): 
• ALT or AST ≥ 3 × ULN 
and 
• TBIL to ≥ 2 × ULN without initial findings of cholestasis (elevated serum ALP 
> 2 × ULN) 
and 
• No other reason can be found to explain the combination of increased ALT or AST 
and TBIL. 
Unless otherwise specified in the protocol, in the event that a participant meets potential Hy’s 
Law criteria, treatment with study intervention must be permanently discontinued. The 
Investigator must notify the Sponsor as soon as possible, but no more than 24 hours later, and 
report the event as an SAE. SAE reporting details are provided in Section 10.2.4. 
For special situations, if the first occurrence of a potential Hy’s Law event is determined to be 
due to alternative etiology other than study intervention, the study intervention can be re-started 
per predefined criteria in the protocol. 
It is critical to initiate close observation immediately upon detection and confirmation of 
early signals of possible hepatollceular injury, and not to wait until the next scheduled visit 
or monitoring interval. 
If additional testing beyond that specified in the protocol is carried out, it is important that the 
testing information is added to the eCRF and safety database. 
Close observation includes the following: 
• Repeating liver enzyme and serum bilirubin tests 2 or 3 times weekly. Frequency of 
retesting can decrease to once a week or less if abnormalities stabilize or the study 
intervention has been discontinued and the participant is asymptomatic. 
• Obtaining a more detailed history of symptoms and prior or concurrent diseases. 
• Obtaining a history of concomitant drug use (including nonprescription medications 
and herbal and dietary supplement preparations), alcohol use, recreational drug use, 
and special diets. 
• Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic 
hepatitis; nonalcoholic steatohepatitis (NASH); hypoxic/ischemic hepatopathy; and 
biliary tract disease. 
• Obtaining a history of exposure to environmental chemical agents. 
• Obtaining additional tests to evaluate liver function, as appropriate (eg, INR, direct 
bilirubin). 


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• Considering gastroenterology or hepatology consultations. 
All participants showing possible hepatocellular injury should be followed until all abnormalities 
return to normal or to the baseline state. Hepatocellular injury may develop or progress even 
after study intervention has been stopped. Results should be recorded on the eCRF and in the 
safety database. Note that longer follow-up can sometimes reveal an off-drug repetition of what 
had appeared to be hepatocellular injury, indicating that liver injury was related to underlying 
liver disease. 
Refer to the US Food and Drug Administration’s Guidance for Industry for additional 
information. 


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10.5. 
Appendix 5: Prohibited Concomitant Medications 
Table 8: 
Examples of Prohibited Concomitant Agents Because of the Potential for 
Pharmacokinetic Drug-Drug Interaction with Aumolertiniba 
 
Medication Class 
Prohibited Agentsb 
Strong CYP3A Inhibitors 
cobicistat, ritonavir, ketoconazole, voriconazole, clarithromycin, 
itraconazole, grapefruitc, grapefruit juicec 
Strong CYP3A Inducers 
phenytoin, carbamazepine, rifabutin, rifapentine, rifampin, St. 
John’s wort 
a This table presents examples of the most common concomitant medications in relation to aumolertinib and is not 
an exhaustive list. Refer to the current prescribing information for osimertinib, pemetrexed, cisplatin, carboplatin, 
paclitaxel, albumin-bound paclitaxel, and gemcitabine for guidance on medications prohibited for concomitant use 
with each of these study interventions. 
b Beginning 14 days (or 5 half-lives, whichever is longer) prior to Day 1 and through the participant’s final study 
visit. 
c Beginning 72 hours prior to Day 1 and through the participant’s final study visit. 
CYP3A = cytochrome P450 3A. 


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10.6. 
Appendix 6: Tumor Identification, Response, and Progression per 
RECIST v1.1 
For study tumor assessments performed per RECIST v1.1, all sites of disease should be assessed 
radiologically by CT with contrast scan (this is the preferred imaging modality; however, 
PET/CT scan may instead be used at Investigator discretion) at the time points shown in the 
applicable SoA (Section 1.3). The same imaging modality (CT with contrast or PET/CT) should 
be used across all scan collections for the individual participant. 
Imaging assessments will be performed (per RECIST v.1.1) by BICR for the primary study 
endpoint and by both BICR and Investigator for the secondary tumor-based efficacy endpoints. 
Objective response data collected for the clinical study report will be based on BICR and 
Investigator assessments as noted above. 
For all participants, CT scan of the chest and abdomen/pelvis with contrast (or PET/CT scan, as 
applicable per Investigator discretion) is to be collected at baseline. Scans that were obtained 
prior to the provision of signed informed consent will not need to be repeated if they were 
performed within 28 days prior to the initiation of study drug dosing. 
All participants with a CR must also have a CT with contrast (or PET/CT, as applicable) scan 
performed as part of confirmation of the CR. Additional scans may be obtained at the discretion 
of the Investigator, if clinically indicated. If a participant shows a radiological response (CR or 
PR), a confirmatory radiological assessment will be performed at least 4 weeks after the response 
was first noted. Participants who have a confirmed CR will have a CT with contrast (or PET/CT, 
as applicable) scan to confirm absence of bony metastases. 
For participants who remain on therapy for 12 months following study enrollment, the timing of 
scans should occur as specified in the applicable SoA in Section 1.3. 
Refer to Section 8.1.2.7 for additional details. 
10.6.1. 
Definitions of Tumor Response and Disease Progression per RECIST v1.1 
The determination of tumor response and progression in this study will be based on 
RECIST v1.1 (Eisenhauer 2009). In addition, assessment of brain metastases (as applicable) 
should follow RANO criteria (refer to Section 10.7). 
The definitions for tumor response per RECIST v1.1 are provided immediately below. 
10.6.1.1. Evaluation of Target Lesion Response 
• CR: Disappearance of all target lesions. Any pathological lymph nodes (whether 
target or nontarget) must have reduction in short axis to < 10 mm. 
• 
PR: At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum of diameters. 
• 
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 1 or more new 
lesions is also considered progression. 


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• 
SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum of diameters while on study. 
A response category of “NE” is to be used when there is inadequate information to otherwise 
categorize the response status. 
10.6.1.2. Evaluation of Nontarget Lesions 
• CR: Disappearance of all nontarget lesions and normalization of tumor marker level. 
All lymph nodes must be < 10 mm short axis. 
• Non-CR/Non-PD: Persistence of 1 or more nontarget lesions and/or maintenance of 
tumor marker level above the normal limits. 
• PD: Unequivocal progression of existing nontarget lesions or the appearance of at 
least 1 new lesion. 
10.6.1.3. Evaluation of Overall Response 
The evaluation of overall response at each time point, based on target and nontarget lesion 
responses at each time point as well as the appearance of new lesions, is described in Table 9. 
The best overall response is the best response recorded from the start of the treatment until 
disease progression. Confirmation of CR and PR is required, as previously described. 
Table 9: 
Evaluation of Overall Response per RECIST v1.1 at Each Time Point 
 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD/not all evaluated 
No 
PR 
SD 
Non-PD/not all evaluated 
No 
SD 
NE 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; RECIST = Response 
Evaluation Criteria in Solid Tumors; SD = stable disease. 
Source: Eisenhauer 2009 


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10.7. 
Appendix 7: Definitions of Response and Progression for Brain 
Metastases per RANO Criteria 
RANO criteria (Chukwueke 2019) definitions of response and progression, which apply to 
assessment of brain metastases in this study, are provided in Table 10. 
Table 10: 
Evaluation of Response and Progression for Brain Metastases per 
RANO Criteria 
 
Criterion 
CR 
PR 
SD 
PD 
Target lesions 
None 
≥ 30% decrease in sum 
LD relative to baseline 
< 30% decrease in sum 
LD relative to baseline, 
but < 20% increase in 
sum LD relative to nadir 
≥ 20% increase in 
sum LD relative to 
nadirb 
Nontarget lesions None 
Stable or improved 
Stable or improved 
Unequivocal PDb 
New lesion(s)a 
None 
None 
None 
Presentb 
Corticosteroids 
None 
Stable or decreased 
Stable or decreased 
NAc 
Clinical status 
Stable or 
improved 
Stable or improved 
Stable or improved 
Worseb 
Requirement for 
response 
All 
All 
All 
Anyc 
a Progression occurs when this criterion is met. 
b “New lesion” is defined as a new lesion not present on prior scans and visible in at least 2 projections. 
• 
If a new lesion is equivocal (eg, because of its small size), continued therapy may be considered and 
follow-up evaluation will clarify whether it represents truly new disease. 
• 
If repeat scans confirm there is definitely a new lesion, then progression should be declared using the date 
of the initial scan showing the new lesion. 
• 
For immunotherapy-based approaches, new lesions alone do not define progression. 
c Increase in corticosteroids alone will not be taken into account in determining progression in the absence of 
persistent clinical deterioration. 
CR = complete response; LD = longest dimension; NA = not applicable; PD = progressive disease; PR = partial 
response; RANO = Response Assessment in Neuro-Oncology; SD = stable disease. 
Source: Chukwueke 2019 


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10.8. 
Appendix 8: Clinical Safety Laboratory Tests 
Clinical safety lab parameters to be tested in this study are detailed below. 
Clinical safety labs for screening and enrollment purposes will be processed using a licensed 
laboratory/laboratory with applicable local accreditation. 
10.8.1. 
Hematology 
Hematology parameters to be tested in the study are as follows: 
 
Hematology Parameters 
Required for All Participants at Time Points Shown in the Applicable SoA (Section 1.3): 
Absolute neutrophil count (ANC)a 
Hemoglobin (Hgb) 
White blood cells (WBC) 
Platelets (PLAT) 
Required Only if Clinically Indicated per Investigator Discretion: 
Hematocrit (HCT) 
Leukocytes (LEUK) with differential (including Eosinophils [ESN], Neutrophils [NEUT], Basophils [BASO], 
Lymphocytes [LYM], and Monocytes [MONO]) 
a For participants in the aumolertinib monotherapy and osimertinib monotherapy arms, ANC is required only at Screening, and 
then only as clinically indicated. 
10.8.2. 
Serum Chemistry 
Serum chemistry parameters to be tested in the study are as follows: 
 
Serum Chemistry Parameters 
Required for All Participants at Time Points Shown in the Applicable SoA (Section 1.3): 
Alanine aminotransferase (ALT) 
Alkaline phosphatase (ALP) 
Aspartate aminotransferase (AST) 
Total bilirubin (TBIL) and indirect bilirubin (IBILI) 
Calculated creatinine clearance (CLCr)a 
Creatine phosphokinase (CPK) 
Creatinine (CREAT)b 
Glucose (GLU)c 
Required Only if Clinically Indicated per Investigator Discretion: 
Albumin (ALB) 
Phosphate (PHOS) 
Bicarbonate (BICARB) 
Potassium (K) 
Calcium (CA) 
Sodium (NA) 
Chloride (CL) 
Triglycerides (TRI) 


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Gamma-GT (GGT) 
Urea (U) or blood urea nitrogen (BUN), at site discretion 
Globulin (GLOBUL) 
Magnesium (Mg) 
a CLCr is to be estimated by Cockroft-Gault equation. 
b For participants in the aumolertinib monotherapy and osimertinib monotherapy arms, CREAT is required only at Screening, 
and then only as clinically indicated. 
c For all participants in all 3 treatment arms, GLU is to be collected in the fasted state at Screening and non-fasted at all other 
time points. 
10.8.3. 
Urinalysis 
Urinalysis testing in the study will be performed by dipstick. 
If an abnormality is noted for protein, blood, nitrite, or leukocyte esterase (and at the discretion 
of the Investigator), a microscopic examination of RBCs, WBCs, bacteria, and casts may be 
performed. 
10.8.4. 
Coagulation 
Prothrombin time (PT) collection/INR calculation are to be performed at Screening for all 
participants. Subsequently, PT/INR are to be assessed only as clinically indicated per 
Investigator discretion. 
Any participant determined to be anti-coagulated should be monitored by local testing. 


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10.9. 
Appendix 9: Pre-Screening EGFR Mutation Testing for Prospective 
Study Participants (as applicable) 
To be eligible for this study, all participants must have one of the required EGFR mutations 
present as confirmed by laboratory testing. If available, existing EGFR mutation test results may 
be used to confirm participant eligibility, provided that they were obtained within ≤ 3 months 
prior to study entry. 
If recommended by the Investigator, prospective study participants for whom EGFR mutation 
testing is not covered or reimbursed by standard of care may undergo such testing for 
confirmatory purposes pre-screening. 
Any such prospective participant will be required to sign the separate Pre-Screening ICF to allow 
blood or tissue sample collection for local EGFR mutation testing prior to the 28-day study 
Screening window. 
At the time the prospective participant signs the Pre-Screening ICF, the Investigator should 
ensure that there is a reasonable possibility the individual would be a candidate for this study, in 
consideration of the study inclusion/exclusion criteria and based on all available information. 
Once the prospective participant has signed the Pre-Screening ICF, the main study ICF is not to 
be signed, nor any study tests or procedures initiated, until the qualifying laboratory test 
result for EGFR mutation status has been obtained. 


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10.10. 
Appendix 10: Patient-Reported Outcomes Questionnaire 
NCI-PRO-CTCAE® CUSTOM SURVEY 
Item subset derived from PRO-CTCAE® Item Library Version 1.0 
English 
Form Created on 26-January-2023 
https://healthcaredelivery.cancer.gov/pro-ctcae/builder.html 
 
As individuals go through treatment for their cancer they sometimes experience different symptoms and side 
effects. For each question, please select the one response that best describes your experiences over the past 
7 days… 
 
 
1a. In the last 7 days, what was the SEVERITY of your DRY MOUTH at its WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
2a. In the last 7 days, what was the SEVERITY of your MOUTH OR THROAT SORES at their WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
2b. In the last 7 days, how much did MOUTH OR THROAT SORES INTERFERE with your usual or daily activities? 
Ο Not at all 
Ο A little bit 
Ο Somewhat 
Ο Quite a bit 
Ο Very much 
3a. In the last 7 days, what was the SEVERITY of your PROBLEMS WITH TASTING FOOD OR DRINK at their WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
4a. In the last 7 days, what was the SEVERITY of your DECREASED APPETITE at its WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
4b. In the last 7 days, how much did DECREASED APPETITE INTERFERE with your usual or daily activities? 
Ο Not at all 
ΟA little bit 
Ο Somewhat 
Ο Quite a bit 
Ο Very much 


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5a. In the last 7 days, how OFTEN did you have NAUSEA? 
Ο Never 
Ο Rarely 
Ο Occasionally 
Ο Frequently 
Ο Almost constantly 
5b. In the last 7 days, what was the SEVERITY of your NAUSEA at its WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
6a. In the last 7 days, how OFTEN did you have VOMITING? 
Ο Never 
Ο Rarely 
Ο Occasionally 
Ο Frequently 
Ο Almost constantly 
6b. In the last 7 days, what was the SEVERITY of your VOMITING at its WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
7a. In the last 7 days, how OFTEN did you have LOOSE OR WATERY STOOLS (DIARRHEA/DIARRHOEA)? 
Ο Never 
Ο Rarely 
Ο Occasionally 
Ο Frequently 
Ο Almost constantly 
8a. In the last 7 days, how OFTEN did you have PAIN IN THE ABDOMEN (BELLY AREA)? 
Ο Never 
Ο Rarely 
Ο Occasionally 
Ο Frequently 
Ο Almost constantly 
8b. In the last 7 days, what was the SEVERITY of your PAIN IN THE ABDOMEN (BELLY AREA) at its WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
8c. In the last 7 days, how much did PAIN IN THE ABDOMEN (BELLY AREA) INTERFERE with your usual or daily 
activities? 
Ο Not at all 
Ο A little bit 
Ο Somewhat 
Ο Quite a bit 
Ο Very much 
9a. In the last 7 days, how OFTEN did you LOSE CONTROL OF BOWEL MOVEMENTS? 
Ο Never 
Ο Rarely 
Ο Occasionally 
Ο Frequently 
Ο Almost constantly 
9b. In the last 7 days, how much did LOSS OF CONTROL OF BOWEL MOVEMENTS INTERFERE with your usual or daily 
activities? 
Ο Not at all 
Ο A little bit 
Ο Somewhat 
Ο Quite a bit 
Ο Very much 


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10a. In the last 7 days, did you have any RASH? 
Ο Yes 
Ο No 
11a. In the last 7 days, what was the SEVERITY of your DRY SKIN at its WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
12a. In the last 7 days, what was the SEVERITY of your ACNE OR PIMPLES ON THE FACE OR CHEST at its WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
13a. In the last 7 days, did you have any HAIR LOSS? 
Ο Not at all 
Ο A little bit 
Ο Somewhat 
Ο Quite a bit 
Ο Very much 
14a. In the last 7 days, what was the SEVERITY of your ITCHY SKIN at its WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
15a. In the last 7 days, did you LOSE ANY FINGERNAILS OR TOENAILS? 
Ο Yes 
Ο No 
16a. In the last 7 days, did you have any RIDGES OR BUMPS ON YOUR FINGERNAILS OR TOENAILS? 
Ο Yes 
Ο No 
17a. In the last 7 days, did you have any CHANGE IN THE COLOR OF YOUR FINGERNAILS OR TOENAILS? 
Ο Yes 
Ο No 
18a. In the last 7 days, did you have any INCREASED SKIN SENSITIVITY TO SUNLIGHT? 
Ο Yes 
Ο No 


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19a. In the last 7 days, what was the SEVERITY of your PROBLEMS WITH CONCENTRATION at their WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
19b. In the last 7 days, how much did PROBLEMS WITH CONCENTRATION INTERFERE with your usual or daily 
activities? 
Ο Not at all 
Ο A little bit 
Ο Somewhat 
Ο Quite a bit 
Ο Very much 
20a. In the last 7 days, what was the SEVERITY of your PROBLEMS WITH MEMORY at their WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
20b. In the last 7 days, how much did PROBLEMS WITH MEMORY INTERFERE with your usual or daily activities? 
Ο Not at all 
Ο A little bit 
Ο Somewhat 
Ο Quite a bit 
Ο Very much 
21a. In the last 7 days, how OFTEN did you have ACHING MUSCLES? 
Ο Never 
Ο Rarely 
Ο Occasionally 
Ο Frequently 
Ο Almost constantly 
21b. In the last 7 days, what was the SEVERITY of your ACHING MUSCLES at their WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
21c. In the last 7 days, how much did ACHING MUSCLES INTERFERE with your usual or daily activities? 
Ο Not at all 
Ο A little bit 
Ο Somewhat 
Ο Quite a bit 
Ο Very much 
22a. In the last 7 days, how OFTEN did you have ACHING JOINTS (SUCH AS ELBOWS, KNEES, SHOULDERS)? 
Ο Never 
Ο Rarely 
Ο Occasionally 
Ο Frequently 
Ο Almost constantly 
22b. In the last 7 days, what was the SEVERITY of your ACHING JOINTS (SUCH AS ELBOWS, KNEES, SHOULDERS) at 
their WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
22c. In the last 7 days, how much did ACHING JOINTS (SUCH AS ELBOWS, KNEES, SHOULDERS) INTERFERE with your 
usual or daily activities? 
Ο Not at all 
Ο A little bit 
Ο Somewhat 
Ο Quite a bit 
Ο Very much 


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23a. In the last 7 days, what was the SEVERITY of your FATIGUE, TIREDNESS, OR LACK OF ENERGY at its WORST? 
Ο None 
Ο Mild 
Ο Moderate 
Ο Severe 
Ο Very severe 
23b. In the last 7 days, how much did FATIGUE, TIREDNESS, OR LACK OF ENERGY INTERFERE with your usual or daily 
activities? 
Ο Not at all 
Ο A little bit 
Ο Somewhat 
Ο Quite a bit 
Ο Very much 
OTHER SYMPTOMS 
Do you have any other symptoms that you wish to report? 
Ο Yes 
Ο No 
Please list any other symptoms: 
1. 
In the last 7 days, what was the SEVERITY of this symptom at its WORST? 
O None 
O Mild 
O Moderate 
O Severe 
O Very 
Severe 
2. 
In the last 7 days, what was the SEVERITY of this symptom at its WORST? 
O None 
O Mild 
O Moderate 
O Severe 
O Very 
Severe 
3. 
In the last 7 days, what was the SEVERITY of this symptom at its WORST? 
O None 
O Mild 
O Moderate 
O Severe 
O Very 
Severe 
4. 
In the last 7 days, what was the SEVERITY of this symptom at its WORST? 
O None 
O Mild 
O Moderate 
O Severe 
O Very 
Severe 


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5. 
In the last 7 days, what was the SEVERITY of this symptom at its WORST? 
O None 
O Mild 
O Moderate 
O Severe 
O Very 
Severe 
Source: PRO-CTCAE® items and information developed by the Division of Cancer Control and Population Sciences in the National 
Cancer Institute at the National Institutes of Health, Bethesda, Maryland, USA. 


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10.11. 
Appendix 11: Abbreviations and Definitions of Terms 
 
Abbreviation 
Definition 
ADL 
Activities of daily living 
AE 
Adverse event 
ALB 
Albumin 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
BASO 
Basophils 
BBB 
Bundle branch block 
BICARB 
Bicarbonate 
BICR 
Blinded independent central review 
CA 
Calcium 
CDx 
Companion diagnostic(s) 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CL 
Chloride 
CLcr 
Creatinine clearance 
CMH 
Cochran-Mantel-Haenszel 
CNS 
Central nervous system 
CONSORT 
Consolidated Standards of Reporting Trials 
CPK 
Creatine phosphokinase 
CR 
Complete response 
CREAT 
Creatinine 
CRF 
Case report form 
CRP 
C-reactive protein 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating tumor deoxyribonucleic acid 
CTFG 
Clinical Trial Facilitation Group 
CTIS 
Clinical Trials Information System 
CYP 
Cytochrome P450 


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Abbreviation 
Definition 
DCR 
Disease control rate 
DepOR 
Depth of response 
DoR 
Duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EGFR 
Epidermal growth factor receptor 
EMA 
European Medicines Agency 
ESN 
Eosinophils 
eTMF 
Electronic trial master file 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FFPE 
Formalin-fixed paraffin-embedded 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GLOBUL 
Globulin 
GLU 
Glucose 
HCT 
Hematocrit 
HDL-C 
High-density lipoprotein cholesterol 
Hgb 
Hemoglobin 
HR 
Hazard ratio 
HRT 
Hormonal replacement therapy 
IA 
Interim analysis 
IB 
Investigator’s Brochure 
IBILI 
Indirect bilirubin 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
Investigational medicinal product 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 


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Abbreviation 
Definition 
IRB 
Institutional Review Board 
IRT 
Interactive response technology 
IV 
Intravenous(ly) 
IVRS 
Interactive voice response system 
IWRS 
Interactive Web response system 
K 
Potassium 
LDL-C 
Low-density lipoprotein cholesterol 
LYM 
Lymphocytes 
MATE 
Multidrug and toxin extrusion 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MONO 
Monocytes 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NA 
Sodium 
NASH 
Non-alcoholic steatohepatitis 
NCI 
National Cancer Institute 
NCI PRO-CTCAE 
National Cancer Institute Patient-Reported Outcomes version of the Common 
Terminology Criteria for Adverse Events 
NE 
Not evaluable 
NEUT 
Neutrophils 
NMPA 
National Medical Products Administration 
NOAEL 
No-observed-adverse-effect level 
NSCLC 
Non-small cell lung cancer 
OAT 
Organic anion transporting 
OATP 
Organic anion transporting polypeptide 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease 
PEG 
Percutaneous endoscopic gastrostomy 
PET 
Positron emission tomography 
PFS 
Progression-free survival 


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Abbreviation 
Definition 
PFS2 
Time to second objective disease progression 
P-gp 
P-glycoprotein 
PHOS 
Phosphate 
PK 
Pharmacokinetic(s) 
PLAT 
Platelets 
PR 
Partial response 
PRO 
Patient-reported outcome 
PROT 
Protein 
PS 
Performance status 
QD 
Once daily 
qwk 
Once weekly 
qXwk 
Once every X weeks 
QoL 
Quality of life 
QTc 
Corrected QT interval 
QTcF 
QT interval with Fridericia’s correction 
QTL 
Quality tolerance limit 
RANO 
Response Assessment in Neuro-Oncology 
RBC 
Red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SAS 
Safety Analysis Set 
SD 
Stable disease 
SoA 
Schedule of Activities 
SUSAR 
Suspected unexpected serious adverse reaction 
TBIL 
Total bilirubin 
TEAE 
Treatment-emergent adverse event 
TFST 
Time to first subsequent anticancer therapy 
TGR 
Tumor growth rate 
TKI 
Tyrosine kinase inhibitor 
tmax 
Time to maximum plasma concentration 


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Abbreviation 
Definition 
TRI 
Triglycerides 
TROP1 
Troponin 1 
TSST 
Time to second subsequent anticancer therapy 
U 
Urea 
ULN 
Upper limit of normal 
URATE 
Urate 
UROBIL 
Urobilinogen 
US 
United States 
WBC 
White blood cell 
WT 
Wild-type 


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11. 
REFERENCES 
ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable 
suspension) (albumin-bound) [package insert]. US Food and Drug Administration (FDA) 
website. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021660s037lbl.pdf. 
Revised September 2013. Accessed 16 June 2022. 
ALIMTA® (pemetrexed disodium) [package insert]. FDA website. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021462s021lbl.pdf. Revised 
February 2009. Accessed 16 June 2022. 
AMEILE® (aumolertinib mesylate tablets) [package insert]. Hansoh Pharmaceuticals. Revised 
14 December 2021. 
Chukwueke UN, Wen PY. Use of the Response Assessment in Neuro-Oncology (RANO) criteria 
in clinical trials and clinical practice. CNS Oncol. 2019 Mar 1;8(1):CNS28. 
cisplatin [package insert]. FDA website. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/018057s089lbl.pdf. 
Revised February 2019. Accessed 16 June 2022. 
Cohen MH, Johnson JR, Chen YF, et al. FDA drug approval summary: erlotinib (Tarceva) 
tablets. Oncologist. 2005 Aug;10(7):461-466. 
Cohen MH, Williams GA, Sridhara R, et al. US FDA Approval summary: Gefitinib (ZD1839; 
Iressa) tablets. Clin Cancer Res. 2004 Feb 15;10(4):1212-1218. 
CTFG. Recommendations related to contraception and pregnancy testing in clinical trials 
Revised: 09/2020. https://www.hma.eu/fileadmin/dateien/Human_Medicines/01- 
About_HMA/Working_Groups/CTFG/2020_09_HMA_CTFG_Contraception_guidance_Versio 
n_1.1.pdf. Accessed 16 June 2022. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: 
Revised RECIST guidelines (Version 1.1). Euro J Cancer. 2009;45:228-247. 
FDA Development Resources: Drug Development and Drug Interactions. Table of Substrates, 
Inhibitors and Inducers (dated 10 March 2020). FDA website. https://www.fda.gov/drugs/drug- 
interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and- 
inducers. Accessed 16 June 2022. 
FDA Guidance for Industry (issued July 2009). Drug-induced liver injury: Premarketing clinical 
evaluation. FDA website. https://www.fda.gov/regulatory-information/search-fda-guidance- 
documents/drug-induced-liver-injury-premarketing-clinical-evaluation. Accessed 16 June 2022. 
GEMZAR (gemcitabine for injection) Powder, Lyophilized, For Solution For Intravenous Use 
[package insert]. FDA website. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020509s077lbl.pdf. 
Revised May 2014. Accessed 16 June 2022. 
Globocan 2020. Globocan website. https://gco.iarc.fr/today/data/factsheets/populations/900- 
world-fact-sheets.pdf. Accessed 16 June 2022. 


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Gong Y, Mason J, Shen YL, et al. An FDA analysis of the association of tumor growth rate and 
overall and progression-free survival in metastatic non-small cell lung cancer (NSCLC) patients. 
J Clin Oncol. 2020;38:15_suppl, 9541. 
Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small-cell 
lung cancer to gefitinib. N Engl J Med. 2005;3:786-792. 
Lu S, Dong X, Jian H, Chen J, et al. Randomized phase III trial of aumolertinib (HS-10296, Au) 
versus gefitinib (G) as first-line treatment of patients with locally advanced or metastatic 
non-small cell lung cancer (NSCLC) and EGFR exon 19 del or L858R mutations (EGFRm). 
J Clin Oncol. 2021;39:15_suppl, 9013. 
Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small cell lung 
cancer with mutated EGFR. N Engl J Med. 2010;362:2380-2388. 
NCI. PRO-CTCAE® Terms of Use. NCI website. https://healthcaredelivery.cancer.gov/pro- 
ctcae/terms_of_use.html. Updated 28 January 2022. Accessed 10 April 2023. 
Nishino M, Lu J, Hino T, et al. Tumor growth rate after nadir is associated with survival in 
patients with EGFR-mutant non-small-cell lung cancer treated with epidermal growth factor 
receptor tyrosine kinase inhibitor. JCO Precis Oncol. 2021 Nov;5:1603-1610. 
Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol. 1982;5:649-655. 
PARAPLATIN® (carboplatin) Injection [package insert]. FDA website. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020452s005lbl.pdf. 
Revised July 2010. Accessed 16 June 2022. 
Stein WD, Gulley JL, Schlom J, et al. Tumor regression and growth rates determined in five 
intramural NCI prostate cancer trials: the growth rate constant as an indicator of therapeutic 
efficacy. Clin Cancer Res. 2011 Feb 15;17(4):907-917. 
TAGRISSO® (osimertinib) [package insert]. FDA website. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208065s021lbl.pdf. 
Revised December 2020. Accessed 16 June 2022. 
TAXOL® (paclitaxel) [package insert]. FDA website. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020262s049lbl.pdf. 
Revised April 2011. Accessed 16 June 2022. 
Wilkerson J. Tumor growth rate analysis. 2016. Retrieved from GitHub: 
https://github.com/wilkersj/tumgr. 
Zhang YL, Yuan JQ, Wang KF, et al. The prevalence of EGFR mutation in patients with 
non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget. 2016 Nov 29; 
7(48):78985-78993. 

SAP_001.pdf: 
EQ143-301 Statistical Analysis Plan 
[Version 1.0] 
     EQRx International, Inc. 
Statistical Analysis Plan 
A Randomized, Three-Arm, Open-Label Phase 3b Clinical 
Trial of Aumolertinib, versus Aumolertinib with 
Chemotherapy, versus Osimertinib for  
Patients with Metastatic NSCLC and an EGFR Mutation 
(TREBLE)
Prepared by: 
 
Date of Plan: 16 December 2022 
Protocol Version: 4.0 
SAP version: 1.0 
NCT Number: NCT05493501
Prepared for: 
EQRx International, Inc. 
50 Hampshire Street 
Cambridge, MA 02139 
 USA 
Confidentiality Statement This document contains confidential information, which should not be copied, referred 
to, released, or published without written approval from EQRx International, Inc. 
1 
Confidential and Proprietary 


EQ143-301 Statistical Analysis Plan 
[Version 1.0] 
     EQRx International, Inc. 
2 
Confidential and Proprietary 
SIGNATURE PAGE 
This document has been prepared by: 
 
[Electronic Signature Page 
Appended] 
 
EQRx International, Inc. 
Signature 
Date 
SPONSOR’S SIGNATORIES 
As representative(s) of the Sponsor, EQRx International, Inc., I (we) confirm the review and 
approval of the planned statistical analyses described herein. This statistical analysis plan was 
subjected to critical review. The information contained herein is consistent with study 
protocol(s) and applicable regulatory guidance and guidelines. 
This document has been reviewed and approved by: 
 
[Electronic Signature Page 
Appended] 
 
EQRx International, Inc. 
Signature 
Date 
 
[Electronic Signature Page 
Appended] 
 
EQRx International, Inc. 
Signature 
Date 


EQ143-301 Statistical Analysis Plan 
[Version 1.0] 
      EQRx International, Inc. 
 
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Confidential and Proprietary  
 
 
Table of Contents 
Table of Contents ...........................................................................................................................3 
Version History ..............................................................................................................................5 
List of Abbreviations .....................................................................................................................6 
1. 
Introduction .....................................................................................................................8 
1.1. 
Objectives and Endpoints .................................................................................................8 
1.2. 
Study Design ...................................................................................................................10 
2. 
Statistical Hypothesis ....................................................................................................13 
2.1.1. 
Multiplicity Adjustment ..................................................................................................13 
3. 
Analysis Sets ..................................................................................................................14 
4. 
Statistical Analyses .......................................................................................................15 
4.1. 
General Considerations ...................................................................................................15 
4.1.1. 
Definitions and Conventions...........................................................................................15 
4.1.2. 
Handling of Dropouts or Missing Data ...........................................................................15 
4.1.3. 
Participant Disposition ....................................................................................................18 
4.1.4. 
Participant Characteristics ..............................................................................................18 
4.2. 
Efficacy Analysis ............................................................................................................19 
4.2.1. 
Analysis of Primary Endpoint .........................................................................................23 
4.2.2. 
Sensitivity Analysis of PFS ............................................................................................23 
4.2.3. 
Analysis of Secondary Endpoints ...................................................................................24 
4.2.4. 
Analysis of Exploratory Endpoints .................................................................................26 
4.3. 
Safety Analyses...............................................................................................................26 
4.3.1. 
Extent of Exposure ..........................................................................................................26 
4.3.2. 
Adverse Events ...............................................................................................................27 
4.3.3. 
Adverse Events of Clinical Interest ................................................................................28 
4.3.4. 
Deaths .............................................................................................................................28 
4.3.5. 
Clinical Laboratory Tests ................................................................................................28 
4.3.6. 
Vital Signs .......................................................................................................................29 
4.3.7. 
ECOG PS ........................................................................................................................29 
4.3.8. 
Physical Examination Findings.......................................................................................29 
4.3.9. 
Electrocardiograms .........................................................................................................30 
4.3.10. ECHO or MUGA (LVEF) ..............................................................................................30 
4.3.11. Additional Safety Assessments .......................................................................................30 
4.4. 
Other Analyses ................................................................................................................30 
4.4.1. 
Patient-reported Outcomes and Quality of Life Analysis ...............................................30 
4.4.2. 
Pharmacokinetic Analyses ..............................................................................................30 
4.4.3. 
Biomarker Analysis ........................................................................................................30 
4.4.4. 
Subgroup Analyses .........................................................................................................31 
4.4.5. 
Protocol Deviation ..........................................................................................................31 
4.5. 
Interim Analyses .............................................................................................................31 
4.6. 
Changes to Protocol-planned Analyses ..........................................................................31 
5. 
Sample Size Determination ..........................................................................................32 


EQ143-301 Statistical Analysis Plan 
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      EQRx International, Inc. 
 
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6. 
Supporting Documentation ..........................................................................................33 
7. 
References ......................................................................................................................34 
 


EQ143-301 Statistical Analysis Plan 
[Version 1.0] 
      EQRx International, Inc. 
 
5 
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Version History 
 
SAP Version 
Date 
Change 
Rationale 
Protocol Version 
1.0 
12/16/2022  
Not applicable 
Original version 
Protocol V4.0 
 


EQ143-301 Statistical Analysis Plan 
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      EQRx International, Inc. 
 
6 
Confidential and Proprietary  
 
 
List of Abbreviations 
Abbreviation  
Definition  
AE  
Adverse event  
ALT  
Alanine aminotransferase  
AST  
Aspartate aminotransferase  
ATC 
Anatomical therapeutic chemical  
BICR 
Blinded independent central review 
CI  
Confidence interval  
CMH  
Cochran-Mantel-Haenszel  
CNS  
Central nervous system  
CPK  
Creatinine phosphokinase  
CR  
Complete response  
CTCAE  
Common Terminology Criteria for Adverse Events  
ctDNA  
Circulating tumor deoxyribonucleic acid  
DCR  
Disease control rate  
DepOR  
Depth of response  
DoR  
Duration of response  
ECG  
Electrocardiogram  
ECOG  
Eastern Cooperative Oncology Group  
EGFR  
Epidermal growth factor receptor  
HR  
Hazard ratio  
IA 
Interim analysis 
ICF  
Informed consent form  
IVRS 
Interactive voice response system 
IWRS  
Interactive Web response system  
MedDRA  
Medical Dictionary for Regulatory Activities  
NCI  
National Cancer Institute  
NCI PRO-CTCAE  
National Cancer Institute Patient-Reported Outcomes version of the 
Common Terminology Criteria for Adverse Events  
NSCLC  
Non-small cell lung cancer  
ORR  
Overall response rate  


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OS  
Overall survival  
PD  
Progressive disease  
PEG  
Percutaneous endoscopic gastrostomy  
PFS  
Progression-free survival  
PFS2  
Time to second objective disease progression  
PK  
Pharmacokinetic(s)  
PR  
Partial response  
PRO  
Patient-reported outcome  
PS  
Performance status  
QoL  
Quality of life  
QTcF  
QT interval with Fridericia’s correction  
RANO  
Response Assessment in Neuro-Oncology  
RECIST  
Response Evaluation Criteria in Solid Tumors  
SAE  
Serious adverse event  
SAP  
Statistical Analysis Plan  
SARS-CoV-2  
Severe acute respiratory syndrome coronavirus 2  
SD  
Stable disease  
TEAE  
Treatment-emergent adverse event(s)  
TFST  
Time to first subsequent anticancer therapy  
TGR 
Tumor growth rate 
TSST  
Time to second subsequent anticancer therapy  
US  
United States  
WT  
Wild-type  
 


EQ143-301 Statistical Analysis Plan 
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      EQRx International, Inc. 
 
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1. 
Introduction 
This SAP focuses on efficacy and safety analyses. PK analysis will be documented in a separate 
PK SAP. 
 
1.1. 
Objectives and Endpoints 
Table 1-1  
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
• 
To assess the efficacy of aumolertinib 
in combination with chemotherapy 
compared with osimertinib 
monotherapy 
• 
PFS, as assessed by blinded independent 
central review (BICR) per RECIST v1.1 
Key Secondary 
• 
To further assess the efficacy of 
aumolertinib in combination with 
chemotherapy compared with 
osimertinib monotherapy 
• 
OS  
 
Other Secondary 
• 
To assess other efficacy measures of 
aumolertinib in combination with 
chemotherapy compared with 
osimertinib monotherapy 
• 
TGR, ORR, DCR, DepOR, and DoR, each 
assessed by BICR per RECIST v1.1 
• 
PFS, TGR, ORR, DCR, DepOR, and DoR, 
each assessed by Investigator per RECIST 
v1.1 
• 
ctDNA clearance 
• 
To assess the efficacy of aumolertinib 
monotherapy compared with 
osimertinib monotherapy 
• 
PFS, TGR, ORR, DCR, DepOR, and DoR, 
each assessed by BICR per RECIST v1.1 
• 
PFS, TGR, ORR, DCR, DepOR, and DoR, 
each assessed by Investigator per  
RECIST v1.1 
• 
OS 
• 
ctDNA clearance 
• 
To assess safety, including toxicities 
mediated by EGFR WT inhibition, in 
the study treatment arms 
• 
TEAEs, vital signs, ECGs, and laboratory 
test results (including chemistry, 
hematology, and urinalysis) by  
treatment arm 
• 
To evaluate selected PROs and QoL, 
including toxicities mediated by EGFR 
WT inhibition, in the study population 
• 
NCI PRO-CTCAE questionnaire 


EQ143-301 Statistical Analysis Plan 
[Version 1.0] 
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Objectives 
Endpoints 
• 
To characterize the PK profile of 
aumolertinib alone and in combination 
with chemotherapy  
• 
Aumolertinib concentration for population 
PK analysis 
Exploratory 
• 
To characterize mechanisms of 
acquired resistance in the treatment 
population 
• 
Exploratory biomarker analysis of plasma 
samples banked for the purpose of 
characterizing resistance mechanisms in 
participants treated with aumolertinib in 
combination with chemotherapy, 
aumolertinib monotherapy, and osimertinib 
monotherapy 
• 
To evaluate CNS efficacy for 
participants in the study treatment arms 
with measurable CNS lesions at 
baseline 
• 
Description of CNS efficacy as measured by 
PFS; OS; and ORR, DCR, DepOR, and DoR 
(each assessed by the Investigator per 
RANO criteria) 
• 
To evaluate additional efficacy 
measures in the study treatment arms 
• 
PFS2, as applicable 
• 
TFST and TSST, as applicable 
• 
To evaluate the correlation between 
TGR and ctDNA clearance with PFS 
and OS in the study treatment arms 
• 
TGR, ctDNA, PFS assessed by the 
Investigator per RECIST v1.1, and OS 
• 
To evaluate the exposure-response 
relationship of aumolertinib alone and 
in combination with chemotherapy 
• 
Exposure-response analysis of safety and 
efficacy endpoints 


EQ143-301 Statistical Analysis Plan 
[Version 1.0] 
      EQRx International, Inc. 
 
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Confidential and Proprietary  
 
 
1.2. 
Study Design 
 
 
 
Abbreviations: del = deletion; EGFR = epidermal growth factor receptor; ECOG PS = Eastern Cooperative 
Oncology Group performance status


EQ143-301 Statistical Analysis Plan  
[Version 1.0] 
EQRx International, Inc. 
 
 
11 
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EQ143-301 (TREBLE) is a Phase 3b multicenter, randomized, 3-arm, open-label study to 
evaluate aumolertinib + chemotherapy combination therapy compared with osimertinib 
monotherapy, and to describe aumolertinib monotherapy in comparison with osimertinib 
monotherapy.  
The intended study population is systemic treatment-naïve participants with metastatic EGFR-
mutant NSCLC. 
The primary study endpoint is efficacy of aumolertinib in combination with chemotherapy 
compared with osimertinib monotherapy, as measured by PFS (assessed by BICR per RECIST 
v1.1). PFS is defined as the time from date of participant randomization to either the first date of 
disease progression (per RECIST v1.1) or the date of death by any cause, whichever occurs first. 
Approximately 500 study participants will be randomized in a 2:2:1 ratio (by the stratified 
permuted block randomization method) into one of 3 treatment arms, as follows: 
1. Aumolertinib with chemotherapy (platinum-based doublet), as follows 
(approximately 200 participants): 
• For adenocarcinoma, either:  
o Aumolertinib + cisplatin with pemetrexed, or 
o Aumolertinib + carboplatin with pemetrexed 
• For squamous cell carcinoma, one of the following:  
o Aumolertinib + cisplatin or carboplatin with paclitaxel; 
o Aumolertinib + cisplatin or carboplatin with albumin-bound paclitaxel; or 
o Aumolertinib + cisplatin or carboplatin with gemcitabine  
2. Osimertinib alone (approximately 200 participants) 
3. Aumolertinib alone (approximately 100 participants) 
 
A cycle of treatment is defined as 21 days for all 3 treatment arms; Cycles 2+ have a window of 
2 days prior to, or 7 days following, the cycle due date. All imaging assessments are to be 
performed as scheduled, regardless of any delays in the participant’s treatment. 
Participants can continue to receive treatment in the study as long as they have not withdrawn 
consent and are judged by the Investigator to continue to receive clinical benefit, in the absence 
of meeting treatment and/or study discontinuation criteria as detailed in the protocol. 
All Participants will be stratified by the following factors:  
• EGFR mutation (ex19del versus L858R) 
• ECOG PS (0 versus 1/2) 
• Race (White versus Asian versus Other Races Combined) 


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In this study, aumolertinib will be orally administered as two 55-mg tablets for a total dose of 
110 mg once daily.  
Participants randomized to receive aumolertinib with chemotherapy will receive up to 4 cycles of 
a platinum-based doublet with aumolertinib at 110 mg once daily; thereafter, at the Investigator’s 
discretion, based on assessment of continued clinical benefit for the individual participant, the 
participant may go on to receive maintenance pemetrexed with once-daily aumolertinib for the 
remainder of their study treatment, provided that they do not meet treatment and/or study 
discontinuation criteria.  
Osimertinib (tablet) will be administered daily at 80 mg once orally.  
 
 


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2. 
Statistical Hypothesis 
The primary analysis is BICR-assessed PFS comparison between aumolertinib + chemotherapy 
vs Osimertinib.  The null hypothesis that the PFS is the same for the two arms will be tested at 2-
sided 0.05 significance level.  
 
The hypotheses for the primary endpoint of BICR-assessed PFS are as follows: 
• H0: Saumo chemo (t) = Sosi (t) 
• HA: Saumo chemo (t) > Sosi (t) 
where Saumo chemo (t) is the function of PFS for the aumolertinib with chemotherapy arm and  
Sosi (t) is the function of PFS of the osimertinib monotherapy arm. 
 
Comparisons on the secondary (except the key secondary) and exploratory endpoints between 
arms (aumolertinib + chemotherapy vs Osimertinib, aumolertinib monotherapy vs. osimertinib) 
will be at nominal significance level of 0.05 based on 2-sided tests. 
2.1.1. 
Multiplicity Adjustment 
The key secondary endpoint of OS (aumolertinib with chemotherapy vs osimertinib 
monotherapy) would be tested sequentially at a 2-sided 0.05 Type I error if the result of the 
primary endpoint analysis (PFS) is statistically significant. 
The Lan DeMets approach, which approximates the O’Brien-Fleming spending function, will be 
used in IAs and final PFS analyses to maintain an overall 2-sided 0.05 Type I error for the 
primary PFS comparison. After the result of the primary endpoint analysis (PFS) is statistically 
significant, the Lan DeMets approach will be used in IAs and final OS analyses to maintain an 
overall 2-sided 0.05 Type I error for the OS comparison. 
 
 


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3. 
Analysis Sets 
For the purposes of analysis, the following analysis sets are defined: 
Table 3-1  
Analysis Sets 
Participant Analysis Set 
Description 
Full analysis set (FAS) 
• The Full Analysis Set will include all randomized 
participants. Participants will be analyzed in the treatment 
arm to which they were randomized, and strata (with 
stratification by EGFR mutation, ECOG PS, and race) 
will be assigned at the time of randomization.  
Safety analysis set (SAS) 
• The Safety Analysis Set will include all participants who 
received at least one dose of study intervention. Safety 
data will be summarized based on the actual treatment 
received. 
CNS analysis set (cFAS) 
• A subset of FAS population that includes all participants 
at Screening/baseline who have been identified as having 
at least 1 measurable brain lesion at baseline based on 
Investigator assessment. 
The full analysis set will be used to analyze endpoints related to the efficacy objectives and the 
safety analysis set will be used to analyze the endpoints and assessments related to safety.  


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4. 
Statistical Analyses 
4.1. 
General Considerations 
 
Summary statistics for continuous variables will include, at the very least, n, median, mean, 
standard deviation, minimum, and maximum. For categorical variables, frequencies and 
percentages will be presented. For time-to-event variables, the Kaplan-Meier method will be 
used for descriptive summaries. Graphical displays will be provided as appropriate. 
All statistical analysis outputs except tumor growth rate analyses will be produced using SAS® 
version 9.4 or a later version in a secure and validated environment. Tumor growth rate analyses 
will be performed in R-4.2.1 or a later version.  
4.1.1. 
Definitions and Conventions 
The date of randomization is the date the participant was randomly assigned to aumolertinib or 
aumolertinib + chemo or osimertinib arm using an IVRS/IWRS.  
The date of first dose is the date of the first dose of study treatment. 
The baseline value of a safety assessment is the last non-missing value observed prior to the first 
dose of study treatment.  
The baseline value of an efficacy assessment is the last non-missing value observed prior to the 
date of randomization.  
The study day of a safety event or assessment will be calculated as:  
• The difference between the date of the event or assessment and the date of first dose plus 
1 for all events or assessments occurring on or after the day of first dose.   
• The difference between the date of the event or assessment and the date of first dose for 
all events or assessments occurring before the day of first dose.  
The study day of an efficacy event or assessment will be calculated as:  
• The difference between the date of the event or assessment and the date of 
randomization plus 1 for all events or assessments occurring on or after the date of 
randomization.  
• The difference between the date of the event or assessment and the date of 
randomization for all events or assessments occurring before the date of randomization.  
One month is defined as 365/12 days.  
4.1.2. 
Visit Window Rules 
Safety summaries of vital signs, laboratory tests, ECG, ECOG PS score and LVEF will be 
presented by the analysis visits.  Non-missing assessments from all scheduled and unscheduled 
visits will mapped to an appropriate analysis visit using a windowing scheme. Analysis visit 
windows are defined in Table 4-1 


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If there is more than one value in the same visit window as defined above, the closest value to 
the scheduled study day will be used in summaries, or the earlier in the case that values are 
equidistant from the nominal visit date. The other visits will not be used in the summary table.  If 
multiple observations on the same day, then the average of those values will be used in summary 
of that visit. For non-numeric results, the best value will be taken as baseline and the worst value 
will be taken for a post-baseline visit as this is the most conservative. In derivation of extreme 
values such as minimum/maximum post-baseline value, all post baseline values including those 
collected at unscheduled visits will be considered. 
Table 4-1  
Visit Windows 
Serial 
number 
Analysis visit 
name 
Scheduled 
study day 
Lower limit of 
the window 
Upper limit of 
the window 
1 
Baseline 
1 
-28 
1 
2 
C2D1 
22 
2 
32 
3 
C3D1 
43 
33 
53 
4 
C4D1 
64 
54 
74 
5 
C5D1 
85 
75 
95 
6 
C6D1 
106 
96 
116 
7 
C7D1 
127 
117 
169 
8 
C11D1 
211 
170 
253 
9 
C15D1 
295 
254 
337 
10 
C19D1 
379 
338 
421 
CxD1 
(x-1)×21+1 
Study Day- 41 
Study Day+ 42 
 
4.1.3. 
Handling of Dropouts or Missing Data  
In general, missing baselines will not be imputed.  On summary tables, the following approaches 
will be used: 
• Categorical data will be summarized based on the denominator of the total number of 
participants in a corresponding treatment arm.  Missing data may be presented as a 
separate category.  
• Continuous data will be summarized based on observed data only. 
4.1.3.1. 
Handling of Partial Dates for Concomitant Medications and Adverse 
Events.  
In general, the imputation should be conservative. The start dates should be imputed to be as 
early as possible, and the end date should be imputed to be as late as possible.  If the partial start 
date of medication or AE cannot indicate whether it starts prior to study treatment or after, the 
medication or AE will be classified as concomitant or treatment-emergent.  
Imputation of concomitant medication and adverse events start dates 


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• If year is missing (or completely missing), do not impute 
• If year is present, and month and day are missing: 
o Impute as January 1st if the year is different to the first dose date or the end date is 
prior to the first dose date 
o Impute as the first dose date if the year is the same as the first dose date and the 
end date is on or after the first dose date.  
• If year and month are present and day is missing: 
o Impute as the first day of the month, if the year or month are different to the first 
dose date or the end date is prior to the first dose date 
o Impute as the first dose date if the year and month are the same as the first dose 
date and the end date is on or after the first dose date.  
Imputation of concomitant medication and adverse events end dates  
• If year is missing (or completely missing), do not impute 
• If year is present, and month and day are missing, impute as the earliest of: 
o December 31st 
o Date of Data cutoff 
o Date of Death 
• If year and month are present and day is missing, impute as the earliest of: 
o The last day of the month 
o Date of Data cutoff 
o Date of Death 
4.1.3.2. 
Handling of Missing Dates/Months/Years for Date of Death 
For subjects who are confirmed dead, if the complete date of death cannot be known, the rules 
for imputation are as follows: 
• If only the day is missing, impute as the 1st date of the month or the known last date of 
survival + 1, whichever is later; 
• If only the month and day are missing, impute as the January 1 of the year or the known 
last date of survival + 1, whichever is later; 
• If the year, month, and day are all missing, impute as the known last date of survival + 1. 
4.1.3.3. 
Handling of Partial Dates for Subsequent Anti-Cancer Therapy 
 
Imputation of start dates 
• If year is missing (or completely missing), do not impute 
• If year is present, and month and day are missing: 
o Impute as January 1st if the year after the last dose date 
o Impute as the last dose date + 1 if the year is the same as the last dose date  
• If year and month are present and day is missing: 
o Impute as the first day of the month, if the year/month is after the last dose date  
o Impute as the last dose date + 1 if the year and month are the same as the last dose 
date  


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Imputation of end dates 
• If year is missing (or completely missing), do not impute 
• If year is present, and month and day are missing, impute as the earliest of  
o December 31st 
o Date of Data cutoff 
o Date of Death 
• If year and month are present and day is missing, impute as the earliest of  
o The last day of the month 
o Date of Data cutoff 
o Date of Death 
Imputation of progression dates of subsequent anti-cancer therapy 
• If year is missing (or completely missing), do not impute 
• If year is present, and month and day are missing, impute as the latest of  
o January 1st  
o Start date of the therapy 
• If year and month are present and day is missing, impute as the latest of  
o The last day of the month 
o Start date of the therapy 
4.1.4. 
Participant Disposition  
A detailed description of participant disposition will be provided.  It will include a summary of 
the number and percentage of participants randomized in the study, and treated in the study, 
reasons for discontinuation from study treatment (randomized population), and reasons for 
discontinuation from study (randomized population).  Reason for discontinuation from both 
study treatment and the study will be summarized by pre-determined categories. Randomized 
population’s disposition data (dates and reasons for both from study treatment and from study) 
will be listed.  
4.1.5. 
Participant Characteristics  
4.1.5.1. 
Demographics and Baseline Characteristics 
Race, Ethnicity, Age, Sex, Height, Baseline Weight, Body mass index (BMI), and smoking 
status will be listed and summarized. 
4.1.5.2. 
Baseline Disease Characteristics 
Disease characteristics will include the following:  
• EGFR gene mutation type (Ex19del or L858R) 
• Histologic type 
• Disease stage at study entry 
• Brain metastasis 
• Baseline ECOG PS 


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4.1.5.3. 
Medical History and Current Condition 
Preexisting conditions are defined as adverse events that begin prior to the first dose of study 
drug. 
Preexisting conditions coded by MedDRA and graded per the NCI CTCAE version 5.0 will be 
presented in tables and listings using MedDRA system organ class and preferred term.  
4.1.5.4. 
Prior Cancer Surgeries/Radiotherapies 
Prior cancer surgeries/radiotherapies will be listed. 
4.1.5.5. 
Prior Cancer Therapies 
Prior cancer therapies will be listed. 
4.1.5.6. 
Subsequent Anti-Cancer Therapies 
Therapies received following study treatment discontinuation will be summarized by arm. 
Therapies will be summarized overall and by category. 
4.1.5.7. 
Concomitant Therapy 
All medications will be coded to the generic preferred name according to the current World 
Health Organization (WHO) drug dictionary. All concomitant medications will be summarized 
for the FAS population based on the Anatomical Therapeutic Chemical (ATC) classification the first 
level (ATC1), the third level (ATC 3) and preferred name. 
4.2. 
Efficacy Analysis 
Participant response will be assessed by BICR and the Investigator per RECIST v1.1. CNS 
efficacy will be evaluated by investigator per RANO-brain metastases criteria (Chukwueke & 
Wen, 2019). 
All efficacy analyses will be performed on the FAS, based on the treatment arm assigned in the 
randomization. Additionally, CNS efficacy will be based on cFAS. 
All stratified models and tests will be based on the stratification information used for 
randomization. If randomization strata have few participants/events due to the three race 
categories, race might be combined to two categories in the stratified models. 
Primary efficacy endpoint will be analyzed when 251 PFS events as assessed by BICR are 
reached on the aumolertinib with chemotherapy and Osimertinib monotherapy arms.   
Please refer to Table 4-2 below for efficacy endpoints and the corresponding definitions.  
 
Table 4-2 
Efficacy Endpoints and Definitions 
Endpoint 
Definition 
Primary Endpoint 


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Progression-free survival (PFS)  
The duration from date of participant randomization to 
either the first date of disease progression or the date of 
death by any cause, whichever occurs first. 
Duration is calculated as end date – start date +1. For 
instance, if a PFS event occurs, then PFS time (in days) 
is defined as event date – date of randomization +1. If a 
censoring event occurs, then PFS time is defined as the 
censoring date – date of randomization +1. 
Please refer to Table 4-3 for details on PFS outcome 
status (PFS event vs. censored) and censoring 
definitions. 
Secondary Endpoints 
Overall survival (OS) 
Duration from randomization until the date of death due 
to any cause.  
If death event did not occur during the follow-up period, 
the participant is censored at the last contact date. 
Objective response rate (ORR) 
Proportion of participants who achieve a CR or PR at any 
time before PD or initiating a subsequent anticancer 
therapy. 
Disease control rate (DCR) 
Proportion of participants who have a best overall 
response of CR or PR or SD. 
Duration of response (DoR)  
 
Duration from the date of first response (CR or PR) until 
the date of PD or death due to any cause, whichever 
occurs first.  
DoR will follow the same outcome and censoring 
definition used for the primary PFS.  
Time to Response (TTR) 
Duration from randomization until to the date of first 
response (CR or PR). 
Depth of Response (DepOR) 
Defined as the relative change in target lesion tumor size 
(calculated as the sum of the longest diameters of the 
target lesions, in the absence of new lesions or 
progression of nontarget lesions) as compared to 
baseline. 


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Tumor growth rate 
A constant exponential growth rate estimated using the 
Sum of Longest Diameters, see Section 4.2.4.2 for 
details. 
Circulating tumor DNA (ctDNA) 
clearance at 6 weeks 
Defined as when a detectable EGFR mutation in ctDNA 
at baseline becomes undetectable or drops below a 
predetermined threshold at 6 weeks.  
Exploratory Endpoints 
Time to second objective disease 
progression (PFS2) 
Duration from randomization until the date of the first 
progression event subsequent to that used in the primary 
analysis of PFS, or death due to any reason, whichever 
occurs first. 
Please refer to Table 4-4 for details on the outcome and 
censoring definitions. 
Time to first subsequent anticancer 
therapies (TFST) 
Duration from randomization to the start date of the first 
anticancer therapy subsequent to the discontinuation of 
the study intervention, or death due to any reason, 
whichever occurs first. 
Any participant not known to have received a first 
subsequent anti-cancer therapy, or to have not died at the 
time of the analysis, will be censored at the last contact 
date. 
Time to second subsequent 
anticancer therapies (TSST) 
Defined as the time from randomization to the start date 
of the second subsequent anticancer therapy after the 
discontinuation of the study intervention, or death due to 
any reason, whichever occurs first. 
Any participant not known to have received a second 
subsequent anti-cancer therapy, or to have not died at the 
time of the analysis, was to be censored at the last 
contact date. 
 
Table 4-3 
Primary PFS outcome and censoring definition 
Situation 
Date of event or censoring 
Outcome 


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No baseline or post-baseline tumor 
assessment  
Randomization 
Censored 
Death or PD after a gap of 2 or more 
consecutively missed tumor assessments  
Date of last adequate tumor 
assessment* before the gap 
Censored 
Death or PD without a gap of 2 or more 
consecutively missed tumor assessments 
Date of death or PD, whichever 
occurs first 
PFS event 
No PD or death on or before  
a. database cut,  
b. discontinuation of study 
treatment plus 14 days,  
c. start of new anti-cancer treatment 
plus 14 days,  
whichever occurs first  
Date of last adequate tumor 
assessment on or prior to the 
earliest occurrence of the events 
listed on the left column 
Censored 
* Adequate tumor assessment will have an overall response of CR, PR, SD, PD.  
Table 4-4 
PFS2 outcome and censoring definition 
Situation 
Date of event or censoring 
Outcome 
Alive and no subsequent anti-cancer 
therapy 
Last contact date 
Censored 
Death (by any cause) prior to starting 
any subsequent anti-cancer therapy 
Date of death 
Event 
No progression or death during the first 
subsequent anti-cancer therapy and have 
started second subsequent anti-cancer 
therapy 
Start date of the second subsequent 
anti-cancer therapy 
Censored 
No progression or death during the first 
subsequent anti-cancer therapy and have 
not started second subsequent anti-
cancer therapy 
The end date of the first 
subsequent anti-cancer therapy, or 
the last contact date if the end date 
is missing 
Censored 
Progression or death (by any cause) 
during the first subsequent anti-cancer 
therapy 
The earlier date of disease 
progression date or date of death 
Event 
 


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4.2.1. 
Analysis of Primary Endpoint 
The primary endpoint of PFS as determined by BICR assessment per RECIST v1.1 will be 
analyzed when 251 PFS events are reached in the aumolertinib with chemotherapy and 
Osimertinib treatment arms. The primary analysis on PFS will be based on BICR assessment and 
using the stratified log-rank test to compare aumolertinib with chemotherapy versus Osimertinib 
monotherapy (2-sided 0.05 level).  
The median PFS will be evaluated with a 95% CI for each treatment arm, using the Kaplan-
Meier method. HR with a 95% CI will be estimated by a stratified Cox proportional hazard 
model, using the Breslow method of tie handling, with treatment as the factor. The strata will be 
the same stratification factors (EGFR mutation, ECOG PS, and race) used in the randomization. 
4.2.2. 
Sensitivity Analysis of PFS 
The following sensitivity analyses of PFS will be conducted in addition to the primary PFS 
analysis.  
4.2.2.1. 
Analysis based on the PFS outcome and censoring definition for Sensitivity 
Analysis 
PFS analysis will be repeated based on the following PFS outcome and censoring definition for 
sensitivity analysis as listed on the Table 4-5.  
Table 4-5 
PFS outcome and censoring definition for Sensitivity Analysis 
Situation 
Date of event or censoring 
Outcome 
No baseline or post-baseline tumor 
assessment  
Randomization 
Censored 
No PD or death before database cut  
Date of last adequate tumor 
assessment* on or prior to the 
database cut 
Censored 
Death or PD before database cut 
Date of PD or death, whichever 
occurs first  
PFS event 
* Adequate tumor assessment will have an overall response of CR, PR, SD, PD.  
4.2.2.2. 
Analysis based on the actual stratification information collected during the 
screening period 
PFS analysis will be repeated based the actual stratification information collected during the 
screening period if more than 10 patients have screening stratification factors different than those 
entered in IRT. When the central retrospective EGFR testing data is available, the PFS analysis 
will be repeated using the central EGFR mutation as one of the stratification factors if more than 
10 patients have central EGFR mutation status different than those entered in IRT. 


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4.2.3. 
Analysis of the Key Secondary Endpoints 
The final OS analysis will be performed when 200 OS events are reached in the aumolertinib 
with chemotherapy and osimertinib monotherapy treatment arms. The OS comparison between 
aumolertinib with chemotherapy vs osimertinib monotherapy would be tested sequentially at a 2-
sided 0.05 Type I error if the result of the primary endpoint analysis (PFS) is statistically significant.  
The OS comparison will use the same methods as the one used for primary PFS analyses. 
4.2.4. 
Analysis of the Other Secondary Endpoints 
Each other secondary endpoints will be analyzed by the following comparisons 
• aumolertinib with chemotherapy vs. osimertinib 
• aumolertinib monotherapy vs. osimertinib 
Secondary tumor-based efficacy endpoints will include both BICR and Investigator assessments 
per RECIST v1.1. 
Statistical comparison will be at nominal significance level of 0.05 based on 2-sided tests. 
4.2.4.1. 
Analysis of Binary Endpoints 
Secondary binary endpoints including ORR and DCR will be analyzed using the CMH test 
stratified by the randomization stratification factors. The CMH estimate of the odds ratio with a 
95% CI will be reported. A 2-sided p-value will be provided to compare aumolertinib with 
chemotherapy vs Osimertinib, and aumolertinib monotherapy vs. osimertinib. For each arm, the 
point estimate for ORR and DCR with its exact 95% CI will be provided. 
ORR and DCR will be calculated among FAS and among the participants with baseline 
measurable diseases in the FAS. 
4.2.4.1. 
Analysis of Time to Event Endpoints 
Other time-to-event secondary endpoints, including PFS, DoR and OS, will be analyzed using 
the stratified log-rank test and the stratified Cox proportional hazard model, as described above 
for the primary endpoint analysis. Specifically, these secondary endpoint analyses will be 
performed to compare aumolertinib with chemotherapy versus osimertinib monotherapy and 
aumolertinib monotherapy versus osimertinib monotherapy. The median event time will be 
evaluated with a 95% CI using the Kaplan-Meier method. 
TTR will be summarized descriptively for each arm. 
4.2.4.1. 
Analysis of ctDNA clearance 
The rate of ctDNA clearance at 6 weeks will be evaluated as follows: 
100 × 
Number of Participants who are ctDNA−negative at 6 weeks 
Number of Participants who are ctDNA−positive at baseline 
ctDNA clearance at C1D1 (predose) is defined as the baseline. 
The rate of ctDNA clearance will be analyzed using the same method as described for binary 
endpoints.  


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4.2.4.2. 
Analysis of Tumor Growth Rate 
The following regression-growth models based on the constant exponential growth rate (g) and 
constant exponential decay (d) were proposed by Stein et al in 2011 (Stein, et al., 2011) and were 
retrospectively studied (Claret, et al., 2018; Gong, et al., 2020; Bruno, Mercier, & Claret, 2014),   
(1) f(t) = exp(-d • t) + exp(g • t) - 1 
(2) f(t) = exp(g • t)  
(3) f(t) = exp(-d • t) 
(4) f(t) = f exp(-d • t) + (1- f) exp(g • t)   
Here, f(t) represents tumor burden (the sum of longest diameters of target lesions) at time t (in 
days), relative to a quantity of 1, at t = 0. g (in days-1) is the tumor growth rate (TGR). d (in days-
1) is the rate of decay. f is the treatment-sensitive fraction of tumor and (1– f) the fraction 
absolutely or relatively resistant to treatment.  
The basic starting model gd is described by Equation (1). In cases where the data demonstrate 
only an increase in tumor burden from the beginning of therapy (i.e., only g differs significantly 
from 0 with p<0.1), d is eliminated, and tumor growth rate is estimated using the gx equation 
[Equation (2)]. Similarly, in cases where the data demonstrate only a reduction in tumor burden 
from the beginning of therapy (i.e., only d differs significantly from 0 with p< 0.1), g is 
eliminated, and the rate of tumor decay is estimated using the dx equation [Equation (3)].  f 
represents the proportion of tumor that is sensitive to therapy. In cases where the data allow the 
estimation of three parameters, f can be estimated using the gdf equation [Equation (4)]. 
Incorporation of time (t) in the equations renders the analysis indifferent to time, or intervals of 
assessment used by the study. 
The tumgr package (https://cran.r-project.org/web/packages/tumgr/index.html) in R sequentially 
applies Equations 1-4 and selects the equation that best fits the tumor’s data. Values for g, d, or 
f were estimated only if the fit of the data had a p-value of <0.1. In cases where all parameters 
were significant predictors of tumor quantity in more than one model, the model that best 
minimized the Akaike Information Criterion (AIC) was selected. 
In this study, we will analyze TGR based on the sum of longest diameters over time using the R 
package tumgr. The participants who had measurable diseases at baseline and at least one post-
baseline tumor assessment will be included in the tumor growth rate analyses. The estimated 
participants’ tumor growth rates will be summarized by treatment arm. Box plots of the tumor 
growth rates will be generated side by side to visualize the tumor growth rates of each arm. For 
all three arms, the estimated median g with its 95% Wilcoxon CI will be reported.  
A sensitivity analysis to only fit the gd model [Equation (1)] will be conducted. 
4.2.4.3. 
Analysis of DepOR 
DepOR will be analyzed among participants with measurable lesions at baseline. Absolute and 
percentage change from baseline in target lesion tumor size (the sum of the longest diameters of 


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target lesions) will be summarized using descriptive statistics at each visit for all 3 treatment 
arms. The best DepOR values will be calculated from assessments before disease progression or 
before starting subsequent anticancer treatment. Waterfall plots will be provided for each arm.  
4.2.5. 
Analysis of Exploratory Endpoints 
4.2.5.1. 
Analysis of PFS2, TFST, and TSST 
Time-to-event endpoints of PFS2, TFST, and TSST will be analyzed on all 3 treatment arms 
using the stratified log-rank test and the stratified Cox proportional hazard model as described 
above for the primary endpoint analysis. The median event time will be evaluated with a 95% CI 
using the Kaplan-Meier method for each arm. 
4.2.5.2. 
Correlation between TGR and ctDNA clearance with PFS and OS in the 
study treatment arms 
PFS and OS KM curves and median survival times by the quartiles of tumor growth rates of each 
treatment arms will be generated to characterize the correlation between tumor growth rates and 
PFS and OS. 
Correlation between ctDNA clearance with PFS and OS will be analyzed for available data. 
4.2.5.3. 
Description of CNS Efficacy 
CNS efficacy will be assessed on the cFAS which includes all participants at Screening/baseline 
who have been identified as having at least 1 measurable brain lesion at baseline based on 
Investigator assessment. 
CNS efficacy endpoints will include PFS, OS, DoR, ORR, DCR, and DepOR based on 
Investigator assessment on the CNS scans per RANO criteria. 
For time-to-event CNS endpoints, including PFS, OS, and DoR, the median event time will be 
evaluated with a 95% CI for each treatment arm using the Kaplan-Meier method.  
For binary CNS endpoints, including ORR and DCR, the point estimate of the rate with its exact 
95% CI will be calculated for each arm.  
DepOR will be analyzed using the same method as for the secondary endpoint of DepOR. 
 
4.3. 
Safety Analyses 
Safety analyses will be performed on the SAS and will be presented by the actual treatment arm 
as defined in Section 3. 
4.3.1. 
Extent of Exposure 
Extent of exposure to study drug parameters listed below will be summarized using descriptive 
statistics. 
Cumulative total actual dose (mg) = sum of the actual daily dose subject administrated.  


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Total exposure time (days) = (date of last dose of study drug - date of first dose of study drug) + 
(1 for oral drugs or dose interval for intravenous drugs).  
Actual exposure time (days) = total exposure time – total duration of days not receiving study 
drug.  
Actual dose intensity (mg/day) = cumulative total actual dose (mg) / total exposure time (days).  
Relative dose intensity (%) = cumulative total actual dose (mg) / total planned dose (mg) *100.  
Medication compliance for oral drugs (%) = actual exposure time (days) / total exposure time 
(days) × 100%.  
The number of participants with any dose adjustment will be presented for entire treatment 
period. The number of participants with dose reductions, dose interruption will also be 
summarized. 
4.3.2. 
Adverse Events 
Adverse events coded by MedDRA and graded per the current version of the NCI CTCAE 
version 5.0 will be presented in tables and listings using MedDRA system organ class and 
preferred term.  
Treatment-Emergent Adverse Events (TEAEs) are defined as AEs that start on or after the first 
dose of any study intervention or a medical history condition worsened in severity after the first 
dose, through 28 days after the last dose of any study intervention. Any events that start after 
28 days after the last dose of any study intervention, or after a participant receives a subsequent 
anticancer therapy, will be included in the data listing but will not be considered as a TEAE.  
Statistical analysis of treatment related AEs will utilize the Investigator-assessed relationship 
between study intervention and the occurrence of each AE, which include “Definitely Related”, 
“Probably Related”, and “Possibly Related” as detailed in Section 10.2.3. (Assessment of 
Causality) of the Protocol V4. If the relationship of AE is missing, then AE will be summarized 
as related to study treatment.  
In the event that a participant has repeat episodes of the same AE, then the event with the highest 
severity and/or strongest causal relationship to treatment will be used for the purpose of 
statistical tabulations. 
Overall Summary of TEAEs will summarize the incidence rate of TEAE, grade ≥ 3 TEAE, SAE, 
AE leading to dose modification (reduction and interruption), permanent treatment 
discontinuation, study discontinuation and death on each treatment arm. All the above-mentioned 
AE parameters that is related study treatment per investigator assessment will also be 
summarized in the AE overview table. 
The following summaries will be produced by PT within SOC: TEAEs, grade ≥ 3 TEAEs, SAEs 
AE leading to dose modification (reduction and interruption), permanent treatment 
discontinuation, study discontinuation and death on each treatment arm. 
All the summary tables mentioned in the last paragraph will be repeated on the treatment related 
AE parameters. 


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TEAEs and related TEAEs will be summarized by System Organ Class, Preferred Term and 
CTCAE Maximum Grade. 
4.3.3. 
Adverse Events of Clinical Interest 
The following events/groups of events were considered AECIs: 
• Diarrhea 
• Hepatotoxicity 
• Elevated blood CPK 
• Interstitial lung disease 
• Cardiac failure 
• QT prolongation 
• Ocular toxicity 
Where available and appropriate, these AECIs will be analyzed using SMQs. However, diarrhea 
has been evaluated based on the single PT, “diarrhea,” and ocular toxicity has been evaluated 
using a company-specific basket of MedDRA PTs.  The search strategy of PTs for each AECI is 
summarized in Appendix 1, which may be updated based on the newer MedDRA version. 
 
A summary of treatment emergent AECI by PT will be performed for each prespecified AECI 
group including: 
• TEAEs 
• Grade > 3 TEAEs 
Additional summaries of time to onset of first AE for each AECI category and each 
preferred term within it; time to onset of first CTCAE grade three or higher will be produced. 
 
In addition to the descriptively summarizing AEs incidence number and percentage by treatment 
arms, 95% Clopper-Pearson confidence interval will be calculated for selected AECI categories 
or preferred term within it including diarrhea, rash and CPK elevation to facilitate informal 
comparisons between two arms, especially aumolertinib arm versus Osimertinib arm. In addition, 
to the investigator reported toxicity, these same events will be analyzed using the patient 
reported outcomes using NCI PRO-CTCAE (see Section 4.4.1). 
4.3.4. 
Deaths 
All deaths will be listed along with the reason for death, if known.  For those deaths attributed to 
an AE, the listing will include the PT of the AE.  A summary of deaths including reasons for 
death will be produced. 
4.3.5. 
Clinical Laboratory Tests 
Selected laboratory tests that are performed at scheduled time points per Protocol will be 
summarized. All lab results will be listed. 
For each treatment arm, the actual value and the change from baseline will be summarized for 
selected clinical hematology and chemistry laboratory tests. 


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The severity of selected hematology and chemistry laboratory tests will be evaluated by the NCI 
CTCAE version 5.0 criteria if the tests have a corresponding CTCAE classification. These 
calculated grades will be summarized by cycle and maximum post-baseline grade over the entire 
study. 
Additionally, the following summary will be produced: 
• Summary of Subjects with Clinically Significant Abnormal Clinical Hematology 
Laboratory Tests by Visit  
• Summary of Subjects with Clinically Significant Abnormal Clinical Biochemistry 
Laboratory Tests by Visit  
• Summary of Subjects with Clinically Significant Abnormal Clinical Urinalysis 
Laboratory Tests by Visit  
• Hematology Results Shift from Baseline according to Clinically Significant by Visit  
• Clinical Biochemistry Results Shift from Baseline according to Clinically Significant by 
Visit  
• Urinalysis Results Shift from Baseline according to Clinically Significant by Visit  
• Summary of Normal or Abnormal Not Clinically Significant Hematology Laboratory 
Tests at Baseline that Turned to Abnormal Clinically Significant after Start of Treatment  
• Summary of Normal or Abnormal Not Clinically Significant Clinical Biochemistry 
Laboratory Tests at Baseline that Turned to Abnormal Clinically Significant after Start of 
Treatment  
• Summary of Normal or Abnormal Not Clinically Significant Urinalysis Laboratory Tests 
at Baseline that Turned to Abnormal Clinically Significant after Start of Treatment  
• Scatter plots of maximum AST/ALT versus maximum total bilirubin during treatment 
with Hy’s Law Ranges 
4.3.6. 
Vital Signs 
For each treatment arm, the actual value and the change from baseline of at each study 
evaluation will be summarized for vital signs including body temperature, systolic and diastolic 
blood pressures, pulse rate (after 5 minutes resting) and respiration rate, as well as body weight. 
4.3.7. 
ECOG PS 
ECOG PS at each study assessment will be listed and summarized. 
4.3.8. 
Physical Examination Findings 
For physical examinations, findings considered clinically significant by the Investigator that 
were present before the participant provided signed informed consent will be reported as medical 
history; findings considered clinically significant by the Investigator that occurred after the 


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provision of signed informed consent, and which meet the definition of an AE (or SAE, as 
applicable) as detailed in protocol Section 10.2, will be reported as AEs/SAEs.  
4.3.9. 
Electrocardiograms 
ECG results will be summarized descriptively. Actual values and changes from baseline will be 
reported for each collection visit/timepoint. The summary of ECG overall interpretation 
(normal/abnormal NCS/abnormal CS) at each post-baseline assessment, as well as shift from 
baseline overall interpretation will be produced. QTcF absolute value categorized by ≤450, >450 
– 480, >480 – 500, >500, and change from baseline at categories of ≤30, >30 – 60, >60 will be 
summarized at each assessment, and the maximum post-baseline value and change from 
baseline. 
4.3.10. ECHO or MUGA (LVEF) 
At each post-baseline assessment, and among all the post-baseline assessments, subjects with 
“LVEF value <50% and decrease from baseline of >=10%” and with “LVEF value >=50% and 
decrease from baseline of >=15%” will be summarized. LVEF at each assessment will be listed. 
4.3.11. Additional Safety Assessments 
Serum Pregnancy Test and SARS-CoV-2 Test are listed separately if data is available. 
4.4. 
Other Analyses 
4.4.1. 
Patient-reported Outcomes and Quality of Life Analysis 
PROs and QoL will be assessed via NCI PRO-CTCAE questionnaire. A descriptive summary 
over time will be provided. 
4.4.2. 
Pharmacokinetic Analyses 
Concentrations of aumolertinib and its metabolite HAS-719 in plasma will be determined using 
validated bioanalytical methods. A population PK model will be developed to characterize the 
PK of aumolertinib and its metabolite (as applicable). Data from this study may be combined 
with data from other studies in a meta-population analysis using nonlinear mixed-effects 
modeling techniques. Exposure-response analysis to evaluate the relationship between 
aumolertinib exposure and efficacy/safety endpoints in this study may be performed if the data 
allows for this analysis to be completed. Details of the population pharmacokinetic and 
exposure-response analyses will be described in a separate pharmacometrics analysis plan.  
4.4.3. 
Biomarker Analysis 
Exploratory biomarker analysis of plasma samples banked for the purpose of characterizing 
resistance mechanisms in participants treated with aumolertinib alone, versus aumolertinib and 
chemotherapy, versus Osimertinib will be dependent on the data availability. Any biomarker data 
generated may be reported separately. 


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4.4.4. 
Subgroup Analyses 
• EGFR mutation (ex19del versus L858R)  
• ECOG PS (0versus 1/2)  
• Brain metastasis (yes versus no) 
4.4.5. 
Protocol Deviation 
Protocol deviations will be listed by participant. The major protocol deviations will be 
summarized by the treatment arm. 
4.5. 
Interim Analyses 
Two interim analyses (IAs) are planned, as follows: 
• The first interim analysis will be performed approximately 12 weeks after enrollment is 
completed in all 3 treatment arms. 
• The second interim analysis will be performed upon occurrence of 70% of the projected 
PFS events. 
The interim analyses will include PFS and the other endpoints listed below: 
• ORR and DCR 
• ctDNA clearance 
• TGR 
• AEs 
The Lan DeMets approach, which approximates the O’Brien-Fleming spending function, will be 
used to maintain an overall 2-sided 0.05 Type I error for the primary PFS comparison. 
The key secondary endpoint of OS (aumolertinib with chemotherapy vs osimertinib 
monotherapy) would be tested sequentially at a 2-sided 0.05 Type I error if the result of the 
primary endpoint analysis (PFS) is statistically significant. Interim OS analyses will be 
conducted at the time of the primary PFS analysis if the PFS analysis is positive (at one of the 
IAs or at the final PFS analysis) and all subsequent planned analysis points. Type I error for OS 
will be controlled using Lan-DeMets method with O’Brien-Fleming boundary.  
All the secondary endpoints for descriptive comparison between aumolertib monotherapy and 
Osimertinib monotherapy will be performed at each IA.  
Efficacy endpoints will be analyzed as described in Section 4.2. Safety endpoints will be 
analyzed as described in Section 4.3. 
4.6. 
Changes to Protocol-planned Analyses 
There are no changes to Protocol (V4.0) planned analyses.  


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5. 
Sample Size Determination 
Assuming a randomization ratio of 1:1 for aumolertinib with chemotherapy: Osimertinib 
monotherapy, a true HR of 0.7 (median PFS improves from 19 months to 27.1 months), and an 
exponential distribution for PFS, 251 PFS events will provide 80% power at a 2-sided Type I 
error of 0.05. If the result of the primary endpoint analysis is statistically significant, a sequential 
testing method will be used to test the key secondary endpoint of OS to control the study overall 
type I error at 2-sided 0.05. Assuming a true HR of 0.70 (ie, median OS improves from 38.6 
months to 55.1 months), and an exponential distribution for OS, 200 OS events will provide 
71.1% power at a 2-sided Type I error of 0.05. 
Approximately 400 participants in total will be enrolled in the aumolertinib with chemotherapy 
and osimertinib treatment arms (200 per arm) to reach 251 PFS events. The sample size of 100 
participants in the aumolertinib monotherapy arm will allow the precision of estimating an 
incidence rate for toxicity to be within ± 10.3% (eg, incidence rate, 50%; Clopper-Pearson 95% 
CI, 39.8%, 60.2%). Therefore, approximately 500 total participants are planned to be randomized 
at a 2:2:1 ratio to receive aumolertinib in combination with chemotherapy, osimertinib 
monotherapy, and aumolertinib monotherapy, respectively.  
Cytel East® version 6.5 was used for the sample size calculations. 
 


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6. 
Supporting Documentation 
AECI 
MedDRA v24.0 SMQ /PT* 
Diarrhea 
PT-Diarrhea 
Hepatotoxicity 
Drug related hepatic disorders – comprehensive search (narrow SMQ) 
[20000006]  
Elevated blood creatine 
phosphokinase 
Rhabdomyolysis/myopathy (SMQ) [20000002]] 
Interstitial lung disease (IDL) 
Interstitial lung disease (narrow-SMQ) [20000042] 
Cardiac failure 
Cardiac failure (narrow-SMQ) [20000004] 
QTc prolongation 
Torsade de pointes/QT prolongation (SMQ) [20000001] 
Ocular toxicity 
Includes the following PTs (selected based on known class effects of 
EGFR TKIs):  
• 
Dry eye  
• 
Lacrimation increased 
• 
Conjunctival disorder 
• 
Conjunctival haemorrhage 
• 
Conjunctivitis 
• 
Ocular congestion 
• 
Eye haemorrhage  
• 
Eye discharge 
• 
Eye swelling 
• 
Ocular discomfort 
• 
Vision blurred 
• 
Visual impairment 
• 
Photophobia 
• 
Eye pain 
 
* The search strategy of preferred terms for AECIs will be updated at the analysis based on a newer MedDRA version per the 
advice from Pharmacovigilance. 


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7. 
References 
Bruno, R., Mercier, F., & Claret, L. (2014). Evaluation of tumor size response metrics to predict 
survival in oncology clinical trials. Clinical pharmacology and therapeutics, 95(4):386-
93. 
Chukwueke, U. N., & Wen, P. Y. (2019). Use of the Response Assessment in Neuro-Oncology 
(RANO) criteria in clinical trials and clinical practice. CNS oncology, 8(1):CNS28. 
Claret, L., Jin, J. Y., Ferté, C., Winter, H., Girish, S., Stroh, M., . . . Bruno, R. (2018). A Model 
of Overall Survival Predicts Treatment Outcomes with Atezolizumab versus 
Chemotherapy in Non-Small Cell Lung Cancer Based on Early Tumor Kinetics. Clinical 
cancer research, 24(14):3292-3298. 
Gong, Y., Mason, J., Shen, Y.-L., Chang, E., Kazandjian, D., Blumenthal, G. M., . . . Beaver, J. 
A. (2020). An FDA analysis of the association of tumor growth rate and overall and 
progression-free survival in metastatic non-small cell lung cancer (NSCLC) patients. 
Journal of Clinical Oncology, 38(15_suppl):9541-9541. 
Stein, W. D., Gulley, J. L., Schlom, J., Madan, R. A., Dahut, W., Figg, W. D., . . . Fojo, T. 
(2011). Tumor regression and growth rates determined in five intramural NCI prostate 
cancer trials: the growth rate constant as an indicator of therapeutic efficacy. Clinical 
cancer research, 17(4):907–917. 
Wilkerson, J. (2016). wilkersj/tumgr: Tumor Growth Rate Analysis. Retrieved from GitHub: 
https://github.com/wilkersj/tumgr