PembRolIzuMab and Stereotactic Body Radiotherapy In Metastatic Non-small-cell lunG Cancer Patients
Phase: PHASE1
Conditions: Metastatic Non-small-cell lunG Cancer
Sponsor: Royal Marsden NHS Foundation Trust

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PRIMING Study Protocol 
 
 
 
 
 
 
 
Study Title: 
PRIMING: PembRolIzuMab and  stereotactic body radiotherapy 
In metastatic Non-small-cell lunG cancer patients  
CCR Number: 
CCR 4590 
Product: 
Pembrolizumab 
Sponsor: 
Royal Marsden NHS Foundation Trust 
EudraCT Number: 
2016-002962-30 
ClinicalTrials.gov 
ID: 
NCT03436056 
IRAS Project ID: 
211803 
REC Reference No: 
17/LO/1591 
Development phase: Phase I dose escalation study 
Protocol Date: 
Draft Protocol Version 1.0 – 14 May 2017 
 
 
 
 
 
 
 
 
Property of: Royal Marsden Clinical Trials Unit (RM-CTU) 
May not be used, divulged or published without the consent of: RM-CTU 

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Contact List 
Chief Investigator: 
 
Dr Fiona McDonald 
Consultant Clinical Oncologist 
The Royal Marsden Hospital 
Downs Road 
Sutton, SM2 5PT 
Tel: 0208 642 6011 x3272/2586 
Email: fiona.mcdonald@rmh.nhs.uk  
 
Sponsor: 
 
Royal Marsden NHS Foundation Trust  
Downs Rd, Sutton, Surrey 
London 
SM2 5PT 
Email: julie.curtis@rmh.nhs.uk  
 
Funder: 
 
Merck Sharp and Dohme (MSD) 
 
Trial Manager: 
 
Ms Andrea Pejenaute  
Royal Marsden – Clinical Trials Unit 
Royal Marsden NHS Foundation Trust 
Downs Road 
Sutton, Surrey 
SM2 5PT 
Tel: 0208 642 6011 x 6667 
Email: Priming.Trial@rmh.nhs.uk  
 
 
Trial Statistician: 
 
Ms Ranga Gunapala  
Royal Marsden NHS Foundation Trust 
The Royal Marsden 
Fulham Road, London  
SW3 6JJ  
Tel: 0207 808 2186 
Email: Ranga.Gunapala@rmh.nhs.uk  
 
 
 
 

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Protocol Development Team 
 
Dr Fiona McDonald 
Chief Investigator 
Consultant Clinical Oncologist 
Royal Marsden NHS Foundation Trust 
fiona.mcdonald@rmh.nhs.uk  
 
Prof Kevin Harrington  
Co-Investigator 
Consultant Clinical Oncologist 
Royal Marsden NHS Foundation Trust 
kevin.harrington@icr.ac.uk  
 
Dr Sanjay Popat 
Co-Investigator 
Consultant Medical Oncologist 
Royal Marsden NHS Foundation Trust 
sanjay.popat@rmh.nhs.uk 
 
 
Dr Mary O’Brien  
Co-Investigator 
Consultant Medical Oncologist 
Royal Marsden NHS Foundation Trust 
mary.obrien@rmh.nhs.uk  
 
Dr Rajiv Kumar 
Clinical Research Fellow  
Royal Marsden NHS Foundation Trust 
rajiv.kumar@rmh.nhs.uk  
 
Ms Ranga Gunapala 
Trial Statistician 
RDSU 
Royal Marsden NHS Foundation Trust 
ranga.gunapala@rmh.nhs.uk    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
List of Abbreviations ....................................................................................................................... 9 
1 
Trial Summary ................................................................................................................................ 12 
1 
BACKGROUND & RATIONALE .......................................................................................................... 15 
1.1 
Background ........................................................................................................................................ 15 
1.1.1 
Immune Evasion in Cancer ......................................................................................................................................... 15 
1.1.2 
Targeting the PD-1/PD-L1 axis .................................................................................................................................... 16 
1.1.3 
Rationale for combining anti-PD-1 effects with radiation .......................................................................................... 17 
1.1.4 
Pembrolizumab Clinical Trial Data .............................................................................................................................. 19 
1.1.4.1 
Pembrolizumab ................................................................................................................................................. 19 
1.1.4.2 
Clinical Trial Data .............................................................................................................................................. 19 
1.2 
Rationale for the Trial ......................................................................................................................... 21 
2 
Study OBJECTIVES & Endpoints ....................................................................................................... 22 
2.1 
Study Objectives & Hypothesis ............................................................................................................ 22 
2.1.1 
Primary Objective & Hypothesis ................................................................................................................................. 22 
2.1.2 
Secondary Objectives ................................................................................................................................................. 22 
2.1.3 
Exploratory Objectives ............................................................................................................................................... 22 
2.2 
Study Endpoints .................................................................................................................................. 22 
2.2.1 
Primary Endpoint ........................................................................................................................................................ 22 
2.2.2 
Secondary Endpoints .................................................................................................................................................. 22 
2.2.3 
Exploratory Endpoints ................................................................................................................................................ 23 
3 
Study DESIGN ................................................................................................................................. 24 
3.1 
Summary of Study Design ................................................................................................................... 24 
3.2 
Treatment Regimen ............................................................................................................................ 24 
3.2.1 
Dose Limiting Toxicities .............................................................................................................................................. 25 
3.3 
Study Schema ..................................................................................................................................... 26 
3.4 
Follow-Up after stopping Pembrolizumab ............................................................................................ 27 
3.4.1 
30 Day Safety Follow-Up Visit ..................................................................................................................................... 27 
3.4.2 
Follow-Up for Discontinued Pembrolizumab without Disease Progression ............................................................... 27 
3.4.3 
Survival Status Follow-Up Phase ................................................................................................................................ 27 
3.5 
Study Termination .............................................................................................................................. 27 
3.5.1 
Criteria for Early Trial Termination ............................................................................................................................. 27 
3.6 
Treatment after End of Study .............................................................................................................. 28 
4 
Selection of Patients ....................................................................................................................... 29 
4.1 
Screening and Enrolment .................................................................................................................... 29 
4.2 
Registration ........................................................................................................................................ 29 
4.3 
Patient Replacement Strategy ............................................................................................................. 29 
4.4 
Entry Criteria ...................................................................................................................................... 30 
4.4.1 
Inclusion criteria ......................................................................................................................................................... 30 
4.4.2 
Exclusion Criteria ........................................................................................................................................................ 32 
5 
Study Plan and procedures ............................................................................................................. 34 

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5.1 
Study Schedule ................................................................................................................................... 34 
5.2 
Administrative Procedures/Assessments ............................................................................................. 36 
5.2.1 
Informed Consent ....................................................................................................................................................... 36 
5.2.2 
Inclusion/Exclusion Criteria ........................................................................................................................................ 36 
5.2.3 
Demographic Data, Medical History and Treatment History ..................................................................................... 37 
5.2.4 
Subsequent Anti-Cancer Therapy Status .................................................................................................................... 37 
5.2.5 
Survival Status ............................................................................................................................................................ 37 
5.2.6 
Prior and Concomitant Medications Review .............................................................................................................. 37 
5.2.6.1 
Prior Medications .............................................................................................................................................. 37 
5.2.6.2 
Concomitant Medications ................................................................................................................................. 37 
5.3 
Clinical Procedures/Assessments ........................................................................................................ 38 
5.3.1 
PD-L1 Assessment ...................................................................................................................................................... 38 
5.3.2 
Adverse Event (AE) Monitoring .................................................................................................................................. 38 
5.3.3 
MRC dyspnoea Score .................................................................................................................................................. 38 
5.3.4 
Full Physical Exam ....................................................................................................................................................... 38 
5.3.5 
Directed Physical Exam ............................................................................................................................................... 38 
5.3.6 
Vital Signs ................................................................................................................................................................... 39 
5.3.7 
Eastern Cooperative Oncology Group (ECOG) Performance Scale............................................................................. 39 
5.3.8 
Pulmonary Function Tests .......................................................................................................................................... 39 
5.3.9 
Pregnancy Tests .......................................................................................................................................................... 39 
5.3.10 
Haematology, Biochemistry and Urinalysis (including, β-hCG, PT, aPTT, fT3, fT4 and TSH) .................................. 39 
5.3.11 
Tumour Imaging and Assessment of Disease ........................................................................................................ 40 
5.3.11.1 
Baseline tumour imaging .................................................................................................................................. 40 
5.3.11.2 
Timing of Disease Assessment .......................................................................................................................... 40 
5.3.11.3 
Confirmation of Disease Response ................................................................................................................... 41 
5.3.11.4 
Confirmation of Disease Progression ................................................................................................................ 42 
5.3.12 
Tumour Tissue Collection and Correlative Studies Blood Sampling ...................................................................... 42 
5.3.12.1 
Archival Tumour tissue samples ....................................................................................................................... 42 
5.3.13 
Tumour Biopsies and Research Blood Samples ..................................................................................................... 43 
5.3.14 
Chain of Custody of Biological Samples ................................................................................................................. 43 
5.4 
Total Blood Volume ............................................................................................................................ 43 
6 
Treatments .................................................................................................................................... 44 
6.1 
Lung SBRT ........................................................................................................................................... 44 
6.1.1 
Planning and Delivery ................................................................................................................................................. 44 
6.1.2 
Toxicity Assessments .................................................................................................................................................. 44 
6.2 
Pembrolizumab .................................................................................................................................. 44 
6.2.1 
Investigational Product ............................................................................................................................................... 44 
6.2.2 
Product Preparation ................................................................................................................................................... 44 
6.2.3 
Storage and Handling ................................................................................................................................................. 45 
6.2.3.1 
Storage .............................................................................................................................................................. 45 
6.2.3.2 
Handling ............................................................................................................................................................ 45 
6.2.4 
Packaging and Labelling Information ......................................................................................................................... 46 
6.2.5 
Returns and Reconciliation ......................................................................................................................................... 46 
6.2.6 
Doses and Treatment Regimens ................................................................................................................................. 46 
6.2.7 
Timing of Dose Administration ................................................................................................................................... 46 
6.2.8 
Blinding/Masking ........................................................................................................................................................ 47 
6.2.9 
Drug Dose Selection/Modification ............................................................................................................................. 47 
6.2.9.1 
Dose Selection ................................................................................................................................................... 47 
6.2.9.2 
Dose Modification ............................................................................................................................................. 48 
6.3 
Concomitant medications ................................................................................................................... 50 
6.3.1 
Prohibited Concomitant Medications ........................................................................................................................ 50 
6.3.2 
Acceptable Concomitant Medications ....................................................................................................................... 51 

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6.4 
Rescue Medications & Supportive Care ............................................................................................... 51 
6.4.1 
Supportive Care Guidelines ........................................................................................................................................ 51 
6.4.1.1 
Diarrhoea .......................................................................................................................................................... 51 
6.4.1.2 
Nausea/vomiting ............................................................................................................................................... 52 
6.4.1.3 
Infection ............................................................................................................................................................ 52 
6.4.1.4 
Immune-related adverse events ....................................................................................................................... 52 
6.4.1.5 
Management of Infusion Reactions .................................................................................................................. 52 
6.5 
Supportive Care Guidelines for Immune-related Adverse Events (irAE) and Immune-related Events of 
Clinical Interest (irECI) ..................................................................................................................................... 52 
6.6 
Supportive Care Guidelines for Pneumonitis ........................................................................................ 57 
6.7 
Diet/Activity/Other Considerations ..................................................................................................... 58 
6.7.1 
Diet ............................................................................................................................................................................. 58 
6.7.2 
Contraception ............................................................................................................................................................. 58 
6.7.3 
Use in Pregnancy ........................................................................................................................................................ 58 
6.7.4 
Use in Nursing Women ............................................................................................................................................... 59 
6.7.5 
Treatment of Overdose of IMP ................................................................................................................................... 59 
6.8 
Permanent Discontinuation of Trial Medication and Withdrawal from the Study .................................. 59 
6.8.1 
Permanent Discontinuation of Trial Medication ........................................................................................................ 59 
6.9 
Withdrawal from the Study ................................................................................................................. 60 
7 
Pharmacovigilance ......................................................................................................................... 62 
7.1 
Adverse events ................................................................................................................................... 62 
7.1.1 
Adverse Event Definition ............................................................................................................................................ 62 
7.1.2 
Adverse Reaction Definition ....................................................................................................................................... 62 
7.1.3 
Disease Progression .................................................................................................................................................... 62 
7.1.4 
New Cancers ............................................................................................................................................................... 62 
7.1.5 
Abnormal Laboratory Test Results ............................................................................................................................. 62 
7.1.6 
Pregnancy and Lactation ............................................................................................................................................ 62 
7.2 
Assessing and Recording Adverse Events ............................................................................................. 63 
7.3 
Evaluating Adverse Events .................................................................................................................. 63 
7.3.1 
Determining AE Severity and Grade ........................................................................................................................... 63 
7.3.2 
Determining AE Causality ........................................................................................................................................... 64 
7.4 
Serious adverse events (SAEs) ............................................................................................................. 64 
7.4.1 
Reporting SAEs ........................................................................................................................................................... 65 
7.4.2 
Events exempt from being reported as SAEs ............................................................................................................. 65 
7.4.3 
Determining SAE Causality and Expectedness ........................................................................................................... 66 
7.5 
Events of Clinical Interest .................................................................................................................... 66 
7.5.1 
Definitions of Evidence of Clinical Interest (ECI) ........................................................................................................ 66 
7.5.2 
Reporting of ECIs ............................................................................................................ Error! Bookmark not defined. 
7.6 
Definition of an Overdose for this Protocol and Reporting of Overdose ................................................ 68 
7.7 
Reporting of Pregnancy and Lactation ................................................................................................. 69 
7.8 
Definition of a Serious Adverse Reaction (SAR) .................................................................................... 69 
7.9 
Definition of Suspected, Unexpected, Serious, Adverse Reactions (SUSARs) ......................................... 70 
7.10 
Reporting of SUSARs ........................................................................................................................... 70 
7.11 
Annual Reporting of Serious Adverse Events........................................................................................ 70 
7.12 
Urgent Safety Measures ...................................................................................................................... 71 
8 
Data analysis and statistical considerations .................................................................................... 72 

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8.1 
Statistical Analyses ............................................................................................................................. 72 
8.1.1 
Primary Endpoint ........................................................................................................................................................ 72 
8.1.2 
Secondary Endpoints .................................................................................................................................................. 72 
8.1.3 
Exploratory Endpoints ................................................................................................................................................ 73 
8.2 
Sample Size ........................................................................................................................................ 73 
9 
Regulatory, Ethical and Legal Issues ............................................................................................... 74 
9.1 
Good Clinical Practice ......................................................................................................................... 74 
9.2 
Independent Ethics Committee (IEC) / Institutional Review Board (IRB) ............................................... 74 
9.3 
Annual Safety Reports and End of Trial Notification ............................................................................. 74 
9.4 
Regulatory Authority Approval ............................................................................................................ 74 
9.5 
Notifications of Serious Breaches to GCP and/or the Protocol .............................................................. 75 
9.6 
Insurance and Liability ........................................................................................................................ 75 
9.7 
Contact with General Practitioner (GP) ................................................................................................ 75 
9.8 
Confidentiality .................................................................................................................................... 75 
9.9 
Data Collection and Documentation .................................................................................................... 76 
9.10 
End of Trial ......................................................................................................................................... 76 
10 Data and study management ......................................................................................................... 77 
10.1 
Source Data ........................................................................................................................................ 77 
10.2 
Language ............................................................................................................................................ 77 
10.3 
Data Collection ................................................................................................................................... 77 
10.4 
Recording of Data ............................................................................................................................... 77 
10.5 
Data Management .............................................................................................................................. 78 
10.6 
Study Management Structure ............................................................................................................. 78 
10.6.1 
Delegations of Responsibilities .............................................................................................................................. 78 
10.6.1.1 
RM-CTU ............................................................................................................................................................. 78 
10.6.1.2 
MSD ................................................................................................................................................................... 78 
10.6.1.3 
Participating Sites ............................................................................................................................................. 78 
10.7 
Protocol Compliance and Amendments ............................................................................................... 79 
10.8 
Trial Management .............................................................................................................................. 79 
10.9 
Safety Review Committee (SRC) .......................................................................................................... 79 
10.10 
Monitoring ..................................................................................................................................... 80 
10.11 
Quality Control and Quality Assurance ............................................................................................ 80 
10.12 
Clinical Study Report ....................................................................................................................... 80 
10.13 
Record Retention ............................................................................................................................ 80 
10.14 
Reporting and Publication ............................................................................................................... 81 
11 APPENDICES ................................................................................................................................... 82 
11.1 
Appendix 1 – ECOG Performance status............................................................................................... 82 
11.2 
Appendix 2 – MRC Dyspnoea scale ...................................................................................................... 83 
11.3 
Appendix 3 - Radiotherapy Planning and Delivery Guidelines ............................................................... 84 

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11.4 
Appendix 4 - Common Terminology Criteria for Adverse Events V4.0 (CTCAE) ....................................... 88 
11.5 
Appendix 5 - Identification, Evaluation and Management of immune related events of clinical interest 
(irECIs) 90 
11.6 
Appendix 6 - Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 ............................................. 97 
11.7 
Appendix 7 - Response Evaluation by Immune Related Response Criteria (irRC) .................................. 103 
12 References ....................................................................................................................................105 
 

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LIST OF ABBREVIATIONS 
# 
Fractions 
AE 
Adverse events 
ALK 
Anaplastic lymphoma kinase gene 
ALT 
Alanine transaminase 
ANC 
Absolute neutrophil count 
APC 
Antigen presenting cell 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate transaminase 
ATP 
Adenosine triphosphate  
C 
Cycle  
CD 
Cluster differentiation 
CI 
Chief Investigator 
CNS 
Central nervous system 
CR  
Complete response 
CRFs 
Case Report Forms 
CT 
Computerised tomography 
CTA 
Clinical Trial Authorisation 
CTCAE 
Common Toxicity Criteria for Adverse Events  
ctDNA 
Circulating tumour deoxyribonucleic acid 
CTLA-4 
Cytotoxic T-lymphocyte antigen-4 
D 
Day 
DCR 
Disease control rate 
DLT 
Dose limiting toxicity 
DSUR 
Development Safety Update Report  
ECI 
Event of clinical interest 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
Epidermal growth factor receptor gene 
FDA 
Food and Drug Administration 
FEV1 
Forced expiratory volume in 1 second 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
Gy  
Gray 
HIV 
Human immunodeficiency virus 
HMGB1  
High-mobility group protein B1 
HR  
Hazard ratio 
i.v. 
Intravenous 
ID 
Identification 
IEC 
Independent Ethics Committee 
IL 
Interleukin 
IMP 
Investigational Medicinal Product 
IR  
Ionising radiation 
irAE 
Immune-related adverse events 
IRD 
Institutional Review Board 
irECI 
Immune-related events of clinical interest  
irRC 
Immune-related response criteria 
ITIM 
Immunoreceptor tyrosine-based inhibition motif 

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ITSM 
Immunoreceptor tyrosine-based switch motif 
Kg 
Kilogram 
L  
Litre 
MAD 
Maximum administered dose 
mg  
Milligram 
MHC 
Major histocompatibility complex 
MHRA 
Medicines and Healthcare Products Regulations 
mmol  
Millimoles 
MRC 
Medical Research Council 
MSD 
Merck Sharp & Dohme  
MTD 
Maximum tolerated dose 
NCI  
National Cancer Institute 
NCRI CTRad 
National Cancer Research Institute Clinical and Translational Radiotherapy Research 
Working Group 
NK 
Natural killer cells 
ORR 
Overall response rate 
OS  
Overall survival  
PD  
Progressive disease 
PD-1 
Programmed cell death protein 1  
PD-L1 
Programmed death ligand-1 
PD-L2 
Programmed death ligand-2 
PFS 
Progression free survival  
PI  
Principal Investigator 
PR 
Partial response 
PT 
Prothrombin time 
QA 
Quality Assurance 
QC 
Quality Control 
RDSU 
Research & Development Statistical Unit 
REC 
Research Ethics Committee 
RECIST 
Response evaluation criteria in solid tumours  
RM-CTU 
Royal Marsden Clinical Trials Unit 
RP2D 
Recommended phase 2 dose 
SAE 
Serious adverse events 
SBRT 
Stereotactic body radiotherapy  
SD 
Stable disease 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SmPC 
Summary of Product Characteristics  
SRS 
Stereotactic radiosurgery 
STAT-3 
Signal transducer and activator of transcription 3  
SUSAR 
Suspected unexpected serious adverse event 
TIL 
Tumour infiltrating lymphocytes 
TLCO 
Carbon monoxide transfer factor 
TPS 
Tumour proportionate score 
UK 
United Kingdom 
ULN  
Upper limit of normal  
USM 
Urgent safety measures 

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Protocol Signatures 
Chief / Principal Investigator Signature: 
I have read and agree to the protocol, as detailed in this document.  I am aware of my responsibilities as an 
Investigator under the UK Clinical Trials Regulations, the guidelines of Good Clinical Practice (GCP) the 
Declaration of Helsinki, the applicable regulations of the relevant NHS Trusts and the trial protocol.  I agree 
to conduct the trial according to these regulations and guidelines and to appropriately direct and assist the 
staff under my control that will be involved in the trial, and ensure that all staff members are aware of their 
clinical trial responsibilities. 
Name:  
Dr Fiona McDonald 
Signature: 
 
Date: 
 
 
Sponsor Signature: 
On behalf of sponsor: 
Name:  
Ms Julie Curtis 
Signature: 
 
Date: 
 
 
Statistician Signature: 
The signatures below constitute approval of this protocol by the signatory. 
Name: 
Ms Ranga Gunapala 
Signature: 
 
Date: 
 
 

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1 
TRIAL SUMMARY 
Abbreviated Title 
Pembrolizumab and stereotactic radiotherapy  
Trial Phase 
Phase I 
Clinical Indication 
Advanced non-small cell lung cancer (NSCLC) 
Trial Type 
Interventional 
Type of control 
Single arm study: No treatment control 
Route of administration Intravenous Pembrolizumab and External Beam Stereotactic Body 
Radiotherapy (SBRT) 
Trial Blinding 
Unblinded, open label, dose escalation phase I study, with a subsequent 
cohort expansion phase. 
Treatment Groups  
Part A – Dose escalation cohort. 
 
DOSE LEVEL 1: Patients will receive an initial dose of pembrolizumab 
in week 1 dosed at 200 mg. They will then receive lung SBRT dosed at 30 
Gy in 3 fractions (#)  (Monday, Wednesday & Friday) in week 3. 
Treatment with pembrolizumab will be continued dosed at 200 mg given 
every 3 weeks. 
 
DOSE LEVEL 2: Patients will receive an initial dose of pembrolizumab 
at week 1 dosed at 200 mg. They will then also receive lung SBRT dosed at 
54 Gy in 3# (Monday, Wednesday & Friday) in week 3. Treatment with 
pembrolizumab will be continued dosed at 200 mg given every 3 weeks. 
If dose limiting toxicities are seen at dose level 1 the study will be terminated.  
Part B – Expansion cohort.  
An additional 12 patients will be recruited for this cohort. Patients will receive 
an initial dose of pembrolizumab at 200 mg in week 1. This will be followed in 
by lung SBRT in week 3, dosed at the maximum tolerated dose determined in 
Part A (3# – Monday, Wednesday & Friday). Treatment with pembrolizumab 
will be continued dosed at 200 mg given every 3 weeks.  
Number of trial patients Up to 24 patients may be recruited to the study depending on the dose levels 
tolerated – up to 12 patients will be recruited to the dose escalation phase in a 
3+3 design, and the dose expansion phase will recruit a further 12 patients. 
Duration of trial 
24 months 
Participation 
Until progression, intolerance or withdrawal from the trial.  
Study Objectives 
Primary 
1. To assess the safety and tolerability of lung SBRT in combination with 
pembrolizumab. 
2. To determine the recommended dose of lung SBRT to be used in 
combination with pembrolizumab in a phase 2 trial. 
Secondary 
1. To describe the safety profile of lung SBRT in combination with 
pembrolizumab. 
2. To assess clinical benefit by calculating the overall responses rates (ORR) 
and disease control rate (DCR). 
3. To assess responses rates in squamous versus non-squamous histological 
subtypes of NSCLC. 
4. To assess response rates in relation to tumour PD-1/PD-L1 expression. 
5. To assess progression free survival (PFS) and overall survival (OS). 
Exploratory 

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1. To identify biomarkers that correlate with immunological response to 
therapy. 
2. To analyse peripheral blood samples for ctDNA. 
Study Endpoints 
Primary 
1. To establish the maximum tolerated dose (MTD) and recommended dose 
for phase 2 trials (RP2D) of lung SBRT that can be safely combined with 
pembrolizumab. 
Secondary 
1. To assess the rates of acute toxicity (defined as up to 12 weeks after the 
last fraction of lung SBRT) using CTC AE v4.0. 
2. To assess the rates of late toxicity (defined as from 12 weeks after last 
fraction of lung SBRT until 28 days after the last dose of pembrolizumab) 
using CTC AE v4.0.  
3. To calculate the ORR and DCR using RECIST v1.1 & irRC. 
4. To calculate the ORR and DCR in a squamous versus non-squamous 
histological subtype using RECIST v1.1 & irRC. 
5. To assess the frequency of PD-1/PD-L1 expression distribution in 
responders and non-responders. 
6. To measure the PFS and OS at 6 and 12 months.  
Exploratory 
1. To characterize tumour infiltrating lymphocytes and tumour antigens in 
the tumour biopsies. These immunohistochemistry analyses will include, 
but not necessarily be limited to, the following markers: CD4, CD8, 
FOXp3, PD-1, PD-L1, and PD-L2. 
2. To assess for levels of ctDNA before and after lung SBRT  
Summary of Main Inclusion 
Criteria 
1. Patients should be ≥18 years old on the day of signing the informed 
consent. 
2. Patients must have a histological or cytological diagnosis of NSCLC.  
3. Patients should have non-radically treatable stage IIIB or IV disease. If 
they are known to have a driver mutation for which there is a small 
molecule targeted therapy, they must have had disease progression or be 
intolerant of this.  
4. Patients must have measurable disease as assessed by RECIST v1.1.  
5. Patient should have an ECOG performance status 0-1.  
6. Patients should be able to tolerate a course of stereotactic radiotherapy as 
assessed by the investigator. 
7. Patients should have disease within the lung, away from critical 
structures, suitable for treatment to part of lesion with lung SBRT. 
8. Patients must have adequate organ function including MRC dyspnoea 
score <3 and adequate baseline lung function tests, with an FEV1 >0.8L or 
>30% of predicted and a TLCO >30% 
Summary of Main Exclusion 
Criteria 
1. Patients who have taken any investigational medicinal product or have 
used an investigational device within 4 weeks of the first dose of 
pembrolizumab. Patients may participate in additional observational 
studies.  
2. Patients who have received prior chemotherapy, targeted small molecule 
therapy or radiotherapy within 4 weeks prior to the first dose of 
pembrolizumab. 
3. Patients with a diagnosis of immunodeficiency or be receiving systemic 
steroid therapy (>7.5 mg of prednisone / >1 mg of dexamethasone or their 

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equivalent dose) or any other form of immunosuppressive therapy within 
7 days prior to the first dose. 
4. Patients with evidence of active autoimmune disease requiring systemic 
treatment within the past 3 months or a documented history of clinically 
severe autoimmune disease, or a syndrome that requires systemic steroids 
or immunosuppressive agents.   
5. Patients who have received prior therapy with an anti-PD-1, anti-PD-L1, 
anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated 
antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody 
or drug specifically targeting T-cell co-stimulation or checkpoint 
pathways). 
6. Patients with evidence of active central nervous system (CNS) metastases 
and/or carcinomatous meningitis.  Patients with previously treated brain 
metastases may participate provided the brain metastases are stable and 
there is no evidence of new or enlarging brain metastases.  
7. Patients who have had previous radiotherapy to the lung or other 
neighbouring region that would preclude the safe administration of lung 
SBRT. 
8. Patients with evidence of interstitial lung disease, or history of 
pneumonitis (including non-infectious pneumonitis) that required 
steroids, or current pneumonitis (including non-infectious pneumonitis). 
Treatment / Main Study 
Procedures 
During the dose escalation phase, patients will receive an initial dose of 
pembrolizumab during week 1 dosed at 200 mg, followed by lung SBRT at one 
of two dosing levels in week 3 (30 Gy in 3# or 54 Gy in 3#). Treatment with 
pembrolizumab will be continued dosed at 200 mg every 3 weeks. 
Additionally, there will be an expansion cohort phase where patients will 
receive an initial dose of pembrolizumab dosed at 200 mg in week 1, followed 
by  lung SBRT which will be given at the MTD in week 3, as determined 
during the dose escalation phase. Treatment with pembrolizumab will be 
continued dosed at 200 mg given every 3 weeks. 
Patients will undergo clinical assessment on the day of each administration of 
pembrolizumab and during the week of lung SBRT. Patients will continue on 
pembrolizumab until disease progression, unacceptable adverse events, 
discontinuation of study medication for any other reason or withdrawal from 
the trial. All clinical assessments should be completed and reviewed before 
the administration of the next dose. 
After the end of treatment each patient will be required to attend a safety 
follow up visit at 30 days or before the initiation of a new cancer treatment, 
whichever comes first. Patients who discontinue for reasons other than 
disease progression will be followed-up every 9 weeks for disease status until 
progression, initiating a new anti-cancer treatment, withdrawing consent, or 
becoming lost to follow-up. Once a patient has suffered disease progression or 
initiated a new cancer treatment they will be followed up every 12 weeks to 
determine their survival status. This will be done by reviewing their medical 
notes and/or contacting the patient or GP directly. Patients will remain on 
this follow-up until death, withdrawal of consent or the end of the study. 
 
 
 

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1 
BACKGROUND & RATIONALE 
1.1 
Background 
Lung cancer is the leading cause of cancer mortality with ~35,000 deaths annually in the United Kingdom 
(UK) in 2012; equivalent to 97 deaths a day. Of over 43,000 cases of lung cancer diagnosed each year in the 
UK, 87% (~37,700) of patients present with non-small cell lung cancer (NSCLC) and 36% (~13,500) of 
NSCLC patients will present with advanced metastatic disease (1). The 5 year survival from lung cancer has 
changed little (from 3% to 8%) over the last 60 years, with progress continuing to lag significantly behind 
other common cancers.  
There is currently no curative therapy for metastatic NSCLC. For patients with good performance status, 
palliative systemic treatment is the standard of care and is offered to patients with the aim of improving 
symptoms, optimising quality of life and prolonging survival. Combinations of platinum agents with 
gemcitabine, vinorelbine, paclitaxel, docetaxel or pemetrexed achieve response rates of 20-30% and a 
median survival of 10-12 months (2, 3). The choice of chemotherapeutic agents is determined in part by the 
histological subtype of NSCLC. Over the last 10 years a greater understanding of the molecular basis of 
NSCLC; particularly adenocarcinoma, has led to the identification of specific mutations which are present in 
approximately 5-10% patients. For these patients, targeted treatments against the epidermal growth factor 
receptor (EGFR) (4-6) or anaplastic lymphoma kinase (ALK) gene rearrangements (7) are also available. 
These agents have the advantage of a lower toxicity profile, and have been shown to improve progression 
free survival (PFS) and overall survival (OS) when compared to standard chemotherapy agents in the first 
and second line settings respectively (7, 8).  
Second-line treatment options are limited and response rates are low. NSCLC patients have been highlighted 
as having an unmet need for further research with the aim of improving the poor outcomes in this common 
disease.  Although traditionally thought to be poorly immunogenic, NSCLC is now one of the most active 
areas of investigation for immunotherapy. It is speculated that the high mutational burden induced by the 
carcinogens in smoke may result in numerous neo-antigens that the immune system can respond to once the 
tumour mediated immunosuppression is blocked. 
1.1.1 Immune Evasion in Cancer 
The importance of intact immune surveillance in controlling outgrowth of neoplastic transformation has 
been known for decades (9).  Accumulating evidence shows a correlation between tumour-infiltrating 
lymphocytes (TILs) in cancer tissue and favourable prognosis in various malignancies (10-14).  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. 
In order to effectively evade the immune system, tumours can employ a variety of mechanisms. An initial 
immunogenic response to tumour cells can occur through the innate immune system for example through 

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natural killer (NK) cell mediated lysis. NSCLC can evade such an attack through down regulation of NK 
ligands such as NKG2D or avoid Fas-induced apoptosis (15, 16). The immune system may then develop an 
adaptive immune response requiring competent cytotoxic T-cells. This is mediated through the MHC 
system. Antigen presenting cells (APC) capture tumour antigens priming them to T-cells in regional lymph 
nodes. NSCLC display reduced major histocompatibility complex (MHC) class 1 expression therefore 
evading the adaptive immune response. After priming, T-cells are released into the circulation and migrate 
to tumour tissue where they find tumour specific antigens and differentiate into effector T-cells. This process 
relies on signals from the T-cell receptor and several co-stimulatory and co-inhibitory molecules. However 
many tumours are able to induce T-cell anergy. This has been effectively demonstrated in NSCLC which 
induce aberrant expansion of CD4+ FoxP3+ regulatory T-cells, thus inhibiting cytotoxic T-cell and NK cell 
activity (17). 
 
The immune checkpoint pathway in T-cell responses and under normal conditions through complex 
processes regulates effector T-cell response. Among the components of this pathway are cytotoxic T-
lymphocyte antigen-4 (CTLA4) which is expressed on the cell surface of a cytotoxic T-cell once it becomes 
active allowing binding with B7-1 and B7-2 on the APC keeping cytotoxic activity in check.  
Another key component of this pathway is the PD-1/PD-L1 immune checkpoint pathway. 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.   
 
1.1.2 Targeting the PD-1/PD-L1 axis 
PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member related to CD28 and CTLA-4 and has been 
shown to negatively regulate antigen receptor signalling upon engagement of its ligands (PD-L1 and/or 
PD-L2) (15, 16).  The structure of murine PD-1 has been resolved (18).  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 CD3 ζ , PKCθ and ZAP70 which are involved in the CD3 
T-cell signalling cascade (15, 19-21).  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 (22, 23).  PD-1 was shown to be expressed on activated lymphocytes including peripheral CD4+ and 
CD8+ T-cells, B-cells, T regs and NK cells (24, 25).  Expression has also been shown during thymic 

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development on CD4-CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells 
(25).   
 
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 (22, 26-28).  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 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 (22).   
 
Although healthy organs express little (if any) PD-L1, a variety of cancers were demonstrated to express 
abundant levels of this T-cell inhibitor.  Abnormal expression PD-L1 is identified in 19% to 100% of NSCLC 
tumours, depending in part on the antibody, histology, and technique reported (29-32) although the figure is 
more likely to around the 50% mark (30, 33). Some groups have noted that PD-L1 expression seems to be 
more commonly observed in sarcomatoid and adenocarcinoma subtypes of lung cancer, and it has been 
associated with poor prognosis (29, 30). TILs seem to be absent in PD-L1+ regions of tumours (30). High 
PD-L1 positive frequencies have also been seen in head and neck, cervical (29%), glioblastoma multiforme 
(25%), bladder (21%) and oesophageal cancer (20%). Within oesophageal cancer, PD-L1 expression is higher 
in the squamous population compared to other histologies (34). PD-L1 expression may be directly regulated 
by signal transducer and activator of transcription 3 (STAT-3) and appears to be further stimulated by 
immunosuppressive cytokines, such as IL-27.  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. 
 
1.1.3 Rationale for combining anti-PD-1 effects with radiation 
It is now well recognised that the host’s immune system senses the effects of ionising radiation (IR) in 
irradiated tissues. Evidence that the integrity of the immune system determines the dose required to control 
experimental tumours is more than 30 years old when reduced therapeutic efficacy was noted in mice that 
lacked an adequate T-cell response (35).  
However it is only recently that the radiation oncology community has started to exploit the clinical 
potential of the immunogenic effect of IR (36). IR induced cell death can generate tumour cell antigens for 
dendritic cell presentation. IR can generate immunogenic cell death perhaps more effectively than 
chemotherapy. The 3 steps required in this process include: cell surface translocation of calreticulin, the 

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extracellular release of high-mobility group protein B1 (HMGB1) a non-histone nuclear protein, and release 
of adenosine triphosphate (ATP). Tumour cells that receive radiation undergo phenotypic changes that 
enhance their susceptibility to immune effectors (37-39). Enhanced expression of death receptors (40, 41), 
MHC class 1 molecules (37, 42, 43), co-stimulatory molecules (44), adhesion molecules (45-47), and stress-
induced ligands (48-50) on tumour cells exposed to radiation increased their recognition and killing by T-
cells in vitro and/or in vivo in several cancer models. 
Theoretically if combined with the ideal immunotherapeutic agent, radiotherapy can engage both the innate 
and adaptive arms of the immune system, with the potential to convert the irradiated lesion into an in situ 
vaccine that elicits tumour-specific T-cells. Preclinical studies have demonstrated this in several tumour 
types with a variety of immunotherapeutic agents including Flt3 ligand, CpG, antiCTLA4, antiCD137 with 
anti-PD-1 and viral therapies. The majority of studies demonstrate release of tumour antigen leading to the 
induction of anti-tumour T-cell effect, while other studies demonstrate up regulation of MHC class I on 
tumour cells. One study examined mice bearing established orthotopic AT-3 mammary tumours and 
strikingly all mice treated with anti–CD137 and anti-PD-1 combined with single- or low-dose fractionated 
radiotherapy were cured. CD8+ T-cells were essential for curative responses to this combinatorial regime. 
CD137 expression on tumour-associated CD8+ T-cells was largely restricted to a subset that highly expressed 
PD-1. PD-1 signalling within the AT-3 tumours was a critical limiting factor to the therapeutic efficacy of 
anti-CD137 therapy, alone and in combination with radiotherapy (51).  
 
Stereotactic Body Radiotherapy (SBRT) has rapidly evolved over the past 5-10 years due to advances in 
radiation technology and is a focused radiation therapy that precisely and accurately delivers high biological 
doses of radiation to tumour lesions while sparing the nearby normal organs. The use of SBRT results in 
high rates of local tumour destruction with minimal side effects.  In the UK, SBRT is actively being 
developed with support from the National Cancer Research Institute Clinical and Translational 
Radiotherapy Research Working Group (NCRI CTRad) quality assurance group to ensure a high-quality 
SBRT National framework with unified protocols for clinical trials. It is therefore timely to appropriately 
evaluate the safety of this new technology in novel drug radiation combinations. Retrospective and 
prospective cohort studies reporting outcomes for SBRT for the treatment of oligo-metastatic disease sites 
have been succinctly reviewed (52).  In general these studies demonstrate high rates of local disease control 
with acceptable rates of toxicity, using a risk adapted approach to dose and fractionation based on the 
surrounding normal tissue structures. There is a wealth of data supporting the safety of a dose of 54 Gy in 3# 
over a week for peripheral lung lesions not in contact with the chest wall (53, 54).  
 
The concept of combining SBRT with immune checkpoint inhibitors has been explored with pre-clinical 
work from some groups suggesting that combined modality treatment with SBRT may be more efficacious 
than low dose radiotherapy. In a mouse orthotropic cell line glioma model, stereotactic radiosurgery (SRS) 

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with 10 Gy was tested in combination with anti-PD-1 antibodies. Anti-PD-1 antibodies led to long term cures 
in a subset of mice, which was not seen with either treatment modality alone (55). Post treatment analysis of 
brain tissue showed increased cytotoxic T-cells in the combined modality arm and decreased regulatory T-
cells. However the interaction between dose and immune effect is far more complex. Verbrugge et al 
demonstrated this complex interaction by irradiating B16-OVA murine with melanoma with up to 15 Gy, 
given in various fraction sizes. For single fractions, tumour control and number of tumour-specific T-cells 
were radiation dose dependent. However, at the highest dose, there was also an increase in regulatory T-
cells, which tend to down regulate the immune response. Fractionated irradiation at 7.5 Gy/# seemed to 
produce the best tumour control and tumour specific T-cell response while still maintaining low regulatory 
T-cell numbers (51). A further study supports fractionating radiation treatment in conjunction with 
immunotherapy, by testing anti-CTLA-4 antibodies with radiation in a mouse breast cancer model. Mice 
were treated with 20 Gy × 1#, 8 Gy × 3#, or 6 Gy × 5# in combination with monoclonal antibody against 
CTLA-4. Authors found that fractionated but not single-dose radiotherapy induces an abscopal effect when 
used with anti-CTLA-4 antibody (56). However, another preclinical study comparing ablative radiation 
doses against fractionated radiation noted that ablative radiation, such as a single dose of 20–25 Gy, 
dramatically increased T-cell activity and tumour control. When 5 Gy × 4# given over 2 weeks were 
compared against a single 20 Gy dose, radiation-initiated immune responses and tumour reduction 
appeared to be abrogated by the fractionated radiation [48]. As is evident the relationship between 
radiotherapy dose, fraction size and immune interplay is a complex one and clinical studies are urgently 
needed to assess how to optimally harness the effect on radiation on the immune system. 
 
1.1.4 Pembrolizumab Clinical Trial Data 
1.1.4.1 Pembrolizumab  
Pembrolizumab (Keytruda®; previously known as SCH 900475/MK3475) is a potent and highly selective 
humanized monoclonal antibody of the IgG4/kappa isotype designed to directly block the interaction 
between PD-1 and its ligands, PD-L1 and PD-L2.   
 
1.1.4.2 Clinical Trial Data  
Pembrolizumab has also showed excellent activity in the second-line setting for advanced NSCLC and was 
granted accelerated drug approval with the Food and Drug Administration (FDA) following the results from 
the expanded phase 1 study, KEYNOTE-001 (57), and the most recent data from KEYNOTE-010 (58). 
KEYNOTE-001 included 495 patients with advanced NSCLC, with both squamous and non-squamous 
histology. Of the patients treated, 81% had received at least one-line of prior treatment. The dose expansion 
assessed multiple doses. After a median follow-up of 10.9 months, the median OS was 12.0 months for all 
patients, and 10.4 months in previously treated patients. The median PFS was 3.7 months for all patients, 

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and 3.0 months in previously treated patients. ORR was 19.4% in all patients, and 18.0% in previously 
treated patients. The median duration of response was again more impressive than the PFS at 12.5 months 
(range: 1.0–23.3 months). When stratified for PD-L1 expression (Table 1), they showed that tumour 
proportionate score (TPS) of 50% was predictive of better response, PFS and OS. Interestingly, the 
response rates in smokers were twice as high when compared with non-smokers and there was little 
difference between squamous and non-squamous histological subtypes (57).  
KEYNOTE-010 was a head-to-head assessment of pembrolizumab (2 mg/kg and 10 mg/kg) with docetaxel 
in the second-line setting. The median OS was again in favour of pembrolizumab (2 mg/kg: 10.4 months, 
HR=0.71, P-value=0.0008; and 10 mg/kg: 12.7 months, HR=0.61, P-value<0.0001) over docetaxel (8.5 
months). The median PFS was 3.9-4.0 months, with no difference across the arms. When stratified for PD-
L1 expression, PD-L1 positive patients (TPS 50%), the median OS was again in favour of pembrolizumab (2 
mg/kg: 14.9 months, HR=0.54, P-value=0.0002; and 10 mg/kg: 17.3 months, HR=0.50, P-value<0.0001) 
over docetaxel (8.2 months). Likewise, for this patient population, the median PFS was again in favour of 
pembrolizumab (2 mg/kg: 5.0 months, HR=0.59, P-value=0.0001; and 10 mg/kg: 5.2 months, HR=0.59, P-
value<0.0001) over docetaxel (4.1 months). The response rate was ~30% in PD-L1 positive patients 
receiving pembrolizumab versus 8% receiving docetaxel, and in all patients, this was 18% versus 9%, 
respectively (58).  
Recent data supports the use of PD-1 inhibition in treatment-naïve advanced NSCLC patients. KEYNOTE-
024 compared pembrolizumab against investigators choice of platinum-based doublet chemotherapy, 
enriched for PD-L1 positive patients (TPS ≥50%). This shown a significant difference in median PFS 
favouring pembrolizumab (10.3 versus 6.0 months), and a significant difference in OS, again in favour of 
pembrolizumab (1-year OS of 80.2% versus 72.4%). The response rate was significantly higher in the 
pembrolizumab arm compared chemotherapy (44.8% versus 27.8%). The toxicity data did not reveal any 
new adverse events that were not already known about pembrolizumab, and again it was in support of 
pembrolizumab over platinum-based doublet chemotherapy (59). KEYNOTE-042 is of a similar design in an 
Asian population, but stratified patients into two PD-L1 positive groups: low expression (1-49%) and high 
expression (≥50%; NCT02220894), the results of which are still awaited. 
Adverse events of grade 3-5 occurred in 13-16% of the patients receiving pembrolizumab, and 35% of the 
patients receiving docetaxel. Treatment discontinuation due to treatment-related adverse events was seen in 
4-5% of patients receiving pembrolizumab compared with 10% receiving docetaxel. Treatment-related 
deaths occurred in three patients in the 2 mg/kg arm (2 with pneumonitis, and 1 with pneumonia), 3 
patients in the 10 mg/kg arm (1 each with myocardial infarction, pneumonia, pneumonitis), and 5 patients 
on docetaxel (1 each with acute cardiac failure, dehydration, febrile neutropenia, interstitial lung disease, 
and respiratory tract infection). Immune-related adverse events occurred in ~20% of patients receiving 
pembrolizumab, with the most common being hyperthyroidism (4-6%), hypothyroidism (8%), and 

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pneumonitis (4-5%). The immune-related adverse events of grade 3-5 severity occurring in 1% of patients 
were pneumonitis (2%) and severe skin reactions (1-2%) (58).  
These data have resulted in pembrolizumab being granted breakthrough therapy designation with the FDA 
for patients with NSCLC whose cancers have progressed on or after platinum-containing chemotherapy, as 
well as targeted agents in those with EGFR mutations and ALK gene rearrangements (60).  
 
KEYNOTE-001 also validated the PD-1 biomarker using the anti-PD-1 antibody clone 22C3 (Merck) and 
immunohistochemistry. Tumour slides were stained and scored for neoplastic membranous staining (i.e. the 
TPS) as <1%, 1-49%, or >50%. Using receiver operatory characteristic curve analysis they found that a PD-L1 
score of >50% (strong) was the best predictor of efficacy of pembrolizumab, with a response rate of 45.2% 
(95%CI: 33.5 – 57.3) and a median PFS of 6.3 months. The media OS has not yet been reached. The 
response rates in patients who scored PD-L1 1-49% was 16.5% (95%CI: 9.9 – 25.1) and in those who scored 
PD-L1 <1% was 10.7% (95%CI: 2.3 – 28.2). As responses were seen across all PD-L1 scores, this clinical trial 
will explore the combination of pembrolizumab and lung SBRT unenriched for PD-L1 strong (57).  
 
1.2 
Rationale for the Trial  
 
The abscopal effect refers to a rare phenomenon of tumour regression at a site distant from the primary site 
of radiotherapy (61). Radiotherapy has been shown to induce abscopal effects in several types of cancer, 
including melanoma, lymphoma, renal-cell carcinoma and NSCLC (62-65). The effect is attributed to 
activation of the systemic immune response. Radiation-induced inflammation is known to increase antigen 
presentation, subsequent tumour recognition, and can ultimately, enhance the tumour-directed immune 
response (66). This effect may be more pronounced in response to ablative rather than conventional dosage 
or fractionation schedules (67). More recently, the abscopal effect has been described in the context of 
patients receiving immunotherapy concurrently with radiotherapy. Formenti et al described a case of 
abscopal response in a patient with advanced NSCLC who received palliative hepatic radiotherapy while on 
ipilimumab. The response was seen 2.5 months following radiotherapy (68). Experimental data from 
multiple cancer models have provided sufficient evidence to propose a paradigm shift, whereby some of the 
effects of radiation are recognised as contributing to systemic antitumor immunity. Therefore, the 
traditional palliative role of radiotherapy in metastatic disease is evolving into that of a powerful adjuvant 
for immunotherapy. This combination strategy adds to the current anticancer arsenal and offers 
opportunities to harness the immune system to extend survival, even among metastatic and heavily 
pretreated cancer patients (36). Combination trials of immunotherapy and SBRT are required to explore the 
potential for radiation enhancing the effects of immunotherapy with the aim of improving outcomes for 
patients with NSCLC (36).  The initial step is to assess the tolerability and safety of immunotherapy with 
SBRT. This clinical trial protocol will look at the safety and tolerability of pembrolizumab, an anti-PD-1 
monoclonal antibody, given in combination with lung SBRT in patients with advanced NSCLC.  

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2 
STUDY OBJECTIVES & ENDPOINTS 
2.1 
Study Objectives & Hypothesis 
2.1.1 Primary Objective & Hypothesis 
 
Objective: To assess the safety and tolerability of lung SBRT with pembrolizumab and to determine 
the RP2D of lung SBRT to be used in combination with pembrolizumab. 
 
Hypothesis: Lung SBRT can be safely administered in combination with pembrolizumab without 
significant DLTs.  
2.1.2 Secondary Objectives  
 
To describe the safety profile of lung SBRT in combination with pembrolizumab. 
 
To assess clinical benefit with overall responses rate (ORR) and disease control rate (DCR). 
 
To assess responses rates in squamous versus non-squamous histological subtypes of NSCLC. 
 
To assess response rates in relation to tumour PD-1/PD-L1 expression. 
 
To assess progression free survival (PFS) and overall survival (OS). 
2.1.3 Exploratory Objectives  
 
To identify biomarkers that correlate with immunological response to therapy. 
 
To analyse peripheral blood samples for ctDNA. 
 
2.2 
Study Endpoints 
2.2.1 Primary Endpoint 
 
To establish the MTD and RP2D of lung SBRT that can be safely combined with pembrolizumab. 
2.2.2 Secondary Endpoints 
 
To assess the rates of acute toxicity (defined as up to 12 weeks after the last fraction of stereotactic 
radiotherapy) using CTC AE v4.0. 
 
To assess the rates of late toxicity (defined as from 12 weeks after last fraction of lung SBRT until 28 
days after the last dose of pembrolizumab) using CTCAE version 4.0. 
 
To calculate the ORR and DCR using RECIST v1.1 & irRC. 
 
To calculate the ORR and DCR in squamous versus non-squamous histological subtype using 
RECIST v1.1 & irRC. 
 
To assess the frequency of PD-1/PD-L1 expression distribution in responders and non-responders. 
 
To measure the PFS and OS at 6 and 12 months.  

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2.2.3 Exploratory Endpoints 
 
To characterise TILs and tumour antigens in the tumour biopsies. These immunohistochemistry 
analyses will include, but not necessarily be limited to, the following markers: CD4, CD8, FOXp3, 
PD-1, PD-L1, and PD-L2. 
 
To assess for levels of ctDNA pre- and post- SBRT. 

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3 
STUDY DESIGN 
3.1 
Summary of Study Design 
This is a single centre non-randomised open label phase 1 trial of lung SBRT to part of a lung lesion in 
patients with advanced NSCLC in combination with pembrolizumab.  This study will recruit up to 24 
patients whose lung cancer has progressed beyond one line of palliative chemotherapy, and an EGFR or ALK 
inhibitor if an EGFR driver mutation or ALK gene rearrangement is present, respectively, and now requires 
further palliative systemic treatment.  
 
3.2 
Treatment Regimen 
The study will be conducted in two parts; an initial lung SBRT dose escalation phase (Part A), followed by a 
lung SBRT dose expansion cohort (Part B). The dose escalation phase is based on a 3+3 design such that 
patients will be treated in cohorts of 3-6 patients. A maximum of 12 patients will be allocated to one of two 
doses of lung SBRT in combination with pembrolizumab to determine the MTD, DLTs and RP2D. If there is 
more than one DLT in cohort 1, this treatment combination will be deemed as being unacceptable, and it 
would lead to termination of the study. Note, there is no de-escalation in cohort 1. During the dose 
expansion cohort, 12 patients will have lung SBRT dosed at the RP2D determined during the dose escalation 
phase in combination with pembrolizumab to obtain additional safety and response data. Maintenance 
pembrolizumab will continue until disease progression, unacceptable toxicities, the patient withdraws 
consent to the trial, or the patient has completed 24 months of treatment. A maximum of 24 patients will be 
treated in the study. 
 
All patients will receive pembrolizumab on cycle (C) 1 day (D) 1, in Part A and B of the study.  All patients 
will receive lung SBRT on C1D15, C1D17, and C1D19 as per lung SBRT protocol (See Appendix 3). Although 
C1D1 can occur +/- 3 days, C1D15, C1D17, and C1D19, must be scheduled for a Monday, Wednesday and 
Friday, respectively. Patients in part A will receive lung SBRT dosed at 30 Gy in 3# in cohort 1, or 54 Gy in 
3# in cohort 2. Patients in Part B will receive the RP2D of lung SBRT, determined in Part A. All patients in 
Part A and Part B will receive pembrolizumab dosed at 200 mg every 3 weeks, until disease progression, 
unacceptable toxicities, the patient withdraws consent from the trial, or the patient has completed 24 
months of treatment. 
 
In the dose escalation phase, a minimum of 3 patients will be required per dose level being assessed. A 
minimum gap of 1 week will be left between the treatment of the first and the second, and between the 
second and the third patients with the combination of pembrolizumab and lung SBRT to mitigate against 
multiple patients suffering from acute toxicity. The DLT period for this study is 12 weeks from the last dose 
of lung SBRT (i.e. at C6D1). The dose escalation will be considered by the Safety Review Committee (SRC) 
once the 3rd or 6th patient in the cohort has completed the DLT period. If no DLT is observed at a dose level, 

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then lung SBRT will be dose escalated to the next dosing level (see Table 1). If 1 out of 3 patients experience a 
DLT, then the cohort will be expanded to 6 patients. If 1 in 6 patients experience a DLT, then the dose will be 
escalated to the next dosing level. However, if ≥ 2 in 6 patients experience a DLT then the maximum 
administered dose (MAD) will have been reached, and the RP2D will be the previous dosing level that will be 
used for the dose expansion cohorts. If the MAD is seen at dose level 1 then the study will be terminated. 
While waiting for 3 or 6 patients to complete the DLT period, no additional patients will be recruited. 
Further patients can only be recruited after the SRC has reviewed the toxicity data for the cohort and taken a 
decision to dose escalate to the next cohort or expand the current cohort to 6 patients.  
 
Once the MTD has been determined the trial enters the dose expansion phase (unless the MTD is dose level 
1). Here, 12 patients will be treated with the RP2D of SBRT combined with pembrolizumab.  
 
If there is ongoing clinical benefit at 24 months, the CI/PI will need to discuss with the sponsor and MSD, 
on a case by case basis for the continuation of pembrolizumab.   
 
Table 1: Lung SBRT dose levels and pembrolizumab dosing during the dose escalation and dose expansion 
phase.  
Dose Level 
Pembrolizumab Dose  
Lung SBRT to part of a lung lesion 
1 
200 mg i.v. over 30 minutes, every 3 
weeks 
30 Gy in 3# (Monday, Wednesday, Friday) 
2 
200 mg i.v. over 30 minutes, every 3 
weeks 
54 Gy in 3# (Monday, Wednesday, Friday) 
Dose expansion  
200 mg i.v. over 30 minutes, every 3 
weeks 
RP2D 
SBRT: Stereotactic Ablative Body Radiotherapy; Gy: Gray; i.v.: intravenous; mg: milligrams; 
RP2D: Recommended Phase 2 Dose; #: fraction.  
 
3.2.1 Dose Limiting Toxicities  
The rate of entry and escalation to the next dose level will depend upon assessment of the toxicity profile of 
patients entered at the previous level. Acute toxicity will be assessed up to and including 3 months following 
the final fraction of radiotherapy (i.e. at C6D1).  The MRC dyspnoea score (Appendix 2) will be used to 
assess dyspnoea at baseline/on treatment and the National Cancer Institute Common Toxicity Criteria for 
Adverse Events (NCI CTCAE) version 4.0 will be used to grade all drug and lung SBRT observed toxicities 
(Appendix 4). The SRC will consider dose escalation once the 3rd or 6th patient in the cohort has completed 
the DLT period and review the toxicities before recruitment to the next dose level can begin or the cohort is 
expanded to 6 patients. 
 
Any DLT must be a toxicity that is considered probably, possibly or definitely related to the combination of 
pembrolizumab and lung SBRT.  DLT is defined as follows: 

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Haematologic: 
 
Neutropenia with fever grade ≥ 3  
 
Thrombocytopaenia with bleeding grade ≥ 3 
Non-Haematologic: 
Any NCI CTCAE ≥ 3 grade non-haematological toxicity that is definitely, probably or possibly related to the 
combination of pembrolizumab and lung SBRT including the following: 
 
Increased MRC dyspnoea score > 2 grades from baseline and/or acute dyspnoea grade ≥ 4 (or 
CTCAE dyspnoea grade ≥ 3) persisting for > 7 days (including weekend). 
 
Pneumonitis/pulmonary infiltrates grade ≥ 3 persisting for > 7 days (including weekend). 
 
Oesophagitis grade ≥3 persisting for > 7 days (including weekend). 
 
Toxicity leading to interruption of radiotherapy for >7 days (including weekend). 
 
Escalation to the next dose level will not proceed until the following criteria are satisfied by the SRC: 
 
If 0 out of 3 patients experience a DLT, escalation to the next dose level can proceed. 
 
If 1 out 3 patients experiences a DLT, a further 3 patients will be recruited at that dose level. 
o If 1 out 6 patients experiences a DLT, then escalation to the next dose level can proceed.   
o If ≥ 2 out of 6 patients experience a DLT, the MAD will have been reached. The RP2D will be 
the dose level prior to when the DLTs were observed or dose level 2 if no DLTs were observed. 
All patients in the expansion cohort will have lung SBRT dosed at the RP2D (see Figure 1). 
 
If 2/3 patients experience a DLT then the MAD will have been reached and the expansion cohort 
phase will begin at the previous dose level unless this occurs at dose level 1.  
 
If dose level 1 is not tolerated due to DLTs, the expansion cohort will not go ahead and the trial will 
be terminated. 
 
3.3 
Study Schema 
 
1
3
2
4
5
6
7
8
9
11
13
12
10
Time (Weeks) 
Dose limiting toxicity period
Lung Stereotactic Body Radiotherapy (30 Gy in 3# OR 54 Gy in 3#)
Priming Treatment Schema
Pembrolizumab 200 mg i.v. every 3 weeks 
15
16
14

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Figure 1: Schematic diagram of study events. All patients will receive a fixed dose of pembrolizumab at 200 
mg i.v. every three weeks. The lung SBRT will be administered at week 3 on Monday, Wednesday and 
Friday. The first cohort will be dosed at 30 Gy in 3# and the second cohort will be dosed at 54 Gy in 3#.    
 
3.4 
Follow-Up after stopping Pembrolizumab 
3.4.1 30 Day Safety Follow-Up Visit 
All patients will be required to attend a safety follow-up visit 30 days after the last dose of pembrolizumab or 
before the initiation of a new anti-cancer treatment, whichever comes first. All adverse events (AEs) and 
serious adverse events (SAEs) that occur prior to the safety follow-up visit should be reported as described in 
section 7.  After the safety follow-up any unresolved AEs at the patient’s last visit should be followed up for 
as long as medically indicated, but without further recording in the CRF.  
 
3.4.2 Follow-Up for Discontinued Pembrolizumab without Disease Progression 
Patients who discontinue pembrolizumab for any reason other than disease progression will move into the 
follow-up phase and should be assessed every 9 weeks (63 ± 7 days) and by radiologic imaging as per 
standard of care to monitor disease status.  Every effort should be made to collect information regarding 
disease status until the start of new anti-cancer therapy, disease progression, death, withdrawal or end of the 
study.  Information regarding post-study anti-cancer treatment will be collected if new treatment is 
initiated. 
 
3.4.3 Survival Status Follow-Up Phase 
Once a patient experiences confirmed disease progression or starts a new anti-cancer therapy, the patient 
moves into the survival follow-up phase and will be followed up every 12 weeks to determine their disease 
status. This will be done by reviewing their medical notes and / or contacting the patient or GP directly. 
Patients will remain on this follow-up until death, withdrawal of consent, or the end of the study, whichever 
occurs first. 
 
3.5 
Study Termination 
The ‘end-of-trial’ is defined as the date when the last patient has completed the ‘off-study’ visit or the final 
follow-up visit, whichever is happens last. 
 
3.5.1 Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 

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3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential health 
hazard to patients 
4. Plans to modify or discontinue the development of the study drug 
5. If DLT is seen at dose level 1 in 2 out of 3 or 2 out of 6 patients 
In accordance with the conditions of supply agreement with MSD, ample notification will be provided to the 
sponsor (via RM-CTU) and sites should alterations to the drug supply change. This is to allow time for 
appropriate adjustments to be made in regards to the patient’s treatment. 
 
3.6 
Treatment after End of Study  
Following participation in the study patient care will be decided by the local doctor according to standard 
practice. 

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4 
SELECTION OF PATIENTS 
4.1 
Screening and Enrolment 
The Investigator at site will keep a record of all patients screened for entry into this study. Copies of the 
screening logs will be filed in the Site File. For each patient, the primary reason for exclusion will be 
recorded. Diagnostic data obtained as part of the patient’s standard care will be used to determine eligibility 
provided they fall within the protocol defined timelines. Written informed consent must be obtained prior to 
the patient undergoing any study specific procedures. 
 
4.2 
Registration 
When the patient signs the consent form they will be allocated a trial ID that will be used to identify the 
patient for all future assessments.  
 
Patients can be registered and allocated a trial ID number by contacting the RM-CTU on: 
Telephone: 020 89156667 
Fax: 020 8915 6762 
Email: Priming.Trial@rmh.nhs.uk 
Between Monday to Friday, 9 am to 4 pm. 
Once all the screening assessments have been completed and the data entered on the CRFs the patient will 
be assessed for eligibility. If eligible the patient will begin on the trial. If the patient is not eligible then the 
local investigator will make alternative arrangements for the treatment of the patient. The trial ID will be a 
unique number that once assigned will become the permanent study identifier for that patient. In the event a 
patient is registered onto the study but does not begin treatment, then that patient’s trial ID will not be 
reassigned. Treatment will begin within 7 days from the date eligibility has been confirmed.  To ensure 
patient confidentiality patients will only be identified on CRFs, other trial specific forms and all 
communication to RM-CTU using their assigned trial ID. It is the CI’s responsibility to maintain a 
confidential record of the identity i.e. full name, date of birth and hospital number for the patients enrolled 
in this study and their assigned trial ID. At the end of the study this record should be archived along with the 
Site File. 
 
4.3 
Patient Replacement Strategy 
Additional patients may be enrolled in a given cohort to ensure that the required number of evaluable 
patients in each cohort is achieved. A  patient that discontinues the trial for progressive disease within 3 
months of the last dose of radiotherapy will not be evaluable for DLTs and therefore will need to be replaced. 
A patient that discontinues the trial for a drug-related AE will not be replaced and will be counted in the 
evaluable population of patients for the respective cohort. However, patients found to have active 

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pneumonitis on C1D1 of pembrolizumab or day 1 of radiotherapy will be removed from the trial and can be 
replaced. Also patients who do not reach follow-up 3 months post completion of lung SBRT for reasons 
other than progression or toxicity can be replaced by new patients in that cohort to ensure there is a 
minimum or 3 (or 6 if required) patients in each cohort. 
 
4.4 
Entry Criteria 
The following eligibility criteria were designed to select patients for whom the protocol treatment is 
considered appropriate. All relevant medical and non-medical conditions should be taken into consideration 
when deciding whether this protocol is suitable for a particular patient. Eligibility criteria may not be waived 
by the investigator.  
4.4.1 Inclusion criteria  
In order to be eligible for participation in this trial, the patient must: 
1. Patients should be ≥18 years old on the day of signing the informed consent. 
2. Patients must have a histological or cytological diagnosis of NSCLC.  
3. Patients should have non-radically treatable stage IIIB or IV disease.  
4. Patients must have measurable disease as assessed by RECIST v1.1.  
5. Patients must have had disease progression or be intolerant of standard first line palliative 
chemotherapy for non-small cell lung cancer. If they are known to have a driver mutation for which 
there is a small molecule targeted therapy, they must have had disease progression or be intolerant of 
this.  
6. Patient should have an ECOG performance status 0-1. 
7. Patients should be able to tolerate a course of stereotactic radiotherapy as assessed by the 
investigator. 
8. Patients should have disease within the lung, away from critical structures, suitable for treatment to 
part of a lesion with lung SBRT. 
9. Patients must have adequate organ function including MRC dyspnoea score <3 and adequate 
baseline lung function tests, with an FEV1 > 0.8L or >30% of predicted and a TLCO > 30% 
10. Demonstrate adequate organ function as detailed in Table 2 (based on bloods within 10 days of 
C1D1). 
11. Have provided tissue from an archival tissue sample or newly obtained tissue sample. 
12. Female patient of childbearing potential should have a negative urine or serum pregnancy within 72 
hours prior to receiving the first dose of study medication (C1D1).  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 

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after the last dose of study medication.  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. 
15. Be willing to provide informed consent for the trial. 
 

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Table 2: Adequate Organ Function Laboratory Values. These should be within 10 days of C1D1. 
System 
Laboratory Value 
Haematological 
 
Absolute neutrophil count (ANC) 
≥1.5 x 109/L 
 
Platelets 
100 x 109/L 
 
Haemoglobin 
≥90 g/L or ≥5.6 mmol/L  
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 
≥60 mL/min for patient with creatinine levels > 1.5 X 
institutional ULN 
aCreatinine clearance should be calculated per institutional standard. 
Hepatic 
 
Serum total bilirubin      OR 
 
Direct bilirubin 
≤ 1.5 X ULN OR 
≤ ULN for patients with total bilirubin levels > 1.5 ULN 
 
AST (SGOT) and ALT (SGPT) 
 
≤ 3.0 X ULN  OR 
≤ 5.0 X ULN for patients with liver metastases 
Coagulation 
Prothrombin Time (PT) 
 
≤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 
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 
 
4.4.2 Exclusion Criteria  
The following patients must be excluded from participating in the trial: 
1. Patients who have taken any investigational medicinal product or have used an investigational device 
within 4 weeks of the first dose of pembrolizumab. Patients may participate in additional 
observational studies.  
2. Patients who have received prior chemotherapy, targeted small molecule therapy or radiotherapy 
within 4 weeks prior to the first dose of pembrolizumab. 
3. Patients with a diagnosis of immunodeficiency or be receiving systemic steroid therapy (>7.5 mg of 
prednisone / >1 mg of dexamethasone or their equivalent dose) or any other form of 
immunosuppressive therapy within 7 days prior to the first dose. 
4. Patients with evidence of active autoimmune disease requiring systemic treatment within the past 3 
months or a documented history of clinically severe autoimmune disease, or a syndrome that 
requires systemic steroids or immunosuppressive agents.   
5. Patients who have received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or 
anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any 
other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways). 

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6. Patients with evidence of active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Patients with previously treated brain metastases may participate provided the brain 
metastases are stable and there is no evidence of new or enlarging brain metastases.  
7. Patients who have had previous radiotherapy to the lung or other neighbouring region that would 
preclude the safe administration of lung SBRT. 
8. Patients with evidence of interstitial lung disease, or history of pneumonitis (including non-
infectious pneumonitis) that required steroids, or current pneumonitis (including non-infectious 
pneumonitis). 
9. Patients with evidence of additional malignancy that is progressing or requires active treatment. 
10. Patients with a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound trial results, interfere with the patient’s participation or is not in the best interest of 
the patient.   
11. Patients with psychiatric or substance abuse disorders that would interfere with patient’s 
participation. 
12. Patients who are pregnant / breastfeeding or expecting to conceive within the duration of the trial, 
starting with the screening visit through 120 days after the last dose. 
13. Patients with a history of HIV, HIV 1/2 antibodies, Hepatitis B or Hepatitis C. 
14. Patients who have received a live vaccine within 30 days prior to the first dose of trial treatment.   
15. Patients with known hypersensitivity to the active substance pembrolizumab or to any of the 
excipients listed in the SmPC. 
 
 

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5 
STUDY PLAN AND PROCEDURES 
5.1 
Study Schedule 
From study entry, patients will be assessed every 21 days, prior to the administration of each dose of 
pembrolizumab. During the week of lung SBRT patients will have an additional clinical review. Patients will 
continue to be assessed and stay on Pembrolizumab until they have disease progression, suffer unacceptable 
toxicities, withdraw the study ends or have completed 24 months of pembrolizumab. Treatment beyond 
progression or beyond 24 months needs to be discussed with the study sponsor and MSD. Patients will be 
required to attend a safety visit 30 days after their last dose of Pembrolizumab.  
 
If the patient has not progressed at the last dose of pembrolizumab they will be reviewed every 9 weeks until 
the start of new anti-cancer therapy, disease progression, death, withdrawal or end of the study. Patients 
that have progressed or begin a new anti-cancer treatment will enter into the survival follow up phase and 
an update will be sought every 12 weeks to assess for disease status until death, withdrawal of consent, or the 
end of the study, whichever occurs first. Survival follow up can be done over the phone. 
 
The schedule of assessments to be performed at each visit is summarised in Table 3. Individual trial 
procedures are described in detail below.  It may be necessary to perform these procedures at unscheduled 
time points if deemed clinically necessary by the  Investigator. Furthermore, additional evaluations/testing 
may be clinically indicated for reasons related to patient safety. In some cases, such evaluation/testing may 
be potentially sensitive in nature (e.g., HIV, Hepatitis B, Hepatitis C, etc.) and will be performed in 
accordance with local regulations. 
 

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Table 3: Study Schedule of Assessments 
Trial Phase: 
Screenin
g period 
 
Dose escalation phase 
 
 
Maintenance phase  
DLT period 
(Pembrolizumab 200 mg 
q3wkly) 
 
Maintenance phase  
Beyond DLT period 
(Pembrolizumab 200 mg 
q3wkly) 
End of 
Treatment 
(If applicable) 
Post-Treatment 
C1, 
D1 
Radiotherapy phase 
(30 Gy in 3# OR  
54 Gy in 3#) 
C2, 
D1 
Safety 
Follow-
up (SFU) 
Follow 
Up Visits 
Survival 
Follow 
Up 
Treatment 
Cycle/Title: 
C1, 
D15 
C1, 
D17 
C1, 
D19 
C3,  
D1 
C4,  
D1 
C5,  
D1 
C6,  
D1 
C7,  
D1 
C8,  
D1 
C9,  
D1 
Discontinuation 
of Pembrolizumab 
30 days 
after last 
dose 
Every 9 
weeks 
from SFU 
Every 12 
weeks 
from SFU 
Scheduling (Day): 
-28 to -1 
 
 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full Physical Exam 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
Directed Phys. Exam 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
MRC dyspnea score 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
 
 
 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ECOG PS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital Signs & Weight 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Haem & Biochem 
X6 
X7 
 
 
 
X7 
X7 
X7 
X7 
X7 
X7 
X7 
X7 
X 
X 
 
 
FT3, FT4 and TSH 
X6 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
 
PT and aPTT 
X6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
X7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pembrolizumab 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Radiotherapy 
 
 
X5 
X5 
X5 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary function3 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Imaging 
CT1 & 
CXR2 
 
 
 
CXR 
CXR 
CXR 
CT 
CXR 
 
CT 
 
 
CT 
 
CT 
 
PD-L1 assessment4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Blood  
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
1. 
Imaging with a CT scan should occur during the screening period as a baseline and then every 9 weeks (3 cycles) for the first 6 months, then every 12 weeks after 6 months (regardless of 
treatment delays). Imaging with CT scanning can occur 7 days before the visit to ensure that the results are available at the visit.  
2. 
Chest x-ray will be performed during the dose limiting toxicity period in order to monitor for pneumonitis.  
3. 
Full pulmonary function tests should be performed every 6 months from radiotherapy. 
4. 
Dose escalation and expansion cohort will not be enriched for PD-L1 strong patients. PD-L1 testing will be batched and performed once all patients are on study.   
5. 
Lung SBRT will be administered at dose level being tested on C1D15, C1D17 and C1D19 during the dose escalation phase, and at the RP2D for C1D15, C1D17 and C1D19 during the dose 
expansion phase. 
6. 
Screening laboratory investigations will be valid for 10 days from C1D1.  
7. 
Safety laboratory investigations will be valid for 3 days from D1 visit.  
  

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5.2 
Administrative Procedures/Assessments 
5.2.1 Informed Consent 
It is the responsibility of the Investigator / designee to give each patient, prior to inclusion in the trial, full 
and adequate verbal and written information regarding the objective and procedures of the trial and the 
possible risks involved. Sufficient time should be allowed for the patient to decide on trial entry. Patients 
must be informed about their right to withdraw from the trial at any time. Written patient information must 
be given to each patient before enrolment. The written patient information is an approved patient 
information sheet (PIS) according to national guidelines.  
 
The Investigator must obtain documented written informed consent from each potential patient prior to 
participating in a clinical trial. Consent must be documented by the patient’s dated signature on a consent 
form along with the dated signature of the person conducting the consent discussion. If the patient is 
illiterate, an impartial witness should be present during the entire informed consent reading and discussion. 
Afterwards, the patient should sign and date the informed consent, if capable. The impartial witness should 
also sign and date the informed consent along with the individual who read and discussed the informed 
consent. Only the Chief Investigator (CI), Co-Investigators and those Sub-Investigator(s) delegated 
responsibility by the CI, having signed the delegation of responsibilities log, are permitted to gain informed 
consent from patients and sign the consent form.  All signatures must be obtained before the occurrence of 
any medical intervention required by the protocol.   
 
A copy of the signed and dated consent form should be given to the patient before participation in the trial. 
The original consent form should be stored in the site file with a copy also being placed in the patient’s 
medical notes. Results from tests conducted as part of patients’ standard care may be used as part of 
screening to determine eligibility as long as the tests were conducted within the acceptable time window.  
 
The initial informed consent form, any subsequent revised written informed consent form and any written 
information provided to the patient must receive the REC approval/favourable opinion in advance of use.  
The patient should be informed in a timely manner if new information becomes available that may be 
relevant to the patient’s willingness to continue participation in the trial.  The communication of this 
information will be provided and documented via a revised consent form or addendum to the original 
consent form that captures the patient’s dated signature. The informed consent will adhere to REC 
requirements, applicable laws and regulations. 
 
5.2.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the Investigator or qualified designee to ensure that 
the patient qualifies for the trial.  

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5.2.3 Demographic Data, Medical History and Treatment History 
Demographic data collected will include date of birth and race/ethnicity. A medical history will be obtained 
by the Investigator or qualified designee.  Medical history will include all active conditions, and any 
condition diagnosed within the prior 10 years that are considered to be clinically significant by the 
Investigator.  Details regarding the disease for which the patient has enrolled in this study will be recorded 
separately and not listed as medical history.  In addition to the medical history the Investigator or qualified 
designee will obtain details the patient’s current disease status and treatment history including prior and 
current details regarding disease status, in addition to all prior cancer treatments including systemic 
treatments, radiation and surgeries. 
 
5.2.4 Subsequent Anti-Cancer Therapy Status 
Patients that discontinue from pembrolizumab for any other reason than disease progression will have a 
follow-up visit every 9 weeks in which the Investigator should review all new anti-cancer therapy initiated 
after the last dose of pembrolizumab.  If a patient initiates a new anti-cancer therapy within 30 days after 
the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the first dose of the new 
therapy.  Once new anti-cancer therapy has been initiated the patient will move into survival follow-up. 
 
5.2.5 Survival Status 
The Investigator or qualified designee will assess the patient for survival status. The assessment will include 
the patient status and if applicable details of patient death or detail if patient has been lost to follow-up. 
 
5.2.6 Prior and Concomitant Medications Review 
5.2.6.1  Prior Medications 
The Investigator or qualified designee will review prior medication use, including any protocol-specified 
washout requirement, and record prior medication taken by the patient within 28 days before starting the 
trial.  Treatment for the disease for which the patient has enrolled in this study will be recorded separately 
and not listed as a prior medication.  
 
5.2.6.2  Concomitant Medications 
In addition the investigator or qualified designee will record all medication, if any, taken by the patient 
during the trial.  All medications related to reportable SAEs and events of clinical interest (ECIs) should be 
recorded as defined in Section 7. 
 

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5.3 
Clinical Procedures/Assessments 
5.3.1 PD-L1 Assessment 
To participate in the trial patients need available tissue of a tumour lesion not previously irradiated 
(tumours progressing in a prior site of radiation are allowed) for PD-L1 characterisation. This specimen will 
be evaluated at a central laboratory for expression status of PD-L1 using PD-L1 IHC 22C3 pharmDx (Dako) 
assay. If no tissue is available then following informed consent they should undergo a biopsy of a tumour 
lesion for biomarker analysis. NOTE: Patients participating in this trial will be unselected for their PD-L1 
status.  
 
5.3.2 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each patient for potential new or worsening AEs as 
specified in the schedule of study assessments (Table 3) and more frequently if clinically indicated.  AEs will 
be graded and recorded from confirmation of entry into the trial until the patients 30 day safety follow up 
visit according to NCI CTCAE v4.0 (see Appendix 4).  Toxicities will be characterised in terms regarding 
seriousness, causality, toxicity grading, and action taken with regard to trial treatment.  
 
All AEs of unknown aetiology associated with pembrolizumab exposure should be evaluated to determine if 
it is possibly an event of clinical interest (ECI) or a potentially an immune-related adverse event (irAE).  See 
Appendix 5 and the separate ECI guidance document regarding the identification, evaluation and 
management of AEs of a potential immunological aetiology.  Please refer to section 7 for detailed 
information regarding the assessment and recording of AEs.   
 
5.3.3 MRC dyspnoea Score 
The investigator or qualified designee will assess the patient’s dyspnoea using the MRC Dyspnoea Score 
(Appendix 2) at screening period and the time points defined in the study schedule of assessments (Table 3).   
 
5.3.4 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam at screening period and the 
time points defined in the study schedule of assessments (Table 3).  Clinically significant abnormal findings 
should be recorded as AEs during the trial.   
 
5.3.5 Directed Physical Exam 
For cycles that do not require a full physical exam as described in the schedule of assessments (Table 3), the 
investigator or qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration.   

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5.3.6 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the administration of each 
dose of trial treatment and at treatment discontinuation as specified in the schedule of study assessments 
(Table 3).  Vital signs should include temperature, pulse, respiratory rate, oxygen saturation, weight and 
blood pressure.  Height will be measured at screening only. 
 
5.3.7 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (Appendix 1) at screening, prior to the 
administration of each dose of trial treatment and discontinuation of trial treatment as specified in the study 
schedule of assessments (Table 3).   
 
5.3.8 Pulmonary Function Tests 
Full lung function tests assessments will be performed at screening, prior to the dosing of pembrolizumab 
(+/- 5 days) and during the maintenance phase of the of the DLT period as specified in the study schedule of 
assessments  (Table 3).  
 
5.3.9 Pregnancy Tests 
Female patients of childbearing potential should have a negative urine or serum pregnancy during screening 
and within 72 hours prior to receiving the first dose of study medication as specified in the study schedule of 
assessments (Table 3).  If the urine test is positive or cannot be confirmed as negative, a serum pregnancy 
test will be required.   
 
5.3.10 Haematology, Biochemistry and Urinalysis (including, β-hCG, PT, aPTT, fT3, fT4 and TSH) 
All Laboratory tests will be performed at screening and then certain assessments at every visit as defined in 
the schedule of study assessments (Table 3). Sample will be analysed by the local study site laboratory using 
standard methods for routine tests. Laboratory tests for screening can be performed within 10 days prior to 
the first dose of treatment.  After this all pre-dose laboratory procedures should be conducted no more than 
72 hours prior to dosing.  Results must be reviewed by the investigator / designee and found to be acceptable 
prior to each dose of trial treatment. The variables detailed in Table 4 will be measured. 
 
 
 
 
 

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Table 4: Required Laboratory Assessments 
Haematology 
Chemistry 
Urinalysis 
Other 
Haematocrit 
Albumin 
Blood 
PT  
Haemoglobin 
Alkaline phosphatase 
Glucose 
aPTT 
Platelet count 
Alanine 
aminotransferase 
(ALT) 
Protein 
Free triiodothyronine (fT3) 
WBC (total and 
differential) 
Aspartate 
aminotransferase 
(AST) 
Specific gravity  
Free thyroxine (fT4) 
Red Blood Cell Count 
Lactate 
dehydrogenase (LDH) 
Microscopic exam (If 
results are abnormal) 
Thyroid stimulating 
hormone (TSH) 
Absolute Neutrophil Count 
Uric Acid 
Urine pregnancy test †  
Absolute Lymphocyte 
Count 
Calcium Corrected 
 
 
 
Chloride 
 
 
 
Glucose 
 
 
 
Phosphate 
 
 
 
Potassium   
 
 
 
Sodium 
 
 
 
Magnesium 
 
 
 
Total Bilirubin 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
 
Creatinine  
 
 
 
Creatinine Clearance  
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum 
pregnancy test will be required.   
 
 
5.3.11 Tumour Imaging and Assessment of Disease 
5.3.11.1 Baseline tumour imaging 
Imaging should be undertaken to confirm that the patient has disease in the thorax, where lung SBRT is 
considered appropriate and the lesion is measurable using RECIST v1.1. The scan will also be assessed for an 
extra-thoracic disease.  
 
5.3.11.2 Timing of Disease Assessment 
Tumour imaging may be performed by CT. The initial tumour imaging will be performed no more than 28 
days prior to confirmation of eligibility. Scans performed as part of routine clinical management are 
acceptable for use as the screening scan if they are of diagnostic quality and performed within the correct 
time window.  
 

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On-study imaging will be performed at screening every 3 cycles (every 9 weeks) for the first 6 months (± 7 
days) then every 12 weeks after 6 months (± 7 days), and should follow calendar days and should not be 
adjusted for delays in cycle starts or extension of pembrolizumab cycle frequencies.  Tumour imaging and 
assessment per local standard of care should be performed for patient management and may include 
additional imaging (e.g. bone scan).  Imaging should continue to be performed until documented disease 
progression, the start of new anti-cancer treatment, withdrawal of consent, death, or the end of the study, 
whichever occurs first.  
 
5.3.11.3 Confirmation of Disease Response  
Per RECIST v1.1 & irRC (Appendix 6 & 7), response should be confirmed by a repeat radiographic 
assessment no less than 4 weeks from the date the response was first documented. The scan for 
confirmation of response may be performed at the earliest 4 weeks after the first indication of response, or at 
the next scheduled scan, whichever is clinically indicated. 
 
Immunotherapeutic agents may produce anti-tumour effects by potentiating endogenous cancer-specific 
immune responses. The response patterns seen with such an approach may extend beyond the typical time 
course of responses seen with cytotoxic agents and can manifest a clinical response after an initial increase 
in tumour burden or even the appearance of new lesions. Therefore standard RECIST v1.1 may not provide 
an accurate response assessment of immunotherapeutic agents such as pembrolizumab. 
 
Therefore, RECIST v1.1 will be used with the following adaptations: 
 
If radiologic imaging shows initial progressive disease (PD), tumour assessment should be repeated 
≥4 weeks later in order to confirm PD with the option of continuing treatment while awaiting 
radiologic confirmation of progression.  
o Patients may continue treatment while waiting for confirmation of PD if they are clinically 
stable as defined by the following criteria: 
 
Absence of signs and symptoms indicating disease progression 
 
No decline in ECOG performance status 
 
Absence of rapid progression of disease 
 
Absence of progressive tumour at critical anatomical sites requiring urgent alternative 
medical intervention. When feasible, patients should not be discontinued until 
progression is confirmed. This allowance to continue treatment despite initial 
radiologic progression takes into account the observation that some patients can have 
a transient tumour flare in the first few months after the start of immunotherapy, but 
with subsequent disease response. Patients that are deemed clinically unstable are not 
required to have repeat imaging for confirmation of progressive disease. 

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 
If repeat imaging shows a reduction in the tumour burden compared to the initial scan 
demonstrating PD, treatment may be continued /resumed.  
 
If repeat imaging confirms progressive disease, patients will be discontinued from study therapy.  
o NOTE: If a patient with confirmed radiographic progression (i.e. 2 scans at least 28 days 
apart demonstrating progressive disease) is clinically stable or clinically improved, and there 
is no further increase in the tumour dimensions at the confirmatory scan, an exception may 
be considered to continue treatment upon consultation with the Sponsor.  
Clinically stable patients should also have at the confirmatory scan no further increase in the 
target lesions, no unequivocal increase in non-target lesions, and no additional new lesions 
develop (non-worsening PD) to continue study treatment. 
In determining whether or not the tumour burden has increased or decreased, investigators should consider 
all target lesions as well as non-target lesions.  
 
5.3.11.4 Confirmation of Disease Progression 
Disease progression should be confirmed at least 4 weeks after the first scan indicating progressive disease 
in clinically stable patients. Patients who have unconfirmed disease progression may continue on treatment 
until progression is confirmed. 
Clinically stable is defined by one or more of the following criteria: 
 
Absence of signs and symptoms indicating disease progression 
 
No decline in ECOG performance status 
 
Absence of rapid progression of disease 
 
Absence of progressive tumour at critical anatomical sites (e.g., cord compression) requiring urgent 
alternative medical intervention 
 
5.3.12 Tumour Tissue Collection and Correlative Studies Blood Sampling 
5.3.12.1 Archival Tumour tissue samples 
For patients where a screening biopsy is not feasible, archival tumour material must be provided. If archived 
biopsy (block or slides) are sent it must contain tumour tissue. If no block is available, 10 or more freshly 
prepared (generated within the last 6 months) unstained 5 micron sections should be provided. Archival 
tumour blocks will be returned to source at the end of the study or, upon request, earlier if required for the 
patient’s clinical management. Cut sections will be retained by the study team. These are archived samples 
and as such participating patients will not need to attend extra visits or undergo extra procedures. All 
collected archival samples will be classed as pre-treatment samples and used as such in the immunological 
evaluation as described below. 
 

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5.3.13 Tumour Biopsies and Research Blood Samples 
For patients without archived samples, tumour biopsies will be obtained during the screening period. If the 
patient consents optional research blood samples will be obtained at C1D1, C2D1, C5D1 and at the end of 
study visit (Table 3). Tumour and blood samples from this study may undergo proteomic, genomic and 
transcriptional analyses. Additional research may evaluate factors important for predicting responsiveness 
or resistance to pembrolizumab therapy and radiotherapy. Assays may include, but are not limited to: 
 
Characterization of TILs and tumour antigens 
Immunohistochemistry (IHC) will be used to assess the number and composition of immune 
infiltrates in order to define the immune cell subsets present within formalin-fixed, paraffin 
embedded (FFPE) tumour tissue before and after exposure to therapy. These IHC analyses will 
include, but not necessarily be limited to, the following: CD4, CD8, FOXp3, PD-1, PD-L1, and PD-L2. 
 
ctDNA & CTCs 
Research blood samples will be analysed for ctDNA and CTCs. Analysis of CTCs will include, but not 
necessarily limited to the following, the diagnostic performance of PD-L1 testing will be assessed in 
CTC compared with IHC, correlation with response and disease progression.  
 
5.3.14 Chain of Custody of Biological Samples 
In all cases, patients will be consented for the collection and use of their biological samples and a full chain 
of custody will be maintained for all samples throughout their lifecycle. The Investigator is responsible for 
maintaining a record of full traceability of biological samples collected from patients while these are in 
storage at the site, either until shipment or disposal. Anyone with custody of the samples e.g. sub-contracted 
service provider will have to keep full traceability of samples from receipt to further shipment or disposal (as 
appropriate). RM-CTU will keep overall oversight of the entire lifecycle through internal procedures and 
monitoring of study site.  
5.4 
Total Blood Volume 
The total volume of blood that will be drawn from each trial patient for the assessments described in the 
sections above is shown in Table 5.  
Table 5:  Volume of blood  
 
Sample volume (ml) 
No. of samples 
Total volume (ml) 
Routine Haematology 
61 
11 
66 
Routine Chemistry 
81 
11 
88 
Routine Total: 
154 
Research Blood Samples  
OPTIONAL 
Up to 60 
4 
240 
Study Total: 
394 
1 Blood volumes may vary according to local practice 

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6 
TREATMENTS 
6.1 
Lung SBRT 
6.1.1      Planning and Delivery 
Radiotherapy planning and delivery should be carried out in accordance with the current RTT QA guidelines 
for stereotactic radiotherapy trials available on request from RM-CTU and included as Appendix 3 within 
the protocol. As only part of a lung lesion may be treated the target coverage planning goals will be for the 
defined target volumes. 
 
6.1.2 Toxicity Assessments  
Dyspnoea score and toxicity grading with CTCAE v4.0 will be recorded and will include pneumonitis, lung 
fibrosis, oesophagitis, skin toxicity, myelitis and fatigue. Side-effects that are seen with lung stereotactic 
radiotherapy include pericarditis, dysphagia, gastrointestinal bleeding, gastrointestinal ulceration, 
esophagitis, gastritis, nausea, vomiting, cough, pneumonitis, dyspnoea, fatigue, skin erythema, chest wall 
pain, and rib fracture. All other AEs will be documented in addition.   
 
6.2 
Pembrolizumab 
6.2.1 Investigational Product 
The Investigational Medicinal Product (IMP) for this study is pembrolizumab. A potent and highly-selective 
humanized mAb of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2. Pembrolizumab potentiates existing immune responses only in the presence of 
antigen and does not non-specifically activate T-cells. Pembrolizumab will be manufactured by MSD 
according to Good Manufacturing Practice and will be provided in the formulation as described in Table 6. 
Additional information about the investigational product can be found in the Summary of Product 
Characteristics (SmPC). 
 
Table 6: Product Description 
Product Name & Potency 
 Formulation 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
6.2.2 Product Preparation 
Please refer to the RM CTU Pharmacy Manual for preparation of the pembrolizumab for infusion.  
 

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6.2.3 Storage and Handling 
6.2.3.1  Storage  
The original solution for infusion should be stored at refrigerated conditions (2 – 8 °C). Vials should be 
stored in the original box to ensure the drug is protected from light. 
 
Prepared infusion solutions may be stored at room temperature for a cumulative time of up to 4 hours. This 
includes room temperature storage of reconstituted drug product solution in vials, room temperature 
storage of admixture solutions in the IV bags and the duration of infusion. In addition, reconstituted vials 
and/or IV bags may be stored under refrigeration at 2 °C to 8 °C (36 °F to 46 °F) for up to 20 hours. If 
refrigerated, allow the vials and/or IV bags to come to room temperature prior to use.  
 
6.2.3.2 Handling 
Infusion solutions should be prepared in 0.9% Sodium Chloride Injection, USP (normal saline) or 5% 
Dextrose Injection, USP (5% dextrose) and the final concentration of pembrolizumab in the infusion 
solutions should be between 1.0 mg/mL and 10.0 mg/mL. Please note, the preferred diluent is 0.9% Sodium 
Chloride and 5% dextrose is only permissible if normal saline is not available. Pembrolizumab should NOT 
be mixed with other diluents unless instructed by the MSD in writing.  Parenteral drug products should be 
inspected visually for particulate matter and discoloration prior to administration. Discard the drug product 
vial if extraneous particulate matter other than translucent to white proteinaceous particles is observed. 
 
Sites should follow their SOPs for drug transport and delivery, with all possible effort to minimise agitation 
of the reconstituted drug product between the pharmacy and the clinic. 
 
PLEASE DO NOT: 
 Use if discoloration is observed. 
 
 Shake or freeze the vial(s). 
 
 Administer the product as an (intravenous (iv) push or bolus). 
 
 Combine, dilute or administer it as an infusion with other medicinal products. 
 
 Co-administer other drugs through the same infusion line.  
 
Further details on the preparation of the drug product can be found in the RM CTU pharmacy manual.  At 
each site the Principle Investigator/designee e.g pharmacist at each participating site is responsible for 
ensuring that all trial Medication 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 

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authorized person at the trial site. Trial medication may not be used for any purpose other than that stated 
in the protocol. 
 
6.2.4 Packaging and Labelling Information 
Pembrolizumab will be supplied by MSD as solution for injection. Pembrolizumab will be packaged, labelled 
and delivered to the participating sites free of charge by MSD. The IMP will be supplied specifically for the 
trial and should not be used for any other purpose than that stated in this protocol. The drug will be labelled 
in accordance to Good Manufacturing Practice Annex 13.  
 
6.2.5 Returns and Reconciliation 
The Principle Investigator/designees is responsible for keeping accurate accountability accurate records for 
pembrolizumab including the amount dispensed to and returned for each patient and the amount remaining 
on site at the conclusion of the trial. Upon completion or termination of the study, all unused and/or 
partially used trial medication will be destroyed at the site per institutional policy. It is the Principle 
Investigator’s/designees 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. 
 
6.2.6 Doses and Treatment Regimens 
All patients will receive pembrolizumab administered as per standard procedures following manufacturer’s 
instructions. Trial treatment should begin on the day of confirmation of eligibility or as close as possible to 
the date on which treatment is allocated/assigned.  
 
Table 7: Pembrolizumab and lung SBRT schedules 
Dose level 
Lung SBRT 
Dose 
Drug 
Dose 
Frequency 
Route of 
Administration 
Dose 
1 
30 Gy in 3# 
Pembrolizumab 
3 weekly 
IV infusion 
200 
mg 
2 
54 Gy in 3#  
Pembrolizumab 
3 weekly 
IV infusion 
200 
mg 
Expansion cohort 
RP2D  
Pembrolizumab 
3 weekly 
IV infusion 
200 
mg 
 
6.2.7 Timing of Dose Administration 
During the induction and maintenance phase, the pembrolizumab should be administered on Day 1 of each 
cycle after all procedures/assessments have been completed as detailed on the schedule of study 
assessments (Table 3). The pembrolizumab administration may be administered up to 3 days before or after 
the scheduled Day 1 during the induction and maintenance phase due to administrative reasons. During the 

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induction and maintenance phase of the trial, the pembrolizumab will be administered on a 3 weekly cycle 
(Table 3).  
 
Maintenance pembrolizumab will continue until disease progression, withdrawal of consent, or 
unacceptable toxicity. Patients obtaining complete response or having completed 24 months of 
pembrolizumab have the option of discontinuing treatment, with a view to restarting treatment on disease 
progression. Retreatment should be discussed with the Chief Investigator. Study related assessment and 
procedures should be as for the beyond DLT Pembrolizumab Maintenance phase (see Table 3).  Patients do 
not need to re-sign the consent form for restarting treatment, provided their consent is on the most up-to-
date version of the Patient Information Sheet Consent Form. 
 
All trial treatments will be administered on an outpatient basis. Pembrolizumab will be administered as a 30 
minute IV infusion (treatment cycle intervals or infusion length may be increased due to toxicity as 
described in Section 6.2.3).  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). The RM CTU 
Pharmacy Manual contains specific instructions for pembrolizumab, reconstitution, preparation of the 
infusion fluid, and administration. In addition, infusion length may be increased due to toxicity as described 
in Section 7 and Table 9. 
 
The RM CTU pharmacy manual contains specific instructions for pembrolizumab reconstitution, 
preparation of the infusion, and administration.  
 
6.2.8 Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, Investigator and patient will know the treatment 
administered. 
 
6.2.9 Drug Dose Selection/Modification 
6.2.9.1 Dose Selection 
Pembrolizumab is being given using standard 200 mg flat dosing every three weeks. The Pembrolizumab 
dosing interval may be increased due to toxicity as described in Section 3.1.1. Details on the preparation and 
administration of pembrolizumab are provided in the RM CTU Pharmacy Manual. These guidelines contain 
specific instructions for pembrolizumab reconstitution, preparation of the infusion fluid and administration.  
 

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6.2.9.2  Dose Modification 
Pembrolizumab will be withheld for drug-related Grade 4 haematological toxicities, and non-haematological 
toxicity ≥ Grade 3 including laboratory abnormalities, and severe or life-threatening AEs as per Table 8 
below.  
 
In case toxicity does not resolve to Grade 0-1 within 12 weeks after last infusion, trial treatment should be 
discontinued after consultation with the Sponsor.  With Investigator and Sponsor agreement, patients with a 
laboratory AE still at Grade 2 after 12 weeks may continue treatment in the trial only if asymptomatic and 
controlled.  For information on the management of AEs, see Section 7 and Table 8. Patients who experience 
a recurrence of the same severe or life-threatening event at the same grade or greater with re-challenge of 
pembrolizumab should be discontinued from trial treatment.  
 
Events of Clinical interest (ECI) can be potential irAEs and dose modifications for these toxicities should 
they occur can be found in Appendix 5 and as per the MSD guidance document for pembrolizumab ECI 
version 3.0. 
 
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). Subjects 
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. 
 
 

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Table 8: Dose modification guidelines for drug-related adverse events. 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
Diarrhoea/Colitis 
2-3 
 
Toxicity resolves to 
Grade 0-1. 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased 
Bilirubin 
2 
Toxicity resolves to 
Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose. 
3-4 
Permanently discontinue 
(see exception below)1 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or  
3-4 
Hold pembrolizumab for 
new onset Type 1 
diabetes mellitus or 
Grade 3-4 hyperglycemia 
associated with evidence 
of beta cell failure. 
Resume pembrolizumab when patients are clinically and 
metabolically stable. 
Hypophysitis 
2-4 
Toxicity resolves to 
Grade 0-1. Therapy with 
pembrolizumab can be 
continued while 
endocrine replacement 
therapy is instituted 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
Hyperthyroidism  
3 
Toxicity resolves to 
Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
 
Therapy with 
pembrolizumab can be 
continued while thyroid 
replacement therapy is 
instituted 
Therapy with pembrolizumab can be continued while 
thyroid replacement therapy is instituted. 
Infusion 
Reaction 
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to 
Grade 0-1.  
If recurrent Grade 
pneumonitis occurs 
pembrolizumab should 
be permanently 
discontinued. 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to 
Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related Toxicity2 
3 or Severe 
Toxicity resolves to 
Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-
threatening event. 
1 For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than 
or equal to 50% relative to baseline and lasts for at least 1 week then patients should be discontinued. 
2 Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  
Permanently discontinue study drug for persistent Grade 2 adverse reactions for which treatment with study drug has 
been held, that do not recover to Grade 0-1 within 12 weeks of the last dose. 
 

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6.3 
Concomitant medications 
Concomitant medications will be recorded at screening and at every visit during the treatment phase of the 
study in the case report form (CRF) in the concomitant therapy section. 
6.3.1 Prohibited Concomitant Medications 
Medications or vaccinations specifically prohibited in the exclusion criteria are also not allowed during the 
ongoing trial.  If there is a clinical indication for one of these or other prohibited medications or vaccinations  
then the patient may be discontinued from trial therapy.  The Investigator should discuss any questions 
regarding this with the chief investigator (or delegate).   
 
The final decision on any supportive therapy or vaccination rests with the Investigator and/or the patient’s 
primary physician.  However, the decision to continue the patient on trial therapy or vaccination schedule 
requires the mutual agreement of the Chief Investigator, and the patient.  
 
Patients are prohibited from receiving the following therapies during the Screening and Treatment Phase of 
this trial: 
 
Anti-cancer systemic chemotherapy or biological therapy  
 
Immunotherapy not specified in this protocol 
 
Investigational agents other than pembrolizumab 
 
Live vaccines within 30 days prior to the first dose of trial treatment and while participating in the 
trial.  Examples of live vaccines include, but are not limited to, the following: measles, mumps, 
rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza 
vaccines for injection are generally killed virus vaccines and are allowed; however intra-nasal 
influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines, and are not allowed.  
 
Glucocorticoids for any purpose other than to modulate symptoms from an event of clinical interest 
of suspected immunologic aetiology.  The use of physiologic doses of corticosteroids may be 
approved after consultation with the Chief Investigator or delegate.  
 
Radiation therapy not specified in this protocol 
o Note:  Subsequent radiotherapy whilst on maintenance treatment to the thorax will not be 
permitted. Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed 
after consultation with the chief investigator, as long as it does not involve re-irradiation to 
any part of the lung. 
Patients who in the assessment by the investigator, require the use of any of the aforementioned for their 
clinical management should be removed from the trial. Patients may receive other medications that the 
investigator deems to be medically necessary. The Exclusion Criteria describes other medications which are 
prohibited in this trial. There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
 

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6.3.2 Acceptable 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 case report form (CRF) including all prescriptions, 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 before the first dose of trial treatment and 30 days 
after the last dose of trial treatment or initiation of other anti-cancer therapies should be recorded.  
Concomitant medications administered after 30 days after the last dose of trial treatment should only be 
recorded for SAEs and overdose and liver toxicity ECIs as defined in Section 7. 
 
6.4 
Rescue Medications & Supportive Care 
6.4.1 Supportive Care Guidelines 
Patients should receive appropriate supportive care measures as deemed necessary by the treating 
investigator including but not limited to the items outlined below: 
 
6.4.1.1 
Diarrhoea 
Patients should be carefully monitored for signs and symptoms of:  
 
Enterocolitis (diarrhoea, abdominal pain, blood or mucus in stool, with or without fever)  
 
Bowel perforation (peritoneal signs and ileus).   
In symptomatic patients, infectious aetiologies should be ruled out, and if symptoms are persistent and/or 
severe, endoscopic evaluation should be considered. 
 
In patients with severe enterocolitis (Grade 3):  
o Pembrolizumab will be permanently discontinued and treatment with systemic 
corticosteroids should be initiated at a dose of 1 to 2 mg/kg/day of prednisone or equivalent.  
When symptoms improve to Grade 1 or less, corticosteroid taper should be started and 
continued over at least 1 month. 
 
In patients with moderate enterocolitis (Grade 2): 
o  Pembrolizumab should be withheld and anti-diarrhoeal treatment should be started.  If 
symptoms are persistent for more than one week, systemic corticosteroids should be initiated 
(e.g., 0.5 mg/kg/day of prednisone or equivalent).  If symptoms are not improving within 48 
hours of starting steroids for grade 3 enterocolitis, consider infliximab . When symptoms 
improve to Grade 1 or less, corticosteroid taper should be started and continued over at least 1 

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month.  Guidelines for continuing treatment with pembrolizumab can be found in Appendix 
5. 
All patients who experience diarrhoea 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 i.v. infusion. 
 
6.4.1.2 Nausea/vomiting 
Nausea and vomiting should be treated aggressively, and consideration should be given in subsequent cycles 
to the administration of prophylactic antiemetic therapy according to standard institutional practice.  
Patients should be strongly encouraged to maintain liberal oral fluid intake. 
 
6.4.1.3 Infection 
Patients with a documented infectious complication should receive oral or i.v. antibiotics or other anti-
infective agents as considered appropriate by the treating investigator for a given infectious condition, 
according to standard institutional practice. 
 
6.4.1.4 Immune-related adverse events 
Please see Section 7.5 below and the separate guidance document in the administrative binder regarding 
diagnosis and management of adverse experiences of a potential immunologic aetiology.   
 
6.4.1.5 Management of Infusion Reactions 
Acute infusion reactions (which can include cytokine release syndrome, angioedema, or anaphylaxis) are 
different from allergic/hypersensitive reactions, although some of the manifestations are common to both 
AEs.  Signs and symptoms usually develop during or shortly after drug infusion and generally resolve 
completely within 24 hours of completion of infusion. Signs/symptoms may include: Allergic 
reaction/hypersensitivity (including drug fever); Arthralgia (joint pain); Bronchospasm; Cough; Dizziness; 
Dyspnoea (shortness of breath); Fatigue (asthenia, lethargy, malaise); Headache; Hypertension; 
Hypotension; Myalgia (muscle pain); Nausea; Pruritus/itching; Rash/desquamation; Rigors/chills; 
Sweating (diaphoresis); Tachycardia; Tumour pain (onset or exacerbation of tumour pain due to treatment); 
Urticaria (hives, welts, wheals); Vomiting. Table 9 below shows treatment guidelines for patients who 
experience an infusion reaction associated with administration of pembrolizumab. 
 
6.5 
Supportive Care Guidelines for Immune-related Adverse Events (irAE) and Immune-related 
Events of Clinical Interest (irECI) 
Immune-related Adverse Events (irAEs) may be defined as an AE of unknown etiology, associated with drug 
exposure and is consistent with an immune phenomenon.  irAEs may be predicted based on the nature of 
the pembrolizumab compound, its mechanism of action, and reported experience with immunotherapies 

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that have a similar mechanism of action.  Special attention should be paid to AEs that may be suggestive of 
potential irAEs.  An irAE can occur shortly after the first dose or several months after the last dose of 
treatment.  If an irAE is suspected, efforts should be made to rule out cancer, infectious, metabolic, toxin or 
other etiologic causes prior to labelling an AE as an irAE.  Patients who develop a Grade 2 or higher irAE 
should be discussed immediately with the Chief Investigator or delegate. 
 
Recommendations to managing irAEs not detailed elsewhere in the protocol are detailed in Table 10. 
 

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Table 9: Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild 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 
Requires infusion interruption 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 
Paracetamol 
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 pre-medicated 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 pre-
medicated 1.5h (± 30 
minutes) prior to infusion 
of pembrolizumab with: 
 
Diphenhydramine 50 mg 
po (or equivalent dose of 
antihistamine). 
 
Paracetamol 500-1000 
mg po (or equivalent dose 
of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly responsive to 
symptomatic medication and/or brief 
interruption of infusion); recurrence of 
symptoms following initial 
improvement; hospitalization indicated 
for other clinical sequelae (e.g., renal 
impairment, pulmonary infiltrates) 
 
Grade 4: 
Life-threatening; Pressor or ventilator 
support indicated 
 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Paracetamol 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
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. 
For Further information, please refer to the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE) at 
http://ctep.cancer.gov 
 
 

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Table 10: General Approach to Handling irAEs 
irAE 
Withhold/Discontinue 
Pembrolizumab? 
Supportive Care 
Grade 1 
No action 
Provide symptomatic treatment 
Grade 2 
May 
withhold 
pembrolizumab. 
For 
recurrent 
grade 
2 
pneumonitis, 
pembrolizumab should be discontinued 
permanently. 
Consider systemic corticosteroids in addition to 
appropriate symptomatic treatment. Steroid taper 
should be considered once symptoms improve to 
Grade 1 or less and tapered over at least 4 weeks. 
Based on limited data from clinical studies in 
subjects whose immune-related adverse reactions 
could not be controlled with corticosteroid use, 
administration 
of 
other 
systemic 
immunosuppressants can be considered. 
Grade 3 and 
Grade 4 
Withhold pembrolizumab 
Discontinue 
if 
unable 
to 
reduce 
corticosteroid dose to < 10 mg per day 
prednisone equivalent within 12 weeks 
of toxicity 
Systemic corticosteroids are indicated in addition 
to appropriate symptomatic treatment.  May 
utilize 1 to 2 mg/kg prednisone or equivalent per 
day. 
Steroid 
taper 
should 
be 
considered 
once 
symptoms improve to Grade 1 or less and tapered 
over at least 4 weeks. 
Based on limited data from clinical studies in 
subjects whose immune-related adverse reactions 
could not be controlled with corticosteroid use, 
administration 
of 
other 
systemic 
immunosuppressants can be considered. 
Please Note:  
If an irAE does not resolve or improve to ≤ Grade 1 within 12 weeks after last administration of 
pembrolizumab, study therapy discontinuation should be considered after discussion with a Merck Clinical 
Director via the RM-CTU trial manager. 
 
Details for managing specific irAEs are summarised below: 
 
Immune-mediated pneumonitis 
Monitor subjects for signs and symptoms of pneumonitis. If pneumonitis is suspected, evaluate with 
radiographic imaging and exclude other causes. Administer corticosteroids for Grade 2 or greater events 
(initial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper), withhold pembrolizumab for 
moderate (Grade 2) pneumonitis, and permanently discontinue pembrolizumab for recurrent moderate 
(Grade 2),  severe (Grade 3) or life-threatening (Grade 4) pneumonitis. 
 
Immune-mediated colitis 
Monitor subjects for signs and symptoms of colitis and exclude other causes of colitis. Administer 
corticosteroids for Grade 2 (if persists for >3 days) or greater events (initial dose of 1-2 mg/kg/day 
prednisone or equivalent followed by a taper), withhold pembrolizumab for moderate (Grade 2) or severe 
(Grade 3) colitis, and permanently discontinue pembrolizumab for life-threatening (Grade 4) colitis. 
 
Immune-mediated hepatitis 
Monitor subjects for changes in liver function (at the start of treatment, periodically during treatment and as 
indicated based on clinical evaluation) and symptoms of hepatitis, and exclude other causes of hepatitis,. 

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Administer corticosteroids (initial dose of 0.5 – 1.0 mg/kg/day for grade 2 events, and 1 – 2 mg/kg/day for 
grade 3 or greater events, of prednisone or equivalent, followed by a taper) and, based on severity of liver 
enzyme elevations, withhold or discontinue pembrolizumab. 
 
Immune-mediated nephritis 
Monitor patients for changes in renal function and exclude other causes of nephritis. Administer 
corticosteroids for grade 2 or greater events (initial dose of 1 – 2 mg/kg/day prednisone or equivalent, 
followed by a taper), withhold pembrolizumab for moderate (Grade 2), and permanently discontinue 
pembrolizumab for severe (Grade 3) or life-threatening (Grade 4) nephrits. 
 
 
Immune-mediated endocrinopathies 
Monitor subjects for signs and symptoms of hypophysitis (including hypopituitarism and secondary adrenal 
insufficiency) and exclude other causes of hypophysitis. Administer corticosteroids to treat secondary 
adrenal insufficiency and other hormone replacement as clinically indicated, withhold pembrolizumab for 
moderate (Grade 2), withhold or discontinue pembrolizumab for severe (Grade 3) or for life-threatening 
(Grade 4) hypophysitis. 
 
Monitor subjects for hyperglycemia or other signs and symptoms of type 1 diabetes. Exclude other causes of 
diabetes. Administer insulin for type 1 diabetes, and withhold pembrolizumab in cases of severe 
hyperglycemia until metabolic control is achieved. 
 
Thyroid disorders have been reported in subjects receiving pembrolizumab and can occur at any time during 
treatment; therefore, monitor subjects for changes in thyroid function (at the start of treatment, periodically 
during treatment and as indicated based on clinical evaluation) and clinical signs and symptoms of thyroid 
disorders. Hyperthyroidism may be managed symptomatically. Withhold pembrolizumab for severe (Grade 
3) hyperthyroidism, and permanently discontinue pembrolizumab for life-threatening (Grade 4) 
hyperthyroidism. Hypothyroidism may be managed with replacement therapy without treatment 
interruption and without corticosteroids. For subjects with severe (Grade 3) or life-threatening (Grade 4) 
endocrinopathy that improves to Grade 2 or lower and is controlled with hormone replacement, 
continuation of pembrolizumab may be considered. 
 
Other immune-related AEs 
The following additional clinically significant, immune-mediated adverse reactions were reported in less 
than 1% (unless otherwise indicated) of subjects treated with pembrolizumab: uveitis, myositis, Guillain-
Barré syndrome, pancreatitis and severe skin reactions (1.1%).   
 

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In addition a set of irAEs have also been classified as immune-related events of clinical interest (irECI) a full 
list of these can been found in events of clinical interest guidance and Appendix 5. Patients with 
symptomatic irECIs should immediately stop receiving pembrolizumab and be evaluated to rule out non 
treatment related causes of the event. Overdose and liver toxicity irECIs irrespective of relationship to the 
study drug should be reported within 24 hours of the investigator being aware to the Sponsor (via RM-CTU) 
who will in turn notify MSD. If the irECI is determined to be associated please refer to ECI guidance 
document and Appendix 5 for the recommendations on the management of these irECIs. If the event is not 
considered to be associated with the study drug the physician should exercise individual clinical judgment 
on the event management based on the patient.  Any additional questions of the collection or information on 
management of irECIs should be directed to the Sponsor (via RM-CTU). 
6.6 
Supportive Care Guidelines for Pneumonitis 
Patients with symptomatic pneumonitis should immediately stop receiving pembrolizumab and have an 
evaluation.  The evaluation may include bronchoscopy and pulmonary function tests to rule out other causes 
such as infection.  If the patient is determined to have study drug associated pneumonitis, the suggested 
treatment plan is detailed in Table 11. 
 
Table 11: Recommended Approach to Handling Pneumonitis 
Study drug 
associated 
pneumonitis 
Withhold/Discontinue 
Pembrolizumab? 
Supportive Care 
Grade 1 
(asymptomatic) 
No action 
Intervention not indicated 
Grade 2 
Withhold pembrolizumab, may 
return to treatment if improves 
to Grade 1 or resolves within 12 
weeks 
Second episode of pneumonitis 
– discontinue pembrolizumab if 
upon re-challenge the patient 
develops a second episode of 
Grade 2 or higher pneumonitis. 
Consider pulmonary consultation with bronchoscopy and 
biopsy/BAL. 
Conduct an in person evaluation approximately twice per week 
Consider frequent Chest X-ray as part of monitoring 
Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg/day 
prednisone or equivalent. When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over no less 
than 4 weeks. 
Consider antibiotics 
Grade 3 and 
Grade 4 
Discontinue pembrolizumab 
Hospitalise patient 
Bronchoscopy with biopsy and/or BAL is recommended. 
Immediately treat with intravenous steroids (methylprednisolone 
125 mg IV). When symptoms improve to Grade 1 or less, a high 
dose oral steroid (prednisone 1 to 2 mg/kg once per day or 
dexamethasone 4 mg every 4 hours) taper should be started and 
continued over no less than 4 weeks. 
If IV steroids followed by high dose oral steroids does not reduce 
initial symptoms within 48 to 72hours, treat with additional anti-
inflammatory measures. Discontinue additional anti-
inflammatory measures upon symptom relief and initiate a 
prolonged steroid taper over 45 to 60 days. If symptoms worsen 
during steroid reduction, initiate a re-tapering of steroids starting 
at a higher dose of 80 or 100mg followed by a more prolonged 
taper and administer additional anti-inflammatory measures, as 
needed add prophylactic antibiotics for opportunistic infections. 
The use of infliximab may be indicated as appropriate. 

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For Grade 2 pneumonitis that improves to ≤ Grade 1 within 12 weeks, the following rules should apply: 
 
First episode of pneumonitis: May increase dosing interval by one week in subsequent cycles 
 
Second episode of pneumonitis: Permanently discontinue pembrolizumab if upon re-challenge the 
patient develops pneumonitis  Grade 2 
 
6.7 
Diet/Activity/Other Considerations 
6.7.1 Diet 
Patients should maintain a normal diet unless modifications are required to manage an AE such as 
diarrhoea, nausea or vomiting. 
 
6.7.2 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 either, two barrier methods or a barrier method plus a hormonal method to prevent 
pregnancy. Patients should start using birth control from screening throughout the study period up to 120 
days after the last dose of study therapy. Male patients with partners of child bearing potential will also be 
required to 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. 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. 
 
6.7.3 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 

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be reported to the Sponsor and to MSD without delay and within 24 hours 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 the Sponsor (via 
RM-CTU) without delay and within 24 hours. If a male patient impregnates his female partner the study 
personnel at the site must be informed immediately and the pregnancy reported to the RM-CTU and 
followed as described above and in Section 7. 
 
6.7.4 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. 
 
6.7.5 Treatment of Overdose of IMP 
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed dose for 
pembrolizumab by 20% over the prescribed dose. Please see section 7 for definitions and reporting 
procedures. 
6.8 
Permanent Discontinuation of Trial Medication and Withdrawal from the Study 
6.8.1 Permanent Discontinuation of Trial Medication 
A patient may be permanently discontinued from the trial medication for any of the following reasons: 
 
The subject withdraws consent. 
 
Confirmed radiographic disease progression, please see Section 6.3.11.4.  
Note: For unconfirmed radiographic disease progression. A patient may be granted an exception 
to continue on treatment with confirmed radiographic progression if clinically stable or clinically 
improved. 
 
Unacceptable adverse experiences 
 
Intercurrent illness that prevents further administration of treatment 
 
The patient has a confirmed positive serum pregnancy test 
 
Noncompliance with trial treatment or procedure requirements 
 
Administrative reasons 
 
Completion of 24 months of pembrolizumab  
Trial patients will not be enrolled more than once. The primary reason for discontinuation should be 
recorded on the CRF. Once the trial medication has been discontinued the patient should complete the end 
of treatment (if applicable) and safety follow-up visit procedures as listed in the schedule of study 

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assessment (Table 3). After the end of treatment, patients will continue to be assessed for AE and SAE 
monitoring until completion of the safety follow up visit. 
 
Follow-up actions for patient discontinuing the trial are as follows: 
 
All patients will be required to: 
o Attend a safety follow-up 30 days after their last dose of pembrolizumab, 
 
If a patient progresses or begins a new anti-cancer treatment they will be required to: 
o Undertake survival status assessments every 12 weeks until death, withdrawal of consent, lost 
to follow up or the end of the study. 
 
If a patient discontinues for reasons other than progression during treatment and does not 
withdraw their consent to follow up they will be required to: 
o Attend follow-up assessments every 9 weeks until disease progression, initiation of a new 
anti-cancer treatment death, end of the study.  Information regarding post-study anti-cancer 
treatment will be collected if new treatment is initiated. 
 
6.9 
Withdrawal from the Study 
Patients have the right to discontinue study treatment any time for any reason, without prejudice to their 
medical care. Withdrawal from the study refers to discontinuation of both study medication and study 
assessments; this can occur at any time according to the following reasons: 
 
Patient decision 
 
Lost to follow-up 
 
Death 
 
PI decision 
Patients may withdraw consent at any time for any reason or have trial treatment stopped 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 enrolment into the trial is inappropriate, the trial plan is violated, or for 
administrative and/or other safety reasons.  When a patient discontinues/withdraws prior to trial 
completion, all applicable activities scheduled for the final trial visit should be performed at the time of 
discontinuation, these are listed in the schedule of study assessments (Table 3).  Any AEs which are present 
at that time should be followed in accordance with the safety requirements outlined in Section 7. 
 
Patients who a) attain a complete response or b) complete 24 months of treatment with pembrolizumab may 
discontinue treatment with the option of restarting treatment on disease progression. Retreatment should 
be discussed with the Chief Investigator. Study related assessment and procedures should be as for the 
beyond Pembrolizumab Maintenance phase (see Table 3). Patients do not need to re-sign the consent form 
for restarting treatment, provided their consent is on the most up-to-date version of the Patient Information 
Sheet Consent Form. After discontinuing treatment following assessment of complete response, these 

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patients should return to the site for a 30 days safety follow-up visit and then proceed to the follow-up 
period of the study. 

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7 
PHARMACOVIGILANCE 
7.1 
Adverse events 
7.1.1 Adverse Event Definition 
An AE is defined as any untoward undesired or unplanned occurrence (including deterioration of a pre-
existing medical condition) in a patient administered a pharmaceutical product or undertaking a protocol-
specified procedure. An AE can therefore be any unfavourable and unintended sign symptom, or disease 
and/or laboratory or physiological observation associated with the use of a medicinal product or protocol-
specified procedure but does not necessarily have to have a causal relationship to this treatment or 
procedure. Any worsening (i.e. any clinically significant adverse change in frequency and/or intensity) of a 
pre-existing condition that is temporally associated with the use of pembrolizumab, is also an AE. Changes 
resulting from normal growth and development that do not vary significantly in frequency or severity from 
expected levels are not to be considered AEs.  Examples of this may include, but are not limited to, onset of 
menses or menopause occurring at a physiologically appropriate time. AEs may also occur in screened 
patients during any pre-allocation baseline period as a result of a protocol-specified intervention, including 
washout or discontinuation of usual therapy, diet, placebo treatment or a procedure.  
 
7.1.2 Adverse Reaction Definition 
An AE assessed by the Principal Investigator and / or Chief Investigator as reasonably likely to be related to 
the administration of a medicinal product or protocol-specified procedure. 
7.1.3 Disease Progression 
Disease progression of the cancer under study is not considered an AE unless it results in hospitalisation. 
7.1.4 New Cancers 
The development of a new cancer should be regarded as an SAE and reported accordingly.  
 
7.1.5 Abnormal Laboratory Test Results 
All clinically important abnormal laboratory test results occurring during the study will be recorded as AEs. 
The clinically important abnormal laboratory tests will be repeated at appropriate intervals until they return 
either to baseline or to a level deemed acceptable by the investigator, or until a diagnosis that explains them 
is made.   
7.1.6 Pregnancy and Lactation 
Pregnancy and lactation are not considered AEs, however these events should be reported to the RM-CTU 
following guidance in section 7.7 

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7.2 
Assessing and Recording Adverse Events 
All AEs will be recorded from the time of the first dose until the safety follow-up in the CRF. They will be 
followed up according to local practice until the event has stabilised or resolved, or the follow-up visit has 
taken place, whichever is the sooner. SAEs will also be recorded throughout the study. The reporting 
timeframe for AEs meeting any serious criteria is described in section 7.4.1.  
Follow-up of AEs with a causality of possible, probable or highly probable will continue until the events 
resolve, stabilise or the patient completes the trial.  Any unresolved AEs at the patient’s last visit should be 
followed up for as long as medically indicated, but without further recording in the CRF.  
If an Investigator learns of any AE that he/she consider serious, including death, at any time after a patient 
has completed the study and he/she considers there is a reasonable possibility that the event is related to 
pembrolizumab, the Investigator should notify the RM-CTU. Late toxicities will be recorded and reported as 
with other AEs. 
The following details will be collected in the CRF for each AE: 
 
AE description / diagnosis 
 
Date of onset and date of resolution 
 
NCI-CTCAE grade maximum intensity 
 
Seriousness 
 
Investigator causality rating against the study medication (yes or no) 
 
Expectedness 
 
Action taken with regard to study medication 
 
Outcome 
For the pre-registration period AEs will not be collected in patients that have not undergone any protocol-
specified procedure or intervention.  If the patient requires a blood draw, fresh tumour biopsy etc. for the 
study then the patient will be required to consent to the main study and AEs will be captured as described 
above. 
7.3 
Evaluating Adverse Events 
AEs will be evaluated by an investigator who is a qualified medical physician. 
7.3.1   Determining AE Severity and Grade 
AE severity and grade will be evaluated according to the NCI Common Terminology for Adverse Events 
(CTCAE), version 4.0. Any AE which changes CTCAE grade over the course of a given episode should be 
closed at the date the severity changed and a new AE recorded on the AE case report forms from that date at 
the new severity. 

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7.3.2 Determining AE Causality 
The Investigator must endeavour to obtain sufficient information to assess the causality of the AE and must 
provide his/her opinion whether the event has any relationship to the administered study treatment / 
procedure. This may require instituting supplementary investigations of significant AEs based on their 
clinical judgement of the likely causative factors and/or include seeking a further opinion from a specialist in 
the field of the AE. 
Causality is the relationship of an AE to the IMP and will be determined as follows: 
Definite: 
 
There is clear evidence to suggest a causal relationship. 
 
Starts within a time related to the IMP administration and 
 
No obvious alternative medical explanation. 
Probable:  
 
There is evidence to suggest a causal relationship  
 
Starts within a time related to the IMP administration and 
 
Cannot be reasonably explained by known characteristics of the patient’s clinical state. 
Possible:  
 
A causal relationship between the IMP and the AE is at least a reasonable possibility. 
 
Starts within a time related to the IMP administration  
 
However, the influence of other factors may have contributed to the event (e.g. the 
patient’s clinical condition, other concomitant treatments). 
Unlikely:  
 
There is little evidence to suggest there is a causal relationship.  
 
There is another reasonable explanation for the event (e.g. the patient’s clinical condition, 
other concomitant treatment). 
 
The time association is such that the trial drug is not likely to have had an association 
with the observed effect. 
Not 
related:  
 
The AE is definitely not associated with the IMP administered. 
 
7.4 
Serious adverse events (SAEs) 
An SAE is defined as any untoward medical occurrence or effect that at any dose that: 
 
 Results in death; 
 Is life-threatening or places the patient, in the view of the investigator, at immediate risk of death from 
the event as it occurred1; 
 Requires in-patient hospitalisation or prolongs existing in-patient hospitalisation2 
 Results in persistent or significant incapacity or disability; 
 Is a new cancer 
 Is a congenital anomaly or birth defect; 
 Is associated with an overdose (whether accidental or intentional).  Any AE associated with an 
overdose is considered a SAE.  
 Is any other medically important event.3 

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1 This does not include an AE which hypothetically might have caused death if had it occurred in a more severe form. 
2 Hospitalisation is defined as an unexpected inpatient admission, regardless of length of stay, even if the 
hospitalisation is a precautionary measure for continued observation. It does not usually apply to scheduled 
admissions that were planned before study inclusion or visits to casualty (without admission). 
3 A medically important event may not result in death, not be life threatening, or not require hospitalisation but may 
be considered a SAE when, based upon appropriate medical judgment, the event that may jeopardise the patient and 
require medical or surgical intervention to prevent one of the outcomes listed above. 
 
7.4.1 Reporting SAEs 
All SAEs regardless of causality, pregnancy or overdose that occur from the first dose until the 30 day safety 
follow-up or the initiation of a new anticancer therapy, whichever is earlier, must be reported on the SAE 
report form within 24 hours of the investigator / designee becoming aware of the event.  
 
The SAE/ECI report form should be sent to 
Email : Priming.Trial@rmh.nhs.uk 
Fax: 020 8915 6762 
who will in turn notify MSD of the event. 
 
The SAE form must be completed, assessed for causality and expectedness against the current version of the 
Investigator Brochure, then signed and dated by the Principal Investigator or an appropriately qualified 
designated individual identified on the delegation log. The report will then be reviewed by the Chief 
Investigator (or a nominated representative) to confirm relatedness and expectedness. The NCI-CTCAE 
version 4.0 must be used to grade each SAE, and the worst grade recorded.  If new or amended information 
on a previously reported SAE becomes available, the Investigator should report this to the Sponsor (via RM-
CTU) on a new SAE report form. The Sponsor (via RM-CTU) will in turn submit the updated report to MSD. 
Please refer to the SAE completion guidelines for further information.  
 
Additionally, any SAE considered by an investigator who is a qualified physician to be related to the IMP or 
protocol-specified procedure that is brought to the attention of the investigator at any time outside of the 
time period specified in the previous paragraph also must be reported immediately to the Sponsor (via RM-
CTU) who will inform MSD. 
 
7.4.2 Events exempt from being reported as SAEs 
Events specified in this section do not require reporting as SAEs in this trial, unless hospitalisation is 
prolonged for any reason and then an SAE form must be completed.  The events must still be recorded in the 
appropriate section of the CRF.   
1. Elective admissions to hospital for procedures which were planned and documented in the medical 
records at the time of consent are not SAEs, and do not require SAE reporting.   

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2. Hospitalisation for administration of the IMP, or to facilitate study procedures such as 
pharmacokinetic sampling according to the trial protocol, is also exempt from being reported as an 
SAE. 
3. Progressive disease and death due to disease are not considered SAEs, unless they fulfil the 
seriousness criteria, as listed in Section 7.5. All cases of progressive disease and death should be 
reported in the CRFs 
7.4.3 Determining SAE Causality and Expectedness 
Assessment of causality and expectedness for all SAEs will be made by the PI/designee and Chief 
Investigator or delegate against the SmPC (Reference Safety Information Appendices).  If updated versions 
of the SmPC are released during the course of the trial then assessment of expectedness will be made against 
the current regulatory approved version. The Reference Safety Information (RSI) for assessing the 
expectedness of adverse events is contained in section 4.8 of the Summary of Product Characteristics 
(SmPC). 
 
7.5 
Events of Clinical Interest 
7.5.1 Definitions of Evidence of Clinical Interest (ECI) 
Selected non-serious and SAEs can also be classified as Events of Clinical Interest (ECI) and must be 
reported as described in section 7.5.2. 
Events of clinical interest for this trial include: 
1. An overdose of pembrolizumab, as defined in Section 7.6 that is not associated with clinical 
symptoms or abnormal laboratory results.  
2. A Drug induced liver injury (DILI) defined as elevated AST or ALT lab value that is greater than or 
equal to 3X the upper limit of normal  
 
 
 
AND / OR 
 
An elevated total bilirubin lab value that is greater than or equal to 2X the upper limit of 
normal  
 
 
 
AND / OR 
An alkaline phosphatase lab value that is greater or equal to 2X the upper limit of normal, as 
determined by way of protocol-specified laboratory testing or unscheduled laboratory testing. 
3. Any AEs identified in the below Table 12 can be classified as immune-related events of clinical 
interest. A detailed narrative of overdose and liver toxicity ECIs should be reported as described in 
section 7.5.2 
 

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A separate guidance document has been provided entitled “Event of Clinical Interest Guidance Document.”  
This document provides guidance regarding identification, evaluation and management of ECIs and irAEs.  
Patients should be assessed for possible ECIs prior to each dose.  Lab results should be evaluated and 
patients should be asked for signs and symptoms suggestive of an immune-related event.  Patients who 
develop an ECI thought to be immune-related should have additional testing to rule out other etiologic 
causes.  If lab results or symptoms indicate a possible immune-related ECI, then additional testing should be 
performed to rule out other etiologic causes.  If no other cause is found, then it is assumed to be immune-
related.  
7.5.2 Reporting of ECIs 
Overdose and liver toxicity ECIs whether or not related to the pembrolizumab, occurring from the first dose 
until 30 days following the last treatment dose, or the initiation of a new anticancer therapy, whichever is 
earlier, must be recorded on the AE e-case report forms and reported using the SAE/ECI report form within 
24 hours of the PI/designee becoming aware of the event to the Sponsor (via RM-CTU) as follows:  
 
The SAE / ECI report form should be sent to 
Email: Priming.Trial@rmh.nhs.uk 
 
Fax: 020 8915 6762 
who will in turn notify MSD of the event. 
 

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Table 12: Immune related Aes considered ECIs 
 
Pneumonitis  - (classified as ECI if ≥ Grade 2) 
Acute interstitial Pneumonitis 
Interstitial Lung Disease  
Pneumonitis 
Colitis  - (classified as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic 
steroids to treat the AE) 
Intestinal Obstruction 
Colitis  
Colitis microscopic 
Enterocolitis 
Enterocolitishemorrhagic 
Gastrointestinal perforation 
Necrotising colitis 
Diarrhoea 
 
Endocrine – (classified as ECI if ≥ Grade 3 or  ≥ Grade 2 and resulting in dose modification or use of 
systemic steroids to treat the AE) 
Adrenal Insufficiency  
Hyperthyroidism 
Hypophysitis 
Hypopituitarism 
Hypothyroidism 
Thyroid disorder 
Thyroiditis 
Hyperglycemia, if ≥Grade 3 and associated with ketosis or metabolic acidosis 
(DKA) 
Type 1 diabetes mellitus (if new onset) 
Hematologic – (classified as ECI if ≥ Grade 3 or any grade resulting in dose modification or use of 
systemic steroids to treat the AE) 
Autoimmune haemolytic anaemia 
Aplastic anaemia 
Thrombotic thrombocytopenic 
purpura 
Idiopathic thrombocytopenia 
purpura 
Disseminated intravascular 
coagulation 
Haemolytic uraemic syndrome 
Any grade 4 anaemia regardless of underlying mechanism 
Hepatic  - (classified as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of 
systemic steroids to treat the AE) 
Hepatitis 
Autoimmune hepatitis  
Transaminase elevations (ALT and/or 
AST) 
Infusion reactions - (classified as ECI for any grade) 
Allergic reaction 
Anaphylaxis 
Cytokine release syndrome  
Serum sickness 
Infusion reactions  
Infusion-like reactions  
Neurologic - (classified as ECI for any grade) 
Autoimmune neuropathy  
Guillain-Barre syndrome 
Demyelinating polyneuropathy 
Myasthenic syndrome 
 
 
Ocular  - (classified as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of 
systemic steroids to treat the AE) 
Uveitis 
Iritis 
 
Renal - (classified as ECI for ≥ Grade 2) 
Nephritis 
Nephritis autoimmune 
Renal Failure 
Renal failure acute 
Creatinine elevations - (report as ECI if ≥ Grade 3 or any grade resulting 
in dose modification or use of systemic steroids to treat the AE) 
Skin - (classified as ECI for any grade) 
Dermatitis exfoliate 
Erythema multiforme 
Stevens-Johnson Syndrome 
Toxic epidermal necrolysis 
 
 
Skin - (classified as ECI for ≥ Grade 3) 
Pruritus 
Rash 
Rash generalised  
Rash maculo-papular 
Any rash clinical significant in the physicians judgement. 
Other  - (classified as ECI for any grade) 
Myocarditis 
Pancreatitis 
Percarditis 
Any other grade 3 event which is considered immune-related by the physician. 
 
7.6 
Definition of an Overdose for this Protocol and Reporting of Overdose 
At present no specific information is available on the treatment of overdose of pembrolizumab. For purposes 
of this trial, an overdose will be defined as any dose exceeding the prescribed dose for pembrolizumab by 
20%. In the event of overdose the patient should be observed closely for signs of toxicity.  Appropriate 
supportive treatment should be provided if clinically indicated. 

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If an AE(s) is associated with (“results from”) the overdose of pembrolizumab, the AE(s) should be recorded 
on the AE CRF and reported as a SAE, even if no other seriousness criteria are met.  
 
If an overdose is taken without any associated clinical symptoms or abnormal laboratory results, the 
overdose is again recorded as an AE on the CRF and reported as a non-serious ECI, using the terminology 
“accidental or intentional overdose without adverse effect.” 
 
All reports of overdose either SAE or ECI must be reported within 24 hours of the PI or designee becoming 
aware of the event to the Sponsor (via RM-CTU) as follows:  
 
The SAE / ECI report form should be sent to 
Email: Priming.Trial@rmh.nhs.uk 
Fax: 020 8915 6762 
who will in turn notify MSD of the event. 
 
 
7.7 
Reporting of Pregnancy and Lactation 
Although pregnancy and lactation are not considered AEs, it is the responsibility of investigators or their 
designees to report any pregnancy or lactation in a patient (spontaneously reported to them), that occurs 
during the trial or within 120 days of completing the trial, or 30 days following cessation of treatment if the 
patient initiates new anticancer therapy, whichever is earlier.  All 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, foetal death, intrauterine death, miscarriage and 
still birth must be reported as SAE (Important Medical Events).  If the pregnancy continues to term, the 
outcome (health of infant) must also be reported with the parents’ consent. Such events must be reported 
within 24 hours to the Sponsor (via RM-CTU) as follows:  
 
The SAE / ECI report form should be sent to 
Email: Priming.Trial@rmh.nhs.uk 
Fax: 020 8915 6762 
who will in turn notify MSD of the event. 
 
 
7.8 
Definition of a Serious Adverse Reaction (SAR) 
A SAR is defined as an SAE that is judged to be related to any dose of study drug administered to the patient. 
 

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7.9 
Definition of Suspected, Unexpected, Serious, Adverse Reactions (SUSARs) 
A SUSAR is a serious adverse reaction, the nature or severity of which is not consistent with the applicable 
product information (e.g. reference safety information appendices of investigator’s brochure for an 
unauthorised investigational product or summary of product characteristics for an authorised product). For 
lung stereotactic radiotherapy, the anticipated side-effects are listed in Section 6.1.2. Hospitalisations due to 
these adverse events, where causality is ascribed to lung stereotactic radiotherapy, will be reported as an 
SAE, but not escalated to a SUSAR.  
7.10 Reporting of SUSARs 
All SUSARs must be reported using the SAE report form within 24 hours of the PI/designee becoming aware 
of the event to the Sponsor (via RM-CTU) as follows:  
The SAE / ECI report form should be sent to 
Email: Priming.Trial@rmh.nhs.uk 
Fax: 020 8915 6762 
who will in turn notify MSD, relevant Independent Ethics Committee (IEC) / Institutional review, 
appropriate regulatory authorities and the participating Principal Investigators of the event. 
 
The Sponsor (via RM-CTU) will in turn notify the MSD, relevant Independent Ethics Committee (IEC) / 
Institutional review, appropriate regulatory authorities and the participating Principal Investigators in 
accordance with regulatory requirements and within the timelines as defined below: 
 
For fatal and life-threatening SUSARs the Sponsor (via RM-CTU) should report at least the 
minimum information as soon as possible and in any case no later than seven days after being made 
aware of the case.  
 
SUSARs which are not fatal and not life-threatening are to be reported within 15 days 
Follow up of patients who have experienced a SUSAR should continue until recovery is complete or the 
condition has stabilised. 
7.11 Annual Reporting of Serious Adverse Events 
The Development Safety Update Report (DSUR) will be submitted annually on the anniversary of regulatory 
approval for the trial. This report will be submitted to regulatory authorities and Independent Ethics 
Committees (IEC) in accordance with all applicable global laws and regulations. Copies will be forwarded 
MSD and Investigators. 

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7.12 Urgent Safety Measures 
The Sponsor or Investigator may take appropriate urgent safety measures (USMs) in order to protect the 
patient of a clinical trial against any immediate hazard to their health or safety.  This includes procedures 
taken to protect patients from pandemics or infections that pose serious risk to human health.  
 
USMs may be taken without prior notification from the competent authority. However the CI/delegate must 
notify the Medicines and Healthcare Products Regulations (MHRA) the Research Ethics Committee (REC) 
and the Sponsor (via RM-CTU) of the new events and the measures taken and the plan for further action 
within 3 days of the measure being implemented.  Should the site initiate a USM, the Investigator must 
inform the Sponsor (via RM-CTU) immediately either by: 
 
Email: Priming.Trial@rmh.nhs.uk 
Telephone: 020 8642 6503 
Fax: 020 8915 6762 
 
 
The notification must include:  
 
The date of the USM;  
 
Who took the decision; and  
 
Why action was taken. 
 
The Sponsor (via RM-CTU) will notify the MHRA and the Main REC within three days of USM initiation.  
RM-CTU will distribute the response and any subsequent amendments to the trial site. 
 
           CI Contact Details 
           Name:                 Dr Fiona McDonald 
           Address:  
The Royal Marsden NHS Foundation Trust 
 
 
 
Downs Rd 
 
 
 
Sutton SM2 5PT 
 
Email:  
fiona.mcdonald@rmh.nhs.uk 
 

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8 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
 
8.1 
Statistical Analyses 
The final analysis will be conducted after one of the following conditions is met. 
• 
The trial is terminated early (for example, due to toxicity). 
• 
All patients have had the opportunity for treatment and have completed their ‘off-study’ visit. 
Once one of the conditions is met, a data cut-off date will be established. All patient visits occurring on or 
before this date will be analysed and summarised in the final clinical study report. Any data collected after 
this date will be summarised in a supplemental report. 
 
All data will be analysed using the statistical software STATA version 13. Quantitative data will be presented 
as number of observations, means, standard deviations, minimum and maximum values. Categorical data 
will be presented as frequencies and proportions. When appropriate, data will be presented either with 95% 
confidence intervals or exact binomial confidence intervals. Baseline characteristics will be summarised for 
all enrolled patients. Patients who died or withdrew before treatment started or did not complete the 
required safety observations will be described and evaluated separately. Treatment administration will be 
described for all cycles. Dose administration, dose modifications or delays and the duration of therapy will 
be described. 
8.1.1 Primary Endpoint 
For the primary endpoint of establishing the MTD and RP2D of lung SBRT that can be safely combined with 
pembrolizumab, the toxicity rate will be stated as the proportion of patients who have had a DLT calculated 
along with an exact binomial 95% confidence interval. All toxicities will be tabulated by type, grade and dose 
level. 
 
8.1.2   Secondary Endpoints 
Acute and late toxicity data will be tabulated by type, grade and dose level with the number, proportions and 
frequencies of grades 1-4 and grade 3-4 grades reported. The duration of clinical benefit assessed by overall 
response rate (ORR) defined as complete response (CR) or partial response (PR) and disease control rate 
(DCR) defined as CR, PR or stable disease (SD) using RECIST v1.1 & irRC (Appendix 6 & 7) will be 
calculated as a proportion of total treated with a 95% confidence interval. Differential response rates, 
defined as mixed responses , where some sites of disease shows a response to treatment, while other sites of 
disease show disease progression, will be measured as (yes/no). This will be calculated as proportions in the 
squamous cell and non-squamous cell histological sub-type giving associated 95% confidence intervals. Any 
differences will be assessed using a Chi squared test for proportions on differential response rates between 
histological subtypes. PD-L1 staining is referred to as tumour proportionate score, reported as a percentage 

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from 0–100%. It is classed as weakly positive (1 – 49%); strongly positive if >50%; and negative if <1%. The 
effect of PD-L1 expression on response rates will be measured using the proportion of patients recorded to 
be weakly positive, strongly positive or  negative and tested using a Chi Squared test for proportions on 
expression level between responders and non-responders. PFS will be measured from the start of 
radiotherapy until radiological or clinical evidence of progression or death and will be censored at date of 
last follow-up for surviving patients. OS will be measured from the start of radiotherapy until death and will 
be censored at date of last follow-up for surviving patients. Median PFS and OS will be calculated using 
Kaplan-Meier methods giving associated 95% confidence intervals, respectively. All patients from Part A and 
Part B will be used to analyse secondary endpoints.  
 
8.1.3 Exploratory Endpoints 
Exploratory endpoints will be presented in a descriptive fashion. We will: 
 
Describe the patterns of  TILs and tumour antigens in archival tumour biopsies. These 
immunohistochemistry analyses will include, but not necessarily be limited to, the following 
markers: CD4, CD8, FOXp3, PD-1, PD-L1, and PD-L2. 
 
Blood will be analysed for ctDNA pre- and post- SBRT.  
 
8.1.4 Timing of analyses 
Toxicity data will be reviewed by the Safety Review Committee prior to any decision regarding dose 
escalation or opening of new dose cohorts. 
Part A can be analysed once the last patient in cohort 2 has completed the DLT period which is 12 weeks 
from the last dose of lung SBRT (i.e. at C6D1). For parts A and B, end of treatment is until disease 
progression, or unacceptable toxicities, or the patient withdraws consent to the trial or when patient has 
completed 24 months of treatment. End of study is when the last patient has completed the off-study or the 
final follow-up visit, whichever happens last. 
 
8.2 
Sample Size 
During the dose escalation phase a standard 3+3 design will be used to recruit patients into two lung SBRT 
dose cohorts, firstly dose level 1 and then dose level 2, and both given the same pembrolizumab fixed dose 
level. Each cohort will require a minimum of 3 and a maximum of 6 patients. This means that there will be a 
minimum of 6 and maximum of 12 patients required for dose escalation. There will then be an additional 12 
patients in the expansion phase. This number has been arbitrarily chosen to get a better appreciation for the 
toxicity profile of the dose/treatment that maybe taken forward in a phase II study. 
 
 

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9 
REGULATORY, ETHICAL AND LEGAL ISSUES 
9.1 
Good Clinical Practice 
The study will be conducted in accordance with the conditions and principles of GCP as defined in the 
clinical trials regulations. 
9.2 
Independent Ethics Committee (IEC) / Institutional Review Board (IRB) 
Before starting the trial, the protocol, patient information sheet, consent form, any other written 
information that will be provided to the patients and any advertisements that will be used and details of any 
patient compensation must be approved by the Royal Marsden Committee for Clinical Research.  Once 
approved, the study will then be submitted to the relevant Ethics Committee for their review and approval.  
Prior to the shipment of IMP and the enrolling any patients the Investigator at each site is responsible for 
any site specific assessments and obtaining local Research &Development approval for the study. All 
participating sites will be required to sign an agreement with RM-CTU which includes requirement to sign 
and adhere to the trial protocol. 
 
Any protocol amendment should be agreed with the SRC and be approved by the Sponsor prior to 
submission and review by the REC.  Once favourable opinion from IEC has been obtained the amendment 
can be implemented.  It is the responsibility of the PI to submit amendment to the R&D department for R&D 
approval Amendments requiring IEC approval may be implemented only after a copy of the IEC/IRB’s 
approval letter has been obtained. Amendments that are intended to eliminate an apparent immediate 
hazard to patients may be implemented prior to receiving Sponsor or IEC/IRB approval. However, in this 
case, approval must be obtained as soon as possible after implementation. 
9.3 
Annual Safety Reports and End of Trial Notification 
It is the responsibility of the Sponsor to submit the DSUR annually to the MHRA/REC on the anniversary of 
the studies MHRA/REC approval. This will facilitate the authorities continuing review of the study. These 
authorities will also be informed of the end of the study by the Sponsor (via RM-CTU) within 90 days of the 
trial completion. Copies of these reports will also be held within the Site File. 
9.4 
Regulatory Authority Approval 
The study will be performed in compliance with UK regulatory requirements. Clinical Trial Authorisation 
(CTA) from the Medicines and Healthcare products Regulatory Authority (MHRA) will be obtained prior to 
the start of the study. In addition, the MHRA must approve amendments (as instructed by the Sponsor ), 
receive SUSAR reports and annual safety updates, and be notified of the end of the trial. 

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9.5 
Notifications of Serious Breaches to GCP and/or the Protocol 
The Sponsor (via RM-CTU) will notify the MHRA and REC in writing of any serious breaches of: 
a. The condition and principles of GCP in connection with the trial. 
b. The protocol. 
This will be done within 7 days if becoming aware of that breach, in accordance with the applicable UK 
regulations as amended from time to time. 
For the Purpose of the regulations a “serious breach” is one which is likely to effect to a significant degree: 
a. The safety or physical integrity of the subjects of the trial; or 
b. The scientific integrity of the trial. 
Systematic or persistent non-compliance by the site with GCP and/or the study protocol, including failure to 
report SAEs occurring on trial within the specified timeframes, may be deemed a serious breach. 
 
9.6 
Insurance and Liability 
The Sponsor has secured indemnity from the manufacturer of pembrolizumab for patients in relation to 
adverse side effects for medicine-induced injury. Indemnity for participating hospitals is provided by the 
usual NHS indemnity arrangements for clinical negligence.  A copy of the relevant insurance 
policy/indemnity scheme or summary shall be provided on request. 
9.7 
Contact with General Practitioner (GP) 
It is the Investigator’s responsibility to inform the patient’s GP by letter that the patient is taking part in the 
study provided the patient agrees to this, and information to this effect is included in the PIS and ICF. A 
copy of the letter should be filed in the Site File. A template letter approved by the IEC/IRB will be provided 
by the Sponsor (via RM-CTU) to all participating sites. 
9.8 
Confidentiality 
The Chief investigator must ensure that the patient’s confidentiality is maintained in compliance with the 
UK Data Protection Act of 1998.  On the CRFs or other documents submitted to the RM-CTU, patients 
should be identified by their initials and a patient study number only.  
 
In compliance with GCP guidelines, it is required that the investigator and institution permit authorised 
representatives of the Sponsor and of the regulatory agency(s) direct access to review the patient’s original 
medical records for verification of study-related procedures and data. Direct access includes examining, 
analysing, verifying, and reproducing any records and reports that are important to the evaluation of the 
study. The investigator is obligated to inform and obtain the consent of the patient to permit named 
representatives to have access to his/her study-related records without violating the confidentiality of the 
patient.  
 

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All pharmacogenetic samples and the information associated with the samples will be coded and stored 
appropriately to ensure confidentiality of the patient’s information and to enable destruction of the samples 
if requested.   Since the evaluations are not expected to benefit the patient directly or to alter the treatment 
course, the results will not be placed in the patient’s medical record and will not be made available to 
members of the family, the personal physician, or other third parties, except as specified in the informed 
consent.  
 
9.9 
Data Collection and Documentation 
It is the Investigator’s responsibility to ensure that all relevant data is clearly recorded in the medical 
records.  The Investigator must allow the RM-CTU direct access to relevant source documentation for 
verification of data entered into the CRF, taking into account data protection regulations. The clinical data 
should be recorded in the CRF and the following must be verifiable by the source data: patient consent, 
medical history, patients eligibility for participation in the trial, study treatment administration 
(pembrolizumab and radiotherapy), routine haematology and biochemistry and response to treatment. 
 
The patients’ medical records, and other relevant data, may also be reviewed by appropriate qualified 
personnel independent from the Sponsor appointed to audit the trial, or by REC.  Details will remain 
confidential and patients’ names will not be recorded outside the hospital. 
The Principal Investigators at each centre are confirming agreement with his/her local NHS Trust to ensure: 
 
Sufficient data is recorded for patients to enable accurate linkage between hospital records and CRFs  
 
Source data and all trial related documentation are accurate, complete, maintained and accessible for 
monitoring and audit visits  
 
Original consent forms are dated and signed by both patient and investigator and are kept together 
in a central log together with a copy of the specific patient information sheet(s) given at the time of 
consent  
 
All essential documents must be retained after the trial ends to comply with current legislation  
No study document will be destroyed without prior written agreement between the Sponsor (via 
RM-CTU) and the PI. Should the PI wish to assign the study records to another party or move them 
to another location, written agreement must be obtained from the Sponsor. 
9.10 End of Trial 
 The ‘end-of-trial’ is defined as the date when the last patient has completed the ‘off-study’ visit or the final 
follow-up visit, whichever happens last. 
 
 

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10 DATA AND STUDY MANAGEMENT 
10.1 Source Data 
All information in original records and certified copies of original records of clinical findings, observations, 
or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial are classified 
as source data. Source data are contained in source documents; these are defined as original documents, 
data, and records e.g., hospital records, clinical and office charts, laboratory notes, memoranda, patients' 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate copies, microfiches, photographic 
negatives, microfilm or magnetic media, x-rays, patient files, and records kept at the pharmacy, at the 
laboratories and at medico-technical departments involved in the clinical trial.  
10.2 Language 
All CRFs will be in English. Generic names for concomitant medications should be recorded in the CRF 
wherever possible. All written material to be used by patients must use vocabulary that is clearly understood, 
and be in the language appropriate for the study site. 
10.3 Data Collection 
The medical records/medical notes should be clearly marked and allows easy identification of a patient’s 
participation in the clinical trial. The Investigator (or delegated member of the site study team) must record 
all data relating to protocol procedures, IMP administration, laboratory data, safety data and efficacy data 
into the CRF.  
10.4 Recording of Data 
Patients’ data will be documented on a trial specific CRF designed by RM-CTU. Upon signing the informed 
consent form, the patient is assigned a trial identification number. 
 
The Investigator is responsible for ensuring the accuracy, completeness, clarity and timeliness of the data 
reported in the CRFs.  Only the Investigator, and those personnel who have completed the Study Team 
Responsibilities Signature Log/Delegation Log as authorised by the PI, should enter or change data in the 
CRFs.  All protocol required investigations must be reported in the CRF.  The Investigators must retain all 
original reports, traces and images from these investigations for future reference.  The data will be entered 
in a clinical trials database (Macro V4) with password-protected access.  If a patient withdraws from the 
study, the reason must be noted on the CRF.  
 
The CRF will be signed by the Investigator or by an authorised staff member. Study specific information will 
be entered into a CRF visit by visit. Data that are derived should be consistent with the source documents or 
the discrepancies should be explained. All CRF data should be anonymous, i.e. identified by study patient 

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number, initials and date of birth. Once the patient is ‘off study’ and the CRF has been fully completed, the 
Investigator must provide a signature to authorise the complete patient data. 
 
10.5 Data Management 
Data management will be carried out by RM-CTU using an electronic database and in accordance with the 
data management plan agreed by the RM-CTU and Research & Developmental Statistical Unit (RDSU). Data 
entry will be carried out by appropriately trained personnel at participating centres. Queries will be raised 
centrally by the trial manager / trial monitor and sent to the participating centre for resolution.  
10.6 Study Management Structure 
10.6.1 Delegations of Responsibilities 
This trial is sponsored by the Royal Marsden NHS Foundation Trust.  This trial will be conducted in 
accordance with the professional regulatory standards required for non-commercial research in the NHS 
under the research governance framework for health and social care and good clinical practice.  The 
following responsibilities have been delegated to: 
10.6.1.1       RM-CTU 
RM-CTU has overall responsibility for facilitating and coordinating the conduct of the trial and is also 
responsible for collating data obtained, and undertaking and reporting all analyses.  
The responsibilities of RM-CTU for the day-to-day management of the trial will include the following.  
 
Ensuring an appropriate ethics opinion has been sought, and any amendments have been approved  
 
Giving notice of amendments to protocol, make representations about amendments to the Main REC 
and MHRA as applicable 
 
Notifying sites that the trial has ended  
 
Raising and resolving queries with local investigators  
 
Keeping records of all SAEs, overdose incidents, pregnancies and ECI’s reported by investigators  
 
Notifying the Main REC, MHRA and Investigators of related SAEs  
10.6.1.2 MSD 
 Provision of pembrolizumab and study support costs 
10.6.1.3 Participating Sites 
 
Putting and keeping in place arrangements to adhere to the principles of GCP  
 
Keeping a copy of all ‘essential documents’ (as defined under the principles of GCP) and ensuring 
appropriate archiving of documentation once the trial has ended  
 
Taking appropriate urgent safety measures 
 
Centres wishing to recruit to this study will be asked to provide evidence that they can deliver 
protocol treatment.  

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 
Responsibilities are defined in an agreement between an individual participating centre and RM-
CTU, which must be signed and in place before recruitment can commence.  
 
10.7 Protocol Compliance and Amendments 
All participating sites will be required to sign an agreement with RM-CTU which includes requirement to 
sign and adhere to the trial protocol. 
 
Any protocol amendment should be agreed with the SRC and be approved by the Sponsor prior to 
submission and review by the relevant Ethics Committee and MHRA where required.  Once favourable 
opinion from REC and if applicable the MHRA has been obtained the amendment can be distributed to sites 
implemented.  It is the responsibility of the Principal Investigator to submit amendment to their R&D 
department for R&D approval. 
10.8 Trial Management 
The RM-CTU will be responsible for the day-to-day coordination and management of the trial. This includes 
all duties relating to safety reporting.  If applicable a trial agreement will be signed between the site and RM-
CTU. Once all relevant trial approvals are in place an initiation (visit or teleconference) will be conducted.  
In addition, training and ongoing advice will be provided by trial training workshop(s), site initiation and 
ongoing site support to each participating site by Trial Management Group (TMG).   
 
10.9 Safety Review Committee (SRC) 
A SRC will be set up and membership will include Chief Investigator, Co-Investigators, Trial Statistician, 
Trial Manager and will be chaired by a member intellectually and financially independent of trial 
investigators. Investigators and other key study personnel will be invited to join the SRC as appropriate. The 
SRC has operational responsibility for the conduct of the trial. The SRC is responsible for monitoring 
recruitment, safety and governance of the trial as well as collaborating with subsequent translational sub-
studies. The SRC will also review any safety concerns and can convene a meeting of the SRC if significant 
concerns exist. 
The role of the SRC is to: 
 
Review relevant safety data and make dose escalation decisions for all studies 
 
Reviews all SAEs and emerging safety data both from RM Sponsored studies and external SUSARS 
received from MSD 
 
Monitor progress of the trials and ensure emerging safety information is evaluated and protocol and 
GCP principles are adhered to.  
 

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10.10 Monitoring 
During the trial RM-CTU is responsible for monitoring data quality in accordance with relevant standard 
operating procedures.  Incoming data will be monitored for protocol compliance and if any inconsistent or 
missing data is identified queries will be sent to the site for resolution.  Any systematic inconsistencies may 
trigger an onsite monitoring visit. The trial statistician will periodically examine the data for anomalies and 
outliers, such as too few or too many events. Queries will be raised by the trial coordinators in such 
situations and communication with the clinical teams will take place. In addition statistical monitoring of 
unusual dates and inconsistent data will take place. Again these will raise queries via the trial coordinators. 
If an on-site monitoring visit is required, RM-CTU will contact the site to agree convenient date.  The site 
must ensure that relevant site file and patient notes are available for review.  RM-CTU staff conducting 
onsite monitoring will review the investigator site file and carry out source data verification to confirm 
compliance with the protocol, trial agreement. 
 
10.11 Quality Control and Quality Assurance 
Quality Control (QC) will be performed according to RM-CTU internal procedures. The study may be 
audited by a Quality Assurance (QA) representative of the Sponsor. All necessary data and documents will be 
made available for inspection. 
 
10.12 Clinical Study Report 
Clinical data will be presented at the end of the trial based on final data listings.  The CI together with the 
trial statistician will prepare a brief clinical study report / publication based on the final data listings.  A 
summary of the report must be provided to the Research Ethics Committee and the MHRA within 1 year 
from the submission of the end of trial notification. 
 
10.13 Record Retention 
Essential documents are documents that individually and collectively permit evaluation of the conduct of the 
trial and substantiate the quality of the data collected. During the clinical trial and after trial closure the 
Investigator must maintain adequate and accurate records to enable both the conduct of a clinical trial and 
the quality of the data produced to be evaluated and verified in accordance with current legislation.   
RM-CTU will maintain essential documents to facilitate the management of the trial, audit and inspection in 
accordance with Royal Marsden General Standard Operating Procedures and in compliance with the clinical 
trial regulatory requirements. 
The medical files of trial subjects shall be retained in accordance with national legislation and in accordance 
with the maximum period of time permitted by the hospital, institution or private practice. All medical 
records and TMF documentation will be retained for a minimum of 5 years after the study has concluded. 

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10.14 Reporting and Publication 
The trial results will be submitted for publication in a relevant medical journal with authorship according to 
the criteria defined by the ICMJE (http://www.icmje.org). These state that authorship credit should be 
based 1) substantial contributions to conception and design, acquisition of data, or analysis and 
interpretation of data; 2) drafting the article or revising it critically for important intellectual content; and 3) 
final approval of the version to be published. Authors should meet conditions 1, 2, and 3.  
Draft publications (manuscripts, abstracts, slides and posters) should be circulated to the relevant parties to 
allow sufficient time for review prior to submission. There will be a fifteen (15) day period to review abstracts 
or posters and a thirty (30) day period to review slides and manuscripts and respond to the author with any 
revisions. 
 

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11 APPENDICES 
11.1 Appendix 1 – ECOG Performance status 
0 
Normal activity. Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., light 
housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry 
out any work activities. Up and about more than 50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair. 
5 
Dead. 
As published: Oken et al Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group.  
Am J Clin Oncol 1982;  5:649-655. (69) 
 

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11.2 Appendix 2 – MRC Dyspnoea scale 
 
Grade 
 
0 
Climbs hills or stairs without dyspnoea 
1 
Walks any distance on flat without dyspnoea 
2 
Walks over 100 yards without dyspnoea 
3 
Dyspnoea on walking 100 yards or less 
4 
Dyspnoea on mild exertion, e.g. undressing 
5 
Dyspnoea at rest 
As published: Bleehen et al. A randomised trial of three or six courses of etoposide 
cyclophosphamide methotrexate and vincristine or six courses of etoposide and ifosfamide in 
SCLC: Survival and prognostic factors. Medical Research Council Lung Cancer Working Party Br 
J Cancer 1993; 68(6): 11506. (70) 
 

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11.3 Appendix 3 - Radiotherapy Planning and Delivery Guidelines 
 
1. Positioning and Immobilisation 
 Patients will be supine and positioned to aid comfort, stability and setup reproducibility. 
Knee and / or ankle supports will be used.  
 For the majority of patients, the arms will be positioned above the head using a chest board 
and consideration will be given to using a vacuum bag to aid comfort and stability, 
particularly for treatment of vertebral lesions. 
 For patients with apical lung lesions, the arms may be positioned by their sides and the 
patient immobilised in a 5-point shell. 
2. Localisation Imaging 
 Respiratory correlated 4DCT  
 Maximum slice thickness will be 3 mm. 
 The extent of the scan is from above the cricoid to below the liver. 
 IV contrast will be considered, unless medically contraindicated, where it will aid target 
delineation e.g. contouring of brachial plexus avoidance structure using vessels as a 
surrogate.  
 
3. Target Delineation 
 GTV = Radiologically visible lesion or part of a lesion up to 3 cm in diameter, not in a 
‘central’ location (See Figure A below), contoured on lung windows. Additional diagnostic 
imaging can be used to aid target delineation. 
 CTV = GTV. No additional margin is added for microscopic disease.  
 ITV = Encompasses either the CTV at maximum inhale and maximum exhale generated by 
fusing the individual GTV from 4DCT dataset as well as any additional tumour seen on cine 
loop. 
 PTV = ITV + 5 mm. 
 
4. Organ at Risk Delineation 
 See Table A below. 
 Additional guidance can be found in the online Radiation Therapy Oncology Group (RTOG) 
normal tissue atlases, available at: https://www.rtog.org/CoreLab/ContouringAtlases.aspx  
 
5. Dose Fractionation Schedules 
 Dose level 1: 30 Gy in 3 fractions over 5 days.  
 Dose level 2: 54 Gy in 3 fractions over 5 days.   
 
6. Physics Planning 
 Type B or Monte Carlo algorithm is mandatory. 
 Dose grid resolution on the final dose calculation must be ≤2 mm.  
 
 

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Table A: Contouring of normal tissue structures. 
Spinal Canal PRV 
 
The spinal canal will be contoured at least 10 cm above and below the extent 
of the PTV and taken to represent the cord.  A centre dependent margin 
should be added to the canal to create the spinal canal PRV dependent on 
immobilization technique (e.g. 3 – 5 mm) on which the dose constraints 
should be assessed. This structure is used to assess both spinal cord and cauda 
equina dose constraints.  
Brachial Plexus 
 
Contouring, on head and neck windowing, will start at the neural foramina at 
the C4-C5 level and move caudally; the region from the lateral aspect of the 
spinal canal laterally to the small space between the anterior and middle 
scalene muscles will be contoured. At the levels at which no neural foramina 
are present, the space or soft tissue between the anterior and middle scalene 
muscles will be contoured. Contouring will continue in the space between the 
anterior and middle scalene muscles; Inferiorly the major trunks of the 
ipsilateral brachial plexus will be contoured by using the subclavian and 
axillary vessels as a surrogate. They will be contoured from the bifurcation of 
the 
brachiocephalic 
trunk 
into 
the 
jugular/subclavian 
veins 
(or 
carotid/subclavian 
arteries), 
following 
along 
and 
ending 
after 
the 
neurovascular structures cross the 2nd rib. 
Lungs 
 
Normal lung will consist of both lungs as one structure (including all inflated 
and collapsed regions of lung and excluding the proximal airways), contoured 
on lung windows, considered together as one organ (minus the GTV when 
treating lung lesions). 
Trachea 
Contouring of the proximal trachea should begin at least 10 cm superior to the 
extent of the PTV or 5 cm superior to the carina (whichever is more superior) 
and continue inferiorly to the superior aspect of the proximal bronchial tree. 
Bronchial Tree 
The proximal bronchial tree will include the most inferior 2 cm of distal 
trachea and the proximal airways on both sides. The following airways will be 
included according to standard anatomical relationships: the distal 2 cm of 
trachea, the carina, the right and left main stem bronchi, the right and left 
upper lobe bronchi, the intermedius bronchus, the right middle lobe 
bronchus, the lingular bronchus, and the right and left lower lobe bronchi. 
Contouring of the lobar bronchi will end immediately at the site of a 
segmental bifurcation. 
Great Vessels 
 
The great vessels (aorta and vena cava) will be contoured using mediastinal 
window to correspond to the vascular wall and all muscular layers out to the 
fatty adventitia. The great vessel should be contoured at least 10 cm above and 
below the extent of the PTV. For right sided lesions, the vena cava will be 
contoured, and for left sided lesions, the aorta will be contoured. 
Oesophagus 
 
The oesophagus should be contoured as a solid structure from the upper 
sphincter (cricoid level) down to the gastro-oesophageal junction using 
mediastinal windowing.  The delineation limit is the outer wall of the 
oesophagus.  
Heart and 
Pericardium 
 
The heart will be contoured along with the pericardial sac using mediastinal 
windowing. The superior aspect is defined as the superior aspect of the 
pulmonary artery (as seen on coronal reconstruction of the CT) and the caudal 
border should be defined by the lowest part of the left ventricle's inferior wall 
that is distinguishable from the liver.  
Chest Wall 
 
The chest wall will be defined as the 2 cm rind of the ipsilateral hemi-thorax 
outside the thoracic cavity and contoured at least 5 cm above and below the 
PTV.   
 
 
 

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7. Target Coverage, Maximum Dose, Conformity Parameters and OAR Dose Constraints 
 Target Coverage: Aim for the dose received by 95% and 99% of the PTV to be greater than 
100% and 90% respectively (D95≥100% and D99>90%).  
 Maximum Dose: This should ideally be within 110-140% (of the prescribed dose, 105-145% 
mandatory) and be located within the GTV. This is equivalent to prescribing to 
approximately the 70-95% isodose (relative to the maximum).  
 Target Dose Conformity: Where possible the conformity constraints should be met (see 
Table B below). 
 OAR dose constraints will be achieved for all patients (see Table C below).  
 If the dose constraint for an OAR is not reached, the dose in the PTV will be reduced in order 
to meet the OAR constraint. Two approaches are possible:  
 Reduced prescription dose: The prescribed dose can be reduced but to no less than 90% of 
the BED.  
 Inhomogeneous PTV dose: In case of overlap of the PTV with OAR, the dose to the CTV (or 
ITV if applicable) can be maintained and the dose within the PTV may be reduced until the 
planned dose to the OAR meets the acceptable variation criteria for the OAR. The dose in 
95% of the PTV should still at least be 80%. 
 
8. Image Guidance for Treatment Verification and Delivery 
 CBCT (or 4D CBCT imaging where appropriate and available) and on-line correction prior to 
each fraction will be performed with manual adjustment under direct visualization of the 
tumour if required.  
 The position of critical OAR will be checked, especially the spinal cord and any changes in 
anatomy.  
 Repeat CBCT scans will be considered after correction prior to treatment delivery and again 
after treatment delivery if clinically indicated for additional verification.  
 
 
 
 
 
 
Figure A: Recommended definition of a central thoracic lung lesion: a lesion within 2 cm in all directions of any 
mediastinal critical structure, including the bronchial tree, oesophagus, heart, brachial plexus, major vessels, spinal 
cord, phrenic nerve, and recurrent laryngeal nerve. 
 
 

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Table B: Dose Conformity Requirements  
PTV (cc) 
R100 
R50 
Dmax (>2 cm from PTV) 
SBRT in 3 # 
Optimal 
Mandatory 
Optimal 
Mandatory 
Optimal 
Mandatory 
<20 
<1.25 
1.25-1.40 
<12 
12-14 
<35.1Gy  
35.1-40.5Gy  
20.1-40 
<1.15 
1.15-1.25 
<9 
9-11 
<37.8Gy  
37.8-43.2Gy  
>40.1-60 
<1.10 
1.10-1.20 
<6 
6-8 
<37.8Gy  
37.8-43.2Gy  
60.1-90 
<1.10 
1.10-1.20 
<5 
5-7 
<37.8Gy  
37.8-43.2Gy  
>90.1 
<1.10 
1.10-1.20 
<4.5 
4.5-6.5 
<37.8Gy  
37.8-43.2Gy  
R100 = Vol(100%)/Vol(PTV) = Ratio of prescription isodose volume to the PTV  
R50 = Vol(50%)/Vol(PTV) = Ratio of 50% prescription isodose volume to the PTV  
Dmax (>2 cm from PTV) = Maximum point dose at least 2 cm from the PTV in any direction 
 
Table C: OAR Dose Constraints 
OAR 
 
Constraint 
SBRT in 3 # 
Optimal 
Mandatory 
Brachial Plexus 
DMax 
 (0.5 cc) 
< 24 Gy 
< 26 Gy 
Normal Lungs 
(Lungs – GTV) 
V20 Gy 
- 
< 10% 
V12.5 Gy 
- 
< 15% 
Trachea and 
Proximal 
Bronchial Tree 
DMax  
(0.5 cc) 
< 30 Gy 
< 32 Gy 
Great Vessels 
DMax  
(0.5 cc) 
- 
< 45 Gy 
Heart 
DMax  
(0.5 cc) 
< 24 Gy 
< 26 Gy 
Oesophagus 
DMax 
 (0.5 cc) 
- 
< 25.2 Gy 
Spinal Cord 
(Spinal Canal 
PRV) 
DMax  
(0.1 cc) 
< 18 Gy 
< 21.9 Gy 
D1.2 cc 
< 12.3 Gy 
- 
Chest Wall 
DMax  
(0.5 cc) 
< 37 Gy 
- 
D30 cc 
< 30 Gy 
- 
Skin 
DMax  
(0.5 cc) 
< 33 Gy 
- 
D10 cc 
< 30 Gy 
- 
 

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11.4 Appendix 4 - Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0 will be utilized for AR reporting. (http://ctep.cancer.gov/reporting/ctc.html) 
1. Quick Reference 
The NCI Common Terminology Criteria for Adverse Events is a descriptive terminology which can 
be utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE 
term. 
2. Components and Organization SOC 
System Organ Class, the highest level of the MedDRA hierarchy, is identified by anatomical or 
physiological system, etiology, or purpose (e.g., SOC Investigations for laboratory test results). 
CTCAE terms are grouped by MedDRA Primary SOCs. Within each SOC, AEs are listed and 
accompanied by descriptions of severity (Grade). 
3. CTCAE Terms 
An Adverse Event (AE) is any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medical treatment or procedure 
that may or may not be considered related to the medical treatment or procedure. An AE is a term 
that is a unique representation of a specific event used for medical documentation and scientific 
analyses. Each CTCAE v4.0 term is a MedDRA LLT (Lowest Level Term). 
4. Definitions 
A brief definition is provided to clarify the meaning of each AE term. 
5. Grades 
Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical 
descriptions of severity for each AE based on this general guideline:  
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated.  
Grade 2 Moderate; minimal, local or non-invasive intervention indicated; limiting age-appropriate 
instrumental ADL*.  
Grade 3 Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL**. 
Grade 4 Life-threatening consequences; urgent intervention indicated.  
Grade 5 Death related to AE. 
6. Activities of Daily Living (ADL) 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. **Self-care ADL refer to bathing, dressing and undressing, feeding self, using 
the toilet, taking medications, and not bedridden. 

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11.5 Appendix 5 - Identification, Evaluation and Management of immune related events of clinical 
interest (irECIs) 
ECI 
Grade 
Action to be taken 
Supportive Care 
Pneumonitis –  
 
Grade 
1 
(Asymptomatic) 
 No action 
 Intervention not indicated 
Grade 2 
 
Report overdose and liver 
toxicity ECIs within 24 hours 
 
Withhold pembrolizumab, 
may restart if Grade 1 or 
resolved within 12 weeks 
 
Consider bronchoscopy and 
biopsy/BAL, ID Consult and 
frequent chest x-ray for 
monitoring. 
 
Conduct in person 
evaluation twice a week 
 
1-2mg/kg/day prednisone or equivalent.  
 
Symptoms grade 1 or less, initiate steroid 
taper for no less than 4 weeks. 
 
Permanently discontinue pembrolizumab is if 
dose cannot be reduced to 10mg prednisone 
or less or equivalent per day within 12 weeks. 
Grade 3 and 4 
 
Report overdose and liver 
toxicity ECIs within 24 hours 
 
Discontinue pembrolizumab 
 
Hospitalise patient  
 
Bronchoscopy with biopsy 
and/or BAL is 
recommended. 
 
 
methylprednisolone 125mg IV.  
 
Symptoms grade 1 or less initiate steroid taper 
for no less than 4 weeks 
o 
Prednisone 1 to 2 mg/kg/day or 
dexamethasone 4mg every 4 hours  
 
If IV steroids do not reduce initial symptoms 
within 48-72 hours treat with additional anti-
inflammatory measures. At symptom relief 
discontinue anti-inflammatory and start 
steroid taper over 45-60 days. If symptoms 
worsen during this period refer to Section 6 
and 7. 
 
1st episode -  May increase dosing interval by one week in subsequent cycles 
 
2nd episode of  - Pneumonitis, permanently discontinue pembrolizumab if upon re-challenge patient develops Pneumonitis  
Grade 2 
Colitis 
Grade 
1 
(Asymptomatic) 
 No action 
 Intervention not indicated 
 – 
 
Grade 2 
(For 
grade 
2 
diarrhoea  that 
persists 
> 
3 
days) 
 
Report overdose and liver 
toxicity ECIs within 24 
hours 
 
Withhold pembrolizumab, 
may restart if Grade 1 or 
resolved within 12 weeks 
 
Symptomatic treatment 
o 
Consider GI consult & 
endoscopy to rule 
out colitis 
 
Prednisone 1-2mg/kg/day or equivalent 
 
Symptoms grade 1 or less, initiate steroid 
taper for no less than 4 weeks. 
 
Permanently discontinue pembrolizumab is if 
dose cannot be reduced to 10mg or less of 
prednisone or equivalent per days within 12 
weeks. 
 
If symptoms worsen or persist >1 week treat 
as grade 3. 

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Grade 3 
 
Report overdose and liver 
toxicity ECIs within 24 
hours 
 
Withhold pembrolizumab 
 
Rule out bowel perforation 
 
Recommend 
gastroenterologist consult 
&biopsy with endoscopy 
 
 
methylprednisolone 125mg IV followed by 
prednisone 1 to 2 mg/kg/day or 
dexamethasone 4mg every 4 hours.  
 
Symptoms grade 1 or less initiate steroid 
taper for no less that 4 weeks.  
 
Taper 6-8 weeks in patients with diffuse or 
severe ulceration and/or bleeding 
 
If IV steroids do not reduce initial symptoms 
within 48-72 hours treat with additional anti-
inflammatory measures. At symptom relief 
discontinue anti-inflammatory and initiate 
steroid taper over 45-60 days. If symptoms 
worsen during this period refer to Section 6 
and 7. 
Grade 4 
 
Report overdose and liver 
toxicity ECIs within 24 
hours 
 
Discontinue pembrolizumab 
 
Manage as per grade 3 
Endocrine 
– 
Hypo 
and hyperthyroidism 
Grade 
1 
(Asymptomatic) 
 No action 
 Intervention not indicated 
Grade 
2 
Hyperthyroidism  
and Grade 2- 4 
Hypothyroidism 
 
Report overdose and liver 
toxicity ECIs - see Section 6 
and 7. 
 
Monitor thyroid function 
until returned to baseline. 
 
Consider consultation with 
endocrinologist. 
 
Pembrolizumab can 
continue while on this 
treatment. 
 
Thyroid hormone and/or steroid replacement 
therapy. 
 
Hyper – non-selective beta blockers for initial 
therapy  
 
Hypo – thyroid hormone replacement therapy 
as per standard of care. 
Grade 
3 
Hyperthyroidism 
 
Report overdose and liver 
toxicity ECIs within 24 
hours 
 
Withhold pembrolizumab, 
may restart if Grade 1 or 
resolved within 12 weeks 
 
Rule out infection and 
sepsis. 
 
IV methylprednisone 1-2mg/kg followed by 
prednisone 1-2mg/kg per day.  
 
Symptoms grade 1 or less initiate steroid 
taper for no less than 4 weeks. Replacement 
of appropriate hormones may be required. 
 
Permanently discontinue pembrolizumab is if 
dose cannot be reduced to prednisone 10mg 
or less or equivalent per day within 12 weeks. 
Grade 
4 
Hyperthyroidism 
 
Report overdose and liver 
toxicity ECIs within 24 
hours 
 
Discontinue pembrolizumab 
 
Manage as per grade 3 
Endocrine 
– 
Hypophysitis or other 
symptomatic 
endocrinopathy 
Grade 
1 
(Asymptomatic) 
 No action 
 Intervention not indicated 
Grade 2 – 4  
 
Report overdose and liver 
toxicity ECIs - see Section 6 
and 7. 
 
Withhold pembrolizumab 
 
Prednisone 40mg p.o. or equivalent per day.  
 
Symptoms grade 1 or less initiate steroid 
taper for no less than 4 weeks. Replacement 
of appropriate hormones may be required. 

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 
Rule out infection and 
sepsis. 
 
Monitor thyroid function 
until returned to baseline. 
 
Consider pituitary gland 
imaging  
 
Hypophysitis with clinically 
significant adrenal 
insufficiency and 
hypotension, dehydration, 
and electrolyte 
abnormalities (such as 
hyponatremia and 
hyperkalemia) constitutes 
adrenal crisis. 
 
Consider endocrinologist 
consult. 
 
Permanently discontinue pembrolizumab is if 
dose cannot be reduced to prednisone 10mg 
or less or equivalent per day within 12 weeks. 
Type 
1 
Diabetes 
Mellitus and ≥ grade 
3 hyperglycaemia 
Type 1 Diabetes 
Mellitus and ≥ 
grade 
3 
hyperglycaemia 
 
Report overdose and liver 
toxicity ECIs if appropriate 
see Section 6 and 7 
 
Hold pembrolizumab if new 
onset of diabetes or grade 
3-4 hyperglycaemia with 
evidence of beta cell 
failure. 
 
Consultation with 
endocrinologist  
 
Consider islet cell 
antibodies and antibodies 
to GAD, IA-2 ZnT8 and 
insulin. 
 
Insulin replacement therapy is recommended 
for Type I diabetes mellitus and for Grade 3-
4hyperglycaemia associated with metabolic 
acidosis or ketonuria. 
 
Evaluate patients with serum glucose and a 
metabolic panel, urine ketones, glycosylated 
haemoglobin, and C-peptide. 
Haematologic 
Grade 
1 
(Asymptomatic) 
 No action 
 Intervention not indicated 
Grade 2 
 
Report overdose and liver 
toxicity ECIs within 24 
hours 
 
Withhold pembrolizumab, 
may restart if Grade 1 or 
resolved within 12 weeks 
 
Consider Haematology 
consultation 
 
Prednisone 1-2mg/kg daily 
 
Permanently discontinue pembrolizumab is if 
dose cannot be reduced to prednisone 10mg 
or less or equivalent per day within 12 weeks. 
Grade 3 
 
Report overdose and liver 
toxicity ECIs within 24 
hours 
 
Withhold pembrolizumab, 
may restart if Grade 1 or 
resolved within 12 weeks 
 
Recommend Haematology 
consultation 
 
IV methlyprednisone 125mg or Prednisone 1-
2mg/kg p.o. (or equivalent) as appropriate. 
 
Permanently discontinue pembrolizumab is if 
corticosteroid dose cannot be reduced to 
prednisone 10mg or less or equivalent per 
day within 12 weeks. 

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Grade 4 
 
Report overdose and liver 
toxicity ECIs within 24 
hours 
 
Discontinue pembrolizumab 
 
Recommend Haematology 
consultation 
 
IV methlyprednisone 125mg or Prednisone 1-
2mg/kg p.o. (or equivalent) as appropriate. 
Hepatic 
– 
Drug 
induced Liver Injury 
(DILI).  
Please 
refer 
to 
Section 6 and 7 for 
definitions of (DILI) 
Grade 
1 
(Asymptomatic) 
 No action 
 Intervention not indicated 
Grade 2 
 
Report overdose and liver 
toxicity ECIs within 24 
hours 
 
Withhold Pembrolizumab if 
AST or ALT >3.0 to 5.0 X 
ULN and/or total bilirubin is 
>1.5to 3.0 X ULN 
 
Monitoring Liver function 
until values return to 
baseline 
 
0.5-1mg/kg/day methlyprednisone 125mg or 
oral equivalent. 
 
LFT grade 1 or less initiate steroid taper for no 
less than 4 weeks. Consider prophylactic 
antibiotics and resume pembrolizumab.  
 
Permanently discontinue pembrolizumab is if 
dose cannot be reduced to prednisone 10mg 
or less or equivalent per day within 12 weeks. 
 
Permanently discontinue pembrolizumab for 
patients with liver mets who begin treatment 
with grade 2 elevation of AST or ALT and AST 
or ALT increase ≥50% relative to baseline and 
lasts ≥ 1 week. 
Grade 3 
 
Report overdose and liver 
toxicity ECIs within 24 
hours 
 
Discontinue pembrolizumab 
if AST or ALT > 5.0 X ULN 
and/or total bilirubin is >3.0 
X ULN 
 
Consider consultation and 
biopsy to establish 
aetiology  
 
High dose IV glucocorticosteroids for 24-
48hours.  
 
Symptoms grade 1 or less initiate steroid 
taper for no less than 4 weeks 
o 
prednisone 1 to 2 mg/kg/day or 
dexamethasone 4mg every 4 hours.  
 
If serum transaminase levels do not decrease 
or symptoms worsen please refer to Section 6 
and 7. 
 
Permanently discontinue pembrolizumab is if 
dose cannot be reduced to prednisone 10mg 
or less or equivalent per day within 12 weeks. 
Grade 4 
 
Report overdose and liver 
toxicity ECIs within 24 
hours 
 
Discontinue pembrolizumab 
 
Manage as per grade 3 
Neurologic 
Grade 
1 
(Asymptomatic) 
 No action 
 Intervention not indicated 
Grade 2 
 
Report overdose and liver 
toxicity ECIs within 24 
hours  
 
Consider withholding 
pembrolizumab 
 
Consider Neurology consult 
and biopsy for diagnosis. 
 
Consider 1-2mg/kg daily of prednisone as 
appropriate 
 
Permanently discontinue pembrolizumab is if 
dose cannot be reduced to prednisone 10mg 
or less or equivalent per day within 12 weeks. 
Grade 3 and 4 
 
Report overdose and liver 
toxicity ECIs within 24 
hours  
 
Discontinue pembrolizumab 
 
Obtain Neurology 
consultation  
 
1-2mg/kg daily of prednisone or equivalent. 
 
If condition worsens consider IVIG or other 
immunosuppressive therapies  
 
Symptoms grade 1 or less, initiate steroid 
taper for no less than 4 weeks.  

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 
Consider biopsy for 
diagnosis. 
Ocular 
Grade 
1 
(Asymptomatic) 
 No action 
 Intervention not indicated 
Grade 2 
 
Report overdose and liver 
toxicity ECIs within 24 
hours  
 
Evaluation by 
ophthalmologist 
recommended  
 
Topical steroids – 1%prednisolone acetate 
suspension and iridocyclitics 
 
Permanently discontinue IF symptoms persist 
despite treatment. 
Grade 3 
 
Report overdose and liver 
toxicity ECIs within 24 
hours  
 
Evaluation by 
ophthalmologist 
recommended 
 
Withhold pembrolizumab & 
consider discontinuation. 
 
1-2mg/kg of prednisone daily. 
 
Symptoms grade 1 or less initiate steroid 
taper for no less than 4 weeks. 
 
Permanently discontinue pembrolizumab is if 
dose cannot be reduced to prednisone 10mg 
or less or equivalent per day within 12 weeks. 
Grade 4 
 
Report overdose and liver 
toxicity ECIs within 24 
hours  
 
Evaluation by 
ophthalmologist 
recommended 
 
Permanently discontinue 
pembrolizumab  
Manage as per grade 3 
Renal 
Grade 
1 
(Asymptomatic) 
 No action 
 Intervention not indicated 
Grade 2 
 
Report overdose and liver 
toxicity ECIs within 24 
hours  
 
Withhold Pembrolizumab 
 
1-2mg/kg of prednisone daily. 
 
Permanently discontinue pembrolizumab is if 
dose cannot be reduced to prednisone 10mg 
or less or equivalent per day within 12 weeks. 
Grade 3 and 4 
 
Report overdose and liver 
toxicity ECIs within 24 
hours  
 
Discontinue Pembrolizumab 
 
Renal consultation and 
biopsy as appropriate 
 
1-2mg/kg of prednisone daily. 
 
Symptoms grade 1 or less initiate steroid 
taper for no less than 4 weeks. 
Skin 
– 
Rash 
and 
pruritus  
Grade 
1 
(Asymptomatic) 
 No action 
 Intervention not indicated 
Grade 2 
 
Symptomatic treatment 
 
Topical glucocorticosteroids or urea-
containing cream in combination with oral 
anti-pruritics 
 
Treatment with oral steroids at PIs discretion 
Grade 3 
 
Report overdose and liver 
toxicity ECIs within 24 
hours  
 
Withhold Pembrolizumab 
 
Consider dermatology 
consult & biopsy for 
diagnosis. 
 
1mg/kg/day prednisone or equivalent or 
dexamethasone 4mg 4xdaily 
 
Symptoms grade 1 or less, initiate steroid 
taper for no less than 4 weeks. 
 
Permanently discontinue pembrolizumab is if 
dose cannot be reduced to prednisone 10mg 
or less or equivalent per day within 12 weeks. 
Grade 4 
 
Report overdose and liver 
toxicity ECIs within 24 
 
Initiate steroids starting with 1-2mg/kg 
prednisone or equivalent.. 

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hours  
 
Discontinue pembrolizumab 
 
Dermatology consultation  
 
Consider biopsy for 
diagnosis & clinical 
photographs 
 
Symptoms grade 1 or less, initiate steroid 
taper for no less than 4 weeks. 
Skin – Dermatitis 
exfoliative, 
erythemamulitforme, 
Stevens Johnson 
syndrome§, toxic 
epidermal 
necrolysis§. 
§ If it is suspected 
that the patient has 
SJS or TEN, 
pembrolizumab 
should be withheld. 
The patient should 
be referred to a 
dermatologist for 
management. If SJS 
and TEN is 
confirmed, then 
pembrolizumab 
should be 
permanently 
discontinued.”  
Grade 
1 
(Asymptomatic) 
 No action 
 Intervention not indicated 
Grade 2 
 
Report overdose and liver 
toxicity ECIs within 24 
hours  
 
Symptomatic treatment 
 
Topical glucocorticosteroids or urea-
containing cream in combination with oral 
anti-pruritics. Treatment with oral steroids at 
PIs discretion 
Grade 3 
 
Report overdose and liver 
toxicity ECIs within 24 
hours  
 
Withhold Pembrolizumab 
 
Consider dermatology 
consultation and biopsy for 
diagnosis. 
 
1mg/kg/day prednisone or equivalent or 
dexamethasone 4mg 4xday.  
 
Symptoms grade 1 or less initiate steroid 
taper for no less than 4 weeks. 
 
Permanently discontinue pembrolizumab is if 
dose cannot be reduced to prednisone 10mg 
or less or equivalent per day within 12 weeks. 
Grade 4 
 
Report overdose and liver 
toxicity ECIs within 24 
hours  
 
Discontinue pembrolizumab 
 
Dermatology consultation   
 
Consider biopsy for 
diagnosis & clinical 
photographs 
 
Initiate steroids starting with 1-2mg/kg 
prednisone or equivalent.. 
 
Symptoms grade 1 or less, initiate steroid 
taper for no less than 4 weeks. 
Other:  
 Myocarditis¶ 
 Pericarditis 
 Pancreatitis 
 Any 
additional 
Grade 3 or higher 
event which the 
physician 
considers to be 
immune related 
¶”Ensure that other 
causes of myocarditis 
are adequately 
evaluated to exclude 
other aetiologies 
Grade 
2 
or 
Grade 1 that do 
not 
improve 
with 
symptomatic 
treatment. 
 
Report overdose and liver 
toxicity ECIs within 24 
hours  
 
Withhold Pembrolizumab 
 
Consider biopsy for 
confirmation of diagnosis. 
 
Systemic corticosteroids may be indicated. 
 
If so: 
 
Treat with systemic corticosteroids at a dose 
of 1 to 2 mg/kg prednisone or equivalent 
once per day. 
 
When symptoms improve to Grade 1 or less, 
steroid taper should be started and continued 
over no less than 4 weeks. 
 
Permanently discontinue for inability to 
reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 
weeks. Otherwise, Pembrolizumab treatment 
may be restarted and the dose modified as 
specified in the protocol 
Grade 3 
 
Report overdose and liver 
toxicity ECIs within 24 
hours  
 
Withhold Pembrolizumab 
 
Treat with systemic corticosteroids at a dose 
of 1 to 2 mg/kg prednisone or equivalent 
once per day. 
 
When symptoms improve to Grade 1 or less, 
steroid taper should be started and continued 
over no less than 4 weeks. 
 
Permanently discontinue for inability to 
reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 
weeks. Otherwise, pembrolizumab treatment 
may be restarted and the dose modified as 
specified in the protocol 

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Grade 4 
 
Report overdose and liver 
toxicity ECIs within 24 
hours  
 
Discontinue pembrolizumab 
 
Treat with systemic corticosteroids at a dose 
of 1 to 2 mg/kg prednisone or equivalent 
once per day. 
 

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11.6 Appendix 6 - Response Evaluation Criteria in Solid Tumours (RECIST) 1.1  
 
Criteria for Evaluating Response in Solid Tumours 
RECIST version 1.1* will be used in this study for assessment of tumour response.  
* As published: Eisenhauer et al. New response evaluation criteria in solid tumours: Revised RECIST 
guideline (version 1.1). Eur J Cancer 2009;45(2):228. (71) 
The following paragraphs are a quick reference and the complete criteria are included in the published 
RECIST document also available at http://www.eortc.be/RECIST.  
 
Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as ≥20 mm by chest x-ray or as ≥10 mm with CT scan, MRI, or 
calipers by clinical exam.  All tumour measurements must be recorded in millimeters (or decimal fractions 
of centimeters). 
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph node must be 
≥15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 
5 mm).  At baseline and in follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest diameter 
<10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered non-measurable 
disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or MRI), are 
considered as non-measurable. ‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 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, but in addition should be those that lend themselves to reproducible 
repeated measurements.  It may be the case that, on occasion, the largest lesion does not lend itself to 
reproducible measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected.  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.  If lymph nodes 
are to be included in the sum, then only the short axis is added into the sum.  The baseline sum diameters 

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will be used as reference to further characterize any objective tumor regression in the measurable dimension 
of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over and above 
the 5 target lesions 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.  
 
Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  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 characterise each identified and 
reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by 
clinical examination unless the lesion(s) being followed cannot be imaged but are assessable by clinical 
exam. 
 
Clinical:  Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules 
and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers (e.g., skin nodules).  In the case 
of skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended.  
 
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and 
surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness.  MRI is also acceptable in certain 
situations (e.g. for body scans).  Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, 
and temporal resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the availability of MRI is 
variable globally.  As with CT, if an MRI is performed, the technical specifications of the scanning sequences 
used should be optimized for the evaluation of the type and site of disease.  Furthermore, as with CT, the 
modality used at follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST guidelines to 

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prescribe specific MRI pulse sequence parameters for all scanners, body parts, and diseases.  Ideally, the 
same type of scanner should be used and the image acquisition protocol should be followed as closely as 
possible to prior scans.  Body scans should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT:  At present, the low dose or attenuation correction CT portion of a combined PET-CT is not always 
of optimal diagnostic CT quality for use with RECIST measurements.  However, if the site can document that 
the CT performed as part of a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral 
contrast), then the CT portion of the PET-CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer lesions over time.  Note, however, that 
the PET portion of the CT introduces additional data which may bias an investigator if it is not routinely or 
serially performed.   
 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement.  Ultrasound examinations cannot be reproduced in their entirety for independent review at a 
later date and, because they are operator dependent, it cannot be guaranteed that the same technique and 
measurements will be taken from one assessment to the next.  If new lesions are identified by ultrasound in 
the course of the study, confirmation by CT or MRI is advised.  If there is concern about radiation exposure 
at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy: Laparoscopy  The utilization of these techniques for objective tumor evaluation is not advised.  
However, such techniques may be useful to confirm complete pathological response when biopsies are 
obtained or to determine relapse in trials where recurrence following complete response (CR) or surgical 
resection is an endpoint. 
 
Tumor markers:  Tumor markers alone cannot be used to assess response.  If markers are initially above the 
upper normal limit, they must normalize for a patient to be considered in complete clinical response.  
Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA response (in recurrent 
prostate cancer) have been published [JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin 
Oncol 26:1148-1159, 2008].  In addition, the Gynecologic Cancer Intergroup has developed CA-125 
progression criteria which are to be integrated with objective tumor assessment for use in first-line trials in 
ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology:  These techniques can be used to differentiate between partial responses (PR) and 
complete responses (CR) in rare cases (e.g., residual lesions in tumour types, such as germ cell tumors, 
where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment when the measurable tumour has met criteria for response or stable disease is mandatory to 

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differentiate between response or stable disease (an effusion may be a side effect of the treatment) and 
progressive disease. 
 
FDG-PET:  While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of progression 
(particularly possible 'new' disease).  New lesions on the basis of FDG-PET imaging can be identified 
according to the following algorithm:  
 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a 
new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If the positive FDG-
PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up CT  scans 
are needed to determine if there is truly progression occurring at that site (if so, the date of PD 
will be the date of the initial abnormal FDG-PET scan).  If the positive FDG-PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing on the basis of the 
anatomic images, this is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases 
where a residual radiographic abnormality is thought to represent fibrosis or scarring.  The use of 
FDG-PET in this circumstance should be prospectively described in the protocol and supported 
by disease-specific medical literature for the indication.  However, it must be acknowledged that 
both approaches may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater than twice that 
of the surrounding tissue on the attenuation corrected image. 
 
Response Criteria 
 
Evaluation of 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. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target lesions, taking as 
reference the baseline sum diameters. 
 

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Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).  In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 
mm.  (Note:  the appearance of one or more new lesions is also considered progressions). 
 
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. 
 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of tumour marker 
level.  All lymph nodes must be non-pathological in size (<10 mm short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a patient to be 
considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker 
level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal progression of 
existing non-target lesions.  Unequivocal progression should not normally trump target lesion status.  It 
must be representative of overall disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating physician 
should prevail in such circumstances, and the progression status should be confirmed at a later time by the 
review panel (or Principal Investigator). 
 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements recorded 
since the treatment started).  The patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
 
 
 

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For Patients with Measurable Disease (i.e. Target Disease) 
 
 
For Patients with Non-Measurable Disease (i.e. Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required 
CR 
CR 
No 
CR 
>4 wks. Confirmation 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 

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11.7 Appendix 7 - Response Evaluation by Immune Related Response Criteria (irRC)  
As published: Wolchok JD et al. Guidelines for the evaluation of immune therapy activity in solid tumors: Immune 
related response criteria. Clin Cancer Res 2009;15(23):7412. (72) 
 
Definition of Tumor Response Using irRC 
The sum of the products of diameters at tumor assessment using the immune-related response criteria 
(irRC) for progressive disease incorporates the contribution of new measurable lesions. Each net Percentage 
Change in Tumor Burden per assessment using irRC criteria accounts for the size and growth kinetics of 
both old and new lesions as they appear. 
 
Definition of Index Lesions Response Using irRC 
 
irComplete Response (irCR): Complete disappearance of all index lesions. This category encompasses 
exactly the same subjects as “CR” by the mWHO criteria. 
 
irPartial Response (irPR): Decrease, relative to baseline, of 50% or greater in the sum of the products of 
the two largest perpendicular diameters of all index and all new measurable lesions (ie., Percentage 
Change in Tumor Burden). Note: the appearance of new measurable lesions is factored into the overall 
tumor burden, but does not automatically qualify as progressive disease until the SPD increases by ≥25% 
when compared to SPD at nadir. 
 
irStable Disease (irSD): Does not meet criteria for irCR or irPR, in the absence of progressive disease. 
 
irProgressive Disease (irPD): At least 25% increase Percentage Change in Tumor Burden (i.e., taking 
sum of the products of all index lesions and any new lesions) when compared to SPD at nadir. 
 
Definition of Non-Index Lesions Response Using irRC 
 
irComplete Response (irCR): Complete disappearance of all non-index lesions. This category 
encompasses exactly the same subjects as “CR” by the mWHO criteria. 
 
irPartial Response (irPR) or irStable Disease (irSD): non-index lesion(s) are not considered in the 
definition of PR, these terms do not apply. 
 
irProgressive Disease (irPD): Increases in number or size of non-index lesion(s) does not constitute 
progressive disease unless/until the Percentage Change in Tumor Burden increases by 25% (i.e., the SPD 
at nadir of the index lesions increases by the required amount). 
 
Impact of New Lesions on irRC 
New lesions in and by themselves do not qualify as progressive disease. However their contribution to total 
tumor burden is included in the SPD which in turn feeds into the irRC criteria for tumor response. 
Therefore, new non-measurable lesions will not discontinue any subject from the study. 
 

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Definition of Overall Response Using irRC 
Overall response using irRC will be based on these criteria: 
 
Immune-Related Complete Response (irCR): Complete disappearance of all tumor lesions (index and 
nonindex together with no new measurable/unmeasurable lesions) for at least 4 weeks from the date of 
documentation of complete response.  
 
Immune-Related Partial Response (irPR): The sum of the products of the two largest perpendicular 
diameters of all index lesions is measured and captured as the SPD baseline. At each subsequent tumor 
assessment, the sum of the products of the two largest perpendicular diameters of all index lesions and 
of new measurable lesions are added together to provide the Immune Response Sum of Product 
Diameters (irSPD). A decrease, relative to baseline of the irSPD compared to the previous SPD baseline, 
of 50% or greater is considered an immune Partial Response (irPR).  
 
Immune-Related Stable Disease (irSD): irSD is defined as the failure to meet criteria for immune 
complete response or immune partial response, in the absence of progressive disease.  
 
Immune-Related Progressive Disease (irPD): It is recommended in difficult cases to confirm PD by serial 
imaging. Any of the following will constitute progressive disease: 
-At least 25% increase in the sum of the products of all index lesions over baseline SPD calculated for the 
index lesions. 
-At least a 25% increase in the sum of the products of all index lesions and new measurable lesions 
(irSPD) over the baseline SPD calculated for the index lesions. 
 
Index 
Lesion 
Definition 
Non-Index 
Lesion 
Definition 
New 
Measurable 
Lesions 
New 
Unmeasurable 
Lesions 
Percent change in 
tumor burden 
(inc measurable 
new lesions) 
Overall 
irRC 
Response 
Complete 
Response 
Complete 
Response 
No 
No 
-100% 
irCR 
Partial 
Response 
Any 
Any 
Any 
> -50% 
irPR 
<-50% to <+25% 
irSD 
>+25% 
irPD 
Stable 
Disease 
Any 
Any 
Any 
<-50% to <+25% 
irSD 
>+25% 
irPD 
Progressive 
Disease 
Any 
Any 
Any 
>+25% 
irPD 
 
Immune-Related Best Overall Response Using irRC (irBOR)  
irBOR is the best confirmed irRC overall response over the study as a whole, recorded between the date of 
first dose until the last tumor assessment before subsequent therapy (except for local palliative radiotherapy 
for painful bone lesions) for the individual subject in the study. For the assessment of irBOR, all available 
assessments per subject are considered. irCR or irPR determinations included in the irBOR assessment must 
be confirmed by a second (confirmatory) evaluation meeting the criteria for response and performed no less 
than 4 weeks after the criteria for response are first met. 

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