Sequencing of Stereotactic Ablative Body Radiotherapy in Combination With PD-1 Blockade Using Pembrolizumab in Metastatic Non-Small Cell Lung Carcinoma
Phase: PHASE1
Conditions: Non-small Cell Lung Cancer
Sponsor: Peter MacCallum Cancer Centre, Australia

SABRseq – version 1.2: Date: 11 September 2018 
Page 1 of 73 
 
 
 
 
Title: Sequencing of Stereotactic Ablative Body Radiotherapy in combination with PD-1 
blockade using Pembrolizumab in Metastatic Non-Small Cell Lung Carcinoma (SABRseq) 
 
 
Short title: Sequencing of SABR and Pembrolizumab in Lung Cancer (SABRseq) 
 
 
Radiation Oncology Coordinating Principal Investigator: 
A/Prof Shankar Siva 
Peter MacCallum Cancer Centre 
Victorian Comprehensive Cancer Centre 
305 Grattan St 
Melbourne VIC 3000 
Email: Shankar.Siva@petermac.org  
 
Medical Oncology Associate Investigator: 
Prof Benjamin Solomon 
Peter MacCallum Cancer Centre 
Victorian Comprehensive Cancer Centre 
305 Grattan St 
Melbourne VIC 3000 
Email: Ben.Solomon@petermac.org  
 
Statistician 
Mathias Bressel 
Peter MacCallum Cancer Centre 
Victorian Comprehensive Cancer Centre 
305 Grattan St 
Melbourne VIC 3000 
 
 
Protocol version: 1.2 
 
 
Date of protocol: 11 September 2018 
 
 
Sponsor:  
Peter MacCallum Cancer Centre 
Victorian Comprehensive Cancer Centre 
305 Grattan St 
Melbourne VIC 3000 
Email: ocr@petermac.org  
 
 
 
 

 
 
SABRseq – version 1.2: Date: 11 September 2018 
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FOREWORD 
 
This document contains confidential information. This information should not be disclosed, 
other than to those involved in the execution or ethical review of the study, without written 
authorisation from sponsor. 
 
COMPLIANCE STATEMENT 
 
This trial will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) and Good Clinical Practice (GCP). In addition, the trial will be conducted 
in compliance will all applicable laws and regulatory requirements relevant to the use of new 
therapeutic agents in Australia and any other participating country. Agreement of the 
investigator(s) to conduct and administer this trial in accordance with the protocol and 
associated regulations will be documented in the trial agreements with the Sponsor and 
other forms required by national authorities in the country where the trial site is located. 
 
The Investigator(s) is responsible for ensuring the privacy, safety and welfare of the patients 
during and after the trial. 
 
The Principal Investigator at each site has the overall responsibility for the conduct and 
administration of the trial at their site, and for conduct with the trial site management, the 
Independent Ethics Committee (IEC) / Institutional Review Board (IRB), and local authorities. 
 
VARIATIONS TO THE PROTOCOL 
 
No changes from the final approved (signed) protocol will be initiated without the ethics 
committee’s prior written approval of favourable opinion of a written amendment, except 
when necessary to eliminate immediate hazards to the patients or when the change involves 
only the logistics or administration.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
SABRseq – version 1.2: Date: 11 September 2018 
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PROTOCOL HISTORY 
 
 
Version No 
Date 
Author 
Reason 
1.0 
19/09/2017 
Shankar Siva 
 
1.1 
08/01/2018 
Shankar Siva 
Updated dose modification from 
MSD/Merck 
1.2 
18/07/2018 
Shankar Siva 
Updated data on PDL1 staining which 
will expand eligibility 
 
 
 
 
 
 
 
 
 

 
 
SABRseq – version 1.2: Date: 11 September 2018 
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SIGNATURE PAGE 
 
The undersigned confirm that the following protocol has been agreed and accepted and that 
the Principal Investigator agrees to conduct the trial in compliance with the approved 
protocol and will adhere to the principles where applicable as outlined in the NHMRC’s 
National Statement on Ethical Conduct of Research in Humans, the TGA’s Clinical Trial 
Handbook, Good Clinical Practice, the Sponsor’s SOPs, Canadian Health Authority and other 
regulatory requirements as amended. 
 
I agree to ensure that the confidential information contained in this document will not be 
used for any other purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of the Sponsor. 
 
I also confirm that I will make the findings of the study publically available through 
publication or other dissemination tools without any unnecessary delay and that an honest 
accurate and transparent account of the study will be given; and that any discrepancies from 
the study as planned in this protocol will be explained. 
 
For and on behalf of the Study SPONSOR 
 
 
 
 
Signature 
 
Date 
 
 
 
Name (print) 
 
Position 
 
 
 
AUSTRALIA 
Principal Investigator: 
 
 
 
 
Signature 
 
Date 
Shankar Siva 
 
Radiation Oncologist 
Name (print) 
 
Position 
 
Associate Investigator 
 
 
 
 
 
 
Signature 
 
Date 
Benjamin Solomon 
 
Medical Oncologist 
Name (print) 
 
Position 
 
NON AUSTRALIAN SITES 
Principal Investigator: 
 
 
 
 
Signature 
 
Date 
 
 
 
Name (print) 
 
Position 

 
 
SABRseq – version 1.2: Date: 11 September 2018 
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ABBREVIATIONS  
 
ANC 
Absolute neutrophil count 
AUC 
Area under the curve 
BaCT 
Centre for Biostatistics & Clinical Trials 
BSA 
Body Surface Area 
CRF 
Case Report Forms 
CRT  
Conformal Radiotherapy 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTV 
Clinical Target Volume 
ECOG 
Eastern Co-operative Oncology Group 
FBE 
Full blood examination 
FDG-PET 
Fluorodeoxyglucose – Positron Emission Tomography 
FDG-PET-CT 
FDG-PET computed tomography 
FFS 
Failure-free survival 
GCP 
Good Clinical Practice 
Hb 
Haemoglobin 
HREC 
Human Research Ethics Committee 
IB 
Investigator’s Brochure 
IHC 
Immunohistochemistry 
MRI 
Magnetic Resonance Imaging 
NCI 
National Cancer Institute 
OS 
Overall survival 
PET 
Positron Emission Tomography 
PICF 
Patient Information Sheet and Consent Form 
Plt 
Platelets 
QA 
Quality Assurance 
RT 
Radiation Therapy 
RTP 
Radiotherapy Treatment Planning 
SABR 
Stereotactic Ablative Body Radiotherapy 
SAE 
Serious Adverse Event 
SUSAR 
Serious unexpected suspected adverse events 
TGA 
Therapeutic Goods Administration 
TMC 
Trial Management Committee  
 
 
 

 
 
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TABLE OF CONTENTS  
 
1. 
Synopsis .................................................................................................................... 9 
2. 
Trial Schema ............................................................................................................ 10 
3. 
Schedule of Events .................................................................................................. 11 
4. 
Background ............................................................................................................. 16 
4.1 
Metastatic Non-Small Cell Carcinoma ................................................................................. 16 
4.2 
Stereotactic Ablative Body Radiotherapy and Evidence in Oligometastatic Malignancies. 16 
4.3 
Stereotactic Radiotherapy for Non-Small Cell Lung Carcinoma .......................................... 17 
4.4 
Stereotactic Ablative Body Radiotherapy for Metastatic Non-Small Cell Lung Carcinoma . 17 
4.5 
Summary of Risks and Benefits ............................................................................................ 18 
4.6 
Immunity and Control of Lung Cancer Metastases ............................................................. 18 
4.7 
Radiotherapy as a Means to Enhance Immune Responses ................................................. 19 
4.8 
Combination Radiotherapy and T Cell Checkpoint Blockade can Augment Immune 
Responses and Reduce T Regulatory Cells ........................................................................................ 20 
4.9 
Pharmaceutical and Therapeutic Background ..................................................................... 21 
4.10 
Preclinical and Clinical Trial Data ......................................................................................... 22 
4.11 
Safety of Pembrolizumab and Dosing Regimen ................................................................... 22 
4.12 
Efficacy of Pembrolizumab in Lung Cancer .......................................................................... 23 
4.13 
Rationale for Trial, Population and Selected Population ..................................................... 25 
4.14 
Rationale for Dose Selection/Regimen/Modification .......................................................... 26 
5. 
Trial Objectives ....................................................................................................... 26 
5.1 
Hypothesis............................................................................................................................ 26 
5.2 
Objectives ............................................................................................................................ 26 
5.3 
Endpoints ............................................................................................................................. 27 
6. 
Trial Design ............................................................................................................. 28 
7. 
Study Population ..................................................................................................... 29 
7.1 
Inclusion Criteria .................................................................................................................. 29 
7.2 
Exclusion Criteria.................................................................................................................. 31 
7.3 
Patient Registration/Randomisation ................................................................................... 32 
7.4 
Treatment Assignment ........................................................................................................ 33 
7.5 
Blinding and Procedures for Unblinding .............................................................................. 33 
7.6 
Patient Treatment Withdrawal/Discontinuation ................................................................. 33 
8. 
Study Assessments .................................................................................................. 34 
8.1 
Pre-randomisation/Screening Assessments – ALL ARMS .................................................... 34 
8.2 
Treatment Phase - ARM 1 (SABR followed by pembrolizumab) .......................................... 35 
8.2.1 
SABR Visit Assessments ................................................................................................... 35 
8.2.2 
Cycle 1 Assessments ........................................................................................................ 35 
8.2.3 
Cycle 2 to Cycle 34 Assessments ..................................................................................... 35 
8.3 
Treatment Phase - ARM 2 (pembrolizumab followed by SABR) .......................................... 36 
8.3.1 
Cycle 1 Assessments ........................................................................................................ 36 
8.3.2 
SABR Visit Assessments ................................................................................................... 36 
8.3.3 
Cycle 2 to Cycle 34 Assessments ..................................................................................... 36 
8.4 
Safety Follow-up – All Arms ................................................................................................. 37 
8.5 
Follow-Up – All Arms ............................................................................................................ 37 
8.6 
Survival Follow-up ................................................................................................................ 37 
8.7 
Concomitant Medications .................................................................................................... 37 
8.8 
Supportive Care/Rescue Medication ................................................................................... 38 

 
 
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8.9 
Diet ....................................................................................................................................... 40 
8.10 
Contraception ...................................................................................................................... 40 
8.11 
Use in Pregnancy .................................................................................................................. 41 
8.12 
Use in Nursing Women ........................................................................................................ 41 
8.13 
Non-Permitted Medications ................................................................................................ 41 
9. 
Trial Radiotherapy Treatment .................................................................................. 42 
9.1 
Megavoltage Radiotherapy .................................................................................................. 42 
9.2 
Statement of Treatment Aim and Rationale ........................................................................ 43 
9.3 
Treatment Schedule ............................................................................................................. 43 
10. Trial Pembrolizumab Treatment .............................................................................. 43 
10.1 
Pembrolizumab Dose Modifications and Delays ................................................................. 43 
10.2 
Continuing Pembrolizumab ................................................................................................. 45 
11. Labeling, Packaging, Storage and Return of Clinical Supplies .................................... 46 
11.1 
Investigational Product ........................................................................................................ 46 
11.2 
Packaging and Labelling Information ................................................................................... 46 
11.3 
Clinical Supplies Disclosure .................................................................................................. 46 
11.4 
Storage and Handling Requirements ................................................................................... 46 
11.5 
Returns and Reconciliation .................................................................................................. 47 
12. Adverse Events ........................................................................................................ 47 
12.1 
Adverse Event Definition ..................................................................................................... 47 
12.2 
Unexpected Adverse Event Definition ................................................................................. 47 
12.3 
Serious Adverse Event Definition ......................................................................................... 48 
12.4 
Attribution............................................................................................................................ 49 
12.5 
Severity Criteria.................................................................................................................... 49 
12.6 
Adverse Events Reporting .................................................................................................... 49 
12.7 
Evaluating Adverse Events ................................................................................................... 50 
12.8 
Serious Adverse Event Reporting ......................................................................................... 50 
12.8.1 
Trial sites/investigators ............................................................................................... 50 
12.8.2 
Sponsor ........................................................................................................................ 51 
12.9 
Events of Clinical Interest..................................................................................................... 52 
12.10 
Overdose Definition and Reporting ................................................................................. 52 
12.11 
Reporting of Pregnancy and Lactation to the Sponsor and to Merck ............................. 53 
13. Response Assessment ............................................................................................. 53 
13.1 
Evaluation of response by RECIST1.1 and irRECIST .............................................................. 53 
13.2 
Peter Mac Metabolic Response Criteria .............................................................................. 53 
13.3 
PERCIST 1.0 Criteria .............................................................................................................. 54 
14. Statistical Considerations ........................................................................................ 54 
14.1 
Statistical Analysis Plan Summary ........................................................................................ 54 
14.2 
Treatment Assignment ........................................................................................................ 54 
14.3 
Populations for Analyses ...................................................................................................... 54 
14.4 
Statistical Methods .............................................................................................................. 55 
14.5 
Safety Analysis ..................................................................................................................... 55 
14.6 
Time-to-Event Endpoint Analysis ......................................................................................... 55 
14.7 
Response Analysis ................................................................................................................ 55 
14.8 
Exploratory Endpoints .......................................................................................................... 56 
14.9 
Sample Size Calculation ....................................................................................................... 56 
14.10 
Early Termination Criteria ............................................................................................... 57 
14.11 
Deviations ........................................................................................................................ 57 

 
 
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15. Trial Management & Administrative Requirements ................................................. 57 
15.1 
Trial Personnel ..................................................................................................................... 57 
15.2 
Audit and Inspection ............................................................................................................ 57 
15.3 
Protocol Deviations .............................................................................................................. 57 
16. Data Handling and Record Keeping .......................................................................... 58 
16.1 
Case Record Form (CRF) ....................................................................................................... 58 
16.2 
Source Documents ............................................................................................................... 58 
16.3 
Archiving of Trial Documents ............................................................................................... 59 
17. Ethical Aspects ........................................................................................................ 59 
17.1 
Informed Consent ................................................................................................................ 59 
17.2 
Confidentiality Regarding Trial Patients .............................................................................. 60 
17.3 
Trial Management Committee (TMC) .................................................................................. 60 
18. Publication and Presentation Policy ......................................................................... 60 
18.1 
Reporting of Results ............................................................................................................. 60 
18.2 
Trial Registry ........................................................................................................................ 61 
19. References .............................................................................................................. 62 
Appendix 1 ..................................................................................................................... 67 
Appendix 2 ..................................................................................................................... 68 
Appendix 3 ..................................................................................................................... 69 
Appendix 4 ..................................................................................................................... 72 
 
 
 

 
 
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1. 
Synopsis 
 
Title 
Sequencing of Stereotactic Ablative Body Radiotherapy in 
combination with PD-1 blockade using Pembrolizumab in 
Metastatic Non-Small Cell Lung Carcinoma 
Short title 
Sequencing of SABR and Pembrolizumab in Lung Cancer 
(SABRSeq) 
Sponsor 
Peter MacCallum Cancer Centre 
Study design 
Phase Ib, two arm randomised study 
Study objectives 
Primary Objective: 
To assess common toxicities associated with pembrolizumab 
when given before or after SABR in patients with metastatic 
NSCLC. 
 
Secondary Objectives: 
 To describe response rate in: a) lesions treated with SABR, 
b) non-irradiated lesions and c) overall response. 
 To describe the event history (local progression, distant 
progression and death) of NSCLC patients treated with SABR 
in combination with pembrolizumab. 
 To estimate progression free survival and overall survival of 
NSCLC patients treated with SABR in combination with 
pembrolizumab. 
 
Exploratory Objectives: 
 Evaluate PD-L1 expression in baseline tissue. 
 Evaluate baseline and longitudinal cellular and molecular 
changes in archival tumour tissue, and/or fresh tumour 
biopsies. This will include, but not limited to tumour 
infiltrating lymphocytes (TILs), CD73 and other markers. 
 Evaluate baseline and longitudinal changes in 
immunological cellular subsets and cytokines within 
peripheral blood.  
Number of sites 
2 sites, one in Australia and one in Canada 
Expected sample size 
32 patients 
Recruiting period 
24 months 

 
 
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2. 
Trial Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior to Treatm Prior to 
Follow-up Phase 
Prior to Treatment Phase 
Metastatic NSCLC with at least 2 sites of disease, and 
1-3 lesions amenable to stereotactic radiotherapy 
(SABR) 
(n=32 patients) 
FDG-PET scan, CT brain, chest/abdo/pelvis 
Tumour biopsy (optional) 
Bloods for translational studies 
Arm 1 (n=16): 
SABR (18-20Gy) to 1-3 
lesions followed 7 (±2) 
days later by 
Pembrolizumab 
200mg every 3 weeks 
for 24 months 
 
Arm 2 (n=16): 
Pembrolizumab 200mg 
every 3 weeks for 24 
months with SABR (18-
20Gy) to 1-3 lesions 
delivered 7 (±2) days 
after first dose of 
Pembrolizumab 
 
Treatment Phase 
3 monthly CT scan (Brain, Chest/Abdo/Pelvis) reported 
with RECIST 1.1 or MRI 
3 monthly whole body bone scan  
(if clinically indicated) 
Follow-up Phase 

SABRseq – version 1: Date: 19th September 2017 
 
 
 
Page 11 of 73 
3. 
Schedule of Events 
 
Table 1: ARM 1 Schedule of events 
 
 
Trial Phase: 
Screening 
Phase 
Treatment Phase 
Follow-up Phase 
Progression 
Trial phase and windows 
Screening 
-28 to -1 
SABR 
Within 4 weeks of 
randomisation 
Day 1 Cycle 1 
7 days ± 2 days 
from SABR 
Day 1 Cycle 2-34 
3 days ± 2 days 
prior to each dose 
of pembrolizumab 
Safety Follow-up 
30 days ± 3 days from 
date of last dose of 
pembrolizumab 
Follow-up 
3 months ± 7 days 
from the last cycle 
of pembrolizumab 
Upon first 
progression1 
Clinical/Administrative Assessments 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
Demographics and Medical History 
X 
 
 
 
 
 
 
Disease Specific Medical History 
including prior therapies 
X 
 
 
 
 
 
 
SINS score for Spinal Targets 
X 
 
 
 
 
 
 
Full Physical Examination 
X 
 
X 
X 
 
 
 
Vital Signs and body measurements 2 
X 
 
X 
X 
 
X 
 
ECOG Performance Status 
X 
 
X 
X 
 
X 
 
Pregnancy Test (β-HCG) 3 
X 
 
X 
X 
 
 
 
Review Adverse Events4 
X 
X 
X 
X 
X 
X 
 
SABR  
 
X 
 
 
 
 
 
Pembrolizumab 
 
 
X 
X 
 
 
 
Review Prior/Concomitant 
Medications 
X 
X 
X 
X 
X 
 
 
New Anti-Cancer Therapy Status  
 
 
 
 
X 
X 
X 
Survival status 
 
 
 
 
 
X 
 

 
 
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Trial Phase: 
Screening 
Phase 
Treatment Phase 
Follow-up Phase 
Progression 
Trial phase and windows 
Screening 
-28 to -1 
SABR 
Within 4 weeks of 
randomisation 
Day 1 Cycle 1 
7 days ± 2 days 
from SABR 
Day 1 Cycle 2-34 
3 days ± 2 days 
prior to each dose 
of pembrolizumab 
Safety Follow-up 
30 days ± 3 days from 
date of last dose of 
pembrolizumab 
Follow-up 
3 months ± 7 days 
from the last cycle 
of pembrolizumab 
Upon first 
progression1 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
Haematology5 
X 
 
X 
X 
 
As clinically 
indicated 
 
Biochemistry6 
X 
 
X 
X 
 
 
Thyroid Function tests 7 
X 
 
X 
X 
 
 
Coagulation profile8 
X 
 
X 
X 
 
 
Virology9 
X 
 
 
 
 
 
 
Tumour Evaluation 
CT scan (Brain, Chest, Abdo, Pelvis) 
reported with RECIST 1.1 or MRI 10 
X 
 
 
X 
 
X 
 
Whole body bone scan 10 (if clinically 
indicated)  
X 
 
 
X 
 
X 
 
Response assessment10 
 
 
 
X 
 
X 
 
FDG-PET10 
X 
 
 
X11 
 
 
 
Translational studies 
Metastatic tumour biopsy sample12 
X 
 
 
 
 
X 
X 
Primary tumour biopsy sample13 
X 
 
 
 
 
 
 
Blood Collection14 
(serum and ctDNA)  
 
X 
X 
X 
 
X 
X 
 
 
 
 
 
 

 
 
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Table 2: ARM 2 Schedule of events 
 
 
Trial Phase: 
Screening 
Phase 
Treatment Phase 
Follow-up Phase 
Progression 
Trial phase and windows 
Screening 
-28 to -1 
Day 1 Cycle 1 
3 days ± 2 days prior 
to the first dose of 
pembrolizumab 
SABR 
7 days ± 2 days 
from cycle 1 
day 1 
Day 1 Cycle 2-34 
3 days ± 2 days 
prior to each dose 
of pembrolizumab 
Safety Follow-up 
30 days ± 3 days from 
date of last dose of 
pembrolizumab 
Follow-up 
3 months ± 7 days 
from the last cycle 
of pembrolizumab 
Upon first 
progression1 
Clinical/Administrative Assessments 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
Demographics and Medical History 
X 
 
 
 
 
 
 
Disease Specific Medical History 
including prior therapies 
X 
 
 
 
 
 
 
SINS score for Spinal Targets 
X 
 
 
 
 
 
 
Full Physical Examination 
X 
X 
 
X 
 
 
 
Vital Signs and body measurements2 
X 
X 
 
X 
 
X 
 
ECOG Performance Status 
X 
X 
 
X 
 
X 
 
Pregnancy Test (β-HCG) 3 
X 
X 
 
X 
 
 
 
Review Adverse Events4 
X 
X 
X 
X 
X 
X 
 
SABR  
 
 
X 
 
 
 
 
Pembrolizumab 
 
X 
 
X 
 
 
 
Review Prior/Concomitant 
Medications 
X 
X 
X 
X 
X 
 
 
New Anti-Cancer Therapy Status  
 
 
 
 
X 
X 
X 
Survival status 
 
 
 
 
 
X 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
Haematology5 
X 
X 
 
X 
 
As clinically 
 

 
 
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Trial Phase: 
Screening 
Phase 
Treatment Phase 
Follow-up Phase 
Progression 
Trial phase and windows 
Screening 
-28 to -1 
Day 1 Cycle 1 
3 days ± 2 days prior 
to the first dose of 
pembrolizumab 
SABR 
7 days ± 2 days 
from cycle 1 
day 1 
Day 1 Cycle 2-34 
3 days ± 2 days 
prior to each dose 
of pembrolizumab 
Safety Follow-up 
30 days ± 3 days from 
date of last dose of 
pembrolizumab 
Follow-up 
3 months ± 7 days 
from the last cycle 
of pembrolizumab 
Upon first 
progression1 
Biochemistry6 
X 
X 
 
X 
 
indicated 
 
Thyroid Function tests 7 
X 
X 
 
X 
 
 
Coagulation profile8 
X 
X 
 
X 
 
 
Virology9 
X 
 
 
 
 
 
 
Tumour Evaluation 
CT scan (Brain, Chest, Abdo, Pelvis) 
reported with RECIST 1.1 or MRI 10 
X 
 
 
X 
 
X 
 
Whole body bone scan 10 (if clinically 
indicated)  
X 
 
 
X 
 
X 
 
Response assessment10 
 
 
 
X 
 
X 
 
FDG-PET10 
X 
 
 
X11 
 
 
 
Translational studies 
Fresh tumour biopsy sample 12 
X 
 
 
 
 
X 
X 
Archival tumour biopsy sample13 
X 
 
 
 
 
 
 
Blood Collection 14 
(serum and ctDNA)  
 
X 
X 
X 
 
X 
X 
 
 
 
 

 
 
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Table 1 and 2 Footnotes 
1. 
Beyond first progression, every effort should be made to record results of subsequent tumour assessments. In additional, details of any new anti-cancer treatment 
commenced is to be collected. 
2. 
Vital signs include blood pressure, heart rate, respiratory rate and temperature. Body measurements including height and weight (height only required at screening). 
3. 
Urine or serum pregnancy test for patient of childbearing potential should be performed within 7 days randomisation and also 72 hours before first dose of 
pembrolizumab. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 
4. 
Baseline abnormalities must be recorded from signature of informed consent to prior to start of treatment. Adverse events (using CTCAE v4.03) are then required to 
be reported on completion of SABR, day 1 of every pembrolizumab cycle and at every follow-up visit.  If at any time, a patient commences a new anti-cancer therapy, 
recording of adverse events is no longer required. 
Laboratory Procedures/Assessments – All diagnostic laboratory tests should be performed within 10 days of randomisation (to determine eligibility), and also on day 1 ± 3 
days of every cycle of pembrolizumab (unless otherwise specified) 
5. 
Haematology:  Haematocrit, haemoglobin, platelet count, white blood cell count (total and differential), red blood cell count, absolute neutrophil count and absolute 
lymphocyte count.  
6. 
Biochemistry:  calcium chloride, glucose, phosphorus, potassium, sodium, magnesium, total protein, Liver Function Tests:  Albumin, Alkaline Phosphatase (ALP), 
Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Lactate Dehydrogenase (LDH), Gamma-Glutamyl Transferase (GGT, total bilirubin (+direct bilirubin 
if total bilirubin is elevated above the ULN), Kidney Function Tests: Urea, creatinine. 
7. 
Thyroid Function tests:  T3, T4 and TSH. To be performed at during screening, day 1 cycle and every 6 weeks thereafter. 
8. 
Coagulation Profile:  PT (INR), aPTT. 
9. 
Virology: HIV, Hepatitis B and C tests only required for those patients at risk of prior or current active infection as determined by the investigator. To be performed 
within 21 days of randomisation. 
Tumour evaluation  
10. Radiological tumour assessments will be performed by CT scan (or MRI as required if tumour is in extremity) at screening (within 6 weeks of randomisation), prior to 
cycle 3, 5, 7 and every 3 cycles thereafter in the treatment phase. Then 3 monthly in the follow-up phase until the last patient recruited completes 24 months of 
follow-up, unless evidence of progression earlier.  Whole body bone scan (WBBS) will be performed if clinically indicated at the same time points. Formal response 
assessment (using RECIST 1.1, irRECIST, Peter Mac Metabolic Response Criteria and PERCIST 1.0.) at each scheduled scan time point. Response should be confirmed 
with repeat imaging 4 to 8 weeks later by the same imaging modality.  CT of brain only required at screening.  
11. FDG PET at baseline and prior to cycle 5 of pembrolizumab. (note: a contemporaneous CT brain/chest/abdo pelvis performed at the same time will fulfill the CT 
requirement 3 month follow-up)  
Biological Evaluations 
12. A fresh biopsy of the primary or metastatic lesion will be performed at screening (within 12 weeks of randomisation). and 3 months post completion of SABR. This will 
ideally be the same site as biopsied before at screening. In event of disease progression, a sample from progressing metastatic site(s), if feasible, is requested.  Refer to 
the SABRseq laboratory manual for further details on handling and shipping of tumour samples. 
13. If a fresh biopsy of the primary or a metastatic lesion cannot be provided (e.g. inaccessible or patient safety concern) an archived specimen can be submitted only 
upon agreement from the study principal investigators. Refer to the SABRseq laboratory manual for further details on handling and shipping of tumour samples. 
14.  To be collected at screening, prior to SABR, prior to each pembrolizumab dose and 3 monthly during follow-up. Refer to the SABRseq laboratory manual for further 
details on blood sample collection, handling and shipping. 

SABRseq – version 1.1: Date: 8th  
Page 16 of 73 
4. 
Background 
4.1 
Metastatic Non-Small Cell Carcinoma  
Non-small cell carcinoma (NSCLC) is the ninth most common cancer in Australia and the 
fourteenth most common cancer worldwide (1, 2). The incidence of NSCLC is rising, 
particularly in patients aged 70 to 90 years (3). Overall, 17% of patients present with 
metastatic disease and another 50% of patients initially treated with curative intent will 
develop metastatic disease (4, 5). Historically patients with metastatic non-small cell 
carcinoma (mNSCLC) have a poor prognosis, with 5-year survival rates of ≤10% (6). In 
patients with metastatic disease, the median survival time ranges from 6 to 12 months, and 
in patients with brain metastases, the mean survival time is 3 months (7, 8).  
 
4.2 
Stereotactic Ablative Body Radiotherapy and Evidence in 
Oligometastatic Malignancies.  
There is a large body of literature on SABR for oligometastatic malignancies.  For practical 
reasons only the landmark SABR oligometastatic studies will be summarized to highlight 
tolerability and efficacy.  
 
Salama and colleagues (1) reported on patients with 1 to 5 metastatic cancer sites based on 
18F-flourodeoxyglucose positron emission tomography (FDG-PET) imaging and a life 
expectancy of at least 3 months who were treated with SABR. Patients received escalating 
doses of RT, starting at a dose 24Gy (three 8Gy fractions) 2Gy per fraction dose-escalations 
and a dose ceiling of 60Gy (three 20Gy fractions). The commonest metastatic sites treated 
were lung (36.3%), lymph nodes (19.4%), liver (19.4%), bone (13.3%) and adrenal glands 
(8.0%).  At a median follow up of 20.9 months no dose limiting toxicity was seen.  One 
patient with a centrally located right upper lobe metastases who received 36Gy (three 12Gy) 
fractions developed haemoptysis 10 months after SABR.  CT and bronchoscopy revealed 
disease recurrence and this patient died shortly afterwards.  More recent studies due to 
toxicity recommend excluding central lung lesions outside the contexts of clinical trials (2). 
 
A number of phase I and II studies of SABR to spinal metastasis have demonstrated 
favourable local disease control rates (86-90%) for patients without spinal cord compression 
(3-6).  Similar to intracranial stereotactic radiosurgery, SABR has been shown to be effective 
in the retreatment of metastases that progress following standard EBRT (7). Additionally, 
SABR has been shown to be very effective in palliating pain associated with spinal 
metastases (8, 9). 
 
Several Phase I and II studies have investigated SABR for hepatic metastases using fixed RT 
doses (10), escalation RT doses (11, 12) and normal tissue complication probabilities (13). 
These studies have consistently demonstrated high rates of disease control in the treated 
metastatic deposits (71-92%). However in general liver metastases control rates have been 
lower than observed in pulmonary or spinal metastases which may reflect challenges in 
defining the true extent of the metastatic target as well as organ motion with respiration. 

 
 
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Several studies examining SABR for oligometastases in the lung with both single dose (14) 
and dose-escalation (15) have demonstrated high rates of treated-metastasis control (89-
96%) with promising 2-year survival rates (38-39%).  
 
4.3 
Stereotactic Radiotherapy for Non-Small Cell Lung Carcinoma 
SABR is a therapeutic regimen associated with a high level of tumour control in the setting of 
primary non-small cell lung cancer.  A systematic review of 3771 patients and 45 studies 
demonstrated a 2-year local control rate of 91% (95% CI: 90-93%) with a 2-year survival of 
70% (95% CI: 67-72%). This was comparable with survival for surgery in stage I NSCLC in the 
cohort of 2038 patients also assessed in this study (68% [95% CI: 66-70]), regardless of 
patient differences in comorbidities (16). Similarly, a recent pooled meta-analysis of 2 
randomised clinical trials that terminated early comparing SABR and surgery for stage I 
NSCLC showed survival compared favourably for the SABR cohort, with. Recurrence-free 
survival at 3 years was 86% (95% CI: 74–100) in the SABR group and 80% (65–97) in the 
surgery group (HR 0·69 [95% CI: 0·21–2·29], log-rank p=0·54)(17). Due to excellent control 
rates and promising survival after SABR in the setting of NSCLC, further clinical trials are 
underway evaluating the clinical efficacy of SABR in comparison to the current standard of 
care, surgery (18). 
 
4.4 
Stereotactic Ablative Body Radiotherapy for Metastatic Non-Small Cell 
Lung Carcinoma 
Several studies have evaluated the efficacy of SABR in the context of oligometastatic NSCLC. 
A prospective phase II clinical trial by de Ruysscher et al. (19) evaluated 41 patients with 
oligometastatic disease. The 2-, and 3-year OS was 23.3%, and 17.5%, respectively in this 
cohort. Median progression-free survival (PFS) was 12.1 months (95% confidence interval 
9.6–14.3); 1-year PFS was 51.3%, and both 2- and 3-year PFS was 13.6%. A systematic review 
by Ashworth et al. (20) of 49 studies reporting on outcomes of 2176 patients with 1-5 
oligometastases treated with surgery or stereotactic radiotherapy. In this study (82%) had a 
controlled primary tumor. Overall survival (OS) outcomes were heterogeneous: 1 year OS: 
15–100%, 2 year OS: 18–90% and 5 year OS: 8.3–86%. The median OS range was 5.9–52 
months (overall median 14.8 months; for patients with controlled primary, 19 months). The 
median time to any progression was 4.5–23.7 months (overall median 12 months). Highly 
significant prognostic factors on multivariable analyses were: definitive treatment of the 
primary tumor, N-stage and disease-free interval of at least 6–12 months. In a subsequent 
individual patient data meta-analysis of 757 oligometastatic NSCLC cases by members of the 
same group (21), median OS was 26 months, 1-year OS 70.2%, and 5-year OS 29.4%. In those 
patients with metachronous presentation of oligometastases, the 5-year OS was 47.8%. 
These results suggest that local aggressive therapies including SABR may be warranted in 
selected patients with metastatic disease. In the context of oligoprogressive disease, the 
Colorado group have reported that the use of SABR at the progressing sites resulted in an 
increased median overall time taking crizotinib from 10.1 months to 28.1 months (22), with a 
subsequent median progression free survival after receiving SABR of 6.2 months (23). 

 
 
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4.5 
Summary of Risks and Benefits  
SABR involves highly hypofractionated radiotherapy given as an ablative treatment.  While 
there is extensive literature suggesting that it is safe and has low rates of major toxicities, 
such studies have tended to have small numbers and relatively short follow up given most 
patients succumb to their metastatic disease.  The risk of treatment depends on the exact 
anatomical site of the metastatic disease irradiated.  There is a low but not negligible risk of 
radiation pneumonitis, bone fractures, radiation enteritis, skin fibrosis, renal impairment and 
proctitis.  There is an exceedingly low risk of transverse myelitis. 
 
SABR is thought to provide long-term local control of irradiated sites of cancer.  It also 
provides good and durable pain relief for painful metastases.  It is postulated that SABR to 
sites of oligometastatic or oligoprogressive non-small cell carcinoma, in selected patients, 
may prolong survival.  Clearly studies that determine whether a survival benefit occurs with 
such treatment remain to be conducted and reported. 
 
It is acknowledged that patients may have received previous radiotherapy to an area where 
SABR is to be delivered in this protocol (equivalent dose of 30 Gy in 10 fractions).  Due to the 
increased dose that is received in this instance, there is an increased risk of radiation toxicity 
in these patients.  This potential increased level of risk has been highlighted in the patient 
information and consent form and must be discussed in each instance prior to informed 
consent. Patients who have received more than this RT equivalent dose schedule to an area 
planned for further SABR treatment are not eligible for this study. Additionally, as there is a 
risk of pneumonitis with both pembrolizumab (discussed below) and radiotherapy, patients 
who have received more than 36Gy in 12 fractions (or equivalent) of radiotherapy to the 
lung within 6 months of study screening will be considered ineligible. 
 
4.6 
Immunity and Control of Lung Cancer Metastases 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumour-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and 
long-term survival in many solid tumours.  
 
 

 
 
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4.7 
Radiotherapy as a Means to Enhance Immune Responses 
Radiotherapy has long been used a cancer therapy and is known for its direct cytotoxic 
effects on tumour cells through generation of DNA damage. However, interest has grown 
around the idea that radiotherapy can have immunological effects. This includes the 
generation of antigenic peptides through cell death which enhance MHC Class I and 
adhesion molecules, as well as the subsequent production of cytokines and peptides that 
can augment immune responses. Therefore, evidence suggests that radiation therapy can 
trigger a tumour-directed immune response. 
 
Radiation also seems to be able to prime the immune system for an adaptive response. 
Direct ionizing radiation elicits innate immune recognition of tumour following tumour cell 
release of “danger signals” (24, 25). Three molecular signals are required for the ‘danger’ 
response: dendritic cell (DC) phagocytosis of dying tumour cells, cross-presentation of 
tumour-derived antigens to T cells and the activation of tumour-specific T cells. 
Translocation of calreticulin [(CRT)/ERp57] to the surface of dying irradiated cancer cells 
provides an “eat-me” signal important for DC recognition and engulfment of dying tumour 
cells (26). The release of inflammatory molecules from radiation-exposed tumour cells such 
as high-motility group protein B1 (HMGB1) and ATP, which bind to toll-like receptor 4 (TLR4) 
or the purinergic receptor P2X7, respectively, also promote antigen processing and cross-
presentation by DC and T cell priming through the release of IL-1β (27, 28). All of these 
molecules provide the tools for an improved recognition and killing by tumour-specific T cells 
(29). The intense localized radiotherapy provided by SABR drives release of tumour antigen, 
which is taken up by resident dendritic cells (DCs) the DCs mature and migrate to the 
draining lymph node, where they induce a tumour-specific T cell response (both CD4+ and 
CD8+). Effector T cells then traffic to the tumour microenvironment where they release 
effector molecules and induce tumour cell apoptosis. 
 
We hypothesize that SABR is more immunogenic than conventional radiation therapy. The 
full immunological potential of radiotherapy may be influenced by the dose and 
fractionation of radiation employed, for both single fraction and fractionated approaches 
(30). The ablative dose / fractionation spectrum employed by SABR heralds a potential for 
even greater augmentation of the tumouricidal immune response than conventional 
radiotherapy (31). Immunogenic responses at sites distant to the SABR therapy has already 
been reported by our group (32) and others (33). Ablative doses result in a greater degree of 
stromal / vascular damage, ceramide-induced endothelial cell damage and increased 
apoptosis of tumour cells (34, 35). This results in a tumour microenvironment enriched with 
tumour-derived antigens, with co-existing DC activation, antigen cross-presentation and 
tumour-specific T cell responses. Thus, in the B16 mouse melanoma model, tumour 
inhibition was more pronounced with ablative doses of radiation as compared to 
conventional radiation(36). Significant cross-priming of T-cells against tumour antigens have 
been demonstrated to be induced by a single dose of 15Gy in the draining lymph nodes (37). 
Our group at the Peter MacCallum Cancer Centre (Peter Mac) identified that single dose 

 
 
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(12Gy) radiotherapy did not deplete established tumours of effector cells (CD8+ T, CD4+ T 
and NK cells) critical to the antitumour activity of radiotherapy when used in combination 
with immunotherapy.  Indeed irradiated mammary tumours were enriched for functionally 
active, tumour-specific T cells and Ly-6C+ memory CD8+ T cells (38). It is unclear whether 
single fraction or hypofractionated RT is optimal in combination with immunotherapy, with 
reports from New York University suggesting 3 x 8Gy fraction therapy resulting in enhanced 
immunogenicity in comparison to single fraction ablation (39, 40). However, more recently, 
single fraction 20Gy ablative RT has been shown to synergize with the T-cell checkpoint 
inhibitor anti-PD-1 in murine models (41), allowing for induction of an anti-tumour immune 
response by relief of tumour-mediated immunosuppression. Similarly a report by Filatenkov 
et al. demonstrated that single fraction 30 Gy to tumour nodules in murine model resulted in 
an intense CD8+ T cell tumor infiltrate, and a loss of myeloid derived suppressor cells 
(MDSCs) (42). In murine models of melanoma and renal cell carcinoma, single fraction 15Gy 
SABR combination with PD-1 blockade has been demonstrated to synergize for additive 
tumour response in both the irradiated and distant tumour sites (43). A further study in a 
melanoma model also found single fraction SABR synergised with anti-PD-1, with a possible 
dose response of 18 Gy of radiotherapy resulted in increased activation and proliferation of 
antigen-specific T-cells when compared to 12Gy (44). 
 
4.8 
Combination Radiotherapy and T Cell Checkpoint Blockade can 
Augment Immune Responses and Reduce T Regulatory Cells 
There is increasing data to suggest that radiotherapy effects may be enhanced from 
coincident or subsequent immunotherapy. In established triple negative mouse breast 
cancer models, the anti-tumour effect of radiotherapy could be enhanced by combining 
immunostimulatory antibodies including anti-PD-1 antibody. In one study from Peter Mac 
(Verbrugge et al; (38)), PD-1 signaling was found to be critical and was synergistic when 
inhibited in order to promote rejection of triple negative mouse tumours. Of note, 
radiotherapy was found not to deplete tumours of functionally active tumour specific 
effector cells. These data support concomitant targeting of immunostimulatory and/or 
inhibitory checkpoints with radiotherapy.  Hence, this research presents an opportunity to 
test the combination of pembrolizumab in the first line setting along with SABR, which is 
typically used in patients with treatment naïve oligometastatic disease and may help change 
the natural history of the disease. 
 
The abscopal effect is a phenomenon when local radiotherapy is associated with regression 
of metastatic cancer distant from the irradiated site. This effect is thought to be mediated by 
activation of the immune system though its biological basis is not well understood. The 
incidence of abscopal effects have been reviewed by our group previously in both the 
preclinical (45) and clinical (46) settings. The abscopal effect is a rare but clinically recognised 
phenomenon. This effect was recently observed in a patient with melanoma treated with 
radiotherapy and ipilumumab (Postow et al. (47)). Tumour shrinkage over time was 
observed in the irradiated site as well as in distant sites. These correlated with changes in 

 
 
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peripheral-blood immune cells (decrease in CD4+ ICOS high cells, increases in HLA-DR 
expression and decreases in myeloid derived suppressor cells (MDSCs CD14+ HLA-DRlow) as 
well as increases in humoral antibody response to a range of antigens after radiotherapy. 
Rationale for this study is supported by evidence of favorable immunological changes 
induced in the peripheral blood by the combination therapy.  
 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on pembrolizumab. 
 
4.9 
Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumour-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and 
long-term survival in many solid tumours. 
 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumours to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 which has been shown to negatively 
regulate antigen receptor signalling upon engagement of its ligands (PD-L1 and/or PD-L2).  
PD-1 and family members are type I transmembrane glycoproteins containing an Ig Variable-
type (V-type) domain responsible for ligand binding and a cytoplasmic tail which is 
responsible for the binding of signalling molecules.  The cytoplasmic tail of PD-1 contains 2 
tyrosine-based signalling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) 
and an immunoreceptor tyrosine-based switch motif (ITSM).  Following T-cell stimulation, 
PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its 
cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ 
and ZAP70 which are involved in the CD3 T-cell signalling cascade.  The mechanism by which 
PD-1 down modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both 
molecules regulate an overlapping set of signalling proteins.  PD-1 was shown to be 
expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T 
regs and Natural Killer cells.  Expression has also been shown during thymic development on 
CD4-CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells.  
The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a 
variety of cell types, including non-hematopoietic tissues as well as in various tumours.  Both 
ligands are type I transmembrane receptors containing both IgV- and IgC-like domains in the 
extracellular region and contain short cytoplasmic regions with no known signalling motifs.  
Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell 
receptor.  PD-L1 is expressed at low levels on various non-hematopoietic tissues, most 

 
 
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notably on vascular endothelium, whereas PD-L2 protein is only detectably expressed on 
antigen-presenting cells found in lymphoid tissue or chronic inflammatory environments.  
PD-L2 is thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 
serves to dampen unwarranted T-cell function in peripheral tissues.  Although healthy 
organs express little (if any) PD-L1, a variety of cancers were demonstrated to express 
abundant levels of this T-cell inhibitor.  PD-1 has been suggested to regulate tumour-specific 
T-cell expansion in participants with melanoma (MEL).  This suggests that the PD-1/PD-L1 
pathway plays a critical role in tumour immune evasion and should be considered as an 
attractive target for therapeutic intervention. 
 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of 
the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in the 
United Stated for the treatment of patients with unresectable or metastatic melanoma and 
disease progression following ipilumumab and, if BRAF V600 mutation positive, a BRAF 
inhibitor. 
 
4.10 
Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
 
4.11 
Safety of Pembrolizumab and Dosing Regimen 
The safety profile of pembrolizumab has been well established from the initial phase I study 
(P001) and subsequent phase II and III studies and it has received approvals for use in 
Melanoma, NSCLC, head and Neck cancer. 
 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based 
on simulations performed using the population PK model of pembrolizumab showing that 
the fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally 
consistent with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain 
individual patient exposures in the exposure range established in melanoma as associated 
with maximal efficacy response and 3) will maintain individual patients exposure in the 
exposure range established in melanoma that are well tolerated and safe.  
 
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians 
and to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity 
in the logistical chain at treatment facilities and reduce wastage.  
 
 

 
 
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4.12 
Efficacy of Pembrolizumab in Lung Cancer 
The safety and efficacy of PD 1 inhibition with pembrolizumab in patients with advanced 
non-small cell has been investigated in a phase I clinical trial (48). Four hundred and ninety 
five patients with advanced NSCLC were treated with pembrolizumab (at a dose of either 
2mg or 10mg per kilogram every 2 weeks or 10 mg per kilogram every 2 weeks). Treatment-
related adverse events occurred in 351 patients (70.9%), with no clear difference according 
to dose or schedule. The most common treatment-related adverse events were fatigue, 
pruritus, and decreased appetite. Adverse events of grade 3 or higher were reported in 47 of 
495 patients (9.5%). The only treatment-related adverse events of an inflammatory or 
immune-mediated nature that occurred in more than 2% of patients were infusion-related 
reactions (in 15 patients [3.0%]), hypothyroidism (in 34 patients [6.9%]), and pneumonitis (in 
18 patients [3.6%]). One infusion reaction led to treatment discontinuation. All the patients 
with hypothyroidism were successfully treated with medical therapy. Pneumonitis of grade 3 
or greater was observed in 9 patients (1.8%), including 1 (0.2%) who died. The overall 
response rate was 19.4% (95% confidence interval [CI], 16.0 to 23.2), which included a 
response rate of 18.0% (95% CI, 14.4 to 22.2) in the 394 previously treated patients and 
24.8% (95% CI, 16.7 to 34.3) in the 101 previously untreated patients. The best overall 
response was stable disease in 21.8% of patients. The response rate was similar regardless of 
dose, schedule, and histologic analysis. 
 
At the time of this analysis, 84.4% of patients with a response had no disease progression, 
and the median duration of response was 12.5 months (range, 1.0 to 23.3) in all patients, 
10.4 months (range, 1.0 to 10.4) in previously treated patients, and 23.3 months (range, 1.0 
to 23.3) in previously untreated patients. Median progression-free survival was 3.7 months 
(95% CI, 2.9 to 4.1) for all the patients, 3.0 months (95% CI, 2.2 to 4.0) for previously treated 
patients, and 6.0 months (95% CI, 4.1 to 8.6) for previously untreated patients. Median 
overall survival was 12.0 months (95% CI, 9.3 to 14.7) for all the patients, 9.3 months (95% 
CI, 8.4 to 12.4) for previously treated patients, and 16.2 months (95% CI, 16.2 to not 
reached) for previously untreated patients. 
 
Biomarker analysis was conducted using the anti–PD-L1 antibody clone 22C3 (Merck) and a 
prototype immunohistochemical assay to determine the PD-L1 status. Among the 1143 
screened patients, 824 had samples that could be evaluated by the clinical-trial assay, with a 
prevalence of 23.2% of patients with a proportion score of at least 50%, 37.6% with a score 
of 1 to 49%, and 39.2% with a score of less than 1% by the clinical-trial assay. After the 
pooling of data from the training and validation groups post hoc, evaluation according to 
quartile suggested that a higher proportion score was associated with a greater response 
rate within the group with a proportion score of 1 to 49% and the group with a score of at 
least 50%. The response rate for patients with a proportion score of at least 50% was 42.3% 
when those without disease that could be measured at baseline were included. Little 
difference in response rate was observed according to dose, schedule, or smoking status. 
 

 
 
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In the first line setting, In an open-label, phase 3 trial (KEYNOTE 24), 305 patients were 
randomly assigned with untreated advanced NSCLC with PD-L1 expression on at least 50% of 
tumour cells to receive either pembrolizumab (at a fixed dose of 200 mg every 3 weeks) or 
the investigator’s choice of platinum-based chemotherapy. Crossover from the 
chemotherapy group to the pembrolizumab group was permitted in the event of disease 
progression. The median progression-free survival was 10.3 months (95% confidence interval 
[CI], 6.7 to not reached) in the pembrolizumab group versus 6.0 months (95% CI, 4.2 to 6.2) 
in the chemotherapy group (hazard ratio for disease progression or death, 0.50; 95% CI, 0.37 
to 0.68; P<0.001). The estimated rate of overall survival at 6 months was 80.2% in the 
pembrolizumab group versus 72.4% in the chemotherapy group (hazard ratio for death, 
0.60; 95% CI, 0.41 to 0.89; P=0.005). The response rate was higher in the pembrolizumab 
group than in the chemotherapy group (44.8% vs. 27.8%), the median duration of response 
was longer (not reached [range, 1.9+ to 14.5+ months] vs. 6.3 months [range, 2.1+ to 
12.6+]), and treatment-related adverse events of any grade were less frequent (occurring in 
73.4% vs. 90.0% of patients), as were grade 3, 4, or 5 treatment-related adverse events 
(26.6% vs. 53.3%). This pivotal trial concluded that in patients with untreated advanced 
NSCLC and PD-L1 expression on at least 50% of tumour cells, pembrolizumab was associated 
with significantly longer progression-free and overall survival and with fewer adverse events 
than was platinum-based chemotherapy. A second study, KEYNOTE 042 compared 
pembrolizumab with chemotherapy  in previously untreated advanced NSCLC with PD-L1 
expression on 1% to 100% of tumor cells.  The study was positive with benefit for 
pembrolizumab over chemotherapy at all groups in the prespecified analysis at >50%, more 
than 20% and more than 1% PD-L1 expression. 
 
In the second line and beyond setting, in a randomised phase 2/3 clinical trial (KEYNOTE-10), 
1034 patients with previously treated non-small-cell lung cancer with PD-L1 expression on at 
least 1% of tumour cells were randomly assigned (1:1:1) in blocks of six per stratum with an 
interactive voice-response system to receive pembrolizumab 2 mg/kg, pembrolizumab 10 
mg/kg, or docetaxel 75 mg/m(2) every 3 weeks. In the total population, median overall 
survival was 10.4 months with pembrolizumab 2 mg/kg, 12.7 months with pembrolizumab 
10 mg/kg, and 8.5 months with docetaxel. Overall survival was significantly longer for 
pembrolizumab 2 mg/kg versus docetaxel (hazard ratio [HR] 0.71, 95% CI 0.58-0.88; 
p=0.0008) and for pembrolizumab 10 mg/kg versus docetaxel (0.61, 0.49-0.75; p<0.0001). 
Median progression-free survival was 3.9 months with pembrolizumab 2 mg/kg, 4.0 months 
with pembrolizumab 10 mg/kg, and 4.0 months with docetaxel, with no significant 
difference for pembrolizumab 2 mg/kg versus docetaxel (0.88, 0.74-1.05; p=0.07) or for 
pembrolizumab 10 mg/kg versus docetaxel (HR 0.79, 95% CI 0.66-0.94; p=0.004). Grade 3-5 
treatment-related adverse events were less common with pembrolizumab than with 
docetaxel (43 [13%] of 339 patients given 2 mg/kg, 55 [16%] of 343 given 10 mg/kg, and 109 
[35%] of 309 given docetaxel). The study concluded that pembrolizumab prolongs overall 
survival and has a favourable benefit-to-risk profile in patients with previously treated, PD-
L1-positive, advanced non-small-cell lung cancer (>1%). These data establish pembrolizumab 

 
 
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as a new treatment option for this population and validate the use of PD-L1 selection. 
 
Therefore for the purposes of this study, patients with PD-L1 staining of ≥ 1% in the 
previously treated setting and those with PD-L1 staining of ≥ 50% in the first line setting are 
of interest, as it is in these groups that pembrolizumab is FDA approved for use. 
 
4.13 
Rationale for Trial, Population and Selected Population 
This study will evaluate the safety profile, efficacy and biological effects of the combination 
of pembrolizumab, a T cell checkpoint inhibitor and SABR for advanced NSCLC with disease 
progression that have 1-3 sites of disease amenable to SABR treatment. The primary 
objective of the study is to assess the safety profile, whilst efficacy and biological effects are 
secondary objectives. The patient cohort must have ≥ 1% PD-L1 staining on tumour biopsy or 
primary resection specimen for patients treated in the firstline or ≥1% PDL1 staining in 
patients who have had prior chemotherapy consistent with the approval status of 
pembrolizumab in lung cancer (US FDA, Canadian Health Authority or the Australian TGA) 
and with recent data from the KEYNOTE-042 study. Our hypothesis is that this treatment 
combination will have a safety profile that is clinically acceptable and demonstrate anti-
tumour efficacy. We will test this hypothesis in the setting of two different sequences of 
SABR and anti-PD1 combinations. 
 
The optimal sequence of checkpoint blockade therapy with radiotherapy into mainstream 
clinical practice is still subject to on-going investigation. Rationale for phased sequential 
treatment of anti-PD-1 therapy with radiotherapy is outlined below. 
 
(i) Prior to Radiotherapy 
* Reverse T cell exhaustion and immunosuppression to restore tumor immunity. There is now 
an intriguing link between immune microenvironment and response to therapies. Indeed, 
work done at the PMCC has demonstrated that tumours deficient of activated effector cells 
are significantly less responsive to the growth-inhibitory effects of localized radiotherapy 
(Haynes NM, Unpublished). PD-1 has the potential to shift the immune microenvironment of 
tumors in favor of immunity by reinvigorating the anti-cancer activity of tissue-resident, 
antigen educated T cells and reversing the suppressive phenotype of myeloid cells and 
plasmacytoid DCs.  
 
(ii) Concurrent and/or Post Radiotherapy 
* Support T-cell based immune responses to newly exposed neoantigens. Activity of 
checkpoint inhibitors is dependent on their being a pre-existing immune response to the 
cancer.  Radiotherapy has the potential to engage immune responses to cancer by increasing 
the mutational load of tumors and in turn the expression of neoantigens needed to evoke 
the cytotoxic activity of T cells. Indeed there is strong evidence that neoantigens play a 
critical role in driving the strength of intratumoral T cell responses and may also influence 
tumor cell sensitivity to cancer immunotherapy (49). In this setting, anti-PD-1 has the 

 
 
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potential to regulate immunosuppression by augmenting the frequency and suppressive 
phenotype of myeloid cells within tumors post radiotherapy. It may also increase the 
function of newly activated tumor-reactive immune cells, by inhibiting PD-1 binding of its 
inhibitory ligand PD-L1; the expression of which can be induced within tumors by radiation 
therapy.  
Whist the overlapping toxicities of SABR and pembrolizumab are not yet fully understood, 
few are expected. Safety will be monitored carefully throughout the trial in all patients (n=16 
per arm). We hypothesize that augmentation of immunity in this subgroup of patients may 
enhance long-term control of the disease. It is anticipated that the findings of this study will 
serve as the basis for larger randomised studies in the future. 
 
4.14 
Rationale for Dose Selection/Regimen/Modification  
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based 
on simulations performed using the population PK model of pembrolizumab showing that 
the fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally 
consistent with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain 
individual patient exposures in the exposure range established in melanoma as associated 
with maximal efficacy response and 3) will maintain individual patients exposure in the 
exposure range established in melanoma that are well tolerated and safe. On this basis the 
chosen dose of 200 mg q3 weekly represents an appropriate standard of care in the setting 
of previously treated NSCLC. 
 
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians 
and to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity 
in the logistical chain at treatment facilities and reduce wastage. This dose is now the 
standard single-agent dose used in NSCLC and Head and Neck Cancer.  
 
5. 
Trial Objectives 
5.1 
Hypothesis 
This investigator driven Phase Ib study will examine the safety, efficacy and biological effects 
of two schedules of pembrolizumab, an antibody targeted against anti-programmed cell 
death 1 (PD-1), which will be given either before or after stereotactic ablative body 
radiotherapy (SABR) for metastatic NSCLC. We hypothesise that both arms i.e. 1) SABR 
followed by anti-PD-1 and; 2)anti-PD-1 with SABR after first cycle of pembrolizumab; will 
have clinically acceptable safety profiles with evidence of local and systemic efficacy; and 
that there will be differences in the immunological responses related to schedule of 
treatment. 
 
5.2 
Objectives 
Primary objective: 
To assess common toxicities associated with pembrolizumab in combination with SABR 
when SABR is given before or after first cycle of pembrolizumab in patients with metastatic 
NSCLC. 

 
 
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Secondary objectives:  
Secondary objectives are to examine the clinical efficacy of the combination:   
 To describe response rate in: a) lesions treated with SABR, b) non-irradiated lesions 
and c) overall response, and compare between treatment arms 
 To describe overall survival (OS) and progression free survival (PFS) and compare 
between treatment arms 
 To describe the event history (progression at an irradiated lesion, progression at a non-
irradiated lesion, appearance of a new lesion, ceasing treatment and death) of NSCLC 
patients treated with SABR in combination with pembrolizumab 
 
Exploratory Objectives 
 Evaluate PD-L1 expression in baseline tissue using immunohistochemistry. 
 Evaluate baseline and longitudinal cellular and molecular changes in archival tumour 
tissue, and/or fresh tumour biopsies. This will include tumour infiltrating lymphocytes 
(TILs), CD73 and other markers. 
 Evaluate longitudinal changes in immunological cellular subsets and cytokines within 
peripheral blood.  
 
5.3 
Endpoints 
Primary Endpoint 
 Toxicities associated with SABR in combination to pembrolizumab are defined as 
adverse events (AE’s) considered possibly, probably or definitely related to the 
treatment. Safety (acute and long term) will be assessed using CTCAE version 4.03. 
 
Secondary Endpoints:  
 Response will be assessed by 4 different methods (RECIST 1.1, irRECIST, Peter Mac 
Metabolic Response Criteria and PERCIST 1.0) and will be assessed a) only considering 
irradiated lesions; b) only considering non-irradiated lesions and; c) considering all 
lesions (overall response rate) 
 Overall survival will be measured from the date of randomisation to the date of death 
from any cause. 
 Progression free survival will be measured from the date of randomisation to the date 
of first progression at any site or date of death due to any cause. 
 Event history is defined as the time from the date of randomisation to the date of each 
event of interest (progression at an irradiated lesion, progression at a non-irradiated 
lesion, appearance of a new lesion, ceasing treatment and death). Patients alive will be 
censored at the date of last follow-up.  
 
Exploratory Endpoints 
A number of translational endpoints will be evaluated including: 
 PD-L1 expression in tumour tissue using immunohistochemistry with the 22C3 
antibody using the DAKO Autolink 48 system. 

 
 
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 Tumour infiltrating lymphocytes (TILs). 
 Changes in host anti-tumour immunity to look for evidence of immune activation and 
relief of immunosuppression in tumour tissue and peripheral blood from the patient 
over time and at time of progression (if this occurs).  
o Blood samples will be collected at multiple time points before, during and after 
trial related therapies. These will be analysed for biomarkers including, but not 
limited to, the following (this is a non-exhaustive list): 
- Absolute lymphocyte counts using a blood analyser. 
- The presence of CD8+ T cells by flow cytometric analysis. 
- Change in frequency of tumour reactive T cells. These may include markers 
for HLA-DR, CD4+, CD8+ T cells, PD-1, TIM-3 signifying antigen presentation 
and experience. 
- Immune cytokines 
 
6. 
Trial Design 
This is a prospective, open label, two arm randomised clinical trial with 1:1 allocation ratio 
evaluating the safety, efficacy and immunological effects of two different sequences of 
pembrolizumab in combination with SABR treatment in NSCLC – pembrolizumab given either 
before or after SABR. 
 
Eligible patients will be randomised to either: 
Arm 1: SABR followed by pembrolizumab; or 
Arm 2: Pembrolizumab followed by SABR after cycle 1 
 
Refer to Trial Schema  
 
Pembrolizumab at a dose of 200 mg will be delivered every 3 weeks for a total duration of 
102 weeks (34 cycles), commencing either 7 days (+/- 2 days) before the first dose of SABR 
or 7 days (+/-2 days) after the last dose of SABR. 
 
Tumour response will be assessed according to RECIST 1.1, and irRECIST, Peter Mac 
Metabolic Response Criteria and PERCIST 1.0. Responses will be characterized in lesions 
treated with SABR and in un-irradiated lesions.  
 
Peripheral blood samples and where possible, tumour tissue will be collected pre, during and 
post-treatment to assess baseline findings and longitudinal changes in immune subsets 
within tumour tissue and peripheral blood. 
 
Evaluable patients are those that receive at least one dose of pembrolizumab and one dose 
of SABR. Non-evaluable patients will be replaced until the planned sample size has been 
reached. 
 

 
 
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7. 
Study Population 
Patients with metastatic NSCLC who meet the inclusion/exclusion criteria described below 
will be eligible for participation in this study. 
 
7.1 
Inclusion Criteria  
In order to be eligible for participation in this trial, the patient must: 
1. Have provided written informed consent for the trial. 
2. Be ≥ 18 years of age on day of signing informed consent. 
3. Have at least one lesion not planned for SABR that is measurable disease based on 
RECIST 1.1.  
4. Patients must have a histologically or cytologically confirmed metastatic non-small cell 
lung cancer.  
5. Patients with disease previously untreated with systemic therapy must have ≥ 1% PD-
L1 staining and patients who have previously received systemic therapy must have ≥ 
1% PD-L1 staining on immunohistochemistry 
6. Patients must have at least 1-3 lesions suitable for treatment with stereotactic 
radiotherapy. 
7. Be willing to provide tissue from a newly obtained core or excisional biopsy of a 
tumour lesion where feasible.  Newly-obtained is defined as a specimen obtained up to 
12 weeks prior to randomisation.  Patients for whom newly-obtained samples cannot 
be provided (e.g. inaccessible or patient safety concern) may submit an archived 
specimen only upon agreement from the study principal investigators. 
8. Have a performance status of 0-1 on the ECOG Performance Scale (see Appendix 1). 
 
 

 
 
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9. Demonstrate adequate organ function as defined in table 3 below, all screening labs 
should be performed within 10 days of randomisation.   
 
Table 3 Adequate Organ Function Laboratory Values 
 
System 
Laboratory Value 
Haematological 
 
Absolute neutrophil count (ANC) 
≥1.5x109/L 
Platelets 
≥100x109L 
Haemoglobin 
≥90 g/L without transfusion or EPO dependency (within 7 days 
of assessment) 
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥30 mL/min for patients with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for patients with total bilirubin levels > 
1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  OR 
≤ 5 X ULN for patients with liver metastases 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5 X ULN unless patient is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
≤1.5 X ULN unless patient is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
10. Life expectancy > 3 months. 
11. Be willing and able to comply with all study requirements, including treatment, 
attending assessments and follow-up. 
12. Female patient of childbearing potential should have a negative urine or serum 
pregnancy within 7 days of randomisation.  If the urine test is positive or cannot be 
confirmed as negative, a serum pregnancy test will be required.   
13. Female patients of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication (See Section 8.10).  
Patients of childbearing potential are those who have not been surgically sterilized or 
have not been free from menses for > 1 year.  
14. Male patients should agree to use an adequate method of contraception starting with 
the first dose of study therapy through 120 days after the last dose of study therapy. 
 
 

 
 
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7.2 
Exclusion Criteria 
The patient must be excluded from participating in the trial if the patient: 
 
1. Has had previous high dose radiotherapy (biological equivalent of >30Gy in 10#) to an 
area to be treated which includes vertebral bodies (see below). 
Note:  Previous high dose radiotherapy is defined as a biological equivalent dose to above that of 
30 Gy in 10 fractions using an alpha/beta ratio (50) of 3. Where a patient has received radiotherapy 
to an equivalent or lower dose than defined above, stereotactic radiotherapy of the area may be 
considered. In doing so, assessment of the volume and total dose received by any overlap region 
must be made, and documented by generating a cumulative plan incorporating both the previous 
and current treatment fields.  It is the treating radiation oncologist’s responsibility to review both 
the current plan and the cumulative plan inclusive of previous radiotherapy. 
2. Has had previous thoracic radiotherapy of > 36Gy within the 6 months prior to 
randomisation. 
3. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Patients with small asymptomatic or previously treated brain metastases 
may participate provided they are stable (without evidence of progression by imaging 
for at least four weeks prior to the first dose of trial treatment and any neurologic 
symptoms have returned to baseline), have no evidence of enlarging brain 
metastases, and are not using steroids for intracranial neurological symptoms at least 
7 days prior to trial randomisation.  This exception does not include leptomeningeal 
disease which is excluded regardless of clinical stability.   
4. Has evidence of Spinal Cord Compression. 
5. Has a Spinal Instability Neoplastic Score ≥ 7 unless lesion reviewed by a neurosurgical 
service and considered stable (see Appendix 2). 
6. Requires surgical fixation of bone lesion for stability. All surgical fixation and 
instrumentation must be completed before randomisation on study. 
7. Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational device 
within 4 weeks of randomisation. 
8. Has a diagnosis of immunodeficiency.  
9. Has a known history of active TB (Bacillus Tuberculosis) 
10. Has a hypersensitivity to pembrolizumab or any of its excipients. 
11. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to 
randomisation or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse 
events due to agents administered more than 4 weeks earlier. 
12. Has diagnosed and/or treated additional malignancy within 5 years prior to 
randomisation with the exception of: curatively treated basal cell carcinoma of the 
skin, squamous cell carcinoma of the skin, curatively treated early stage cervical 

 
 
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cancer, breast cancer or prostate cancer with no evidence of active disease. Other 
exceptions may be considered following  consultation with the principal investigator 
13. Has active autoimmune disease that has required systemic treatment in the past 2 
years 
(i.e. 
with 
use 
of 
disease 
modifying 
agents, 
corticosteroids 
or 
immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, 
etc.) is not considered a form of systemic treatment.  
14. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis. 
15. Has had any systemic anti-cancer therapy or radiation therapy within 4 weeks prior 
to randomisation 
16. Has known interstitial lung disease 
17. Has an active infection requiring systemic therapy. 
18. Has a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the trial, interfere with the patient’s 
participation for the full duration of the trial, or is not in the best interest of the 
patient to participate, in the opinion of the treating investigator. 
19. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
20. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
21. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
22. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
23. Has received a live vaccine within 30 days of randomisation. 
Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are 
allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and 
are not allowed. 
 
7.3 
Patient Registration/Randomisation 
Recruitment will cover a 2-year period.  Screening for individual patients will take place 
within 28 days prior to randomisation onto the study.  
 
The Investigator should ensure that all requirements are met prior to randomisation of 
eligible patients on the trial: 
 Patient meets all inclusion and exclusion criteria requirements 
 Patient has signed and dated all applicable consent forms 
 All screening assessments have been completed and recorded in the patient’s medical 
records complete with all relevant source documents 

 
 
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Eligible patients will be randomised electronically using the online SABRseq electronic data 
capture (EDC) system. Confirmation of randomisation and randomisation ARM will be 
provided electronically (via email) as well as, a unique 5-digit patient identification number. 
 
Patients will not be randomised if treatment has commenced or if consent has not been 
given. Once a patient is randomised on a trial, randomisation will not be cancelled. 
 
Following randomisation, patients should begin protocol treatment within 28 days  
 
7.4 
Treatment Assignment 
Thirty-two patients will be randomised between the two arms in a 1:1 allocation ratio. 
Stratified randomisation will be used to assign the patients to the treatment arms. 
Stratification will occur by the number of metastases to be treated with SABR (two groups: 1 
metastasis vs 2 or 3 metastases) and by line of therapy (two groups: previously untreated vs 
previously treated). 
 
The next treatment to be assigned will not be known by any person prior to eligibility criteria 
being established and the intention to randomise the patient being declared.  
 
7.5 
Blinding and Procedures for Unblinding 
This is an open-label trial; therefore, the Sponsor, investigator and patient will know the 
treatment administered 
 
7.6 
Patient Treatment Withdrawal/Discontinuation 
Patients may withdraw consent at any time for any reason or be withdrawn from the trial 
treatment at the discretion of the investigator should any untoward effect occur.  In 
addition, a patient may be withdrawn by the investigator or the Sponsor if continued 
enrolment into the trial is inappropriate for administrative and/or other safety reasons.   
 
A trial patient may discontinue trial treatment for any of the following reasons: 
 Disease progression 
 Unacceptable adverse event 
 Intercurrent illness which prevents further treatment 
 Withdrawal of consent for treatment or from trial by the patient 
 The investigator believes it is in the best interest of the patient 
 The patient becomes pregnant or begins breastfeeding 
 Noncompliance with the protocol 
 
When a patient discontinues/withdraws prior to completion of protocol treatment, patients 
should attend the site for a 30-day (post end of trial treatment) safety follow-up visit for 
assessment of AEs and efficacy. Any AEs which are present at the time of 

 
 
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discontinuation/withdrawal should be followed in accordance with the safety requirements. 
The reason for discontinuation will be recorded on a CRF. 
 
Discontinuation of trial treatment does not necessarily indicate withdrawal from the trial. 
Patients are expected to have follow-up assessments after treatment discontinuation if 
patients’ agree and reason for trial treatment discontinuation permits.  
 
Total withdrawal would occur in the circumstance that the patient decides to completely 
withdraw from all treatment aspects of the trial, and does not agree to any further 
scheduled follow up assessments. The patients’ total withdrawal must be documented in the 
medical records and transcribed onto the relevant CRF. No further information will be 
collected from this patient for the purpose of this trial. 
 
8. 
Study Assessments 
 
The following assessments will occur during the trial. A schedule of assessments is provided 
on page 11.  
 
8.1 
Pre-randomisation/Screening Assessments – ALL ARMS 
The following assessments must be performed 28 days prior to randomisation (unless 
otherwise specified): 
 Informed consent 
 Assessment of PD-L1 expression on new (fresh) biopsy sample or archival tissue 
 Review of inclusion and exclusion criteria 
 Demographics  
 SINS score for spinal lesions (if applicable i.e. known spinal metastases) 
 Comprehensive medical history (including disease specific medical history) 
 Physical examination  
 Vital signs and body measurements 
 Documentation of prior medications at time of screening 
 Documentation of ECOG performance status 
 Radiological evaluation with a CT Brain, Chest/Abdomen and Pelvis or MRI must be 
performed within 6 weeks of randomisation 
 Whole body bone scan  (if clinically indicated) within 6 weeks of randomisation 
 FDG-PET scan 
 Laboratory studies no more than 10 days prior to randomisation including FBE, 
biochemistry and coagulation, hepatic, kidney and thyroid function tests 
 Virology (HIV, Hepatitis B and C) within 21 days prior to randomisation, if clinically 
indicated 
 Pregnancy test in female patients with child bearing potential within 7 days prior to 
randomisation  

 
 
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 New (fresh) biopsy sample within 12 weeks of randomisation, if applicable 
 Blood samples for correlative studies 
 
8.2 
Treatment Phase - ARM 1 (SABR followed by pembrolizumab) 
8.2.1 
SABR Visit Assessments  
The following assessments must be performed prior to the first dose of SABR: 
 Documentation of concomitant medications  
 Blood samples for correlative studies 
 
8.2.2 
Cycle 1 Assessments  
The following assessments must be performed 7 days ± 2 days after the last dose of SABR: 
 Physical examination  
 Vital signs and weight 
 Documentation of concomitant medications  
 Documentation of ECOG performance status 
 Laboratory studies including FBE, biochemistry and coagulation, hepatic, kidney and 
thyroid function tests 
 
Pregnancy test in female patients with child bearing potential.  
 
Blood samples for correlative studies 
 
8.2.3 
Cycle 2 to Cycle 34 Assessments 
The following assessments will be performed within 3 days prior to pembrolizumab dosing in 
each cycle, unless otherwise specified.  
 Physical examination  
 Vital signs and weight 
 Documentation of concomitant medications  
 Documentation of ECOG performance status 
 Laboratory studies including FBE, biochemistry and coagulation, hepatic and kidney  
 Thyroid function tests (every 6 weeks) 
 Radiological evaluation with a CT Chest/Abdomen and Pelvis or MRI (prior to cycle 3, 
5, 7 and every 3 cycles thereafter) 
 FDG-PET scan prior to cycle 5 
 Whole body bone scan (prior to cycle 3, 5, 7 and every 3 cycles thereafter, only if 
clinical indicated)  
 Response assessment (prior to cycle 3, 5, 7 and every 3 cycles thereafter) 
 Adverse events assessment 
 Pregnancy test in female patients with child bearing potential.  
 
Blood samples for correlative studies 
 
 
 

 
 
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8.3 
Treatment Phase - ARM 2 (pembrolizumab followed by SABR) 
8.3.1 
Cycle 1 Assessments  
The following assessments must be performed within 3 days prior to the first dose of 
pembrolizumab in cycle 1: 
 Physical examination  
 Vital signs and weight 
 Documentation of concomitant medications  
 Documentation of ECOG performance status 
 Laboratory studies including FBE, biochemistry and coagulation, hepatic and kidney 
function tests 
 Pregnancy test in female patients with child bearing potential.  
 
Blood samples for correlative studies 
 
8.3.2 
SABR Visit Assessments 
The following assessments will be performed at the SABR visit, 7 days from Cycle 1 Day 1 (± 2 
days):  
 Documentation of concomitant medications  
 
Blood samples for correlative studies 
 
8.3.3 
Cycle 2 to Cycle 34 Assessments 
The following assessments will be performed within 3 days prior to pembrolizumab dosing in 
each cycle, unless otherwise specified:  
 Physical examination  
 Vital signs and weight 
 Documentation of concomitant medications  
 Documentation of ECOG performance status 
 Laboratory studies including FBE, biochemistry and coagulation, hepatic and kidney  
  Thyroid function tests (every 6 weeks) 
 Radiological evaluation with a CT Chest/Abdomen and Pelvis or MRI (prior to cycle 3, 
5, 7 and every 3 cycles thereafter, only if clinical indicated) 
 FDG-PET scan prior to cycle 5 
 Whole body bone scan (prior to cycle 3, 5, 7 and every 3 cycles thereafter, only if 
clinical indicated)  
 Response assessment (prior to cycle 3, 5, 7 and every 3 cycles thereafter, only if 
clinical indicated) 
 Adverse events assessment 
 Pregnancy test in female patients with child bearing potential.  
 
Blood samples for correlative studies 
 
 
 

 
 
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8.4 
Safety Follow-up – All Arms 
The following assessments will be performed during the safety follow-up visit to be 
conducted approximately 30 days after the last dose of trial treatment or before the 
initiation of a new anti-cancer treatment, whichever comes first.   
 
Adverse events assessment: Patients with an AE of Grade > 1 will be followed until 
the resolution of the AE to Grade 0-1 or until the beginning of a new anti-neoplastic 
therapy, whichever occurs first.  SAEs that occur within 30 days of the end of 
treatment or before initiation of a new anti-cancer treatment should also be followed 
and recorded.   
 
New anti-cancer therapy status.  
 
8.5 
Follow-Up – All Arms 
Patients who complete the treatment phase, or discontinue trial treatment for a reason 
other than disease progression will move into the follow-up phase.  The following 
assessments will be performed every 3 months up until the last patient has completed 24 
months of follow-up, until the start of new anti-neoplastic therapy, disease progression, 
death or end of the study.   
 Physical examination  
 Vital signs and weight 
 Documentation of ECOG performance status 
 Laboratory studies including FBE, biochemistry and coagulation, hepatic and kidney 
function tests (only if clinically indicated) 
 Radiological evaluation with a CT Chest/Abdomen and Pelvis or MRI 
 Whole body bone scan (only if clinical indicated)  
 Response assessment  
 Adverse Event assessment 
 
Blood samples for correlative studies 
 New anti-cancer therapy status  
 Fresh biopsy sample 3 months after the last dose of SABR if considered safe  
 
8.6 
Survival Follow-up 
Patients who discontinue trial treatment due to progression, progress during following-up or 
commence a new systemic treatment will be followed for survival only. Survival status will 
be assessed every 3 months until death, withdrawal of consent, or the end of the study, 
whichever occurs first. Where possible, every effort should be made to record results of 
subsequent tumour assessments and any new anti-cancer therapies.  
 
8.7 
Concomitant Medications 
All treatments that the investigator considers necessary for a patient’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards 
of medical care.  All concomitant medication will be recorded on the relevant CRF including 

 
 
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all prescription, over-the-counter (OTC), herbal supplements, and IV medications and fluids.  
If changes occur during the trial period, documentation of drug dosage, frequency, route, 
and date may also be included on the CRF. 
 
All concomitant medications received within 28 days prior to randomisation and 30 days 
after the last dose of trial treatment should be recorded.   
 
8.8 
Supportive Care/Rescue Medication 
Patients should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below (table 4). Where appropriate, 
these guidelines include the use of oral or intravenous treatment with corticosteroids as well 
as additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids.  Note that several courses of steroid tapering may be necessary as 
symptoms may worsen when the steroid dose is decreased. For each disorder, attempts 
should be made to rule out other causes such as metastatic disease or bacterial or viral 
infection, which might require additional supportive care. The treatment guidelines are 
intended to be applied when the investigator determines the events to be related to 
pembrolizumab.  
 
Table 4 Supportive care measure of adverse events of immunologic etiology 
 
Adverse event 
type 
CTCAE version 
4.03 Grade 
Treatment 
Pneumonitis 
Grade 2 
Treat with systemic corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. In the event of 
recurrent grade 2 pneumonitis, pembrolizumab should be discontinued. 
 
Grade 3-4  
For, immediately treat with intravenous steroids.  Administer additional anti-
inflammatory measures, as needed. 
Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration. 
Diarrhoea/Colitis 
General 
Patients should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhoea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).   
All patients who experience diarrhoea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.  For Grade 2 or higher diarrhoea, 
consider GI consultation and endoscopy to confirm or rule out colitis. 
 
Grade 2 that persists 
> 3 days 
Administer oral corticosteroids.  
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks 
 
Grade 3 or 4 that 
persists > 1 week 
Treat with intravenous steroids followed by high dose oral steroids.  
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks  
Type 1 diabetes 
mellitus 
 
If new onset, including diabetic ketoacidosis, insulin replacement therapy is 
recommended 
Hyperglycemia 
Grade 3-4 
If associated with ketosis (ketonuria) or metabolic acidosis, evaluate patients with serum 
glucose and a metabolic panel, urine ketones, glycosylated haemoglobin, and C-peptide. 
Insulin replacement therapy is recommended 
Hypophysitis 
Grade 2 
Treat with corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of appropriate 
hormones may be required as the steroid dose is tapered 
 
Grade 3-4 
Treat with an initial dose of IV corticosteroids followed by oral corticosteroids. When 
symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. Replacement of appropriate hormones may be required as 
the steroid dose is tapered 

 
 
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Hyperthyroidism or  
Hypothyroidism 
General 
Thyroid disorders can occur at any time during treatment. Monitor patients for changes 
in thyroid function (at the start of treatment, periodically during treatment, and as 
indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid 
disorders 
 
Grade 2 
hyperthyroidism  
Grade 2-4 
hypothyroidism 
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested as 
initial therapy. 
In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care. 
 
Grade 3-4 
hyperthyroidism  
 
Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. When 
symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. Replacement of appropriate hormones may be required as 
the steroid dose is tapered. 
Hepatic 
Grade 2 
Monitor liver function tests more frequently until returned to baseline values (consider 
weekly). 
Treat with IV or oral corticosteroids 
 
Grade 3-4 
Treat with intravenous corticosteroids for 24 to 48 hours.  
When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks 
Renal Failure  
or Nephritis 
Grade 2 
Treat with corticosteroids 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks 
 
Grade 3-4 
Treat with systemic corticosteroids. 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
 
Management of Infusion related reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of completion of 
infusion.  
 
Table 5 below shows treatment guidelines for patients who experience an infusion related 
reaction associated with administration of pembrolizumab. 
 
Table 5: Infusion Related Reaction Treatment Guidelines 
CTCAE version 4.03  
Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild transient reaction; infusion 
interruption not indicated; 
intervention not indicated 
 
Increase monitoring of vital signs as medically indicated until the 
patient is deemed medically stable in the opinion of the 
investigator. 
None 
Grade 2 
Therapy or infusion interruption 
indicated but responds promptly 
to symptomatic treatment (e.g., 
antihistamines, NSAIDS, narcotics, 
IV fluids); prophylactic medications 
indicated for <=24 hrs  
 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically indicated until the 
patient is deemed medically stable in the opinion of the 
investigator. 
If symptoms resolve within one hour of stopping drug infusion, the 
infusion may be restarted at 50% of the original infusion rate (e.g., 
from 100 mL/hr to 50 mL/hr).  Otherwise dosing will be held until 
symptoms resolve and the patient should be premedicated for the 
next scheduled dose. 
Patients who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from further 
trial treatment administration 
Patient may be 
premedicated 1.5h (± 30 
minutes) prior to infusion of 
pembrolizumab with: 
 
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine). 
 
Acetaminophen 
500-1000 
mg po (or equivalent dose 
of antipyretic). 
Grade 3: 
Prolonged (e.g., not rapidly 
responsive to symptomatic 
medication and/or brief 
Stop Infusion. 
Additional appropriate medical therapy may include but is not 
limited to: 
IV fluids 
No subsequent dosing 

 
 
SABRseq – version 1.2: Date: 11 September 2018 
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interruption of infusion); 
recurrence of symptoms following 
initial improvement; 
hospitalization indicated for clinical 
sequelae 
 
 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
Grade 4: 
Life-threatening 
consequences; 
urgent intervention indicated 
Increase monitoring of vital signs as medically indicated until the 
patient is deemed medically stable in the opinion of the 
investigator. Hospitalization may be indicated. 
Patient is permanently discontinued from further trial treatment 
administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration 
 
8.9 
Diet 
Patients should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhoea, nausea or vomiting. 
 
8.10 
Contraception 
Pembrolizumab may have adverse effects on a foetus in utero.  Furthermore, it is not known 
if pembrolizumab has transient adverse effects on the composition of sperm.  Non-pregnant, 
non-breast-feeding women may be enrolled if they are willing to use 2 methods of birth 
control or are considered highly unlikely to conceive.  Highly unlikely to conceive is defined 
as 1) surgically sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has 
not had menses for greater than 1 year will be considered postmenopausal), or 3) not 
heterosexually active for the duration of the study.  The two birth control methods can be 
used; two barrier methods or a barrier method plus a hormonal method to prevent 
pregnancy. Patients should start using birth control from study Visit 1 throughout the study 
period up to 120 days after the last dose of study pembrolizumab.  
 
The following are considered adequate barrier methods of contraception: diaphragm, 
condom (by the partner), copper intrauterine device, sponge, or spermicide.  Appropriate 
hormonal contraceptives will include any registered and marketed contraceptive agent that 
contains an oestrogen and/or a progestational agent (including oral, subcutaneous, 
intrauterine, or intramuscular agents). 
 
Patients should be informed that taking the study medication may involve unknown risks to 
the foetus (unborn baby) if pregnancy were to occur during the study.  In order to 
participate in the study they must adhere to the contraception requirement (described 
above) for the duration of the study and during the follow-up period.  If there is any question 
that a patient will not reliably comply with the requirements for contraception, that patient 
should not be entered into the study. 
 
 
 

 
 
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8.11 
Use in Pregnancy 
If a patient inadvertently becomes pregnant while on treatment with pembrolizumab, the 
patient will immediately be removed from the study.  The site will contact the patient at 
least monthly and document the patient’s status until the pregnancy has been completed or 
terminated.  The outcome of the pregnancy will be reported to the Sponsor and to Merck 
without delay and within 24 hours to the Sponsor and within 2 working days to Merck if the 
outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn). 
 
The study investigator will make every effort to obtain permission to follow the outcome of 
the pregnancy and report the condition of the foetus or newborn to Merck and the Sponsor.  
If a male patient impregnates his female partner the study personnel at the site must be 
informed immediately and the pregnancy reported to the Sponsor and to Merck and 
followed as described above and in Section 8.11. 
 
8.12 
Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, patients who are breast-feeding are not eligible for enrolment. 
 
8.13 
Non-Permitted Medications 
Patients are prohibited from receiving the following therapies during the screening and 
treatment phase of this trial: 
● Antineoplastic systemic chemotherapy or biological therapy  
● Immunotherapy not specified in this protocol 
● Chemotherapy not specified in this protocol 
● Investigational agents other than pembrolizumab 
● Radiation therapy  
Note:  Radiation therapy to a symptomatic lesion(s) or to the brain may be allowed 
at the investigator’s discretion.   
● Live vaccines within 30 days prior to randomisation and while participating in the 
trial.  Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine.  
● Systemic glucocorticoids for a chronic inflammatory disorder. The use of physiologic 
doses of corticosteroids on a regular repetitive basis for a medical condition may be 
approved after consultation with the Principal Investigator. 
 
Patients who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Patients may receive other medications that the investigator deems to be medically 
necessary. 
 

 
 
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The exclusion criteria describe other medications that are prohibited in this trial. 
 
There are no prohibited therapies during the follow-up phase. 
 
9. 
Trial Radiotherapy Treatment 
 
The treatment regimen involves the delivery of a single fraction of highly conformal SABR to 
1 to 3 metastases; delivered with either photons, electrons or mixed modalities. The 
maximal number of metastases within this range should be irradiated, however, at least one 
metastases defined as measurable disease must not be irradiated. The first dose of 
pembrolizumab will be delivered either 7 days (+/- 2 days after (ARM 1) or 7 days (+/- 2 days) 
before (ARM 2) the SABR treatment and will be continued for up to 24 months (34 cycles). 
 
9.1 
Megavoltage Radiotherapy 
The investigational treatment will be prescribed to the covering isodose, ensuring that 99% 
of the PTV is covered by 100% of the dose (D99=100%). When this coverage cannot be 
achieved whilst respecting surrounding organs at risk, a lower coverage of D95=100% is 
acceptable. Intensity Modulated Radiation Therapy (IMRT) is not compulsory but will be 
considered if very steep dose gradients have to be achieved or targets ‘wrap around” a 
critical structure.  This is the near minimum dose to the target as considered by the 
International Commission of Radiation Units and Measurements (ICRU) in their report 
83(51). Multi-field photon treatment, intensity modulated radiation therapy (IMRT), dynamic 
conformal arcs, electrons and volumetric modulated arc therapies (VMAT) can all be 
considered.  
 
A single fraction of SABR approach will be utilized, which is the most commonly used 
fractionation schedule utilized at the Peter MacCallum Cancer Centre. The dose will be 
prescribed using a 'stereotactic' paradigm to an isodose line no less than 70% of the 
maximum dose, aiming for a prescription isodose of 80%. This should result in a maximum 
dose to the PTV of between 125% and 143%. This allows for larger target dose in 
homogeneities but results in a steeper dose fall off outside of the target volume.  
 
If more than one lesion is to be treated in a single patient, treatment of all lesions ideally 
would be given in one setting for patient convenience.  However for practical or logistic 
reasons this may not always be possible and in such cases all lesions should be treated 
within a time window spanning not more than 7 calendar days. In the case where targets are 
treated on different days, then treatments should ideally be delivered on consecutive days. 
Dose for each lesion will be independently verified before treatment and image guidance 
will be used to ensure accurate patient positioning. 
 
For further details, refer to the SABRseq Radiotherapy Manual. 
 

 
 
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9.2 
Statement of Treatment Aim and Rationale 
Treatment rationale is to provide long-term local and distant disease control in patients with 
NSCLC using a single fraction of stereotactic ablative radiotherapy (to 1-3 sites) in 
conjunction with pembrolizumab.  
 
9.3 
Treatment Schedule 
Study therapy should commence within 28 days of patient randomisation on the study. A 
single dose of 20 Gy should be prescribed, although a single 18Gy fraction can be used as an 
alternative for a centrally located lung lesion or a spinal lesion with a SINS score of > 7 after 
review at SABR chart round. Ideally all treatments should be performed on the same day. 
One or more lesions must be deemed suitable for treatment with SABR; up to 3 lesions may 
be treated. The choice of treatment sites for SABR is at clinician discretion, but should 
encompass different types of metastatic sites where possible (e.g. bone and/or lymph node 
and/or visceral organ). The maximal number of metastases within this range should be 
irradiated, however, at least one metastases defined as measurable disease must not be 
irradiated. The use of single 4mg dose of prophylactic dexamethasone prior to SABR 
treatment is permitted. 
 
10. 
Trial Pembrolizumab Treatment 
 
Pembrolizumab treatment should begin either 7 days (+/- 2 days) before the first SABR 
treatment or 7 days (+/- 2 days) after the last SABR treatment 
 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks for 34 
cycles.  Sites should make every effort to target infusion timing to be as close to 30 minutes 
as possible.  However, given the variability of infusion pumps from site to site, a window of -
5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
 
Pembrolizumab treatment should be administered on Day 1 of each cycle after all 
procedures/assessments have been completed as detailed in Sections 8.2 and 8.3. Trial 
treatment may be administered up to 3 days before or after the scheduled Day 1 of each 
cycle due to administrative reasons. 
 
All trial treatments will be administered on an outpatient basis. 
 
10.1 
Pembrolizumab Dose Modifications and Delays 
Adverse events associated with pembrolizumab exposure may represent an immunologic 
etiology.  These adverse events may occur shortly after the first dose or several months after 
the last dose of treatment.  Pembrolizumab must be withheld for drug-related toxicities and 
severe or life-threatening AEs as per Table 7 below. See Section 8.8 for supportive care 
guidelines, including use of corticosteroids. Dose reductions are not permitted. 
 

 
 
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Table 7: Dose Modification Guidelines for Drug-Related Adverse Events 
General instructions: 
1. 
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. 
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to 
Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not 
resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day 
within 12 weeks.  
3. 
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other 
immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
 
Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
 Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
 
 
Monitor participants for signs 
and symptoms of pneumonitis 
 
Evaluate participants with 
suspected pneumonitis with 
radiographic imaging and 
initiate corticosteroid 
treatment 
 
Add prophylactic antibiotics 
for opportunistic infections 
Grade 3 or 4, or 
recurrent Grade 
2 
Permanently 
discontinue 
Diarrhea / Colitis  
Grade 2 or 3 
Withhold 
 Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
 
 
Monitor participants for signs 
and symptoms of enterocolitis 
(ie, diarrhea, abdominal pain, 
blood or mucus in stool with 
or without fever) and of bowel 
perforation (ie, peritoneal 
signs and ileus). 
 
Participants with ≥ Grade 2 
diarrhea suspecting colitis 
should consider GI 
consultation and performing 
endoscopy to rule out colitis.  
 
Participants with 
diarrhea/colitis should be 
advised to drink liberal 
quantities of clear fluids.  If 
sufficient oral fluid intake is 
not feasible, fluid and 
electrolytes should be 
substituted via IV infusion. 
Grade 4 
Permanently 
discontinue 
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
 Administer corticosteroids 
(initial dose of 0.5- 1 mg/kg 
prednisone or equivalent) 
followed by taper 
 
Monitor with liver function 
tests (consider weekly or more 
frequently until liver enzyme 
value returned to baseline or 
is stable 
Grade 3 or 4  
Permanently 
discontinue 
 Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -
cell failure 
Withhold 
 Initiate insulin replacement 
therapy for participants 
with T1DM  
 Administer anti-
hyperglycemic in 
participants with 
hyperglycemia  
 
 
Monitor participants for 
hyperglycemia or other signs 
and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
 
Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated.   
 
 
Monitor for signs and 
symptoms of hypophysitis 
(including hypopituitarism and 
adrenal insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue1  

 
 
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Hyperthyroidism  
Grade 2 
Continue  
 Treat with non-selective 
beta-blockers (eg, 
propranolol) or 
thionamides as appropriate  
 
Monitor for signs and 
symptoms of thyroid 
disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
 
Initiate thyroid 
replacement hormones 
(eg, levothyroxine or 
liothyroinine) per standard 
of care 
 
Monitor for signs and 
symptoms of thyroid 
disorders.  
 
Nephritis and 
Renal 
dysfunction 
Grade 2 
Withhold  
 
Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by 
taper. 
 
Monitor changes of renal 
function 
 
Grade 3 or 4  
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
 
Based on severity of AE 
administer corticosteroids 
 
Ensure adequate evaluation 
to confirm etiology and/or 
exclude other causes 
 
Grade 3 or 4 
Permanently 
discontinue 
All other 
immune-related 
AEs 
Intolerable/ 
persistent Grade 
2 
Withhold 
 
Based on type and severity 
of AE administer 
corticosteroids  
 
Ensure adequate evaluation 
to confirm etiology and/or 
exclude other causes 
 
Grade 3 
Withhold or 
discontinue 
based on the 
type of event.  
Events that 
require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent Grade 
3  
Permanently 
discontinue 
1. 
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, 
pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or 
achieved metabolic control (in case of T1DM).   
 
Dosing interruptions are permitted in the case of medical/surgical events or logistical 
reasons not related to study therapy (e.g., elective surgery, unrelated medical events, 
patient vacation, and/or holidays). Patients should be placed back on study therapy within 3 
weeks of the scheduled interruption, unless otherwise discussed with the Sponsor. The 
reason for interruption should be documented in the patient's study record. 
 
If treatment is delayed by more than 20 days from the planned date of dose administration, 
patient will be considered to have missed the dose for that cycle and will proceed to the 
next cycle. Missed cycle doses will not be made up. 
 
10.2 
Continuing Pembrolizumab 
In the event of radiological progression, pembrolizumab may be continued if there is 
evidence of clinical benefit in the opinion of the investigator if there are no signs or 

 
 
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symptoms indicating unequivocal disease progression, no decline in ECOG performance 
status attributed to disease progression and no growth of the tumour in critical sites. If 
radiological progression is still documented pembrolizumab may still be continued until 
there is unequivocal symptomatic deterioration attributed to disease progression that 
requires initiation of new systemic therapy. Radiotherapy to progressing or symptomatic 
sites as per standard clinical practice is allowed. 
 
11. 
Labeling, Packaging, Storage and Return of Clinical Supplies 
11.1 
Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
 
Clinical Supplies will be provided by Merck as summarized in Table 8. 
 
Table 8: Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
11.2 
Packaging and Labelling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
 
11.3 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the patient, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided. 
 
11.4 
Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
 
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
 
 
 

 
 
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11.5 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the patients and the 
amount remaining at the conclusion of the trial.  
 
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, 
local and institutional guidelines and procedures, and provided that appropriate records of 
disposal are kept. 
 
12. 
Adverse Events 
12.1 
Adverse Event Definition 
An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical 
investigation patient administered a pharmaceutical product (or any other protocol specified 
intervention including radiation therapy, surgery or use of a device) and which does not 
necessarily have to have a causal relationship with this treatment.  
 
An AE can therefore be any unfavourable and unintended sign, symptom or disease 
temporally associated with the use of a medicinal product, whether or not related to the 
medicinal product (or associated with the use of any other protocol specified intervention 
including radiation therapy, surgery or use of a device).  
 
AEs include: ‘Adverse Drug Reactions’, i.e. a reaction, in contrast to an event, is characterised 
by the fact that a causal relationship between the drug and the occurrence is suspected. 
 
For unapproved medicines:  any noxious and unintended response to a medicinal product, 
related to any dose. The phrase “response to an unapproved medicinal product” means that 
a causal relationship between the product and an adverse event is at least a reasonable 
possibility, i.e. the relationship cannot be ruled out. (‘Unapproved medicinal product’ here 
includes approved products used at levels or in ways that are unapproved). 
 
Regarding marketed medical products: a noxious and unintended response to a drug that 
occurs at doses normally used in humans for prophylaxis, diagnosis or therapy of diseases or 
for modification of physiological function. 
 
12.2 
Unexpected Adverse Event Definition 
An unexpected adverse event (UAE) is an AE for which the nature or severity of the event is 
not consistent with the information in the relevant source documents e.g. the IB, published 
information, product information (or with the applicable side effect risk profile for radiation 
therapy, surgery or use of a device).  

 
 
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UAEs also include unexpected adverse drug reactions (UADR) - The nature and severity of 
the ADR is not consistent with the information in the Investigators Brochure for an 
unapproved investigational product, or the product information/package insert/summary of 
product characteristics for an approved product. 
 
12.3 
Serious Adverse Event Definition 
Adverse events and adverse drug reactions are considered ‘serious’ if they threaten life or 
function.  
 
Due to the significant information they provide, serious adverse events (SAE) (including 
Serious Adverse Drug Reactions) require expedited reporting. SAEs are defined as any 
adverse event or adverse drug reaction which: 
 Results in death (i.e. fatal/grade 5 CTCAE) 
 Is life-threatening (i.e. grade 4 CTCAE) 
 Requires inpatient hospitalisation or prolongation of existing hospitalisation 
 Results in persistent or significant disability/incapacity; or 
 Is a congenital anomaly/birth defect 
 Is a new cancer (that is not a condition of the study) 
 Is associated with an overdose 
 Other significant medical event* 
 
*Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is also appropriate in other situations, such as important medical events that may 
not be immediately life threatening or result in death or hospitalization but may jeopardize 
the patient or may require intervention to prevent one of the other outcomes listed in the 
definition above. These should usually be considered serious. 
 
The following are NOT considered SAEs: 
 Hospitalizations not intended to treat an acute illness or adverse event (e.g., social 
reasons such as pending placement in long-term care facility). 
 Surgery or procedure planned before entry into the study. Note: Hospitalizations 
that were planned before the signing of the PICF, and where the underlying 
condition for which the hospitalization was planned has not worsened, will not be 
considered serious adverse events. Any adverse event that results in a prolongation 
of the originally planned hospitalization is to be reported as a new serious adverse 
event. 
 Disease progression should NOT be reported as an adverse event or serious adverse 
event term; instead, signs and symptoms of clinical sequelae resulting from disease 
progression/lack of drug efficacy will be reported if they fulfill the serious adverse 
event definition.  
 A standard procedure for protocol therapy administration will not be reported as a 
serious adverse event. Hospitalization or prolonged hospitalization for a 

 
 
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complication of therapy administration will be reported as a serious adverse event. 
 The administration of blood or platelet transfusion. Hospitalization or prolonged 
hospitalization for a complication of such transfusion remains a reportable serious 
adverse event. 
 A procedure for protocol/disease-related investigations (e.g., surgery, scans, 
endoscopy, sampling for laboratory tests, bone marrow sampling, pharmacokinetic 
or biomarker blood sampling). Hospitalization or prolonged hospitalization for a 
complication of such procedures remains a reportable serious adverse event. 
 Prolonged hospitalization for technical, practical, or social reasons in the absence of 
an adverse event. 
 
12.4 
Attribution  
Attribution of cause requires at least a reasonable possibility of a causal relationship 
between the event and the use of the investigational drug or any other protocol-specified 
intervention.  
 
All protocol-specified interventions (including pharmaceutical products, radiation therapy, 
surgery or use of a device) administered prior to the date of the event must be attributed a 
degree of causality from one of the following codes: 
 
RELATIONSHIP ATTRIBUTION 
DESCRIPTION 
Unrelated 
Unrelated 
The AE is clearly NOT related to the intervention 
Unlikely 
The AE is doubtfully related to the intervention 
Related 
Possible 
The AE may be related to the intervention 
Probable 
The AE is likely related to the intervention 
Definite 
The AE is clearly related to the intervention 
 
12.5 
Severity Criteria 
An assessment of severity grade will be made using the NCI-CTCAE (version 4.03).  Where 
parameters are not addressed within the criteria, severity of AEs should be graded as: 
 
Mild 
Aware of sign or symptom, but easily tolerated 
Moderate 
Discomfort enough to cause interference with usual activities 
Severe 
Incapacitating with inability to work or perform usual activities 
Life-threatening 
Patient is at immediate risk of death 
Fatal 
Death 
 
12.6 
Adverse Events Reporting  
All adverse events, which occur whilst the patient is enrolled on the trial, must be reported 
in the patients’ medical records and recorded on the relevant CRF.  
 
 

 
 
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12.7 
Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.03. All adverse events 
regardless of CTCAE grade must also be evaluated for seriousness. Laboratory values need 
reporting as AEs only if abnormal and deemed clinically significant by the investigator. 
 
12.8 
Serious Adverse Event Reporting 
12.8.1 Trial sites/investigators 
All SAEs that occur from the time a patient has signed consent for the Trial to within 30 days 
of the final protocol-specified treatment are required to be reported to the Sponsor whether 
or not considered related to the treatment under investigation.  
 
The Principal Investigator (PI) must: 
 Determine whether an AE is ‘Serious’  
 For SAEs, the PI must then ascertain the suspected cause 
 The attribution to the SAE must be recorded in the patients’ medical records and 
reported on the SAE form.  
 
SAEs must be reported by completing the SABRseq SAE form and emailing/faxing to the 
following: 
 
Sponsor (or delegate) 
Safety_BaCT@petermac.org   
Merck Global Safety 
+1-215-993-1220 
Merck Canada INC 
1-800-369-3090 or +1-514-428-4934 
 
SAE forms are required at the following points: 
 
Initial Report 
Within one working day/24 hours of discovery or notification of the 
event.  If the reporting of an SAE is delayed by more than 24 hours, 
an explanation must be provided on the SAE form.   
Incomplete Reports 
If all details are not available at the time of the initial report a 
completed report must be sent within the next 10 days. 
Updated Report 
If the event is not resolved (or ‘on-going’) at the time of the initial 
report, the SAE Form must be submitted every 30 days until the 
event is resolved, death has occurred or the condition has stabilised. 
If a change occurs in a stable condition (i.e. either worsens or 
improves), then a new SAE Form should be faxed 
 
The Investigator is ultimately responsible for reporting the SAE and must sign the final SAE 
report(s). Should this Investigator not be available to sign the initial SAE form within the 24-
hour period, a comment to this effect must be written on the form and the form signed by 

 
 
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the clinician attending to the patient at the time and faxed to the Sponsor. The investigator 
must sign the SAE form as soon as possible and re-fax to the Sponsor. 
 
The Investigator at the Trial Site is responsible for determining the local SAE reporting 
requirements of the responsible HREC and subsequently notifying the HREC of SAEs as 
required.  
 
All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the patients participation in the study, must be followed until any of the 
following occurs: 
 The event resolves 
 The event stabilizes 
 The event returns to baseline, if a baseline value/status is available 
 The event can be attributed to agents other than the study drug or to factors 
unrelated to study conduct 
 It becomes unlikely that any additional information can be obtained (patient or 
health care practitioner refusal to provide additional information, lost to follow-up 
after demonstration of due diligence with follow-up efforts) 
 
12.8.2 Sponsor 
The Sponsor is responsible for: 
 Implementing and maintaining a suitable recording system to record information 
from all SAEs received from Trial Sites. 
 Ensuring that the Coordinating Principal Investigator (CPI) is notified of each SAE to 
enable the SAE to be assessed by the CPI and any other appropriate reviewers for 
nature (expected/unexpected), causality and whether the appropriate regulatory 
authority need to be notified of the SAE. 
 Notifying the appropriate regulatory authority in accordance with the regulatory 
authority’s detailed guidance of any SUSARs that are fatal or life threatening as 
soon as possible but no later than 7 days after the site gained first knowledge of the 
event. Incomplete reports must be completed and forwarded as soon as possible 
within 8 additional calendar days. All other serious, unexpected ADRs should be 
reported to the TGA within 15 days after the site gained first knowledge of the 
event. 
 Considering information provided by (non-serious) adverse event data. 
 Informing each trial site of new information arising from serious and non-serious 
adverse events and adverse drug reactions that may affect the conduct of the Trial, 
or the rights, interests, safety or wellbeing of trial patients. 
 Notifying the appropriate regulatory authority of any significant issue that has 
arisen from analysis of overseas reports or action that has been taken by another 
country’s regulatory authority within 72 hours of first knowledge. 
 

 
 
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12.9 
Events of Clinical Interest  
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be recorded as such on the Adverse Event case report forms and reported 
within 24 hours to the Sponsor and within 2 working days to Merck Global Safety. (Attn: 
Worldwide Product Safety; FAX +1 215 993-1220). 
 
For the time period beginning at first treatment through 90 days following cessation of 
treatment, or 30 days following cessation of treatment if the patient initiates new anticancer 
therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not related to 
protocol treatment, must be reported within 24 hours to the Sponsor and within 24 hours to 
Merck Global Safety. 
 
 
Events of clinical interest for this trial include: 
1. an overdose of pembrolizumab, as defined in Section 12.10 Definition of an 
Overdose for This Protocol and Reporting of Overdose to the Sponsor, that is not 
associated with clinical symptoms or abnormal laboratory results.  
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 
2X the upper limit of normal and, at the same time, an alkaline phosphatase lab 
value that is less than 2X the upper limit of normal, as determined by way of 
protocol-specified laboratory testing or unscheduled laboratory testing. 
 
12.10  Overdose Definition and Reporting  
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose). No specific information is available on the 
treatment of overdose of pembrolizumab. Appropriate supportive treatment should be 
provided if clinically indicated. In the event of overdose, the patient should be observed 
closely for signs of toxicity. Appropriate supportive treatment should be provided if clinically 
indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of pembrolizumab, 
the adverse event(s) is reported as a serious adverse event, even if no other seriousness 
criteria are met. 
 
If a dose of pembrolizumab meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a 
non-serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect” on the relevant Adverse Event eCRF. 
 
All reports of overdose with and without an adverse event must be reported within 24 hours 
to the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX +1-215 993-1220). 

 
 
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12.11 Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
Although pregnancy and lactation are not considered adverse events, it is the responsibility 
of investigators or their designees to report any pregnancy or lactation in a patient 
(spontaneously reported to them), including the pregnancy of a male patient's female 
partner that occurs during the trial or within 120 days of completing the trial completing the 
trial, or 30 days following cessation of treatment if the patient initiates new anticancer 
therapy, whichever is earlier. All patients and female partners of male patients who become 
pregnant must be followed to the completion/termination of the pregnancy. Pregnancy 
outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted 
ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as serious 
events (Important Medical Events). If the pregnancy continues to term, the outcome (health 
of infant) must also be reported. 
 
Such events must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX +1 215 993-1220) 
 
13. 
Response Assessment 
Response and progression will be evaluated in this study using RECIST 1.1, irRECIST, Peter 
Mac Metabolic Response Criteria and PERCIST 1.0.  
 
13.1 
Evaluation of response by RECIST1.1 and irRECIST 
The same imaging modality as used at screening (i.e. CT or MRI scans) should be used at 
every visit.  Changes only in the largest diameter (unidirectional measurement) of the 
tumour lesions are used in the RECIST v1.1 criteria. For tumour lymph nodes, the short axis 
must be measured. Lesions are measurable or non-measurable using the definitions 
described below.  Refer to Appendix 3 and 4. 
 
13.2 
Peter Mac Metabolic Response Criteria  
Metabolic response in a lesion will be assessed according to the method given in MacManus 
et al.  Scans are read visually displayed side by side with liver uptake normalised between 
images. Response categories are defined as follows (comparison is with baseline PET scans in 
each case): 
 Complete metabolic response (CMRV): Activity within the tumour site has decreased 
to be equal to or less than adjacent soft tissue in the radiation treatment volume.  
 Partial metabolic response (PMRV): Any appreciable reduction in intensity of tumour 
FDG uptake or in tumour volume. 
 Stable metabolic disease (SMDV): No appreciable change in intensity of tumour FDG 
uptake or in tumour volume. 
 Progressive metabolic disease (PMDV): Appreciable increase in tumour FDG uptake or 
in tumour volume. 
 

 
 
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13.3 
PERCIST 1.0 Criteria 
A region of interest (ROI) is used to assess the maximum SUL peak. This ROI is typically the 
region of the baseline tumour with the highest uptake, but it can also be another lesion that 
was previously present and is the most active lesion after treatment.  
 Complete metabolic response (CMR): complete resolution of 18F-FDG uptake within 
the measurable target lesion so that it is less than mean liver activity and 
indistinguishable from surrounding background blood-pool levels. Disappearance of 
all other lesions to background blood-pool level.  
 Partial metabolic response (PMR): reduction greater or equal to 30% in the target 
measurable tumour 18F-FDG SUL peak.  
 Stable metabolic disease (SMD): disease other than CMR, PMR or PMD. 
 Progressive metabolic disease (PMD):  Greater than 30% increase in 18F-FDG SUL 
peak OR visible increase in extent of 18F-FDG tumour uptake (75% of total lesion 
glycolysis volume with no decline in SUL OR the advent of new 18F-FDG-avid lesions 
that are typical of cancer and not related to treatment effect or infection. 
 
14. 
Statistical Considerations 
14.1 
Statistical Analysis Plan Summary 
This is a prospective, two-arm randomised, open label, Phase Ib study assessing safety, 
efficacy and biological effects of two different treatment sequences of the combination of 
SABR with pembrolizumab in patients with metastatic NSCLC.  
 
14.2 
Treatment Assignment 
Patients will be randomised in the ratio of 1:1 between the two arms. Once randomisation is 
assigned, cancellation will not be permitted. Patients will be stratified by number of 
metastases to be treated with SABR (two groups: 1 metastasis vs 2 or 3 metastases), and by 
line of therapy (two groups: previously treated vs previously untreated). 
 
14.3 
Populations for Analyses 
• Treated patient population is defined as the patients who completed at least one SABR 
treatment and received at least one dose of pembrolizumab. This is the primary 
population for the safety and efficacy analyses.  
• Response-evaluable patients are those treated patients who have CT or PET scans 
performed at respective follow-up visit. This is the analysis population for the response 
endpoint. 
 
Patients that are not part of the treated population will be replaced and no follow-up 
information will be collected. 
 
 
 

 
 
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14.4 
Statistical Methods 
Demographics and baseline characteristics of patients will be summarized using descriptive 
statistics. No imputation for missing values is intended. All statistical tests comparing the 
two arms will be 2-sided, 5% alpha will be used and no adjustment for multiplicity is 
intented. 
 
14.5 
Safety Analysis 
Safety will be assessed using CTCAE v4.03 and the maximum toxicity grade per patient of 
each adverse event will be derived and presented in table format according to arm and 
overall. The number of patients who suffer from grade 3 or higher toxicities (for each toxicity 
type and overall) will be provided considering all patients who have received at least one 
dose of pembrolizumab and completed at least one SABR treatment.  The safety analysis will 
be conducted twice: once for all AE’s, regardless of relatedness to treatment and once 
considering only AE’s related to the treatment (i.e. classified as possibly, probably or 
definitely related). 
 
14.6 
Time-to-Event Endpoint Analysis 
A cut-off date for follow-up will be determined at the time of analysis. The cut-off date will 
be chosen to enable data on follow-up to that date to be collected, where possible, on all 
living patients. All events occurring after this date will be ignored in the analysis in order to 
minimise reporting bias. Progression free survival and overall survival will be described for 
each arm using Kaplan-Meier methods. Estimates at key time points will be provided with 
95% confidence interval. Stratified log-rank test will be used to compare the curves between 
arms. 
 
An event history chart will be used to describe the individual patient’s events of interest. 
Each patient in each arm will be represented as a line with different symbols identifying 
when the patient had a progression on irradiated lesions, progression on a non-irradiated 
lesions, appearance of new lesions, when treatment ceased, when they died and when 
censoring occurred. 
 
14.7 
Response Analysis 
All tumour response measurements (pre- and post-treatment) must be recorded using the 
definitions of RECIST 1.1. RECIST assessments will take into account post-treatment 
inflammatory processes that occur after SABR treatment in pulmonary and liver tissues. PET 
response criteria will also be assessed and reported. If a criterion is met in more than one 
response type then the response type will be classified at the lowest possible level. The 
initial assessment of response will be determined after all protocol treatment has been 
completed, whether or not all of the planned treatment was received. In addition, irRECIST, 
PERCIST and Peter Mac Metabolic Response criteria will be considered in conjunction to 
RECIST 1.1. Metabolic response criteria and PERCIST 1.0 results or assessments will not be 
entered by site clinical staff and will be reported centrally. Overall patient’s response rates 

 
 
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(CR+PR at all lesions) at 6 and 12 months after commencement of SABR treatment will be 
described as percentages with exact 95% confidence interval. Overall response for all 
irradiated lesions and un-irradiated lesions will also be assessed separately. Lesion size of 
measurable lesions may be plotted over time to describe patient response trajectories. 
Overall response rates will be compared between treatment arms using Fisher’s exact test.  
 
14.8 
Exploratory Endpoints 
Exploratory endpoints will be described graphically and simple descriptive statistics will be 
provided for each variable at each time point. 
 
14.9 
Sample Size Calculation  
This is a Phase Ib study with a sample size of 32 patients (16 in each arm).  This study will 
assess the common toxicities associated with the combination of SABR and pembrolizumab. 
The sample size was determined such that, within each arm, the probability of observing 
toxicity in at least one patient was 80% for toxicities with true incidence rates of at least 
10%. Table 9 illustrates different scenarios for true toxicity rates ranging from 5% to 30% 
with the respective probability of at least one patient presenting with the toxicity within the 
arm and overall.  
 
Table 9: Probability of at least one patient presenting with a toxicity for different true 
toxicity rates  
True toxicity rate 
Within each arm (n=16) 
Overall (n=32) 
5% 
0.560 
0.806 
10% 
0.815 
0.966 
15% 
0.926 
0.994 
20% 
0.972 
0.999 
 
The table below shows the expected confidence interval for different response rate 
scenarios within each arm. 
 
Table 10: Response rate and confidence intervals for different number of responses with 
n=16 
Number of responses 
Response rate (95% confidence interval) 
6 
37.5 (15 – 65) 
8 
50 (25 – 75) 
10 
62.5 (35 – 85) 
12 
75 (48 – 93) 
Recruitment will occur over a two-year period. The principal analyses will be 24 months after 
the last patient has commenced treatment. An interim analysis assessing patterns of failure 

 
 
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and response to therapy based on post-therapy PET response will be performed once all 
recruited patients have completed 5 cycles of pembrolizumab therapy. 
 
14.10 Early Termination Criteria 
Consideration of suspension of patient accrual will occur if an unacceptable rate of toxicity is 
detected. The expected rates of grade 3+ pneumonitis and colitis are expected to be less 
than 5%. If at any given time during the trial 3 or more patients present with treatment 
related pneumonitis or colitis of grade 3-4 toxicity, data will be reviewed by the TMC and 
consideration will be given to permanently suspend recruitment and close the trial 
 
14.11  Deviations  
Any deviations from the statistical plan should be described and justified in the protocol (i.e. 
protocol amendment) or in the statistical report.  
 
15. 
Trial Management & Administrative Requirements 
15.1 
Trial Personnel  
The Investigator(s) is responsible for ensuring that all trial personnel are qualified for their 
designated roles and provides information about the trial to all staff members involved in 
the trial or any element of patient management, both before starting the practical 
performance of the trial and during the course of the trial (e.g. when new staff become 
involved). 
 
Additional information available during the trial should be given, as agreed upon, either by 
the investigator or delegate and always when a new staff member becomes involved in the 
trial. 
 
15.2 
Audit and Inspection 
According to ICH/GCP Guidelines, the Sponsor may audit the investigational site to compare 
raw data, source data and associated records with the interim (if applicable) or final report 
of the trial to assure that data have been accurately reported. The Sponsor’s Clinical Quality 
Assurance department is responsible for the auditing of the trial. Auditing may be contracted 
to an external body. 
 
The Investigator(s) must accept that regulatory authorities may conduct an inspection to 
verify compliance of the trial with GCP. 
 
15.3 
Protocol Deviations 
The protocol must be read thoroughly and the instructions must be followed. However, 
exceptions will be made in emergency situations when the protection, safety and wellbeing 
of the patient requires immediate intervention based on the judgement of the Investigator 
or a responsible, appropriately trained and credentialed professional(s) designated by the 

 
 
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Investigator as a sub-investigator. 
 
In the event of a significant deviation due to an emergency, accident or error, the 
Investigator or designee must contact the Principal Investigator and notify the Sponsor (OCR) 
at the earliest possible time by telephone. This allows for an early joint decision to be made 
as to whether or not the patient should continue in the trial.  
 
16. 
Data Handling and Record Keeping 
16.1 
Case Record Form (CRF)  
In this trial the CRF will be electronic (eCRF). The investigator or the designated site person 
must complete the CRF and supporting documentation for each patient within a timely 
manner of the visit occurring. 
 
The Clinical Trial Manager(s) will review the completed data for accuracy, completeness and 
consistency. The Clinical Trial Manager will submit requests for correction / clarification of 
data (e.g. queries) to the Investigator or designee when inconsistencies are identified during 
review, monitoring (if applicable) or during the edit check process. 
 
All corrections and alterations to CRF data must be made by the investigator or by the 
designated site personnel in a timely manner and in according to the instructions provided. 
Completed CRFs should be reviewed and signed by the Principal Investigator or designated 
site personnel. All persons appointed by the Investigator to participate in the trial must be 
indicated on the delegation of authority log. 
 
16.2 
Source Documents 
The investigator is required to prepare and maintain adequate and accurate case histories 
(i.e. medicals) designed to record all observations and other data pertinent to the trial for 
each trial patient. The medical records must contain adequate information to allow for 
verification of patient identity throughout the trial. 
 
Any date recorded directly on the CRF, as agreed by the Sponsor for which no other written 
or electronic record will be maintained in the patient’s medical record, will be considered 
source data (e.g. results from physical examinations, vital signs testing or the drug 
administration procedure). 
 
The eCRF and the patient’s medical records pertinent to the trial may be reviewed by a 
designated monitor, auditors and possibly by representatives from the IRB/IEC and 
regulatory bodies such as the TGA, US Food and Drug Administration (FDA) or the Canadian 
Health Authority to the extent permitted by regulation. 
 
The investigator is required to retain a patient identification code list to allow unambiguous 
identification of each patient included in the trial. This list should contain the patient’s full 
name, data of birth, and dates of participation and trial identification number. This list is 

 
 
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held in confidentiality at the Investigator site. 
 
Source documents pertaining to the trial must be maintained by investigational sites and de-
identified copies provided to BaCT in accordance with the source data verification checklist 
(provided by BaCT).  Source documents should include a patient’s medical records, hospital 
charts, clinic charts, the investigator’s patient study files, as well as the results of any 
diagnostic tests such as x-rays, CT/MRI scans, laboratory tests, ECGs etc.  
 
16.3 
Archiving of Trial Documents 
Trial data and other essential documentation must be retained for a period of at least 15 
years (MHRA Guidelines). 
 
It is the responsibility of the Sponsor to inform the Investigator(s) / site(s) when these 
documents need no longer be retained. The original record of CRFs will be archived by the 
Sponsor for at least 15 years. No trial document or image will be destroyed without prior 
written agreement between the Sponsor and the Investigator(s). Should the Investigator(s) 
wish to assign the trial records to another party or move to another location, advance 
written notice will be given to the Sponsor. 
 
17. 
Ethical Aspects 
17.1 
Informed Consent 
This trial will be conducted in compliance with 21 CFR Part 50 for informed consent. Written 
informed consent will be obtained from each patient before any procedures or assessments 
are done and after the aims, methods, anticipated benefits, and potential hazards are 
explained. Explanation will also be provided to the patients that they are free to refuse entry 
into the trial and free to withdraw from the trial at any time without prejudice to future 
treatment. 
 
The patient’s willingness to participate in the trial will be documented in writing on a 
consent form, which will be signed by the patient with the date and time of that signature 
indicated. The Investigator(s) will keep the original consent forms and copies will be given to 
the patient. In addition, the process of obtaining consent will be documented in the patient’s 
medical record by the person conducting the informed consent discussion. 
 
Written and/or oral information about the trial in a language understandable by the patient 
will be given to all patients. The information provided must include an adequate explanation 
of the aims, methods, anticipated benefits, potential hazards, and insurance arrangements 
in force. 
 
 
 

 
 
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17.2 
Confidentiality Regarding Trial Patients 
The Investigator must ensure the privacy of the patients, including their personal identity 
and all personal medical information, will be maintained at all times. In CRFs and other 
documents submitted, patients will not be identified by their names, but by an identification 
code (e.g. patient ID number). 
 
A monitor, properly authorised persons on behalf of the Sponsor’s quality assurance unit or 
competent authorities may scrutinise personal medical information for the purpose of 
verifying data recorded on the CRF. Personal medical information will always be treated as 
confidential, according to local privacy regulations. 
 
17.3 
Trial Management Committee (TMC) 
The TMC will initially meet to assess safety after 3 patients in each arm has completed 8 
cycles of pembrolizumab. Thereafter, the TMC will meet at 6 monthly intervals.  
The TMC will comprise the following members:  
• Radiation Oncology Principal Investigator 
• Medical Oncology Principal Investigator 
• An Independent Research Physician  
• Clinical Trial Manager  
• Trial Statistician  
 
The C/PI will receive and review SAEs in real time. 
 
The TMC will receive periodic safety reports therefore facilitating a response to potential 
safety issues. The TMC will also oversee study planning, monitoring, progress, review of 
information from related research, and implementation of recommendations from other 
study committees and external bodies (e.g. ethics committees). The primary mandate of the 
TMC would be to protect patient safety. If adverse events of a particularly serious type are 
more common than anticipated, the study can be considered for termination. Please see 
SABRseq TMC terms of reference for further information.  
 
The TMC will consider whether to continue the study as planned, modify, or stop it, based 
on reports provided by BaCT or other information. 
 
18. 
Publication and Presentation Policy 
18.1 
Reporting of Results 
The Trial Management Committee will be responsible for decisions regarding presentations 
and publications arising from this trial according to the Sponsor Authorship, Publication and 
Spokesmanship Guidelines. 
 
The statistician will perform the primary analysis of trial results, for publication. The principal 
investigator will publish the primary trial results.  

 
 
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Publications and abstracts must be presented to the TMC Sponsor (OCR) for review and 
approved prior to submission.  
 
18.2 
Trial Registry 
TheC/PI is responsible for registering all trials with an appropriate clinical trials registry prior 
to the accrual of the first patient.  
 

 
 
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Appendix 1 
 
ECOG Performance Status Criteria 
 
 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work. 
2 
Ambulatory and capable of all self care but unable to carry out any work activities. Up and 
about more than 50% of waking hours. 
3 
Capable of only limited self care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled. Cannot carry on any self care. Totally confined to bed or chair. 
5 
Dead 
 
As published in Am. J. Clin. Oncol.:  
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: 
Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-
655, 1982. 
 
 
 
 

 
 
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Appendix 2 
 
Spine Instability Neoplastic Score (SINS) 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Appendix 3 
 
RECIST 1.1 criteria- Response Evaluation Criteria in Solid Tumours 
 
These instructions are based on the guidelines recommended in Eisenhower et al., 2009 . 
 
3. Disease and lesion definitions 
 
3.1 Measurable Disease  
Measurable tumour lesions are defined as those that can be accurately measured in at least 
one dimension (longest diameter to be recorded) as  
- ≥10 mm with CT scan or clinical examination.  
- Bone lesions are considered measurable only if assessed by CT scan and have an 
identifiable soft tissue component that meets these requirements (soft tissue 
component > 10 mm by CT scan).   
- Malignant lymph nodes must be ≥ 15mm in the short axis to be considered 
measurable; only the short axis will be measured and followed.  
All tumour measurements must be recorded in millimetres. Previously irradiated lesions are 
not considered measurable unless progression has been documented in the lesion. 
 
3.2 Non-measurable Disease  
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph 
nodes with ≥ 10 to < 15 mm short axis) as well as truly non-measurable lesions. Lesions 
considered truly non-measurable include: leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitis cutis/pulmonis, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques. 
All measurements should be taken and recorded in metric notation, using callipers if 
clinically assessed.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the treatment.  
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. 
Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules and palpable lymph nodes). For the case of skin lesions, documentation by colour 
photography, including a ruler to estimate the size of the lesion, is recommended.  
 
3.3 Methods of Measurement 
 CT and MRI are the best currently available and reproducible methods to measure 
target lesions selected for response assessment. Conventional CT and MRI should be 
performed with cuts of 10 mm or less in slice thickness contiguously.  Spiral CT should 
be performed using a 5 mm contiguous reconstruction algorithm.  This applies to 
tumours of the chest, abdomen and pelvis.  Head and neck tumours and those of 
extremities usually require specific protocols.  
 Lesions on chest X-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable.  

 
 
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3.4 Baseline documentation of “Target” and “Non-Target” lesions 
 All measurable lesions up to a maximum of two lesions per organ and 5 lesions in 
total, representative of all involved organs should be identified as target lesions and 
recorded and measured at baseline. 
 Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs and should be those that lend 
themselves to reproducible repeated measurements. On occasion, the largest lesion 
may not lend itself to reproducible measurement, in which circumstance the next 
largest lesion, which can be measured reproducibly, should be selected. 
 Only the short axis of lymph nodes identified as target lesions contribute to the 
baseline sum. The short axis of the node is the diameter normally used by 
radiologists to judge if a node is involved by solid tumour. 
 A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) 
for all target lesions will be calculated and reported as the baseline sum diameters. 
The baseline sum diameters will be used as reference by which to characterise the 
objective tumour. 
 All other lesions (or sites of disease) including pathological lymph nodes should be 
identified as non-target lesions and should also be recorded at baseline. 
Measurements of these lesions are not required, but the presence, absence, or in 
rare cases ‘unequivocal progression’ of each should be noted throughout follow-up. 
In addition, it is possible to record multiple non-target lesions involving the same 
organ as a single item on the case report form (e.g. multiple enlarged pelvic lymph 
nodes or multiple liver metastases’. 
 
3.5 RECIST 1.1 Response Criteria  
 
Target lesions 
Non-target lesions 
Complete 
Response 
(CR) 
Disappearance of all target lesions. Any 
pathological lymph nodes (whether target or 
non-target) must have reduction in short axis 
to <10 mm 
Disappearance of all non-
target lesions and 
normalisation of tumour 
marker level. All lymph 
nodes must be non-
pathological in size (<10 mm 
short axis) 
Partial 
Response 
(PR) 
At least a 30% decrease in the sum of 
diameters of target lesions, taking as 
reference the baseline sum diameters 
Persistence of one or more 
non-target lesion(s) or/and 
maintenance of tumour 
marker level above the 
normal limits 
Progressive 
Disease (PD) 
At least a 20% increase in the sum of 
diameters of target lesions, taking as 
reference the smallest sum on study (this 
includes the baseline sum if that is the 
smallest on study). In addition, the sum must 
also demonstrate an absolute increase of at 
least 5 mm. The appearance of one or more 
new lesions is also considered progression. 
Appearance of one or more 
new lesions and/or 
unequivocal progression of 
existing non-target lesions 
(1) 

 
 
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Stable 
Disease (SD) 
Neither sufficient shrinkage to qualify for PR 
nor sufficient increase to qualify for PD, taking 
as reference the smallest sum diameters while 
on study. 
 
(1) Although a clear progression of “non target” lesions only is exceptional, in such circumstances, the opinion of 
the treating physician should prevail and the progression status should ideally be confirmed later on by the 
review panel (or Study Chair). 
3.6 Confirmation 
 The main goal of confirmation of objective response is to avoid overestimating the 
response rate observed.  In cases where confirmation of response is not feasible, it 
should be made clear when reporting the outcome of such studies that the responses 
are not confirmed.  
 To be assigned a status of PR or CR, changes in tumour measurements must be 
confirmed by repeat assessments that should be performed no less than 4 weeks 
after the criteria for response are first met.  Longer intervals as determined by the 
study protocol may also be appropriate.  
 In the case of SD, follow-up measurements must have met the SD criteria at least 
once after study entry at a minimum interval (in general, not less than 6-8 weeks) 
that is defined in the study protocol.  
3.7 Evaluation of overall response 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
Not evaluable 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
Source: Eisenhauer et al, 2009 (see References) 
 
 

 
 
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Appendix 4 
 
irResponse Evaluation Criteria in Solid Tumors (irRECIST) 
 
Adapted from irRECIST - ESMO 2014 abstract 4958 
 
1.0. Baseline: Measurable Lesion Definitions and Target Lesion Selection 
 Follow the definitions from RECIST 1.1. 
 Measurable lesions must be accurately measured in at least one dimension with a 
minimum size of: 
o 10 mm in the longest diameter by CT or MRI scan (or no less than double the 
slice thickness) for non-nodal lesions and ≥15 mm in short axis for nodal 
lesions 
o 10 mm caliper measurement by clinical exam 
o 20 mm by chest X-ray 
1.1. Baseline: Non-measurable Lesion Definitions  
 Follow the definitions from RECIST 1.1 
 Non-target lesions will include: 
o Measurable lesions not selected as target lesions 
o All sites of non-measurable disease, such as neoplastic masses that are too 
small to measure because their longest uninterrupted diameter is < 10 mm 
(or < two times the axial slice thickness), ie. the longest perpendicular 
diameter is ≥10 and < 15 mm. 
o Other types of lesions that are confidently felt to represent neoplastic tissue, 
but are difficult to measure in a reproducible manner. These include bone 
metastases, leptomeningeal metastases, malignant ascites, pleural or 
pericardial effusions, ascites, inflammatory breast disease, lymphangitis 
cutis/pulmonis, cystic lesions, ill-defined abdominal masses, skin lesions, etc. 
1.2. Baseline: Target and Non-Target Lymph Node Lesion Definitions 
 Follow the definitions from RECIST 1.1 
1.3. Baseline: Non-Target Lesion Selection 
 All lesions or sites of disease not recorded as target lesions should be recorded as 
non-target lesions at baseline. There is no limit to the number of non-target lesions 
that can be recorded at baseline. 
1.4. Baseline: Bone Lesions 
 Follow the definitions from RECIST 1.1. 
 Regardless of the imaging modality blastic bone lesions will not be selected as target 
lesions. Lytic or mixed lytic-blastic lesions with a measurable soft tissue component 
≥10 mm can be selected as target lesions. 
1.5. Baseline: Brain Lesions  
 Lesions detected on brain scans can be considered as both target or non-target 
lesions. 
1.6. Baseline: Cystic and Necrotic Lesions as Target Lesions 
 Lesions that are partially cystic or necrotic can be selected as target lesions. The 
longest diameter of such a lesion will be added to the Total Measured Tumour 
Burden (TMTB) of all target lesions at baseline. If other lesions with a non-liquid/non-
necrotic component are present, those should be preferred. 
 

 
 
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1.7. Baseline: Lesions With Prior Local Treatment 
 During target lesion selection, the radiologist will consider information on the 
anatomical sites of previous intervention (e.g. previous irradiation, RF-ablation, TACE, 
surgery, etc.). 
 Lesions undergoing prior intervention will not be selected as target lesions unless 
there has been a demonstration of progress in the lesion. 
1.8. Baseline: No Disease at Baseline 
 If a patient has no measurable and no non-measurable disease at baseline the 
radiologist will assign ‘No Disease’ (irND) as the overall tumor assessment for any 
available follow-up timepoints unless new measurable lesions are identified and 
contribute to the TMTB. 
2.0. Follow-up: Recording of Target and New Measurable Lesion Measurements 
 The longest diameters of non-nodal target and new non-nodal measurable lesions, 
and short axes of nodal target and new nodal measurable lesions will be recorded. 
Together they determine the Total Measured Tumor Burden (TMTB) at follow-up. 
2.1. Follow-up: Definition of Measurable New Lesions 
 In order to be selected as new measurable lesions (≤ 2 lesions per organ, ≤ 5 lesions 
total, per timepoint), new lesions must meet criteria as defined for baseline target 
lesion selection and meet the same minimum size requirements of 10 mm in long 
diameter and minimum 15 mm in short axis for new measurable lymph nodes. New 
measurable lesions shall be prioritized according to size, and the largest lesions shall 
be selected as new measured lesions. 
2.2. Follow-up: Non-Target Lesion Assessment 
 The RECIST 1.1 definitions for the assessment of non-target lesions apply. 
 The response of non-target lesions primarily contributes to the overall response 
assessments of irCR and irNon-CR/Non-PD (irNN). Non-target lesions do not affect 
irPR and irSD assessments. Only a massive and unequivocal worsening of non-target 
lesions alone, even without progress in the TMTB is indicative of irPD. 
2.3. Follow-up: New Non-Measurable Lesions Definition and Assessment 
 All new lesions not selected as new measurable lesions are considered new non-
measurable lesions and are followed qualitatively. Only a massive and unequivocal 
progression of new non-measurable lesions leads to an overall assessment of irPD for 
the timepoint. Persisting new non-measurable lesions prevent irCR. 
2.4. irRC Overall Tumor Assessments 
 irCR, complete disappearance of all measurable and non-measurable lesions. Lymph 
nodes must decrease to < 10 mm in short axis. Confirmation of response is not 
mandatory. 
 irPR, decrease of ≥ 30% in TMTB relative to baseline, non-target lesions are irNN, and 
no unequivocal progression of new non-measurable lesions. 
 irSD, failure to meet criteria for irCR or irPR in the absence of irPD. 
 irNN, no target disease was identified at baseline and at follow-up the patient fails to 
meet criteria for irCR or irPD. 
 irPD, minimum 20% increase and minimum 5 mm absolute increase in TMTB 
compared to nadir, or irPD for non-target or new non-measurable lesions. 
Confirmation of progression is recommended minimum 4 weeks after the first irPD 
assessment. 
 irNE, used in exceptional cases where insufficient data exists. 
 irND, in adjuvant setting when no disease is detected.