A Phase II Prospective Immune Neoadjuvant Therapy Study od Durvalumab (MEDI4736) in Early Stage Non-small Cell Lung Cancer
Phase: PHASE2
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: Intergroupe Francophone de Cancerologie Thoracique

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IFCT-1601 - IONESCO 
 
A PHASE II PROSPECTIVE IMMUNE 
NEOADJUVANT THERAPY STUDY OF 
DURVALUMAB (MEDI4736) IN EARLY STAGE 
NON-SMALL CELL LUNG CANCER 
N° EUDRACT: 2016-001849-15 
Sponsor 
 
10 rue de la Grange-Batelière 75009 PARIS – France 
 
Coordinating investigator 
Pr Marie Wislez 
Service de Pneumologie 
Hôpital Tenon 
4 rue de la Chine 75970 PARIS CEDEX 20 
Email : marie.wislez@aphp.fr 
 
 

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Project code 
Protocol IFCT-1601 
 
Sponsor 
Intergroupe Francophone de Cancérologie Thoracique (IFCT), 
10 rue de la Grange-Batelière, 75009 Paris 
 
Coordinating investigator 
Pr Marie Wislez 
Service de Pneumologie 
Hôpital Tenon, 4 rue de la Chine 75970 PARIS CEDEX 20 
Email: marie.wislez@aphp.fr 
 
Steering Committee 
Françoise Le Pimpec-Barthes, Julien Mazières, Bernard Milleron, Franck Morin, Virginie Westeel, Marie 
Wislez, Gérard Zalcman  
 
Biological experts 
Martine Antoine, Pierre Laurent-Puig, Eric Tartour 
 
Statistician 
Ms Alexandra Langlais 
 

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PROTOCOL IFCT- IONESCO APPROVAL AND SIGNATORIES  
A phase II prospective immune adjuvant therapy study of durvalumab in early stage Non-Small Cell Lung 
Cancer 
 
Sponsor 
IFCT 
Name 
date 
(jj-mm-aa) 
Signature 
President 
Pierre-Jean 
Souquet 
25-02-19 
Director 
Franck Morin 
25-02-19 
 
Biostatistician 
Alexandra 
Langlais 
25-02-19 
 
Responsibilities 
delegated by the 
sponsor 
Name 
date 
(jj-mm-aa) 
Signature 
Coordinating 
Investigator 
Marie Wislez 
25-02-19 
 
Je reconnais avoir pris connaissance de l’ensemble du protocole  
EUDRACT : 2016-001849-15 
et accepte de conduire cet essai en accord avec les Bonnes Pratiques Cliniques, la Loi de Recherche 
Biomédicale (4 aout 2004) et tel qu’il est décrit dans ce document. 
INVESTIGATEUR COORDINATEUR: 
Nom :     Marie Wislez 
 
Date : 25/02/2019 
Signature :                

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TABLE OF CONTENTS 
 
 
1 
BACKGROUND INFORMATION AND RATIONALE .................................................. 5 
2 
BACKGROUND THERAPEUTIC INFORMATION .................................................... 9 
3 
OBJECTIVES ........................................................................................ 15 
4 
TRIAL DESIGN...................................................................................... 16 
5 
STUDY POPULATION .............................................................................. 17 
6 
INCLUSION ......................................................................................... 20 
7 
PRE-TREATMENT EVALUATION .................................................................. 20 
8 
TREATMENT PLAN ................................................................................ 22 
9 
EVALUATION DURING AND AFTER PROTOCOL TREATMENT ................................. 26 
10 
SURGERY AND PATHOLOGICAL ASSESSMENT .................................................. 29 
11 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS ........................................ 30 
12 
SERIOUS ADVERSE EVENT REPORTING ......................................................... 33 
13 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING ............ 36 
14 
CENTRAL REVIEW PROCEDURES AND TISSUE COLLECTION .................................. 38 
15 
STATISTICAL CONSIDERATIONS.................................................................. 40 
16 
ADMINISTRATIVE SECTION ....................................................................... 42 
17 
FINAL REPORT AND PUBLICATIONS ............................................................. 46 
18 
REFERENCES ....................................................................................... 48 
 
 
 

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1 
BACKGROUND INFORMATION AND RATIONALE 
Lung cancer is still the leading cause of cancer related-deaths worldwide, with an overall all-stage 5-year 
survival of approximately 17%[1]. The primary treatment of early stage (I-IIIA) NSCLC is curative surgery. 
Although patients treated with curative surgery have a better prognosis, the 5-year survival for patients 
treated with surgery alone remains low, ranging from 67% (stage IA) to 23% (stage IIIA)[2]. 
The poor survival rates following surgical resection for patients with stage II and III disease have led several 
groups to investigate the utility of perioperative chemotherapy in improving lung survival outcomes. Several 
randomized trials comparing postoperative chemotherapy versus no chemotherapy have shown a significant 
overall survival benefit from postoperative chemotherapy in completely resected patients with NSCLC stage 
II and IIIA. A large meta-analysis based on individual patient data suggested that adjuvant cisplatin-based 
chemotherapy could yield an overall survival (OS) advantage of 5% at 5 years [3]. 
Likewise other randomized trials have demonstrated preoperative chemotherapy improves survival and 
recently the analyses also based on individual patients data of 15 randomized trials showed a significant 
benefit of preoperative chemotherapy on survival with the same survival improvement of 5% at 5 years [4]. 
Then, neoadjuvant chemotherapy has also become accepted in many countries [4]. Theoretically the neo-
adjuvant approach has a number of advantages: it can reduce the tumour volume and facilitate the control 
of micro-metastatic diffusion or prevent it; The neo-adjuvant treatment allows a careful evaluation of 
chemotherapy response giving critical information on tumour biology in adequate tumour samples: the 
compliance of chemotherapy in untreated patients is certainly better than after surgery and its dose 
intensity higher. On the other hand, its toxicities and a delay to surgery could be disadvantages, although up 
to now these issues seem to be scarcely relevant. 
Lastly, the observed pathological response on surgical specimen after neoadjuvant therapy has been 
identified as a potential surrogate of survival in patients with NSCLC [5–7]. Pathological response has been 
recently proposed as new primary endpoint for clinical trials, allowing the inclusion of a smaller number of 
patients and to obtain more rapidly main objective. This leads to a boost of interest in neoadjuvant trials. 
1.1 Why targeting PD-1/PD-L1? 
Despite the established benefit of adjuvant chemotherapy after curative surgery for NSCLC, 30-60% of 
patients, depending on stage, will eventually relapse and die of their disease [8]. Furthermore, not all 
patients with early stage disease are eligible or willing to undergo chemotherapy following complete 
surgical resection [9]. As such, the long-term prognosis of patients with NSCLC, even among those with early 
stage disease, remains poor. Novel therapies are, therefore, required to improve the clinical outcomes of 
completely resected NSCLC. 
Based on their success in the advanced disease NSCLC setting [10] molecularly targeted therapies are now 
evaluated in the adjuvant setting following complete surgical resection for NSCLC. The lack of success of the 
two recent phase III adjuvant trials targeting the EGFR pathway could be related to the lack of restricting 
enrolment to patients with activating mutations [11,12]. Targeted therapies continue to be an attractive 
option in the perioperative setting given their good toxicity profiles.  
In the context of early stage NSCLC, immunotherapeutic interventions that can both induce cell-mediated 
immunity against proliferating cancer cells following complete resection and establish immunologic memory 
that may guard against future recurrences through active immune surveillance is a particularly attractive 
therapeutic option. 

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Immune responses of the human immune system directly target tumours as part of the body’s natural 
defence mechanisms. Cancers, however, can develop strategies that allow them to actively evade detection 
and immune-mediated apoptosis. The up-regulation of surface proteins, including programmed death-1 (PD-
1), is one such strategy. Specifically, abnormal cell-surface expression of its ligand PD-L1 on tumors has 
been shown to induce T cell anergy, affording tumors protection against killer T-cell elimination [13]. 
Further, in the tumor microenvironment, PD-1 expressed on activated T cells has also been shown to limit T 
cell antitumor activity on cells reaching the tumor, when bound to its ligand, PD-L1[14]. Although, 
historically NSCLC has been considered to be non-immunogenic [15], emerging data suggests that lung 
cancers may actively evade attack by the immune system by expressing the PD-L1 ligand, allowing them to 
evade immune detection [16,17].  
In preclinical studies, blocking the interaction between PD-1 and PD-L1 has been shown to induce immune 
responses in vitro[18]and enhance antitumor T cell cytotoxic activity. Clinically, blockade of the PD-1 
inhibitory checkpoint pathway by inhibiting PD-L1/ PD-1 engagement, has been shown to induce tumour 
regression across many cancer types, including melanoma, renal cell, colon and lung cancers [16,19–22]. In 
lung cancer, inhibition of the PD-1 checkpoint pathway by antibodies targeting either PD-1 or its ligand PD-
L1 have yielded encouraging results, suggesting a “class effect” and validating this pathway as a therapeutic 
target in NSCLC. Phase I NSCLC cohorts of heavily pre-treated patients have yielded dose-dependent 
objective responses ranging from 10%-32% [16,20–23] with responses observed in patients with both 
squamous and non-squamous histology. Immunotherapy with anti-PD-1 or anti-PD-L1 antibodies across many 
tumor types has been generally well tolerated, with common drug related adverse events mainly limited to 
grade 1 or 2 fatigue, diarrhea, rash, pruritus, nausea and decreased appetite.  
1.2 Why targeting PD-1 in a neoadjuvant setting? 
Targeting of PD-1 receptors and its ligand PD-L1, and inhibiting their engagement is an attractive 
therapeutic option in the early stage NSCLC, which may reactivate host immune responses and enable long-
term tumor control.  
We aim to launch a phase II trial, administrating PD-L1 antibody in clinical stage IB (>4cm) or stage II, NSCLC 
before surgery. 
Neoadjuvant trial will allow the analysis in early stage NSCLC of 1) CT scan response (RECIST and immune 
response criteria), 2) 18-FDG metabolic response 3) pathological response 4) and to study immune response 
after PD-1 antibody infusions on large tissue sample such as surgical piece. We will be able to phenotype the 
immune reaction in responders and non-responders and we will be able to study immune reaction before 
(blood and tissue at diagnosis) and after PD-1 antibody infusion (blood and surgical tissue). All these 
observations will be correlated to disease-free survival and survival. 
Some studies suggested an association between treatment response and pre-treatment PD-L1 tumor or 
immune cells expression[16,20], however, the role of PD-L1 expression as a biomarker for clinical response 
to PD-1 pathway inhibition has yet to be validated. Mandatory pre- and post-treatment tissue will allow the 
analysis of predictive and prognostic significance of PD-L1 expression, as well as other cytokine/biomarker 
expression. 
Because stage IB (>4cm) or stage II NSCLC are frequently curable with surgery, we chose as first endpoint 
feasibility of complete surgical resection. Complete resection is defined as complete removal of the primary 
tumour with no residual macroscopic or microscopic tumor left behind; moreover, a systematic or lobe-
specific nodal dissection must have been performed, and the highest mediastinal lymph node must be 

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negative [24]. We plan only three infusions of PD-L1 antibody (one infusion every two weeks) with a 
schedule allowing surgery to be performed not later than 6 weeks after inclusion.  
The number of post-operative events and a tolerance report will be achieved on the first 15 patients to 
discuss the pursuit of the trial. 
In the IFCT-0002 trial [25], including 528 patients with stage I and II NSCLC, 91.6% of patients achieved 
complete resections. In the other trials this rate was lower (see table) but with smaller number of patients, 
more advanced stages and also older studies. For all these reasons and because this trial is in continuity 
with IFCT 0002 trial, we decided to take 90% as the threshold below which the rate of complete oncologic 
resection observed was unacceptable. 
Durvalumab is a novel IgG1-kappa PD-L1 inhibitor with potent and specific binding to PD-L1 at picomolar 
concentrations, with directed mutations in the Fc region, limiting off-target cytotoxicity in PD-L1-expressing 
immune cells [26]. Durvalumab has been shown to increase T-cell activation in vitro by blocking PD-L1/PD-1 
engagement [26] and induces antitumor responses in tumor-bearing mice, with corresponding changes in 
peripheral immune markers [26]. Durvalumab has also been shown to inhibit tumor growth in vivo xenograft 
models [26]. 
In advanced NSCLC, inhibition of the PD-1 immune checkpoint pathway has been shown to induce durable 
clinical responses across all histologies and is therefore of broad clinical relevance. durvalumab has a 
favorable safety profile and limited off-target T cell effects and has good pharmacokinetic and 
pharmacodynamic properties. Results of early trials with durvalumab in advanced cancers are consistent 
with a class effect of early and sustained tumour control that has been observed previously with other 
inhibitors of the PD-1 immune checkpoint pathway. durvalumab is particularly attractive as a therapeutic 
strategy in the adjuvant setting as it may generate immunologic memory and persistent activity in memory B 
cells, allowing for active and sustained surveillance and killing of tumour cells and possibly long term cure. 
NSCLC patients with PD-L1 expression positive resected tumours may be particularly sensitive to 
immunotherapy with durvalumab given accumulating evidence in patients with advanced disease. Even if 
the primary endpoint is the complete resection for early stage, the expected benefit is to obtain a signal in 
term of response and increase of disease free survival. 
Durvalumab has been shown to have a favourable pharmacokinetic (PK) profile that exhibits nonlinear PK at 
doses up to 1.0 mg/kg, with dose-dependent increases in target engagement and target suppression at doses 
≥ 0.3 mg/kg every two weeks [22]. Immune-related reactions that are possible with this class of drug (e.g. 
enterocolitis, dermatitis, hepatotoxicity, endocrinopathy, pneumonitis) have been reported in less than 5% 
of patients on durvalumab.  To date, there have been no cases of infusion reaction or IgE-induced allergic 
reactions with durvalumab.  
Study Hypothesis: A theoretical feasibility rate equal to or lower rate of complete resection than P0=85% is 
considered as unacceptable after immune treatment. A test for single binomial proportion for a two-stage 
design with a 1:1 randomization and O’Brien-Fleming (OF) stopping rules will be used. P0 = 85% P1 = 95% 
Power = 90% and α risk (one-sided) = 5%. Based on these assumptions, 81 patients are required. 
 
 
 

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Table 1: Neoadjuvant trials with number of patients considered with complete resection  
Trial 
First 
author 
Reference 
Stage 
N  
Neoadjuvan
t arm 
N  
Surgery 
(%)* 
N  
Exploratory 
thoracotomy  
N  
Surgery  
for complete 
resection  
(%)* 
N  
Complete 
resection  
(%)* 
MIP91 
Depierre 
[27] 
IB 
II 
IIIA 
187 
167 
(89,3) 
5 
162 
(86,6) 
ND 
S9900 
Pisters 
[28] 
IB 
II 
IIIA 
non 
N2 
169 
152 
(89,9) 
5 
147 
(86,9) 
142 
(84) 
NATCH 
Felip 
[29] 
IA 
>2cm 
IB 
II 
T3N1 
201 
181 
(90) 
7 
ND 
ND 
CHEST 
Scagliotti 
[30] 
IB 
II 
T3N1 
129 
110 
(85,2) 
ND 
ND 
97 
(75,1) 
IFCT 
0002 
Westeel 
[25] 
I, II 
528 
509 
(96,4) 
4 
505 
(95,6) 
484 
(91,6) 
* % has been calculated in intention to treat (ITT), i.e. using the number of patients included in the 
neoadjuvant arm of the corresponding trial. 
 
 

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2 
BACKGROUND THERAPEUTIC INFORMATION 
2.1 Durvalumab Background 
Investigators should be familiar with the current durvalumab Investigator Brochure (IB). 
Durvalumab is being developed as a potential anticancer therapy for patients with advanced solid tumors. 
Durvalumab is a human monoclonal antibody (MAb) of the immunoglobulin G1 kappa (IgG1κ) subclass that 
inhibits binding of programmed cell death ligand 1 (PD-L1) (B7 homolog 1 [B7-H1], cluster of differentiation 
[CD]274) to programmed cell death 1 (PD-1; CD279) and CD80 (B7-1). Durvalumab is composed of 2 identical 
heavy chains and 2 identical light chains, with an overall molecular weight of approximately 149 kDa. 
Durvalumab contains a triple mutation in the constant domain of the immunoglobulin (Ig) G1 heavy chain 
that reduces binding to complement protein C1q and the fragment crystallizable gamma (Fcγ) receptors 
involved in triggering effector function. 
2.1.1 
Summary of non-clinical experience 
The non-clinical experience is fully described in the current version of the durvalumab Investigator’s 
Brochure.  
Durvalumab binds with high affinity and specificity to human PD-L1 and blocks its interaction with PD-1 and 
CD80. In vitro studies demonstrate that durvalumab antagonizes the inhibitory effect of PD-L1 on primary 
human T cells, resulting in their restored proliferation and release of interferon gamma (IFN-γ). 
Additionally, durvalumab demonstrated a lack of antibody-dependent cell-mediated cytotoxicity (ADCC) and 
complement-dependent cytotoxicity (CDC) in cell-based functional assays. In vivo studies show that 
durvalumab inhibits tumor growth in a xenograft model via a T lymphocyte (T-cell) dependent mechanism. 
Moreover, an anti-mouse PD-L1 antibody demonstrated improved survival in a syngeneic tumor model when 
given as monotherapy and resulted in complete tumor regression in > 50% of treated mice when given in 
combination with chemotherapy. Combination therapy (dual targeting of PD-L1 and cytotoxic T-lymphocyte-
associated antigen 4 [CTLA-4]) resulted in tumor regression in a mouse model of colorectal cancer.  
Cynomolgus monkeys were selected as the only relevant species for evaluation of the pharmacokinetics 
(PK)/pharmacodynamics and potential toxicity of durvalumab. Following intravenous (IV) administration, the 
PK of durvalumab in cynomolgus monkeys was nonlinear. Systemic clearance (CL) decreased and 
concentration half-life (t1/2) increased with increasing doses, suggesting saturable target binding-mediated 
clearance of durvalumab. No apparent gender differences in PK profiles were observed for durvalumab.  
In general, treatment of cynomolgus monkeys with durvalumab was not associated with any durvalumab -
related adverse effects that were considered to be of relevance to humans. Adverse findings in the non-
Good Laboratory Practice (GLP) PK/pharmacodynamics and dose range-finding study, and a GLP 4-week 
repeat-dose toxicity study were consistent with antidrug antibody (ADA)-associated morbidity and mortality 
in individual animals. The death of a single animal in the non-GLP, PK/pharmacodynamics, and dose range-
finding study was consistent with an ADA-associated acute anaphylactic reaction. The spectrum of findings, 
especially the clinical signs and microscopic pathology, in a single animal in the GLP, 4-week, repeat-dose 
study was also consistent with ADA immune complex deposition, and ADA: durvalumab immune complexes 
were identified in a subsequent non-GLP, investigative immunohistochemistry study. Similar observations 
were reported in cynomolgus monkeys administered human mAbs unrelated to durvalumab. Given that 
immunogenicity of human mAbs in nonclinical species is generally not predictive of responses in humans, the 
ADA-associated morbidity and mortality were not considered for the determination of the no-observed-
adverse-effect level (NOAEL) of durvalumab.  

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Finally, data from the pivotal 3-month GLP toxicity study with durvalumab in cynomolgus monkeys showed 
that subchronic dosing of durvalumab was not associated with any adverse effects. Therefore, the NOAEL of 
durvalumab in all the general toxicity studies was considered to be 100 mg/kg, the highest dose tested in 
these studies. In addition to the in vivo toxicology data, no unexpected membrane binding of durvalumab to 
human or cynomolgus monkey tissues was observed in GLP tissue cross-reactivity studies using normal human 
and cynomolgus monkey tissues. 
2.1.2 
Summary of clinical experience 
Clinical experience with durvalumab is fully described in the current version of the durvalumab 
Investigator’s Brochure. 
As of the DCO dates (15Apr2015 to 18Sep2015), a total of 1,910 subjects have been enrolled and treated in 
30 ongoing durvalumab clinical studies, including 20 sponsored and 10 collaborative studies (Table 1.2-1). Of 
the 1,910 subjects, 1,279 received durvalumab monotherapy, 454 received durvalumab in combination with 
tremelimumab or other anticancer agents, 14 received other agents (1 gefitinib, 13 MEDI6383), and 163 have 
been treated with blinded investigational product. No studies have been completed or terminated 
prematurely due to toxicity. 
2.1.3 Pharmacokinetics and Product Metabolism  
Study CD-ON-durvalumab-1108: As of 09 Feb2015, PK data were available for 378 subjects in the dose-
escalation and dose-expansion phases of Study CD-ON-durvalumab-1108 following treatment with 
durvalumab 0.1 to 10 mg/kg every 2 weeks (Q2W) or 15 mg/kg every 3 weeks (Q3W). The maximum 
observed concentration (Cmax) increased in an approximately dose-proportional manner over the dose range 
of 0.1 to 15 mg/kg. The area under the concentration-time curve from 0 to 14 days (AUC0-14) increased in a 
greater than dose-proportional manner over the dose range of 0.1 to 3 mg/kg and increased dose-
proportionally at ≥ 3 mg/kg. These results suggest durvalumab exhibits nonlinear PK likely due to saturable 
target-mediated CL at doses < 3 mg/kg and approaches linearity at doses ≥ 3 mg/kg. Near complete target 
saturation (soluble programmed cell death ligand 1 [sPD-L1] and membrane bound) is expected with 
durvalumab ≥ 3 mg/kg Q2W. Exposures after multiple doses showed accumulation consistent with PK 
parameters estimated from the first dose. In addition, PK simulations indicate that following durvalumab 10 
mg/kg Q2W dosing, > 90% of subjects are expected to maintain PK exposure ≥ 40 µg/mL throughout the 
dosing interval. 
As of 09 Feb2015, a total of 388 subjects provided samples for ADA analysis. Only 8 of 388 subjects (1 
subject each in 0.1, 1, 3, and 15 mg/kg cohorts, and 4 subjects in 10 mg/kg cohort) were ADA positive with 
an impact on PK/pharmacodynamics in 1 subject in the 3 mg/kg cohort. 
Safety  
The safety profile of durvalumab as monotherapy and combined with other anticancer agents was consistent 
with the pharmacology of the target and other agents in the immune checkpoint inhibitor class. No tumor 
types appeared to be associated with unique AEs. Immune-related AEs (irAEs), which are important risks of 
immune checkpoint inhibitors, have been observed with durvalumab and include colitis, pneumonitis, 
hepatitis/hepatotoxicity, neuropathy/neuromuscular toxicity, endocrinopathy, dermatitis, and nephritis. In 
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combination therapy. These events are manageable by available/established treatment guidelines as 
described in the study protocols (see paragraph 7.5). 
AEs reported with durvalumab monotherapy in key clinical studies are described below. 
Adverse Event Profile of durvalumab Monotherapy 
Study CD-ON-durvalumab-1108: The safety profile of durvalumab monotherapy in the 694 subjects with 
advanced solid tumors treated at 10 mg/kg Q2W in Study CD-ON-durvalumab-1108 has been broadly 
consistent with that of the overall 1,279 subjects who have received durvalumab monotherapy (not 
including subjects treated with blinded investigational product) across the clinical development program. 
The majority of treatment-related AEs were manageable with dose delays, symptomatic treatment, and in 
the case of events suspected to have an immune basis, the use of established treatment guidelines for 
immune-mediated toxicity. As of 07 May2015, among the 694 subjects treated with durvalumab 10 mg/kg 
Q2W in Study CD-ON-durvalumab-1108, a total of 378 subjects (54.5%) experienced a treatment-related AE, 
with the most frequent (occurring in ≥ 5% of subjects) being fatigue (17.7%), nausea (8.6%), diarrhea (7.3%), 
decreased appetite (6.8%), pruritus (6.3%), rash (6.1%), and vomiting (5.0%). A majority of the treatment-
related AEs were Grade 1 or Grade 2 in severity with ≥ Grade 3 events occurring in 65 subjects (9.4%). 
Treatment-related ≥ Grade 3 events reported in 3 or more subjects (≥ 0.4%) were fatigue (12 subjects, 
1.7%); increased aspartate aminotransferase (AST; 7 subjects, 1.0%); increased gamma-glutamyltransferase 
(GGT; 6 subjects, 0.9%); increased alanine aminotransferase (ALT; 5 subjects, 0.7%); and colitis, vomiting, 
decreased appetite, and hyponatremia (3 subjects, 0.4% each). Six subjects had treatment-related Grade 4 
AEs (upper gastrointestinal hemorrhage, increased AST, dyspnea, neutropenia, colitis, diarrhea, and 
pneumonitis) and 1 subject had a treatment-related Grade 5 event (pneumonia). Treatment-related serious 
adverse events (SAEs) that occurred in ≥ 2 subjects were colitis and pneumonitis (3 subjects each). A 
majority of the treatment-related SAEs were ≥ Grade 3 in severity and resolved with or without sequelae. 
AEs that resulted in permanent discontinuation of durvalumab were considered as treatment related in 
18 subjects (2.6%), with colitis being the most frequent treatment-related AE resulting in discontinuation 
(3 subjects). A majority of the treatment-related AEs resulting in discontinuation of durvalumab were 
≥ Grade 3 in severity and resolved with or without sequelae.  
Study D4191C00003/ATLANTIC: The safety profile of durvalumab monotherapy in Study CD-ON-
durvalumab-1108 is generally consistent with that of Study D4191C00003/ATLANTIC in subjects with locally 
advanced or metastatic non-small-cell lung cancer (NSCLC) treated with durvalumab 10 mg/kg Q2W. As of 
05May2015, 264 of 303 subjects (87.1%) reported any AE in Study D4191C00003/ATLANTIC. Overall, events 
reported in ≥ 10% of subjects were dyspnea (18.8%), fatigue (17.8%), decreased appetite (17.5%), cough 
(14.2%), pyrexia (12.2%), asthenia (11.9%), and nausea (11.2%). Nearly two-thirds of the subjects 
experienced AEs that were Grade 1 or 2 in severity and manageable by general treatment guidelines as 
described in the current durvalumab study protocols. Grade 3 or higher AEs were reported in 107 of 303 
subjects (35.3%). A total of 128 subjects (42.2%) reported AEs that were considered by the investigator as 
related to investigational product. Treatment-related AEs (all grades) reported in ≥ 2% of subjects were 
decreased appetite (6.6%); fatigue (5.9%); asthenia (5.0%); nausea (4.6%); pruritus (4.3%); diarrhea, 
hyperthyroidism, hypothyroidism, and pyrexia (3.3% each); rash (2.6%); weight decreased (2.3%); and 
vomiting (2.0%). Treatment-related Grade 3 AEs reported in ≥ 2 subjects were pneumonitis (3 subjects) and 

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increased GGT (2 subjects). There was no treatment-related Grade 4 or 5 AEs. Ninety-four of 303 subjects 
(31.0%) reported any SAE. SAEs that occurred in ≥ 1.0% of subjects were dyspnea (6.6%); pleural effusion, 
general physical health deterioration (2.3% each); pneumonia (2.0%); hemoptysis, pulmonary embolism (1.3% 
each); and pneumonitis, respiratory failure, disease progression (1.0% each). Nine subjects had an SAE 
considered by the investigator as related to durvalumab. Each treatment-related SAE occurred in 1 subject 
each with the exception of pneumonitis, which occurred in 3 subjects. Fifteen of 303 subjects (5.0%) have 
died due to an AE (pneumonia [3 subjects]; general physical health deterioration, disease progression, 
hemoptysis, dyspnea [2 subjects each]; pulmonary sepsis, respiratory distress, cardiopulmonary arrest 
[verbatim term (VT)], hepatic failure, and sepsis [1 subject each]). None of these events was considered 
related to durvalumab. Twenty-three of 303 subjects (7.6%) permanently discontinued durvalumab 
treatment due to AEs. Events that led to discontinuation of durvalumab in ≥ 2 subjects were dyspnea, 
general physical health deterioration, and pneumonia. Treatment-related AEs that led to discontinuation 
were increased ALT and increased hepatic enzyme, which occurred in 1 subject each. 
Efficacy  
Study CD-ON-durvalumab-1108: Overall, 456 of 694 subjects treated with durvalumab 10 mg/kg Q2W were 
evaluable for response (defined as having ≥ 24 weeks follow-up, measurable disease at baseline, and ≥ 1 
follow-up scan, or discontinued due to disease progression or death without any follow-up scan). In PD-L1 
unselected patients, the objective response rate (ORR), based on investigator assessment per Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1, ranged from 0% in uveal melanoma (n = 23) to 20.0% in 
bladder cancer (n = 15), and disease control rate at 24 weeks (DCR-24w) ranged from 4.2% in triple-negative 
breast cancer (TNBC; n = 24) to 39.1% in advanced cutaneous melanoma (n = 23). PD-L1 status was known 
for 383 of the 456 response evaluable subjects. Across the PD-L1-positive tumors, ORR was highest for 
bladder cancer, advanced cutaneous melanoma, hepatocellular carcinoma (HCC; n = 3 each, 33.3% each), 
NSCLC (n = 86, 26.7%), and squamous cell carcinoma of the head and neck (SCCHN; n = 22, 18.2%). In the 
PD-L1-positive subset, DCR-24w was highest in advanced cutaneous melanoma (n = 3, 66.7%), NSCLC (n = 86, 
36.0%), HCC and bladder cancer (n = 3 each, 33.3% each), and SCCHN (n = 22, 18.2%).  
Study D4190C00007: Of the 32 subjects with myelodysplastic syndrome (MDS) treated in Study 
D4190C00007, 21 subjects had at least 1 post-baseline disease assessment. Among these subjects, the best 
overall responses were marrow complete remission (mCR) in 4 subjects (19.0%); stable disease (SD) in 4 
subjects (19.0%); and progressive disease (PD) in 5 subjects (23.8%). The remaining 8 subjects (38.1%) did 
not meet the criteria for complete remission (CR), mCR, partial remission (PR), SD, or PD at the date of 
assessment. 
Study CD-ON-durvalumab-1161: Of the 65 subjects with metastatic or unresectable melanoma treated with 
the combination of durvalumab and BRAF inhibitor (BRAFi; dabrafenib)/MEK inhibitor (MEKi; trametinib), 
63 subjects were evaluable for response. A total of 35 subjects (55.6%) had a best overall response of 
confirmed or unconfirmed PR. The disease control rate (DCR; CR + PR [regardless of confirmation] + SD ≥ 12 
weeks) was 79.4%.  
Fixed Dosing  
A population PK model was developed for durvalumab using monotherapy data from a Phase 1 study (study 
1108; N=292; doses= 0.1 to 10 mg/kg Q2W or 15 mg/kg Q3W; solid tumors). Population PK analysis indicated 

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only minor impact of body weight (WT) on PK of durvalumab (coefficient of ≤ 0.5). The impact of body WT-
based (10 mg/kg Q2W) and fixed dosing (750 mg Q2W) of durvalumab was evaluated by comparing predicted 
steady state PK concentrations (5th, median and 95th percentiles) using the population PK model. A fixed 
dose of 750 mg was selected to approximate 10 mg/kg (based on median body WT of ~75 kg). A total of 1000 
patients were simulated using body WT distribution of 40–120 kg. Simulation results demonstrate that body 
WT-based and fixed dosing regimens yield similar median steady state PK concentrations with slightly less 
overall between-subject variability with fixed dosing regimen.   
Similar findings have been reported by others [Ng et al 2006, Wang et al. 2009, Zhang et al, 2012,Narwal et 
al 2013]. Wang and colleagues investigated 12 monoclonal antibodies and found that fixed and body size-
based dosing perform similarly, with fixed dosing being better for 7 of 12 antibodies [3]. In addition, they 
investigated 18 therapeutic proteins and peptides and showed that fixed dosing performed better for 12 of 
18 in terms of reducing the between-subject variability in pharmacokinetic/pharmacodynamics parameters 
[Zhang et al 2012].  
A fixed dosing approach is preferred by the prescribing community due to ease of use and reduced dosing 
errors. Given expectation of similar pharmacokinetic exposure and variability, we considered it feasible to 
switch to fixed dosing regimens. Based on average body WT of 75 kg, a fixed dose of 750 mg Q2W 
durvalumab (equivalent to 10 mg/kg Q2W), 1500 mg Q4W durvalumab (equivalent to 20 mg/kg Q4W) is 
included in the current study. Fixed dosing of durvalumab is recommend only for subjects with > 30kg body 
weight due to endotoxin exposure.  Patients with a body weight less than or equal to 30 kg should be dosed 
using a weight-based dosing schedule .  
2.2 Pharmaceutical Data durvalumab 
Supplied as a vialed liquid solution containing 500 mg (nominal) durvalumab. The solution contains 50 
mg/mL durvalumab, 26 mM histidine/histidine-HCI, 275 mM trehalose dihydrate, 0.02% (w/v) polysorbate 
80, at pH 6.0. 
Stability: 
The shelf life of durvalumab will be indicated on the vial label. Durvalumab must be used within the 
individually assigned expiry date on the label. 
Storage: 
durvalumab must be stored at 2°C to 8°C. 
It is recommended that durvalumab is stored in opaque containers during storage to prevent excessive 
exposure to light. 
Solution Preparation: 
The dose of investigational product for administration must be prepared using aseptic technique. Total in-
use storage time from needle puncture of durvalumab vial to the start of administration should not exceed 4 
hours at room temperature or 24 hours at 2 to 8°C (36 to 46°F). If in-use storage time exceeds these limits, 
a new dose must be prepared from new vials. durvalumab does not contain preservatives and any unused 
portion must be discarded. 
No incompatibilities have been observed between durvalumab and polyethylene, polypropylene, 
polyvinylchloride (PVC), or polyolefin copolymers. Saline bags must be latex free. 

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Doses will be administered using a 250 mL IV bag of normal saline (0.9% (weight/volume) sodium chloride 
injection) and delivered through an IV administration set with a 0.2-μm in-line filter via an infusion pump 
into a peripheral vein. 
Patient weight at baseline should be used for dosing calculations in patients ≤30 kg unless there is a ≥
10% change in weight.  Dosing day weight can be used for dosing calculations instead of baseline weight per 
institutional standard.   
For patients <30kg, calculate the dose volume of durvalumab and number of vials needed for the subject to 
achieve the accurate dose according to Appendix VI. 
Patient weight at baseline should be used for dosing calculations unless there is a > 10% change in weight. 
An additional volume of 0.9% (weight/volume) saline equal to the calculated volume of durvalumab to be 
added to the IV bag must be removed from the bag prior to addition of durvalumab. The calculated volume 
of durvalumab is then added to the IV bag, and the bag is mixed by gentle inversion to ensure homogeneity 
of the dose in the bag. Infusion solutions must be allowed to equilibrate to room temperature prior to 
commencement of administration. 
Route of Administration: 
Intravenous.  
Following preparation of durvalumab the entire contents of the IV bag should be administered as an IV 
infusion over approximately 60 minutes (±5 minutes), using a 0.2-μm in-line filter. The IV line will be flushed 
with a volume of normal saline equal to the priming volume of the infusion set used after the contents of 
the IV bag are fully administered, or complete the infusion according to institutional policy to ensure the 
full dose is administered and document if the line was not flushed.  
2.3 Justification of durvalumab Dose/s, Schedule and Duration of 
Administration 
The optimal duration of an immunotherapy used as neoadjuvant therapy to improve complete resection of 
the tumour is unknown.  
For this trial, to minimize the delay for surgery, durvalumab will be administered at a dose of 750 mg for 
3 planned doses, every 2 weeks for one month. Only early NSCLC will be included Stage IB (only T = 4 cm in 
greatest dimension, N0), Stage IIA (T2b,N0) and some of Stage IIB : (T1-2,N1) and (T3 : > 5 cm and < 7 cm in 
greatest dimension surrounded by lung or associated with separate tumor nodule(s) in the same lobe but 
without mediastinum or chest wall involvements, or superior sulcus tumors, N0)  on the basis of clinical 
evaluation (8th classification TNM, UICC 2015). 
 
 
 
 
 
 

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3 
OBJECTIVES 
3.1 Primary Objective 
To assess the impact of neo-adjuvant therapy with durvalumab given by intravenous infusion for one month 
on the complete resection (see section 10).  
3.2 Secondary Objectives 
- Tolerance, adverse effects and tolerability of durvalumab. 
- Delay between start of treatment and surgery. 
- Response Rate (RECIST 1.1). 
- Metabolic response rate on TEP-FDG on pre-treatment PET-CT and pre-operative PET-CT after 3 
durvalumab infusions, on both primary tumor and eventual nodes. 
- Post-operative adverse events (AE). 
- Pathological response (as assessed by microscopic histological examination, with at least one slide assessed 
by cm of tumor in the greatest diameter, i.e. 5 to 30 slides assessed). Major Pathological Response on 
surgical tissue (tumor + nodes) as centrally reviewed by a panel of IFCT Pathologists, on both tumor and 
resected nodes, and defined as semi-quantitative evaluation of less than 10% or remaining tumor cells, in 
surgical primary tumor and nodes samples. 
- Disease Free Survival (DFS) 
- Overall survival (OS) 
3.3 Exploratory objective 
- Evaluation of predictive/prognostic significance of PD-1/PD-L1 expression (using at least SP263 antibody) 
on both pre-operative and surgical samples, and both tumor and infiltrating immune cells 
- Evaluation of changes in plasma/serum cytokines and other biomarkers before and after treatment  
- Characterization of the immune reactivity of tumors  
- Analysis of the intestinal microbiome  
 
 

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4 
TRIAL DESIGN 
This is a multi-centre, prospective, single-arm phase II trial of the human monoclonal antibody directed 
against programmed cell death ligand-1 (PD-L1) durvalumab in neoadjuvant treatment in primary resectable 
stage IB (only T = 4 cm in greatest dimension, N0), stage IIA (T2b,N0) and some of stage IIB : (T1-2,N1) and 
(T3 : > 5 cm and < 7 cm in greatest dimension surrounded by lung or associated with separate tumor 
nodule(s) in the same lobe but without mediastinum or chest wall involvements, or superior sulcus tumors, 
N0) non-small cell lung cancer patients.  
 
Stage IB/IIA and 
some of stage IIB  
NSCLC 
ECOG PS 0 or 1 
age ≥ 18 years 
pre-therapeutic 
tissue required 
I 
N 
C 
L 
U 
S 
I 
O 
N 
 
 
 
 
 
 
 
Anti-PD-L1 
durvalumab 
750 mg IV* 
Day1, 15, 29 
 
Surgery 
between 2 days and 
2 weeks after last 
infusion 
 
Surgical snap-
frozen1 
tissue(tumor+nodes) 
required 
Follow up for disease 
status and survival  
4 weeks, 6 months and one 
year after surgery 
 
 
Planned Sample Size: 81 patients 
20 centres 
* 10 mg/kg for patient weighting less than 30 kg (see appendix VI). 
1. Optional  
 
 

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5 
STUDY POPULATION 
This trial will study patients with clinically Stage IB (only T = 4 cm in greatest dimension, N0), Stage IIA 
(T2b,N0) and some of Stage IIB : (T1-2,N1) and (T3 : > 5 cm and < 7 cm in greatest dimension surrounded by 
lung or associated with separate tumor nodule(s) in the same lobe but without mediastinum or chest wall 
involvements, or superior sulcus tumors, N0) non-small cell lung cancer (NSCLC). Staging will be according to 
the TNM staging system for lung cancer (8th edition). 
5.1 Eligibility Criteria 
There will be NO EXCEPTIONS to eligibility requirements at the time of inclusion. Questions about eligibility 
criteria should be addressed prior to inclusion. 
The eligibility criteria for this study have been carefully considered. Eligibility criteria are standards used to 
ensure that patients who enter this study are medically appropriate candidates for this therapy.  
Patients must fulfil all of the following criteria to be eligible for admission to the study: 
1 
Histologically confirmed diagnosis of primary non-small cell carcinoma of the lung.  
2 
Tissue block of diagnosis must be available for submission after inclusion (one HES slide and one paraffin 
embedded block). 
3 
Patients must be classified clinically as Stage IB (only T = 4 cm in greatest dimension, N0), Stage IIA 
(T2b,N0) and some of Stage IIB : (T1-2,N1) and (T3 : > 5 cm and < 7 cm in greatest dimension 
surrounded by lung or associated with separate tumor nodule(s) in the same lobe but without 
mediastinum or chest wall involvements, or superior sulcus tumors, N0) on the basis of clinical 
evaluation (8th classification TNM, UICC 2015). In case of invasion of the main bronchus (distance < 2 
cm from carina), a biopsy of the carina is required. A pre-surgical PET scan of the thorax and a MRI or 
CT scan of the brain as well as thorax abdomen pelvis CT scan must be done prior to surgery and before 
inclusion. If preoperative CT and/or PET are suspicious for mediastinal nodal involvement, invasive 
mediastinal staging with mediastinoscopy or EBUS-TBNA must be performed. Station 5 or 6 lymph 
nodes may be accessed by anterior mediastinotomy or VATS.  
4 
Pre-operative (neo-adjuvant) platinum based or other chemotherapy except the treatment of the 
protocol is not permissible. Pre-operative radiation therapy is not permissible 
5 
The patient must have an ECOG performance status of 0, 1.  
6 
Hematology (done within 14 days prior to inclusion and with values within the ranges specified below): 
If anemic, patients should be asymptomatic and should not be decompensated. Transfusions are 
permissible. 
Haemoglobin ≥ 9,0 g/dL 
Absolute neutrophil count 
> 1.5 x 109/L or > 1,500/l 
Platelets > 100 x 109/L or > 100,000/l 
7 
Biochemistry (done within 14 days prior to inclusion and with values within the ranges specified below): 
Total bilirubin* 
within normal institutional limits 
Alkaline phosphatase 
< 2.5 x institutional upper limit of normal 
AST(SGOT) and ALT(SGPT) 
< 2.5 x institutional upper limit of normal 
Creatinine Clearance 
> 40 ml/min  

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TSH 
within normal institutional limits 
* excluding Gilbert’s syndrome 
Creatinine clearance to be measured directly by 24 hour urine sampling or as calculated by 
Cockcroft Formula: 
Females: GFR = 1.04 x (140-age) x weight in kg 
 
 serum creatinine in μmol/L 
Males: GFR  
= 1.23 x (140-age) x weight in kg 
 
 serum creatinine in μmol/L 
8 
Other investigations detailed in Section 6 must have been performed within the timelines indicated. 
9 
Patient consent must be appropriately obtained in accordance with applicable local and regulatory 
requirements. Each patient must sign a consent form prior to inclusion in the trial to document their 
willingness to participate.  
10 Patients must be accessible for treatment and follow-up. Investigators must assure themselves the 
patients included on this trial will be available for complete documentation of the treatment, adverse 
events, and follow-up. 
11 Protocol treatment is to begin within 7 days of patient inclusion. 
12 Age of at least 18 years. 
13 Female subjects must either be of non-reproductive potential (ie, post-menopausal by history: ≥60 
years old and no menses for 1 year without an alternative medical cause; OR history of hysterectomy, 
OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative 
serum pregnancy test upon study entry.   
14 Females of childbearing potential who are sexually active with a non-sterilized male partner or men 
who are sexually active with women of childbearing potential must use a highly effective method of 
contraception prior the first dose of investigational product, and must agree to continue using such 
precautions for 4 months after the final dose of investigational product. Periodic abstinence, the 
rhythm method, and the withdrawal method are not acceptable methods of contraception.  
5.2 Ineligibility Criteria 
Patients who fulfil any of the following criteria are not eligible for admission to the study: 
1 
Patients with a history of other malignancies, except: adequately treated non-melanoma skin cancer, 
curatively treated in-situ cancer, or other solid tumours curatively treated with no evidence of disease 
for > 5 years following the end of treatment and which, in the opinion of the treating physician, do not 
have a substantial risk of recurrence of the prior malignancy. 
2 
A combination of small cell and non-small cell lung cancer or pulmonary carcinoid tumour. 
3 
History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune 
hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular 
thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, 
Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. NOTE: patients with 
Grave’s disease and/or psoriasis not requiring systemic therapy within the last two years from inclusion 
are not excluded.  

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4 
History of primary immunodeficiency, history of allogenic organ transplant, use of immunosuppressive 
agents within 28 days of inclusion* or a prior history of severe (grade 3 or 4) immune mediated toxicity 
from other immune therapy. 
* NOTE: Intranasal/inhaled corticosteroids or systemic steroids that do not to exceed 10 mg/day of 
prednisone or equivalent dose of an alternative corticosteroid are permissible. 
5 
Live attenuated vaccination administered within 30 days prior to inclusion. 
6 
History of hypersensitivity to durvalumab or any excipient. 
7 
Patients who have experienced untreated and/or uncontrolled cardiovascular conditions and/or have 
symptomatic cardiac dysfunction (unstable angina, congestive heart failure, myocardial infarction 
within the previous year or cardiac ventricular arrhythmias requiring medication, history of 2nd or 3rd 
degree atrioventricular conduction defects). Patients with a significant cardiac history, even if 
controlled, should have a LVEF > 50% within 12 weeks prior to inclusion. 
8 
Concurrent treatment with other investigational drugs or anti-cancer therapy. 
9 
Patients with active or uncontrolled infections or with serious illnesses or medical conditions which 
would not permit the patient to be managed according to the protocol. This includes but is not limited 
to: 
 
known prior history of tuberculosis; 
 
known acute hepatitis B or C by serological evaluation; 
 
known Human immunodeficiency virus infection. 
10 Current or prior use of immunosuppressive medication within 28 days before the first dose of 
durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at 
physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid 
11 Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab 
12 Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis) 
13 Known history of previous clinical diagnosis of tuberculosis 
14 Female subjects who are pregnant, breast-feeding or male or female patients of reproductive potential 
who are not employing an effective method of birth control 
15 Any condition that, in the opinion of the investigator, would interfere with evaluation of study 
treatment or interpretation of patient safety or study results 
 
 

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6 
INCLUSION 
Prior to the inclusion of any new patients in the IFCT-1601 IONESCO trial, the site should first submit by  
e-mail to ionesco@ifct.fr the reports of initial CT scan and PET scan as well as the report of the 
multidisciplinary meeting if possible. A review of the imaging will take place by the steering committee if 
there is any doubt about the eligibility of the patient. Validation of the inclusion of the new patient will be 
sent to the site as soon as possible. 
 
7 
PRE-TREATMENT EVALUATION 
Investigations 
Timing 
History and 
Physical Exam 
including: 
• history including cigarette smoking 
• physical examination including height, weight, 
pulse, blood pressure 
• performance status 
• Concomitant medication 
Within 14 days prior to inclusion 
Haematology 
• CBC including haemoglobin, differential 
leukocyte, platelet count 
Within 14 days prior to inclusion 
Biochemistry 
• 
AST (SGOT) and ALT (SGPT) 
• 
Alkaline phosphatase 
• 
Total bilirubin (if total bilirubin is ≥ 2xULN 
(and no evidence of Gilbert’s syndrome) 
then fractionate into direct and indirect 
bilirubin 
• 
Gamma glutamyltransferase  
• 
albumin 
• 
creatinine 
• 
Urea  
• 
CRP 
• 
TSH 1 
• 
INR/APTT 
• 
Lactate dehydrogenase  
• 
Uric acid 
• 
Lipase  
• 
Amylase (if lipase > 2,5N) 
• 
Magnesium 
• 
Potassium 
• 
Bicarbonate sodium 
• 
Calcium 
• 
Chloride 
 
• 
Total protein 
 
Within 14 days prior to inclusion 
• 
HIV antibody 
• 
Hepatitis A antibody,  
• 
Hepatitis B surface antigen 
• 
Hepatitis C antibody 
 
 
 

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Radiology 
• baseline CT chest and upper abdomen (must 
include adrenal glands) 2 
Within 28 days prior to inclusion 
• MRI or CT of brain  
• PET scan  
Within 28 days prior to inclusion 
• other baseline imaging (e.g. bone scan) 
Required, within 28 days of 
inclusion, only if suspicious 
signs/symptoms are present  
Other 
Investigations 
• ECG 
Within 2 months prior to inclusion 
if clinically indicated 
• urinalysis 
• lung function tests: FEV1, FVC, TLCO and SaO2 on 
room air  
• pregnancy test if applicable 
Within 2 months prior to inclusion 
• LVEF 3 
Within 12 weeks prior to inclusion 
• Serum, plasma for correlatives 
• Feces 
• Tumor block available 
Prior to Cycle 1, day 1 dosing 4 
1 If TSH is abnormal, both T3 and T4 should be measured (both are recommended but at least one of T3 or   
T4 is mandatory if TSH is abnormal). 
2 Must be contrast enhanced CT scan; low dose surveillance CT is not acceptable. To ensure comparability, 
the baseline scans and subsequent scans to assess response must be performed using identical techniques 
(i.e. scans performed immediately following bolus contrast administration using a standard volume of 
contrast, the identical contrast agent, and preferably the same scanner). CT appearance consistent with 
post-operative change is expected and does not preclude inclusion. 
3 MUGA or ECHO, only for patients with significant cardiac history. 
4 Serum, plasma and feces for correlatives must be taken after consent is obtained but prior to day 1 
dosing of cycle 1 – may be done after inclusion providing it is done prior to day 1 dosing or within 14 days 
prior to inclusion. 
 
 

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8 
TREATMENT PLAN 
The responsibility for treatment of patients rests with the individual investigator. Protocol treatment is to 
begin within 7 working days of inclusion. 
8.1 Drug Administration 
Agent(s) 
Route 
Duration 
Dose and Schedule** 
durvalumab  
 
IV 
60 
minutes* 
750 mg***on weeks 0, 2, 4  
 
* 
See Section 7.5.1 for duration in the case of an infusion reaction. 
**  
From inclusion. 
*** 
Two week interval between infusions must be maintained; if infusion cannot 
be administered, it should be omitted until the next planned infusion.  
 
Do not administer durvalumab unless treatment day tests meet the following 
criteria: 
      Haemoglobin ≥ 9 g/dL 
Absolute neutrophil count 
> 1.0 x 109/L  
Platelets 
> 100 x 109/L  
Liver function tests 
< grade 1 or as per Section 7.5.4 
All other related adverse events should be < grade 2. See Section 7.5.4 for 
additional details. 
8.2 Premedication  
Premedication is not expected to be required. See Section 7.5.1 with respect to premedication of patients 
that have had a prior < Grade 2 infusion-related reaction.  
8.3 Patient Monitoring  
8.3.1 
Monitoring of dose administration 
Subjects will be monitored before, during and after the infusion with assessment of vital signs at the times 
specified in the Schedule of Assessment. Subjects are monitored (pulse rate, blood pressure) every 30 
minutes during the infusion period (including times where infusion rate is slowed or temporarily stopped). 
In the event of a ≤Grade 2 infusion-related reaction, the infusion rate of study drug may be decreased by 
50% or interrupted until resolution of the event (up to 4 hours) and re-initiated at 50% of the initial rate 
until completion of the infusion.  For subjects with a ≤Grade 2 infusion-related reaction, subsequent 
infusions may be administered at 50% of the initial rate.  Acetaminophen and/or an antihistamine (e.g., 
diphenhydramine) or equivalent medications per institutional standard may be administered at the 
discretion of the investigator.  If the infusion-related reaction is Grade 3 or higher in severity, study drug 

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will be discontinued. The standard infusion time is one hour, however if there are interruptions during 
infusion, the total allowed time from infusion start to completion of infusion should not exceed 4 hours at 
room temperature, with maximum total time at room temperature not exceeding 4 hours (otherwise 
requires new infusion preparation).   
As with any antibody, allergic reactions to dose administration are possible.  Appropriate drugs and medical 
equipment to treat acute anaphylactic reactions must be immediately available, and study personnel must 
be trained to recognize and treat anaphylaxis.  The study site must have immediate access to emergency 
resuscitation teams and equipment in addition to the ability to admit subjects to an intensive care unit if 
necessary. 
Patients will be monitored during the infusion and for a 30 minute observation period after the infusion with 
assessment of vital signs as per local procedures.  
All patients should be closely monitored according to guidelines in Section 8 and be advised to contact the 
treating centre in the case of significant toxicities. 
8.4 Dose Adjustments  
The major toxic effects of durvalumab which are anticipated to limit dosing are hypersensitivity/ infusion 
related reactions and possible class related immune related AEs, based on the mechanism of action of 
durvalumab leading to T-cell activation and proliferation. Potential immune related AEs include 
enterocolitis, dermatitis, hepatitis, pneumonitis and endocrinopathies [Brahmer 2010; Hodi 2010]. Patients 
should be monitored for signs and symptoms of immune related AEs. In the absence of an alternate aetiology 
(e.g. infection or relapse) signs or symptoms of enterocolitis, dermatitis, hepatitis, and endocrinopathy 
should be considered to be immune-related. 
The guidelines which follow outline dose adjustments for several of these toxic effects. If a patient 
experiences several adverse events and there are conflicting recommendations, please use the 
recommended dose adjustment that requires the greatest dose hold or discontinuation (see Appendix II). 
Adverse events will be graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE) (see 
Appendix III). 
Dose reductions are not permitted, but dose adjustments (slowing/interruption of infusion rate, omission 
of a dose, or permanent discontinuation) will be made for hematologic and other adverse events. 
If the infusion cannot be administered, it should be omitted until the next planned infusion. 
8.5 Management of Toxicity 
The following general guidance should be followed for management of toxicities (see Appendix II): 
1. Treat each of the toxicities with maximum supportive care (including slowing / interrupting / 
omitting the agent suspected of causing the toxicity where required). 
2. If the symptoms promptly resolve with supportive care, consideration should be given to 
continuing the same dose of durvalumab along with appropriate continuing supportive care.  
In addition to the dose adjustments shown in Section 7.4, the following are recommended: 
 
Patient evaluation to identify any alternative aetiology. 

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 
In the absence of a clear alternative aetiology, all events of an inflammatory nature should be 
considered to be immune-related. 
 
Symptomatic and topical therapy should be considered for low-grade events. 
 
Systemic corticosteroids should be considered for a persistent low-grade event or for a severe 
event. 
 
More potent immunosuppressives should be considered for events not responding to systemic 
steroids. 
Investigators should exercise clinical judgment in managing actual patients alongside the guidelines 
presented in the protocol(s).  An event that exhibits rapid progression and/or the likelihood for high 
morbidity/mortality requires that clinical judgment be exercised above and beyond toxicity management 
guidelines to ensure that treatment is optimally tailored to any given patient’s specific case. For example, 
the general principles outlined in the toxicity management guidelines describe prompt initiation of 
corticosteroids for both Grade 2 events (that have persisted for 4-5 days) and Grade 3-4 events; clinical 
judgment applied to this baseline guidance for an event that exhibits rapid progression and/or the likelihood 
for high morbidity/mortality – such as myocarditis – would warrant prompt initiation of high-dose 
corticosteroids without delay even for grade 2 cases. Similarly, clinical judgment for patients with suspected 
myocarditis should lead investigators to obtain a cardiology consult and institute a thorough diagnostic 
work-up (that includes exclusion of other alternate causes such as infection), and the appropriate 
management that includes discontinuing drug (permanently if biopsy-proven immune-mediated myocarditis) 
and, as already noted, the prompt use of steroids or other immunosuppressives. 
8.6 Duration of Therapy 
Treatment with durvalumab will continue for 1 month taken from date of first infusion irrespective of 
treatment omissions.  
8.7 Patient Compliance  
Trained medical personnel will administer durvalumab. Treatment compliance will be monitored by drug 
accountability, as well as recording durvalumab administration in the patient’s medical record and case 
report form (CRF). 
8.8 Concomitant Therapy 
8.8.1 Permitted 
 
Concomitant medications or treatments (e.g. acetaminophen, diphenhydramine) deemed 
necessary to provide adequate prophylactic or supportive care except for those medications 
identified as “excluded” as listed in Section 7.8.2. 
 
Use of immunosuppressive medications for the management of acute immune related adverse 
events as outlined in Section 7.5 is acceptable. In addition, intranasal/inhaled corticosteroids or 
systemic steroids that do not to exceed 10 mg/day of prednisone or equivalent dose of an 
alternative corticosteroid are permissible. 

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8.8.2 Not Permitted 
 
The chronic use of immunosuppressive medications including, but not limited to systemic 
corticosteroids at doses beyond 10 mg/day of prednisone or equivalent, methotrexate, 
azathioprine, and tumour necrosis factor alpha blockers.  
 
Live attenuated vaccines within 30 days of dosing with study agent. Inactivated viruses such as 
those in the influenza vaccine are permitted. 
 
Prohibited and Rescue Medications 
Rescue/supportive medication/class of 
drug: 
Usage: 
Concomitant medications or treatments 
(eg, acetaminophen or diphenhydramine) 
deemed necessary by the Investigator to 
provide 
adequate 
prophylactic 
or 
supportive 
care, 
except 
for 
those 
medications identified as “prohibited” as 
listed above 
To be administered as prescribed by the 
Investigator 
Best 
supportive 
care 
(including 
antibiotics, nutritional support, growth 
factor support, correction of metabolic 
disorders, optimal symptom control, and 
pain management [including palliative 
radiotherapy, etc]) 
Should be used when necessary for all patients 
 
Concurrent administration with other anti-cancer therapy, radiation therapy or investigational 
treatment. 
Blood donation 
Subjects should not donate blood while participating in this study and for at least 90 days following the last 
infusion of durvalumab.  
 
 

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9 
EVALUATION DURING AND AFTER PROTOCOL TREATMENT 
All patients entered on study must be evaluated according to the schedule outlined in Appendix I. 
9.1 Evaluation during Protocol Treatment 
Investigations 
Timing 
Physical Exam 
including: 
• physical examination including blood 
pressure 
• performance status 
• Concomitant medication 
Prior to each infusion until off protocol 
therapy. 
Hematology1 
• CBC including haemoglobin, 
differential leukocyte, platelet count 
Prior to each infusion until off protocol 
therapy.  
Biochemistry1 
• 
AST (SGOT) and ALT (SGPT) 
• 
alkaline phosphatase 
• 
Total bilirubin (if total bilirubin 
is ≥ 2x ULN (and no evidence of 
Gilbert’s syndrome) then 
fractionate into direct and 
indirect bilirubin 
• 
Gamma glutamyltransferase  
• 
albumin 
• 
creatinine 
• 
Urea  
• 
CRP 
• 
Magnesium 
• 
Potassium 
• 
Bicarbonate sodium 
• 
Calcium 
• 
Chloride 
 
• 
Total protein 
 
Prior to each infusion until off protocol 
therapy. 
• TSH 2  
one month after the first infusion 
• INR/APTT 
As clinically indicated. 
Radiology4 
• CT scan chest and upper abdomen3 
 prior to surgery 
 
• PET scan 
 prior to surgery 
Other 
Investigations 
• ECG 
• urinalysis 
• pregnancy test if applicable 
As clinically indicated. 
• lung function tests: FEV1, FVC, TLCO4 
and SaO2 on room air  
Only if pulmonary symptoms/suspicion 
of pneumonitis (see Section 7.5). 
Correlatives  
• serum, plasma 
At the time of 3rd infusion 
Adverse Events 
Patients must be evaluated after each cycle for adverse events 
1 Bloodwork Timing: Pre-treatment blood draws may be done the day prior to treatment if necessary, and when 
treatment is to begin on a Monday, may be done on the previous Friday (maximum 72 hours prior to treatment).  
2 If TSH is abnormal, both T3 and T4 should be measured (both are recommended but at least one of T3 or T4 is 
mandatory if TSH is abnormal). 
3 Must be contrast enhanced CT scan; low dose surveillance CT is not acceptable. To ensure comparability, the 
baseline scans and subsequent scans to assess response must be performed using identical techniques (i.e. scans 
performed immediately following bolus contrast administration using a standard volume of contrast, the identical 
contrast agent, and preferably the same scanner). When relapse is first documented at any site, complete restaging 
is required to identify all sites of relapse. 
4 These exams should have been analysed before surgery by primary physician and surgeon to confirm the operability.  
 
 

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9.2 Evaluation after protocol treatment but prior to disease 
relapse/new invasive primary malignancy 
The following investigations are to be performed for the period after discontinuation of durvalumab 
and surgery.  
All patients must be seen at 4 weeks after surgery. Follow up visits then occur at 6 months and one 
year and then according to current guidelines. 
Investigations 
Timing 
Physical Exam 
including: 
• physical examination including 
blood pressure 
• performance status 
• Concomitant medication 
• Adverse events 
Every follow up visit 
Hematology 
• CBC including hemoglobin, 
differential, platelet count 
Only at 4 weeks after surgery. Thereafter as 
clinically indicated only or to follow durvalumab 
related AEs until resolution to grade 0-1. 
Biochemistry 
• 
AST (SGOT) and ALT 
(SGPT) 
• 
alkaline phosphatase 
• 
Total bilirubin (if total 
bilirubin is ≥ 2x ULN (and 
no evidence of Gilbert’s 
syndrome) then 
fractionate into direct and 
indirect bilirubin 
• 
Gamma 
glutamyltransferase  
• 
albumin 
• 
creatinine 
• 
Urea  
• 
CRP 
• 
Magnesium 
• 
Potassium 
• 
Bicarbonate sodium 
• 
Calcium 
• 
Chloride 
 
• 
Total protein 
Only at 4 weeks after surgery. Thereafter as 
clinically indicated only or to follow durvalumab 
related AEs until resolution to grade 0-1. 
• TSH1 
At 4 week after surgery and then as clinically 
indicated, or to follow durvalumab related AEs 
until resolution to grade 0-1.2 
• INR/APTT 
As clinically indicated. 
Radiology3 
• CT scan chest and upper 
abdomen 3 
• other imaging as clinically 
indicated if suspicion of relapse 
or new primary invasive 
malignancy 4 
6 monthly for one year and then according to 
current guidelines. 
Other 
Investigations 
• ECG 
 
4 weeks after surgery then as clinically indicated 
• urinalysis 
• pregnancy test if applicable 
As clinically indicated. 
• lung function tests: FEV1, FVC, 
TLCO and SaO2 on room air 
Only if pulmonary symptoms or suspicion of 
pneumonitis (see Section 7.5 for full 
recommendations). 

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1 If TSH is abnormal, both T3 and T4 should be measured (both are recommended but at least one of T3 
or T4 is mandatory if TSH is abnormal). 
2 TSH may be completed within 7 days prior to visit. 
3 Must be contrast enhanced CT scan, low dose surveillance CT is not acceptable. To ensure 
comparability, the baseline scans and subsequent scans to assess response must be performed using 
identical techniques (i.e. scans performed immediately following bolus contrast administration using a 
standard volume of contrast, the identical contrast agent, and preferably the same scanner). 
4 When relapse is first documented at any site, complete restaging is required to identify all sites of 
relapse. 
9.3 Evaluation after disease relapse or new invasive primary 
malignancy (during or after protocol treatment) 
Should a patient relapse or develop a new invasive primary malignancy (as defined in Section 10) during the 
trial, details should be entered in the EDC disease event form and patient follow-up will be altered. All 
study patients must have a visit 4 weeks, 6 months and one year after surgery.  
Treatments received by the patient after relapse and for new primary malignancies will be left to the 
discretion of the patient and his/her physician, but all treatments will be recorded in the EDC case report 
forms. All sites of NSCLC relapse or new primary malignancies will be recorded on the case report forms.  
Follow up visit according to the centre practice. 
Investigations 
Timing 
Physical Exam 
including: 
• subsequent anti-cancer therapy  
• physical examination including 
pulse, blood pressure 
• performance status 
Every follow up visit. 
Hematology 
• CBC including hemoglobin, 
differential, platelet count 
Only at 4 week post surgery.  
Thereafter as clinically indicated only or to 
follow durvalumab related AEs until 
resolution to grade 0-1. 
Biochemistry 
• AST (SGOT) and ALT (SGPT) 
• alkaline phosphatase 
• bilirubin 
• creatinine 
Only at 4 week post surgery.  
Thereafter as clinically indicated only or to 
follow durvalumab related AEs until 
resolution to grade 0-1. 
• TSH1 
At 4 week and then as clinically indicated, or 
to follow durvalumab related AEs until 
resolution to grade 0-1.2 
• INR/APTT 
As clinically indicated. 
Radiology 
• CT scan chest and upper abdomen 
other imaging as clinically 
indicated if suspicion of relapse 
or new primary invasive 
malignancy  
According to current guidelines. 
Other Investigations 
• ECG 
• urinalysis 
• pregnancy test if applicable 
As clinically indicated. 
• Lung function tests: FEV1, FVC, 
TLCO and SaO2 at room 
atmosphere  
Repeat if pulmonary symptoms/suspicion of 
pneumonitis. 
Adverse Events 
Patients must be evaluated for durvalumab related adverse events  
at each visit, including late events. 
1 If TSH is abnormal, both T3 and T4 should be measured (both are recommended but at least one of 
T3 or T4 is mandatory if TSH is abnormal). 
2 TSH may be completed within 7 days prior to scheduled visit. 

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10 SURGERY AND PATHOLOGICAL ASSESSMENT 
10.1 Surgery 
After durvalumab administration and prior to surgery, a second PET scan as well as a second thorax CT scan 
must be done to evaluate Response to durvalumab treatment. 
We plan only three infusions of PD-L1 antibody (one infusion every two weeks) with a schedule allowing 
surgery to be performed not later than 6 weeks after first infusion. Surgery will be performed between 2 
days and 2 weeks after the last infusion.  
Before surgery, all adverse events must recover to a grade ≤ 1.  
Surgery may consist of lobectomy, sleeve resection, bilobectomy or pneumonectomy as determined by the 
attending surgeon based on the intraoperative findings. Patients who have had only segmentectomies or 
wedge resections are not eligible for this study. Resection may be accomplished by open or VATS 
techniques. 
Lymph node mapping is defined by The International Association for the Study of Lung Cancer (IASLC) lymph 
node map. The nodal tissue must be labelled according to the recommendations of the American Thoracic 
Society. Surgeons are encouraged to dissect or sample all accessible nodal levels in accordance with the 
European Society of Thoracic Surgeons guidelines. Accordingly, a minimum of three lobe specific mediastinal 
nodal stations (N2), one of which must include station 7, and at least one N1 station - inclusive of the ones 
removed with the pulmonary specimen - must have been sampled at the end of the procedure.  
Description of surgical resection (complete or not) is mandatory (see section 10).  
10.2 Pathological assessment 
A standard approach to post neoadjuvant therapy pathologic assessment is required to use pathological 
complete response as a demonstration of treatment efficacy. This requires a multidisciplinary 
communication and information on the pre-treatment tumor size and location, pre-treatment cTNM and 
evaluation of the clinical response on tumor and mediastinal nodes, critical for the pathologist to perform 
adequate sampling of the presumed tumor bed and immediately adjacent tissue. Residual tumor is often 
softer and tumor size and extent is difficult to assess after neoadjuvant therapy. The pathologist must also 
be informed of the clinical trial and histological type of the pretreatment biopsy.   
This standard approach include a precise macroscopic description of the surgically resected NSCLC with  
macroscopic size in two dimensions of the largest cross section, location  of the tumor and distance to close 
margin i.e. pleural surface and bronchial sleeve resection. Extent of macroscopic necrosis for tumor and 
node must be reported with semi quantitative assessment. Diagram (or images of the sliced resection) is 
useful to annotate the tissue section. The number of blocks sampled in the tumor area must be reported. 
10.3 Surgical snap frozen tissue and paraffin embedded block 
Paraffin embedded blocks must be available. Frozen Tissue (one block for tumor and nodes, only collected if 
there is grossly obvious residual invasive cancer on macroscopic examination), fresh tumor (and if available 
metastatic lymph nodes) and normal tissue will be collected if available.  Local policy must permit the 
submission of tissue blocks. Tissue blocks from the surgically resected NSCLC must be submitted for: 
-pathological examination with at least one slide assessed by cm of tumor in the greatest diameter as well 
as each removed lymph node 

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-PD-L1 assessment on paraffin tissue 
-Other biomarkers 
- Study of the immune reactivity of tumors in response to immunotherapy 
11 CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS 
11.1 Definitions 
11.1.1 Complete resection 
All gross disease must have been removed at the end of surgery. All surgical margins of resection must be 
negative for tumour.  
Margins are classified by the pathologist as: 
R0 - no cancerous cells seen microscopically; this is the desired result 
R1 - cancerous cells can be seen microscopically 
R2 - even gross examination by the naked eye shows tumor tissue on the margin, indicating more remains on 
the patient. 
11.1.2 Pathological response 
Extent of sampling is determined by the pre-treatment size in addition to macroscopic pathologic 
evaluation: at least one slide assessed by cm of tumor in the greatest diameter, i.e. 5 to 30 slides assessed, 
all surgically removed lymph node should be entirely submitted for histological evaluation, sectioned in two 
parts.  
Pathological response will be assessed by microscopic histological examination on all the sections performed 
during the macroscopic sampling. The reporting of the 2D size of the largest distance between residual 
disease tumor cell nests in a cross section of the entire area of the tumor is required with relevant sections 
recorded on the pathology report. 
In absence of tumor cells, the presence of treatment effect may provide additional information to 
treatment response, in comparison with lymph node pre-treatment status obtained by CT scan and 
mediastinal evaluation. 
The cellularity is assessed across the largest cross section of residual microscopic disease as the average 
invasive cancer cellularity and compared and calibrated to online cellularity provided by a computer-
generated standard to improve reproducibility (AACR Symmans WF) and RCB score MDAnderson. 
Major Pathological Response on surgical tissue (tumor + nodes) will be defined as centrally reviewed by a 
panel of IFCT Pathologists, on both tumor and resected nodes, as semi-quantitative evaluation of less than 
10% or remaining tumor cells, in surgical primary tumor and nodes samples (ref).  
11.1.3 Evaluable for Toxicity 
All patients will be evaluable for toxicity from the time of their first treatment with durvalumab. 

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11.1.4 Disease-free Survival 
Disease-free survival shall be measured from the day of inclusion until any of the following events: day of 
documented equivocal or definite relapse (local, regional or distant), diagnosis of a new primary invasive 
cancer (except squamous cell carcinoma and basal cell carcinoma of skin and any in situ cancer, completely 
excised and presumed cured), or death from any cause.  
NOTE: Patients with Equivocal Changes should be re-imaged at the next planned time or earlier if clinically 
indicated. If relapse/new primary malignancy is confirmed the date of event is taken from the date that 
equivocal changes were first described. 
Relapse will be categorized as local/regional or distant. 
11.1.5 Local or Regional Relapse 
Local or regional relapse is defined as relapse in the area of the tumour bed, hilum or mediastinal lymph 
nodes. 
11.1.6 Distant Relapse 
Distant relapse is defined as spread of disease beyond the area of the tumour bed, hilum or mediastinal 
lymph nodes. 
11.1.7 Overall Survival 
Overall survival is defined as the time from inclusion to the time of death (from any cause) or to the date 
the patient was last known to be alive. 
11.2 Evidence of Disease Relapse 
When relapse is first documented at any site, complete restaging is required to identify all sites of relapse. 
11.2.1 Local or Regional Relapse 
1. Definite - positive cytology, aspiration, or biopsy 
2. Suspicious - radiological changes suggesting relapse 
11.2.2 Distant Relapse 
This is documented only when definite evidence is available but may be dated retrospectively to first 
onset of a suspicious sign as defined below. 
1.  Definite (one of 1a or 1b) 
a)  Biopsy or cytology proven disease. 
b)  New lesions present on clinical examination, ultrasound, CT, or MRI scan that are strongly 
suggestive of metastatic cancer, that cannot be attributed to other disease, and that 
cannot reasonably be confirmed by biopsy or cytology. PET imaging can be used to 
confirm findings from other imaging modalities. 
2. Suspicious 

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a) New lesions present on clinical examination, ultrasound, CT, or MRI scan that are 
suggestive of metastatic cancer, that are unlikely to be attributable to other disease, and 
that cannot reasonably be confirmed by biopsy or cytology. 
11.3 Dating of First Relapse 
This should always be based on the first onset of a sign but never on the onset of a symptom. The date of 
first detection of a palpable lesion is acceptable only when the diagnosis of tumour involvement is 
subsequently established. The diagnosis of recurrent disease by radiographs or scans should be dated from 
the date of the first positive record, even if this is determined in retrospect 
11.4 Management Following Relapse 
Patient management following local, regional or distant relapse is at the discretion of the investigator.  
11.5 New Primary Malignancy 
Should be pathologically confirmed and recorded in the case report forms. 
Patient management following new primary malignancy is at the discretion of the investigator, but all 
treatments need to be documented.  
 
 

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12 SERIOUS ADVERSE EVENT REPORTING 
12.1 Definition of Serious Adverse Event 
A serious adverse event is one that at any dose (including overdose): 
• Results in death. 
• Is life-threatening.1 
• Requires inpatient hospitalization or prolongation of existing hospitalization2. 
• Results in persistent or significant disability or incapacity.3 
• Is a congenital anomaly or birth defect. 
• Is an important medical event.4 
 
1 “Life-threatening” means that the subject was at immediate risk of death at the time of the serious 
adverse event; it does not refer to a serious adverse event that hypothetically might have caused death if it 
were more severe. 
2 The following hospitalizations are not considered SAEs: 
- 
Hospitalization < 24h 
- 
Planned hospitalization required by the protocol (e.g., for study drug administration or to perform an 
efficacy measurement for the study) 
- 
Hospitalization for a preexisting condition, provided that all of the following criteria are met: 
- 
The hospitalization was planned prior to the study or was scheduled during the study when elective 
surgery became necessary because of the expected normal progression of the disease. 
- 
The patient has not experienced an adverse event. 
- 
Routine health assessment requiring admission for baseline/trending of health status (eg, routine 
colonoscopy) 
- 
Admission encountered for another life circumstance that carries no bearing on health status and 
requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, caregiver respite, 
family circumstances, administrative reason). 
3 “Persistent or significant disability or incapacity” means that there is a substantial disruption of a person’s 
ability to carry out normal life functions. 
4 Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in situations where none of the outcomes listed above occurred. 
12.1.1 Definition of adverse events of special interest (AESI) 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to understanding 
of the Investigational Product and may require close monitoring and rapid communication by the 

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investigator to the sponsor. An AESI may be serious or non-serious. The rapid reporting of AESIs allows 
ongoing surveillance of these events in order to characterize and understand them in association with the 
use of this investigational product. 
AESIs for durvalumab include but are not limited to events with a potential inflammatory or immune-
mediated mechanism and which may require more frequent monitoring and/or interventions such as 
steroids, immunosuppressants and/or hormone replacement therapy. These AESIs are being closely 
monitored in clinical studies with durvalumab monotherapy and combination therapy. An immune-related 
adverse event (irAE) is defined as an adverse event that is associated with drug exposure and is consistent 
with an immune-mediated mechanism of action and where there is no clear alternate aetiology. Serologic, 
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an irAE diagnosis. 
Appropriate efforts should be made to rule out neoplastic, infectious, metabolic, toxin, or other etiologic 
causes of the irAE.  
If the Investigator has any questions in regards to an adverse event (AE) being an irAE, the Investigator 
should promptly contact IFCT. 
AESIs observed with durvalumab include: 
 
Colitis 
 
Pneumonitis 
 
ALT/AST increases / hepatitis / hepatotoxicity  
 
Neuropathy / neuromuscular toxicity (i.e. events of encephalitis, peripheral motor and sensory 
neuropathies, Guillain-Barré, and myasthenia gravis) 
 
Endocrinopathy (i.e. events of hypophysitis, adrenal insufficiency, and hyper- and hypothyroidism) 
 
Dermatitis 
 
Nephritis 
 
Pancreatitis  (or labs suggestive of pancreatitis - increased serum lipase, increased serum amylase)   
Further information on these risks (e.g. presenting symptoms) can be found in the current version of the 
durvalumab Investigator Brochure. 
Important medical events that may not be immediately life-threatening or result in death or hospitalization 
but may jeopardize the patient or may require intervention to prevent one of the other outcomes listed in 
the definition above should also usually be considered serious. Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug 
abuse. 
A diagnosis of cancer during the course of a treatment should be considered as medically important. The 
List of Critical Terms (1998 adaptation of World Health Organization Adverse Reaction Terminology Critical 
Terms List, provided in the “Instructions for completing the ‘Serious Adverse Event/Expedited Report from a 
Clinical Trial’ form”) should be used as guidance for adverse events that may be considered serious because 
they are medically important. 
Clarification of the difference in meaning between “severe” and “serious” 
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor medical 

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significance (such as severe headache). This is not the same as “serious”, which is based on the outcome or 
action criteria usually associated with events that pose a threat to life or functioning. Seriousness (not 
severity) serves as a guide for defining regulatory reporting obligations. 
SAEs/AEs will be reported up to one month after surgery, and SAEs notification will be made within 24 
hours. 
12.2  Period of Observation 
For the purposes of this study, the period of observation for collection of adverse events extends from the 
date of signature of the informed consent until 100 days after the last day of study treatment except for 
adverse events related to study drug, which must be reported during follow-up period until resolution or 
initiation of further anti-tumor therapy. 
If an Investigator detects a serious adverse event in a study subject after the end of the period of 
observation, and considers the event possibly related to prior study treatment, he or she should contact the 
Sponsor to determine how the adverse event should be documented and reported. 
At each visit/assessment AEs will be assessed from information collected from the source documents and 
information transcribed into the CRF. 
12.3  Documentation and Reporting of Adverse Events by Investigator 
All adverse events that occur during the observation period set in this protocol must be documented on the 
pages provided in the case report form in accordance with the instructions for the completion of adverse 
event reports in clinical studies. These instructions are provided in the case report form itself. 
The following approach will be taken for documentation: 
• All adverse events (whether serious or non-serious, or considered as an alert term) must be documented 
on the “Adverse Event” page of the case report form. 
• If the adverse event is serious, the investigator must complete, in addition to the 
“Adverse Event” page in the case report form, a “Serious Adverse Event/Expedited 
Report from a Clinical Trial” form at the time the serious adverse event is detected. 
This form must be faxed to the IFCT’s Pharmacovigilance department. 
Every attempt should be made to describe the adverse event in terms of a diagnosis. If a clear diagnosis has 
been made, individual signs and symptoms will not be recorded unless they represent atypical or extreme 
manifestations of the diagnosis, in which case they should be reported as separate events. If a clear 
diagnosis cannot be established, each sign and symptom must be recorded individually. 
All patients who have adverse events, whether considered associated with the use of the investigational 
products or not, must be monitored to determine the outcome. The clinical course of the adverse event will 
be followed up according to accepted standards of medical practice, even after the end of the period of 
observation, until a satisfactory explanation is found or the investigator considers it medically justifiable to 
terminate follow-up. All questions on the completion and supply of adverse event report forms and any 
further forms issued to the investigator at a later date to clarify unresolved issues should be addressed to 
the IFCT. 

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12.4  Immediate Reporting by Investigators to IFCT 
Serious adverse events and adverse events that fulfil a reason for expedited reporting to Pharmacovigilance 
must be documented on a “Serious Adverse Event/Expedited Report from a Clinical Trial” form in 
accordance with the “Instructions for completing the ‘Serious Adverse Event/Expedited Report from a 
Clinical Trial’ form”. This form must be completed and supplied to the Sponsor within 24 hours or at the 
latest on the following working day. The “Serious Adverse Event/Expedited Report from a Clinical Trial” 
form and the instructions are provided in the investigator’s study file. 
The initial report must be as complete as possible, including details of the current illness and (serious) 
adverse event, and an assessment of the causal relationship between the event and the investigational 
product(s). The report will be completed in the electronic case report form. In case of unavailability of the 
CRF, a paper report will be sent by e-mail to sae@ifct.fr. An acknowledgment of receipt will be sent to the 
site.  
Information not available at the time of the initial report (e.g., an end date for the adverse event or 
laboratory values received after the report) must be documented on a follow-up “Serious Adverse 
Event/Expedited Report from a Clinical Trial” form. 
The “Instructions for completing the ‘Serious Adverse Event/Expedited Report from a Clinical Trial’ form” 
give more detailed guidance on the reporting of serious adverse events, adverse events that comply with 
alert terms, and adverse events initially reported as non-serious that become serious. In the latter situation, 
when a non-serious event becomes serious, details must be forwarded immediately to the Sponsor on a 
“Serious Adverse Event/Expedited Report from a Clinical Trial” form. 
12.5 Reporting of pregnancy 
The investigator is required to report to the sponsor any pregnancy where the embryo/fetus could have 
been exposed to durvalumab. This means pregnancies occurring in female participants, female partners of 
male participants, or females exposed through direct contact with the agent during their pregnancy (for 
example, environmental exposure involving direct contact with the agent). Pregnancies occurring up to 90 
days after the completion of durvalumab must also be reported. 
12.6 Overdose 
An overdose is defined as a subject receiving a dose of durvalumab in excess of that specified in the 
Investigator’s Brochure, unless otherwise specified in this protocol. 
Any overdose of a study subject with durvalumab, with or without associated AEs/SAEs, is required to be 
reported within 24 hours of knowledge of the event to IFCT. Patient Safety or designee using the designated 
Safety e-mailbox (see Section 10.3.2 for contact information). If the overdose results in an AE, the AE must 
also be recorded as an AE (see Section 10.3). Overdose does not automatically make an AE serious, but if the 
consequences of the overdose are serious, for example death or hospitalization, the event is serious and 
must be recorded and reported as an SAE (see Section 10.1.2 and Section 10.3.2). There is currently no 
specific treatment in the event of an overdose of durvalumab.  
The investigator will use clinical judgment to treat any overdose.  
 
 

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13 PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING 
13.1 Criteria for Discontinuing Protocol Treatment 
Patients may stop protocol treatment in the following instances: 
 
Intercurrent illness which would, in the judgement of the investigator, affect assessments of 
clinical status to a significant degree, and require discontinuation of protocol therapy. 
 
Unacceptable toxicity as defined in Section 7.5 and Appendix II. 
 
Disease relapse or new primary invasive malignancy as defined in Section 10. 
 
Request by the patient. 
 
Pregnancy or intent to become pregnant 
 
Initiation of alternative anticancer therapy including another investigational agent. 
 
Completion of therapy as outlined in Section 7. Efforts should be made to maintain the 
investigations schedule and continue follow-up, even if patients discontinue protocol treatment 
prematurely and/or no longer attend the participating institution. 
13.2 Withdrawal of study 
The Reasons for withdrawal of study are:  
 
- Withdrawal of consent by the patient, 
 
- Relapse or 2nd cancer, 
 
- Death, 
Patients have the right to withdraw their consent and ask to leave the study at any time and for whatever 
reason (they are not required to explain). This should not affect their right to a subsequent management. 
The investigator must do everything to avoid withdrawal of consent. 
13.3 Duration of Protocol Treatment  
Treatment will continue for one month from the date of the first infusion.  
13.4 Therapy After Protocol Treatment  
Anti-cancer therapy after surgery is at the discretion of the investigator. Adjuvant platinum based 
chemotherapy and adjuvant radiation are allowed, according the current guidelines. 
Subsequent anti-cancer therapy will be collected on the CRFs. 
13.5 Follow-up Off Protocol Treatment 
All patients will be seen at 4 weeks, 6 months and one year after surgery. Thereafter, patients without 
evidence of disease relapse or new primary malignancy will be followed as per schedule outlined in Section 
8.2. Patients that have relapsed disease or new primary malignancy as per definitions in Section 10 will 
continue to be followed until death as outlined in Section 8.3. 

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14 CENTRAL REVIEW PROCEDURES AND TISSUE COLLECTION 
14.1 Central Radiology Review 
Central radiology review of equivocal cases by a review committee may be conducted. A retrospective 
radiology review of all cases may also be undertaken. 
14.2 Central Pathology Review 
This central pathological review includes the pre-treatment biopsy with sending of one representative HES 
section and paraffin bloc. All slides of tumor and nodes must also be sending. 
14.3 Tissue Collection 
Tissue collection for pre-treatment (one block, frozen tumor if available) and post treatment (fresh tumor 
and normal tissue, formalin fixed, paraffin embedded and frozen tumor and node tissue if available) is 
mandatory from existing tumour specimens be submitted to a central reference laboratory for analysis.  
The tissue may be used by researchers now or in the future to better understand the nature of non-small 
cell lung cancer and how patients respond to treatments. Samples will be used for research purposes only 
and will not be sold. A scientific review process of any proposals to use the tissue will take place and any 
proposals approved will have undergone ethics approval. Patients will not be identified by name. The only 
identification of tissue will be by a patient study number assigned at the time of registration to the trial the 
surgical/ histology number and/or patient initials. Material issued to researchers will be anonymized and 
only identified by a coded number. This process is applicable to all tissues collected as part of this study, 
irrespective of the location of the Tissue/Tumour Bank (see Section 13.3.5). 
Testing specifically for hereditary genetic defects predisposing to malignant disease will not be carried out 
without the expressed consent of the patient.  
All patients on whom a diagnostic tumour block is collected will be aware of this retrieval and will have 
given their consent. 
14.3.1 Serum and plasma  
Serum and plasma will be collected before first infusion and after 3rd infusion of durvalumab. 
Anti-tumour immune responses are key contributors to the anti-tumour effects of anti-PD-L1 therapies. 
Serological responses (cytokines, antibodies and metabolites) provide rich sources of correlative data that 
can be used to understand the biological consequences of this novel therapy and may provide important 
biomarkers that will facilitate future patient management. 
13.3.2 Feces 
Feces will be collected before first infusion of durvalumab. 
Currently, only few parameters have been identified as predictive biomarker of response, such as positive 
expression of PD-L1, and high mutational loads of tumors that appears to be associated with a higher 
response rate to anti-PD1 mAb. New lines of evidence demonstrated the biological significance of the gut 
microbiome (diverse range of symbiotic microorganisms) has an important contributor of pulmonary 
pathologies such as asthma and COPD (see APPENDIX V). 

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14.3.2 Tumour and Tissue Banks 
Blocks and all other samples will be carefully banked at the IFCT Repository. 
14.3.3 Translational study 
See Appendix V 
 
 

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15 STATISTICAL CONSIDERATIONS 
15.1 Objectives and Design 
This is a multi-centre, prospective unblinded, single-arm phase II trial of the human monoclonal antibody 
directed against programmed cell death ligand-1 (PD-L1) durvalumab in neoadjuvant treatment in primary 
resectable stage IB (only T = 4 cm in greatest dimension, N0), stage IIA (T2b,N0) and some of stage IIB : (T1-
2,N1) and (T3 : > 5 cm and < 7 cm in greatest dimension surrounded by lung or associated with separate 
tumor nodule(s) in the same lobe but without mediastinum or chest wall involvements, or superior sulcus 
tumors, N0) non-small cell lung cancer patients. 
The primary objective is surgical resection R0 after maximum 3 cycles of immune therapy.  
Secondary objectives will evaluate study treatment effect: 
- Response Rate (RECIST 1.1) and metabolic response rate on TEP-FDG 
- Tolerance and Post-operative adverse events (30 days after surgery) 
- Delay between surgery and start of treatment 
- Evaluation of predictive/prognostic significance of PD-1/PD-L1 expression  
- Disease Free Survival (DFS) 
- Overall survival (OS)  
- Evaluation of changes in plasma/serum cytokines and other biomarkers before and after treatment  
- Major Pathological Response on surgical tissue  
15.2 Sample Size, Power  
The maximum sample size (N) is calculated based on α, β, and the expected effect size, using a test for 
single binomial proportion for a two-stage design with a 1:1 randomization and O’Brien-Fleming (OF) 
stopping rules, allowing for early stopping for futility after Stage I. The software East 6.0 was used. 
The rate of complete resection equal to or lower than 85% (P0) is considered as unacceptable after immune 
treatment. On the other hand, we can conclude to a good rate of complete resection if it is 95% (P1). The 
computation is based on the following assumption, considering the probability of compliance: P0 =85%; P1 = 
95%; statistical power of 0.90; type I error rate (one-sided) of 0.05.  
The null hypothesis that the rate of complete resection is P0 = 85% will be tested against a one-sided 
alternative. In the first stage, 39 patients will be accrued.  If there are 34 or fewer responses in these 39 
patients, the study will be stopped for futility. Otherwise, 38 additional patients will be accrued for a total 
of 77. The null hypothesis will be rejected if 71 or more responses are observed in 77 patients. To take into 
account 5% of ineligible patients, 81 patients will be included. 
Duration of accrual: 18 months and 1 year follow-up. 
15.3 Analysis population 
- The population of tolerance is defined as all patients who received one dose of treatment 

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- The population the intent to treat (ITT) will include all patients included 
- The population of eligible patients will consist of ITT patients presenting no deviation judged major on the 
criteria for inclusion and non-inclusion 
The deviations to the protocol will be reviewed by the principal investigators and then classified into minor 
or major deviations, and listed. 
15.4 Study Endpoints and Analysis 
The primary endpoint will be performed on all eligible patients based on patient percentage surgical 
resection R0 after a maximum of 3 cycles of chemotherapy. It will be presented associated with confidence 
interval of 95%. 
DFS is a secondary endpoint, defined as the time from the date of inclusion to the date of first documented 
disease relapse or the occurrence of a new invasive primary malignancy or death from any cause. Patients 
who are alive and disease/new invasive primary malignancy-free at the time of each analysis will be 
censored at their last disease assessment date. 
OS is a secondary endpoint, defined as the time from the inclusion to the date of death of any cause, or 
censored at their last known alive date. All analysis on DFS will be carried out for the OS endpoint. 
The analysis of secondary endpoints will be performed on patient eligible. 
Although PD-L1 expression as measured by immunohistochemistry is hypothesized to be a potential 
predictive marker, this is as yet not validated in either the adjuvant or palliative settings. Further, the cut-
off defining PD-L1 positivity has not been validated. This trial will also explore the utility of PD-L1 as a 
predictive biomarker as well as the optimal cut-off for positivity. 
15.5 Safety Monitoring 
All patients who receive at least one dose of MEDI4376 will be included in the safety analysis. Descriptive 
summary tables will be presented on safety parameters  
Immune adverse events of special interest will be analysed including: pneumonitis, endocrinopathies, 
dermatologic (rash/pruritus) and hepatic (elevation of transaminases/bilirubin).  
The number of post-operative events and a tolerance report will be achieved on the first 15 patients to 
discuss the pursuit of the trial. 
A definitive discontinuation of the study in real time is planned in case of occurrence of a new death (any 
cause combined) occurring within 90 days of the intervention among the 12 consecutive first patients 
enrolled after the resuming of the trial (46th patient and the following).  
Tolerance data (90-day postoperative follow-up) for these 57 patients will be analyzed by the steering 
committee. 
 
 

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16 ADMINISTRATIVE SECTION 
16.1 Sponsor obligations 
16.1.1 Before the trial 
The sponsor will: 
 
Ensure regulatory requirements are met before the trial is implemented 
 
Ensure that all administrative procedures are in place for each department in the associated 
establishments 
 
Provide the complete protocol and its appendices, the adverse event report form, CPP (Independent ethics 
committee) permission, statement of insurance and authorisation from the French health authority 
(ANSM). 
The sponsor and their representatives will: 
 
Provide centres with the instructions and documents needed to conduct the trial properly (protocol, data 
collection form and investigator file) 
 
Organise an orientation session to train study investigators and coordinators (during this session, all 
protocol sections will be reviewed and how to fill out case report forms and study procedures will be 
explained) 
16.1.2 During the trial 
The sponsor and their representatives will: 
 
Regularly visit the investigating centres 
 
Be available at all times for consultation and remain in contact with the personnel of the 
investigating centre by email, telephone and/or fax 
 
Examine and evaluate the data in the case report form and look for possible errors in data collection 
In cooperation with the principal investigator, the sponsor will provide all of the investigators involved with 
the study with any new information that may interfere with conducting the trial. 
16.1.3 In terms of the trial 
It is the sponsor's responsibility to make sure that the procedures are completed at the end of the trial. 

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16.2 Investigator obligations 
The investigator agrees to conduct the study in compliance with the 1974 Declaration of Helsinki, revised in 
1975 and 1989, good clinical practice, and effectual French regulations. 
In regards to the French law of 9 August 2004, the investigator from each centre agrees to collect the 
informed written consent from each patient participating in the trial. One copy of the consent form will be 
given to the patient and the other will be kept in the patient's clinical file. Patients must be able to give 
their informed consent freely and not be under guardianship or suffer from any type of mental impairment 
that may affect their judgement.  
The investigator also agrees to fill out the case report form needed for study follow-up. 
The investigator also agrees to: 
 
Inform the sponsor of any serious or unexpected adverse event occurring during the trial within 
the time periods described in chapter 7.1 using the appropriate form. 
 
Agree to monitoring with access to source documents to validate data from the case report forms 
and if needed, agree to an internal or external audit by the sponsor or a representative from the 
regulatory authorities 
 
Archive trial documents (copies of case report forms, written consent forms) for a period of at 
least 15 years 
 
Include at least one patient during the first six months following the trial's implementation 
 
Make sure that there is no interference with another trial for the same indications 
 
Respect the confidentiality of the documents provided 
16.3  Ethical considerations 
16.3.1 Participant information and consent 
Before conducting this biomedical research on a person, they must provide their free, informed and 
express consent after being informed of the purpose of the research, the study procedures and duration, 
the benefits, and potential risks and constraints of the study, as well as the type of product being 
researched and the opinion of the CPP (art. L.1122-1). 
The patient and investigator or representing physician will personally date and sign the consent form 
(original copy archived by the investigator, a copy will be given to the patient or their legal representative). 

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16.3.2 Request for CNIL authorisation for automated data processing 
This biomedical research will produce scientific information. This coded, directly or indirectly personal 
information is part of the legal framework of file use (Law n° 78-17 from 6 January 1978 and law n° 94-548 
from 1 July 1994) 
The sponsor (IFCT) has authorisation (n°1227585) to process personal data for the purpose of Biomedical 
Research on medication and diseases under the law of 20 December 1988 modified by law n° 2004-806 of 9 
August 2004. 
To the extent that this biomedical research is conducted within the strict regulatory and legal requirements (the 
"Huriet-Sérusclat" law of 20 December 1988 modified by law n° 2004-806 of 9 August 2004) and according to 
standard methods, the CNIL has adopted a standard method (MR001 according to article 54 from the law of 
6 January 1978 modified), which now covers all personal data processing conducted as part of biomedical 
research - including pharmacogenetic trials - as defined in the public health code, and commitment to 
comply with said method. 
16.3.3 Amendment and additional clauses procedures 
The study's principal investigator or sponsor will suggest any substantial change in the protocol, and will 
then inform the other party. This will be an amendment submitted to the CPP and AFSSAPS. No change can 
be made without agreement from the committee. The sponsor will inform each investigator and send them 
the amendment and related statement of intent. 
16.4 Quality control and assurance 
Regulatory considerations: medical procedures for this trial comply with the most recent recommendations from 
the Declaration of Helsinki and public health law no. 2004-806 of 9 August 2004 related to the protection 
and safety of humans. 
Confidentiality: the protocol and its appendixes, as well as all of the data, are confidential as noted at the 
beginning of the protocol. 
Data monitoring: The IFCT's Clinical Research Unit will monitor this trial in order to ensure accurate, 
complete and reliable data collection. It will also provide logistical support to investigating centres. An 
inspection by an employee obligated to professional secrecy mandated by Regulatory Authorities may be 
required to ensure that all of the source documents needed are available and that the clinical trial is being 
conducted according to Good Clinical Practices and the law from 9 August 2004.  
16.4.1 Study schedule 
The protocol should begin at 2nd quarter of 2016. The trial recruitment period is expected to be 32 months, 
follow-up is one year. The trial should be ended by mid-June 2020.  

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16.4.2 Early study termination 
The sponsor and coordinating investigator will issue any early termination of the study. The sponsor will 
provide written notification. This letter will be sent to the Competent Authority (ANSM) and to each 
investigator, as well as the CPP. 
16.4.3 Statement of commitment 
New investigators 
Investigators can only participate in the trial after submitting a written request to the sponsor. It should 
include the following items: 
 
A statement of commitment indicating the expected number of patients that the investigator 
can include in the protocol per year 
 
A recent CV with French medical board registration number 
Site opening 
Before inclusions can begin, a site must be officially opened; in other words, the investigator's name, 
institution, telephone and fax number, and email address must be duly issued to the sponsor, CPP and 
Ministry (initial and additional authorisation statement). The investigator must have all of the documents needed 
to conduct the trial properly (protocol, investigator brochure, case report form). He must have obtained 
agreement from the facility's pharmacist to distribute treatments and resolve any problems with the study 
coordinator. He must have informed the director of his facility by letter of his participation. An agreement must 
be signed between the director of his facility and the sponsor. 
16.5 Study organisation 
The Steering Committee makes all of the decisions concerning the study's implementation, execution, 
analysis and reporting. It meets three times per year two times, and periodically sends information on the 
study's progress to investigators.  
It is comprised of members of the editorial board, study statisticians and a sponsor representative. 
The Coordination Centre will be the Clinical Research Unit (Unité de Recherche Clinique - URC) of the IFCT, 
located at 10 rue de la Grange-Batelière, 75009 PARIS. Its purpose is to ensure that the trial is being 
conducted as intended in the protocol: patient inclusion management, data collection, data management, 
SAE management, organisation of investigator and committee meetings. It informs the Steering Committee 
of any issues concerning the trial's progress. 
Moreover, the Steering Committee can organise regular investigator meetings during which the files of included 
patients will be reviewed. The purpose of this review panel will be to jointly verify compliance and 

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understanding of the eligibility criteria and treatment methods dictated by the protocol. In addition, it will 
conduct a progress analysis for retrospective validation.  
17 FINAL REPORT AND PUBLICATIONS 
Once the study is finished, a clinical trial report will be published by the study's principal investigators and 
statistician. The coordinating investigator will sign the final version of the clinical trial report for this study, 
and by doing so will indicate his approval of the report's analyses, results and conclusions.  
 
The key participants in a clinical study are the principal investigator, investigators, IFCT-employee team 
members, and members of the management and scientific boards who all collaborate to various degrees 
from designing the trial to writing the final report. 
1. The coordinator can choose between first and last place. In both cases, he must have participated 
significantly in designing the trial, inclusions and writing the article. 
2. If the investigator chooses the first place, last place goes to the president, one of the secretaries, or 
one of the other elected members of the Management Board or Scientific Council. The person must be 
chosen based on their participation in designing the trial, inclusions and writing the article. If there 
is difficulty in choosing this person, a secret vote by the management board will decide. 
3. If the investigator chooses the last place, the next-to-last place goes to the president, one of the 
secretaries, or another elected member of the Management Board or Scientific Council under the 
same conditions, unless he/she takes the first position if, in agreement with the principal 
investigator, he writes the article. If there is difficulty in choosing this person, a secret vote by the 
management board will decide. 
4. Investigators appear by the order in which eligible patients were included. All other investigators must 
appear in a list in the appendix. 
5. Two members of the same team cannot sign the same article unless one of them appears as a 
coordinating investigator, Management Board member, or Scientific Council member signing as such 
in first, second, or next-to-last place. 
6. Members of the IFCT employee team play a vital role in clinical studies. For this reason, those who 
were involved in designing the trial, managing it or writing the article must systematically appear in 
the acknowledgements or as signatories. The director will provide their names to the principal 
investigator (coordinator). If they appear as signatories, they cannot be included in the first six or 
last two positions. There can be no more than two if the number of signatories is more than 10 and 
only one if the number is equal to or less than 10. 

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7. If a university statistician has worked on developing or processing trial data, he can sign with the 
approval of the principal investigator (coordinator) in a place on which they both agree (generally 
3rd or 4th place). 
8. Under no circumstances can someone sign for having provided a patient with routine care that was 
unrelated to the research. 
9. All investigators (one per IFCT investigating centre) will be listed after each article in a table that 
may also include pathologists, surgeons and radiation therapists from the centre based on the 
article, so that this citation appears on Medline. 
10. For ancillary studies (biological, radiology, or others), if the article or abstract has a maximum of 10 
signatures, the principal investigator (coordinator) of the biological study can choose between first 
and last position. In both cases, he must have participated widely in the study's design, financing, 
inclusions and writing the article. The rules above apply to last position if he chooses last position. 
Next-to-last place can go to the research lab director who contributed most to the study. The last but 
two place can go to the study's principal investigator (coordinator) if it is not taken by the biological 
study's principal investigator. The first four places can be taken by scientists or physicians, with the 
IFCT or not, who contributed the most to the ancillary study. This may also include the university 
statistician if suggested by the coordinating investigator and management board office, and validated by 
the management board. If there are a maximum of 10 signatures, three to four places in the middle will 
be reserved for the best clinical contributors (in the sense that they contributed the most in terms of 
pathology specimens). In the case of articles with 20 signatures, two to three places will be reserved 
for pathologists who contributed the most to the study (either in collecting specimens or reviewing 
the IFCT's pathology panel). All of the labs that participated in the study shall be represented by one 
signatory, the remaining signatory places must be attributed to clinicians according to the rules 
above, including one permanent member of the IFCT team who contributed the most to the study 
(decision made by the CI + Director + President), as well as the CI for the clinical study. 
11. All articles should include the mention "..on behalf of IFCT" at the end of the signatories list, and 
include the acronym IFCT-XXYY in the title of the clinical trial to which the ancillary study is related. 
12. The IFCT can receive assistance with the English formatting of an article, but can never delegate the 
writing itself to an agency or industry. 
These rules were created and validated by the IFCT Management Board in September 2010. 

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18 REFERENCES 
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cancer (NSCLC): RADIANT results. J ClinOncol 2014;32:5s. 
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completely resected non-small-cell lung cancer: results of the NCIC CTG BR19 study. J ClinOncol Off J Am 
SocClinOncol 2013;31:3320–6. 
[10]Creelan BC. Update on immune checkpoint inhibitors in lung cancer. Cancer Control J Moffitt Cancer 
Cent 2014;21:80–9. 
[11] Fife BT, Bluestone JA. Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 
pathways.Immunol Rev 2008;224:166–82. 
[12] Holt GE, Podack ER, Raez LE. Immunotherapy as a strategy for the treatment of non-small-cell lung 
cancer. Therapy 2011;8:43–54. 
[13]Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and 
immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443–54. 
[14] Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the 
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[15] Fife BT, Pauken KE, Eagar TN, Obu T, Wu J, Tang Q, et al. Interactions between PD-1 and PD-L1 
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[16]Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 
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[17] Horn L, HerbstHerbst RS, Spige D. An analysis of the relationship of clinical activity to baseline EGFR 
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[18] Grosso J, Horak CE, Inzunza D, Cardona DM, Simon JS, Gupta AK, et al. Association of tumor PD-L1 
expression and immune biomarkers with clinical activity in patients (pts) with advanced solid tumors treated 
with nivolumab (anti-PD-1; BMS-936558; ONO-4538). J ClinOncol 2013;31. 
[19]Khleif S, Lutzky J, Segal N, Antonia S, Blake-Haskins A, Stewart R, et al. an anti-PD-L1 antibody with 
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[20]Brahmer JR, Tykodi SS, Chow LQM, Hwu W-J, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 
antibody in patients with advanced cancer. N Engl J Med 2012;366:2455–65. 
[21]Gyorki DE, Yuan J, Mu Z, Zaidi B, Pulitzer M, Busam K, et al. Immunological insights from patients 
undergoing surgery on ipilimumab for metastatic melanoma. Ann SurgOncol 2013;20:3106–11. 
[22]Carthon BC, Wolchok JD, Yuan J, Kamat A, Ng Tang DS, Sun J, et al. Preoperative CTLA-4 blockade: 
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Assoc Cancer Res 2010;16:2861–71. 
[23]Tarhini AA, Edington H, Butterfield LH, Lin Y, Shuai Y, Tawbi H, et al. Immune monitoring of the 
circulation and the tumor microenvironment in patients with regionally advanced melanoma receiving 
neoadjuvantipilimumab. PloS One 2014;9:e87705. 
[24] Hellmann MD, Chaft JE, William WN, Rusch V, Pisters KMW, Kalhor N, et al. Pathological response after 
neoadjuvant chemotherapy in resectable non-small-cell lung cancers: proposal for the use of major 
pathological response as a surrogate endpoint. Lancet Oncol 2014;15:e42–50. 
[25]Mouillet G, Monnet E, Milleron B, Puyraveau M, Quoix E, David P, et al. Pathologic Complete Response to 
Preoperative Chemotherapy Predicts Cure in Early-Stage Non-Small-Cell Lung Cancer: Combined Analysis of 
Two IFCT Randomized Trials. J ThoracOncol Off PublIntAssoc Study Lung Cancer 2012;7:841–9. 
[26]Pataer A, Kalhor N, Correa AM, Raso MG, Erasmus JJ, Kim ES, et al. Histopathologic response criteria 
predict survival of patients with resected lung cancer after neoadjuvant chemotherapy. J ThoracOncol Off 
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APPENDIX I - PATIENT EVALUATION FLOW SHEET 
 
 
 
 
APPENDIX II – TOXICITY MANAGEMENT 
Required investigations
Pre-study
Prior to each infusion
Prior to surgery
4 weeks after surgery
6 months and one year 
after surgery
History
X
X
X
X
Physical exam  
X
X
X
X
Smoking history
X
ECOG
X
X
X
X
Collection of adverse events
X
X
X
X
CBC, Differential leukocyte, platelet count
X
X
X
As clinically indicated
AST, ALT, alkaline Phosphatase, bilirubin, 
gamma glutamyltransferase, albumin, 
serum creatinine, urea, lactate 
dehydrogenase, uric acid, lipase, amylase 
(if lipase > 2,5N), magnesium, potassium, 
bicarbonate sodium, calcium, chloride, 
total protein, HIV antibody1, Hepatitis A 
antibody1, Hepatitis B surface antigen1, 
Hepatitis C antibody1
X
X
X
As clinically indicated
TSH2
X
X3
X
As clinically indicated
CRP
X
X
INR/APTT
X
CT chest and upper abdomen (must include 
adrenal glands)3
X
X
X
CT or MRI brain
X
PET scan thorax
X
X
Other imaging
ECG
X
X
As clinically indicated
Pregnancy test (if applicable)
X
Lung function  tests (FEV1, FVC, TLCO and 
SaO2 on room air)
X
Urinalysis
X
LVEF
X5
Bio-IFCT : serum, plasma
X
X6
As clinically indicated
1 Pre-study only
2 If TSH is abnormal, both T3 and T4 should be measured (both are recommended but at least one of T3 or T4 is mandatory if TSH is abnormal).
3 One month after the first infusion only
4 When relapse is first documented at any site, complete restaging is required to identify all site of relapse
5 MUGA or ECHO, only for patients with significant cardiac history.
6 3rd infusion only
As clinically indicated4
As clinically indicated
As clinically indicated
As clinically indicated
As clinically indicated
As clinically indicated

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Dose Modifications 
Toxicity Management 
Immune-
mediated 
Adverse Events 
(imAEs) 
(Overall 
Management 
For toxicities 
not noted 
below) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug administration modifications of study drug/study 
regimen will be made to manage potential immune-
related AEs based on severity of treatment-emergent 
toxicities graded per NCI CTCAE v4.03. 
In addition to the criteria for permanent discontinuation 
of study drug/regimen based on CTC grade/severity (table 
below) , permanently discontinue study drug/study 
regimen for  the following conditions:  
 
Inability to reduce corticosteroid to a dose of ≤10 
mg of prednisone per day (or equivalent) within 
12 weeks after last dose of study drug/regimen 
 
Recurrence of a previously experienced Grade 3 
treatment-related AE following resumption of 
dosing. 
It is recommended that management of immune-mediated 
adverse events (imAEs) follows the guidelines presented in 
this table 
− 
It is possible that events with an inflammatory or 
immune mediated mechanism could occur in nearly all 
organs, some of them not noted specifically in these 
guidelines. 
− 
Whether specific immune-mediated events (and/or 
laboratory indicators of such events) are noted in 
these guidelines or not, patients should be thoroughly 
evaluated to rule out any alternative etiology (e.g., 
disease progression, concomitant medications, and 
infections) to a possible immune-mediated event.  
− 
In the absence of a clear alternative etiology, all such 
events should be managed as if they were immune 
related. General recommendations follow. 
− 
. 
− 
Symptomatic and topical therapy should be considered 
for low-grade (Grade 1 or 2, unless otherwise 
specified) events  
− 
For persistent  (greater than 3 to 5 days) low-grade 
(Grade 2)  or severe (Grade ≥3) events  promptly start 
prednisone PO 1-2mg/kg/day or IV equivalent  
− 
Some events with high likelihood for morbidity and/or 
mortality – e.g., myo-carditis, or other similar events 
even if they are not currently noted in the guidelines – 
should progress rapidly to high dose IV corticosteroids 
(methylprednisolone at 2 to 4 mg/kg/day) even if the 
event is Grade 2, and if clinical suspicion is high 
and/or there has been clinical confirmation. Consider, 
as necessary, discussing with the study physician, and 
promptly pursue specialist consultation. 
− 
If symptoms recur or worsen during corticosteroid 
tapering 28 days of taper), increase the corticosteroid 
dose (prednisone dose  [e.g. up to 2-4mg/kg/day or IV 
equivalent])   until stabilization or improvement of 
symptoms, then resume corticosteroid tapering at a 
slower rate (> 28 days of taper) 
 
− 
More 
potent 
immunosuppressives 
such 
as 
TNF 
inhibitors (e.g. infliximab) – (also refer to the 
individual sections of the imAEs for specific type of 
immunosuppressive) should be considered for events 
not responding to systemic steroids. Progression to use 
of more potent immunosuppressives should proceed 
more rapidly in events with high likelihood for 
morbidity and/or mortality – e.g., myocarditis, or 
other similar events even if they are not currently 
noted in the guidelines – when these events are not 
responding to systemic steroids. 
− 
With long-term steroid and other immunosuppressive 
use, 
consider 
need 
for 
Pneumocystis 
jirovecii 
pneumonia (PJP, formerly known as Pneumocystis 
carinii 
pneumonia) 
prophylaxis, 
gastrointestinal 
protection, and glucose monitoring. 
Discontinuation of study drug/study regimen is 
not mandated for Grade 3/Grade 4 inflammatory 
reactions attributed to local tumor response (e.g., 
Grade 1 
No dose modification 
Grade 2 
Hold study drug/study regimen dose until 
grade 2 resolution to ≤ Grade 1 
• If toxicity worsens then treat as Grade 3 
or Grade 4 
• If toxicity improves to baseline then treat 
at next scheduled treatment date 
Study drug/study treatment can be resumed 
at the next scheduled dose once event 
stabilizes to grade ≤1 and 5-7 days have 
passed after completion of steroid taper 
Patients with endocrinopathies who may 
require prolonged or continued steroid 
replacement can be retreated with study 
drug/study regimen on the following 
conditions: 1) the event stabilizes and is 
controlled , 2) the patient is clinically 
stable as per Investigator or treating 
physician’s clinical judgement, and 3) 
doses of prednisone are at less than or 
equal to 10mg/day or equivalent. 
Grade 3 
Depending on the individual toxicity, may 
permanently discontinue study drug/study 
regimen. Please refer to guidelines below 
Grade 4 
Permanently discontinue study drug/study 
regimen  
Note: For Grade ≥3 asymptomatic amylase or lipase 
levels, hold study drug/study regimen, and if complete 
work up shows no evidence of pancreatitis, study 
drug/study regimen may be continued or resumed. 
Note: Study drug/study regimen should be permanently 
discontinued in Grade 3 events with high likelihood for 
morbidity and/or mortality – e.g., myocarditis, or other 
similar events even if they are not currently noted in the 
guidelines. Similarly, consider whether study drug/study 
regimen should be permanently discontinued in Grade 2 

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events with high likelihood for morbidity and/or mortality 
– e.g., myocarditis, or other similar events even if they 
are not currently noted in the guidelines – when they do 
not rapidly improve to Grade <1 upon treatment with 
systemic steroids and following full taper 
Note: There are some exceptions to permanent 
discontinuation of study drug for Grade 4 events (i.e., 
hyperthyroidism, hypothyroidism, Type 1 diabetes 
mellitus). 
inflammatory reaction at sites of metastatic 
disease and lymph nodes). Continuation of study 
drug/study regimen in this situation should be 
based upon a benefit-risk analysis for that 
patient. 
 
 
 
 
 
 
Grade of the 
Event (NCI CTCAE 
version 4.03) 
Dose Modifications 
Toxicity Management 
 
Pneumonitis/ 
Interstitial Lung 
Disease (ILD) 
Grade of 
Pneumonitis 
(CTCAE version 
4.03)  
Any Grade 
- Monitor patients for signs and symptoms of 
pneumonitis or ILD (new onset or worsening 
shortness of breath or cough).  Patients 
should be evaluated with imaging and 
pulmonary function tests including other 
diagnostic procedures as described below 
- Initial work-up may include clinical 
evaluation, monitoring of oxygenation via 
pulse oximetry (resting and exertion), 
laboratory work-up and high-resolution CT 
scan.  
Grade 1  
(Asymptomatic, 
clinical or 
diagnostic 
observations only, 
intervention not 
indicated) 
No dose modification required. 
However, consider holding study 
drug/study regimen dosing as 
clinically appropriate and during 
diagnostic work-up for other 
etiologies 
For Grade 1 (Radiographic Changes Only) 
-     Monitor and closely follow up in 2-4 days for 
clinical symptoms, pulse oximetry (resting 
and exertion) and laboratory work-up and 
then as clinically indicated 
-    Consider Pulmonary and  Infectious disease 
consult 
Grade 2  
(Symptomatic, 
medical 
intervention 
indicated, limiting 
instrumental ADL)  
 Hold study drug/study regimen dose 
until grade 2 resolution to ≤ Grade 1 
• If  toxicity worsens then treat as 
Grade 3 or Grade 4  
• If toxicity improves to baseline 
then the decision to reinitiate 
study drug/regimen at next 
scheduled treatment date will be 
based upon treating physician’s 
clinical judgment.  
Study drug/study treatment can be 
resumed at the next scheduled 
dose once event stabilizes to 
grade ≤1 and 5-7 days have 
passed after completion of 
steroid taper   
  
For Grade 2 (Mild to Moderate New Symptoms) 
- Monitor symptoms daily and consider 
hospitalization 
- Promptly start systemic steroids (e.g., 
prednisone 1-2mg/kg/day or IV equivalent) 
- Reimaging as clinically indicated 
- If no improvement within 3-5 days, additional 
workup should be considered and prompt 
treatment with IV methylprednisolone 2-
4mg/kg/day started  
- 
If still no improvement within 3-5 days 
despite IV methylprednisolone at 2-
4/g/kg/day, promptly start 
immunosuppressive therapy such as TNF 
inhibitors (e.g. infliximab at 5mg/kg every 2 
weeks). Caution: Important to rule out 
sepsis and refer to infliximab label for 
general guidance before using infliximab  
- Once improving, gradually taper steroids over 
≥4 weeks  and consider prophylactic 
antibiotics, antifungal or anti-PJP treatment 
(refer to current  NCCN guidelines for 
treatment of  cancer-related infections 

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[Category 2B recommendation])123 
- Consider pulmonary and infectious disease 
consult 
- Consider as necessary  discussing with study 
physician 
Grade 3 or 4  
(Grade 3: Severe 
symptoms; 
limiting self-care 
ADL; oxygen 
indicated;  
 
Grade 4: life 
threatening 
respiratory 
compromise, 
urgent 
intervention 
indicated [e.g. 
tracheostomy or 
intubation])  
Permanently discontinue study 
drug/study regimen 
 
For Grade 3 or 4 (severe or new symptoms, 
new/worsening hypoxia, life threatening):  
- Promptly initiate empiric IV 
methylprednisolone 1 to 4 mg/kg/day or 
equivalent  
- Obtain Pulmonary and Infectious disease  
consult; consider, as necessary, discussing 
with study physician 
- Hospitalize the patient 
- Supportive Care (oxygen, etc.) 
- If no improvement within 3-5 days, additional 
workup should be considered and prompt 
treatment with additional 
immunosuppressive therapy such as TNF 
inhibitors (e.g. infliximab at 5mg/kg every 2 
weeks dose) started. Caution: rule out sepsis 
and refer to infliximab label for general 
guidance before using infliximab  
- Once improving, gradually taper steroids over 
≥28 days  and consider prophylactic 
antibiotics, antifungals and in particular,  
anti-PJPtreatment (please refer to current  
NCCN guidelines for treatment of  cancer-
related infections [Category 2B 
recommendation])1 
Diarrhea/ Colitis 
Grade of Diarrhea 
(CTCAE version 
4.03) 
Any Grade 
- Monitor for symptoms that may be related to 
diarrhea/enterocolitis (abdominal pain, 
cramping, or changes in bowel habits such as 
increased frequency over baseline or blood in 
stool) or related to bowel perforation (such 
as sepsis, peritoneal signs and ileus) 
- Patients should be thoroughly evaluated to 
rule out any alternative etiology (e.g., 
disease progression, other medications, 
infections including testing for clostridium 
difficile toxin,  etc.) 
- Steroids should be considered  in the absence 
of clear alternative etiology, even for low 
grade events, in order to prevent potential 
progression to higher grade event 
- Use analgesics carefully; they can mask 
symptoms of perforation and peritonitis 
Grade 1 
(Diarrhea: stool 
frequency of <4 
over baseline per 
day) 
(Colitis: 
asymptomatic; 
clinical or 
diagnostic 
observations only)  
No dose modification 
For Grade 1 :  
-    Close monitoring for worsening symptoms 
-     Consider symptomatic treatment including 
hydration, electrolyte replacement, dietary 
changes (e.g., American Dietetic Association 
colitis diet), and loperamide. Use of 
probiotics as per treating physician’s clinical 
judgment. 
Grade 2 
(Diarrhea: stool 
frequency of 4-6 
Hold study drug/study regimen until 
resolution to ≤ Grade 1 
• 
If  toxicity worsens then treat as 
For Grade 2 diarrhea:  
- Consider symptomatic treatment including 
hydration, electrolyte replacement, dietary 

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over baseline per 
day)  
(Colitis: 
abdominal pain; 
mucus or blood in 
stool) 
Grade 3 or Grade 4 
• 
If toxicity improves to baseline 
then treat at next scheduled 
treatment date 
Study drug/study regimen can be 
resumed at the next scheduled 
dose once event stabilizes to 
grade ≤1 and 5-7 days have 
passed after completion of 
steroid taper    
changes (e.g., American Dietetic Association 
colitis diet), and loperamide and/or 
budesonide  
- Promptly start  prednisone 1 to 2  mg/kg/day 
or IV equivalent  
- If event is not responsive within 3-5 days or 
worsens despite prednisone at 1-2 mg/kg/day 
or IV equivalent, GI consult should be 
obtained for consideration of further workup 
such as imaging and/or colonoscopy to 
confirm colitis and rule out perforation,   and 
prompt treatment with IV 
methylprednisolone 2-4mg/kg/day started.  
- If still no improvement within 3-5 days 
despite 2-4mg/kg IV methylprednisolone, 
promptly start  immunosuppressives such as  
(infliximab at 5mg/kg once every 2 weeks)3. 
Caution: Important to rule out bowel 
perforation and refer to infliximab label for 
general guidance before using infliximab   
- Consider, as necessary, discussing with study 
physician if no resolution to ≤ Grade 1 in 3-4 
days 
- Once improving, gradually taper steroids over 
≥28 days  and consider prophylactic 
antibiotics, antifungals and anti-
PJPtreatment (please refer to current  NCCN 
guidelines for treatment of  cancer-related 
infections [Category 2B recommendation]) 
Grade 3 or 4(Grade 
3 diarrhea: stool 
frequency of ≥7 over 
baseline per 
day;Grade 4 
diarrhea: life 
threatening 
consequences) 
(Grade 3 colitis: 
severe abdominal 
pain, change in 
bowel habits, 
medi-cal 
intervention indi-
cated, peritoneal 
signs; 
Grade 4 colitis: 
life-threatening 
consequences, 
urgent 
intervention 
indicated) 
Grade 3 
Permanently discontinue study 
drug/study regimen for Grade 3 if 
toxicity does not improve to Grade 
≤1 within 14 days; study drug/study 
regimen can be resumed after 
completion of steroid taper. 
 
Grade 4 
Permanently discontinue  
study drug/study regimen. 
For Grade 3 or 4: 
- Promptly initiate empiric IV 
methylprednisolone 2 to 4 mg/kg/day or 
equivalent  
- Monitor stool frequency and volume and 
maintain hydration   
- Urgent GI consult and imaging and/or 
colonoscopy as appropriate 
- If still no improvement within 3-5 days of IV 
methylprednisolone  2 to 4mg/kg/day or 
equivalent, promptly start further 
immunosuppressives (e.g. infliximab at 
5mg/kg once every 2 weeks).   
- Caution: Ensure GI consult to rule out bowel 
perforation and refer to infliximab label for 
general guidance before using infliximab.  
- Once improving, gradually taper steroids over 
≥28 days and consider prophylactic 
antibiotics, antifungals and anti-PJPPCP 
treatment (please refer to current  NCCN 
guidelines for treatment of  cancer-related 
infections [Category 2B recommendation]) 
Hepatitis 
(Elevated LFTs) 
Infliximab should 
not be used for 
management of 
Immune Related 
Hepatitis 
Grade of Liver 
Function Test 
Elevation (CTCAE 
version 4.03) 
Any Grade 
Any Grade  
- Monitor and evaluate liver function test: AST, 
ALT, ALP and total bilirubin  
- 
Evaluate for alternative etiologies (e.g., 
viral hepatitis, disease progression, 
concomitant medications)  
Grade 1  
(AST or ALT >ULN 
and ≤3.0×ULN 
and/or TB > ULN 
No dose modification 
If  it worsens, treat as Grade 2 event 
For Grade 1 AST or ALT and/or TB elevation       
  -     Continue LFT monitoring per protocol   

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PLEASE SEE 
shaded area 
immediately 
below this 
section to find 
guidance for 
management of 
“Hepatitis 
(elevated LFTS)” 
in HCC patients 
 
and  ≤1.5×ULN)  
Grade 2  
(AST or ALT > 3 to 
5 times ULN 
and/or TB >1.5-
3.0 times ULN) 
• Hold Study drug/study regimen 
dose until grade 2 resolution to 
≤ Grade 1 
• If  toxicity worsens then treat as 
Grade 3 or Grade 4 
•If toxicity improves to Grade ≤1 or 
baseline, resume study 
drug/study regimen after 
completion of steroid taper. 
For Grade 2 AST or ALT and or TB elevation :  
- Regular and frequent checking of LFTs (e.g. 
every 1-2 days) until elevations of these are 
improving or resolved.   
- If no resolution to ≤ Grade 1 in 1-2 days, 
consider, as necessary, discussing with study 
physician. 
- If event is persistent (> 3-5 days) or worsens, 
promptly start prednisone 1-2mg/kg/day or 
IV equivalent.  
- If still no improvement within 3-5 days 
despite 1-2mg/kg/day of prednisone or IV 
equivalent, consider additional work up and 
prompt treatment with IV 
methylprednisolone 2-4mg/kg/day started. 
- If still no improvement within 3-5 days 
despite 2-4mg/kg/day of IV 
methylprednisolone, promptly start 
immunosuppressives (i.e. mycophenolate 
mofetil)1. Discuss with study physician if 
mycophenolate mofetil is not available.  
Infliximab should NOT be used. 
- Once improving, gradually taper steroids over 
≥28 days  and consider prophylactic 
antibiotics, antifungals and anti-PJP 
treatment (please refer to current  NCCN 
guidelines for treatment of  cancer-related 
infections [Category 2B recommendation]) 
(Grade 3: AST or  
ALT >5.0×ULN and 
≤20.0×ULN and/or  
TB >3.0×ULN and  
≤10.0×ULN) 
For elevations in transaminases ≤ 8 × 
ULN, or elevations in bilirubin ≤ 5 
× ULN: 
-Hold study drug/study regimen dose 
until resolution to ≤ Grade 1 or 
baseline   
-Resume study drug/study regimen if 
elevations downgrade to Grade ≤1 
or baseline within 14 days and 
after completion of steroid taper. 
-Permanently discontinue study   
drug/study regimen if the elevations 
do not downgrade to ≤ Grade 1 or 
baseline within 14 days  
For elevations in transaminases > 8 × 
ULN or elevations in bilirubin > 5 × 
ULN, discontinue study drug/study 
regimen 
Permanently discontinue study 
drug/study regimen for any case 
meeting Hy’s law criteria (AST 
and/or ALT > 3x ULN + bilirubin > 
2x ULN without initial findings of 
For Grade 3 or 4 AST or ALT and/or TB elevation: 
- Promptly initiate empiric IV 
methylprednisolone at 1 to 4 mg/kg/day or 
equivalent  
- If still no improvement within 3-5 days 
despite 1 to 4 mg/kg/day methylprednisolone 
IV or equivalent , promptly start treatment 
with immunosuppressive therapy 
(mycophenolate mofetil)  Discuss with study 
physician if mycophenolate is not available. 
Infliximab should NOT be used. 
- Perform hepatology consult, abdominal 
workup, and imaging as appropriate. 
- Once improving, gradually taper steroids over 
≥28 days  and consider prophylactic 
antibiotics, antifungals and anti-PJP 

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cholestasis (i.e. elevated alkaline 
P04) and  in the absence of any 
alternative cause4 
treatment (please refer to current  NCCN 
guidelines for treatment of  cancer-related 
infections [Category 2B recommendation]) 
Grade 4  
(AST or  
ALT >20×ULN 
and/or  
TB >10×ULN) 
Permanently discontinue study 
drug/study regimen  
Hepatitis 
(elevated LFTs) 
Infliximab 
should 
not be used for 
management 
of 
immune-related 
hepatitis.  
 
See instructions at  
bottom of shaded 
area  
if transaminase rise 
is  
not isolated but (at 
any time) occurs in 
setting  
of either increasing 
bilirubin or signs of 
DILI/liver 
decompensation 
  
 
 
Any Grade 
 
General Guidance 
For Any Grade: 
− Monitor and evaluate liver function test: AST, 
ALT, ALP, and TB. 
− Evaluate for alternative etiologies (e.g., viral 
hepatitis, 
disease 
progression, 
concomitant 
medications, worsening of liver cirrhosis [e.g., 
portal vein thrombosis]). 
− For HBV+ patients: evaluate quantitative HBV 
viral load, quantitative HBsAg, or HBeAg 
− For HCV+ patients: evaluate quantitative HCV 
viral load 
− Consider consulting hepatologist/Infectious 
disease 
specialist 
regarding 
change/implementation 
in/of 
antiviral 
medications for any patient with an elevated 
HBV viral load >2000 IU/ml 
− Consider consulting hepatologist/Infectious 
disease 
specialist 
regarding 
change/implementation 
in/of 
antiviral 
HCV 
medications if HCV viral load increased by ≥2-
fold 
− For HCV+ with HBcAB+: Evaluate for both 
HBV and HCV as above 
 
 
Grade 1 
(Isolated AST or 
ALT >ULN and 
≤5.0×ULN, 
whether normal or 
elevated at 
baseline) 
• No dose modifications. 
• If ALT/AST elevations represents 
significant worsening based on 
investigator assessment, then treat 
as Grade 2 event. 
 
For all grades, see instructions at 
bottom of shaded area if 
transaminase rise is not isolated but 
(at any time) occurs in setting of 
either increasing bilirubin or signs of 
DILI/liver decompensation 
 
Grade 2 
(Isolated AST or 
ALT >5.0×ULN and 
≤8.0×ULN, if 
normal at 
baseline) 
 
• Hold study drug/study regimen 
dose until Grade 2 resolution to 
Grade ≤1 or baseline. 
• If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
For Grade 2: 
− Regular and frequent checking of LFTs (e.g., 
every 1 to 3 days) until elevations of these are 
improving or resolved. 
− Recommend consult hepatologist; consider 
abdominal 
ultrasound, 
including 
Doppler 
THIS shaded area 
is guidance only 
for management 
of 
“Hepatitis 
(elevated LFTs)” 
in HCC patients  

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(Isolated AST or 
ALT >2.0×baseline 
and ≤12.5×ULN, if 
elevated >ULN at 
baseline) 
If toxicity improves to Grade ≤1 or 
baseline, resume study drug/study 
regimen after completion of steroid 
taper. 
assessment of liver perfusion. 
− Consider, as necessary, discussing with study 
physician. 
− If event is persistent (>3 to 5 days) or 
worsens, and investigator suspects toxicity to be 
immune-mediated AE, recommend to start 
prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
− If still no improvement within 3 to 5 days 
despite 1 to 2 mg/kg/day of prednisone PO or IV 
equivalent, consider additional workup and 
treatment with IV methylprednisolone 2 to 4 
mg/kg/day. 
− If still no improvement within 3 to 5 days 
despite 
2 
to 
4 
mg/kg/day 
of 
IV 
methylprednisolone, 
consider 
additional 
abdominal workup (including liver biopsy) and 
imaging (i.e., liver ultrasound), and consider 
starting 
immunosuppressives 
(i.e., 
mycophenolate mofetil).a Discuss with study 
physician if mycophenolate mofetil is not 
available. Infliximab should NOT be used. 
Grade 3 
(Isolated AST or 
ALT >8.0×ULN and 
≤20.0×ULN, if 
normal at 
baseline) 
 
(Isolated AST or 
ALT >12.5×ULN 
and ≤20.0×ULN, if  
elevated >ULN at 
baseline) 
• Hold study drug/study regimen 
dose until resolution to Grade ≤1 or 
baseline 
• Resume study drug/study regimen 
if elevations downgrade to Grade ≤1 
or baseline within 14 days and after 
completion of steroid taper. 
• Permanently discontinue study 
drug/study regimen if the elevations 
do not downgrade to Grade ≤1 or 
baseline within 14 days 
Permanently discontinue study 
drug/study regimen for any case 
meeting Hy’s law criteria, in the 
absence of any alternative cause4 
For Grade 3: 
− Regular and frequent checking of LFTs (e.g., 
every 1-2 days) until elevations of these are 
improving or resolved. 
− Consult hepatologist (unless investigator is 
hepatologist); 
obtain 
abdominal 
ultrasound, 
including Doppler assessment of liver perfusion; 
and consider liver biopsy. 
− Consider, as necessary, discussing with study 
physician. 
− If 
investigator 
suspects 
toxicity 
to 
be 
immune-mediated, promptly initiate empiric IV 
methylprednisolone at 1 to 4 mg/kg/day or 
equivalent. 
− If no improvement within 3 to 5 days despite 
1 to 4 mg/kg/day methylprednisolone IV or 
equivalent, obtain liver biopsy (if it has not been 
done already) and promptly start treatment with 
immunosuppressive 
therapy 
(mycophenolate 
mofetil). 
Discuss 
with 
study 
physician 
if 
mycophenolate is not available. Infliximab 
should NOT be used. 
− Once the patient is improving, gradually 
taper steroids over ≥28 days and consider 
prophylactic antibiotics, antifungals, and anti-
PCP treatment (refer to current NCCN guidelines 
for 
treatment 
of 
cancer-related 
infections 
[Category 2B recommendation]). 
 
Grade 4 
(Isolated AST or 
ALT >20×ULN,  
whether normal or 
elevated at 
baseline) 
Permanently discontinue study 
drug/study regimen. 
For Grade 4: 
Same as above  
(except would recommend obtaining liver biopsy 
early) 

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If transaminase rise is not isolated but (at any time) occurs in setting of either increasing total/direct bilirubin (y (if it has not been 
done already) and promptly start treatment with immunosuppressive therapy (mycophenolate nd rule out perforation, 
- 
Manage dosing for Grade 1 transaminase rise as instructed for Grade 2 transaminase rise 
- 
Manage dosing for Grade 2 transaminase rise as instructed for Grade 3 transaminase rise 
- 
Grade 3-4: Permanently discontinue study drug/study regimen 
 
Nephritis or Renal 
Dysfunction 
(Elevated 
Serum 
Creatinine)  
Grade of Elevated 
Serum Creatinine 
(CTCAE version 
4.03) 
 
Any Grade  
 
 
 
 
- Consult with Nephrologist 
- Monitor for signs and symptoms that may be 
related to changes in renal function (e.g. 
routine urinalysis, elevated serum BUN and 
creatinine, decreased creatinine clearance, 
electrolyte imbalance, decrease in urine 
output, proteinuria, etc.)  
- Patients should be thoroughly evaluated to 
rule out any alternative etiology (e.g., 
disease progression, infections etc.) 
- Steroids should be considered in the absence 
of clear alternative etiology even for low 
grade events (Grade 2) , in order to prevent 
potential progression to higher grade event 
Grade 1 [Serum 
Creatinine > 1-
1.5X baseline;  > 
ULN to 1.5X ULN]  
No dose modification 
For Grade 1 elevated creatinine:  
-      Monitor serum creatinine weekly and any 
accompanying symptom 
 
If creatinine returns to baseline, resume its 
regular monitoring per study protocol. 
 
If it worsens, depending on the severity , 
treat as Grade 2 or Grade 3 or 4  
-      Consider symptomatic treatment including 
hydration, electrolyte replacement, diuretics, 
etc. 
Grade 2 [Serum 
Creatinine>1.5-
3.0X baseline; 
>1.5X-3.0XULN] 
 
Hold study drug/study regimen until 
resolution to ≤ Grade 1 or baseline 
• 
If  toxicity worsens then treat as 
Grade 3 or Grade 4 
• 
If toxicity improves to baseline 
then treat at next scheduled 
treatment date 
Study drug/study regimen can be 
resumed at the next scheduled 
dose once event stabilizes to 
grade ≤1 for 5-7 days have 
passed after completion of 
steroid taper    
For Grade 2 elevated creatinine:  
- Consider symptomatic treatment including 
hydration, electrolyte replacement, diuretics, 
etc.  
- Carefully monitor serum creatinine  every 2-3 
days and as clinically warranted 
- Consult Nephrologist and consider renal 
biopsy if clinically indicated 
- If event is persistent (> 3-5 days) or worsens,  
promptly start  prednisone 1 to 2 mg/kg/day 
or IV equivalent  
- If event is not responsive within 3-5 days or 
worsens despite prednisone at 1-2 mg/kg/day 
or IV equivalent, additional workup should be 
considered and prompt treatment with IV 
methylprednisolone at 2-4mg/kg/day started.  
- Once improving gradually taper steroids over 
≥28 days and   consider prophylactic 
antibiotics, antifungals and anti-PJP 
treatment (please refer to current NCCN 
guidelines for treatment of cancer-related 
infections [Category 2B recommendation]).  
- When event returns to baseline, resume study 
drug/study regimen and routine serum 

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creatinine monitoring per study protocol. 
Grade 3 or 4  
(Grade 3:  Serum 
Creatinine > 3.0 X 
baseline; >3.0-6.0 
X ULN 
 
Grade 4: Serum 
Creatinine > 6.0 X 
ULN)  
Permanently discontinue study 
drug/study regimen 
- Carefully monitor serum creatinine  on  daily 
basis 
- Consult Nephrologist and consider renal 
biopsy if clinically indicated 
- Promptly  start  prednisone 1 to 2  mg/kg/day 
or IV equivalent  
- If event is not responsive within 3-5 days or 
worsens despite prednisone at 1-2 mg/kg/day 
or IV equivalent, additional workup should be 
considered and prompt treatment with IV 
methylprednisolone 2-4mg/kg/day started.  
- Once improving,  gradually taper steroids 
over orsens despite prednisone at 1-2 
mg/kg/day or IV equivalent, addition-PJP 
treatment (please refer to current  NCCN 
guidelines for treatment of  cancer-related 
infections [Category 2B recommendation]  
Rash (excluding 
Bullous skin 
formations) 
Grade of Skin Rash  
(Please refer to 
NCICTCAE version 
4.03 for definition 
of severity/grade 
depending on  
type of skin rash)  
Any Grade 
Monitor for signs and symptoms of dermatitis 
(rash and pruritus)  
**IF THERE IS ANY BULLOUS FORMATION, THE 
STUDY PHYSICIAN SHOULD BE CONTACTED 
AND STUDY DRUG DISCONTINUED** 
Grade 1  
No dose modification 
For Grade 1: 
- Consider symptomatic treatment including 
oral antipruritics (e.g., diphenhydramine or 
hydroxyzine) and topical therapy (e.g., urea 
cream) 
 
Grade 2 
For persistent (> 1- 2 weeks) Grade 2 
events, hold scheduled study 
drug/study regimen until 
resolution to ≤ Grade 1 or 
baseline  
 
If  toxicity worsens then 
treat as Grade 3  
 
If  toxicity improves then  
resume administration at 
next scheduled dose 
 
Study drug/study regimen 
For Grade 2 : 
- Obtain dermatology consult  
- Consider symptomatic treatment including 
oral antipruritics (e.g., diphenhydramine or 
hydroxyzine) and topical therapy (e.g., urea 
cream) 
- Consider moderate-strength topical steroid  
- If no improvement of rash/skin lesions occurs 
within 3-5 days or is worsening despite 
symptomatic treatment and/or use of 
moderate strength topical steroid, consider, 

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can be resumed at the next 
scheduled dose once event 
stabilizes to grade ≤1 and 
5-7 days have passed after 
completion of steroid taper   
as necessary, discussing with study physician 
and promptly start systemic steroids 
prednisone  1-2 mg/kg/day or IV equivalent   
- Consider skin biopsy if persistent for >1-2 
weeks or recurs 
Grade 3 
Hold study drug/study regimen until 
resolution to ≤ Grade 1 or 
baseline 
 If temporarily holding the study 
drug/study regimen does not 
provide improvement of the 
Grade 3 skin rash  to ≤ Grade 1 or 
baseline within 30 days, then 
permanently discontinue Study 
drug/study regimen  
For Grade 3 or 4: 
- Consult dermatology  
-  Promptly initiate empiric IV 
methylprednisolone 1 to 4 mg/kg/day or 
equivalent  
- Consider hospitalization 
- Monitor extent of rash [Rule of Nines] 
- Consider skin biopsy (preferably more than 1) 
as clinically feasible. 
- Once improving, gradually taper steroids over 
≥28 days and consider prophylactic 
antibiotics, antifungals and anti-
PJPtreatment (please refer to current NCCN 
guidelines for treatment of  cancer-related 
infections [Category 2B recommendation]) 
- Consider, as necessary, discussing with Study 
Physician 
Grade 4 
Permanently discontinue study 
drug/study regimen  
Endocrinopathy 
(e.g., 
hyperthyroidism, 
hypothyroidism, 
Type 1 diabetes 
mellitus, 
hypophysitis,   
hypopituitarism, 
adrenal 
insufficiency;  
exocrine event of 
amylase/lipase 
increased also 
included in this 
section) 
Any Grade  
(Depending on the 
type of 
endocrinopathy, 
refer to NCI CTCAE 
version 4.03 for 
defining the CTC 
grade/severity)  
 
- Consider consulting endocrinologist for endocrine 
eventsConsider, as necessary, discussing with 
study physician 
- Monitor patients for signs and symptoms of 
endocrinopathies.  Non-specific symptoms 
include headache, fatigue, behavior changes, 
changed mental status, vertigo, abdominal 
pain, unusual bowel habits, polydipsia, 
polyuria, hypotension and weakness. 
- Patients should be thoroughly evaluated to 
rule out any alternative etiology (e.g., 
disease progression including brain 
metastases, infections, etc.) 
- 
Depending on the suspected endocrinopathy, 
monitor and evaluate thyroid function tests: 
TSH, free T3 and free T4 and other relevant 
endocrine  and related labs (e.g., blood 
glucose and ketone levels, HgA1c)  
- 
For modest asymptomatic elevations in 
serum amylase and lipase, corticosteroid 
treatment is not indicated as long as there 
are no other signs or symptoms of pancreatic 
inflammation  
- 
If a patient experiences an AE that is 
thought to be possibly of autoimmune nature 
(e.g., thyroiditis, pancreatitis, hypophysitis, 
diabetes insipidus), the investigator should 
send a blood sample for appropriate 
autoimmune antibody testing  

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Grade 1 
(Depending on the 
type of 
endocrinopathy, 
refer to NCI CTCAE 
version 4.03 for 
defining the CTC 
grade 1) 
No dose modification 
For Grade 1: (including those with asymptomatic 
TSH elevation) 
- Monitor patient with appropriate endocrine 
function tests 
- For suspected hypophysitis/hypopituitarism, 
consider consultation of an endocrinologist to 
guide assessment of early-morning ACTH, 
cortisol, TSH and free T4; also consider 
gonadotropins, sex hormones, and prolactin 
levels, as well as cosyntropin stimulation test 
(though it may not be useful in diagnosing 
early secondary adrenal insufficiency) 
- If TSH < 0.5X LLN, or TSH >2X ULN or 
consistently out of range in 2 subsequent 
measurements, include FT4 at subsequent 
cycles as clinically indicated and consider 
consultation of an endocrinologist 
Grade 2  
(Depending on the 
type of 
endocrinopathy, 
refer to NCI CTCAE 
version 4.03 for 
defining the CTC 
grade/severity 2) 
 
 
For Grade 2 endocrinopathy other 
than hypothyroidism and Type 1 
diabetes mellitus, hold study 
drug/study regimen dose until  
subject is clinically stable 
• If  toxicity worsens then treat as 
Grade 3 or Grade 4  
• If toxicity improves to baseline 
then treat at next scheduled 
treatment date 
Study drug/study regimen can be 
resumed at the next scheduled 
dose once event stabilizes to 
grade ≤1 and 5-7 days have 
passed after completion of 
steroid taper 
   Patients with endocrinopathies 
who may require prolonged or 
continued steroid replacement 
(e.g., adrenal insufficiency) can 
be retreated with study 
drug/study regimen on the 
following conditions: 1) the event 
stabilizes and is controlled ,2) 
the patient is clinically stable as 
per Investigator or treating 
physician’s clinical judgement, 
and 3) doses of prednisone are at 
less than or equal to 10mg/day or 
equivalent. 
For Grade 2: (including those with symptomatic 
endocrinopathy) 
- Consult endocrinologist to guide evaluation of 
endocrine function and, as indicated by 
suspected endocrinopathy and as clinically 
indicated,  consider pituitary scan 
- For all patients with abnormal endocrine 
work up, except for those  with isolated 
hypothyroidism or Type 1 DM, and as guided 
by an endocrinologist,  consider short-term, 
corticosteroids (e.g., 1-2mg/kg/day 
methylprednisolone or IV equivalent) and 
prompt initiation of treatment with relevant 
hormone replacement (e.g., hydrocortisone, 
sex hormones).  
- Isolated hypothyroidism may be treated with 
replacement therapy, without study 
drug/study regimen interruption, and without 
corticosteroids 
 
- Isolated Type 1 diabetes mellitus (DM) may be 
treated with appropriate diabetic therapy, 
without study drug/study regimen 
interruption, and without corticosteroids 
- Once patients on steroids are improving, 
gradually taper immunosuppressive steroids 
(as appropriate and with guidance of 
endocrinologist) over ≥28 days and consider 
prophylactic antibiotics, antifungals and anti-
PJP treatment (please refer to current NCCN 
guidelines for treatment of  cancer-related 
infections [Category 2B recommendation]) 
- For patients with normal endocrine work up 
(lab or MRI scans), repeat labs/MRI as 
clinically indicated. 

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Grade 3 or 4 
(Depending on the 
type of 
endocrinopathy, 
refer to NCI CTCAE 
version 4.03 for 
defining the CTC 
grade/severity 3 
or 4)  
For Grade 3 or 4 endocrinopathy 
other than hypothyroidism and Type 
1 diabetes mellitus, hold study 
drug/study regimen dose until 
endocrinopathy symptom(s) are 
controlled.  
Study drug/study regimen can be 
resumed once event stabilizes and 
after completion of steroid taper. 
Patients with endocrinopathies who 
may require prolonged or continued 
steroid replacement (e.g., adrenal 
insufficiency) can be retreated with 
study drug/study regimen on the 
following conditions: 
1. 
The event stabilizes and is 
controlled. 
2. 
The patient is clinically stable 
as per investigator or treating 
physician’s clinical judgement. 
3. 
Doses of prednisone are 
≤10 mg/day or equivalent 
 
For Grade 3 or 4: 
- 
Consult endocrinologist to guide evaluation 
of endocrine function and, as indicated by 
suspected endocrinopathy and as clinically 
indicated, consider pituitary scan. 
Hospitalization recommended 
- 
For all patients with abnormal endocrine 
work up, except those with isolated 
hypothyroidism or Type 1 DM, and as guided 
by an  endocrinologist, promptly initiate 
empiric IV methylprednisolone 1 to 
2 mg/kg/day or equivalent, as well as 
relevant hormone replacement (e.g., 
hydrocortisone, sex hormones) 
- 
Isolated hypothyroidism may be treated with 
replacement therapy, without treatment 
interruption and without  study drug/study 
regimen interruption, and without 
corticosteroids 
- 
Isolated Type 1 diabetes mellitus may be 
treated with appropriate diabetic therapy, 
without study drug/study regimen 
interruption, and without corticosteroids For 
adrenal crisis, severe dehydration, 
hypotension, or shock: immediately initiate 
intravenous corticosteroids with 
mineralocorticoid activity 
- 
Once patients on steroids are improving, 
gradually taper immunosuppressive steroids 
(as appropriate and with guidance of 
endocrionologist) over ≥4 weeks and 
consider prophylactic antibiotics, antifungals 
and anti-PJP treatment (please refer to 
current NCCN guidelines for treatment of  
cancer-related infections [Category 2B 
recommendation]) 
- 
 

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Immune mediated  
Neurotoxicity (to 
include but not 
limited to limbic 
encephalitis . 
autonomic 
neuropathy, 
excluding 
Myasthenia Gravis 
and Guillain-Barre)   
 
Grade of 
Neurotoxicity  
Depending on the 
type of 
neurotoxicity , 
refer to NCI CTCAE 
version 4.03 for 
defining the CTC 
grade/severity 
Any Grade  
 
 
 
 
 
 
 
Patients should be evaluated to rule out any 
alternative 
etiology 
(e.g., 
disease 
progression, infections, metabolic syndromes 
and medications, etc.)  
Monitor patient  for general symptoms 
(headache, nausea, vertigo, behavior 
change, or weakness) 
Consider appropriate diagnostic testing (e.g. 
electromyogram and nerve conduction 
investigations) 
Symptomatic treatment with neurological consult 
as appropriate 
 
Grade 1 
 No dose modifications 
See “Any Grade” recommendations 
above. 
Grade 2 
 
For acute motor 
neuropathies or  
neurotoxicity, hold study 
drug/study regimen dose 
until resolution to ≤ Grade 
1 
 
For sensory 
neuropathy/neuropathic 
pain, consider holding study 
drug/study regimen dose 
until resolution to ≤ Grade 
1. 
o If toxicity worsens 
then treat as Grade 3 
or Grade 4  
o If  toxicity improves to 
baseline then treat at 
next scheduled 
treatment date 
 
Study drug/study regimen 
can be resumed once event  
improves to Grade ≤1 and 
after completion of steroid 
taper. 
Consider, as necessary, discussing with the study 
physician  
Obtain  Neurology Consult  
Sensory neuropathy/neuropathic pain may be 
managed by appropriate medications (e.g., 
gabapentin, duloxetine, etc.) 
Promptly start systemic steroids prednisone 1-
2mg/kg/day or IV equivalent  
If no improvement within 3-5 days despite 1-
2mg/kg/day prednisone or IV equivalent 
consider additional workup and promptly 
treat with additional immunosuppressive 
therapy (e.g. IVIG)  
 
 
Grade 3 
 
Hold Study drug/study 
regimen dose until 
resolution to ≤ Grade 1 
 
Permanently discontinue 
Study drug/study regimen if 
Grade 3  imAE  does not 
resolve to ≤ Grade 1 within 
30 days. 
For Grade 3 or 4: 
- 
Consider, as necessary, discussing with 
study physician 
- 
Obtain Neurology Consult 
- 
Consider hospitalization 
- 
Promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day or 
equivalent  
- 
If no improvement within 3-5 days 
despite IV corticosteroids, consider 
additional workup and promptly treat 
with additional immunosuppressants 
(e.g. IVIG)  
- 
Once stable, gradually taper steroids 
over ≥4 weeks 
Grade 4 
 
 
Permanently discontinue 
study drug/study regimen 

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Immune-mediated 
peripheral 
neuromotor 
syndromes, such as 
Guillain-Barre and 
Myasthenia Gravis 
 
Any Grade 
− 
The prompt diagnosis of immune-
mediated peripheral neuromotor 
syndromes is important, since certain 
patients may unpredictably experience 
acute decompensations which can result 
in substantial morbidity or in the worst 
case, death. Special care should be 
taken for certain sentinel symptoms 
which may predict a more severe 
outcome, such as prominent dysphagia, 
rapidly progressive weakness, and signs 
of respiratory insufficiency or autonomic 
instability 
− 
Patients should be evaluated to rule out 
any alternative etiology (e.g., disease 
progression, infections, metabolic 
syndromes and medications, etc.). It 
should be noted that the diagnosis of 
immune-mediated peripheral 
neuromotor syndromes can be 
particularly challenging in patients with 
underlying cancer, due to the multiple 
potential confounding effects of cancer 
(and its treatments) throughout the 
neuraxis. Given the importance of 
prompt and accurate diagnosis, it is 
essential to have a low threshold to 
obtain a neurological consult 
− 
Neurophysiologic diagnostic testing 
(e.g., electromyogram and nerve 
conduction investigations, and  
“repetitive stimulation” if myasthenia is 
suspected) are routinely indicated upon 
suspicion of such conditions and may be 
best facilitated by means of a neurology 
consultation  
− 
Important to consider that the use of 
steroids as the primary treatment of 
Guillain-Barre is not typically considered 
effective. Patients requiring treatment 
should be started  with IVIG and 
followed 
by 
plasmapheresis 
if 
not 
responsive to IVIG  
Grade 1 
No dose modification 
Consider, as necessary, discussing with the study 
physician 
Care should be taken to monitor patients for 
sentinel symptoms of a potential 
decompensation as described above 
Obtain a neurology consult  
Grade 2 
Hold study drug/study regimen dose 
until resolution to ≤ Grade 1 
Permanently discontinue study 
drug/study regimen if it does not 
resolve to ≤ Grade 1 within 30 
days or if there are signs of 
respiratory insufficiency or 
autonomic instability 
 
Grade 2Discuss with the study physician  
Care should be taken to monitor patients for 
sentinel symptoms of a potential 
decompensation as described aboveObtain a 
Neurology Consult Sensory 
neuropathy/neuropathic pain may be 
managed by appropriate medications (e.g., 
gabapentin, duloxetine, etc.) 
MYASTHENIA GRAVIS 
o 
Steroids may be successfully used to 
treat Myasthenia Gravis. Important to 
consider 
that 
steroid 
therapy 
(especially with high doses) may result 
in transient worsening of myasthenia 

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and should typically be administered 
in 
a 
monitored 
setting 
under 
supervision 
of 
a 
consulting 
neurologist. 
o 
Patients unable to tolerate steroids 
may be candidates for treatment with 
plasmapheresis or IVIG. Such decisions 
are best made in consultation with a 
neurologist, taking into account the 
unique needs of each patient. 
o 
If Myasthenia Gravis-like neurotoxicity 
present, consider starting 
acetylcholine esterase (AChE) 
inhibitor therapy in addition to 
steroids. Such therapy, if successful, 
can also serve to reinforce the 
diagnosis. 
GUILLAIN-BARRE:  
o 
Important to consider here that the 
use of steroids as the primary 
treatment of Guillain-Barre is not 
typically considered effective.  
o 
Patients requiring treatment should be 
started with IVIG and followed by 
plasmapheresis if not responsive to 
IVIG. 
Grade 3 
Hold study drug/study regimen dose 
until resolution to ≤ Grade 1 
Permanently discontinue Study 
drug/study regimen if Grade 3  
imAE does not resolve to ≤ Grade 
1 within 30 days or if there are 
signs of respiratory insufficiency 
or autonomic instability 
For severe or life threatening (Grade 3 or 4) 
events:  
- 
Consider, as necessary, discussing with 
study physician 
- 
Recommend hospitalization 
- 
Monitor symptoms and obtain 
neurological consult 
MYASTHENIA GRAVIS 
o 
Steroids may be successfully used to 
treat Myasthenia Gravis.  It should 
typically be administered in a 
monitored setting under supervision 
of a consulting neurologist. 
o 
Patients unable to tolerate steroids 
may be candidates for treatment 
with plasmapheresis or IVIG. 
o 
If Myasthenia Gravis-like 
neurotoxicity present, consider 
starting acetylcholine esterase 
(AChE) inhibitor therapy in addition 
to steroids. Such therapy, if 
successful, can also serve to 
reinforce the diagnosis. 
GUILLAIN-BARRE:  
o 
Important to consider here that the 
use of steroids as the primary 
treatment of Guillain-Barre is not 
typically considered effective.  
o 
Patients requiring treatment should 
be started with IVIG and followed by 
plasmapheresis if not responsive to 
IV IG 
Grade 4 
Permanently discontinue study 
drug/study regimen  

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Myocarditis 
Any Grade 
General Guidance 
Discontinue drug permanently if 
biopsy-proven immune-mediated 
myocarditis. 
For Any Grade: 
− 
The prompt diagnosis of immune-mediated 
myocarditis is important, particularly in patients 
with baseline cardiopulmonary disease and 
reduced cardiac function.  
− 
Consider, as necessary, discussing with the 
study physician. 
− 
Monitor patients for signs and symptoms of 
myocarditis (new onset or worsening chest pain, 
arrhythmia, shortness of breath, peripheral 
edema). As some symptoms can overlap with lung 
toxicities, simultaneously evaluate for and rule 
out pulmonary toxicity as well as other causes 
(e.g., pulmonary embolism, congestive heart 
failure, 
malignant 
pericardial 
effusion). 
A 
Cardiology consultation should be obtained early, 
with prompt assessment of whether and when to 
complete a cardiac biopsy, including any other 
diagnostic procedures. 
− 
Initial 
work-up 
should 
include 
clinical 
evaluation, 
BNP, 
cardiac 
enzymes, 
ECG, 
echocardiogram 
(ECHO), 
monitoring 
of 
oxygenation via pulse oximetry (resting and 
exertion), and additional laboratory work-up as 
indicated. 
Spiral 
CT 
or 
cardiac 
MRI 
can 
complement 
ECHO 
to 
assess 
wall 
motion 
abnormalities when needed. 
− 
Patients should be thoroughly evaluated to 
rule out any alternative etiology (e.g., disease 
progression, other medications, or infections) 
Grade 1 
(asymptomatic 
with 
laboratory 
(e.g., 
BNP) 
or 
cardiac 
imaging 
abnormalities) 
No dose modifications required 
unless clinical suspicion is high, in 
which case hold study drug/study 
regimen dose during diagnostic 
work-up for other etiologies. If study 
drug/study regimen is held, resume 
after complete resolution to Grade 
0. 
For Grade 1 (no definitive findings): 
- Monitor and closely follow up in 2 to 4 days for 
clinical symptoms,  BNP, cardiac enzymes, ECG, 
ECHO, pulse oximetry (resting and exertion), and 
laboratory work-up as clinically indicated. 
- Consider using steroids if clinical suspicion is 
high. 
Grade 2, 3 or 4 
(Grade 2: 
Symptoms with 
mild to moderate 
activity or 
exertion) 
 
 (Grade 3: Severe 
with symptoms at 
rest or with 
minimal activity or 
exertion; 
intervention 
indicated) 
 
(Grade 4: Life-
threatening 
consequences; 
urgent 
intervention 
- If Grade 2 -- Hold study 
drug/study regimen dose until 
resolution to Grade 0. If toxicity 
rapidly improves to Grade 0, 
then the decision to reinitiate 
study drug/study regimen will be 
based upon treating physician’s 
clinical judgment and after 
completion of steroid taper. If 
toxicity does not rapidly 
improve, permanently. 
discontinue study drug/study 
regimen. 
- If Grade 3-4, permanently 
discontinue study drug/study 
For Grade 2-4: 
− 
Monitor symptoms daily, hospitalize. 
− 
Promptly start IV methylprednisolone 2 
to 4 mg/kg/day or equivalent after 
Cardiology consultation has determined 
whether and when to complete 
diagnostic procedures including a 
cardiac biopsy. 
− 
Supportive care (e.g., oxygen). 
− 
If no improvement within 3 to 5 days 
despite IV methylprednisolone at 2 to 
4 mg/kg/day, promptly start 
immunosuppressive therapy such as TNF 
inhibitors (e.g., infliximab at 5 mg/kg 
every 2 weeks). Caution: It is important 
to rule out sepsis and refer to infliximab 
label for general guidance before using 
infliximab. 
− 
Once the patient is improving, gradually 
taper steroids over ≥28 days and 

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indicated (e.g., 
continuous IV 
therapy or 
mechanical 
hemodynamic 
support)) 
regimen. 
consider prophylactic antibiotics, 
antifungals, or anti-PJP treatment (refer 
to current NCCN guidelines for 
treatment of cancer-related infections 
[Category 2B recommendation]) 
 
Myositis 
/Polymyositis 
(“Poly/myositis”) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor patients for signs and symptoms 
of poly/myositis. Typically, muscle 
weakness/pain occurs in proximal 
muscles including upper arms, thighs, 
shoulders, hips, neck and back, but 
rarely affects the extremities including 
hands and fingers; also difficulty 
breathing and/or trouble swallowing can 
occur and progress rapidly. Increased 
general feelings of tiredness and fatigue 
may occur, and there can be new-onset 
falling, difficulty getting up from a fall, 
and trouble climbing stairs, standing up 
from a seated position, and/or reaching 
up. 
− 
If poly/myositis is suspected, a 
Neurology consultation should be 
obtained early, with prompt guidance 
on diagnostic procedures. Myocarditis 
may co-occur with poly/myositis; refer 
to guidance under Myocarditis. Given 
breathing complications, refer to 
guidance under Pneumonitis/ILD.  
Given possibility of an existent (but 
previously unknown) autoimmune 
disorder, consider Rheumatology 
consultation. 
− 
Consider, as necessary, discussing with 
the study physician. 
− 
Initial work-up should include clinical 
evaluation, creatine kinase, aldolase, 
LDH, BUN/creatinine, erythrocyte 
sedimentation rate or C-reactive protein 
level, urine myoglobin, and additional 
laboratory work-up as indicated, 
including a number of possible 
rheumatological/antibody tests (i.e., 
consider whether a rheumatologist 
consultation is indicated and could 
guide need for rheumatoid factor, 
antinuclear antibody, anti-smooth 
muscle, antisynthetase [such as anti-Jo-
1], and/or signal-recognition particle 
antibodies). Confirmatory testing may 
include electromyography, nerve 
conduction studies, MRI of the muscles, 
and/or a muscle biopsy. Consider 
Barium swallow for evaluation of 
dysphagia or dysphonia. 
Patients should be thoroughly evaluated to rule 
out any alternative etiology (e.g., disease 

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progression, other medications, or infections). 
Grade 1 
(mild pain) 
No dose modifications 
For Grade 1: 
− 
Monitor and closely follow up in 2 to 4 
days for clinical symptoms and initiate 
evaluation as clinically indicated 
− 
Consider Neurology consult 
− 
Consider, as necessary, discussing with 
the study physician 
Grade 2 
(moderate pain 
associated with 
weakness; pain 
limiting 
instrumental 
activities of daily 
living [ADLs]) 
Hold study drug/study regimen dose 
until resolution to Grade ≤1. 
− 
Permanently discontinue study 
drug/study regimen if it does 
not resolve to Grade ≤1 within 
30 days or if there are signs of 
respiratory insufficiency 
For Grade 2: 
− 
Monitor symptoms daily and consider 
hospitalization. 
− 
Obtain Neurology consult, and initiate 
evaluation. 
− 
Consider, as necessary, discussing with 
the study physician. 
− 
If clinical course is rapidly progressive 
(particularly if difficulty breathing 
and/or trouble swallowing), promptly 
start IV methylprednisolone 2 to 
4 mg/kg/day systemic steroids along 
with receiving input from Neurology 
consultant  
− 
If clinical course is not rapidly 
progressive, start systemic steroids 
(e.g., prednisone 1 to 2 mg/kg/day PO 
or IV equivalent); if no improvement 
within 3 to 5 days, continue additional 
work up and start treatment with IV 
methylprednisolone 2 to 4 mg/kg/day 
− 
If after start of IV methylprednisolone at 
2 to 4 mg/kg/day there is no 
improvement within 3 to 5 days, 
consider start of immunosuppressive 
therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 
weeks). Caution: It is important to rule 
out sepsis and refer to infliximab label 
for general guidance before using 
infliximab. 
− 
Once the patient is improving, gradually 
taper steroids over ≥28 days and 
consider prophylactic antibiotics, 
antifungals, or anti-PJP treatment (refer 
to current NCCN guidelines for 
treatment of cancer-related infections 
[Category 2B recommendation]) 

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Grade 3 or 4 
(pain associated 
with severe 
weakness; limiting 
self-care ADLs) 
For Grade 3: 
Hold study drug/study regimen dose 
until resolution to Grade ≤1. 
Permanently discontinue study 
drug/study regimen if Grade 3 imAE 
does not resolve to Grade ≤1 within 
30 days or if there are signs of 
respiratory insufficiency. 
 
For Grade 4: 
Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4 (severe or life-threatening 
events): 
− 
Monitor symptoms closely; recommend 
hospitalization. 
− 
Obtain Neurology consult, and complete 
full evaluation. 
− 
Consider, as necessary, discussing with 
the study physician. 
− 
Promptly start IV methylprednisolone 2 
to 4 mg/kg/day systemic steroids along 
with receiving input from Neurology 
consultant. 
− 
If after start of IV methylprednisolone at 
2 to 4 mg/kg/day there is no 
improvement within 3 to 5 days, 
consider start of immunosuppressive 
therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 
weeks). Caution: It is important to rule 
out sepsis and refer to infliximab label 
for general guidance before using 
infliximab. 
− 
Consider whether patient may require IV 
IG, plasmapheresis. 
− 
Once the patient is improving, gradually 
taper steroids over ≥28 days and 
consider prophylactic antibiotics, 
antifungals, or anti-PJP treatment (refer 
to current NCCN guidelines for 
treatment of cancer-related infections 
[Category 2B recommendation])1 

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Infusion-Related Reactions 
Severity 
Grade 
Dose Modifications 
Toxicity Management 
Any 
Grade 
 
- 
Management per institutional standard at the discretion of 
investigator 
- 
Monitor patients for signs and symptoms of infusion-related reactions 
(e.g., fever and/or shaking chills, flushing and/or itching, alterations 
in heart rate and blood pressure, dyspnea or chest discomfort, skin 
rashes etc.) and anaphylaxis (e.g., generalized urticaria, angioedema, 
wheezing, hypotension, tachycardia, etc.) 
Grade 1 
The infusion rate of study drug/study 
regimen may be decreased by 50% or 
temporarily 
interrupted 
until 
resolution of the event 
For Grade 1 or Grade 2: 
- 
Acetaminophen and/or antihistamines may be administered per 
institutional standard at the discretion of the investigator  
- 
Consider premedication per institutional standard prior to subsequent 
doses 
Grade 2 
 
The infusion rate of study drug/study 
regimen may be decreased 50% or 
temporarily interrupted until 
resolution of the event  
Subsequent infusions may be given at 
50% of the initial infusion rate 
Grade 
3/4 
 
 
Permanently 
discontinue 
study 
drug/study regimen 
For Grade 3 or 4: 
Manage severe infusion-related reactions per institutional standards 
(e.g., IM epinephrine, followed by IV diphenhydramine and ranitidine, 
and IV glucocorticoid) 
 
Non-Immune-Mediated Reactions 
(Note:  As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 
2, please discuss with Study Physician”  
CTC 
Grade/Severity 
Dose Modification  
Toxicity Management  
Any Grade 
Note: dose modifications are not required for adverse events not deemed to be related 
to study treatment (i.e. events due to underlying disease) or for laboratory 
abnormalities not deemed to be clinically significant. 
Treat accordingly as 
per 
institutional 
standard  
1 
No dose adjustment  
Treat accordingly as 
per 
institutional 
standard  
2 
Hold study drug/study regimen until resolution to ≤ Grade 1 or baseline 
Treat accordingly as 
per 
institutional 
standard  
3 
Hold study drug/study regimen until resolution to ≤ Grade 1 or baseline 
For AEs that downgrade to ≤ Grade 2 within 7 days or resolve to ≤ Grade 1 or baseline 
within 14 days, resume study drug/study regimen administration at next scheduled 
dose. Otherwise, discontinue study drug/study regimen 
Treat accordingly as 
per 
institutional 
standard  
 
 

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Non-Immune-Mediated Reactions 
(Note:  As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 
2, please discuss with Study Physician”  
CTC 
Grade/Severity 
Dose Modification  
Toxicity Management  
4 
Discontinue Study drug/study regimen (Note for Grade 4 labs, decision to discontinue 
would be based on accompanying clinical signs/symptoms and as per Investigator’s 
clinical judgment and in consultation with the sponsor)  
Treat accordingly as 
per 
institutional 
standard  
Abbreviations: 
AChE = acetylcholine esterase; ADA = American Dietetic Association; ADL = Activities of daily living ; AE = adverse 
event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CT = computed 
tomography; GI = gastrointestinal; IDS=Infectious Disease Service; ILD = interstitial lung disease; IM = intramuscular; 
imAE = immune-mediated adverse event; IV = intravenous; NCI CTCAE = National Cancer Institute Common Terminology 
Criteria for Adverse Events; NCCN = National Comprehensive Cancer Network ; PJP = Pneumocystis jirovecii pneumonia 
(formerly known as Pneumocystispneumocystis carinii pneumonia); PO = by mouth; TNF = tumor necrosis factor; TSH = 
thyroid stimulating hormone; ULN = upper limit of normal. 
1 ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD  
2 NCI CTCAE version 4.03 
3 ASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD 
4 FDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation 
 
 

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APPENDIX III - NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS  
 
The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for Adverse Event (AE) reporting. All appropriate treatment areas should 
have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from 
the CTEP web site (https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
 

 
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APPENDIX IV - THE TNM CLASSIFICATION OF MALIGNANT TUMOURS 
 
The 8th Edition of the TNM Classification of Malignant Tumours has recently been released. To facilitate this 
process, educational resources have been made available to promote the use of staging (visit 
http://www.cancerstaging.org). These staging criteria should be used for new trials. 
 
 

 
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APPENDIX V – TRANSLATIONAL STUDIES 
A. Exploration of the tumor microenvironment and characterization of tumor genotype 
 
1 BACKGROUND  
Up until now, there are no biomarkers which are routinely used for the selection of patients or as early 
surrogate markers of clinical responses.  
PD-L1 expression has been correlated with clinical response to anti-PD-1 in adenocarcinoma (1), but not in 
squamous cell carcinoma of the lung (2). Surprinsgly, patient with lung cancer not expressing PD-L1 could 
respond to the blockade of the PD-1-PD-L1 pathway. Other studies showed that pre-existing infiltrating 
CD8+T cells before therapy and their in situ amplification also correlated with the efficacy of anti-PD-1/PD-
L1 (3). However, in other trials it was rather the activation status of intratumoral CD8+T cells and not only 
their simple presence which characterized responsive tumors to immunotherapy (4). In line with these 
results, various groups showed that parameters (IFNg, PD-1, Perforin, granzyme.. ) reflecting the presence 
of activated T cells secondary to the recognition of tumors provide complementary clues to identify 
potential clinical responders (5, 6).  
Recent work also reported that the phenotype of tumors has to be taken into account for the classification 
of tumors. Indeed, the most responsive tumors to anti-PD-1/PD-L1 – i.e. melanoma and lung cancer - where 
those with the highest frequency of tumor mutations (7). These tumor mutations generate neoepitopes not 
recognized as self antigen and result in the amplification of anti-tumor CD8+T cells. A linear relationship was 
shown between the mutational load of the tumors and the levels of infiltrating CD8+T cells (8) (9). 
Nevertheless, some exceptions exist such as renal cell carcinomas, which are not considered as tumor with a 
high mutation rate and yet respond to anti-PD-1 (10). In preclinical models, activation of the WNT/b-catenin 
signaling pathway resulted in the inhibition of T cell infiltration (11). These data emphasizes the link 
between the phenotype of tumors and the shaping of tumor microenvironment. A composite biomarker 
integrating the phenotype of the tumor (mutational load) and an immune signature from the tumor 
microenvironment may be considered as the most relevant to identify robust biomarkers. 
This ancillary study with thus focus on the analysis of the tumor microenvironement using new automated 
multiparametric immunofluorescence technique combined to the analysis of the genotype of the tumors by 
transcriptomic analysis and NGS technology. 
 
2 PROJECT AIMS 
2.1 Exploring the tumor microenvironment 
2.1.1 Basic analysis of PD-L1 expression by tumor cells and its interaction on CD8+T cells 
From the literature, the routine biomarker which could be detected on paraffine section on monoparametric 
immunohistochemistry could be PD-L1, CD8 and PD-1.  The simultaneous presence of PD-L1 on tumor cells 
with the interpretation issue (see below) and the tumor infiltration by PD-1+CD8+T cells may represent a 
good composite biomarker to predict clinical response to anti-PDL1 (3) 
 
2.1.2 Revisiting the predictive role of PD-L1 and PD-L2  
Usually PD-L1 expression is performed by Immunohistochemistry using various antibodies with various 
criteria of positivity in term of cut-off (1% to 50%) or the location of the staining (tumor cells, stroma…) 

 
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(12). Since PD-1 expressed by T cells could receive a negative signal by PD-L1 likely expressed on various 
cells from the tumor microenvironment, we will detect and characterize the cells expressing PD-L1 and PD-
L2. We will use the Immunofluorescence technique to simultaneously analyze the PD-L1 expression on 
various cells including tumor cells, macrophages, dendritic cells, endothelial cell, T cells. PD-L1 staining has 
already been published by E Tartour’s group (13). We have also developed an original staining for PD-L2 
(unpublished results). 
 
2.1.3 Characterization of effector T cells in the tumor microenvironment before anti-PD-L1 therapy. 
Pre-existing anti-tumor CD8+T cells appear to be a prerequisite for the clinical success of PD-1-PD-L1 
blockade. The simple presence of CD8+T cells may be insufficient to be sure that these cells are really 
directed against the tumor. The location of these cells at the invasive margin and inside tumours will also be 
determined. Various additional markers could be measured to better endow these cells with anti-tumor 
properties. Indeed, we could in situ address their activation and proliferation status (HLA-DR, CD38, Ki67).  
Recently it has been shown that resident memory T cells may represent the specific T cells which persist in 
the tumor inflammation site (14). The levels of these intratumor T cells could represent a good surrogate 
marker of pre-existing anti-tumor T cells (15). These cells are characterized by the expression of CD103 and 
CD49a and could be detected by double or triple immunofluorescence studies as already published by our 
group.  
 
2.1.4 Profile of immune checkpoint on T cells to assess the levels of exhaustion of T cells  
In various models the more the T cells express checkpoint inhibitors, the more they are exhausted and 
difficult to reactivate (16). From these observations, we think that it is relevant to characterize the profile 
of inhibitory costimulatory molecules expressed by T cells to evaluate possible resistance mechanisms to 
anti-PD-1/PD-L1 therapy. PD-1, Tim-3, Lag-3, CTLA-4, Icos stainings have been developed in E Tartour’s lab 
(Ms submitted). An interesting study also showed that high co-expression of Eomes and PD-1 also 
characterized the more exhausted T cells (17).  
 
2.1.5 Characterization of the proliferative immune cells after anti-PD-L1 therapy. 
Many cells in the tumor microenvironment could express PD-1 such as CD4+T cells, NK cell, B cells, 
macrophages, innate lymphoid cells. Most studies have focused on the role of CD8+T cells as the major 
effectors during PD-1-PD-L1 blockade. Thanks to this neoadjuvant protocol, we could assess if the anti-PD-L1 
mAb leads to an activation or amplification of other cells in the tumor microenvironment by comparing their 
levels and their activating status before and after therapy. The location of these cells inside and outside of 
the core of the tumor will also be compared. This unique study may identity new targets of anti-PD-L1 with 
some potential value as predictive biomarker of response. This study could also decipher early surrogate 
markers.  
 
2.1.5 Assessing other immunosuppressive mechanisms in the tumor microenvironment and in the periphery. 
Inhibitory receptors such as PD-1 represent one mechanism likely explaining the anergy of T cells in the 
tumor. However immunosuppression in the tumor microenvironment could also be related to suppressive 
cells such as regulatory T cell or myeloid derived suppressive cells (MDSC), as well as molecules inhibiting 
immune effector cells (IDO, IL-10, TGFb). In some cases, the levels of inflammatory molecules such as IL-6 

 
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correlate with the immunosuppressive state (18). We have previously shown that in other immunotherapies 
with IL-2, inflammatory status correlate with resistance to this therapy (19). We thus propose to monitor 
regulatory T cells (CD4+Foxp3+CD127-) and Myeloid derived suppressive cells both granulocytic and 
monocytic in the tumor microenvironment and in the blood. Indeed, the level of expression of immune 
checkpoint on T cells is very high in the tumor microenvironment and very low in the blood for a same 
patient, precluding the use of blood for immune checkpoint profile (20) (13). In contrast, high levels of 
regulatory T cells and MDSC could be detected in the blood of lung cancer patients (21) (22) (23) (24) . 
Profile of inflammatory and immunosuppressive cytokines by Luminex assay will also be performed. 
High levels of immunosuppression could explained some resistance to PD1/PD-L1 blockade and the ratio 
between effector T cells and an immunosuppression score to be determined may represent a clue to better 
understand resistance mechanism. 
 
2.2 Characterization of tumor genotype 
Various studies reported that the presence of T cells in cancer lesions correlates with high mutational 
burden (8)(9). A strong correlation between mutational load and clinical response was shown in patients 
with non-small cell lung cancer and colon cancer with micro-satellite instability treated with anti-PD1 
antibody (25). 
Whole-exome sequencing (100x coverage) will be performed on tumor samples and their corresponding 
germline DNA obtained from autologous PBMC of included patients. Somatic mutations will be identified by 
comparing the nucleic acid sequences between tumors and PBMC using well-established bionformatic 
pipelines. The presence of mRNA encoding this mutation will be confirmed by RNAseq analysis. The presence 
of neoantigens will then be compared between responders and non-responders to sort out a signature 
associated with response to the treatment.  
After exome sequencing and identification of the most represented neoantigens among anti-PD1-treated 
patients who derived a long-term or a minimal clinical benefit, we will select mutated CD8 T-cell peptides 
using HLA Peptide Binding predictive programs and test their ability to bind to specific HLA molecules.  
 
3 METHODS  
3.1 PD-L1 expression measurement in tumor tissue 
At least SP263 antibody will be used for PD-L1 expression measurement in paraffin tumor tissue. 
3.2 In situ multiparametric analysis of immune infiltrates 
We have developed since several years a fluorescent multiparametric platform to allow multiparametric in 
situ analysis of tissue cell infiltration. We have acquired a fluorescent spectral scanner (Perkins*) coupled to 
a software with the ability to automatically identify various cellular profile characterized by their size, 
shape, morphology. These cellular results combined with the capacity to integrate and process multiple 
fluorescent signals represent a unique opportunity to accurately characterize the phenotype of immune cells 
in the tumor microenvironment.  The use of immunofluorescence is especially adapted to address the 
clinical significance of the co-expression of various biomarkers at the cellular levels and to explore the 
interaction between the different immune cells present in the TME. 
 
 

 
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3.3 Measurement of immunosuppressive cells in the blood before and after therapy 
After Ficoll (Sigma-Aldrich) separation, human Peripheral Blood Mononuclear Cells (PBMC) will be stained 
with combinations of the following monoclonal antibodies and corresponding isotype controls (eBioscience, 
USA): APC- anti-human CD4, FITC-anti-human CD25. Intra-cytoplasmic Foxp3 staining will be performed 
using the PE-anti-human Foxp3 staining kit according to the manufacturer's instructions. Regulatory T cells 
will be identified as CD3+CD4+CD25hi Foxp3+ T cells. CD25hi gate will be adjusted to contain CD4+ T cells that 
express CD25 more brightly than CD4–CD25+ cells as previously described (26). This technique is already 
standardized in the immunological lab of HEGP (27) .  
MDSC analysis will be performed on whole blood after Ficoll-Paque density gradients to eliminate 
neutrophils. The following labeled anti-human monoclonal antibodies were used for staining : anti-lineage 
(LIN) FITC including anti-CD3, -CD19, -CD56, -CD14 (Becton Dickinson, Pont de Claix, France ), PE labeled 
anti-CD33 (Biolegend-Ozyme, Saint-Quentin Yvelines, France), APC labeled anti-HLA-DR (Beckman Coulter, 
Villepinte, France).  The % of granulocytic MDSC will be defined as the percent of 
CD33+Linneg (including CD14neg cells) HLA-DRneg in total PBMC  as proposed by Fricke (28).  For the 
measurement of CD14+HLA-DRlow/- also called monocytic MDSC (29), whole blood were stained with the 
following monoclonal antibodies: FITC labeled Anti-CD14 (BDBioscience), APC labeled anti-HLA-DR (Beckman 
Coulter). Measurement of MDSC has already been reported by our team (30). 
 
3.4 Mutational analysis and neoepitopes identification 
The laboratory of Biochemistry of HEGP has acquired an expertise to whole exome sequencing and RNAseq, 
with more than 100 patients analyzed per year. From DNA extracted of fresh frozen or paraffin embedded 
tissues, whole exome sequencing will be performed accordingly to the following process.  
Generated exome and transcriptome libraries are pooled in order to be sequenced either, on an Illumina 
NextSeq500 system, or an Illumina HiSeq4000 system. Runs are performed using 75 bases paired-end reads 
(PE reads). Libraries pooling is made such as the minimum amount of data per library type is the following: 
(i) Tumor DNA exome library, 80 million PE reads, 12 Gb, in order to achieve 115X minimum of depth. (ii) 
Constitutional DNA exome library, 50 million PE reads, 7.5 Gb  in order to achieve 75X minimum of depth 
(iii) RNASeq, 66 million PE reads, 10 Gb. 
With these specification mean performances obtained on clinical research samples in 2015 are the following:  
Tumor DNA exome : 135X; Constitutional DNA exome : 88X; RNASeq : 11 Gb. 
After standard bioinformatics analysis, an in-house algorithm compares normal and tumor genotypes from 
exome sequencing data to determine the somatic nature of the variation. A somatic score is calculated for 
each variant ranging from 1 to 30, a score of 30 translating the highest confidence index. We will then 
examined the landscape of neoantigens using previously described methods (30) Briefly, this   approach   
identifies mutant nonamers with ≤500 nM binding affinity for patient-specific class  I human lymphocyte 
antigen (HLA) alleles, which are considered candidate neoantigens. The quantity of neoantigens per tumor 
will be correlated with mutation burden and with response. 
 
 
 
4 RESSOURCES REQUIRED FOR THIS ANCILLARY STUDY 
- 
Paraffin tissue section before and after anti-PD-L1 therapy 

 
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- 
Frozen tissue before (optional) and after anti-PD-L1 therapy 
- 
Whole Blood : 42 ml before and after anti-PD-L1 therapy 
 
5 ORIGINALITY OF THIS STUDY  
- It integrates a comprehensive analysis of tumor microenvironment by a new automated multiparametric 
technology. 
- It will measure immune biomarkers selected on their role in the mechanisms of action of anti-PD-L1 mAb 
- It combines analysis of the tumor microenvironment with the phenotype of tumor cells, especially 
neoepitopes characterization. 
- It could provide new innovative composite biomarker to predict clinical response to anti-PD-L1. 
 
6 REFERENCES 
 
1. 
Borghaei H, et al. (2015) Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung 
Cancer. N Engl J Med 373(17):1627-1639. 
2. 
Brahmer J, et al. (2015) Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung 
Cancer. N Engl J Med 373(2):123-135. 
3. 
Tumeh PC, et al. (2014) PD-1 blockade induces responses by inhibiting adaptive immune resistance. 
Nature 515(7528):568-571. 
4. 
Herbst RS, et al. (2014) Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in 
cancer patients. Nature 515(7528):563-567. 
5. 
Ribas A, et al. (2015) Association of response to programmed death receptor 1 (PD-1) blockade with 
pembrolizumab (MK-3475) with an interferon-inflammatory immune gene signature. ASCO, (J Clin 
Oncol). 
6. 
Seiwert T, et al. (2015) Inflamed-phenotype gene expression signatures to predict benefit from the 
anti-PD-1 antibody pembrolizumab in PD-L1+ head and neck cancer patients. ASCO, (J Clin Oncol). 
7. 
Schumacher TN & Schreiber RD (2015) Neoantigens in cancer immunotherapy. Science 348(6230):69-
74. 
8. 
Brown SD, et al. (2014) Neo-antigens predicted by tumor genome meta-analysis correlate with 
increased patient survival. Genome research 24(5):743-750. 
9. 
Rooney MS, Shukla SA, Wu CJ, Getz G, & Hacohen N (2015) Molecular and genetic properties of 
tumors associated with local immune cytolytic activity. Cell 160(1-2):48-61. 
10. 
Motzer RJ, et al. (2015) Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J 
Med 373(19):1803-1813. 
11. 
Spranger S, Bao R, & Gajewski TF (2015) Melanoma-intrinsic beta-catenin signalling prevents anti-
tumour immunity. Nature 523(7559):231-235. 
12. 
Patel SP & Kurzrock R (2015) PD-L1 Expression as a Predictive Biomarker in Cancer Immunotherapy. 
Molecular cancer therapeutics 14(4):847-856. 
13. 
Badoual C, et al. (2013) PD-1-expressing tumor-infiltrating T cells are a favorable prognostic 
biomarker in HPV-associated head and neck cancer. Cancer Res 73(1):128-138. 
14. 
Sandoval F, et al. (2013) Mucosal Imprinting of Vaccine-Induced CD8+ T Cells Is Crucial to Inhibit the 
Growth of Mucosal Tumors. Sci Transl Med 5(172):172ra120. 
15. 
Nizard M, Roussel H, & Tartour E (2015) Resident Memory T Cells as Surrogate Markers of the Efficacy 
of Cancer Vaccines. Clin Cancer Res. 
16. 
Blackburn SD, et al. (2009) Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors 
during chronic viral infection. Nature immunology 10(1):29-37. 
17. 
Pauken KE & Wherry EJ (2015) Overcoming T cell exhaustion in infection and cancer. Trends Immunol 
36(4):265-276. 
18. 
Lippitz BE (2013) Cytokine patterns in patients with cancer: a systematic review. Lancet Oncol 
14(6):e218-228. 

 
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19. 
Tartour E, et al. (1996) Predictors of clinical response to interleukin-2--based immunotherapy in 
melanoma patients: a French multiinstitutional study. J Clin Oncol 14(5):1697-1703. 
20. 
Ahmadzadeh M, et al. (2009) Tumor antigen-specific CD8 T cells infiltrating the tumor express high 
levels of PD-1 and are functionally impaired. Blood 114(8):1537-1544. 
21. 
Huang A, et al. (2013) Increased CD14(+)HLA-DR (-/low) myeloid-derived suppressor cells correlate 
with extrathoracic metastasis and poor response to chemotherapy in non-small cell lung cancer 
patients. Cancer Immunol Immunother 62(9):1439-1451. 
22. 
Schneider T, et al. (2015) Serum inflammatory factors and circulating immunosuppressive cells are 
predictive markers for efficacy of radiofrequency ablation in non-small-cell lung cancer. Clinical and 
experimental immunology 180(3):467-474. 
23. 
Aerts JG & Hegmans JP (2013) Tumor-specific cytotoxic T cells are crucial for efficacy of 
immunomodulatory antibodies in patients with lung cancer. Cancer Res 73(8):2381-2388. 
24. 
Phillips JD, et al. (2015) Preferential expansion of pro-inflammatory Tregs in human non-small cell 
lung cancer. Cancer Immunol Immunother 64(9):1185-1191. 
25. 
Rizvi NA, et al. (2015) Cancer immunology. Mutational landscape determines sensitivity to PD-1 
blockade in non-small cell lung cancer. Science 348(6230):124-128. 
26. 
Miyara M, et al. (2006) The immune paradox of sarcoidosis and regulatory T cells. J Exp Med 
203(2):359-370. 
27. 
Adotevi O, et al. (2010) A decrease of regulatory T cells correlates with overall survival after 
sunitinib-based antiangiogenic therapy in metastatic renal cancer patients. J Immunother 33(9):991-
998. 
28. 
Fricke I, et al. (2007) Vascular endothelial growth factor-trap overcomes defects in dendritic cell 
differentiation but does not improve antigen-specific immune responses. Clin Cancer Res 
13(16):4840-4848. 
29. 
Gabrilovich DI, Ostrand-Rosenberg S, & Bronte V (2012) Coordinated regulation of myeloid cells by 
tumours. Nat Rev Immunol 12(4):253-268. 
30. 
Gey A, et al. (2015) Granulocytic myeloid-derived suppressor cells inversely correlate with plasma 
arginine and overall survival in critically ill patients. Clinical and experimental immunology 
180(2):280-288. 
31.  
Snyder  A et al., (2014) Genetic Basis for Clinical Response   to CTLA-4 Blockade in Melanoma N Engl 
J Med 371, 2189-99  
  
B. Immune reactivity of tumors in response to immunotherapy 
 
1 BACKGROUND  
Immunotherapy leads to significant responses in patients with advanced lung tumors but its benefit is 
observed in a small fraction of patients (1,2). In this context, predictors of response/resistance represent 
unmet clinical needs and new immunomodulators, targeting other immune pathways, are developed in order 
to circumvent the resistance mechanisms of first-in-class immunomodulators. It is likely that the use of 
combination strategies will increase the number of cancer patients that might benefit from immunotherapy.  
Mass cytometry allows a simultaneous single cell analysis of 40 parameters, giving the opportunity to deeply 
characterize the tumor microenvironment establishing an immune atlas of human cancer. It helps to clarify 
immune subsets that could functionally be explored by RNA sequencing analysis. This type of analysis was 
recently conducted in stage I lung adenocarcinoma lesions compared to health paired tissue and revealed 
significantly altered myeloids cell and lymphoid compartments. Changes in antigen cross-presenting cell 
subsets and immunosuppressive macrophages were observed compared to healthy tissues, that likely 
compromise anti-tumor T cell immunity during the priming (3) and probably prevent immune check-point 
inhibitor activity. Mass cytometry analyses can be performed on FFPE and fresh tumor tissue. 

 
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In parallel, in order to guide immunomodulator utilization in a personalized manner, we developed an “In 
Sitro” assay to perform immunological investigations on the tumor itself (Fig.1). This assay consists in 
stimulating freshly dissociated tumors with immunomodulators in vitro. Using flow cytometry and ELISA, it 
allows to delineate at the individual level, for each agent used, the specific pattern of immune parameters 
of the tumor microenvironment that might dictate the functional outcome (4). 
 
Figure 1: The In Sitro Assay. This method is based on mechanical and enzymatic dissociation of fresh 
tumors that are stimulated with immunomodulators in vitro. Then cells and supernatants are harvested at 
various time points to analyze the dynamic immunological and functional changes operating with the 
assessed immunomodulators. 
 
 
 
2 
PROJECT AIMS 
 
The research aims are: (i) Define the atlas of immune cells infiltrating lung cancer using mass cytometry. 
Here, we are going to use tumorectomie pieces (lung and nodes, if present) post-anti-PD-1 treatment. We 
will compare paired tissue (healthy and tumor) in order to highlight tissue-specific changes. Thanks to 
multiparametric immuno-histochemistry, we will analyse the geodistribution of the main populations of 
interest before and after treatment using FFPE slices (or paraffin embedded tissue). The difficulty lies on 
the acquisition of new technological and scientific assests using mass cytometry. We went over this point by 
harnessing a preexisting collaboration with experts in the field (Merad’s lab, Mount Sinai).  
 
(ii) Identify mass cytometry-based hallmarks of response and resistance to neoadjuvant PD-1 blockade in 
lung carcinoma.  
An unsupervised hierarchical clustering of immune populations according to patients’ response (pathological 
response) will be performed attempting to dissect hallmarks and identified immune(s) population(s) related 
to treatment response. This work will be performed in collaboration with clinicians and bioinformaticians in 
our lab. The difficulties are in bioinformatics analyses. In order to optimize this key step, we benefit from 
Velerio IEBBA’s help (PhD and bioinformatician) in our lab and ensure the well processing of the datas with 
frequent meeting and discussion about the project and immunology.  
 
(iii) Comprehensive understanding of at least one main mechanism of resistance to PD-1 blockade.  
Depending on the most striking and exciting results, we will proceed by cell sorting the subset of cells of 
interest, and perform single-cell transcriptomic analyses to identify new targets of resistance.  

 
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(iv) In sitro functional assays to circumvent resistance to PD-1 blockade in lung carcinoma.  
The description of the composition and activity of the immune infiltrate in lung cancer post-PD-1 blockade 
might aid in identifying new immune targets and new combination of treatments. The idea is to revert 
resistance to anti-PD1 monoclonal antibody on freshly operated tumors using a unique or a combination of 
reagents targeting other molecular pathways ex vivo, in the in sitro approach described above (4). Based on 
preexisting collaborations with several pharmaceutical partners, we have access to a variety of innovative 
immuno-oncological compounds that could be tested on surgically removed anti-PD1-resistant bladder 
tumors after mechanical and enzymatic dissociation. These compounds belong to several categories of 
products (immune checkpoint inhibitors such as Lag3, Tim3, 4ABB, OX40, TIGIT, activating receptors such as 
ICOS, enzymatic checkpoints such as CD73, ADA, IDO, and epigenetic modifiers to ameliorate T cell 
functions such as Lysine-specific demethylase...). If our library of compounds harbors a molecule which fits 
with our novel mechanism of resistance, we will test it by the in sitro approach (early and late functional 
assays). The main milestone is to not find/possess a good candidate for compensating PD-1 resistance. But 
we would describe the cancer immune atlas of lung cancer in responding and non-responding patients which 
might permit the discovery of new drug targets, help in understanding the dynamic of immune response 
during PD-1 treatment and providing a robust basis for pharmaceutical and diagnosis improvement. 
 
3 METHODS  
In order to define the immunological atlas of lung cancer exposed to the anti-PD1 monoclonal antibody, the 
post-treatment surgical specimens (tumor tissue, tissues healthy as well as invaded and normal ganglia if 
available) will be analyse by time-of-flight cytometry (CytoF) (Helios, FLUIDIGM). This will allow to define 
the immune changes related to lung tissue (healthy vs tumor) and changes in tumor progression (primary 
tumor vs. lymph node). After the establishment of a detailed map of intratumoral immune populations, a 
study on the dynamics of the immune populations undergoing treatment will be carried out. This second 
study from slides or paraffin blocks will be performed by immunohistochemical analysis in multiplex. 
 
4 RESSOURCES REQUIRED FOR THIS ANCILLARY STUDY 
Only samples from patients that accepted to participate to this optional ancillary study will be collected for 
further analyses. 
Of note, only samples that are useless for patient diagnosis will be collected for this ancillary study. 
Four FFPE tissue slices from pretreatment biopsy 
Fresh tumor, healthy tissue and if available metastatic lymph nodes from resected patients treated with 
neoadjuvant immunomodulators. To get enough CD45+ cells, ideally a surgically resected piece of 1cm3 is 
needed. 
 
5 ORIGINALITY OF THIS STUDY  
The study of the immune microenvironmental environment is necessary for the discovery of relevant 
biomarkers and the understanding of the mechanism of action of the anti-PD-L1 antibody. 
 
 
 

 
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6 REFERENCES 
1.  
Garon, E. B. et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 
372, 2018–2028 (2015).  
2.  
Borghaei, H. et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung 
Cancer. N. Engl. J. Med. 373, 1627–1639 (2015).  
3.  
Lavin, Y. et al. Innate Immune Landscape in Early Lung Adenocarcinoma by Paired Single-Cell 
Analyses. Cell 169, 750–765.e17 (2017).  
4.  
Jacquelot, N. et al. Predictors of responses to immune checkpoint blockade in advanced melanoma. 
Nat. Commun. 8, 592 (2017). 
 
 
C. Analysis of the gut microbiome in the context of anticancer immunotherapy 
 
 
1 BACKGROUND AND PROJECT AIMS 
Prospective collection of stool samples from patients enrolled in the Ionesco study before the instauration of 
immunotehrapy treatment to perform metagenomic analyses in order to (i) compare fecal dysbiosis in NSCLC 
patients at the diagnosis with matched healthy volunteers from the MetaHIT study results, (ii) identify 
metagenomics signatures that predict treatment response/resistance and immune related toxicities and (iii) 
correlate gut microbiome composition with data obtained in the Immune atlas part. 
Anti-PD1/anti-PD-L1 mAbs represents a major paradigm shift in cancer therapy. However, despite the 
unprecedented efficacy of these innovative and treatments determination of novel biomarker is of 
paramount interest. 
Currently, only few parameters have been identified as predictive biomarker of response, such as positive 
expression of PD-L1, and high mutational loads of tumors that appears to be associated with a higher 
response rate to anti-PD1 mAb. New lines of evidence demonstrated the biological significance of the gut 
microbiome (diverse range of symbiotic microorganisms) has an important contributor of pulmonary 
pathologies such as asthma and COPD (1). The gut-lung axis interaction plays a key role in immune set tone 
and ultimately could be an important factor in lung cancer carcinogenesis and further studies are 
warranted. 
Beyond the direct interactions between host immune system and microbiome, an additional layer of 
complexity exists associated to cancer therapies. 
Our group and co-investigators have paved the way by demonstrating the pivotal role of microbiome on 
cyclophosphamide (CTX) and platinum based chemotherapy (2,3). We have extended these findings to 
immune checkpoint blockade (ICB) by the anti-CTLA4 Ab (Ipilimumab) and identified Bacteroides spp. 
responsible for IL-12 production increasing systemic Th1, which improves anti-CTLA response in mice (4). 
Recently, three independent groups, including ours, highlighted that gut microbiome composition at 
baseline predicts response to PD1/PDL1 blockade in RCC, NSCLC and melanoma (5–7). Furthermore, the 
cause effect-relationship between gut commensals and treatment response was demonstrated using, avatar 
murine model. Oral gavage of dysbiotic mice with immunogenic bacteria enriched in responder patients 
restored anti-PD1 anti-cancer activity. 
In this study we plan to collect samples at baseline. 

 
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3 METHODS  
The sample used will be the stool sample at the diagnosis (or, failing that, the one made before the 3rd 
injection of durvalumab). An analysis of its composition will be performed by metagenomics to establish the 
composition of the intestinal microbiota of the patient before treatment. 
 
4 RESSOURCES REQUIRED FOR THIS ANCILLARY STUDY 
The collection kit (provided by gustave roussy cancer campus) is given to the patient at the screening visit. 
Patients bring back their sample at the hospital the day of the first administration of immunotherapy. This 
corresponds to a single sample, collected at baseline, prior immunotherapy. 
According to our previous data, if the baseline sample couldn’t have been collected, it is possible to collect 
feces until before the 3rd administration of durvalumab, without observing significant variation of the gut 
microbiome. 
Depending on the center location, two protocols of collection are available. 
In ile de france fresh samples are transferred from the centre to grcc by a courier. Samples are aliquoted 
and stored at -80°c at grcc (procedure). 
Outside of ile de france, patient aliquots themselves their samples in tubes containing a stabilization 
solution. Samples are stored on site at -80°c (procedure bis). 
 
 
5 ORIGINALITY OF THIS STUDY  
This project offers a unique opportunity to study the role of the gut microbiota in predicting the 
neoadjuvant response to durvalumab in lung cancer and to study the covariation of its composition with the 
intraluminal immune environment post-treatment. 
 
6 REFERENCES 
1.  
Arrieta M-C, Stiemsma LT, Dimitriu PA, Thorson L, Russell S, Yurist-Doutsch S, et al. Early infancy 
microbial and metabolic alterations affect risk of childhood asthma. Sci Transl Med. 30 sept 
2015;7(307):307ra152.  
2.  
Viaud S, Saccheri F, Mignot G, Yamazaki T, Daillère R, Hannani D, et al. The intestinal microbiota 
modulates 
the 
anticancer 
immune 
effects 
of 
cyclophosphamide. 
Science. 
22 
nov 
2013;342(6161):971-6.  
3.  
Iida N, Dzutsev A, Stewart CA, Smith L, Bouladoux N, Weingarten RA, et al. Commensal bacteria 
control cancer response to therapy by modulating the tumor microenvironment. Science. 22 nov 
2013;342(6161):967-70.  
4.  
Vétizou M, Pitt JM, Daillère R, Lepage P, Waldschmitt N, Flament C, et al. Anticancer 
immunotherapy 
by 
CTLA-4 
blockade 
relies 
on 
the 
gut 
microbiota. 
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27 
nov 
2015;350(6264):1079-84.  
5.  
Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, et al. Gut microbiome influences 
efficacy 
of 
PD-1-based 
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Science. 
5 
janv 
2018;359(6371):91-7.  

 
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6.  
Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, et al. Gut microbiome 
modulates 
response 
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immunotherapy 
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patients. 
Science. 
05 
2018;359(6371):97-103.  
7.  
Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y, Alegre M-L, et al. The commensal microbiome is 
associated 
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APPENDIX VI – DURVALUMAB DOSE CALCULATION FOR SUBJECT WITH WEIGTH < 30 kg 
 
The durvalumab dosing should be done depending on subject weight (if subject is < 30kg)): 
1. Cohort dose: X mg/kg 
2. Subject weight: Y kg 
3. Dose for subject: XY mg = X (mg/kg) × Y (kg) 
4. Dose to be added into infusion bag:  
Dose (mL) = XY mg / 50 (mg/mL)  
where 50 mg/mL is durvalumab nominal concentration  
The corresponding volume of durvalumab should be rounded to the nearest tenth mL (0.1 mL). Dose 
adjustments for each cycle only needed for greater than 10% change in weight. 
5. The theoretical number of vials required for dose preparation is the next greatest whole number of vials 
from the following formula: 
Number of vials = Dose (mL) / 10 (mL/vial) 
Example:  
1. Cohort dose: 10 mg/kg 
2. Subject weight: 30 kg 
3. Dose for subject: 300 mg = 10 (mg/kg) × 30 (kg) 
4. Dose to be added into infusion bag:  
Dose (mL) = 300 mg / 50 (mg/mL) = 6.0 mL 
5. The theoretical number of vials required for dose preparation:  
Number of vials = 6.0 (mL) / 10.0 (mL/vial) = 1 vials