Maintenance Systemic Therapy Versus Local Consolidative Therapy (LCT) Plus Maintenance Systemic Therapy for Limited Metastatic Non-Small Cell Lung Cancer (NSCLC): A Randomized Phase II/III Trial
Phase: PHASE2
Conditions: Recurrent Non-Small Cell Lung Carcinoma, Stage IV Non-Small Cell Lung Cancer
Sponsor: NRG Oncology

NRG ONCOLOGY 
 
NRG-LU002 
 
(ClinicalTrials.gov NCT #03137771)  
 
 
MAINTENANCE SYSTEMIC THERAPY VERSUS LOCAL CONSOLIDATIVE 
THERAPY (LCT) PLUS MAINTENANCE SYSTEMIC THERAPY FOR LIMITED 
METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC): A RANDOMIZED 
PHASE II/III TRIAL 
 
 
Amendment 11: October 18, 2023 

NRG-LU002                                                 1                  Version Date:   October 18, 2023 
 
NRG ONCOLOGY 
NRG-LU002 
(ClinicalTrials.gov NCT #03137771) (18-MAY-2018) 
 
MAINTENANCE SYSTEMIC THERAPY VERSUS LOCAL CONSOLIDATIVE 
THERAPY (LCT) PLUS MAINTENANCE SYSTEMIC THERAPY FOR LIMITED 
METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC): A RANDOMIZED 
PHASE II/III TRIAL (18-MAY-2018) 
 
This trial is part of the National Clinical Trials Network (NCTN) program, which is sponsored 
by the National Cancer Institute (NCI). The trial will be led by NRG Oncology with the 
participation of the network of NCTN organizations: the Alliance for Clinical Trials in 
Oncology; ECOG-ACRIN Medical Group; and SWOG.  
 
 
Coordinating Center:  
NRG Oncology 
Four Penn Center 
1600 JFK Blvd, Suite 1020 
Philadelphia, PA 19103 
 
Study Team (22-FEB-2023) 
 
Principal Investigator/Radiation Oncology 
Puneeth Iyengar, MD, PhD 
UT Southwestern Medical Center 
5323 Harry Hines Blvd 
Dallas, TX, 75235 
214-645-7603/Fax: 214-645-8526 
puneeth.iyengar@utsouthwestern.edu 
 
Co-Investigator/Radiation Oncology (SWOG) 
Daniel Gomez, MD 
Memorial Sloan Kettering Cancer Center 
1275 York Ave. 
New York, NY 10021 
212-639-2485 
gomezd@mskcc.org 
 
 
 
Radiation Oncology Co-Chair 
Robert Timmerman, MD 
UT Southwestern Medical Center 
5801 Forest Park Road 
Dallas, TX  75390-9183 
214-645-7651/Fax: 214-645-7624 
Robert.Timmerman@UTSouthwestern.edu 
 
 
 
 
 
 
 

NRG-LU002                                                 2                  Version Date:   October 18, 2023 
NRG ONCOLOGY 
NRG-LU002 
 
MAINTENANCE SYSTEMIC THERAPY VERSUS LOCAL CONSOLIDATIVE 
THERAPY (LCT) PLUS MAINTENANCE SYSTEMIC THERAPY FOR LIMITED 
METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC): A RANDOMIZED 
PHASE II/III TRIAL 
 
Study Team (Continued)   
Radiation Oncology Co-Chair 
Charles Simone, MD 
New York Photon Center 
225 East 126 Street 
New York, MD 10035 US 
646-968-9012 
csimone@nyproton.com 
Radiation Oncology Co-Chair 
Clifford Robinson, MD 
Washington University School of Medicine  
4921 Parkview Place, Floor LL 
Campus Box 8224 
St. Louis, MO 63110 
crobinson@radonc.wustl.edu 
 
Medical Oncology Co-Chair 
David Gerber, MD 
UT Southwestern Medical Center 
5323 Harry Hines Blvd., Mail Code 8852 
Dallas, TX  75390-8852 
214-648-4180/Fax:  214-648-1955 
david.gerber@utsouthwestern.edu 
 
Medical Oncology Co-Chair 
Saiama N. Waqar, MBBS, MSCI 
Washington University School of Medicine 
660 S Euclid Ave, Campus Box 8056 
Saint Louis, MO 63110 
314-747-8475/Fax:  314-362-7086 
saiamawaqar@wustl.edu 
 
Surgical Co-Chair 
Jessica S. Donington, MD MSCR 
The University of Chicago Medicine 
5841 South Maryland Avenue 
Mc5040 
Chicago, IL 60637 US 
773-702-0819 
jdonington@uchicago.edu 
 
Surgical Co-Chair 
Stephen G. Swisher, MD 
M D Anderson Cancer Center 
1400 Pressler, Unit 1447 
Houston, Texas 77030-4009 
713-792-8659/Fax:  713-563-1918 
sswisher@mdanderson.org 
 
Medical Physics Co-Chair 
Michael Weldon, MSc, DABR 
Department of Radiation Oncology 
The Ohio State University 
460 W. 10th Ave. Room A201 
Columbus, OH 43210 
614-293-2077/Fax: 614-685-5219 
michael.weldon@osumc.edu 
 
Medical Physics Co-Chair 
Jackie Wu, PhD 
Duke University Radiation Oncology 
201 Trent Dr., Box 3295 
Durham, NC 27710 
919-681-1841/Fax:  919-681-7183 
jackie.wu@duke.edu 
 
 
 
 
NRG ONCOLOGY 

NRG-LU002                                                 3                  Version Date:   October 18, 2023 
NRG-LU002 
 
MAINTENANCE SYSTEMIC THERAPY VERSUS LOCAL CONSOLIDATIVE 
THERAPY (LCT) PLUS MAINTENANCE SYSTEMIC THERAPY FOR LIMITED 
METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC): A RANDOMIZED 
PHASE II/III TRIAL 
 
Study Team (Continued) 
  
 
Quality of Life Co-Chair 
Ben Movsas, MD 
Henry Ford Health System 
2799 West Grand Blvd 
Detroit MI 48202 
313-916-5188/Fax 313-916-3264 
bmovsas1@hfhs.org 
 
Pathology Co-Chair 
Jeffry P. Simko, MD, PhD 
University of California, San Francisco 
Dept. of Pathology 
Box 4066, 1825 4th St., Room M2360 
San Francisco, CA 94143 
415-353-7581/Fax:  415-353-1612 
jeff.simko@ucsf.edu 
 
 
Translational Co-Chair 
Maximilian Diehn, MD, PhD 
Stanford University  
Lorry Lokey Stem Cell Research Bldg 
Rm G2120A, 265 Campus Dr. 
Stanford, CA 94305-5458 
650-721-1550/Fax:  650-725-8231 
diehn@stanford.edu 
Translational Co-Chair 
Adam P. Dicker, MD, PhD 
Jefferson University 
Bodine Center, Ste. G-301 
111 South 11th St. 
Philadelphia, PA 19107 
215-955-6702/Fax:  215-955-0412 
Adam.Dicker@jefferson.edu 
 
 
NCORP Community Chair 
Bryan Faller, MD 
Heartland NCORP 
Missouri Baptist Medical Center 
3015 N. Ballas Rd. 
Saint Louis, MO 63105 
314-996-5514 
Bryan.faller@bjc.org 
 
Senior Statistician 
Chen Hu, PhD 
NRG Oncology Statistical and Data 
Management Center & John Hopkins 
University School of Medicine 
50 South 16th Street, Suite 2800 
Philadelphia, PA  19102 
215-940-4842/Fax: 215-928-0153 
HuC@NRGOncology.org 

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The following NCTN Group Study Champions have been added to this trial:  
  
 
The Alliance for Clinical Trials Oncology 
Pranshu Mohindra, MD 
University of Maryland School of Medicine, 
Baltimore  
22 S. Green St., Rm GGJ35 
Baltimore, MD 21201 
410-328-6080/Fax:  410-328-5279 
PMohindra@som.umaryland.edu 
 
 
SWOG 
Daniel Gomez, MD 
Division of Radiation Oncology 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, NY 10021  
212-639-2485 
gomezd@mskcc.org 
 
Sukhmani Kaur Padda, MD 
Cedars Sinai Medical Center 
Department of Hematology/Oncology 
8700 Beverly Blvd., SCCT 1S31 
Los Angeles, CA 90036  
310-423-0377 
sukhmani.padda@cshs.org 
 
 
ECOG-ACRIN 
Devika Das, MD 
700 South 19th Street 
Research Services 151 
Birmingham, AL 35233 
205-933-8101 
Devika.Das@va.gov 
 
 
 
 
 
 
NRG Oncology Contact Information(18-OCT-2023) 
 
Data Manager:   
For questions concerning eligibility or data 
submission 
Leila Williams 
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA  19102 
215-717-3211 
Williamsl@NRGOncology.org  

NRG-LU002                                                 5                  Version Date:   October 18, 2023 
 
Tammy Bausinger 
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA  19102 
215-574-3223 
BausingerT@NRGOncology.org 
 
 
RTQA Dosimetrist:  
For questions concerning RT data submission 
Jennifer Presley, B.S., R.T., (R)(M)(T), ARRT 
IROC Philadelphia – RT QA Center 
ACR Center for Innovation and Research 
50 South 16th Street, Suite 2800 
Philadelphia, PA  19102 
215-574-3153 
jpresley@acr.org 
 
RTQA:   
For questions concerning data submission to 
TRIAD 
Triad-Support@acr.org 
 
 
 
 
Protocol Development: 
For questions concerning protocol and 
informed consent versions & amendments  
Jennifer Petrask 
NRG Oncology  
50 South 16th Street, Suite 2800 
Philadelphia, PA  19102 
215-717-3909 
PetraskJ@ NRGOncology.org 
 
 
Lung Cancer Committee Chair: 
Jeffrey D. Bradley, MD  
University of Pennsylvania/Abramson Cancer 
Center Philadelphia, PA 19104 
215-662-4853 
Jeffrey.bradley@pennmedicine.upenn.edu 

NRG-LU002                                                 6                  Version Date:   October 18, 2023 
 
Protocol Agent (30-MAR-2021) 
Agent 
Supply 
NSC # 
IND # 
Pemetrexed 
Commercial 
698037 
Exempt 
Gemcitabine 
Commercial 
613327 
Exempt 
Pembrolizumab 
Commercial 
776864 
Exempt 
Atezolizumab 
Commercial 
783608 
Exempt 
Nivolumab 
Commercial 
748726 
Exempt 
Ipilimumab 
Commercial 
732442 
Exempt 
 
 
 
Participating Sites:  
 U.S. 
 Canada 
 Approved International Member Sites 
 
 
Document History 
 
Version Date 
Broadcast Date 
Amendment 11 
October 18, 2023 
N/A 
Amendment 10 
August 18, 2023 
N/A 
Amendment 9 
February 22, 2023 
N/A 
Amendment 8 
October 25, 2021 
N/A 
Amendment 7 
July 19, 2021 
N/A 
Amendment 6 
May 26, 2021 
N/A 
Amendment 5 
March 30, 2021 
N/A 
Amendment 4 
March 02, 2020 
N/A 
Amendment 3 
November 22, 2019 
N/A 
Amendment 2 
June 22, 2018 
N/A 
Amendment 1 
May 18, 2018 
N/A 
Activation 
March 17, 2017 
April 7, 2017 
 
 
 
 
  
 
 
This protocol was designed and developed by NRG Oncology. It is intended to be 
used only in conjunction with institution-specific IRB approval for study entry.  No 
other use or reproduction is authorized by NRG Oncology nor does NRG Oncology 
assume any responsibility for unauthorized use of this protocol. 

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NRG ONCOLOGY 
NRG-LU002 
 
CONTACT INFORMATION (18-AUG-2023) 
 
For regulatory 
requirements: 
For patient enrollments: 
For data submission: 
Regulatory documentation 
must be submitted to the 
Cancer Trials Support Unit 
(CTSU) via the Regulatory 
Submission Portal. 
 (Sign in at 
https://www.ctsu.org, and 
select the Regulatory > 
Regulatory Submission.)  
 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately by phone or 
email: 1-866-651-CTSU 
(2878), or 
CTSURegHelp@coccg.org 
to receive further instruction 
and support. 
 
Contact the CTSU 
Regulatory Help Desk at 1-
866-651-CTSU (2878), or 
CTSURegHelp@coccg.org 
for regulatory assistance. 
Refer to the patient enrollment 
section of the protocol for 
instructions on using the 
Oncology Patient Enrollment 
Network (OPEN). OPEN is 
accessed at 
https://www.ctsu.org/OPEN_S
YSTEM/ or 
https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN-related 
questions by phone or email:  
1-888-823-5923, or 
ctsucontact@westat.com. 
 
 
Data collection for this study 
will be done exclusively 
through Medidata Rave.  
Refer to the data submission 
section of the protocol for 
further instructions.  
 
 
The most current version of the study protocol and all supporting documents must be 
downloaded from the protocol-specific page located on the CTSU members’ website 
(https://www.ctsu.org).  Permission to view and download this protocol and its supporting 
documents is restricted and is based on person and site roster assignment housed in the Roster 
Maintenance application and in most cases viewable and manageable via the Roster Update 
Management System (RUMS) on the CTSU members’ website.   
For clinical questions (i.e. patient eligibility or treatment-related) Contact the study data 
manager listed on the NRG Oncology contact information table on the protocol cover page. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative.  

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For imaging data submission questions: 
IROCimagearchive@acr.org; please include trial number in the email subject line. 
 
For TRIAD access and installation support: 
TRIAD-Support@acr.org 
Triadhelp.acr.org 
 
TRIAD Software Installation: 
https://triadinstall.acr.org/triadclient/ 
 

NRG-LU002                                                 9                  Version Date:   October 18, 2023 
TABLE OF CONTENTS 
SCHEMA  ..........................................................................................................................12 
1.0 OBJECTIVES ............................................................................................................14 
1.1      Primary Objectives .................................................................................................14 
1.2       Secondary Objectives.............................................................................................14 
2.0 BACKGROUND ........................................................................................................14 
2.1  
Rationale for Selected Approach and Trial Design  ..............................................14 
2.2  
Significance of the Study  ......................................................................................20 
2.3 
Rationale for Use of Maintenance Systemic Therapy for Metastatic Non-
Small Cell Lung Cancer  ........................................................................................22 
2.4 
Rationale for Use of Stereotactic Body Radiation Therapy (SBRT) for 
Limited Metastatic Non-Small Cell Lung Cancer .................................................23 
2.5       Rationale for Surgery for Limited Metastatic Non-Small Cell Lung Cancer ........27 
2.6      Translational Research ............................................................................................29 
3. 
     PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILITY CRITERIA ...29 
3.1 
Patient Selection Guidelines  .................................................................................29 
3.2 
Eligibility Criteria  .................................................................................................29 
3.3 
Ineligibility Criteria ...............................................................................................31 
4.  REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP .....33 
ASSESSMENTS DURING TREATMENT ......................................................................34 
5. TREATMENT PLAN/REGIMEN DESCRIPTION......................................................37 
5.1 
Systemic Therapy ...................................................................................................37 
5.2      Local Consolidative therapy (LCT): .......................................................................39 
5.3 
Surgery ...................................................................................................................39 
5.4 
Radiation Therapy in the Form of Stereotactic Body Radiation Therapy or 
Hypofractionation ..................................................................................................41 
5.5 
General Concomitant Medication and Supportive Care Guidelines ......................69 
5.6 
Duration of Therapy ...............................................................................................70 
6. TREATMENT MODIFICATIONS/MANAGEMENT .................................................70 
6.1      Systemic Therapy Dose Modifications ...................................................................70 
6.2      Management of Toxicity Related to Systemic Therapy .........................................71 
7. 
      ADVERSE EVENTS REPORTING REQUIREMENTS ..................................110 
7.1       Protocol Agents ....................................................................................................110 
7.2       Adverse Events and Serious Adverse Events ......................................................110 
7.3       Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
MK-3475 ..............................................................................................................112 
7.4       Comprehensive Adverse Events and Potential Risks (CAEPR) List for 
Atezolizumab .......................................................................................................117 

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7.5   Comprehensive Adverse Events and Potential Risks list (CAEPR) for Nivolumab122 
7.6       Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Ipilimumab ...........................................................................................................128 
7.7 
Adverse Events for Commercial Study Agents ...................................................134 
7.8 
Expedited Reporting of Adverse Events ..............................................................134 
8.   REGISTRATION, STUDY ENTRY, AND WITHDRAWAL PROCEDURES ......137 
8.1       Cancer Trials Support Unit Registration Procedures ...........................................138 
8.2 
RT-Specific Pre-Registration Requirements ........................................................142 
8.3       Patient Enrollment ...............................................................................................144 
9.0       DRUG INFORMATION ....................................................................................145 
9.1 
Commercial Agent:  Pemetrexed .........................................................................145 
9.2 
Commercial Agent:  Gemcitabine .......................................................................146 
9.3 
Commercial Agent:  Pembrolizumab ...................................................................146 
9.4 
Commercial Agent:  Atezolizumab .....................................................................146 
9.5 
Commercial Agent:  Nivolumab ..........................................................................146 
9.6 
Commercial Agent:  Ipilimumab .........................................................................147 
10.       PATHOLOGY/BIOSPECIMEN .........................................................................147 
10.1 
Biospecimen Submission Tables .........................................................................147 
10.2     Tissue Selection for Exploratory Marker Testing ................................................147 
11      SPECIAL STUDIES (NON-TISSUE) ...................................................................150 
11.1   Patient-Reported Outcomes (PROs) and Health-Related Quality of Life .............150 
11.2   Background  ...........................................................................................................150 
11.3   FACT-TOI .............................................................................................................151 
11.4   QUALITY-ADJUSTED SURVIVAL, EUROQOL (EQ-5D-5L) .........................151 
11.5   CANCER PATIENT TOBACCO USE QUESTIONNAIRE (C-TUQ) ................152 
12.     MODALITY REVIEWS .......................................................................................152 
12.1   Radiation Therapy Quality Assurance Reviews ....................................................152 
12.2    Medical Oncology Modality Quality Assurance Reviews ....................................153 
12.3 
Surgical Quality Assurance Reviews ...................................................................153 
13.      ASSESSMENT OF EFFECT ...............................................................................153 
14.      DATA QUALITY PORTAL ................................................................................154 
14.1     Data Management/Collection  .............................................................................154 
14.2     Summary of Data Submission .............................................................................155 
14.3     Global Reporting/Monitoring ..............................................................................155 
15.       STATISTICAL CONSIDERATIONS.................................................................156 
15.1 
Study Design  .......................................................................................................156 
15.2 
Study Endpoints ...................................................................................................156 
15.3 
Primary Objective and Study Design ...................................................................156 
15.4 
Study Monitoring of Primary Objectives .............................................................160 
15.5 
Accrual/Study Duration Considerations  .............................................................161 

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15.6 
Secondary Endpoints and Statistical Analysis Plans ...........................................161 
15.7 
Gender/Ethnicity/Race Distribution .....................................................................164 
REFERENCES ................................................................................................................165 
 

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NRG-LU002 
SCHEMA (30-MAR-2021) 
 
 
*    Patients must be registered after 4 courses of first-line/induction systemic therapy but before 
the administration of course 6. 
 
**   Acceptable systemic therapy for NRG-LU002 is listed in Sections 5 and 9. 
 
*** Randomization will be 2:1 between Arm 2 and 1. 
 
Systemic Therapy (see Section 5 for a list of treatment options):  
(Arm 1): Maintenance systemic therapy should begin/continue within 2 weeks of randomization.   
(Arm 2):  Radiation should begin within 2 weeks of randomization and maintenance systemic 
therapy should begin/continue within 2 weeks of the completion of radiation.  Maintenance 
systemic therapy must begin/continue within 3 weeks after completion of surgery if last local 
therapy modality. 
 
Radiotherapy and Surgery for Local Therapy:   
Investigators are strongly encouraged to directly contact the study PI and/or radiation 
oncology/surgery co-chairs about any questions concerning eligibility or concerns regarding 
 
Patients with metastatic 
NSCLC having completed 
at least 4 cycles or courses* 
of first-line/induction 
systemic therapy  
 
 
Restaging studies reveal no 
evidence of progression and 
limited metastatic disease 
(0-3 discrete extracranial 
sites), all of which must be 
amenable to SBRT/ 
radiation +/- Surgery 
 
 
A minimum of one disease 
site (metastasis or primary) 
needs to be present after 
first-line/induction systemic 
therapy and treatable with 
local consolidative  therapy 
 
 
 
 
 
 
 
 
 
 
S 
T 
R 
A 
T 
I 
F 
Y 
 
 
 
Histology:  
 
 
Squamous vs.  
Non-squamous 
 
Systemic Therapy: 
Immunotherapy-
containing 
Induction Regimens 
vs. Cytotoxic 
Chemotherapy- 
Only Induction 
Regimens** 
 
 
 
 
 
 
 
 
 
R 
A 
N 
D 
O 
M 
I 
Z 
E 
 
Arm 1: 
Maintenance systemic therapy 
alone** 
 
Arm 2: 
SBRT/radiation or SBRT/ 
radiation and Surgery to all sites 
of metastases (0-3 discrete 
sites) and/or irradiation (SBRT 
or hypofractionated RT) of the 
primary site followed by 
maintenance systemic therapy.  
All Arm 2 patients, even if 
treated with Surgery, must have 
one site of disease (metastasis 
or primary) treated with 
radiation*** 
 
If a metastatic site is best 
treated with hypofractionated 
radiation, this will be permitted 
if SBRT or surgery not 
indicated 
 
*** As noted in Section 5 
 

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radiation delivery (i.e., SBRT in the setting of concurrent SBRT/hypofractionated RT to the 
primary, SBRT in the setting of prior RT to the primary, SBRT to multiple sites, etc.) or surgical 
approaches ( i.e., resection after thoracic radiation, extent of resections, resection techniques for 
metastatic sites, timing of resections and delivery of SBRT).   

NRG-LU002                                                 14                  Version Date:   October 18, 2023 
1.0 OBJECTIVES 
1.1      Primary Objectives (18-MAY-2018) 
1.1.1   Phase II: 
To evaluate the impact of adding LCT (local consolidative therapy) to maintenance 
systemic therapy versus maintenance systemic therapy alone on progression-free survival 
for patients with metastatic NSCLC with no evidence of progression and limited 
metastatic sites after first-line systemic therapy 
 1.1.2   Phase III: 
To evaluate the impact of adding LCT to maintenance systemic therapy versus 
maintenance systemic therapy alone on overall survival for patients with metastatic 
NSCLC with no evidence of progression and limited metastatic sites after first-line 
systemic therapy 
1.2       Secondary Objectives (18-MAY-2018) 
1.2.1    To evaluate the impact of adding LCT to maintenance systemic therapy versus 
maintenance systemic therapy alone on in-field local failure; 
1.2.2 To evaluate the impact of adding LCT to maintenance systemic therapy versus 
maintenance systemic therapy alone on the time to development of new lesions; 
1.2.3    To evaluate the impact of adding LCT to maintenance systemic therapy versus 
maintenance systemic therapy alone on toxicity; 
1.2.4    To evaluate the impact of adding LCT to maintenance systemic therapy versus 
maintenance systemic therapy alone on duration of maintenance systemic therapy usage. 
1.2.5 To evaluate the effect of adding LCT to systemic therapy in limited stage IV NSCLC on 
Quality of Life (QOL) 
1.2.6 To collect biospecimens and evaluate the correlation between clinical outcomes and 
circulating tumor DNA (ctDNA) 
 
2.0 BACKGROUND  
2.1  
Rationale for Selected Approach and Trial Design (30-MAR-2021) 
Approximately 50-60% of all non-small cell lung cancer (NSCLC) patients present with 
stage IV disease (National Cancer Institute SEER Cancer Statistics Review 2019). 
Likewise, a significant proportion of stage I-III NSCLC patients eventually develops 
metastases after their initial definitive therapy. Traditionally, systemic therapy has been 
the treatment of choice for these patients. First-line cytotoxic chemotherapy provides a 
partial response or stable disease in more than two-thirds of patients with metastatic 
NSCLC (Brodowicz 2006, Ramalingam 2008). Maintenance systemic therapy also 
improves outcomes in patients with metastatic non-small cell lung cancer. Subsets of 
maintenance systemic therapy patients have significant OS outcomes tied to progression-
free survival (PFS) improvements, suggesting that better local control may help improve 
PFS and subsequently OS.  In reviewing a consecutive series of stage IV NSCLC patients 
treated with systemic therapy alone, the majority failed at original sites of gross disease 
(Rusthoven 2009).   
 
 

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The landscape of systemic therapy options for patients whose tumors do not harbor a 
targetable molecular alteration (eg, EGFR, ALK) has evolved from platinum based 
chemotherapy to immunotherapy plus or minus platinum-based chemotherapy for 
immunotherapy-eligible patients. Chemotherapy with a platinum doublet continues to be 
the standard of care for individuals who are not candidates for immunotherapy in the first 
line setting. As of October 2020, National Comprehensive Cancer Network (NCCN)-
recommended regimens include the following: 
 
If tumor PD-L1 expression ≥50%: 
• Atezolizumab (anti-PDL1) monotherapy 
 
If tumor PD-L1 expression ≥1%: 
• Pembrolizumab (anti-PD1) monotherapy 
• Nivolumab (anti-PD1) plus ipilimumab (anti-CTLA4) 
 
For any PD-L1 expression: 
• Pembrolizumab plus (carboplatin or cisplatin)-pemetrexed (non-squamous) 
• Pembrolizumab plus carboplatin-(paclitaxel or albumin-bound paclitaxel) 
(squamous) 
• Atezolizumab (anti-PDL1) plus carboplatin-paclitaxel + bevacizumab (non-
squamous) 
• Atezolizumab plus carboplatin and albumin-bound paclitaxel (non-squamous) 
• Nivolumab + ipilimumab plus pemetrexed + (carboplatin or cisplatin) 
(chemotherapy for first two cycles only) (non-squamous) 
• Nivolumab + ipilimumab plus paclitaxel + carboplatin (chemotherapy for first 
two cycles only) (squamous) 
 
Approvals for these regimens reflect their improved efficacy and acceptable toxicity 
profiles compared to chemotherapy-alone regimens and are summarized in the table 
below: 
 
REGIMEN 
STUDY 
RESPONSE 
RATE 
MEDIAN 
PFS 
(MONTHS) 
MEDIAN OS 
(MONTHS) 
REFERENCE 
Atezolizumab 
IMpower110 38.3% 
8.1 
15.7 
Herbst RS etal. 
NEJM 2020 
Atezolizumab plus 
carboplatin or 
cisplatin and 
pemetrexed 
IMpower 
132 
38-72% 
(based on 
PD-L1 
expression) 
7.6 
18.1 
Papadimitrakopoulou 
VA et al. WCLC 
Meeting 2018 
Atezolizumab plus 
carboplatin and 
albumin-bound 
paclitaxel 
IMpower130 49.2% 
7.2 
18.6 
West H et al. Lancet 
Oncol 2019 
Atezolizumab plus 
carboplatin, 
IMpower150 63.5% 
8.3 
19.2 
Socinski MA et al. 
NEJM 2018 

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paclitaxel and 
bevacizumab 
Pembrolizumab 
(PD-L1>50%) 
KEYNOTE-
024 
44.8% 
10.3 
NR 
Reck M et al. NEJM 
2016 
Pembrolizumab 
(PD-L1>1%) 
KEYNOTE-
042 
27-39% 
(based on 
TPS score) 
5.4-7.1 (based 
on TPS score) 
17.7 
Mok TS et al. Lancet 
2019 
Pembrolizumab 
plus carboplatin or 
cisplatin and 
pemetrexed 
KEYNOTE-
189 
47.6% 
8.8 
NR 
Gandhi, L et al. 
NEJM 2018 
Pembrolizumab 
plus carboplatin and 
paclitaxel or 
albumin-bound 
paclitaxel 
KEYNOTE-
407 
57.9% 
6.4 
15.9 
Paz-Ares L et al. 
NEJM 2018 
Nivolumab plus 
ipilimumab 
CheckMate 
227 
35.9% 
- 
17.1 
Hellman M et al. 
NEJM 2019 
Nivolumab + 
ipilimumab plus + 
(platinum doublet 
(chemotherapy for 
first two cycles 
only) 
CheckMate 
9LA 
38% 
6.7 
15.6 
Reck M. et al. JCO 
2020 
*NR: not reached 
 
For patients with contraindications to immune checkpoint inhibitors, there remain 
numerous platinum-doublet regimens, some including the antiangiogenic agent 
bevacizumab (NCCN Guidelines). NCCN recommended first-line platinum-based 
options include: 
• Carboplatin and albumin-bound paclitaxel 
• Carboplatin or cisplatin and gemcitabine 
• Carboplatin or cisplatin and paclitaxel 
• Cisplatin or carboplatin and etoposide 
• Carboplatin or cisplatin and pemetrexed (non-squamous) 
• Carboplatin or cisplatin, pemetrexed and bevacizumab (non-squamous) 
• Carboplatin, paclitaxel and bevacizumab (non-squamous) 
 
In patients with no evidence of disease progression following 4-6 cycles of platinum-
based chemotherapy plus or minus immunotherapy and/or bevacizumab, maintenance 
therapy may be continued in patients with preserved performance status, who are 
tolerating treatment well. Continuation of systemic therapy that was included in the first-
line regimen is referred to as continuation maintenance therapy, while switching to a 
maintenance drug which was not part of the original systemic therapy regimen is known 
switch maintenance. 
 

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Depending on the induction regimen, continuation maintenance therapy may include: 
 
• Continuation of atezolizumab monotherapy  
• Continuation of pembrolizumab monotherapy 
• Continuation of  nivolumab plus ipilimumab 
• Pemetrexed plus pembrolizumab OR pembrolizumab monotherapy OR 
pemetrexed monotherapy after platinum-pemetrexed + pembrolizumab 
• Pembrolizumab monotherapy after carboplatin-(paclitaxel or albumin-bound 
paclitaxel) + pembrolizumab 
• Atezolizumab monotherapy after carboplatin-(paclitaxel or albumin-bound 
paclitaxel) + atezolizumab 
• Atezolizumab plus bevacizumab OR atezolizumab monotherapy OR bevacizumab 
monotherapy after carboplatin-paclitaxel + atezolizumab + bevacizumab 
• Pemetrexed and bevacizumab maintenance therapy after platinum, pemetrexed 
and bevacizumab 
• Bevacizumab maintenance therapy after platinum-paclitaxel and bevacizumab 
 
NOTE: Although approved for advanced non-squamous NSCLC, bevacizumab-
containing regimens are not permitted in NRG-LU002 due to the potential for increased 
complications from local therapy.  
 
Role of local therapy in advanced NSCLC 
A large number of patients with stage IV NSCLC found at initial diagnosis or those who 
develop metastases after curative intent treatment for earlier-stage disease are clinically 
found to have metastases in limited distinct anatomic locations, within the same or 
different organ sites (lung, liver, adrenal, bone, etc.). Mehta et al reported that 74% of 
patients presenting with newly diagnosed stage IV NSCLC had metastases in one to two 
organs, and 50% had three or fewer metastatic sites in addition to the primary lung cancer 
(Mehta 2004). In a consecutive series of patients with metastatic NSCLC, more than 50% 
had disease patterns amenable to stereotactic body radiation therapy (SBRT) in an 
oligometastatic distribution (Rusthoven 2009). Ultimately, based on these and other 
reports, approximately 50% of all stage IV patients would potentially be eligible for 
studies evaluating therapies in a limited metastatic NSCLC disease population.   
 
Historically, subsets of patients with limited metastatic sarcoma and colorectal primaries 
have had extended PFS and OS after aggressive, local therapy to these metastatic deposits 
(Hellman 1995, Weichselbaum 2011, Fong 1999, Pastorino 1997, Strong 2007). 
Knowing that more than half of all stage IV NSCLC patients have lesions potentially 
amenable to local non-invasive treatments in the form of SBRT provides a clear rationale 
for determining if local therapies add value to systemic therapy in patients with limited 
metastatic NSCLC in enhancing control and survival endpoints (Rusthoven 2009).   
 
The oldest series supporting use of local consolidative therapy (LCT) for stage IV 
NSCLC involved use of lung resection and brain radiation for patients with isolated brain 
metastasis with evidence for prolongation of survival and improved survival compared to 
chemotherapy alone. (Patchell 1990, Burt 1992) Resection by lobectomy remains a 

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standard treatment option for patients with isolated brain metastasis, with improved 
survival for node negative patients and those undergoing complete resection (Kozower 
2013). The majority of series using surgery in oligometastatic disease are single 
institution retrospective series and are dominated by metastasis to the brain and adrenal 
glands.  
 
Previously, non-randomized, prospective and retrospective data suggested a potential 
survival benefit from radiation for limited metastatic NSCLC.  In a single arm 
prospective trial, either radiation or surgery was used in consolidation of NSCLC patients 
with synchronous NSCLC metastases in an oligometastatic distribution, demonstrating 
significant survival outcomes when compared to historical findings for similar patients 
treated with only systemic therapy (De Ruysscher 2012). Radiotherapy alone in 
consolidation following first-line chemotherapy in stage IV NSCLC to 5 or fewer 
locations of limited metastatic disease plus the primary tumor demonstrated a positive 
outcome even in patients who progressed through first-line therapy, with an OS of 22.7 
months and PFS of 7.6 months (Salama 2012). A parallel experience of oligometastatic 
NSCLC patients treated with definitive doses of local irradiation to all disease sites 
suggested an OS of 22 months (Xanthopoulos 2015). Other groups have observed similar 
survival findings retrospectively with radiation given in a consolidative fashion for 
oligometastatic disease (highlighted in subsequent sections).   
 
Prospective, multi-institutional single-arm, phase II data from UT Southwestern and the 
University of Colorado in patients with progressive disease who received second-line 
erlotinib plus SBRT to 6 or fewer locations of limited disease (metastatic sites plus 
primary) showed a PFS of nearly 15 months and OS of nearly 20.4 months. EGFR 
mutation testing on tissue available from half of the patients enrolled (24 total patients in 
the phase II study) found all to be EGFR wild type, suggesting that most of the survival 
benefit came from the radiation (Iyengar 2014).  A phase II, single-arm study published 
in the Annals of Oncology from Europe reported that treatment of limited metastatic 
NSCLC up front in the first-line setting with hypofractionated radiation established an 
OS of 23 months (Collen 2014).  A meta-analysis of oligometastatic NSCLC, mostly 1-3 
lesions treated with surgery or radiation, described OS in the range of 26 months 
(Ashworth 2014).  More recently, a phase II randomized study was completed which 
demonstrated that local consolidation with radiation or surgery of limited metastatic 
NSCLC stable after induction systemic therapy provided a tripling of PFS and an 
improvement in OS when compared to systemic therapy alone (Gomez 2019).  A second 
study, SABR-COMET, had a small subset of patients with oligometastatic NSCLC 
randomized to standard of care versus consolidative radiation plus standard of care and 
also showed an OS benefit (Palma 2019).  Finally, another phase II randomized study 
evaluating local therapy in the form of radiation alone plus maintenance chemotherapy vs 
maintenance chemotherapy alone demonstrated a nearly three-fold improvement in the 
primary endpoint of PFS in limited metastatic NSCLC patients who had stable 
disease/response after induction chemotherapy (Iyengar 2017). 
 
Combining LCT with maintenance systemic therapy in stage IV/metastatic NSCLC 
patients with limited metastatic disease patterns who have partial responses or stable 

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disease after first-line therapy may provide a new paradigm for improving OS and PFS.  
We predict that the LCT will aid the maintenance systemic therapy in eliminating disease 
in sites most at risk for developing progression/recurrence, the very initial locations that 
characterized the patient’s metastatic designation.  LCT may also permit patients to 
remain on systemic therapy regimens that offer partial, but significant tumor kill capacity.  
Furthermore, it is most likely that patients will demonstrate stable disease or decreased 
disease burden after first-line systemic therapy rather than during or from maintenance 
systemic therapy.  Hence, with the current study, we are aiming to consolidate treatment 
with surgery or SBRT after induction systemic therapy, when we believe that response 
can be optimized. 
 
Importantly, we are including surgery as a local therapy option in the study for multiple 
reasons.  Surgery has been a mainstay of treatment for oligometastatic disease in sarcoma 
and colorectal cancer, offering a survival benefit.  Secondly, in Gomez et al, 
approximately 20% of patients received surgery as part of their consolidative treatment, 
with no delay in resumption of systemic therapy and no detriment to the PFS benefits 
(Gomez 2016).  Furthermore, nearly all patients who had surgery also had a metastatic 
site treated with radiation.  Finally, it is apparent that some oligometastatic patients could 
safely and effectively receive surgery for their disease and be the treatment modality of 
choice in a thoracic multidisciplinary setting. As such, we have permitted surgery to 
represent a local therapy option in our randomized study for metastatic disease. 
 
Patients receiving any standard of care/FDA approved first line therapy will be eligible 
with the following maintenance therapies permitted – pemetrexed, gemcitabine, 
pembrolizumab, pembrolizumab-pemetrexed, atezolizumab, and nivolumab and 
ipilimumab combinations. 
 
We offer the current study with OS as the primary end point. Specifically, we will be 
evaluating in a randomized fashion how the addition of LCT to maintenance systemic 
therapy may improve OS in a population of limited metastatic NSCLC patients. In a 
review of completed maintenance cytotoxic chemotherapy and induction/maintenance 
immunotherapy trials for stage IV NSCLC, and taking into account the potential that 
limited metastatic/oligometastatic patients may have more favorable survival, we 
anticipate median OS in the maintenance systemic therapy alone arm to be approximately 
13 months (measured from initiation of maintenance therapy) for patients receiving 
cytotoxic therapies and several months longer for patients receiving immunotherapy-
containing combinations.  Along with all of the large, randomized maintenance studies 
detailed previously, disease burden was evaluated in 759 stage IV NSCLC patients 
having received cytotoxic therapies with a correlation to survival (Gerber 2013).  It was 
concluded that the patients with the least burden of disease, measured by lowest quartile 
baseline sum longest diameter, a potential surrogate for patients with oligometastatic or 
limited metastatic disease, had the greatest survival – in the range of 12-14 months 
(measured from time of diagnosis) – after receiving systemic therapy alone.  Including 
patients receiving immunotherapy, median OS for all those eligible for treatment may be 
expected in the range of approximately 17-20 months. 
 

NRG-LU002                                                 20                  Version Date:   October 18, 2023 
We anticipate LCT to lead to a significantly longer median OS in this patient population, 
an estimate based on 1) findings from two small, but randomized phase II trials showing 
approximate tripling of PFS with the addition of local therapy (Gomez 2016, Iyengar 
2017) and more recently an update suggesting OS benefit for patients with and without 
targetable mutations (Gomez 2019) and OS findings from SABR-COMET demonstrating 
that the subset of NSCLC patients receiving local therapy do better (Palma 2019), and 2) 
findings from retrospective and single-arm prospective evaluations in which 
oligometastatic NSCLC patients were treated with local modalities of treatment in 
addition to systemic therapy. When SBRT was administered prospectively in a second-
line setting for a patient population with poorer prognoses than those with response after 
first-line treatment, the median OS for patients progressing through first-line therapy was 
20.4 months (Iyengar 2014). Another prospective study utilized SBRT-like 
hypofractionation to all oligometastatic disease sites and found a median OS of 23 
months (Collen 2014). A meta-analysis that evaluated a large population of limited 
metastatic NSCLC patients treated with surgery or SBRT suggested a median OS of 26 
months (Ashworth 2014).  Retrospective evaluations were also considered, evaluated, 
and incorporated, including the University of Chicago experience that suggested a 22-
month OS in patients with limited metastatic NSCLC (1-5 metastases) treated with 
radiation to disseminated disease deposits (Salama 2012). 
 
2.2  
Significance of the Study (30-MAR-2021) 
Lung cancer is a leading cause of cancer-related mortality. Nearly 230,000 new cases of 
lung cancer were diagnosed in 2019 in the United States with approximately 160,000 
deaths (National Cancer Institute SEER Cancer Statistics Review 2019). While advances 
in local and systemic therapy have been achieved in recent years, there remains a great 
need for improvement in clinical management that improves median survivals, objective 
responses, and duration of responses. Approximately half of patients present with 
advanced-stage NSCLC and are treated with chemotherapy/systemic therapy alone 
(Brodowicz 2006). With only cytotoxic chemotherapy as platinum doublet, disease 
remains poorly controlled and fatal, with estimates of median survival of 11 months in 
the first line setting (Ramalingam 2008). Immunotherapy offers improved median 
survival in subsets of patients, but there is significant room to improve the percentage of 
patients with durable responsiveness. From a recently concluded immunotherapy study, 
at 6 months, an estimated rate of OS was 80.2% in the pembrolizumab group versus 
72.4% in the chemotherapy group (HR=0.60, p=0.005) (Reck 2016). 
 
The principle of oligometastases was popularized in 1995 by Hellman and Weichselbaum 
who hypothesized that metastatic disease occurs in a step-wise manner, initially with 
limited metastases followed by progression to widespread disease. Early on, metastases 
were thought to be limited in number and location based on interaction of tumor cells 
with target organs in a “seed and soil” pattern (Hellman 1995, Weichselbaum 2011). 
With improvements in imaging, including PET/CT and MRI, identification of isolated 
metastatic deposits has now been accomplished with higher sensitivity and specificity 
than ever before. A significantly greater proportion of patients may now be identified 
early in the metastatic spectrum and offered potentially curative local treatment, creating 
a new paradigm in the management of limited volume metastatic NSCLC. The traditional 

NRG-LU002                                                 21                  Version Date:   October 18, 2023 
grouping of all patients with metastatic disease into a single clinical characterization may 
also be less relevant with potential implications in changing of tumor staging based on 
survival outcomes.  With additional data that metastases do not always progress in 
multiple sites and that stage IV patients primarily progress after induction chemotherapy 
in original sites of gross disease if at all, a role for local therapy becomes ever more 
relevant. 
 
Support for the benefit provided by local treatment of oligometastatic or limited 
metastatic disease was first derived from surgical metastasectomy experiences.  
Patients traditionally treated with surgery of hepatic, pulmonary, or adrenal metastases 
had improved rates of survival with resection, especially in the setting of colorectal 
cancers and sarcoma (Fong 1999, Pastorino 1997, Strong 2007).  Resection by lobectomy 
has been the standard of care for the treatment of individuals diagnosed with isolated 
brain metastasis and no evidence for N2 disease (Kozower 2013, NCCN 2019).  
Furthermore, advancements in systemic therapy began to help convert a greater 
proportion of patients with widely metastatic disease to a limited volume metastatic state. 
 
Meta-analyses, retrospective studies, and single-arm prospective trials using radiation 
therapy in a consolidative fashion all have suggested enhanced survival in limited 
metastatic NSCLC patients compared to historical findings for all comers of stage IV 
NSCLC disease (Salama 2012, Xanthopoulos 2015, Iyengar 2014, Collen 2014, 
Ashworth 2014, De Ruysscher 2012). With current first-line platinum doublet 
chemotherapy in NSCLC, up to 70%-80% of patients achieve either a partial response or 
stable disease (Brodowicz 2006, Ramalingam 2008, Gerber 2013). In those patients who 
do show progression of disease, up to 65% progress only at sites present at the start of 
first-line chemotherapy (Rusthoven 2009). This group represents a large cohort of 
NSCLC patients who may be candidates for early local treatment of limited metastatic 
disease, sites at greatest risk for progression and consequently contributing most to 
reduced survival.  
 
More recently, a phase II randomized study was completed which demonstrated that local 
consolidation with radiation or surgery of limited metastatic NSCLC stable after 
induction systemic therapy provided a tripling of PFS when compared to systemic 
therapy alone (Gomez 2016). Recent updates of this trial also now suggest an OS benefit 
to local consolidative therapy (Gomez 2019). This study permitted inclusion of patients 
with tumors carrying targetable mutations and allowed patients to have surgery or 
chemoradiation as local therapy and either receive maintenance chemotherapy or 
observation.  A second phase II randomized study in a limited metastatic NSCLC patient 
population (without tumors with targetable mutations) that responded to first line therapy 
included two cohorts of patients – those getting maintenance chemotherapy and those 
getting SBRT plus maintenance chemotherapy.  The patients receiving radiation also had 
a near tripling of PFS (Iyengar 2017). Finally, though with very limited oligometastatic 
NSCLC patients with metachronous disease only, SABR-COMET showed a significant 
improvement in OS (Palma 2020).   
 

NRG-LU002                                                 22                  Version Date:   October 18, 2023 
Maintenance therapy with cytotoxic and targeted agents has now shown small but 
statistically significant benefits in both PFS and OS (Gerber 2013) for NSCLC. Most 
would argue, however, that a median 2-month OS benefit could and should be improved 
if there were means. By intervening with non-invasive focal stereotactic radiation therapy 
or surgery prior to maintenance systemic therapy, there is the potential for greater 
benefits in PFS and OS.  In parallel, immunotherapy has established a new paradigm for 
treating metastatic NSCLC patients, but to improve upon these regimens with respect to 
durability and the number of patients with any benefit may require addition of local 
therapy. 
 
Additionally, it is critical that we establish a true OS and PFS for limited metastatic 
patient populations treated with systemic therapy with or without consolidative local 
therapy.  From retrospective data, meta-analyses, and prospective (randomized and non-
randomized) evaluations of all patients receiving local interventions, there is a signal to 
suggest a significant OS in limited metastatic NSCLC patients.  Yet, we cannot be certain 
that the OS is not related to the limited metastatic disease state rather than to the 
therapeutic intervention.  It is another hopeful sign that OS rates are high, suggesting a 
lack of survival limiting toxicity from local therapies in these evaluations. None of the 
studies offered as evidence for a potential benefit from local therapy were randomized, 
however. For these reasons, it is incumbent on us not only to use this trial to potentially 
show a survival benefit with local therapy use in metastatic NSCLC, but also to 
demonstrate a true, unbiased OS and PFS for patients treated with systemic therapy alone 
who have limited metastatic disease. 
 
Ultimately, more frequent use of SBRT for limited metastatic/oligometastatic NSCLC is 
being employed off protocol and without randomized data in clinics globally with 
retrospective studies, single-arm studies, and meta-analyses as justification. Data from an 
international survey with more than 1000 respondents from 43 countries showed that: 1) 
83% began SBRT use after 2005 for metastases; 2) 61% were using SBRT to treat ≤ 3 
sites of limited metastatic/ oligometastatic disease for improving durable disease control 
and for research purposes; and 3) lung, liver, and spine represented the most common 
sites of SBRT treatment, sites highly representative of NSCLC disease spread (Lewis 
2015). The main reason cited for the 39% who did not use SBRT for oligometastatic 
disease was lack of randomized data.  Furthermore, 63% of those using SBRT for 
metastatic disease stated that they would increase use of the modality for this specific 
indication, and 59% of those not using SBRT for metastatic disease stated they 
anticipated initiating programs (Lewis 2015). As suggested by the survey, in 3 years, 
nearly 88% of radiation oncologists will be using SBRT for oligometastatic disease in a 
consolidative manner or for salvage of oligoprogression.  Accordingly, we need to 
establish with a phase III randomized study whether this treatment approach is justified, 
necessary, beneficial, and safe.  With increasing use of SBRT for these scenarios, a 
greater urgency for completing our randomized trial exists. 
 
2.3 
Rationale for Use of Maintenance Systemic Therapy for Metastatic Non-Small Cell 
Lung Cancer (30-MAR-2021) 
The introduction of maintenance chemotherapy has led to statistically significant, albeit 
modest, gains in PFS and OS following standard first-line platinum doublet 

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chemotherapy (Brodowicz 2006, Gerber 2013). These findings have certainly improved 
with the use of immunotherapy and immunotherapy-cytotoxic chemotherapy 
combinations, though a significant number of NSCLC patients still do not benefit from 
these regimens and for those that do outcomes may not be durable.  
  
A contemporary meta-analysis has proven the benefit of switch maintenance over 
continuation maintenance in both OS and PFS in the stage IV NSCLC population 
(Behera 2012). Unfortunately, these drugs alone provide modest gains and have a 
proclivity for recurrences in previously identified sites.  
 
2.4 
Rationale for Use of Stereotactic Body Radiation Therapy (SBRT) for Limited 
Metastatic Non-Small Cell Lung Cancer (30-MAR-2021) 
Stereotactic body radiation therapy (SBRT) is an emerging treatment paradigm defined in 
the American Society of Therapeutic Radiology and Oncology guidelines as a “treatment 
method to deliver a high dose of radiation to the target, utilizing either a single dose or a 
small number of fractions with a high degree of precision within the body” (Potters 
2010). SBRT allows for the delivery of ablative or significant non-ablative treatment 
doses using highly conformal radiotherapy to an increasing number of sites/locations in 
the body. By providing treatment in a short course of therapy, patients are not subjected 
to prolonged treatment times that may compromise quality of life.  Treatment is delivered 
non-invasively and with an increasing body of data supporting its tolerability with limited 
toxicity. 
 
Until two small phase II randomized trials by Gomez et al 2016 and Iyengar et al 2017, 
there were no completed, prospective randomized studies that examine the role of locally 
aggressive therapy in the form of radiation/SBRT (or surgery) for limited metastatic stage 
IV NSCLC. The NCCTG initiated a randomized phase III trial in patients with stage IV 
NSCLC, treating 1 to 3 locations of metastatic disease following 4-6 cycles of systemic 
therapy. SBRT was not used. When randomized to radiation, patients were treated with 
traditional fractionation to 60 Gy in 30 fractions or 45 Gy in 15 fractions (Schild 2008). 
A second study from the University of Chicago randomized patients with oligometastatic 
NSCLC to SBRT during the third and fourth cycle of docetaxel first-line chemotherapy 
(Vokes NCT00887315).  Neither study was completed for several potential reasons – 
including a lack of desire of patients to receive 6 weeks of radiation treatment after 6 
cycles of chemotherapy for the former study, low reimbursement below institutional costs 
to enroll and provide data for the latter study, and loosely written SBRT sections that 
failed to pass peer review due to lack of dose-volume guidelines for various organs, also 
for the latter study.  For our current trial, the length of radiation treatment after first-line 
systemic therapy would be limited by design with use of SBRT for metastatic disease 
deposits and potentially a hypofractionated course for the primary disease or metastases 
that cannot be treated with SBRT as needed.  
 
A randomized phase II trial comparing radiation or surgery plus maintenance 
chemotherapy versus maintenance chemotherapy for oligometastatic NSCLC was 
recently closed early from predetermined stopping rules after the local therapy (radiation 
or surgery) plus systemic therapy arm had significantly better PFS (Gomez 2016, 

NRG-LU002                                                 24                  Version Date:   October 18, 2023 
NCT01725165).  The study demonstrated that local consolidation with radiation or 
surgery of limited metastatic NSCLC stable after induction systemic therapy provided a 
tripling of PFS when compared to systemic therapy alone (Gomez 2016). This study 
permitted inclusion of patients with tumors carrying targetable mutations and allowed 
patients to have surgery or chemoradiation as local therapy and either receive 
maintenance chemotherapy or observation.  A recent update suggested an OS 
improvement with local therapy (Gomez 2019).  Another randomized phase II trial only 
permitting SBRT in consolidation for limited metastatic NSCLC with up to 6 sites 
including the primary tumor (Iyengar 2014, NCT02045446) also showed a near tripling 
in PFS with local therapy, the primary endpoint.  Finally, a study in Europe and Canada 
has used SBRT to consolidate metachronous oligometastatic disease from multiple 
different primaries (Palma 2016, NCT01446744) now reports an OS benefit with local 
therapy for all histologies (Palma 2019).   
 
A Dutch study by De Ruysscher and colleagues (2012) showed that aggressive local 
treatment with radiation or surgery for synchronous oligometastatic NSCLC led to 
promising survival outcomes in a single arm phase II study.  We subsequently evaluated 
other studies to gain a sense of OS benefits with local therapies in these limited 
metastatic NSCLC patient populations.  Data from a prospective, phase II single-arm 
study, opened at University of Texas Southwestern Medical Center at Dallas and the 
University of Colorado Medical Center, demonstrated impressive outcomes in both PFS 
and OS in patients with stage IV NSCLC treated with SBRT plus erlotinib compared to 
previously established findings. The patient population chosen in this study was unique, 
with treatment delivered to patients who progressed through first-line platinum doublet 
chemotherapy but demonstrated limited metastases (up to 6 locations including primary 
disease). Historically, the outcomes in this population of NSCLC patients progressing 
through first-line therapy are quite poor. In this multi-institutional study, however, PFS 
was nearly 15 months with median OS of 20.4 months (measured from the time of 
disease progression (Iyengar 2014). Furthermore, among 13 patients tested for EGFR 
mutations, none were positive. It is known that the benefits of erlotinib are most 
pronounced in patients who possess the EGFR mutation, which lends support to the 
credence that in the study by Iyengar et al, local radiotherapy with SBRT may have 
contributed substantially to the prolonged PFS and OS observed (Iyengar 2014). 
Furthermore, a phase II, single-arm study published in the Annals of Oncology from 
Europe reported that limited metastatic NSCLC treated up front in the first-line setting 
with hypofractionated radiation established an OS of 23 months (Collen 2014).  Finally, a 
meta-analysis of oligometastatic NSCLC, mostly 1-3 lesions treated with surgery or 
radiation, described OS in the range of 26 months (Ashworth 2014). 
 
Non-randomized prospective and retrospective data from the University of Chicago is 
available for patients with oligometastatic NSCLC treated with hypofractionated 
radiation to 1 to 5 locations of metastatic or primary disease following systemic therapy. 
Patients were treated to all known locations of active disease at a minimum of 2 weeks 
following first-line systemic therapy. The most commonly used fractionation schedule 
was 50 Gy in 10 fractions. A total of 62 lesions were treated in 25 patients with a median 
of 2 lesions treated per patient. The median lesion size was 2.65 cm. Treatment was well 

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tolerated with only 2 patients suffering grade 3 toxicity. With a median follow-up of 14 
months, the median PFS was 7.6 months and median OS was 22.7 months. Progressive 
disease was identified in 52% of patients following initial first-line chemotherapy. 
Analysis of PFS and OS in patients with progressive versus stable/regressive disease 
following first-line chemotherapy showed the former population to possess significantly 
worse PFS and OS relative to the latter. Despite the significant number of patients with 
progressive disease, the results of this study show a PFS that is higher than those 
historically achieved by maintenance chemotherapy alone with a parallel significant OS 
(Hasselle 2012).  Having potentially learned from previous experiences, the University of 
Chicago only initiated radiation after first-line therapy was completed but still used 10 
fraction hypofractionated regimens.   
 
Further support for selection of stage IV NSCLC patients with stable or partial response 
to first-line chemotherapy for aggressive local radiation therapy with SBRT is available 
from the University of Rochester. Patients with up to 5 locations of limited metastatic 
disease of any histology were treated to all areas of disease with SBRT. There were 121 
patients enrolled prospectively with 74% treated to 50 Gy in 5 fractions. Patients who 
achieved a response or stable disease to initial systemic therapy prior to SBRT showed 
significantly higher rates of OS and freedom from distant metastases compared to those 
with progressive disease following initial systemic therapy (Milano 2012). 
 
Another evaluation of patients treated at the University of Rochester compared outcomes 
of patients with stage III NSCLC treated with curative intent radiotherapy against patients 
with limited volume stage IV NSCLC who received SBRT. Oligometastases as an 
inclusion criteria was expanded in this review to include patients treated with 8 or fewer 
sites of disease. Patients with stage III NSCLC were treated to an average dose of 60 Gy 
via a 3-D conformal technique with or without chemotherapy. Patients with limited 
volume metastases were treated with SBRT to a dose of 50-60 Gy in 5-10 fractions. 
Patients with limited volume stage IV NSCLC treated with SBRT had higher rates of 5-
year survival relative to patients with stage III NSCLC treated definitively, 14% versus 
7%, respectively. Though the 5-year survival data for Stage III patients was lower than 
expected in this study, the survival of patients with limited volume stage IV NSCLC is 
comparable to historical data of patients with stage III NSCLC treated definitively 
(Cheruvu 2011). 
 
The most commonly treated anatomic sites of extracranial metastatic disease with SBRT 
are locations within the lung and liver. A multi-institutional phase I/II trial from the 
University of Colorado enrolled patients with 1-3 pulmonary metastases from a solid 
tumor, cumulative tumor diameter < 7 cm, and adequate pulmonary function (FEV1 > 1.0 
L, DLCO > 40%).  The planning target volume (PTV) was constructed from the gross 
tumor volume (GTV) by expanding 5 mm radially/10 mm craniocaudally and 7 mm 
radially/15 mm craniocaudally, when using active breathing control and abdominal 
compression, respectively. In the initial phase, the SBRT dose was escalated from 48 Gy 
to 60 Gy in 3 fractions. The percent of normal lung receiving more than 15 Gy (V15) was 
restricted to less than 35%.  Dose-limiting toxicities (DLT) included acute grade 3 lung 
or esophageal toxicities or any acute grade 4 toxicity. Thirty-eight patients were enrolled 

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on the study, 9 patients in the phase I portion and 29 on phase II, receiving 60 Gy in 3 
fractions, for a total of 63 lesions treated. With a median follow-up of 15.4 months, the 
actuarial in-field local control at 2 years was 96% with a median overall survival of 19 
months. Treatment was well tolerated with only 7.9% of the population suffering grade 3 
toxicity with no grade 4 or 5 toxicity (Rusthoven 2009). 
 
A second multi-institutional phase I/II trial from the University of Colorado enrolled 
patients with 1-3 liver metastases from any solid tumor, cumulative maximum tumor 
diameter < 6 cm, adequate liver and kidney function, and no chemotherapy 14 days 
before or after SBRT.  In the phase I portion, the SBRT dose was escalated from 36 Gy to 
60 Gy in 3 fractions. Thirteen patients were treated with a dose of less than 60 Gy and 36 
patients treated at 60 Gy, with 63 total hepatic lesions irradiated.  Volume delineation 
was similar to that in the lung oligometastases trial, with the PTV defined as GTV 
expanded by 5 mm radially/10 mm craniocaudally and 7 mm radially/15 mm 
craniocaudally, with active breathing control and abdominal compression, respectively.  
At least 700 cc of normal liver had to receive a total dose <15 Gy and the sum of the left 
and right kidney volume receiving 15 Gy had to be less than 35%. With a median follow-
up of 16 months, the 2-year actuarial in-field local control was 92% with a median OS of 
20.5 months. Treatment was well tolerated with 1 patient suffering grade 3 soft-tissue 
toxicity, no grade 4 or 5 toxicity, and no instances of radiation induced liver dysfunction 
(RILD) (Rusthoven 2009). 
 
Finally, a prospective dose escalation study at the University of Chicago enrolled patients 
with 1 to 5 metastases of any histology to receive SBRT to any location amenable to 
treatment. The starting dose was 24 Gy in 3 fractions. Treatment dose was escalated at 2 
Gy per fraction intervals with a ceiling of 60 Gy in 3 fractions. A total of 61 patients were 
evaluated with 113 treated lesions. The final dose cohort with sufficient follow-up and 
enrollment was 42 Gy. With a median follow-up of 20.9 months, the median PFS was 5.1 
months. Patients with 1 to 3 metastases were found to have significantly longer PFS than 
patients with 4 to 5 metastases. It is significant to note that in this study, 55% of patients 
had a limited pattern of disease progression to 3 or fewer locations after initial therapy, 
areas that were amenable to further SBRT (Salama 2012).   
 
With the inclusion of immunotherapy as an induction and continuation/ “maintenance” 
regimen for this study, there may be some question regarding patient tolerance with the 
further addition of local therapy, especially radiation/SBRT.  Multiple studies have now 
been completed in the phase I setting evaluating both concurrent and sequential use of 
immunotherapy with SBRT and other forms of radiation in the concurrent or sequential 
setting.  Welsh and colleagues report no increased toxicity when combining SBRT with 
various types of immunomodulators (Welsh 2017).  Other groups have demonstrated 
similar findings. 
 
Based on available retrospective studies, meta-analyses, single-arm, and multiple recently 
completed phase 2 randomized, prospective trials, we believe a strong case can be made 
that: 1) Failures in metastatic NSCLC occur most frequently in sites of original gross 
disease, 2) Local therapy in the form of surgery and/or radiation can drastically reduce 

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the local failures, 3) SBRT or surgery can be used safely to treat these limited metastatic 
disease foci with efficacy and timelines, 4) Maintenance systemic therapy alone offers 
improving survival benefits though ultimately durability of benefit could be improved, 5) 
There is significant OS findings with use of LCT but in smaller studies, and 6) There is a 
need to determine what the true OS and PFS is for limited metastatic NSCLC patient 
populations independent of local therapy in a large randomized phase 3 trial. Taken 
together, these observations provide a strong rationale for the design and conduct of this 
study.   
 
This study uses 1, 3, or 5 fraction SBRT regimens that have biologically equivalent doses 
(BED) based on the Universal Survival Model (Park 2008).  These SBRT doses also have 
similar BEDs to the hypofractionated 45Gy in 15fx regimen allowed in the treatment of 
primary/hilar/mediastinal disease or metastatic disease that cannot receive SBRT, 
permitting a more apropos comparison of local control between irradiated disease sites. 
The different fractionation schemes were created to give physicians flexibility in 
delivering the SBRT however they choose and within their comfort level.  The doses 
offered represent our efforts to reduce any likelihood of radiation induced toxicity that 
would limit patients from receiving the appropriate subsequent maintenance 
chemotherapy.  RTOG 0236 demonstrated a 17% grade 3 or higher toxicity with use of 
20Gy x 3fx (without heterogeneity corrections). Our consolidative radiation in this trial is 
aimed to aid systemic therapy in controlling gross deposits of metastatic disease without 
the associated toxicity from ablative SBRT.  Hence, we are using lower ablative doses, 
which, in multiple multi-institutional trials, demonstrate a long term local control rate in 
the range of 96%, even without systemic therapy or treatments not felt to be beneficial 
(Iyengar 2014). 
 
2.5       Rationale for Surgery for Limited Metastatic Non-Small Cell Lung Cancer (30-
MAY-2021) 
Historically, surgery for patients with stage IV cancer was limited to palliation, but in the 
1980s series began to appear that reported prolonged survival following complete 
resection of primary tumors and oligometastatic disease (Magilligan 1976). It is now 
recognized that there is a subset of patients where an isolated metastasis represents the 
entire disease burden and removal can confer significant survival prolongation.  
 
The use of surgery for metastases from numerous primary locations, including the lung, 
has increased significantly over the past decade. Metastasectomy for primary non-small 
cell lung cancer (NSCLC) being second in incidence only to colon cancers (Bartlett 
2015). An analysis from the National Inpatient Sample (NIS) uncovered a 5.8% average 
annual percent increase resections of NSCLC metastases between 2000 and 2011 
(Bartlett 2015). This increase is attributed to several factors, including more efficacious 
and better tolerated chemotherapies and the introduction of targeted agents, which have 
slowed the progression of metastatic spread and altered patterns of resistance. 
Simultaneously, there have been significant improvements in surgical techniques, with 
increased use of minimally invasive approaches, making resection better tolerated and 
negating long interruption from systemic treatments. 
 

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The majority of patients considered for resection of metastatic NSCLC fall into three 
categories, those with isolated metastasis to the brain, adrenal glands, or contralateral 
lung. Occasional patients with isolated metastasis to other sites are considered, but 
evidence for prolonged survival following local therapy is sparse. Patients who present de 
novo with a single metastasis after full staging should be evaluated for curative resection 
of both sites.  
 
Some of the oldest series on surgical treatment of stage IV NSCLC relate to treatment of 
isolated brain metastasis (Wronski 1995, Nakagawa 1994) Up to one quarter of all 
patients with stage IV NSCLC harbor brain metastasis. Adenocarcinomas are associated 
with higher rates of brain metastasis, but in 10% of patients with metastatic 
adenocarcinoma the brain is the only site of involvement (Kozower 2013) Aggressive 
curative intent treatment of the primary and metastatic site is encouraged in those with 
good performance status and in whom both sites are amenable to complete resection or 
ablation (Kozower 2013). Curative intent local treatments can only be considered after a 
thorough search for disease at other sites. Mediastinal lymph node involvement portends 
poor prognosis (Granone 2001, Bonnette 2001, Girard 2006, Furak 2005, Modi 2009). 
Multiple brain metastases are not an absolute contraindication to this aggressive 
treatment approach, but most recommend three or fewer lesions (Kozower 2013). 
Treatment of the brain lesion can be by resection or radiosurgery ablation. Five year 
survival following definitive treatment of isolated brain metastasis and primary NSCLC 
is 15%, and not significantly impacted by synchronous or metachronous presentation. 
Prognosis is improved in patients who are younger, female, have lower t-stage, and good 
performance status (Granone 2001, Bonnette 2001, Girard 2006).  
 
In well-selected patients with isolated adrenal metastasis from NSCLC, survival 
following complete resection of primary and metastasis is 25% (Raz 2011, Lucchi 2005, 
Strong 2007, Mercier 2005, Porte 2001).  Similar to those with isolated brain metastasis, 
mediastinal lymph node involvement portend worse prognosis (Porte 2001).  Histology 
and laterality appear to have no impact on survival and adjuvant chemotherapy is 
recommended. Operative mortality is extremely low in reported series and the majority of 
patients die of disease progression. 
 
The appearance of bilateral NSCLC lesions with the same histology is a staging 
challenge. In the absence of other disease it is difficult to distinguish bilateral primary 
tumors from stage IVa disease. Analysis of mutational status and genetic clonality 
difference are being investigated, but not clinically reliable at this time.  The clinical 
judgement of an experienced multi-modality team is essential (Kozower 2013) and the 
criteria described by Martini and Melamed in 1975 remains relevant (Martini 1975). As 
with isolated brain and adrenal metastasis, an exhaustive search for additional metastatic 
disease and invasive mediastinal staging are recommended prior to considering curative 
resection to both lesions. Parenchymal sparing resections are typically recommended 
when possible in this setting. 

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2.6      Translational Research  
A major goal of translational research in NSCLC is the identification of non-invasive 
biomarkers for response assessment, outcome prediction, and/or early detection. One 
potential non-invasive biomarker that has recently gained increasing attention is 
circulating tumor DNA (ctDNA) (Diaz 2011). Tumors continually shed DNA into the 
circulation, where it can be isolated as a component of cell-free DNA (cfDNA). Within 
plasma, ctDNA is present in a background of wild type DNA, and except in very 
advanced cases usually makes up significantly less than 1-5% of cfDNA. Detection of 
ctDNA can be accomplished by a variety of methods, although next generation 
sequencing (NGS)-based approaches have become increasingly feasible and attractive 
given their ability to detect multiple mutations at one time (Chaudhuri 2015). One NGS-
based method called CAPP-Seq was designed specifically for NSCLC and can detect the 
presence of ctDNA with high sensitivity specificity (Newman 2014, Newman 2016).  See 
Section 10.2 for more details. 
 
3.      PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILITY CRITERIA 
 
Note: Per NCI guidelines, exceptions to inclusion and exclusion criteria are not 
permitted.  For questions concerning eligibility, please contact the Biostatistical/Data 
Management Center (via the contact list on the protocol title page). For radiation therapy-
related eligibility questions, please contact RTQA (via the contact list on the protocol title 
page).  
 
3.1 
Patient Selection Guidelines (18-MAY-2018) 
Although the guidelines provided below are not inclusion/exclusion criteria, investigators 
should consider these factors when selecting patients for this trial. Investigators also 
should consider all other relevant factors (medical and non-medical), as well as the risks 
and benefits of the study therapy, when deciding if a patient is an appropriate candidate 
for this trial. 
3.1.1 Patients must have the psychological ability and general health that permits completion of 
the study requirements and required follow up. 
3.1.2 Women of childbearing potential and men who are sexually active should be willing and 
able to use medically acceptable forms of contraception during treatment on this study 
and for up to 180 days after completion of all treatment to prevent pregnancy or fathering 
a child.  
3.2 
Eligibility Criteria (30-MAR-2021) 
A patient cannot be considered eligible for this study unless ALL of the following 
conditions are met.  
3.2.1 Pathologically proven diagnosis of NSCLC, with metastases (stage IV disease) present 
prior to registration. This includes patients newly diagnosed with metastatic disease or 
those initially diagnosed and treated for stage I-III NSCLC who ultimately develop 
limited metastases.  Limited metastases is defined as 3 or fewer sites of metastatic 
disease; 
o Some examples of what constitutes sites can be found in Section 5.4. 
3.2.2 Appropriate stage for study entry based on the following diagnostic workup: 

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• 
History/physical examination by a radiation oncologist (and a surgeon if surgery is 
planned) within 30 days prior to registration; 
• 
Imaging proof of limited metastatic disease and response to therapy/stable disease, by 
at least diagnostic quality CT chest through the adrenals or PET/CT, within 30 days 
prior to registration;  
3.2.3 Age ≥ 18 years;  
3.2.4 Zubrod Performance Status 0, 1, or 2 within 30 days prior to registration;  
3.2.5 Adequate organ and hematologic/bone marrow function within 14 days prior to 
registration, defined as follows: 
• Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 × upper limit of 
normal (ULN) or ≤ 5 × ULN with metastatic liver disease  
• Total bilirubin ≤ 1.5 × ULN 
• Absolute neutrophil count (ANC) ≥ 500 cells/mm3 
• Platelets ≥ 50,000 cells/mm3 
• Renal: 
o Creatinine ≤ 1.5 x ULN; or  
o Creatinine Clearance > 45 mL/min if creatinine > 1.5 x ULN (calculated CrCl 
based on Cockcroft-Gault equation) 
3.2.6 HIV-infected patients on effective anti-retroviral therapy with undetectable viral load 
within 6 months are eligible for this trial. 
3.2.7    For patients who will undergo resection of disease (if randomized to Arm 2 and 
dispositioned to receive surgery), adequate pre-surgical work-up for anticipated surgery, 
as defined by institutional guidelines.  
3.2.8 Negative serum pregnancy test within one week prior to registration for females of 
childbearing potential; 
3.2.9 Patients must have received first-line/induction systemic therapy comprising of 
immunotherapy and/or platinum-based chemotherapy (at least 4 cycles or courses but less 
than 6, i.e. 4-5 cycles/courses), and achieved stable disease or a partial response. Though 
the intention is for every course/cycle to be identical in an induction regimen, Some but 
not all of the 4-5 cycles may omit an immunotherapy or platinum compound if the 
treating physician determines it is in the patient’s best interest secondary to toxicity or 
other institutional parameter.   
- For patients treated with nivolumab, ipilimumab and 2 cycles of chemotherapy, 
the 4-5 cycles requirement will be met by 4-5 total doses of nivolumab. 
- For patients treated with nivolumab and ipilimumab, this requirement will be 
met by 2 doses of ipilimumab and 4-5 doses of nivolumab. 
3.2.10  After induction systemic therapy, patients must have a minimum of one site of disease, 
primary or metastasis, present for potential consolidation with local therapy. All sites of 
disease present after induction systemic therapy, primary and metastases (up to 3) are 
able to be consolidated with local therapy; 
o Some examples of what constitutes specific radiation treatment sites defining 
distinct metastatic disease sites can be found in Section 5.4 
3.2.11  Prior systemic therapy as part of concurrent treatment approach for previously diagnosed 
stage I-III NSCLC, adjuvant or neo-adjuvant therapy for stage I-III NSCLC, as adjuvant 
therapy for previously resected or irradiated NSCLC, or for other previous cancers is 
permitted;  

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3.2.12  For de novo stage IV NSCLC patients (patients with metastatic disease at first 
presentation), primary disease must be treatable with local therapy in the form of SBRT 
or hypofractionated radiation.  If the primary disease is found in the peripheral or central 
lung parenchyma without nodal disease, for instance, SBRT may be employed at the 
discretion of the treating institution.  If primary disease is more advanced with 
involvement of the mediastinum (T4 tumor, N1-N3 disease, etc.), these volumes should 
be technically treatable with hypofractionated radiation; surgery should only be used for 
metastatic tumors that can be completely resected by lobectomy, segmentectomy, or wide 
wedge resection. 
3.2.13  If primary disease in the thoracic cavity was previously treated with local therapy in the 
form of surgery or radiation, any new local/regional disease recurrence should be 
technically treatable with SBRT or hypofractionated radiation after induction systemic 
therapy. 
3.2.14  The patient or a legally authorized representative must provide study-specific informed 
consent prior to registration. 
3.2.15  Radiotherapy for patients with brain metastases prior to registration is acceptable. 
3.2.16  Patients with brain metastases are eligible if these lesions have been previously treated or 
resolved and the patients have no clinical or radiographic evidence of progression prior to 
registration.   
3.2.17  Subjects may receive palliative radiotherapy for symptomatic metastases or primary 
disease prior to registration provided that there is at least one other non-irradiated lesion 
amenable to LCT at the time of registration.  
3.3 
Ineligibility Criteria (30-MAR-2021) 
Patients with any of the following conditions are NOT eligible for this study. 
3.3.1 Clinical or radiologic evidence of new, untreated, and/or progressive brain metastases 
prior to registration after induction systemic therapy.    
3.3.2    Cutaneous metastasis of NSCLC. 
3.3.3    Metastatic disease invading the esophagus, stomach, intestines, or mesenteric lymph 
nodes if not a candidate for surgery for these lesions. 
3.3.4 Prior invasive malignancy (except non-melanomatous skin cancer, low or intermediate 
risk prostate cancer, or in situ carcinoma of breast, oral cavity, skin, or cervix) unless 
disease free for a minimum of one year.  
3.3.5    Metastases located within 3 cm of previously irradiated (< 3Gy per fraction) structures if 
not a candidate for surgery for these lesions and if: 
   • Spinal cord previously irradiated to > 40 Gy 
   • Brachial plexus previously irradiated to > 50 Gy 
   • Small intestine, large intestine, or stomach previously irradiated to > 45 Gy 
   • Brainstem previously irradiated to > 50 Gy 
   • Lung previously irradiated with prior V20Gy > 35% 
3.3.6 Patients with NSCLC who have driver mutations for which targeted therapies (non-
cytotoxic, non-immunotherapy based systemic therapy including but not limited to 
tyrosine-kinase inhibitors) are available. Such designations would include but not be 
limited to treatments targeting EGFR mutant or ALK positive NSCLC.  

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3.3.7 If a patient has progressed in previous areas of primary disease that received definitive 
doses of radiation, these patients would require re-irradiation in previous high dose 
anatomic areas and are not eligible for this study.  
3.3.8 Patients with malignant pleural effusions that do not resolve after first-line systemic 
therapy. Patients with pleural effusions that have become too small for thoracentesis at 
the time of registration would be permitted on study, indicating a significant response to 
first-line systemic therapy. 
3.3.9    Patients with more than 3 discrete locations of extra-cranial metastatic disease after first-
line systemic therapy requiring more than 3 radiation/surgery plans to cover these distinct 
metastatic disease entities. 
3.3.10 Acute bacterial or fungal infection requiring intravenous antibiotics at the time of 
registration. 
3.3.11 Pregnancy or women of childbearing potential and men who are sexually active and not 
willing/able to use medically acceptable forms of contraception during treatment and for 
180 days after the completion of all treatment.  This exclusion is necessary because the 
treatment involved in this study may be significantly teratogenic.  Women who are 
breastfeeding (and unwilling to discontinue) are also excluded. 
3.3.12  Participation in any investigational drug study for the treatment of cancer within 4 weeks 
prior to registration. 
3.3.13 For patients who received immunotherapy during induction, patients on chronic steroids 
or who have active autoimmune disease for which they received systemic treatment in the 
previous 2 years with corticosteroids, disease modifying agents, or immunosuppressive 
drugs are not eligible. Replacement therapy (thyroxine, insulin or physiological 
corticosteroid replacement for adrenal or pituitary insufficiency) is allowed.  Patients 
with active interstitial lung disease or who have a history of pneumonitis for which they 
had received glucocorticoids are not eligible.  
3.3.14  Use of bevacizumab or other antiangiogenic therapy in first-line or planned maintenance 
therapy (due to potential for increased complications from local therapy); 

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4.  REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP (30-
MAR-2021) 
 
PRE-TREATMENT ASSESSMENTS  
Assessments 
Prior to 
Registration 
(calendar days) 
Prior to Treatment 
(calendar days) 
Arm 2 Patients 
if Surgery is 
Selected as LCT 
Pathologic proof of 
NSCLC 
X 
 
 
Evaluation by a 
radiation oncologist 
30 days 
 
 
Evaluation by a 
thoracic surgeon 
 
 
Within 30 days 
prior to registration 
Performance status 
30 days 
 
 
Diagnostic CT chest 
through the adrenals or 
PET/CT 
30 days 
 
 
Complete Metabolic 
Panel (CMP)* 
14 days 
 
 
CBC/differential (with 
ANC) 
 
14 days 
 
 
TSHŧ 
(only required for 
patients receiving 
immunotherapy) 
 
As clinically indicated 
 
Serum pregnancy test (if 
applicable) 
7 days 
 
 
PROs:  EQ-5D-5L, 
FACT-L, C-TUQ 
 
 
X 
(after consent, prior to initiation 
of systemic therapy/RT) 
 
FFPE tissue, whole 
blood, serum and 
plasma collection for 
banking for consenting 
patients 
 
X 
 
 
* CMP to include:  Sodium, Potassium, CO2, Chloride, BUN, Creatinine, ALT, AST, Total 
Bilirubin, Blood Glucose, and Calcium to be reported on study specific CRFs. 
ŧ   With reflex to T4; then T3 only if clinically indicated afterwards 

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ASSESSMENTS DURING TREATMENT 
Assessments 
Weekly During 
Radiation 
During Maintenance 
Systemic Therapy 
Arm 2 Patients  
if Surgery is 
Selected as LCT 
History and Physical 
Exam  
X 
Prior to every cycle of 
systemic therapy (as 
appropriate for standard of 
care for specific 
maintenance regimen) 
 
Post-surgical consult 
 
 
2-4 weeks after 
surgery 
CT chest through the 
adrenals 
 
After every 9 weeks of 
maintenance systemic therapy 
 
CT abdomen/pelvis 
 
After every 9 weeks of 
maintenance systemic therapy 
(only required if metastatic 
lesions in these anatomic 
areas were known at 
registration) 
 
Toxicity Assessment 
Graded per NCI 
CTCAE, v5.0 
X 
Prior to every administration 
of maintenance systemic 
therapy 
 
CBC/differential (with 
ANC) 
 
As clinically indicated / per 
institutional guidelines 
 
TSHŧ (only required for 
patients receiving  
immunotherapy) 
 
As clinically indicated 
 
Complete Metabolic 
Panel* 
 
As clinically indicated/per 
institutional guidelines 
 
PRO:  FACT-L** 
 
1, 3, 6, 9 and 12 months 
after patient registration 
 
PRO: EQ-5D-5L, C-
TUQ** 
 
3, 6 and 12 months 
after patient registration 
 
Serum and plasma 
collection for banking 
for consenting patients 
 
Once approximately 3 months 
after the initiation of 
maintenance systemic therapy  
 
*   Sodium, Potassium, CO2, Chloride, BUN, Creatinine, ALT, AST, Total Bilirubin, Blood 
Glucose, Calcium 
ŧ     With reflex to T4; then T3 only if clinically indicated afterwards 
** PROs should continue on this schedule even if the patient progresses or stops treatment early 
and enters follow-up. 

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ASSESSMENTS IN FOLLOW UP 
Assessments 
From End of Last Dose of Maintenance Systemic 
Therapy (+/- 30 days);  
Vital Status 
q3 mos. x 2 yrs, then q6 mos. x 3 yrs, then annually  
CT chest through the adrenals 
q3 mos. x 2 yrs, then q6 mos. x 3 yrs, then annually  
CT abdomen/pelvis 
q3 mos. x 2 yrs, then q6 mos. x 3 yrs, then annually 
only required if metastatic disease was identified in 
abdomen or/and pelvis at registration 
History and Physical Examination 
q3 mos. x 2 yrs, then q6 mos. x 3 yrs, then annually  
Toxicity Assessment Graded per NCI 
CTCAE, v5.0 
q3 mos. x 2 yrs, then q6 mos. x 3 yrs, then annually 
CBC/differential (with ANC) 
Per institutional guidelines or as clinically indicated 
Complete Metabolic Panel* 
Per institutional guidelines or as clinically indicated 
Serum and plasma collection for 
banking for consenting patients 
At the time of first progression 
(local or distant) 
* Sodium, Potassium, CO2, Chloride, BUN, Creatinine, ALT, AST, Total Bilirubin, Blood 
Glucose, Calcium

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Definition of Disease Assessments 
 
Evaluation of Target Lesions 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eisenhauer 2009].  Changes in the largest diameter (LD) (unidimensional 
measurement) of the tumor lesions and the shortest diameter (SD) in the case of malignant lymph 
nodes are used in the RECIST criteria.  For those patients receiving immunotherapy, irRC 
guidelines for treatment response should be employed (Nishino 2013, Garon 2014)  
 
The following terms and definitions may guide investigators but official RECIST criteria should 
be employed for all study evaluations. 
 
Complete Response (CR) 
Disappearance of the target lesion; this determination will be made based on CT image 
evaluation. 
 
Partial Response (PR) 
At least a 30% decrease in the LD of the target lesion, taking as reference the baseline LD; this 
determination will be made based on CT image evaluation. 
 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for CR/PR above nor sufficient increase to qualify for LE 
below, taking as reference the smallest LD since the treatment started 
 
Local Enlargement (LE) 
At least a 20% increase in the LD of target lesion, taking as reference the smallest LD recorded 
since the treatment started; this determination will be made based on CT image evaluation 
 
Local Failure (LF) 
Refers to the primary treated tumor and corresponds to meeting both of the following two 
criteria: 1) Increase in tumor dimension of 20% as defined above for local enlargement (LE); 2) 
The appearance of a measurable tumor at a resection suture line; 3) The measurable tumor with 
criteria meeting LE should be avid on Positron Emission Tomography (PET) imaging with 
uptake of a similar intensity as the pretreatment staging PET, OR the measurable tumor should 
be biopsied confirming viable carcinoma.  
 
For outcome analysis, Marginal Failures (MF; see below) will also be counted as LF; however, 
they should be distinguished specifically as MF, not LF, on all report forms. The EORTC criteria 
for post-treatment PET evaluation will be used as a basis for evaluation in cases more difficult to 
assign as to whether the uptake is pathological for cancer recurrence vs. inflammation. 
 
Local Control (LC) 
The absence of Local Failure. 
 
Evaluation of Non-Target Lesions 

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Marginal Failure (MF) 
Refers to the appearance of a measurable tumor appearing since treatment within 1.0 cm of the 
treated PTV or the resection suture line and meeting the following two criteria: 1) Enlarging 
tumor dimensions corresponding to a 20% increase in the longest diameter compared to initial 
appearance on imaging evaluation. Ideally, this determination will be made based on CT image 
evaluation; 2) The measurable tumor within 1.0 cm of the treated PTV or resection suture line 
should be avid on Positron Emission Tomography (PET) imaging with uptake of a similar 
intensity as the pre-treatment staging PET, OR the measurable tumor should be biopsied 
confirming viable carcinoma. 
 
Regional Failure (RF) 
Refers to the appearance of measurable tumor within lymph nodes along the natural lymphatic 
drainage typical for the location of the treated primary disease only with dimension of at least 1.0 
cm on imaging studies (preferably CT scans) within the lung, bronchial hilum, or the 
mediastinum. Equivocally appearing enlarged lymph nodes should be positive on PET imaging 
or biopsied to confirm involvement with carcinoma. 
 
Metastatic Dissemination (MD) 
Refers to the appearance of cancer deposits characteristic of metastatic dissemination from non-
small cell lung cancer. Appropriate evaluations for making this determination include physical 
examination and imaging studies. PET scan OR biopsy to confirm MD is encouraged but not 
required. 
 
5. TREATMENT PLAN/REGIMEN DESCRIPTION 
5.1 
Systemic Therapy (19-JUL-2021) 
There will be a 2:1 randomization between Arms 2 and 1 on study.  By a 2:1 ratio, more 
patients will be randomized to the arm of treatment receiving local therapy in the form of 
radiation or radiation and surgery.  NOTE:  All patients in the trial will receive 
maintenance therapy.   
 
Systemic therapy protocol treatment must begin either: 
• within 2 weeks of registration on the maintenance systemic therapy (Arm 1) 
• within 2 weeks of the completion of all local therapy if no surgery included or within 
3 weeks after all LCT if surgery is included (Arm 2) 
 
Systemic therapy - approved regimens and associated references:   
Patients may receive only one of the following regimens as noted below.  There is no 
expectation that any one particular cytotoxic regimen would result in superior outcomes 
to any other cytotoxic regimen since none have been compared head-to-head in any 
randomized study.  Similarly, there is no expectation of superior outcomes among any of 
the immunotherapy regimens.  Since immunotherapy-containing regimens are expected 
to have different PFS and OS outcomes versus cytotoxic chemotherapy regimens, the 
induction/maintenance regimen of choice will be stratified based on the presence or 
absence of immunotherapy.  Selection of regimen is at the discretion of the treating 
physician in agreement with the patient. These regimens include FDA approved and/or 

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NCCN recommended therapies.   
 
General Treatment Considerations for All Systemic Therapy Regimens 
Agents will be administered per institutional standard.   
 
Agents are either dosed by BSA or flat dose.  BSA-based chemotherapy dosing may be 
modified for changes in weight according to institutional policies for dose rounding. 
 
Premedications should be given according to the package insert and institutional 
guidelines for each agent.   
 
For all chemotherapy agents, the duration of treatment is until progression or significant 
toxicity.    
 
For immune therapy agents, the duration of treatment is until progression or significant 
toxicity, or up to 2 years.  The same approved immunotherapy regimen used prior to 
radiation in induction/first line treatment must be continued following radiation. 
 
The following are recommended dose administration, but agents should be administered 
per institutional standard. Additionally, refer to the FDA package insert for complete 
details on safety and treatment information. 
 
5.1.2 Pemetrexed or Pemetrexed plus Pembrolizumab  
 
Administration: 500 mg/m2 administered by IV over 10 minutes on Day 1 of a 21 day 
cycle.  For pemetrexed plus pembrolizumab regimen, both are administered on day 1 of 
each 21 day cycle.  See Section 5.1.4 for pembrolizumab dosing. 
 
NOTE:  Pemetrexed administration requires vitamin supplementation with folic acid and 
vitamin B12 (patients should receive B12 and folate supplementation per package insert).   
 
See section 5.1.4 for pembrolizumab dosing. 
 
5.1.3 Gemcitabine 
Administration1250 mg/m2 over 30 minute IV infusion on Days 1 and 8 of a 21 day cycle 
is recommended.  Lower starting dose of 1000 mg/m2 allowed per investigator discretion. 
 
5.1.4 Pembrolizumab  
Administration:  200 mg as IV infusion over 30 minutes on day 1 of a 21 day cycle.   (For 
sites in Canada, weight-based dosing (2 mg/kg) of pembrolizumab is acceptable if 
standard of care.) 
 
Note: the regimen of pembrolizumab 400 mg IV every 6 weeks is not permitted on the 
NRG-LU002 trial.    
 
5.1.5 Atezolizumab 

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Administration: 1200 mg as IV infusion on day 1 of a 21-day cycle, administered over 60 
minutes.  If the first infusion is tolerated, all subsequent infusions may be delivered over 
30 minutes.  Refer to the FDA package insert for administration instructions. 
 
5.1.6 Nivolumab plus ipilimumab: 
Administration:  nivolumab 3 mg/kg as IV infusion over 30 minutes on days on 1, 15, 
and 29 of a 42-day cycle plus ipilimumab 1 mg/kg as IV infusion over 30 minutes on day 
1 of a 42-day cycle. 
 
OR 
 
Nivolumab 360 mg as IV infusion over 30 minutes on day 1 and 22 of a 42-day cycle 
plus ipilimumab 1 mg/kg as IV infusion over 30 minutes on day 1 of a 42-day cycle. 
 
5.2      Local Consolidative therapy (LCT): (30-MAR-2021) 
Can be in the form of hypofractionated radiation/SBRT to the primary tumor and 
metastatic sites or surgery of metastatic sites, and is to be determined by the treating 
institutions using the following caveats: 
• Minimally invasive resections of metastatic sites are encouraged.  
• At least one site of disease needs to be present after induction systemic therapy 
(primary or metastasis) for consolidation.   
• At least one site (metastatic or primary) must be treated by SBRT/hypofractionated 
radiation.  All sites must be treated by either RT or surgery. 
• All LCT should ideally be completed within 5 weeks of randomization for patients 
who receive radiation alone (detailed in Section 5.4.7 with acceptable and 
unacceptable deviations).  
• All LCT should ideally be completed within 6 weeks of randomization if surgery is 
incorporated with the radiation. Acceptable deviation if all LCT (incorporating some 
form of surgery) completed between 6-8 weeks.  Unacceptable deviation beyond 8 
weeks. 
• Maintenance systemic therapy should begin within 2 weeks after all LCT if no surgery 
inclusion or within 3 weeks after all LCT if surgery included. 
 
5.3 
Surgery (18-MAY-2018) 
Questions regarding Surgery should be directed to Dr. Donington (preferably by e-mail 
or alternatively by phone). 
5.3.1 Patients with no radiologic evidence of progression in the chest or elsewhere, including 
patients who have stable disease on re-evaluation, may proceed to surgery of only 
metastatic disease. 
5.3.2 All surgery should be performed within 6 weeks of randomization.  Occasionally, an 
extra week will be required to recover from toxicity of first line therapy.  If longer than a 
week is deemed necessary, surgical co-chair should be notified. Site will document the 
reason(s) for delay on the Surgical Evaluation Form. 
5.3.3   Surgical Guidelines for Resection for Metastatic Sites 

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Extra-cranial metastatic sites eligible for resection include: contralateral lung, mediastinal 
or cervical lymph nodes, liver, spinal/paraspinal masses, bone, adrenal glands, abdomino-
pelvic lymph nodes and spleen. 
 
Complete resections with negative margins should be achieved, but anatomic resections 
are not required.  Minimally invasive techniques should be used whenever possible. 
 
The attending thoracic surgeon must review and sign all post-surgical forms.  Post-
operative complications are reported in the same manner and with the same forms as for 
resection of primary tumors. 
5.3.4 The attending thoracic surgeon must review and sign all post-surgical forms. 
5.3.5 The use of video-assisted thoracic surgery (VATS) or robotic assisted thoracic surgery 
(RATS) are encouraged and should be used at each surgeon’s discretion. 
5.3.6 Post-Operative Period 
 
Post-operative care is at the discretion of individual institution, with attention to minimal 
use of IV fluids in perioperative period, early ambulation and aggressive pulmonary 
toilet. 
5.3.7 Surgical Adverse Events 
All acute and late adverse events from protocol surgery will be reported and scored for 
severity using the NCI Common Terminology Criteria for Adverse Events (CTCAE) per 
Section 7.2.1.  A copy of the CTCAE can be downloaded from the CTEP home page 
(http://ctep.info.nih.gov).  
 
 
Peri-Operative Complications 
Major morbidities are scored as any event occurring within 30 days or during the same 
hospitalization as surgery.  The complications of surgery will be documented on the 
Surgical Evaluation Form as part of the secondary objectives of this study. All patients 
undergoing surgical resection will be included in the analysis of surgical Adverse Events.  
Data collection also will include Surgical Operative and Surgical Pathology Reports 
documenting surgical approach, duration of surgery; estimated blood loss; blood 
transfusions required intra- and perioperatively; and length of hospital stay.   The 
Adverse Events attributed to thoracic surgery will include any of the following 
complications listed below: 
• Pneumonitis/pneumonia/pulmonary infiltrates (includes pneumonia/empyema that 
was diagnosed during the postoperative period; specify the organism causing the 
infection). 
• Infection (other than pulmonary).  
NOTE: This includes wound infection of surgical incisions. When there is a 
wound infection, specify the organism causing the infection in the space provided, 
and record which surgical incision[s] was infected. 
• Fistula (includes any fistula that developed within the postoperative period;  
NOTE:  A patient with a bronchopleural fistula associated with an intrathoracic 
infection should be reported as having both the intrathoracic infection and a 
fistula, pulmonary/upper respiratory). 
• Prolonged air leak, defined as air leaks longer than 5 days (includes bronchial 
stump leak). 

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• Pleural space issue (non-malignant) [includes any effusion, pneumothorax, and 
chylothorax within the postoperative period that requires treatment beyond peri-
operative chest tube x 5 days or secondary interventions]. 
• Cardiac ischemia/infarction (includes any myocardial infarction that occurred 
within the postoperative period). 
• Thrombosis/thrombus/embolism (includes any pulmonary embolus that occurred 
within the postoperative period). 
• Supraventricular and nodal arrhythmia (includes any new atrial arrhythmia that 
developed within the postoperative period that requires treatment). 
• Ventricular arrhythmia (includes any new ventricular arrhythmia that developed 
within the postoperative period that requires treatment). 
• Hemorrhage/bleeding associated with surgery, intra-operative or postoperative 
(Postoperative period is defined as ≤ 72 hours after surgery; includes hemorrhage 
that required reoperation for control). 
• Death. 
5.4 
Radiation Therapy in the Form of Stereotactic Body Radiation Therapy or 
Hypofractionation (30-MAR-2021) 
Stereotactic body radiation therapy (SBRT), also known as stereotactic ablative 
radiotherapy (SAbR), is a treatment strategy used to deliver highly focused and accurate 
radiation dose to demarcated targets outside of the brain where the entire course of 
therapy for an individual target is delivered in few fractions (≤5, oligofractionation).  The 
definition of SBRT and its appropriate conduct have been extensively reviewed by 
several professional radiotherapy societies.  For this protocol, the ACR/ASTRO 
consensus definition of SBRT and the related conduct guidelines for SBRT, along with 
guidelines from the AAPM Task Group 101, will be used. When and if there is a 
discrepancy between these professional society guidelines and this protocol, the protocol 
should be followed.   
 
This trial aims to assess whether LCT can help systemic therapy improve survival in 
limited metastatic NSCLC.  The expectation is that resection or SBRT will be used in 
part or all of the treatment of metastatic disease or of the primary disease when feasible. 
If SBRT is not used to treat the primary disease or metastases (when not amenable to 
SBRT due to normal tissue constraints), a treatment of 45 Gy can be delivered in 15 
fractions to the primary (may include mediastinal nodes/hilum) or metastases using 
IMRT or a 3D Conformal approach. In this trial, with the flexibility offered by the SBRT 
schemas and by the 45Gy/15fx regimen, stage III like disease intrathoracically should be 
treatable as primary disease.  Earlier radiation sections highlight the rationale for primary 
disease site treatment with radiation at the same time as SBRT treatment of metastatic 
disease. We leave to the discretion of the physician of the study participant what defines 
bulky disease or multistation disease not amenable to radiation treatment on the study. 
For details refer to Section 3.2. 
 
Some examples of what constitutes specific radiation treatment sites defining distinct 
metastatic disease sites include: 

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a) A lesion in each adrenal gland represents 2 of 3 sites of metastatic disease allowed 
to be treated on protocol;  
b) Similarly to NRG study RTOG 0631, disease in 2 contiguous vertebral bodies 
(with up to 6 cm of paraspinal extension) can represent one site of disease in the 
spine; non-contiguous lesions in vertebral bodies separated by one vertebral body 
free of disease should be viewed as 2 sites of treatment; and  
c) Two lesions in such close proximity to one another that treatment with one 
isocenter is more accurate and safer in the liver, lungs, or other similar anatomic 
locations should be viewed as one site of metastatic disease treatment. Anatomic 
sites that may be treated with SBRT are listed below. 
 
Please see Section 2.4 for rationale for fractionation strategy for treating metastases.  
 
5.4.1 Treatment Technology Requirements 
SBRT is a highly focused technique requiring many facets of modern technology in order 
to safely treat patients with large fractions of highly conformal doses.  To successfully 
treat an SBRT patient, centers must satisfy a set of minimum technology requirements as 
well as use appropriate modalities for treatment. 
 
General treatment technology requirements for SBRT are given in Table 5.4.1A.  
Questions regarding appropriate technology for this protocol can be directed to the 
protocol PI or medical physics co-chair. 
 
Table 5.4.1A  Quick Reference Summary of Treatment Technology Requirements 
Technology 
Requirement 
Comments 
Beam 
Modality 
MV Photons 
ViewRay & Linac allowed; Charged 
particle beams (including electrons, 
protons, and heavier ions) are not 
allowed 
Beam Energy 1 to 10 MV; 10-18 MV may be used 
in selected cases with >10 cm from 
skin to target. For targets in the lung, 
>50 % of target dose should be 
delivered by beams with energy ≤10 
MV 
Minimize use of high energy in lung.  6 
MV or lower energies should be 
predominately used in low-density tissue.  
 
Treatment 
Technique 
3DCRT (static, arc) or intensity 
modulated techniques (IMRT, 
VMAT) 
Tomographic and robotic techniques 
allowed. 
Image 
Guidance 
Treatment Machine must be 
equipped to provide daily kV or MV 
image guidance.  The minimum 
requirements for image guidance are 
given in Section 5.4.10. 
Non-ionizing guidance (RF transponders, 
optical surface imaging) is allowed, but 
kV or MV image verification is still 
required. 
 
5.4.2 Simulation 

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Proper immobilization and assessment and, if necessary, management of internal motion are 
essential for SBRT treatment.  Quick reference guidelines for simulation are given in Table 
5.4.2A with additional details below.   
 
Table 5.4.2A  Quick Reference Summary of General Simulation Guidelines 
Topic/Parameter 
Guideline 
Immobilization 
Proper immobilization with appropriate clinical devices to ensure 
reproducibility is required.  Patient comfort should be prioritized.  
Motion 
Assessment 
Ascertain the characteristics of target (and normal tissue) motion with regard 
to magnitude (amplitude), timing (period), and regularity to determine the 
need or success of motion control.  This is carried out both in simulation and 
treatment using real time monitoring (e.g., fluoroscopy, 4-D CT, beacon 
tracking, etc.) 
Motion Control 
Motion control is strongly encouraged when the GTV excursion is more than 
1 cm in any direction. Typical motion control maneuvers include inhibition 
strategies (e.g., abdominal compression and active breath hold), tracking 
based on a motion model, and gating to part of the breathing cycle, but others 
may be applicable.  Internal organ management maneuvers must be reliable 
enough to insure that the GTV does not deviate beyond the confines of the 
PTV with any significant probability (i.e., < 5%). 
CT Slice 
Thickness 
2 mm or less is recommended.  Maximum slice thickness should be 5mm 
when more than 10cm from the target but no more than 3mm shall be used 
within 10cm of the target.  PTV size should be taken into consideration when 
choosing the slice thickness.  Slices of 1-2 mm are recommended for tumors 
that are 1 cm or less in the largest dimension.  IV contrast is recommended 
but not required.  3D reformatting is permitted as per primary institution.  
Same slice thickness maximums, contrast recommendations, and 3D 
reformatting principles hold for PET/CT and MR imaging as well. 
Use of Contrast 
IV contrast is encouraged for better delineation between tumor, atelectasis, 
and vascular structures as well as better definition of normal tissue contours.  
Oral contrast can be used at the clinical discretion of the treating physician.  
Generally, contrast scans are acceptable for dose calculations, although 
density overrides may be applied in areas of strong contrast (such as oral 
contrast in esophagus).  For additional information on use of contrast, please 
see Section 5.4.3. 
 
Immobilization 
Patients should be positioned in a stable position capable of allowing accurate reproducibility of 
the target positions from treatment to treatment. Positions uncomfortable for the patient should 
be avoided so as to prevent uncontrolled movement during treatments. A variety of 
immobilization systems may be used, including stereotactic frames that surround the patient on 
three sides and large, patient contoured rigid pillows (conforming to patients’ external contours) 
with reference to the stereotactic coordinate system. At a minimum, patients should be uniformly 
supported with large cushions or patient contoured rigid pillows rather than simply lying on the 
treatment couch, which is uncomfortable for the period of time required for SBRT simulation, 
setup, and delivery.  Arms should be supported and knees elevated. Patients with COPD often 

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prefer that their head is elevated above their chest.  Patient immobilization must be reliable 
enough to insure that the gross tumor volume (GTV) does not deviate beyond the confines of the 
planning treatment volume (PTV) with any significant probability (i.e., < 5%) during the 
treatment. 
 
Assessment and Management of Internal Organ Motion 
Special considerations must be made to account for the effect of internal organ motion (e.g., 
primarily breathing associated motion but also bowel peristalsis motion) on target positioning 
and reproducibility. As a first step, it is required that the treatment team quantify the specific 
motion of a target so as to determine if management strategies listed in the next section are 
required to meet protocol guidelines. The patient should be in normal free breathing at time of 
initial tumor motion assessment. Deep inspiration or expiration breath hold is not allowed for 
initial tumor motion assessment as such assessment generally overestimates free breathing tumor 
motion. Options for motion assessment include real time fluoroscopy and 4-D CT scanning.  Any 
strategy, including 4-D CT should incorporate appropriate image review and quality assurance to 
ensure suitability for treatment planning and target delineation. 
 
In some tumor locations, assessed tumor motion measurement indicates that tumor motion would 
exceed the required small tumor expansions per this protocol (resulting in marginal miss or 
excessive volume of irradiation) unless a motion management strategy is employed. Respiratory 
motion management (RMM) including abdominal compression, active breathing control, breath 
hold, end expiratory gating, or fiducial marker tracking, is recommended for any metastasis to be 
treated with motion ≥ 1 cm. A recommended approach would be to use an IGTV technique for 
motion <1cm but for motion > 1cm (typically too large for a free breathing IGTV) motion 
management including but not limited to abdominal compression, active-breathing control 
(ABC), gating, breath hold, etc. should be used. 
 
Internal organ management maneuvers must be reliable enough to insure that the GTV does not 
deviate beyond the confines of the PTV with any significant probability (i.e., < 5%). 
 
If a treatment for multiple metastases (i.e., lung and spine) is designed on a CT scan employing 
motion management (i.e., abdominal compression), all metastases should be treated with the 
chosen motion management technique in order to generate an accurate composite dose 
calculation.  
 
Table 5.4.2B highlights the recommended and minimum requirement for motion assessment and 
treatment planning imaging. 
 
Table 5.4.2B Motion Assessment/Management Guidelines for Simulation 
Treatment 
Technique 
Recommended Method 
for Motion Assessment 
During Simulation 
Minimum Method 
for Motion 
Assessment During 
Simulation 
Scan(s) Required for 
Treatment Planning 
Free breathing 
treatment using 
an IGTV 
approach, 
4DCT or fluoroscopy as 
long as tumor can be 
directly visualized 
Repeated slow 
acquisition CT 
scanning through the 
target (to sample 
Average scan from a full 
field of view 4DCT for 
dose calculations; MIP 
may be desirable to aid 

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including 
abdominal 
compression 
motion) fused to the 
planning CT dataset  
IGTV definition; Free-
breathing scans are not 
recommended for 
treatment planning.   
Gating with a 
gating window 
4DCT 
Exhale CT plus 
fluoroscopy (free-
breathing + 
fluoroscopy strongly 
discouraged due to 
baseline shift) 
Reconstructed average of 
gating window scans from 
4DCT  
Breath hold 
(i.e. ABC) 
Reproducibility of breath 
hold confirmed 
(examples: multiple low 
dose scans over tumor, 
repeat fluoroscopy or 
scout images) 
N/A 
Scan in breath hold 
position (Inhale 
recommended since it 
maximizes lung volume) 
Tracking 
4DCT or breath hold CT 
N/A 
4DCT or breath hold CT 
 
5.4.3    Imaging for Structure Definition, Image Registration/Fusion and Follow-up 
 
All patients will undergo CT-based treatment planning in custom made immobilization devices. 
CT scan range must allow simultaneous view of the patient anatomy and fiducial system for 
stereotactic targeting (if used), and be adequate to ensure contouring of all targeted metastases, 
as well as necessary organs at risk (OAR), defined below. High-resolution CT scans should be 
obtained with uniform slice thickness of ≤ 3mm throughout. Slices of 1-2 mm are recommended 
for tumors that are 1 cm or less in the largest dimension. If a single CT scan cannot be obtained 
due to a large spatial separation between metastases (i.e., cervical and femoral metastases), or 
planning system slice number limitation, multiple CT scans are allowed provided that OAR are 
entirely encompassed in a single CT scan. CT imaging should be performed so that a composite 
dose distribution including all treated metastases can be created. Ideally, all metastases will be 
treated in one treatment position. When treating multiple metastases such as a lung and 
extremity, varying the treatment position may be necessary (i.e., simulation with arms up and 
arms to the side). Thus, more treatment positions can be used at the discretion of the treating 
oncologist, but every effort should be made to obtain a composite distribution.  
 
For detailed information regarding recommended imaging modalities for specific disease sites, 
please see Table 5.4.4A. 
 
Use of Contrast Agents 
IV contrast is encouraged for better delineation between tumor, atelectasis, and vascular 
structures as well as better definition of normal tissue contours.  The use of IV contrast will be 
required for liver metastases. For other metastases (central & peripheral lung, cervical/ 
mediastinal, abdominal-pelvic, and spinal/paraspinal), the use of IV contrast is encouraged but 
will be left to the discretion of the treating physician. The use of other contrast agents is left to 
the discretion of the treating oncologist. Oral contrast can be used at the clinical discretion of the 
treating physician.  Generally, contrast scans are acceptable for dose calculations, although 

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density overrides should be considered in areas of strong contrast (such as oral contrast in 
esophagus). Or duplicate planning datasets obtained prior to injection of intravenous contrast 
may be used for dose calculation. 
 
5.4.4 Definition of Target Volumes and Margins 
 
Note: All structures must be named for digital RT data submission as listed in the table below.  
The structures marked as “Required” in the table must be contoured and submitted with the 
treatment plan. Structures marked as “Required when applicable” must be contoured and 
submitted when applicable. 
 
Resubmission of data may be required if labeling of structures does not conform to the standard 
DICOM name listed.  Capital letters, spacing and use of underscores must be applied exactly as 
indicated. 
 
Treatment Sites 
The following treatment sites will be allowed on this protocol:  All sites that can be treated with 
SBRT that fulfill normal tissue tolerances as described in this protocol will be permitted.  
 
Metastases should be assigned to one of the following seven metastatic locations to determine 
the required options available for dosing schedules: 
1. Lung Peripheral 
2. Lung Central 
3. Mediastinal/Cervical Lymph Nodes 
4. Liver 
5. Spinal/Paraspinal 
6. Osseous 
7. Abdominal-pelvic (including abdomino-pelvic lymph nodes/adrenal glands) 
 
Patients can have up to only 3 (excluding primary site) discrete active extracranial lesions as 
identified by diagnostic CT or PET/CT which was acquired within 30 days of patient protocol 
registration.  Patients with discrete lesions in very close proximity to one another that can and 
should be safely incorporated into one SBRT treatment field (e.g. liver lesions, lung lesions, 
mediastinal lymph nodes) while achieving 1, 3, or 5 fraction dose constraints will be considered 
one area of potentially 3 anatomic locations (sites) treated. Specific locations not allowed 
treatment with SBRT on this protocol due to the lack of established tolerance doses of SBRT are 
described as follows:  metastatic disease involving the gastrointestinal tract, i.e. invading the 
esophagus, stomach, intestines, or mesenteric lymph nodes will not be permitted. 
1. Lung Peripheral:  Metastases within the lung parenchyma with GTV outside of the 
proximal bronchial tree as described above.  
 
2. Lung Central: GTV within 2 cm of proximal bronchial tree as described in RTOG 
0813/0915: 
Tumor within or touching the zone of the proximal bronchial tree, defined as a volume 2 
cm in all directions around the proximal bronchial tree (carina, right and left main 
bronchi, right and left upper lobe bronchi, intermedius bronchus, right middle lobe 

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bronchus, lingular bronchus right and left lower lobe bronchi) [See Figure 5.4.4A]. 
Tumors that are immediately adjacent to mediastinal or pericardial pleura (PTV touching 
the pleura) also are considered central tumors and are eligible for this protocol. A visual 
representation is shown below in Figure 5.4.4A. 
 
Figure 5.4.4A  Zones of Proximal Bronchial Tree for Central Lung Lesions 
 
 
 
3. Mediastinal/Cervical LN: Mediastinal: GTV arising within the anatomic space between 
the lungs, above the diaphragm, and below the thoracic inlet at the level of the top of the 
sternal notch.  Cervical Lymph nodes:  GTV occurring within cervical lymph node 
Levels I-VI and/or retropharyngeal spaces 
• Sternal metastases will be assigned to the mediastinal/cervical lymph node location 
based on potential for normal tissue toxicity. 
 
4. Liver:  GTV arising within the liver. 
• Rib metastases immediately adjacent to the liver will be assigned to the liver 
metastasis location based on potential for normal tissue toxicity. 
 
5. Spinal/paraspinal:  Metastases will be assigned to the spinal/paraspinal site if the GTV 
arises within the vertebral bodies expanded by 1 cm. Spinal metastases, shown in Figure 
5-4.4B in black, can involve:  
(a) The vertebral body only OR 
(b) The vertebral body and pedicle OR 
(c) Posterior elements only 
 

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Figure 5.4.4B 
 
For each of these metastases, the PTV delineation will include: 
(a) the involved vertebral body and both pedicles [solid red line in Figure 5.4.4B-
(a)] OR 
(b) a more generous delineation of the involved vertebral body and both pedicles 
[dashed red line in Figure 5.4.4B-(b)] OR  
(c) the involved vertebral body, both pedicles, and the anterior and posterior 
elements of the spine [solid red line in Figure 5.4.4B-(b)] OR 
(d) the spinous process and laminae [solid red line in Figure 5.4.4B-(c)] 
▪ The target volume may be chosen at the discretion of the treating 
Radiation Oncologist based on the extent of tumor involvement. 
▪ Spinal metastases with epidural extension will only be included if 
there is > 3 mm gap between the edge of the epidural metastasis and 
edge of the spinal cord. 
▪ Metastases arising in the ribs within 1 cm of the edge of the vertebral 
body should be included in the spinal metastasis location, but osseous 
metastases planning guidelines are to be used. 
▪  
6. Osseous: GTV arising within an osseous structure, part of the axial skeleton, not included 
in the spinal definition. 
• Rib metastases that are within 1 cm of the vertebral bodies will be classified 
into the spinal metastasis location given the similar normal tissues at risk. 
• Rib/scapular metastases within the thorax adjacent to lung parenchyma will be 
classified into the lung metastasis location given the similar normal tissues at 
risk. 
• Rib/osseous metastases adjacent (< 1cm) to mediastinal or cervical structures 
will be classified into the mediastinal/cervical lymph node location given the 
similar normal tissues at risk. 

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• Rib metastases adjacent (< 1cm) to the liver will be classified into the liver 
location given the similar normal tissues at risk 
• Rib metastases adjacent to the stomach/abdominal wall will be classified into 
the intra-abdominal location given the similar normal tissues at risk 
• 
Sternal metastases will be considered part of the mediastinal/cervical lymph 
nodes location given the similar normal tissues at risk. 
 
7. Abdominal-pelvic: GTV arising within the anatomic space defined by the diaphragm 
superiorly, the genitourinary diaphragm inferiorly including the peritoneal and 
retroperitoneal spaces, not including liver, osseous, or spinal metastases. 
 
Target Volume Definition Based on Metastatic Location: 
      Table 5.4.4A 
 
                                                Metastatic Location 
 
Site 1 
Site 2 
Site 3 
Site 4 
Site 5 
Site 6 
Site 7 
Planning 
Parameter 
Lung 
Central 
Lung 
Peripheral 
Mediastin
al/Cervical 
Liver 
Spinal 
Osseous 
Abdomin
al/Pelvic 
CT 
window/lev
el 
Pulmonar
y/ 
Mediastin
al 
Pulmonary/ 
Mediastinal 
 
Pulmonar
y/Mediasti
nal 
Hepatic 
Bone/Soft 
Tissue 
Bone/soft 
tissue 
Soft 
Tissue 
Additional 
Studies 
PET/CT 
PET/CT 
PET/CT 
 
PET/CT 
MRI 
PET/CT 
MRI 
PET/CT 
MRI 
PET/CT 
MRI 
Anatomy 
of focus for 
multi-
modality 
fusion 
Bony 
Anatomy 
Bony 
Anatomy 
Bony 
Anatomy 
Liver 
Bony 
Anatomy 
Bony 
Anatomy 
Bony 
Anatomy 
GTV 
definition 
Metastasis 
Metastasis 
Metastasis 
Metastasis 
Metastasis Metastasis 
Metastasis 
CTV 
definition 
= 
GTV/IGT
V* 
= 
GTV/IGTV
* 
= 
GTV/IGT
V* 
=GTV/IG
TV* 
=GTV 
= GTV 
= GTV/ 
IGTV* 
PTV axial 
expansion 
= CTV + 
5mm** 
= CTV + 
5mm** 
= CTV + 
5mm** 
= CTV + 
5mm** 
= PTV in 
RTOG  
0631** 
(see Figure 
5.4.4) 
= CTV +  
3-5mm** 
= CTV + 
5mm** 
PTV 
craniocaudal 
expansion  
= CTV + 
5-7mm** 
= CTV + 
5-7mm** 
= CTV + 
5-7mm** 
= CTV + 
5-7 mm** 
= PTV in 
RTOG 
0631** 
(see 
Figure 
5.4.4) 
= CTV +   
3-5mm** 
 = CTV + 
5-7 mm** 
*NOTE: A GTV to IGTV expansion of greater than 1cm in any one direction is strongly 
discouraged and alternative respiratory management technique is suggested. 
 

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**NOTE: When osseous/rib metastases are classified into other specific metastatic 
locations, the planning guidelines for that metastatic location should be used. If rib 
metastases are grouped into the spinal metastasis location, then the metastasis should be 
contoured as defined for osseous metastases, but the prescription doses for the spinal 
region should be used.  
 
+NOTE: Mediastinal lymph nodes should undergo motion assessment and an IGTV 
should be generated to account for motion.  
 
Target Volume Definition For The Primary Disease if Included in Treatment or Metastases  
(not amendable to SBRT) Treated with Hypofractionation: 
For the treatment of the primary disease or metastases with a hypofractionated approach of 45 
Gy in 15 fractions, the GTV will be contoured as above and an IGTV will be created from all 
phases.  An expansion of 5-8 mm for CTV is expected, with a PTV expansion of 5 mm at 
minimum with daily imaging but no more than 1 cm. 
 
Table 5.4.4B Description and Naming of Required Target Volumes 
Standard Name 
Description 
GTVXY_2400 
GTV receiving 1 fraction with 
site "X" *, number Y of site X 
IGTVXY_2400  
IGTV receiving 1 fraction with 
site "X" *, number Y of site X 
PTVXY_2400 
PTV receiving 1 fraction with 
site "X" *, number Y of site X 
GTVXY_3000 
GTV receiving 3 fraction with 
site "X" *, number Y of site X 
IGTVXY_3000 
IGTV receiving 3 fraction with 
site "X" *, number Y of site X 
PTVXY_3000 
PTV receiving 3 fraction with 
site "X" *, number Y of site X 
GTVXY_3400 
GTV receiving 5 fraction with 
site "X" *, number Y of site X 
IGTVXY_3400 
IGTV receiving 5 fraction with 
site "X" *, number Y of site X 
PTVXY_3400 
PTV receiving 5 fraction with 
site "X" *, number Y of site X 
GTV_4500 
GTV of primary site/metastases 
IF treated with conventional 
fractionation 
IGTV_4500 
IGTV of primary site/metastases 
IF treated with conventional 
fractionation 
CTV_4500 
CTV of primary site/metastases 
IF treated with conventional 
fractionation 

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PTV_4500 
PTV of primary site/metastases 
IF treated with conventional 
fractionation 
* For the Standard Names above, X equals 1-7, dependent on anatomic treatment site listed in 
Sec. 5.4.4, Y equals a, b, c… 
 
All structures listed in this table are required when applicable and must be labeled as indicated. 
 
Each lesion should be labeled by their anatomic treatment site, with exception of the primary site 
or metastases if they are receiving conventional fractionation.  They should also be distinguished 
by adding a letter after the site number, a for the 1st lesion, b for the 2nd and c for the third.  An 
example of this would be PTV1a_2400, PTV1b_2400 and PTV4a_3000, which would 
correspond with having two peripheral lung lesions (sites 1a and 1b) receiving 1 fraction, and 
one liver lesion (site 4a) receiving three fractions.   
 
Detailed Specifications  
Note: Instructions on IGTV and PTV creation based on treatment technique is given at the end of 
this section. 
 
Specific SBRT planning parameters depend on the location of the treated metastasis as well as 
the mechanism used for motion management/evaluation. The table below defines appropriate 
planning CT window/leveling, recommended additional modality scans to be fused, as well as 
how to define the GTV, IGTV, CTV, and PTV for each metastatic location. Only rigid 
registration will be permitted for multi-modality fusion. In general, the GTV is defined as the 
entirety of the metastasis as seen on planning CT scan aided by additional diagnostic imaging 
studies (i.e., PET/CT or MRI). Use of additional diagnostic studies is left to the discretion of the 
treating physician. The CTV=GTV; there is no margin added for microscopic extension. In 
general, either a helical CT or 4DCT will be used for defining the GTV/IGTV depending upon 
the tumor motion encountered, although both scans may be acquired at the time of simulation.  
 
Targets in lung will generally be drawn using CT pulmonary windows; however, soft tissue 
windows, ideally with contrast, should be used to avoid inclusion of adjacent vessels, atelectasis, 
or mediastinal or chest wall structures within the GTV. Information from fusion of multimodality 
imaging (e.g. PET) may be helpful in delineating tumor from normal tissue. For example, in the 
presence of large amounts of atelectasis or fibrotic changes, PET may be necessary to aid in 
GTV definition.  IV contrast used with the planning CT is useful to differentiate more subtle 
atelectasis from tumor since atelectasis does not enhance. When a multimodality image serves as 
the primary image for GTV delineation, an additional margin to account for registration 
uncertainty should be considered when transferring the GTV to the primary image.   
 
The motion encompassing GTV will be defined at the IGTV. Note that the term “ITV” is 
explicitly avoided to prevent confusion between a motion encompassing CTV and GTV: 

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The PTV shall be defined as the IGTV (or GTV when strict motion control is applied) plus an 
uncertainty/set-up error margin.  That uncertainty/set-up margin shall be 5 +/- 2 mm in all 
directions.  If institutional interfraction uncertainties suggest that this would not be a sufficient 
PTV margin for the workflow and equipment involved, please contact the protocol PIs and 
physics co-chair for additional guidance.  Note that PTV margins are not to account for internal 
motion uncertainty (which is accounted for within the definition of the IGTV).  The addition of 
an inverse planning optimization “helper” structure can be made to increase coverage to account 
for dose gradients (i.e. for coplanar VMAT in the cranial/caudal direction) as deemed necessary 
by the treating institution.  General guidelines for IGTVs and GTVs, based on treatment 
technique, are summarized below in Table 5.4.4C. 
 
Table 5.4.4C Guidelines for Definition of IGTV and PTV corresponding to Treatment 
Technique  
Treatment Technique 
Definition of IGTV 
Definition of PTV  
IGTV using 4DCT 
(includes abdominal 
compression) 
Boolean union of GTV defined on all 
phases of 4DCT or a maximum intensity 
projection image (1) 
Refer to Table 5.4.4A 
Gating with a gating 
window 
Boolean union of GTV defined on the 
gated phases of 4DCT  
Breath hold (i.e. ABC) 
An appropriate margin (2-5 mm) to 
account for breath hold reproducibility or 
uncertainty is recommended 
Tracking 
An appropriate margin (2-5 mm) to 
account for tracking reproducibility or 
uncertainty is recommended 
(1) If a Maximum Intensity Projection dataset is used for IGTV delineation, care must be taken 
to verify the IGTV against the GTV defined above on each individual phase.  In addition, the 
MIP is not appropriate for tumors located near boundaries with soft tissue density, such as near 
the diaphragm or mediastinum. 
 
5.4.5  Definition of Critical Structures and Margins 
Note: All structures must be named for digital RT data submission as listed in the table below.     

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Resubmission of data may be required if labeling of structures does not conform to the standard 
DICOM name listed.  Capital letters, spacing and use of underscores must be applied exactly as 
indicated. 
 
The following table outlines the naming of the various normal and critical structures for 
submission to TRIAD.  
 
Table 5.4.5A  
Note:  X represents the anatomic treatment site 1-7 as listed in Sec. 5.4.4. 
Standard Name 
Description  
PTV as listed in Table 5.4.4B above  
See Table 5.4.4B above  
 
PTV20 
PTV expanded by 20mm 
E-PTVX 
 
All tissue excluding the PTV. Generated by 
subtracting the PTV receiving a dose of xxxx cGy 
from the external contour. 
External minus PTV with site "X" *(including all 
subsites “Y), with dose (e.g. E-PTV2_2400) 
E-PTVX_Ev20  
All tissue excluding the 20 mm expanded PTV. 
Generated by subtracting the 20 mm expanded PTV 
receiving a dose of xxxx Gy from the external 
contour. 
(External minus PTV20mm)  
 
BileDuct_Common  
 
Common Bile duct 
Bladder 
Bladder 
BrachialPlex_L 
Left Brachial Plexus 
BrachialPlex_R 
Right Brachial Plexus 
BrachialPlexus 
 
Total Brachial plexus 
Bronchus 
Bronchial tree 

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Bronchus+20 
  
Proximal bronchial tree expanded by 2cm 
 
CaudaEquina 
Cauda equina 
Chestwall 
Chest wall 
Colon 
Colon 
Duodenum 
Duodenum 
Esophagus_NAdj 
Esophagus Non-Adjacent Wall 
Jejunum_Ileum 
Both ileum and jejunum 
Esophagus 
Esophagus 
External 
Body surface 
Femur_L 
Left whole Femur 
Femur_R 
Right whole Femur 
Femurs 
Combined Left and Right Femurs 
GreatVes 
Great Vessels 
Great Vessels of the heart (aorta, vena cava S&I, 
pulmonary A&V) 
GreatVes_NAdj 
Great Vessels Non-Adjacent Wall 
Heart 
Heart 
Larynx 
Larynx 
Liver 
Liver 
Liver-GTV  
Liver minus GTV 
Lung_L 
Left Lung 
Lung_R 
Right Lung 
Lungs 
Combined Left and Right Lungs 
Lungs-GTV 
Combined Left and Right Lungs minus GTV  
Rectum 
Rectum 
Kidney_Cortex 
Renal cortex for both Kidneys 
Rib 
Ribs within 10 cm of the PTV should be contoured by 
outlining the bone and marrow 
SacralPlex 
Sacral plexus 

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Skin 
Outer 0.5 cm of the body surface (rind)  
SpinalCord 
Spinal cord 
Stomach 
Stomach 
Trachea 
Trachea 
Trachea_NAdj 
Trachea non-adjacent wall 
Ureter 
Ureter 
* X equals 1-7, dependent on anatomic treatment site (1 – 7) described in Section 5.4.4 
General, critical structures should be contoured if they are found within an axial slice within 10 
cm in the craniocaudal. 
 
Critical structure contours will be drawn in axial planes of the primary planning dataset.  In 
general, critical structures should be contoured if they are found within an axial slice within 10 
cm in the craniocaudal direction of any PTV slice treated on protocol.  As such, they may be 
further than 10 cm direct separation and still required to be contoured.  If a named critical 
structure is further than 10 cm from any PTV, then it need not be contoured or submitted. 
 
All metastases-specific organs at risk (OAR) must be contoured. The specific OAR to be 
contoured will depend on the location of metastases to be treated. The contour of structures that 
have a lumen (bronchus, trachea, esophagus, etc.) will include both the “wall” and the “lumen” 
to result in a cylindrical structure.  In general, OAR within 10 cm of any single metastasis should 
be contoured. To identify these OARs, all PTVs will be expanded by 10 cm and any OAR that 
overlaps with PTV + 10 cm must be contoured.  Structures must be labeled as shown above in 
Tables 5.4.4B and 5.4.5 or resubmission may be required. 
 
Spinal Cord  
The spinal cord will be contoured based on the bony limits of the spinal canal. The spinal cord 
should be contoured starting at least 10 cm above the superior extent of any PTV and continuing 
on every CT slice to at least 10 cm below the inferior extent of any PTV. NOTE: For the spinal 
cord, constraints are absolute limits, and treatment delivery that exceeds defined limits will 
constitute a major protocol violation.  
 
Cauda Equina 
Starting at the conus (end of spinal cord, typically around L1 or L2) include the entire spinal 
canal into the sacrum to the filum. 
 
Esophagus  
The esophagus will be contoured using mediastinal windowing on CT to correspond to the 
mucosal, submucosa, and all muscular layers out to the fatty adventitia. The esophagus should be 
contoured starting at least 10 cm above the superior extent of any PTV and continuing on every 
CT slice to at least 10 cm below the inferior extent of any PTV.  
 
Brachial Plexus  
The defined ipsilateral brachial plexus originates from the spinal nerves exiting the 
neuroforamina on the involved side from around C5 to T2. However, for the purposes of this 
protocol, only the major trunks of the brachial plexus will be contoured. The brachial plexus will 

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be contoured starting proximally at the bifurcation of the brachiocephalic trunk into the 
jugular/subclavian veins (or carotid/subclavian arteries) and following along the route of the 
subclavian vein to the axillary vein ending after the neurovascular structures cross the second rib. 
If any PTV is more than 10 cm away from the brachial plexus, this structure does not need to be 
contoured.  
 
Sacral Plexus 
Include the nerve roots from L5 to S3 on each side from the neuroforamina to the coalescing of 
the nerves at the obturator internus muscle. 
 
Heart  
The heart will be contoured along with the pericardial sac. The superior aspect (or base) for 
purposes of contouring will begin at the level of the inferior aspect of the aortic arch (aorto-
pulmonary window) and extend inferiorly to the apex of the heart.  
 
Trachea and Proximal Bronchial Tree  
The trachea and proximal bronchial tree will be contoured as two separate structures using 
mediastinal windows on CT to correspond to the mucosal, submucosa and cartilage rings and 
airway channels associated with these structures. For this purpose, the trachea will be divided 
into two sections: the proximal trachea and the distal 2 cm of trachea. The proximal trachea will 
be contoured as one structure, and the distal 2 cm of trachea will be included in the structure 
identified as proximal bronchial tree.  
 
Proximal 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. 
 
Proximal Bronchial Tree  
The proximal bronchial tree will include the most inferior 2 cm of distal trachea and the proximal 
airways on both sides as indicated in the diagram in above. The following airways will be 
included according to standard anatomic relationships: the distal 2 cm of trachea, the carina, the 
right and left mainstem 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.  
 
Whole Lung  
Both the right and left lungs should be contoured individually (Lung_L, Lung_R) and also 
combined as one structure (Lungs). Contouring should be carried out using pulmonary windows. 
All inflated and collapsed lung should be contoured; however, gross tumor (GTV) and 
trachea/ipsilateral bronchus as defined above should not be included for the structure created and 
-labeled as Lungs-GTV.   
 
PTV + 2 cm (PTV20) 
As part of the QA requirements for “low dose spillage” listed above, a maximum dose to any 
point 2 cm away in any direction is to be determined (D2cm). To facilitate this QA requirement, 

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an artificial structure 2 cm larger in all directions from the PTV is required. Most treatment 
planning systems have automatic contouring features that will generate this structure without 
prohibitive effort at the time of treatment planning. If possible this structure should be 
constructed as a single contour that is 2 cm larger than the PTV.  
 
Skin  
The skin will be defined as the outer 0.5 cm of the body surface. As such it is a rind of uniform 
thickness (0.5 cm) which envelopes the entire body in the axial planes. The cranial and caudal 
surface of the superior and inferior limits of the planning CT should not be contoured as skin 
unless skin is actually present in these locations (e.g., the scalp on the top of the head).  
 
Rib  
Ribs within 10 cm of the PTV should be contoured by outlining the bone and marrow. Typically, 
several portions of adjacent ribs will be contoured as one structure. Adjacent ribs, however, 
should not be contoured in a contiguous fashion (i.e., do not include the inter-costal space as part 
of the ribs).  
 
Stomach 
The entire stomach and its contents should be contoured as a single structure as a continuation of 
the esophagus and ending at the first part of the duodenum. 
 
Duodenum 
The wall and contents of the 1st, 2nd, and 3rd parts of the duodenum will be contoured as one 
structure beginning where the stomach ends and finishing as the superior mesenteric artery 
crosses over the third part of the duodenum. 
 
Jejunum/Ileum 
As a conglomerate of bowel loops within the abdomen distinguished from stomach, duodenum, 
and colorectum. 
 
Colon 
From the ileocecal area to include the ascending, transverse, descending and sigmoid colon as 
one structure. 
 
Rectum 
The entire rectum with contents from the peritoneal reflection of the sigmoid to the anus. 
 
Bladder 
The entire bladder wall without urine. 
 
Renal Cortex (right and left combined as one) 
Specifically, the parallel functioning nephrons of the renal cortices of the kidneys (not the 
hilum). 
 
Liver 

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The entire liver as well as an additional structure created to exclude the GTV targets where 
applicable. (Liver – GTV). 
 
Bile ducts 
May use the portal vein from its juncture with the splenic vein to its right and left bifurcation in 
the liver as a surrogate to identify the bile ducts. 
 
Femur 
Individual left and individual right femur as well as a combined structure (Femur_L, Femur_R, 
Femurs). 
 
Other Structures  
The constraints tables above contain other structures. These are required if the structure is within 
10 cm of the PTV. 
 
5.4.6 Treatment Planning Guidelines for radiation administration 
 
Treatment planning for SBRT should be approached with care and experience is recommended 
for sites enrolling on an SBRT protocol.  Table 5.4.6A summarizes the general planning 
guidelines for this protocol. 
 
Table 5.4.6A General Treatment Planning Guidelines 
 
Topic/Parameter 
Guidelines 
Planning Technique 
3DCRT, conformal arc, and intensity-modulated techniques (IMRT, 
VMAT) allowed.  Tomographic and robotic techniques also allowed with 
appropriate credentialing having been completed.  See Section 8.2 for 
further details. 
Number of Beams 
As planning dictates although ≥10 beams are recommended for static 
beam plans due to skin toxicity considerations.  Similarly, arcs should 
cover an appropriate range so as to deliver a safe dose to the skin. 
Beam Arrangement 
Coplanar or non-coplanar (non-coplanar are encouraged), non-
overlapping, non-opposing beams or arc therapy (non-coplanar arcs 
encouraged).  Combination of static and arc beams allowed.  Gantry 
clearance verification prior to treatment should be a mandatory part of 
patient specific QA. 
Beam Energy 
As planning dictates although lower energies preferred for lung (see 
5.4.1A) 
Block Margin (for 
3DCRT) 
Generally 0 +/- 2 mm, but iterated to achieve coverage specifications.  
Negative margin blocks are frequently useful to create steep gradients 
along the axial limits of the PTV while positive margin (e.g., +2 mm) are 
often needed on the cranial and caudal limits of the PTV 

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Minimum Field Size 
As planning dictates although only the smallest field size accurately 
commissioned (e.g. small field output factors are within 5% of published 
standards or values) at the institution should be used.  Because of 
concerns with small field dosimetry, field sizes above 2 cm x 2 cm are 
preferable. 
Dataset for Dose 
Calculation 
IGTV Approach – Average CT (AveIP) from 4DCT or a slow acquisition 
CT which captures motion if 4DCT not available (Free breathing CT is 
not appropriate) 
Breath Hold – CT taken at treatment breath hold 
Gated – Average from gating window phases from 4DCT or the median 
phase in the gating window 
Tracking – 4DCT or breath hold CT 
 
Scans with contrast are generally acceptable for dose calculations.  
However, density/material overrides are recommended in areas of strong 
contrast when dose calculation accuracy may be affected (such as oral 
contrast in the esophagus).       
Dose Calculation 
Algorithm 
Modern algorithms that accurately handle tissue heterogeneity and scatter 
should be used.  IROC maintains an updated list of approved algorithms. 
Density corrections must be applied.  Density overrides of the GTV are 
not recommended for photon treatment.   
Dose Grid 
Resolution 
3 mm x 3 mm dose grid resolution or smaller is required.  Use of 2 mm x 
2 mm is recommended, especially for targets less than 2 cm in diameter. 
 
Protocol specific fractionation details as well as prescription definition and compliance 
guidelines are given in Tables 5.4.6B and 5.4.6C. 
 
Table 5.4.6B Protocol Specific Fractionation Details 
 
Item 
Details 
1 Fraction 
SBRT 
3 Fraction 
SBRT 
5 Fraction 
SBRT 
Primary Site/ 
Metastases 
Not 
Amenable to 
SBRT 
Number of 
Fractions 
1 
3 
5 
15 
Dose Per 
Fraction (Gy) 
24 
10 
6.8 
3 
Total Treatment 
Duration 
See section 5.4.7 
 
Table 5.4.6C Protocol Specific Target Dose Details and Recommendations 

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Metric 
Guideline Value 
1 Fraction 
SBRT 
3 Fraction 
SBRT 
5 Fraction 
SBRT 
Primary Site/ 
Metastases 
Not Amenable 
to SBRT 
D95% [Gy] for PTV 
(ie. Dose covering 95% 
of PTV) 
24 
30 
34 
45 
D99% [Gy] for PTV 
(ie. Dose covering 99% 
of PTV) 
21.6 
27 
30.6 
40.5 
Dose Heterogeneity 
within PTV 
Typical normalization 60-90% with hotspot 
within GTV.   
A volume of no 
more than 0.03 
cc inside the 
PTV exceeds 
110%, The 
minimum PTV 
dose to a 
volume of 0.03 
cc falls below 
90% 
R100% (Rx Isodose 
volume/PTV) 
<1.2 Desired.  Exceptions can be made for small 
PTVs requiring a block margin to satisfy field 
size criteria.  Effort should be made to avoid 
dose > 105% of the prescription dose outside of 
the PTV.   
N/A 
R50% (50% Rx Isodose 
volume/PTV) 
Effort should be made to have the 50% isodose 
surface be as small as possible.  Detailed tables 
of recommendations are given below for single 
targets. 
N/A 
 
 
Table 5.4.6D Recommendations for Allowable Dose Spillage 
 
PTV 
Volume 
(cc)      
 
 
Ratio of 50% Isodose Volume 
to the PTV, R50% 
 
Maximum Dose at 2 cm from PTV 
in any direction as % of nominal Rx dose 
D2cm[%] 
 
Per Protocol 
Variation Acceptable 
Per Protocol 
Variation Acceptable 
1.8 
<5.9 
<7.5 
<50.0 
<57.0 
3.8 
<5.5 
<6.5 
<50.0 
<57.0 
7.4 
<5.1 
<6.0 
<50.0 
<58.0 
13.2 
<4.7 
<5.8 
<50.0 
<58.0 
22.0 
<4.5 
<5.5 
<54.0 
<63.0 

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34.0 
<4.3 
<5.3 
<58.0 
<68.0 
50.0 
<4.0 
<5.0 
<62.0 
<77.0 
70.0 
<3.5 
<4.8 
<66.0 
<86.0 
95.0 
<3.3 
<4.4 
<70.0 
<89.0 
126.0 
<3.1 
<4.0 
<73.0 
<91.0 
163.0 
<2.9 
<3.7 
<77.0 
<94.0 
 
5.4.7 Compliance criteria 
Treatment Duration  
  
Interfractional Interval must be no less than 36 hours and no greater than 8 days. 
 
Treatment duration will be defined per metastatic site treated with SBRT and treatment of 
primary disease and/or metastases requiring hypofractionated 15 fraction regimen. 
 
 
Per Protocol:  
• Single Fraction Treatment: SBRT should be completed within 2 weeks of 
randomization 
• 3 fraction treatment:  All 3 fractions of SBRT should be completed within 2 
weeks of first SBRT dose and within 4 weeks of randomization 
• 5 fraction treatment:  All 5 fractions of SBRT should be completed within 3 
weeks of first SBRT dose and within 5 weeks of randomization 
• 15 fraction treatment:  All 15 fractions of radiation should be completed within 3 
weeks of first hypofractionated dose, ideally within 4 weeks of randomization and 
at the latest within 5 weeks of randomization 
  
 
Variation Acceptable:  
• All SBRT treatment completing > 3 but < 4 weeks 
• Primary site hypofractionated RT completing >3 weeks but <5 weeks 
 
 
Deviation Unacceptable:  
• All SBRT treatment completed > 4 weeks 
• Primary site hypofractionated RT completed >5 weeks 
 
If the primary disease and/or metastases not amenable to SBRT is treated with 45 Gy in 15 
fractions, this treatment should ideally be completed over 21 days and any metastatic areas 
needing treatment with SBRT can be given on the appropriate days within that three week 
period. For a given lesion (target) treated with SBRT, a minimum of 36 hours and a maximum of 
8 days should separate consecutive treatments of that same lesion. While up to 2 metastatic 
lesions may be treated on the same day with SBRT, the treating physician may choose to 
separate treatments to alternating lesions by one or more days so long as all treatment is 
completed per protocol.  All SBRT treatments should ideally be completed within 21 days of 
first treatment and no later than 28 days.   
 

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Ample time should be scheduled for each treatment to insure careful execution of the SBRT for 
each lesion.  No more than 2 anatomic sites should be treated with SBRT on any given day. Try 
to avoid long treatment sessions (e.g., treating 3 anatomic sites in one day with SBRT or 
hypofractionated treatment of primary plus 2 sites of metastases with SBRT) as the resulting 
discomfort for the patient from prolonged immobilization may confound accuracy. If there are 
multiple metastatic sites (2 or 3) being treated with 5 fraction SBRT regimens in addition to a 
primary disease site treated with the hypofractionated regimen, there may be a necessity to treat 
that primary disease and both metastatic sites on the same day as a means of getting the patient to 
maintenance systemic therapy in a clinically appropriate time frame.  Ideally, radiation and 
surgery should be completed within 5 weeks of start of local treatment. 
 
Treatment Plan Compliance 
The compliance criteria listed here will be used to score each case.  Given the limitations 
inherent in the treatment planning process, the numbers given in this section can be different than 
the prescription table.  The Per Protocol and Variation Acceptable categories are both considered 
to be acceptable.  The Per Protocol cases can be viewed as ideal plans, and the Variation 
Acceptable category can include more challenging plans that do not fall at or near the ideal 
results.  A final category, called Deviation Unacceptable, results when cases do not meet the 
requirements for either Per Protocol or Variation Acceptable. Plans falling in this category are 
considered to be suboptimal and additional treatment planning optimization is recommended.  
Institutions are encouraged to contact the PI or medical physics co-chair prior to submitting a 
case with a known unacceptable deviation. 
 
PTV Dosimetry Compliance for SBRT 
Tables in Section 5.4.7 describe acceptable variations in the protocol dosimetric parameters. 
These criteria should be evaluated for each metastasis independently (i.e., while suppressing 
dose from all other metastases), particularly for metastases treated on separate days. This may 
not be possible for metastases treated on the same day using a single plan (e.g., VMAT). 
Dosimetric parameters outside of the variation acceptable range will be scored as Deviation 
Unacceptable.  Please refer to Table 5.4.6B above for allowable prescription and fractionation 
options.   
 
Table 5.4.7A 
Name of Structure 
Dosimetric parameter 
Per 
Protocol 
Variation 
Acceptable 
PTVXY_2400 
 
D95%[Gy] 
24 
16-27 
Excluding 24 
PTVXY_3000 
D95%[Gy] 
30 
24.5-33 
Excluding 30 
PTVXY_3400 
D95%[Gy] 
34 
28-37.5 
Excluding 34 
Note:  X equals the Treatment Site number 1 (1-7) and Y is the sequence of lesion if multiple are 
in one area (a, b, c) 
 
PTV Dosimetry Compliance for Primary Site/Metastases Not Amendable to SBRT 
Table 5.4.7B 

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Name of 
Structure 
Dosimetric parameter 
Per 
Protocol 
Variation 
Acceptable 
PTV_4500 
 
D95%[Gy] 
45 
42-48 
(excluding 45) 
 
Organ at Risk Dosimetry Compliance for SBRT 
 
Table 5.4.7C Normal Structure Constraints and Compliance Criteria  
 
 
1 
Fraction 
3 
Fractions 
5 
Fractions 
 
Serial Tissue 
Volume 
Per 
Protocol 
(Gy) 
Per 
Protocol 
(Gy) 
Per 
Protocol 
(Gy) 
Endpoint 
(≥Grade 3) 
Optic Pathway 
D0.03cc[Gy] 
10 
17.4 
25 
neuritis 
D0.2cc[Gy] 
8 
15.3 
23 
Cochlea 
D0.03cc[Gy] 
9 
14.4 
22 
hearing loss 
Brainstem (not 
medulla) 
D0.03cc[Gy] 
15 
23.1 
31 
cranial 
neuropathy 
D0.5cc[Gy] 
10 
15.9 
23 
Spinal Cord and 
medulla 
D0.03cc[Gy] 
14 
22.5 
28 
myelitis 
D0.35cc[Gy] 
10 
15.9 
22 
D1.2cc[Gy] 
8 
13 
15.6 
Cauda Equina 
D0.03cc[Gy] 
16 
22.5 
31.5 
neuritis 
D5cc[Gy] 
14 
21.9 
30 
Sacral Plexus 
D0.03cc[Gy] 
16 
22.5 
31.5 
neuropathy 
D5cc[Gy] 
14.4 
22.5 
30 
Esophagus* 
D0.03cc[Gy] 
15.4 
25.2 
35 
stenosis/fistula 
D5cc[Gy] 
11.9 
17.7 
19.5 
Brachial Plexus 
D0.03cc[Gy] 
16.4 
26 
32.5 
neuropathy 
D3cc[Gy] 
13.6 
22 
27 
Heart/Pericardiu
m 
D0.03cc[Gy] 
22 
30 
38 
pericarditis 
D15cc[Gy] 
16 
24 
32 
Great vessels 
D0.03cc[Gy] 
37 
45 
53 
aneurysm 
D10cc[Gy] 
31 
39 
47 

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Trachea and 
Large Bronchus* 
D0.03cc[Gy] 
20.2 
30 
40 
stenosis/fistula 
D4cc[Gy] 
17.4 
  
  
D5cc[Gy] 
  
25.8 
32 
Bronchus- 
smaller airways 
D0.03cc[Gy] 
13.3 
23.1 
33 
stenosis with 
atelectasis 
D0.5cc[Gy] 
12.4 
18.9 
21 
Rib 
D0.03cc[Gy] 
33 
50 
57 
Pain or fracture 
D5cc[Gy] 
28 
40 
45 
Skin 
D0.03cc[Gy] 
27.5 
33 
38.5 
ulceration 
D10cc[Gy] 
25.5 
31 
36.5 
Stomach 
D0.03cc[Gy] 
22 
30 
35 
ulceration/fistula 
D5cc[Gy] 
17.4 
22.5 
26.5 
Bile duct 
D0.03cc[Gy] 
30 
36 
41 
stenosis 
Duodenum* 
D0.03cc[Gy] 
17 
22.2 
26 
ulceration 
D5cc[Gy] 
11.2 
15.6 
18.5 
D10cc[Gy] 
9 
12.9 
14.5 
Jejunum/Ileum* 
D0.03cc[Gy]  
22 
27 
32 
enteritis/obstruct
ion 
D30cc[Gy]  
12.5 
17.4 
20 
Colon* 
D0.03cc[Gy]  
29.2 
34.5 
40 
colitis/fistula 
D20cc[Gy]  
18 
24 
28.5 
Rectum* 
D0.03cc[Gy]  
44.2 
49.5 
55 
proctitis/fistula 
D3.5cc[Gy] 
39 
45 
50 
D20cc[Gy] 
22 
27.5 
32.5 
Ureter 
D0.03cc[Gy] 
35 
40 
45 
stenosis 
Bladder wall 
D0.03cc[Gy] 
25 
33 
38 
cystitis/fistula 
D15cc[Gy] 
12 
17 
20 

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Penile bulb 
D3cc[Gy] 
16 
25 
30 
impotence 
Femoral Heads  
D10cc[Gy] 
15 
24 
30 
necrosis 
 
 
 
 
 
 
 
  
  
1 
Fraction 
3 
Fraction 
5 
Fraction 
  
Parallel Tissue 
Constraint** 
Per 
Protocol 
(cc or 
%) 
Per 
Protocol 
(cc or 
%) 
Per 
Protocol 
(cc or 
%) 
Endpoint 
(≥Grade 3) 
Lungs-GTV 
CV7Gy[cc] 
>1500 
  
  
Basic Lung 
Function 
CV10.5Gy[cc] 
  
>1500 
  
CV12.5Gy[cc] 
  
  
>1500 
V8Gy[%] 
<37 
  
  
Pneumonitis 
V11Gy[%] 
  
<37 
  
V13.5Gy[%] 
  
  
<37 
Liver 
CV11Gy[cc] 
>700 
  
  
Basic Liver 
Function 
CV17.1Gy[cc] 
  
>700 
  
CV21Gy[cc] 
  
  
>700 
Renal cortex 
(Right & Left) 
CV9.5Gy[cc] 
>200 
  
  
Basic Renal 
Function 
CV15Gy[cc] 
  
>200 
  
CV18Gy[cc] 
  
  
>200 
*Avoid circumferential irradiation 
 
** A complementary volume (CV) or “cold volume” is the volume of tissue receiving the 
indicated dose or less.  CVxGy[cc] are complementary or cold volume objectives for parallel 
tissues, where "xGy" is the threshold dose and the critical volumes are displayed in the table.  To 
use these objectives as conventional DVH-based inverse planning objectives, the planner can 
convert using the total structure volume and the equation Vthreshold dose[%] <   [1 - (Vcritical / Vtotal)]  
x 100% (note the change to "less than").  For example, for the CV12.5Gy[cc] metric and a total 
lung volume of 4000cc, the corresponding maximum volume objective V12.5Gy[%] should be 
kept less than [1 - (1500 / 4000)]  x 100%,  or < 62.5%. 
 
 

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NOTE: For the spinal cord, these are absolute limits, and treatment delivery that exceeds 
these limits will constitute a major protocol violation. For the non-spinal cord tissues, 
acceptable deviation following the planning priorities allows a maximum point dose no more 
than 105% of the prescription dose while fully respecting the defined volume constraint (for 
serial tissues) OR exceeding the parallel tissue critical volume dose maximum by no more than 
5%. Unacceptable deviation exceeds the volume constraint for serial tissues, exceeds the 
maximum point dose for serial tissues by more than 105% of the prescription dose, or exceeds 
the parallel tissue critical volume dose maximum by more than 5%. 
 
Organ at Risk Dosimetry Compliance for Primary Site for Primary Site/Metastases Not 
Amenable to SBRT  
 
Table 5.4.7D 
 
Structure 
Constraint 
Per Protocol 
(Gy or %) 
Variation 
Acceptable* 
 
Lungs minus primary GTV 
 
V18Gy[%] 
37 
40 * 
Mean[Gy] 
18 
19.7 
Great Vessels 
D0.03cc[Gy] 
54.3 
59.6 
D10cc[Gy] 
48.9 
53.7 
Skin 
D0.03cc[Gy] 
55 
60.8 
D10cc[Gy] 
49 
53.8 
 
Esophagus (non-adjacent wall) 
 
D5cc[Gy] 
45 
51.3 
D0.03cc[Gy] 
54 
59.4 
 
Brachial Plexus 
 
D0.03cc[Gy] 
50.6 
52.5 
D3cc[Gy] 
44.5 
48.0 
 
Spinal Cord 
 
D0.03cc[Gy] 
42 
46 
D5cc[Gy] 
39.0 
42.8 
Bronchus_Main 
D0.03cc[Gy] 
45.6 
50.1 
D5cc[Gy] 
39.5 
43.4 

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Rib 
D0.03cc[Gy] 
52.2 
57.3 
D5cc[Gy] 
48.9 
53.7 
 
Heart 
 
D0.03cc[Gy] 
48.9 
53.7 
D15cc[Gy] 
39.5 
42.0 
 
CAUTION: If a primary site is adjacent to the one of the metastatic SBRT sites, please 
contact the Study PI for further instructions.    
 
5.4.8    Treatment Planning Priorities and Instructions    
Successful treatment planning criteria are listed in the previous section. In general, 
attempts should be made to successfully satisfy all of the criteria without deviation. In 
some circumstances, improvements can be made to the dosimetry plan beyond simply 
meeting the specified goals. In other circumstances, clinicians are faced with the prospect 
of not ideally meeting one or more of the criteria (i.e., accepting an acceptable deviation). 
In this section, we provide priorities in which a most ideal plan for protocol purposes is 
realized. Figure 5.4.8A demonstrates these priorities graphically. Suggested priority of 
planning goals in order of importance is:  
 
Table 5.4.8A Treatment Planning Priorities 
Planning 
Priority 
Instructions 
1 
Respect spinal cord, cauda equina, sacral plexus, brachial plexus, luminal GI 
structures (esophagus, stomach, duodenum, jejunum, ileum, colon) dose constraints 
in Table 5.4.7C. 
2 
Meet dose “compactness” constraints including the prescription isodose surface 
coverage, high dose spillage (location and volume), and intermediate dose spillage 
(D2cm, and R50) as these define the “essence” of SBRT.  
3 
Meet critical structure constraints other than those listed in 1.  
 
NOTE: No studies of OAR limits for multiple metastases have been reported in the literature. 
Thus, organ limits from previously developed protocols, as shown in Tables 5-7, 5-8 and 5-9 
below, will be utilized. 
 

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Figure 5.4.8A Graphical representation of preferred planning tradeoffs in areas of overlap.  
See Table 5.4.8A for more detail. 
 
5.4.9 Patient specific QA 
Any patient-specific QA that needs to be acquired should follow institutional guidelines.  For 
intensity-modulated techniques, patient specific QA is required.   
 
5.4.10 Daily Treatment Localization/IGRT   
Daily image guidance is required for all SBRT treatments.  Table 5.4.10A lists details of IGRT 
and the minimum requirements for IGRT in lung.  Techniques should be consistent with Tables 
5.4.2B and 5.4.4B.  It is very strongly recommended that all calculated IGRT shifts of 1 mm and 
greater (using primary localization imaging) be applied. 
 
Table 5.4.10A Guidelines/Instructions for Acceptable IGRT 
Treatment 
Technique 
Acceptable Methods for Daily Image 
Guidance 
Matching Instructions 
IGTV/free 
breathing 
(includes 
abdominal 
compression) 
Volumetric Imaging 
Volumetric Imaging (i.e. CBCT or CT on 
rails) is strongly recommended 
 
 
Initial rigid alignment followed 
by soft tissue match with average 
CT and  slow CBCT 
 
4DCT to 4D-CBCT can be used 
when capability exists 
Planar Imaging 
If volumetric imaging is not available, then 
an 
appropriate 
tumor 
surrogate 
(i.e. 
implanted fiducials) must be able to be 
accurately imaged in the treatment position 
with 2D imaging.  The patient surface is not 
an appropriate surrogate for tumor setup 
although surface based imaging may be used 
during treatment to assess unexpected patient 
motion. 
 
Note that when orthogonal 2D imaging (with 
or without implanted fiducials) is employed 
for sites where respiratory motion is 
expected and not controlled via motion 
management techniques, care must be taken 
to ensure accurate targeting of the IGTV 
within the treatment. For example, static kV 
imaging at an undetermined breath hold 
position would not be adequate IGRT for 
treating a free-breathing lung tumor.   
 
Repeat 
imaging 
during 
treatment 
is 
1. Rigid alignment to bony 
anatomy 
2. Repeat imaging to ensure 
tumor surrogate is within 
IGTV 
3. Repeat imaging at each 
treatment port to ensure 
tumor surrogate remains 
within the IGTV is very 
strongly recommended 
 

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recommended to verify that the tumor is in 
the IGTV 
 
If any significant baseline shifts are noted, 
resimulation should be strongly considered 
Gating with 
a gating 
window 
The baseline gating position/phase should be 
verified using appropriate imaging 
techniques  
 
Volumetric Imaging (i.e. CBCT or CT on 
rails) is strongly recommended for the initial 
localization to verify isocenter and tumor 
trajectory 
Initial rigid alignment followed 
by soft tissue match for baseline 
gating position 
Breath hold 
(i.e. ABC) 
Volumetric imaging recommended; planar at 
breath hold position acceptable – repeated 
imaging recommended to ensure 
reproducibility of breath hold 
 
All imaging should be done at breath hold 
treatment position 
Initial rigid alignment followed 
by soft tissue match of tumor or 
surrogate  
 
Tracking 
Volumetric imaging or real-time 
fluoroscopic imaging of tumor surrogate 
required based on treatment machine 
capabilities. 
Initial rigid alignment followed 
by soft tissue match of tumor or 
surrogate in baseline position 
 
 
5.4.11  Case Review  
NOTE: PRE-TREATMENT REVIEWS are required for the first patient enrolled from 
each institution.  The first case enrolled at each institution case will require approval prior 
to administering any protocol RT.  
 
The Principal Investigators, Dr. Iyengar, and/or designated Radiation Oncology Co-
Chairs, will perform ongoing remote RT Quality Assurance Review after cases enrolled 
have been received at IROC Philadelphia-RT. The Pre-Treatment review process requires 
three (3) business days to complete a pre-treatment review once all complete and correct 
data is received at IROC Philadelphia-RT. If an unacceptable deviation occurs, the next 
case may require a Pre-Treatment Review.  
 
After institutions have passed the pre-treatment review of the first patient enrolled, 
review of all other cases will be ongoing and performed remotely.  
5.5 
General Concomitant Medication and Supportive Care Guidelines  
5.5.1 Permitted Supportive/Ancillary Care and Concomitant Medications 
 
All supportive therapy for optimal medical care will be given during the study period at 
the discretion of the attending physician(s) within the parameters of the protocol and 
documented on each site’s source documents as concomitant medication. Palliative and 
supportive care for disease-related symptoms will be offered to all patients. 

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In addition, the following standard treatments are allowed for concurrent medical 
conditions: 
• Epoetin alfa (Epogen, Procrit). Please follow guidelines of the American Society of 
Clinical Oncology and the American Society of Hematology for the use of epoetin in 
subjects with cancer and FDA alert on March 09, 2007.  
• Hematopoietic growth factors, including filgrastim (Neupogen), or other granulocyte 
colony stimulating factors (G-CSF). Please follow American Society of Clinical 
Oncology (ASCO) guidelines for the use of white blood cell growth factors. 
http://jco.ascopubs.org/content/24/19/3187.  
• Prophylactic antiemetics may be administered according to standard practice.  
• Megestrol acetate (Megace) may be administered for treatment of cachexia or 
unexplained, significant weight loss. 
• Supportive therapy for toxicities associated with pemetrexed, or gemcitabine therapy, 
according to the FDA approved label or institutional practice.   
• Use of topical corticosteroids, topical antibiotics, and systemic antibiotics, according 
to standard of care (SOC) or institutional guidelines. 
• Bisphosphonates, according to SOC or institutional guidelines. 
5.5.2 Prohibited Therapies 
 
Filgrastim, sargramostim or pegfilgrastim are not allowed during radiation treatment. 
 
During maintenance therapy, defer to institutional standard and the FDA package insert 
for contraindicated therapies. 
5.5.3 Participation in Other Trials  
 
Patients will not be allowed to participate in other therapeutic trials unless there is 
evidence of progression on maintenance systemic therapy. 
5.6 
Duration of Therapy  
In the absence of treatment delays due to adverse event(s), treatment may continue as 
specified in the above treatment modality sections or until one of the following criteria 
applies: 
▪ 
Disease progression, 
▪ 
Intercurrent illness that prevents further administration of treatment, 
▪ 
Unacceptable adverse event(s), as described in Section 6 
▪ 
Patient decides to withdraw consent for participation in the study, or 
▪ 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
6. TREATMENT MODIFICATIONS/MANAGEMENT 
6.1      Systemic Therapy Dose Modifications (30-MAR-2021) 
When systemic therapy related toxicity is observed, dose delays and/or reductions in drug 
administration are allowed per package insert and institutional standards as described 
below.  
 

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There are no dose reductions for immune checkpoint inhibitors (atezolizumab, 
ipilimumab, nivolumab, pembrolizumab). These agents are either administered at full 
dose, temporarily withheld, or permanently discontinued. 
 
For patients receiving combination maintenance therapy, if toxicity is reasonably 
attributed to a single agent, one agent may be modified and the other administered as 
previously. 
 
If clinically appropriate, dose may be re-escalated in future cycles after dose reduction. 
Similarly, for combination maintenance therapy (eg, pemetrexed plus pembrolizumab; 
nivolumab plus ipilimumab), if one agent is withheld, it may be re-introduced in future 
cycles.   
 
Please refer to package insert for details on dosing and supportive care and other 
guidelines 
 
6.2      Management of Toxicity Related to Systemic Therapy (18-OCT-2023) 
Please note that institutions are permitted to follow their local institutional standards for 
dose modifications as standard of care, and in accordance with package insert guidelines 
for these agents. 
 
6.2.1  MK-3475 (pembrolizumab) Dose Modification and Toxicity Management Table  
Pembrolizumab-related toxicity can be managed and treatment can be held, per 
investigator discretion, in accordance with package insert guidance and the table below. 
 
General instructions: 
1. For non-endocrine-related severe and life-threatening irAEs, investigators should 
consider the use of IV corticosteroids followed by oral steroids.  Other 
immunosuppressive treatment should begin if the irAEs are not controlled by 
corticosteroids.  Some non-endocrine irAEs do not require steroids.  For example, 
celiac disease induced by pembrolizumab can be controlled by diet alone. 
2. For non-endocrine-related toxicities, pembrolizumab must be permanently 
discontinued if the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day 
within 12 weeks of the last pembrolizumab treatment.  
3. 
Generally, when corticosteroids are used, investigators should begin a taper when 
the irAE is ≤Grade 1 and continue at least 4 weeks. 
4. 
If pembrolizumab has been withheld due to a non-endocrine irAE, pembrolizumab 
may generally resume after the irAE has decreased to ≤Grade 1 after a corticosteroid 
taper. 
irAEs 
Toxicity 
grade 
(CTCAE 
V5.0) 
Action with 
pembrolizumab  
Corticosteroid 
and/or other 
therapies  
Monitoring 
and follow-up  

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Pneumonitis  
Grade 2 
Withhold  
Administer 
corticosteroids 
(initial dose of 
1 to 2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper 
Add prophylactic 
antibiotics for 
opportunistic 
infections 
 
Monitor 
participants 
for signs 
and 
symptoms 
of 
pneumonitis 
Evaluate 
participants 
with 
suspected 
pneumonitis 
with 
radiographic 
imaging and 
initiate 
corticosteroi
d treatment 
 
Recurrent 
Grade 2,  
Grade 3 or 4  
Permanently 
discontinue 
Diarrhea / 
Colitis  
Grade 2 or 3 
Withhold 
Administer 
corticosteroids 
(initial dose of 
1 to 2 mg/kg 
prednisone or 
Monitor 
participants 
for signs 
and 
symptoms 

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Recurrent 
Grade 3 or 
Grade 4 
Permanently 
discontinue 
equivalent) 
followed by 
taper 
Patients who do not 
respond to 
corticosteroids 
should be seen 
by a 
gastroenterologi
st for 
confirmation of 
the diagnosis 
and 
consideration of 
secondary 
immune 
suppression 
 
 
of 
enterocolitis 
(i.e., 
diarrhea, 
abdominal 
pain, blood 
or mucus in 
stool with or 
without 
fever) and 
of bowel 
perforation 
(i.e. 
peritoneal 
signs and 
ileus) 
Specifically 
assess for 
celiac 
disease 
serologicall
y, and 
exclude 
Clostridium 
difficile 
infection 
Participants 
with ≥Grade 
2 diarrhea 
suspecting 
enterocolitis 
should 
consider GI 
consultation 
and 
performing 
endoscopy 
to rule out 
enterocolitis 
and assess 
mucosal 
severity 
Participants 
with 
diarrhea/coli
tis should be 
advised to 
drink liberal 
quantities of 
clear fluids. 
If sufficient 
oral fluid

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AST or ALT 
elevation or 
Increased 
Bilirubin 
Grade 2 a 
Withhold 
Administer 
corticosteroids 
(initial dose of 
0.5 to 1 mg/kg 
prednisone or 
equivalent) 
followed by 
taper 
Monitor with 
liver 
function 
tests 
(consider 
weekly or 
more 
frequently 
until liver 
enzyme 
value 
returned to 
baseline or 
is stable) 
Grade 3 b or 4 
c 
Permanently 
discontinue 
Administer 
corticosteroids 
(initial dose of 
1 to 2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper 

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Type 1 diabetes 
mellitus 
(T1DM) or 
Hyperglycemia 
Grade 1 or 2 
Continue 
 
Investigate for 
diabetes.  In 
the absence 
of 
corticosteroi
ds or 
diabetes 
medication 
non-
adherence, 
any grade 
hyperglyce
mia may be 
an 
indication of 
beta-cell 
destruction 
and 
pembrolizu
mab-
induced 
diabetes 
akin to type 
1 diabetes.  
This should 
be treated as 
a Grade 3 
event.  
Given this 
risk, 
exercise 
caution in 
utilizing 
non-insulin 
hypoglycem
ic agents in 
this setting.  
After a 
thorough 
investigatio
n of other 
potential 
causes, 
which may 
involve a 
referral to 
an 
endocrinolo
gist, follow 
institutional 
guidelines.   
Monitor glucose

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New onset 
T1DM 
(evidence of 
-cell failure) 
or  
Grade 3 or 4 
hyperglycemia 
Withhold d 
Resume 
pembrolizumab 
when symptoms 
resolve and 
glucose levels 
are stable 
Initiate treatment 
with insulin 
If patient is found 
to have diabetic 
ketoacidosis or 
hyperglycemic 
hyperosmolar 
syndrome, treat 
as per 
institutional 
guidelines with 
appropriate 
management 
and laboratory 
values (e.g. 
anion gap, 
ketones, blood 
pH, etc.) 
reported 
 
Monitor for 
glucose 
control 
Strongly 
consider 
referral to 
endocrinolo
gist 
Obtain C-
peptide level 
paired with 
glucose, 
autoantibod
y levels (e.g. 
GAD65, 
islet cell 
autoantibodi
es), and 
hemoglobin 
A1C level 
 
Hypophysitis 
Grade 2 
Withhold 
Administer 
corticosteroids 
Monitor for 
signs and 

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Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
and initiate 
hormonal 
replacements as 
clinically 
indicated 
symptoms 
of 
hypophysitis 
(including 
hypopituitar
ism and 
adrenal 
insufficienc
y) 
Provide adrenal 
insufficienc
y 
precautions 
including 
indications 
for stress 
dose 
steroids and 
medical 
alert jewelry 
Strongly 
consider 
referral to 
endocrinolo
gist 
Hyperthyroidism 
Grade 2 
Consider 
withholding. 
Resume 
pembrolizumab 
when symptoms 
are controlled, 
and thyroid 
function is 
improving 
Treat with 
nonselective 
beta-blockers 
(e.g., 
propranolol) or 
thionamides as 
appropriate 
Initiate treatment 
with anti-
thyroid drug 
such as 
methimazole or 
carbimazole as 
needed 
Monitor for 
signs and 
symptoms 
of thyroid 
disorders 
Strongly 
consider 
referral to 
endocrinolo
gist 
 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 

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Hypothyroidism 
Grade 2, 3 or 
4 
Continue 
Initiate thyroid 
replacement 
hormones (e.g., 
levothyroxine 
or liothyronine) 
per standard of 
care 
Monitor for 
signs and 
symptoms 
of thyroid 
disorders 
Nephritis: 
grading 
according to 
increased 
creatinine or 
acute kidney 
injury 
Grade 2 
Withhold 
Administer 
corticosteroids 
(prednisone 
1 to 2 mg/kg or 
equivalent) 
followed by 
taper 
Monitor 
changes of 
renal 
function 
Strongly 
consider 
referral to 
nephrologist 
Grade 3 or 4 
Permanently 
discontinue 
Cardiac Events 
(including 
myocarditis, 
pericarditis, 
arrhythmias, 
impaired 
ventricular 
function, 
vasculitis) 
Asymptomatic 
cardiac 
enzyme 
elevation with 
clinical 
suspicion of 
myocarditis 
(previously 
CTCAE v4.0 
Grade 1), or 
Grade 1 
Withhold 
Based on severity 
of AE 
administer 
corticosteroids 
 
Ensure adequate 
evaluation 
to confirm 
etiology 
and/or 
exclude 
other causes 
Strongly 
consider 
referral to 
cardiologist 
and cardiac 
MRI 
Consider 
endomyocar
dial biopsy 
If event resolves 
to Grade 1 
or better, 
taper 
corticosteroi
ds over ≥1 
month 

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Grade 2, 3 or 
4 
Permanently 
discontinue 
Initiate treatment 
with 
corticosteroids 
equivalent to 1-
2 mg/kg/day IV 
methylprednisol
one and convert 
to 1-2 
mg/kg/day oral 
prednisone or 
equivalent upon 
improvement 
If event does not 
improve within 
48 hours after 
initiating 
corticosteroids, 
consider adding 
an 
immunosuppres
sive agent 
Initiate treatment 
per institutional 
guidelines and 
consider 
antiarrhythmic 
drugs, 
temporary 
pacemaker, 
extracorporeal 
membrane 
oxygenation 
(ECMO), 
ventricular 
assist device 
(VAD), or 
pericardiocente
sis as 
appropriate 
Ensure adequate 
evaluation 
to confirm 
etiology 
and/or 
exclude 
other causes 
Strongly 
consider 
referral to 
cardiologist 
and cardiac 
MRI 
Consider 
endomyocar
dial biopsy 
If event resolves 
to Grade 1 
or better, 
taper 
corticosteroi
ds over ≥1 
month 
Exfoliative 
Dermatologic 
Conditions 
Suspected 
SJS, TEN, or 
DRESS 
Withhold 
Based on severity 
of AE 
Ensure adequate 
evaluation 

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Confirmed 
SJS, TEN, or 
DRESS 
Permanently 
discontinue 
administer 
corticosteroids 
to confirm 
etiology or 
exclude 
other causes 
Strongly 
consider 
referral to 
dermatologi
st 
Consider skin 
biopsy for 
evaluation 
of etiology 
All Other irAEs 
Persistent 
Grade 2 
Withhold 
Based on severity 
of AE 
administer 
corticosteroids 
Ensure adequate 
evaluation 
to confirm 
etiology or 
exclude 
other causes 
Grade 3 
Withhold or 
discontinue 
based on the 
event e  
Recurrent 
Grade 3 or 
Grade 4  
Permanently 
discontinue 
 
Infusion-Related Reactions 
Infusion 
Reactions 
NCI CTCAE 
Grade 
Treatment  
Premedication at 
subsequent dosing 
Mild reaction; 
infusion 
interruption not 
indicated; 
intervention 
not indicated 
  
Grade 1 
Increase monitoring of vital signs as 
medically indicated until the 
participant is deemed medically 
stable in the opinion of the 
investigator. 
None 

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Infusion 
Reactions 
NCI CTCAE 
Grade 
Treatment  
Premedication at 
subsequent dosing 
Requires 
therapy or 
infusion 
interruption but 
responds 
promptly to 
symptomatic 
treatment (e.g., 
antihistamines, 
NSAIDs, 
narcotics, IV 
fluids); 
prophylactic 
medications 
indicated for 
≤24 hrs. 
Grade 2 
• Stop Infusion. 
• Additional 
appropriate 
medical therapy may include 
but is not limited to: 
• IV fluids 
• Antihistamines 
• NSAIDs 
• Acetaminophen 
• Narcotics 
• Increase monitoring of vital 
signs as medically indicated 
until 
the 
participant 
is 
deemed medically stable in 
the 
opinion 
of 
the 
investigator. 
• If symptoms resolve within 1 
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 participant 
should be premedicated for 
the next scheduled dose. 
Participants who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued from 
further study drug treatment 
Participant may be 
premedicated 1.5h (± 
30 minutes) prior to 
infusion 
of 
study 
intervention with: 
Diphenhydramine 50 
mg PO (or equivalent 
dose 
of 
antihistamine). 
Acetaminophen 500-
1000 mg PO (or 
equivalent dose of 
analgesic). 

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Infusion 
Reactions 
NCI CTCAE 
Grade 
Treatment  
Premedication at 
subsequent dosing 
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 3 
• Stop Infusion. 
• Additional 
appropriate 
medical therapy may include 
but is not limited to: 
• Epinephrine** 
• IV fluids 
• Antihistamines 
• NSAIDs 
• Acetaminophen 
• Narcotics 
• Oxygen 
• Pressors 
• Corticosteroids (e.g. 
methylprednisolone 2 
mg/kg/day or dexamethasone 
10 mg every 6 hours) 
• Increase monitoring of vital 
signs as medically indicated 
until 
the 
participant 
is 
deemed medically stable in 
the 
opinion 
of 
the 
investigator. 
• Hospitalization 
may 
be 
indicated. 
**In 
cases 
of 
anaphylaxis, 
epinephrine 
should 
be 
used 
immediately. 
Participant 
is 
permanently 
discontinued from further study drug 
treatment. 
 
No subsequent 
dosing. 
 
Life-
threatening; 
pressor or 
ventilator 
support 
indicated 
 
Grade 4 
Admit participant to intensive care 
unit (ICU) and initiate hemodynamic 
monitoring, mechanical ventilation, 
and/or IV fluids and vasopressors as 
needed. Monitor other organ 
function closely. 
Manage constitutional symptoms 
and organ toxicities as per 
institutional practice. 
Follow Grade 3 recommendations as 
applicable. 
No subsequent 
dosing. 
 

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Infusion 
Reactions 
NCI CTCAE 
Grade 
Treatment  
Premedication at 
subsequent dosing 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; 
CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash with 
Eosinophilia and Systemic Symptom; ECMO=extracorporeal membrane oxygenation; 
GI=gastrointestinal; ICU=intensive care unit; IO=immuno-oncology; ir=immune related; 
IV=intravenous; MRI=magnetic resonance imaging; PO=per os; SJS=Stevens-Johnson 
Syndrome; T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper 
limit of normal; VAD=ventricular assist device. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a AST/ALT: >3.0 to 5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline 
abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline if baseline 
abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the 
investigator or treating physician. If control achieved or ≤Grade 2, pembrolizumab may be 
resumed. 
e Events that require discontinuation include but are not limited to: encephalitis and other 
clinically important irAEs (e.g. vasculitis and sclerosing cholangitis). 
 
Appropriate resuscitation equipment should be available at the bedside and a physician readily 
available during the period of drug administration. For further information, please refer to the 
Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at http://ctep.cancer.gov. 
 
 
6.2.2    Atezolizumab Dose Modification and Toxicity Management 
Atezolizumab-related toxicity can be managed and treatment can be held, per investigator 
discretion, in accordance with institutional standards and the FDA package insert, and the 
following table for additional guidance:  
 
Atezolizumab Toxicity Management Guidelines  
Refer to the atezolizumab FDA label for toxicity management information. In addition to the 
FDA label, NCCN immunotherapy-related toxicity guidelines, and institutional standards, the 
following are recommended toxicity management guidelines for certain AEs of concern, 
including immune-related pneumonitis, hepatitis, colitis, endocrinopathies, pancreatitis, 
neuropathies, meningoencephalitis, and potential ocular toxicities, as well as guidelines for the 
management of Infusion Related Reactions and Anaphylaxis. 
 
General AE Management and Dose Modification Guidelines 
There will be no dose reduction for atezolizumab in this study.   
 
Patients may temporarily suspend study treatment for up to 84 days (12 weeks) beyond the 
scheduled date of delayed infusion if study drug-related toxicity requiring dose suspension is 
experienced.  If atezolizumab is held because of AEs for 84 days beyond the scheduled date of 

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infusion, the patient will be discontinued from atezolizumab and will be followed for safety and 
efficacy as specified in this protocol.  If the AE resolves within 84 days and the patient is 
receiving corticosteroid therapy for the event, atezolizumab may be held for longer than 84 days 
(up to 4 weeks) in order to allow tapering of the steroid dose to ≤10 mg oral prednisone or 
equivalent. 
 
Dose interruptions for reasons other than toxicity, such as surgical procedures, may be allowed.  
The acceptable length of interruption will be at the discretion of the study PI in consultation with 
CTEP. 
 
The primary approach to grade 1 to 2 irAEs is supportive and symptomatic care with continued 
treatment with atezolizumab; for higher-grade irAEs, atezolizumab should be withheld and oral 
and/or parenteral steroids administered.  Recurrent grade 2 irAEs may also mandate withholding 
atezolizumab or the use of steroids.  Assessment of the benefit risk balance should be made by 
the investigator, with consideration of the totality of information as it pertains to the nature of the 
toxicity and the degree of clinical benefit a given patient may be experiencing prior to further 
administration of atezolizumab.  Atezolizumab should be permanently discontinued in patients 
with life threatening irAEs. 
 
Management of Specific AEs 
Management of certain AEs of concern, including immune-related pneumonitis, hepatitis, colitis, 
endocrinopathies, pancreatitis, neuropathies, meningoencephalitis, and potential ocular toxicities 
are presented in the Atezolizumab Investigator’s Brochure.  See the Agent Administration 
Guidelines in this document, including the “Administration of First and Subsequent 
Atezolizumab Infusions” table for guidelines for the management of Infusion Related Reactions 
and Anaphylaxis. 
 
Atezolizumab has been associated with risks such as the following:  IRRs and immune−related 
hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, hypothyroidism, hyperthyroidism, 
adrenal insufficiency, hypophysitis, Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, facial paresis, myelitis, meningoencephalitis, myocarditis, pericardial 
disorders, nephritis, myositis, and severe cutaneous adverse reactions.  Immune-mediated 
reactions may involve any organ system and may lead to hemophagocytic 
lymphohistiocytosis and macrophage activation syndrome. 
 
Pleural and pericardial effusion 
Patients experiencing dyspnea, chest pain, or unexplained tachycardia should be evaluated for 
the presence of a pericardial effusion.  Patients with pre-existing pericardial effusion should be 
followed closely for pericardial fluid volume measurements and impact on cardiac function.  
When intervention is required for pericardial or pleural effusions, atezolizumab should be held, 
and appropriate workup includes cytology, lactate dehydrogenase (LDH), glucose, cholesterol, 
protein concentrations (with pleural effusions), and cell count. 
 
Pulmonary events 
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been associated 
with the administration of atezolizumab.  Patients will be assessed for pulmonary signs and 

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symptoms throughout the study and will have computed tomography (CT) scans of the chest 
performed at every tumor assessment. 
 
All pulmonary events should be thoroughly evaluated for other commonly reported etiologies 
such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary embolism, heart 
failure, chronic obstructive pulmonary disease, or pulmonary hypertension.  Management 
guidelines for pulmonary events are provided in the table below. 
 
Event 
Management 
Pulmonary event, 
Grade 1  
● Continue atezolizumab and monitor closely. 
● Re-evaluate on serial imaging. 
● Consider patient referral to pulmonary specialist. 
Pulmonary event, 
Grade 2 
● Withhold atezolizumab for up to 12 weeks after event onset. a 
● Refer patient to pulmonary and infectious disease specialists and 
consider bronchoscopy or BAL. 
● Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral 
prednisone. 
● If event resolves to Grade 1 or better, resume atezolizumab. b 
● If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. 
● For recurrent events, treat as a Grade 3 or 4 event. 
Pulmonary event, 
Grade 3 or 4 
● Permanently discontinue atezolizumab.  
● Bronchoscopy or BAL is recommended. 
● Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral 
prednisone. 
● If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
● If event resolves to Grade 1 or better, taper corticosteroids over 
≥1 month. 
BAL  =  bronchoscopic alveolar lavage 
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
≤10 mg/day oral prednisone.  The acceptable length of the extended period of time must be 
determined by the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent 
of ≤10 mg/day oral prednisone before atezolizumab can be resumed. 
 

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Hepatic events 
Immune-mediated hepatitis has been associated with the administration of atezolizumab.  
Eligible patients must have adequate liver function, as manifested by measurements of total 
bilirubin and hepatic transaminases, and liver function will be monitored throughout study 
treatment.  Management guidelines for hepatic events are provided in the table below. 
 
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or vomiting should 
have liver function tests (LFTs) performed immediately and reviewed before administration of 
the next dose of study drug. 
 
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or neoplastic 
etiologies should be considered and addressed, as appropriate. 
 
Event 
Management 
Hepatic event, 
Grade 1 
• Continue atezolizumab. 
• Monitor LFTs until values resolve to within normal limits or to baseline 
values.  
Hepatic event, 
Grade 2 
All events: 
• Monitor LFTs more frequently until return to baseline values.  
Events of 5 days’ duration: 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral 
prednisone. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. 
Hepatic event, 
Grade 3 or 4 
• Permanently discontinue atezolizumab. 
• Consider patient referral to gastrointestinal specialist for evaluation and 
liver biopsy to establish etiology of hepatic injury.  
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral 
prednisone. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over 1 
month. 
LFT  =  liver function test. 
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be determined by the 
investigator. 
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 
10 mg/day oral prednisone before atezolizumab can be resumed.  
 

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Gastrointestinal events 
Immune-mediated colitis has been associated with the administration of atezolizumab.  
Management guidelines for diarrhea or colitis are provided in the table below.   
 
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies.  For events of significant duration or magnitude or associated with signs of systemic 
inflammation or acute-phase reactants (e.g., increased C-reactive protein, platelet count, or 
bandemia):  Perform sigmoidoscopy (or colonoscopy, if appropriate) with colonic biopsy, with 
three to five specimens for standard paraffin block to check for inflammation and lymphocytic 
infiltrates to confirm colitis diagnosis. 
 
Event 
Management 
Diarrhea or 
colitis, Grade 1 
• Continue atezolizumab. 
• Initiate symptomatic treatment. 
• Endoscopy is recommended if symptoms persist for 7 days. 
• Monitor closely. 
Diarrhea or 
colitis, Grade 2 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Initiate symptomatic treatment. 
• Patient referral to GI specialist is recommended. 
• For recurrent events or events that persist  5 days, initiate treatment with 
corticosteroids equivalent to 1−2 mg/kg/day oral prednisone.  
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. 
Diarrhea or 
colitis, Grade 3 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to GI specialist for evaluation and confirmatory biopsy. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. 
Diarrhea or 
colitis, Grade 4 
• Permanently discontinue atezolizumab. 
• Refer patient to GI specialist for evaluation and confirmation biopsy. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over 1 month. 
GI = gastrointestinal. 
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be determined by the 
investigator. 

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Event 
Management 
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 
10 mg/day oral prednisone before atezolizumab can be resumed.  
 
Endocrine disorders 
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders have been 
associated with the administration of atezolizumab.  Management guidelines for endocrine 
events are provided in the table below. 
 
Patients experiencing one or more unexplained AEs possibly indicative of endocrine dysfunction 
(including headache, fatigue, myalgias, impotence, mental status changes, and constipation) 
should be investigated for the presence of thyroid, pituitary, or adrenal endocrinopathies.  The 
patient should be referred to an endocrinologist if an endocrinopathy is suspected.  Thyroid 
stimulating hormone (TSH) and free T3 and T4 levels should be measured to determine whether 
thyroid abnormalities are present.  Pituitary hormone levels and function tests [e.g., TSH, growth 
hormone, luteinizing hormone, follicle-stimulating hormone, testosterone, prolactin, 
adrenocorticotropic hormone (ACTH) levels, and ACTH stimulation test] and MRI of the brain 
(with detailed pituitary sections) may help to differentiate primary pituitary insufficiency from 
primary adrenal insufficiency.  The table below describes dose management guidelines for 
hyperthyroidism, hypothyroidism, symptomatic adrenal insufficiency, and hyperglycemia. 
 
Event 
Management 
Asymptomatic 
hypothyroidism 
• Continue atezolizumab. 
• Initiate treatment with thyroid replacement hormone. 
• Monitor TSH weekly. 
Symptomatic 
hypothyroidism 
• Withhold atezolizumab. 
• Initiate treatment with thyroid replacement hormone. 
• Monitor TSH weekly. 
• Consider patient referral to endocrinologist. 
• Resume atezolizumab when symptoms are controlled and thyroid 
function is improving. 
Asymptomatic 
hyperthyroidism 
TSH 0.1 mU/L and 0.5 mU/L: 
• Continue atezolizumab. 
• Monitor TSH every 4 weeks. 
TSH 0.1 mU/L: 
• Follow guidelines for symptomatic hyperthyroidism. 
Symptomatic 
hyperthyroidism 
• Withhold atezolizumab. 
• Initiate treatment with anti-thyroid drug such as methimazole or 
carbimazole as needed. 
• Consider patient referral to endocrinologist. 
• Resume atezolizumab when symptoms are controlled and thyroid 
function is improving. 
• Permanently discontinue atezolizumab.  
Symptomatic adrenal 
• Withhold atezolizumab for up to 12 weeks after event onset. a 

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Event 
Management 
insufficiency, Grade 2−4  • Refer patient to endocrinologist. 
• Perform appropriate imaging. 
• Initiate treatment with corticosteroids equivalent to 
1−2 mg/kg/day IV methylprednisolone and convert to 
1−2 mg/kg/day oral prednisone or equivalent upon improvement. 
• If event resolves to Grade 1 or better and patient is stable on 
replacement therapy, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better or patient is not 
stable on replacement therapy while withholding atezolizumab, 
permanently discontinue atezolizumab.  
Hyperglycemia, Grade 1 
or 2  
• Continue atezolizumab. 
• Investigate for diabetes.  If patient has Type 1 diabetes, treat as a 
Grade 3 event.  If patient does not have Type 1 diabetes, treat as 
per institutional guidelines. 
• Monitor for glucose control. 
Hyperglycemia, Grade 3 
or 4 
• Withhold atezolizumab. 
• Initiate treatment with insulin. 
• Monitor for glucose control. 
• Consider referral to endocrinologist, particularly if patient is 
deemed to have atezolizumab-induced diabetes; if so, obtain C-
peptide level paired with glucose, autoantibody levels (e.g. 
GAD65, islet cell autoantibodies), and hemoglobin A1C level. 
• If patient is found to have diabetic ketoacidosis or hyperglycemic 
hyperosmolar syndrome, treat as per institutional guidelines with 
appropriate management and laboratory values (e.g. anion gap, 
ketones, blood pH, etc.) reported.   
• Resume atezolizumab when symptoms resolve and glucose levels 
are stable. 
Hypophysitis (pan-
hypopituitarism), Grade 
2 or 3  
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to endocrinologist. 
• Perform brain MRI (pituitary protocol). 
• Initiate treatment with corticosteroids equivalent to 
1−2 mg/kg/day IV methylprednisolone and convert to 
1−2 mg/kg/day oral prednisone or equivalent upon improvement. 
• Initiate hormone replacement if clinically indicated. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab.  
• For recurrent hypophysitis, treat as a Grade 4 event. 
Hypophysitis (pan-
hypopituitarism), Grade 
4  
• Permanently discontinue atezolizumab.  
• Refer patient to endocrinologist. 
• Perform brain MRI (pituitary protocol). 
• Initiate treatment with corticosteroids equivalent to 
1−2 mg/kg/day IV methylprednisolone and convert to 
1−2 mg/kg/day oral prednisone or equivalent upon improvement. 

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Event 
Management 
• Initiate hormone replacement if clinically indicated. 
MRI = magnetic resonance imaging; TSH = thyroid-stimulating hormone. 
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be determined by the 
investigator. 
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 
10 mg/day oral prednisone before atezolizumab can be resumed.  
 
Ocular events 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events). 
Management guidelines for ocular events are provided in the table below. 
 
Event 
Management 
Ocular event, 
Grade 1  
• Continue atezolizumab. 
• Patient referral to ophthalmologist is strongly recommended. 
• Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
• If symptoms persist, treat as a Grade 2 event. 
Ocular event, 
Grade 2 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Patient referral to ophthalmologist is strongly recommended. 
• Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. 
Ocular event, 
Grade 3 or 4 
• Permanently discontinue atezolizumab. 
• Refer patient to ophthalmologist. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral 
prednisone.   
• If event resolves to Grade 1 or better, taper corticosteroids over 
1 month. 
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be determined by the 
investigator. 
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 
10 mg/day oral prednisone before atezolizumab can be resumed.  
 
Immune-mediated Cardiac Events 
Immune-mediated myocarditis and pericarditis have been associated with the administration of 
atezolizumab.  Management guidelines for cardiac events are provided in the table below. 
 
Immune-mediated Myocarditis 
Immune-mediated myocarditis has been associated with the administration of atezolizumab.  

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Immune-mediated myocarditis should be suspected in any patient presenting with signs or 
symptoms suggestive of myocarditis, including, but not limited to, laboratory (e.g., B-NP [B-
Natriuretic Peptide]) or cardiac imaging abnormalities, dyspnea, chest pain, palpitations, fatigue, 
decreased exercise tolerance, or syncope. Myocarditis may also be a clinical manifestation of 
myositis or associated with pericarditis (see section on pericardial disorders below) and should 
be managed accordingly.   
Immune-mediated myocarditis needs to be distinguished from myocarditis resulting from 
infection (commonly viral, e.g., in a patient who reports a recent history of gastrointestinal 
illness), ischemic events, underlying arrhythmias, exacerbation of preexisting cardiac conditions, 
or progression of malignancy.  All patients with possible myocarditis should be urgently 
evaluated by performing cardiac enzyme assessment, an electrocardiogram (ECG), a chest X-ray, 
an echocardiogram, and a cardiac MRI as appropriate per institutional guidelines.  A cardiologist 
should be consulted.  An endomyocardial biopsy may be considered to enable a definitive 
diagnosis and appropriate treatment, if clinically indicated. 
 
Patients with signs and symptoms of myocarditis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in the table below. 
 
Event 
Management 
Immune-related 
myocarditis, Grade 2 
• Withhold atezolizumab for up to 12 weeks after event onset a. 
• Refer patient to cardiologist. 
• Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate. 
• Consider treatment with corticosteroids equivalent to 
1−2 mg/kg/day IV methylprednisolone and convert to 
1−2 mg/kg/day oral prednisone or equivalent upon improvement. 
• If symptoms resolve to below Grade 2 (i.e. patient is completely 
asymptomatic), resume atezolizumab. b 
• If symptoms do not resolve to below Grade 2 while withholding 
atezolizumab, permanently discontinue atezolizumab. 
Immune-related 
myocarditis, Grade 3-4 
• Permanently discontinue atezolizumab. 
• Refer patient to cardiologist. 
• Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day 
IV methylprednisolone and convert to 1−2 mg/kg/day oral 
prednisone or equivalent upon improvement. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If symptoms resolve to below Grade 2, taper corticosteroids 
over 1 month. 
ECMO = extracorporeal membrane oxygenation; VAD = ventricular assist device. 
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be documented by the 

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Event 
Management 
investigator. 
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 
10 mg/day oral prednisone before atezolizumab can be resumed. 
 
Immune-mediated Pericardial Disorders 
Immune-mediated pericarditis should be suspected in any patient presenting with chest pain and 
may be associated with immune-mediated myocarditis (see section on myocarditis above). 
 
Immune-mediated pericardial effusion and cardiac tamponade should be suspected in any patient 
presenting with chest pain associated with dyspnea or hemodynamic instability. 
 
Patients should be evaluated for other causes of pericardial disorders such as infection 
(commonly viral), cancer related (metastatic disease or chest radiotherapy), cardiac injury related 
(post myocardial infarction or iatrogenic), and autoimmune disorders, and should be managed 
accordingly. 
 
All patients with suspected pericardial disorders should be urgently evaluated by performing an 
ECG, chest X-ray, transthoracic echocardiogram, and cardiac MRI as appropriate per 
institutional guidelines.  A cardiologist should be consulted.  Pericardiocentesis should be 
considered for diagnostic or therapeutic purposes, if clinically indicated. 
 
Patients with signs and symptoms of pericarditis, pericardial effusion, or cardiac tamponade, in 
the absence of an identified alternate etiology, should be treated according to the guidelines in 
the table below.  Withhold treatment with atezolizumab for Grade 1 pericarditis and conduct a 
detailed cardiac evaluation to determine the etiology and manage accordingly. 
 
Event 
Management 
Immune-mediated 
myocarditis, Grade 
2−4 
 
Immune-mediated 
pericardial disorders, 
Grade 2−4 
• Permanently discontinue atezolizumab.  
• Refer patient to cardiologist. 
• Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, VAD, or 
pericardiocentesis as appropriate. 
• Initiate treatment with corticosteroids equivalent to 1−2 
mg/kg/day IV methylprednisolone and convert to 
1−2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month. 
 
Infusion-Related Reactions and Cytokine-Release Syndrome 
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  However, 
patients who experience an infusion-related reaction (IRR) or cytokine-release syndrome (CRS) 

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with atezolizumab may receive premedication with antihistamines, antipyretics, and/or 
analgesics (e.g., acetaminophen) for subsequent infusions.  Metamizole (dipyrone) is prohibited 
in treating atezolizumab-associated IRRs because of its potential for causing agranulocytosis. 
 
IRRs are known to occur with the administration of monoclonal antibodies and have been 
reported with atezolizumab.  These reactions, which are thought to be due to release of cytokines 
and/or other chemical mediators, occur within 24 hours of atezolizumab administration and are 
generally mild to moderate in severity. 
 
CRS is defined as a supraphysiologic response following administration of any immune therapy 
that results in activation or engagement of endogenous or infused T cells and/or other immune 
effector cells.  Symptoms can be progressive, always include fever at the onset, and may include 
hypotension, capillary leak (hypoxia), and end-organ dysfunction (Lee et al., 2019).  CRS has 
been well documented with chimeric antigen receptor T-cell therapies and bispecific T-cell 
engager antibody therapies but has also been reported with immunotherapies that target PD-1 or 
PD-L1 (Rotz et al., 2017; Adashek and Feldman 2019) including atezolizumab. 
 
There may be significant overlap in signs and symptoms of IRRs and CRS, and in recognition of 
the challenges in clinically distinguishing between the two, consolidated guidelines for medical 
management of IRRs and CRS are provided in the table below. 
 
Management Guidelines for Infusion-Related Reactions and Cytokine-Release Syndrome 
 
Event 
Management 
Grade 1a  
Feverb with or 
without 
constitutional 
symptoms 
● Immediately interrupt infusion. 
● Upon symptom resolution, wait 30 minutes and then restart infusion at 
half the rate being given at the time of event onset. 
● If the infusion is tolerated at the reduced rate for 30 minutes, the infusion 
rate may be increased to the original rate. 
● If symptoms recur, discontinue infusion of this dose. 
● Administer symptomatic treatment,c including maintenance of IV fluids 
for hydration. 
● In case of rapid decline or prolonged CRS (> 2 days) or in patients with 
significant symptoms and/or comorbidities, consider managing as per 
Grade 2. 
● For subsequent infusions, consider administration of oral premedication 
with antihistamines, anti-pyretics, and/or analgesics, and monitor closely 
for IRRs and/or CRS. 
Grade 2a 
Feverb with 
hypotension not 
requiring 
vasopressors 
and/or 
Hypoxia 
● Immediately interrupt atezolizumab infusion. 
● Upon symptom resolution, wait for 30 minutes and then restart infusion at 
half the rate being given at the time of event onset. 
● If symptoms recur, discontinue infusion of this dose. 
● Administer symptomatic treatment.c 
● For hypotension, administer IV fluid bolus as needed. 
● Monitor cardiopulmonary and other organ function closely (in the ICU, if 
appropriate).  Administer IV fluids as clinically indicated and manage 

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requiring low-
flow oxygend 
by nasal cannula 
or blow-by 
constitutional symptoms and organ toxicities as per institutional practice. 
● Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis).  
If no improvement within 24 hours, initiate workup and assess for signs 
and symptoms of HLH or MAS. 
● Consider IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
● Consider anti-cytokine therapy.e 
● Consider hospitalization until complete resolution of symptoms. If no 
improvement within 24 hours, manage as per Grade 3, that is, hospitalize 
patient (monitoring in the ICU is recommended), permanently discontinue 
atezolizumab. 
● If symptoms resolve to Grade 1 or better for 3 consecutive days, the next 
dose of atezolizumab may be administered.  For subsequent infusions, 
consider administration of oral premedication with antihistamines, anti-
pyretics, and/or analgesics and monitor closely for IRRs and/or CRS. 
● If symptoms do not resolve to Grade 1 or better for 3 consecutive days, 
contact the Principal Investigator. 
Grade 3a 
Feverb with 
hypotension 
requiring a 
vasopressor 
(with or without 
vasopressin)  
and/or 
Hypoxia 
requiring high-
flow oxygend 
by nasal 
cannula, face 
mask, non-
rebreather mask, 
or venturi mask 
● Permanently discontinue atezolizumab. 
● Administer symptomatic treatment.c 
● For hypotension, administer IV fluid bolus and vasopressor as needed. 
● Monitor cardiopulmonary and other organ function closely; monitoring in 
the ICU is recommended.  Administer IV fluids as clinically indicated and 
manage constitutional symptoms and organ toxicities as per institutional 
practice. 
● Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis).  
If no improvement within 24 hours, initiate workup and assess for signs 
and symptoms of HLH or MAS. 
● Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
● Consider anti-cytokine therapy.e 
● Hospitalize patient until complete resolution of symptoms.  If no 
improvement within 24 hours, manage as per Grade 4, that is, admit 
patient to ICU and initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as needed; for patients who 
are refractory to anti-cytokine therapy, experimental treatments may be 
considered at the discretion of the investigator. 
Grade 4a 
Feverb with 
hypotension 
requiring 
multiple 
vasopressors 
(excluding 
vasopressin) 
and/or 
Hypoxia 
● Permanently discontinue atezolizumab. 
● Administer symptomatic treatment.c 
● Admit patient to ICU and initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as needed.  Monitor other 
organ function closely.  Manage constitutional symptoms and organ 
toxicities as per institutional practice. 
● Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis).  
If no improvement within 24 hours, initiate workup and assess for signs 
and symptoms of HLH or MAS. 
● Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 

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requiring 
oxygen by 
positive pressure 
(e.g., CPAP, 
BiPAP, 
intubation and 
mechanical 
ventilation) 
dexamethasone 10 mg every 6 hours). 
● Consider anti-cytokine therapy.e  For patients who are refractory to anti-
cytokine therapy, experimental treatmentsf may be considered at the 
discretion of the investigator. 
●  Hospitalize patient until complete resolution of symptoms. 
ASTCT= American Society for Transplantation and Cellular Therapy; BiPAP= bi-level positive airway 
pressure; CAR= chimeric antigen receptor; CPAP= continuous positive airway pressure; 
CRS= cytokine-release syndrome; HLH= hemophagocytic lymphohistiocytosis; IRR = infusion-related 
reaction; MAS= macrophage activation syndrome. 
Note: The management guidelines have been adapted from NCCN guidelines for management of 
CAR T-cell-related toxicities (Version 2.2019). 
a. Grading system for management guidelines is based on ASTCT consensus grading for CRS.  
NCI CTCAE (version as specified in the protocol) should be used when reporting severity 
of IRRs, CRS, or organ toxicities associated with CRS on the Adverse Event eCRF. Organ 
toxicities associated with CRS should not influence overall CRS grading.  
b. Fever is defined as temperature ≥38°C not attributable to any other cause. In patients who 
develop CRS and then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, fever is 
no longer required when subsequently determining event severity (grade).  In this case, the 
grade is driven by the presence of hypotension and/or hypoxia. 
c. Symptomatic treatment may include oral or IV antihistamines, anti-pyretics, analgesics, 
bronchodilators, and/or oxygen.  For bronchospasm, urticaria, or dyspnea, additional 
treatment may be administered as per institutional practice. 
d. Low flow is defined as oxygen delivered at ≤6 L/min, and high flow is defined as oxygen 
delivered at >6 L/min. 
e. There are case reports where anti-cytokine therapy has been used for treatment of CRS with 
immune checkpoint inhibitors (Rotz et al. 2017; Adashek and Feldman 2019), but data are 
limited, and the role of such treatment in the setting of antibody-associated CRS has not 
been established. 
f. Refer to Riegler et al. for information on experimental treatments for CRS. 
 
Pancreatic events 
Symptoms of abdominal pain associated with elevations of amylase and lipase, suggestive of 
pancreatitis, have been associated with the administration of atezolizumab.  The differential 
diagnosis of acute abdominal pain should include pancreatitis.  Appropriate workup should 
include an evaluation for ductal obstruction, as well as serum amylase and lipase tests.  
Management guidelines for pancreatic events, including pancreatitis, are provided in the table 
below. 
 
Event 
Management 
Amylase and/or lipase 
elevation, Grade 2 
Amylase and/or lipase 1.5−2.0  ULN: 
• Continue atezolizumab. 
• Monitor amylase and lipase weekly. 
• For prolonged elevation (e.g., 3 weeks), consider treatment 

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Event 
Management 
with corticosteroids equivalent to 10 mg/day oral prednisone. 
Asymptomatic with amylase and/or lipase 2.0−5.0  ULN: 
• Treat as a Grade 3 event. 
Amylase and/or lipase 
elevation, Grade 3 or 4 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to GI specialist. 
• Monitor amylase and lipase every other day. 
• If no improvement, consider treatment with corticosteroids 
equivalent to 1−2 mg/kg/day oral prednisone. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab. c 
• For recurrent events, permanently discontinue atezolizumab. 
Immune-related pancreatitis, 
Grade 2 or 3 
 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to GI specialist. 
• Initiate treatment with corticosteroids equivalent to 
1−2 mg/kg/day IV methylprednisolone and convert to 
1−2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab.  
• For recurrent events, permanently discontinue atezolizumab. 
Immune-related pancreatitis, 
Grade 4 
• Permanently discontinue atezolizumab. 
• Refer patient to GI specialist. 
• Initiate treatment with corticosteroids equivalent to 
1−2 mg/kg/day IV methylprednisolone and convert to 
1−2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month. 
GI = gastrointestinal. 
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be determined by the 
investigator. 
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 
10 mg/day oral prednisone before atezolizumab can be resumed.  
 
Dermatologic events 
Treatment-emergent rash has been associated with atezolizumab.  The majority of cases of rash 
were mild in severity and self-limited, with or without pruritus.  A dermatologist should evaluate 

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persistent and/or severe rash or pruritus.  Although uncommon, cases of severe cutaneous 
adverse reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been 
reported with atezolizumab.  A biopsy should be considered unless contraindicated.  
Management guidelines for dermatologic events are provided in the table below. 
 
Event 
Management 
Dermatologic 
event, Grade 1  
● Continue atezolizumab. 
● Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g., antihistamines). 
Dermatologic 
event, Grade 2  
● Continue atezolizumab. 
● Consider patient referral to dermatologist for evaluation and if 
indicated, biopsy. 
● Initiate treatment with topical corticosteroids. 
● Consider treatment with higher-potency topical corticosteroids if event 
does not improve. 
Dermatologic 
event, Grade 3  
● Withhold atezolizumab for up to 12 weeks after event onset. a 
● Refer patient to dermatologist for evaluation and if indicated, biopsy. 
● Initiate treatment with corticosteroids equivalent to 10 mg/day oral 
prednisone, increasing dose to 1-2 mg/kg/day if event does not 
improve within 48-72 hours. 
● If event resolves to Grade 1 or better, resume atezolizumab. b 
● If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab.  
Dermatologic 
event, Grade 4 
● Permanently discontinue atezolizumab.  
Stevens-Johnson 
syndrome or toxic 
epidermal 
necrolysis (any 
grade) 
Additional guidance for Stevens-Johnson syndrome or toxic 
epidermal necrolysis: 
• Withhold atezolizumab for suspected Stevens-Johnson syndrome or 
toxic epidermal necrolysis. 
• Confirm diagnosis by referring patient to a specialist (dermatologist, 
ophthalmologist, or urologist as relevant) for evaluation and, if 
indicated, biopsy. 
• Follow the applicable treatment and management guidelines above. 
● If Stevens-Johnson syndrome or toxic epidermal necrolysis is 
confirmed, permanently discontinue atezolizumab. 
Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be determined by the 
investigator. 
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 
10 mg/day oral prednisone before atezolizumab can be resumed. 
 

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Neurologic disorders 
Myasthenia gravis and Guillain-Barré syndrome have been observed with single agent 
atezolizumab.  Patients may present with signs and symptoms of sensory and/or motor 
neuropathy.  Diagnostic work-up is essential for an accurate characterization to differentiate 
between alternative etiologies.  Management guidelines for neurologic disorders and specific 
guidelines for myelitis, are provided in the tables below. 
 
Event 
Management 
Immune-mediated 
neuropathy, Grade 1 
• Continue atezolizumab. 
• Investigate etiology. 
• Any cranial nerve disorder (including facial paresis) should be 
managed as per Grade 2 management guidelines below. 
Immune-mediated 
neuropathy, including 
facial paresis,  Grade 2  
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Investigate etiology. 
• Initiate treatment as per institutional guidelines. 
• For general immune-mediated neuropathy: 
o If event resolves to Grade 1 or better, resume atezolizumab. b 
o If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c 
• For facial paresis: 
o If event resolves fully, resume atezolizumab. b 
o If event does not resolve fully while withholding atezolizumab, 
permanently discontinue atezolizumab. c 
 
Immune-mediated 
neuropathy, including 
facial paresis, Grade 3 
or 4 
• Permanently discontinue atezolizumab. c  
• Refer patient to neurologist. 
• Initiate treatment as per institutional guidelines. 
Myasthenia gravis and 
Guillain-Barré 
syndrome (any grade) 
• Permanently discontinue atezolizumab. c 
• Refer patient to neurologist. 
• Initiate treatment as per institutional guidelines. 
• Consider initiation of corticosteroids equivalent to 1−2 mg/kg/day 
oral or IV prednisone. 
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on an 
assessment of benefit−risk by the investigator and in alignment with the protocol requirements 
for the duration of treatment and documented by the investigator. 
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 
10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re−challenge patients with 
atezolizumab should be based on investigator's assessment of benefit−risk and documented by 
the investigator (or an appropriate delegate). 
 

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Event 
Management 
Immune-mediated 
myelitis, Grade 1 
• 
Continue atezolizumab unless symptoms worsen or do not 
improve. 
• 
Investigate etiology and refer patient to a neurologist.  
Immune-mediated 
myelitis, Grade 2 
• 
Permanently discontinue atezolizumab.  
• 
Investigate etiology and refer patient to a neurologist. 
• 
Rule out infection. 
• 
Initiate treatment with corticosteroids equivalent to 
1-2 mg/kg/day oral prednisone. 
Immune-mediated 
myelitis, Grade 3 or 4 
• 
Permanently discontinue atezolizumab. 
• 
Refer patient to a neurologist. 
• 
Initiate treatment as per institutional guidelines. 
 
Immune-Mediated Meningoencephalitis 
Immune-mediated meningoencephalitis is an identified risk associated with the administration of 
atezolizumab.  Immune-mediated meningoencephalitis should be suspected in any patient 
presenting with signs or symptoms suggestive of meningitis or encephalitis, including, but not 
limited to, headache, neck pain, confusion, seizure, motor or sensory dysfunction, and altered or 
depressed level of consciousness.  Encephalopathy from metabolic or electrolyte imbalances 
needs to be distinguished from potential meningoencephalitis resulting from infection (bacterial, 
viral, or fungal) or progression of malignancy, or secondary to a paraneoplastic process. 
 
All patients being considered for meningoencephalitis should be urgently evaluated with a CT 
scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or edema.  If deemed 
safe by the treating physician, a lumbar puncture should be performed, and a neurologist should 
be consulted. 
 
Patients with signs and symptoms of meningoencephalitis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in the table below. 
 
Event 
Management 
Immune-related 
meningoencephalitis, 
all grades 
• Permanently discontinue atezolizumab. 
• Refer patient to neurologist. 
• Initiate treatment with corticosteroids equivalent to 1−2 
mg/kg/day IV methylprednisolone and convert to 
1−2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over 
1 month. 
 
Renal events 
Immune-mediated nephritis has been associated with the administration of atezolizumab.  
Eligible patients must have adequate renal function.  Renal function, including serum creatinine, 
should be monitored throughout study treatment.  Patients with abnormal renal function should 

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be evaluated and treated for other more common etiologies (including prerenal and postrenal 
causes, and concomitant medications such as non-steroidal anti-inflammatory drugs).  Refer the 
patient to a renal specialist if clinically indicated.  A renal biopsy may be required to enable a 
definitive diagnosis and appropriate treatment. 
 
Patients with signs and symptoms of nephritis, in the absence of an identified alternate etiology, 
should be treated according to the guidelines in the table below. 
 
Event 
Management 
Renal event, 
Grade 1 
• Continue atezolizumab. 
• Monitor kidney function, including creatinine, closely until values 
resolve to within normal limits or to baseline values.  
Renal event, 
Grade 2 
• Withhold atezolizumab for up to 12 weeks after event onset. a 
• Refer patient to renal specialist. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral 
prednisone. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. 
Renal event, 
Grade 3 or 4 
• Permanently discontinue atezolizumab. 
• Refer patient to renal specialist and consider renal biopsy. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral 
prednisone. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over 1 
month. 
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be determined by the 
investigator. 
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 
10 mg/day oral prednisone before atezolizumab can be resumed. 
 
Immune-Mediated Myositis 
Immune-mediated myositis has been associated with the administration of atezolizumab.  
Myositis or inflammatory myopathies are a group of disorders sharing the common feature of 
inflammatory muscle injury; dermatomyositis and polymyositis are among the most common 
disorders.  Initial diagnosis is based on clinical (muscle weakness, muscle pain, skin rash in 
dermatomyositis), biochemical (serum creatine kinase increase), and imaging 
(electromyography/MRI) features, and is confirmed with a muscle biopsy. 
 
Patients with signs and symptoms of myositis, in the absence of an identified alternate etiology, 
should be treated according to the guidelines in table below. 
 
Event 
Management 

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Event 
Management 
Immune-mediated 
myositis, Grade 1 
• Continue atezolizumab. 
• Refer patient to rheumatologist or neurologist.  
• Initiate treatment as per institutional guidelines. 
Immune-mediated 
myositis, Grade 2 
• Withhold atezolizumab for up to 12 weeks after event onset a and 
contact Medical Monitor. 
• Refer patient to rheumatologist or neurologist. 
• Initiate treatment as per institutional guidelines. 
• Consider treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• If corticosteroids are initiated and event does not improve within 48 
hours after initiating corticosteroids, consider adding an 
immunosuppressive agent. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. 
Immune-mediated 
myositis, Grade 3 
• Withhold atezolizumab for up to 12 weeks after event onset a and 
contact Medical Monitor. 
• Refer patient to rheumatologist or neurologist. 
• Initiate treatment as per institutional guidelines.   
• Respiratory support may be required in more severe cases. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone, or higher-dose bolus if patient is severely 
compromised (e.g., cardiac or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert to 1−2 mg/kg/day oral 
prednisone or equivalent upon improvement. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, resume atezolizumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor.  
• For recurrent events, treat as a Grade 4 event. 
Immune-mediated 
myositis, Grade 4 
• Permanently discontinue atezolizumab and contact Medical Monitor. 
• Refer patient to rheumatologist or neurologist. 
• Initiate treatment as per institutional guidelines. 
• Respiratory support may be required in more severe cases. 
• Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone, or higher-dose bolus if patient is severely 
compromised (e.g., cardiac or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert to 1−2 mg/kg/day oral 
prednisone or equivalent upon improvement. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over 

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Event 
Management 
1 month. 
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be agreed upon by the 
investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 
10 mg/day oral prednisone before atezolizumab can be resumed.  
 
Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome 
Immune-mediated reactions may involve any organ system and may lead to hemophagocytic 
lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS). 
 
Patients with suspected HLH should be diagnosed according to published criteria by McClain 
and Eckstein (2017).  A patient should be classified as having HLH if five of the following eight 
criteria are met: 
● 
Fever ≥ 38.5°C 
● 
Splenomegaly 
● 
Peripheral blood cytopenia consisting of at least two of the following: 
– 
Hemoglobin  90 g/L (9 g/dL) (100 g/L [10 g/dL] for infants  4 weeks old) 
– 
Platelet count  100 × 109/L (100,000/mcL) 
– 
ANC  1.0 × 109/L (1000/mcL) 
● 
Fasting triglycerides 2.992 mmol/L (265 mg/dL) and/or fibrinogen 1.5 g/L 
(150 mg/dL) 
● 
Hemophagocytosis in bone marrow, spleen, lymph node, or liver 
● 
Low or absent natural killer cell activity 
● 
Ferritin 500 mg/L (500 ng/mL) 
● 
Soluble interleukin 2 (IL-2) receptor (soluble CD25) elevated ≥ 2 standard 
deviations above age-adjusted laboratory-specific norms 
 
Patients with suspected MAS should be diagnosed according to published criteria for systemic 
juvenile idiopathic arthritis by Ravelli et al. (2016).  A febrile patient should be classified as 
having MAS if the following criteria are met: 
 
● 
Ferritin 684 mg/L (684 ng/mL) 
● 
At least two of the following: 
– 
Platelet count ≤ 181 × 109/L (181,000/mcL) 
– 
AST ≥48 U/L 
– 
Triglycerides 1.761 mmol/L (156 mg/dL) 
– 
Fibrinogen ≤3.6 g/L (360 mg/dL) 
 
Patients with suspected HLH or MAS should be treated according to the guidelines in below. 
 
Event 
Management 
Suspected HLH 
● Permanently discontinue atezolizumab and contact Medical 

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Event 
Management 
or MAS 
Monitor. 
● Consider patient referral to hematologist. 
● Initiate supportive care, including intensive care monitoring if 
indicated per institutional guidelines. 
● Consider initiation of IV corticosteroids and/or an 
immunosuppressive agent. 
● If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
● If event resolves to Grade 1 or better, taper corticosteroids over 
≥1 month. 
HLH=  hemophagocytic lymphohistiocytosis; MAS= macrophage activation syndrome. 
 
6.2.3 Nivolumab Dose Modification and Toxicity Management 
Nivolumab and ipilimumab-related toxicity can be managed and treatment can be held, 
per investigator discretion, in accordance with institutional standards and the FDA 
package insert, and the following table for additional guidance:  
 
All dose modifications apply to both ipilimumab AND to nivolumab. 
 
Decisions to delay nivolumab dose must be made on specified safety criteria.  Treatment 
with nivolumab will be delayed (or discontinued) if the subject experiences at least one 
adverse event, specified below, considered by the investigator to be “possibly,” 
probably,” or “definitely” related to nivolumab treatment.  
 
 
 
≤ Grade 1  
Management/Next Dose for Nivolumab/Ipilimumab 
No change in dose.   
Grade 2  
Hold until ≤ Grade 1 OR baseline (exceptions as noted below).  
Grade 3  
Hold until ≤ Grade 1 OR baseline and patient no longer on steroid treatment if 
initiated (exceptions as noted below).  Permanently discontinue for events with a 
high likelihood of morbidity or mortality with recurrent events.  
Grade 4  
Discontinue nivolumab. 
Recommended management:  As clinically indicated   
  
o 
Any Grade 2 drug-related uveitis or eye pain or blurred vision that does 
not respond to topical therapy and does not improve to Grade 1 severity 
within the re-treatment period OR requires systemic treatment should 
discontinue nivolumab 
  
o 
Any Grade 3 or 4 drug-related laboratory abnormality or electrolyte 
abnormality, that can be managed independently from underlying organ 

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pathology with electrolyte replacement, hormone replacement, insulin or that 
does not require treatment does not require discontinuation.   
 
o 
Any AE, laboratory abnormality, or intercurrent illness which, in the 
judgment of the investigator, presents a substantial clinical risk to the subject 
with continued study drug dosing should discontinue nivolumab/ipilimumab.   
  
Skin Rash and 
Oral  
Lesions   
Management/Next Dose for Nivolumab/Ipilimumab  
≤ Grade 1  
No change in dose*.  
Grade 2  
Hold* until 1≤ Grade resolved.  Resume dose.   
Grade 3  
Hold* until ≤ Grade 1.  Resume dose at investigator discretion   
Grade 4  
Discontinue nivolumab/ipilimumab 
*Patients with purpuric or bullous lesions must be evaluated for vasculitis, Steven-Johnson syndrome, 
toxic epidermal necrolysis (TEN), and autoimmune bullous disease including oral lesions of bullous 
pemphigus/pemphigoid.  Pruritus may occur with or without skin rash and should be treated 
symptomatically if there is no associated liver or GI toxicity.  Note skin rash typically occurs early and 
may be followed by additional events particularly during steroids tapering.    
 
   
Liver Function:  
AST, ALT, 
Bilirubin 
Management/Next Dose for Nivolumab/Ipilimumab 
≤ Grade 1 
Hold at investigator discretion until ULN or baseline.  Resume dose.  
Grade 2  
Grade 2 (3X UNL to 5X UNL): Hold until grade 1 (UNL-3X UNL) or baseline.  
Resume dose at investigator discretion. 
Grade 3  
Grade 3 (5X UNL to 20X UNL) Hold until grade 1 or baseline.  Resume at same dose 
at investigator discretion with return to grade 1 or baseline within 7 days without 
steroids.  If persistent or steroids are required, discontinue nivolumab/ipilimumab.   
Grade 4  
Discontinue nivolumab/ipilimumab.  
Continued treatment of active immune mediated hepatitis may exacerbate ongoing inflammation.   
Holding drug to evaluate liver function test (LFT) changes and early treatment are recommended.  LFT 
changes may occur during steroid tapers from other events and may occur together with other GI events 
including cholecystitis/pancreatitis.  
Please note:  Grades for liver function follow UNL rather than multiples of baseline. 
 
   
 
≤ Grade 1  
Management/Next Dose for Nivolumab/Ipilimumab  
Hold until baseline.  Then resume dose.  
Grade 2  
Hold until baseline.  Then resume dose.  
Grade 3  
Resume at same dose level at investigator discretion if resolved to grade 1 within 7 
days without steroids and no evidence of colitis.  If persistent or steroids are 
required discontinue nivolumab.  

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Grade 4  
Discontinue nivolumab/ipilimumab.  
Patients with Grade 2 symptoms but normal colonoscopy and biopsies may be retreated after resolution.   
Patients who require systemic steroids should discontinue nivolumab/ipilimumab.   
Please evaluate pituitary function prior to starting steroids if possible without compromising acute care. 
Evaluation for all patients for additional causes includes C. diff, acute and self-limited infectious and 
foodborne illness, ischemic bowel, diverticulitis, and IBD.   
 
  
Pancreatitis 
Amylase/Lipase   
Management/Next Dose for Nivolumab/Ipilimumab  
≤ Grade 1  
Continue dose if asymptomatic at investigator discretion.   
Grade 2  
Continue dose if asymptomatic at investigator discretion.  If symptomatic, resume 
at same dose  when resolved  
Grade 3  
Continue at same dose if asymptomatic at investigator discretion.  Patients should 
have imaging study when clinically indicated (grade 3 symptomatic pancreatitis) 
before resuming treatment.  Patients who develop diabetes mellitus should 
discontinue nivolumab/ipilimumab.   
Grade 4  
Hold until grade 2.  Resume dose if asymptomatic.  Patients who are symptomatic 
should have imaging study prior to resuming treatment and when clinically 
indicated.  Patients who develop grade 4 symptomatic pancreatitis or diabetes 
mellitus should discontinue nivolumab/ipilimumab.   
Patients may develop symptomatic and radiologic evidence of pancreatitis as well as diabetes mellitus 
and diabetic ketoacidosis (DKA).  Lipase elevation may occur during the period of steroid withdrawal 
and with other immune-mediated events or associated with colitis, hepatitis, and patients who have 
asymptomatic lipase elevation typically have self-limited course and may be retreated.   
   
Pneumonitis  
Management/Next Dose for Nivolumab/Ipilimumab  
≤ Grade 1  
Hold dose pending evaluation and resolution to baseline including baseline pO2.  
Resume dose after pulmonary and/or infectious disease (ID) consultation 
excludes lymphocytic pneumonitis.   
Grade 2  
Hold dose pending evaluation. Resume dose after pulmonary and/or ID 
consultation excludes ipilimumab and associated lymphocytic pneumonitis as the 
cause of the pneumonitis.  Off study if steroids are required.  
Grade 3  
Hold dose pending evaluation.  Resume dose after pulmonary and/or ID 
consultation excludes ipilimumab and associated lymphocytic pneumonitis as the 
cause of the pneumonitis Discontinue nivolumab/ipilimumab 
Grade 4  
Discontinue nivolumab/ipilimumab.  
Distinguishing inflammatory pneumonitis is often a diagnosis of exclusion for patients who do not 
respond to antibiotics and have no causal organism identified, including influenza.  Most patients with 
respiratory failure or hypoxia will be treated with steroids.  Bronchoscopy may be required and analysis 
of lavage fluid for lymphocytic predominance may be helpful.  Patients with new lung nodules should 
be evaluated for sarcoid like granuloma.  Please consider recommending seasonal influenza killed 

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vaccine for all patients.  
 
  
 Other GI 
NauseaVomiting   
Management/Next Dose for Nivolumab/Ipilimumab  
≤ Grade 1  
Continue dose.   
Grade 2  
Hold pending evaluation for gastritis, duodenitis, and other immune AEs or other 
causes.  Resume at same dose after resolution to ≤ Grade 1.    
Grade 3  
Hold pending evaluation until ≤ Grade 1.  Resume dose.  If symptoms do not 
resolve within 7 days with symptomatic treatment, patients should discontinue 
nivolumab/ipilimumab.  
Grade 4  
Discontinue nivolumab/ipilimumab 
Patients with Grade 2 or 3 N-V should be evaluated for upper GI inflammation and other immune 
related events. 
   
Fatigue 
Management/Next Dose for Nivolumab/Ipilimumab  
  
Grade 2 
Continue dose. 
Grade 3  
Hold until ≤ Grade 2.  Resume at same dose.  
Grade 4  
Discontinue nivolumab/ipilimumab.  
Fatigue is the most common AE associated with immune checkpoint therapy.  Grade 2 or greater fatigue 
should be evaluated for associated or underlying organ involvement including pituitary, thyroid, and 
hepatic, or muscle (CPK) inflammation.   
  
 Neurologic events  
Management/Next Dose for Nivolumab/Ipilimumab  
≤ Grade 1  
Hold dose pending evaluation and observation.  Resume dose when resolved to 
baseline.   
Grade 2  
Hold dose pending evaluation and observation.  Hold until ≤ Grade 1. 
Discontinue nivolumab/ipilimumab if treatment with steroids is required.  
Resume at same dose level for peripheral isolated n. VII (Bell’s palsy).   
Grade 3  
Discontinue nivolumab/ipilimumab 
Grade 4  
Discontinue nivolumab/ipilimumab 
Patients with any CNS events including aseptic meningitis, encephalitis, symptomatic hypophysitis, or 
myopathy, peripheral demyelinating neuropathy, cranial neuropathy (other than peripheral n. VII), GB 
syndrome, and myasthenia gravis should be off study. 
 
   

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Management/Next Dose for Nivolumab/Ipilimumab  
≤ Grade 1  
*Hold pending evaluation for evidence of adrenal insufficiency or hypophysitis.  
Asymptomatic thyroid stimulating hormone (TSH) elevation may continue 
treatment while evaluating the need for thyroid replacement.  
Grade 2  
Hold until patients are on a stable replacement hormone regimen.  If treated with 
steroids, patients must be stable off steroids for 2 weeks.   
Resume dose.   
Grade 3  
Hold until patients are on a stable replacement hormone regimen.  If treated with 
steroids, patients must be stable off steroids for 2 weeks.  
Resume dose.  
Grade 4  
Discontinue nivolumab/ipilimumab.  
Note all patients with symptomatic pituitary enlargement, exclusive of hormone deficiency, but 
including severe headache or enlarged pituitary on MRI should be considered Grade 3 events.  Isolated 
thyroid or testosterone deficiency may be treated as Grade 2 if there are no other associated deficiencies 
and adrenal function is monitored.   
Please evaluate pituitary function before beginning steroid therapy or replacement therapy of any kind.  
*Note patients with thyroiditis may be retreated on replacement therapy.  Patients must be evaluated to 
rule out pituitary disease prior to initiating thyroid replacement.  
 
Patients with grade 3 thyroiditis and skin rash may continue therapy as for grade 2 events with 
resolution and stable replacement treatment. 
 
Patients with thyroiditis or hypopituitarism who are stable as above may be restarted with replacement 
hormones including thyroid hormone and physiologic doses of corticosteroids.  
 
Please note that grading and for hypophysitis with symptoms of headache, visual or neurologic changes 
or radiologic evidence of pituitary enlargement and other CNS events such as aseptic meningitis or 
encephalitis should be considered grade 3 events.  
 
Prior to starting corticosteroids or hormone replacement for any reason, appropriate endocrine testing 
including cortisol, ACTH, TSH and T4 must be obtained to document baseline.  
 
   
Renal 
Management/Next Dose for Nivolumab/Ipilimumab  
≤ Grade 1  
Monitor closely and continue therapy.  
Grade 2  
Hold until ≤ Grade 1.  Resume dose.  
Grade 3  
Hold until ≤ Grade 1.  Resume dose.  
Grade 4  
Discontinue nivolumab 
Patients with fever should be evaluated as clinically appropriate.  Patients may experience isolated 
fever during infusion reactions or up to several days after infusion.  Evaluation over the course of 1-2 
weeks should be done for other autoimmune events that may present as fever.   
   

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Infusion reaction   
Management/Next Dose for Nivolumab/Ipilimumab  
≤ Grade 1  
Monitor closely and continue therapy.  
Grade 2  
Hold until ≤ Grade 1.  Resume at same dose level.  
Grade 3  
Hold until ≤ Grade 1.  Resume at same dose level.  
Grade 4  
Discontinue nivolumab/ipilimumab 
Patients with fever should be evaluated as clinically appropriate.  Patients may experience isolated 
fever during infusion reactions or up to several days after infusion.  Evaluation over the course of 1-2 
weeks should be done for other autoimmune events that may present as fever.   
  
 Fever   
Management/Next Dose for Nivolumab/Ipilimumab  
≤ Grade 1  
Evaluate and continue at dose.  
Grade 2  
Hold until ≤ Grade 1.  Resume at dose.  
Grade 3  
Hold until ≤ Grade 1.  Resume at dose.  
Grade 4  
Discontinue nivolumab/ipilimumab 
Patients with fever should be evaluated as clinically appropriate.  Patients may experience isolated 
fever during infusion reactions or up to several days after infusion.  Evaluation over the course of 1-2 
weeks should be done for other autoimmune events that may present as fever.   
See section 6.4.1 – Treatment of Nivolumab/Ipilimumab -Related Infusion Reactions.    
 
 
Cardiac *   
Management/Next Dose for  
Nivolumab + Ipilimumab Cardiac Toxicities  
Less than grade 2 Hold dose pending evaluation and observation.**  Evaluate for signs and 
symptoms of CHF, ischemia, arrhythmia or myositis.  Obtain history EKG, CK 
(for concomitant myositis), CK-MB.  Repeat troponin, CK and EKG 2-3 days.  If 
troponin and labs normalize without evidence of myocarditis may resume 
therapy.   If labs worsen or symptoms develop then treat as below.   
Grade ≥2 with 
suspected 
myocarditis 
Hold dose.**  Admit to hospital.  Cardiology consult.  Rule out MI and other 
causes of cardiac disease.  Cardiac Monitoring.  Cardiac Echo.  Consider cardiac 
MRI and cardiac biopsy.  Initiate high dose methylprednisolone and immune 
suppression as clinically indicated.  If no improvement within 24 hours consider 
adding either infliximab, ATG or tacrolimus.. May resume therapy if there is a 
return to baseline and myocarditis is excluded or considered unlikely. 
Grade ≥2 with 
confirmed 
myocarditis   
Discontinue nivolumab and ipilimumab.  Admit to CCU (consider transfer to 
nearest Cardiac Transplant Unit).  Treat as above.  Consider high dose 
methylprednisolone   
Add ATG or tacrolimus if no improvement. Discontinue nivolumab and 
ipilimumab. 
*Including CHF, LV systolic dysfunction, Myocarditis, CPK, and troponin  
**Patients with evidence of myositis without myocarditis may be treated according as “other event”   
Note:  The optimal treatment regimen for immune mediated myocarditis has not been established.  
Since this toxicity has caused patient deaths, an aggressive approach is recommended.   

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            Treatment of Nivolumab/Ipilimumab-Related Infusion Reactions 
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely 
to be immunogenic and induce infusion or hypersensitivity reactions.  However, if such a 
reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, 
urticaria, angioedema, pruritis, arthralgias, hypo- or hypertension, bronchospasm, or 
other symptoms.  
 
All Grade 3 or 4 infusion reactions should be reported as an SAE if criteria are met.  
Infusion reactions should be graded according to NCI CTCAE version 5.0 guidelines. 
 
Treatment recommendations are provided below and may be modified based on local 
treatment standards and guidelines as medically appropriate: 
 
Remain at bedside and monitor subject until recovery from symptoms.  
 
For Grade 1 symptoms  
(Mild reaction; infusion interruption not indicated; intervention not indicated)  
 
Infusion rate may be slowed or interrupted and restarted at 50% of the original infusion 
rate when symptoms resolve; if no further complications ensue after 30 minutes, the rate 
may be increased to 100% of the original infusion rate.  Monitor patient closely.   
 
The following prophylactic premedications are recommended for future infusions:  
diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen) at least 30 minutes before additional nivolumab and ipilimumab 
administrations, slowing infusion rate as above. 
 
For Grade 2 symptoms   
(Moderate reaction requires therapy or infusion interruption but responds promptly to 
symptomatic treatment [e.g., antihistamines, non-steroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids]; close observation for recurrence 
and treatment  medications may need to be continued for 24-48 hours).   
 
Stop the nivolumab and ipilimumab infusions, begin an IV infusion of normal saline, and 
reat the subject with diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 
to 1000 mg (acetaminophen); remain at bedside and monitor patient until resolution of 
symptoms.  Corticosteroid or bronchodilator therapy may also be administered as 
appropriate.  If the infusion is interrupted, then restart the infusion at 50% of the original 
infusion rate when symptoms resolve; if no further complications ensue after 30 minutes, 
the rate may be increased to 100% of the original infusion rate.  Monitor patient closely.  
If symptoms recur, re administer diphenhydramine 50 mg IV, and remain at bedside and 
monitor the patient until resolution of symptoms.  The amount of study drug infused must 
be recorded on the electronic case report form (eCRF). 
 
The following prophylactic premedications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and (acetaminophen) (or paracetamol) 325 to 

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1000 mg should be administered at least 30 minutes before additional nivolumab and 
ipilimumab administrations.  If necessary, corticosteroids (recommended dose: up to 25 
mg of IV hydrocortisone or equivalent) may be used. 
 
For Grade 3 or Grade 4 symptoms:  
(Severe reaction) 
 
Grade 3 symptoms: 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 symptoms: (life threatening; pressor or ventilatory support indicated).  
Nivolumab and ipilimumab will be permanently discontinued 
 
Immediately discontinue infusion of nivolumab and ipilimumab.  Begin an IV infusion of 
normal saline, and bronchodilators, epinephrine 0.2 to 1 mg of a 1:1,000 solution for 
subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution injected slowly for 
IV administration, and/or diphenhydramine 50 mg IV with methylprednisolone 100 mg 
IV (or equivalent), as needed.  Patient should be monitored until the investigator is 
comfortable that the symptoms will not recur.   
 
Investigators should follow their institutional guidelines for the treatment of anaphylaxis.  
Remain at bedside and monitor patient until recovery from symptoms.  
 
Other guidance: 
In the case of late-occurring hypersensitivity symptoms (e.g., appearance of a localized or 
generalized pruritus within 1 week after treatment), symptomatic treatment may be given 
(e.g., oral antihistamine, or corticosteroids).  Additional treatment prior to next dose as 
per guidelines above.  
 
Please note that late occurring events including isolated fever and fatigue may represent 
the presentation of systemic inflammation.  Please evaluate accordingly. 
 
7.       ADVERSE EVENTS REPORTING REQUIREMENTS 
7.1       Protocol Agents (30-MAR-2021) 
 
    Commercial Agents 
    The commercial agents in NRG-LU002 are pemetrexed, gemcitabine,  atezolizumab, 
ipilimumab, nivolumab, and pembrolizumab.  
7.2       Adverse Events and Serious Adverse Events (18-MAY-2018) 
7.2.1 The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE), version 4.0 will be utilized until March 31, 2018, 
for all AE reporting, CTEP-AERS, and case report forms.  CTCAE version 5.0 will be 
utilized for CTEP-AERS reporting beginning April 1, 2018; all study case report forms 

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will continue to use CTCAE version 4.0 through the broadcast of Amendment 1, at which 
point adverse event reporting in case report forms will be collected in CTCAE version 
5.0.  
 
All appropriate treatment areas should have access to a copy of CTCAE versions 4.0 and 
5.0, which can be downloaded from the CTEP web site (https://ctep.cancer.gov/ 
protocolDevelopment/electronic_applications/ctc.htm 
 
7.2.2 Definition of an Adverse Event (AE) 
Any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related.  Therefore, an AE can be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not 
considered related to the medicinal (investigational) product (attribution of unrelated, 
unlikely, possible, probable, or definite). (International Conference on Harmonisation 
[ICH], E2A, E6).  
 
For multi-modality trials, adverse event reporting encompasses all aspects of protocol 
treatment including radiation therapy, surgery, device, and drug. 
 
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, the 
pregnancy of a study participant must be reported via CTEP-AERS in an expedited 
manner. 

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7.3       Comprehensive Adverse Events and Potential Risks list (CAEPR) for MK-3475                      
(pembrolizumab, NSC 776864) (22-FEB-2023) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system.  
 
     Version 2.7, December 13, 20221 
 
 Adverse Events with Possible  
 Relationship to Pembrolizumab (MK-3475) 
 (CTCAE 5.0 Term) 
[n= 3793] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia2 
 
 
 
Blood and lymphatic 
system disorders - Other 
(immune 
thrombocytopenic 
purpura)2 
 
Lymph node pain2 
 
CARDIAC DISORDERS 
 
 
Myocarditis2 
 
 
Pericarditis2 
ENDOCRINE DISORDERS 
 
Adrenal insufficiency2 
 
 
 
Endocrine disorders - 
Other 
(hypoparathyroidism) 
 
Endocrine disorders - Other 
(thyroiditis)2 
 
 
Hyperthyroidism2 
 
 
Hypophysitis2 
 
 
Hypopituitarism2 
 
 
Hypothyroidism2 
 
EYE DISORDERS 
 
 
Uveitis2 
 
 
Eye disorders - Other 
(Vogt-Koyanagi-Harada 
syndrome) 
GASTROINTESTINAL DISORDERS 

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 Adverse Events with Possible  
 Relationship to Pembrolizumab (MK-3475) 
 (CTCAE 5.0 Term) 
[n= 3793] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
Abdominal pain 
 
 
Colitis2 
 
 
Diarrhea2 
 
 
Mucositis oral2 
 
 
Nausea 
 
 
Pancreatitis2 
 
 
Small intestinal mucositis2 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
Chills2 
 
Fatigue 
 
 
 
Fever2 
 
HEPATOBILIARY DISORDERS 
 
Hepatobiliary disorders - 
Other (autoimmune 
hepatitis)2 
 
 
 
Hepatobiliary disorders - 
Other (sclerosing 
cholangitis) 
IMMUNE SYSTEM DISORDERS 
 
 
Anaphylaxis2 
 
 
Cytokine release 
syndrome2 
 
 
Immune system disorders 
- Other (acute graft-
versus-host-disease)2,3 
 
 
Immune system disorders 
- Other (hemophagocytic 
lymphohistiocytosis)2 
 
Immune system disorders - 
Other (sarcoidosis)2 
 
 
 
Serum sickness2 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
 
 
 Infusion related reaction 
INVESTIGATIONS 
 
Alanine aminotransferase 
increased2 
 

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 Adverse Events with Possible  
 Relationship to Pembrolizumab (MK-3475) 
 (CTCAE 5.0 Term) 
[n= 3793] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
Alkaline phosphatase 
increased 
 
 
Aspartate aminotransferase 
increased2 
 
 
Blood bilirubin increased 
 
 
 
GGT increased 
 
 
Serum amylase increased 
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
 
 
Hyponatremia 
 
 
 
Metabolism and nutrition 
disorders - Other (diabetic 
ketoacidosis)2 
 
 
Metabolism and nutrition 
disorders - Other (type 1 
diabetes mellitus)2 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Arthralgia2 
 
 
Arthritis2 
 
 
Back pain 
 
 
Joint range of motion 
decreased 
 
 
Myalgia2 
 
 
Myositis2 
 
NERVOUS SYSTEM DISORDERS 
 
 
Guillain-Barre syndrome2 
 
 
Nervous system disorders 
- Other (myasthenic 
syndrome)2 
 
 
Nervous system disorders 
- Other (neuromyopathy)2 
 
 
Nervous system disorders 
- Other (non-infectious 
encephalitis)2 
 
 
Nervous system disorders 
- Other (non-infectious 
meningitis)2 

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 Adverse Events with Possible  
 Relationship to Pembrolizumab (MK-3475) 
 (CTCAE 5.0 Term) 
[n= 3793] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
Nervous system disorders 
- Other (non-infectious 
myelitis) 
 
 
Nervous system disorders 
- Other (optic neuritis) 
 
 
Nervous system disorders 
- Other (polyneuropathy)2 
 
 
Paresthesia 
 
 
Peripheral motor 
neuropathy2 
RENAL AND URINARY DISORDERS 
 
 
Renal and urinary 
disorders - Other 
(autoimmune nephritis)2 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
 Cough 
 
 
 Pneumonitis2 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
Bullous dermatitis2 
 
 
 
 Erythema multiforme2 
 
Erythroderma 
 
 
 
Palmar-plantar 
erythrodysesthesia 
syndrome 
 
Pruritus2 
 
 
Rash acneiform2 
 
 
Rash maculo-papular2 
 
 
Skin and subcutaneous tissue 
disorders - Other 
(dermatitis)2 
 
 
Skin hypopigmentation2 
 
 
 
Stevens-Johnson 
syndrome2 
 
 
Toxic epidermal 
necrolysis 
 
Urticaria2 
 
VASCULAR DISORDERS 

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 Adverse Events with Possible  
 Relationship to Pembrolizumab (MK-3475) 
 (CTCAE 5.0 Term) 
[n= 3793] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
Vasculitis2 
 
 1This table will be updated as the toxicity profile of the agent is revised.  Updates will be 
distributed to all Principal Investigators at the time of revision.  The current version can be 
obtained by contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail. 
 
2Immune-mediated adverse reactions have been reported in patients receiving Pembrolizumab 
(MK-3475).  Adverse events potentially related to Pembrolizumab (MK-3475) may be 
manifestations of immune-mediated adverse events. In clinical trials, most immune-mediated 
adverse reactions were reversible and managed with interruptions of Pembrolizumab (MK-
3475), administration of corticosteroids and supportive care. 
 
3Acute graft-versus-host disease has been observed in patients treated with Pembrolizumab (MK-
3475) who received hematopoeitic stem cell transplants. 
 
Adverse events reported on Pembrolizumab (MK-3475) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that Pembrolizumab 
(MK-3475) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system 
disorders - Other (pancytopenia); Disseminated intravascular coagulation; Hemolysis 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Chest pain - cardiac; Heart failure; 
Myocardial infarction; Pericardial effusion; Pericardial tamponade; Ventricular arrhythmia 
EYE DISORDERS - Eye pain 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Constipation; 
Duodenal hemorrhage; Dysphagia; Gastritis; Gastrointestinal disorders - Other (diverticulitis); 
Gastrointestinal disorders - Other (intestinal obstruction); Gastrointestinal disorders - Other 
(intussusception); Oral pain; Rectal hemorrhage; Small intestinal perforation; Upper 
gastrointestinal hemorrhage; Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema face; 
Edema limbs; Facial pain; Gait disturbance; General disorders and administration site conditions 
- Other (general physical health deterioration); Generalized edema; Malaise; Non-cardiac chest 
pain; Pain 
INVESTIGATIONS - CPK increased; Cholesterol high; Creatinine increased; Fibrinogen 
decreased; Lymphocyte count decreased; Neutrophil count decreased; Platelet count decreased; 
Weight loss; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; 
Hyperglycemia; Hyperkalemia; Hypertriglyceridemia; Hyperuricemia; Hypoalbuminemia; 

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Hypokalemia; Hypophosphatemia; Metabolism and nutrition disorders - Other (failure to thrive); 
Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; 
Generalized muscle weakness; Joint effusion2; Musculoskeletal and connective tissue disorder - 
Other (groin pain); Pain in extremity 
NERVOUS SYSTEM DISORDERS - Aphonia; Depressed level of consciousness; Dysarthria; 
Edema cerebral; Encephalopathy; Headache; Hydrocephalus; Lethargy; Meningismus; Nervous 
system disorders - Other (brainstem herniation); Seizure; Syncope; Tremor 
PSYCHIATRIC DISORDERS - Agitation; Confusion 
RENAL AND URINARY DISORDERS - Acute kidney injury; Nephrotic syndrome; 
Proteinuria; Renal and urinary disorders - Other (hydronephrosis); Urinary incontinence; Urinary 
tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Pelvic pain 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Dyspnea; Hypoxia; 
Laryngeal inflammation; Pleural effusion; Pleuritic pain2; Pneumothorax; Respiratory failure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Skin and 
subcutaneous tissue disorders - Other (drug eruption) 
VASCULAR DISORDERS - Hypertension; Peripheral ischemia; Thromboembolic event 
 
 
Note: Pembrolizumab (MK-3475) in combination with other agents could cause an exacerbation 
of any adverse event currently known to be caused by the other agent, or the combination may 
result in events never previously associated with either agent. 
 
 
7.4       Comprehensive Adverse Events and Potential Risks (CAEPR) List for 
Atezolizumab (MPDL3280A, NSC 783608)  (18-OCT-2023) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list 
of reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. Refer to the 'CTEP, NCI Guidelines: Adverse Event 
Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
for further clarification. Frequency is provided based on 3097 patients. Below is the CAEPR 
for Atezolizumab (MPDL3280A). 
 
Version 2.4, September 14, 20231 
Adverse Events with Possible  
 Relationship to Atezolizumab (MPDL3280A) 
 (CTCAE 5.0 Term) 
[n= 3097] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia 
 
CARDIAC DISORDERS 
 
 
Heart failure2 

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Adverse Events with Possible  
 Relationship to Atezolizumab (MPDL3280A) 
 (CTCAE 5.0 Term) 
[n= 3097] 
 
 
Myocarditis2 
 
 
Pericardial effusion2 
 
 
Pericardial tamponade2 
 
 
Pericarditis2 
ENDOCRINE DISORDERS 
 
 
Adrenal insufficiency2 
 
 
Endocrine disorders - 
Other (diabetes)2 
 
Hyperthyroidism2 
 
 
 
Hypophysitis2 
 
Hypothyroidism2 
 
EYE DISORDERS 
 
 
Eye disorders - Other 
(ocular inflammatory 
toxicity)2 
 
 
Uveitis2 
GASTROINTESTINAL DISORDERS 
 
Abdominal pain 
 
 
 
Colitis2 
 
Diarrhea 
 
 
Dysphagia 
 
 
Nausea 
 
 
 
Pancreatitis2 
 
Vomiting 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
Fatigue 
 
 
 
Fever3 
 
 
Flu like symptoms3 
 
HEPATOBILIARY DISORDERS 
 
 
Hepatic failure2 
 
 
Hepatobiliary disorders - 
Other (hepatitis [immune 
related hepatitis])2 
IMMUNE SYSTEM DISORDERS 
 
Allergic reaction3 
 
 
 
Anaphylaxis3 
 
 
Cytokine release 
syndrome3 
 
 
Immune system disorders 

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Adverse Events with Possible  
 Relationship to Atezolizumab (MPDL3280A) 
 (CTCAE 5.0 Term) 
[n= 3097] 
- Other (hemophagocytic 
lymphohistiocytosis 
(HLH)/macrophage 
activation syndrome 
(MAS))2 
 
 
Immune system disorders 
- Other (systemic immune 
activation)2 
INFECTIONS AND INFESTATIONS 
Infection4 
 
 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
 
Infusion related reaction3  
INVESTIGATIONS 
 
Alanine aminotransferase 
increased2 
 
 
Alkaline phosphatase 
increased2 
 
 
Aspartate 
aminotransferase 
increased2 
 
 
Blood bilirubin increased2  
 
 
Creatinine increased 
 
GGT increased 
 
 
Lipase increased* 
 
 
 
Platelet count decreased 
 
Serum amylase increased*  
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
 
 
 
Hyperglycemia2 
 
Hypokalemia 
 
 
Hyponatremia 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Arthralgia2 
 
 
Back pain 
 
 
 
Generalized muscle 
weakness 
 
Myalgia 
 
 
 
Myositis2 
NERVOUS SYSTEM DISORDERS 

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Adverse Events with Possible  
 Relationship to Atezolizumab (MPDL3280A) 
 (CTCAE 5.0 Term) 
[n= 3097] 
 
 
Ataxia2 
 
 
Encephalopathy2 
 
 
Guillain-Barre syndrome2 
 
 
Myasthenia gravis2 
 
 
Nervous system disorders 
- Other (meningitis non-
infective)2 
 
 
Nervous system disorders 
- Other (facial paresis)2 
 
 
Nervous system disorders 
- Other (encephalitis non-
infective)2 
 
 
Nervous system disorders 
- Other (immune-mediated 
myelitis)2 
 
 
Paresthesia2 
 
 
Peripheral motor 
neuropathy2 
 
 
Peripheral sensory 
neuropathy2 
RENAL AND URINARY DISORDERS 
 
 
Acute kidney injury 
 
 
Renal and urinary 
disorders - Other 
(nephritis)2 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
Cough 
 
 
Dyspnea 
 
 
Hypoxia 
 
 
Nasal congestion 
 
 
 
Pleural effusion2 
 
 
Pneumonitis2 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
 
Bullous dermatitis2 
 
 
Erythema multiforme2 
 
Pruritus 
 
 
Rash acneiform 
 
 
Rash maculo-papular 
 
 
 
Skin and subcutaneous 

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Adverse Events with Possible  
 Relationship to Atezolizumab (MPDL3280A) 
 (CTCAE 5.0 Term) 
[n= 3097] 
tissue disorders - Other 
(Drug reaction with 
eosinophilia with systemic 
symptoms [DRESS])2 
 
 
Skin and subcutaneous 
tissue disorders - Other 
(Exanthematous 
pustulosis)2 
 
 
 
 
Skin and subcutaneous 
tissue disorders - Other 
(lichen planus)2 
 
 
 
Stevens-Johnson 
syndrome2 
 
 
Toxic epidermal 
necrolysis2 
 
*Denotes adverse events that are <3%. 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should be included 
in the e-mail. 
 
2Atezolizumab, being a member of a class of agents involved in the inhibition of “immune checkpoints,” may result 
in severe and possibly fatal immune-mediated adverse events probably due to T-cell activation and proliferation. 
Immune-mediated adverse reactions have been reported in patients receiving atezolizumab. Adverse events 
potentially related to atezolizumab may be manifestations of immune-mediated adverse events. In clinical trials, most 
immune-mediated adverse reactions were reversible and managed with interruptions of atezolizumab, administration 
of corticosteroids and supportive care. 
 
3Infusion reactions, including high-grade hypersensitivity reactions, anaphylaxis, and cytokine release syndrome, 
which have been observed following administration of atezolizumab, may manifest as fever, chills, shakes, itching, 
rash, hypertension or hypotension, or difficulty breathing during and immediately after administration of 
atezolizumab. 
 
4Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
Adverse events reported on atezolizumab (MPDL3280A) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that atezolizumab 
(MPDL3280A) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system 
disorders - Other (pancytopenia); Febrile neutropenia 
CARDIAC DISORDERS - Cardiac arrest; Ventricular tachycardia 

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GASTROINTESTINAL DISORDERS - Constipation; Dry mouth; Ileus 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema 
limbs; Malaise; Multi-organ failure 
HEPATOBILIARY DISORDERS - Portal vein thrombosis 
INVESTIGATIONS - Lymphocyte count decreased; Neutrophil count decreased; Weight loss; 
White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Hypophosphatemia; Tumor lysis 
syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Muscle 
cramp: Pain in extremity 
NERVOUS SYSTEM DISORDERS - Headache 
PSYCHIATRIC DISORDERS - Confusion; Insomnia; Suicide attempt 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Breast pain 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary 
hemorrhage; Pulmonary hypertension; Respiratory failure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin2; Hyperhidrosis 
VASCULAR DISORDERS - Hypertension; Hypotension; Thromboembolic event 
 
Note: Atezolizumab (MPDL3280A) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other agent, or the 
combination may result in events never previously associated with either agent. 
7.5   Comprehensive Adverse Events and Potential Risks list (CAEPR) for Nivolumab 
(NSC 748726) (18-OCT-2023) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. Refer to the 'CTEP, NCI Guidelines: Adverse Event 
Reporting Requirements'  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. Frequency is provided based on 2069 patients. Below is the CAEPR for 
Nivolumab. 
 
 
Version 2.5, June 10, 20231 
 
 Adverse Events with Possible  
 Relationship to Nivolumab 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
 
Anemia 
 
 
                                             
Blood and lymphatic 
system disorders - Other 
(lymphatic dysfunction) 
 
CARDIAC DISORDERS 
 

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 Adverse Events with Possible  
 Relationship to Nivolumab 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
Cardiac disorders - Other 
(cardiomyopathy) 
 
 
 
Myocarditis 
 
 
 
Pericardial tamponade2 
 
 
 
Pericarditis 
 
ENDOCRINE DISORDERS 
 
 
Adrenal insufficiency3 
 
 
 
Hyperthyroidism3 
 
 
 
Hypophysitis3 
 
 
 
Hypothyroidism3 
 
 
EYE DISORDERS 
 
 
 
Blurred vision 
 
 
 
Dry eye 
 
 
 
Eye disorders - Other 
(diplopia)3 
 
 
 
Eye disorders - Other 
(Graves opthalmopathy)3  
 
 
Eye disorders - Other 
(optic neuritis 
retrobulbar)3 
 
 
 
Eye disorders - Other 
(Vogt-Koyanagi-Harada)3  
 
Uveitis 
 
 
GASTROINTESTINAL DISORDERS 
 
 
Abdominal pain 
 
 
 
Colitis3 
 
 
 
 
Colonic perforation3 
 
 
Diarrhea 
 
 
 
Dry mouth 
 
 
 
 
Enterocolitis 
 
 
 
Gastritis 
 
 
 
Mucositis oral 
 
 
Nausea 
 
 
 
Pancreatitis4 
 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
Fatigue 
 
 
 
 
Fever 
 
 

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 Adverse Events with Possible  
 Relationship to Nivolumab 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
Injection site reaction 
 
 
HEPATOBILIARY DISORDERS 
 
 
 
Hepatobiliary disorders - 
Other (Immune-related 
hepatitis) 
 
IMMUNE SYSTEM DISORDERS 
 
 
 
Allergic reaction3 
 
 
 
Autoimmune disorder3 
 
 
 
Cytokine release 
syndrome5 
 
 
 
Immune system disorders - 
Other (GVHD in the 
setting of allotransplant)3,6 
 
 
 
Immune system disorders - 
Other (sarcoid granuloma, 
sarcoidosis)3 
 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
 
 
Infusion related reaction7  
 
INVESTIGATIONS 
 
 
Alanine aminotransferase 
increased3 
 
 
 
Aspartate 
aminotransferase 
increased3 
 
 
 
Blood bilirubin increased3  
 
 
CD4 lymphocytes 
decreased 
 
 
 
Creatinine increased 
 
 
 
Lipase increased 
 
 
 
Lymphocyte count 
decreased 
 
 
 
Neutrophil count 
decreased 
 
 
 
Platelet count decreased 
 
 
 
Serum amylase increased  
 
METABOLISM AND NUTRITION DISORDERS 
 
 
Anorexia 
 
 

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 Adverse Events with Possible  
 Relationship to Nivolumab 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
Hyperglycemia 
 
 
 
Metabolism and nutrition 
disorders - Other (diabetes 
mellitus with ketoacidosis) 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
 
Arthralgia 
 
 
 
 
Musculoskeletal and 
connective tissue disorder 
- Other (polymyositis) 
 
 
 
Myositis 
 
 
 
Rhabdomyolysis 
 
NERVOUS SYSTEM DISORDERS 
 
 
 
Encephalopathy3 
 
 
 
Facial nerve disorder3 
 
 
 
Guillain-Barre syndrome3  
 
 
Myasthenia gravis3 
 
 
 
Nervous system disorders 
- Other (demyelination 
myasthenic syndrome) 
 
 
 
Nervous system disorders 
- Other (encephalitis)3 
 
 
 
Nervous system disorders 
- Other 
(meningoencephalitis) 
 
 
 
Nervous system disorders 
- Other 
(meningoradiculitis)3 
 
 
 
Nervous system disorders 
- Other (myasthenic 
syndrome) 
 
 
 
Peripheral motor 
neuropathy 
 
 
 
Peripheral sensory 
neuropathy 
 
 
 
Reversible posterior 
leukoencephalopathy 
syndrome3 
 
RENAL AND URINARY DISORDERS 
 

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 Adverse Events with Possible  
 Relationship to Nivolumab 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
Acute kidney injury3 
 
 
 
Renal and urinary 
disorders - Other 
(Immune-related nephritis) 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
 
Pleural effusion3 
 
 
 
Pneumonitis3 
 
 
 
 
Respiratory, thoracic and 
mediastinal disorders - 
Other (bronchiolitis 
obliterans with organizing 
pneumonia (BOOP))3 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
 
 
Erythema multiforme3 
 
 
Pruritus3 
 
 
 
Rash maculo-papular3 
 
 
 
 
Skin and subcutaneous 
tissue disorders - Other 
(bullous pemphigoid) 
 
 
Skin and subcutaneous 
tissue disorders - Other 
(Sweet's Syndrome)3 
  
 
 
Skin hypopigmentation3 
 
 
 
 
Stevens-Johnson 
syndrome 
 
 
 
Toxic epidermal 
necrolysis 
 
 
1This table will be updated as the toxicity profile of the agent is revised. Updates will be 
distributed to all Principal Investigators at the time of revision. The current version can be 
obtained by contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail. 
 
2Pericardial tamponade may be related to possible inflammatory reaction at tumor site. 
 
3Nivolumab being a member of class of agents involved in the inhibition of “immune 
checkpoints”, may result in severe and possibly fatal immune-mediated adverse events probably 
due to T-cell activation and proliferation.  This may result in autoimmune disorders that can 
include (but are not limited to) autoimmune hemolytic anemia, acquired anti-factor VIII immune 

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response, autoimmune aseptic meningitis, autoimmune hepatitis, autoimmune nephritis, 
autoimmune neuropathy, autoimmune thyroiditis, bullous pemphigoid, exacerbation of Churg-
Strauss Syndrome, drug rash with eosinophilia systemic symptoms [DRESS] syndrome, facial 
nerve disorder (facial nerve paralysis), limbic encephalitis, hepatic failure, pure red cell aplasia, 
pancreatitis, ulcerative and hemorrhagic colitis, endocrine disorders (e.g., autoimmune 
thyroiditis, hyperthyroidism, hypothyroidism, autoimmune hypophysitis/hypopituitarism, 
thyrotoxicosis, and adrenal insufficiency), sarcoid granuloma, myasthenia gravis, polymyositis, 
and Guillain-Barre syndrome. 
 
4Pancreatitis may result in increased serum amylase and/or more frequently lipase. 
 
5Cytokine release syndrome may manifest as hemophagocytic lymphohistiocytosis with 
accompanying fever and pancytopenia. 
 
6Complications including hyperacute graft-versus-host disease (GVHD), some fatal, have 
occurred in patients receiving allo stem cell transplant (SCT) after receiving Nivolumab.  These 
complications may occur despite intervening therapy between receiving Nivolumab and allo-
SCT. 
 
7Infusion reactions, including high-grade hypersensitivity reactions which have been observed 
following administration of nivolumab, may manifest as fever, chills, shakes, itching, rash, 
hypertension or hypotension, or difficulty breathing during and immediately after administration 
of nivolumab. 
 
 
Adverse events reported on Nivolumab trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that Nivolumab caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Atrioventricular block complete; Heart failure; 
Ventricular arrhythmia 
EAR AND LABYRINTH DISORDERS - Vestibular disorder 
EYE DISORDERS - Eye disorders - Other (iridocyclitis); Optic nerve disorder; Periorbital 
edema 
GASTROINTESTINAL DISORDERS - Constipation; Duodenal ulcer; Flatulence; 
Gastrointestinal disorders - Other (mouth sores); Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema 
limbs; Malaise; Pain 
HEPATOBILIARY DISORDERS - Bile duct stenosis 
IMMUNE SYSTEM DISORDERS - Anaphylaxis; Immune system disorders - Other 
(autoimmune thrombotic microangiopathy); Immune system disorders - Other (limbic 
encephalitis) 
INFECTIONS AND INFESTATIONS - Bronchial infection; Lung infection; Sepsis; Upper 
respiratory infection 
INVESTIGATIONS - Blood lactate dehydrogenase increased; GGT increased; Investigations - 
Other (protein total decreased); Lymphocyte count increased; Weight loss 

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METABOLISM AND NUTRITION DISORDERS - Dehydration; Hyperuricemia; 
Hypoalbuminemia; Hypocalcemia; Hyponatremia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; 
Musculoskeletal and connective tissue disorder - Other (musculoskeletal pain); Musculoskeletal 
and connective tissue disorder - Other (polymyalgia rheumatica); Myalgia; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other 
(Histiocytic necrotizing lymphadenitis) 
NERVOUS SYSTEM DISORDERS - Dizziness; Headache; Intracranial hemorrhage 
PSYCHIATRIC DISORDERS - Insomnia 
RENAL AND URINARY DISORDERS - Hematuria; Renal and urinary disorders - Other 
(tubulointerstitial nephritis) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchospasm; 
Cough; Dyspnea; Hypoxia 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; 
Pain of skin; Photosensitivity; Rash acneiform; Skin and subcutaneous tissue disorders - Other 
(rosacea) 
VASCULAR DISORDERS - Flushing; Hypertension; Hypotension; Vasculitis 
 
 
Note: Nivolumab in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
 
7.6       Comprehensive Adverse Events and Potential Risks list (CAEPR) for Ipilimumab,            
(MDX-010, NSCs 732442 and 720801)  (30-MAR-2021) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system.  Refer to the 'CTEP, NCI Guidelines: Adverse Event 
Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. Frequency is provided based on 2678 patients. Below is the CAEPR for 
Ipilimumab (MDX-010). 
 
Version 2.10, March 29, 20191 
 
Adverse Events with Possible  
Relationship to Ipilimumab (MDX-010) 
(CTCAE 5.0 Term) 
[n= 2678] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
 
Blood and lymphatic 
system disorders - Other 
(acquired hemophilia) 
CARDIAC DISORDERS 

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Adverse Events with Possible  
Relationship to Ipilimumab (MDX-010) 
(CTCAE 5.0 Term) 
[n= 2678] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
Atrial fibrillation 
 
 
 
Myocarditis2 
 
 
Pericardial effusion 
EAR AND LABYRINTH DISORDERS 
 
Hearing impaired 
 
ENDOCRINE DISORDERS 
 
Adrenal insufficiency2 
 
 
Hyperthyroidism2 
 
 
Hypophysitis2 
 
 
Hypopituitarism2 
 
 
Hypothyroidism2 
 
 
Testosterone deficiency2 
 
EYE DISORDERS 
 
Eye disorders - Other 
(episcleritis)2 
 
 
Uveitis2 
 
GASTROINTESTINAL DISORDERS 
 
Abdominal pain 
 
 
Colitis2 
 
 
 
Colonic perforation3 
 
Constipation 
 
Diarrhea 
 
 
 
Enterocolitis 
 
 
Esophagitis 
 
 
 
Ileus 
Nausea 
 
 
 
Pancreatitis2 
 
 
Vomiting 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
Chills 
 
Fatigue 
 
 
 
Fever 
 
 
 
General disorders and 
administration site 
conditions - Other 
(Systemic inflammatory 
response syndrome [SIRS]) 

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Adverse Events with Possible  
Relationship to Ipilimumab (MDX-010) 
(CTCAE 5.0 Term) 
[n= 2678] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
Multi-organ failure 
HEPATOBILIARY DISORDERS 
 
Hepatobiliary disorders - 
Other (hepatitis)2 
 
IMMUNE SYSTEM DISORDERS 
 
Autoimmune disorder2 
 
 
 
Immune system disorders - 
Other (GVHD in the 
setting of allotransplant)4 
INFECTIONS AND INFESTATIONS 
 
 
 Infections and infestations 
- Other (aseptic 
meningitis)2 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
 
Infusion related reaction 
 
INVESTIGATIONS 
 
Alanine aminotransferase 
increased 
 
 
Aspartate aminotransferase 
increased 
 
 
 
Lymphocyte count 
decreased 
 
Neutrophil count decreased 
 
 
Weight loss 
 
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
 
 
Dehydration 
 
 
Hyperglycemia 
 
 
 
Metabolism and nutrition 
disorders - Other 
(exacerbation of pre-
existing diabetes mellitus) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Arthralgia 
 
 
Arthritis 
 
 
 
Generalized muscle 
weakness 

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Adverse Events with Possible  
Relationship to Ipilimumab (MDX-010) 
(CTCAE 5.0 Term) 
[n= 2678] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
Musculoskeletal and 
connective tissue disorder - 
Other (polymyositis)2 
 
NERVOUS SYSTEM DISORDERS 
 
 
Ataxia 
 
Facial nerve disorder2 
 
 
Guillain-Barre syndrome2 
 
 
Headache 
 
 
Myasthenia gravis2 
 
 
 
Nervous system disorders - 
Other (immune-mediated 
encephalitis)2 
 
 
Peripheral motor 
neuropathy 
 
 
Peripheral sensory 
neuropathy 
 
Trigeminal nerve disorder 
 
PSYCHIATRIC DISORDERS 
 
 
Psychiatric disorders - 
Other (mental status 
changes) 
RENAL AND URINARY DISORDERS 
 
Acute kidney injury 
 
 
Renal and urinary disorders - 
Other (granulomatous 
tubulointerstitial nephritis) 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
Pneumonitis 
 
 
 
Respiratory failure 
 
 
Respiratory, thoracic and 
mediastinal disorders - 
Other (bronchiolitis 
obliterans with organizing 
pneumonia) 
 
 
Respiratory, thoracic and 
mediastinal disorders - 
Other (lung infiltration) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 

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Adverse Events with Possible  
Relationship to Ipilimumab (MDX-010) 
(CTCAE 5.0 Term) 
[n= 2678] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
Erythema multiforme 
 
Pruritus 
 
Rash maculo-papular  
 
 
Skin and subcutaneous tissue 
disorders - Other (Sweet's 
Syndrome) 
 
 
 
Stevens-Johnson syndrome 
 
 
Toxic epidermal necrolysis 
 
Urticaria 
 
VASCULAR DISORDERS 
 
Hypotension 
 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be 
distributed to all Principal Investigators at the time of revision.  The current version can be 
obtained by contacting PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail. 
 
2Ipilimumab can result in severe and fatal immune-mediated adverse events probably due to T-
cell activation and proliferation.  These can include (but are not limited to) autoimmune 
hemolytic anemia, acquired anti-factor VIII immune response, autoimmune aseptic meningitis, 
autoimmune hepatitis, autoimmune thyroiditis, hepatic failure, pure red cell aplasia, pancreatitis, 
ulcerative and hemorrhagic colitis, endocrine disorders (e.g., autoimmune thyroiditis, 
hyperthyroidism, hypothyroidism, autoimmune hypophysitis/hypopituitarism, and adrenal 
insufficiency), ocular manifestations (e.g., uveitis, iritis, conjunctivitis, blepharitis, and 
episcleritis), sarcoid granuloma, myasthenia gravis, polymyositis, and Guillain-Barre syndrome.  
The majority of these reactions manifested early during treatment; however, a minority occurred 
weeks to months after discontinuation of ipilimumab especially with the initiation of additional 
treatments. 
 
3Late bowel perforations have been noted in patients receiving MDX-010 (ipilimumab) in 
association with subsequent IL-2 therapy. 
 
4Complications including hyperacute graft-versus-host disease (GVHD), may occur in patients 
receving allo stem cell transplant (SCT) after receiving Ipilimumab (MDX-010).  These 
complications may occur despite intervening therapy between receiving Ipilimumab (MDX-010) 
and allo-SCT. 
 
5In rare cases diplopia (double vision) has occurred as a result of muscle weakness (Myasthenia 
gravis). 

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6Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic 
hemorrhage, Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, 
Gastric hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, 
Jejunal hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic 
hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal 
hemorrhage under the GASTROINTESTINAL DISORDERS SOC. 
 
7Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS 
SOC. 
 
Adverse events reported on Ipilimumab (MDX-010) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that Ipilimumab 
(MDX-010) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Anemia; Blood and lymphatic system 
disorders - Other (pure red cell aplasia)2; Febrile neutropenia 
CARDIAC DISORDERS - Conduction disorder; Restrictive cardiomyopathy 
EYE DISORDERS - Extraocular muscle paresis5; Eye disorders - Other (retinal pigment 
changes) 
GASTROINTESTINAL DISORDERS - Colonic ulcer; Dyspepsia; Dysphagia; 
Gastrointestinal disorders - Other (gastroenteritis); Gastrointestinal hemorrhage6; Proctitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Flu like 
symptoms; Non-cardiac chest pain 
HEPATOBILIARY DISORDERS - Hepatic failure2 
IMMUNE SYSTEM DISORDERS - Allergic reaction 
INFECTIONS AND INFESTATIONS - Infection7 
INVESTIGATIONS - Creatinine increased; Investigations - Other (rheumatoid factor); Lipase 
increased; Platelet count decreased; Serum amylase increased; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Joint 
range of motion decreased; Myalgia; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Dizziness; Dysphasia; Ischemia cerebrovascular; Seizure 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Depression; Insomnia 
RENAL AND URINARY DISORDERS - Proteinuria 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Allergic rhinitis; 
Cough; Dyspnea; Laryngospasm 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; 
Skin hypopigmentation 
VASCULAR DISORDERS - Flushing; Hypertension; Vascular disorders - Other (temporal 
arteritis) 
 
Note: Ipilimumab (BMS-734016; MDX-010 Transfectoma-derived) in combination with other 
agents could cause an exacerbation of any adverse event currently known to be caused by the 

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other agent, or the combination may result in events never previously associated with either 
agent. 
7.7 
Adverse Events for Commercial Study Agents (30-MAR-2021) 
All systemic agents used in NRG-LU002 are commercially supplied.  Refer to the 
package insert for detailed pharmacologic and safety information. 
7.8 
Expedited Reporting of Adverse Events (18-MAY-2018) 
All serious adverse events that meet expedited reporting criteria defined in the reporting 
table below will be reported via the CTEP Adverse Event Reporting System, CTEP-
AERS, accessed via the CTEP web site,  
https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613 
 
Submitting a report via CTEP-AERS serves as notification to the NRG 
Biostatistical/Data Management Center and satisfies NRG requirements for expedited 
adverse event reporting. 
 
CTEP-AERS provides a radiation therapy-only pathway for events experienced that 
involve radiation therapy only. These events must be reported via the CTEP-AERS 
radiation therapy-only pathway. 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be 
made to the NRG Biostatistical/Data Management Center by phone, (number to be 
provided). An electronic report must be submitted immediately upon re-establishment of 
the Internet connection. 
7.8.1 Expedited Reporting Methods 
• Per CTEP NCI Guidelines for Adverse Events Reporting Requirements, a CTEP-
AERS 24-hour notification must be submitted within 24 hours of learning of the 
adverse event. Each CTEP-AERS24-hour notification must be followed by a 
complete report within 5 days.  
• Supporting source documentation is requested by NRG as needed to complete 
adverse event review. Supporting source documentation should include the protocol 
number, patient ID number, and CTEP-AERS ticket number on each page. For 
guidance to submit supporting documentation contact NRG Oncology at 1-215-574-
3191. 
• A serious adverse event that meets expedited reporting criteria outlined in the AE 
Reporting Tables but is assessed by the CTEP-AERS as “an action not 
recommended” must still be reported to fulfill NRG safety reporting obligations. Sites 
must bypass the “NOT recommended” assessment; the CTEP-AERS allows 
submission of all reports regardless of the results of the assessment.  

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7.8.2 Expedited Reporting Requirements for Adverse Events  
For Arm 1 and Arm 2 Maintenance Therapy 
Any Phase Study Utilizing a Commercial Agent1 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or 
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the 
NCI via CTEP-AERS within the timeframes detailed in the table below. 
Attribution 
Grade 4 
Grade 5 
Unexpected 
Expected 
Unexpected 
Expected 
Unrelated 
Unlikely 
 
10 day 
10 day 
Possible 
Probable 
Definite 
24-h/5 day 
 
24-h/5 day 
24-h/5 day 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of protocol treatment and 
have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
Unexpected Grade 4 and all Grade 5 AEs 
 

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For Arm 2:  Local Consolidative Therapy 
Any Phase Study Utilizing Radiation Therapy (including chemoRT studies) and Surgery1 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or 
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the 
NCI via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
24-Hour 5 Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE. 
 
1Serious adverse events that occur more than 30 days after the last administration of protocol treatment and 
have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 3 adverse events 
 

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Additional Protocol-Specific Instructions or Exceptions to Expedited Reporting 
Requirements - None 
 
7.8.3 Reporting to the Site IRB/REB 
Investigators will report serious adverse events to the local Institutional Review Board 
(IRB) or Research Ethics Board (REB) responsible for oversight of the patient according 
to institutional policy. 
7.8.4 Secondary Malignancy  
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or systemic therapy). A 
secondary malignancy is not considered a metastasis of the initial neoplasm.  
 
CTEP requires all secondary malignancies that occur during or subsequent to treatment 
with an agent under an NCI IND/IDE be reported via CTEP-AERS. In addition, 
secondary malignancies following radiation therapy must be reported via CTEP-AERS. 
Three options are available to describe the event: 
• 
Leukemia secondary to oncology systemic therapy (e.g., acute myelocytic leukemia 
[AML])  
• 
Myelodysplastic syndrome (MDS) 
• 
Treatment-related secondary malignancy 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in each protocol.  
 
Second Malignancy:  
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT 
a metastasis from the initial malignancy).  Second malignancies require ONLY routine 
reporting via CDUS unless otherwise specified. 
 
8.   REGISTRATION, STUDY ENTRY, AND WITHDRAWAL PROCEDURES (18-OCT-
2023) 
Food and Drug Administration (FDA) regulations require sponsors to select qualified 
investigators. National Cancer Institute (NCI) policy requires all individuals contributing to NCI-
sponsored trials to register with their qualifications and credentials and to renew their registration 
annually. To register, all individuals must obtain a Cancer Therapy Evaluation Program (CTEP) 
credentials necessary to access secure NCI Clinical Oncology Research Enterprise (CORE) 
systems. Investigators and clinical site staff who are significant contributors to research must 
register in the Registration and Credential Repository (RCR). The RCR is a self-service online 
person registration application with electronic signature and document submission capability.      
RCR utilizes five person registration types. 
• Investigator (IVR) — MD, DO, or international equivalent; 
• Non Physician Investigator (NPIVR) — advanced practice providers (e.g., NP or PA) or 
graduate level researchers (e.g., PhD); 
• Associate Plus (AP) — clinical site staff (e.g., RN or CRA) with data entry access to 
CTSU applications such as the Roster Update Management System [RUMS], OPEN, 
Rave, acting as a primary site contact, or with consenting privileges; 

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• Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored trials; 
and 
• Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
RCR requires the following registration documents: 
Documentation Required 
IVR NPIVR AP 
A 
AB 
FDA Form 1572 
✔ 
✔ 
Financial Disclosure Form 
✔ 
✔ 
✔ 
NCI Biosketch (education, training, employment, license, and 
certification) 
✔ 
✔ 
✔ 
GCP training 
✔ 
✔ 
✔ 
Agent Shipment Form (if applicable) 
✔ 
CV (optional) 
✔ 
✔ 
✔ 
 
IVRs and NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) 
covering their practice sites on the FDA Form 1572 in RCR to allow the following:  
• Addition to a site roster; 
• Selection as the treating, credit, or drug shipment  investigator or consenting person in 
OPEN; 
• Ability to be named as the site-protocol Principal Investigator (PI) on the IRB approval; 
and 
• Assignment of the Clinical Investigator (CI) task on the Delegation of Tasks Log (DTL).  
 
In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN, must be rostered at the 
enrolling site with a participating organization. Refer to the NCI RCR page on the CTEP 
website for additional information. For questions, please contact the RCR Help Desk by email 
at < RCRHelpDesk@nih.gov>. 
8.1       Cancer Trials Support Unit Registration Procedures (18-OCT-2023) 
Permission to view and download this protocol and its supporting documents is restricted 
and is based on the person and site roster assignment housed in the Roster Maintenance 
application and in most cases viewable and manageable via the Roster Update 

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Management System (RUMS) on the Cancer Trials Support System Unit (CTSU) 
members’ website.  
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
8.1.1    IRB Approval  
As of March 1, 2019, all U.S.-based sites must be members of the NCI Central 
Institutional Review Board (NCI CIRB) in order to participate in Cancer Therapy 
Evaluation Program (CTEP) and Division of Cancer Prevention (DCP) studies open to the 
National Clinical Trials Network (NCTN) and NCI Community Oncology Research 
Program (NCORP) Research Bases. In addition, U.S.-based sites must accept the NCI 
CIRB review to activate new studies at the site after March 1, 2019. Local IRB review 
will continue to be accepted for studies that are not reviewed by the CIRB, or if the study 
was previously open at the site under the local IRB. International sites should continue to 
submit Research Ethics Board (REB) approval to the CTSU Regulatory Office following 
country-specific regulations.  
Sites participating with the NCI CIRB must submit the Study Specific Worksheet (SSW) 
for Local Context to the CIRB using IRBManager to indicate their intent to open the study 
locally. The NCI CIRB’s approval of the SSW is automatically communicated to the 
CTSU Regulatory Office, but sites are required to contact the CTSU Regulatory Office at 
CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI CIRB 
approvals across their Signatory Network. Site preferences can be set at the network or 
protocol level. Questions about establishing site preferences can be addressed to the 
CTSU Regulatory Office by email or calling 1-888-651-CTSU (2878).Sites using their 
local IRB or REB, must submit their approval to the CTSU Regulatory Office using the 
Regulatory Submission Portal located in the Regulatory section of the CTSU website. 
Acceptable documentation of local IRB/REB approval includes: 
• Local IRB documentation; 
• IRB-signed CTSU IRB Certification Form; and/or 
• Protocol of Human Subjects Assurance Identification/IRB 
Certification/Declaration of Exemption Form. 
 
In addition, the Site-Protocol Principal Investigator (PI) (i.e., the investigator on the 
IRB/REB approval) must meet the following criteria for the site to be able to have an 
Approved status following processing of the IRB/REB approval record: 
• Have an active CTEP status; 
• Have an active status at the site(s) on the IRB/REB approval on at least one 
participating organization’s roster; 
• If using NCI CIRB, be active  on the NCI CIRB roster under the applicable CIRB 
Signatory Institution(s) record; 
• Include the IRB number of the IRB providing approval in the Form FDA 1572 in 
the RCR profile;  

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• List all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 in 
the RCR profile; and 
• Have the appropriate CTEP registration type for the protocol. 
  
Additional Requirements for Protocol NRG-LU002 Site Registration 
Additional requirements to obtain an approved site registration status include: 
• An active Federal Wide Assurance (FWA) number; 
• An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO);  
• An active roster affiliation with the NCI CIRB roster under at least one CIRB 
Signatory Institution (US sites only); and 
• Compliance with all protocol-specific requirements (PSRs). 
 
Protocol-Specific Requirements for NRG-LU002 
• IRB/REB approved consent (International and Canadian sites only: English and 
native language versions*. The English version must be submitted to NRG 
Regulatory prior to IRB review: regulatory-phl@NRGOncology.org).  
*Note: International and Canadian Institutions must provide certification/verification 
of IRB/REB consent translation to NRG Oncology (described below).  
 
• IROC Credentialing Status Inquiry (CSI) Form – this form is submitted to IROC 
Houston to verify credentialing status or to begin a new modality credentialing 
process. 
• This is a study with a radiation and/or imaging (RTI) component and the enrolling 
site must be aligned to an RTI provider.  To manage provider associations or to 
add or remove associated providers, access the Provider Association page from the 
Regulatory section of the CTSU members’ website at 
https://www.ctsu.org/RSS/RTFProviderAssociation.  Site must be linked to at least 
one Imaging and Radiation Oncology Core (IROC) provider to participate on trials 
with an RTI component.  Enrolling sites are responsible for ensuring that the 
appropriate agreements and IRB approvals are in place with their RTI provider. 
An individual with a primary role on a treating site roster can update the provider 
associations, though all individuals at a site may view provider associations.  To 
find who holds primary roles at your site, view the Person Roster Browser under 
the RUMS section on the CTSU members’ website. 
*Translation of documents is critical. The institution is responsible for all translation 
costs. All regulatory documents, including the IRB/REB approved consent, must be 
provided in English and in the native language. Certification of the translation is optimal 
but due to the prohibitive costs involved NRG will accept, at a minimum, a verified 
translation. A verified translation consists of the actual REB approved consent document 
in English and in the native language, along with a cover letter on organizational 
letterhead/stationery that includes the professional title, credentials, and signature of the 
translator as well as signed documentation of the review and verification of the translation 

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by a neutral third party. The professional title and credentials of the neutral third party 
translator must be specified as well. 
 
Additional Requirements for sites in Canada  
 
All institutions in Canada must conduct this trial in accordance with International 
Conference on Harmonization-Good Clinical Practice (ICH-GCP) Guidelines [per section 
6.2.5 of ICH E6(R2)]. This trial is being conducted under a Clinical Trial Application 
(CTA) with Health Canada. As a result essential documents must be retained for 15 years 
following the completion of the trial at the participating site (15years post final analysis, 
last data collected, or closure notification to REB, whichever is later), or until notified by 
the sponsor, NRG Oncology, that documents no longer need to be retained [per C.05.012 
(4) of the FDR].  In addition, upon request by the auditor, REB or regulatory authority, 
the investigator/institution must make all required trial-related records available for direct 
access [per section 4.9.7 of ICH].  
Downloading Site Registration Documents:   
Download the site registration forms from the NRG-LU002 protocol page located on the 
CTSU members’ website. Permission to view and download this protocol and its 
supporting documents is restricted to institutions and their associated investigators and 
staff on a participating roster. To view/download site registration forms:   
• Log on to the CTSU members’ website (https://www.ctsu.org)  
• Click on Protocols in the upper left of the screen 
o Enter the protocol number in the search field at the top of the protocol tree, or 
o Click on the By Lead Organization folder to expand, then select NRG and 
protocol number NRG-LU002 
• Click on Documents, Protocol Related Documents, and use the Document Type 
filter and select Site Registration, to download and complete the forms provided. 
(Note: For sites under the CIRB initiative, IRB data will load automatically to the 
CTSU.)  
 
Submitting Regulatory Documents:  
 
Submit required forms and documents to the CTSU Regulatory Office using the 
Regulatory Submission Portal on the CTSU members’ website.  
 
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to 
the Regulatory section and select Regulatory Submission. 
 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately by phone or email: 1-866-651-
CTSU (2878), or CTSURegHelp@coccg.org to receive further instruction and support. 
Checking Your Site’s Registration Status: 

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Site registration status may be verified on the CTSU members’ website.   
 
• Click on Regulatory at the top of the screen; 
• Click on Site Registration; and 
• Enter the site’s 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, 
Protocol Status, and/or IRB Type. 
 
Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined within the protocol. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling investigator’s 
status with the NCI or their affiliated networks. 
8.2 
RT-Specific Pre-Registration Requirements (18-OCT-2023) 
For detailed information on the specific technology requirement required for this study, 
please refer to the table below and utilize the web link provided for detailed instructions. 
The check marks under the treatment modality columns indicate whether that specific 
credentialing requirement is required for this study. Specific credentialing components 
may require you to work with various QA centers; however, IROC Houston will notify 
your institution when all credentialing requirements have been met and the institution is 
RT credentialed to enter patients onto this study. IROC will automatically send the 
approval to the Regulatory Support System (RSS) to comply with the protocol-specific 
requirement, unless otherwise noted at the bottom of the IROC Credentialing Approval 
notification.   

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RT 
Credentialing 
Requirements 
 
Web Link for Procedures and Instructions:   http//irochouston.mdanderson.org 
 
Treatment 
Modality 
Key Information 
SBRT 
IMRT 
 
Facility 
Questionnaire 
 
 
The IROC Houston electronic facility questionnaire (FQ) should be completed or 
updated with the most recent information about your institution. To access this FQ 
go to http://irochouston.mdanderson.org/questionnaires. 
Credentialing 
Status Inquiry 
Form 
 
 
To determine whether your institution needs to complete any further credentialing 
requirements, please complete the “Credentialing Status Inquiry Form” found 
under credentialing on the IROC Houston QA Center website 
(http://irochouston.mdanderson.org) 
Phantom 
Irradiation 
 
 
An IROC Houston anthropomorphic phantom must be successfully completed (if 
the institution has not previously met this credentialing requirement) if the 
institution plans to deliver SBRT or IMRT. Credentialing for IMRT allows the 
institution to also use 3D-CRT SBRT, but credentialing for 3D-CRT SBRT does 
not allow the institution to use IMRT.  Flattening-filter-free (FFF) photon beam 
delivery, Tomotherapy and Cyberknife treatment delivery modalities must be 
credentialed individually. Instructions for requesting and irradiating the phantom 
are available on the IROC Houston website under credentialing 
(http//irochouston.mdanderson.org). 
IGRT 
Verification 
Study 
 
 
Institutions must be credentialed for soft tissue IGRT by IROC Houston.  Find 
details on the IROC Houston QA Center website 
(http://irochouston.mdanderson.org) Institutions that have previously been 
approved for IGRT may not need to repeat credentialing. 
Pre-Treatment 
Review 
 
  
Pre-treatment review of first case per institution by Study Co-Chairs. 
 
Credentialing Issued to: 
Institution 
 
 
IROC Houston QA Center will notify the institution and NRG Oncology 
Headquarters that all desired credentialing requirements have been met.  The site 
will need to upload a PDF of approval email from IROC Houston to the CTSU 
Regulatory Portal for RSS to be updated. 
 
 
 
 
 
 
 
8.2.1 Digital Radiation Therapy Data Submission Using Transfer of Images and Data 
Transfer of Images and Data (TRIAD) is the American College of Radiology’s 
(ACR) image exchange application. TRIAD provides sites participating in clinical 
trials a secure method to transmit images. TRIAD anonymizes and validates the 
images as they are transferred. 
TRIAD Access Requirements: 
• Active CTEP registration with the credentials necessary to access secure 
NCI/CTSU IT systems; 
• Registration type of:  Associate (A), Associate Plus (AP), Non-Physician 
Investigator (NPIVR), or Investigator (IVR). Refer to the CTEP 
Registration Procedures section for instructions on how to request a 
CTEP-IAM account and complete registration in RCR; and 

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• TRIAD Site User role on an NCTN, ETCTN, or other relevant roster. 
All individuals on the Imaging and Radiation Oncology Core provider roster have 
access to TRIAD, and may submit images for credentialing purposes, or for 
enrollments to which the provider is linked in OPEN. 
TRIAD Installation: 
To submit images, the individual holding the TRIAD Site User role will need to 
install the TRIAD application on their workstation. TRIAD installation 
documentation is available at https://triadinstall.acr.org/triadclient/. 
This process can be done in parallel to obtaining your CTEP-IAM account 
username and password and RCR registration. 
For questions, contact TRIAD Technical Support staff via email TRIAD-
Support@acr.org or 1-703-390-9858. 
 
8.3       Patient Enrollment  (18-OCT-2023) 
Patient registration can occur only after evaluation for eligibility is complete, eligibility 
criteria have been met, and the study site is listed as ‘approved’ in the CTSU RSS.  
Patients must have signed and dated all applicable consents and authorization forms.  
 
Informed Consent: Patients must be aware of the neoplastic nature of their disease and 
informed of the procedure(s) to be followed, the experimental nature of the therapy, 
alternatives, potential benefits, side-effects, risks, and discomforts prior to signing the 
informed consent in accordance with institutional and federal guidelines. Current 
IRB/REB/REC approval of this protocol and a consent form is required prior to patient 
consent and registration. The model consent form created for this study adheres to the 
NCI informed consent template requirements.    
 
8.3.1 Oncology Patient Enrollment Network (OPEN) 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis.  OPEN is integrated with CTSU regulatory and roster data and 
with the LPOs registration/randomization systems or the Theradex Interactive Web 
Response System (IWRS) for retrieval of patient registration/ randomization assignment. 
OPEN will populate the patient enrollment data in NCI’s clinical data management 
system, Medidata Rave. 
 
Requirements for OPEN access:   
• Active CTEP registration with the credentials necessary to access secure NCI/CTSU 
IT systems.To perform enrollments or request slot reservations:  Must be on a LPO 
roster, ETCTN corresponding roster, or participating organization roster with the role 
of Registrar. Registrars must hold a minimum of an Associate Plus (AP) registration 
type; 
• Have an approved site registration for a protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 

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transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR.  
 
Prior to accessing OPEN site staff should verify the following: 
• Patient has met all eligibility criteria within the protocol stated timeframes; and  
• All patients have signed an appropriate consent form and Health Insurance 
Portability and Accountability Act (HIPAA) authorization form (if applicable).  
 
Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information.  You may print this confirmation for your 
records.  
 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ 
website. Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org.  For any additional questions contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
 
In the event that the OPEN system is not accessible, participating sites can contact NRG 
web support for assistance with web registration: websupport@acr.org or call the NRG 
Registration Desk at 215-574-3191, Monday through Friday, 8:30 a.m. to 5:00 p.m. ET. 
The registrar will ask the site to fax in the eligibility checklist and will need the registering 
individual’s e-mail address and/or return fax number. This information is required to 
assure that mechanisms usually triggered by the OPEN web registration system (e.g. drug 
shipment and confirmation of registration) will occur.  
9.0       DRUG INFORMATION (18-AUG-2023) 
General Patient Care Implications 
Patients must use highly effective contraception, including men with vasectomies if he is 
having sex with a woman of childbearing potential or with a woman who is pregnant 
while on study drug, for 6 months following the last dose of study drug because the study 
treatment may be teratogenic. Highly effective contraception is defined as hormonal 
contraceptives (oral contraceptives, Nuvaring, Depo Provera), intrauterine device, true 
abstinence, two barrier methods of birth control including condoms with cervical cap or 
diaphragm, patient has received surgical sterilization, patient is monogamous with a post-
menopausal partner. 
9.1 
Commercial Agent:  Pemetrexed (30-MAR-2021) 
US sites must refer to the package insert and sites in Canada must refer to the product 
monograph for detailed pharmacologic and safety information. 
9.1.1 Adverse Events 
 
Please refer to the package insert. 
9.1.2 Availability/Supply  
 
Please see Section 5.1 for administration details. Please refer to the current FDA-
approved package insert provided with each drug and the site-specific pharmacy for 
toxicity information and instructions for drug preparation, handling, and storage.  Sites in 
Canada must refer to the product monograph for this information. 

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9.2 
Commercial Agent:  Gemcitabine (30-MAR-2021) 
US sites must refer to the package insert and sites in Canada must refer to the product 
monograph for detailed pharmacologic and safety information. 
9.2.1 Adverse Events 
 
Please refer to the package insert. 
9.2.2 Availability/Supply  
Please see Section 5.1 for administration details. Please refer to the current FDA-
approved package insert provided with each drug and the site-specific pharmacy for 
toxicity information and instructions for drug preparation, handling, and storage.  Sites in 
Canada must refer to the product monograph for this information. 
9.3 
Commercial Agent:  Pembrolizumab  (30-MAR-2021) 
US sites must refer to the package insert and sites in Canada must refer to the product 
monograph for detailed pharmacologic and safety information. 
9.3.1 Adverse Events 
Please refer to the package insert and the Comprehensive Adverse Events and Potential 
Risks (CAEPR) in section 7.3. 
9.3.2 Availability/Supply 
 
Please see Section 5.1 for administration details. Please refer to the current FDA-
approved package insert provided with each drug and the site-specific pharmacy for 
toxicity information and instructions for drug preparation, handling, and storage.  Sites in 
Canada must refer to the product monograph for this information. 
9.4 
Commercial Agent:  Atezolizumab  (30-MAR-2021) 
US sites must refer to the package insert and sites in Canada must refer to the product 
monograph for detailed pharmacologic and safety information. 
9.4.1 Adverse Events 
 
Please refer to the package insert and the Comprehensive Adverse Events and Potential  
 
Risks (CAEPR) in section 7.4. 
9.4.2 Availability/Supply  
 
Please see Section 5.1 for administration details. Please refer to the current FDA-
approved package insert provided with each drug and the site-specific pharmacy for 
toxicity information and instructions for drug preparation, handling, and storage.  Sites in 
Canada must refer to the product monograph for this information. 
9.5 
Commercial Agent:  Nivolumab  (30-MAR-2021) 
US sites must refer to the package insert and sites in Canada must refer to the product 
monograph for detailed pharmacologic and safety information. 
9.5.1 Adverse Events 
Please refer to the package insert and the Comprehensive Adverse Events and Potential 
Risks (CAEPR) in section 7.5. 
9.5.2 Availability/Supply  
 
Please see Section 5.1 for administration details. Please refer to the current FDA-
approved package insert provided with each drug and the site-specific pharmacy for 
toxicity information and instructions for drug preparation, handling, and storage.  Sites in 
Canada must refer to the product monograph for this information. 

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9.6 
Commercial Agent:  Ipilimumab  (30-MAR-2021) 
US sites must refer to the package insert and sites in Canada must refer to the product 
monograph for detailed pharmacologic and safety information. 
9.6.1 Adverse Events 
Please refer to the package insert and the Comprehensive Adverse Events and Potential 
Risks (CAEPR) in section 7.6. 
9.6.2 Availability/Supply  
Please see Section 5.1 for administration details. Please refer to the current FDA-
approved package insert provided with each drug and the site-specific pharmacy for 
toxicity information and instructions for drug preparation, handling, and storage.  Sites in 
Canada must refer to the product monograph for this information. 
 
10.       PATHOLOGY/BIOSPECIMEN    
 
10.1 
Biospecimen Submission Tables 
10.1.1 Optional Specimen Submissions 
Patients must be offered the opportunity to consent to optional specimen collection. If the 
patient consents to participate, the site is required to submit the patient’s specimens as 
specified per protocol. Sites are not permitted to delete the specimen component from the 
protocol or from the sample consent. 
10.2     Tissue Selection for Exploratory Marker Testing: (30-MAR-2021) 
For patients who have consented to participate in the tissue/blood component of the study 
the following must be provided in order for the case to be evaluable for the Biospecimen 
Resource: 
10.2.1  Marker to be tested and its usage  
Circulating tumor DNA (ctDNA) will be an exploratory biomarker in this study. It is 
possible that only a subgroup of patients who meet trial eligibility will benefit from the 
addition of SBRT to maintenance chemotherapy and ctDNA will be evaluated as a 
potential strategy for identifying this subgroup for the purposes of selecting patients for 
future studies. We hypothesize that levels of ctDNA levels at enrollment will predict 
outcomes. Specifically, we hypothesize that patients with low levels ctDNA after 
completion of first-line/induction systemic therapy will have significantly better PFS than 
patients with high levels of ctDNA. To explore this hypothesis we will perform NGS-
based ctDNA detection using CAPP-Seq on the pre-treatment plasma samples in order to 
quantify the amount of ctDNA in haploid tumor genome equivalents/ml of plasma as 
previously described (Newman 2016). Additionally we will also analyze the first on-
treatment plasma sample (~3 months from initiation of maintenance chemotherapy) by 
CAPP-Seq. The absolute concentration at the 3 month time point and the change between 
the pre-treatment and 3 month time point will be explored for association with PFS and 
OS.  
10.2.2  Testing requirements and reporting: 
Testing will be performed retrospectively after completion of the trial. 
10.2.3  Method of testing:  
Testing for ctDNA will be performed using CAPP-Seq which was designed specifically 
for NSCLC and can detect the presence of ctDNA with high sensitivity and specificity 

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(Newman 2014, Newman 2016).  Cell-free DNA will be isolated from plasma and all 
samples with at least 5ng of cell-free DNA will be analyzed using CAPP-Seq. Results 
will be reported as percent and absolute concentration of ctDNA.  
10.2.4  Location of testing:   
Biospecimens will be stored in the NRG Oncology Biospecimen Bank (see address and 
contact information below). Testing will be performed centrally in Dr. Max Diehn’s lab 
after completion of the trial. 
 
10.2.5  Tissue Submission for testing:  See Biospecimen Submission tables below. 
 
See detailed specimen collection/processing/shipping instructions on the protocol-specific 
page of the CTSU website. 
 
Specimen Collection for Banking for Future Research 
Specimens are being collected for future translational research projects.  
 
• Required Forms: ST form, pathology reports.  All forms must be completely filled out 
with an NRG Label including the Study #, Case #, NRG Institution name and # or 
Institution NCI ID, and patient initials. The pathology accession number and date of 
procedure must remain visible on the pathology report but all other PHI information must 
be redacted/removed. 
• Kits are available for Frozen biospecimens from the NRGBB-SF. Sites should include the 
following information in their email:  their ship to Fed Ex address with room number, 
confirm site has IRB approval for study, how many patients site enrolled in past month.  
Detailed Processing and shipping instructions are provided on the protocol-specific page 
of the CTSU website.   
• Shipping days for Frozen Specimens: Monday-Wednesday (U.S. sites); Monday-Tuesday 
(Canada and Non-North American). International sites must contact the bank before 
shipping. Check NRG Broadcasts for bank holiday closures. We are unable to accept 
shipments on Saturdays or holidays. Check Fed Ex site for storm delays and do not ship 
during severe weather. 
• Shipping costs: A single use prepaid Fed Ex label is provided for each case in LU002 kits 
provided to the site for batch shipping frozen biospecimens to the NRGBB-SF. Ship all 
Biospecimens for Optional Study #3 for banking to: 
NRG Oncology Biospecimen Bank – San Francisco 
2340 Sutter Street- Room S341 
UCSF  
San Francisco, CA 94115 
415-476-7864/Fax 415-476-5271 
Email: NRGBB@ucsf.edu 
 
For questions about banking biospecimens contact:  
NRG Oncology Biospecimen Bank – San Francisco 
NRGBB@ucsf.edu   
415-476-7864/Fax 415-476-5271 
 
Specimen Type 
Collection Time Points 
Collection Information and  
Shipping 

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Requirements/Instructions 
for Site 
H&E slide(s) of 
Primary tumor if 
available. If primary 
is not available then 
an H&E from the 
metastasis is 
acceptable 
 
 
 
 
Pre-treatment: obtained as 
part of routine diagnostic 
procedures 
 
H&E stained slide, ST form and 
pathology report. H&E slide can 
be a duplicate cut slide, does not 
have to be the diagnostic slide. 
Ship ambient to NRGBB-
SF 
FFPE Block - same 
block as H&E slide 
submitted above 
 
 
 
Pre-treatment: obtained as 
part of routine diagnostic 
procedures 
Site should make every effort to 
submit the block that corresponds 
to the H&E for this study. If Site 
is unable to submit a Block then 
the following alternative is 
acceptable:  
A) Two 2mm (or 3mm) punches 
(tumor size dependent) 
embedded in paraffin with a 
corresponding H&E. (Punch 
kits available from NRGBB-
SF upon request.). If sites 
are unable to embed the 
punches they may send the 
punches to the biobank to be 
embedded. 
 
Note: Unstained slides are not an 
acceptable alternative for 
tissue/punch blocks for banking 
studies. 
 
Ship to NRGBB-SF 
 (use cold packs during 
warm weather) 
Serum- Red top tube 
Pre-treatment:  Any time 
prior to start of protocol 
treatment  
 
During treatment:  Once 
approximately 3 months 
after the initiation of 
maintenance systemic 
therapy  
 
Post treatment:  At the 
time of first progression 
 
Process serum and aliquot 
minimum of 0.5ml per vial into 5 
cryovials.  Store at -80°C (-70°C 
to -90°C) until ready to batch ship 
on Dry ice.  
Forms: ST form 
 
Ship on Dry Ice by 
Overnight Courier to 
NRGBB-SF 
Plasma- 2 Purple 
Top EDTA tubes 
(10 mls each, 
centrifuged and 
processed for plasma 
collection) 
Pre-treatment:  Any time 
prior to start of protocol 
treatment  
 
During treatment:  Once 
approximately 3 months 
after the initiation of 
maintenance systemic 
therapy 
Process plasma and aliquot a 
minimum of 1.8 ml plasma into 
each of five 2 ml cryovials. Place 
into biohazard bag and 
immediately freeze tubes upright 
at -70 to -90º C. Store frozen until 
ready to ship. 
Forms: ST form 
 
Ship on Dry Ice by 
Overnight Courier to 
NRGBB-SF 

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Post treatment:  At the 
time of first progression 
 
Whole Blood- 
EDTA tube 
 
Pre-treatment:  Any time 
prior to start of protocol 
treatment  
 
 
 
Collect blood, mix and aliquot 1 
ml of whole blood per vial into 
three (3) 2 ml cryovials.  Store at 
-80°C (-70°C to -90°C) until 
ready to batch ship on Dry ice.  
Forms: ST form 
 
Ship on Dry Ice by 
Overnight Courier to 
NRGBB-SF 
 
11      SPECIAL STUDIES (NON-TISSUE) 
11.1   Patient-Reported Outcomes (PROs) and Health-Related Quality of Life (QOL) (22-
June-2018) 
          Objective: 
• To evaluate the effect of adding LCT to systemic therapy in limited stage IV 
NSCLC on QOL 
 
          Hypotheses: 
The primary HRQOL hypothesis is that QOL using FACT-TOI at 3-month (from study 
registration) will be superior in the LCT + systemic therapy arm compared to the systemic 
therapy alone arm as the addition of SBRT is expected to improve tumor response and 
improve disease-related QOL.  
 
Secondary exploratory objectives are: 
• To describe the levels and change in baseline at each assessment of the EQ-5D 
index and EQ-5D VAS in each of the study arms  
• To analyze the effect of smoking status on outcome using the Cancer Patient 
Tobacco Use Questionnaire (C-TUQ) 
11.2   Background (18-MAY-2018) 
Health related quality-of-life (QOL) is an important endpoint in clinical trials to assess the 
overall disease burden and treatment effect from the patient’s perspective using patient 
reported outcomes (PROs). In this study, if the SBRT arm shows superior OS compared to 
systemic therapy alone, a new standard of care will be defined for limited metastatic 
NSCLC, provided that the QOL and toxicity profiles are acceptable to the patient. 
Especially in the setting of metastatic disease, in which patients have a difficult prognosis, 
it is critical that trials investigating further refinement of therapeutic strategies factor in 
QOL in addition to overall survival.  Obtaining QOL data at baseline, during treatment, 
and follow up after treatment provides baseline prognostic data as well as reporting the 
effect of treatment on HRQOL from the patient’s perspective. Baseline QOL data was 
found to be a prognostic variable in addition to clinical factors in predicting survival in 
cancer patients (Quinten 2014, Urba 2012) in a pooled analysis of 7417 cancer patients 
entered on randomized trials. These data suggest that obtaining baseline QOL data are of 
superior prognostic significance than obtaining physician graded performance scale scores 
such as Karnofsky performance scales or ECOG scales prior to initiation of treatment.  

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The primary QOL objective in this study is to measure functional, physical and lung 
cancer specific QOL in lung cancer patients using the change from baseline (at study 
registration) of FACT-TOI at 3 months (using each patient as his or her own control). A 
clinically meaningful between-group change from baseline is defined as FACT-TOI of ≥5 
points between arms. The FACT-TOI instrument will also measure longitudinal QOL in 
both arms and will be administered at the following time points: baseline (prior to 
registration), and within 2 weeks of each of the following time points:  1, 3, 6, 9 and 12 
months following study registration. 
11.3   FACT-TOI 
In order to analyze the difference in QOL between all arms, we plan to use a brief, 
validated instrument that is user friendly and has clinical relevance. FACT-TOI is a 
measure that sums the functional well-being (FWB), physical well-being (PWB), and the 
lung cancer subscale (LCS) of the Functional Assessment of Cancer Therapy – Lung 
(FACT-L) QOL instrument, which has been extensively used for measuring QOL in 
patients with lung cancer. In a review of literature reported that the FACT-L scale has 
been used in more than 5,000 patients and has been found to be sensitive to changes in 
performance status, treatment response. FACT has been translated into many languages. 
NRG Oncology has obtained permission to use the FACT for this study in English, 
Spanish, and French. The full FACT-L questionnaire can be completed in less than 10 
minutes. This instrument has not only been shown to be prognostic for survival, but also 
sensitive to changes in QOL on serial evaluations throughout treatment. Importantly, the 
FACT-TOI has been associated with clinically meaningful changes in patients with lung 
cancer. The lung cancer sub-scale (LCS) consists of 9 items, involving lung cancer 
specific symptoms. All items are rated on a 5-item (point) Likert Scale, from 0 (not at all) 
to 4 (very much). It has been determined that a 5-point difference on the FACT-TOI is 
associated with a meaningful difference in clinical and subjective indicators. Thus, a 
difference of 5 points will be considered clinically significant. Handling of missing data 
will be in accordance with the FACIT Administration and Scoring Guidelines, described 
at www.facit.org. 
11.4   QUALITY-ADJUSTED SURVIVAL, EUROQOL (EQ-5D-5L)  (18-MAY-2018) 
The EuroQol (EQ-5D) is a well-accepted instrument to measure general QOL and cost-
utility analysis (Pickard 2007) and will be used to assess quality-adjusted survival for this 
study. It is a two-part questionnaire that the patient can complete in 5 minutes (Schulz 
2002) and has been translated into multiple languages. NRG Oncology has obtained 
permission to use the EQ-5D for this study in English, Spanish, and French. The first part 
consists of 5 items covering 5 dimensions, including mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression.  Each dimension can be graded on 3 levels 
including: 1-no problem, 2-moderate problems, and 3-extreme problems. There are 243 
potential health states.  The second part is a visual analogue scale (VAS) valuing current 
health state, measured on a 20 cm, 10 point-interval scale.  Either the index score or the 
VAS score can be used in the quality-adjusted survival analysis (Wu 2002). The benefit of 
measuring quality-adjusted survival is that the product, quality-adjusted survival, can be 
compared to the outcomes of other interventions across disease sites and can be used by 

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health policy makers to rank interventions. The EQ5D will be used to evaluate the effect 
of adding SBRT to systemic therapy on quality-adjusted survival.  
 
Protocol-eligible patients will be included in the quality-adjusted survival analysis only if 
they have provided baseline and at least 1 subsequent measurement.  
 
Patients will complete the EQ-5D-5L version within 2 weeks of each of the following time 
points: Baseline (prior to registration), and at 3, 6 and 12 months following study 
registration. 
11.5   CANCER PATIENT TOBACCO USE QUESTIONNAIRE (C-TUQ) (18-MAY-2018) 
There is much evidence that smoking is associated with poorer outcomes, including 
survival, in patients with cancer (Land 2016a).  However, tobacco use has not been 
uniformly assessed in clinical trials.  The NCI-AACR Cancer Patient Tobacco Use 
Assessment Task Force recently developed and tested a Cancer Patient Tobacco Use 
Questionnaire (C-TUQ).  Revisions to item wording, response options, etc, resulted in a 
questionnaire that showed navigational ease as well as good question comprehension and 
response accuracy (Land 2016b).  Thus, the NCI-AACR Task Force recommends that C-
TUQ be used as a standardized instrument in clinical trials.   In this study, we plan to use 
the core items (1,4, 5 and 6) plus the following extension items (7 and 11-14).  Items 4 and 
5 are only needed at baseline.  C-TUQ will be collected within 2 weeks of each of the 
following time points:  baseline, 3 months, 6 months, and 12 months.  As continued 
smoking has been associated with worse survival in lung cancer patients undergoing 
treatment, the C-TUQ will be important to better understand the results of this study. 
 
12.     MODALITY REVIEWS 
12.1   Radiation Therapy Quality Assurance Reviews 
A pre-treatment review for the first patient registered at each institution must be submitted 
to TRIAD for review PRIOR TO DELIVERY of radiation treatment. The plan(s) will be 
reviewed centrally by the Radiation Oncology Study Chair/Co-Chair and feedback 
regarding protocol compliance will be forwarded to the participating institution. Based on 
the results of any of the reviews described above, a request for additional pre-treatment 
reviews might be necessary. In general, the treatment plan for subsequent patients enrolled 
at a site will not be required to be centrally reviewed prior to treatment, but will be 
reviewed for protocol compliance at a later date. Allow 3 business days for the results of 
the pre-treatment review process. The pre-treatment review process will not start until all 
required data is submitted to TRIAD.  
 
RT Quality Assurance Review 
For those cases enrolled after the pre-treatment review requirement has been met, the 
Radiation Oncology Co-Chair will perform an RT Quality Assurance Review after IROC 
Philadelphia-RT has received complete data for the first 20 cases enrolled. The review 
team will perform the next review after IROC Philadelphia-RT has received complete data 
for the next 20 cases enrolled. The final cases will be reviewed within 3 months after this 

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study has reached the target accrual or as soon as IROC Philadelphia-RT has received 
complete data for all cases enrolled, whichever occurs first.  
12.2    Medical Oncology Modality Quality Assurance Reviews 
The Medical Oncology Co-Chair, David Gerber, MD or Saiama N. Waqar, MD, MSCI, 
will perform a Systemic Therapy Assurance Review of all patients who receive or are to 
receive systemic therapy in this trial.  The goal of the review is to evaluate protocol 
compliance.  The review process is contingent on timely submission of systemic therapy 
treatment data as specified in Section 14.2. The scoring mechanism is: 1) Per Protocol, 2) 
Acceptable Variation, 3) Unacceptable Deviation, and 4) Not Evaluable.   
 
The Medical Oncology Co-Chairs will perform a Quality Assurance Review after NRG 
Headquarters has received complete data for the first 20 cases enrolled. The Medical 
Oncology Co-Chairs will perform the next review after NRG Headquarters has received 
complete data for the next 20 cases enrolled. The final cases will be reviewed within 3 
months after this study has reached the target accrual or as soon as NRG Headquarters has 
received complete data for all cases enrolled, whichever occurs first. 
12.3 
Surgical Quality Assurance Reviews (18-MAY-2018) 
The surgical co-chair, Dr. Donington will perform a Quality Assurance Review for 
verification of protocol compliance on a continuous basis. The final cases will be 
reviewed within 3 months after this study has reached the target accrual or as soon as 
complete data for all cases enrolled has been received at RTOG Headquarters, whichever 
occurs first.  
 
Goals of Surgical Quality Assurance:  
1. to assure correct appropriate staging and evaluation of patients following first line 
therapy,  
2. to assure safety of patients undergoing resection,  
3. to assure adequate resection of metastatic sites  
 
Deviations Minor:  
1. Resections outside the defined window (unless prior approval from the Surgery Co-
Chair was obtained), 
2. Wedge resection of metastatic tumor with inadequate tumor to closest surgical margin 
distance 
 
Deviations Unacceptable:  
Those deviations that affect patient safety/outcome, which will result in an institutional 
suspension and mediation prior to further participation in the study.   
13.      ASSESSMENT OF EFFECT 
           Not Applicable 

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14.      DATA QUALITY PORTAL (18-OCT-2023) 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data Management. 
The Rave Home section displays a table providing summary counts of Total 
Delinquencies and Total Queries. DQP Queries, DQP Delinquent Forms, DQP 
Form Status and the DQP Reports modules are available to access details and 
reports of unanswered queries, delinquent forms, forms with current status, and 
timeliness reports. Site staff should review the DQP modules on a regular basis to 
manage specified queries and delinquent forms. 
The DQP is accessible by site staff who are rostered to a site and have access to 
the CTSU website. Staff who have Rave study access can access the Rave study 
data via direct links available in the DQP modules. 
CTSU Delinquency Notification emails are sent to primary contacts at sites twice 
a month. These notifications serve as alerts that queries and/or delinquent forms 
require site review, providing a summary count of queries and delinquent forms 
for each Rave study that a site is participating in. Additional site staff can 
subscribe and unsubscribe to these notifications using the CTSU Report and 
Information Subscription Portal on the CTSU members’ website. 
To learn more about DQP use and access, click on the Help Topics button 
displayed on the Rave Home, DQP Queries, DQP Delinquent Forms, DQP Form 
Status, and DQP Reports modules. 
14.1     Data Management/Collection (18-OCT-2023) 
Medidata Rave is a clinical data management system being used for data collection for 
this trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system 
and role assignments. Requirements to access Rave via iMedidata: 
• 
Active CTEP registration with the credentials necessary to access secure 
NCI/CTSU IT systems; and  
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, 
Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
             Rave role requirements: 
o Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an 
Associate Plus (AP) registration type; 
o Rave Investigator role must be registered as a Non-Physician Investigator  
(NPIVR) or an Investigator (IVR); and 
o Rave Read Only or RAVE SLA role must have at a minimum an 
Associates (A) registration type. 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types 
and documentation required. 

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Upon initial site registration approval for the study in the Regulatory application, all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation 
email from iMedidata. To accept the invitation, site staff must either click on the link in 
the email or log in to iMedidata via the CTSU members’ website under Data 
Management > Rave Home and click to accept the invitation in the Tasks pane located in 
the upper right corner of the iMedidata screen. Site staff will not be able to access the 
study in Rave until all required Medidata and study-specific trainings are 
completed. Trainings will be in the form of electronic learnings (eLearnings) and can be 
accessed by clicking on the eLearning link in the Tasks pane located in the upper right 
corner of the iMedidata screen. If an eLearning is required for a study and has not yet 
been taken, the link to the eLearning will appear under the study name in the Studies pane 
located in the center of the iMedidata screen; once the successful completion of the 
eLearning has been recorded, access to the study in Rave will be granted, and a Rave 
EDC link will replace the eLearning link under the study name.  
Site staff who have not previously activated their iMedidata/Rave account at the time of 
initial site registration approval for the study in the Regulatory application will receive a 
separate invitation from iMedidata to activate their account. Account activation 
instructions are located on the CTSU website in the Data Management section under the 
Rave resource materials (Medidata Account Activation and Study Invitation Acceptance). 
Additional information on iMedidata/Rave is available on the CTSU members’ website 
in the Data Management > Rave section or by contacting the CTSU Help Desk at 1-888-
823-5923 or by e-mail at ctsucontact@westat.com.   
14.2     Summary of Data Submission 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who 
will enroll in future studies using similar agents. Adverse events are reported in a routine 
manner at scheduled times during the trial using Medidata Rave®. Additionally, certain 
adverse events must be reported in an expedited manner for more timely monitoring of 
patient safety and care. See Sections 7.4 to 7.4.3 for information about expedited and 
routine reporting.   
 
Summary of Data Submission: Refer to CTSU website. 
 
See Section 8 for TRIAD account access and installation instructions. 
14.3     Global Reporting/Monitoring 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0.  
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to 
CTEP on a quarterly basis by FTP burst of data. Reports are due January 31, April 30, 
July 31, and October 31. Instructions for submitting data using the CDUS can be found 
on the CTEP Web site (http://ctep.cancer.gov/reporting/cdus.html). 

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15.       STATISTICAL CONSIDERATIONS 
15.1 
Study Design (18-MAY-2018) 
The study is an open-label, randomized, integrated phase II/III trial to evaluate 
maintenance systemic therapy with and without LCT for limited metastatic non-small cell 
lung cancer.  Patients will be enrolled and randomized 2:1 between LCT + maintenance 
systemic therapy arm and maintenance systemic therapy alone arm. 
15.2 
Study Endpoints (18-MAY-2018) 
15.2.1  Primary Endpoints 
Phase II:  The primary endpoint is progression-free survival (PFS).  PFS is defined as the 
time from randomization to any documented progression or death due to any cause, 
whichever occurs first.  
Phase III:  The primary endpoint is overall survival (OS), which is defined as the time 
between the date of randomization and the date of death due to any cause.  
15.2.2  Secondary Endpoints   
• Time to in-field local failure, defined as the time from randomization to in-field 
failure or marginal failure (evidence of tumor viability); 
• Time to development of new lesions, defined as the time from randomization to the 
first occurrence of any new lesions that have not been treated with local consolidative 
therapy;  
• Toxicities (CTCAE v5); 
• Duration of maintenance systemic therapy usage; 
• Quality of life as measured through FACT-TOI, EQ-5D and C-TUQ instruments; 
• Association between progression-free survival and ctDNA 
15.3 
Primary Objective and Study Design (19-JUL-2021) 
15.3.1 Primary Hypothesis and Endpoints 
The primary hypothesis of this study is that LCT and maintenance systemic therapy (Arm 
2) will improve the progression-free survival (phase II) and overall survival (phase III), 
compared to the maintenance systemic therapy alone (Arm 1) for limited metastatic 
NSCLC patients.  This study population does not have reliable historical data in the 
contemporary era of immunotherapy.  Based on published data including KEYNOTE 
021, KEYNOTE 024G, KEYNOTE 407, plus findings from Socinski 2018, we assume 
the NRG-LU002 cohorts to approximate the following groups of treatments:  1) 
pembrolizumab monotherapy based on FDA-approved indications; 2) pembrolizumab 
and pemetrexed based on FDA-approved indications; 3) cytotoxic chemotherapy based 
on FDA-approved indications; 4) atezolizumab monotherapy based on FDA-approved 
indications; and 5) ipilimumab and nivolumab based on FDA-approved indications.   We 
therefore project that, for the standard maintenance systemic therapy, the 6 month and 12 
month rates of PFS are approximately 60% and 39%, and 12 month and 24 month rates 
of OS are 68% and 47%, respectively.   
 
For the phase II portion, we consider a hazard reduction of 40% in PFS (HRPFS =0.6) 
with LCT to warrant a phase III study.  For the entire study, we aim to demonstrate a 
hazard reduction of 32% in OS (HROS = 0.68) with LCT. 

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Assuming PFS and OS follow approximately exponential distributions, the HRPFS of 0.6 
target corresponds to improving 12-month PFS rate from 39% to 57%, or from 45% to 
62%; the HROS of 0.68 target corresponds to improving 24-month OS from 47% to 60%, 
or from 54% to 66%.  Meanwhile, we recognize that the changing landscape of systemic 
therapies and inclusion of immunotherapy in the induction regimen make it extremely 
challenging to accurately project the potential benefits in the scale of rates of OS and 
PFS, so the aforementioned improvements in PFS and OS rates are just for illustrations. 
The sample size calculation is based on HR, which is robust to the underlying 
assumptions for the control arm.  We also have stratified patients based on inclusion of 
immunotherapy in the induction regimen to mitigate this issue.   
 
15.3.2  Statistical Analysis Plan for Primary Endpoints 
For both phase II and phase III portions of this study, the respective primary analyses for 
PFS and OS will be performed on a modified intent-to-treat (mITT) basis, such that all 
randomized eligible cases will be included in the treatment arm to which they were 
randomized regardless of what treatment the patients actually received. This is the 
primary dataset for analyses of demography, protocol deviations, baseline characteristics, 
and efficacy outcome research.   
 
The primary analysis for the phase II portion based on PFS is to be conducted when at 
least 138 PFS events are available. We will compare the distributions of PFS between 
treatment arms using a one-sided log-rank test stratified by histology and systemic 
therapy type in all randomized eligible patients.  The rates at various timepoints (e.g., 
every 6 months after randomization) and medians of PFS for each arm will be estimated 
using the Kaplan-Meier method (1958). The associated 95% confidence interval (CI) will 
be calculated using Greenwood’s formula and based on a log-log transformation applied 
on the survival function.  Results from an unstratified analysis will also be provided.   
 
At the time of phase II primary analysis, we will also estimate the HROS and use it as a 
parallel criterion to determine if the experimental regimen is worth continuing to a phase 
III analysis.  In particular, we consider the experimental regimen is likely to be safe with 
respect to OS if the estimated HROS≤ 1.53 (control is reference) when at least 70 deaths 
are available.  This criterion is motivated by the futility monitoring rule proposed by 
Freidlin et al. (2010).  Considering the data are not mature enough for any reliable 
inefficacy evaluation on OS at the time of phase II primary analysis based on PFS, to 
avoid substantial accrual suspension, we plan to perform this early “harm” look of OS 
when 25% of the full OS information, i.e., at least 70 deaths, have been observed.    
 
In summary, the primary phase II analysis will be conducted when at least 138 PFS 
events and 70 deaths are both available.  The accrual for the trial is to be suspended if 
216 eligible patients have been randomized in the event that we have not observed either 
138 PFS events or 70 deaths.  Contingent upon the primary phase II analysis the accrual 
will proceed into the phase III portion, i.e., if the estimated HRPFS ≤ 0.83 (equivalently, 
Z≥1.036) and HROS ≤ 1.53 (equivalently, Z≤1.645), based on stratified Cox PH model. 
 

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The primary analysis for the entire phase III trial, if applicable, will be conducted when at 
least 278 deaths are available.  OS will be analyzed using the same methods as the 
primary phase II analysis for PFS.  The study will be interpreted as positive if the one-
sided p-value from the stratified log-rank test is less than 0.025, with proper adjustments 
based on group sequential method per the planned interim analysis plan (see Section 
15.4).  In an exploratory nature, the analysis for PS may be updated at the time of 
conducting phase III analysis, if applicable. 
 
15.3.3 Sample Size and Power Calculations:  
The overall sample size of this phase II/III study is 378 eligible patients (125 patients in 
the maintenance systemic therapy arm and 253 patients in the LCT + maintenance 
systemic therapy arm), and the final analysis for OS will occur when at least 278 deaths 
(full OS information) have been observed. This design will provide at least 85% power to 
detect a hazard ratio for OS (HROS) of 0.68 (approximately) at a 0.025 significance level 
(1-sided) using the stratified log-rank test.  Guarding against ineligibility or lack-of-data 
of up to 5%, the targeted accrual of randomized patients for the entire phase II/III study is 
400. 
 
The phase II portion is meant to provide at least 95% power to detect a hazard ratio for 
PFS (HRPFS) of 0.60 (approximately) at a significance level (1-sided) of 0.15.  We 
consider this phase II portion as a randomized phase II screening design (Rubinstein 
2005) to justify the choice of type 1 and type 2 errors for PFS analysis.  Based on the 
aforementioned assumptions, at least 138 PFS events will be needed to detect a HRPFS of 
0.6, and the estimated HRPFS using Cox model needs to be less than 0.83 to be considered 
promising enough for a further study.   
 
The sample size and power calculation were performed based on software EAST and 
Monte Carlo simulations using R. 
 
15.3.4 Sample Size and Power Calculations for Quality-of-Life (QOL) Research 
 
The primary QOL endpoint is the clinically meaningful deterioration of FACT-TOI at 3 
months from baseline.  A clinically meaningful deterioration is defined as a decline of 5 
points or more in FACT-TOI.  The primary QOL hypothesis is that fewer patients in the 
experimental arm will experience clinically meaningful deterioration at 3 months than 
those in the control arm.   
 
 
We project that about 70% of all randomized patients (~264 eligible patients) will be 
available for evaluation at both baseline and 3 months.  Power analysis suggests that 264 
evaluable patients at both baseline and 3 months will provide about 90% power to detect 
about a 20% difference in deterioration rate in control and experimental arms at a two-
sided alpha of 0.05.  
 
15.3.5 Power Calculations for Translational Research  
The translational research objectives are considered exploratory in nature. While the 
predictive and prognostic potential for ctDNA remains to be of primary interest, the assay 
technology may evolve over time. As such, no marker assays will be conducted on the 

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collected specimens until sufficient clinical outcome data is ready for statistical analysis. 
When this information is available from the parent study, a full correlative study protocol 
for the marker studies detailing the scientific hypothesis, research plan, clinical outcome, 
assay methods for each biomarker, and a more complete statistical section (with adequate 
power justification and analysis plan) will be submitted and subjected to CTEP review in 
accordance with National Clinical Trials Network (NCTN) policies. 
 
To determine if the study may offer exploratory yet still meaningful findings whether a 
to-be-determined cutoff of ctDNA may predict PFS changes in patients treated with RT, 
we provide the following table as a preliminary evaluation for the interaction effects 
between “marker” status and treatment assignments.  Based on the design parameters and 
the method proposed by Peterson and George [Peterson 1993], and using all patients to 
be available at the end of study, we summarize the statistical power to detect interaction 
effects (ratio of hazard ratios) of 0.33, at 2-sided significance level of 0.05.  We denote 
monthly hazard rates as λ, expected number of events of respective subgroups as E[N], 
and the hazard ratio between marker + and - as Δ.  The subscripts indicate the 
corresponding treatment arms. The assumed monthly hazard rates and associated 
expected number of events are listed in the following Table accordingly. 
 
Prevalence 
of Marker 
+/- 
 
Arm 1 
Arm 2 
Interaction 
 
 
Marker - 
Marker + 
Δ1 
Marker - 
Marker + 
Δ2 
Δ21= 
Δ2/ 
Δ1 
Power 
0.2 
λ 
0.085 
0.085 
1.0 
0.059 
0.0194 
0.33 0.33 
79.1% 
 
E[N] 
66 
17 
109 
13 
 
λ 
0.0788 
0.118 
1.5 
0.055 
0.027 
0.5 
0.33 
84.1% 
 
E[N] 
64 
19 
105 
16 
 
λ 
0.075 
0.150 
2.0 
0.052 
0.035 
0.67 0.33 
88.4% 
 
E[N] 
62 
21 
102 
20 
0.33 
λ 
0.085 
0.085 
1.0 
0.059 
0.0194 
0.33 0.33 
91.9% 
 
E[N] 
55 
27 
99 
23 
 
λ 
0.0788 
0.118 
1.5 
0.055 
0.027 
0.5 
0.33 
94.5% 
 
E[N] 
52 
31 
93 
29 
 
λ 
0.075 
0.150 
2.0 
0.052 
0.035 
0.67 0.33 
95.5% 
 
E[N] 
50 
33 
88 
33 
 

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Based on the table above, the proposed study will have a reasonably good power to detect 
a strong predictive (interaction) effect (HR=0.33) with marker prevalence as low as 20%.   
15.4 
Study Monitoring of Primary Objectives (30-MAR-2021) 
The NRG Oncology Data Monitoring Committee (DMC) will review the study twice a 
year with respect to patient accrual and morbidity. An interim study summary report will 
be prepared at each meeting accordingly until the initial study results have been released.  
In general, the interim reports will contain information about patient accrual rate, a 
projected completion date for the accrual phase, patient exclusion rates and reasons 
following registration, compliance rate of treatment delivery, distributions of 
pretreatment characteristics and important prognostic baseline variables, and the 
frequencies and severity of treatment-related adverse events.  The interim reports will not 
contain the results from the treatment comparisons with respect to the efficacy endpoint. 
The DMC also will review the study on an “as needed” basis.  
 
For the phase II portion with respect to its primary endpoint PFS, one interim futility 
analysis will be conducted based on Freidlin (2010) when 69 PFS events (50% of full 
PFS information for phase II) are available.  If the observed HRPFS>1, the two-sided 95% 
confidence interval for HRPFS (on the scale of logHRPFS) would not contain the 
alternative hypothesis that HRPFS=0.6.  In this case we would consider terminating the 
study as the experimental regimen will be viewed as ineffective.  The final analysis of 
PFS for phase II portion will occur when at least 1) 138 PFS events are available and 2) 
70 deaths are both available.   
 
For the phase III portion with respect to its primary endpoint OS, two interim analyses for 
futility and efficacy are planned prior to its final analysis when at least 278 deaths are 
available.  They will be conducted approximately when we observe 50% (139 deaths) and 
75% (209 deaths) of the full OS information (278 deaths).  Based on the proportion of 
information available, the Lan-DeMets implementation of O’Brien-Fleming boundary is 
used to determine the critical value for the interim analyses for efficacy, and a Linear 
20% Inefficacy Boundary (LIB20), as proposed by Freidlin (2010), is used for interim 
analyses for futility.  All interim analyses will be based on mITT population.  
 
The following Table summarizes the interim efficacy/futility monitoring schedule with 
respect to OS for the entire phase III study:  
 
Interim and Final Analysis for OS 
   
Analysis 
Projected 
Time (month) 
under H1** 
Percent 
Information 
Number 
of Events 
Efficacy boundary 
Futility boundary 
Z> 
Z< 
Interim 1 
48 
50% 
139 
2.963 
0.055 
Interim 2 
63 
75% 
209 
2.356 
0.298 
Final 
87 
100% 
278 
2.015 
- 
*   Early look for detriment in experimental arm, left-tail p<0.05 will prompt stopping. 
** Including the 6 months accrual bump-up period (see details in Section 15.5).  

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At each protocol-planned interim analysis, the results from the test assessing the 
treatment efficacy and futility will be reported to the NRG Oncology Data Monitoring 
Committee (DMC).  The responsible senior statistician may recommend early reporting 
of the results and/or stopping accrual (if applicable) of the trial if the critical value 
exceeds the specified boundary in a sequential design for either efficacy or futility.  The 
accrual rate, treatment compliance, treatment safety, and the importance of the study are 
also considered in making such a recommendation.  The DMC will then make a 
recommendation about the trial to the NRG Oncology leadership and study team. 
15.5 
Accrual/Study Duration Considerations (18-MAY-2018) 
The study is event-driven and plans to randomize up to 378 eligible patients with 2:1 
ratio into the experimental and control arms. Guarding against ineligibility or lack-of-data 
rate of up to 5%, the targeted accrual of randomized patients for the entire phase II/III 
study is 400.  During the first 6 months following activation, little accrual is anticipated 
while the trial is being approved by institutional review boards (IRBs). Assuming a 
uniform monthly accrual rate of 9.5 patients (9 eligible patients to be randomized) and 
minimal accrual in the first 6 months for ramp-up, the accrual for the phase II portion is 
projected to last approximately 30 months (2.5 years). Another 18 months (1.5 years) will 
be needed to complete the entire phase III accrual.  The entire phase III study is projected 
to last approximately 87 months (7.2 years) since the phase II portion initiation to reach 
the required 278 deaths, without accounting for the accrual suspension for conducting the 
phase II analysis.  
 
The above projected study durations are based on the hypothesized design parameters.  If 
the actual study parameters deviate from the hypothesized ones, the actual study duration 
may be different from the projection. In this case the protocol will be amended 
accordingly to reflect the revised duration. 
15.6 
Secondary Endpoints and Statistical Analysis Plans (18-MAY-2018) 
15.6.1 Statistical Analysis Plan for Safety Endpoints  
The As-Treated (AT) patient population will be used for the analysis of safety data in this 
study. The AT population consists of all randomized eligible subjects based on the 
treatment they actually received.   
 
For each patient, the maximum severity reported will be used in the summaries. Adverse 
events will be summarized regardless of relationship to protocol treatment as assessed by 
the investigator. All adverse events, adverse events leading to withdrawal, interruption or 
modification of protocol treatment, Grade ≥ 3 adverse events, and serious adverse events 
will be summarized. Deaths and cause of death will be summarized.  Treatment-related 
adverse events using NCI Common Terminology Criteria for Adverse Events per Section 
7.2.1 will be presented in statistical analysis reports/publications in CTCAE, v. 5.  AE 
rates will be reported with the frequency and severity (e.g., type, grade, and attribution) 
by arm, the analysis will be performed at the time of both phase II and phase III (if 
applicable) primary endpoint analyses.  
 
15.6.2 Statistical Analysis Plan for Efficacy Endpoints  

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The analyses for all efficacy secondary endpoints will be performed on a modified intent-
to-treat (mITT) basis.  Statistical inferences will be conducted in an exploratory nature 
and for hypothesis generating purposes.   
 
Times to in-field/local failure and new lesions will be analyzed as competing risks data, 
where deaths without respective failures will be considered as competing events.   Rates 
at various timepoints (i.e., every 6 months after randomization) for each arm will be 
estimated using the cumulative incidence function.  The associated 95% confidence 
interval (CI) will be calculated using the Delta method and based on a log-log 
transformation applied on the estimated cumulative incidence functions.  
 
Statistical inferences of the development of each failure between arms will be based on 
cause-specific hazards using the log-rank test and Cox proportional hazard model.  
Gray’s test and the Fine-Gray model will also be used to provide statistical inferences 
between arms based on cumulative incidence functions and subdistribution hazards.   
 
15.6.3 Statistical Analysis Plan for Quality-of-Life (QOL) Endpoints  
The QOL analyses will be performed based on all randomized patients. FACT-TOI 
completion rates will be summarized at each assessment point as the proportion of 
assessments actually received out of the expected number (i.e., the number of subjects 
still in follow-up). 
 
The primary QOL endpoint, FACT-TOI deterioration rate at 3 months, is defined as the 
proportion of randomized subjects who have a 5 point or greater decrease from baseline 
in FACT-TOI at 3 months from baseline.  FACT-TOI deterioration rates at 3 months and 
associated 95% confidence interval will be calculated for each treatment group, based on 
all randomized subjects.  Clopper-Pearson method will be used for calculating 95% CI.  
The deterioration rates of each arm will also be compared using Cochran-Mantel-
Haenszel Test, stratified by histology.  
 
FACT-TOI at baseline and at each subsequent assessment, as well as their change from 
baseline will be summarized using descriptive statistics by treatment group as 
randomized. The summary at baseline and at each time point is based on all randomized 
subjects with a measurement at respective time point. The change from baseline analysis 
will only include subjects who have an assessment at baseline and at the subsequent time 
point. 
 
The scores at baseline and subsequent time points, as well the changes from baseline at 
each time point for each treatment group will be compared using the two-sample t-test. If 
the parametric assumptions are not met, then the Mann-Whitney test will be used.  Effect 
size of FACT-TOI changes at different time points will be calculated based on Cohen’s d, 
i.e., dividing the difference between arms in mean score changes by the pooled standard 
deviation of the baseline score means.   
 

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Longitudinal data analysis will also be performed to characterize the trend of scores over 
time across the two treatment groups using hierarchical formulation of the linear mixed 
model. The model will include treatment groups, stratification factors and time. 
 
EQ-5D consists of the EQ-5D descriptive system and the EQ visual analogue scale (EQ 
VAS). The EQ-5D descriptive system comprises the following 5 dimensions: mobility, 
self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 
levels: no problems, slight problems, moderate problems, severe problems and extreme 
problems. The EQ VAS records the subject’s self-rated health state on a 100-point 
vertical, visual analogue scale (0 = worst imaginable health state; 100 = best imaginable 
health state.   
 
Subjects’ overall health state on a visual analog scale (EQ-VAS) at each assessment time 
point will be summarized using descriptive statistics by treatment group, as randomized. 
Proportion of subjects reporting problems for the five EQ-5D dimensions at each 
assessment time point will be summarized by level of problem and by treatment group, as 
randomized.  Percentages will be based on number subjects assessed at assessment time 
point.   
 
C-TUQ will be summarized using descriptive statistics by treatment group, as 
randomized. The core items (1, 4, 5 and 6) plus the following extension items (7 and 11-
14) are of primary interest in this analysis. Items 4 and 5 are only analyzed at baseline.  
Proportions of patients who changed their smoking behavior after diagnosis, as collected 
in item 7, will be summarized at the different timepoints (treatment completion, 3, 6 and 
12 months). In addition, if there are reasonably sufficient compliant cases in each arm, 
the association between active smoking status and FACT at 3 months by arms will be 
explored. Likewise, the prognostic value (with respect to survival) of active smoking 
status at baseline, during and end of treatment will be explored if there are a reasonable 
number of compliant cases. We anticipate more experiences will be shared across the 
clinical oncology community with the increasing utility of C-TUQ in the course of this 
trial. If needed and applicable, additional details may be specified in Statistical Analysis 
Plan or amended in the protocol prior to conducting the primary analysis of quality of life 
component.   
 
15.6.4  Statistical Analysis Plan for Translational Research Endpoints  
 
The translational research will be performed among all randomized patients with usable 
specimens. All translational research analyses are exploratory in nature.   
 
The association between baseline ctDNA concentration and efficacy outcome, e.g., 
progression-free survival, will be assessed using the Cox proportional hazard model 
stratified by ≤1 vs. > 1 haploid tumor genome equivalent/ml of plasma.  Proper 
assessments for the chosen functional form of ctDNA concentration and model 
assumption will be applied.  Analyses will be performed both separately for each arm, 
and jointly across all patients with an interaction term (if applicable).  In addition, the 
absolute concentration at the 3 month time point and the change between the pre-
treatment and 3 month time point will be summarized descriptively, and will be explored 

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for association with landmark PFS and OS at 3 months using a Cox proportional hazard 
model.   
15.7 
Gender/Ethnicity/Race Distribution (18-MAY-2018) 
 
 
Racial Categories 
DOMESTIC PLANNED ENROLLMENT REPORT 
Ethnic Categories 
Not Hispanic or 
Latino 
Hispanic or Latino 
 
Total 
Female 
Male 
Female 
Male 
American Indian/Alaska 
Native 
3 
3 
0 
0 
6 
Asian 
3 
5 
0 
0 
8 
Native Hawaiian or Other 
Pacific Islander 
3 
3 
0 
0 
6 
Black or African American 
19 
21 
0 
0 
40 
White  
133 
149 
6 
12 
300 
More Than One Race 
0 
0 
0 
0 
0 
Total 
161 
181 
6 
12 
360 
 
 
 
Racial Categories 
INTERNATIONAL (including Canadian participants) 
PLANNED ENROLLMENT REPORT 
Ethnic Categories 
Not Hispanic or 
Latino 
Hispanic or Latino 
 
Total 
Female 
Male 
Female 
Male 
American Indian/Alaska 
Native 
0 
0 
0 
0 
0 
Asian 
0 
0 
0 
0 
0 
Native Hawaiian or Other 
Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
3 
3 
0 
0 
6 
White  
11 
13 
4 
6 
34 
More Than One Race 
0 
0 
0 
0 
0 
Total 
14 
16 
4 
6 
40 

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APPENDIX I:  RETIRED STUDY CHAIRS (22-FEB-2023) 
 
NRG Oncology acknowledges the following study chair who participated in the development 
and recruitment for this trial until retirement: 
 
Radiation Oncology Co-Chair 
Hak Choy, MD 
UT Southwestern Medical Center 
5801 Forest Park Rd. 
Dallas, TX 75390 
214-645-7600/Fax: 214-645-9193 
Hak.Choy@UTSouthwestern.edu