A Randomized Trial of Consolidative Immunotherapy With vs Without Thoracic Radiotherapy and / or Stereotactic Body Radiation Therapy (SBRT) After First-Line Systemic Therapy for Metastatic NSCLC
Phase: PHASE3
Conditions: Metastatic Lung Cancer, Stage IV Lung Cancer
Sponsor: Wake Forest University Health Sciences

A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
Wake Forest Baptist Comprehensive 
 Center 
WFBCCC # 62718 
ClinicalTrials.gov:  NCT03867175
Protocol version date 04/01/22 
 Page 1 of 52 
Principal Investigator:
Michael Farris, M.D. 
Department of Radiation Oncology 
Wake Forest University School of Medicine 
Medical Center Boulevard 
Winston-Salem, NC 27157 
Radiation Oncology Co-Investigators: 
William Blackstock, M.D. 
Department of Radiation Oncology Chair 
Wake Forest School of Medicine 
Heather Pacholke, M.D. 
Department of Radiation Oncology 
Radiation Oncology at Hayworth Cancer Center 
601 N Elm Street 
High Point, NC 27262 
Marc Leyrer, M.D. 
Department of Radiation Oncology 
J. Allen Knox Radiation Therapy Center
557 Brookdale Dr 
Statesville, NC 28677 
Ryan T. Hughes, M.D. 
Department of Radiation Oncology 
Wake Forest School of Medicine 
Christina Cramer MD 
Department of Radiation Oncology 
Wake Forest School of Medicine 
Medical Oncology Co-Investigators: 
William J Petty, M.D. 
Hematology and Oncology 
Wake Forest School of Medicine 
Jimmy Ruiz, M.D. 
Hematology and Oncology 
Wake Forest School of Medicine 
Stefan Grant M.D. 
Hematology and Oncology  
Wake Forest School of Medicine 
Thomas Lycan Jr. D.O. 
Wake Forest School of Medicine 
Medical Physics Co-Investigator: 
Biostatistician:   
William H. Hinson, Ph.D. 
Radiation Oncology 
Wake Forest School of Medicine 
Research Nurses: 
Sharon Averill 
Susan E. Wildman, BSN, RN, CCRC 
Sheri Whittington RN 
Study Coordinator:        
   Data Manager: 
Sharon Averill 
Regulatory Contact: 
Participating Institution(s):    
Beverly Levine, Ph.D. 
Biostatistics Core 
Comprehensive Cancer Center 
Wake Forest University School of Medicine  
Deonna Asbury 
Cindy Miller, A.A.S. 
Wake Forest University School of Medicine  
Winston Salem campus (Coordinating Center) 
Radiation Oncology at Hayworth Cancer Center 
J. Allen Knox Radiation Therapy Center
Version Date:  04/01/22 
Confidential 

A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62718 
 
Protocol version date 04/01/22 
  
 
 
 
 
                                         Page 2 of 52 
 
 
 
Table of Contents 
SCHEMA ....................................................................................................................................................... 5 
1.0 
Introduction and Background ........................................................................................................... 5 
2.0 
Objectives ...................................................................................................................................... 10 
2.1 
Primary Objective(s) ....................................................................................................................... 10 
2.2 
Secondary Objective(s) .................................................................................................................. 11 
3.0 
Patient Selection ............................................................................................................................ 11 
3.1 
Inclusion Criteria for Enrollment ..................................................................................................... 12 
3.2 
Exclusion Criteria from Enrollment ................................................................................................. 12 
3.3 
Eligibility for Randomization ........................................................................................................... 13 
3.4 
Inclusion of Women and Minorities ................................................................................................ 13 
4.0 
Registration Procedures................................................................................................................. 13 
5.0 
Outcomes ....................................................................................................................................... 14 
5.1 
Primary Outcome ........................................................................................................................... 14 
5.2 
Secondary Outcome ...................................................................................................................... 14 
6.0       Pembrolizumab ............................................................................................................................... 14 
6.2 
Pembrolizumab dose modifications  (for immune-related adverse events) ................................... 15 
6.3 
Treatment associated nausea and vomiting .................................................................................. 19 
7.0 
Radiation Therapy Details .............................................................................................................. 20 
7.1 
Timing of Radiation ........................................................................................................................ 20 
7.2 
Radiotherapy Dose and treatment methods .................................................................................. 20 
7.3 
Radiation Simulation “Planning” Details ......................................................................................... 20 
7.4 
Technical Factors ........................................................................................................................... 21 
7.5 
Definition of Target Volumes .......................................................................................................... 21 
7.6 
Dosimetric Guidelines/Critical Structure Constraints ..................................................................... 21 
8.0 
Study Activities and Patient Assessment ....................................................................................... 23 
8.1 
Study Calendar .............................................................................................................................. 23 
8.2 
Study Activities – Required Evaluations ........................................................................................ 24 
8.3 
Data Management Procedures ...................................................................................................... 24 
8.4 
During Follow Up ............................................................................................................................ 24 
8.5 
Duration of Therapy ....................................................................................................................... 25 
8.6 
Duration of Follow Up ..................................................................................................................... 25 
8.7 
Response determination: ............................................................................................................... 25 
8.8 
Regional failure: ............................................................................................................................. 25 

A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62718 
 
Protocol version date 04/01/22 
  
 
 
 
 
                                         Page 3 of 52 
 
8.9 
Distant disease: .............................................................................................................................. 25 
8.10 
Survival Definitions ......................................................................................................................... 25 
9.0 
Adverse Events List and Reporting Requirements ........................................................................ 26 
9.1 
Adverse Event List for Radiotherapy ............................................................................................. 26 
9.2 
Adverse Event List for Pembrolizumab .......................................................................................... 26 
9.3 
Adverse Event Characteristics ....................................................................................................... 27 
9.4 
DSMC SAE Reporting Requirements ............................................................................................ 27 
9.5 
WFUHS IRB AE Reporting Requirements ..................................................................................... 27 
9.6 
Study Management ........................................................................................................................ 28 
10.0 
Data Management .......................................................................................................................... 30 
10.0 
Pharmaceutical Information ........................................................................................................... 30 
10.1 
Pharmaceutical Accountability ....................................................................................................... 30 
10.2 
Pembrolizumab FDA pharmaceutical information (Keytruda) ........................................................ 30 
11.0 
Laboratory Correlative Studies ...................................................................................................... 32 
11.1 
Future exploratory blood biomarker studies .................................................................................. 32 
12.0 
Statistical Considerations ............................................................................................................... 32 
12.1 
Power and Sample size ................................................................................................................. 32 
12.2 
Estimated Accrual Rate.................................................................................................................. 32 
13.0 
Data Analysis ................................................................................................................................. 33 
13.1 
Analysis of Primary Objective ........................................................................................................ 33 
13.2  
Analysis of Secondary Objective ................................................................................................... 33 
Reference List ............................................................................................................................................. 34 
Appendix A: Enrollment Eligibility Checklist ................................................................................................ 35 
Appendix B: Protocol Registration .............................................................................................................. 37 
Appendix C: Eligibility for Randomization ................................................................................................... 38 
Appendix D: Numbering Sites of Disease ................................................................................................... 38 
Appendix E: Radiotherapy Technical Parameters ...................................................................................... 38 
Appendix F: 30-day Treatment Follow-up Form ......................................................................................... 39 
Appendix G: Treatment Response Evaluation ............................................................................................ 40 
Appendix H: NCI Comorbidity ..................................................................................................................... 41 
Appendix  I: Pulmonary Function Testing ................................................................................................... 41 
Appendix J: Follow-up Collection Form ...................................................................................................... 42 
Appendix K: Progression of Disease .......................................................................................................... 42 
Appendix L: Survival Form .......................................................................................................................... 43 

A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62718 
 
Protocol version date 04/01/22 
  
 
 
 
 
                                         Page 4 of 52 
 
Appendix M: Study Withdrawal ................................................................................................................... 43 
Appendix N: Withdrawal of Consent ........................................................................................................... 44 
Appendix O: Off-Study Form ....................................................................................................................... 44 
Appendix P: Protocol Deviation Form ......................................................................................................... 45 
Appendix Q: Off Treatment ......................................................................................................................... 45 
Appendix R: Mandatory DSMC SAE Reporting Guidelines ........................................................................ 46 
Appendix S: Adverse Event Log ................................................................................................................. 52 
 
 
 

A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62718 
 
Protocol version date 04/01/22 
  
 
 
 
 
                                         Page 5 of 52 
 
SCHEMA 
  
 
1.0 
Introduction and Background 
 
In 2017, there were approximately 222,500 new cases of lung cancer diagnosed in the US, with an estimated 155,870 
deaths1. Approximately 60% of newly diagnosed non-small cell lung cancers (NSCLC) present with metastatic disease 
on diagnosis2. Chemotherapy is generally accepted as the first-line treatment in most patients with metastatic disease. 
Outcomes with traditional platinum doublet-based chemotherapy alone in these patients remains poor with median 
overall survival of approximately 11 months3. However, for the subset of patients with limited disease burden who show 
any response to chemotherapy, it is becoming increasingly more common in modern practice to aggressively manage 
all known metastatic sites with local therapies.    
 
1.1 Oligometastatic Radiation 
 
The concept of oligometastatic disease was initially proposed by Hellman and Weichselbaum in 19954,5. This proposal, 
that a diffusely metastatic state is preceded by an intermediate phase of truly limited metastatic disease in discrete 
“seed” sites, has become particularly attractive in the modern era. Enormous advancements have been made in both 
imaging, and therapy delivery, allowing for earlier detection, as well as more precise and well tolerated treatments than 
previously possible. Such improvements have also presented new challenges of determining exactly how many sites 
of disease represent “too many” to still be considered limited oligometastatic disease. This remains unclear which 
subgroups of metastatic patients will have the best outcomes; however, such uncertainties should not preclude 
investigation into the potential benefits of local therapy for these patients.  
 
In the subgroup of metastatic patients who truly have a limited disease burden and a favorable response to first line 
systemic therapies, aggressive localized treatment of persistent disease could theoretically be curative. Clinical data 
from a variety of disease settings have empirically supported this hypothesis.   
 
Numerous reports have shown that the original sites of gross metastatic disease are those most likely to first progress 
after initial chemotherapy5,6. In a retrospective review of 64 patients treated with first-line systemic therapy at the 
University of Colorado Cancer Center, first extra-cranial progression was limited to sites of initial disease present prior 
to the start of systemic therapy in 64% (i.e. local progression)6. In those patients who would have been eligible for local 
radiation therapy, the median time to first local progression was 3.0 months from the start of first-line systemic therapy. 
The median time to progression in previously uninvolved sites was 5.7 months. Six-month progression-free survival 
probability in patients with local-first progression was 17.4% compared to 45.5% in patients with distant or combined 
local and distant progression. This suggests that an effective local therapy, when judiciously applied in the metastatic 
setting, might improve time to progression in a substantial proportion of patients.   
 

A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62718 
 
Protocol version date 04/01/22 
  
 
 
 
 
                                         Page 6 of 52 
 
A retrospective review from the University of Rochester compares the outcomes of NSCLC patients treated with 
curative chemoradiotherapy for stage III disease compared with patients having limited (≤ 8) metastatic sites who 
received stereotactic body radiation therapy (SBRT) to all sites of disease7. Those with limited metastatic disease 
exhibited favorable survival outcomes compared to the stage III patients (5-year overall survival [OS] 14% v. 7%, 
respectively). 
 
In 2012, De Ruysscher et al. reported long-term results from a prospective single arm trial of radical local therapy in 
oligometastatic NSCLC. Patients had less than five metastases at diagnosis and underwent a combination of local 
therapies to all sites of disease including surgery, conventional chemo-radiation, or SBRT at the physician’s discretion. 
Median progression-free survival (PFS) was 12.1 months and median OS was 13.5 months. Of patients with recurrent 
disease, in-field failure was 5%. Treatment was overall well-tolerated8.  
 
There are a few key differences between the above paradigm and our proposed schema: surgery and fractionated 
radiotherapy were allowed, each brain metastasis counted as an individual site, chemotherapy was not standardized, 
and the use of immunotherapy was not reported. Despite these limitations, this study provides evidence for the overall 
safety and feasibility of radical therapy to all sites of oligometastatic NSCLC.  
 
In another prospective, phase II trial from Belgium, 26 patients with oligometastatic NSCLC (≤ 5 metabolically active 
sites) were treated with SBRT to 50 gray (Gy) in 10 fractions to the primary and metastatic sites after induction 
chemotherapy9. Acute grade 3 toxicity occurred in 8% and there were no grade ≥ 4 toxicities. Median PFS was 11.2 
months and median OS was 28.4 months. In-field failure occurred in 15%. After failure, further aggressive local salvage 
therapies were performed in 19 patients.  
 
Petty (2018) recently reported results of a Wake Forest lead prospective multi-institutional phase II study. They 
analyzed outcomes in metastatic NSCLC patients who did not progress after 3-6 cycles of first line systemic therapy 
and had up to five total sites of disease including the untreated primary and or nodal disease. All residual sites were 
treated with SBRT without maintenance chemotherapy. Although the trial was closed early due to slow accrual, results 
were promising with a median PFS of 11 months (95% confidence interval [CI], 7.4-15.9) and a median OS of 22.2 
months (95% CI, 13.3-45.8). The 5-year OS and PFS was 29%10. 
 
In 2016, Gomez et al., presented results of their multicenter phase II randomized study in which patients with stage IV 
NSCLC with three or fewer non-progressive metastatic lesions after first-line systemic therapy, were randomized to 
either local consolidation with SBRT or surgery to all metastatic sites with or without maintenance chemotherapy vs 
maintenance alone, which could include consolidative chemotherapy or observation. The study was stopped early due 
to clear benefit in the consolidative local therapy arm with median progression free survival of 11.9 months vs 3.9 
months. HR 0.35 (90% CI, 0.18–0.66), log-rank p = 0.0054. Aggressive local therapy was well tolerated with no grade 
4 or 5 toxicities. Of the 13 patients in the local consolidation arm, 10 failures were distant, 1 was locoregional, and 2 
were both. Conversely, in the 17 patients on maintenance only, there were 6 distant failures, 4 locoregional, and 7 both 
local and distant failures2. 
 
This illustrated a shift from the typical pattern of first local progression at original sites of metastatic disease.   
Furthermore, this study showed that by aggressively treating all oligometastatic sites, the time to appearance of new 
lesions was increased. In the local consolidative therapy group, the time to the appearance of a new lesion was longer 
at 11.9 months (90% CI, 5.7-not evaluable) than in the maintenance arm at 5.7 months (3.1-7.0) p = 0.0497, which 
lends credence to the concept that ablation of all known sites of disease can prevent those sites from seeding further 
metastatic cascades.  
 
Similarly, Iyengar et al. (2018) presented another randomized single institution experience from UT Southwestern 
showing favorable outcomes with local consolidation then maintenance chemotherapy as presented in Table 1 below11. 
 
 
 
 
 
 
 
 
 

A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62718 
 
Protocol version date 04/01/22 
  
 
 
 
 
                                         Page 7 of 52 
 
Table 1. Prospective trials of radical therapy to all sites of oligometastatic NSCLC 
 
Number 
of Sites 
Dose/Fractionation 
Median PFS 
(mo) 
Median OS 
(mo) 
In-field Failure (%) 
(De Ruysscher et 
al. 2012) 
1-5 
EQD2 ≥ 60 Gy 
Surgery allowed 
12.1 
13.5 
5.1 
(Collen et al. 
2014) 
1-5 
50 Gy/10 fx 
11.2 
23.0 
15 
(Gomez et al. 
2016) 
1-3 
Variable 
11.9 
NR 
12* 
(Petty et al. 
2018) 
1-5 
Variable 
11.0 
22.2 
12 
(Iyengar et al. 
2017) 
1-6 
21-27 Gy/1 fx 
26.5-33 Gy/3 fx 
30-37.5 Gy/5 fx 
45 Gy/15 fx 
9.7 
NR 
0 
EQD2, equivalent dose in 2-Gy daily fractions; Fx, fraction(s); NR, not reached; OS, overall survival; PFS, 
progression-free survival 
*Reported locoregional failure 
 
 
1.2 Stereotactic Radiation for Brain Metastases 
 
In patients with advanced NSCLC, the brain is a frequent site of metastases. Data from the University of Maryland 
suggest that, in patients with solitary brain metastases and aggressively treated primary disease, that durable 
progression-free and overall survival can be achieved in a proportion of patients12. This study included 42 patients with 
NSCLC who presented with stage I-III thoracic disease with a solitary, synchronous brain metastasis. All patients 
received gamma knife radiosurgery (median dose 18 Gy prescribed to 50% isodose line (IDL) with or without whole 
brain radiation therapy. Sixty-two percent also received definitive treatment to the primary site with chemoradiation or 
surgery. Overall, the 5-year survival was 21%, and was 35% specifically in patients receiving definitive treatment to the 
thoracic primary site. 
 
1.3 Emerging Data for Immunotherapy  
 
In the short time interval since publication of the studies above, an abundance of promising immunotherapy data has 
emerged and is starting to dramatically alter the systemic therapy landscape for numerous malignancies13-15. The 
importance of intact immune surveillance in controlling outgrowth of neoplastic transformation has been known for 
decades. The Programmed Death Receptor Ligand (PD-L1) pathway presents a particularly attractive immunotherapy 
target, as it is involved in both antigen and self-recognition, and is a major pathway hijacked by tumors to suppress 
immune control.  
 
PD-1 and family members are type I transmembrane glycoproteins containing an immunoglobulin (Ig) Variable-type (V-
type) domain responsible for ligand binding and a cytoplasmic tail, which is responsible for the binding of signaling 
molecules. The normal function of PD-1, expressed on the cell surface of activated T-cells under healthy conditions, is 
to down-modulate unwanted or excessive immune responses, including autoimmune reactions. The cytoplasmic tail of 
PD-1 contains two tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and an 
immunoreceptor tyrosine-based switch motif (ITSM). Following T-cell stimulation, PD 1 recruits the tyrosine 
phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of 
effector molecules such as CD3ζ, PKCθ and ZAP70, which are involved in the CD3 T-cell signaling cascade. The 
mechanism by which PD-1 down modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both 
molecules regulate an overlapping set of signaling proteins. 
 

A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62718 
 
Protocol version date 04/01/22 
  
 
 
 
 
                                         Page 8 of 52 
 
Tumor cells expressing PD-L1 can modulate the immune response to appear non-foreign and avoid destruction. 
Expression of PD-L1 and PD-L2 has been found in multiple solid tumor types including melanoma, NSCLC, and some 
lymphoid malignancies16. PD-L2 is thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 
serves to dampen unwarranted T-cell function in peripheral tissues. Although healthy organs express little (if any) PD-
L1, a variety of cancers were demonstrated to express abundant levels of this T-cell inhibitor. Several studies have 
shown that the cancer microenvironment manipulates the PD-L1/PD-1 pathway and that the induction of PD-L1 
expression on tumor cells leads to the inhibition of immune responses against cancer, permitting cancer progression 
and metastasis17.  In a combined analysis of the Checkmate 017 and 057 assessing PD-L1 expression levels in 
squamous cell and non-squamous cell NSCLC, the proportion of PD-L1 positivity at cutoff expression levels of 1%, 5%, 
10% and 50% in primary tumors was roughly 28.1%, 27.4%, 22.6%, and 13.0% respectively. The overall concordance 
of primary and metastatic tumor PD-L1 expression was 75.2%18. These data suggest that PD-L1 should be considered 
as an attractive target for therapeutic intervention. 
  
 
1.4 Immunotherapy alone 
 
The evidence that PD-L1 is commonly up-regulated in NSCLC and that PD-1 is expressed on the majority of tumor 
infiltrating lymphocytes, represented the rationale for the development of monoclonal antibodies against PD-L1 or PD-
1, and several agents are currently under investigation19.   As covered in detail below, Pembrolizumab is approved in 
the frontline setting alone for patients with advanced NSCLC and PD-L1 tumor proportion score (TPS) of 50% or greater 
and in combination with pemetrexed and carboplatin for patients with non-squamous histology.  It is also approved in 
the second line setting for patients with PD-L1 TPS > 1%. 
  
The first anti-PD1 antibody approved for NSCLC was nivolumab. In the Checkmate 017 trial, 272 patients with 
advanced/metastatic squamous cell NSCLC whose disease progressed during or after first-line chemotherapy were 
randomized to nivolumab, 3 mg/kg every two weeks, or docetaxel, 75 mg/m2 every three weeks. The median overall 
survival (OS) was 9.2 months with nivolumab versus six months with docetaxel. The response rate was 20% with 
nivolumab versus 9% with docetaxel. The median progression free survival (PFS) was 3.5 months with nivolumab 
versus 2.8 months with docetaxel. In this study, PD-L1 was neither prognostic nor predictive of benefit. Treatment-
related adverse events of grade 3 or 4 were reported in 7% of the patients in the nivolumab group as compared with 
55% of those in the docetaxel group. The most frequently reported (in ≥ 3% of patients) treatment-related select adverse 
events of any grade were hypothyroidism (4% with nivolumab vs. 0% with docetaxel), diarrhea (8% vs. 20%), 
pneumonitis (5% vs. 0%), increased blood creatinine level (3% vs. 2%), and rash (4% vs. 6%). Three treatment-related 
select AEs of grade 3 were reported in the nivolumab group, with one case each of tubulointerstitial nephritis, colitis, 
and pneumonitis; no grade 4 events were reported. No patients died in the immunotherapy arm versus three patients 
in the docetaxel arm20. 
  
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the IgG4/kappa isotype 
designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Pembrolizumab was later 
approved in the second-line setting based off the KEYNOTE-010 study. It was a randomized phase 2/3 trial which 
assessed pembrolizumab in patients with previously treated advanced non-squamous and squamous NSCLC who 
were PD-L1 positive (≥ 1%). There were three arms in this trial: pembrolizumab at 2 mg/kg, pembrolizumab at 10 mg/kg, 
and docetaxel at 75 mg/m² every three weeks. The median OS was 10.4 months for the lower dose of pembrolizumab, 
12.7 months for the higher dose, and 8.5 months for docetaxel. OS was significantly longer for both doses of 
pembrolizumab when compared with docetaxel. When compared with docetaxel, there were fewer grade 3 to 5 
treatment-related AEs at either dose of pembrolizumab (pembrolizumab 2 mg/kg: 13% [43/339] of patients, 
pembrolizumab 10 mg/kg: 16% [55/343], and docetaxel: 35% [109/309]). A total of six treatment-related deaths 
occurred in patients receiving pembrolizumab (three at each dose) and five treatment-related deaths occurred in the 
docetaxel arm21.   
  
Due to the good response of pembrolizumab in the second-line setting, it was studied as a potential first-line agent. 
The KEYNOTE-024 trial was an open-label, phase 3 trial, which randomized 305 patients with untreated advanced 
NSCLC with PD-L1 expression on at least 50% of tumor cells without the presence of a driver mutation to 
pembrolizumab 200 mg every three weeks versus platinum-based chemotherapy of the investigators choice.  
Crossover from the chemotherapy group was permitted at the time of progression.  Primary end point of the study was 
PFS with OS, ORR, and safety being key secondary endpoints. At a median follow-up of 11.2 months, median PFS 
was significantly longer in the pembrolizumab arm 10.3 months versus 6.0 months. At a median follow-up of 25.2 
months, OS was significantly longer with pembrolizumab versus chemotherapy at 30.0 months versus 14.2 months, 
despite significant crossover in the chemotherapy arm. The 12-month and 18-month OS data favored the 
immunotherapy arm, 70.3% vs 54.8% at 12 months; 51.5% vs 34.5% at 18 months. The response rate was higher in 
the immunotherapy arm 45.5% vs 29.8% in the chemotherapy arm.  The median time to response was similar in both 

A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62718 
 
Protocol version date 04/01/22 
  
 
 
 
 
                                         Page 9 of 52 
 
arms, 2.1 and 2.2 months. Median duration of response was not reached in the pembrolizumab arm compared to 7.1 
months in the chemotherapy arm. Of the 82 patients who crossed over to immunotherapy arm from the chemotherapy 
arm, the ORR was 20.7%. Treatment related AE’s of any grade were less frequent when compared to the chemotherapy 
arm as were grade 3, 4, or 5 treatment-related AEs (26.6% vs 53.3%)22.  
  
1.5 Combination immunotherapy and chemotherapy 
 
Chemotherapy is known to modulate immunologic effects; thus, it was hypothesized that combining chemotherapy with 
an anti-PD-1 inhibitor may have a synergistic effect23. Initially, the KEYNOTE-021 phase 2 study showed the safety 
and efficacy of combining chemotherapy and immunotherapy in the front line treatment of stage IV NSCLC. These 
findings were confirmed by two large, double-blind phase 3 registration trials (KEYNOTE-189 and KEYNOTE-407), one 
for each major subtype of NSCLC.  
For non-squamous subtype, KEYNOTE-189 found that the addition of pembrolizumab to pemetrexed/platinum (either 
carboplatin or cisplatin) significantly improved overall survival (median OS not reached vs. 11.3 months, HR 0.49; 
survival at 12 months 69% vs. 49%). Toxicity was only moderately increased with the addition of immunotherapy, as 
AE’s due to any cause led to treatment discontinuation in 14% (vs 8% control) and death in 7% (vs. 6% control). The 
treatment arm had higher rates of idiosyncratic autoimmune AE’s (Table 3: 23% vs. 12%), diarrhea (31% vs. 21%), 
pyrexia (20% vs. 15%), peripheral edema (19% vs. 13%), and thrombocytopenia (18% vs. 15%). This study excluded 
patients with the targetable mutations EGFR or ALK24. 
For squamous subtype, KEYNOTE-407 found that the addition of pembrolizumab to carboplatin/taxane (either 
paclitaxel or nab-paclitaxel) significantly improved overall survival (15.9 mo vs. 11.3 mo, 0.64; 95% CI, 0.49 to 0.85). 
Similar to KEYNOTE-189, toxicity was only moderately increased with the addition of immunotherapy, as AE’s due to 
any cause led to treatment discontinuation in 13% (vs. 6% control) and death in 8% (vs. 6% control). The treatment 
arm had higher rates of idiosyncratic autoimmune AE’s (Table 3: 29% vs. 9%), alopecia (46% vs. 36%), neutropenia 
(38% vs. 33%), nausea/vomiting (36% vs. 32%; 16% vs. 12%), thrombocytopenia (31% vs. 23%), diarrhea (30% vs. 
23%), arthralgia (21% vs. 14%), and peripheral neuropathy (21% vs. 16%)25.  
 
1.6 Immunotherapy as consolidation after radiation 
Immunotherapy has been studied as consolidation therapy after concurrent chemotherapy and radiation. The PACIFIC 
investigators designed a phase III study which compared anti-PD-L1 antibody, durvalumab, with placebo in patients 
with stage III NSCLC who did not have disease progression after two or more cycles of platinum-based 
chemoradiotherapy. Patients were randomly assigned in a 2:1 ratio, to receive intravenous durvalumab 10mg/kg or 
placebo every two weeks for up to 12 months. The study drug was administered 1 to 42 days after the patients had 
received chemoradiotherapy. The co-primary end-points were PFS (as assessed by means of blinded independent 
central review) and OS. Of 713 patients who underwent randomization, 709 received consolidation therapy (473 
received durvalumab and 236 received placebo). The median PFS from randomization was 16.8 months with 
durvalumab versus 5.6 months with placebo (stratified hazard ratio for disease progression or death, 0.52; 95% CI, 
0.42 to 0.65; P < 0.001); the 12-month PFS was 55.9% versus 35.3%, and the 18-month PFS was 44.2% versus 27.0%. 
The response rate was higher with durvalumab than with placebo (28.4% vs. 16.0%; P < 0.001), and the median 
duration of response was longer (72.8% vs. 46.8% of the patients had an ongoing response at 18 months). The median 
time to death or distant metastasis was longer with durvalumab than with placebo (23.2 months vs. 14.6 months; P < 
0.001). Grade 3 or 4 adverse events occurred in 29.9% of the patients who received durvalumab and 26.1% of those 
who received placebo; the most common adverse event of grade 3 or 4 was pneumonia (4.4% and 3.8%, respectively). 
A total of 15.4% of patients in the durvalumab group and 9.8% of those in the placebo group discontinued the study 
drug because of adverse events. Based off this study, the FDA approved durvalumab as consolidation therapy after 
concurrent chemoradiotherapy in stage III NSCLC13.   
 
1.7 Immunotherapy and SBRT 
 
Data now suggest that radiation therapy (RT) can modulate a systemic immune response to the tumor. Radiation 
releases tumor-associated antigens and facilitates the release of tumor associated antigens by dendritic cells (DC) and 
cross complementation on major histocompatibility complex-1 (MHC-1)26. Radiation also appears to enhance DC 
activation and immune priming against tumor cells27. Preclinical evidence suggests that when radiotherapy and 
immunotherapy are administered concomitantly, a synergistic antitumor response is observed28. Thus, RT can act as 
an in-situ tumor vaccine and provide long-lived immunologic memory29.  
 

A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62718 
 
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A retrospective subgroup analysis of 97 patients with progressive locally advanced, or metastatic NSCLC from Keynote 
001, compared patients who received pembrolizumab and had any prior history of radiation vs those who had never 
received radiation. In those patients who had any prior history of radiation the median PFS and OS were significantly 
improved from 2.1 months to 4.4 months and from 5.3 months to 10.7 months respectively.  In those who had only 
received extracranial RT, the improvements in median PFS and OS were more pronounced from 2 months to 6.3 
months and 5.3 months to 11.6 months respectively30.   
 
Although limited and retrospective, this supports the hypothesis that radiation may sensitize immunotherapy or allow 
for better tumor cell antigen exposure after radiation induced cell death.  There has been concern however that immune 
sensitization with radiation could potentially lead to over stimulation of the immune response and substantial toxicity.  
This is currently an area of intense research.  
 
In a phase 1 dose-finding clinical trial performed by the University of Chicago, patients with progressively metastatic 
solid tumors (after initial standard-of-care therapies) with at least two tumors amenable to SBRT were treated to a range 
of doses prior to initiation of immunotherapy. Pembrolizumab (200 mg IV every 3 weeks) was given within seven days 
after the final fraction of SBRT. The primary outcome was optimal RT dose; secondary outcomes included adverse 
events ≥ grade 3, response rates, tumor control and survival. Seventy-three patients had 1-3 sites of metastatic disease 
treated with SBRT. No per-protocol reductions in radiotherapy dose were required. A total of six patients experienced 
grade 3 toxicity (pneumonitis, 3; colitis, 2; hepatotoxicity, 1) for an overall rate of dose-limiting treatment-related toxicity 
rate of 9.7%, providing evidence of safety and feasibility for stereotactic radiotherapy shortly followed by PDL1 
blockade31.  
 
1.8 First Line Chemotherapy for Metastatic Lung Cancer  
 
Patients with advanced stage IV NSCLC who are negative for sensitizing EGFR mutations, ALK rearrangements, ROS1 
rearrangements, and with PD-L1 < 50% and who have a good performance status benefit from platinum-based 
chemotherapy. NCCN guidelines recommended chemotherapy regimens include platinum agents (cisplatin and 
carboplatin), taxanes (paclitaxel, docetaxel, albumin-bound paclitaxel), vinorelbine, etoposide, pemetrexed, and 
gemcitabine. Schiller and colleagues (2002) compared the rates of progression-free and overall survival using four 
widely accepted third-generation chemotherapy doublets as first-line treatment for advanced NSCLC: cisplatin and 
paclitaxel, cisplatin and gemcitabine, cisplatin and docetaxel or carboplatin and paclitaxel32.  No differences in clinical 
outcome were detected, with median times to progression of 3.1-4.2 months and median overall survival of 7.4-8.1 
months. The drug regimen with the highest likelihood of benefit with toxicity deemed acceptable to both the physician 
and patient should be given as initial treatment. The histology (non-squamous versus squamous) should be taken into 
account prior to selection of therapy. Scagliotti et al. (2008) published a phase III, randomized study comparing OS 
between treatment regimens in treatment naive, stage IIIB or IV NSCLC and PS 0-1. Overall survival was statistically 
superior for cisplatin/pemetrexed versus cisplatin/gemcitabine in patients with adenocarcinoma (n = 847; 12.6 v 10.9 
months, respectively) and large-cell carcinoma histology (n = 153; 10.4 v 6.7 months) respectively. In contrast, for 
patients with squamous cell histology, there was a significant improvement in survival with cisplatin/gemcitabine versus 
cisplatin/pemetrexed (n = 473; 10.8 v 9.4 months, respectively). For cisplatin/pemetrexed, rates of grade 3 or 4 
neutropenia, anemia, and thrombocytopenia (P = .001); febrile neutropenia (P =.002); and alopecia (P = .001) were 
significantly lower, whereas grade 3 or 4 nausea (P = .004) was more common. This was the first prospective phase 
III study in NSCLC to show survival differences based on histologic type33.   
 
The study is designed to ascertain if oligometastatic SBRT in combination with local radiation therapy followed by 
consolidative immunotherapy improves the outcomes for patients with stage IV NSCLC when compared to those 
patients receiving consolidative immunotherapy alone.  
2.0 
Objectives 
2.1 
Primary Objective(s) 
 
2.1.1 
We plan to compare progression-free survival of patients randomized to 
radiation and consolidative immunotherapy against those receiving 
consolidative immunotherapy alone. 
 
 

A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62718 
 
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2.2 
Secondary Objective(s) 
 
2.2.1 
We plan to estimate overall survival in all patients and will compare 
overall survival of those randomized to radiation and consolidative 
immunotherapy against those receiving consolidative immunotherapy 
alone. 
 
2.2.2 
In patients who experience subsequent failures after initiating protocol 
directed therapy, we will assess whether these failures occurred at 
known or new sites of disease. 
 
2.2.3 
We plan to evaluate toxicity associated with the addition of consolidative 
radiation therapy to upfront chemoimmunotherapy followed by additional 
consolidative immunotherapy. This will include calculating rates of 
adverse events depending on treatment site. Potential toxicities 
reported would include pneumonitis, esophagitis, chest wall pain, 
dermatologic toxicity, renal dysfunction, gastrointestinal toxicity 
including nausea, vomiting, and diarrhea, hepatotoxicity, and abdominal 
pain. These toxicities would be assessed according to site of irradiation 
by the treating physician and graded as per CTCAE 5.   
3.0 
Patient Selection  
 
ENROLLMENT 
• Patients are eligible for enrollment if they have metastatic NSCLC and have undergone at least 4 cycles of upfront standard of care systemic 
therapy (usually this will consist of combination chemo immunotherapy, but in some cases may be chemotherapy or immunotherapy alone).  
Patients must have a CT chest abdomen pelvis (ideally with IV contrast) performed after the point of completion of 4 cycles of systemic therapy, 
but no later than 180 days from the first day of systemic therapy.  This CT scan must be completed within 180 days of the first day of systemic 
therapy, and must demonstrate no evidence of disease progression per RECIST v1.1.   
 
• Patients may start their standard of care maintenance immunotherapy at the discretion of their treating medical oncologist prior to enrollment. 
Patients must be enrolled AND randomized no later than 180 days from the first day of cycle 1 of systemic therapy. The first day of cycle 1 of 
combined systemic therapy is considered day # 1.  At most, an additional 179 days may elapse from this point to remain eligible for inclusion on 
this study.   
 
RANDOMIZATION 
• Once enrolled, patients will have a restaging PET/MRI brain (exceptions below) 
   If restaging scans demonstrate ≤ eight sites of non-progressive active residual disease, then patients are eligible       
   for randomization.  If restaging scans demonstrate progression of disease, then these patients will not be   
   eligible for randomization, but will be followed by their primary medical oncologist or radiation oncologist every 3  
   months for overall survival only.       
 
          * If a PET has been performed within 30 days of enrollment with no evidence of progression  
             per RECIST v1.1, then this scan may be used and does not have to be repeated prior to randomization 
 
          * If an MRI brain has been performed within 90 days of enrollment with no evidence of progression per  
             RECIST v1.1, then this scan may be used and does not have to be repeated prior to randomization 
 
• Randomization should occur within 21 days of enrollment. 
• Once randomized, protocol directed therapy should occur within 21 days from randomization  
(ie. start of consolidative RT or resumption of maintenance immunotherapy) 
 
If randomized to consolidative radiation therapy then maintenance immunotherapy:  
Maintenance immunotherapy may NOT be delivered concurrently with consolidative radiation. Concurrently is defined as on the same day of any 
radiation treatment or on any day between the first and last treatment of radiation.  Resumption of maintenance immunotherapy after completion of 
radiation therapy is at the discretion of the treating medical oncologist. They may resume maintenance immunotherapy as early as 24 hrs after the 
last radiation treatment, but resumption should be no later than 8 weeks from the last radiation treatment.  If treatment related toxicities prohibit 
administration of maintenance immunotherapy, then restarting this therapy is at the discretion of the treating medical oncologist.  In such cases, 
patients will remain on study until they experience progression or death. If they experience progression, patients will be followed for overall survival 
only per appendix L past the point of progression.  
 
If randomized to continued maintenance immunotherapy alone:  
Patients will begin or resume maintenance immunotherapy no later than 21 days following randomization. 
  
 
 

A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62718 
 
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3.1 
Inclusion Criteria for Enrollment 
 
3.1.1 
Patients who are 18 years or older  
 
3.1.2 
Performance Status 0-2 (ECOG)  
at time of consult with radiation oncology 
 
3.1.3 
Pathologically proven NSCLC with evidence of metastatic disease. 
 
 
3.1.4 
Must have received 4 cycles of standard of care systemic therapy 
(usually this will consist of combination chemo immunotherapy), with a 
CT chest abdomen pelvis that was performed after completion of these 
4 cycles and demonstrates no evidence of progression per RECIST 
v1.1   
 
3.1.5 
To be eligible for enrollment and randomization, patients must be within 
180 days from their first dose of standard of care systemic therapy.  
Cycle 1 day 1 is defined as day 1.  If enrolled on day 180, the patient 
would need to be randomized the same day. 
 
3.1.6 
Persistent active disease must be amenable to radiation treatment per 
the treating radiation oncologist, and patients must have at least one 
residual site of disease which can be identified by CT or PET/CT and 
targeted with radiation. 
 
   
3.1.7 
Patients who previously had earlier stage NSCLC treated definitively 
and have now developed new distant disease, are eligible for inclusion if 
they have undergone at least 4 cycles of standard of care systemic 
therapy for their metastatic recurrence, and they meet all criteria above.  
 
 
3.1.8 
There are no strict size or tumor number limitations in a given organ 
(lung, liver, abdomen pelvis, or spine).  This is at the discretion of the 
treating radiation oncologist. 
 
 
3.2 
Exclusion Criteria from Enrollment 
 
3.2.1 
More than 180 days has elapsed since day 1 of cycle 1 of standard of 
care systemic therapy. 
 
3.2.2 
Pregnant or lactating women  
 
3.2.3 
The patient has received treatment for other carcinomas within the last 
three years (Except for cured non-melanoma skin cancer, low-risk 
prostate cancer, T1/T2 glottic cancer, stage 0 or stage I breast cancer, 
non-invasive bladder cancer, or treated in-situ cervical cancer).  Prior 
lung cancer diagnosis now with oligometastatic recurrence is not an 
exclusion criteria. 
 
3.2.4 
Patients with major activating mutations in EGFR (del19, L858R, and 
T790M) or ROS 1 or ALK gene rearrangements are excluded 
 
 
 

A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62718 
 
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3.3 
Eligibility for Randomization 
Once enrolled on study, patients will have a PET/MRI brain for restaging.  
Patients with no evidence of progression and 8 or fewer sites of active persistent 
disease per the treating physician are eligible for randomization.   
 
If a PET has been performed within 30 days of enrollment with no evidence of 
progression per RECIST v1.1, then this scan may be used and does not have to 
be repeated prior to randomization 
 
If an MRI brain has been performed within 90 days of enrollment with no 
evidence of progression per RECIST v1.1, then this scan may be used and does 
not have to be repeated prior to randomization 
 
3.4 
Inclusion of Women and Minorities  
 
Men and women of all races and ethnicities who meet the above-described 
eligibility criteria are eligible to participate in this study. The study consent form 
will also be provided in Spanish for Spanish-speaking participants.  
 
Based on WFBCCC population estimates, we may expect approximately 44% of 
participants to be women. We may enroll approximately 10-13% Black or African 
American. Based on our catchment area and hospital demographics we do not 
expect accruals of individuals of Hispanic/ Latino, American Indian/Alaska 
Native or Asian ancestry; however, no individual will be excluded from the study if 
they satisfy the above inclusion/exclusion criteria. Should we not meet or exceed 
these estimates, the PI will engage the Office of the Center of Health Equity to 
discuss strategies to enhance recruitment in these target populations. 
4.0 
Registration Procedures 
 
All patients entered on any WFBCCC trial, whether treatment, companion, or cancer  
control trial, must be linked to the study in EPIC within 48 hours of Informed Consent.   
Randomization and protocol designated treatment must take place within 8 weeks of the  
last dose of first line systemic therapy.   
You must perform the following steps to ensure prompt registration of your patient: 
 
1. 
Complete the Eligibility Checklist (Appendix A) 
2. 
Complete the Protocol Registration Form (Appendix B) 
3. 
Alert the Cancer Center registrar by phone, and then send the signed Informed  
       Consent Form, Eligibility Checklist, Protocol Registration Form to the registrar 
       These forms may be sent by either by fax or e-mail. 
4. 
Fax/e-mail ALL eligibility source documents with registration. Patients will not be  
       registered without all required supporting documents. 
 
Contact Information: 
Protocol Registrar PHONE 
 
Protocol Registrar FAX 
 
Protocol Registrar E-MAIL 
           
*Protocol Registration is open from 8:30 AM - 4:00 PM, Monday-Friday. 
Note: If labs were performed at an outside institution, provide a printout of the  
results. Ensure that the most recent lab values are sent.  
To complete the registration process, the Registrar will:   
Assign a patient study number, register the patient on the study,  
Randomize through Wake Forest OnCore 
 
Institutions outside of Winston Campus Wake Forest Baptist University Medical 
Center will contact the protocol registrar and randomization will be assigned through 
the Wake Forest OnCore program.  Randomization will then be communicated to the 

A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62718 
 
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outside institution by the Wake Forest protocol registrar.  If technically feasible at the 
time that this study begins, we will allow outside institutions remote access to our 
Wake Forest OnCore program for direct data entry and randomization. 
5.0 
Outcomes 
5.1 
Primary Outcome 
 
5.1.1 
Progression-free survival from the date of starting first line standard of 
care systemic therapy.   
 
 
5.2 
Secondary Outcome 
 
5.2.1 
Overall survival over 5 years from the date of starting first line standard 
of care systemic therapy.   
 
5.2.2 
In patients who experience subsequent failures after initiating protocol 
directed therapy, we will assess whether these failures occurred at 
known or new sites of disease. 
  
5.2.3 
Frequency of adverse events per CTCAE v5.0 
6.0       Pembrolizumab  
 
In order to maintain dose-intensity and cumulative dose-delivery, reasonable efforts should 
be made to minimize dose reductions and treatment delays. Any subject whose treatment 
is delayed should be evaluated on a weekly basis until adequate hematologic and non-
hematologic parameters have been met.  Patients may elect to delay doses of maintenance 
treatment for up to 3 weeks due to personal preference and this will not constitute a 
protocol deviation. 
 
Toxicities may require the dose reduction of one or more of the study required medications. 
The investigator will carefully assess all treatment associated toxicities and, whenever 
possible, determine if the toxicities can reasonably be attributed to a single agent or a 
causal relationship with one of the agents can reasonably be ruled out. If appropriate, dose 
reductions should not affect the dose of other products. 
 
CTC-AE measures will occur at each cycle of consolidation immunotherapy.  Dose 
modifications and treatments for adverse events will be managed at the discretion of the 
treating physicians per their standard practice.   Guidance statements regarding dose 
modifications and ae management are provided as suggestions for treating physicians but 
are not mandatory. Reasons for dose delays, dose modifications, or addition of steroid 
treatments must be documented by the treating physician.  
 
• Toxicity grades are defined using the National Cancer Institute Common Terminology  
Criteria for Adverse Events (NCI-CTCAE) version 5.0 
• Dose escalations are not allowed 
 
 
6.1 
Pembrolizumab dose and timing of administration 
 
Patients randomized to immunotherapy will begin treatment within 8 weeks of the 
last dose of their upfront systemic therapy.  Patients randomized to radiation 
followed by immunotherapy will begin treatment within 8 weeks of the last 
treatment of radiation.  Immunotherapy consolidation treatment of non-squamous 
histology may include concurrent pemetrexed with pembrolizumab consolidation, 

A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62718 
 
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per standard institutional practice. The initial dose of pembrolizumab will be 
utilized during consolidative immunotherapy either alone or in combination with 
pemetrexed.    
  
 
 
In patients randomized to consolidative immunotherapy after radiation may begin 
as early as 24 hours after the last treatment of radiation therapy at the discretion 
of the treating medical oncologist; however it must be administered no later than 
8 weeks from the last treatment of radiotherapy.   
 
In patients who are randomized to receive consolidative immunotherapy alone, 
they must resume maintenance immunotherapy within 8 weeks of their last dose 
of chemo immunotherapy or maintenance immunotherapy.  
 
6.2 
Pembrolizumab dose modifications  
(for immune-related adverse events) 
 
Pembrolizumab dose delays and treatment of pembrolizumb related adverse 
events will be at the investigators discretion.  For general management of 
immune-related adverse events due to pembrolizumab consider: 
 
1) 
Patient evaluation to identify any alternative etiology. 
2) 
In the absence of a clear alternative etiology, all events of an inflammatory 
nature should be considered to be immune-related. 
3) 
Symptomatic and topical therapy should be considered for low-grade events. 
4) 
Systemic corticosteroids should be considered for a persistent low-grade 
event or for a severe event. 
5) 
More potent immunosuppressives should be considered for events not 
responding to systemic steroids. 
 
While treatment delays and treatment of adverse events will occur at the 
investigator’s discretion, the tables below are provided for general guidance and 
management of pembrolizumab immune-related adverse effects. 
 

A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
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WFBCCC # 62718 
 
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A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
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WFBCCC # 62718 
 
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A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
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WFBCCC # 62718 
 
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A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
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WFBCCC # 62718 
 
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6.3 
Treatment associated nausea and vomiting 
Nausea and vomiting may be acute (onset 1–4 hours after infusion) or delayed 
(begins or persists ≥ 24 hours after infusion). To combat chemotherapy-induced 
nausea and vomiting, the following algorithm should be used: 
 
a) 
Nonsteroidal anti-emetics, such as a 5-HT3 antagonist (e.g., ondansetron), 
should be utilized for first-line management of symptoms 
b) 
If dexamethasone on Day 1 followed by nonsteroidal antiemetics on 
subsequent days does not sufficiently manage symptoms, dexamethasone 8 
mg orally may be administered on Day 2 and/or Day 3. 
 

A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
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WFBCCC # 62718 
 
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7.0 
Radiation Therapy Details  
 
7.1 
Timing of Radiation 
If randomized to the consolidative radiation arm, then radiation therapy will begin 
within 21 days of randomization.    
 
7.2 
Radiotherapy Dose and treatment methods 
The total dose will be flexible based on the judgment of the treating radiation 
oncologist to respect normal tissue tolerances.  Guidelines for suggested normal 
tissue constraints are listed below in section 7.6.  Meeting these constraints are 
recommended, but not required for inclusion on the protocol.  Ultimately, dose 
selection is at the discretion of the treating radiation oncologist.  In general, 
for lung, liver, axial skeleton, and adrenal tumors, a dose of either 54 Gy in 3 
fractions (fxs) or 5000 cGy in 5 fx using SBRT techniques will be appropriate if 
the GTV measures less than 5 cm. For tumors in these organs that are larger 
than 5 cm, or where normal tissue constraints are grossly exceeded, a dose of 
3000-6000 cGy in 10 – 15 fractions may be more appropriate instead. In the case 
of an untreated primary with involved mediastinal lymph nodes, fractionated 
radiotherapy over the course of 30 – 33 treatments with or without concurrent 
chemotherapy may be necessary at the discretion of the treating physician and 
this is allowed.  
 
Primary Site (Primary Lung Lesion, Mediastinal/Hilar/Supraclavicular Disease) 
Radiation to the primary site can be delivered with 3D conformal therapy, 
Intensity Modulated Radiation Therapy (IMRT), or proton beam therapy (PBT) at 
the discretion of the treating radiation oncologist.  The radiation dose to the 
primary site will be determined by the treating physician and based on normal 
tissue tolerance and institutional standards. Concurrent chemotherapy is 
permitted. 
 
In addition, it is acceptable to utilize a simultaneous integrated or sequential 
boost to further increase dose to the CTV or GTV, at the physician’s discretion. 
 
Metastatic Sites 
Radiation to the metastatic sites can be delivered with 2D/conventional 
techniques, 3D conformal therapy, IMRT, SRS, or PBT, at the discretion of the 
treating radiation oncologist. The radiation dose to metastatic sites will be 
determined by the treating physician and based on normal tissue tolerance and 
institutional standards. 
7.3 
Radiation Simulation “Planning” Details 
Patients will be simulated on a CT scanner (for fractionated radiotherapy or SRS 
when MRI contraindicated) or using volumetric MRI (for SRS) and immobilized 
based on the site of disease. Immobilization devices will be at the discretion of 
the treating radiation oncologist. Typical immobilization devices include a head 
and neck mask for metastatic sites in this region, an upper body cradle for 
disease in the thorax with the arms elevated if possible, and a lower body cradle 
for disease in the abdomen, pelvis, or lower extremities. A stereotactic head 
frame or aquaplast mask will be used for SRS. Four-dimensional CT scanning 
will be utilized at the treating radiation oncologist’s discretion, to assess for 
internal motion.  The use of IV contrast will be at the discretion of the treating 
radiation oncologist.  In order to ascertain the extent of tumor motion within the 
patient (primarily due to respiratory motion), commercially available 4-
dimensional (4D) respiratory timed images should be obtained and utilized when 
possible at the discretion of the treating physician.  Breath hold techniques that 
are reproducible at the time of simulation and treatment will be allowed in lieu of 
4D imaging at the discretion of the treating physician.  
 

A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
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WFBCCC # 62718 
 
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7.4 
Technical Factors 
7.4.1 
Photon energies of 6 or 10MV will be allowed. 
7.4.2 
Co-planar or non-coplanar beams will be used.  
7.4.3 
Correction for the heterogeneity of tissue must be used.   
  
7.5 
Definition of Target Volumes 
Target volumes will be approved by the treating radiation oncologist, using the 
information obtained through clinical examination, radiologic images, the 
simulation planning study, and histologic specimens. When feasible and 
necessary, the patient’s diagnostic images (CT scan, MRI study, or PET/CT 
imaging) will be fused with the simulation scan to delineate the suggested target 
volumes below.  Gross Tumor Volume (GTV) – All known disease detected by 
the above methods, including nodal disease. Internal Gross Tumor Volume 
(IGTV or ITV) – GTV plus internal motion, if 4D scanning is obtained at the time 
of simulation.Clinical Target Volume (iCTV) – iGTV plus the region at risk for 
microscopic spread. This target volume will be added at the physician’s 
discretion, given that all patients in this study will have metastatic disease and 
thus the utility of accounting for microscopic spread is limited. Planning Target 
Volume (PTV) – iGTV or iCTV plus a margin to account for patient movement 
and daily setup error.  Organ at Risk Volumes (OAR) – Delineation of the 
pertinent organs at risk, to include the lung, heart, esophagus, spinal cord, 
kidney, and liver. 
7.6 
Dosimetric Guidelines/Critical Structure Constraints  
Guidelines for suggested normal tissue constraints are listed below for various 
fractionation regimens.  Meeting these constraints are strongly recommended, 
but not required for inclusion on the protocol.  Ultimately, dose selection is at the 
discretion of the treating radiation oncologist.   
 
In the setting of SBRT treatments (typically defined as 3 – 10 treatments) the 
external border of the PTV will be covered by a lower isodose surface than 
typically used in conventional radiotherapy planning, however this may range 
from 60-100%.  This may be decided upon at the discretion of the treating 
radiation oncologist and per their institutional policies. The prescription dose will 
be delivered to the margin of the PTV and the maximal dose to any single 
metastatic lesion or the “hotspot”, must exist within the PTV for that lesion.   
 
 
 
 
 
 
 
 
 
 
 
 
 

A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
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WFBCCC # 62718 
 
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THREE FRACTIONS 
 
 
FIVE FRACTIONS 
 
 
TEN FRACTIONS 
Spine Radiosurgery (Special Cases) 
                                                           
Recommended dose constraints for fractionated radiation  
< 3 Gy per fraction: 
Lung 
V20Gy (Rt + Lt lung minus PTV) 
< 37% 
Mean (Rt + Lt lung minus GTV)    
< 20 Gy 
Esophagus 
Mean 
< 34 Gy  
Heart 
V60 Gy 
< 33% 
V45 Gy 
< 66% 
V 40 Gy 
< 100%  
Brachial Plexus 
Max dose 
< 66 Gy 
Spinal Cord 
Max dose 
< 48  Gy 
 

A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic Body Radiation Therapy (SBRT) after First-line 
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WFBCCC # 62718 
 
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8.0 
Study Activities and Patient Assessment   
8.1 
Study Calendar  
Study 
Details 
Enrollment1 
Prior to 
Randomization 
1 mo F/U7 
Every 3 mo 
For 3 years 
Every 6 mo 
For 2 years 
History, Physical 
 
All 
 
PE 
PS 
PE 
PS 
PE 
PS 
PFT’s (Spirometry, Lung volume & DLCO) 
 
 
X3 
 
 
 
RT-related Toxicities and  
Immunotherapy related toxicities 
Graded per NCI 
CTCAE, v. 5.0 
X4 
 
X 
X 
X 
MRI of Brain 
FDG PET/CT 
Base of skull to mid-thigh 
  
 
 
X5 
 
 
 
CT of Chest Abdomen and Pelvis 
To include lungs, liver, 
and adrenal glands 
X2 
 
X6 
X6 
X6 
Serum or urine  
pregnancy test 
Within 1 week prior to 
RT (if childbearing potential) 
X 
 
 
 
 
Blood sample collection8 
 
 
X 
X 
 
 
Response Assessment 
Determined by a 
radiologist utilizing 
RECIST criteria 
X 
 
X 
X 
X 
Appendix H 
 
X 
 
 
 
 
Appendix C,D 
 
 
X 
  
  
  
Appendix E 
 
 
 
X 
 
 
Appendix F 
 
 
 
X 
 
 
Appendix G, J, L9 
 
 
 
X 
X 
X 
1. 
Enrollment and randomization must occur after completion of 4 cycles of standard of care systemic therapy, but no later than 180 days from the first day of cycle 1 of standard of care systemic therapy.  
Randomization will occur no later than 21 days from time of enrollment.   
2.     CT Chest Abdomen pelvis demonstrating no evidence of progression per RECIST v1.1, must be performed after completion of 4 cycles of standard of care systemic therapy prior to enrollment 
        Ideal if CT prior to enrollment has IV contrast but not required. 
3.     PFTs within at least 6 months of enrollment 
4. 
Baseline evaluation should document any residual toxicity from previous therapies.  
5. 
PET and MRI brain must be completed prior to randomization,  
a. 
If PET has been performed within 30 days of enrollment, scan does not need to be repeated. 
b. 
If MRI brain has been performed within 90 days of enrollment, scan does not need to be repeated.   
6. 
Followup CT Chest abdomen pelvis to be performed with IV contrast unless medically contraindicated by renal function or contrast allergy.  
a. 
For patients randomized to the radiation arm – the first CT will be performed 1 month after the last treatment of radiation per standard of care 
b. 
For patients randomized to the immunotherapy arm – the first CT will be performed 1 month after the completion of the 2nd cycle of immunotherapy per standard of care 
c. 
The schedule above is standard of care for imaging followup.  Should a patient be enrolled after starting maintenance immunotherapy and after their first 3 month followup scan, then they may be allowed to switch to 6 months 
interval imaging at 3yrs from the end of chemo-immunotherapy, rather than a full 3 yrs from the date of randomization in accordance with standard of care. At discretion of treating oncologist.   
7. 
Definition of 1 mo. or 30 day followup 
a. 
For patients randomized to RT, this time point is considered 30 days +/- 14 days from end of all radiation therapy treatments 
b. 
For patients randomized to immunotherapy alone, this time point is considered 30 days +/- 14 days from the end of the 2nd cycle of on protocol maintenance immunotherapy 
8. 
Two tubes of whole blood may be collected at time of registration or any time prior to initiating any protocol directed therapy and at the 1 month follow up +/- 2 weeks.    
9. 
If patients progress and are not eligible for randomization, or if they progress at any point on the study, they are only followed w appendix L for survival after the point of progression 
FOLLOWUP VISITS AND CT SCANS HAVE A FLEXIBILITY WINDOW OF +/- 8 WEEKS AROUND THE TIME POINT LISTED ON THE STUDY CALENDAR

 
A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
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WFBCCC # 62718 
 
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8.2 
Study Activities – Required Evaluations 
 
8.2.1 
A medical history, physical examination, weight, NCI 
comorbidities, and assessment of ECOG performance status 
within 12 weeks of enrollment.  ECOG status will be documented 
at time of the radiation oncology consult in the electronic medical 
record.    
 
8.2.2 
A CT chest abdomen pelvis demonstrating no evidence of 
progression per RECIST v1.1 that has been performed after 
completion of 4 cycles of chemo-immunotherapy but no later than 
180 days from the first day of chemo-immunotherapy.  
 
8.2.3 
A PET/CT and MRI brain will be performed, either prior to 
randomization or a PET that is within 30 days of enrollment, or 
MRI brain within 90 days of enrollment may be used for purposes 
of randomization. 
  
8.2.4 
Biopsy or cytology demonstrating a diagnosis of non-small cell 
lung carcinoma. 
 
8.2.5 
Two tubes of whole blood will be collected via routine blood draw 
and saved for future exploratory biomarker studies as listed on the 
study calendar, at time of registration and at the 1 month follow up 
+/- 2 weeks.  For radiation patients this is 1 month after the last 
treatment of radiation. For immunotherapy only patients, this is 1 
month after the second dose of maintenance immunotherapy on 
study. 
 
8.2.6 
Serum or urine pregnancy test within 1 week of RT in women of 
child bearing potential.   
  
8.3 
Data Management Procedures 
Data should be submitted to Sharon Averill by fax or email: 
Fax #: (336) 713-37748 
Email: saverill@wakehealth.edu                                 
 
 
8.4 
During Follow Up 
8.4.1 
The dates of follow up and protocol related assessments are defined as 
below. Follow up and protocol directed assessments must be performed 
+/- 8 weeks from each specified FU time point. 
 
For patients randomized to radiation: 
Patients will undergo CT imaging of chest/abdomen/pelvis at 1 month 
after the last treatment of radiation is completed.  Subsequently, they 
will undergo CT imaging of chest/abdomen/pelvis every 3 months for 3 
years, then every 6 months for 2 years per standard of care.  
 
For patients randomized to continue maintenance immunotherapy: 
alone, they will undergo CT imaging of chest/abdomen/pelvis at 1 month 
after the 2nd cycle of protocol directed maintenance immunotherapy has 
been delivered.  Subsequently, they will undergo CT imaging of 
chest/abdomen/pelvis every 3 months for 3 years, then every 6 months 
for 2 years per standard of care.  
 
Should a patient be enrolled after starting maintenance immunotherapy 
and after their first 3 month followup scan, then they may be allowed to 

 
A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62718 
 
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switch to 6 months interval imaging at 3yrs from the end of chemo-
immunotherapy, rather than a full 3 yrs from the date of randomization 
in accordance with standard of care. At discretion of treating oncologist.   
 
If a patient, has suspicion of progression but requires closer interval 
followup than 3 months or additional imaging, this is allowable at the 
discretion of the treating physician.  If ultimately, they are deemed to not 
have progressive disease, they would then resume the schedule listed 
in the study calendar above. 
 
 
8.4.2 
Patients who progress on or after protocol directed therapy will be 
followed for survival only as per Appendix L without further protocol 
follow up requirements.  This includes progression of the protocol 
treated tumors, non-protocol treated tumors and the development of 
new metastatic disease. Tumor progression will be determined by 
RECIST criteria.   
8.5 
Duration of Therapy 
 
In the absence of treatment delays due to adverse events, treatment may 
continue for until one of the following criteria applies: 
 
• 
Disease progression 
• 
Intercurrent illness that prevents further administration of treatment, 
• 
Unacceptable adverse event(s), 
• 
Patient decides to withdraw from 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. 
                                
                             If a patient is unable to complete a total of 2 years of maintenance             
Immunotherapy due to toxicity, declining therapy, or intercurrent illness, or any 
other reason, they will continued to be followed on study until a progression 
event, death, or withdrawal from study.  
 
8.6 
Duration of Follow Up                         
All patients should be followed for study endpoints for a minimum of six months.  
Afterwards patients without progression will be followed as listed in the study 
calendar. 
8.7 
Response determination:   
The use of international criteria proposed by the Response Evaluation Criteria in 
Solid Tumors (RECIST) Committee is required for response assessment.  During 
follow up, PET imaging can be used to assist in adjudicating decisions regarding 
local failure as the SBRT process can in itself result in increases in the imaging 
abnormality on either a temporary or permanent but stable basis due to 
radiotherapy treatment effects such as tissue fibrosis.   
   
8.8 
Regional failure:   
New nodal disease ≥ 1cm in size within the lung, hilum, or mediastinum. 
                      Equivocal nodes should be assessed with FDG PET or biopsy  
8.9 
Distant disease:  
Appearance of distant cancer deposits consistent with metastatic spread.  
PET-CT or biopsy encouraged but not required.  
8.10 
Survival Definitions 
 

 
A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
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Progression-Free Survival 
Progression-Free Survival is defined as the duration from the start of first line standard of care 
systemic therapy to the time of progression, death, or date of last contact; those lost to follow-up 
will be censored. 
 
 
Overall Survival  
Overall Survival is defined as the duration from the start of first line standard of care systemic 
therapy to the date of death or date of last contact; those lost to follow-up will be censored. 
9.0 
Adverse Events List and Reporting Requirements 
9.1 
Adverse Event List for Radiotherapy  
 
Risks and side effects related to the SBRT 
More common (>10% of patients): 
• Damage to surrounding normal lung  
  and/or collapse of a portion of treated lung 
• Cough 
• Increased phlegm production  
• Changes in the lungs as the tumor shrinks; these changes will be    
  recognized by your radiation doctor on your x-rays or scans as expected  
  "scarring" that is developing. In most patients, no noticeable symptoms   
  will result from this lung damage. 
• Fatigue 
• Redness of irritation of the skin in the treatment area 
• Hair loss in the treatment area 
• Some soreness of the ribs with an increased risk of rib fracture. 
Less common (<10% of patients): 
• Difficulty breathing, increased shortness of breath  
• Fever  
• Fracture or compression of the treated bones of the spine,  
  which can result in pain and may need surgical treatment  
 
 
Rare (<1% of patients) 
Some patients can have the following symptoms associated with lung scarring: 
• Shortness of breath, cough, fever, and/or pain in the chest wall.  
• These patients may require oxygen for a short time or permanently.  
• Lung damage can be life threatening.  
• Pericarditis 
• Damage to the heart muscle, which can cause heart attack, heart failure, or death  
• Damage to the spinal cord, which can cause numbness, weakness, tingling, and/or inability to use the arms and/or legs  
• Damage to the esophagus, which can cause problems with swallowing  
• Damage to the stomach or bowel which can lead to ulceration or perforation with a risk of infection and death.  
• Damage to the large blood vessels surrounding the heart, which could cause coughing up of blood and possibly death  
• Severe pain or skin damage leading to an open wound. 
• The following are likely with SBRT to the bones of the spine in the neck: 
• Inflammation of the lining of the mouth and esophagus  
• Inflammation of the vocal cords, leading to hoarseness or loss of voice 
Risks and side effects related to non-SBRT or more “fractionated” radiation to the chest:  
 
More common (>10% of patients): 
• Temporary, difficulty, pain, or a burning sensation when swallowing  
• Temporary fatigue 
• Tanning, redness of the skin, and hair loss within the treatment area,  
• Skin in the treatment area may remain permanently dry 
  chest hair may not grow back  
• Decrease in blood counts while undergoing treatment 
  causing bleeding, and bruising    
• Cough and some difficulty in breathing due to lung damage 
Less common (<10% of patients): 
• Narrowing of the esophagus causing difficulty swallowing  
   (rarely requiring internal dilation or a feeding tube) 
 
Rare but serious (late) (<1% of patients)  
• Pericarditis – irritation of the heart sac causing a rapid heart rate, or chest pain.    
• Myocarditis – irritation of the heart muscle causing shortness of breath, chest pain, 
  or permanent heart muscle damage  
• Transverse myelitis – irritation of the spinal cord causing weakness or paralysis  
• Bleeding from the airway  
• Narrowing of the airway causing shortness of breath 
9.2 
Adverse Event List for Pembrolizumab 
 
In general, immunotherapy has a risk (>10%) of developing autoimmune complication(s), such as inflammation of the 
thyroid (hypothyroidism or hyperthyroidism), colon (colitis), lungs (pneumonitis), liver (hepatitis), or pituitary gland 
(hypophysitis), which can lead to the symptoms noted below. Autoimmune complications can potentially be life-
threatening or permanent. In some cases they may be reversible with urgent administration of steroids and/or other 
immunosuppressant(s). 
More common (>10% of patients): 
• constipation 
• depressed mood 
• diarrhea 
• dry skin and hair 
• feeling cold 
• flushing 
• hair loss 
• hoarseness or husky voice 
Less common (<10% of patients): 
• general feeling of discomfort or illness 
• fever 
• nervousness 
• pain symptoms 
• sensitivity to heat or cold 
• slowed heartbeat 
• stomach cramps 
• sweating 

 
A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62718 
 
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• joint or muscle pain 
• muscle cramps or stiffness 
• skin rash or itching 
• unusual tiredness or weakness 
• stuffy or runny nose 
 
• swelling of the face, feet, or lower legs 
• tenderness 
• cough or thickening of bronchial secretions 
• trouble breathing, chest pain, or chest tightness 
• trouble sleeping 
• upper right abdominal or stomach pain 
• watery or bloody diarrhea 
• weight change 
• yellow eyes and skin 
Rare (<1% of patients) 
• bloating 
• dark, bloody, or cloudy urine 
• blurred vision or other change in vision 
• darkening of the skin 
• dizziness 
• drowsiness 
• eye pain 
• fainting 
• fast heartbeat 
• indigestion 
• loss of appetite 
• mental depression 
• nausea or vomiting 
• pains in the stomach, side, or abdomen, possibly radiating to the back 
• redness or irritation of the eye 
• sensitivity of the eye to light 
• skin blistering, peeling, loosening, or tearing 
9.3 
Adverse Event Characteristics 
 
CTCAE term (AE description) and grade:  The descriptions and grading 
scales found in the revised NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 5.0 will be utilized for AE reporting. All appropriate 
treatment areas should have access to a copy of the CTCAE version 5.0. A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov). 
 
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ (see Appendix D) 
for expedited reporting purposes only.   
 
Attribution of the AE: 
 
Definite – The AE is clearly related to the study treatment. 
Probable – The AE is likely related to the study treatment. 
Possible – The AE may be related to the study treatment. 
Unlikely – The AE is doubtfully related to the study treatment. 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
9.4 
DSMC SAE Reporting Requirements 
 
The Data and Safety  Monitoring Committee (DSMC) is responsible for reviewing SAEs for 
WFBCCC Institutional studies as outlined in Appendix D. DSMC currently requires that all 
unexpected 4 and all grade 5 SAEs on these trials be reported to them for review. All 
WFBCCC Clinical Protocol and Data Management (CPDM) staff members assisting a 
Principal Investigator in investigating, documenting and reporting an SAE qualifying for 
DSMC reporting are responsible for informing a clinical member of the DSMC as well as 
the entire committee via the email notification procedure of the occurrence of an SAE.  
9.5 
WFUHS IRB AE Reporting Requirements 
 
Any unanticipated problems involving risks to subjects or others and adverse events shall 
be promptly reported to the IRB, according to institutional policy. Reporting to the IRB is 
required regardless of the funding source, study sponsor, or whether the event involves an 
investigational or marketed drug, biologic or device. Reportable events are not limited to 
physical injury, but include psychological, economic and social harm. Reportable events 
may arise as a result of drugs, biological agents, devices, procedures or other 

 
A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
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WFBCCC # 62718 
 
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interventions, or as a result of questionnaires, surveys, observations or other interactions 
with research subjects. 
 
All members of the research team are responsible for the appropriate reporting to the IRB 
and other applicable parties of unanticipated problems involving risk to subjects or others. 
The principal investigator, however, is ultimately responsible for ensuring the prompt 
reporting of unanticipated problems involving risk to subjects or others to the IRB. The 
principal investigator is also responsible for ensuring that all reported unanticipated risks 
to subjects and others which they receive are reviewed to determine whether the report 
represents a change in the risks and/or benefits to study participants, and whether any 
changes in the informed consent, protocol or other study-related documents are required. 
 
Any unanticipated problems involving risks to subjects or others occurring at a site where 
the study has been approved by the WFUHS IRB (internal events) must be reported to the 
WFUHS IRB within 7 calendar days of the investigator or other members of the study 
team becoming aware of the event. 
 
Any unanticipated problems involving risks to subjects or others occurring at another site 
conducting the same study that has been approved by the WFUHS IRB (external events) 
must be reported to the WFUHS IRB within 7 calendar days of the investigator or other 
members of the study team becoming aware of the event. 
 
Any event, incident, experience, or outcome that alters the risk versus potential benefit of 
the research and as a result warrants a substantive change in the research protocol or 
informed consent process/document in order to insure the safety, rights or welfare of 
research subjects. 
9.6 
Study Management 
  
9.6.1 
Personnel from the Comprehensive Cancer Center at the Wake Forest 
University Health Sciences will monitor the trial. All case report forms 
and source documentation must be sent to Wake Forest University 
Health Sciences for review by the Clinical Research Associates to 
assure proper conduct of the trial and proper collection of the data. 
Queries will be issued to the site by WFUHS which should be 
addressed in a timely manner. 
  
9.6.2 
Required Documentation 
  
9.6.2.1 
Before the study can be initiated at any site, the following 
documentation must be provided to the Clinical Research 
Management Office of Wake Forest University Health 
Sciences. 
9.6.2.2 
A copy of the official IRB approval letter for the protocol 
and informed consent 
9.6.2.3 
CVs and medical licensure for the principal investigator 
and any associate investigators who will be involved in the 
study 
9.6.2.4 
A copy of the IRB-approved consent form 
9.6.2.5 
CLIA Laboratory certification and institution lab normal 
values 
 
9.6.3 
Amendments to the Protocol 
  
9.6.3.1 
Should amendments to the protocol be required, the 
amendments will be originated and documented by the 
principal investigator at WFUHS. It should also be noted 
that when an amendment to the protocol substantially 
alters the study design or the potential risk to the patient, a 
revised consent form might be required. 

 
A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62718 
 
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9.6.4 
Study Monitoring / Auditing Procedure 
  
9.6.4.1 
Personnel from CCCWFU will monitor periodically to 
assure proper conduct of the trial and proper collection of 
the data.  The investigator at the site will allow the monitor 
to review all source documents used in the preparation of 
the case reports. The Protocol office at CCCWFU can be 
reached at 336- 713-6513. The Affiliate site will be audited 
via scanning all protocol related documents (charts, 
regulatory, drug logs etc.) and emailing them to the study 
team at the designated time which will be determined by 
the principal investigator and communicated to the site by 
letter. The study team will consist of the principal 
investigator, study staff and other designated individuals 
as needed. The site will be given at least 4 weeks’ notice. 
The affiliate site must have persons(s) available via phone 
during the audit process if questions arise. 
  
9.6.4.2 
The overall study principal investigator will review with the 
affiliate principal investigator the scoring of patient 
response or progression on a periodic basis once accrual 
has commenced at that site either through site visit or 
electronic means. 
  
9.6.5 
Record Retention 
9.6.5.1 
Study documentation includes all case report forms, data 
correction forms or queries, source documents, 
correspondence, monitoring logs/letters, and regulatory 
documents (e.g., protocol and amendments, IRB 
correspondence and approval, signed patient consent 
forms). 
9.6.5.2 
Source documents include all recordings of observations 
or notations of clinical activities and all reports and records 
necessary for the evaluation and reconstruction of the 
clinic research study. 
9.6.5.3 
Regulations and directives require that all study 
documentation pertaining to the conduct of a clinical trial 
must be retained by the study investigator. Study 
documents should be kept on file until six years after the 
completion and final study report. 
  
9.6.6 
Obligations 
9.6.6.1 
The principal investigator is responsible for the conduct of 
the clinical trial at the site in accordance with title 21 of the 
Code of Federal Regulations and/or the Declaration of 
Helsinki. The principal investigator is responsible for 
personally overseeing the treatment of all study patients. 
The principal investigator must assure that all study site 
personnel, including sub-investigators and other study 
staff members, adhere to the study protocol all regulations 
and guideline regarding clinical trials both during and after 
study completion. 
  
9.6.6.2 
The principal investigator at each institution or site will be 
responsible for assuring that all the required data will be 
collected and entered onto the Case Report forms. 
Periodically, monitoring contacts will be made and the 
principal investigator will provide access to his/her records 
for verification of proper data entry. At the completion of 

 
A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
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WFBCCC # 62718 
 
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the study, all case reports forms will be reviewed by the 
principal investigator. 
 
10.0 
Data Management 
 
If technically feasible at the time that this study begins, we will allow outside institutions 
remote access to our Wake Forest OnCore program for direct data entry and 
randomization.  Otherwise, all institutions will provide registration information to the Wake 
Forest protocol registrar and will be assigned randomization through the Wake Forest 
OnCore program.  All other data collected as per the appendices below will be provided 
directly to Sharon Averill by fax or email: 
 
 
 
11.0 
Pharmaceutical Information 
11.1 
Pharmaceutical Accountability 
Pembrolizumab is commercially available 
11.2 
Pembrolizumab FDA pharmaceutical information (Keytruda)  
 
 
Product description:   
Pembrolizumab is a humanized monoclonal antibody that blocks the interaction 
between PD-1 and its ligands, PD-L1 and PD-L2. Pembrolizumab is an IgG4 
kappa immunoglobulin with an approximate molecular weight of 149 kDa.  
 
KEYTRUDA for injection is a sterile, preservative-free, white to off-white 
lyophilized powder in single-use vials. Each vial is reconstituted and diluted for 
intravenous infusion. Each 2 mL of reconstituted solution contains 50 mg of 
pembrolizumab and is formulated in L-histidine (3.1 mg), polysorbate 80 (0.4 
mg), and sucrose (140 mg). May contain hydrochloric acid/sodium hydroxide to 
adjust pH to 5.5.  
 
KEYTRUDA injection is a sterile, preservative-free, clear to slightly opalescent, 
colorless to slightly yellow solution that requires dilution for intravenous infusion. 
Each vial contains 100 mg of pembrolizumab in 4 mL of solution. Each 1 mL of 
solution contains 25 mg of pembrolizumab and is formulated in: L-histidine  
 
(1.55 mg), polysorbate 80 (0.2 mg), sucrose (70 mg), and Water for Injection, 
USP. 
Informed consent document 
EPIC 
Protocol registration form 
WISER/OnCore 
Adverse Events Log  
WISER/OnCore 
30-day Treatment Follow-up  
WISER/OnCore 
Off-Study Form 
WISER/OnCore 
Treatment Response Evaluation Form 
WISER/OnCore 
Evaluation of Best Overall Response 
WISER/OnCore 
NCI Comorbidity Index 
WISER/OnCore 
Radiotherapy Technical Parameters 
WISER/OnCore 
Patient Baseline Characteristics 
WISER/OnCore 
Pulmonary Function Testing 
WISER/OnCore 
Protocol Deviation Form 
WISER/OnCore 
Follow-up Collection Form 
WISER/OnCore 
Study Incomplete/Withdrawal Form 
WISER/OnCore 
Withdrawal of Consent 
WISER/OnCore 
Survival Form 
WISER/OnCore 
Off-Treatment Form 
WISER/OnCore 

 
A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
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WFBCCC # 62718 
 
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Solution preparation:   
Reconstitution of KEYTRUDA for Injection (Lyophilized Powder) • Add 2.3 mL of 
Sterile Water for Injection, USP by injecting the water along the walls of the vial 
and not directly on the lyophilized powder (resulting concentration 25 mg/mL). 
 
Slowly swirl the vial. Allow up to 5 minutes for the bubbles to clear. Do not shake 
the vial. 
 
Preparation for Intravenous Infusion 
Visually inspect the solution for particulate matter and discoloration prior to 
administration. The solution is clear to slightly opalescent, colorless to slightly 
yellow. Discard the vial if visible particles are observed. 
 
Dilute KEYTRUDA injection (solution) or reconstituted lyophilized powder prior to 
intravenous administration. 
 
Withdraw the required volume from the vial(s) of KEYTRUDA and transfer into an 
intravenous (IV) bag containing 0.9% Sodium Chloride Injection, USP or 5% 
Dextrose Injection, USP. Mix diluted solution by gentle inversion. The final 
concentration of the diluted solution should be between 1 mg/mL to 10 mg/mL. 
 
Discard any unused portion left in the vial 
 
Storage requirements:   
 
Do not freeze. The product does not contain a preservative. Store the 
reconstituted and diluted solution from the KEYTRUDA 50 mg vial either: 
• At room temperature for no more than 6 hours from the time of reconstitution. 
This includes room temperature storage of reconstituted vials, storage of the 
infusion solution in the IV bag, and the duration of infusion. 
 
• Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from 
the time of reconstitution. If refrigerated, allow the diluted solution to come to 
room temperature prior to administration. 
 
Store the diluted solution from the KEYTRUDA 100 mg/4 mL vial either: 
• At room temperature for no more than 6 hours from the time of dilution. This 
includes room temperature storage of the infusion solution in the IV bag, and the 
duration of infusion. 
• Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from 
the time of dilution. If refrigerated, allow the diluted solution to come to room 
temperature prior to administration. 
 
Stability:   
Include the stability of the original dosage form, reconstituted solution, and final 
diluted product, as applicable 
 
Route of administration:   
Administer infusion solution intravenously over 30 minutes through an 
intravenous line containing a sterile, non-pyrogenic, low-protein binding 0.2 
micron to 5 micron in-line or add-on filter. Do not co-administer other drugs 
through the same infusion line. 
 
Disposal:   
Dispose of per the Wake Forest waste stream 

 
A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
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WFBCCC # 62718 
 
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12.0 
Laboratory Correlative Studies 
12.1 
Future exploratory blood biomarker studies 
Wake Forest (the sponsor) will conduct future biomedical research on blood and 
tumor tissue samples collected during this clinical trial. This research may include 
genetic analysis to be used for exploratory biomarker testing or analysis of 
circulating tumor cell DNA.   
  
Samples will be stored in the Wake Forest biorepository    
  
Common side effects of a biopsy or blood draw are a small amount of bleeding at 
the time of the procedure, pain at the biopsy site, which can be treated with 
regular pain medications, and bruising. Rarely, an infection can occur. In the 
event of recurrence, an additional biopsy to confirm the pathology of disease is 
strongly recommended.  In the event that a biopsy is performed, as part of 
standard of care, a portion of the tumor sample will be sent to the Wake Forest 
Tumor Bank. 
  
Submission of blood and tissue samples for future biomedical research is a 
required component of this protocol.   
  
Two tubes of whole blood will be collected via routine blood draw and saved for 
future exploratory biomarker studies, These may be collected at time of 
registration or any time prior to initiating any protocol directed therapy and at the 
1 month follow up +/- 2 weeks.  Patients would routinely have standard 
bloodwork performed at these time points off protocol and this will not require 
extra visits.    
13.0 
Statistical Considerations 
13.1 
Power and Sample size 
 
Based on previously published research and clinical experience, the predicted 
median progression-free survival (PFS) of patients treated with consolidation 
immunotherapy without SBRT is roughly 8 months24 measured from date of first 
chemo-immunotherapy treatment.  We estimate that, considering this 8 month 
median survival in the “control” arm, with our projected sample size of 112 
patients (randomized 2:1 to SBRT + immunotherapy vs immunotherapy alone), 
and considering a two-sided alpha of 0.05 and power of 0.80, that we will be able 
to detect a median survival of approximately 15 months from start of chemo-
immunotherapy in the SBRT + immunotherapy arm. This calculation assumes a 
54 month accrual period and a 5 year total follow-up period. This difference in 
median survivals (8 months vs 15 months) corresponds to a hazard ratio of 0.53. 
Randomization will be stratified by number of metastatic sites (1-3, 4-6, or 7-8.) 
 
Given the design of this trial, not all enrolled patients will be eligible for 
subsequent randomization.  We estimate that ~10% may have evidence of 
progression of disease on restaging with PET/MRI.  Such patients would remain 
on study, but will only be followed for survival.  Given this potential for a 10% 
decrease in randomizable patients, the final number needed to enroll is 125 , in 
order to randomize 112.  
13.2 
Estimated Accrual Rate 
We estimate that we will accrue roughly 1 - 4 patients per month. 
 
 
 

 
A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62718 
 
Protocol version date 04/01/22 
  
 
 
 
 
                                         Page 33 of 52 
  
13.3 
Estimated Study Length 
We estimate approximately 4- 5 years for total enrollment.  Data will be collected 
until patient death or for a period of 5 years whichever occurs first. 
 
13.4 
Interim Analysis Plan  
We have no planned formal interim analyses; however when we reach 50% of 
our planned accrual if 25% or greater have reached G3 or higher pneumonitis we 
will halt the study.   
14.0 
Data Analysis 
14.1 
Analysis of Primary Objective 
Actuarial progression-free survival will be determined using the product-limit 
method of Kaplan and Meier. We will compare unadjusted median PFS between 
the 2 arms using a log-rank test.  We will also use a proportional hazards model 
to compare progression-free survival between the two groups, adjusting for key 
covariates such as age, performance (ECOG) status, response to initial systemic 
therapy vs stable disease, the presence or absence of brain metastases, PD-L1 
expression (< 1% vs > 50%), tumor histology (adenocarcinoma vs non-
adenocarcinoma),  number of disease sites treated (1-3 sites vs 4-6 sites vs 7-8 
sites) and length of time between date of first chemotherapy-immunotherapy 
treatment and randomization date..  
 
14.2  
Analysis of Secondary Objective 
 
 
 
The proportions with local control (LC) of SBRT-treated lesions, and overall 
survival (OS) parameter estimates, both secondary outcomes, will be first 
examined in simple univariate and bivariate analyses (e.g., means, medians, 
85% confidence intervals around key parameter estimates.).   LC will be 
assessed only in patients with at least 4-months of radiographic follow -up. The 
reason for specifying a minimum of 4 months follow-up to score LC was to avoid 
uncertainty associated with early transient radiographic changes within the high 
dose region; patients who died without a minimum of 4 months post-SBRT 
imaging study follow-up are not considered evaluable for LC but are evaluable for 
PFS and OS.34-37   
 
Data will be collected for planned subset analysis of in-field local control of 
irradiated sites, progression-free and overall survival according to (1) tumor 
histology (adenocarcinoma vs other histology) and (2) response to initial 
chemotherapy (response vs stable disease). 
 
In all randomized patients, time to progression at known sites of disease, as well 
as time to development of new disease sites, and number of new disease sites 
will be collected.    
 
Overall survival comparison between the two randomized groups will be 
assessed with methods analogous to PFS described above in 13.1.  Additionally, 
we will also examine OS in the group of patients who were enrolled but not 
randomized; however, we will not conduct statistical comparisons of this group 
with either randomized group. 
 
All safety measures, including acute and late toxicity, will be reported using 
descriptive statistics (mean, median, SD, proportions, and 95% confidence 
intervals). This will include calculating frequency/risk of adverse events by 
treatment site. Potential toxicities reported would include pneumonitis, 
esophagitis, chest wall pain, dermatologic toxicity, renal dysfunction, 
gastrointestinal toxicity including nausea, vomiting, and diarrhea, hepatotoxicity, 
and abdominal pain. These toxicities would be assessed according to site of 
irradiation by the treating physician and graded as per CTCAE 5. 

 
A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62718 
 
Protocol version date 04/01/22 
  
 
 
 
 
                                         Page 34 of 52 
  
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small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. Lancet Oncol. 2016;17(12):1672-
1682. 
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Belani CP, Schreeder MT, Steis RG, et al. Cetuximab in combination with carboplatin and docetaxel for patients with metastatic or advanced-stage nonsmall cell 
lung cancer: a multicenter phase 2 study. Cancer. 2008;113(9):2512-2517. 
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Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol. 1995;13(1):8-10. 
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Weichselbaum RR, Hellman S. Oligometastases revisited. Nat Rev Clin Oncol. 2011;8(6):378-382. 
6. 
Rusthoven KE, Hammerman SF, Kavanagh BD, Birtwhistle MJ, Stares M, Camidge DR. Is there a role for consolidative stereotactic body radiation therapy 
following first-line systemic therapy for metastatic lung cancer? A patterns-of-failure analysis. Acta Oncol. 2009;48(4):578-583. 
7. 
Cheruvu P, Metcalfe SK, Metcalfe J, Chen Y, Okunieff P, Milano MT. Comparison of outcomes in patients with stage III versus limited stage IV non-small cell lung 
cancer. Radiat Oncol. 2011;6:80. 
8. 
De Ruysscher D, Wanders R, van Baardwijk A, et al. Radical treatment of non-small-cell lung cancer patients with synchronous oligometastases: long-term results 
of a prospective phase II trial (Nct01282450). J Thorac Oncol. 2012;7(10):1547-1555. 
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Collen C, Christian N, Schallier D, et al. Phase II study of stereotactic body radiotherapy to primary tumor and metastatic locations in oligometastatic nonsmall-cell 
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Petty WJ, Urbanic JJ, Ahmed T, et al. Long-Term Outcomes of a Phase 2 Trial of Chemotherapy With Consolidative Radiation Therapy for Oligometastatic Non-
Small Cell Lung Cancer. Int J Radiat Oncol Biol Phys. 2018;102(3):527-535. 
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Iyengar P, Wardak Z, Gerber DE, et al. Consolidative Radiotherapy for Limited Metastatic Non-Small-Cell Lung Cancer: A Phase 2 Randomized Clinical Trial. 
JAMA Oncol. 2018;4(1):e173501. 
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Flannery TW, Suntharalingam M, Regine WF, et al. Long-term survival in patients with synchronous, solitary brain metastasis from non-small-cell lung cancer 
treated with radiosurgery. Int J Radiat Oncol Biol Phys. 2008;72(1):19-23. 
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Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 2017;377(20):1919-1929. 
14. 
Kang SP, Gergich K, Lubiniecki GM, et al. Pembrolizumab KEYNOTE-001: an adaptive study leading to accelerated approval for two indications and a companion 
diagnostic. Ann Oncol. 2017;28(6):1388-1398. 
15. 
Kazandjian D, Suzman DL, Blumenthal G, et al. FDA Approval Summary: Nivolumab for the Treatment of Metastatic Non-Small Cell Lung Cancer With 
Progression On or After Platinum-Based Chemotherapy. Oncologist. 2016;21(5):634-642. 
16. 
Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev. 2010;236:219-242. 
17. 
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252-264. 
18. 
Kim S, Koh J, Kwon D, et al. Comparative analysis of PD-L1 expression between primary and metastatic pulmonary adenocarcinomas. Eur J Cancer. 
2017;75:141-149. 
19. 
Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443-2454. 
20. 
Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373(2):123-
135. 
21. 
Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): 
a randomised controlled trial. Lancet. 2016;387(10027):1540-1550. 
22. 
Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 
2016;375(19):1823-1833. 
23. 
Apetoh L, Ladoire S, Coukos G, Ghiringhelli F. Combining immunotherapy and anticancer agents: the right path to achieve cancer cure? Ann Oncol. 
2015;26(9):1813-1823. 
24. 
Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med. 
2018;378(22):2078-2092. 
25. 
Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. N Engl J Med. 2018;379(21):2040-2051. 
26. 
Demaria S, Formenti SC. Role of T lymphocytes in tumor response to radiotherapy. Front Oncol. 2012;2:95. 
27. 
Golden EB, Frances D, Pellicciotta I, Demaria S, Helen Barcellos-Hoff M, Formenti SC. Radiation fosters dose-dependent and chemotherapy-induced 
immunogenic cell death. Oncoimmunology. 2014;3:e28518. 
28. 
Herter-Sprie GS, Koyama S, Korideck H, et al. Synergy of radiotherapy and PD-1 blockade in Kras-mutant lung cancer. JCI Insight. 2016;1(9):e87415. 
29. 
Formenti SC, Demaria S. Radiation therapy to convert the tumor into an in situ vaccine. Int J Radiat Oncol Biol Phys. 2012;84(4):879-880. 
30. 
Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a 
randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016;17(11):1497-1508. 
31. 
Luke JJ, Lemons JM, Karrison TG, et al. Safety and Clinical Activity of Pembrolizumab and Multisite Stereotactic Body Radiotherapy in Patients With Advanced 
Solid Tumors. J Clin Oncol. 2018;36(16):1611-1618. 
32. 
Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002;346(2):92-
98. 
33. 
Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients 
with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26(21):3543-3551. 
34. 
Henderson MA, Hoopes DJ, Fletcher JW, et al. A pilot trial of serial 18F-fluorodeoxyglucose positron emission tomography in patients with medically inoperable 
stage I non-small-cell lung cancer treated with hypofractionated stereotactic body radiotherapy. Int J Radiat Oncol Biol Phys. 2010;76(3):789-795. 
35. 
Herfarth KK, Hof H, Bahner ML, et al. Assessment of focal liver reaction by multiphasic CT after stereotactic single-dose radiotherapy of liver tumors. Int J Radiat 
Oncol Biol Phys. 2003;57(2):444-451. 
36. 
Matsuo Y, Nagata Y, Mizowaki T, et al. Evaluation of mass-like consolidation after stereotactic body radiation therapy for lung tumors. Int J Clin Oncol. 
2007;12(5):356-362. 
37. 
Schefter TE, Kavanagh BD, Timmerman RD, Cardenes HR, Baron A, Gaspar LE. A phase I trial of stereotactic body radiation therapy (SBRT) for liver metastases. 
Int J Radiat Oncol Biol Phys. 2005;62(5):1371-1378. 
 
 
 
 
 
 
 
 
 
 
 
 

 
A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62718 
 
Protocol version date 04/01/22 
  
 
 
 
 
                                         Page 35 of 52 
  
Appendix A: Enrollment Eligibility Checklist  
 
 
IRB 
Protocol 
No.  
 
WFBCCC 
Protocol  
No. 
62718 
Study Title: A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or 
Stereotactic Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
Principal Investigator:  Michael Farris, M.D. 
 
ENROLLMENT 
• Patients are eligible for enrollment if they have metastatic NSCLC and have undergone at least 4 cycles of upfront standard of 
care systemic therapy.    Patients must have a CT chest abdomen pelvis (ideally with IV contrast) performed after the point of 
completion of 4 cycles of standard of care systemic therapy, but no later than 180 days from the first day of systemic therapy.  
This CT scan must be completed within 180 days of the first day of systemic therapy, and must demonstrate no evidence of 
disease progression per RECIST v1.1. 
 
• Patients may start their standard of care maintenance immunotherapy at the discretion of their treating medical oncologist prior 
to enrollment. Patients must be enrolled AND randomized no later than 180 days from the first day of cycle 1 of standard of 
care systemic therapy. The first day of cycle 1 of systemic therapy is considered day # 1.  At most, an additional 179 days may 
elapse from this point to remain eligible for inclusion on this study.   
 
RANDOMIZATION 
• Once enrolled, patients will have a restaging PET/MRI brain (exceptions below) 
   If restaging scans demonstrate ≤ eight sites of non-progressive active residual disease, then patients are eligible       
   for randomization.  If restaging scans demonstrate progression of disease, then these patients will not be   
   eligible for randomization, but will be followed by their primary medical oncologist or radiation oncologist every 3  
   months for overall survival only.       
 
          * If a PET has been performed within 30 days of enrollment with no evidence of progression  
             per RECIST v1.1, then this scan may be used and does not have to be repeated prior to randomization 
 
          * If an MRI brain has been performed within 90 days of enrollment with no evidence of progression per  
             RECIST v1.1, then this scan may be used and does not have to be repeated prior to randomization 
 
• Randomization should occur within 21 days of enrollment. 
• Once randomized, protocol directed therapy should occur within 21 days from randomization  
(ie. start of consolidative RT or resumption of maintenance immunotherapy) 
 
If randomized to consolidative radiation therapy then maintenance immunotherapy:  
Maintenance immunotherapy may NOT be delivered concurrently with consolidative radiation. Concurrently is defined as on the 
same day of any radiation treatment or on any day between the first and last treatment of radiation.  Resumption of maintenance 
immunotherapy after completion of radiation therapy is at the discretion of the treating medical oncologist. They may resume 
maintenance immunotherapy as early as 24 hrs after the last radiation treatment, but resumption should be no later than 8 weeks 
from the last radiation treatment.  If treatment related toxicities prohibit administration of maintenance immunotherapy, then 
restarting this therapy is at the discretion of the treating medical oncologist.  In such cases, patients will remain on study until 
they experience progression or death. If they experience progression, patients will be followed for overall survival only per 
appendix L past the point of progression.  
 
If randomized to continued maintenance immunotherapy alone:  
Patients will begin or resume maintenance immunotherapy no later than 21 days following randomization. 
 
 
 
 
 
 
 
 

 
A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62718 
 
Protocol version date 04/01/22 
  
 
 
 
 
                                         Page 36 of 52 
  
Inclusion Criteria 
(as outlined in study protocol section 3.0) 
Must answer yes to all questions below, otherwise 
patient is not eligible 
Criterion is 
met 
Criterion is 
NOT met 
Source Used to 
Confirm * 
Document dates 
and lab results 
18 years or older  
□ 
□ 
 
Performance Status 0-2 (ECOG)  
at time of consult with radiation oncology 
□ 
□ 
 
Pathologically proven NSCLC  
with evidence of metastatic disease 
□ 
□ 
 
Must have received 4 cycles of standard of care systemic therapy, 
with a CT chest abdomen pelvis that was performed after 
completion of these 4 cycles and demonstrates no evidence of 
progression per RECIST v1.1 
□ 
□ 
 
To be eligible for enrollment and randomization, patients must be 
within 180 days from their first dose of systemic therapy.  Cycle 1 
day 1 is defined as day 1.  If enrolled on day 180, the patient would 
need to be randomized the same day. 
□ 
□ 
 
Persistent active disease must be amenable to radiation treatment 
per the treating radiation oncologist, and patients must have at 
least one residual site of disease which can be identified by CT or 
PET/CT and targeted with radiation. 
□ 
□ 
 
Patients who previously had earlier stage NSCLC treated 
definitively and have now developed new distant disease, are 
eligible for inclusion if they have undergone at least 4 cycles of 
chemo-immunotherapy for their metastatic recurrence, and they 
meet all criteria above. 
□ 
□ 
 
There are no strict size or tumor number limitations in a given organ 
(lung, liver, abdomen pelvis, or spine).  This is at the discretion of 
the treating radiation oncologist. 
□ 
□ 
 
Exclusion Criteria 
(as outlined in study protocol) 
Criteria NOT 
present 
Criteria is 
present 
Source Used to 
Confirm * 
More than 180 days has elapsed since day 1 of cycle 1 of systemic 
therapy. 
□ 
□ 
 
Pregnant or lactating women 
□ 
□ 
 
The patient has received treatment for other carcinomas within the 
last three years (Except for cured non-melanoma skin cancer, low-
risk prostate cancer, T1/T2 glottic cancer, stage 0 or stage I breast 
cancer, non-invasive bladder cancer, or treated in-situ cervical 
cancer).  Prior lung cancer diagnosis now with oligometastatic 
recurrence is not an exclusion criteria. 
□ 
□ 
 
Patients with major activating mutations in EGFR (del19, L858R, and 
T790M) or ROS 1 or ALK gene rearrangements are excluded 
 
□ 
 
□ 
 
Patient eligibility for immunotherapy is at the discretion of the treating medical oncologist. 
Immunologic conditions including Lupus, rheumatoid arthritis, psoriasis or other conditions requiring immune suppression are NOT strict exclusions 
 
This subject is      
 eligible / 
 ineligible     for enrollment in this study. 
 
OnCore Assigned PID: ___ ___ ___ ___ ___ ___ ___ ___ 
 
 
 
 
 
 
 
 
Signature of research professional confirming eligibility: _______________________  
Date: ___ ___ / ___ ___ / ___ ___ (MM/DD/YYYY) 
 
Signature of Treating Physician:  _____________________________________  
Date:  ___ ___ / ___ ___ / ___ ___ (MM/DD/YYYY) 
 
Signature of Principal Investigator**:  _____________________________________  
Date:  ___ ___ / ___ ___ / ___ ___ (MM/DD/YYYY) 
 
* Examples of source documents include clinic note, pathology report, laboratory results, etc. When listing the source, specifically 
state which document in the medical record was used to assess eligibility. Also include the date on the document. Example: 
“Pathology report, 01/01/14” or “Clinic note, 01/01/14” **Principal Investigator signature can be obtained following registration if 
needed 
 

 
A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62718 
 
Protocol version date 04/01/22 
  
 
 
 
 
                                         Page 37 of 52 
  
Appendix B: Protocol Registration 
DEMOGRAPHICS 
Patient: Last Name: _____________________ 
First Name: ___________________________ 
MRN:          ___ ___ ___ ___ ___ ___ ___ ___ 
DOB __ __/__ __/__ __ (MM/DD/YYYY) 
ZIPCODE:  
___ ___ ___ ___ ___ 
 
 
SEX:   
 
 Male     
 Female 
Ethnicity (choose one):   
 Hispanic 
 Non-Hispanic 
Race (choose all that apply): 
 WHITE           
 BLACK           
 ASIAN 
 PACIFIC ISLANDER                
  NATIVE AMERICAN 
Height:   ___ ___.___ inches 
Weight: ___ ___ ___.___lbs.(actual) 
Surface Area: ___ ___.___m2   
 
Primary Diagnosis: ____________________________________________________________ 
Date of Diagnosis: __ __/__ __/__ __ (MM/DD/YYYY) 
 
Performance Status: ___  ECOG   
 
Protocol Registrar can be contact by calling 336-713-6767 between 8:30 AM and 4:00 PM, Monday – Friday. 
Compete the eligibility checklist in WISER and then give the completed Eligibility Checklist and Protocol Registration 
Form must be hand delivered, faxed or e-mailed to the registrar at 336-713-6772 or registra@wakehealth.edu, 
respectively. 
 
PROTOCOL INFORMATION 
Date of Registration: 
__ __/__ __/__ __ (MM/DD/YYYY) 
MD Name (last) : 
______________________       
Date protocol treatment started: 
___ ___ / ___ ___ / ___ ___ 
Informed written consent: 
(consent must be signed prior to registration) 
 YES  
 NO 
 
Date Consent Signed: 
___ ___ / ___ ___ / ___ ___ 
 
PID # (to be assigned by OnCore): 
___ ___ ___ ___ ___ ___ ___ ___ 
 
 
 

 
A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62718 
 
Protocol version date 04/01/22 
  
 
 
 
 
                                         Page 38 of 52 
  
Appendix C: Eligibility for Randomization 
Randomize within 21 days of enrollment 
 
OnCore Assigned PID: ___ ___ ___ ___ ___ ___ ___ ___ 
 
 
This subject is      
 eligible / 
 ineligible for randomization in this study. 
 
 
 
 
 
 
 
 
 
Signature of research professional confirming eligibility for randomization : _______________________  
Date: __ __/__ __/__ __ (MM/DD/YYYY) 
 
Signature of Treating Physician:  _____________________________________  
Date:  __ __/__ __/__ __ (MM/DD/YYYY) 
Signature of Principal Investigator**:  _____________________________________  
Date:  __ __/__ __/__ __ (MM/DD/YYYY) 
 
Appendix D: Numbering Sites of Disease  
 
Completed prior to randomization by the treating radiation oncologist 
 
How many total active sites of persistent disease are present after PET/MRI restaging _____   
 
 
Location and number of extracranial disease sites to be treated 
_________________________________________________ 
 
 
CNS lesions (Y/N)______ managed w resection/SRS ______ (Y/N) 
Signature _________________________  Date________________ 
 
 
Appendix E: Radiotherapy Technical Parameters   
 
Radiotherapy Technical Parameters/Data Collection Form completed by the treating radiation oncologist  
The following information will be collected for EACH extra cranial tumor treated with radiation 
 
 
Tumor Location (side/lobe if applicable): 
 
Dose Prescribed (Gy):   
 
Total number of fractions: 
 
Treatment volumes (cm3):    
GTV: 
PTV:  
% PTV receiving prescribed dose: 
 
Volume of isodose for 50% prescription dose:  
 
Volume of isodose for 100% prescription dose:  
 
Was the plan 3D, VMAT, or IMRT? 
 
 
 
 
 
 
 
 
 

 
A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62718 
 
Protocol version date 04/01/22 
  
 
 
 
 
                                         Page 39 of 52 
  
Appendix F: 30-day Treatment Follow-up Form 
Definition of 1 mo. or 30 day followup 
1. 
For patients randomized to RT, this time point is considered 30 days +/- 14 days from end of all radiation therapy 
treatments 
2. 
For patients randomized to immunotherapy alone, this time point is considered 30 days +/- 14 days from the end of the 
2nd cycle of on protocol maintenance immunotherapy 
 
 
Study Number: __ __ __ __ __ 
PID: ___ ___ ___ ___ ___ ___ ___ ___ 
 
Investigator: Michael Farris M.D. 
Date: __ __/__ __/__ __ (MM/DD/YYYY) 
Instructions: Complete this form to follow-up with patients for adverse events.  
 
Name of Person Competing form_____________________________ 
 
Did the subject have any adverse events in the last 30 days?   Yes 
   No 
 
If yes, please report on AE log in WISER  
(Note*: If an SAE occurs in this period, report the event as required in Appendix S ): 
 
 
Was the subject removed from the study?  Yes 
   No 
 
If yes, complete the Off-Study Form 
 
Did the subject withdraw from the study?  Yes 
   No 
 
If Yes, complete the Withdrawal of Consent Form 
 
 

 
A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62718 
 
Protocol version date 04/01/22 
  
 
 
 
 
                                         Page 40 of 52 
  
Appendix G: Treatment Response Evaluation 
 
 
 
Study Number: __ __ __ __ __ 
PID: ___ ___ ___ ___ ___ ___ ___ ___ 
 
Investigator: Michael Farris, M.D. 
__ __/__ __/__ __ (MM/DD/YYYY) 
 
Study Visit: 
 
 After first-line systemic therapy 
 Follow-Up: __ __/__ __/__ __ (MM/DD/YYYY) 
 Other visit: (please specify) ________________ 
 
Date of Scan: __ __/__ __/__ __ (MM/DD/YYYY) 
 
Imaging Modality: 
 CT 
 PET/CT 
 MRI  
 Other____________  
 
Evaluation of Target Lesions 
 
   Complete Response (CR) 
 
   Partial Response (PR) 
 
   Progressive Disease (PD):  
 
   Stable Disease (SD) 
 
   NE  
 
Evaluation of Non-Target Lesions 
 
   Complete Response (CR) 
 
   Non-CR/Non-PD 
 
   Progressive Disease (PD):  
 
   NE  
 
Overall Response this Visit 
   Complete Response (CR) 
   Partial Response (PR) 
 
   Progressive Disease (PD):  Date of progression ___ ___ /___ ___ /___ ___ 
 
   Stable Disease 
 
   NE 
 
 
Treating Physician Signature: ______________________ 
Date: ___ ___ /___ ___ /___ ___ 
 
PI Signature: ___________________________________ 
Date: ___ ___ /___ ___ /___ ___ 
 
 
 

 
A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62718 
 
Protocol version date 04/01/22 
  
 
 
 
 
                                         Page 41 of 52 
  
Appendix H: NCI Comorbidity 
 
Instructions: Fill this form out to record comorbidities. 
 
1. 
Medical Comorbidities 
 Acute Myocardial Infarction (1) 
 History of Myocardial Infarction (1) 
 Congestive Heart Failure (1) 
 Peripheral Vascular Disease (1) 
 Cerebrovascular Disease (1) 
 Chronic Obstructive Pulmonary Disease (COPD) (1) 
 Dementia (1) 
 Paralysis (Hemiplegia or Paraplegia) (2) 
 Diabetes (1) 
 Diabetes with Complications (2) 
 Renal Disease (2) 
 Mild Liver Disease (1) 
 Moderate/Severe Liver Disease (3) 
 Peptic Ulcer Disease (1) 
 Rheumatologic Disease (1) 
 AIDS (6) 
 
(Additional):_______________________________________________________________________ 
 
Appendix  I: Pulmonary Function Testing 
 
 
 
  
PID Number ___________________ 
 
  
DOB _________________________ 
1. Date of Test 
/              /       
 
5. Forced Vital Capacity (FVC):    ______Liters 
6. Observed Forced Expiratory Volume in first second (FEV1):    _______Liters 
7. Predicted FEV1:  _______Liters 
8. % Predicted FEV1:   _______% 
9. DLCO/VA:  _______% 
 
 
 
 

 
A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62718 
 
Protocol version date 04/01/22 
  
 
 
 
 
                                         Page 42 of 52 
  
Appendix J: Follow-up Collection Form 
  
PID Number ___________________ 
 
DOB __________________________ 
1. Date of follow-up 
   
__ __/__ __/__ __ (MM/DD/YYYY) 
2.  Visit Interval           
 
Interval from date of day 1 of cycle 1 of chemo immunotherapy: _____________days  
 
3.  Were there any delayed patient complications related to the radiotherapy procedure since the 
last visit?  Y*/N 
      If yes, complete AE form 
                                 
4. Since the last visit have there been any additional chemotherapy?  Y*/N 
                                
     If yes, specify agents used: 
  
5.  ECOG Performance Status ___________ 
  
 
6. Weight (lbs) ___________ 
 
7. Height (inches) __________ 
 
 
 
 
 
NEW THERAPIES 
8. Is the patient receiving any new therapies for lung cancer? Y*/N 
 
    If yes, what therapies specifically   __________ 
 
                                 
Appendix K: Progression of Disease 
 
Has there been progression of disease _____ (Y/N)  
 
Date of progression: __ __/__ __/__ __ (MM/DD/YYYY) 
 
For patients randomized to the radiation arm:  
Is progression inside or outside prior RT field (defined by 50% Isodose line)  _____________ 
Organ site of progression? _____________ 
For patients randomized to the immunotherapy alone arm: 
Is progression at a site of disease that was present prior to first line chemo-immunotherapy   _____________ 
 
 
 
 
 

 
A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62718 
 
Protocol version date 04/01/22 
  
 
 
 
 
                                         Page 43 of 52 
  
Appendix L: Survival Form 
Instructions: Fill this form out at protocol indicated survival assessments 
 
1. 
Last known Survival Status:  
 Alive 
 Dead 
 Lost to Follow-up: Date of last contact  __ __/__ __/__ __ (MM/DD/YYYY) 
 
2. 
Expired Date __ __/__ __/__ __ (MM/DD/YYYY) 
Is this an approximate date? 
 Yes 
 No 
 
3. 
Last known Alive Date __ __/__ __/__ __ (MM/DD/YYYY)            
 
4. 
Survival Status source: __________________________________________ 
Instructions: Source can be EMR, obituary, family member etc. Phone call with patient 
Add to comments in WISER follow-up section 
 
5. 
Comment:____________________________________________________________________ 
 
Appendix M: Study Withdrawal 
  
PID Number ___________________ 
 
DOB __________________________ 
1. Date Study Treatment Stopped or Withdrawal 
__ __/__ __/__ __ (MM/DD/YYYY)            
2. Please check ONE of the following: 
  Patient did not complete radiation therapy 
   Patient withdrew or discontinued early 
3. If withdrawn or discontinued early, indicate ONE primary below: 
 Patient registered but not treated:   Specify reason: __________ 
 Radiotherapy attempted, but not completed 
 Progression during treatment 
 Unanticipated Adverse Event/Serious Adverse Event 
 Patient Died:  Date of Death __ __/__ __/__ __ (MM/DD/YYYY)           
   Unknown date 
             
Specify Cause of Death: ________________________________ 
   Unknown cause 
 Lost to follow-up:      Date of Last Contact __ __/__ __/__ __ (MM/DD/YYYY)            
 Unknown :    Date Last Known to be Alive __ __/__ __/__ __ (MM/DD/YYYY)             
 Patient no longer willing to participate in study 
 

 
A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62718 
 
Protocol version date 04/01/22 
  
 
 
 
 
                                         Page 44 of 52 
  
Appendix N: Withdrawal of Consent  
 
 
 
Withdrawal of consent for the intervention and medical record use 
 
 I withdraw consent for further study intervention/treatment.  
 
Yes   
No Initials: ______ 
 
 I withdraw from further research activities (surveys, questionnaires, research assessments and other non-invasive research 
activities).  
 
Yes   
No Initials: ______ 
 I withdraw my consent to allow the further collection of research-related information from my medical record to be used in this 
research.  
 
Yes  
No Initials: ______ 
 Specimen collection/use withdrawal ( no research specimen collection, skip section) 
 I withdraw my consent for any use of my specimen for this current research.  
 
Yes 
 No Initials: ______ 
 I withdraw my consent for any use of my specimen for future research.  
 
Yes 
No Initials: ______ 
 I acknowledge that any data or deidentified materials that have already been created from my specimen may still be used for 
research.   
Initials: ______ 
Patient signature: ________________________________    Date  __ __/__ __/__ __ (MM/DD/YYYY)            
Investigator signature: _____________________________    Date __ __/__ __/__ __ (MM/DD/YYYY)            
 
 
Appendix O: Off-Study Form  
 
 
Study Number: __ __ __ __ __ 
PID: ___ ___ ___ ___ ___ ___ ___ ___ 
 
Investigator: Michael Farris M.D. 
Date __ __/__ __/__ __ (MM/DD/YYYY)            
 
Instructions: Complete this form if the patient has completed or is removed from the study.  
 
Name of Person Competing form_____________________________ 
 
 
Off study date  __ __/__ __/__ __ (MM/DD/YYYY)            
Reason: 
Adverse Event/Side Effects/Complications;  
Death; (if death fill out Survival Form) 
Enrolling Physician Decision;  
Other;  
Patient lost to follow-up; Date of last contact  __ __/__ __/__ __ (MM/DD/YYYY)            
Patient refused follow-up;  
Protocol-defined follow-up completed 
 
Explain________________________________________________________________________________________________
___ 
 
Did the patient withdraw consent to participate in the study?  Yes 
   No 
  
(If Yes, have the patient fill out the Withdrawal of Consent form) 
 

 
A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62718 
 
Protocol version date 04/01/22 
  
 
 
 
 
                                         Page 45 of 52 
  
Appendix P: Protocol Deviation Form  
 
PID Number ___________________ 
                      
DOB __________________________   
Deviation Date:  __ __/__ __/__ __ (MM/DD/YYYY)                    
                
  
Interval from date of day 1 of cycle 1 of chemo immunotherapy: _____________days 
 
 Deviation 
 Patient does not meet inclusion/exclusion criteria: Specify reason for deviation. 
_________________________________________________________________________________________ 
 Patient did not sign informed consent prior to procedure:  Specify reason for deviation. 
_________________________________________________________________________________________ 
 Missed visit:  Specify reason for deviation.  
_________________________________________________________________________________________ 
 Visit not completed per protocol: Specify reason for deviation.  
_________________________________________________________________________________________ 
 Visit out of window: Specify reason for deviation. 
_________________________________________________________________________________________ 
 Missed test, exam: Specify reason for deviation 
_________________________________________________________________________________________ 
 Other, Specify 
_________________________________________________________________________________________ 
Appendix Q: Off Treatment 
 
Instructions: Fill out this form when a patient goes off treatment. 
 
Off Treatment:  
1. 
Off Treatment Date __ __/__ __/__ __ (MM/DD/YYYY)            
2. 
Off Treatment Reason:  
 Adverse Event/Side Effects/Complications 
 Alternative Therapy 
 Cytogenetic resistance 
 Death on Study (if death fill out the Survival Form) 
 Disease progression before active treatment 
 Disease progression, relapse before active treatment 
 Enrolling Physician Decision 
 Lost to follow-up: Date of last contact  __ __/__ __/__ __ (MM/DD/YYYY)            
 No treatment, per protocol criteria 
 Patient off treatment for other complicating disease 
 Patient withdrawal or refusal after beginning protocol therapy 
 Patient withdrawal or refusal prior to beginning protocol therapy 
 Treatment completed per protocol criteria 
 Other 
  
Explain:_______________________________________________________________________________________ 
3. 
Is the patient evaluable for response?  
 Yes 
 No 
 Not assessed 
If No or Not assessed, please explain:_______________________________________________________________ 
 
 
 
 

 
A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62718 
 
Protocol version date 04/01/22 
  
 
 
 
 
                                         Page 46 of 52 
  
Appendix R: Mandatory DSMC SAE Reporting Guidelines 
 
Data and Safety Monitoring Committee 
(DSMC) Serious Adverse Event (SAE) 
Notification SOP 
Date: 02/11/2021 
 
Mandatory DSMC SAE Reporting Requirements in WISER 
This document describes reporting requirements of adverse events from WFBCCC Investigator Initiated interventional 
trials to the Data and Safety Monitoring Committee (DSMC). A trial is considered a WFBCCC Investigator Initiated 
interventional trial if the following criteria are met: 
 
1) 
The Principal Investigator (PI) of the trial is a member of a department at the Wake Forest University 
Baptist Medical Center. 
2) 
WFBCCC is considered as the primary contributor to the design, implementation and/or monitoring of the 
trial. 
3) 
The trial is designated as “Interventional” using the Clinical Research Categories definitions 
provided by the NCI in the Data Table 4 documentation. 
(https://cancercenters.cancer.gov/GrantsFunding/DataGuide#dt4) 
 
There are two distinct types of WFBCCC Investigator Initiated interventional trials based on where patient enrollment 
occurs.  These include: 
 
1) Local WFBCCC Investigator Initiated interventional trials defined as trials where all patients are enrolled from 
one of the WFBCCC sites. These include the main outpatient Cancer Center clinics (located in Winston-Salem) 
as well as WFBCCC affiliate sites located in Bermuda Run (Davie Medical Center), Clemmons, Lexington, High 
Point, or Wilkesboro. 
2) Multi-Center WFBCCC Investigator Initiated interventional trials defined as trials where patients are enrolled 
from other sites in addition to WFBCCC sites.   
There are three types of trials that are included in this category: 
a. Trials sponsored by the NCI Community Oncology Research Program (NCORP) that are conducted at 
multiple sites where the PI is a member of a department at the Wake Forest University Baptist 
Medical Center. 
b. Trials sponsored by Industry that are conducted at multiple sites and the PI is a member of a 
department at the Wake Forest University Baptist Medical Center. 
c. Trials sponsored by WFBCCC that are conducted at multiple sites and the PI is a member of a 
department at the Wake Forest University Baptist Medical Center. 
 
All Adverse Events (AEs) and Serious Adverse Events (SAEs) that occur on any patients enrolled on WFBCCC Investigator 
Initiated Interventional trials must be entered into the WISER system. The only exception to this requirement is for 
patients enrolled on NCORP trials at non- WFBCCC sites. AEs and SAEs for NCORP patients enrolled at WFBCCC sites must 
be entered into the WISER system. Once these AEs and SAEs are entered in WISER, certain actions must be taken 
regarding the reporting of specific Adverse Events to the DSMC. 
 
 
 
All Adverse Events that occur during protocol intervention (defined below) and are coded as either 1) unexpected grade 
4, 2) unplanned inpatient hospitalization > 24 hours (regardless of grade), or grade 5 (death) must be reported to the 
DSMC using the using the SAE console in WISER. 
 
A research nurse or clinical research coordinator when made aware that an adverse event meets one of the above 
criteria has occurred on a WFBCCC Investigator Initiated interventional trial, is responsible for informing a clinical 
member of the DSMC by phone (or in-person) about the adverse event. The nurse/coordinator should contact the 
treating physician prior to calling the DSMC clinical member to obtain all details of the SAE, as well as all associated 

 
A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62718 
 
Protocol version date 04/01/22 
  
 
 
 
 
                                         Page 47 of 52 
  
toxicities to be recorded along with the SAE. In addition, this nurse or coordinator is responsible for entering the adverse 
event information into the SAE console in WISER.  Once the adverse event has been entered into the SAE console an 
email informing the entire DSMC will be generated. 
 
THESE REPORTING REQUIREMENTS APPLY TO any staff member on the study team for a WFBCCC Institutional 
Interventional trial. Ultimately, the protocol PI has the primary responsibility for AE identification, documentation, 
grading and assignment of attribution to the investigational agent/intervention. However, when an AE event as 
described above is observed, it is the responsibility of the person who observed the event to be sure that it is reported 
to the DSMC. 
 
What is considered during protocol intervention? 
During protocol intervention is considered to be the time period while a patient is on study treatment or during the time 
period within 30 days of last study treatment (even if patient begins a new (non-study) treatment during the 30 days). This 
window of 30 days should be the standard window to be used in all protocols unless a specific scientific rationale is 
presented to suggest that a shorter window can be used to identify events. If it is a trial sponsored by Industry and the 
sponsor requires a longer window for monitoring of SAEs, then the longer window of time specified by the sponsor should 
be followed. 
 
What is considered as an Unexpected Grade 4 event? 
Any grade 4 event that was not specifically listed as an expected adverse event in the protocol should be considered as 
unexpected. A grade 4 adverse event can be considered to be unexpected if it is an event that would not be expected based 
on the treatment being received or if it is unexpected based on the health of the patient. In either case, if there is any 
uncertainty about whether a grade 4 adverse event is expected or unexpected it should be reported to DSMC. 
 
DSMC notification responsibilities of the person (e.g., nurse) handling the reporting/documenting of the SAE in WISER: 
1. Make a phone call (or speak in person) to the appropriate clinical member of the DSMC according to the 
schedule as listed below (page if necessary). 
2. Enter a new SAE into the SAE module that is located in the Subject>> CRA Console in WISER WITHIN 24 HOURS of 
first knowledge of the event. Information can be entered and saved, but the DSMC members will not be 
notified until a date is entered into the  DSMC Notification Date Field. This will ensure that all persons that need 
to be made aware of the event (i.e., PI, study team members and DSMC members) will be notified; remember to 
file a copy of the confirmation. 
3. Document that the appropriate person(s) on the DSMC has been contacted. Indicate the name of the DSMC 
clinician that was contacted and the date and time contacted in the Event Narrative field in the SAE console of the 
particular subject. 
4. Document whether or not the protocol should be suspended based on the discussion with the DSMC clinician. 
This is the major function of the email notification. Enter whether the protocol should be suspended in the Event 
Narrative Field. 
5. Follow up/update the clinical member(s) of DSMC regarding any new developments or information obtained 
during the course of the SAE investigation and reporting process. 
 
Elements needed to complete the SAE form in the Subject Console in WISER (see Screen Shot 3): 
1. Event Date 
2. Reported Date 
3. Reported by 
4. If Grade 5, enter Death Date 
5. If Grade 5, enter Death occurred: within 30 days 
6. Event Narrative: Brief description (include brief clinical history relevant to this event, including therapies believed 
related to event). Begin narrative with the DSMC clinician who was notified and Date/Time notified. In addition, 
state attribution by DSMC clinician as either “Unrelated”, “Unlikely”, “Possibly”, “Probably”, or “Definitely”.  
Always include the following here: 
i. 
DSMC clinician name, date/time contacted and comments 
ii. Date of last dose before the event 

 
A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62718 
 
Protocol version date 04/01/22 
  
 
 
 
 
                                         Page 48 of 52 
  
iii. Is suspension of the protocol needed? Y/N 
7. Treating Physician comments 
8. PI comments, if available 
9. Protocol Attribution after discussion with DSMC clinician 
10. Outcome (Fatal/Died, Intervention for AE Continues, Migrated AE, Not Recovered/Not Resolved, 
Recovered/Resolved with Sequelae, Recovered/Resolved without Sequelae, Recovering and Resolving) 
11. Consent form Change Required? Y/N 
12. SAE Classification *This is required in order for the email notification to be sent* 
13. Adverse Event Details – Enter all details for each AE associated with the SAE. 
a. Course start date 
b. Category 
c. AE Detail 
d. Comments 
e. Grade/Severity 
f. 
Unexpected Y/N 
g. DLT Y/N 
h. Attributions 
i. 
Action 
j. 
Therapy 
k. Click ADD to attach the AE Detail to the SAE. 
14. Enter Date Notified DSMC -- *This is required for the email notification to be sent* 
15. Click Submit. The auto-generated notification email will disseminate within 5 minutes. If you do not receive an 
email within 5 minutes, check that you have entered the “Date Notified DSMC” and the “SAE Classification”. If 
these have been entered and the email still has not been received, take a screen shot of the SAE in WISER and 
immediately email it out to all of the STRC members listed in this SOP. In the subject line, indicate that this is a 
manual transmission of the SAE in lieu of the auto-generated email. It is required that a notification goes to the 
DSMC members immediately so that their assessment can be obtained within the 24 hour period requirement. 
Contact the Cancer Center Programmer/Analyst to alert that there is an issue with the auto-generated email. 
 
The Clinical Members of DSMC to Notify by Phone or Page: 
 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
Sunday 
Lesser 
Hughes 
Goodman 
Reed 
Porosnicu 
Seegars 
Lesser 
Hughes 
Goodman 
Reed 
Porosnicu 
Seegars 
Lesser 
Hughes 
Goodman 
Reed 
Porosnicu 
Seegars 
Lesser 
Hughes 
Goodman 
Reed 
Porosnicu 
Seegars 
Lesser 
Hughes 
Goodman 
Reed 
Porosnicu 
Seegars 
Lesser 
Hughes 
Goodman 
Reed 
Porosnicu 
Seegars 
Lesser 
Hughes 
Goodman 
Reed 
Porosnicu 
Seegars 
 
  
 
 
 
 
 
 
Definition of Unavailable: 
As a general guideline if the first clinician that is contacted does not respond to the phone call or page within 30 minutes, 
then initiate contact with the next DSMC clinician listed in the table above on the particular day the SAE is being reported. 
Allow up to 30 minutes for the new DSMC clinician to respond to a phone call or page before contacting the next member in 

 
A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62718 
 
Protocol version date 04/01/22 
  
 
 
 
 
                                         Page 49 of 52 
  
the table. These times (30 minutes) are a general guideline. Best judgment as a clinical research professional should be used 
giving considerations of the time of day, severity of the SAE, and other circumstances as to when it is appropriate to contact 
backup clinicians. If the event occurs near the end of day, then leave messages (voice or email) as appropriate and proceed 
with submitting the DSMC notification form. It is important to take reasonable steps and to document that some type of 
contact has been initiated to one or more of the clinical members of DSMC. 
 
DSMC CLINICAN RESPONSIBILITY: 
It is the responsibility of the DSMC clinician to review all reported events, evaluate the events as they are reported; and 
communicate a response to the Investigator, event reporter and the members of DSMC. The review will include but not be 
limited to the information reported; there may be times when additional information is needed in order for an assessment 
to be made and further communication directly with the investigator may be warranted. DSMC reserves the right to 
disagree with the Investigator's assessment. If DSMC does not agree with the Investigator, DSMC reserves the right to 
suspend the trial pending further investigation. If there is any immediate danger or harm that could be present for a future 
patient based on the information provided in the DSMC report then an immediate suspension of enrollment should be 
considered. 
 
 
AMENDMENTS TO PREVIOUS REPORTS 
If all pertinent information is unavailable with the initial submission, once the additional information is available do not 
submit a new report. Rather, go to the original email that was sent to the DSMC and using that email “reply to all”. Entitle 
this new email “Amendment for (list date of event and patient ID)” this will avoid duplications of the same event. List the 
additional information being reported. This information needs to be entered into WISER as well. To do this, go to the 
Subject console and click SAEs on the left column. Click on the appropriate SAE number that needs updating. Then click 
Update. This will allow additional information to be added. 
 
Acronyms 
AE – Adverse Event 
DSMC-Data and Safety Monitoring Committee 
SAE-Serious Adverse Event 
WFBCCC – Wake Forest Baptist Comprehensive Cancer Center 
NCI-National Cancer Institute 
WISER –Wake Integrated Solution for Enterprise Research 
 
 
 
 
 
 
Screen Shots: 
 
The following screen shots come from the SAE Console within the Subject Console in WISER. 
Screen Shot 1: 

 
A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62718 
 
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                                         Page 50 of 52 
  
 
Screen Shot 2:
 

 
A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic 
Body Radiation Therapy (SBRT) after First-line Systemic Therapy for Metastatic NSCLC 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62718 
Protocol version date 04/01/22 
  
 
 
 
 
                                         Page 51 of 52 
 
Screen Shot 3: 
 
 
 
Screen Shot 4: 
 
 
 
 
 
 
 
 

A Randomized Trial of Consolidative Immunotherapy with vs without Thoracic Radiotherapy and / or Stereotactic Body Radiation Therapy (SBRT) after First-line 
Systemic Therapy for Metastatic NSCLC 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC # 62718 
 
Protocol version date 04/01/22 
 
 
 
 
 
Page 52 of 52 
Appendix S: Adverse Event Log 
 
WFBCCC Adverse Event (AE) Log 
PI: _________________   Subject PID: 
________________ 
MRN: ________________ 
Cycle #: _________            Cycle Start Date: ____________      Cycle Start Time: ___________         Cycle End Date: ____________           Cycle End Time: ____________                                         
Adverse 
Event 
CTC Term 
Lab 
Value 
Grade   
(1-5)  
per  
CTC 
Start 
Date 
End 
Date 
Attribution 
DEF= Definite  
PROB= Probable 
POSS= Possible 
UNLK= Unlikely 
UNRL= Unrelated 
Expected 
N=No    
Y=Yes 
Serious Adverse 
Event Detail         
NO=No                 
LT=Life Threatening  
DTH= Death  
DIS=Disability  
HOS=Hospitalized           
CA=Caused congenital anomaly      
RI=Required intervention to 
prevent impairment  
Dose 
Limiting 
Toxicity 
(DLT)      
N=No      
Y=Yes 
Action Taken NO=None          
DR= Dose Reduced  
RI=Regimen Interrupted          
TD=Therapy discontinued 
INTR=Interrupted then reduced 
Therapy 
Given   
NO=None  
SYM=Symptomatic  
SUP= Supportive    
VSUP=Vigorous 
supportive 
Reportable? 
IRB-IRB                 
DSMC-DSMC             
FDA-FDA                 
SPON-Sponsor  
(all that apply) 
Adverse 
Event 
Report 
(AER) 
Filed      
N=No    
Y=Yes 
Outcome   
R= Recovered  
TX=Still under 
treatment/ observation 
A=Alive with sequalae 
D=Died   
Treating 
MD 
Initials/ 
Date 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Serious Adverse Event: Hospitalization; Disability; Birth Defect; Life-threatening; Death. 
CTCAE Version 5 - https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf 
DSMC- Safety and Toxicity Review Committee 
Version 1/10/18