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RTOG Foundation Collaboration with Bristol-Myers Squibb  
  
RTOG 3505 A Limited Participation Study RANDOMIZED, DOUBLE BLINDED PHASE III TRIAL OF CISPLATIN AND
ETOPOSIDE PLUS THORACIC RADIATION THERAPY FOLLOWED BY
NIVOLUMAB/PLACEBO FOR LOCALLY ADVANCED NON-SMALL CELL LUNG
CANCER
Sponsor: RTOG Foundation Principal Investigator/Medical Oncology David E. Gerber, MD Study Co-Chairs Medical Oncology Corey Langer, MD Radiation Oncology James J. Urbanic, MD Medical Physics Robert Jeraj, PhD Quality of Life Ben Movsas, MD Translational Science Bo Lu, MD Pathology Kirk Jones, MD Senior Statistician Chen Hu, PhD
Closure Date: November 11, 2017 Termination Date: **January 23, 2019** Protocol Acceptance  
 On behalf of the RTOG Foundation, Inc. Walter J. Curran, Jr., MD Date: January 29, 2019 RTOG Foundation Chairman RTOG Foundation Collaboration with Bristol-Myers Squibb  
  
RTOG 3505 A Limited Participation Study RANDOMIZED, DOUBLE BLINDED PHASE III TRIAL OF CISPLATIN AND
ETOPOSIDE PLUS THORACIC RADIATION THERAPY FOLLOWED BY
NIVOLUMAB/PLACEBO FOR LOCALLY ADVANCED NON-SMALL CELL LUNG
CANCER
Sponsor: RTOG Foundation  
Principal Investigator/Medical Oncology David E. Gerber, MD Study Co-Chairs Medical Oncology Corey Langer, MD Radiation Oncology James J. Urbanic, MD Medical Physics Robert Jeraj, PhD Quality of Life Ben Movsas, MD Translational Science Bo Lu, MD Pathology Kirk Jones, MD  
Senior Statistician Chen Hu, PhD
Protocol Acceptance  
 On behalf of the RTOG Foundation, Inc. Walter J. Curran, Jr., MD Date: January 30, 2017 RTOG Foundation Chairman RTOG 3505  
  
(ClinicalTrials.gov NCT \# NCT02768558)(5/10/16)
A Limited Participation Study RANDOMIZED, DOUBLE BLINDED PHASE III TRIAL OF CISPLATIN AND
ETOPOSIDE PLUS THORACIC RADIATION THERAPY FOLLOWED BY
NIVOLUMAB/PLACEBO FOR LOCALLY ADVANCED NON-SMALL CELL LUNG
CANCER  
| Principal Investigator/Medical Oncology David E. Gerber, MD Harold C. Simmons Cancer Center UT Southwestern Medical Center 5323 Harry Hines Blvd, Mail Code 8852 Dallas, TX 75390-8852 214-648-4180/FAX 214-648-1955 David.Gerber@UTSouthwestern.edu   | Translational Science Co-Chair Bo Lu, MD Thomas Jefferson University 111 South 11th Street Philadelphia, PA 19107 215-955-6705/FAX 215-955-0310 bo.lu@jefferson.edu                                                                                                                                                                                                           |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Radiation Oncology Co-Chair James J. Urbanic, MD University of California, San Diego 1200 Garden View Road, Suite 210 Encinitas, CA 92024 858-246-0500/FAX 858-246-0501 jurbanic@ucsd.edu                                                              | Medical Physics Co-Chair Robert Jeraj, PhD University of Wisconsin Carbone Cancer  Center 7033 WIMR, 1111 Highland Ave Madison, WI 53705 608-263-8619/FAX 608-262-2413 rjeraj@wisc.edu Pathology Co-Chair Kirk Jones, MD Department of Pathology Box 0102 505 Parnassus Ave, Moffitt Room M565 UCSF San Francisco, CA 94115 415-476-7864/FAX 415-476-5271 kirk.jones@ucsf.edu |
| Study Team continued on next pageMedical Oncology Co-Chair Corey Langer, MD 6 PCAM 3400 Civic Center Blvd University of Pennsylvania Philadelphia, PA 19104 215-615-5888/FAX 215-615-5122 corey.langer@uphs.upenn.edu                                  |                                                                                                                                                                                                                                                                                                                                                                               |
rtog foundation rtog 3505
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RANDOMIZED, DOUBLE BLINDED PHASE III TRIAL OF CISPLATIN AND
ETOPOSIDE PLUS THORACIC RADIATION THERAPY FOLLOWED BY
NIVOLUMAB/PLACEBO FOR LOCALLY ADVANCED NON-SMALL CELL LUNG
CANCER  
| Quality of Life/PRO Co-Chair Ben Movsas, MD 2799 West Grand Blvd Henry Ford Hospital Detroit MI 48202 313-916-5188 /FAX 313-916-3264 Bmovsas1@hfhs.org   | Senior Statistician Chen Hu, PhD Johns Hopkins Sidney Kimmel  Comprehensive Cancer Center/RTOG  Foundation 1818 Market Street, Suite 1720 Philadelphia, PA 19103 215-928-0153 chu@acr.org   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| RTOG Foundation Headquarters Contact Information                                                                                                         |                                                                                                                                                                                             |
| Data Managers:                                                                                                                                           | Jeff Serianni, jserianni@acr.org                                                                                                                                                            |
| For questions concerning eligibility or data submission                                                                                                  | Amy Krystkiewicz,  akrystkiewicz@acr.org                                                                                                                                                    |
| ACR Core Laboratory/RTQA:  For questions concerning RT planning or RT data  requirements                                                                 | Jennifer Presley, jpresley@acr.org                                                                                                                                                          |
| ACR Core Laboratory/RTQA:                                                                                                                                | Triad-Support@acr.org                                                                                                                                                                       |
| For questions concerning data submission to TRIAD ACR Diagnostic Imaging                                                                                 | Emilie Connors, 215-574-3201,                                                                                                                                                               |
| For questions concerning central imaging review                                                                                                          | econnors@acr.org                                                                                                                                                                            |
| Serious Adverse Event Coordinator For questions concerning serious adverse event  reporting procedures, timelines, and queries                           | Sara McCartney, 267-940-9404,  smccartney@acr.org                                                                                                                                           |
| Project Manager: For questions concerning regulatory  documentation, investigational drug supply and/or  shipment issues.                                | Erin Cunningham, 215-717-0831,  ecunningham@acr.org                                                                                                                                         |
| Membership:                                                                                                                                              | RTOG-Membership@acr.org                                                                                                                                                                     |
| For questions concerning contracts and reimbursement For Code Breaks, 8:30 a.m. to 5 p.m. ET                                                             | 215-574-3150, ask for the  Supporting Statistician                                                                                                                                          |
| For Code Breaks after business hours or on weekends                                                                                                      | 215-459-3576                                                                                                                                                                                |
| or holidays                                                                                                                                              |                                                                                                                                                                                             |  
RANDOMIZED, DOUBLE BLINDED PHASE III TRIAL OF CISPLATIN AND
ETOPOSIDE PLUS THORACIC RADIATION THERAPY FOLLOWED BY
NIVOLUMAB/PLACEBO FOR LOCALLY ADVANCED NON-SMALL CELL LUNG
CANCER
Participating Sites: A list of participating sites can be accessed on the RTOG website.  
| Protocol Agents   |               |        |                       |
|-------------------|---------------|--------|-----------------------|
| Agent             | Supply        | IND #  | IND Sponsor           |
| Cisplatin         | Commercial    | Exempt | N/A                   |
| Etoposide         | Commercial    | Exempt | N/A                   |
| Nivolumab/Placebo | Bristol-Myers | 130197 | RTOG Foundation, Inc. |
| Squibb            |               |        |                       |  
Document History  
| Version Date   | Release Date     |                   |
|----------------|------------------|-------------------|
| Amendment 2    | January 30, 2017 | February 22, 2017 |
| Amendment 1    | May 27, 2016     | June 6, 2016      |
| Approved Only  | April 25, 2016   |                   |  
This protocol was designed and developed by RTOG Foundation, Inc. It is intended to be used only in conjunction with institution-specific IRB approval for study entry. No other use or reproduction is authorized by RTOG nor does RTOG assume any responsibility for unauthorized use of this protocol.
rtog foundation rtog 3505
table of contents

| 1.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | OBJECTIVES 8 1.1 Primary Objective 8 1.2 Secondary Objectives 8                                                                                                                                                                                                                                                                                                                                                                                                 |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 2.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | BACKGROUND 8 2.1 There is a strong rationale to combine immunotherapy and radiation  therapy (RT) 9 2.2 The PD-1/PD-L1 immune regulatory checkpoint represents a new and  effective target for cancer treatment 10 2.3 Nivolumab (BMS-936558, previously MDX-1106 and ONO-4538), an  anti-PD-1 monoclonal antibody, has emerged as one of the most  promising immunotherapies for lung cancer 11 2.4 Rationale for the Study Design 17 2.5 Biomarker Studies 22 |
| 3.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILITY CRITERIA 23 3.1 Patient Selection Guidelines 24 3.2 Eligibility Criteria 24 3.3 Ineligibility Criteria 27                                                                                                                                                                                                                                                                                                     |
| 4.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP 29                                                                                                                                                                                                                                                                                                                                                                                                       |
| 5. TREATMENT PLAN/Regimen description 36 5.1 Chemotherapy/Other Agent-Based Therapy 37 5.2 Radiation Therapy 38 5.3 General Concomitant Medication and Supportive Care Guidelines 46 5.4 Emergency Unblinding Procedure 47 5.5 Duration of Therapy 47 6. TREATMENT MODIFICATIONS/managEment 47 6.1 Chemoradiotherapy Dose Modifications 47 6.2 Cisplatin and Etoposide Dose Modifications 48 6.3 Nivolumab/Placebo Dose Modifications 49 7. ADVERSE EVENTS REPORTING REQUIREMENTS 55 7.1 Protocol Agents 55 7.2 Adverse Events (AEs) 56 7.3 Serious Adverse Events (SAEs) 57 7.4 Serious Adverse Event (SAE) Reporting Requirements 58 8. REGISTRATION AND STUDY ENTRY PROCEDURES 62 8.1 Regulatory Requirements 62 8.2 RT Registration Requirements 62 8.3 Patient Enrollment 62 |                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |  
| 9.0                                                                                                                                                                       | DRUG INFORMATION .............................................................................................................................62        |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------|
| 9.1                                                                                                                                                                       | Investigational Study Agent...............................................................................................62                            |
| 9.2                                                                                                                                                                       | CC                                                                                                                                                      |
| 10. Pathology/BIOSPECIMENS .....................................................................................................................64                        |                                                                                                                                                         |
| 10.1 Tissue/Specimen Submission                                                                                                                                           |                                                                                                                                                         |
| 10.2                                                                                                                                                                      | Mandatory Studies ...................................................................................................................65                 |
| 10.3 Optional Specimen Collection for RTOG 3505 Research and Banking....................66                                                                                |                                                                                                                                                         |
| 11.                                                                                                                                                                       | SPECIAL studies (Non-Tissue)                                                                                                                            |
| 1.1 Toxicity, Patient-Reported Outcomes (PROs), and Health-Related Quality                                                                                                |                                                                                                                                                         |
| of Life (QOL)                                                                                                                                                             |                                                                                                                                                         |
| 12.                                                                                                                                                                       | Modality Reviews .                                                                                                                                      |
| 12.1 Radiation Therapy Quality Assurance Reviews ..................................................................73                                                     |                                                                                                                                                         |
| 12.2  Drug Quality Assurance Reviews .............................................................................................73                                      |                                                                                                                                                         |
| 13.                                                                                                                                                                       | DATA AND RECORDS .                                                                                                                                      |
| 13.1                                                                                                                                                                      | Summary of Dosimetry Digital RT Data Submission (Submit to ACR Core                                                                                     |
| Laboratory/RTQA see the study-specific guide on the RTOG Foundation                                                                                                       |                                                                                                                                                         |
| 3505 protocol page of the RTOG website, www.rtog.org, for details of                                                                                                      |                                                                                                                                                         |
| TRIAD.)                                                                                                                                                                   |                                                                                                                                                         |
| 13.2 Summary of Diagnostic Imaging Digital Data Submission (Submit to ACR                                                                                                 |                                                                                                                                                         |
| Imaging Corelab; see the study-specific guide on the RTOG Foundation                                                                                                      |                                                                                                                                                         |
| 3505 protocol page of the RTOG website, www.rtog.org, for details of                                                                                                      |                                                                                                                                                         |
| TRIAD.))                                                                                                                                                                  |                                                                                                                                                         |
| 14.                                                                                                                                                                       | STATISTICAL CONSIDERATIONS                                                                                                                              |
| 14.1                                                                                                                                                                      | Study Design ........................................................................................................................................75 |
| 14.2                                                                                                                                                                      | Study Endpoints ..................................................................................................................................75    |
| 14.3                                                                                                                                                                      | Primary Objectives Study Design .........................................................................................76                             |
| 14.4                                                                                                                                                                      | Study Monitoring ..............................................................................................................................79       |
| 14.5                                                                                                                                                                      | Accrual/Study Duration Considerations ..........................................................................82                                      |
| 14.6                                                                                                                                                                      | Dose Level Guidelines                                                                                                                                   |
| 14.7                                                                                                                                                                      | Secondary Endpoints ................................................................................................................83                  |
| 14.8                                                                                                                                                                      | Exploratory Hypothesis and Endpoints ..............................................................................85                                   |
| REFERENCES .                                                                                                                                                              |                                                                                                                                                         |
| APPENDIX I ............................................................................................................................................................92 |                                                                                                                                                         |
| APPENDIX II                                                                                                                                                               |                                                                                                                                                         |
| Appendix III.................................................................................................................................................105          |                                                                                                                                                         |
| APPENDIX IV.                                                                                                                                                              |                                                                                                                                                         |
rtog foundation rtog 3505
rtog 3505

Randomized, Double Blinded Phase III Trial of Cisplatin and Etoposide plus Thoracic Radiation Therapy Followed by Nivolumab/Placebo for Unresectable Locally Advanced Non-Small Cell Lung Cancer  
  
* Verification that archived tissue block is available for submission as the completed submission will be required at least 5 weeks prior to Step 2 Registration
**Assessment for progression after chemoRT; if evidence of distant metastases or local disease progression, will not be randomized
rtog foundation rtog 3505
1. objectives 1.1 primary objective

To compare the overall survival (OS) for patients with Stage III unresectable nonsmall lung cancer treated with or without nivolumab following concurrent chemoradiation.  
o Overall survival is defined as the time from randomization to death due to any cause.  
To compare progression-free survival (PFS) based on an assessment by an Independent Radiology Review Committee (IRRC) according to RECIST 1.1 criteria for patients with Stage III unresectable non-small lung cancer treated with or without nivolumab following concurrent chemoradiation.  
o PFS is defined as the time from randomization to documented progressive disease or death due to any cause, whichever occurs first; o PFS will be determined by IRRC per guidelines of Section 4.3.  
1.2 **Secondary Objectives**
To compare toxicities in the control and experimental arms; To compare Functional Assessment of Cancer Therapy - Trial Outcome Index for lung cancer (FACT-TOI) at 15 months; To evaluate OS and PFS in patients with (1) PD-L1-positive, (2) PD-L1-negative and PD-L1 not evaluable/undetermined tumors; 1.3 Exploratory Objectives To evaluate biomarkers and biomarker correlatives; To determine the proportion of patients alive at 12 and 24 months; To determine the proportion of patients progression free at 12 and 24 months according to RECIST 1.1; To evaluate PROMIS fatigue at 3 months, EQ-5D utilities and EQ-VAS before and after progression; To evaluate PFS based on investigator assessment
rtog foundation rtog 3505
2. background

We have reached a plateau in outcomes for locally advanced non-small cell lung cancer (LANSCLC). Despite aggressive therapy with concurrent chemoradiation, fewer than 20-25% of patients with stage III NSCLC achieve 5-year survival and are presumably cured. To date, modifications of chemotherapy have not improved these outcomes. The addition of 3 cycles of consolidation docetaxel after concurrent cisplatin-etoposide with thoracic radiation had no impact on overall survival compared to chemoradiation alone (Hanna 2008). A similar, much larger trial performed in Southeast Asia showed no survival advantage whatsoever for consolidative docetaxel/cisplatin after definitive chemoradiation compared to chemoradiation alone (Ahn JS 2015). Finally, a study of maintenance gefitinib after completion of cisplatinbased concurrent chemoradiation in unselected patients with LA-NSCLC demonstrated a decrease in survival (Kelly 2008). The addition of the anti-EGFR monoclonal antibody cetuximab to chemoradiation did not extend survival (Bradley 2015). Furthermore, in 2015, there is no evidence that achievable radiotherapy (RT) doses above 60 Gy using standard 3D technology are better than 60 Gy, suggesting that opportunities exist for outcome improvement lie in modification of medical components of chemoradiation regimens. In an interim analysis of the Radiation Therapy Oncology Group (RTOG) 0617 clinical trial, patients receiving a radiation dose of 74 Gy had a median progression-free survival of 9.8 months, compared to 11.8 months for patients receiving 60 Gy. The highdose RT arms were closed after overall survival results crossed the futility boundary (Bradley 2015).  
2.1 **There is a strong rationale to combine immunotherapy and radiation therapy (RT).**
While NSCLC is typically considered relatively non-immunogenic, RT is thought to augment tumor immunogenicity (Iyengar 2013). The abscopal effect refers to the observation that RT to a local area results in an antitumor effect distant to the radiation site. One proposed mechanism for this phenomenon is inducing the release of circulating tumor antigen or inflammatory factors that could then mediate an augmented immune response against distant malignant lesions expressing similar tumor antigens. Supporting this hypothesis, local RT has been shown to increase the activity of natural killer cells (Uchida 1989).  
Conversely, the therapeutic effects of ablative RT on local tumors are dependent on antitumor immune responses (Iyengar 2013). Of note, Formenti and colleagues demonstrated that the abscopal effect of radiotherapy is in part immune mediated and that T cells are required to mediate distant tumor effects of radiotherapy (Demaria 2004). In a preclinical model, ablative RT dramatically increased T-cell priming in draining lymphoid tissues, leading to reduction of the primary tumor or distant metastases in a CD8+ T-cell-dependent fashion. In the same model, these RT-initiated immune responses were greatly amplified by local immunotherapy (Lee 2009). Particularly relevant to the current proposal, RT has been shown to increase tumor expression of PD-L1, and combined RT plus PD-1-pathway targeting results in synergistic suppression of tumor-infiltrating myeloid-derived suppressor cells (MDSCs), thereby promoting anti-tumor immunity (Deng 2014). To date, the most extensive experience combining immune modulating therapies with radiation therapy for lung cancer has been with L-BLP25 (Tecemotide), a mucin-1 (MUC1) antigen specific cancer vaccine. In a phase 3 trial, 1513 patients with stage III NSCLC previously treated with chemotherapy and radiation (either concurrent or sequential) were randomized to L-BLP25 (Tecemotide) or placebo. Approximately 65% of patients received concurrent chemoradiation, and 35% received sequential chemoradiation. 274 patients were excluded from the primary analysis population as a result of a clinical hold, resulting in analysis of 829 patients in the tecemotide group and 410 in the placebo group in the modified intention-to-treat population. Although the study failed to meet its primary endpoint of improved OS in the overall study population, a pre-planned subgroup analysis demonstrated an improvement in median OS from 20.6 months to 30.8 months (HR 0.78; 95% CI, 0.640.95; P=0.016) in those patients who had received concurrent chemoradiation prior to randomization (Butts 2014, Mitchell 2015). Although no firm conclusions can be drawn from this experience, these results suggest that concurrent chemoradiation may provide the optimal platform on which to add immunotherapies. With the availability of immunotherapies such as the anti-Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) monoclonal antibody ipilimumab (FDA approved for melanoma) and agents targeting the programmed death-1 (PD-1) pathway, the potential benefit of combining these agents with RT has become evident clinically. For instance, a recent case report described a patient with metastatic melanoma had evidence of slow progression of a paraspinous mass, hilar lymph nodes, and a liver lesion while receiving ipilimumab. The patient received palliative RT to the paraspinous mass. There was no radiographic improvement noted 6 weeks later. However, after re-initiation of ipilimumab, the paraspinous mass resolved completely. Furthermore, the hilar lymph nodes and liver metastasis (both of which had previously progressed during ipilimumab treatment but had not been irradiated) also responded (Postow 2012). Among cancer types, lung cancer may be a particularly attractive setting to incorporate immunotherapy into treatment paradigms. A number of studies have suggested that tumor mutational burden is associated with benefit from immunotherapy (Rizvi 2015, Le 2015). Presumably, increased mutational burden results in increased tumor antigenicity, thereby priming the tumor for immune attack. As shown in Figure 1 below, lung cancer carries one of the highest mutational burdens of any malignancy. In this figure, each dot represents a sample, the red horizontal lines represent median numbers of mutations, and the vertical axis (log scale) shows the number of mutations per megabase.
rtog foundation rtog 3505
2.2 the pd-1/pd-l1 immune regulatory

In contrast to CTLA-4 (which exerts its regulatory effects in the priming phase of the immune response in regional lymph nodes), the negative regulatory effects of the PD-1 pathway occur in the effector phase of the immune response in peripheral tissues. Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2, resulting in dephosphorylation of multiple effector molecules involved in the CD3 T-cell signaling cascade (Talmadge 2007). PD-1 is expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regulatory cells (Tregs), and natural killer (NK) cells (Hodi 2010). Although healthy organs express little (if any) PD-L1, numerous cancers are 10 known to express abundant levels of PD-L1. PD-1 has been suggested to regulate tumorspecific T-cell expansion in patients with melanoma, suggesting that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and therefore represents an attractive target for therapeutic intervention. Indeed, no fewer than six monoclonal antibodies targeting this pathway have entered clinical development for the treatment of various malignancies (BMS-936558/MDX1106/nivolumab [Opdivo; Bristol-Myers Squibb]; CT-011 [CureTech]; MK-3475/pembrolizumab [Keytruda; Merck]; BMS-936559/MDX-1105 [Bristol-Myers Squibb]; Medi-4736/durvalumab [MedImmune]; MPDL-3280A/atezolizumab [Genentech]), of which nivolumab and pembrolizumab have been approved for melanoma and NSCLC.
rtog foundation rtog 3505
2.3 nivolumab (bms-936558 previously mdx-1106

Nivolumab is a fully human, IgG4 (kappa) monoclonal antibody that binds PD-1 on activated immune cells to disrupt engagement of receptor with ligands PD-L1 (B7-H1/CD274) and PD-L2 (B7-DC/CD273). This action results in counteracting inhibitory signals and augmenting host antitumor responses. In early clinical trials, nivolumab monotherapy demonstrated clinical activity in multiple tumor types, including melanoma, renal cell carcinoma, and NSCLC (Brahmer 2010). In a multicenter phase I trial enrolling NSCLC, melanoma, renal cell carcinoma, castration-resistant prostate cancer, and colorectal cancer, radiographic response rate in advanced, previously treated NSCLC was 18% (14 of 76 patients) (Topalian 2012). In some cases, these responses were prolonged. For 8 of the 14 responding cases, responses lasted ≥ 24 weeks; in 2 cases, responses lasted more than one year. In 7% of cases, stable disease lasted ≥ 24 weeks.  
Response rates varied according to treatment dose, histology, and biomarkers. In the 1.0 mg/kg cohort, response rate was 6%. In the 3.0 mg/kg arm, response rate was 27%. In the 10.0 mg/kg arm, response rate was 20%. For squamous cases, response rate was 17% (9/54)
[22% at the 3.0 mg/kg level], compared to 18% (13/74) [26% at the 3.0 mg/kg level] in nonsquamous cases. For tumors negative for PD-L1 by immunohistochemistry, there were no radiographic responses (0/17). For PD-L1-positive tumors, response rate was 36% (9/25; P=0.006) (Brahmer 2013).  
While treatment in this study was overall well tolerated, there were instances of immunerelated adverse events. The most common treatment-related adverse events included fatigue, rash, diarrhea, pruritus, decreased appetite, and nausea. Apparent immune-related adverse events included pneumonitis, vitiligo, colitis, hepatitis, hypophysitis, and thyroiditis. In total, grade 3 or 4 treatment-related adverse events occurred in 14% of patients. Pneumonitis occurred in 3% of patients (1% grade 3-4). There were 3 deaths attributed to pneumonitis (2 NSCLC, 1 colorectal cancer). In many cases, early pneumonitis was reversible with stopping treatment, initiating glucocorticoids, or both. Nivolumab has also been given in combination with platinum doublet chemotherapy for advanced NSCLC. In a phase I trial dose de-escalation trial, 43 patients were treated with nivolumab plus either gemcitabine-cisplatin, pemetrexed-cisplatin, or carboplatin-paclitaxel (Rizvi 2013). No DLTs were observed with any combination when nivolumab was administered 10 mg/kg every 3 weeks.  Grade 3 pneumonitis developed in 3 patients (7%).  
Other apparent immune-related grade 3-4 toxicities included rash, nephritis, and colitis.  
More recently, two phase 3 clinical trials (Checkmate 057 and Checkmate 017) comparing nivolumab to single-agent docetaxel chemotherapy in previously treated advanced NSCLC have been conducted (see Table 1).  Both trials have demonstrated improved overall survival with nivolumab compared to docetaxel.  
| Table 5.4.1.1-1:                                                                           | Summary of Key Efficacy Results - All Randomized Subjects in CA209057 and CA209017   |                   |                   |                   |
|--------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------|-------------------|-------------------|-------------------|
| CA209057 (NSQ NSLC)                                                                        | CA209017 (SQ NSCLC)                                                                  |                   |                   |                   |
| Nivolumab                                                                                  | Docetaxel                                                                            | Nivolumab         | Docetaxel         |                   |
| Efficacy Parameter                                                                         | N=292                                                                                | N=290             | N=135             | N=137             |
| PRIMARY ENDPOINT                                                                           |                                                                                      |                   |                   |                   |
| Overall Survival                                                                           |                                                                                      |                   |                   |                   |
| Hazard Ratio                                                                               | 0.73 (0.59, 0.89)                                                                    | 0.59 (0.43, 0.81) |                   |                   |
| 12.2 (9.7, 15.0)                                                                           | 9.4 (8.1, 10.7)                                                                      | 9.2 (7.3, 13.3)   | 6.0 (5.1, 7.3)    |                   |
| Median (95% CI) (Months) d                                                                 |                                                                                      |                   |                   |                   |
| Rate at 12 Months (95% CI)                                                                 | 50.5 (44.6, 56.1)                                                                    | 39.0 (33.3, 44.6) | 42.1 (33.7, 50.3) | 23.7 (16.9, 31.1) |
| SECONDARY ENDPOINTS                                                                        |                                                                                      |                   |                   |                   |
| Objective Response Rate                                                                    |                                                                                      |                   |                   |                   |
| n (%)                                                                                      | 56 (19.2)                                                                            | 36 (12.4)         | 27 (20.0)         | 12 (8.8)          |
| 95% CI                                                                                     | (14.8, 24.2)                                                                         | (8.8, 16.8)       | (13.6, 27.7)      | (4.6, 14.8)       |
| Progression-free Survival                                                                  | 0.62 (0.47, 0.81)                                                                    |                   |                   |                   |
| Hazard Ratio (95% CI) 2                                                                    | 0.92 (0.77, 1.11)                                                                    |                   |                   |                   |
| Median (95% CI) (Months)                                                                   | 2.3 (2.2, 3.3)                                                                       | 4.2 (3.5, 4.9)    | 3.5 (2.1, 4.9)    | 2.8 (2.1, 3.5)    |
| 8.1 (5.1, 12.0)                                                                            |                                                                                      |                   |                   |                   |
| Rate at 12 Months (95% CI)                                                                 | 18.5 (14.1,23.4)                                                                     | 20.8 (14.0, 28.4) | 6.4 (2.9, 11.8)   |                   |
| Source: CA209057 CSR 60                                                                    |                                                                                      |                   |                   |                   |
| a Stratified Cox proportional hazards model. The hazard ratio is nivolumab over docetaxel. |                                                                                      |                   |                   |                   |
| b 95.92% CI                                                                                |                                                                                      |                   |                   |                   |  
The Checkmate 057 trial enrolled patients with non-squamous NSCLC; the trial met its primary endpoint of improving OS. In the unselected population, for patients receiving nivolumab (N=287), median overall survival (OS) was 12.2 months compared with 9.4 months for docetaxel (N=268) (HR 0.73, HR 0.59-0.89, p=0.0015) (Figure 2). Fewer grade 3 to 5 adverse events were reported for nivolumab (10%) when compared with docetaxel (54%) in the Checkmate 057 trial. Clinical benefit was particularly evident for patients whose tumors had PD L1 staining of 1% or more, with OS of 17.2 to 19.4 months compared with 89 months for docetaxel (HR 0.59) (Borghaei H 2015). Conversely, there did not appear to be a benefit for nivolumab over docetaxel in the PDL1-negative population (HR 0.9).  
In the Checkmate 057 trial, treatment-related select adverse events observed included infusion-related reactions (3%; no grade 3-4), rash (9%; <1% grade 3-4), pneumonitis (3%;
1% grade 3-4), ALT/AST increased (3%; <1% grade 3-4), diarrhea (8%; 1% grade 3-4), and hypothyroidism (7%; no grade 3-4) (Borghaei H 2015).  
Currently, the National Comprehensive Cancer Network (NCCN) guidelines (version RTOG Foundation 3505 7.2015) recommend nivolumab as subsequent therapy for PS 0-2 patients with metastatic nonsquamous NSCLC who have progressed on or after platinum-based chemotherapy (category 2A). The NCCN panel does not recommend testing for PD L1, because many patients with metastatic NSCLC benefit from nivolumab including PD L1 negative population. Checkmate 017 enrolled patients with squamous NSCLC and also met its primary endpoint of improving OS (Brahmer 2015). Patients were randomized to nivolumab (3 mg/kg IV over 60 minutes every 2 weeks) (n=135) versus standard of care docetaxel (75 mg/m2IV every 3 weeks) (n=137). In a prespecified interim analysis, compared to docetaxel, nivolumab resulted in a 41% reduction in the risk of death (HR 0.59; 95% CI, 0.44-0.79; P=0.00025). Median OS was 9.2 months in the nivolumab arm (95% CI, 7.3-13.3 months) and 6 months in the docetaxel arm (95% CI, 5.1-7.3 months). As shown in Figure 2, there is early and persistent separation of survival curves, with suggestion of a "tail" that may represent longerterm survival in approximately 20% of patients. Notably, the trial included patients regardless of tumor PD-L1 status.  
In the nivolumab arm, the most common adverse reactions (reported in ≥20% of patients)
were fatigue (50%), dyspnea (38%), musculoskeletal pain (36%), decreased appetite (35%), cough (32%), nausea (29%), and constipation (24%). Serious adverse events occurred in 59% of patients receiving nivolumab. The most frequent serious adverse events reported in ≥2% of patients were dyspnea, pneumonia, chronic obstructive pulmonary disease exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain. Pneumonitis occurred in 7 patients (6%). There were five grade 3 cases, and two grade 2 cases. All patients discontinued nivolumab and experienced complete resolution following high-dose corticosteroids. Median time to onset of pneumonitis was 3.3 months (range 1.413.5 months). Overall, nivolumab was discontinued due to adverse events in 27% of patients, and 29% of patients receiving nivolumab had a drug delay for an adverse event. With at least 10 months of minimum follow up for all patients, the confirmed objective response rate (ORR), the study's primary endpoint, was 15% (95% CI, 9-22%), of which all were partial responses. Median time to onset of response was 3.3 months (range 1.7-8.8 months) after treatment initiation. Among responders, 67% had ongoing responses with durability of response ranging from 1.9+ to 11.5+ months. Among this cohort, 59% had durable responses of ≥6 months. Currently, the NCCN guidelines (version 7.2015) recommend nivolumab as subsequent therapy for PS 0-2 patients with metastatic squamous NSCLC who have progressed on or after platinum-based chemotherapy (category 1). More recently, nivolumab was compared to chemotherapy in the first-line setting. The CheckMate 026 trial randomized patients with previously untreated advanced NSCLC with
≥1% PD-L1 positive cells to nivolumab or histology-dependent platinum-doublet therapy. There was no significant difference in the primary endpoint of PFS in the PD-L1 ≥5%
population. Median PFS was 4.2 months with nivolumab and 5.9 months with chemotherapy (HR 1.15; 95% CI, 0.91-1.45; P=0.25) (Socinski 2016). Importantly, these results are not directly relevant to the present trial because of differences in (1) the clinical setting and (2)
the control arm.  
  
| Safety Summary of CheckMate 017 presented at ASCO 2015 Nivolumab                | Docetaxel   |         |       |    |
|---------------------------------------------------------------------------------|-------------|---------|-------|----|
|                                                                                 | n = 131     | n = 129 |       |    |
| Any                                                                             | Grade       | Any     | Grade |    |
| Grade                                                                           | 3–5 a       | Grade   | 3–5   |    |
| Treatment-related AEs,  %                                                       | 58          | 7       | 86    | 57 |
| Treatment-related AEs                                                           | b           | 2       | 10c   | 7  |
| leading to                                                                      | 3           |         |       |    |
| discontinuation, %  Treatment-related  deaths, %                                | 0           | 2 d     |       |    |
| No grade 5 events were reported with nivolumab. b 1% pts had increased ALT/AST, |             |         |       |    |  
No grade 5 events were reported with nivolumab. b1% pts had increased ALT/AST, increased lipase, myasthenic syndrome, or rash, and 2% pts had pneumonitis. cPeripheral neuropathy (3%) and fatigue (2%). dInterstitial lung disease, pulmonary hemorrhage, and sepsis (1 pt each).  
| Treatment-related AEs (≥10% of patients) in CheckMate 017 presented at ASCO 2015 Nivolumab  Docetaxel  n = 131  n = 129  Any  Grade 3– Any  Grade 3– Grade  4  Grade  4  Total patients with an  event, % 58 7 86 55  Fatigue 16 1 33 8  Decreased appetite 11 1 19 1  Asthenia 10 0 14 4  Nausea 9 0 23 2  Diarrhea 8 0 20 2  Vomiting 3 0 11 1  Myalgia 2 0 10 0   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
15  
| Anemia                | 2   | 0   | 22   | 3   |
|-----------------------|-----|-----|------|-----|
| Peripheral neuropathy | 1   | 0   | 12   | 2   |
| Neutropenia           | 1   | 0   | 33   | 30  |
| Febrile neutropenia   | 0   | 0   | 11   | 10  |
| Alopecia              | 0   | 0   | 22   | 1   |  
| Treatment-related Select AEs of CheckMate 017 presented at ASCO 2015 Nivolumab Docetaxel n = 131  n = 129  Any  Grade  Any  Grade   | Grade 3–4   |         |             |         |
|-------------------------------------------------------------------------------------------------------------------------------------|-------------|---------|-------------|---------|
| Grade                                                                                                                               | 3–4         |         |             |         |
| Endocrine, %                                                                                                                        | 4           | 0       | 0           | 0       |
| Hypothyroidism                                                                                                                      | 4           | 0       | 0           | 0       |
| Gastrointestinal, %  Diarrhea Colitis                                                                                               | 8 8 1       | 1 0 1   | 20 20 0     | 2 2 0   |
| Hepatic,a %  ALT increased AST increased                                                                                            | 2 2 2       | 0 0 0   | 2 1 1       | 1 1 1   |
| Pulmonary, %  Pneumonitis Lung infiltration Interstitial lung disease                                                               | 5 5 1 0     | 1 1 0 0 | 1 b 0 0 1 b | 0 0 0 0 |
| Renal,c %  Blood creatinine  increased Tubulointerstitial  nephritis                                                                | 3 3 1       | 1 0 1   | 2 2 0       | 0 0 0   |
| Skin,d %                                                                                                                            | 9           | 0       | 9           | 2       |
| Hypersensitivity/Infusion  reaction, %  Hypersensitivity Infusion-related  reaction                                                 | 1 0 1       | 0 0 0   | 2 2 1       | 1 1 0   |  
The overall safety experience with nivolumab, as a monotherapy or in combination with other therapeutics, is based on experience in approximately 4,000 subjects treated to date. For monotherapy, the safety profile is similar across tumor types. The only exception is pulmonary inflammation adverse events (AEs), which may be numerically greater in subjects with NSCLC. This may be because in some cases, it can be difficult to distinguish between nivolumab-related and unrelated causes of pulmonary symptoms and radiographic changes. There is no pattern in the incidence, severity, or causality of AEs related to nivolumab dose level (Investigator Brochure, version 14).  
To date, across the clinical trial experience in 691 patients with solid tumors, fatal immunemediated pneumonitis has occurred in 0.7% (5/691) of patients receiving nivolumab. All five fatal cases occurred in a dose-finding study with nivolumab doses of 1 mg/kg (2 patients), 3 mg/kg (2 patients), and 10 mg/kg (1 patient). Perhaps reflecting cumulative experience with and knowledge of this potential toxicity, there were no fatal cases of pneumonitis in the phase 3 Checkmate 017 and Checkmate 057 trials. In the Checkmate 017 trial in previously treated advanced squamous NSCLC, pneumonitis occurred in 5% of patients receiving nivolumab, of which there was only one Grade 3 case and no Grade 4 cases. The median time to onset of treatment-related pulmonary events was 15.1 weeks (range, 2.6 to 85.1). All but one patient with pulmonary events received corticosteroids. All cases resolved, with median time to resolution of 5.0 weeks (range 0.6 to 12.1). Among these resolved cases, one patient experienced subsequent recurrence of pneumonitis, which responded to corticosteroid treatment. A total of 4/131 (3%) patients discontinued nivolumab due to pneumonitis. In the Checkmate 057 trial, any grade pneumonitis was 3% and grade 3 and above pneumonitis was 1%. The low rate of pneumonitis and the good response to supportive therapy seen in the most recent nivolumab trials suggests that, with appropriate monitoring and precautions, this agent could be studied in combination with thoracic radiation therapy. Although nivolumab has not yet been studied in combination with RT, data are available for nivolumab-treated patients who previously received RT. While the precise timing and nature of treatments were not captured, of the 129 patients with NSCLC treated on the phase 1, dose-escalation, cohort expansion trial (CA209-003), 75 (58%) had previously received RT. In the overall patient population of 129 NSCLC cases, there were 9 cases of pneumonitis (7.0%) and three cases of grade 3-4 pneumonitis (2.3%), suggesting that the overwhelming majority of NSCLC patients treated with nivolumab after prior RT do not develop pneumonitis. There also is limited experience for patients receiving RT during or after nivolumab therapy. Among approximately 3,000 patients across tumor types (NSCLC, renal cell carcinoma, melanoma) treated with nivolumab to date, approximately 50 were treated with palliative RT during or immediately following nivolumab therapy. Sites of palliative RT included brain (whole brain RT as well as stereotactic radiation), bone, and thorax (for obstructive lesions). No serious adverse events were associated with these cases of palliative RT administration.
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2.4 rationale for the study

Study population: Enrollment is not restricted to patients with PD-L1-positive tumors for numerous reasons. Despite early reports suggesting that PD-L1-positive patients appear to derive particular benefit from PD-1- and PD-L1-targeted therapies, the definition of PD-L1positivity remains unclear. Furthermore, in preclinical models, RT has been shown to increase tumor expression of PD-L1 (Deng 2014), which would limit the correlation of outcomes with pre-RT tissue biomarkers. The observation that tumor PD-L1 expression may be prognostic in general lung cancer populations—but not among cases treated with radiation or chemotherapy (Sun 2014)—further suggests that baseline assessment of this biomarker may not adequately define the target population most likely to benefit. Finally, in the CheckMate 017 and 057 trials, nivolumab was associated with improved OS in an unselected population. Notably, in the CheckMate 057 trial (non-squamous NSCLC), there was no benefit for nivolumab over docetaxel in the PDL1-negative population (HR 0.90; 95% CI, 0.66-1.24). Nevertheless, these results cannot be extrapolated to this clinical trial due to important clinical and biologic differences between populations and treatment paradigms. For these reasons, this trial does not restrict enrollment to PD-L1-positive NSCLC. To investigate the association between this biomarker and clinical outcomes, we will correlate baseline tumor PD-L1 expression with clinical outcomes in this trial. Chemotherapy regimen: Concurrent cisplatin-etoposide (EP) plus thoracic RT to 60 Gy is an established and proven therapy for stage III NSCLC, with clinical outcomes superior to sequential regimens or to RT alone. This regimen has been successfully combined with
"consolidation" chemotherapy, such as docetaxel 75 mg/m2q21d with acceptable toxicity profiles (Hanna 2008). In a randomized phase 2 trial, the regimen had improved outcomes compared to a carboplatin-paclitaxel-based regimen (3-year OS 33% vs 13%) (Wang 2012), although survival differences between the regimens have not been noted in population-based observational studies (Ezer 2014, Santana-Davila 2015). This regimen (EP-RT) is ideally suited to combination with consolidation nivolumab because, in contrast to carboplatinpaclitaxel chemoradiation regimens, (a) the entire chemotherapy course is administered during the 6 to 7 weeks of thoracic radiation and (b) the steroid requirement (which could hypothetically reduce the efficacy of nivolumab) is lower. Finally, rates of radiation pneumonitis—a toxicity that could hypothetically be exacerbated by immunotherapy—may be lower with concurrent cisplatin-etoposide than with concurrent carboplatin-paclitaxel (approximately 5% versus 15%) (Hanna 2008, Belani 2005). Immunotherapeutic agent: Compared to anti-CTLA-4 antibodies (eg, ipilimumab, tremelimumab), anti-PD-1 antibodies such as nivolumab appear to have greater anti-tumor effect in NSCLC, as evidenced by the unprecedented overall survival results in previously treated advanced NSCLC seen in the Checkmate 017 and Checkmate 057 studies. They also appear to result in substantially lower rates of certain autoimmune toxicities, including colitis and hypophysitis. As of October 2015, nivolumab has been U.S. FDA approved for the treatment of both squamous and non-squamous previously treated advanced NSCLC. Timing, duration, dose, and schedule of nivolumab: There is preclinical evidence supporting the administration of immunotherapy before, during, and after RT. However, administration of immunotherapy before chemoradiation could delay potentially curative treatment for this aggressive disease. Furthermore, several clinical and laboratory observations support the evaluation of a sequential (consolidation) approach. Administration of the immunotherapeutic L-BLP25 vaccine after completion of concurrent chemoradiation was found to be well tolerated and have efficacy in stage III NSCLC (Butts 2014). In a 3-arm phase II study in advanced NSCLC, the anti-CLTA-4 antibody ipilimumab yielded the greatest benefit in a phased approach (ie, starting with chemotherapy Cycle \#3 rather than Cycle \#1), suggesting that tumor debulking prior to immunotherapy may enhance efficacy (Lynch 2012). Furthermore, as no chemotherapy will be given with nivolumab, no steroid premedication will be administered, thereby theoretically optimizing immune stimulation. Patients with severe toxicities from concurrent chemoradiation will be identified prior to administration of nivolumab and will have additional time to recuperate from their toxicities. Finally, clinical observations of anti-CTLA-4 antibodies suggest that immunotherapy administration following RT may provide synergistic effects (Postow 2012). The initiation of nivolumab 4-12 weeks after completion of chemoradiation reflects previous experience with combined modality regimens for locally advanced disease, prior experience with nivolumab and palliative radiation therapy, and optimization of potential synergistic effects. In concurrent chemoradiation regimens that continue chemotherapy after completion of thoracic radiation, the first post-radiation chemotherapy cycle is commonly given 3-4 weeks after thoracic radiation has ended (Hanna 2008, Belani 2005). In the START phase 3 trial of tecemotide (MUC1 vaccine) after chemoradiotherapy, vaccine was initiated 4-12 weeks after chemoradiotherapy completion and was well tolerated (Butts 2014). As described above, administration of palliative RT with at least a 14-day window between RT and nivolumab dosing in multiple disease settings has not been associated with increased toxicity. Finally, relatively early initiation of immunotherapy may also capitalize on residual and ongoing radiation-induced tumor antigenic stimulation (Iyengar 2013, Uchida 1989). The administration of nivolumab for up to 1 year is based on theoretical rationale, selected cases of apparent clinical benefit, experience in advanced NSCLC, and tolerability. This duration covers the time period when patients are at greatest risk of recurrence or progression. Furthermore, preclinical studies have demonstrated that continued stimulation of the immune system contributes to the anticancer effects of CTLA-4 blockade. The potential value of repeated dosing also has been seen in human studies of the anti-CTLA-4 antibody ipilimumab. In one dramatic and illustrative case, a heavily pretreated patient with ovarian cancer and increasing CA-125 (GVAX vaccine refractory) was enrolled onto a monotherapy ipilimumab (MDX-010) study (Hodi 2008). After the first dose of ipilimumab (MDX-010), her CA-125 decreased dramatically. Re-dosing at the time of CA-125 increase resulted in an even more rapid decline in her CA-125. Repeated dosing following CA-125 increases occurred 4 times to date and with clear and dramatic reductions in CA-125. There are also data on the tolerability of prolonged anti-PD-1 therapy from phase 1 trials in advanced NSCLC. A number of patients who continued nivolumab beyond 6 months (and a smaller number beyond 12 months) due to prolonged radiographic response or stable disease were able to do so without apparent cumulative toxicity (Topalian 2012). Finally, disease-related considerations suggest that a one-year duration of nivolumab is optimal. Among patients with stage 3 NSCLC who achieve disease control after chemoradiation, approximately 75% of cases that eventually progress will do so within the first 12 months after completion of chemoradiation, suggesting that this is the highest risk period (Butts 2013). Post-treatment fluorodeoxyglucose (FDG) uptake not representing disease recurrence or progression has been reported up to 15 months after completion of chemoradiation (Larici 2011). If such radiographic findings correspond to physiologic effects related to tumor antigenic stimulation, then this period of time might represent the optimal period to capitalize on the abscopal effect. Nivolumab dose, infusion time, and schedule: In this trial, patients assigned to the nivolumab arm will receive a fixed dose of 240 mg IV infused over 30 minutes every two weeks for 16 weeks, followed by nivolumab 480 mg IV infused over 30 minutes every 4 weeks for 36 weeks (52 weeks total). Nivolumab monotherapy has been extensively studied in NSCLC populations in studies CA209003, CA209063, CA209017, and CA209057 with body weight normalized dosing (mg/kg). Nivolumab pharmacokinetics (PK) and exposures of subjects in these studies have been characterized by population pharmacokinetic (PPK) analysis of data collected in these studies, together with PK data from several Phase 1, 2, and 3 clinical studies of nivolumab monotherapy in solid tumors. Nivolumab PK was determined to be linear, with dose proportional exposures over a dose range of 0.1 to 10 mg/kg. Nivolumab clearance and volume of distribution were found to increase with increasing body weight, but the increase was less than proportional, indicating that a mg/kg dose represents an over-adjustment for the effect of body weight on nivolumab PK. Conversely, given the relationship between nivolumab PK and body weight, a flat-dose is expected to lead to lower exposures in heavier subjects, relative to the exposures in lighter subjects. Table 2 presents summary statistics of the estimated nivolumab steady-state trough, peak and time-averaged concentration (Cminss, Cmaxss, and Cavgss, respectively; document on file) in NSCLC subjects receiving 3 mg/kg, together with corresponding statistics of exposures predicted for a flat nivolumab dose of 240 mg. It should be noted that a dose of 240 mg nivolumab is identical to a dose of 3 mg/kg for subjects weighing 80 kg, which is the approximate median body weight of NSCLC subjects in the three Phase 2 and 3 clinical studies of nivolumab monotherapy in NSCLC subjects (CA209017, CA209057, and CA209063). As evident from the data presented below, the geometric mean values of Cminss, Cmaxss, and Cavgss with flat dosing are slightly (< 15%) higher than that produced by a 3 mg/kg dose, and the coefficient of variation (cv%) in these measures of exposure are only slightly (< 10%) greater than that of 3 mg/kg dosing. Nivolumab has been shown to be safe and well tolerated up to a dose level of 10 mg/kg, and the relationship between nivolumab exposure produced by 3mg/kg and efficacy has been found to be relatively flat. The summary statistics of nivolumab steady state exposure are listed in below Table 2. Rationale for 480mg Q4W Dosing Nivolumab 480 mg every 4-week schedule (Q4W) will be more convenient for subjects. Based on pharmacokinetic modeling, the 480 mg Q4W (after steady state is reached with 240 mg every 2 weeks) will provide steady-state average concentrations similar to 3 mg/kg or 240 mg Q2W, which has been shown to provide longer survival in NSCLC patients. However, 480 mg Q4W is expected to result in higher (approximately 20%) steady-state maximum concentration (peaks), and lower (approximately 10%) steady-state trough concentrations compared to steady state of 3 mg/kg Q2W. Nivolumab was adequately tolerated up to 10 mg/kg, the highest dose level tested, and no maximum tolerated dose was identified. In addition, the exposure-response relationship for safety is flat. Thus, a slight increase in the steady-state maximum concentration is not expected to increase the safety risk of nivolumab. Furthermore, a marginal decrease in steady-state trough concentration is not expected to reduce the efficacy as high trough concentrations and > 90% intra-tumoral receptor occupancy are still maintained at 480 mg Q4W dose. Nivolumab 480 mg Q4W is expected to have similar efficacy and safety profile to 240mg Q2W. Rationale for Shorter Infusion Times for Nivolumab Prolonged infusion times place a burden on patients and treatment centers. Establishing that nivolumab can be safely administered using shorter infusion times of 30 minutes duration for nivolumab in subjects will diminish the burden provided no change in safety profile. Previous clinical studies of nivolumab monotherapy have used a 60-minute infusion duration for nivolumab. However, nivolumab has been administered at up to 10 mg/kg with the same infusion duration: nivolumab has been administered safely over 60 minutes at doses ranging up to 10 mg/kg safely over long treatment duration. In Study CA209010, (a Phase 2, randomized, double blinded, dose-ranging study of nivolumab in subjects with advanced/metastatic clear cell RCC) a dose association was observed for infusion site reactions and hypersensitivity reactions (1.7% at 0.3 mg/kg, 3.7% at 2 mg/kg and 18.5% at 10 mg/kg). All the events were grade 1-2 and were manageable. An infusion duration of 30 minutes for 3 mg/kg nivolumab (30% of the dose provided at 10 mg/kg) is not expected to present any safety concerns compared to the prior experience at 10 mg/kg nivolumab dose infused over a 60-minute duration. Overall, infusion reactions including high-grade hypersensitivity reactions have been uncommon across nivolumab clinical studies. Overall, a change in safety profile is not anticipated with 30-minute infusion of nivolumab. Radiotherapy credentialing and review. Across studies and disease types, there has been no pattern to suggest that prior RT predisposes patients to recall reactions or other toxicities in the prior radiation field, nor does pneumonitis appear to be associated with the presence of intra-thoracic malignancy. However these data-sets are quite limited and largely related to patients treated in the metastatic setting with the thoracic radiotherapy having occurred at some time prior to the nivolumab using a variety of radiotherapy doses and techniques but often in the palliative range. Definitive chemoradiotherapy carries a real risk for lung injury. Therefore, this trial testing adjuvant nivolumab will require substantial radiotherapy treatment credentialing/benchmarking and periodic case review of the radiotherapy dosimetry. Through an active quality assurance program, we hope to minimize the chance for increased toxicity related to sub-optimal radiotherapy techniques. Additionally, central review of follow-up imaging will occur. This is being required for three main reasons: 1) Co-primary end-point of PFS; 2) Correlation with any potential increase in lung toxicity; 3) Scientific understanding of potential differences in imaging changes that could occur in immunotherapy cohort compared to placebo cohort.
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2.5 biomarker studies 2.5.1 tumor

The effect of tumor PD-L1 expression on treatment response to anti-PD-1 targeted immunotherapy is a key focus of ongoing investigation. Identification of predictive biomarkers of response to therapy protects patients from exposure to risks of ineffective therapies and improves cost-effectiveness. Submission of formalin-fixed and paraffin embedded tumor samples (blocks) from core or excisional biopsy is required for all patients at the time of study enrollment. Preferably, an archived tumor block sample should be shipped for this study. If an archived tumor block sample is not available, then two 2mm punches from the core needle biopsy blocks may be provided for analysis. If punches are not available, at a minimum, one H&E and 5 positively charged unstained slides may be sent (see details in Section 3.2.15). NOTE: core or excisional biopsy is required. Fine needle aspirates (FNA) and cytology specimens are not adequate for PD-L1 analysis. Analysis of PD-L1 expression will be performed by use of the 28-8 antibody to PD-L1 (BMS) using the Dako IHC platform (Taube 2012). PD-L1 membrane staining will be assessed by light microscopy. Either complete circumferential or partial linear plasma membrane staining will constitute positive PD-L1 staining. While cytoplasmic staining may be observed, it will not be used in the evaluation of tissue sample status. Alternative biomarkers may be evaluated as determined by additional data associated with disease progression or response to nivolumab.  
2.5.2 Optional tumor tissue collection and studies An optional image-guided core needle (at least 18 gauge) tumor biopsy upon evidence of progressive disease (PD) after step 2 registration, may be performed according to institutional practice, provided it is not associated with unacceptable clinical risk. If a standard-of-care diagnostic biopsy to confirm recurrence is obtained, at least two core biopsies, minimum, should be obtained as part of this recurrence biopsy. Paraffin embedded tissue from this biopsy will be used for confirmation of recurrence and for additional research by the RTOG. Patients consenting to have their tissue submitted at recurrence will have a tube of whole blood collected. These samples will be shipped and stored at the Biospecimen Bank at UCSF.
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optional tumor samples (immune-related or

The remaining tumor samples after the PD-L1 staining will be shipped back and stored at UCSF. They will be used for the following studies: The expression and spatial distribution of immune-related or response-related markers by Multiplex immunohistochemistry may also include, but may not be limited to, PD-L1, CTLA-4, CD3, CD4, CD8, CD45RO, forkhead box P3, granzyme B, OX40, PD1, cleaved caspase 3 and Ki67. Archived material (or biopsies if available) may also be analyzed for the presence of key mutations which may include but are not limited to: EGFR, K-ras, N-ras, B-raf, anaplastic lymphoma kinase and the met proto oncogene to evaluate their potential relevance and correlations with response to nivolumab.  
2.5.3 Optional blood collection for Blood borne biomarkers Blood samples will be analyzed to evaluate protein, nucleic acid, and cellular biomarkers that relate to nivolumab. PBMC will also be isolated from whole blood and will be preserved, and may be used for subsequent flow cytometry or assessment of the diversity of the immune cell repertoire based on VDJ coding region analysis, the relationship to clinical responses, and changes in response to treatment with nivolumab. Blood collected for analysis of immune cell gene expression profiles within the peripheral compartments will be evaluated for any relationship with efficacy endpoints. Serum samples will also be collected for analysis of circulating soluble factors in relation to immune status at baseline and in response to treatment. Factors to be analyzed may include but are not limited to: the presence of IFN-γ tumour necrosis factor-α, interleukin (IL)-2, IL-6, IL-10, IL-8, IL-12, and levels of soluble PD-L1 using Luminex platform. Autoantibody profiles Recent studies have found that more than 25% of healthy individuals have strong IgG
humoral immune responses to a variety of self-antigens, indicating that a "benign" form autoimmunity is much more common than autoimmune disease (Wandstrat 2006, Li 2011, Tan 1997). This autoimmunity is directed against a variety of self-antigens. These findings indicate that many healthy individuals exhibit significant autoimmunity that is regulated in the peripheral immune system by pathways such as those triggered by CTLA-4 and PD1. Consistent with this, CTLA-4 and PD1 are both known to potentiate autoimmune disease, suggesting that the inhibition of these regulatory pathways aggravates pre-existing autoimmunity. Based on this, we hypothesize that checkpoint therapy immune-related adverse events often result from the activation of pre-existing autoimmunity. We will test this hypothesis by utilizing a variety of novel technologies developed in the Department of Immunology at UT Southwestern to quantify autoimmune responses. Specifically, the UT Southwestern core facility has the ability to measure IgG autoantibody reactivity against more than 120 antigens simultaneously with as little as 5 l of serum or plasma. We will screen the autoantibodies in sera from individuals before, during, and after nivolumab therapy using this system. The protein array system that we have developed for autoantibody screening can also be used to assess antibodies against any antigen. Consequently, a panel of tumor-type-specific antigens will also be incorporated into these arrays so that we can follow the level and specificity of anti-tumor humoral immunity elicited by checkpoint therapy in individual patients and correlate this with disease progression.
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3. patient selection eligibility and

Note: Exceptions to inclusion and exclusion criteria are not permitted. For questions concerning eligibility, please contact the Biostatistical/Data Management Center (via the contact list on the RTOG website). For radiation therapy-related eligibility questions, please contact ACR Core Laboratory/RTQA (via the contact list on the RTOG website). This does not include diagnostic imaging questions as described in Section 2.  
3.1 **Patient Selection Guidelines**
Although the guidelines provided below are not inclusion/exclusion criteria, investigators should consider these factors when selecting patients for this trial. Investigators also should consider all other relevant factors (medical and non-medical), as well as the risks and benefits of the study therapy, when deciding if a patient is an appropriate candidate for this trial.  
3.1.1 Patients must have the psychological ability and general health that permits completion of the study requirements and required follow up.  
3.1.2 Women of childbearing potential (WOCBP) and men who are sexually active should be willing and able to use medically acceptable forms of (hormonal or barrier method of birth control; abstinence) contraception prior to study entry and for the duration of study participation. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug/placebo. Men who are sexually active with WOCBP should use any contraceptive method with a failure rate of less than 1% per year. Men receiving nivolumab/placebo and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile) as well as azoospermic men do not require contraception 3.1.3 Submission of tumor tissue for PD-L1 expression analysis is required for all patients.  
Investigators should check with their site Pathology department regarding release of biospecimens before approaching patients about participation in the trial. (See details of tumor tissue submission in Section10.)
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3.2 eligibility criteria a patient

3.2.1 Pathologically (histologically or cytologically) proven diagnosis of NSCLC with unresectable, medically inoperable disease, or patients who refuse resection stage IIIA or stage IIIB disease (AJCC 7th edition)
Unresectable stage IIIA disease is defined by multiple and/or bulky N2 mediastinal lymph nodes on computed tomography (CT) scan such that, in the opinion of the treating investigator, the patient was not a candidate for surgical resection.  
N2 disease must have been documented by biopsy, or at a minimum by fluorodeoxyglucose positron emission tomography (PET) or CT if nodes were more than 2 cm.  
T4 disease is often considered resectable at the discretion of a thoracic surgeon.  
Patients with T4N0 or T4N1 disease can be enrolled if their case is reviewed by a thoracic surgeon and felt to be unresectable or if they are either medically inoperable or refuse surgery.  
Stage IIIB patients have N3 or T4N2 status. N3 status must have been documented by the presence of a contralateral (to the primary tumor) mediastinal lymph node or supraclavicular or scalene lymph node proven by biopsy, or at a minimum by fluorodeoxyglucose PET or more than 2 cm on CT scan. Patients with disease extending into the cervical region (defined as disease extending above cricoid cartilage) are not eligible.  
Patients with either N2 or N3 adenopathy and Tx disease will be eligible and categorized as Stage IIIA or IIIB based on their nodal status.  
3.2.2 Appropriate stage for study entry based on the following diagnostic workup:
History/physical examination, including documentation of height, weight, BSA, and vital signs, within 30 days prior to registration; CT scan with IV contrast (CT scan without contrast acceptable if IV contrast is medically contraindicated) of the lung and upper abdomen through the adrenal glands within 60 days prior to registration (recommended within 30 days prior to registration);
MRI of the brain with contrast (or CT with contrast if MRI is medically contraindicated) within 60 days prior to registration; **note**: the use of intravenous contrast is required for the MRI or CT (unless medically contra-indicated).  
Whole-body FDG-PET/CT within 60 days prior to registration; **note**: patients do not need to have a separate CT of chest and upper abdomen with contrast if PET/CT imaging includes a high quality CT chest with contrast.  
3.2.3 Age ≥ 18 years; 3.2.4 The trial is open to both genders; 3.2.5 Zubrod Performance Status of 0-1 within 30 days prior to registration; 3.2.6 Adequate hematologic function within 14 days prior to registration defined as follows:
Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3; Platelets ≥ 100,000 cells/mm3; Hemoglobin ≥ 9.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥9.0 g/dl is acceptable.);
3.2.7 Adequate renal function within 14 days prior to registration defined as follows:
Serum creatinine within normal institutional limits or creatinine clearance ≥60 ml/min 3.2.8 Adequate hepatic function within 14 days prior to registration defined as follows:
Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for the institution (except subjects with Gilbert Syndrome, who can have total bilirubin <3.0 mg/dL);
ALT, AST ≤ 3.0 x ULN for the institution; 3.2.9 Adequate respiratory function within 180 days prior to registration defined as follows:
FEV1 > 1.2 liters; DLCO ≥ 50% predicted; 3.2.10 Patients with post-obstructive pneumonia are eligible provided they no longer require intravenous antibiotics at registration; 3.2.11 Patients must be at least 3 weeks from prior thoracotomy (if performed); if prior thoracotomy then measurable disease on imaging must be present 3.2.12 A pleural effusion, which is a transudate, cytologically negative and non-bloody, are eligible if the radiation oncologist feels the tumor can be encompassed within a reasonable field of radiotherapy; if pleural fluid is too small a volume to effectively sample by thoracentesis and does not show increased metabolic activity on CT/PET imaging, the patient will be remain eligible.  
3.2.13 Negative serum pregnancy test within three days prior to registration for women of childbearing potential 25  
3.2.14 The patient must provide study-specific informed consent prior to study entry. Patients who lack the psychological or intellectual capacity to consent for themselves are excluded.  
3.2.15 Sites must verify that archived tissue will be available prior to Step 1 registration to the trial although the actual submission can be immediately after Registration Step 1 but at least 5 weeks prior to Registration Step 2.
Recognizing the difficulties obtaining adequate tissue for analysis from locally advanced lung cancer patients, there are three options available. We would encourage investigators to provide the preferred amount of samples to assist in the greatest scientific yield. NOTE: core or excisional biopsy is required for this study. Fine needle aspirates (FNA) and cytology specimens are not adequate for PD-L1 analysis.  
Preferred: H&E slide and archived tissue tumor block. If sites wish the block to be returned they may submit the block and the Biospecimen Bank will cut the unstained for the required study and then punch and return the block Alternative: If an archived tumor block sample cannot be shipped for this study, then two 3mm punches from the core needle biopsy blocks may alternatively be provided for analysis in addition to the H&E slide. Minimum: One (1) H&E stained slide (required) and five positively charged unstained slides cut at 3-4 microns from the same block as the H&E. Unstained slides must be stored at 4⁰C same day as being cut and shipped with a cold pack at 4⁰C within 5 business days after being cut. Do NOT store or ship unstained slides at room temperature.
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step 2 registration (after completion

3.2.17 Must be randomized less than 12 weeks following completion of chemoradiotherapy to ensure nivolumab/placebo begins no later than 12 weeks following completion of chemoradiotherapy.  
3.2.18 Laboratory values must meet the following criteria and must be obtained within 21 *days* prior to randomization WBC ≥ 2000/μL Neutrophils ≥ 1000/μL
Platelets ≥ 50 x103/μL
Hemoglobin > 9.0 g/dL (Note: The use of transfusion or other intervention to achieve Hgb ≥9.0 g/dl is acceptable.)
Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min
(if using the Cockcroft-Gault formula below):
Female CrCl = (140 - age in years) x weight in kg x 0.85 72 x serum creatinine in mg/dL Male CrCl = (140 - age in years) x weight in kg x 1.00 72 x serum creatinine in mg/dL
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ast/alt <= 3 x uln

Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)
3.2.19 All toxicities attributed to prior chemoRT therapy other than alopecia, fatigue, or peripheral neuropathy must have resolved to ≤Grade 2 (NCI CTCAE version 4)
before administration of nivolumab or placebo.  
3.2.20 Negative serum pregnancy test for women of childbearing potential within 7 days of randomization 3.2.21 Agreement of women of childbearing potential to use highly effective contraception during receipt of study drug and up to 161 days (23 weeks) from the last dose of nivolumab/placebo and men receiving nivolumab/placebo who are sexually active with women of childbearing potential to use highly effective contraception during receipt of study drug for 31 weeks from the last dose of nivolumab/placebo.  
3.2.22 Mandatory submission per 3.2.15 is required for PD-L1 and other biomarker analysis.
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3.3 ineligibility criteria patients with

3.3.2 Prior or current invasive malignancy (except non-melanomatous skin cancer, localized bladder and prostate cancer) unless disease free for a minimum of 2 years (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible);
3.3.3 Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields. For example, patients with prior breast radiotherapy treatments would likely be excluded; 3.3.4 Prior systemic treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways; 3.3.5 A condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease; 3.3.6 Severe, active co-morbidity defined as follows:
An active, known or suspected autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger; Known immunosuppressive disease, for example HIV infection or history of bone marrow transplant or CLL;
Chronic Obstructive Pulmonary Disease (COPD) exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration. COPD requiring chronic oral steroid therapy; Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months; Transmural myocardial infarction within the last 6 months; Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration; History of symptomatic or previously established interstitial lung disease; Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection; History of severe hypersensitivity reaction to any monoclonal antibody or allergy to study drug components; As there is potential for hepatic toxicity with nivolumab, drugs with a predisposition to hepatotoxicity should be used with caution in patients treated with nivolumabcontaining regimen; 3.3.7 Pregnancy, nursing females, or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic.
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step 2 registration (after completion

3.3.8 Failure to complete minimum required amounts of chemoradiation (defined as at least 50%
of intended days of chemotherapy administration and at least 54 Gy total dose of radiation)
3.3.9 Bilateral lung V20 >37% on radiation therapy treatment plan used for concurrent chemoradiotherapy 3.3.10 Grade 3 and above pulmonary toxicity of dyspnea, hypoxia, or pneumonitis experienced during chemoradiation 3.3.11 Evidence of disease progression after chemoradiation or evidence of metastastic disease
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4. requirements for study entry

4.1 Assessment tables at registration, treatment, and follow-up time points:  
| 1                                                                                                                                                           |                                               |                    |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------|--------------------|
| Assessments                                                                                                                                                 | Prior to Registration Step 1                  | Prior to Treatment |
| (calendar days)                                                                                                                                             | (calendar days)                               |                    |
| Mandatory tissue submission                                                                                                                                 | Verify available                              |                    |
| for PD-L1 analysis (see note) History and physical exam                                                                                                     | 30                                            |                    |
| Zubrod performance status                                                                                                                                   | 30                                            |                    |
| Tumor measurements                                                                                                                                          | 30                                            |                    |
| Rad Onc exam                                                                                                                                                | 30                                            |                    |
| Med Onc exam                                                                                                                                                | 30                                            |                    |
| CBC/differential; ANC,                                                                                                                                      | 14                                            |                    |
| platelets; hemoglobin Na, K, CO2, Cl,                                                                                                                       | 14                                            |                    |
| Mg, Ca, LDH                                                                                                                                                 | 14                                            |                    |
| Serum creatinine                                                                                                                                            | 14                                            |                    |
| Total bilirubin, AST, ALT,                                                                                                                                  | 14                                            |                    |
| Alk Phos Serum pregnancy test                                                                                                                               | 3                                             |                    |
| Cytology/Pathology Report                                                                                                                                   | 90                                            |                    |
| confirming NSCLC Whole body FDG-PET/CT                                                                                                                      | 60                                            |                    |
| (base of skull to mid thigh) CT chest with contrast and                                                                                                     | 60                                            |                    |
| include adrenals* MRI of brain (CT if MRI                                                                                                                   | 60                                            |                    |
| contraindicated) Pulmonary function testing                                                                                                                 | 90                                            |                    |
| (PFTs/DLCO) Informed consent                                                                                                                                | Within 30 days including Day  of registration |                    |
| FACT-L, PROMIS, EQ-5D5L                                                                                                                                                             | X 1                                           |                    |
| Specimen collection for                                                                                                                                     | If patient consents: 14. See                  |                    |
| banking                                                                                                                                                     | Section 10.                                   |                    |
| * Patients do not need to have a separate CT of chest and upper abdomen with contrast if  FDG-PET/CT imaging includes a high quality CT chest with contrast |                                               |                    |  
Notes for Pre-Treatment Assessment Mandatory submission: Preferred: H&E slide and archived tissue tumor block. If sites wish the block to be returned they may submit the block and the Biospecimen Bank will cut the unstained for the required study and then punch and return the block Alternative: If an archived tumor block sample cannot be shipped for this study, then two 3mm punches from the core needle biopsy blocks may alternatively be provided for analysis in addition to the H&E slide. Minimum: One (1) H&E stained slide (required) and five positively charged unstained slides cut at 3-4 microns from the same block as the H&E. Unstained slides must be stored at 4⁰C same day as being cut and shipped with a cold pack at 4⁰C within 5 business days after being cut. Do NOT store or ship unstained slides at room temperature. Sites must verify that tissue is available prior to Step 1 registration to the trial although the actual submission can be immediately after Registration Step 1 but at least 5 weeks prior to Registration Step 2. NOTE: core or excisional biopsy is required for this study. Fine needle aspirates (FNA) and cytology specimens are not adequate for PD-L1 analysis.  
| Assessments                                                                                                                     | Weekly during Concurrent   | At week 1 and 5 only during   |
|---------------------------------------------------------------------------------------------------------------------------------|----------------------------|-------------------------------|
| Treatment                                                                                                                       | concurrent chemoRT         |                               |
| Performance status                                                                                                              | X                          |                               |
| Rad Onc Evaluation                                                                                                              | X                          |                               |
| Med Onc evaluation                                                                                                              | X 1                        |                               |
| CBC/differential; platelets                                                                                                     | X 1 1                      |                               |
| Na,K,CO2, Cl,                                                                                                                   | X 1                        |                               |
| Mg, Ca, LDH                                                                                                                     | X                          |                               |
| Total bilirubin, ALT, AST                                                                                                       | X 1                        |                               |
| Serum creatinine or                                                                                                             | X 1                        |                               |
| creatinine clearance Adverse event evaluation                                                                                   | X                          | 2                             |
| Specimen collection for                                                                                                         | X                          |                               |
| banking 1 C1D1 testing does not need to be repeated if performed within 7 days of starting protocol  therapy. 2Day 1 and Day 42 |                            |                               |  
| Prior to                                                                                                     |                                               |
|--------------------------------------------------------------------------------------------------------------|-----------------------------------------------|
| Treatment with                                                                                               |                                               |
| nivolumab/placebo -14 days                                                                                   |                                               |
| Medical history and                                                                                          | 21                                            |
| height Assessments                                                                                           | Prior to Registration Step 2 (calendar days)  |
| Physical examination  including vital signs  (blood pressure,  weight)                                       | 21                                            |
| Zubrod performance                                                                                           | 21                                            |
| status Na, K, CL, Mg, Phos,                                                                                  | 21                                            |
| Ca, LDH Total bilirubin, AST,  ALT, Alk Phos, amylase, lipase,  glucose, albumin                             | 21                                            |
| BUN; Serum creatinine                                                                                        | 21                                            |
| CBC/differential;                                                                                            | 21                                            |
| platelets Thyroid function (TSH,  free T3 and free T4),  fasting am cortisol                                 | 21 1                                          |
| Serum pregnancy test                                                                                         | X                                             |
| AE evaluation                                                                                                | X                                             |
| CT of chest with  contrast and include  adrenals                                                             | 30 (and at least 14) after chemoRT  completed |
| Mandatory Tissue Submission for PD-L1  Analysis                                                              | 35 and ideally                                |
| immediately after  Registration Step 1                                                                       |                                               |
| FACT-L, PROMIS,                                                                                              | X 2                                           |
| EQ-5D-5L                                                                                                     |                                               |
| 1Within one week of study randomization 2After Step 2 registration, prior to initiation of nivolumab/placebo |                                               |  
| ASSESSMENTS DURING NIVOLUMAB/PLACEBO TREATMENT (1 YEAR)                                      |                          |                |
|----------------------------------------------------------------------------------------------|--------------------------|----------------|
| Assessments                                                                                  | On Day 1 of each Cycle   | Every 3 months |
| Physical examination  including vital signs (blood  pressure, weight)                        | X                        |                |
| Zubrod performance status                                                                    | X                        |                |
| Na, K, CL, Mg, Phos, Ca,                                                                     | X                        |                |
| LDH Total bilirubin, AST, ALT, Alk Phos, amylase, lipase, glucose, albumin                   | X                        |                |
| CBC/differential; platelets                                                                  | X                        |                |
| BUN, creatinine                                                                              | X                        |                |
| TSH                                                                                          | X 1                      |                |
| AM cortisol                                                                                  | As needed if symptomatic |                |
| 2                                                                                            |                          |                |
| Serum or urine Pregnancy                                                                     | X                        |                |
| test AE evaluation                                                                           | X                        |                |
| CT of chest with contrast                                                                    | X 3                      |                |
| and include adrenals Specimen collection for                                                 | X                        |                |
| banking FACT-L, PROMIS, EQ-5D5L                                                                                              | X 4                      |                |
| 1 Every 6 weeks during q2 week dosing, then every 8 weeks during q4 week dosing; assess free |                          |                |  
1 Every 6 weeks during q2 week dosing, then every 8 weeks during q4 week dosing; assess free T3 and free T4 if clinically indicated (e.g. abnormal TSH or symptomatic)
2Every 4 weeks3After completion of chemoradiotherapy, radiographic assessment with CT chest with contrast including adrenals will occur prior to starting nivolumab/placebo as a component of Step 2 Registration. Further radiographic assessment will occur every 3 months for 2 years (including the year of nivolumab/placebo). The first day of nivolumab/placebo will be used for calculation of the 3 month intervals. After 2 years, radiographic disease assessment should be performed every 6 months during year 3-5 then annually thereafter. FDG-PET/CT should be done to confirm clinically uncertain progression or treatment related effects at the discretion of the treating investigator. This imaging may be done locally.  
4At 3, 6, 9 and 12 months; should be collected regardless of disease status of the patient  
| ASSESSMENTS IN FOLLOW UP POST NIVOLUMAB/PLACEBO Assessments Every 3 mos until 2  years post chemoRT then  every 6mos until 5 years  post chemoRT, then  yearly History and physical exam X Zubrod performance status X Tumor status X Med Onc exam X AE Evaluation X CBC with diff, Plts X 1 Na, K, CL, Mg, Phos, Ca, LDH,  X 1 glucose Total bilirubin, ALT, AST, Alk  X 1 Phos, albumin 1 Serum creatinine, BUN X TSH* X 1 Serum or Urine Pregnancy test X 1 CT Chest with contrastand X 2 include adrenals 3 FACT-L, PROMIS, EQ-5D-5L X * Assess free T3 and free T4 if clinically indicated (e.g. abnormal TSH or   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
FACT-L, PROMIS, EQ-5D-5L X
3
* Assess free T3 and free T4 if clinically indicated (e.g. abnormal TSH or symptomatic)
1 At 35 days from the last dose (± 7 days) or coinciding with the date of discontinuation of study drug (± 7 days) if the date of discontinuation is greater than 42 days from the last dose. Repeat in 80 days (from first follow-up assessment) only if study drug related toxicity persists. Pregnancy test must be performed at both time points. Assess free T3 and free T4 if clinically indicated.  
2After completion of chemoradiotherapy, radiographic assessment with CT
chest with contrast including adrenals will occur prior to starting nivolumab/placebo as a component of Registration Step 2. Further radiographic assessment will occur every 3 months for 2 years (including the year of nivolumab/placebo). The first day of nivolumab/placebo will be used for calculation of the 3 month intervals. After 2 years, radiographic disease assessment should be performed every 6 months during year 3-5 then annually thereafter. FDG-PET CT should be done to confirm clinically uncertain progression or anatomic changes in the thorax likely due to the effects of chemoradiotherapy, at the discretion of the treating investigator. This imaging may be done locally.  
3FACT-L, PROMIS, and EQ-5D-5L are collected at 15 and 18 months from start of nivolumab/placebo; should be collected regardless of disease status of the patient. EQ-5D-5L is collected at 2, 3, 4, and 5 years from start of nivolumab/placebo.  
Follow-up of Patients Discontinuing Therapy Early After completion of study treatment, subjects who discontinue for reasons other than progressive disease will have post-treatment follow-up for disease status until disease progression, initiating a non-study cancer treatment, withdrawing consent or becoming lost to follow-up. After documented disease progression each subject will be followed for overall survival until death, withdrawal of consent, or the end of the study (whichever occurs first).
rtog foundation rtog 3505
4.2 definition of disease assessments

Tumor assessments will be made using modified RECIST 1.1 criteria. The same measurable and non-measurable lesions will be followed from baseline across on-study time points using RECIST 1.1 guidelines. A RECIST 1.1 tumor assessment will be derived for each on-study time point for each enrolled subject, from which the primary objective of the trial will be determined. In subjects whose in-field disease status is ambiguous, but who have not developed systemic progression, treatment may continue. Follow-up scans will be reviewed by ACR Diagnostic Imaging Core Lab in consultation with the study PIs, if necessary to determine status based on the below guidelines. Patients with uncertain progression may require repeat imaging at 6 weeks rather than 3 months if disease status remains uncertain. Refer to Appendix II for detailed definitions of RECIST v1.1 response assessment
rtog foundation rtog 3505
4.3 central image collection and

Imaging exams will be collected at the following time points. Images must be submitted in digital format to the ACR DI Core Lab for archiving:
Baseline (prior to study treatment)
Post-chemoRT All mandated follow-up imaging: every 3 months for 2 years; every 6 months for years 35; then yearly At disease progression And at request when treatment occurs beyond progression and subsequent tumor evaluations Imaging studies (defined in Section 4.1) as well as the Image Transmittal Worksheet will be submitted to the ACR DI Core Lab within 2 weeks of image acquisition for all image data sets, excluding imaging visits where disease progression is suspected. Where disease progression is suspected, all imaging studies performed from baseline to date of progression must be submitted to ACR DI Core Lab within 3 business days of the date progression is determined.
rtog foundation rtog 3505
4.3.2 independent review of progression

At the time of investigator-assessed progression, sites must request an Independent Review of Progression from the ACR DI Core Lab. This Independent Review of Progression at the time of investigator-assessed progression is a separate process from the IRRC review to assess the primary endpoint. All subjects who are assessed to have RECIST 1.1 progression by the treating investigator must have all available tumor assessments submitted for an Independent Review of Progression. The Independent Review of Progression will be conducted by a blinded, third party, independent radiologist contracted by ACR DI who will assess the scans for RECIST 1.1 progression. When the review is complete, results from the central radiology review and local interpretation will be compared. If the central reviewer agrees with the local assessment of progression, subsequent therapy may be initiated per investigators' clinical decision, and protocol therapy may be discontinued or continued based on the guidelines in section 6.3.5 (Treatment Beyond Disease Progression). If there is discordance between the local and central reviews (central review does not confirm progression), a central adjudicator from the imaging committee organized by the ACR DI Core Lab will review both the local and central results and determine which interpretation
(local or central) with which they agree. The adjudicator's decision is then the final decision of the ACR DI committee on the progression review. If the adjudicator agrees with the local assessment of progression, subsequent therapy may be initiated per investigators' clinical decision, and protocol therapy may be discontinued or continued based on the guidelines in section 6.3.5 (Treatment Beyond Disease Progression). If the adjudicator agrees with the central reviewer and does not confirm progression, these cases will be discussed with the individual sites and a consensus decision will be made as to the participation of the patient on the trial therapy. The adjudicator's decision will become the interpretation which must be used by the local site's treating physician if the patient is to remain on protocol therapy. It is the local site treating physician's responsibility to determine whether to base clinical decisions on the local read or the central read if there is discordance; however, if the patient is to remain on protocol therapy, interpretation from the centralized review must be used. In those cases when the site investigators disagree with final adjudicated central review interpretation, subsequent therapy may be initiated per investigators' clinical decision, and protocol therapy may be discontinued. The local site investigators also have the option of continuing therapy beyond their local interpretation of progression based on section 6.3.5. If treating the patient beyond progression with nivolumab the unusual situation is created in which the local site has reported progression, the central review with adjudication disagrees and the patient is continuing on nivolumab. In this specific situation the patient remains on study and continues tumor assessments outlined by protocol until central review determines RECIST 1.1 progression. For any patient being treated beyond progression based on the criteria outlined in Section 6.3.5, central imaging review must occur again at the time further progression is documented by the local site. This further progression is defined as an additional 10% increase in tumor burden volume from time of initial PD. This includes an increase in the sum of all target lesions and/ or the development of new measurable lesions. If this further progression is confirmed by central review treatment should be discontinued permanently. If clinically acceptable, subsequent therapy should begin only after RECIST 1.1 progression has been assessed by the central reviewers. The independent review of progression will occur within 5-7 working days of receipt of all needed imaging at ACR. Subjects who start subsequent therapy without prior assessment of RECIST 1.1 progression by the central review process must continue tumor assessments (if clinically feasible) according to the protocolspecified schedule and submit them for central review. When RECIST 1.1 progression is assessed by the investigator (whether assessed before or after the start of palliative local therapy or subsequent therapy), the central review center must be notified. Tumor assessments may be discontinued when the independent central radiologist assesses the subject to have met RECIST 1.1 criteria for progression.
rtog foundation rtog 3505
4.3.3 independent radiology review committee

For all randomized subjects with Baseline imaging and at least one on-study time-point, a timepoint-by-timepoint imaging evaluation will be performed by an Independent Radiology Review Committee (IRRC), consisting of two (2) trained radiologist reviewers and an adjudicator, if warranted. The two primary reviewers will determine time point and cross time point response assessments. Neither primary reviewer will have access to the other primary reviewer's annotations or tumor response data. Upon completion of both reviewers' read, comparison of key adjudication variables for each of the independent reviewers is performed and if warranted, adjudication is conducted. The IRRC review is not subject to input from clinical sites or imaging facilities. All tumor assessments will be provided by ACR DI Core Lab for statistical analysis as described in the protocol. Dosimetry information from the radiation therapy treatment plan may be requested and used to better understand the imaging changes seen. This is particularly critical due to the possibility of evolving radiation lung fibrosis during the time period of nivolumab/placebo treatment. At the time of the final analysis for PFS, the IRRC will review tumor assessments in all randomized subjects to determine RECIST 1.1 response for the analyses of PFS. This IRRC review for the final PFS analysis will be a separate process from the blinded independent radiology review at the time of investigator-assessed progression.
rtog foundation rtog 3505
5. treatment plan/regimen description

This will be a randomized, double-blind, placebo-controlled phase 3 clinical trial. Patients will be treated with standard concurrent chemoradiation (thoracic radiation to 60 Gy plus cisplatin-etoposide), followed by randomization to nivolumab or placebo, which will be started 4-12 weeks after completion of concurrent chemoradiation administered every 2 weeks as an intravenous infusion over 30 minutes for up to a total of 1 year.  
Concurrent chemoradiation: Chemotherapy and radiotherapy are to begin within 48 hours of each other. Day 1 of radiotherapy must be Monday, Tuesday, or Wednesday, but no later in the week. Treatment must begin within 14 days after registration.
rtog foundation rtog 3505
5.1 chemotherapy/other agent-based therapy 5.1.1

Concurrent chemoradiation **must begin within 14 days after step 1 registration.** Consists of one treatment course
rtog foundation rtog 3505
cisplatin dose administration

Cisplatin 50mg/m2is given intravenously on days 1 and 8, and days 29 and 36 of concurrent therapy. After administering appropriate antiemetics, cisplatin will be infused over 1-2 hours along with vigorous hydration. Cisplatin Supportive Care Guidelines Patients must receive intravenous hydration and and polyantiemetics on day 1, day 8, day 29, and day 36 cisplatin therapy. These should be administered according to institutional practice and the patient's baseline electrolyte levels. As an example, one commonly employed regimen is as follows: prior to cisplatin, begin intravenous hydration with 1,000 ml NS + 20 meq KCL + 4 gms MgSO4 at 250 cc/hr over two hours. The cisplatin may be preceded and followed by 12.5 grams of mannitol, IV push. After cisplatin infusion, complete the remaining 500 cc of hydration fluid over two hours. The patient should be encouraged to drink as much liquid as possible overnight if an outpatient; otherwise, an additional two liters of fluid should be given IV over the next 12 hours if the patient is an inpatient. Appropriate polyantiemetic regimens must be used prior to and following the administration of cisplatin *(e.g., phenothiazine, antihistamine, benzodiazepine plus* dexamethasone - OR - *ondansetron or 5HT3 antagonist with or without dexamethasone* and PRN benzodiazepines, as well as neurokinin/substance P inhibitors). Etoposide Dose Administration Etoposide 50mg/m2is given intravenously on days 1-5, and days 29-33 of concurrent therapy. Infuse etoposide over at least 45-60 minutes. Infusions of 30 minutes or less greatly increase the risk of hypotension.
rtog foundation rtog 3505
5.1.2 nivolumab/placebo

Nivolumab is approved in US and Europe to treat metastatic melanoma. On March 5, 2015, nivolumab was US FDA approved for the treatment of patients with metastatic squamous NSCLC with progression on or after platinum-based chemotherapy. Subsequently, nivolumab was also approved in Europe for this indication in NSCLC. On October 9, 2015, nivolumab was US FDA approved for the treatment of patients with metastatic nonsquamous NSCLC with progression on or after platinum-based chemotherapy.  
Nivolumab/placebo must begin within 4-12 **weeks after completion of chemoradiation**
If subjects meet all eligibility criteria and have recovered sufficiently from treatment with chemoradiation, initial consolidation therapy with nivolumab/placebo will be started a minimum of 4 weeks and a maximum of 12 weeks after chemoradiation is complete. Treatment with a dose of nivolumab/placebo 240 mg IV will occur on day 1 of each 2 week cycle for 16 weeks followed by 480 mg on day 1 of each 4 week cycle until progressive disease or unacceptable toxicity develop or until the subject has completed 52 weeks of therapy with nivolumab/placebo. Nivolumab should be dosed no sooner than 12 days during the every 2 week administration and no sooner than 26 days during the every 4 week administration.  
Nivolumab/Placebo *Dose Administration* Nivolumab/placebo 240 mg is given intravenously every 2 weeks for 16 weeks then dosed 480 mg every 4 weeks for 36 weeks for a total of 52 weeks (1 year).  
For both the 240 mg and the 480 mg doses, nivolumab/placebo is to be administered as a 30minute IV infusion and diluted in 0.9% Sodium Chloride Solution or 5% Dextrose solution.  
Patients may be dosed no less than 12 days from the previous dose of drug; and dosed up to 3 days after the scheduled date if necessary.  
There will be no dose modifications for nivolumab/placebo See Section 6.0 for nivolumab/placebo dose delay and management 5.2 **Radiation Therapy**
Protocol treatment must begin within 14 days **after Step 1 registration.** Note: All participating institutions will be credentialed for lung photons 3DCRT or IMRT prior to registering patients to the study. For detailed information on the specific technology requirement required for this study, please refer to the study specific guide on the RTOG Foundation 3505 protocol page of the RTOG website, www.rtog.org Protocol treatment will be scored according to the Compliance Criteria table in Section **5.2.8.**
It is recommended that radiation therapy be delivered after chemotherapy per Section 5. Day 1 of radiotherapy must be Monday, Tuesday, or Wednesday, but no later in the week.  
5.2.1Treatment Technology This protocol requires the use of photons delivered either using 3D-CRT or IMRT techniques.Tomotherapy is allowed if appropriately credentialed for its use. Use of CyberKnife is not permitted for thistrial. The use of IGRT is highly encouraged but not required. No margin reduction will be allowed whether IGRT is used or not, and separate IGRT credentialing will not be required. Institutions must complete the pre-registration credentialing requirements before registering patients on this study.
rtog foundation rtog 3505
5.2.2 immobilization and simulation immobilization

Proper immobilization is critical for this protocol. Patient setup reproducibility must be achieved using appropriate clinical devices. Simulation Imaging Contiguous CT slices of maximum 3 mm slice thickness should be obtained starting from the level ofthe cricoid cartilage and extending inferiorly through the entire liver volume. I.V. contrast-enhanced CT- simulation is recommended but not required in this study. CTs and PET/CTs should be used to guide tumor and normal organ volume definition. In the event that contrast-enhanced datasets are used for treatment planning, the density of the contrast should be overridden to a representative background electrondensity.
rtog foundation rtog 3505
motion management technique

Motion management is highly recommended for this protocol. In instances in which motion management is not possible, larger expansion volumes will be used to adequately coverthe motion-related uncertainties. The types of motion management allowed on this study are 4DCT with ITV, active breath-hold, gated treatment, and abdominal compression. IMRT will be restricted to patients with less than 1cm of tumor motion on 4D imaging or utilizing of gating, ABC, or breath hold methods. Abdominal compression as a method of minimizing respiratory motion is allowed.  
5.2.3 Imaging for Structure Definition, Image Registration/Fusion and Follow up A whole-body FDG-PET/CT and an IV contrast enhanced CT scan or MRI exam (if CT
scan with contrast is medically contraindicated, when MR of the chest is submitted, a noncontrast chest CT should also be submitted) of the lung and upper abdomen through the adrenal glands are required within 60 days prior to registration. These exams will be used for disease staging and to assist in volume delineation in all eligible patients (see Section 4.0).  
The ACR Imaging Core Lab group will collect the pre-chemoradiation treatment FDGPET/CT and dedicated contrast enhanced chest CT. ACR Imaging Core Lab will also collectall mandated follow-up CT (and/or MRI) scans of the chest and upper abdomen post-treatment, at the time of progression, and at the time point immediately prior to progression. See Section 8.2.1 for digital data imaging submission details. If FDG-PET/CT is obtained at any of the above time points including at time of progression, this should be should be submitted as well. ACR Imaging Core Lab also will be involved in the analysis of submitted imaging data as part of the confirmation of local progression review and central review of radiographic response/recurrence.  
5.2.4 Accounting for Tumor Motion Approaches and Internal and Setup Margins Internal margin **(IM)**: The IM used will be dictated by the motion management decision made at time of simulation. It is required for all cases, with the exception of instances in which simulation is done with 4DCT to develop a MIP of tumor volume (see number 4 below). 1. If the simulation is done with a free-breathing CT only, the IM will be 1 cm in the superior- inferior direction and 0.5 cm in the axial direction. 2. If simulation is done with abdominal compression, the IM will be 0.7 cm in the superior-inferior direction and 0.5 cm in the axial direction. 3. If simulation is done using an active breath-hold or gated breathing technique, the IM willbe 0.5 cm in all directions. 4. If simulation is done using a 4DCT to develop a maximum intensity projection of the tumor volume based on the entire tumor motion, no IM is needed. (This is the
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encouraged and preferred method)

Setup Margin (SM): The SM will be 0.5 cm in all directions. No margin reduction will be allowed, even when using IGRT. The final PTV is constructed by expanding the just ITV or sum of the CTV + IM by the SM based on the definitions from Table A or B in section 5.2.5.  
5.2.5 Definition of Target Volumes and Margins All structures must be labeled for digital RT data submission as listed in the table below. Capital letters, spacing and use of underscores must be applied exactly as indicated. Resubmission of data may be required if labeling of structures does not conform to the DICOMstandard name listed.  
The structures marked as "Required" in the table must be contoured and submitted with the treatment plan. There are two tables below. The first table applies to patients being treated using method 1, 2, or 3 from section 5.2.4. The second table applies only to patients being treated with method 4 of section 5.2.4 (4DCT with maximum intensity projection of the tumor volume based on the entire tumor motion) Contouring of the ITV_6000 is necessary only when the ITV approach is used.  
| DICOM Standard                                                                             | Description          | Detailed Specification                                                                                                                                                                                                                                                                                                                                                                                                                           |
|--------------------------------------------------------------------------------------------|----------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Name GTV_6000                                                                              | GTV to receive 60 Gy | The primary tumor and clinically positive lymph nodes seen on the planning CT (> 1cm short axis diameter) and pre-treatment  PET scan (SUV > 3) will constitute the GTV. This  volume(s) may be disjointed. In the event of a  collapsed lobe or lung segment, the use of PET to  distinguish tumor from fluid/atelectasis is  encouraged. An ITV is defined at this point as the enveloping GTV motion over the course of a  respiratory cycle. |
| Required for free  breathing, active breath  hold or gating motion  management  techniques |                      |                                                                                                                                                                                                                                                                                                                                                                                                                                                  |  
| CTV_6000   | CTV to receive 60 Gy          | The CTV is defined to be the GTV plus a 0.5 cm  margin to account for microscopic tumor  extension. If an ITV is used then a 0.5 cm margin  is added to the ITVto form a CTV. The CTV  should be adjusted to not expand into other  organs such as esophagus, major blood vessels,  or bone.                                                                                                                                           |
|------------|-------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| PTV_6000   | PTV to receive 60 Gy Required | The PTV will be equal to the CTV+IM+SM. IM and SM are defined in Section 5.2.4 above. In  cases in which the PTV expansion extends  outside of the skin, towards the spinal cord or into the spinal canal, it can be assumed that tumor  motion will not occur in this direction, and thePTV margin in this direction can be limited. PTV margin can be limited up to 0.5 cm towards this  particular dimension (skin or spinal cord). |
| Required   |                               |                                                                                                                                                                                                                                                                                                                                                                                                                                        |
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table b 4d ct with

| DICOM Standard                                                               | Description                                                                             | Detailed Specification                                                                                                                                                                                                                                                                                                                                       |
|------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Name iGTV_6000                                                               | Defined as the  enveloping GTV motion  over the course of the  entire respiratory cycle | The primary tumor and clinically positive lymph  nodes seen on the planning CT (> 1 cm short axis  diameter) and pre-treatment PET scan (SUV > 3)  over the course of a respiratory cycle. This  volume(s) may be disjointed. In the event of a  collapsed lobe or lung segment, the use of PET to  distinguish tumor from fluid/atelectasis is  encouraged. |
| Required when a 4DCT  is used to encapsulate  entire breathing cycle  volume |                                                                                         |                                                                                                                                                                                                                                                                                                                                                              |
| ITV_6000                                                                     | ITV to receive 60 Gy                                                                    | The ITV will be equal to the iGTV plus a 0.5 cm clinical margin as appropriate to account for  microscopic tumor extension.                                                                                                                                                                                                                                  |
| Required when iGTV is  drawn                                                 |                                                                                         |                                                                                                                                                                                                                                                                                                                                                              |  
| PTV_6000   | PTV to receive 60 Gy   | The PTV will be equal to the ITV+SM. SM is  defined in Section 5.2.4 above. In cases in which  the PTV expansion extends outside of the skin,  towards the spinal cord or into the spinal canal, it  can be assumed that tumor motion will not occur  in this direction, and thePTV margin in this  direction can be limited. PTV margin can be  limited up to 0.5 cm towards this particular  dimension (skin or spinal cord).   |
|------------|------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Required   |                        |                                                                                                                                                                                                                                                                                                                                                                                                                                   |  
5.2.6 Definition of Critical Structures and Margins Note: All required structures must be labeled for digital RT data submission exactly as listed in the first column of the table below. Capital letters and spacing must be used exactly as indicated. Resubmission of data may be required if labeling of structures does not conform to theDICOM Standard Name listed.  
| structures does not conform to theDICOM Standard Name listed. DICOM Standard Description Detailed Specification Name SpineCanal Spinal Canal Boundaries: The bony limits of the spinal canal Cranial Top of C1 (or first CT slice) Caudal Bottom of L2 (or last slice of CT) Lungs Both Lungs minus GTV_6000 (or  iGTV_6000) Required Boundaries: Use Lung OAR Atlas* Other notes: Both lungs merged into 1 structure  and excluding the overlap with GTV_6000/iGTV_6000 Required Esophagus Required Boundaries: The esophagus contour should include  the mucosa, submucosa, and all muscular layers  out to the fatty adventitia. Cranial: Bottom of cricoid cartilage Caudal: GE junction BrachialPlexus Required for upper  The ipsilateral brachial plexus should be contoured  lobe tumors for upper lobe tumors Heart Required Cranial: Ascending Aorta Caudal: Apex External Required External contour of patient encompassingall internal organs on each slice NonPTV Required External (as described above) minus PTV *Investigators can access the Lung OAR Atlas at http://www.rtog.org/CoreLab/ContouringAtlases/LungAtlas.aspx   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
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5.2.7 dose prescription

Note: The information provided in this section can be used for adjusting the dose constraintsfor treatment planning purposes. This table together with the planning priorities in Section 5.2.9 should be used during dose optimization. It is important to remember that ideal plans might not be achievable in all cases. Thus, the Compliance Criteria table could be different than the information given here. Cases will be scored using the Compliance Criteria table.  
| Target Standard   | Dose (Gy)   | Fraction   | # of                    | Dose                        |
|-------------------|-------------|------------|-------------------------|-----------------------------|
| Name              | Size (Gy)   | fractions  | specification technique |                             |
| PTV_6000          | 60          | 2.0        | 30                      | Covering exactly 95% of PTV |  
5.2.8 Compliance Criteria The compliance criteria listed below will be used to score each case. Given the limitations inherent in the treatment planning process, the numbers given in this section can be different than the prescription table. The Per Protocol and Variation Acceptable categories are both considered to be acceptable. The Per Protocol cases can be viewed as ideal plans, and the Variation Acceptable category can include more challenging plans that do not fall at or near the ideal results. A final category, called Deviation Unacceptable, results when cases do not meet the requirements for either Per Protocol or Variation Acceptable. Plans falling in this category are considered to be suboptimal and additional treatment planning optimization isrecommended.  
| Target Volume Constraints and ComplianceCriteria                                                         |                   |              |                                   |      |
|----------------------------------------------------------------------------------------------------------|-------------------|--------------|-----------------------------------|------|
| Name of                                                                                                  | Dosimetric        | Per Protocol | Variation                         |      |
| Structure                                                                                                | parameter         | Acceptable   |                                   |      |
| PTV_6000                                                                                                 | D95%(Gy)          | 60           | 58.8 to 61.2Gy  (excluding 60 Gy) |      |
| *Dmin(Gy)                                                                                                | ≥ 57              | ≥54 Gy       |                                   |      |
| *Dmax(Gy)                                                                                                | ≤ 72              | ≤75 Gy       |                                   |      |
| * Dmin and Dmax values are for a volume of 0.03 cc. Normal Structure Constraints and Compliance Criteria |                   |              |                                   |      |
| Name of                                                                                                  | Dosimetric        | Per Protocol | Variation                         |      |
| Structure                                                                                                | parameter         | Acceptable   |                                   |      |
| SpineCanal                                                                                               | D0.03cc(Gy) (max) | ≤ 50         | *                                 | none |
| Lungs                                                                                                    | V5Gy(%)           | ≤ 65         | ≤ 70                              |      |
| V20Gy(%)                                                                                                 | ≤ 35              | ≤ 37         |                                   |      |
| Dmean(Gy)                                                                                                | ≤ 20              | ≤ 22         |                                   |      |
| Esophagus                                                                                                | V35Gy(%)          | ≤ 50         | ≤ 55                              |      |
| V70Gy(%)                                                                                                 | ≤ 20              | ≤ 25         |                                   |      |
| Dmean(Gy)                                                                                                | ≤ 34              | ≤ 37         |                                   |      |
| BrachialPlexus                                                                                           | Dmax(Gy)          | ≤63          | ≤ 66                              |      |
| Heart                                                                                                    | V30Gy(%)          | ≤ 50         | ≤ 55                              |      |
| V45Gy(%)                                                                                                 | ≤ 35              | ≤ 40         |                                   |      |
| D0.03cc(Gy) (max)                                                                                        | ≤ 70 Gy           | ≤ 75 Gy **   |                                   |      |
| *The Variation Acceptable category extends the Per Protocol category numbers to allow                    |                   |              |                                   |      |  
for more challenging treatment planning problems. The Variation Acceptable range does not include the Per Protocol values. Plans will be scored as Deviation Unacceptable when Per Protocol and Variation Acceptable constraints are not met. ** When this value cannot be achieved, treatment plans must be modified to move dose distribution hotspots away from the heart to avoid having the case scored as a Deviation Unacceptable.  
| Delivery Compliance Criteria Per Protocol Variation Acceptable                  |           |            |
|---------------------------------------------------------------------------------|-----------|------------|
| Start date (days after                                                          | 14 days   | 15-30 days |
| step 1 registration) RT Elapsed Days                                            | < 45 days | 46-51 days |
| Interruptions (other than                                                       | 0-2 days  | 3-7 days   |
| holidays or weekends)                                                           |           |            |
| Note: Cases will be scored as Deviation Unacceptable when the time limits given |           |            |  
Note: Cases will be scored as Deviation Unacceptable when the time limits given  
above arenot met.  
5.2.9 Treatment Planning Priorities and Instructions Critical Structure and Target priorities are listed in order of decreasing importance:
SpineCanal PTV
Lungs Esophagus Heart BrachialPlexus If lung dose constraints are exceeded, several solutions can be entertained:
For 3D-CRT: Increase the weighting of AP/PA treatments by 1, and reduce theobliques. This can be done as long as the cord dose, which takes precedence, is not exceeded.  
For 3D-CRT or IMRT: Reduce the CTV to the minimum range suggested aboveand/or reduce the PTV by choosing another motion management option with smallerinternal margins. It is recommended that the esophagus not be circumferentially irradiated with > 60 Gy (i.e. the 60 Gy isodose line should not encompass the entire axial cross-section of the esophagus at any level).  
5.2.10 Dose Calculations Required algorithms Acceptable choices of algorithm are listed at http://irochouston.mdanderson.org/rpc/Services/Anthropomorphic_%20Phantoms/TP S%20-%20algorithm%20list%20updated.pdf. Any algorithm used for this study must be credentialed by MD Anderson Dosimetry Lab.  
Primary dataset for dose calculation The primary dataset for dose calculation must be a free-breathing CT that was acquiredalong with 4DCT, an average intensity pixel CT (AveIP) generated from the 4DCT, thebreath- hold/gated CT, or the free-breathing CT acquired with no other motion management. Maximum Intensity Pixel (MIP) generated images from 4DCTs may not be used as the primary dose calculation dataset. Dose matrix resolution Dose grid size should be ≤ 3 mm in all directions.  
5.2.11 Patient-Specific QA
Any patient-specific QA that needs to be acquired should follow institutional guidelines.  
5.2.12 Daily Treatment Localization/IGRT
Image-guided radiation therapy (IGRT) is radiation therapy using imaging to facilitate accuracy and precision throughout its entire process from target and normal tissue delineation, to radiation delivery, to adaptation of therapy to anatomic and biological changes over time inindividual patients. In this section we use the terminology IGRT to focus on image-guidance at the time of radiation delivery to ensure its adherence to the planned treatment. A reliable method of daily image guidance will be utilized. This can include but is not limited to daily conebeam imaging, fiducial marker tracking systems, kV - kV
matching. Daily conebeam imaging aligned to the tumor and soft-tissue anatomy is considered the preferred approach.  
5.2.13 R.T. Quality Assurance Reviews The Radiation Oncology Principal Investigator, James Urbanic, MD, and appointed delegates will perform an RT Quality Assurance Review after complete data for the first 20 cases enrolled has been receivedat ACR Core Laboratory/ RTQA. Dr Urbanic and delegates will perform additional reviews after complete data for the next 20 cases enrolled has been received at ACR Core Laboratory/ RTQA. This pattern will occur throughout the study accrual period. These final cases will be reviewed within 3 months after this study has reached the target accrual or as soon as complete data for all cases enrolled has been received at ACR Core Laboratory/ RTQA, whichever occurs first.  
5.2.14 Radiation Therapy Adverse Events Reversible or permanent alopecia, bone marrow toxicity, skin pigmentation, and esophagitis are expected side effects of radiation therapy. Cardiac Toxicity Radiation-induced myocarditis rarely occurs at doses lower than 50 Gy. Neurologic Toxicity Radiation-induced transverse myelitis rarely occurs at doses lower than 50 Gy. Esophagitis Esophageal complaints are common with combined modality therapy. Esophagitis does not constitute a reason to interrupt or delay radiotherapy or chemotherapy provided oral intake is sufficient to maintain hydration. Patients should be advised to avoid alcoholic, acidic, or spicy foods or beverages. Viscous Xylocaine, Carafate, or other medications should be used for symptomatic relief. Occasionally, narcotics may be required. It is not necessary to biopsy acute esophagitis in the first 2 weeks of combined therapy since it is rarely due to underlying viral or fungal disease. Acute esophagitis may 45 persist for 4-6weeks. If Grade 4 (CTCAE, v. 4) esophagitis occurs, and a treatment interruption is being considered, every effort should be made to limit it to ≤ 3 treatment days. Patients requiringhospitalization because of esophagitis may have their treatment interrupted.
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pulmonary toxicity

Pneumonitis is possible in the later weeks of chemoradiotherapy and during the weeks that follow. In general, pneumonitis is a diagnosis of exclusion and is treated with a combination of corticosteroids and supportive care at the discretion of the treating physician. Radiographic evidence of radiation change and subsequent fibrosis of the lung will occur within lung volume receiving ≥ 20 Gy, usually within the first 6 months after initiation of treatment. It is essential to spare as much normal lung as possible in order to avoid symptomatic lung injury.
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5.3 general concomitant medication and

All supportive therapy for optimal medical care will be given during the study period at the discretion of the attending physician(s) within the parameters of the protocol and documented on each site's source documents as concomitant medication.  
Subjects are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses > 10 mg daily prednisone are permitted. A brief (less than 3 weeks) course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of nonautoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by a contact allergen) is permitted. Steroids are also permitted for the prevention/treatment of nausea/vomiting during chemoradiation and are permitted, as indicated, for treatment of toxicities such as radiation pneumonitis. Other permitted supportive/ancillary medications include but are not limited to the following:
Anticonvulsants Antiemetics Anticoagulants Antidiarrheals Analgesics Hematopoietic Growth Factors Nutritional supplementation Highly active antiretroviral therapy (HAART)
5.3.2 Prohibited Therapies The following medications are prohibited during the study (unless utilized to treat a drug related adverse event):
Immunosuppressive agents Immunosuppressive doses of systemic corticosteroids (except as stated in above Permitted Therapy for Nivolumab)
Any concurrent anti-neoplastic therapy (i.e., chemotherapy, hormonal therapy, immunotherapy, or standard or investigational agents for treatment of NSCLC
Myeloid growth factors 5.3.3 Participation in Other Trials Patients may not participate in other clinical trials that are intended to treat the diagnosed lung cancer or intended to reduce toxicity of therapy.  
5.4 **Emergency Unblinding Procedure**
The decision to break the unblinding code must be based on an extraordinary clinical circumstance for which knowledge of drug assignment will affect clinical judgment.  
Sites can call RTOG Foundation Headquarters during business hours (8:30 AM to 5 PM ET), at 215-574-3150 and ask to speak to the Supporting Study Statistician. For after hours, weekends, and holidays, call 215-459-3576.  
5.5 **Duration of Therapy**
In the absence of treatment delays due to adverse event(s), treatment may continue as specified in the above treatment modality sections for up to one year or 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 consent for participation in the study, or General or specific changes in the patient's condition render the patient unacceptable for further treatment in the judgment of the investigator.  
Sponsor discontinuation of study
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6. treatment modifications/management

There are no dose modifications for nivolumab/placebo. Instead, the dose will be delayed or discontinued as specified below
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6.1 chemoradiotherapy dose modifications

Key to the successful and safe administration of nivolumab/placebo will be close monitoring of toxicities arising from the antecedent concurrent chemoradiation. Treatment modifications for in-field toxicities will be as follows:  
| Toxicity          | CTCAE grade     | XRT               | Cisplatin      | Etoposide      |
|-------------------|-----------------|-------------------|----------------|----------------|
| Esophagus/pharynx | 4               | Hold treatment    | Hold treatment | Hold treatment |
| until ≤ Grade 2   | until ≤ Grade 2 | until ≤ Grade 2   |                |                |
| Esophagus/pharynx | 3               | No change or hold | Hold treatment | Hold treatment |
| ≤ 5 days          | until ≤ Grade 2 | until ≤ Grade 2   |                |                |
| Esophagus/pharynx | 2               | No change         | No change      | No change      |
| Pulmonary         | 4               | Discontinue       | Hold treatment | Hold treatment |
| until ≤ Grade 2   | until ≤ Grade 2 |                   |                |                |
| Pulmonary         | 3               | Hold treatment    | Hold treatment | Hold treatment |
| until ≤ Grade 2   | until ≤ Grade 2 | until ≤ Grade 2   |                |                |
| Skin              | 4               | Hold treatment    | Hold treatment | Hold treatment |
| until ≤ Grade 2   | until ≤ Grade 2 | until ≤ Grade 2   |                |                |
| Skin              | 3               | No change         | No change      | No change      |  
Radiation therapy is held for neutropenia (ANC < 500/mcl); radiation therapy may be restarted when the ANC ≥ 500/mcl.  
If treatment is interrupted ≥ 3 weeks for pneumonitis discontinue all protocol therapy  
6.2 Cisplatin and Etoposide Dose Modifications Concurrent chemoradiotherapy consists of a single, 8 week treatment course. The grades of adverse events below refer to CTCAE, v. 4.
Cisplatin (50 mg/m2**) is administered intravenously on days 1 and 8, and days 29 and 36** of concurrent chemoradiation. Etoposide (50 mg/m2**) is administered intravenously on**
days 1-5 and days 29-33 **of concurrent chemoradiation.** If cisplatin and/or etoposide are held for greater than 2 consecutive weeks, the drugs will be held permanently for the duration of concurrent therapy. The following dose levels are used for dose modifications during both the concurrent chemoradiation phase. There will be no dose reduction below level -1.  
| Dose Level   | Cisplatin   | Etoposide   |
|--------------|-------------|-------------|
| 0            | 50 mg/m2    | 50 mg/m2    |
| -1           | 40 mg/m2    | 40 mg/m2    |  
Hematologic Toxicity Dose modification on Day 1 and Day 29 during concurrent chemoradiation  
| ANC                                                                        | Platelet   | Cisplatin and Etoposide Dose   |                           |
|----------------------------------------------------------------------------|------------|--------------------------------|---------------------------|
| ≥ 1,500/mcl                                                                | and        | ≥ 100,000/mcl                  | Continue w/ previous dose |
| < 1,500/mcl                                                                | or         | < 100,000/mcl                  | Hold*                     |
| *Check weekly and resume therapy at previous dose (no dose reduction) when |            |                                |                           |  
Febrile neutropenia occurring during chemoradiation will result in a decrease of the cisplatin and etoposide dose level by –1. Febrile neutropenia occurring despite dose reduction during chemoradiation will result in discontinuation of chemotherapy. Radiation therapy is held for neutropenia (ANC < 500/mcl); radiation therapy may be restarted when the ANC ≥ 500/mcl.  
The use of myeloid growth factors **will be prohibited** during the entire treatment due to potential interaction with concurrent or previous RT.
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renal toxicity

Dose modification on Day 1 and Day 29 of cisplatin and etoposide:  
| CrCl < 50 ml/min   | Hold therapy. Administer fluids and repeat  creatinine in one week.   |
|--------------------|-----------------------------------------------------------------------|  
| If after one week CrCl ≥ 50 ml/min   | Administer both cisplatin and etoposide at  full dose, but increase pre- and postcisplatin hydration.                           |
|--------------------------------------|---------------------------|
| If after one week CrCl < 50 ml/min   | Discontinue chemotherapy. |  
Day 8 and Day 36 cisplatin modifications Omit cisplatin if grade 4 neutropenia on day 8 or day 36; no modification for grades 1-3 myelotoxicity Omit cisplatin if patient develops ≥ Grade 2 renal toxicity, Grade 4 esophagitis, or febrile neutropenia If cisplatin omitted on day 8, it should not be given again until day 29; if cisplatin omitted on day 36, it should not be given again
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hepatic toxicity

Give the following doses for etoposide only:  
| Bilirubin      | Etoposide       |
|----------------|-----------------|
| < 1.5 mg/dl    | Same dose level |
| 1.5 -3.0 mg/dl |  1 dose level  |
| ≥ 3.0 mg/dl    | Hold*           |  
*Hold until <3.0 mg/dl then resume with one level dose reduction
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gastrointestinal toxicity

Nausea/Vomiting: For ≥ grade 3 nausea or vomiting despite maximum antiemetics, decrease cisplatin by one dose level for the next dose. If nausea and vomiting improve, cisplatin dose should be re-escalated to the previous dose, if possible. Neurotoxicity (Peripheral) Cisplatin doses should be modified for neurologic toxicity (see below). Serum magnesium and calcium levels should be checked; vitamin B12 levels may need to be evaluated especially in older patients. Grade 1: Give cisplatin at full dose.  
Grade ≥ 2: Hold cisplatin until neurotoxicity resolves to ≤ grade 1, then resume with one dose level reduction. Continue treatment with etoposide. If cisplatin is held for ≥ 21 days, discontinue cisplatin.  
Ototoxicity: Discontinue cisplatin for ≥ grade 3 ototoxicity.  
Hypomagnesemia and Hypokalemia: is not an indication for stopping therapy. Oral and parenteral supplementation is indication for serum levels < LLN. All Other Treatment-Related Toxicities that Exceed grade 2: (except alopecia, nausea, vomiting, fatigue and anorexia, and grade 3 myelosuppression on days 8 and 36), hold cisplatin and etoposide until the toxicities have resolved to grade 2 or less and resume cisplatin and etoposide with one dose level reduction.
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6.3 nivolumab/placebo dose modifications

There are no nivolumab/placebo dose modifications. Depending on toxicities, nivolumab/placebo is either given at full dose, withheld, or discontinued.  
49 6.3.1 Management Algorithms for Immuno-Oncology Agents Immuno-oncology (I-O) agents are associated with adverse events that can differ in severity and duration than adverse events caused by other therapeutic classes. Nivolumab is considered an immuno-oncology agent in this protocol. Management algorithms have been developed to assist investigators in assessing and managing the following groups of adverse events: Gastrointestinal, Renal, Pulmonary, Hepatic, Endocrinopathies, Skin, and Neurological. See the nivolumab Investigator Brochure for the treatment algorithms. Early recognition and intervention are recommended according to the management algorithms found in the Investigator Brochure. In addition, the Investigator Brochure (IB) includes ophthalmologic evaluations for any visual symptoms in order to evaluate for nivolumab related uveitis. Investigators should follow the algorithms for immune-related events. Note: The algorithms are essential guides for AE management, but the guidance provided in these algorithms should not replace the investigator's medical judgment but should complement it. For patients expected who require more than 4 weeks of corticosteroids or other immunosuppressants to manage an adverse event, consider the following recommendations:
Antimicrobial/antifungal prophylaxis per institutional guidelines to prevent opportunistic infections such as Pneumocystis jiroveci and fungal infections.  
Early consultation with an infectious disease specialist should be considered.  
Depending on the presentation, consultation with a pulmonologist for bronchoscopy or a gastroenterologist for endoscopy may also be appropriate.  
In patients who develop recurrent adverse events in the setting of ongoing or prior immunosuppressant use, an opportunistic infection should be considered in the differential diagnosis. Additional details on the safety of nivolumab, including results from clinical studies, are available in the IB.
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6.3.2 dose delay criteria

Because of the potential for clinically meaningful nivolumab-related AEs requiring early recognition and prompt intervention, management algorithms have been developed for suspected AEs of selected categories. [see the nivolumab Investigator Brochure] Nivolumab/placebo administration should be delayed for CTCAE, v. 4 toxicities as indicated in the management algorithms that in the opinion of the treating physician are related to the study drug. Nivolumab/placebo administration should be delayed for the following:
Any Grade ≥ 2 non-skin, drug-related adverse event, with the following exceptions:
o Grade 2 drug-related fatigue or laboratory abnormalities do not require a treatment delay Any Grade 3 skin, drug-related adverse event  
Any Grade 3 drug-related laboratory abnormality, with the following exceptions for asymptomatic amylase or lipase, AST, ALT, or total bilirubin:
o Grade 3 amylase or lipase abnormalities that are not associated with symptoms or clinical manifestations of pancreatitis do not require a dose delay. It is recommended to consult with the principal investigator for Grade 3 amylase or lipase abnormalities.  
o If a patient has a baseline AST, ALT, or total bilirubin that is within normal limits, delay dosing for drug-related Grade ≥ 2 toxicity o If a patient has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity range, delay dosing for drug-related Grade ≥ 3 toxicity Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of the investigator, warrants delaying the dose of study medication.
6.3.3 Criteria to Resume Treatment Patients may resume treatment with nivolumab/placebo when the drug-related AE(s)
resolve to Grade ≤1 or baseline value, with the following exceptions:
Patients may resume treatment in the presence of Grade 2 fatigue Patients who have not experienced a Grade 3 drug-related skin AE may resume treatment in the presence of Grade 2 skin toxicity Patients with baseline Grade 1 AST/ALT or total bilirubin who require dose delays for reasons other than a 2-grade shift in AST/ALT or total bilirubin may resume treatment in the presence of Grade 2 AST/ALT OR total bilirubin Patients with combined Grade 2 AST/ALT AND total bilirubin values meeting discontinuation parameters should have treatment permanently discontinued Drug-related pulmonary toxicity, diarrhea, or colitis, must have resolved to baseline before treatment is resumed Drug-related endocrinopathies adequately controlled with only physiologic hormone replacement may resume treatment If the criteria to resume treatment are met, the patient should restart treatment at the next scheduled time point per protocol. However, if the treatment is delayed past the next scheduled time point per protocol, the next scheduled time point will be delayed until dosing resumes. Cycle number is to be counted continuously (without skipping numbers) in case the nivolumab/placebo dose is delayed or interrupted. If treatment is delayed > 6 weeks the subject must be permanently discontinued from study therapy, except as specified in discontinuation section.
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for patients treated with corticosteroids

Grade 2 events must resolve to < Grade 1 before considering retreatment.  
All patients treated with steroids for grade ≥2 drug related immune mediated adverse events should have nivolumab/placebo held until resolution to < Grade 1 for at least 2 weeks following complete removal from steroid treatment except for maintenance replacement doses for adrenal insufficiency (preferably no greater than 10mg prednisone All patients treated with steroids for grade ≥3 events should have nivolumab/placebo discontinued. Patients with grade 3 thyroiditis and skin rash may continue therapy as for grade 2 events with resolution and stable replacement treatment. Patients with hepatitis, pancreatitis, pneumonitis, and colitis are at risk for exacerbation with retreatment if there is residual inflammation and should resolve to Grade 0 or baseline before retreatment. Baseline can mean the initial grade *i.e.* grade <2 where permitted on study. Patients with thyroiditis or hypopituitarism who are stable as above may be restarted with replacement hormones including thyroid hormone and physiologic doses only of corticosteroids. Please note that grading for hypophysitis with symptoms of headache, visual or neurologic changes or radiologic evidence of pituitary enlargement and other CNS events such as aseptic meningitis or encephalitis should be considered grade 3 events. New immune-related events or exacerbation of existing events during steroid treatment or taper suggest the presence of ongoing immune activation and should require permanent discontinuation of nivolumab. A patient who is treated with steroids, evaluated, and found to not have an autoimmune or inflammatory event requiring steroid treatment, may be restarted if asymptomatic off steroids for 2 weeks and other restarting criteria are met.  
6.3.4 Discontinuation Criteria Treatment should be permanently discontinued for the following:
Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to topical therapy and does not improve to Grade 1 severity within the re-treatment period OR requires systemic treatment Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following exceptions for drug-related laboratory abnormalities, uveitis, pneumonitis, bronchospasm, diarrhea, colitis, neurologic adverse event, hypersensitivity reactions, and infusion reactions o Grade 3 drug-related uveitis, pneumonitis, bronchospasm, diarrhea, colitis, neurologic adverse event, hypersensitivity reaction, or infusion reaction of any duration requires discontinuation o Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation except those noted below Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires discontinuation Any drug-related liver function test (LFT) abnormality that meets the following criteria require discontinuation:
o AST or ALT > 8 x ULN
o Total bilirubin > 5 x ULN
o Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN
Any Grade 4 drug-related adverse event or laboratory abnormality, except for the following events which do not require discontinuation:
o Isolated Grade 4 amylase or lipase abnormalities that are not associated with symptoms or clinical manifestations of pancreatitis and decrease to < Grade 4 within 1 week of onset.  
o Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical sequelae and are corrected with supplementation/appropriate management within 72 hours of their onset Any dosing interruption lasting > 6 weeks with the following exceptions:
o Dosing interruptions to allow for prolonged steroid tapers to manage drug-related adverse events are allowed. Prior to re-initiating treatment in a patient with a dosing interruption lasting > 6 weeks, the Principal Investigator must be consulted. Tumor assessments should continue as per protocol even if dosing is interrupted o Dosing interruptions > 6 weeks that occur for non-drug-related reasons may be allowed if approved by the Investigator. Prior to re-initiating treatment in a patient with a dosing interruption lasting > 6 weeks, the Principal Investigator must be consulted. Tumor assessments should continue as per protocol even if dosing is interrupted Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of the Investigator, presents a substantial clinical risk to the patient with continued nivolumab/placebo dosing 6.3.5 Treatment Beyond Disease Progression Accumulating evidence indicates a minority of subjects treated with immunotherapy may derive clinical benefit despite initial evidence of PD. Patients will be permitted to continue treatment beyond initial RECIST 1.1 defined progressive disease (PD) as long as the following criteria are met: 1. Investigator-assessed clinical benefit and do not have rapid disease progression 2. Tolerance of study drug 3. Stable performance status 4. Treatment beyond progression will not delay an imminent intervention to prevent serious complications of disease progression 5. Patient provides written informed consent prior to receiving additional nivolumab/placebo treatment, using the ICF addendum describing any reasonably foreseeable risks or discomforts, or other alternative treatment options. The decision to continue treatment beyond initial progression should be discussed with the Principal Investigator and documented in the study records. A radiographic assessment/ scan should be performed within 4-6 weeks of original PD to determine whether there has been a decrease in the tumor size, or continued PD. If PD is not confirmed on the 4-6 week imaging after initial progression, the patient should then revert to imaging on the 12 week cycle with the timing to start from the scan of initial disease progression. The assessment of clinical benefit should be balanced by clinical judgment as to whether the patient is clinically deteriorating and unlikely to receive any benefit from continued treatment with nivolumab. If the investigator feels that the patient continues to achieve clinical benefit by continuing treatment, the subject should remain on the trial and continue to receive monitoring according to the assessment schedule. Further progression is defined as an additional 10% increase in tumor burden volume from time of initial PD. This includes an increase in the sum of all target lesions and/ or the development of new measurable lesions. Treatment should be discontinued permanently upon documentation of further disease progression. Patients with global deterioration of health status who require discontinuation of treatment without objective evidence of disease progression at the time of treatment discontinuation should be reported as 'symptomatic deterioration'. Every effort should be made to document objective progression (i.e. radiographic confirmation) even after discontinuation of treatment.  
6.3.6Treatment of Nivolumab/Placebo-Related Infusion Reactions Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to be immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritis, arthralgias, hypo- or hypertension, bronchospasm, or other symptoms. All Grade 3 or 4 infusion reactions should be reported as an SAE if criteria are met. Infusion reactions should be graded according to NCI CTCAE v. 4.0 guidelines. Treatment recommendations are provided below and may be modified based on local treatment standards and guidelines as appropriate:
For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; intervention not indicated)
Remain at bedside and monitor the patient until recovery from symptoms. The following prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) at least 30 minutes before additional nivolumab/placebo administrations.  
For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption but responds promptly to symptomatic treatment [e.g., antihistamines, non-steroidal antiinflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic medications indicated for 24 hours). Stop the nivolumab/placebo infusion, begin an IV infusion of normal saline, and treat the patient with diphenhydramine 50 mg IV (or equivalent) and/or paracetamol (acetaminophen) 325 to 1000 mg; remain at bedside and monitor patient until resolution of symptoms. Corticosteroid or bronchodilator therapy may also be administered as appropriate. If the infusion is interrupted, then restart the infusion at 50% of the original infusion rate when symptoms resolve; if no further complications ensue after 30 minutes, the rate may be increased to 100% of the original infusion rate. Monitor the patient closely. If symptoms recur then no further nivolumab/placebo will be administered at that visit. Administer diphenhydramine 50 mg IV, and remain at bedside and monitor the patient until resolution of symptoms. The amount of study drug infused must be recorded on the electronic case report form (eCRF). The following prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) should be administered at least 30 minutes before additional nivolumab/placebo administrations. If necessary, corticosteroids (recommended dose: up to 25 mg of IV hydrocortisone or equivalent) may be used. For Grade 3 or Grade 4 symptoms: (Severe reaction, Grade 3: prolonged [i.e., not rapidly responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms following initial improvement; hospitalization indicated for other clinical sequelae [e.g., renal impairment, pulmonary infiltrates]. Grade 4: life threatening; vasopressor or ventilatory support indicated). Immediately discontinue infusion of nivolumab/placebo. Begin an IV infusion of normal saline, and treat the subject as follows. Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution injected slowly for IV administration, and/or diphenhydramine 50 mg IV with methylprednisolone 100 mg IV (or equivalent), as needed. The patient should be monitored until the investigator is comfortable that the symptoms will not recur. Nivolumab/placebo will be permanently discontinued. Investigators should follow their institutional guidelines for the treatment of anaphylaxis. Remain at bedside and monitor the patient until recovery from symptoms. In the case of late-occurring hypersensitivity symptoms (e.g., appearance of a localized or generalized pruritis within 1 week after treatment), symptomatic treatment may be given (e.g., oral antihistamine, or corticosteroids).
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7. adverse events reporting requirements

The investigational agent administered in RTOG 3505 is being made available under an IND
sponsored by RTOG Foundation and distributed by a third party drug distributor. The placebo will be prepared by an unblinded pharmacist on site. For nivolumab/placebo, determination of whether an adverse event meets expedited reporting criteria, see the reporting table in Section 7.4 of the protocol. Commercial Agents The commercial agents in RTOG 3505 are cisplatin and etoposide.  
7.1.1 Adverse Events for Investigational Study Agents Investigators must obtain the current version of the BMS-936558 (nivolumab) Investigator Brochure (IB) for comprehensive pharmacologic and safety information. The IB can be accessed on the RTOG Foundation 3505 protocol page of the RTOG website, www.rtog.org. Sites must use their username and password to access the protocol page and the IB.  
7.1.2 Adverse Events for Commercial Study Agents
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refer to the package insert

7.2 **Adverse Events (AEs)**
This study will use the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 for adverse event reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 4.0.  
7.2.1 Definition of an Adverse Event (AE)
Any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. Therefore, an AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not considered related to the medicinal (investigational) product (attribution of unrelated, unlikely, possible, probable, or definite). (International Conference on Harmonisation [ICH], E2A, E6). For multi-modality trials, adverse event reporting encompasses all aspects of protocol treatment including radiation therapy, surgery, device, and drug. AEs, as defined above, experienced by patients accrued to this protocol should be reported on the AE section of the appropriate case report form (see Section 13). All nonserious adverse events (not only those deemed treatment-related) are to be collected continuously during the treatment period and for a minimum of 100 days following the last dose of study treatment. Follow-up is also required for nonserious AEs that cause interruption or discontinuation of study drug and for those present at the end of study treatment as appropriate. All identified nonserious AEs must be recorded and described on the nonserious AE page of the CRF.  
The following laboratory test result abnormalities should be captured on the nonserious AE CRF page and SAE Report Form if they meet seriousness criteria:
Any laboratory test result that is clinically significant or meets the definition of an SAE
Any laboratory test result abnormality that required the subject to have study drug discontinued or interrupted Any laboratory test result abnormality that required the subject to receive specific corrective therapy.
It is expected that wherever possible, the clinical rather than laboratory term would be used by the reporting investigator (e.g., anemia versus low hemoglobin value).
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definition of immune-mediated adverse events

IMAEs include events, regardless of causality, occurring within 100 days of the last dose. IMAEs are specific events (that include pneumonitis, diarrhea/colitis, hepatitis, nephritis/renal dysfunction, rash, and endocrine [adrenal insufficiency, hypothyroidism/thyroiditis, hyperthyroidism, diabetes mellitus, and hypophysitis]) for which patients received immunosuppressive medication for treatment of the event, with the exception of endocrine events (hypothyroidism/thyroiditis, hyperthyroidism,  
| Preferred Terms Included in Analysis of IMAEs to Support Warnings and Precautions   |                                                                                                                                      |
|-------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------|
| IMAE Category                                                                       | PTs included under IMAE Category                                                                                                     |
| Pneumonitis                                                                         | Pneumonitis, Interstitial lung disease                                                                                               |
| Diarrhea/Colitis                                                                    | Diarrhea, Colitis, Enterocolitis                                                                                                     |
| Hepatitis                                                                           | Hepatotoxicity, Hepatitis, Hepatitis acute, Autoimmune  hepatitis, AST increased, ALT increased, Bilirubin  increased, ALP increased |
| Adrenal insufficiency                                                               | Adrenal insufficiency                                                                                                                |
| Hypothyroidism/Thyroiditis                                                          | Hypothyroidism, Thyroiditis                                                                                                          |
| Thyroiditis acute (collapsed with thyroiditis for                                   |                                                                                                                                      |
| frequency), Autoimmune thyroiditis (collapsed with  thyroiditis for frequency)      |                                                                                                                                      |
| Hyperthyroidism                                                                     | Hyperthyroidism                                                                                                                      |
| Hypophysitis                                                                        | Hypophysitis                                                                                                                         |
| Diabetes mellitus                                                                   | Diabetes mellitus, Diabetic ketoacidosis                                                                                             |
| Nephritis and renal                                                                 | Nephritis, Nephritis allergic, Tubulointerstitial nephritis,                                                                         |
| dysfunction                                                                         | Acute renal failure, Renal failure, Increased creatinine                                                                             |
| Rash                                                                                | Rash, Rash maculopapular                                                                                                             |  
hypophysitis, diabetes mellitus, adrenal insufficiency), which are included regardless of treatment since these events are often managed without immunosuppression. The table below provides a summary of the IMAEs category and their respective preferred terms.  
NOTE: If the event is a Serious Adverse Event (SAE) (see next section), further reporting will be required. Reporting AEs only fulfills Data Management reporting requirements.
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7.3 serious adverse events (saes)

Serious Adverse Events that meet expedited reporting criteria defined in the table below will be reported via the SAE report form in RAVE. SAEs that require 24h notification are defined in the expedited reporting table.  
Definition of an SAE: Any adverse drug event (experience) occurring at any dose that results in any of the following outcomes:
Death; A life-threatening adverse drug experience; Inpatient hospitalization or prolongation of existing hospitalization for ≥24 hours; A persistent or significant disability/incapacity; A congenital anomaly/birth defect; Other serious/important medical events;
Important medical events that may not result in death, be life threatening, or require hospitalization may be considered an SAE, when, based upon medical judgment, they may jeopardize the patient and may require medical or surgical intervention to prevent one of the outcomes listed in the definition.  
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, the pregnancy of a study participant must be reported in an expedited manner.
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7.4 serious adverse event (sae)

It is the responsibility of the investigator to document all adverse events which occur during the study. All serious adverse events that meet expedited reporting criteria defined in the reporting table below will be reported via the RTOG SAE Report Form in RAVE. RTOG will report SAEs to Bristol-Myers Squibb within 24 hours of awareness. RTOG will report unexpected and related SAEs to the FDA and Bristol-Myers Squibb via the MedWatch Form per the requirements set forth in the Code of Federal Regulations, Section 312.32.  
7.4.1 Reporting SAEs Following the subject's written consent to participate in the study, all SAEs, whether related or not related to study drug, must be collected, including those thought to be associated with protocol-specified procedures. All SAEs must be reported per the reporting table below that occur from time of consent and within 100 days of the last dose of study drug. Subjects who are randomized and never receive treatment must have SAEs collected for 30 days from the date of randomization. If applicable, SAEs must be collected that relate to any later protocol-specified procedure (e.g., a follow-up skin biopsy). The investigator should report any SAE that occurs after these time periods and that is believed to be related to study drug or protocol-specified procedure. An SAE report should be completed for any event where doubt exists regarding its seriousness. If the investigator believes that an SAE is not related to study drug, but is potentially related to the conditions of the study (such as withdrawal of previous therapy or a complication of a study procedure), the relationship should be specified in the narrative section of the SAE Report Form. The SAE report should comprise a full written summary, detailing relevant aspects of the SAE in question. The SAE summary also must include the investigator's assessment of relatedness to all components of protocol treatment. Amend the SAE report with follow-up information, when it becomes available. In the rare event when Internet connectivity is disrupted, a 24-hour notification must be made to RTOG Operations Office by phone, 215574-3191. An electronic report must be submitted immediately upon re-establish of the Internet connection. SAEs that occur during the follow-up period beginning 100 days after end of treatment and are considered by the investigator to be related to protocol treatment must be reported expeditiously via the SAE Report Form. All SAEs must be reported in RAVE within the designated timeframe outlined in the reporting table below. RTOG will complete a preliminary review of the SAE details and will **contact the site with queries, as applicable. RTOG will report the SAE to** Bristol-Myers Squibb within 24 hours of notification of the event. RTOG will report to the FDA per 21 CFR 312.
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pregnancy

Patients who become pregnant during the study should discontinue the study immediately.  
Investigators should report a pregnancy, including a male participant's impregnation of his partner, expeditiously as a grade 3 SAE coded in the CTCAE v.4 as "pregnancy, puerperium and perinatal conditions, other—pregnancy" on the SAE report form (in RAVE) and submit the Pregnancy Report Form in Rave within 14 days of notification. RTOG will report the pregnancy to Bristol-Myers Squibb within 24 hours of notification of the event. Patients should be instructed to notify the investigator if it is determined after completion of the study that they become pregnant, including a male participant's impregnation of his partner, either during the treatment phase of the study or within 100 calendar days after the end of treatment. The pregnancy outcome for patients on study should be reported to RTOG. RTOG will report the status to Bristol-Myers Squibb.
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any phase study utilizing a

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