Conditions: Non-small Cell Lung Cancer Stage III
Keywords: NSCLC IIIA/B
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 94
Healthy volunteers: no

Brief summary:
The aim of the study is to investigate the tolerability (how severe the side effects are) and the efficacy (how well the treatment works) when nivolumab is added to the current standard treatment (chemotherapy and radiotherapy) given to patients with advanced NSCLC.

Detailed description:
Over the past decade, concomitant chemotherapy and radiotherapy has become the first choice treatment for most patients with stage III non-small-cell lung carcinoma (NSCLC).

However, only about 30% of patients are alive 5 years after con¬comitant therapy. These figures remain approximately the same with the addition of surgery. After chemo-radiotherapy, at least 30-40% of the patients show local tumour progression on CT scans as first site of relapse. Also after surgery, about 30% of patients fail locally as a first site of recurrence. In addition, more than half of the patients eventually develop distant metastases that may have been present but undetected at the time of staging or that may have come from persistent or recurring local disease. It is thus obvious that new approaches that preferentially tackle both local and distant disease sites are needed to improve long-term survival and cure rates.

Attempts to improve the long-term survival include radiotherapy dose escalation/acceleration, new chemotherapy combinations, and adding biological agents and cancer vaccines to standard regimens. At present, none of these have demonstrated an improved outcome.

Improved understanding of the immune profile of NSCLC has led to immunotherapeutic strategies, including inhibitory molecules responsible for abrogating an anti-cancer immune response such as PD-1 and CTLA-4. Nivolumab, an investigational monoclonal antibody that inhibits the immune checkpoint receptor PD-1 expressed on activated T cells, has demonstrated positive results in several trials in previously treated patients with advanced NSCLC. However, rare cases of severe or fatal pneumonitis have been reported throughout clinical trials using anti-PD1 or anti-PDL1 compounds.

Pre-clinical data consistently show a clear beneficial effect by combining local radiotherapy and anti-PD-1. Not only was the local tumour control increased, but an "abscopal" effect on distant metastases could be observed. Radiotherapy clearly acted as an "in situ" tumour vaccination resulting in the induction of specific anti-tumour immunity in all sites of the body that could result in a clinical anti-tumour effect because of the combination with anti-PD-1.

In these models, the concurrent administration of anti-PD-1/PD-L1 antibodies was more efficient to provoke an anti-tumour immune response than the sequential approach.

While the role of immunotherapy is currently being evaluated as monotherapy or in combination with chemotherapy or tyrosine kinase inhibitors in all lines of treatment of advanced NSCLC, as monotherapy in early NSCLC adjuvant setting as well as monotherapy in consolidation after completion of definitive chemo-radiotherapy, it has not yet been assessed in combination with radiotherapy. Anecdotal data of concurrent treatment in the palliative setting suggest acceptable safety and a good tolerability of such combination.

The NICOLAS trial was initially developed to prospectively assess the safety of checkpoint inhibition concurrently with chemo-radiotherapy.

In summary, there is a definite unmet need in multi-disciplinary care to improve the prognosis of patients diagnosed with stage III NSCLC, with a strong rationale supporting the combination of chemo-radiotherapy with anti-PD-1. A major theoretical concern is the development of pneumonitis, a rare toxicity of both radiotherapy and checkpoint inhibitors. The main aim of the ongoing current trial is therefore to evaluate the pneumonitis rate in patients being treated with chemo-radiotherapy in combination with nivolumab treatment.

Rationale for protocol amendment 2:

Since the NICOLAS trial was initiated, the landscape of combining chemo-radiotherapy with immune-checkpoint inhibition, such as anti-PD-1 antibodies, has changed rapidly, opening a new window of opportunity.

There is a very strong interest of the multidisciplinary lung cancer community to investigate the optimal integration of anti-PD-1 treatment into chemo-radiotherapy. Currently, 11 sites from 5 countries are activated for the NICOLAS trial and recruiting strongly (ahead of schedule). Using this momentum will allow us to rapidly recruit additional patients in order to reach the power to not only determine the feasibility in terms of pneumonitis grade 2 and abouve, but also to evaluate the efficacy of the concurrent treatment.

So far, during the regular safety review, the ETOP IDMC did not observe any additional toxicity compared the chemo-radiotherapy alone.

A first planned analysis of the PACIFIC trial (stage III NSCLC treated with concurrent chemotherapy and radiotherapy, followed by the anti-PD-L1 durvalumab or observation, NCT02125461) showed an increased progression-free survival (PFS), which was co-primary endpoint together with overall survival (OS). The full details are not known, yet, but it appears that the pre-clinical rationales of combined chemo-radiotherapy and anti-PD-1 treatment can be successfully transferred into clinical trials, without serious toxicities.

A recent secondary analysis of the Keynote 001 trial indicates synergistic affects of radiotherapy and immunotherapy. This international, multicentre phase I trial assessed the effect of pembrolizumab monotherapy in patients with progressive locally advanced or metastatic NSCLC. Patients were assigned to multiple expansion cohorts to allow for the inclusion of patients who were naïve to systemic therapy and those who had progression after one or two previous regimens.

The results from this study showed that the effect of pembrolizumab was significantly higher in patients who received previous radiotherapy than in patients without previous radiotherapy.

These findings were well in line with pre-clinical studies that underlined the ability of radiotherapy to enhance antitumour immune response.

In the absence of of serious pulmonary toxicity, the apperant benefit of chemo-radiotherapy and anti-PD-1 and the high interest of the NICOLAS study group, we propose to amend the NICOLAS trial protocol to expand on the number of patients in order to reach sufficient power for an efficacy readout (progression-free survival).

Arms:
arm 1: 4 doses of nivolumab 360mg concurrently with standard chemo-radiotherapy, followed by 480mg for up to 1 year from start of nivolumab treatment.

Interventions: intervention 1: Nivolumab
Intervention descriptions: intervention 1: Nivolumab is a fully human monoclonal antibody that targets the programmed death-1 (PD-1) cell surface membrane receptor. PD-1 is a negative regulatory molecule expressed by activated T and B lymphocytes.Binding of PD-1 to its ligands, 1 (PD-L1) and 2 (PD-L2), results in the down-regulation of lymphocyte activation. Nivolumab inhibits the interaction of programmed cell death Protein 1 (PD-1)with its ligands, PD-L1 and PD-L2, resulting in enhanced T-cell proliferation.

Protocol document:
Prot_000.pdf: 
ETOP 6-14 NICOLAS AMD2 v3.0 20170704 
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f 
 
 
 
 
ETOP 6-14 NICOLAS 
 
 
 
A phase II trial evaluating the safety and efficacy of the addition of 
concurrent anti-PD-1 nivolumab to standard first-line chemotherapy and 
radiotherapy in locally advanced 
stage IIIA/B Non-Small Cell Lung Carcinoma 
 
 
NICOLAS: NIvolumab COmbination with standard first-line 
chemotherapy and radiotherapy in Locally Advanced Stage IIIA/B 
Non-Small Cell Lung Carcinoma 
 
 
 
Sponsor: European Thoracic Oncology Platform (ETOP) 
 
 
 
 
EudraCT number: 2014-005097-11 
 
 
BMS number: CA209-208 
 
 
 
ETOP c/o IBCSG Coordinating Center, Effingerstrasse 40, CH- 3008 Bern 
Phone: +41 31 511 94 00 
Fax: +41 31 511 94 01 
 
 
 
Version 3.0 
 
 


ETOP 6-14 NICOLAS AMD2 v3.0 20170704 
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Contacts 
 
Trial Chair 
Solange Peters, MD-
PhD 
 
 
 
 
Address 
 
 
Tel:  
 
Fax: 
Email: 
Département d'Oncologie 
Centre Hospitalier Universitaire Vaudois  
1011 Lausanne, Switzerland 
+41 79 556 01 92 
+41 21 314 67 89 (assistant) 
+41 21 314 07 37 
solange.peters@etop-eu.org 
Trial Chair 
Dirk De Ruysscher, 
MD, PhD 
 
 
 
 
Address 
 
 
Tel:  
Fax: 
Email: 
Maastro Clinic 
Dr. Tanslann 12 
6229 ET Maastricht, The Netherlands 
+31 88 44 55 666 
+31 88 44 55 774 
dirk.deruysscher@maastro.nl 
ETOP Chairman 
Rolf Stahel, MD 
Address 
 
 
 
 
Tel:  
Fax: 
Email:  
Laboratory of Molecular Oncology 
Clinic of Oncology 
University Hospital Zuerich  
Raemistrasse 91 
8091 Zürich, Switzerland  
+41 44 255 22 19 
+41 44 255 97 80 
rolf.stahel@usz.ch 
Statistics 
Urania Dafni, ScD 
Marie Kassapian 
Address 
 
 
Tel:  
Fax: 
Email: 
Frontier Science Foundation - Hellas 
116 Papadiamantopoulou Str. 
15773, Zografou, Athens, Greece 
+302107710902 
+302107710903 
udafni@frontier-science.gr 
mkassapian@frontier-science.gr 
Project Manager 
 
 
 
 
Data Management 
Mark Finlayson, PhD 
 
 
 
 
Anne-Christine 
Piguet, PhD 
Address 
 
 
 
Tel:  
Tel: 
Fax: 
Email:  
ETOP Coordinating Office 
c/o IBCSG Coordinating Centre 
Effingerstrasse 40 
3008 Bern, Switzerland 
+41 31 511 94 34 
+41 31 511 94 21 
+41 31 511 94 01 
NICOLAS@etop-eu.org 
Drug supply 
Barbara Ruepp, 
PharmD 
Address 
 
 
 
Tel:  
Fax: 
Email:  
ETOP Drug Supply Office 
c/o IBCSG Coordinating Centre 
Effingerstrasse 40 
3008 Bern, Switzerland 
+41 31 511 94 16 
+41 31 389 92 29 
drugsupply@etop-eu.org 
Safety and Regulatory 
Affairs 
Barbara Ruepp, 
PharmD 
Address 
 
 
 
Tel:  
Fax: 
Email:  
ETOP Safety and Regulatory Office 
c/o IBCSG Coordinating Centre 
Effingerstrasse 40 
3008 Bern, Switzerland 
+41 31 511 94 16 
+41 31 389 92 29 
regulatoryoffice@etop-eu.org 
etopsafetyoffice@etop-eu.org 


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Medical Affairs and 
Safety 
Manuela Rabaglio, 
MD 
Address 
 
 
 
Tel:  
Fax: 
Email:  
ETOP Medical Affairs 
c/o IBCSG Coordinating Centre 
Effingerstrasse 40 
3008 Bern, Switzerland 
+41 31 511 94 20 
+41 31 389 92 29 
manuela.rabaglio@ibcsg.org 
etopsafetyoffice@etop-eu.org 
ETOP Coordinating 
Office 
 
 
 
 
 
 
Anita Hiltbrunner 
Heidi Roschitzki, PhD 
Susanne Roux 
Address 
 
 
Tel:  
Fax: 
Email: 
c/o IBCSG Coordinating Centre 
Effingerstrasse 40 
3008 Bern, Switzerland 
+41 31 511 94 00 
+41 31 511 94 01 
NICOLAS@etop-eu.org 
anita.hiltbrunner@etop-eu.org 
heidi.roschitzki@etop-eu.org 
susanne.roux@etop-eu.org 
Remote Data Entry 
system ETOPdata 
Anne-Christine 
Piguet, PhD 
 
Technical assistance 
 
ETOPDataManagement@etop-eu.org 
 
richard.king@etop-eu.org 
 
In collaboration with Bristol-Myers Squibb  




ETOP 6-14 NICOLAS AMD2 v3.0 20170704 
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Principal Investigator protocol signature page amendment 2 
 
A phase II trial evaluating the safety and efficacy of the addition of concurrent 
anti-PD-1 nivolumab to  
standard first-line chemotherapy and radiotherapy in locally advanced  
stage IIIA/B Non-Small Cell Lung Carcinoma 
 
ETOP 6-14 NICOLAS 
 
I have read the protocol and agree that it contains all necessary details for conducting this 
trial. I will conduct the trial as outlined in the following protocol and in compliance with GCP, 
and will apply due diligence to avoid protocol deviations. I will provide copies of the protocol 
and all drug information relating to pre-clinical and prior clinical experience furnished to me 
by ETOP, to all physicians responsible to me who participate in this trial. I will discuss this 
material with them to assure that they are fully informed regarding the drug and the conduct 
of the trial. I agree to keep accurate records on all patient information including patient's 
informed consent statement, drug shipment and return forms, and all other information 
collected during the trial for a minimum period of 15 years. 
 
 
Name of Principal Investigator:___________________________________________ 
 
 
Institution’s name and place:___________________________________________ 
 
 
 
_____________________________________________________ ______________ 
 
 
Signature 
Date 
 


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TABLE OF CONTENTS  
Section 
Page 
 
1. 
Protocol summary ...................................................................................................... 9 
2. 
Trial schedule ........................................................................................................... 16 
3. 
List of abbreviations ................................................................................................ 19 
4. 
Background and rationale ........................................................................................ 22 
4.1. 
Disease background ............................................................................................. 22 
4.2. 
Chemo-radiotherapy ............................................................................................ 22 
4.3. 
Radiation pneumonitis ......................................................................................... 24 
4.4. 
Targeted agents in non-small cell lung carcinoma .............................................. 25 
4.5. 
Immunotherapy for non-small cell lung carcinoma ............................................ 25 
4.6. 
Nivolumab ........................................................................................................... 25 
4.7. 
Biomarker research for nivolumab ...................................................................... 27 
4.8. 
Overall risk/benefit assessment ........................................................................... 27 
4.9. 
Rationale for trial design ..................................................................................... 28 
5. 
Objectives and endpoints ......................................................................................... 30 
5.1. 
Primary objective ................................................................................................. 30 
5.2. 
Secondary objectives ........................................................................................... 30 
5.3. 
Primary endpoint ................................................................................................. 30 
5.4. 
Key secondary endpoint ...................................................................................... 30 
5.5. 
Other secondary endpoints .................................................................................. 30 
6. 
Trial design, duration and termination ..................................................................... 31 
7. 
Patient selection ....................................................................................................... 33 
7.1. 
Inclusion criteria .................................................................................................. 33 
7.2. 
Exclusion criteria ................................................................................................. 34 
8. 
Patient screening and enrolment .............................................................................. 36 
8.1. 
Screening ............................................................................................................. 36 
8.2. 
Enrolment ............................................................................................................ 36 
8.3. 
Start of chemo-radiotherapy ................................................................................ 36 
8.4. 
Start of nivolumab ............................................................................................... 36 
9. 
Investigational product ............................................................................................ 37 
9.1. 
Description of investigational drug ..................................................................... 37 
9.2. 
Packaging and labelling ....................................................................................... 37 
9.3. 
Receipt of the drug .............................................................................................. 37 
9.4. 
Storage and handling ........................................................................................... 37 
9.5. 
Unused trial drug supplies ................................................................................... 38 
10. 
Trial treatments ........................................................................................................ 38 
10.1. 
Overview of treatment ......................................................................................... 38 
10.2. 
Chemotherapy dosage, administration and schedule ........................................... 38 
10.3. 
Chemotherapy delay and dose modification for toxicity..................................... 39 
10.4. 
Thoracic radiation ................................................................................................ 41 
10.5. 
Nivolumab treatment ........................................................................................... 42 
10.6. 
Prohibited and restricted therapies during trial treatment ................................... 46 
10.7. 
Treatment duration .............................................................................................. 47 
10.8. 
Contraception, nursing, pregnancy ...................................................................... 48 
11. 
Safety of investigational products ........................................................................... 50 
11.1. 
Nivolumab ........................................................................................................... 50 
11.2. 
Cisplatin ............................................................................................................... 53 


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11.3. 
Carboplatin .......................................................................................................... 55 
11.4. 
Etoposide ............................................................................................................. 58 
11.5. 
Vinorelbine .......................................................................................................... 61 
11.6. 
Pemetrexed .......................................................................................................... 61 
12. 
Adverse events and reporting .................................................................................. 61 
12.1. 
Adverse event definition and reporting ............................................................... 61 
12.2. 
Definition of Serious Adverse Event (SAE)........................................................ 62 
12.3. 
Definition of Serious Adverse Reaction (SAR) .................................................. 64 
12.4. 
Definition of Suspected Unexpected Serious Adverse Reaction (SUSAR) ........ 64 
12.5. 
Protocol-specified significant events ................................................................... 65 
12.6. 
Reporting SAEs and protocol specified significant events ................................. 65 
12.7. 
Non-serious adverse event definition and reporting ............................................ 66 
12.8. 
Pregnancy ............................................................................................................ 66 
13. 
Response evaluation ................................................................................................ 67 
13.1. 
RECIST v1.1 criteria ........................................................................................... 67 
13.2. 
Determination of time point response ................................................................. 68 
13.3. 
Determination of best overall response ............................................................... 68 
14. 
Endpoints definition ................................................................................................. 69 
14.1. 
Grade ≥3 pneumonitis (CTCAE v4.0) observed any time during 6 months from 
the end of radiotherapy ....................................................................................... 69 
14.2. 
Progression-free survival ..................................................................................... 69 
14.3. 
Time to first pneumonitis of grade ≥3 ................................................................. 69 
14.4. 
Objective response ............................................................................................... 69 
14.5. 
Time to treatment failure ..................................................................................... 69 
14.6. 
Overall survival ................................................................................................... 69 
14.7. 
Toxicity ................................................................................................................ 69 
15. 
Trial procedures ....................................................................................................... 70 
15.1. 
Baseline evaluations before enrolment ................................................................ 70 
15.2. 
CT schedule for disease evaluation ..................................................................... 71 
15.3. 
During chemotherapy .......................................................................................... 71 
15.4. 
During nivolumab treatment and radiotherapy .................................................... 71 
15.5. 
End of treatment visit .......................................................................................... 72 
15.6. 
Evaluations in the follow-up phase before progression ....................................... 73 
15.7. 
Evaluations after progression in follow-up ......................................................... 73 
16. 
Case report forms and documentation ..................................................................... 73 
16.1. 
Case report forms schedule .................................................................................. 73 
17. 
Statistical considerations ......................................................................................... 76 
17.1. 
Primary and key secondary objectives ................................................................ 76 
17.2. 
Sample size determination ................................................................................... 76 
17.3. 
Evaluation of primary and secondary endpoints ................................................. 77 
18. 
Criteria for termination of the trial .......................................................................... 79 
18.1. 
General criteria for termination of the trial ......................................................... 79 
18.2. 
Discontinuation of protocol treatment for individual patients ............................. 80 
18.3. 
Withdrawal of consent ......................................................................................... 80 
19. 
Ethics aspects, regulatory approval, and Patient Informed Consent ........................ 81 
19.1. 
Ethical Review Board/Ethics Committee ............................................................ 81 
19.2. 
Regulatory approval procedures .......................................................................... 81 
19.3. 
Informed consent ................................................................................................. 81 
20. 
Governance and administrative issues ..................................................................... 82 
20.1. 
Final report .......................................................................................................... 82 


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20.2. 
Steering Committee ............................................................................................. 82 
20.3. 
Independent Data Monitoring Committee ........................................................... 82 
20.4. 
Publication ........................................................................................................... 82 
20.5. 
Clinical trial insurance ......................................................................................... 83 
20.6. 
Quality assurance and quality control ................................................................. 83 
20.7. 
Protocol adherence .............................................................................................. 83 
20.8. 
Data protection .................................................................................................... 83 
20.9. 
Record retention .................................................................................................. 84 
21. 
References ................................................................................................................ 85 
 
Appendices: 
1. Template for patient information and informed consent form  
2. RECIST criteria V1.1 
 
Index of tables 
Table 1: ECOG Performance Status: ..................................................................................... 34 
Table 2: Overview chemotherapy options ............................................................................. 38 
Table 3: Chemotherapy dose modifications for haematological toxicity .............................. 39 
Table 4: Chemotherapy dose modifications for hepatic toxicity ........................................... 39 
Table 5: Cisplatin dose modifications for renal toxicity ........................................................ 40 
Table 6: Carboplatin dose modifications for renal toxicity ................................................... 40 
Table 7: Chemotherapy dose modifications for other toxicities ............................................ 41 
Table 8 Treatment-related AEs in first-line treatment of nivolumab / chemotherapy in 
CA209012 .............................................................................................................................. 51 
Table 9 Efficacy of First-Line Treatment of Nivolumab/Chemotherapy Combination in 
CA209012 .............................................................................................................................. 52 
Table 10: Adverse reactions for etoposide............................................................................. 58 
Table 11: Determination of time point response.................................................................... 68 
Table 12: Case report forms ................................................................................................... 73 
 


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1. 
Protocol summary 
 
A phase II trial evaluating the safety and efficacy of the addition of 
concurrent anti-PD-1 nivolumab to 
standard first-line chemotherapy and radiotherapy in locally advanced  
stage IIIA/B Non-Small Cell Lung Carcinoma 
 
 
Sponsor: European Thoracic Oncology Platform (ETOP) 
Pharma Partner: Bristol-Myers Squibb 
Population: Documented stage IIIA/B NSCLC, amenable to concurrent chemo-radiotherapy. 
Design: A single arm multicenter phase II trial 
 
Sample size: 78 patients 
Rationale: Over the past decade, concomitant chemotherapy and radiotherapy has become 
the first choice treatment for most patients with stage III non-small-cell lung carcinoma 
(NSCLC). 
However, only about 30% of patients are alive 5 years after concomitant therapy. These 
figures remain approximately the same with the addition of surgery. After chemo-
radiotherapy, at least 30-40% of the patients show local tumour progression on CT scans as 
first site of relapse. Also after surgery, about 30% of patients fail locally as a first site of 
recurrence. In addition, more than half of the patients eventually develop distant metastases 
that may have been present but undetected at the time of staging or that may have come from 
persistent or recurring local disease. It is thus obvious that new approaches that preferentially 
tackle both local and distant disease sites are needed to improve long-term survival and cure 
rates. 
Screening, eligibility 
and enrolment
Stage 
IIIA / B
NSCLC
Radiotherapy 
chemo  
cycle 3
chemo  
cycle 1
chemo  
cycle 2
until PD
Whole body 
FDG-PET
CT scans year 1: every 9 weeks, year 2: every 12 weeks, beyond 2 years: every 6 months
Nivolumab: 360 mg Q3W 4 doses, followed by 480 mg Q4W up to 1 year


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Dose-limiting toxicity of thoracic radiotherapy includes radiation pneumonitis (RP). Starting 
from two months after the end of radiotherapy, about 15% of the patients develop increasing 
dyspnoea and cough, provoked by a mixed T-lymphocyte infiltrate in lung areas that have 
been irradiated. RP may happen up to 6 months post-treatment, however about three quarters 
of RP cases occur 3 months after radiotherapy. Besides dose and volume parameters of the 
radiotherapy, such as the mean lung dose (MLD) or the V20 (that is the percentage of the lungs 
that received more than 20 Gy), the most important risk factor for developing RP is the 
inflammatory status of the lungs before therapy. The more baseline inflammation, the higher 
is the risk of RP. Inflammation in the lungs can be visualized and quantified by measuring the 
18F-fluoro-D-deoxyglucose (FDG) in the lung parenchyma by standard FDG-PET-CT scans 
obtained at the time of staging. As the relative FDG uptake in the lung vs. the aorta is used, 
no specific calibration of the PET-scanner is required.  
Attempts to improve the long-term survival include radiotherapy dose escalation/acceleration, 
new chemotherapy combinations, and adding biological agents and cancer vaccines to 
standard regimens. At present, none of these have demonstrated an improved outcome. 
Improved understanding of the immune profile of NSCLC has led to immunotherapeutic 
strategies, including inhibitory molecules responsible for abrogating an anti-cancer immune 
response such as PD-1 and CTLA-4. Bristol-Myers Squibb’s nivolumab, an investigational 
monoclonal antibody that inhibits the immune checkpoint receptor PD-1 expressed on 
activated T cells, has demonstrated positive results in several trials in previously treated 
patients with advanced NSCLC. However, rare cases of severe or fatal pneumonitis have been 
reported throughout clinical trials using anti-PD-1 or anti-PD-L1 compounds.  
Pre-clinical data consistently show a clear beneficial effect by combining local radiotherapy 
and anti-PD-1.[1] Not only was the local tumour control increased, but an “abscopal” effect 
on distant metastases could be observed. Radiotherapy clearly acted as an “in situ” tumour 
vaccination resulting in the induction of specific anti-tumour immunity in all sites of the body 
that could result in a clinical anti-tumour effect because of the combination with anti-PD-1. 
In these models, the concurrent administration of anti-PD-1/PD-L1 antibodies was more 
efficient to provoke an anti-tumour immune response than the sequential approach. 
The initial dose and schedule of nivolumab while combined with chemotherapy will be 
360 mg i.v.. The rationale for flat dosing is based on the expected similarity of safety and 
efficacy to the approved 3 mg/kg dose. Based on a wide therapeutic window of nivolumab 
monotherapy, the range of exposures with flat dosing are not expected to affect the efficacy 
because the exposures predicted for the 360 mg Q3W dose is on the flat part of the exposure 
response curve. For safety, doses up to 10 mg/kg nivolumab Q2W have been well tolerated 
across multiple tumours and an increase in exposure is not associated with a probability of 
increasing adverse events. Therefore, the flat dose (360 mg Q3W) for nivolumab 
monotherapy is recommended for further invetion in this trial. 
From nivolumab cycle five on, nivolumab will be administered at 480 mg Q4W for up to 
1 year from commencement of nivolumab treatment. Based on pharmacokinetic modelling, 
the 480 mg Q4W will provide similar steady-state average concentrations as 3 mg/kg or 
240 mg Q2W for 4 months. The 4-weekly schedule will be more convenient for patients. 


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While the role of immunotherapy is currently being evaluated as monotherapy or in 
combination with chemotherapy or tyrosine kinase inhibitors in all lines of treatment of 
advanced NSCLC, as monotherapy in early NSCLC adjuvant setting as well as monotherapy 
in consolidation after completion of definitive chemo-radiotherapy, it has not yet been 
assessed in combination with radiotherapy. Anecdotal data of concurrent treatment in the 
palliative setting suggest acceptable safety and a good tolerability of such combination. The 
NICOLAS trial was initially developed to prospectively assess the safety of checkpoint 
inhibition concurrently with chemo-radiotherapy. 
In summary, there is a definite unmet need in the multidisciplinary care to improve the 
prognosis of patients diagnosed with stage III NSCLC, with a strong rationale supporting the 
combination of chemo-radiotherapy with anti-PD-1. A major theoretical concern is the 
development of pneumonitis, a rare toxicity of both radiotherapy and checkpoint inhibitors. 
The main aim of the ongoing current trial is therefore to evaluate the pneumonitis rate in 
patients being treated with chemo-radiotherapy in combination with nivolumab treatment. 
Rationale for protocol amendment 2 
Since the NICOLAS trial was initiated, the landscape of combining chemo-radiotherapy with 
immune-checkpoint inhibition, such as anti-PD-1 antibodies, has changed rapidly, opening a 
new window of opportunity. 
There is a very strong interest of the multidisciplinary lung cancer community to investigate 
the optimal integration of anti-PD-1 treatment into chemo-radiotherapy. Currently, 11 sites 
from 5 countries are activated for the NICOLAS trial and recruiting strongly (ahead of 
schedule). Using this momentum will allow us to rapidly recruit additional patients in order 
to reach the power to not only determine the feasibility in terms of pneumonitis grade 2 and 
abouve, but also to evaluate the efficacy of the concurrent treatment. 
So far, during the regular safety review, the ETOP IDMC did not observe any additional 
toxicity compared the chemo-radiotherapy alone. 
Additionally, a first planned analysis of the PACIFIC trial (stage III NSCLC treated with 
concurrent chemotherapy and radiotherapy, followed by the anti-PD-L1 durvalumab or 
observation, NCT02125461) showed an increased progression-free survival (PFS), which was 
co-primary endpoint together with overall survival (OS). The full details are not known, yet, 
but it appears that the pre-clinical rationales of combined chemo-radiotherapy and anti-PD-1 
treatment can be successfully transferred into clinical trials, without serious toxicities. 
A recent secondary analysis of the Keynote 001 trial indicates synergistic affects of 
radiotherapy and immunotherapy.[2] This international, multicentre phase I trial assessed the 
effect of pembrolizumab monotherapy in patients with progressive locally advanced or 
metastatic NSCLC. Patients were assigned to multiple expansion cohorts to allow for the 
inclusion of patients who were naïve to systemic therapy and those who had progression after 
one or two previous regimens.  
The results from this study showed that the effect of pembrolizumab was significantly higher 
in patients who received previous radiotherapy than in patients without previous radiotherapy 


ETOP 6-14 NICOLAS AMD2 v3.0 20170704 
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(median PFS: 4.4 months versus 2.1 months, hazard ratio 0.56, p=0.019; median OS: 10.7 
months versus 5.3 months, hazard ratio 0.58, p=0.026). 
These findings were well in line with pre-clinical studies that underlined the ability of 
radiotherapy to enhance antitumour immune response.[2]  
In the absence of of serious pulmonary toxicity, the apperant benefit of chemo-radiotherapy 
and anti-PD-1 and the high interest of the NICOLAS study group, we propose to amend the 
NICOLAS trial protocol to expand on the number of patients in order to reach sufficient power 
for an efficacy readout (progression-free survival). 
Objectives and endpoints: To assess the safety and efficacy of nivolumab administration to 
standard first-line chemotherapy and radiotherapy in locally advanced stage IIIA/B NSCLC, 
as defined by the rate of grade >3 pneumonitis (CTCAE V4.0) 6 months post-radiotherapy 
and, if safety is proven, to assess the progression-free survival. 
Primary endpoint:  
 Grade >3 pneumonitis (CTCAE V4.0) observed any time during 6 months from 
the end of radiotherapy 
Key secondary endpoint: 
 1-Year progression-free survival 
Other secondary endpoints:  
 Time to first pneumonitis of grade >3 
 Objective response rate by RECIST v1.1 
 Time to treatment failure 
 Overall survival  
 Adverse events graded according to CTCAE V4.0 
Most important eligibility criteria (see protocol section 7 for complete list):  
Inclusion criteria at enrolment: 
 Histologically or cytologically confirmed locally advanced stage IIIA or III B (T0-3 
N2-3 or T4 N0-3 M0) non-small cell lung carcinoma (NSCLC), according to 7th 
TNM classification. 
 Nodal status N2 or N3 need to be proven (by biopsy, EBUS, mediastinoscopy or 
thoracoscopy) except for overt cT4 disease 
 Measurable disease according to RECIST v1.1 
 Previous delivery of a maximum of one 3-weekly cycle of platinum-based 
chemotherapy 
 ECOG performance status 0-1 
 Adequate hepatic, haematological and renal function  
 All AEs from previous therapies (including the first chemotherapy cycle in the 
context of this trial) resolved to grade <2 (except fatigue, alopecia, nausea lack of 
appetite or peripheral neuropathy) 
Exclusion criteria at enrolment: 


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 Metastatic disease (as determined by PET-CT and brain MRI (preferred) or high-
quality brain CT with intravenous contrast at the time of staging, performed within 
35 days before the beginning of first chemotherapy cycle) 
 Previous radiotherapy to the chest, including radiotherapy for breast cancer 
 Prior chemotherapy, radiotherapy or molecular targeted therapy for NSCLC (with 
the exception of one cycle of chemotherapy given prior to enrolment into this trial) 
 Active, known or suspected autoimmune disease 
Treatment: 
Chemotherapy consists of 3 cycles of cisplatin* in combination with vinorelbine, etoposide 
or pemetrexed. 
Option 
Drug 
Dose 
Dose frequency 
1 
Cisplatin plus vinorelbine 
Cisplatin* 
80 mg/m2 
d1, Q3W, 3 cycles** 
Vinorelbine  chemo-radiotherapy 
30 mg/m2 
d1 + d8 cycle 1 
20 mg/m2 
d1 + d8 cycles 2 & 3 
2 
Cisplatin plus etoposide 
Cisplatin* 
80 mg/m2 
d1, Q3W, 3 cycles** 
Etoposide 
100 mg/m2 
d1-d3, Q3W, 3 cycles** 
3 
Cisplatin plus pemetrexed (for non-squamous histological subtypes) 
Cisplatin* 
75 mg/m2 
d1, Q3W, 3 cycles** 
Pemetrexed 
500 mg/m2 
d1, Q3W, 3 cycles** 
* 
If cisplatin cannot be used, it can be replaced by carboplatin AUC5 at d1. 
** The first chemotherapy cycle is administered before enrolment. 
Concurrent radiotherapy and nivolumab treatment 
Patients must be enrolled before the start of chemotherapy cycle 2 and prior to the start of 
radiotherapy and nivolumab treatment.  
Radiotherapy 
Radiotherapy will consist of a physical dose of at least 60 Gy delivered concurrently with 
chemotherapy cycles 2 and 3 (see ESMO 2013 and EORTC radiotherapy guidelines). 
Nivolumab treatment  
Nivolumab therapy will start concurrently with radiotherapy. 
The first four doses of nivolumab are administered at 360 mg as intravenous infusion (approx. 
30 minutes) every 3-weeks with the first two doses given on day 1 of chemotherapy cycle 2 
and on day 1 of chemotherapy cycle 3. Thereafter, nivolumab is administered at 480 mg every 
4 weeks for up to 1 year from start of nivolumab treatment, unless treatment stops earlier due 
to unacceptable toxicity, disease progression, withdrawal of consent or the trial is terminated 
by the sponsor. 
Statistical considerations: 
A total sample size of 78 patients, receiving concurrent therapy is needed for the study, 
assuming a 5% loss-of-follow-up rate. First, testing for safety will be performed to evaluate 


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the 6-month post-radiotherapy pneumonitis-free rate and if the safety endpoint is met, an 
efficacy analysis will be performed regarding the one-year PFS.  
The primary safety hypothesis corresponds to the 6-month pneumonitis-free rate of grade ≥3:  
Null hypothesis states that 6-month pneumonitis-free rate of grade ≥3 is less than or equal to 
π0=67%, vs the one-sided alternative that the rate is above 67%, tested at π1=85%:  
H0: π0 ≤67% vs H1: π1>π0, at π1=85% 
For a one-sided alpha of 0.05 and power of 83%, the required sample size for the safety 
evaluation is 41 evaluable patients allowing for one interim safety analysis at 21 patients 
without any requirement for trial interruption. In the safety evaluation phase of the trial 43 
patients will be recruited allowing for around 5% competing risk rate. If additional patients 
are non-evaluable for the primary endpoint, up to 3 patients will be replaced. 
An interim safety analysis will be performed when 21 patients have completed a 3-month 
follow-up on nivolumab after chemotherapy and radiotherapy, assuming approximately 70% 
of the cases of pneumonitis occur by 3 months after the end of radiotherapy.  
If at the safety interim analysis, none of the 21 patients has developed pneumonitis of grade 
≥3 by 3 months, then the safety phase of the trial could stop early with the conclusion that the 
treatment is feasible and safe. The trial will continue to reach the total sample size required to 
test the efficacy hypothesis. If the only patients developing pneumonitis of grade ≥3 by 3 
months have done so before starting nivolumab, the Independent Data Monitoring Committee 
(IDMC) could choose to focus on the patients who started nivolumab for claiming feasibility. 
If the trial does not reach the safety conclusion at the interim, the final safety analysis will be 
performed when 41 patients have completed the 6-month follow-up. If at least 33 out of 
41 patients reach 6 months pneumonitis-free, the 6-month pneumonitis-free rate will be 
considered as promising, and the trial will continue to allow for the treatment to be tested for 
efficacy.  
Based on a hierarchical design,[3] a secondary efficacy hypothesis (secondary-Hs) is tested 
after the pneumonitis null hypothesis (primary-Hp) is rejected. 
Based on preliminary baseline information regarding stage, it is believed that for the observed 
case-mix, the 1-year PFS rate that could be achieved with current best provided care is 
estimated to be around 45%.[4, 5] The aim of the combination under investigation will be to 
improve the 1-year PFS by at least 15%, that is, to achieve a 1-year PFS rate of at least 60%. 
Efficacy hypothesis (Hs): 
Hs0: PFS0 ≤45% vs Hs1: PFS1> PFS0, at PFS1=60% 
A sample size of 74 evaluable patients will provide a power of 83%, for testing the above 
efficacy hypothesis, using an exact test for a single proportion, at the one-sided alpha of 0.05. 
Assuming 5% non-evaluable patients, a total sample size of 78 patients need to enter the study. 
The final efficacy hypothesis is tested after the safety null hypothesis is rejected either at the 
interim or the final safety analysis, when 74 evaluable patients under concurrent chemo-


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radiotherapy have reached one-year follow-up (from time of enrolment into the trial) or have 
experienced PD. 
The 78 patients will be enrolled under the protocol amendments (protocol versions 2.0 and 
3.0). Patients included under the original protocol (version 1.0) will be evaluated separately. 
A detailed statistical analysis plan (SAP) will be produced as a separate document.  
Safety evaluations will be reviewed by the IDMC at their regular meeting every three months. 
 
Total trial duration (for amendment 2):  
After a run-in period of 3 months for the activation of the centres, patient accrual is expected 
to be completed within 7 months. The trial will end with the preparation of the final report, 
scheduled at 2.5 years after the inclusion of the first patient.  


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2. 
Trial schedule  


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Baseline before 
enrolment 0(2)  
Chemotherapy (3) 
Radiotherapy (4) and 
nivolumab (5) treatment 
End of 
treatment (6) 
Post-treatment visits (7) 
before PD (8) 
after PD (8) 
Written informed consent: (9) 
 
 
 
 
 
 
Medical history 
 
 
 
 
 
 
Physical exam: PS, blood pressure, weight, height (at 
baseline) 
 
Every cycle (17) 
Every dose (18) 
 
 According to 
local standards 
 
Adverse events (10) 
Baseline symptoms 
Every cycle (17) 
Every dose (18) 
 
 
 
Concomitant medication 
 
Every cycle (17) 
Every dose (18) 
 
 
 
Further-line therapy 
 
 
 
 
 
 
Survival 
 
 
 
 
 
 
HIV status, hepatitis B/C 
 
 
 
 
 
 
Pregnancy test if applicable (11) 
 
 
At dose 1, then every 2nd dose 
 
 
 
TSH, with reflex free T3 and T4 (12) 
 
 
At dose 1, then every 2nd dose 
 
 
 
Haematology: haemoglobin, platelets, leukocytes, 
neutrophils 
 
Every cycle (17) 
Every dose (18) 
 
 
 
Renal function: serum creatinine, calculated creatinine 
clearance (13) 
 
Every cycle (17) 
Every dose (18) 
 
 
 
Serum urea level 
 
 
Every dose (18) 
 
 
 
Hepatic function: ALT, AST, AP, total bilirubin 
 
Every cycle (17) 
Every dose (18) 
 
 
 
Ca, Mg, Na, K, Cl, LDH, Glucose, amylase, lipase 
 
 
Every dose (18) 
 
 
 
Pulmonary function: FEV1, DLco (%) 
 
 
 
 
 
 
Electrocardiogram 
 
 
 
 
 
 
Whole body FDG-PET CT (14) 
 
 
 
 
 
 
Brain MRI or CT (15) 
 
 
 
 
 
 
Tumour assessment by CT scans (16) 
 
 
Year 1: every 9 weeks, year 2: every 12 weeks,  
thereafter every 6 months 
 
Chemotherapy (3) 
 
 
 
 
 
 
Radiotherapy (4) 
 
 
 
 
 
 
Nivolumab (5) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mandatory 
 
 
 
 
 
 


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(1) 
Baseline: to be done within 28 days prior to enrolment 
(2) 
Patients must be enroled prior to the start of radiotherapy and nivolumab treatment, e.g. between chemotherapy cycle one and two, ideally on day 1 of chemotherapy cycle 2 
(3) 
Chemotherapy consists of 3 cycles of cisplatin in combination with vinorelbine, etoposide or pemetrexed administered in 3-week (3 days) cycles. If cisplatin cannot be used, it can be 
replaced by carboplatin (AUC5). The first cycle is given prior to enrolment into the trial. After enrolment, the chemotherapy cycle 2 must start 21 days (3 days) after the start of cycle 1. 
Enrolment must occur before the start of concurrent radiotherapy and nivolumab treatment. 
(4) 
Radiotherapy consists of a physical dose of at least 60 Gy delivered concurrently with nivolumab and chemotherapy cycles 2 and 3. Please note that patients must be enrolled before 
radiotherapy starts. If the administration of chemotherapy is delayed due to toxicity, radiotherapy should start within 3 days of the start of chemotherapy cycle 2 in the. 
(5) 
Nivolumab treatment: The initial 4 doses of nivolumab will be administered at 360 mg as intravenous infusion (approx. 30 minutes) every 3-weeks (±3 days). The first 2 doses are administered 
concurrently with the last two chemotherapy cycles. From dose 5 on, nivolumab is administered at 480 mg every 4 weeks (±3 days) for up to 1 year from start of nivolumab treatment, unless 
nivolumab treatment stops earlier due to unacceptable toxicity, disease progression, withdrawal of consent or the trial is terminated by the sponsor. Please note that dose 5 will start 3 weeks 
(±3 days) after dose 4. 
(6) 
End of treatment visit: to be scheduled within 30 days following the decision to stop nivolumab treatment or within 30 days after planned treatment start if treatment never started. 
(7) 
Post treatment follow-up will continue for 2 years after the last patient started nivolumab treatment. Up to progression these visits should be scheduled to be done at the same time as the CT 
scans. After progression the post treatment visits will be every 6 months (4 weeks). 
(8) 
Treatment beyond PD: Patients with tumour volume increase detected after nivolumab treatment start but without appearance of new lesions or rapid clinical deterioration should continue 
to be treated with nivolumab and clinically observed with an imaging scheduled 6 weeks (1 week) later to allow detection of a subsequent tumour response (see section 10.7) for more 
information). 
(9) 
Written informed consent must be obtained prior to any trial specific evaluations and intervention within 7 weeks before enrolment. 
(10) Adverse events: Symptoms present at baseline will be recorded on the adverse event form. Adverse events should be documented until 100 days following the last dose of nivolumab. For 
more information please refer to section 12. 
(11) Pregnancy test: Women of childbearing potential, including women who had their last menstrual period in the last 2 years, must have a negative serum or urine pregnancy test within 7 days 
before study enrolment. The test must be repeated within 24 hours before beginning nivolumab treatment and then before every 2nd nivolumab administration. Pregnancy tests should be 
repeated at approximately 30 days and approximately 70 days after nivolumab treatment stops. 
(12) TSH, free T3 and T4 to be done before the first nivolumab administration. TSH must be repeated before every 2nd nivolumab administration. Free T3 and T4 have only to be repeated in case 
of abnormal TSH value. 
(13) Calculated according to the formula of Cockroft-Gault. 
(14) Whole body FDG-PET (with max SUV measurements) at baseline within 35 days before beginning of the first chemotherapy cycle. Contrast enhanced CT of thorax / upper abdomen (from 
top of thorax until adrenal glands and full liver and kidney included) is needed in addition to or in combination with PET. 
(15) Brain MRI (preferred) or high-quality CT with intravenous contrast at the time of staging mandatory within 35 days before beginning of first chemotherapy cycle. 
(16) Tumour assessment: CT of thorax / upper abdomen (from top of thorax until adrenal glands and full liver and kidney included, preferred) or alternatively CT of thorax and ultrasonography 
of upper abdomen every 9 weeks (1 week) from enrolment in the first year, every 12 weeks (2 weeks) in the second year and thereafter every 6 month (4 weeks), until progression of 
disease. First CT scan will be done at baseline within 35 days before start of chemotherapy (in combination with the whole body FDG-PET see footnote (14)). 
(17) Evaluations during chemotherapy: To be done within 24 hours prior to chemotherapy administration. 
(18) Evaluations during nivolumab therapy: To be done within 3 days before administration of the next nivolumab dose. 


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3. 
List of abbreviations 
AE 
Adverse Event 
ALK 
Anaplastic Lymphoma Kinase 
ALT 
Alanine Transaminase 
ANC 
Absolute Neutrophil Count 
AP 
Alkaline Phosphatase 
APL 
Acute Promyelocytic Leukaemia 
AST 
Aspartate Transaminase 
AUC  
Area Under the Curve 
BMS 
Bristol-Myers Squibb 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
CD279 
Cluster of Differentiation 279 
COPD 
Chronic Obstructive Pulmonary Disease 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
Cytotoxic T-lymphocyte Antigen-4 
CTV 
Clinical Target Volume 
DILI  
Drug-Induced Liver Injury 
DLCO 
Diffusing Capacity for Carbon Monoxide 
DVH 
Dose Volume Histogram 
EBUS 
Endobronchial Ultrasound  
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form(s) 
EEA 
European Economic Area 
EGFR 
Epidermal Growth Factor Receptor 
EORTC 
European Organisation for Research and Treatment of Cancer 
ERB 
Ethical Review Board 
ESMO 
European Society for Medical Oncology 
ETOP 
European Thoracic Oncology Platform 
FDG-PET 
Fluorodeoxyglucose Positron Emission Tomography 
FEV1 
Forced Expiratory Volume in 1 Second 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte-Colony Stimulating Factor 
GFR 
Glomerular Filtration Rate 
GI 
Gastrointestinal  
GM-CSF 
Granulocyte-Macrophage Colony-Stimulating Factor 
GTV 
Gross Tumour Volume  
Hb 
Haemoglobin 


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HIV 
Human Immunodeficiency Virus 
IASLC 
International Association for the Study of Lung Cancer 
IB 
Investigator’s Brochure 
IC 
Informed Consent 
ICH 
International Conference on Harmonization 
ICRU 
International Commission on Radiation Units 
IDMC 
Independent Data Monitoring Committee 
IHC 
Immunohistochemistry 
IMP 
Investigational Medicinal Product 
IMRT 
Intensity Modulated Radiotherapy 
IRB 
Institutional Review Board 
ITV 
Intratracheal ventilation 
IUD 
Intrauterine Device 
i.v. 
Intravenous 
LDH 
Lactate Dehydrogenase 
LFT  
Liver Function Test  
LFU 
Lost to Follow-Up 
MEL 
Melanoma 
MIP 
Maximum Intensity Projection 
MLD 
Mean Lung Dose 
MRI 
Magnetic Resonance Imaging 
NE 
Not Evaluable 
NSCC 
Non-Squamous-Cell Carcinoma 
NSCLC 
Non-Small Cell Lung Carcinoma 
OAR 
Organs at Risk 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PD-1 
Programmed Cell Death Protein 1 
PFS 
Progression Free Survival 
PR 
Partial Response 
PS 
Performance Status 
PTV  
Planning Target Volume 
RCC 
Renal Cell Carcinoma 
RDE 
Remote Data Entry 
RECIST 
Response Evaluation Criteria in Solid Tumours 
RP 
Radiation Pneumonitis 
RT 
Radiotherapy 
RTOG  
Radiation Therapy Oncology Group 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 


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SCC 
Squamous-Cell Carcinoma 
SCLC 
Small Cell Lung Carcinoma 
SD 
Stable Disease 
SPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SUV 
Standard Uptake Volume 
TFP3 
Time to first grade ≥3 pneumonitis 
TKI 
Tyrosine Kinase Inhibitor 
TNM 
Tumour, Nodes, Metastasis 
TTF 
Time to treatment failure 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal Lab Value 
VMAT 
Volumetric Arc Therapy 
WBC 
White Blood Cell 
WC 
Withdrawal of Consent 
4DCT 
Four-Dimensional Computed Tomography 
5-HT 
5-Hydroxytryptamin 


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4. 
Background and rationale 
4.1. 
Disease background 
Primary lung cancer is the most common malignancy after non-melanocytic skin cancer with 
deaths from lung cancer exceeding those from any other type of malignancy worldwide [6]. 
While it has been the most important cause of cancer mortality in men since the 1960s, it has 
equalled breast cancer as a cause of mortality in women since the 1990s. 
Lung cancer accounts for 12% of all incident cases of cancer. Non-small cell lung carcinoma 
(NSCLC) account for 80-85% of lung cancers, while small cell lung cancer (SCLC) has been 
decreasing in frequency in many countries over the last two decades [7]. 
Stage III NSCLC represents a heterogeneous group of patients even in the revised new version 
of the IASLC/TNM staging system 7. This stage includes either locally advanced primary 
tumours (T4-situation) with local infiltration of vital mediastinal organs or involvement of loco 
regional mediastinal lymph nodes (N2 or N3-nodes). Consecutively, the IIIA subset remains to 
be differentiated from the IIIB subset of NSCLC. Definitive cure rates and long-term prognosis 
also differ significantly between substages IIIA and IIIB [8]. 
Based on the underlying aetiology for developing lung cancer, patients in stage III present with 
variable clinical conditions and physical status. Long-term smokers – still the majority of the 
lung cancer population – typically harbour significant smoking induced comorbidities such as 
reduced pulmonary function due to chronic obstructive pulmonary disease (COPD), significant 
cardiac problems related to coronary heart disease as well as vascular problems due to smoking-
induced arteriosclerosis (peripheral and cerebral extension). Thus the comorbidity profile of 
the mostly elderly lung cancer patients in stage III may significantly hamper curative-intent 
radical treatment strategies.  
Over the past decade, concomitant chemotherapy and radiotherapy has become the first choice 
treatment for stage III NSCLC. 
 However, only about 30% of patients are alive 5 years after concomitant therapy. These figures 
remain approximately the same with the addition of surgery. After chemo-radiotherapy at least 
30-40% of the patients show local tumour progression. Also, after surgery about 30% of 
patients fail locally as a first site of recurrence. On top of these figures, more than half of the 
patients develop distant metastases that may have been present but undetected at the time of 
staging or that may have come from persistent or recurring local disease. It is clear that novel 
approaches that preferentially address both local and distant disease sites are needed to improve 
long-term survival and cure rates. 
4.2. 
Chemo-radiotherapy 
Some patients are defined as having potentially resectable stage III NSCLC when a dedicated 
multidisciplinary assessment, including an experienced thoracic surgeon, judges a complete 
resection (R0) may be feasible after induction treatment.  
The role of surgery was initially investigated in two phase III trials: EORTC 0841 and INT-
0139/RTOG-9309. In the EORTC trial, patients with stage IIIA-N2, deemed unresectable at 


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baseline evaluation, received cisplatin-based induction chemotherapy followed by either 
surgery or radiotherapy (60 Gy/ 30 fractions) in responding patients [9]. In this trial, in which 
no FDG-PET staging was used, there was no significant difference in OS (overall survival), 
being about 15% in both groups. In the INT/RTOG trial, patients with resectable stage IIIA-N2 
at the time of staging received two cycles of cisplatin-etoposide concurrent with radiotherapy 
to a dose of 45 Gy/25 fractions followed by either surgery or completion to so-called full dose 
radiotherapy (61 Gy) [10]. Again, in this trial without FDG-PET-CT staging, no significant 
difference in OS was observed (5-year OS in the surgery arm 27% vs. 20% in the non-surgery 
group, p=0.10), but due to the better disease-free survival in the surgery arm, the exceptionally 
high mortality in right-sided pneumonectomy patients and the higher OS in the unplanned 
“matched” lobectomy subgroup analysis, the debate on the role of surgery in the treatment of 
stage III disease continued. 
The two recent randomised trials investigated different questions: Does sequential 
chemotherapy plus radiotherapy (44 Gy / 22 fractions / 3 weeks ) before surgery improve the 
event-free survival compared to induction chemotherapy followed by surgery (the SAKK 
SAKK 16/00 trial) [11] or does surgery improve the OS when added to induction chemotherapy 
followed by concurrent chemo-radiotherapy (45 Gy/30 fractions every 3 weeks; 1.5 Gy twice-
daily) vs induction chemotherapy followed by full-dose concurrent chemo-radiotherapy 
(45 Gy/30 fractions every 3 weeks, followed by 2 Gy once-daily) in an isotoxic, accelerated 
way (total dose 65 Gy-71 Gy) (the ESPATUE trial [5]). In both studies, contemporary staging 
such as brain imaging and FDG-PET-CT was used. 
Neither trial showed a difference in the primary endpoint between both arms. At first glance, 
this would imply that for patients with resectable stage IIIA-N2 NSCLC at diagnosis, either 
induction chemotherapy followed by surgery or definitive concurrent chemo-radiotherapy are 
equal options. In unresectable or inoperable disease, concurrent chemo-radiotherapy remains 
the first choice [12]. 
Based on the non-significant difference in the primary endpoint result in these randomized 
trials, the choice of treatment varies across countries and centres. The optimal treatment plan 
is discussed in a multidisciplinary tumour board, taking into account the local treatment 
expertise. Both definitive chemo-radiotherapy as well as induction therapy followed by surgery 
or in some cases preoperative chemo-radiotherapy are options.  
Altogether, for the majority of stage III NSCLC, definitive chemo-radiotherapy will be 
preferred. Induction chemotherapy followed by radiotherapy, mostly to a dose of 60-66 Gy in 
30-33 fractions in 6-7 weeks, so-called sequential chemo-radiation, was compared to 
concurrent chemo-radiotherapy at the same dose in many phase III trials and in a meta-analysis 
[13, 14]. Concurrent chemotherapy and radiotherapy lead to higher 5-year survival rates at the 
cost of a higher rate of reversible oesophagitis. In fit patients, this is the standard treatment [13-
16]. A detailed look at the relationship of overall treatment duration and outcome in these 
studies has confirmed that prolonged treatment time is an issue in this setting, as it is in other 
tumour types. Overall treatment times over 4 weeks lead to a worse long-term survival. For 
concurrent radiochemotherapy protocols, a prolonged treatment time exceeding seven weeks 
would be perceived as suboptimal. 


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Chemotherapy is an integral part of the treatment of locally advanced NSCLC as it improves 
survival in all subgroups of patients, whether treatment included surgery or radiotherapy, as 
shown in meta-analyses based on individual patient data [20, 21]. 
In the absence of randomized studies defining an optimal chemotherapy regimen, no strict 
recommendation can be given as to a preferable combination. Of the six randomized studies in 
the meta-analyses, five used cisplatin-based schedules and only one carboplatin. In the latter 
study, a weekly infusion was used, but this relates to only 91 patients out of a total of 1205 in 
the meta-analysis. Cisplatin-based schedules are therefore recommended [16]. Moreover, in a 
recent meta-analysis on risk factors for symptomatic radiation pneumonitis, elderly patients 
who received carboplatin-paclitaxel chemotherapy were at highest risk [22]. Of the five 
phase III studies that used cisplatin concurrently with radiotherapy, two used only 2 cycles of 
platin combinations during radiotherapy, one trial used 2 cycles of platin combinations 
concomitantly during radiotherapy followed by 2 cycles of consolidation chemotherapy and 
two used daily cisplatin alone. There was no significant heterogeneity in the benefit between 
these schedules, although the daily administration of cisplatin has not been adopted widely 
because of practical issues. Therefore, 2 (to a maximum of 4) cycles of cisplatin-based doublet 
chemotherapy are recommended. The most commonly used drugs together with cisplatin are 
etoposide (at full systemic dose 100-120 mg/m²) and vinorelbine (at 60% of systemic dose, 
15 mg/m²).  
In the PROCLAIM trial, cisplatin-etoposide was compared to cisplatin-pemetrexed given 
concurrently with 66 Gy in 33 fractions of thoracic radiotherapy [23, 24]. No differences in 
PFS and OS were observed. Cisplatin-pemetrexed concurrent with radiotherapy was well 
tolerated. 
In all trials an average cisplatin dose of 80 mg/m2 per cycle was administered. There is no 
evidence for extended induction or consolidation chemotherapy [25-28]. 
Attempts to improve the long-term survival include radiotherapy dose escalation / acceleration 
[4], new chemotherapy combinations, and the addition of biological agents and cancer vaccines 
to standard regimens. Technical radiotherapy modifications, including intensity-modulated 
radiotherapy have also been investigated. However, none of these have thus far improved the 
OS of patients with stage III NSCLC, except for acceleration of radiotherapy in the non-
concurrent setting [17]. 
4.3. 
Radiation pneumonitis 
Dose-limiting toxicity of thoracic radiotherapy includes radiation pneumonitis (RP). Starting 
from two months after the end of radiotherapy, about 15% of the patients develop increasing 
dyspnoea and cough, provoked by a mixed T-lymphocyte infiltrate in lung areas that have been 
irradiated. RP typically may happen up to 6 months post-treatment, but about three quarters of 
RP cases have already occurred within 3 months after radiotherapy.  
Besides dose and volume parameters of the radiotherapy such as the mean lung dose (MLD) or 
the V20 (i.e., the percentage of the lungs that received more than 20 Gy), the most important 
risk factor for developing RP is the inflammatory status of the lungs before therapy. The more 
baseline inflammation, the higher is the risk of RP. Inflammation in the lungs can be visualized 


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and quantified by measuring the 18F-fluoro-D-deoxyglucose (FDG) in the lungs by standard 
FDG-PET-CT scans obtained at the time of staging. As the relative FDG uptake in the lung vs. 
the aorta is used, no specific calibration of the PET-scanner is required.   
4.4. 
Targeted agents in non-small cell lung carcinoma 
In metastatic NSCLC several chemotherapy regimens have shown comparable efficacy with 
different toxicity profiles that are taken into account for treatment selection. Targeted agents 
are now among the therapeutic options for patients with NSCLC and specific molecular 
characteristics. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors attain high 
response rates in patients whose tumours have activating EGFR mutations. Crizotinib also 
achieves high response rates in anaplastic lymphoma kinase (ALK)-translocated and ROS1-
translocated NSCLC patients. 
More recently, promising results have been reported with immune-checkpoint blockers 
(targeting cytotoxic T-lymphocyte–associated antigen 4 [CTLA4], programmed cell death 
protein 1 [PD-1] or its ligand PD-L1) in advanced NSCLC with objective responses in around 
20% of patients. Clinical results obtained with immune-checkpoint inhibitors illustrate how 
immunotherapy can induce long-lasting disease control. 
4.5. 
Immunotherapy for non-small cell lung carcinoma 
Improved understanding of the immune profile of NSCLC has led to immunotherapeutic 
strategies, including inhibitory molecules such as PD-1 and CTLA-4 responsible for abrogating 
an anti-cancer immune response.  
PD-1 is a key immune-checkpoint receptor expressed by activated T cells. Compared with 
CTLA4, PD-1 modulates a later stage of the immune response. Instead of affecting the initial 
stage of T-cell activation (priming) in the regional lymph node, PD-1 regulates the activation 
of T cells in peripheral tissues. Like CTLA-4, PD-1 can be found on the surface of the activated 
Treg lymphocytes and also on B lymphocytes or natural killer cells. PD-1 binds to its ligands 
PD-L1 (B7-H1) and PD-L2 (B7-DC), which are expressed on antigen presenting cells but also 
on cancer cells. 
Indeed, one important mechanism for tumour cells to escape the immune system is by 
overexpressing PD-1 ligands on their surface. Expression of immune-checkpoint ligands can 
be innate through constitutive oncogenic signalling or induced in response to inflammatory 
signals, such as interferon gamma, that are produced by an active antitumour immune response. 
PD-L1 expression was described in many histological cancer types and in particular in lung 
cancer where approximately 50% of NSCLCs are reported to express PD-L1.  
Several trials using anti-PD-1 and anti-PD-L1 antibodies from different pharma companies are 
ongoing and a significant amount of additional clinical data will be available soon.  
4.6. 
Nivolumab 
Nivolumab (BMS-936558; anti-PD-1) is a fully human monoclonal immunoglobulin G4 
(IgG4) antibody (HuMAb) that targets the programmed cell death protein 1 (PD-1, cluster of 
differentiation 279 [CD279]) cell surface membrane receptor. The co-inhibitory receptor PD-1, 


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a member of the CD28 superfamily of molecules, has important T cell regulatory functions. It 
is inducibly expressed on activated T cells, B cells, a subset of myeloid cells and a fraction of 
T memory cells, and it has been shown to mediate inhibition of T cell responses in peripheral 
tissues and tumours. Engagement of PD-1 by its natural ligands, PD-L1 and PD-L2, results in 
an inhibition of T cell proliferation, survival and cytokine secretion [29, 30]. Nivolumab 
abrogates this interaction between PD-1 and its ligands. 
Monoclonal antibodies targeting both PD-1 and PD-L1 are being developed, which have 
demonstrated significant clinical activity against several tumour types. Nivolumab (BMS-
936558) is a fully humanized antibody that targets the PD-1 receptor, preventing its activation 
by PD-L1 or PD-L2. 
A phase I trial tested nivolumab in 296 patients with advanced solid cancers, including 129 
NSCLC patients [31, 32]. Nivolumab was administered intravenously once every 2 weeks at 
doses of 1, 3 or 10 mg/kg. The majority of patients were heavily pre-treated (54% of NSCLC 
patients had already received 3 lines of chemotherapy). Previous treatments included platinum-
based chemotherapy (99%) and tyrosine kinase inhibitors (28%). Of the 129 NSCLC patients, 
17% had objective responses (n =22). Responses in NSCLCs were seen at all dose levels, but 
were higher with higher doses: 3% at 1 mg/kg, 24% at 3 mg/kg, and 20% at 10 mg/kg. 
Objective responses were observed in squamous and nonsquamous NSCLCs: 17% of 
squamous-cell carcinoma (SCC; n =9 of 54) and 18% of nonsquamous-cell carcinoma (NSCC; 
n =13 of 74). Median OS across all dose cohorts was 9.2 months for SCC and 9.6 months for 
NSCC. Prolonged responses were reported in both histologies with sustained OS: 44% / 41% 
SCC and 44% / 17% NSCC were alive at 1 and 2 years, respectively. 
Toxicity was mild, consisting mainly of fatigue, skin rash, GI toxicity (diarrhoea) or 
endocrinopathy. Grade 3-4 toxicities were extremely rarely observed, and described to 
potentially affect lung or GI tract including hepatitis. Rare cases of fatal pneumonits were 
reported. 
The probability of severe pneumonitis is less than 5% with nivolumab alone. After radiotherapy 
with or without chemotherapy, the incidence of severe pneumonitis is approximately 15%. It is 
unknown if nivolumab influences the incidence of pneumonitis after radiotherapy. 
In addition, two phase III trials showed an OS benefit against docetaxel in the second-line 
setting. 
The first one (CheckMate 017) focussed on squamous histology advanced NSCLC patients. 
272 patients were assigned to receive nivolumab at a dose of 3 mg/kg of body weight every 
2 weeks, or docetaxel at a dose of 75 mg/m2 of body-surface area every 3 weeks. The median 
overall survival was 9.2 months (95% confidence interval [CI], 7.3 to 13.3) with nivolumab 
versus 6.0 months (95% CI, 5.1 to 7.3) with docetaxel. The risk of death was 41% lower with 
nivolumab than with docetaxel (hazard ratio, 0.59; 95% CI, 0.44 to 0.79; P<0.001). At 1 year, 
the overall survival rate was 42% (95% CI, 34 to 50) with nivolumab versus 24% (95% CI, 17 
to 31) with docetaxel. The response rate was 20% with nivolumab versus 9% with docetaxel 
(P=0.008). The median PFS was 3.5 months with nivolumab versus 2.8 months with docetaxel 
(hazard ratio for death or disease progression, 0.62; 95% CI, 0.47 to 0.81; P<0.001). The 


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expression of the PD-1 ligand (PD-L1) was neither prognostic nor predictive of benefit. 
Treatment-related adverse events of grade 3 or 4 were reported in 7% of the patients in the 
nivolumab group as compared with 55% of those in the docetaxel group [33, 34]. 
The second trial, CheckMate 057 used the same design in the non-squamous subgroup. Patients 
in the CheckMate 057 study had progressed after treatment with platinum-based doublet 
chemotherapy (and, if eligible, a tyrosine kinase inhibitor), a guideline-recommended first-line 
therapy for nonsquamous NSCLC [35]. They were randomly assigned to subsequent treatment 
with nivolumab (3 mg/kg every 2 weeks; 292 patients) or docetaxel (75 mg/m2 every 3 weeks; 
290 patients); both drugs were continued until progression or discontinuation due to toxicity. 
The primary efficacy endpoint of the study was overall survival (OS). Treatment with 
nivolumab significantly improved median OS, with a hazard ratio for death of 0.73 (95% CI: 
0.59, 0.89; P=0.00155) compared with docetaxel. One-year OS was 50.5% with nivolumab 
versus 39.0% with docetaxel. Other study endpoints included PFS, ORR, and nivolumab 
efficacy by PD-L1 expression [35]. 
 
4.7. 
Biomarker research for nivolumab 
Biomarker efforts within the nivolumab (BMS-936558, anti-PD-1) program include 
identification of predictive biomarkers for patient stratification or enrichment in order to 
maximize the therapeutic index of the drug. Currently, the lead candidate predictive biomarker 
for nivolumab is PD-L1 (B7-H1) expression as assessed by immunohistochemistry (IHC) based 
on a preliminary, retrospective analysis of a subset of subjects from the nivolumab 
monotherapy study CA209-003, which included NSCLC, melanoma (MEL) and renal cell 
carcinoma (RCC) subjects. Based on this initial data [36], Bristol-Myer Squibb (BMS) is 
partnering with Dako to develop a diagnostic IHC assay to reliably and reproducibly measure 
PD-L1 expression in NSCLC, MEL, and RCC tumour tissue samples. The Phase III NSCLC 
program, currently including studies CA209-017 (second-line, squamous NSCLC, vs 
docetaxel) and CA209-057 (second/third-line, non-squamous NSCLC, vs docetaxel) 
incorporate mandatory tumour tissue collection and pre-specified, retrospective assessment of 
PD-L1 IHC expression. 
Historically, different antibodies and scoring methods have been used to assess PD-L1 status 
by IHC, which has provided a broad range of positivity rates in the tumour types of interest. 
Most reports suggest that PD-L1 positivity is linked to a poor prognosis, although there are 
conflicting reports suggesting that PD-L1 positive status portends a good prognosis. There is a 
priority in understanding the prognostic role of PD-L1 in NSCLC, while providing additional 
information around the rate of positivity in this tumour type, notably using the Dako-developed 
assay for nivolumab.  
4.8. 
Overall risk/benefit assessment 
Radiochemotherapy is a curative intent strategy in locally advanced NSCLC. However despite 
optimal delivery of therapy either local or distant relapse will be observed in the majority of 
patients in the first two years following completion of treatment. Several strategies have failed 


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to improve the prognosis of these patients: induction or consolidation chemotherapy, EGFR 
tyrosine kinase inhibitor maintenance treatment, consolidation vaccination as well as higher 
dose of daily fractionated radiotherapy up to 70 Gy. 
There is an urgent need to identify new ways to improve the cure rate in locally advanced 
NSCLC. As seen in advanced disease, immunotherapy looks a very promising approach. 
Additionally, the setting of minimal residual disease after chemo-radiotherapy probably offers 
a good opportunity for immune modulation. 
Nivolumab added to chemotherapy has been evaluated in several cohorts of chemotherapy-
naive subjects with advanced NSCLC in trial CA209012. Nivolumab 10 mg/kg was combined 
with gemcitabine plus cisplatin and pemetrexed plus cisplatin. Nivolumab doses of 5 mg/kg 
and 10 mg/kg were combined with paclitaxel and carboplatin [37]. 
The safety profile of nivolumab plus platinum-doublet chemotherapy reflects additive toxicities 
of the individual agents, which were manageable using established safety guidelines. 
Nivolumab has not been tested in the context of definitive chemo-radiotherapy for stage III 
disease. To date there is no data concerning an interaction with palliative radiotherapy in the 
stage IV setting. 
The unmet need in this curative context presents a very favourable risk/benefit ratio; the major 
concerns are the cumulative risk of radiotherapy induced pneumonitis and reported rare cases 
of nivolumab-related pneumonitis. 
4.9. 
Rationale for trial design 
Most comparative studies of concurrent chemo-radiotherapy vs sequential administration used 
cisplatin/etoposide or cisplatin/vinca alkaloid (typically: cisplatin plus vinorelbine) 
combination chemotherapy. There are no comparative phase III trials using the 
paclitaxel/carboplatin regimen. Thus, when delivered perioperatively, cisplatin based 
combinations are considered the treatment of choice, in the absence of contra-indication – with 
vinorelbine and etoposide as the best standard combination. 
Pre-clinical data show a clear beneficial effect of combining local radiotherapy and anti-PD-1. 
This led not only to an increase in the local tumour control but to an “abscopal” effect on distant 
metastases. Radiotherapy acted as an “in situ” tumour vaccination resulting in the induction of 
specific anti-tumour immunity in all sites of the body that could result in a clinical anti-tumour 
effect because of the combination with an anti-PD-1 agent like nivolumab. 
There is a need to improve the prognosis of patients with stage III NSCLC, and a strong 
rationale to combine chemo-radiotherapy with anti-PD-1. A major theoretical concern is the 
development of pneumonitis. The main aim of the current trial proposal is therefore to evaluate 
the pneumonitis rate in patients being treated with concurrent chemo-radiotherapy and 
nivolumab treatment. 
The initial dose and schedule of nivolumab while combined with chemotherapy will be 360 mg 
i.v. Q3W. The rationale for the flat dose is based on the expected similarity of safety and 
efficacy to the approved 3 mg/kg dose. Based on a wide therapeutic window of nivolumab 
monotherapy, the range of exposures with flat dosing are not expected to affect efficacy because 


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the exposures predicted for the 360 mg Q3W dose is on the flat part of the exposure response 
curve. For safety, doses up to 10 mg/kg nivolumab Q2W have been well tolerated across 
multiple tumours and an increase in exposure is not associated with a probability of increasing 
adverse events. Therefore, a flat dose of 360 mg Q3W for nivolumab monotherapy will be 
investigated in this trial. 
From cycle 5 on, nivolumab will be administered at 480 mg Q4W for up to 1 year. Based on 
pharmacokinetic modelling, the 480 mg Q4W dose will provide similar steady-state average 
concentrations as 3 mg/kg or 240 mg Q2W dose. The every 4-week schedule will be more 
convenient for patients. 
While the role of immunotherapy is currently being evaluated as monotherapy or in 
combination with chemotherapy or TKIs in all lines of treatment of advanced NSCLC, as 
monotherapy in early NSCLC adjuvant setting as well as monotherapy in consolidation after 
completion of definitive chemo-radiotherapy, it is not to date being assessed in combination 
with radiotherapy. While anecdotal data of concurrent treatment in the palliative setting suggest 
safety and a good tolerability of such a combination, a formal prospective assessment is 
required before embarking on any trial comparing concurrent versus sequential checkpoint 
inhibitors and radiotherapy designs. 
The rationale for concurrent checkpoints and radiotherapy resides in the description of cases of 
unexpected immune sensitization offered by such a combination, with the demonstration of 
tumour responses to localized radiotherapy after immune simulation in non-irradiated sites – 
called the abscopal effect. A strong rationale is also provided by pre-clinical models, showing 
a synergistic effect of such approaches in various in vitro and in vivo models [38]. 
4.9.1. 
Rational for protocol amendment 2 
Since the NICOLAS trial has been initiated, the landscape of combining chemo-radiotherapy 
with immune-checkpoint inhibition, such as anti-PD-1 antibodies, has changed rapidly, 
opening a new window of opportunity. 
There is a very strong interest within multidisciplinary lung cancer community to investigate 
the optimal integration of anti-PD-1 treatment into chemo-radiotherapy. Currently, 11 sites 
from 5 countries are activated for the NICOLAS trial and recruiting strongly (ahead of 
schedule). Using this momentum will allow us to rapidly recruit additional patients in order to 
reach the power to not only investigate toxicity, but also to evaluate the efficacy of the 
concurrent treatment. 
So far, during the regular safety review, the ETOP IDMC did observe any additional toxicit 
compared the chemo-radiotherapy alone. 
Additionally, a first planned analysis of the PACIFIC trial (stage III NSCLC treated with 
concurrent chemotherapy and radiotherapy, followed by the anti-PD-L1 durvalumab or 
observation, NCT02125461) showed an increased progression-free survival (PFS), which was 
co-primary endpoint together with overall survival (OS). The full details are not yet known, but 
it appears that the pre-clinical rationales of combined chemo-radiotherapy and anti-PD-1 
treatment are successfully transferred into clinical trials, without serious toxicities. 


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A recent secondary analysis of the Keynote 001 trial indicates synergistic affects of 
radiotherapy and immunotherapy.[2] This international, multicentre phase I trial assessed the 
effect of pembrolizumab monotherapy in patients with progressive locally advanced or 
metastatic NSCLC. Patients were assigned to multiple expansion cohorts to allow for the 
inclusion of patients who were naïve to systemic therapy and those who had progression after 
one or two previous regimens.  
The results from this study showed that the effect of pembrolizumab was significantly higher 
in patients who received previous radiotherapy than in patients without previous radiotherapy 
(median PFS: 4.4 months versus 2.1 months, hazard ratio 0.56, p=0.019; median OS: 10.7 
months versus 5.3 months, hazard ratio 0.58, p=0.026). 
These findings were well in line with preclinical studies that demonstrated the ability of 
radiotherapy to enhance antitumour immune response.[2]  
In the absence of of serious pulmonary toxicity, the apparent benefit of chemo-radiotherapy 
and anti-PD-1 and the high interest of the NICOLAS study group, we propose to amend the 
NICOLAS trial protocol to expand on the number of patients in order to reach sufficient power 
for an efficacy readout (progression-free survival). 
5. 
Objectives and endpoints 
5.1. 
Primary objective 
To assess the safety and efficacy of the concurrent nivolumab administration with standard 
first-line chemotherapy and radiotherapy in locally advanced stage IIIA/B NSCLC, as defined 
by the rate of grade ≥3 pneumonitis (CTCAE V4.0) 6 months post-radiotherapy and, if safety 
is proven, to assess the progression-free survival (see section 17: Statistical Considerations). 
5.2. 
Secondary objectives 
5.2.1. 
To evaluate secondary measures of clinical efficacy including time to first grade ≥3 
pneumonitis (TFP3), objective response rate (ORR), time to treatment failure (TTF) 
and overall survival (OS).  
5.2.2. 
To assess the safety and the tolerability of the treatment. 
5.3. 
Primary endpoint 
5.3.1. 
Grade ≥3 pneumonitis (CTCAE V4.0) observed any time during 6 months from end 
of radiotherapy; for definition, see section 14.1. 
5.4. 
Key secondary endpoint 
5.4.1. 
1-Year progression-free survival by RECIST v1.1 
5.5. 
Other secondary endpoints 
5.5.1. 
Time to first grade ≥3 pneumonitis 


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5.5.2. 
Objective response determined by RECIST v1.1 
5.5.3. 
Time to treatment failure 
5.5.4. 
Overall survival 
5.5.5. 
Adverse events graded according to CTCAE V4.0 
For definitions, see section 14. 
6. 
Trial design, duration and termination 
This phase II trial aims at evaluating the addition of anti-PD-1 nivolumab consolidation to 
standard first-line chemotherapy and radiotherapy in locally advanced stage IIIA/B NSCLC 
with safety as primary endpoint and efficacy as key secondary endpoint. 
Patients will receive 4 doses of nivolumab 360 mg Q3W, concurrently with standard chemo-
radiotherapy, followed by 480 mg Q4W for up to 1 year from start of nivolumab treatment, 
unless treatment stops earlier due to unacceptable toxicity, disease progression, withdrawal of 
consent or the trial is terminated by the sponsor.  
After a run-in period of 3 months for the activation of the centres, patient accrual is expected 
to be completed within 9 months. Follow-up will continue until 2 years from start of nivolumab 
treatment of the last recruited patient. The trial will end with the preparation of the final report, 
scheduled at 2.5 years after the inclusion of the first patient.  
 
Screening, eligibility 
and enrolment
Stage 
IIIA / B
NSCLC
Radiotherapy 
chemo  
cycle 3
chemo  
cycle 1
chemo  
cycle 2
until PD
Whole body 
FDG-PET
CT scans year 1: every 9 weeks, year 2: every 12 weeks, beyond 2 years: every 6 months
Nivolumab: 360 mg Q3W 4 doses, followed by 480 mg Q4W up to 1 year


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Eleven sites from five European countries will participate. 
Screening, eligibility 
and enrolment
Nivolumab:
480mg Q4W 
up to 1 year
Stage 
IIIA / B
NSCLC
chemo  
cycle 1
chemo  
cycle 2
chemo  
cycle 3
Radiotherapy 
Radiotherapy 
chemo  
cycle 3
chemo  
cycle 1
chemo  
cycle 2
Investi-
gator‘s 
choice
until PD
Whole body 
FDG-PET
CT scans year 1: every 9 weeks, year 2: every 12 weeks, beyond 2 years: every 6 months
Nivolumab: 360 mg Q3W, 4 doses
Nivolumab: 240mg Q2W, 8 doses


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7. 
Patient selection 
Written Informed Consent (IC) must be signed and dated by the patient and the investigator 
prior to any trial-related evaluation and/or intervention. 
7.1. 
Inclusion criteria  
7.1.1. 
Histologically or cytologically confirmed non-small cell lung carcinoma 
7.1.2. 
Locally advanced stage IIIA or IIIB (T0-3 N2-3 or T4N0-3 M0) NSCLC, according 
to 7th TNM classification.  
Within 35 days before beginning of first platinum-based chemotherapy cycle: 
- 
Nodal status N2 or N3 must be proven (by biopsy, EBUS, mediastinoscopy or 
thoracoscopy) except for overt cT4 disease. 
- 
Whole body FDG-PET plus contrast enhanced CT of thorax / upper abdomen 
(from top of thorax until adrenal glands, and full liver and kidney included) in 
addition to or in combination with PET.  
- 
brain MRI (preferred) or high-quality brain CT with intravenous contrast at the 
time of staging mandatory. 
7.1.3. 
Measurable disease (according to RECIST v1.1 criteria) 
7.1.4. 
Age ≥18 years 
7.1.5. 
Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 (see Table 1) 
7.1.6. 
Life expectancy >3 months 
7.1.7. 
Previous delivery of a maximum of one 3-weekly cycle of platinum-based 
chemotherapy 
7.1.8. 
All AEs from previous therapies (including the first chemotherapy cycle in the 
context of this trial) resolved to grade <2 (except fatigue, alopecia, nausea, lack of 
appetite and peripheral neuropathy). 
7.1.9. 
Adequate haematological function:  
- 
WBC ≥2000/μL 
- 
haemoglobin ≥9 g/dL 
- 
neutrophil count ≥1×109/L 
- 
platelet count ≥100 × 109/L  
7.1.10. Adequate liver function: 
- 
Total bilirubin ≤2 x ULN (except patients with Gilbert Syndrome, who can have 
total bilirubin < 3.0 mg/dl) 
- 
ALT ≤3 × ULN 
- 
Alkaline phosphatase ≤5 x ULN. 
7.1.11. Adequate renal function: Calculated creatinine clearance (according to Cockroft-


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Gault, see 10.2): 
- 60ml/min for patient receiving cisplatin 
- 30ml/min for patient receiving carboplatin  
7.1.12. Pulmonary function FEV1 of 1.0 L or >40% predicted value and DLCO >30% 
predicted value 
7.1.13. Patient capable of proper therapeutic compliance, and accessible to correct follow-
up. 
7.1.14. Women of childbearing potential, including women who had their last menstrual 
period in the last 2 years, must have a negative serum or urine pregnancy test within 
7 days before trial enrolment. The test must be repeated within 24 hours before 
beginning nivolumab treatment and then before every 2nd nivolumab administration. 
Pregnancy tests should be repeated at approximately 30 days and approximately 
70 days after nivolumab treatment stops.  
7.1.15. Written Informed Consent (IC) for trial treatment must be signed and dated by the 
patient and the investigator prior to any trial-related evaluation and/or intervention.  
 
Table 1: ECOG Performance Status: 
PS 0 
Fully active, able to carry on all pre-disease performance without restriction 
PS 1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light housework, office work 
PS 2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
PS 3 
Capable of only limited self care, confined to bed or chair more than 50% of waking 
hours 
PS 4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
7.2. 
Exclusion criteria  
7.2.1. 
Patients with mixed small-cell and non-small-cell histologic features 
7.2.2. 
Patients with pleural or pericardial effusions proven to be malignant 
7.2.3. 
Prior chemotherapy, radiotherapy or molecular targeted therapy for NSCLC (with 
the exception of one cycle of chemotherapy given prior to enrolment into this trial, 
see 7.1.7) 
7.2.4. 
Patients with an active, known or suspected autoimmune disease. Patients are 
permitted to enrol if they have vitiligo, type I diabetes mellitus, residual hypo-
thyroidism 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. 


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7.2.5. 
Patient who has had in the past 3 years any previous or concomitant malignancy 
EXCEPT adequately treated basal or squamous cell carcinoma of the skin, in situ 
carcinoma of the cervix or bladder, in situ ductal carcinoma of the breast. 
7.2.6. 
Patient with other serious diseases or clinical conditions, including but not limited to 
uncontrolled active infection and any other serious underlying medical processes that 
could affect the patient’s capacity to participate in the trial. 
7.2.7. 
Ongoing clinically serious infections requiring systemic antibiotic or antiviral, 
antimicrobial, antifungal therapy. 
7.2.8. 
Known or suspected hypersensitivity to nivolumab or any of its excipients 
7.2.9. 
Substance abuse, medical, psychological or social conditions that may interfere with 
the patient’s participation in the trial or evaluation of the trial results. 
7.2.10. Established pathological diagnosis of underlying interstitial lung disease or 
pulmonary fibrosis  
7.2.11. Women who are pregnant or in the period of lactation 
7.2.12. Sexually active men and women of childbearing potential who are not willing to use 
an effective contraceptive method (see section 10.8) during the trial treatment and 
for a period of at least 7 months (male participants) and 5 months (female 
participants) following the last administration of nivolumab. 
7.2.13. Patients receiving any concurrent anticancer systemic therapy 
7.2.14. HIV, active Hepatitis B or Hepatitis C infection 
7.2.15. Previous radiotherapy to the thorax (prior to inclusion), including radiotherapy for 
breast cancer 
7.2.16. Planned radiotherapy to lung of mean dose >20 Gy or V20 >35% 
7.2.17. Patient who received treatment with an investigational drug agent during the 3 weeks 
before enrolment in the trial 
7.2.18. Metastatic disease (mandatory assessment of the brain either by MRI or high-quality 
CT with intravenous contrast at the time of staging as well as systemic PET and CT 
scan) 
7.2.19. Prior 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 
Please refer to section 10.6 for prohibited and restricted therapies during trial treatment. 
 
 


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8. 
Patient screening and enrolment 
This trial will use a web-based registration system. Each participating centre will access the 
system directly to enrol patients. Specific details for enrolment of patients are in the ETOPdata 
User Manual which will be available on the trial specific section on the ETOP website 
(http://www.etop-eu.org). 
8.1. 
Screening 
Note that written informed consent must be obtained from the patient prior to any trial-related 
evaluation and/or intervention (with the exception of the first chemotherapy cycle that is 
administered before enrolment into the trial). Detailed trial procedures are described in 
section 15. 
8.2. 
Enrolment  
Patients must be enrolled prior to the start of radiotherapy and nivolumab treatment, e.g. 
between chemotherapy cycle one and two, ideally on day 1 of chemotherapy cycle 2. 
Verify eligibility and enrol the patient in the RDE facility ETOPdata according to the 
information in the ETOPdata User Manual (available on the trial specific section on the ETOP 
website). The date the Informed Consent was signed by the patient and the date signed by the 
investigator are both required to complete the eligibility checklist. 
Please complete and submit the Eligibility for Enrolment tab. Then submit the eCRF in 
ETOPdata in order to enrol the patient. Detailed trial procedures are described in section 15. 
 
8.3. 
Start of chemo-radiotherapy 
Chemotherapy consists of 3 cycles. The first cycle is given prior to enrolment into the trial. 
After enrolment, the second chemotherapy cycle should start 21 (3) days after day 1 of 
cycle 1, except for delay due to chemotherapy toxicities from first cycle (see section 10.3).  
Radiotherapy is applied concurrently and must start at the same time as chemotherapy cycle 2. 
In case the administration of chemotherapy is delayed due to toxicity, radiotherapy should start 
within 3 days of start of chemotherapy cycle 2. 
 
8.4. 
Start of nivolumab 
Nivolumab treatment will start concurrently with radiotherapy and starts on the same day as 
chemotherapy cycle 2. In case of chemotherapy delays due to toxicity, nivolumab will be 
administered when chemotherapy recommences. Nivolumab is always administered at the 
same time as chemotherapy, i.e. the same delay will apply for both chemotherapy and 
nivolumab. 


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9. 
Investigational product 
Nivolumab is the Investigational Medicinal Product (IMP) used in this trial. BMS will provide 
the IMP at no cost for the entire duration of this trial. 
The Drug Supply Manual (available on the trial specific section on the ETOP website) will 
describe detailed drug supply logistics as well as labelling, packaging, handling, drug 
accountability and destruction of unused drugs. 
9.1. 
Description of investigational drug 
Nivolumab (also referred to as BMS-936558 or MDX-1106) is a fully human monoclonal 
immunoglobulin G4 (IgG4-S228P) antibody (HuMAb) that targets the programmed cell death 
protein 1 (PD-1) cell surface membrane receptor. 
PD-1, a transmembrane protein, is a member of the CD28 family of T-cell costimulatory 
receptors. PD-1 is highly expressed on activated T cells and B cells. Two ligands specific for 
PD-1 have been identified: PD-L1 and PD-L2. PD-L1 and PD-L2 have been shown to down-
regulate T-cell activation upon binding to PD-1. Binding of PD-1 to its ligands results in the 
down-regulation of lymphocyte activation. Inhibition of the interaction between PD-1 and its 
ligands promotes immune responses and antigen-specific T-cell responses to both foreign 
antigens as well as self-antigens. Nivolumab is expressed in Chinese hamster ovary (CHO) 
cells and is produced using standard mammalian cell cultivation and chromatographic 
purification technologies.  
The clinical study product is a sterile solution for intravenous administration. 
9.2. 
Packaging and labelling 
Nivolumab is available in concentrations of 100 mg/vial (10 mg/ml). Nivolumab is 
administered via intravenous (i.v.) infusion only. 
9.3. 
Receipt of the drug  
Nivolumab will be supplied by BMS directly to the sites. The investigational site will check 
the condition of nivolumab upon arrival. Any damaged shipments will be replaced. See the 
Drug Supply Manual for details. 
Accurate records of nivolumab received at, dispensed from, returned to, and disposed of by the 
study site should be recorded on the Drug Accountability Log. In the event that nivolumab is 
destroyed at site a certification of destruction form should be generated and retained in the Trial 
Master File. 
9.4. 
Storage and handling 
Nivolumab must be stored at 2°- 8°C, protected from light and freezing. Nivolumab must be 
stored in a secure area according to local regulations. See Drug Supply Manual for details. 


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9.5. 
Unused trial drug supplies 
If nivolumab is to be destroyed on site, it is the investigator’s responsibility to ensure that 
arrangements have been made for disposal and that procedures for proper disposal have been 
established according to applicable regulations, guidelines, and institutional procedures. 
Appropriate records of the disposal must be maintained. Provide a certificate of destruction to 
ETOP upon disposal. Please refer to the Drug Supply Manual for details. 
10. 
Trial treatments 
10.1. 
Overview of treatment  
Trial treatment consists of chemotherapy (cisplatin in combination with vinorelbine, etoposide 
or pemetrexed) concurrently with radiotherapy and anti PD-1 nivolumab treatment. 
10.2. 
Chemotherapy dosage, administration and schedule 
Chemotherapy consists of 3 cycles of cisplatin in combination with vinorelbine, etoposide or 
pemetrexed. The first cycle is given prior to enrolment into the trial. After enrolment, the 
second chemotherapy cycle must start 21 days (3 days) after the start of cycle 1, except for 
delay due to chemotherapy toxicities from first cycle (see section 10.3). 
Radiotherapy is given concurrently with chemotherapy cycle two and three (see Section 10.4) 
Chemotherapy is administered according to local guidelines. The chemotherapy doses should 
be based on the patient’s calculated pre-treatment body surface area (BSA) using actual body 
weight. 
Table 2: Overview chemotherapy options 
Option 
Drug 
Dose 
Dose frequency 
1 
Cisplatin plus vinorelbin 
Cisplatin* 
80 mg/m2 
d1, Q3W, 3 cycles** 
Vinorelbine  chemo-radiotherapy 
30 mg/m2 
d1 + d8 cycle 1** 
20 mg/m2 
d1 + d8 cycles 2 & 3 
2 
Cisplatin plus etoposide 
Cisplatin* 
80 mg/m2 
d1, Q3W, 3 cycles** 
Etoposide 
100 mg/m2 
d1-d3, Q3W, 3 cycles** 
3 
Cisplatin plus pemetrexed (for non-squamous histological subtypes) 
Cisplatin* 
75 mg/m2 
d1, Q3W, 3 cycles** 
Pemetrexed 
500 mg/m2 
d1, Q3W, 3 cycles** 
* 
If cisplatin cannot be used, it can be replaced by carboplatin AUC5 at d1. 
** 
The first chemotherapy cycle is administered before enrolment. 
Carboplatin dose must be calculated according to Calvert formula and calculated creatinine 
clearance (CrCl) according to the formula of Cockroft-Gault (see below). 
Calvert Formula: Dose (in mg) = Target AUC × (GFR+ 25) 
Cockroft-Gault: 
CrCl (mL
min) = [140-age (years)×actual body weight (kg)]
72 × serum creatinine (mg
dL)
×{0.85 if female} 
AUC: Area under curve; GFR: Glomerular filtration rate (calculated creatinine clearance) 


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10.3. 
Chemotherapy delay and dose modification for toxicity 
Chemotherapy toxicity should be managed according to local standards. 
The policy should be to delay and give at full dose, rather than reduced dose. The dose 
modification schedule should be followed, but clinical judgment and local standards should be 
used in individual cases. Common side effects are listed in sections 11.2. - 11.6. 
Nivolumab administration will follow any chemotherapy delay. 
Repeated dose delays are allowed as required, but the sum of all delays should not exceed 
6 weeks. If chemotherapy cannot be administered after a three-week delay, chemotherapy 
should be discontinued. Note: patients who cannot complete chemotherapy due to toxicity may 
continue trial treatment if radiotherapy can be given at a curative dose. In such a case, 
nivolumab administration will continue concurrently with radiotherapy. 
10.3.1. Haematological toxicity  
Dose modifications are based on each pre-treatment blood count.  
Table 3: Chemotherapy dose modifications for haematological toxicity 
ANC x 109/l 
 
Platelets x 109/l 
Cisplatin + etoposide or 
vinorelbine + pemetrexed 
or 
carboplatin + etoposide or 
vinorelbine + pemetrexed 
>1.5 at day 1 of cycle 
and  
>100  
Full dose  
≤1.5 at day 1 of cycle 
or  
≤100  
Delay until recovery ANC 
>1.5 and platelets >100 
Febrile neutropenia 
episode or treatment 
delay for grade 4 
neutropenia >7 days 
 
 
First event: full dose and G-
CSF support is recommended. 
Second event or if G-CSF 
support was already delivered: 
20% dose reduction of both 
drugs and continuing G-CSF 
support.  
 
 
Grade 4 thrombocyto-
penia requiring medical  
intervention or grade ≥2 
bleeding with 
thrombocytopenia 
First event: 20% dose 
reduction of both drugs  
Second event: 35% dose 
reduction of both drugs 
 
10.3.2. Hepatic toxicity 
Table 4: Chemotherapy dose modifications for hepatic toxicity 


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AST/ALT 
 
Bilirubin 
Cisplatin 
or  
carboplatin 
Etoposide, 
vinorelbine or 
pemetrexed 
 
2-5 x ULN at day 1 
of cycle 
and 
≤2 x ULN 
Full dose 
Full dose 
>5 x ULN at day 1 
of cycle 
or 
>2 x ULN 
Delay one week then reassess using the 
same criteria. 
A delay up to three weeks is allowed (if 
a longer delay is necessary trial 
treatment must be stopped). 
First event: 20% dose reduction of 
etoposide at cycle 2, no reduction in 
vinorelbine or carboplatin. 
Second event: 35% dose reduction of 
etoposide at cycle 3, 25% reduction 
vinorelbine. 
10.3.3. Renal toxicity 
Request calculated creatinine clearance before each course of chemotherapy. 
Table 5: Cisplatin dose modifications for renal toxicity 
Calculated creatinine clearance 
at day 1 of cycle 
Cisplatin 
Etoposide, vinorelbine or 
pemetrexed 
>50 ml/min 
Full dose 
Full dose 
<45 ml/min 
Switch to carboplatin 
AUC5 
If pemetrexed is used, 
switch to vinorelbine or 
etoposide with 20% dose 
reduction 
25-50 ml/min 
Switch to carboplatin  
AUC5  
20% dose reduction 
<25 ml/min 
Off trial treatment 
Off trial treatment 
Carboplatin dosing: 
If carboplatin is to be used, the dose uses target area under the curve (AUC) of 5 and must be 
calculated according to the Calvert formula: 
Dose (in mg) = Target area under curve × (GFR+ 25) 
Carboplatin, pemetrexed and etoposide will be given 3-weekly. 
Table 6: Carboplatin dose modifications for renal toxicity 


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Calculated creatinine clearance 
at day 1 of cycle 
Carboplatin 
Etoposide, vinorelbine or 
pemetrexed 
>50 ml/min 
Full dose 
Full dose 
<45 ml/min 
Full dose 
If pemetrexed is used, 
switch to vinorelbine or 
etoposide with 20% dose 
reduction 
25-50 ml/min 
Full dose 
20% dose reduction 
<25 ml/min 
Off trial treatment 
Off trial treatment 
10.3.4. Other toxicities at any time during chemo-radiotherapy treatment 
Table 7: Chemotherapy dose modifications for other toxicities 
Peripheral neuropathy grade >2  
Switch to carboplatin AUC5 
100% dose of etoposide  
25% dose reduction vinorelbine 
Any grade 3-4 toxicities other than 
mucositis, nausea/vomiting, fatigue  
or alopecia 
25% dose reduction for cisplatin/carboplatin and 
etoposide, vinorelbine or pemetrexed after recovery 
to grade ≤1. 
A delay up to three weeks is allowed (if a longer 
delay is necessary trial treatment must be stopped). 
10.4. 
Thoracic radiation 
Radiotherapy will consist of a physical dose of at least 60 Gy delivered concurrently with the 
chemotherapy cycles two and three (see ESMO 2013 [16] and EORTC radiotherapy [19] 
guidelines) and must start at the same time as chemotherapy cycle 2. In case the administration 
of chemotherapy must be delayed due to toxicity, radiotherapy should start 3 days of start of 
chemotherapy cycle 2. 
 
10.4.1. Doses, fractionation and treatment techniques 
As there is an ongoing debate about the optimal radiotherapy dose and scheduling, the only 
requirement in this trial is that each individual patient should have received a radiotherapy dose 
that is considered to be able to eradicate the primary tumour and the involved lymph nodes. A 
physical dose of at least 60 Gy is required.  
The fractionation schedule and the treatment techniques are left over to the discretion of the 
clinician, but it is recommended to use the ESMO guidelines [16] and the EORTC technical 
recommendations [19]. 


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10.4.2. Organs at risk (OAR) 
In order to be able to correlate toxicity with doses to the OARs, the following OAR should be 
contoured and some dose-volume histogram (DVH) parameters recorded (see below):  
Mandatory 
Lungs: The mean lung dose is calculated using the total (left and right) lung volume minus the 
total (primary tumour plus lymph nodes) gross tumour volume (GTV). 
Optional 
Oesophagus: the outer contour being delineated from the cricoid to the gastro-oesophageal 
junction. The mean and the maximal dose will be recorded. 
Heart. Contouring done according to the RTOG guidelines by Kong et al (www.rtog.org). The 
mean and the maximal dose will be recorded. 
10.5. 
Nivolumab treatment 
10.5.1. Start of nivolumab treatment 
Patients may only start nivolumab treatment if all adverse events from previous chemotherapy 
have resolved to grade <2 (except fatigue, alopecia, nausea, lack of appetite or peripheral 
neuropathy). 
Nivolumab treatment starts together with radiotherapy, 21 (3) days after start of the first 
chemotherapy cycle. The first two nivolumab doses are administered concurrently with 
chemotherapy cycles 2 and 3. In case of chemotherapy delays due to toxicity, nivolumab will 
be administered when chemotherapy recommences. 
10.5.2. Nivolumab dose and schedule 
The initial 4 doses of nivolumab will be administered at 360 mg as intravenous infusion 
(approx. 30 minutes) every 3-weeks (3 days). The first 2 doses are administered concurrently 
with the last two chemotherapy cycles. 
Separate infusion bags and filters must be used for each infusion. Nivolumab is to be 
administered first and the infusion must be promptly followed by a saline flush to clear the line 
of nivolumab before starting the chemotherapy infusion, no sooner than 30 minutes after 
completion of the nivolumab infusion. 
From dose 5 on, nivolumab is administered at 480 mg every 4 weeks (3 days) for up to 1 year 
from start of nivolumab treatment, unless nivolumab treatment stops earlier due to unacceptable 
toxicity, disease progression, withdrawal of consent or the trial is terminated by the sponsor. 
Please note that dose 5 will start 3 weeks (3 days) after dose 4. 
10.5.3. Nivolumab administration 
Nivolumab may be diluted in normal saline or 5% dextrose solution. It is to be administered as 
i.v. infusion (approx. 30 minutes). It is not to be administered as an i.v. push or bolus injection. 
At the end of the infusion, the line must be flushed with a sufficient quantity of normal saline. 


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10.5.4. Dose Modifications 
Dose reductions or dose escalations of nivolumab are not permitted. 
10.5.5. Nivolumab delay and discontinuation for toxicity 
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 current Investigator Brochure (IB) [39], available 
on the trial specific section on the ETOP website. IB udpates will be distributed by ETOP 
whenever an update is available.) 
The next nivolumab dose must be delayed in case of persisting drug-related adverse event of 
grade ≥2. 
Dose delay criteria apply for all drug-related adverse events (regardless of whether or not the 
event is attributed to nivolumab).  
If treatment is delayed >6 weeks (i.e., more than 9 weeks since the last dose for Q3W and 
10 weeks for Q4W schedules), the patient must permanently discontinue nivolumab treatment, 
except as specified below in section 10.5.7. 
Nivolumab is always administered at the same time as chemotherapy, i.e. the same delay will 
apply for both chemotherapy and nivolumab. 
10.5.6. Criteria to resume nivolumab treatment 
Patients may resume treatment, if treatment interruption was ≤6 weeks, with study drug when 
the drug-related AE(s) resolve to Grade ≤1, with the following exceptions: 
 Patients may resume treatment in the presence of Grade 2 fatigue, increased 
creatinine, lack of appetite, peripheral neuropathy or alopecia  
 Patients who have not experienced a Grade 3 drug-related skin AE may resume 
treatment in the presence of Grade 2 skin toxicity  
 Drug-related pulmonary toxicity, diarrhoea, 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 above criteria to resume treatment are met, the patient should restart treatment at the time 
point when the next dose would have been administered had there been no interruption. 
10.5.7. Criteria to discontinue nivolumab treatment 
Treatment must be permanently discontinued for the following: 
 Patients with combined Grade ≥2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters should have treatment permanently discontinued 


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 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 6 weeks after last 
dose OR requires systemic treatment  
 Grade 3 drug-related uveitis, pneumonitis, bronchospasm, diarrhoea, colitis, 
neurologic adverse event, hypersensitivity reaction, or infusion reaction of any 
duration requires discontinuation 
 Any Grade 3 non-skin, drug-related adverse event lasting >7 days require 
discontinuation, except grade 3 drug-related laboratory abnormalities not listed 
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 requires 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 >3 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 nivolumab dosing interruption lasting >6 weeks (i.e., more than 9 weeks since 
the last dose Q3W and 10 weeks for Q4W), with the following exceptions: 
o Dosing interruptions to allow for prolonged steroid tapering to manage drug-
related adverse events are allowed. Prior to re-initiating treatment in a patient with 
a dosing interruption lasting >6 weeks, ETOP (NICOLAS@etop-eu.org) must be 
consulted. Tumour 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 ETOP. Prior to re-initiating treatment in a patient with a 
dosing interruption lasting >6 weeks, ETOP (NICOLAS@etop-eu.org) must be 
consulted. Tumour assessments should continue as per protocol even if dosing is 
interrupted. 


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 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 dosing 
10.5.8. Treatment of Nivolumab 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, pruritus, 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 CTCAE v.4 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 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 administrations. 
For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [e.g., antihistamines, non-steroidal anti-
inflammatory drugs, narcotics, corticosteroids, bronchodilators, i.v. fluids]; prophylactic 
medications indicated for 24 hours). 
Stop the nivolumab infusion, begin an i.v. infusion of normal saline, and treat the patient with 
diphenhydramine 50 mg i.v. (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen); remain at bedside and monitor patient until resolution of symptoms. 
Corticosteroid or bronchodilator therapy may also be administered as appropriate. If the 
infusion is interrupted, then restart the infusion at 50% of the original infusion rate when 
symptoms resolve; if no further complications ensue after 30 minutes, the rate may be increased 
to 100% of the original infusion rate. Monitor patient closely. If symptoms recur then no further 
nivolumab will be administered at that visit. Administer diphenhydramine 50 mg i.v., 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 administrations. If necessary, corticosteroids 
(recommended dose: up to 25 mg of i.v. hydrocortisone or equivalent) may be used. 


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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; pressor or ventilatory 
support indicated).  
Immediately discontinue infusion of nivolumab. Begin an i.v. infusion of normal saline, and 
treat the patient 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 i.v. administration, and/or diphenhydramine 50 mg i.v. with methylprednisolone 
100 mg i.v. (or equivalent), as needed. Patient should be monitored until the investigator is 
comfortable that the symptoms will not recur. Nivolumab will be permanently discontinued. 
Investigators should follow their institutional guidelines for the treatment of anaphylaxis. 
Remain at bedside and monitor patient until recovery from symptoms. In the case of late-
occurring hypersensitivity symptoms (e.g., appearance of a localized or generalized pruritus 
within 1 week after treatment), symptomatic treatment may be given (e.g., oral antihistamine, 
or corticosteroids). 
Specific management algorithms for immune-related gastro-intestinal, renal, pulmonary, 
hepatic, skin, endocrine and neurological adverse events are included as appendices in the IB 
[39] and in separate guidelines for management algorithms which can be downloaded from the 
trial specific section of the ETOP website. 
10.6. 
Prohibited and restricted therapies during trial treatment 
10.6.1. Accepted treatment during trial treatment (chemo-radiotherapy and nivolumab 
treatment) 
 G-CSF is allowed according to local standards  
 Use of corticosteroids is allowed if used as premedication for 
chemotherapy/radiotherapy or on study management of an AE. 
 Safe alternative medicine if potential interactions with trial drugs can be excluded.  
 Inhaled or topical steroids and adrenal replacement doses >10 mg daily prednisone 
equivalents are permitted in the absence of active autoimmune disease. 
 Patients are permitted to use topical, ocular, intra-articular, intranasal, and 
inhalational corticosteroids (with minimal systemic absorption). Physiologic 
replacement doses of systemic corticosteroids are permitted, even if >10 mg/day 
prednisone equivalents. A brief course of corticosteroids for prophylaxis (e.g., 
contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-
type hypersensitivity reaction caused by contact allergen) is permitted. 
10.6.2. Prohibited treatments during trial treatment (chemo-radiotherapy and nivolumab 
treatment) 


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 Any non-trial cytotoxic or immunotherapy anticancer treatment  
 Treatment with inhibitor or agonist of T-cell costimulation 
 Systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) 
or other immunosuppressive medications within 14 days of nivolumab 
administration.  
 Live vaccines within 30 days prior to the first dose of nivolumab treatment and 
during nivolumab treatment. 
 GM-CSF 
 Immune check-point blockers (PD-1; PD-L1, CTLA-4) 
 Immunosuppressive agents 
10.6.3. Precautions 
Women of childbearing potential and sexually active men must use effective contraception 
from the start of the trial treatment throughout the trial period up to 7 months (male participants) 
and 5 months (female participants) after the last dose of any trial treatment. Please refer to 
section 10.8 for highly effective contraception methods. 
10.7. 
Treatment duration 
Patients remain on treatment until one of the following events, whichever occurs first: 
 Documented progression according to RECIST v1.1 (except at local progression 
after nivolumab treatment start until confirmation by CT scan after 6 (2) weeks, see 
below) 
 Secondary malignancy resulting in need for systemic treatment 
 Unacceptable toxicity 
 Medical condition that prevents further treatment 
 Patient withdraws consent 
 Patient becomes pregnant 
 1 year of nivolumab treatment has been completed, or stopped early due to 
unacceptable toxicity, disease progression, withdrawal of consent or the study is 
stopped by the sponsor 
Nivolumab is expected to trigger immune-mediated responses, which require activation of the 
immune system prior to the observation of clinical responses. Such immune activation may 
take weeks to months to be evident. Some patients may have objective volume increase of 
tumour lesions following the start of nivolumab dosing. In some patients, tumour volume or 
other disease parameter increases may represent infiltration of lymphocytes into the original 
tumour or blood. In conventional studies, such tumour volume or relevant laboratory parameter 
increases during the first weeks of the study would constitute PD and lead to discontinuation 


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of imaging to detect response, thus disregarding the potential for subsequent immune-mediated 
clinical response.  
Therefore, patients with tumour volume increase detected after start of nivolumab (IMP) 
treatment but without appearance of new lesions or rapid clinical deterioration (see below) 
should continue to be treated with IMP and CT scan should be repeated after 6 (1) weeks to 
allow detection of a subsequent tumour response. This will improve the overall assessment of 
the clinical activity of IMP and more likely capture its true potential to induce clinical 
responses. This must follow the definition below: 
Treatment beyond disease progression 
Accumulating evidence indicates a minority of patients treated with immunotherapy may 
derive clinical benefit despite initial evidence of PD. 
Patients treated with IMP will be permitted to continue treatment beyond initial RECIST v1.1 
defined PD after nivolumab treatment start if they meet all of the following criteria: 
1. Investigator-assessed clinical benefit, and no rapid disease progression 
2. All other study protocol eligibility criteria met 
3. Tolerance of study drug 
4. Stable performance status 
5. Only local progressive disease of known stage III-defining NSCLC lesions (absence 
of new lesion) 
A radiographic assessment / scan should be performed 6 (1) weeks from this original PD scan 
to determine whether there has been a decrease in the tumour size or disease stabilization, or 
alternatively continued PD which would terminate the trial treatment. 
For the patients who continue nivolumab beyond progression, further progression is defined as 
an additional >10% increase in tumour dimension or new lesions as assessed per RECIST v1.1 
criteria from time of initial PD. Patients who continue treatment beyond initial investigator-
assessed, RECIST v1.1-defined progression will be considered to have had progressive disease 
at the time of the initial progression event.  
If nivolumab has been stopped for any reason, the patient enters the follow-up phase of the trial. 
Patients who discontinue trial treatment should be assessed by the investigator who must 
document the case on the appropriate CRF.  
10.8. 
Contraception, nursing, pregnancy 
10.8.1. Contraception 
Female patients who are not of childbearing potential due to being postmenopausal (2 year 
without menstruation) or surgically sterilised (oophorectomy, hysterectomy and/or tubal 
ligation) do not need to use contraception to be eligible for the trial. All other patients are 
considered to be of childbearing potential. 


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Women of childbearing potential and sexually active men must use highly effective 
contraception from the start of trial treatment throughout the trial period up to 7 months (male 
participants) and 5 months (female participants) after the last dose of any trial treatment. 
The following contraception methods are considered highly effective: 
 Hormonal (estrogen and progesterone) contraception (oral, intravaginal, transdermal) 
associated with inhibition of ovulation 
 Progesterone-only hormonal contraception (oral, injectable, implantable) associated 
with inhibition of ovulation 
 Intrauterine device (IUD) or intrauterine hormone releasing systems (IUS) 
 Bilateral tubal occlusion 
 Vasectomy 
Patients should start using birth control from the start of trial treatment throughout the trial 
period up to 7 months (male participants) and 5 months (female participants) after the last dose 
of any trial treatment. 
Women who become pregnant while participating in the trial must discontinue trial medica-
tion immediately. The pregnancy must be reported following procedures detailed in 
Section 12.9. Also any pregnancy that occurs in a female partner of a male trial participant must 
be reported. 
Patients should be informed that taking the trial medication may involve unknown risks to the 
fetus if pregnancy were to occur during the trial. In order to participate in the trial they must 
adhere to the contraception requirement (described above). If there is any doubt whether a 
patient will reliably comply with the requirements for contraception, that patient should not be 
entered into the trial. 
10.8.2. Use in pregnancy 
If a patient inadvertently becomes pregnant while on treatment with nivolumab, trial treatment 
will be stopped immediately for the patient and the event reported immediately, see 
Section 12.9. The site will contact the patient at least monthly and document the patient’s status 
until the pregnancy has been completed or terminated. The outcome of the pregnancy will be 
reported to ETOP without delay and within 24 hours if the outcome is a serious adverse 
experience (e.g. death, abortion, congenital anomaly, or other disabling or life-threatening 
complication to the mother or newborn). The trial investigator will make every effort to obtain 
permission to follow the outcome of the pregnancy and report the condition of the foetus or 
newborn to ETOP.  
10.8.3. Use in nursing women 
It is unknown whether nivolumab is excreted in human milk. Since many drugs are excreted in 
human milk, and because of the potential for serious adverse reactions in the nursing infant, 
patients who are breast-feeding are not eligible for this trial. 


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11. 
Safety of investigational products 
The chemotherapy regimens constitute standard chemotherapy, and are not investigational.  
11.1. 
Nivolumab 
11.1.1. Safety profile of nivolumab 
The overall safety experience with nivolumab is based on experience in approximately 
4,000 patients as either a monotherapy or in combination with other therapeutics. In general for 
monotherapy, the safety profile is similar across tumour types. The only exception is pulmonary 
inflammation AEs which may be numerically greater in patients with NSCLC possibly because 
in some cases it can be difficult to distinguish between nivolumab-related and unrelated causes 
of pulmonary symptoms and radiographic changes. The most frequently reported treatment 
related AE, fatigue is almost always low grade. 
Most related AEs are thought to be due to the effects of inflammatory cells on specific 
tissues/organs. These include the following: pulmonary, gastrointestinal, hepatic, skin, 
endocrine, and renal AEs as well as hypersensitivity/infusion reaction. 
In general, the approach to suspected nivolumab-related AEs is similar across any involved 
organ system. Safety management algorithms for organ-specific AEs are found in guidance 
document on specific management principles (IB Appendix 2) [39]. Patients should have a 
thorough diagnostic work-up to evaluate potential drug and non-drug related diagnoses. For 
suspected nivolumab-related AEs, based on the severity of the event, management with 
immunosuppressants may be necessary. In general, dose delays and observation are adequate 
for low-grade AEs. For moderate and high-grade AEs immunosuppresion with corticosteroids 
should be utilized. Once the AE has begun to improve, corticosteroids can be tapered over 
approximately 3-6 weeks (depending on the severity of the AE). The management of AEs 
considered related to any combination treatment is similar to the management of AEs caused 
by either agent 
alone and utilizes the same safety management 
algorithms. 
Rarely, a patient receiving immunosuppression for nivolumab-related AEs may develop an 
opportunistic infection. Patients with inflammatory events of any organ category expected to 
require more than 4 weeks of corticosteroid or other immunosuppressive agents to manage the 
adverse event should be considered for antimicrobial/antifungal prophylaxis per institutional 
guidelines to prevent opportunistic infections such as pneumocystis jiroveci (formerly P carinii) 
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 addition, a 
concomitant opportunistic infection should be considered in the differential diagnosis if a 
patient develops recurrent adverse events in the setting of ongoing or prior immunosuppressive 
use. Nivolumab should not be used in patients with active autoimmune disease given the 
mechanism of action of the antibody. 


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11.1.2. Safety when combining nivolumab with chemotherapy 
The interaction of a tumour with the immune system is complex. Tumors and the tumour 
microenvironment are known to express a variety of factors that impede a robust immune 
response from eliminating the tumour. Soluble and membrane-bound factors have been shown 
to inhibit the cytolytic activity of tumour infiltrating T-cells (e.g., PD-L1 expression; TGF-
beta). In addition, some tumour-derived factors are able to enhance immune system counter-
regulatory systems (e.g., increased T-regulatory cells). Finally, suboptimal tumour antigen 
delivery and presentation has been postulated as another mechanism by which tumours can 
successfully evade immune system recognition.  
Cancer therapeutics such as chemotherapy may modulate tumour/immune-system interactions 
in favor of the immune system. Chemotherapy can result in tumour cell death with a resultant 
increase in tumour antigen delivery to antigen-presenting cells. Tumour cell death may also 
lead to a reduction in soluble and membrane-bound factors inhibiting tumour-infiltrating T-
cells. Chemotherapy may also disrupt immune system regulatory networks by decreasing 
numbers of T-regulatory cells. 
Nivolumab added to chemotherapy has been evaluated in several cohorts of chemotherapy-
naive subjects with advanced NSCLC in study CA209012. Nivolumab 10 mg/kg was combined 
with gemcitabine plus cisplatin and pemetrexed plus cisplatin. Nivolumab 10 mg/kg, and 
5 mg/kg, was combined with paclitaxel and carboplatin [37]. 
The safety profile of nivolumab plus platinum-doublet chemotherapy reflects additive toxicities 
of the individual agents, which were manageable using established safety guidelines. No dose-
limiting toxicities were observed during the first 6 weeks of treatment. The frequency of most 
immune-related AEs was higher than what had been observed for nivolumab monotherapy. 
However, these treatment-related AEs, including pneumonitis, were effectively managed and 
did not lead to any deaths.  Pneumonitis of any grade was reported in 7 patients (13%); Grade 
3-4 in 4 subjects (7%). Twelve (21%) patients discontinued due to treatment-related AEs. 
The observed response rates of nivolumab and chemotherapy were similar to that of platinum-
doublet chemotherapy alone, though the duration of responses was longer. The median duration 
of response across all the nivolumab plus chemotherapy cohorts was 27.3 weeks. The 1-year 
survival rate for all cohorts combined was 71% [37]. 
Table 8 Treatment-related AEs in first-line treatment of nivolumab / chemotherapy in 
CA209012 
 
Total (N=56) 
All Grades 
Grade 3 
Grade 4 
Subjects 
with 
any 
treatment-related 
AE, 
% (n) 
95 (53) 
41 (23) 
4 (2) 


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Treatment-related AE, % (n) 
Fatigue  
71(40) 
5 (3) 
0 
Nausea 
46 (26) 
2 (1) 
0 
Decreased Appetite 
36 (20) 
2 (1) 
0 
Alopecia 
30 (17) 
0 
0 
Anemia 
27 (15) 
4 (2) 
0 
Rash 
27 (15) 
2 (1) 
0 
Arthralgia 
21 (12) 
0 
0 
Diarrhea 
21 (12) 
2 (1) 
0 
Constipation 
20 (11) 
0 
0 
Peripheral Neuropathy 
20 (11) 
0 
0 
 
Table 9 Efficacy of First-Line Treatment of Nivolumab/Chemotherapy Combination in 
CA209012 
 
Nivolumab 10 mg/kg 
Nivolumab  
5 mg/kg 
Gem/Cis 
(n=12) 
Pem/Cis 
(n=15) 
Pac/Carb 
(n=15) 
Pac/Carb 
(n=14) 
ORR, % 
33 
47 
47 
43 
SD, % 
58 
47 
27 
43 
Median Duration 
of Response, 
Weeks 
45 
24.4 
27.3 
27.3 
12-mo OS rate, % 
50 
87 
72 
86 
18-mo OS Rate, 
% 
33 
60 
40 
62 
Median OS, 
Weeks 
51 
83 
65 
Not Reached 
 


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11.2. 
Cisplatin 
The most frequently reported adverse events (>10%) of cisplatin were haematological 
(leucopenia, thrombocytopenia and anaemia), gastrointestinal (anorexia, nausea, vomiting and 
diarrhoea), ear disorders (hearing impairment), renal disorders (renal failure, nephrotoxicity, 
hyperuricaemia) and fever.  
Serious toxic effects on the kidneys, bone marrow and ears have been reported in up to about 
one third of patients given a single dose of cisplatin; the effects are generally dose-related and 
cumulative.  
Nephrotoxicity: Renal toxicity has been noted in about one third of patients given a single dose 
of cisplatin when prior hydration has not been employed. It is first noted during the second 
week after a dose and is manifested by elevations in plasma urea and serum creatinine, serum 
uric acid and/or decrease in creatinine clearance.  
Renal toxicity becomes more prolonged and severe with repeated courses of the drug. Renal 
function must return to acceptable levels before another dose of cisplatin can be given.  
Renal function impairment has been associated with renal tubular damage. The administration 
of cisplatin using a 6-8 hour infusion with intravenous hydration and mannitol has been used 
to reduce nephrotoxicity. However renal toxicity still can occur after utilisation of these 
procedures.  
Gastrointestinal toxicity: Nausea and vomiting occur in the majority of patients, usually 
starting within 1 hour of treatment and lasting up to 24 hours. Anorexia, nausea and occasional 
vomiting may persist for up to a week.  
Ocular Toxicity: There have been reports of optic neuritis, papilloedema and cerebral 
blindness following treatment with cisplatin. Improvement and/or total recovery usually occurs 
following immediate discontinuation. Blurred vision and altered colour perception have been 
reported after the use of regimens with higher doses of cisplatin or greater dose frequencies 
than those recommended.  
Ototoxicity: Ototoxicity has occurred in up to 31% of patients treated with a single dose of 
cisplatin 50 mg/m2. Ototoxicity may be more severe in children and more frequent and severe 
with repeated doses.  
Careful monitoring should be performed prior to initiation of therapy and prior to subsequent 
doses of cisplatin.  
Unilateral or bilateral tinnitus, which is usually reversible, and/or hearing loss in the high 
frequency range may occur.  
The overall incidence of audiogram abnormalities is 24%, but large variations exist. These 
abnormalities usually appear within 4 days after drug administration and consist of at least a 15 


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decibel loss in pure tone threshold. The damage seems to be cumulative and is not reversible. 
The audiogram abnormalities are most common in the 4000-8000 Hz frequencies.  
Haemotoxicity: Myelosuppression is observed in about 30% of patients treated with cisplatin. 
Leucopenia and thrombocytopenia are more pronounced at higher doses. The nadirs in 
circulating platelets and leucocytes generally occur between days 18-23 (range 7.3 to 45) with 
most patients recovering by day 39 (range 13 to 62). Leucopenia and thrombocytopenia are 
more pronounced at doses greater than 50 mg/m2. Anaemia (decreases of greater than 2 g% 
haemoglobin) occurs at approximately the same frequency, but generally with a later onset than 
leucopenia and thrombocytopenia. Subsequent courses of cisplatin should not be instituted until 
platelets are present at levels greater than 100,000/mm2 and white cells greater than 4,000/mm2. 
A high incidence of severe anaemia requiring transfusion of packed red cells has been observed 
in patients receiving combination chemotherapy including cisplatin.  
Anaphylaxis: Reactions possibly secondary to cisplatin therapy have been occasionally 
reported in patients who were previously exposed to cisplatin. Patients who are particularly at 
risk are those with a prior history or family history of atopy. Facial oedema, wheezing, 
tachycardia, hypotension and skin rashes of urticarial non-specific maculopapular type can 
occur within a few minutes of administration. Serious reactions seem to be controlled by i.v. 
adrenaline, corticosteroids or antihistamines.  
Serum Electrolyte Disturbances: Hypomagnesaemia, hypocalcaemia, hyponatraemia, 
hypokalaemia and hypophosphataemia have been reported to occur in patients treated with 
cisplatin and are probably related to renal tubular damage. Hypomagnesaemia and 
hypocalcaemia may result in tetany. Generally, normal serum electrolyte levels are restored by 
administering supplemental electrolytes and discontinuing cisplatin. Inappropriate antidiuretic 
hormone syndrome has also been reported.  
Neurotoxicity: Usually characterised by peripheral neuropathies and paresthesia in both upper 
and lower extremities. Peripheral neuropathy, while reversible, may take a year or more to 
recover. Loss of taste and seizures have also been reported. Neuropathies resulting from 
cisplatin treatment may occur after prolonged therapy; however, neurological symptoms have 
been reported to occur after a single dose. The neuropathy may progress after stopping 
treatment.  
Hyperuricaemia: Hyperuricaemia occurring with cisplatin is more pronounced with doses 
greater than 50 mg/m2. Allopurinol effectively reduces uric acid levels.  
Other Toxicities: Vascular toxicities coincident with the use of cisplatin in combination with 
other antineoplastic agents have been reported rarely. These events may include myocardial 
infarction, cerebrovascular accident, thrombotic microangiopathy (haemolytic uraemic 
syndrome) or cerebral arteritis. There are also reports of Raynaud's phenomenon occurring in 
patients treated with the combination of bleomycin, vinblastine with or without cisplatin. It has 
been suggested that hypomagnesaemia developing coincident with the use of cisplatin may be 


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an added, although not essential factor, associated with this event. However the cause of this 
Raynaud's phenomenon is currently unknown.  
Other toxicities reported to occur infrequently are cardiac abnormalities including tachycardia 
and arrhythmia.  
Local soft tissue toxicity has been reported rarely following extravasation of cisplatin. 
Infiltration of solutions of cisplatin may result in tissue cellulitis, fibrosis and necrosis. 
11.3. 
Carboplatin 
The following adverse reactions have been reported:  
Frequency definition:  
 Very common (≥1/10)  
 Common (≥1/100, <1/10)  
 Uncommon (≥1/1,000, <1/100)  
 Rare (≥1/10,000, <1/1,000)  
 Very rare (<1/10,000) 
 not known (cannot be estimated from the available data)  
 
Cardiac and vascular disorders 
Very rare: Cardiovascular events (cardiac failure, embolism) as well as cerebrovascular events 
(apoplexy) have been reported in single cases (causal relationship with carboplatin not 
established). Single cases of hypertension have been reported.  
Blood and lymphatic system disorders  
Very common: Myelosuppression is the dose-limiting toxicity of carboplatin. Myelosuppres-
sion may be more severe and prolonged in patients with impaired renal function, extensive prior 
treatment, poor performance status and age >65. Myelosuppression is also worsened by therapy 
combining carboplatin with other compounds that are myelosuppressive. Myelosuppression is 
usually reversible and not cumulative when carboplatin is used as a single agent and at the 
recommended dosages and frequencies of administration.  
At maximum tolerated dosages of carboplatin administered as a single agent, 
thrombocytopenia, with nadir platelet counts of less than 50 x 109/L, occurs in about a third of 
the patients. The nadir usually occurs between days 14 and 21, with recovery within 35 days 
from the start of therapy.  
Leucopenia has also occurred in approximately 20% of patients but its recovery from the day 
of nadir (day 14-28) may be slower and usually occurs within 42 days from the start of therapy. 
Neutropenia with granulocyte counts below 1 x 109/L occurs in approximately 1/5 of patients. 
Haemoglobin values below 9.5 mg/100 mL have been observed in 48% of patients with normal 
baseline values. Anaemia occurs frequently and may be cumulative. 
Common: Haemorrhagic complications, usually minor, have also been reported. 


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Uncommon: Infectious complications have occasionally been reported. 
Rare: Cases of febrile neutropenia have been reported. Single cases of life-threatening 
infections and bleeding have occurred. 
Respiratory, thoracic and mediastinal disorders  
Very rare: Pulmonary fibrosis manifested by tightness of the chest and dyspnoea. This should 
be considered if a pulmonary hypersensitivity state is excluded (see general disorders below). 
Interstitial pneumonitis under high dose therapy. 
Nervous system disorders 
Common: The incidence of peripheral neuropathies after treatment with carboplatin is 6%. In 
the majority of the patients neurotoxicity is limited to paraesthesia and decreased deep tendon 
reflexes. The frequency and intensity of this side effect increases in elderly patients and those 
previously treated with cisplatin. Paraesthesia present before commencing carboplatin therapy, 
particularly if related to prior cisplatin treatment, may persist or worsen during treatment with 
carboplatin.  
Uncommon: Central nervous symptoms have been reported, however, they seem to be 
frequently attributed to concomitant antiemetic therapy.  
On prolonged therapy with carboplatin: convulsions, peripheral neuropathies have been 
reported. 
Eye disorders 
Rare: Transient visual disturbances, sometimes including transient sight loss, have been 
reported rarely with platinum therapy. This is usually associated with high dose therapy in 
renally impaired patients. Optic neuritis has been reported in post marketing surveillance.  
Ear and labyrinth disorders  
Very common: Subclinical decrease in hearing acuity, consisting of high-frequency (4000-
8000 Hz) hearing loss determined by audiogram, has been reported in 15% of the patients 
treated with carboplatin.  
Common: Clinical ototoxicity (clinical hearing deficits). Only 1% of patients present with 
clinical symptoms, manifested in the majority of cases by tinnitus. In patients who have been 
previously treated with cisplatin and have developed hearing loss related to such treatment, the 
hearing impairment may persist or worsen.  
At higher than recommended doses in combination with other ototoxic agents, clinically 
significant hearing loss has been reported to occur in paediatric patients when carboplatin was 
administered.  
Gastrointestinal disorders 
Very common: Nausea without vomiting occurs in about a quarter of patients receiving 
carboplatin vomiting has been reported in over half of the patients and about one third of these 
suffer severe emesis. Nausea and vomiting are generally delayed until 6 to 12 hours after 
administration of carboplatin, usually disappear within 24 hours after treatment and are usually 


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responsive to (and may be prevented by) anti-emetic medication. A quarter of patients 
experience no nausea or vomiting. Vomiting that could not be controlled by drugs was observed 
in only 1% of patients. Vomiting seems to occur more frequently in previously treated patients, 
particularly in patients pre-treated with cisplatin.  
Painful gastrointestinal disorders occurred in 17% of patients.  
Common: Diarrhoea (6%), constipation (4%), mucositis.  
Rare: Taste alteration. Cases of anorexia have been reported. Haemorrhagic colitis under high 
dose therapy. 
Renal and urinary disorders  
Very common: Renal toxicity is usually not dose-limiting in patients receiving carboplatin, nor 
does it require preventive measures such as high volume fluid hydration or forced diuresis. 
Nevertheless, increasing uric acid and blood urea nitrogen levels or serum creatinine levels can 
occur.  
Common: Renal function impairment, as defined by a decrease in the creatinine clearance 
below 60 mL/min, may also be observed. The incidence and severity of nephrotoxicity may 
increase in patients who have impaired kidney function before carboplatin treatment. 
Impairment of renal function is more likely in patients who have previously experienced 
nephrotoxicity as a result of cisplatin therapy. 
It is not clear whether an appropriate hydration programme might overcome such an effect, but 
dosage reduction or discontinuation of therapy is required in the presence of moderate alteration 
of renal function (creatinine clearance 41-59 mL/min) or severe renal impairment (creatinine 
clearance 21-40 mL/min). Carboplatin is contra-indicated in patients with a creatinine 
clearance at or below 20 mL/min.  
Skin and subcutaneous tissue disorders 
Common: Alopecia, rash, skin irritation. 
Metabolism and nutrition disorders 
Very common: Decreases in serum electrolytes (sodium, magnesium, potassium and calcium) 
have been reported after treatment with carboplatin but have not been reported to be severe 
enough to cause the appearance of clinical signs or symptoms.  
Rare: Cases of hyponatraemia have been reported.  
Neoplasms benign, malignant and unspecified (including cysts and polyps) 
Uncommon: Secondary malignancies (including promyelocytic leukaemia which occurred 6 
years after monotherapy with carboplatin and preceding irradiation) have been reported 
following administration of carboplatin as a single agent or in combination therapy (causal 
relationship not established).  
General disorders and administration site conditions 
Very common: Hyperuricaemia is observed in about 1/4 of patients. Serum levels of uric acid 
can be decreased by allopurinol. Asthenia.  


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Common: Malaise, urticaria, flu-like syndrome, erythematous rash, pruritus 
Uncommon: Fever and chills without evidence of infection; injection site reactions such as 
pain, erythema, swelling, urticaria and necrosis  
Rare: Haemolytic uraemic syndrome.  
Immune system disorders 
Common: Allergic reactions to carboplatin have been reported in less than 2% of patients, e.g., 
skin rash, urticaria, erythematous rash, and fever with no apparent cause or pruritus. These 
reactions are similar to those observed after administration of other platinum containing 
compounds and should be managed with appropriate supportive therapy.  
Rare: Anaphylaxis, anaphylactic shock, angio-oedema and anaphylactoid reactions, including 
bronchospasm, urticaria, facial oedema and facial flushing, dyspnoea, hypotension, dizziness, 
wheezing, and tachycardia have occurred. These were reactions similar to those seen after 
cisplatin therapy, but in a few cases no cross-reactivity was present. 
 
Hepatobiliary disorders  
Very common: Abnormalities of liver function tests (usually mild to moderate) have been 
reported with carboplatin in about one third of the patients with normal baseline values. The 
alkaline phosphatase level is increased more frequently than SGOT, SGPT or total bilirubin. 
The majority of these abnormalities regress spontaneously during the course of treatment.  
Rare: Severe hepatic dysfunction (including acute liver necrosis) has been reported after 
administration of higher than recommended carboplatin dosages.  
 
11.4. 
Etoposide 
The following adverse reactions have been reported: 
Table 10: Adverse reactions for etoposide 
 System 
Organ Class 
Very common  
(>1/10) 
Common  
(>1/100, <1/10) 
Uncommon  
(>1/1,000, 
<1/100) 
Rare  
(>1/10,000, 
<1/1,000) 
Very rare  
(<1/10,000)  
Not known 
Infections and 
infestations  
Infections 
have been 
reported in 
patients with 
bone marrow 
depression  
Neoplasms 
benign and 
malignant  
Leukaemia 
secondary to 
oncology 
chemo-therapy*  
Acute 
promyelo-
cytic 
leukaemia 


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 System 
Organ Class 
Very common  
(>1/10) 
Common  
(>1/100, <1/10) 
Uncommon  
(>1/1,000, 
<1/100) 
Rare  
(>1/10,000, 
<1/1,000) 
Very rare  
(<1/10,000)  
Not known 
Blood and 
lymphatic 
systems 
disorders  
Myelosuppression
**, leucopenia, 
thrombo-
cytopenia, anaemia  
Immune 
system 
disorders  
Anaphylactic-
like 
reactions***  
Metabolism 
and nutrition 
disorders  
Anorexia  
Hyperuri-
caemia  
Nervous 
system 
disorders  
Central nervous 
system disorders 
(fatigue, 
drowsiness)  
Peripheral 
neuropathies  
Insults, 
paresthesiae
, optic 
neuritis, 
taste 
disturbance  
Eye disorders  
Reversible 
loss of 
vision, 
transient 
cortical 
blindness  
Cardiac 
disorders  
Arrhythmia, 
myocardial 
infarction, 
cyanosis  
Vascular 
disorders  
Hypotension%, 
haemorrhage 
(in patients with 
severe 
myelosuppressi
on)  
Phlebitis+ 
Respiratory, 
thoracic and 
mediastinal 
disorders  
Bronchospasm
, coughing, 
laryngospasm  
Apnoea, 
interstitial 
pneumonitis 
or 
pulmonary 
fibrosis  
Gastrointestina
l disorders  
Nausea, vomiting  
Abdominal 
pain, diarrhoea, 
stomatitis  
Mucositis, 
oesophagitis  
Constipatio
n, 
swallowing 
disorders 
(dysphagia)  
Hepatobiliary 
disorders  
 
Hepatic 
dysfunction  
 
 
 
 


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 System 
Organ Class 
Very common  
(>1/10) 
Common  
(>1/100, <1/10) 
Uncommon  
(>1/1,000, 
<1/100) 
Rare  
(>1/10,000, 
<1/1,000) 
Very rare  
(<1/10,000)  
Not known 
Skin and 
subcutaneous 
tissue disorders  
Reversible 
alopecia 
(sometimes 
progressing to total 
baldness)  
Rash, urticaria, 
pigmentation 
and pruritus  
Toxic 
epidermal 
necrolysis, 
radiation 
“recall” 
dermatitis, 
hand-foot 
syndrome  
Renal and 
urinary 
disorders  
Etoposide has been 
shown to reach 
high 
concentrations in 
the liver and 
kidney, thus 
presenting a 
potential for 
accumulation in 
cases of functional 
impairment  
General 
disorders and 
administration 
site conditions  
Fatigue  
Asthenia; 
after extra-
vasation, 
irritation of 
soft tissue 
and inflam-
mation 
occur 
occasionally  
Investigations  
Bilirubin 
increased, 
SGOT 
increased, 
alkaline 
phosphatase 
increased  
* 
The risk of secondary leukaemia among patients with germ-cell tumours after treatment with etoposide is 
about 1%. This leukaemia is characterised with a relatively short latency period (mean 35 months), 
monocytic or myelomonocytic FAB subtype, chromosomal abnormalities at 11q23 in about 50% and a good 
response to chemotherapy. A total cumulative dose (etoposide >2 g/m²) is associated with increased risk.  
Etoposide is also associated with development of acute promyelocytic leukaemia (APL). High doses of 
etoposide (>4,000 mg/m2) appear to increase the risk of APL.  
** 
Myelosuppression is dose limiting, with granulocyte nadirs occurring 5 to 15 days after drug administration 
and platelet nadirs occurring 9 to 16 days after drug administration. Bone marrow recovery is usually 
complete by day 21, and no cumulative toxicity has been reported.  
Fatal cases of myelosuppression have been reported.  
Infections have been reported in patients with bone marrow depression.  
*** Anaphylactic-like reactions characterised by fever, flushing, tachycardia, bronchospasm, and hypotension 
have been reported (incidence 0.7-2%), also apnoea followed by spontaneous recurrence of breathing after 


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withdrawal of etoposide infusion, increase in blood pressure. The reactions can be managed by cessation of 
the infusion and administration of pressor agents, corticosteroids, antihistamines and/ or volume expanders 
as appropriate.  
Anaphylactoid-like reactions may occur after the first intravenous administration of etoposide.  
Erythema, facial and tongue oedema, coughing, sweating, cyanosis, convulsions, laryngospasm and 
hypertension have also been observed. The blood pressure usually returns to normal within few hours 
following cessation of therapy.  
% 
Transient hypotension following rapid intravenous administration has been reported in 1% to 2% of patients. 
It has not been associated with cardiac toxicity or electrocardiographic changes. To prevent this rare 
occurrence, it is recommended that etoposide be administered by slow intravenous infusion over a 30- to 60-
minute period. If hypotension occurs, it usually responds to supportive therapy after cessation of the 
administration. When restarting the infusion, a slower administration rate should be used.  
+ 
Phlebitis has been observed following bolus injection of etoposide. This adverse reaction can be avoided by 
i.v. infusion over 30 to 60 minutes.  
Etoposide has been shown to reach high concentrations in the liver and kidney, thus presenting a potential 
for accumulation in cases of functional impairment. 
11.5. 
Vinorelbine 
Please refer to the latest version of the Summary of Product Characteristics (SPC) at: 
http://www.medicines.org.uk/emc/medicine/16029 
The most commonly reported adverse drug reactions are bone marrow depression with 
neutropenia, leukopenia and anaemia, neurologic disorders, gastrointestinal toxicity with 
nausea, vomiting, stomatitis and constipation, transient elevations of liver function tests, 
alopecia and local phlebitis. 
11.6. 
Pemetrexed 
Please refer to the latest version of the Summary of Product Characteristics (SPC) at: 
http://www.medicines.org.uk/emc/medicine/31354 
The most commonly reported undesirable effects related to pemetrexed, whether used as 
monotherapy or in combination, are bone marrow suppression manifested as anaemia, 
neutropenia, leukopenia, thrombocytopenia; and gastrointestinal toxicities, manifested as 
anorexia, nausea, vomiting, diarrhoea, constipation, pharyngitis, mucositis, and stomatitis. 
Other undesirable effects include renal toxicities, increased aminotransferases, alopecia, 
fatigue, dehydration, rash, infection/sepsis and neuropathy. Rarely seen events include Stevens-
Johnson syndrome and Toxic epidermal necrolysis. 
12. 
Adverse events and reporting 
12.1. 
Adverse event definition and reporting 
The main criterion for tolerability is the occurrence of toxicities and adverse events. The 
severity and causality will be classified according to the CTCAE Version 4. The CTCAE is 
available for downloading on the internet (http://evs.nci.nih.gov/ftp1/CTCAE/About.html). 


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An adverse event in this trial is defined as any new untoward medical occurrence or worsening 
of a pre-existing medical condition that occurs from the day of signing informed consent until 
100 days after the final dose of nivolumab, regardless of whether it is considered related to the 
trial treatment. After the last dose, only AEs considered possibly related to nivolumab by the 
Investigator have to be reported. 
The causal relationship to study drug is determined by a physician and should be used to assess 
and report all adverse events (AE). The causal relationship can be one of the following: 
Related (possible, probable, definite): There is a reasonable causal relationship between study 
drug administration and the AE. 
Not related (unrelated, unlikely): There is not a reasonable causal relationship between study 
drug administration and the AE.  
In addition, any known untoward event that occurs subsequent to the adverse event reporting 
period that the investigator assesses as possibly related to the protocol treatment should be 
considered an adverse event. 
Symptoms of the targeted cancer (if applicable) should not be reported as adverse events. 
The adverse event severity grade provides a qualitative assessment of the extent or intensity of 
an adverse event, as determined by the investigator or as reported by the patient. The severity 
grade does not reflect the clinical seriousness of the event, only the degree or extent of the 
affliction or occurrence (e.g. severe nausea, mild seizure), and does not reflect the relationship 
to study drug. 
Severity grade for other adverse events not covered in the toxicity grading scale: 
1 = Grade 1 
Mild 
2 = Grade 2 
Moderate 
3 = Grade 3 
Severe 
4 = Grade 4 
Life-threatening 
5 = Grade 5 
Fatal 
Note: 
 Baseline symptoms will be recorded on the CRF and changes in grade as well as 
resolution of an AE during treatment have to be reported. 
 Laboratory abnormalities for non-safety parameters will be documented on the AE 
CRF from grade ≥3 only 
 AEs should not be reported in a narrative description. 
 Status of pneumonitis will be specially recorded in the eCRFs. 
12.2. 
Definition of Serious Adverse Event (SAE) 
12.2.1. SAEs during trial treatment 
An SAE is defined in this trial as any undesirable medical occurrence/adverse drug experience 
that occurs from the provision of informed consent or within 100 days after the final dose of 
nivolumab that, at any dose, results in any of the following:  


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 is fatal (any cause) 
 life-threatening, 
 requires or prolongs inpatient hospitalization, 
 results in persistent or significant disability/incapacity 
 is a congenital anomaly or birth defect 
 is a secondary malignancy 
 is a  medically important event 
 Although overdose is not always serious by regulatory definition, this event must be 
handled as SAE. 
 Pregnancy (see section 12.8). 
Second (non-NSCLC) malignancies are always considered SAEs, no matter when they are 
diagnosed.  These events should be reported on the Serious Adverse Event Forms. 
Other significant/important medical events which may jeopardise the patient are also 
considered serious adverse events. 
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must 
be reported as an SAE. 
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, X-rays, and any other potential safety assessments, whether or not these 
procedures are required by the protocol, should also be recorded as a nonserious or serious AE, 
as appropriate, and reported accordingly. 
All laboratory test results captured as part of the study should be recorded following 
institutional procedures. Test results that constitute SAEs should be documented and reported 
as such. 
The following laboratory abnormalities should be documented and reported appropriately: 
 any laboratory test result that is clinically significant or meets the definition of an 
SAE 
 any laboratory abnormality that required the patient to have study drug discontinued 
or interrupted, as well as dose modifications during chemo-radiotherapy 
 any laboratory abnormality that required the patient to receive specific corrective 
therapy.  
Serious also includes any other event that the investigator or the ETOP Safety Office judges to 
be serious or which is defined as serious by the regulatory agency in the country in which the 
event occurred. 
An unexpected adverse event is one that is not listed as a known toxicity of the investigational 
drug in the summary of product characteristics and in the IB. 


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A related adverse event is one for which the investigator assesses that there is a reasonable 
possibility that the event is related to the investigational drug. All adverse events judged as 
having a reasonable suspected causal relationship to the trial medication qualify as adverse 
reactions. 
Events not considered to be serious adverse events are hospitalizations occurring under the 
following circumstances:  
 elective surgery  
 occur on an outpatient basis and do not result in admission (hospitalization <24 h)  
 are part of the normal treatment or monitoring of the studied treatment 
 progression of disease (by convention, clinical events related to the primary cancer 
being studied or to the primary cancer progression are not to be reported as SAEs, 
even if they meet any of the seriousness criteria from the standard SAE definition, 
unless the event is more severe than expected and therefore the investigator 
considers that their clinical significance deserves reporting). 
12.2.2. SAEs after end of trial treatment 
During the follow-up phase (beyond 100 days of discontinuation of dosing), the following 
events always have to be reported as SAE: 
 fatal, life-threatening and other medically significant events possibly, probably or 
definitely related to late effects of trial treatment 
 disabling events 
 second primary cancer 
 congenital anomaly 
 Pregnancy (see section 12.8) 
12.3. 
Definition of Serious Adverse Reaction (SAR) 
SARs are all SAEs considered to be related (possibly, probably, definitely) to the trial 
treatment. 
12.4. 
Definition of Suspected Unexpected Serious Adverse Reaction (SUSAR) 
The expectedness assessment is the responsibility of the sponsor of the trial. A SUSAR is a 
serious adverse reaction that is assessed as unexpected on the basis of the following reference 
documents: 
 For cisplatin, carboplatin, vinorelbine, etoposide: European Summary of Product 
Characteristics (SmPC) 
 For nivolumab: Investigator's Brochure. 
 


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12.5. 
Protocol-specified significant events 
12.5.1. Drug-induced liver injury (DILI): 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event.  All occurrences of potential DILIs, 
meeting the defined criteria, must be reported as SAEs. Potential drug-induced liver injury is 
defined as: 
1) ALT or AST elevation >3 times upper limit of normal (ULN)  
AND 
2) Total bilirubin >2 times ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase) 
AND 
3) No other immediately apparent possible causes of AST/ALT elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing 
chronic or acute liver disease, or the administration of other drug(s) known to be 
hepatotoxic. 
A hepatic AE management algorithm has been established (Appendix to the IB) for appropriate 
management of drug-induced liver injury (DILI) cases. 
12.5.2. Reporting protocol specified significant events 
Protocol Specified Significant Events must be documented and reported by submitting the 
completed SAE Report Tab (initial and follow-up) in the RDE system  
 Within 24 hours after knowledge of the event if the event is serious 
 Within 5 days after knowledge of the event if the event is not serious (Indicate in 
“Description” section that this is a “non-serious adverse event of special interest”)  
12.6. 
Reporting SAEs and protocol specified significant events 
Following the patient’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 collected that occur within 100 days of the 
last administered trial medication.  
If applicable, SAEs must be collected that relate to any protocol-specified procedure (e.g., a 
follow-up skin biopsy).  The investigator should report any SAE that occurs after these time 
periods that is suspected to be related to study drug or protocol-specified procedure.  
Any SAE must be reported by submitting the completed SAE Initial Report Tab in the RDE 
system within 24 hours of awareness. 
Protocol Specified Significant Events are to be reported by submitting the completed SAE 
Initial Report Tab in the RDE system, even if they do not meet any of the seriousness criteria. 
Please submit the completed SAE Report Tab (initial and follow-up) in the RDE system within 


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24 hours, if the event is serious, or within 5 days, if the event is non-serious, after knowledge 
of the event. Indicate in “Description” section if “non-serious adverse event of special interest” 
yes or no. 
Submission is done via the electronic data capture system, or in case of unavailability, by 
sending the SAE form by fax to the ETOP Safety Office: 
+41 31 389 92 29 
The SAE outcome must be reported within 14 days after onset by submitting the SAE Follow-
up Report eCRF online. In case the SAE is reported as ongoing after 14 days, the follow-up 
report has to be submitted again with the final outcome. 
The ETOP Safety Office will notify principal investigators of any SAR meeting the criteria for 
expedited reporting (SUSAR) within the timelines specified in GCP. 
The local Ethics committee must be informed by the principal investigator about local SAEs 
(if applicable by local law). 
The 
ETOP 
Safety 
Office 
will 
inform 
Bristol-Myers 
Squibb 
(by 
e-mail 
to 
worldwide.safety@bms.com) on all SAEs regardless of relatedness, and other appropriate 
persons about all SAEs at least possibly related to trial medication (per either investigator or 
ETOP Safety Office review) within 24 hours of receipt. 
The ETOP Safety Office will record the SAE and prepare a summary report of all SAEs 
received. Listings of SAEs will be prepared as required. 
12.7. 
Non-serious adverse event definition and reporting 
A nonserious adverse event is an AE not classified as serious.  
The collection of nonserious AE information should begin after patient has signed informed 
consent. All nonserious adverse events (not only those deemed to be treatment-related) should 
be collected continuously during the treatment period and for a minimum of 100 days following 
the last dose of study treatment.  
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious. 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.  
12.8. 
Pregnancy 
Patients who are not of childbearing potential due to being postmenopausal (2 years without 
menstruation) or surgical sterilisation (oophorectomy, hysterectomy and/or tubal ligation) do 
not need to use contraception to be eligible for the trial. 
Women of childbearing potential and sexually active men must use highly effective 
contraception from the start of trial treatment throughout the trial period up to 7 months  (male 
participants) and 5 months (female participants) after the last dose of any trial treatment. Please 
refer to section 10.8 for approved contraception methods. 


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In the case of pregnancy occurring during the course of the trial or within 1 year after treatment 
discontinuation, the investigator shall immediately (within 24 hours after awareness of 
pregnancy) notify ETOP by completing the pregnancy form in ETOPdata in accordance with 
the SAE reporting procedures. Follow-up information regarding the course of the pregnancy, 
including perinatal and neonatal outcome and, where applicable, offspring information must be 
reported (within 14 days) on the Pregnancy Form in ETOPdata. 
All neonatal deaths that occur within 28 days of birth should be reported, irrespective of 
causality, as SAEs. In addition, any infant death after 28 days, irrespective of causality should 
also be reported within 24 hours of the investigator’s knowledge of the event using the SAE 
forms. 
Any pregnancy that occurs in a female partner of a male trial participant should be reported to 
ETOP. Information on this pregnancy will be collected on the Pregnancy Form. 
13. 
Response evaluation 
13.1. 
RECIST v1.1 criteria 
Radiological tumour assessment by CT scans of thorax / upper abdomen (from top of thorax 
until adrenal glands and full liver and kidney included) will be done according to the schedule 
indicated below, until tumour progression is determined according to RECIST v1.1 criteria. 
The same imaging technique, acquisition, and processing parameters should be used in a patient 
throughout the trial. 
 
At baseline: 
within 28 days before start of first chemotherapy cycle 
Year 1: 
every 9 weeks (±1 week) from enrolment 
Year 2: 
every 12 weeks (±2 weeks) 
Beyond 2 years: 
every 6 months (±4 weeks) until 2 years after the last patient started 
 
nivolumab treatment 
 
The patient’s response to chemo-radiotherapy treatment and nivolumab consolidation treatment 
will be assessed by RECIST v1.1 criteria [40] (see appendix 2). The response assessment 
according to RECIST v1.1 should be done by the local radiologist and reported on the CRF. 
 
 


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13.2. 
Determination of time point response 
Table 11: Determination of time point response 
Target lesions 
Non-target lesions 
New lesions 
Resulting overall 
response 
CR 
CR 
No 
CR 
CR 
Non-CR / non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
unless the sum of diam. 
of evaluated lesions 
indicates PD 1) 
PD 
Any  
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes  
PD 
1) From reference [40]: When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable (NE) at that time point. If only a subset of lesion measurements are made at an assessment, usually 
the case is also considered NE at that time point, unless a convincing argument can be made that the 
contribution of the individual missing lesion(s) would not change the assigned time point response. This would 
be most likely to happen in the case of PD. For example, if a patient had a baseline sum of 50mm with three 
measured lesions and at follow-up only two lesions were assessed, but those gave a sum of 80 mm, the patient 
will have achieved PD status, regardless of the contribution of the missing lesion. 
13.3. 
Determination of best overall response 
Best overall response is defined as best response across all time points. Confirmation of partial 
or complete response by an additional scan is not requested in this trial.  
 
 


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14. 
Endpoints definition 
14.1. 
Grade ≥3 pneumonitis (CTCAE v4.0) observed any time during 6 months 
from the end of radiotherapy 
This is the primary endpoint. It is defined as the number of patients reaching up to 6 months 
post chemo-radiation treatment without any episode of CTCAE v4.0 grade ≥3 pneumonitis. It 
will be used as the primary endpoint for all patients followed for at least 6 months beyond 
radiotherapy.  
14.2. 
Progression-free survival  
This is the key secondary endpoint. It is defined as the time from the date of enrolment until 
documented progression or death, if progression is not documented. Censoring will occur at 
the last tumour assessment only if patient is lost to follow-up. Patients who continue treatment 
beyond initial investigator-assessed, RECIST v1.1-defined progression will be considered to 
have had progressive disease at the time of the initial progression event [40]. For patients 
receiving nivolumab treatment, PFS will be evaluated both from date of enrolment and from 
date of first nivolumab dose. 
14.3. 
Time to first pneumonitis of grade ≥3 
TFP3 is defined as the time from the date of enrolment until first documented pneumonitis of 
grade ≥3. Censoring will occur at the last assessment only if patient is lost to follow-up or has 
died. 
14.4. 
Objective response 
Objective response is defined as best overall response (CR or PR) across all assessment time-
points during the period from enrolment to termination of trial treatment. Objective response 
to nivolumab treatment will be determined using RECIST v1.1 criteria (see section 13).  
14.5. 
Time to treatment failure 
Time to treatment failure (TTF) is defined as time from enrolment to discontinuation of 
treatment for any reason, including disease progression, treatment toxicity, and death. 
Censoring will occur at the time of last tumour assessment only if the patient is lost to follow-
up. 
14.6. 
Overall survival  
Defined as time from the date of enrolment until death from any cause. Censoring will occur at 
the last follow-up date. 
14.7. 
Toxicity 
Adverse events classified according to CTCAE version 4.  


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15. 
Trial procedures 
This section gives an overview of procedures, clinical and laboratory evaluations and follow-
up investigations. 
15.1. 
Baseline evaluations before enrolment 
The following examinations must be done within 35 days before start of chemotherapy 
treatment: 
15.1.1. Whole body FDG-PET 
15.1.2. Contrast enhanced CT of thorax / upper abdomen (from top of thorax until adrenal 
glands and full liver and kidney included) is needed in addition to or in combination 
with PET-CT  
15.1.3. Brain MRI or contrast enhanced CT 
15.1.4. TNM categories 
 
The following examinations must be done within 28 days before enrolment. If examinations 
were done prior to 28 days before enrolment, they have to be repeated. 
15.1.5. Obtain written informed consent prior to any trial-related evaluation and/or 
intervention (within 7 weeks before enrolment) 
15.1.6. Medical history including symptoms, smoking history, medications, comorbidities 
and allergies 
15.1.7. Physical examination according to local standards, including blood pressure 
[mmHg], ECOG performance status, body weight [kg] and height 
15.1.8. Haematology: haemoglobin, platelets, leukocytes, neutrophils 
15.1.9. HIV, hepatitis B and C status 
15.1.10. Renal function: serum creatinine and creatinine clearance calculated according to 
Cockroft-Gault (see section 10.2) 
15.1.11. Hepatic function: ALT, AST, AP, total bilirubin 
15.1.12. Pulmonary function: relative FEV1 and DLCO (%) 
15.1.13. Electrocardiogram 
15.1.14. Pregnancy test for women with childbearing potential within 7 days before 
enrolment. 
15.1.15. Record all concomitant medications 


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15.2. 
CT schedule for disease evaluation 
All patients will have a CT of thorax and upper abdomen (from top of thorax until adrenal 
glands and full liver and kidney included, preferred) or alternatively (and only after the first CT 
at baseline) CT of thorax and ultrasonography of upper abdomen until progression: 
At baseline: 
Whole body FDG-PET within 35 days before start of first 
 
chemotherapy cycle. CT is needed in addition to or in combination with 
 
PET. 
Year 1: 
every 9 weeks (±1 week) from enrolment 
Year 2: 
every 12 weeks (±2 weeks) 
Beyond 2 years: 
every 6 months (±4 weeks) until 2 years after the last recruited patient 
 
started nivolumab treatment  
Also refer to section 10.7 for the management of patients with tumour volume increase after 
start of nivolumab dosing. 
 
15.3. 
During chemotherapy 
Tumour assessment will be done according to the schedule indicated in section 15.2. 
Patients will be assessed clinically prior to each cycle of chemotherapy, within 24 hours before 
the first dose of the next cycle of chemotherapy: 
15.3.1. Physical examination according to local standards, including blood pressure, 
performance status, and body weight 
15.3.2. Recording of symptoms / adverse events  
15.3.3. Record all changes in concomitant medications 
15.3.4. Haematology (haemoglobin, platelets, leukocytes, neutrophils).  
15.3.5. Serum creatinine and creatinine clearance calculated according to Cockroft-Gault 
(see section 10.2) 
15.3.6. Hepatic function: ALT, AST, AP, total bilirubin 
15.4. 
During nivolumab treatment and radiotherapy 
15.4.1. Tumour assessment will be done according to the schedule indicated in section 15.2.  
15.4.2. Pregnancy test for women with childbearing potential must be repeated within 
24 hours before beginning nivolumab treatment and then every 2nd dose during 
nivolumab treatment. Pregnancy tests should be repeated at approximately 30 days 
and approximately 70 days after nivolumab treatment stop. 
The evaluations listed below will be done within 3 days before the administration of every 
dose of nivolumab 


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15.4.3. Recording of symptoms / adverse events 
15.4.4. Physical examination according to local standards, including blood pressure, 
performance status, and body weight 
15.4.5. Ca, Mg, Na, K, Cl, LDH, Glucose, amylase, lipase 
15.4.6. Serum urea level  
15.4.7. Haematology: haemoglobin, platelets, leukocytes, neutrophils  
15.4.8. Serum creatinine and creatinine clearance calculated according to Cockroft-Gault 
(see section 10.2) 
15.4.9. Hepatic function: ALT, AST, AP, total bilirubin 
15.4.10. TSH, free T3 and T4 before the first nivolumab administration. TSH must be 
repeated before every 2nd nivolumab administration. Free T3 and T4 have only to be 
repeated in case of abnormal TSH value. 
15.4.11. Record all changes in concomitant medications 
15.5. 
End of treatment visit 
At the end of all trial treatment and irrespective of the reason for stopping treatment, an end 
of treatment visit at the centre is to be scheduled within 30 days following the decision to stop 
nivolumab treatment or within 30 days after planned treatment start if treatment never started. 
In case treatment was delayed due to AEs and could not be resumed, the end of treatment visit 
should be performed within 10 weeks after the last dose. The following procedures should be 
performed: 
15.5.1. Recording of symptoms / adverse events 
15.5.2. Physical examination according to local standards, including performance status, 
blood pressure and weight 
15.5.3. Haematology: haemoglobin, platelets, leukocytes, neutrophils 
15.5.4. Hepatic function: ALT, AST, AP, total bilirubin 
15.5.5. Serum creatinine and creatinine clearance calculated according to Cockroft-Gault 
(see section 10.2) 
15.5.6. Pregnancy tests should be repeated at approximately 30 days and approximately 
70 days after nivolumab treatment stops. 
15.5.7. CT thorax and upper abdomen, if not done within the last 6 weeks 
15.5.8. Record all changes in concomitant medications 


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15.6. 
Evaluations in the follow-up phase before progression 
Follow up visits after trial treatment stop will take place at the time of the CT scans (see section 
15.2) and the following evaluations will be done: 
15.6.1. Physical examination according to local standards, including performance status 
15.6.2. CT thorax / upper abdomen (see section 15.2) 
15.6.3. Pregnancy tests should be repeated at approximately 30 days and approximately 
70 days after nivolumab treatment stop 
15.7. 
Evaluations after progression in follow-up 
Follow up visits after progression will take place every 6 months (starting from date of 
progression, 4 weeks). 
The following evaluations will be done: 
15.7.1. Pregnancy tests should be repeated at approximately 30 days and approximately 
70 days after nivolumab treatment stops 
15.7.2. Survival  
15.7.3. Further lines of treatment  
Patients who do not start nivolumab treatment will be followed up for survival alone (please 
complete the follow up tab in ETOPdata), no further CT scans need to be reported. Follow up 
visits can take place at the standard visits of the patient to the hospital but should ideally be 
reported within similar timelines as stated above for patients who started nivolumab treatment. 
Follow-up will continue until 2 years from the start of nivolumab treatment of the last recruited 
patient. 
16. 
Case report forms and documentation 
16.1. 
Case report forms schedule 
CRFs will only be available on-line at the Remote Data Entry (RDE) facility ETOPdata. No 
paper forms will be used, with the exception of a paper SAE form and pregnancy form in case 
of system unavailability.  
Table 12: Case report forms 
Tab in ETOPdata 
To be completed 
Eligibility for Enrolment 
Within 28 days of start of baseline assessments 
Baseline 
Within 14 days after enrolment 


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Tab in ETOPdata 
To be completed 
Tumour Assessments 
Baseline: Within 14 days after enrolment; 
Year 1: within 14 days after each CT thorax and upper 
abdomen is performed [every 9 weeks starting from 
enrolment, (+/- 1 week)]; 
Year 2: within 14 days after each CT thorax and upper 
abdomen is performed [every 12 weeks (+/-2 weeks)]; 
Beyond year 2: within 14 days of end of each 6 month 
period (+/-4 weeks), until documented progression or until 
2 years from start of nivolumab treatment of the last 
recruited patient 
Concomitant Medications 
Continuously from date of enrolment to 30 days after end of 
trial treatment. 
In case of any change in concomitant medications (new 
medication, stop medication): 
 
Within 14 days after each chemotherapy cycle. 
 
Within 14 days after each nivolumab cycle. 
 
Within 14 days after end-of-treatment visit. 
Trial Treatments 
Within 14 days after end of each chemotherapy and/or 
nivolumab administration. Please also don't forget to 
complete the Concomitant Medications and the Adverse 
Events CRFs at the end of each cycle.  
Thoracic Radiotherapy 
Within 14 days after end of radiotherapy 
Nivolumab Treatments 
Within 14 days after each administration 
Adverse Events 
 
Continuously from date of enrolment up to 100 days 
after end of nivolumab treatment, in case of any changes 
in adverse events (new events, change in severity grade 
of an event, end of an event). 
 
Within 14 days after enrolment (to record symptoms 
present at enrolment). 
 
Within 14 days after end of each chemotherapy cycle. 
 
Within 14 days after each nivolumab dose. 
 
Within 14 days after end-of-treatment visit. 
 
Within 14 days after follow-up visits. 
 


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Tab in ETOPdata 
To be completed 
SAE Initial Reports 
Within 24h of awareness of SAE; 
Can be submitted via ETOPdata or via fax to ETOP safety 
office in case of unavailability of ETOPdata. 
SAE Follow-up Reports 
Within 14 days of completion of initial report. 
If event was not resolved after 14 days, submit an additional 
report again within 7 days of resolution of event. 
End of Treatment 
Within 14 days after end-of-treatment visit (which is to take 
place within 30 days following the decision to stop trial 
treatment) 
Follow-up 
Before progression: 
Year 1: after completion of chemo-radiotherapy: Within 
14 days after follow-up visits [performed every 9 weeks 
(1 week)]. 
Year 2: after completion of chemo-radiotherapy: Within 
14 days after follow-up visits [performed every 
12 weeks(2 weeks)]; 
Beyond 2 years: after completion of chemo-radiotherapy: 
Within 14 days after follow-up visits (which take place 
every 6 months (+/- 4 weeks), until death, for a maximum of 
2 years from start of nivolumab treatment of the last 
recruited patient; 
After progression: 
Within14 days after follow-up visits, which take place every 
6 months (+/- 4 weeks), until death, for a maximum of 
2 years from start of nivolumab treatment of the last 
recruited patient; 
To be completed at death. 
Pregnancy 
Within 24 hours of first documentation of pregnancy; 
Within 14 days of end of pregnancy. 
WC/LFU (Withdrawal of 
consent / Lost to follow-up) 
Within 14 days of awareness of withdrawal of consent or 
loss to follow-up. 
Consult the CRF completion guideline for detailed instructions on how to complete, save and 
submit the electronic CRFs. 


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17. 
Statistical considerations  
17.1. 
Primary and key secondary objectives 
To assess the safety and efficacy of the concurrent administration of nivolumab with standard 
first-line chemotherapy and radiotherapy for locally advanced stage IIIA/B NSCLC. Safety is 
defined by an adequately high 6-month pneumonitis-free rate of grade ≥3, or equivalently by 
an acceptably low rate of grade ≥3 pneumonitis (CTCAE V.4) observed any time within 
6 months post-radiotherapy. If safety is proven then the one-year PFS is evaluated as key 
secondary endpoint. 
17.2. 
 Sample size determination 
17.2.1. Safety evaluation 
A 6-month post-radiotherapy rate of grade ≥3 pneumonitis (CTCAE V.4) of 15% is the 
expected rate after chemo-radiotherapy alone, while a rate above 33% is deemed unacceptably 
high. Thus, the interest is to reject a ≤67% 6-month pneumonitis-free rate of grade ≥3, targeting 
a 6-month pneumonitis-free rate of 85%.  
The design of the safety evaluation is based on an exact group sequential test of the proportion 
π (6-month pneumonitis-free rate of grade ≥3) and estimation of the sample size uses the 
binomial probability distribution of number of successes, where success for a patient is defined 
as reaching 6 months post radiation treatment pneumonitis-free [41-44]. Using the exact group 
sequential test (with O’Brien-Fleming boundaries) [45], we incorporate in the design one 
interim look to have the opportunity of reaching an early conclusion on the feasibility of the 
treatment. At the interim look, the 3-month pneumonitis rate of grade ≥3 is evaluated 
(pneumonitis defined as having occurred up to 3 months after end of RT), while at the final 
analysis, the 6-month pneumonitis rate of grade ≥3 is of interest. 
The primary safety hypothesis corresponds to the 6 months without pneumonitis of grade ≥3:  
The null hypothesis states that 6-month pneumonitis-free rate of grade ≥3 is less than or equal 
to 67%, vs the one-sided alternative that the rate is above 67%, tested at π1=85%:  
H0: π0≤67% vs H1: π1>π0, at π1=85% 
For a one-sided alpha of 0.05 and power of 83%, the required sample size for the safety 
evaluation is 41 patients evaluable for pneumonitis 6 months after end of RT, allowing for one 
interim safety analysis on the first 21 patients without any requirement for trial interruption. In 
the safety evaluation phase of the trial, 43 patients will be recruited allowing for about 5% 
competing risk rate rendering the patient not evaluable for pneumonitis. The 5% competing 
risk rate includes patients who are lost to follow-up or die without evidence of pneumonitis of 
grade ≥3.  
As approximately 70% of the cases of pneumonitis are expected to occur by 3 months after the 
end of radiotherapy, a planned interim safety analysis on 21 patients will be performed at 3-
months evaluating the pneumonitis-free rate at this time point. 


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In addition, a hierarchical design [3] is adopted that allows the examination of a secondary 
efficacy hypothesis (secondary-Hs) after the pneumonitis null hypothesis (primary-Hp) is 
rejected. This strategy allows testing for efficacy in this study cohort (Hs), while keeping the 
Family Wise Error (FWER) strongly at the desired level alpha. The hypothesis of treatment 
efficacy will be of interest only if the pneumonitis toxicity is acceptable either at the scheduled 
interim or at the end of the safety phase of the study. If the pneumonitis null hypothesis (Hp) is 
rejected either at the interim or the final primary safety analysis, the study will continue to 
include all required patients to test the efficacy hypothesis (Hs). 
17.2.2. Efficacy evaluation 
Based on preliminary baseline information regarding stage, it is believed that for the observed 
case-mix, the one-year PFS rate that could be achieved with current best provided care is 
estimated to be around 45%.[4, 5] The aim of the combination under investigation will be to 
improve the one-year PFS by at least 15%, that is, to achieve a one-year PFS rate of at least 
60%. 
Efficacy hypothesis (Hs): 
Hs0: PFS0 ≤45% vs Hs1: PFS1> PFS0, at PFS1=60% 
A sample size of 74 evaluable patients will provide a power of 83%, for testing the above 
efficacy hypothesis, using an exact test for a single proportion, at the one-sided alpha of 0.05. 
Assuming 5% non-evaluable patients, a total sample size of 78 patients need to enter the study. 
17.3. 
Evaluation of primary and secondary endpoints 
17.3.1. Overview of planned analyses and statistical methods 
The total study duration for the primary safety endpoint analysis will be approximately 20 
months including a 3-month start-up period, 9 months accrual (of the first 43 pateints), two 
months for completing radiotherapy and 6 months follow-up after radiotherapy. 
The study duration for the key secondary efficacy endpoint will be approximately 22 months, 
including a 3-month start-up period, 7 months accrual (of the additional patients) and 12 months 
follow-up for evaluating the one-year PFS rate. 
The overall testing strategy can be described as follows: 
Interim analysis for grade ≥3 pneumonitis 3 months after nivolumab start (N=21 patients). 
If pneumonitis null hypothesis is not rejected = no decision reached  trial continues to final 
analysis for safety (pneumonitis grade ≥3) with a total of 41 patients. 
 Safety analysis for grade ≥3 pneumonitis 6 months after completion of radiotherapy (N=41 
patients)  
If pneumonitis null hypothesis is not rejected, toxicity is of concern and trial will end. 
If pneumonitis null hypothesis is rejected, there is no toxicity concern and trial continues to 
efficacy analysis. 


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If pneumonitis null hypothesis is rejected  trial continues to final analysis for efficacy 
evaluation with a total of 74 patients. 
The efficacy analysis will be performed on patients receiving concurrent treatment under 
protocol versions 2.0 and 3.0. Information on patients on sequential treatment and/or enrolled 
under the original protocol (version 1) will be presented separately (see 17.3.6). 
The binomial exact one-sample test will be used for both the interim and the final safety 
analysis, as well as the efficacy evaluation (if trial continues) [41-44]. The safety conclusion 
will be based on examining whether or not the observed number of pneumonitis-free patients 
crossed the corresponding O’Brien-Fleming boundary. 
The 6-month pneumonitis-free rate of grade ≥3 along with corresponding exact binomial two-
sided 90% confidence intervals will be presented. 
Kaplan-Meier estimates will be provided for Progression-free Survival, Overall Survival, Time 
to Pneumonitis of grade ≥3 and Time to Treatment Failure. 
Other toxicities will be presented. The worst grade of toxicity/ adverse events observed over 
the whole treatment period according to CTCAE v.4 will be displayed.  
Statistical analysis for the primary, secondary endpoints will be described in detail in the 
Statistical Analysis Plan (SAP) document. 
17.3.2. Interim safety analysis 
The expectation for the safety interim analysis is that approximately 70% of pneumonitis (grade 
≥3) cases have already occurred by 3 months after chemo-radiotherapy, the null and alternative 
hypothesis for the interim analysis are formulated as follows:  
Null hypothesis states that the 3-month pneumonitis-free rate of grade ≥3 is less than or equal 
to 76.9%, vs the one-sided alternative that the rate is above 76.9%, tested at π1=89.5%: 
H0: π0Interim ≤76.9% vs H1: π1 Interim >π0 Interim, at π1 Interim =89.5% 
To take into account that the interim safety analysis considers a modified hypothesis (the focus 
is on the 3-month pneumonitis-free rate of grade ≥3 instead of the corresponding 6-month rate), 
a piecewise exponential model is assumed for the 6-month pneumonitis-free rate of grade ≥3. 
In 100,000 simulations based on the above assumptions, a one-sided alpha of 0.044 and power 
of at least 83% are achieved with an interim analysis on the first 21 patients reaching the 3-
month post chemo-radiotherapy follow-up time point. If at this interim analysis none of the 21 
patients has developed pneumonitis of grade ≥3, then the safety phase of the trial will be 
stopped early (interim alpha is 0.004). In that case, the interim null hypothesis for safety that 
the 3-month pneumonitis-free rate is ≤76.9% can be rejected and the conclusion that the 
treatment is safe can be reached early. Otherwise it is decided that the trial continues and the 
final safety analysis will be performed when 41 patients reach the 6-month follow-up time 
point.  
The EAST Design package [41] was used for calculations and simulations were run in the R 
statistical package. 


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17.3.3. Final safety evaluation 
The primary safety hypothesis evaluates the 6-month post-radiotherapy rate of grade ≥3 
pneumonitis (CTCAE V.4):  
The null hypothesis states that 6-month pneumonitis-free rate of grade ≥3 is less than or equal 
to 67%, vs the one-sided alternative that the rate is above 67%, tested at π1=85%:  
H0: π0≤67% vs H1: π1>π0, at π1=85% 
If at least 33 out of the 41 patients are pneumonitis-free up to 6 months, the final null hypothesis 
for safety of a 6-month pneumonitis-free rate of ≤67% will be rejected, and the treatment will 
be accepted as feasible and therefore eligible to be further tested for efficacy. 
17.3.4. Regular safety evaluation 
Safety evaluations will be performed 4 times per year and submitted to the IDMC for advice. 
The trial will continue while safety is being evaluated. 
17.3.5. Final efficacy analysis 
The final efficacy hypothesis is tested after the safety null hypothesis is rejected either at the 
interim or the final safety analysis, when 74 evaluable patients receiving concurrent therapy 
have reached one-year follow-up (from time of enrolment into the trial) or have experienced 
PD. 
The 78 patients will be enrolled under the protocol amendmens (v2.0 and v3.0). Patients 
included under the original protocol (v1.0) will be evaluated separately. 
A detailed SAP will be produced as a separate document.  
17.3.6. Evaluation of patients enrolled under the original protocol 
The follow-up of patients enrolled under the original trial protocol (v1.0) will continue as 
originally planned, that is until 2 years from start of nivolumab treatment of the last recruited 
patient. These patients will only be evaluated in terms of safety and toxicity and the evaluation 
results will be reported separately. More specifically, patients included under the original trial 
protocol will be evaluated for adverse events, disease progression, death and treatment 
discontinuation. Results will be presented in terms of absolute and relative frequencies. 
Because of the low accrual reached by the time of protocol amendment 1 activation no formal 
statistical test will be performed. 
Patients that were enroled under protocol v2.0 (amendment 1) will be included in the final 
safety and efficacy analysis as decribed in sections 17.3.3 and 17.3.5 above. 
18. 
Criteria for termination of the trial 
18.1. 
General criteria for termination of the trial 
The trial may be discontinued early in parts or completely if the information on the product 
leads to doubt as to the benefit/risk ratio, by decision of ETOP or Trial Steering Committee, or 
at the suggestion of the IDMC based on the interim safety evaluations. 


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The trial can be terminated at any time if the authorization and approval to conduct the trial is 
withdrawn by ethics committee or regulatory authority decision, insufficient accrual, emerging 
new data impacting the scientific value of the trial or ethical grounds. 
18.2. 
Discontinuation of protocol treatment for individual patients  
Protocol treatment should be stopped in the following situations: 
 Disease progression according to RECIST v 1.1. Except patients with tumour volume 
increase detected after nivolumab treatment start but without appearance of new lesions 
or rapid clinical deterioration (see section 10.7 for more information), who are allowed 
to continue nivolumab treatment. 
 Occurrence of unacceptable toxicities of radiotherapy or nivolumab. Stopping protocol 
treatment is determined by medical judgment of the treating physician. Note: patients 
who cannot complete chemotherapy at the full dose due to toxicity may continue trial 
treatment if radiotherapy can be given at a curative dose. 
 Inter-current severe illnesses which would in the judgment of the investigator affect 
assessments of the clinical status to a significant degree and require discontinuation of 
protocol therapy. Note: Diagnosis of another neoplastic disease (second malignant 
tumour) does not mandate a stop of trial therapy; patients may continue to receive 
protocol treatment after the appearance of a second primary tumour, stopping protocol 
treatment is determined by the medical judgment of the treating physician. 
 Request by the patient. Patients have the right to refuse further trial treatment at any 
time during the trial. Such patients will remain in the trial and will be transferred to the 
follow-up phase. 
 If a patient refuses to have the treatments or follow-up examinations and tests needed 
to determine whether the treatment is safe and effective. 
The decision for discontinuation of protocol treatment of individual patients is taken by the 
treating physician based on his medical evaluation and taking into account the patient’s 
individual situation. 
18.3. 
Withdrawal of consent 
Patients have the right to withdraw consent for further trial participation at any time without 
having to specify the reason. The data recorded up to the time point of withdrawal will continue 
to be evaluated in the trial. The investigator should ask the patient for consent to continue to 
collect information on her/his disease and survival status. 
It should be documented in both the medical records and in the eCRF, according to the 
instructions in the CRF completion guidelines, if the patient accepts to be contacted for 
survival status despite withdrawal trial consent. For the patient’s safety, an end of treatment 
visit should be performed and documented in the eCRF if the patient agrees to this. 


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19. 
Ethics aspects, regulatory approval, and Patient Informed Consent 
The Investigator will ensure that this trial is conducted in full conformance with the principles 
of the “Declaration of Helsinki” or with the laws and regulations of the country in which the 
research is conducted, whichever affords the greater protection to the individual. The trial must 
fully adhere to the principles outlined in “Guideline for Good Clinical Practice” ICH Tripartite 
Guideline (January 1997) or with local law if it affords greater protection to the patient. For 
studies conducted in the EU/EEA countries, the Investigator will ensure compliance with the 
EU Clinical Trial Directive (2001/20/EC). 
19.1. 
Ethical Review Board/Ethics Committee 
All protocols and the patient informed consent forms must have the approval of a properly 
constituted committee or committees responsible for approving clinical trials. The ERB/IRB 
decision must contain approval of the designated investigator, the protocol (identifying protocol 
title and version number), and of the patient informed consent. 
The ERB/IRB written, signed approval letter/form must contain approval of the designated 
investigator, the protocol (identifying protocol title and version number), and of the patient 
informed consent. Documentation of Ethics Committee approval must be sent to the ETOP 
Coordinating Office prior to enrolment of the first patient. 
Any modifications made to the protocol must be submitted to the appropriate ERB/IRB for 
information or approval in accordance with local procedures and regulatory requirements and 
to Health Authorities if required.  
Once approved or acknowledged by the appropriate ERB/IRB and by the Health Authorities 
(if required), the investigator shall implement the protocol modifications. Protocol 
modifications for urgent safety matters may be directly implemented following the instructions 
of ETOP. 
19.2. 
Regulatory approval procedures 
If applicable, in addition to the approval of the Ethics Committee according to national 
legislation, the protocol, other protocol related documents including patient information and 
informed consent and other documents as required locally must be submitted to and be 
approved by the health authority. Documentation of health authority approval must be sent to 
the ETOP Coordinating Office prior to Participating Centre activation.  
19.3. 
Informed consent  
Informed consent for each patient will be obtained prior to initiating any trial procedures in 
accordance with the “Patient Information and Informed Consent" (See Appendix 1). One 
signed and dated copy of the informed consent must be given to each patient and the original 
copy must be retained in the investigator's trial records.  The informed consent form must be 
available in the case of data audits. Verification of signed informed consent and the date signed 
are required for inclusion to this trial. 


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The "Declaration of Helsinki" recommends that consent be obtained from each potential patient 
in biomedical research trials after the aims, methods, anticipated benefits, and potential hazards 
of the trial, and discomfort it may entail, are explained to the individual by the physician. The 
potential patient should also be informed of her/his right to not participate or to withdraw from 
the trial at any time. The process of obtaining the informed consent must be documented in the 
patient record. 
If the patient is in a dependent relationship to the physician or gives consent under duress, the 
informed consent should be obtained by an independent physician. By signing this protocol, 
the investigator agrees to conduct the trial in accordance with Good Clinical Practice and the 
"Declaration of Helsinki." 
ETOP recognises that each institution has its own local, national, and international guidelines 
to follow with regard to informed consent. Therefore, we provide a template information sheet 
and informed consent form (Appendix 1), which can be edited to incorporate information 
specific to your institution. The template Patient Information Sheet and Informed Consent 
(PIS/IC) has been written according to ICH guidelines which state the Informed Consent should 
adhere to GCP and to the ethical principles that have origin in the “Declaration of Helsinki”. 
The final version needs to receive the Institutional Review Board/ Local Ethics Committee 
approval in advance of its use. Centres need to send their locally modified PIS/IC to ETOP for 
review and approval before submitting to their Ethics Committee.  
20. 
Governance and administrative issues 
20.1. 
Final report 
A final clinical trial report will be written and distributed to Health Authorities as required by 
applicable regulatory requirements. 
20.2. 
Steering Committee 
A Steering Committee will be constituted for this trial. The Steering Committee is responsible 
for maintaining the scientific integrity of the trial, for example, by recommending changes to 
the protocol in light of emerging clinical or scientific data from other trials. Membership will 
include the trial co-chairs, trial statisticians, ETOP officials, representatives from some 
participating institutions and groups, and a representative from Bristol-Myers Squibb. 
20.3. 
Independent Data Monitoring Committee 
The trial will be presented for review to the ETOP IDMC at each of their meetings which take 
place 4 times a year. Accrual and safety will be monitored.  
20.4. 
Publication 
The results of the trial will be published according to the ETOP publication guidelines. 


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20.5. 
Clinical trial insurance 
ETOP will contract the appropriate liability insurance for this trial. Patients who suffer injuries 
due to the trial should report them immediately to their physician. The local institution should 
report all alleged claims immediately to the ETOP Coordinating Office. 
20.6. 
Quality assurance and quality control 
ETOP conducts trials according to the ICH Good Clinical Practice (GCP) guidelines.  The Trial 
Data Manager reviews each CRF as it is received. In addition, the ETOP Medical Reviewer 
reviews each case at specific time points.  ETOP conducts periodic audit visits to ensure proper 
trial conduct, verify compliance with GCP, and perform source data verification. 
The Investigator should ensure that source documents are made available to appropriately 
qualified personnel from ETOP or its designees, or to ethics committee and health authority 
inspectors after appropriate notification. 
At regular intervals during the clinical trial, the centre will be contacted, through monitoring 
visits, letters or telephone calls, by a representative of the monitoring team to review trial 
progress, investigator and patient compliance with clinical trial protocol requirements and any 
emergent problems. These monitoring visits will include but not be limited to review of the 
following aspects: patient informed consent, patient recruitment and follow-up, SAE 
documentation and reporting, AEs with pre-specified monitoring documentation and reporting, 
AE documentation, dispensing IMP, compliance with protocol, drug accountability, 
concomitant therapy use and quality of data. 
20.7. 
Protocol adherence 
Investigators ascertain that they will apply due diligence to avoid protocol deviations. Under 
no circumstances should the investigator contact ETOP or personnel monitoring the trial to 
request approval of a protocol deviation, as no deviations are permitted. The investigator should 
document and explain any deviations from the approved protocol. The investigator should 
promptly report any deviations to the Sponsor and to the EC concerned in accordance with the 
applicable EC policies and procedures. If the investigator feels a protocol deviation would 
improve the conduct of the trial this must be considered a protocol amendment, and unless such 
an amendment is developed and activated by the sponsor and approved by the IRB/IEC/REB 
it cannot be implemented. All protocol deviations will be recorded. 
20.8. 
Data protection 
The samples and data collected will be coded to protect patient confidentiality. Each patient 
will have a unique identifier assigned by the RDE facility ETOPdata. Sites are responsible to 
keep a patient log locally in order to be able to link the unique identifier to the record of the 
patient.  
Regulatory authorities and pertinent Ethics Committees (IRB/ERB) may have access to patient 
data on-site. ETOP audit or monitoring personnel will also have access to such data on-site. 


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20.9. 
Record retention 
The centre must retain all essential documents according to ICH GCP. This includes copies of 
the patient trial records, which are considered as source data, patient informed consent 
statement, laboratory printouts, drug inventory and destruction logs, and all other information 
collected during the trial. These documents are to be stored until at least 15 years after the 
termination of the trial. ETOP guarantees access and availability of the data entered into 
ETOPdata for at least 15 years after the termination of the trial. 
Longer retention may be required for participating centres according to national regulations. 
In the event that the Principal Investigator retires or changes employment, custody of the 
records may be transferred to another competent person who will accept responsibility for those 
records. Written notice of such transfer has to be given to ETOP and the local Ethics Committee 
at least one month in advance. 
 
 


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SAP_001.pdf: 
Page 1 of 19 
 
 
NICOLAS 
ETOP 6-14 
 
A phase II trial evaluating the safety and efficacy of the addition of 
concurrent anti-PD-1 nivolumab to 
standard first-line chemotherapy and radiotherapy in locally advanced 
stage IIIA/B Non-Small Cell Lung Carcinoma 
 
 
Statistical Analysis Plan (SAP) 
Final efficacy analysis 
 
A clinical trial of ETOP 
 
 
 
 
SAP VERSION 
V.1.1 
SAP VERSION DATE 
10 June 2019 
 
 


Page 2 of 19 
Contents 
INTRODUCTION ............................................................................................................................................... 4 
1 
Trial oversight (as per protocol - Version 3.0)......................................................................................... 5 
1.1 
Objectives .................................................................................................................................... 5 
1.2 
Endpoints .................................................................................................................................... 5 
1.3 
Εligibility criteria .......................................................................................................................... 6 
1.4 
Previous protocol versions .......................................................................................................... 6 
1.5 
Statistical design, sample size & power ...................................................................................... 7 
1.6 
Total trial duration ...................................................................................................................... 8 
2 
General considerations ........................................................................................................................... 9 
2.1 
Analysis Timing ............................................................................................................................ 9 
2.2 
Data Retrieval Information.......................................................................................................... 9 
3 
Statistical considerations ...................................................................................................................... 10 
3.1 
Study’s endpoints ...................................................................................................................... 10 
3.1.1 
Primary safety endpoint (previously analysed)..................................................................... 10 
3.1.2 
Key-secondary efficacy endpoint .......................................................................................... 10 
3.1.3 
Other secondary endpoints................................................................................................... 10 
3.2 
(Serious) Adverse Events ........................................................................................................... 11 
3.3 
Analysis populations ................................................................................................................. 12 
3.3.1 
Interim safety analysis cohort (applicable for previous formal safety analysis) ................... 12 
3.3.2 
Safety cohort ......................................................................................................................... 12 
3.3.3 
Efficacy cohort ....................................................................................................................... 12 
4 
Study analysis ........................................................................................................................................ 13 
4.1 
Patient accrual & Baseline characteristics ................................................................................ 13 
4.2 
Treatment administration and follow-up information ............................................................. 13 
4.3 
Efficacy analysis ......................................................................................................................... 14 
4.3.1 
Key-secondary endpoint: One-year PFS ................................................................................ 14 
4.3.2 
Further efficacy analysis based on PFS ................................................................................. 14 
4.3.3 
Analyses of other secondary efficacy endpoints .................................................................. 15 


Page 3 of 19 
4.3.4 
Subgroup analysis.................................................................................................................. 15 
4.3.5 
Exploratory analysis for patients receiving nivolumab ......................................................... 15 
4.4 
Safety analysis ........................................................................................................................... 16 
4.5 
Missing Data .............................................................................................................................. 17 
4.6 
Sensitivity analysis ..................................................................................................................... 17 
4.7 
Presentation of results .............................................................................................................. 18 
5 
Technical details .................................................................................................................................... 19 
 


Page 4 of 19 
INTRODUCTION 
The aim of this Statistical Analysis Plan (SAP) is to describe an analytic and solid framework that will 
be followed in order for the final efficacy analysis of the NICOLAS trial to be implemented (based on 
NICOLAS protocol version 3; protocol amendment-2 [AM2]).  
A short description of the contents of this statistical analysis plan is provided below: 
1. NICOLAS trial outline: trial’s schema, eligibility criteria, objectives, trial duration, previous 
protocol versions, sample size & power 
2. General considerations: Analysis timing, data retrieval 
3. Statistical considerations: definition of primary and secondary endpoints, (serious) 
adverse events definition, analysis populations 
4. Study Analysis: Baseline characteristics, treatment administration and follow-up, efficacy 
analysis, safety analysis, handling of missing data 
5. Technical issues, including testing and reporting conventions. 
6. List of Tables and Figures 


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1 Trial oversight (as per protocol - Version 3.0) 
NICOLAS is a single-arm multicenter phase II trial, evaluating the safety and efficacy of the addition 
of concurrent anti-PD-1 nivolumab to standard first-line chemotherapy and radiotherapy in locally 
advanced stage IIIA/B Non-Small Cell Lung Carcinoma. 
 
 
SCHEMA 1. Trial design under protocol V3.0 
1.1 
Objectives  
Primary objective 
The primary objective of the study is to assess the safety and efficacy of the concurrent nivolumab 
administration with standard first-line chemotherapy and radiotherapy in locally advanced stage IIIA/B 
NSCLC, as defined by the rate of grade ≥3 pneumonitis (CTCAE V4.0) 6 months post-radiotherapy and, 
if safety is proven, to assess the progression-free survival. 
Secondary objectives  
• 
The secondary objectives of the study include the following measures of clinical efficacy:  time to 
first grade≥3 pneumonitis (TFP3), objective response rate (ORR), time to treatment failure (TTF) 
and overall survival (OS). 
• 
To assess the safety and the tolerability of the treatment. 
1.2 
Endpoints  
Primary endpoint:  
• 
Grade≥3 pneumonitis (CTCAE V4.0) observed any time during 6 months from end of radiotherapy. 
Key secondary endpoint (if valid):  
• 
One-year progression-free survival by RECIST v1.1  
Secondary endpoints:  


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• 
Time to first grade≥3 pneumonitis 
• 
Objective response determined by RECIST v1.1  
• 
Time to treatment failure 
• 
Overall survival 
• 
Adverse events graded according to CTCAE V4.0 
1.3 
Εligibility criteria  
Inclusion criteria at enrolment (briefly stated; for more details, refer to trial protocol):  
• 
Histologically or cytologically confirmed locally advanced stage IIIA or III B (T0-3 N2-3 or T4 N0-3 
M0) non-small cell lung carcinoma (NSCLC), according to 7th TNM classification 
• 
Nodal status N2 or N3 need to be proven (by biopsy, EBUS, mediastinoscopy or thoracoscopy) 
except for overt cT4 disease 
• 
Measurable disease according to RECIST v1.1 
• 
Previous delivery of a maximum of one 3-weekly cycle of platinum-based chemotherapy 
• 
ECOG performance status 0-1 
• 
Adequate hepatic, hematological and renal function 
• 
All AEs from previous therapies (including the first chemotherapy cycle in the context of this trial) 
resolved to grade <2 (except fatigue, alopecia, nausea lack of appetite or peripheral neuropathy) 
Exclusion criteria at enrolment (briefly stated; for more details, refer to trial protocol):  
• 
Metastatic disease (as determined by PET-CT and brain MRI (preferred) or high-quality brain CT 
with intravenous contrast at the time of staging, performed within 35 days before the beginning 
of first chemotherapy cycle) 
• 
Previous radiotherapy to the chest, including radiotherapy for breast cancer 
• 
Prior chemotherapy, radiotherapy or molecular targeted therapy for NSCLC (with the exception 
of one cycle of chemotherapy given prior to enrolment into this trial) 
• 
Active, known or suspected autoimmune disease 
 
1.4 
Previous protocol versions 
In the original protocol, radiotherapy (RT) (≥60Gy), was delivered either concurrently with 
chemotherapy in cycles 2 and 3 or sequentially, while nivolumab administration started after 
completion of the chemo-radiotherapy phase. Two protocol amendments have been approved 
(AM1, AM2).  
In AM1, enrollment was allowed by cycle 2, while Nivolumab administration was starting 
concurrently with RT.  


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In AM2, only concurrent chemo-radiotherapy was allowed (sequential chemo-RT was not allowed 
anymore). Chemotherapy was administered in 3 cycles, and nivolumab first in four doses (360 mg) 
every 3 weeks and thereafter, every 4 weeks (480 mg) for up to one year.  
The main change that occurred in AM2, has been the adaptation of the statistical design (and 
corresponding increase of sample size), so as to facilitate, beyond the safety evaluation, the 
efficacy evaluation of trial treatment. The key-secondary efficacy endpoint (one-year PFS rate), 
has been introduced in AM2, and is designed to be hierarchically tested, conditional on proven 
adequate safety, as described in more detail in the next section.  
 
1.5 
Statistical design, sample size & power 
A total sample size of 78 patients, receiving concurrent therapy is needed for the study’s 
objectives, assuming a 5% loss-of-follow-up rate. First, testing for safety is designed to evaluate 
the 6-month post-radiotherapy pneumonitis-free rate and if the safety endpoint is met, an efficacy 
analysis will be performed regarding the one-year progression-free survival (PFS) (hierarchical 
design). 
More particularly, the primary safety hypothesis corresponds to the 6-month pneumonitis-free 
rate of grade ≥3: Null hypothesis states that 6-month pneumonitis-free rate of grade ≥3 is less 
than or equal to π0=67%, vs the one-sided alternative that the rate is above 67%, tested at π1=85%:  
H0: π0 ≤67% vs H1: π1>π0, at π1=85% 
For a one-sided alpha 0.05 and power 83%, the required sample size for the safety evaluation is 
41 evaluable patients allowing for one interim safety analysis at 21 patients without any 
requirement for trial interruption. In the safety evaluation phase of the trial 43 patients will be 
recruited allowing for around 5% competing risk rate. If additional patients are non-evaluable for 
the primary endpoint, up to 3 patients will be replaced. 
An interim safety analysis is designed to be performed when 21 patients have completed a 3-
month follow-up on nivolumab after chemotherapy and radiotherapy, assuming approximately 
70% of the cases of pneumonitis occur by 3 months after the end of radiotherapy. If at the safety 
interim analysis, none of the 21 patients has developed pneumonitis of grade ≥3 by 3 months, 
then the safety phase of the trial could stop early with the conclusion that the treatment is feasible 
and safe. The trial will continue to reach the total sample size required to test the efficacy 
hypothesis. If the only patients developing pneumonitis of grade ≥3 by 3 months have done so 
before starting nivolumab, the Independent Data Monitoring Committee (IDMC) could choose to 
focus on the patients who started nivolumab for claiming feasibility. 
If the trial does not reach the safety conclusion at the interim, the final safety analysis will be 
performed when 41 patients have completed the 6-month follow-up. If at least 33 out of 41 
patients reach 6 months pneumonitis-free, the 6-month pneumonitis-free rate will be considered 
as promising, and the trial will continue to allow for the treatment to be tested for efficacy. 


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Based on a hierarchical design, a key-secondary efficacy hypothesis (secondary-Hs) is tested after 
the pneumonitis null hypothesis (primary-Hp) is rejected. The one-year PFS rate that could be 
achieved with current best provided care is estimated to be around 45%. The aim of the 
combination under investigation is to improve the one-year PFS by at least 15%, that is, to achieve 
a one-year PFS rate of at least 60%. 
Efficacy hypothesis (Hs): Hs0: PFS0 ≤45% vs Hs1: PFS1> PFS0, at PFS1=60% 
A sample size of 74 evaluable patients provides 83% power, for testing this efficacy hypothesis, 
based on the exact binomial test for single proportion, at the one-sided alpha of 0.05. Assuming 
5% non-evaluable patients, a total sample size of 78 patients need to enter the study. 
The final efficacy hypothesis is tested after the safety null hypothesis is rejected either at the 
interim or the final safety analysis, when 74 evaluable patients under concurrent chemo-
radiotherapy have reached one-year follow-up (from time of enrolment into the trial) or have 
experienced a PFS event. 
The 78 patients will be enrolled under the protocol amendments (protocol versions 2.0 and 3.0). 
Patients included under the original protocol (version 1.0) will be evaluated separately. 
1.6 
Total trial duration 
After a run-in period of 3 months for the activation of the centres, patient accrual is expected to be 
completed within 9 months (under AM2 and taking into account the accrual accomplished under 
AM1).  
The study duration for the key secondary efficacy endpoint will be approximately 22 months, including 
a 3-month start-up period, 7 months accrual (of the additional patients) and 12 months follow-up for 
evaluating the one-year PFS rate. 
Follow-up will continue until 2 years from start of nivolumab treatment of the last recruited patient. 
The trial will end with the preparation of the final report, scheduled at 2.5 years after the inclusion of 
the first patient. 


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2 General considerations 
2.1 
Analysis Timing 
According to the statistical design, the final efficacy analysis (key secondary endpoint) is scheduled 
to be performed when the last enrolled patient has completed 1 year on follow-up (and given that 
the safety hypothesis has been already proven).  
 
2.2 
Data Retrieval Information 
The final analysis will be based on the final database download, to be performed as soon as all 
patients have completed one-year of follow-up or have a PFS event before that. 
Based on this database extraction, a series of queries will be created in order to clean the data as 
much as possible. The queries will be forwarded to the data manager of the protocol and a 
prespecified period of time will be given for the queries to be answered. Corrections and responses 
based on these queries, will be used for correcting the previously downloaded database.  


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3 Statistical considerations 
3.1 
Study’s endpoints 
3.1.1 Primary safety endpoint (previously analysed) 
The primary (safety) endpoint is grade ≥3 pneumonitis (CTCAE v4.0) observed any time during 6 
months from the end of radiotherapy. It is defined as the number of patients reaching up to 6 
months post chemo-radiation treatment without any episode of CTCAE v4.0 grade ≥3 
pneumonitis. 
3.1.2 Key-secondary efficacy endpoint 
Progression-free survival (PFS) is the key secondary (efficacy) endpoint. It is defined as the time 
from the date of enrolment until documented progression or death, if progression is not 
documented. Censoring will occur at the last tumour assessment.  
Of note, patients who continue treatment beyond initial investigator-assessed, RECIST v1.1-
defined progression will be considered to have had progressive disease at the time of the initial 
progression event. 
3.1.3 Other secondary endpoints 
Other, secondary endpoints, according to the protocol, include the following: 
• Time to first pneumonitis of grade ≥3 (TFP3), defined as the time from the date of 
enrolment until first documented pneumonitis of grade ≥3. Censoring will occur at the last 
assessment only if patient is lost to follow-up or has died.  
• Objective response, defined as best overall response (Complete or Partial Response) 
across all assessment time-points during the period from enrolment to termination of 
trial treatment.  
• Time to treatment failure (TTF), defined as time from enrolment to treatment failure for 
any reason, including disease progression, treatment toxicity, refusal/withdrawal and 
death (even after treatment completion). Censoring will occur at the time of last tumour 
assessment only if the patient is lost to follow-up.  
• Overall survival (OS), defined as the time from the date of enrolment until death from 
any cause. Censoring will occur at the last follow-up date. 
• Toxicity, defined as adverse events classified according to CTCAE version 4. 
 
Other exploratory endpoints that will be assessed for descriptive purposes are: 
• Time to treatment discontinuation (TTD), defined as the time from enrolment to 
treatment discontinuation for any reason.  
• Duration of response (DoR), defined as the time from documentation of tumour response 
(either partial or complete response) to disease progression or death. 


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More details on the exact definition and calculation of efficacy endpoints is provided in the 
supplement, Table S1, while a detailed description of AEs and SAEs is provided in a next 
section.  
 
3.2 
(Serious) Adverse Events  
The main criterion for treatment tolerability is the occurrence of toxicities and adverse events. 
The severity and causality will be classified according to the NCI CTCAE Version 4. The CTCAE is 
available for downloading (http://evs.nci.nih.gov/ftp1/CTCAE/About.html). 
An adverse event (AE) is defined as any untoward medical occurrence that occurs from the first 
dose of study medication until 30 days after the final dose, regardless of whether it is considered 
related to a medication. In addition, any known untoward event that occurs subsequent to the 
adverse event reporting period that the investigator assesses as possibly related to the protocol 
treatment should be considered an adverse event.  
 Serious Adverse Events  
A Serious Adverse Event (SAE) is defined in general as any undesirable medical occurrence/adverse 
drug experience that occurs during or within 30 days after stopping study treatment that, at any 
dose, results in any of the following: 
• 
is fatal (any cause), 
• 
life-threatening, 
• 
requires or prolongs inpatient hospitalization, 
• 
results in persistent or significant disability/incapacity, 
• 
is a congenital anomaly or birth defect, 
• 
is a secondary malignancy, 
• 
requires significant medical intervention. 
Other significant/important medical events which may jeopardize the patient are also considered 
serious adverse events. Serious also includes any other event that the investigator or the ETOP 
Safety Office judges to be serious or which is defined as serious by the regulatory agency in the 
country in which the event occurred. 
 Severity Grade 
The adverse event severity grade provides a qualitative assessment of the extent or intensity of 
an adverse event, as determined by the investigator or as reported by the subject. The severity 
grade does not reflect the clinical seriousness of the event, only the degree or extent of the 
affliction or occurrence (e.g. severe nausea, mild seizure), and does not reflect the relationship to 
study drug. 


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Severity grade for other adverse events not covered in the toxicity grading scale: 
1=Grade 1 
Mild 
2=Grade 2 
Moderate 
3=Grade 3 
Severe 
4=Grade 4 
Life-threatening 
5=Grade 5 
Fatal 
 
 Multiple recordings of an event for the same patient 
There are some cases where a patient may experience the same event (AE/SAE) more than once. 
In such cases, the event will be counted only once for the calculation of the total number of events 
reported for the overall safety cohort. Nevertheless, if an SAE occurs more than once, all narratives 
will be included. 
 
3.3 
Analysis populations 
3.3.1 Interim safety analysis cohort (applicable for previous formal safety analysis) 
The cohort for the interim safety analysis includes the first 21 enrolled patients who have 
completed 3 months on FU post RT. Competing risks for the safety evaluation (death or treatment 
discontinuation before completion of a 3-month FU after end of RT) are excluded. 
3.3.2 Safety cohort 
The safety cohort will encompass all patients who have received at least 1 dose of trial treatment. 
In the present context, the main safety analysis will focus on the patients under the concomitant 
chemo-radiotherapy schedule, while a secondary analysis will include all patients enrolled either 
under the concomitant or the sequential treatment schedule. 
3.3.3  Efficacy cohort 
The efficacy cohort will be consisted of all eligible patients enrolled in the trial (ITT population) 
under AM1 and AM2 (i.e. protocol versions V2 and V3), excluding the patients that have received 
the sequential chemo-radiotherapy treatment schedule. 
 
 


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4 Study analysis 
In this section, we present in detail the analyses that will be performed in the frame of final efficacy 
analysis. 
4.1 
Patient accrual & Baseline characteristics 
The following information will be provided in tabular or graphical format: 
• Patient accrual by center including both the enrolled and the non-enrolled patients.  
• For those patients that were eventually not enrolled in the trial, an additional table will be 
provided, indicating the patient ID number, the center, the eligibility status (ineligible, draft, 
error) and the reason for non-enrolment. 
• Observed vs. expected accrual will be graphically displayed. 
• A consort diagram will be created to graphically depict the flow of patients and the phases of 
the trial.  
• Summary of the baseline patient and tumour characteristics (gender, age, smoking history, 
ECOG performance status, histology, stage, T/N/M classification). Regarding the categorical 
characteristics, the frequencies of the different levels of each of them, along with the 
respective percentage will be presented. If missing cases exist, a separate category named 
“Missing” will be created. All continuous characteristics will be summarised using the 
following descriptive statistics: n (non-missing sample size), mean, 95% CI for the mean, 
median, maximum and minimum.  
 
4.2 
Treatment administration and follow-up information 
Treatment information will be summarized as: 
• Number of patients that started treatment 
• For the chemo-radiotherapy phase: 
o Number of patients that completed chemotherapy 
o Number of patients that completed radiotherapy 
o Number of treatment failures during chemo-radiotherapy (and reasons of 
failure) 
• For the nivolumab phase 
o Statistics (median, range) for the number of nivolumab cycles administered per 
patient 
o Number of complete per-protocol treatments 
o Number of nivolumab failures 


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• For patients who complete per protocol treatment, information on whether or not they 
experience a PFS event thereafter will be also provided. 
• Number of patients that did not receive any dose of trial treatment, along with reasons 
for not doing so. 
• For those patients that progressed information on further lines of treatment will be 
also provided.  
Follow-up time of the patients will be presented as: 
• Median follow-up (FU) of the patients along with the respective interquartile range 
(IQR) and the number (%) of patients that are still on FU. A Kaplan-Meier (K-M) will be 
also provided for a graphical representation of follow-up time. 
 
4.3 
Efficacy analysis 
The efficacy analysis will be conducted based on the efficacy cohort and will include presentation 
of the following: 
4.3.1 Key-secondary endpoint: One-year PFS 
For the key-secondary endpoint of progression free survival (PFS) at one-year, a summary table 
will be produced, presenting the total number of patients evaluable at the one-year time point, 
the number of patients that are progression-free, along with the corresponding proportion and 
90% exact binomial confidence interval. According to the statistical design, with 1-sided alpha 0.05 
and power 80%, for 74 evaluable patients we need 41 patients to reach one-year progression-free 
(without PFS event) so as to be able to reject the null hypothesis of one-year PFS rate ≤45% versus 
the alternative evaluated at PFS rate 60%.  In the present frame of formal evaluation of one-year 
PFS, loss before a PFS event or earlier than one-year of follow-up, and never starting treatment 
are considered as competing risks. 
4.3.2 Further efficacy analysis based on PFS 
PFS will be further analysed as follows:  
• The total number of PFS events observed, will be presented. In addition, 6-month, 12-
month and 18-month PFS estimates, median PFS and respective 95% CIs will be 
provided.  
• Graphical representation of PFS, will be performed via a Kaplan-Meir plot.  
• To assess the effect of clinicopathological variables on PFS (gender, age, smoking 
history, ECOG performance status at diagnosis, histology, stage), Cox proportional 
hazards models will be fitted. Initially, univariate Cox models will be fitted to the data 
and the statistical significance of each candidate predictors will be tested at the 5% 
significance level (results presented in table and forest plot). Subsequently, a 
multivariable Cox model will be estimated, adjusted for the clinicopathological 
variables of interest. The backward elimination method, with a removal criterion at 


Page 15 of 19 
10% will be used to conclude on the statistically significant variables of the model. The 
HRs and corresponding 95% CIs for all significant PFS predictors (in the multivariable 
Cox model) will be summarized in a forest plot.  
• Furthermore, PFS will be analysed separately by subgroups of interest (as defined in a 
following section). For each subgroup number of PFS events, 6/12/18-month PFS 
estimates, median PFS and corresponding 95% CI as well as Kaplan-Meier plots will be 
presented.  
• Finally, a waterfall plot will be created to graphically depict the percent tumour change, 
a swimmer plot to illustrate efficacy information by patient (time-on-treatment, time 
to response and progression, follow-up), and a spider plot to graphically overview the 
changes in tumour size over time. 
 
4.3.3 Analyses of other secondary efficacy endpoints 
The other time-to-event endpoints (OS, TTF, TTD, TFP3) will be estimated by the Kaplan Meier 
method. The median time estimations for all survival endpoints along with the respective 95% CI’s, 
as well as the number (%) of failures (as per endpoint definition for “failure”) will be provided. 
Additionally, for TTF, the rate of treatment failures per month of FU will be provided, derived from 
the total number of treatment failures over the total number of FU time (in months).  
Clinical efficacy will be further described by objective response rate (ORR) as defined by RECIST 
v1.1. ORR will be presented along with a 95% exact binomial CI.  Median DOR, along with 95% CI 
will be presented. Graphical representation of duration of response will be performed via Kaplan-
Meier and swimmer plots. 
Definition of the endpoints described in the trial protocol, as well as necessary dates, cohorts and 
specific clarifications are all indicated in details in the table provided in the Appendix. 
 
4.3.4 Subgroup analysis 
To determine whether the treatment effect is consistent across various subgroups the treatment 
effect for all efficacy endpoints will be estimated separately for each category of the following pre-
specified variables. 
• 
Histology (squamous vs non-squamous) 
• 
Stage (IIIa vs IIIb) 
• 
Gender 
 
4.3.5 Exploratory analysis for patients receiving nivolumab 
For patients having received at least one dose of nivolumab treatment, PFS and the other 
secondary efficacy endpoints (OS, TTF, TTD, TFP3, ORR, DOR) will be also evaluated having as 
starting point the date of first nivolumab dose. 


Page 16 of 19 
The results that will be included in the exploratory analysis are: 
• 
Number of PFS events, 6/12/18-month PFS estimates, median PFS and corresponding 95% 
CI, as well as multivariable Cox regression. 
• 
Analogous results for OS, TTF, TTD, TFP3, DOR 
• 
 ORR with 95% exact binomial CI.   
 
4.4 
Safety analysis 
The safety analysis will be based on the safety cohort and will include presentation of the: 
• Overview of the number of patients who experienced an AE and/or an SAE, as well as the 
number of patients in the safety cohort who did not experience an event. The respective 
percentages will also be shown. 
• Number of AEs/SAEs and rate of AE/SAE occurrence per month of FU. Again, both rates will 
be calculated based on the total number of AEs and SAEs, respectively, over the total 
number of FU time (in months). 
• Number of patients experiencing a specific number of AEs/SAEs. 
• Distribution of (S)AEs by grade and CTCAE category. Six columns, one for each grade and 
one for all (any) grades, will be shown. An additional column indicating which events were 
SAEs -or started as AEs and became SAEs later on- will be available. In this column, the 
frequency of the SAEs and the severity grade will be given. The percentages that will 
accompany the frequencies will be based on the respective frequency of an event over the 
total number of patients in the safety cohort. This table will include all (S)AEs irrespective 
of their relation to the trial treatment. 
• Analogous table focusing only on the treatment related (S)AEs. 
• Number and corresponding percentages of treatment related (S)AEs by grade, leading 
either to treatment discontinuation or death  
• Distribution of the maximum severity grade experienced by the patients 
• For all fatal SAEs, cause of death will be provided. 
• For all pneumonitis of grade ≥3, detailed, by patient, information for the event (start/end 
date, outcome) as well as for the radiotherapy administered (event start date compared 
to radiotherapy end date, total dose, mean lung dose, V20 lung dose) will be provided. For 
comparison purposes, descriptive statistics of the mean lung dose (mean with 95% CI and 
median with IQR) will be provided for patients with pneumonitis of lower grade (1-2) or 
without such an event. 
• Analogous by-patient tables for all dyspnoea of grade ≥3, including information on mean 
heart dose, as well as for all esophagitis of grade ≥3, including oesophageal mean dose. 


Page 17 of 19 
• Results of logistic regression models, modelling the occurrence of adverse events of 
primary interest (pneumonitis, dyspnoea, esophagitis) by grade and adjusting for the mean 
dose of radiation. 
 
4.5 
Missing Data 
- 
Baseline characteristics 
For categorical baseline characteristics if missing cases exist, a separate category named “Missing” 
will be created. As far as continuous values, missing cases will not be replaced by any statistics 
calculated over non-missing data. 
- 
Dates: 
If the day of the month is missing for any date used in the analysis, the 15th of the month will be 
used to replace the missing date unless the calculation results in a negative time duration (e.g., 
date of onset cannot be prior to day one date). In this case, the date resulting in one day of 
duration will be used. If the day of the month and the month are missing for any date used in a 
calculation, i.e., January 1 will be used to replace the missing date. Missing dates for adverse 
events will be imputed based on the similar principle. 
- 
Incomplete tumour assessment information 
In patients who have no on-study assessments: 
- 
If death is recorded prior to the first planned tumour assessment, the death date will be 
considered as the date of the PFS event. 
- 
If clinical progression is recorded prior to the first planned tumour assessment, the date of 
the reported clinical progression will be considered as the date of the PFS event. 
 
4.6 
Sensitivity analysis 
In a sensitivity analysis framework, the efficacy analysis will be repeated using the safety, instead 
of efficacy, cohort. 
In particular, the results that will be included in the sensitivity analysis are: 
• 
Number of PFS events, 6/12/18-month PFS estimates, median PFS and corresponding 95% 
CI, as well as multivariable Cox regression. 
• 
Analogous results for OS, TTF, TTD, TFP3, DOR 
• 
 ORR with 95% exact binomial CI.   


Page 18 of 19 
 
4.7 
Presentation of results 
The results will be presented through tables and figures. A summary of the results will also 
accompany the main report. First, a short synopsis of the results will be presented through bullets, 
where only the most important findings will be shown. Following that, a more detailed description 
of the results will be provided, sectioned in the following order: 
• 
Patient accrual and baseline characteristics  
• 
Treatment administration  
• 
Efficacy analysis 
• 
Safety analysis  
All tables and figures will be included in an appendix. 
 


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5 Technical details 
Data will be primarily analysed using the SAS software package (version 9.4 or later), while the R 
statistical software will be also used for specific analyses and plots.  
A second statistician, the reviewing statistician, will independently reproduce all analysis and 
summary statistics. The reviewing statistician will have an overview of the entire analysis and will 
explicitly check the code producing tables and figures, as well as any other pieces of code as 
desired. 
 
Reporting conventions  
P-values ≥0.001 will be reported to 3 decimal places; p-values >0.010 will be reported with two 
significant digits; p-values less than 0.001 will be reported as “<0.001”. The mean, 95% confidence 
limits, quantiles, and any other statistics, will be reported to one decimal. Hazard ratios (HRs) and 
their 95% CI’s will be reported to two decimals. Estimated parameters, not on the same scale as 
raw observations (e.g. regression coefficients) will be reported to 3 significant figures.