Radical-Dose Image Guided Radiation Therapy in Treating Patients With Metastatic Non-small Cell Lung Cancer Undergoing Immunotherapy
Phase: NA
Conditions: Stage IV Non-Small Cell Lung Cancer
Sponsor: Stanford University



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TABLE OF CONTENTS 
 
PROTOCOL SYNOPSIS ............................................................................................................... 6 
SCHEMA ....................................................................................................................................... 10 
1. 
OBJECTIVES ....................................................................................................................... 12 
1.1. Primary Objective ................................................................................................................. 12 
1.2. Secondary Objectives ............................................................................................................ 12 
1.3. Exploratory Objectives ......................................................................................................... 12 
2. 
BACKGROUND ................................................................................................................... 12 
2.1 Introduction ........................................................................................................................... 12 
2.2 Trial Design ........................................................................................................................... 13 
2.3 Previous Studies .................................................................................................................... 14 
2.4 Translational Research ......................................................................................................... 15 
2.5 Study Design .......................................................................................................................... 15 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES ......................... 16 
3.1 Inclusion Criteria .................................................................................................................. 16 
3.2 Exclusion Criteria ................................................................................................................. 16 
3.3 Informed Consent Process .................................................................................................... 16 
3.4 Randomization Procedures .................................................................................................. 17 
3.5 Study Timeline ...................................................................................................................... 17 
4. 
TREATMENT PLAN ........................................................................................................... 17 
4.1 Pre-treatment tests ................................................................................................................ 17 
4.2 Drug therapy ......................................................................................................................... 17 
4.3 Radiation Therapy ................................................................................................................ 18 
4.4 General Concomitant Medication and Supportive Care Guidelines ................................ 21 
4.5 Criteria for Removal from Study ........................................................................................ 21 
4.6 Alternatives ............................................................................................................................ 21 
5. 
INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION.................. 21 
5.1 Investigational Agent/Device/Procedure ............................................................................. 21 
5.2 Study agent #1: nivolumab (Opdivo) .................................................................................. 21 
5.3 Study agent #2: pembrolizumab (Keytruda) ...................................................................... 22 
5.4 Study agent #3: atezolizumab (Tecentriq) .......................................................................... 22 
6. 
DOSE MODIFICATIONS ................................................................................................... 22 
7. 
ADVERSE EVENTS AND REPORTING PROCEDURES ............................................. 22 
7.1 Potential Adverse Events ...................................................................................................... 22 

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7.2 Adverse Event Reporting ..................................................................................................... 22 
8. 
CORRELATIVE/SPECIAL STUDIES .............................................................................. 23 
9. 
STUDY CALENDAR ........................................................................................................... 23 
10. MEASUREMENTS .............................................................................................................. 25 
10.1 Primary Outcome .................................................................................................................. 25 
10.2 Secondary outcome #1 .......................................................................................................... 26 
10.3 Secondary outcome #2 .......................................................................................................... 27 
10.4 Secondary outcome #3 .......................................................................................................... 27 
10.5 Secondary outcome #4 .......................................................................................................... 28 
10.6 Secondary outcome #5 .......................................................................................................... 29 
11. REGULATORY CONSIDERATIONS ............................................................................... 30 
11.1 Institutional Review of Protocol .......................................................................................... 30 
11.2 Data and Safety Monitoring Plan ........................................................................................ 30 
11.3 Data Management Plan ........................................................................................................ 30 
12. STATISTICAL CONSIDERATIONS ................................................................................ 31 
12.1 Primary and Secondary Endpoints ..................................................................................... 31 
12.2 Analysis Plan ......................................................................................................................... 31 
12.3 Sample Size Justification ...................................................................................................... 33 
12.4 Patient Accrual ...................................................................................................................... 33 
12.5 Interim Analyses ................................................................................................................... 34 
13. REFERENCES ...................................................................................................................... 35 
APPENDICES ............................................................................................................................... 38 
II. 
Subject Information: ............................................................................................................. 38 
IV. Inclusion/Exclusion Criteria ................................................................................................. 38 
Statement of Eligibility ................................................................................................................. 39 
Protocol Pre-review Checklist ..................................................................................................... 40 
 
 
 
 
 

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PROTOCOL SYNOPSIS 
 
TITLE 
Radical RADiotherapy and Immunotherapy for metastatic CAncer 
of the Lung (RRADICAL) 
STUDY PHASE 
2 
INDICATION 
Most patients with metastatic non-small cell lung cancer 
(NSCLC) now receive immunotherapy with anti-PD-1/anti-PD- 
L1 agents (currently approved agents: nivolumab, 
pembrolizumab, and atezolizumab), but only 20% of patients have 
an objective response to this therapy. We hope to improve the 
proportion of lung cancer patients who benefit from 
immunotherapy through the addition of radical-dose (RT) for 
cytoreduction and immune system priming. 
In this phase II trial, patients who have been started on 
immunotherapy and have not had marked progression will receive 
radical-dose RT, preferably stereotactic ablative radiation therapy 
(SABR), to the highest risk lesions (generally progressive or 
bulky masses). We hypothesize that eliminating as much tumor 
bulk as possible with radiotherapy will prolong or even induce the 
efficacy of immunotherapy. 
The goal is to prolong duration of benefit from immunotherapy 
through cytoreduction and immune system priming. We will 
evaluate whether progression-free survival is improved compared 
to historical controls who received immunotherapy without 
radiation therapy. 
Inclusion Criteria: 
1. Has stage IV non-small cell lung cancer, or initially stage I-
III disease with distant metastatic recurrence 
2. Age ≥ 18 
3. Has been receiving anti-PD-1 or anti-PD-L1 
immunotherapy for at least four weeks 
(refer to section 4.2.1) 
4. Has had restaging imaging after initiation of 
immunotherapy, at least 4 weeks after pre-immunotherapy 
baseline imaging. CT or PET/CT of at least chest/upper 
abdomen must be performed within 4 weeks prior to 
registration. For patients with history of brain metastases, 
brain MRI or CT is required within 4 weeks of 
registration; for other patients brain MRI or CT is required 
within 12 weeks of registration. Diagnostic PET/CT 
performed as part of radiation simulation can be used as 
the restaging imaging. 

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5. Most recent imaging shows measurable disease as defined 
by RECIST 1.1 
6. Evaluation by a Stanford medical oncologist must 
show: 
a. The patient is expected to continue on 
immunotherapy for at least three more months 
b. Imaging must show response, stable disease, or 
modest progression 
c. If there is modest progression, the patient must be 
clinically stable in terms of performance status and 
overall disease-related symptoms 
7. Has at least one extracranial tumor safely treatable with 
radical-dose radiation therapy and that has not been 
previously treated with radiation 
8. ECOG performance status 0-2 
9. Has the ability to understand and the willingness to sign a 
written informed consent document. 
Exclusion Criteria: 
1. Untreated brain metastases, if not planned to be treated in this 
course of radiation therapy 
2. Pregnancy or women of childbearing potential not willing/able 
to use contraception during protocol treatment 
INVESTIGATIONAL 
PRODUCT OR 
PROCEDURE 
Addition of radical-dose radiation therapy to standard-of-care 
anti-PD-1/anti-PD-L1 immunotherapy 
PRIMARY 
OBJECTIVE(S) 
• 
Determine if progression-free survival at 24 weeks with this 
treatment combination is improved compared to historical 
controls who received immunotherapy without radiation therapy 
(see section 12.2) 
SECONDARY 
OBJECTIVE(S) 
• 
Assess acute (0-6 months) and late (>6 months) grade 3-5 
toxicity 
• 
Assess overall survival 
• 
Correlate circulating tumor DNA (ratio of post-RT to pre-RT 
level) with radiographic response 
• 
Correlate immune markers in peripheral blood with 
radiographic response 
• 
Assess dose-limiting toxicity 
TREATMENT 
SUMMARY 
This trial’s target population is NSCLC patients who have 
recently started immunotherapy, and have either response, stable 
disease, or modest progression on follow-up imaging. Patients 
with substantial progression are excluded because they are 
unlikely to benefit from immunotherapy even with the addition of 
RT. The eligible patients are at high risk for progressing within 
the next few months if they stay on immunotherapy. In this 
single-arm phase II trial (with an additional prospective registry 
control group), patients will remain on immunotherapy, with the 
addition of radical-dose radiation therapy to up to four lesions. 

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The hypothesis is that radiation therapy will achieve 
cytoreduction and immune system priming, and thereby delay 
disease progression and benefit patients. As much of the overall 
disease bulk will be targeted as is considered safe, in order to 
achieve maximal cytoreduction. Stereotactic ablative radiation 
therapy (SABR) will be given whenever possible because of its 
higher expected effectiveness and reduced acute toxicity 
compared to conventional radiation therapy. 
This study will test whether the addition of RT improves disease 
control compared to patients not receiving RT. The primary 
endpoint is progression-free survival 24 weeks after study entry 
(PFS24), which will be compared to historical controls treated 
with immunotherapy without the addition of RT (see section 
12.2). If we are able to demonstrate that RT delays progression 
with acceptable rate of toxicity, the RT+immunotherapy 
combination strategy could be tested in a randomized phase III 
trial. 
Patients who are eligible but decline to enroll on the therapeutic 
arm of the study, or are ineligible only due to enrollment in a 
different trial, will be offered enrollment on a separate registry 
arm, where they will receive standard of care immunotherapy 
without the addition of radiation, and will be followed for 
progression and other clinical endpoints. This will serve as an 
internal check on the historical controls’ PFS24 estimate. 
Intervention and Mode of Delivery: 
Patients will continue on the same anti-PD-1 or anti-PD-L1 
immunotherapy that they were previously receiving. Systemic 
treatment on protocol will continue until RECIST progression or 
unacceptable toxicity. 
Upon study entry, radical-dose radiation therapy will be given to 
1-4 extracranial lesions. The lesions to be treated are at the 
discretion of the treating radiation oncologist. Factors in favor of 
selecting a lesion include large size, progression on most recent 
imaging, causing symptoms, and being in a threatening location 
(further growth is likely to cause symptoms). A conglomerate of 
masses or closely spaced masses can be considered to be one 
lesion. 
Treatment of brain metastases is not part of protocol therapy. 
Brain metastases, if present, will be treated as per standard of 
care, generally with radiation therapy. 
SAMPLE SIZE 
At least 43 patients in interventional arm, plus approximately 30 
patients in companion registry study. 

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STATISTICAL 
CONSIDERATIONS 
Definition of primary outcome/endpoint: 
Progression-free survival at 24 weeks (PFS24) is proportion of 
patients without RECIST 1.1 disease progression or death 24 
weeks from date of study entry. 
Definition of secondary outcomes/endpoints: 
• 
Acute toxicity is defined as toxicity that occurs 0-6 months 
after first day of radiation therapy. Late toxicity is toxicity that 
occurs >6 months after first day of radiation therapy. Toxicity is 
measured with CTCAE v4. 
• 
Overall survival is defined as time from study entry to death 
• 
For the ctDNA and immune marker endpoints, best 
radiographic response is defined using RECIST 1.1 criteria 
• 
Dose-limiting toxicity is defined as any grade 3-5 toxicity 
related to study radiation therapy, except certain expected 
toxicities. 
Analytic plan for primary objective: 
Progression will be evaluated by follow up CT, PET/CT, and 
brain MRI imaging and clinic visits 
Analytic plan for secondary objectives: 
• 
Potential adverse events will be monitored by treating 
physicians at each follow up visit, and scored using CTCAE v4 
with type and grade 
• 
Patients will be followed for progression and death through 
clinic visits, scans, and chart reviews 
• 
For the ctDNA and immune marker endpoints, change in 
biomarker level from before to after radiation will be 
correlated with best radiographic response 
• 
For the dose-limiting toxicity endpoint, a single interim 
analysis will be performed and observed rate will be 
compared to acceptable rate. 
Sample size justification: 
The null hypothesis is that PFS24 for the study population will be 
the same as a similar population treated with immunotherapy 
alone without addition of radiation therapy (see section 12.2). 
PFS24 with nivolumab in unselected patients is 30-40%. We 
assume that PFS24 in our patient population would be 35%. 
The alternate hypothesis is that the study patients’ PFS24 is 
improved over historical controls, at 52%. The exact binomial test 
will be used to test this hypothesis. PFS will be measured from 
the date of study entry. Based on historical data, for the study 
population we estimate that 24 week progression-free survival 
(PFS24) after continuing immunotherapy alone (without radiation 
therapy) is 35%. The alternate hypothesis is that their PFS24 is 
52%. With one-sided alpha of 0.1 and at least 80% power, 39 
patients are required. Assuming 10% dropout/unevaluable 
patients, total enrollment will be at least 43 patients. 

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SCHEMA 
Primary outcome:  Progression-free survival at 24 weeks compared to historical controls 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
Adverse event 
CBC 
Complete blood count 
CMP  
Complete metabolic panel 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DNA 
Deoxyribonucleic acid 
ECOG PS 
Eastern Cooperative Oncology Group performance status 
FDG-PET 
Fluorodeoxyglucose positron emission tomography 
GTV 
Gross tumor volume 
NSCLC 
Non-small cell lung cancer 
OS 
Overall Survival 
PD-1 
Programmed death protein 1 
PD-L1 
Programmed death-ligand 1 
PFS 
Progression-free Survival 
PTV 
Planning target volume 
RECIST 
Response evaluation criteria in solid tumors 
SABR 
Stereotactic ablative radiotherapy 
RT 
Radiation therapy 
PFS24 
Progression-free survival 24 weeks after study entry 

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1. 
OBJECTIVES 
 
1.1. 
Primary Objective 
• Determine if progression-free survival at 24 weeks with this treatment combination is 
improved compared to historical controls who received immunotherapy without radiation 
therapy 
 
1.2. 
Secondary Objectives 
• Assess acute (0-6 months) and late (>6 months) grade 3-5 toxicity 
• Assess overall survival 
• Correlate circulating tumor DNA (ratio of post-RT to pre-RT level) with radiographic 
response 
• Correlate immune markers in peripheral blood with radiographic response 
• Assess dose-limiting toxicity 
 
1.3. 
Exploratory Objectives 
• Analyze progression-free survival with immune-related response criteria 
• Measure time to discontinuation of study immunotherapy agent 
• Assess patterns of progression 
2. 
BACKGROUND 
 
2.1 Introduction 
Of the 221,000 patients diagnosed with lung cancer each year in the US, around 60% present 
with metastatic incurable disease. Conventionally, radiation therapy (RT) has played a purely 
palliative role in these patients with metastatic disease, with no routine role for higher dose, 
advanced RT used to assist with overall disease control. 
Cancer immunotherapy harnesses the body’s immune system to recognize and attack cancer 
cells. Recently, three immunotherapeutic agents (nivolumab, pembrolizumab, and atezolizumab) 
have been approved by the FDA for use in metastatic non-small cell lung cancer (NSCLC) that 
has progressed on first-line chemotherapy [Brahmer, Borghaei, Garon, Rittmeyer], with more 
anticipated soon. The development of these anti-programmed death 1 (anti-PD-1)/ anti- 
programmed death-ligand 1 (anti-PD-L1) agents represent an important advance in the treatment 
of NSCLC. The clinical benefit of the new agents is noteworthy. In a recent trial of squamous 
cell lung cancer, nivolumab improved 1-year overall survival from 24% to 42% when compared 
to docetaxel [Brahmer]. The large majority of metastatic NSCLC patients will be treated with 
immunotherapy at some point in their disease course. However, only 20% of these patients have 
an objective response to anti-PD-1/anti-PD-L1 treatment and median overall survival after 
starting this treatment is less than one year. This indicates a need for new treatment approaches, 
especially in patients who do not have a good radiographic response to immunotherapy. 
Local external beam radiation therapy can also act to stimulate the immune system, through 
mechanisms such as exposure of tumor-specific antigens to T cells [Gandhi]. Preclinical data in a 
mouse model of melanoma have shown a synergistic antitumor effect of radiation therapy and 
immunotherapy with anti-PD-1/anti-PD-L1 therapy [Twyman-Saint Victor]. The added tumor 
shrinkage from radiation therapy is seen even at tumor sites not exposed to radiation, known as 

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the abscopal effect. There are emerging data that patients with reduced disease bulk have higher 
response rates to anti-PD-1/anti-PD-L1 therapy, which provides a second rationale for adding 
radiation therapy to immunotherapy [Lee]. 
 
2.2 
Trial Design 
This trial’s target population is NSCLC patients who have recently started immunotherapy, and 
have either response, stable disease, or modest progression on follow-up imaging. Patients with 
substantial progression are excluded because they are unlikely to benefit from immunotherapy 
even with the addition of RT. The eligible patients are at high risk for progressing within the next 
few months if they stay on immunotherapy. In this single-arm phase II trial (with an additional 
prospective registry control group), patients will remain on immunotherapy, with the addition of 
radical-dose radiation therapy to up to four sites of disease. The hypothesis is that radiation 
therapy will achieve cytoreduction and immune system priming, and thereby delay disease 
progression and benefit patients. As much of the overall disease bulk will be targeted as is 
considered safe, in order to achieve maximal cytoreduction. Stereotactic ablative radiation 
therapy (SABR) will be given whenever possible because of its higher expected effectiveness 
and reduced acute toxicity compared to conventional radiation therapy. 
This trial differs from other recently opened trials of combination of RT and immunotherapy. 
Most other trials are attempting to demonstrate response in non-target lesions after radiation 
(abscopal effect). Based on recent experience combining RT with immunotherapy we are 
skeptical that a majority of patients will exhibit this dramatic response to RT. Instead, we 
hypothesize that eliminating as much tumor bulk as possible with radiotherapy will 
prolong or even induce the efficacy of immunotherapy. 
This study will test whether the addition of RT improves disease control compared to patients 
not receiving RT. The primary endpoint is progression-free survival 24 weeks after study entry 
(PFS24), which will be compared to historical controls treated with immunotherapy without the 
addition of RT. If we are able to demonstrate that RT delays progression with acceptable rate of 
toxicity, the RT+immunotherapy combination strategy could be tested in a randomized phase III 
trial. 
Patients who are eligible but decline to enroll on the therapeutic arm of the study, or are 
ineligible only due to enrollment in a different trial, will be offered enrollment on a separate 
registry arm, where they will receive standard of care immunotherapy without the addition of 
radiation, and will be followed for progression and other clinical endpoints. This will serve as an 
internal check on the historical controls’ PFS24 estimate. 
We expect that the large majority of patients enrolling on this study will be receiving 
immunotherapy as second-line or later therapy. This informs the historical control PFS24 
estimate. There are several ongoing trials studying the best way to give anti-PD-1/anti-PD-L1 
immunotherapy for NSCLC (first-line versus later line of therapy; whether PD-L1 biomarker 
testing is needed and what PD-L1 level/test is most helpful). For instance, a randomized trial 
recently suggested that first-line pembrolizumab improves outcomes compared to platinum- 
based chemotherapy, and showed improved PFS24 compared to immunotherapy used as a later 
line of therapy [Reck]. We will record line of therapy for patients entering the study, in order to 
make sure the trial patients’ outcomes are compared to an appropriate historical control patient 

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population. 
The specific 1-4 lesions to be treated with RT will be decided by the treating radiation 
oncologist, using criteria specified in section 4.3.1. The criteria are intended to cause more 
threatening lesions to be treated with RT, so that even if a systemic effect of RT is not observed, 
the RT will provide some benefit from local palliation. 
 
2.3 
Previous Studies 
Radical-dose RT in metastatic NSCLC 
A randomized trial recently reported in abstract form provides support for radiation therapy as a 
means to improve survival in stage IV NSCLC [Gomez 2016]. 49 patients with newly diagnosed 
oligometastatic NSCLC (3 or fewer metastases) were randomized to standard systemic therapy, 
or local treatment to all sites of disease with radiation therapy or surgery, followed by standard 
systemic therapy. Median progression-free survival was dramatically improved in the local 
therapy arm, at 14.4 months vs. 3.9 months (p=0.01). The overall survival endpoint is not 
mature. 
Efficacy of RT and immunotherapy 
In mouse studies using a variety of tumor types, the addition of RT to anti-PD-1/anti-PD-L1 
therapy has been shown to improve tumor control at both irradiated and non-irradiated sites 
[Sharabi, Park, Twyman-Saint Victor]. The combination of RT and immunotherapy seems to be 
most effective when the radiation dose per fraction is high, similar to clinical treatments with 
hypofractionated approaches like SABR [Gandhi]. This is one rationale for the use of 
hypofractionated, radical-dose radiation therapy (2 weeks or fewer, higher biologically effective 
dose than standard palliative RT) in the current trial. 
Safety of RT and immunotherapy 
The safety of anti-PD-1/anti-PD-L1 immunotherapy and radical-dose radiation therapy to 
multiple lesions has been demonstrated separately and in combination. Multiple phase II-III 
studies of nivolumab, pembrolizumab, and atezolizumab showed acceptable toxicity rates for 
NSCLC patients [Brahmer, Borghaei, Garon, Rittmeyer]. Radical-dose radiation therapy to 
multiple disease sites with SABR has also been shown to be safe. In a prospective study of 121 
patients receiving SABR to 1-5 metastases in a variety of locations, grade 3-5 toxicity rate was 
very low at 1% [Milano]. Another similar study also showed severe toxicity rate under 10%, 
with grade 3-5 complications from 8/113 metastases treated (7% rate) [Salama]. Because of the 
pattern of metastatic spread of NSCLC, many treated lesions in the current trial will be in the 
chest. Simultaneous treatment to multiple lesions in the thorax has been shown to be safe, with 
5/63 (8%) of patients experiencing grade 3+ acute/late toxicity [Owen]. 
Several recent prospective studies support the safety of the combination of anti-PD-1/anti-PD- 
L1immunotherapy with radiation therapy as is used in the current protocol. A phase 1 study 
evaluated safety of REGN2810, an anti-PD-1 antibody [Papadopoulos 2016]. 34 of the patients 
received high dose radiation therapy (9 Gy x 3 fractions or 6 Gy x 5 fractions) concurrently with 
REGN2810. There were no dose-limiting toxicites. In a second study, 11 patients received 
palliative radiation therapy followed by the anti-PD-1 antibody pembrolizumab [Segal]. There 
were no grade 3+ drug-related adverse events and the combination was considered to be safe. 

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Retrospective data also support the safety of the approach taken in this trial. One report described 
safe treatment of 12 lesions with radiation therapy in seven patients receiving pembrolizumab 
[Das]. Unpublished data also show that around 50 patients in nivolumab clinical trials also 
received RT while on nivolumab, and did not have any serious adverse events [personal 
communication from Dr. Corey Langer, University of Pennsylvania]. 
 
2.4 
Translational Research 
Translational research correlative studies will be performed. The goal of these is to identify 
biomarkers of a good response to the combination of RT and immunotherapy, to improve patient 
selection for this treatment strategy in the future. 
The first study will involve measuring the level of pre-RT circulating tumor DNA (ctDNA) and 
change in ctDNA level after radiation therapy [Newman]. Blood will be collected pre- and post- 
radiation therapy. Also, whenever possible, tumor tissue will be collected, consisting of a punch 
from a paraffin embedded tissue block or several unstained slides. Samples will be sent to the 
Diehn lab at Stanford for processing and analysis. 
The goal of the ctDNA correlative study is to identify a biomarker of early response to radiation 
treatment. The significance of change in ctDNA level after radiation therapy has not been well 
studied, especially in patients with metastatic disease. We hypothesize that patients with greater 
post-radiation therapy reduction in ctDNA level will later be found to have better radiographic 
response. This could be due to cancer cell death both in the radiation treated lesion and non- 
irradiated lesions (from immune potentiation). If it is found that patients with greater ctDNA 
change have more benefit from radiation therapy, this biomarker could be useful. For instance, 
one lesion could be treated with radiation and change in ctDNA level measured. If a large change 
was seen, additional lesions could be irradiated to attempt to trigger an abscopal response. 
The second study will involve markers of immune response in peripheral blood. Immune cell 
subtypes such as activated T cells and myeloid-derived suppressor cells have been shown in 
preclinical studies to be associated with the increased immune response from the addition of RT 
to checkpoint blockade immunotherapy [Deng]. Flow cytometry has been able to detect these 
changes after RT in several preclinical studies [Deng, Sharabi]. Peripheral blood flow cytometry 
will be performed before and after RT, including with sensitive mass spectrometry methods 
partially developed at Stanford [Lin, Chang]. We will perform exploratory analysis to see if pre- 
RT levels of various cell subsets, or relative change after RT, predicts for longer progression-free 
survival. In patients who have pre-RT research biopsy performed as part of a fiducial placement 
procedure, immune markers will also be examined for the tumor tissue. 
 
2.5 
Study Design 
For clinicaltrials.gov documentation: 
The primary purpose of the protocol is treatment. 
The interventional model is parallel. 
There are two interventional arms. 
The study is open. No masking is used. 
The study is not randomized. 
The primary outcome is efficacy. 

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The FDA has approved nivolumab, pembrolizumab, and atezolizumab for the treatment setting 
used in this trial, so no Investigational New Drug application is required. 
 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
Refer to the Participant Eligibility Checklist in Appendix A. 
 
3.1 
Inclusion Criteria 
 
1. Has stage IV non-small cell lung cancer, or initially stage I-III disease with distant 
metastatic recurrence 
2. Age ≥ 18 
3. Has been receiving anti-PD-1 or anti-PD-L1 immunotherapy for at least four weeks (refer 
to section 4.2.1) 
4. Has had restaging imaging after initiation of immunotherapy, at least 4 weeks after pre- 
immunotherapy baseline imaging. CT or PET/CT of at least chest/upper abdomen must 
be performed within 4 weeks prior to registration. For patients with history of brain 
metastases, brain MRI or CT is required within 4 weeks of registration; for other patients 
brain MRI or CT is required within 12 weeks of registration. Diagnostic PET/CT 
performed as part of radiation simulation can be used as the restaging imaging. 
5. Most recent imaging shows measurable disease as defined by RECIST 1.1 
6. Evaluation by a Stanford medical oncologist must show: 
a. The patient is expected to continue on immunotherapy for at least three more 
months 
b. Imaging must show response, stable disease, or modest progression 
c. If there is modest progression, the patient must be clinically stable in terms of 
performance status and overall disease-related symptoms 
7. Has at least one extracranial tumor safely treatable with radical-dose radiation therapy and 
that has not been previously treated with radiation 
8. ECOG performance status 0-2 
9. Has the ability to understand and the willingness to sign a written informed consent 
document. 
3.2 
Exclusion Criteria 
 
1. Untreated brain metastases, if not planned to be treated in this course of radiation therapy 
2. Pregnancy or women of childbearing potential not willing/able to use contraception 
during protocol treatment 
 
3.3 
Informed Consent Process 
All participants must be provided a consent form describing the study with sufficient information 
for participants to make an informed decision regarding their participation.  Participants must 
sign the IRB approved informed consent prior to participation in any study specific procedure. 
The participant must receive a copy of the signed and dated consent document. The original 
signed copy of the consent document must be retained in the medical record or research file. 

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Remote consenting may be conducted. 
 
3.4 
Randomization Procedures 
N/A 
 
3.5 
Study Timeline 
 
Primary Completion: 
We estimate the primary completion date will be Feb. 25, 2022. 
 
Study Completion: 
We estimate the study completion date will be Feb. 25, 2023. 
 
4. TREATMENT PLAN 
4.1 
Pre-treatment tests 
• History and physical 
• Laboratory testing: CBC with differential and complete metabolic panel. Pregnancy 
test or documentation of adequate contraception for women of childbearing potential. 
 
4.2 
Drug therapy 
4.2.1 
Immunotherapy administration 
 
Patients will continue on the same anti-PD-1 or anti-PD-L1 immunotherapy that they 
were previously receiving. Currently available anti-PD-1/anti-PD-L1drugs include 
nivolumab, generally dosed every 2 weeks or every 4 weeks, pembrolizumab, 
generally dosed every 3 weeks, and atezolizumab, generally dosed every 3 weeks. It 
is acceptable to give cytotoxic chemotherapy along with immunotherapy, but no 
chemotherapy can be given from 7 days before first day of protocol radiation therapy 
to 7 days after last day of protocol radiation therapy. For 
chemotherapy/immunotherapy combinations, only standard of care regimens are 
allowed. Currently the allowed combinations are 
carboplatin/pemetrexed/pembrolizumab and pemetrexed/pembrolizumab [Langer]. 
 
Laboratory monitoring for patients on immunotherapy will be performed as per 
standard of care. For labs required at study entry (CBC w/ diff and CMP), the medical 
or radiation oncologist will review and initial with date on any abnormal laboratory 
value/report. 
 
As systemic therapy will be given as per standard of care, it is acceptable for 
immunotherapy to be given by a physician outside of Stanford ie. local oncologist, 
however, a Stanford physician will need to evaluate the subject at protocol specified 
follow up time points. Additionally, study visits may be conducted via video (i.e., 
MyHealth video, telehealth, telemedicine) or phone. 
 

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If there is RECIST 1.1 disease progression or unacceptable toxicity, the patient will be 
considered to be off of protocol therapy and will not be required to be seen at protocol 
specified follow up time points. After progression, it will be the decision of the treating 
medical oncologist whether to continue immunotherapy, switch to another therapy, or 
discontinue active therapy. 
 
The treating medical oncologist may also decide to stop immunotherapy for other 
reasons such as an excellent sustained radiographic response to treatment. In this case, 
the patient should continue on the protocol follow-up schedule. 
 
4.2.2 
Modality Review 
 
For patients receiving immunotherapy at an outside facility, immunotherapy quality 
assurance review will be performed by one of the Medical Oncologist study 
investigators. This will include verifying that correct medication dosing and dose 
schedule are being used. 
 
4.2.3 
Anticipated Adverse Events 
 
Adverse events from immunotherapy: 
 
The adverse events from nivolumab, pembrolizumab, and atezolizumab are outlined in 
the package inserts. The most common adverse reactions are fatigue, musculoskeletal 
pain, decreased appetite, cough, and constipation. Other serious adverse events 
reported included pneumonitis, immune-mediated colitis, hepatitis, endocrinopathies, 
nephritis, rash, and encephalitis. 
 
Management of pneumonitis: 
 
Pneumonitis is of particular concern in patients with lung cancer who have recently 
received radiation therapy. Immune mediated pneumonitis can mimic infection, 
radiation pneumonitis, or lymphangitic spread of disease. If the patient is believed to 
have moderate immune-mediated pneumonitis, immunotherapy should be held until 
pneumonitis resolves. Steroids should be initiated. If a patient is believed to have 
severe/life-threatening immune-mediated pneumonitis, steroids should be initiated, 
and pulmonary consultation should be sought. Immunotherapy should be permanently 
discontinued. If pneumonitis is thought to be due to radiation therapy rather than 
immunotherapy, the medication can be continued. 
4.3 
Radiation Therapy 
4.3.1 
Radiation therapy overview 
Radical-dose radiation therapy will be given to 1-4 extracranial lesions. Radiation 
therapy must be given at Stanford. The lesions to be treated are at the discretion of the 
treating radiation oncologist. Factors in favor of selecting a lesion include large size, 
progression on most recent imaging, causing symptoms, and being in a threatening 
location (further growth is likely to cause symptoms). A conglomerate of masses or 

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closely spaced masses can be considered to be one lesion. 
Treatment of brain metastases is not part of protocol therapy. Brain metastases, if 
present, will be treated as per standard of care, generally with radiation therapy. 
It is acceptable to treat the 1-4 lesions concurrently or sequentially, as long as total 
planned course of treatment is 10 daily sessions or less. Radiation therapy should be 
completed in around two weeks, though it is acceptable to extend this if necessary, for 
instance due to department holidays or linear accelerator downtime. Ideally, radiation 
therapy will start on the day of an immunotherapy infusion. However, this will not 
always be possible for logistical reasons. If a RT session falls on the day of an 
infusion, the two treatments can be given in either order. 
If a lesion has previously been treated with external beam radiation therapy, it is not 
eligible to be treated on this study. However, it is acceptable for a radiation field to 
about a prior field. 
 
4.3.2 
Radiation dose 
 
Either stereotactic or conventional image-guided radiation therapy can be used. 
SABR is preferred when feasible. Four radiation therapy schedules are allowed. The 
treating physician will choose between ablative and non- ablative dosing based on 
lesion location and size. Lesions abutting critical normal structures should have non-
ablative dosing. Examples of these structures include spinal cord, small bowel, 
brachial plexus, large vessels/airways, and esophagus. 
 
Dose schedules: 
 
Ablative: 
50 Gy in 5 fractions, or 50 Gy in 10 
fractions Non-ablative: 
27 Gy in 3 fractions, or 40 Gy in 10 fractions 
 
4.3.3 
Simulation 
 
When possible, the simulation CT will be used as the baseline study for response 
assessment. Therefore, the simulation CT borders should generally be extended to 
include all known areas of extracranial disease. During radiotherapy simulation, 
customized immobilization devices will be formed for each patient. For targets in thorax 
or upper abdomen, 4-dimensional CT (4 D CT) will be acquired in the treatment 
position. 
Acquisition of a PET CT in the treatment position is encouraged but not required. 
 
4.3.4 
Treatment planning 
 
The treating physician will contour the GTV. No explicit expansion for microscopic 
extension will be added to form the clinical target volume (CTV), i.e., CTV = GTV. 
The only exception is tumors in the spine, which will have a custom CTV margin 

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added as per International Spine Radiosurgery Consortium guidelines, because of the 
high risk of failure when GTV alone is treated [Cox 2012]. For treatments in the chest 
and upper abdomen, breathing induced tumor motion will be assessed using the 4DCT 
data and managed by deep inspiration breath hold, respiratory gating, dynamic tumor 
tracking, or motion inclusive technique, and the internal target volume (ITV) will be 
designed accordingly. Up to a 7mm setup margin will be added to the ITV (or GTV for 
treatments outside of the chest/upper abdomen) to form the final planning target 
volume (PTV). It is acceptable to reduce the PTV margin in the vicinity of critical 
normal structures such as spinal cord, bowel, or esophagus. 
The treatment plan will be generally be normalized such that at least 95% of each PTV 
is covered by the prescription dose. It is acceptable to cover less than 95% of the PTV 
with prescription dose in cases of PTV overlap with critical normal structures. An 
inhomogeneous dose distribution (i.e., maximum point dose ~120-150% of prescription 
dose) is acceptable as long as the hot spot is centered in the GTV and normal tissue 
constraints are met. 
Treatment will be delivered using 6-15 MV photons using a linear accelerator with daily 
kilovoltage (kV) X-ray imaging and/or daily cone beam CT for anatomy based 
matching. Intensity modulated radiation therapy (IMRT), particularly volumetric 
modulated arc therapy (VMAT), is highly encouraged. 3D conformal therapy can also 
be used. If 3D conformal therapy is used, it may be necessary to treat two sets of fields 
daily: one set that covers the full tumor, and another that covers only the part of the 
tumor not overlapping critical normal structures. For example, for a tumor abutting the 
spinal cord, the periphery of the tumor could receive a dose of 30 Gy in 10 fractions 
while the central part of the tumor receives a total of 40 Gy in 10 fractions using a 
separate set of fields that avoid the spinal cord. 
Highly conformal treatment will be given. The ratio of the volume receiving greater 
than or equal to the prescription dose to the PTV volume should ideally be < 1.2. 
4.3.5 
Critical structures 
 
Because of the variety of fractionation schedules and disease sites within the body to be 
treated, absolute normal tissue dose requirements are not specified in this protocol. 
Stanford institutional guidelines on normal tissue doses exist for each disease site and 
will be used. 
Dose constraints will be based on the individual radiation plans for the 1-4 treated 
lesions. A plan sum should also be generated if multiple lesions are treated, to make 
sure that additive organ doses are not excessive. 
When a small part of a critical structure overlaps the PTV, it is acceptable for the dose to 
0.03 mL of the critical structure to be up to 110% of prescription dose within the overlap 
region. 
 
4.3.6 
R.T. Quality Assurance Review 
Every radiation plan will be prospectively reviewed by the protocol investigators. 

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4.3.7 
Radiation therapy adverse events 
Potential radiation therapy adverse events depend on the treated location. We expect 
that most treated lesions will be in the thorax. Therefore, acute toxicity could include 
esophagitis causing pain with swallowing, fatigue, skin reaction, or cough. 
Subacute/late toxicity could include radiation pneumonitis, lung fibrosis, chest wall 
fracture/rib pain, hemoptysis, large airway necrosis, heart failure, pericarditis, 
esophageal stricture. 
Symptomatic radiation pneumonitis should be treated with inhaled or oral steroids. 
Severe cases should be treated with high dose oral steroids for at least a one month 
taper. 
For treatment of extra-thoracic disease sites, acute toxicity could include skin reaction, 
fatigue, nausea, vomiting, dysphagia, and mucositis. Subacute/late toxicity could 
include skin changes/alopecia, brachial plexopathy, stroke, myelitis, bowel 
obstruction/perforation/fistula, spinal compression fracture, other bone fracture, 
radiation-induced river disease, kidney failure, change in bowel/bladder habits, sexual 
dysfunction.  
 
4.4 
General Concomitant Medication and Supportive Care Guidelines 
Guidelines for use of medications for treatment toxicity are listed in sections 4.2.3 and 4.3.7. 
Other supportive care, such as management of pain, will be as per standard Stanford Cancer 
Center clinical practices. 
 
4.5 
Criteria for Removal from Study 
Patients will be removed from the treatment plan and switched to usual care at time of: 
1. Unacceptable toxicity 
2. Progression of disease 
3. Patient withdrawal of consent 
 
4.6 
Alternatives 
Patients are allowed to withdraw consent for study treatment at any time, and would be 
switched back to standard of care treatment with systemic therapy and/or radiation therapy. 
 
5. 
INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION 
5.1 
Investigational Agent/Device/Procedure 
No investigational agents or devices will be used in this study. The study tests a combination 
of two standard of care treatments: anti-PD-1/anti-PD-L1immunotherapy (current approved 
agents are nivolumab, pembrolizumab, or atezolizumab); and conformal image-guided 
radiation therapy. 
5.2 
Study agent #1: nivolumab (Opdivo) 
Nivolumab is a monoclonal antibody that blocks the interaction between PD-1 and its ligands, 

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PD-L1 and PD-L2. This releases PD-1 pathway mediated inhibition of the immune response, 
including the anti-tumor immune response. It is FDA approved for treatment of metastatic 
NSCLC with progression on platinum-based chemotherapy or EGFR/ALK targeted therapy. 
For details of pharmacokinetics and toxicity data, please see the most updated package insert. 
5.3 
Study agent #2: pembrolizumab (Keytruda) 
Pembrolizumab is a monoclonal antibody that blocks the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2. This releases PD-1 pathway mediated inhibition of the immune 
response, including the anti-tumor immune response. It is FDA approved for treatment of 
metastatic NSCLC in patients whose tumors have ≥50% PD-L1 expression, or have ≥1% PD-
L1 expression and progressed on prior therapy. For details of pharmacokinetics and toxicity 
data, please see the most updated package insert. 
5.4 
Study agent #3: atezolizumab (Tecentriq) 
Atezolizumab is a monoclonal antibody that binds to PD-L1 and blocks its interactions with 
both PD-1 and B7.1 receptors. This releases inhibition of the immune response, including the 
anti- tumor immune response. It is FDA approved for treatment of metastatic NSCLC with 
progression on platinum-based chemotherapy or EGFR/ALK targeted therapy. For details of 
pharmacokinetics and toxicity data, please see the most updated package insert. 
 
6. 
DOSE MODIFICATIONS 
Typically, patients who experience toxicity from anti-PD-1/anti-PD-L1immunotherapy do not 
have dose reduction. Instead, immunotherapy is continued at current dose or discontinued per 
the judgement of the treating medical oncologist. Since immunotherapy administration on this 
study is per standard of care, the decision on termination of the immunotherapy agent will be 
made by the treating medical oncologist. 
 
If a patient is experiencing unacceptable toxicity from radiation therapy while radiation 
therapy is ongoing, radiation therapy will be discontinued. 
 
7. 
ADVERSE EVENTS AND REPORTING PROCEDURES 
7.1 
Potential Adverse Events 
See sections 4.2.3 and 4.3.7. 
 
7.2 
Adverse Event Reporting 
Adverse events will be graded according to CTCAE v4.03. Baseline and follow up toxicities 
will be evaluated and documented either by the medical or radiation oncologist. At each 
follow-up study visit, required Adverse Events and any other grade 3-5 Adverse Events will 
be clearly noted in source documentation and listed on study specific Case Report Forms 
(CRFs). The Protocol Director (PD) or designee will assess each Adverse Event (AE) to 
determine whether it is unexpected according to the Informed Consent, Protocol Document, or 
Investigator’s Brochure, and related to the investigation. All Serious Adverse Events (SAEs) 
occurring less than 6 months after the conclusion of study RT (unless patient has entered 
long-term follow-up phase due to disease progression/unacceptable toxicity) will be reported 
and tracked until resolution. 
 

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SAEs CTCAE Grade 3 and above, and all subsequent follow-up reports will be reported to the 
Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) using the study 
specific CRF regardless of the event’s relatedness to the investigation. Following review by 
the DSMC, events meeting the IRB definition of ‘Unanticipated Problem’ will be reported to 
the IRB using eProtocol within 10 working days of DSMC review, or within 5 working days 
for deaths or life-threatening experiences. 
 
8. 
CORRELATIVE/SPECIAL STUDIES 
8.1 
Analysis of plasma and core biopsy specimens for biomarker development 
8.1.1 Collection of specimens 
For patients who consent to the optional blood testing component, peripheral blood 
specimens will be drawn before and after radiation therapy, and optionally at follow-up 
visits. The first specimen will be drawn on the first day of RT (before RT), or up to 14 
days before that. The second specimen will be drawn on the last day of RT (after RT), 
or up to 14 days after that. Also, if a patient has pre-radiation CT-guided biopsy or 
fiducial placement for routine clinical purposes, research cores may be obtained during 
that procedure. Collection of specimens is optional. Patients will elect whether they 
want to participate in this portion of the study on the consent form. This correlative 
study will be performed at Stanford University. 
 
8.1.2 Handling of specimens 
a) For each blood collection, up to 50 ml will be drawn (purple/violet tubes, 
EDTA preserved). EDTA tubes must be stored as soon as possible between 1-
6°C until processed. The samples are viable for up to 24 hours after collection if 
stored at proper temperature 
b) After collection, blood will be centrifuged at low RPM. The plasma will be 
removed and centrifuged at high RPM, then stored at -80°C. ctDNA analysis will be 
performed on this specimen in collaborator’s labs at Stanford University. The 
remaining cellular material will then be stored at -80°C for later immune marker 
analysis. 
c) Core biopsy specimens: The core biopsy samples will be brought immediately to 
the pathology department for processing. 
De-identified specimens may be saved for future research. If additional correlative work is 
proposed pending scientific advances, this may require the cooperation of other laboratories. 
 
8.1.3 Coding of specimens for privacy protection 
At the time of registration each patient will be given a specific confidential identification 
number (IDN). Specimens will be stored under the patient’s IDN. The information can 
be shared with other investigators listed on this protocol. Study data will be maintained 
in password protected computer files (protected online database). Only research 
personnel will have access to this information. 
 
9. 
STUDY CALENDAR 
This study calendar is for patients enrolled in the interventional arm who will receive 
radiation therapy on study. For patients in the separate registry arm, clinic visits, 

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laboratory draws, and scans will be per standard of care and are not mandated to be 
on a specific schedule. For interventional arm patients, after disease progression or 
unacceptable toxicity, the patient enters the long-term follow-up period and 
visit/imaging schedule will be at the discretion of the treating medical oncologist and 
not mandated by the study. 
 
All treatment and evaluation items in the study calendar are part of standard 
medical care, except for the peripheral blood biomarker lab draw which is a 
research procedure. Also, if a patient has pre-radiation CT-guided biopsy or 
fiducial placement for routine clinical purposes, research cores may be obtained 
during that procedure. 
 
 
Action 
Pre 
Entry1 
Pre- 
RT 
Day 1 
of RT 
Last 
day of 
RT 
8 weeks 
after sim2 
16 weeks 
after sim2 
24 weeks 
after sim2 
36 weeks 
after sim3 
48 weeks 
after sim3 
Every 12 weeks 
until disease 
progression or 
unacceptable 
toxicity3 
After 
disease 
progression 
or un-
acceptable 
toxicity 
History & 
Physical 
Exam 
X 
X 
X 
X 
X 
X 
X11 
ECOG PS 
X 
X 
X 
X 
X 
X 
X11 
Labs 
 
 
 
 
 
 
 
   CBC/diff. 
X9 
 
 
 
 
 
 
   CMP 
X9 
 
 
 
 
 
 
CT Thorax 
(Chest), or 
PET/CT 
X 
X 
X 
X 
X 
X 
X11 
Brain MRI or 
CT, if known 
brain 
metastases 
X 
X 
X 
X 
X 
X 
X11 
Vital 
status 
evaluation 
 
X 
X 
X 
X 
X 
X 
X10 
Study 
consent 
X12 
 
 
 
 
 
 
 
Toxicity 
evaluation 
X 
X 
X 
X 
X 
X 
X11 
 
Fiducial 
placement (as 
clinically 
indicated) 
X 
Research 
cores during 
fiducial 
placement 
(optional) 
X 
Radiation 
therapy 
X 
X 
Lesion 
measure- 
ments 
X4 
X5 
X5 
X5 
X5 
X5 
X5 

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Peripheral 
blood 
biomarkers (if 
consented for 
this portion of 
study) 
X6 
X7 
X8 
X8 
X8 
X8 
X8 
X8 
Sim=simulation 
 
1 Within 4 weeks prior to enrollment  
2 +/- 2 weeks 
3 +/- 4 weeks 
4 After the last day of RT or up to 4 weeks following the completion of RT: For each radiation treated lesion, document 
diameter on sim CT, location and radiation dose.  
5 Document size of each radiation treated lesion. Also document RECIST response compared to radiation SIM CT. For 
follow-up time points starting with 108 weeks: if imaging studies were not performed, lesion measurements are not 
required. 
6 Blood drawn before first fraction of RT or any time up to 14 days before first fraction. 
7 Blood drawn after last fraction of RT or any time up to 14 days after last fraction. 
8 Optional 
9 Labs collected prior to study and prior to each cycle of immunotherapy at the discretion of the treating medical 
oncologist. 
10After disease progression/unacceptable toxicity, vital status will be recorded every 6-12 months by chart review and/or 
telephone calls. 
11Adverse events will be recorded until the 96-week follow-up visit. Starting with the 108-week follow-up visit, adverse 
events will not be recorded, and the history & physical exam, ECOG PS, and imaging studies will all be optional. 
12 Within 60 days prior to first dose of study radiation therapy 
 
10. 
MEASUREMENTS 
10.1 
Primary Outcome 
Title: Progression-free survival at 24 weeks (PFS24) 
Time frame: 24 weeks after study entry 
Safety issue: no 
 
10.1.1 Relevant Subset 
 
Patients who enroll on the interventional arm and receive radiation therapy on protocol will be 
analyzed. 
 
Patients who meet eligibility criteria but choose not to enroll on protocol treatment will be 
offered the option of participating in a registry arm. These patients will receive standard of 
care treatment and follow-up (including imaging), not dictated by the protocol. They will be 
followed for endpoints including radiographic progression, discontinuation of immunotherapy, 
and death. 
 
10.1.2 Measurement Definition 
 
Progression-free survival at 24 weeks (PFS24) is proportion of patients without RECIST 1.1 
disease progression or death 24 weeks from date of study entry. 

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10.1.3 Measurement Methods 
 
The baseline imaging study on the interventional arm will be the radiation simulation CT 
when possible. If not all known lesions are visible on the simulation CT, the most recent 
prior diagnostic CT or PET/CT can be used instead. Progression will be evaluated by follow 
up CT, PET/CT, and brain MRI imaging and clinic visits. Progression compared to 
simulation CT will be defined as per the RECIST 1.1 criteria. 
 
10.1.4 Measurement Time Points 
 
Patients on the interventional arm will undergo CT scans to cover all known sites of disease at 
8 week intervals (±2 weeks) for the first 24 weeks, and then at 12 week intervals (±4 weeks). 
PET-CT is an acceptable alternative. Patients with known brain metastases will have brain 
MRI or CT at 3-4 month intervals (up to 6 month intervals acceptable if last treatment for brain 
metastases is 1 year or more prior to the scan). After disease progression or unacceptable 
toxicity, imaging schedule will be at the discretion of the treating medical oncologist. 
 
10.1.5 Response Review 
 
There are no plans for response review by an independent third party. 
 
10.2 
Secondary outcome #1 
Title: Acute (0-6 months) and late (>6 months) grade 3-5 toxicity 
Time frame: 0-4 years after study entry 
Safety issue: yes 
 
10.2.1 Relevant Subset 
 
Patients who enroll on the interventional arm and receive radiation therapy on protocol will be 
analyzed. 
 
10.2.2 Measurement Definition 
 
Acute toxicity is defined as toxicity that occurs 0-6 months after first day of radiation therapy. 
Late toxicity is toxicity that occurs >6 months after first day of radiation therapy. Toxicity is 
measured with CTCAE v4. 
 
10.2.3 Measurement Methods 
 
Toxicity will be assessed at follow-up clinic visits. Also, patients will be followed 
for hospitalization and other medical events. 
 
10.2.4 Measurement Time Points 
 

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Follow-up clinic visits at 8 week intervals (±2 weeks) for the first 24 weeks, and then at 12 
week intervals (±4 weeks) until disease progression.  
 
If there is RECIST 1.1 disease progression or unacceptable toxicity, the patient will be 
considered to be off of protocol therapy and will not be required to be seen at protocol specified 
follow up time points. The patient will then be followed for survival outcomes collected during 
standard of care visits, with study data collection typically occurring every 6-12 months. If the 
patient is lost to follow-up and not seen at Stanford, phone calls will be performed to check for 
survival status annually. 
 
10.2.5 Response Review 
 
There are no plans for response review by an independent third party. 
 
10.3 
Secondary outcome #2 
Title: Overall survival 
Time frame: 0-4 years after study entry 
Safety issue: no 
 
10.3.1 Relevant Subset 
 
Patients who enroll on the interventional arm and receive radiation therapy on protocol will be 
included in this analysis. Patients who enroll on the registry arm will also be analyzed as a 
separate arm. 
 
10.3.2 Measurement 
Definition Time from study 
entry to death. 
10.3.3 Measurement Methods 
 
The electronic medical record will be monitored for patient deaths.  
 
10.3.4 Measurement Time Points 
 
There is no specific time point for this measurement. 
 
10.3.5 Response Review 
 
There are no plans for response review by an independent third party. 
 
10.4 
Secondary outcome #3 
Title: Correlation of circulating tumor DNA (ratio of post-RT to pre-RT level) with 

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radiographic response 
Time frame: 0 to approximately 1 year after study entry 
Safety issue: no 
 
10.4.1 Relevant Subset 
 
Patients who enroll on the interventional arm, receive radiation therapy on protocol, and 
have pre- and post-RT research blood draws will be included in this analysis. 
 
10.4.2 Measurement Definition 
 
• ctDNA measured as percentage of total circulating free DNA 
• Radiographic tumor assessments using RECIST 1.1 criteria, using radiation 
simulation CT as baseline scan. Best response after RT will be recorded. 
 
 
10.4.3 Measurement Methods 
 
ctDNA levels will be measured using CAncer Personalized Profiling by deep 
Sequencing (CAPP-Seq).  
 
10.4.4 Measurement Time Points 
 
• ctDNA specimens (also see section 8.1.1): The first specimen will be drawn on the 
first day of RT (before RT), or up to 14 days earlier. The second specimen will be 
drawn on the last day of RT (after RT), or up to 14 days later. 
• Radiographic response: Each post-RT restaging imaging study will be scored 
for RECIST 1.1 response, until best response is achieved. 
 
10.4.5 Response Review 
 
There are no plans for response review by an independent third party. 
 
10.5 
Secondary outcome #4 
Title: Correlation of immune markers in peripheral blood with radiographic response 
Time frame: 0 to approximately 1 year after study entry 
Safety issue: no 
 
10.5.1 Relevant Subset 
 
Patients who enroll on the interventional arm, receive radiation therapy on protocol, and have 
pre- and post-RT research blood draws will be included in this analysis. 
 
10.5.2 Measurement Definition 
 

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• Immune markers including frequency of myeloid-derived suppressor cells and 
antigen- specific CD8+ T cells 
• Radiographic tumor assessments using RECIST 1.1 criteria, using radiation 
simulation CT as baseline scan. Best response after RT will be recorded. 
 
Measurement Methods 
 
Immune markers will be measured using flow cytometry performed by the Human Immune 
Monitoring Core at Stanford. 
 
10.5.3 Measurement Time Points 
 
• Peripheral blood flow cytometry specimens (also see section 8.1.1): The first 
specimen will be drawn on the first day of RT (before RT), or up to 14 days earlier. 
The second specimen will be drawn on the last day of RT (after RT), or up to 14 
days after. 
• Radiographic response: Each post-RT restaging imaging study will be scored 
for RECIST 1.1 response, until best response is achieved. 
 
10.5.4 Response Review 
 
There are no plans for response review by an independent third party. 
 
10.6 
Secondary outcome #5 
Title: Dose-limiting toxicity (DLT) 
Time frame: 0-4 years after study entry 
Safety issue: yes 
 
10.6.1 Relevant Subset 
 
Patients who enroll on the interventional arm and receive at least one dose of radiation therapy 
on protocol will be analyzed. 
 
10.6.2 Measurement Definition 
 
Any grade 3-5 toxicity related to study radiation therapy, except the following: 
• 
grade 4 radiation dermatitis or mucositis that reduces to grade 2 or lower within 1 month 
after completion of study radiation therapy 
• 
grade 3 radiation dermatitis, mucositis, pain, dysphagia, diarrhea, fatigue, anorexia, 
weight loss, esophagitis, endocrine disorder 
 
10.6.3 Measurement Methods 
 
Toxicity will be assessed at follow-up clinic visits. Also, patients will be followed 
for hospitalization and other medical events. 
 

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10.6.4 Measurement Time Points 
 
Follow-up clinic visits at 8 week intervals (±2 weeks) for the first 24 weeks, and then at 12 
week intervals (±4 weeks) until disease progression or unacceptable toxicity.  
 
10.6.5 Response Review 
 
There are no plans for response review by an independent third party. 
 
 
11. 
REGULATORY CONSIDERATIONS 
11.1 
Institutional Review of Protocol 
The protocol, the proposed informed consent and all forms of participant information related 
to the study (e.g. advertisements used to recruit participants) will be reviewed and approved 
by the Stanford IRB and Stanford Cancer Institute Scientific Review Committee (SRC). Any 
changes made to the protocol will be submitted as a modification and will be approved by the 
IRB prior to implementation. The Protocol Director will disseminate the protocol amendment 
information to all participating investigators. 
 
11.2 
Data and Safety Monitoring Plan 
The Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) will be 
the monitoring entity for this study. The DSMC will audit study-related activities to 
determine whether the study has been conducted in accordance with the protocol, local 
standard operating procedures, FDA regulations, and Good Clinical Practice (GCP). 
This may include review of the following types of documents participating in the study: 
regulatory binders, case report forms, eligibility checklists, and source documents.  In 
addition, the DSMC will regularly review serious adverse events and protocol deviations 
associated with the research to ensure the protection of human subjects. Results of the 
DSMC audit will be communicated to the IRB and the appropriate regulatory authorities 
at the time of continuing review, or in an expedited fashion, as needed. 
While study accrual is ongoing, the study team will provide the DSMC with a yearly 
report that lists a summary of the frequency and severity of grade 3-5 adverse events 
observed so far. 
The DSMC will also review results of the single interim safety analysis (see section 
12.2), and based on this review will provide a determination of whether patient accrual 
should continue. 
 
11.3 
Data Management Plan 
The Protocol Director, or his/her designee, will prepare and maintain adequate and accurate 
participant case histories with observations and data pertinent to the study. Study specific 
Case Report Forms (CRFs) will document treatment outcomes for data analysis. Case report 
forms will be developed using REDCap database system and will be maintained by the 
Clinical Research Coordinator assigned to this study. 

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The study team will hold monthly meetings. Topics for discussion will include screening of 
candidates, eligibility, accrual progress, data entry completeness, adverse event grading and 
attribution, and serious adverse events. 
 
 
12. 
STATISTICAL CONSIDERATIONS 
12.1 
Primary and Secondary Endpoints 
Primary endpoint 
Determine if progression-free survival at 24 weeks (PFS24, measured from study 
entry) with this treatment combination is improved compared to historical controls 
who received immunotherapy without radiation therapy  
 
Secondary endpoints 
• Acute (0-6 months) and late (>6 months) grade 3-5 toxicity (CTCAE v4) 
• Overall survival 
• Correlation of circulating tumor DNA (ratio of post-RT to pre-RT level) 
with radiographic response 
• Correlation of immune markers in peripheral blood with radiographic response 
• Dose-limiting toxicity 
 
Exploratory endpoints 
• Progression-free survival with immune-related response criteria 
• Time to discontinuation of study immunotherapy agent 
• Patterns of response and progression, including abscopal responses 
 
12.2 
Analysis Plan 
 
12.2.1 Primary endpoint 
 
For the primary endpoint, the null hypothesis is that progression-free survival at 24 
weeks from study entry (PFS24) for the radiation-treated study population will be the 
same as a similar population treated with immunotherapy alone without addition of 
radiation therapy. Most patients in our study will be treated with immunotherapy as 2
nd 
or later line of therapy. PFS24 with 2nd line nivolumab in unselected NSCLC patients is 
30% for adenocarcinoma subtype and 40% for squamous cell subtype [Brahmer 2015, 
Borghaei 2015]. As almost all metastatic NSCLC patients treated at Stanford have 
adenocarcinoma, but we are excluding patients with the worst prognosis (those with 
rapid progression on immunotherapy), we assume a baseline PFS24 of 35%. Also, the 
current trial is enrolling a broader group of patients than those treated on the phase III 
nivolumab studies; for instance, we allow ECOG performance status of 0-2 as opposed 
to 0-1 on those studies. This would be expected to result in a lower PFS24. 
 
The alternate hypothesis is that the study patients’ PFS24 is improved over the 35% 

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historical control rate, at 52%. The exact binomial test will be used to test this 
hypothesis. PFS will be measured from the date of study entry. The alternate hypothesis 
PFS24 was initially set at 50% when the study was started, but was adjusted to 52% 
after several studies showed a greater than 15% improvement in PFS24 with the addition 
of radiotherapy to immunotherapy [Theelen, Welsh]. One phase 2 trial showed a PFS24 
of approximately 52% with immunotherapy plus radiotherapy, versus 35% with 
immunotherapy alone, exactly matching our revised values [Theelen, Fig. 2]. 
 
All patients who undergo protocol radiation therapy will be analyzed (“per-protocol” 
analysis). Patients who enroll on the study but do not receive any protocol treatment 
will be excluded from analysis. Since patients with a variety of responses to 
immunotherapy are allowed on study, we will perform an exploratory analysis testing 
whether pre-RT radiographic response to immunotherapy influences post-RT PFS. 
 
PFS24 and other survival endpoints will also be calculated for the registry arm patients. 
For both interventional arm and registry arm, start date for these endpoints will be date 
of study entry. The registry arm PFS24 will serve as an internal check on the historical 
controls’ PFS24 estimate, but there is no plan to formally compare the interventional 
arm and registry arm PFS24 due to lack of statistical power for this comparison. 
 
12.2.2 Secondary endpoints 
 
Interim safety analysis 
 
A patient on this study had fatal radiation pneumonitis that was likely related to study 
radiation therapy. Also, since study activation, several retrospective studies have 
shown higher than previously expected rates of radiation pneumonitis in patients 
treated with radiation therapy combined with anti-PD-1/anti-PD-L1 immunotherapy 
[Tian, Shaverdian]. This raised concern for a potentially high rate of radiation 
pneumonitis or other severe toxicities among patients in this study. After its August 
2020 annual review of the study, the DSMC requested to review aggregate toxicity 
data. 
 
It was decided in collaboration with the DSMC to immediately conduct a single 
interim safety analysis to help make a decision about whether to complete enrollment. 
At the time of this decision, 42 patients had enrolled and received protocol treatment. 
The procedures for the interim analysis of these 42 patients are described here. 
 
We define dose-limiting toxicities (DLT) in section 10.6. In general, DLT is defined as 
any grade 3-5 toxicity related to study radiation therapy, except for certain expected 
toxicities. We wished to exclude a rate of DLTs that is much higher than that seen in 
prior studies of high-dose hypofractionated lung radiation alone. Analyzable patients 
for the interim safety analysis will be eligible patients who enrolled in the treatment 
arm and received at least one dose of study radiation therapy. 
 
In the RTOG 0915 study of SBRT for peripheral lung cancers, the rate of protocol-

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specified AEs (generally, grade 3-5 AEs attributed to radiation) was 11.9% (10/84) 
[Videtic]. In the RTOG 0813 study of SBRT radiation for central lung cancers, the rate 
of dose-limiting toxicity was 5.6% (5/89); the rate of grade 3-5 toxicity was 22% 
(20/92) [Bezjak]. Note that in RTOG 0813 DLTs were only counted if they occurred in 
the first year after treatment, whereas the rate of grade 3-5 toxicity also includes AEs 
that occurred later. 
 
Based on these published rates of AEs with radiation alone (without concurrent 
immunotherapy as in the current study, which could raise the risk of AEs), we will 
consider an acceptable true rate of DLTs from the protocol radiotherapy to be 20% or 
less, while a DLT rate of >35% would be unacceptable. 
 
If observed DLT rate is 19.0% (8/42) or less, 95% confidence interval for DLT rate 
would be 10.0-33.3% or less, and we would recommend to the DSMC that study 
enrollment be continued. 
 
If observed DLT rate is 33.3% (14/42) or more, 95% confidence interval for DLT rate 
would be 21.0-48.4% or more, the true DLT rate is very likely to be >20% and we 
would recommend to the DSMC that study enrollment be stopped. 
 
If observed DLT rate is in between these values (9 to 13 out of 42), it is consistent with 
a range of true DLT rates that includes both safe and unsafe rates. In this case, we will 
ask the DSMC to make a decision about whether to continue or stop enrollment. 
 
Other secondary endpoints 
 
Adverse events will be tabulated by organ system and severity. Proportions of patients 
with adverse events will be estimated with 95% confidence intervals. 
 
Plasma biomarkers (e.g. cell free DNA level) will be summarized using medians and 
interquartile ranges; changes in biomarkers will be assessed using the Wilcoxon signed 
rank test. Correlation of biomarkers with radiographic response will be evaluated using 
a Wilcoxon rank sum test on patients with and without the event of interest. If feasible, 
these analyses will be supplemented by more formal analyses with the Cox model. 
 
 
12.3 
Sample Size Justification 
The null hypothesis is that PFS24 for the interventional arm population will be the 
same as a similar population treated with immunotherapy alone without addition of 
radiation therapy. A null hypothesis PFS24 of 35% is assumed (see section 12.2). The 
alternate hypothesis is that the study patients’ PFS24 is improved over historical 
controls, at 52%. The exact binomial test will be used to test this hypothesis. With one-
sided alpha of 0.1 and at least 80% power, 39 evaluable patients are required. 
Assuming 10% dropout/unevaluable patients, total enrollment will be at least 43 
patients. 

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12.4 
Patient Accrual 
[This section was not edited after the revised sample size was determined, but is left 
in place for historical documentation purposes.] 
We anticipate that this study will take 2.5 years to accrue with another 6 months 
required for follow up. We estimate that an additional 30 patients will enroll on the 
companion registry study. 
 
The yearly accrual estimate of 22 patients on the interventional arm is based on the 
monthly number of patients starting anti-PD-1/anti-PD-L1immunotherapy at Stanford 
Cancer Center (data from Stanford Cancer Institute Research Database). Around 75 
patients started these drugs over a 7 month period in 2016 (yearly rate of ~130 
patients). We estimate that 70% of patients starting these drugs have stage IV NSCLC. 
Assuming that 50% of those patients are eligible for this study, and 65% agree to go on 
the interventional arm, yearly accrual would be 30 patients, a comfortable margin 
above our required 22 patient yearly accrual. Of the 35% of patients who do not agree 
to enroll in the interventional arm, if 75% of these patients agree to enroll on the 
registry arm, then total registry arm enrollment will meet the target of 30. Assuming 
10% of these patients are lost to follow-up/unevaluable, 27 patients on the registry arm 
will be available for analysis. 
12.5 
Interim Analyses 
There will be a single interim analysis for safety after at least 42 patients have received 
protocol treatment; see section 12.2. 
 
 
 

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13. 
REFERENCES 
Bezjak A, Paulus R, Gaspar LE, et al. Safety and Efficacy of a Five-Fraction Stereotactic 
Body Radiotherapy Schedule for Centrally Located Non–Small-Cell Lung Cancer: NRG 
Oncology/RTOG 0813 Trial. Journal of Clinical Oncology. 2019;37(15):1316-1325. 
Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus Docetaxel in Advanced Squamous- 
Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015 Jul 9;373(2):123-35. 
Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced 
Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015 Sep 27. [Epub ahead of 
print]. 
Chang S,Kohrt H, Maecker H. Monitoring the Immune Competence of Cancer Patients to 
Predict Outcome. Cancer Immunol Immunother. 2014 Jul; 63(7): 713–719. 
Cox BW, Spratt DE, Lovelock M, Bilsky MH, Lis E, Ryu S, Sheehan J, Gerszten PC Chang 
E, Gibbs I, Soltys S, Sahgal A, Deasy J, Flickinger J, Quader M, Mindea S, Yamada Y. 
International Spine Radiosurgery Consortium consensus guidelines for target volume 
definition in spinal stereotactic radiosurgery. Int J Radiat Oncol Biol Phys. 2012 Aug 
1;83(5):e597-605. 
Das LC, Haraf D, Brisson R, et al. Evaluation of patients with progressive metastatic head and 
neck cancer treated with PD-1 inhibition with Pembrolizumab and radiation therapy: 
Assessment of local and systemic effects. European Cancer Congress 2015 (abstract). 
Gandhi SJ, Minn AJ, Vonderheide RH, et al. Awakening the immune system with radiation: 
Optimal dose and fractionation. Cancer Lett. 2015 Nov 28;368(2):185-90. 
Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung 
cancer. N Engl J Med. 2015 May 21;372(21):2018-28. 
Gomez D, Blumenschein G, Lee J, et al. Local consolidative therapy (LCT) to improve 
progression-free survival (PFS) in patients with oligometastatic non-small cell lung cancer 
(NSCLC) who receive induction systemic therapy (IST): Results of a multi-institutional phase 
II randomized study. 2016 ASCO Annual Meeting. 
Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without 
pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 
2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016 Nov;17(11):1497-1508. 
doi: 10.1016/S1470-2045(16)30498-3. 
Lee J, Park J, Gebski V, et al. Pembrolizumab for advanced NSCLC: patterns of response and 
progression. IASLC World Conference on Lung Cancer, 2015 (abstract). 
Lin D, Gupta S, Maecker H. Intracellular Cytokine Staining on PBMCs Using CyTOF Mass 
Cytometry. Bio-protocol 5(1): e1370, 2015. http://www.bio-protocol.org/e1370 
Milano MT, Katz AW, Zhang H, Okunieff P. Oligometastases treated with stereotactic body 
radiotherapy: long-term follow-up of prospective study. Int J Radiat Oncol Biol Phys. 2012 
Jul 1;83(3):878-86. 
Newman AM, Bratman SV, To J, et al. An ultrasensitive method for quantitating circulating 
tumor DNA with broad patient coverage. Nat Med. 2014 May; 20(5): 548–554. 

Radical RADiotherapy and Immunotherapy for metastatic CAncer of the Lung (RRADICAL) 
   
Protocol version 1.5         
Page 36 of 40 
Aug 4, 2021 
 
Owen D, Olivier KR, Mayo CS, Miller RC, Nelson K, Bauer H, Brown PD, Park SS, Ma 
DJ, Garces YI. Outcomes of stereotactic body radiotherapy (SBRT) treatment of multiple 
synchronous and recurrent lung nodules. Radiat Oncol. 2015 Feb 18;10:43. 
Papadopoulos K, Crittenden M, Johnson M, et al. A first in human study of REGN2810, a 
monoclonal, fully human antibody to programmed death-1 (PD1), in combination with 
immunomodulators including hypofractionated radiotherapy (hfRT). 2016 ASCO Annual 
Meeting. 
Park SS, Dong H, Liu X, Harrington SM, Krco CJ, Grams MP, Mansfield AS, Furutani KM, 
Olivier KR, Kwon ED. PD-1 Restrains Radiotherapy-Induced Abscopal Effect. Cancer 
Immunol Res. 2015 Jun;3(6):610-9. 
Pollom EL, Alagappan M, von Eyben R, Kunz PL, Fisher GA, Ford JA, Poultsides GA, Visser 
BC, Norton JA, Kamaya A, Cox VL, Columbo LA, Koong AC, Chang DT. Single- versus 
multifraction stereotactic body radiation therapy for pancreatic adenocarcinoma: outcomes and 
toxicity. Int J Radiat Oncol Biol Phys. 2014 Nov 15;90(4):918-25. 
Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, Gottfried M, Peled N, 
Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, 
Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus 
Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016 Oct 8. 
[Epub ahead of print]. 
Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in patients with 
previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre 
randomised controlled trial. Lancet. 2017 Jan 21;389(10066):255-265. 
Rusthoven KE, Kavanagh BD, Cardenes H, Stieber VW, Burri SH, Feigenberg SJ, Chidel 
MA, Pugh TJ, Franklin W, Kane M, Gaspar LE, Schefter TE. Multi-institutional phase I/II 
trial of stereotactic body radiation therapy for liver metastases. J Clin Oncol. 2009 Apr 
1;27(10):1572-8. 
Salama JK, Hasselle MD, Chmura SJ, Malik R, Mehta N, Yenice KM, Villaflor VM, Stadler 
WM, Hoffman PC, Cohen EE, Connell PP, Haraf DJ, Vokes EE, Hellman S, Weichselbaum 
RR. Stereotactic body radiotherapy for multisite extracranial oligometastases: final report of a 
dose escalation trial in patients with 1 to 5 sites of metastatic disease. Cancer. 2012 Jun 
1;118(11):2962-70. 
Segal N, Kemeny N, Cercek A, et al. Nonrandomized phase II study to assess the efficacy of 
pembrolizumab (Pem) plus radiotherapy (RT) or ablation in mismatch repair proficient 
(pMMR) metastatic colorectal cancer (mCRC) patients. 2016 ASCO Annual Meeting. 
Sharabi AB, Nirschl CJ, Kochel CM, Nirschl TR, Francica BJ, Velarde E, Deweese TL, 
Drake CG. Stereotactic Radiation Therapy Augments Antigen-Specific PD-1-Mediated 
Antitumor Immune Responses via Cross-Presentation of Tumor Antigen. Cancer Immunol 
Res. 2015 Apr;3(4):345-55. 
Shaverdian N, Beattie J, Thor M, et al. Safety of thoracic radiotherapy in patients with prior 
immune-related adverse events from immune checkpoint inhibitors. Annals of Oncology. 
Published online September 2020. doi:10.1016/j.annonc.2020.09.016 

Radical RADiotherapy and Immunotherapy for metastatic CAncer of the Lung (RRADICAL) 
   
Protocol version 1.5         
Page 37 of 40 
Aug 4, 2021 
 
Siddiqui F, Patel M, Khan M, McLean S, Dragovic J, Jin JY, Movsas B, Ryu S. Stereotactic 
body radiation therapy for primary, recurrent, and metastatic tumors in the head-and-neck 
region. Int J Radiat Oncol Biol Phys. 2009 Jul 15;74(4):1047-53. 
Theelen W et al. Effect of Pembrolizumab After Stereotactic Body Radiotherapy vs 
Pembrolizumab Alone on Tumor Response in Patients With Advanced Non-Small Cell Lung 
Cancer: Results of the PEMBRO-RT Phase 2 Randomized Clinical Trial. JAMA Oncol. 2019 
Sep 1;5(9):1276-1282. 
Tian S, Switchenko JM, Buchwald ZS, et al. Lung Stereotactic Body Radiation Therapy and 
Concurrent Immunotherapy: A Multicenter Safety and Toxicity Analysis. International Journal 
of Radiation Oncology*Biology*Physics. 2020;108(1):304-313. 
doi:10.1016/j.ijrobp.2019.12.030  
Twyman-Saint Victor C, Rech AJ, Maity A, et al. Radiation and dual checkpoint blockade 
activate non-redundant immune mechanisms in cancer. Nature. 2015 Apr 16;520(7547):373-7. 
Vanpouille-Box C, Alard A, Aryankalayil MJ, et al. DNA exonuclease Trex1 
regulates radiotherapy-induced tumour immunogenicity. Nat Commun. 2017 Jun 
9;8:15618. Yamamoto M, Serizawa T, Shuto T, Akabane A, Higuchi Y, et al. 
Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a 
multi-institutional prospective observational study. Lancet Oncol. 2014 
Apr;15(4):387-95. doi: 10.1016/S1470-2045(14)70061- 0. 
Videtic GMM, Hu C, Singh AK, et al. A Randomized Phase 2 Study Comparing 2 
Stereotactic Body Radiation Therapy Schedules for Medically Inoperable Patients 
With Stage I Peripheral Non-Small Cell Lung Cancer: NRG Oncology RTOG 0915 
(NCCTG N0927). International Journal of Radiation Oncology*Biology*Physics. 
2015;93(4):757-764. 
Welsh J et al. Pembrolizumab with or without radiation therapy for metastatic non-
small cell lung cancer: a randomized phase I/II trial. J Immunother Cancer 2020 
Oct;8(2):e001001. 
 
 
 
 

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APPENDICES 
APPENDIX A: Participant Eligibility Checklist 
 
 
Protocol Title: 
Radical RADiotherapy and Immunotherapy for metastatic 
CAncer of the Lung (RRADICAL) 
Protocol Number: 
 IRB 40088 
Principal Investigator: 
Michael Gensheimer, MD 
 
II. Subject Information: 
 
 
III. Study Information: 
 
SRC Approved 
 IRB Approved 
 Contract signed  
 
 
IV. Inclusion/Exclusion Criteria 
Inclusion Criteria 
(From IRB approved protocol) 
Yes 
No 
Window 
Last day 
to 
Register  
Supporting 
Documentation* 
1. Has stage IV non-small cell lung cancer, or 
initially stage I-III disease with distant 
metastatic recurrence 
 
 
 
 
      
2. Age ≥ 18 
 
 
 
 
      
3. Has been receiving anti-PD-1 or anti-PD-L1 
immunotherapy for at least four weeks (refer 
to section 4.2.1) 
 
 
 
 
      
4. Has had restaging imaging after initiation of 
immunotherapy, at least 4 weeks after pre-
immunotherapy baseline imaging. CT or 
PET/CT of at least chest/upper abdomen 
must be performed within 4 weeks prior to 
registration. For patients with history of brain 
metastases, brain MRI or CT is required 
within 4 weeks of registration; for other 
patients brain MRI or CT is required within 
12 weeks of registration. Diagnostic PET/CT 
performed as part of radiation simulation can 
be used as the restaging imaging. 
 
 
 
 
      
5. Most recent imaging shows measurable 
disease as defined by RECIST 1.1 
 
 
 
 
      
6. Evaluation by a Stanford medical oncologist 
must show: 
a. 
The patient is expected to 
continue on immunotherapy for 
at least three more months 
b. Imaging must show response, 
stable disease, or modest 
progression 
 
 
                
    
 
              
   
    
 
 
 
 
    
 
 
 
    
 
 
 
 
 
 
 
      
 
 
 
Subject Name/ID: 
Gender: 
Male 
Female 

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APPENDIX B: Protocol Pre-review Checklist 
 
The protocols will be pre-reviewed prior to the assignment of an SRC meeting date in 
order to ensure that protocols contain all the required elements and information in the 
appropriate format.  This Checklist is intended to be helpful in the protocol writing 
process. 
Appendix B is not part of the protocol.  Please delete it after completing the protocol. 
 
Protocol Pre-review Checklist 
 
No 
Description 
Yes 
No 
1 
Protocol is in the appropriate template for either Interventional or 
Non-interventional study 
2 
Title page includes names and addresses of Principal Investigator, 
Co-investigators, Biostatistician and Coordinator as appropriate 
3 
Sponsor information is included if appropriate 
4 
Title page includes protocol version and date 
5 
Protocol document has page numbers 
6 
Schema is legible 
7 
List of Abbreviations is relevant to this protocol 
8 
Table of contents is complete 
9 
Instructions in the template are deleted 
10 
Section titles are appropriately designated and numbered 
11 
All the sections in the template are complete 
12 
Study calendar is complete 
13 
Protocol contains adequate background/rationale information 
14 
Objectives and measurements of outcome are clearly stated 
15 
The sections on objectives, eligibility, outcome measurements, 
statistics and study calendar are consistent 
16 
Monitoring plan refers to Stanford DSMC 
17 
Statistical section is appropriate for this study 
18 
Appropriate references are included 
19 
Protocol includes eligibility checklist 
20 
Protocol includes questionnaires as needed 
21 
Protocol includes CRF statement 
22 
Protocol document is well organized 
 
Note: Some of the requirements are applicable to only Interventional studies as 
specified in the template.