Clinical trial NCT03197467
Conditions: Non-small Cell Lung Cancer (NSCLC)
Sponsor: AIO-Studien-gGmbH
Start date: 2018-06-18; Completion date: 2023-05-05
Enrollment: 30 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
NEOMUN is designed as an open-label, single arm, prospective, monocenter, phase II study of pembrolizumab in a neoadjuvant setting in patients with non-small cell lung cancer of Stage II/IIIA suitable for curative intent surgery.

Detailed description:
The study is designed as an open-label, single arm, prospective, monocenter, phase II study of pembrolizumab in a neoadjuvant setting in patients with resectable NSCLC stage II/IIIA suitable for curative intent surgery, taking place in Germany. Planned sample size is N=30.

Investigational drug is Pembrolizumab at fixed dose, given 200 mg q3w i.v. for 2 cycles. After completion of immunotherapy lobectomy/ bilobectomy with curative intent is scheduled.

Primary objectives are to assess feasibility and safety of a neoadjuvant application of pembrolizumab and to assess antitumor activity of pembrolizumab with regard to clinical and pathologic tumor response. Secondary objective is to assess the impact of neoadjuvant pembrolizumab on patient disease free and overall survival. Exploratory objective is o explore potential predictive biomarkers for pembrolizumab efficacy (immune cell imaging).

Arms: arm 1: Pembrolizumab at fixed dose: 200 mg q3w i.v. for 2 cycles
Interventions: intervention 1: Pembrolizumab
Intervention descriptions: intervention 1: Pembrolizumab at fixed dose: 200 mg q3w i.v. for 2 cycles

Protocol documents:
Prot_000.pdf: 
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0316-ASG / NEOMUN 
 
EudraCT-No. 2017-000105-20 
 
Version 5.0, 22-SEP-2020 
0316-ASG / NEOMUN 
 
Neoadjuvant anti PD-1 immunotherapy in resectable non-
small cell lung cancer 
 
Short title: 
NEOMUN 
 
Sponsor: 
AIO-Studien-gGmbH 
Kuno-Fischer-Straße 8 
14057 Berlin, Germany  
 
Coordinating Investigator (LKP)  
Priv.-Doz. Dr. med. Martin E. Eichhorn 
 
 
 
 
 
69126 Heidelberg, Germany  
 
 
EudraCT Nr.:  
2017-000105-20 
 
Protocol identification number: 
0316-ASG 
 
Protocol version:  
Version 5.0 (22-SEP-2020) 
 
 
 
 
Confidentiality 
 
The contents of the protocol are confidential and may neither be communicated 
verbally nor in writing without the agreement of the study sponsor. 
NCT03197467


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EudraCT-No. 2017-000105-20 
 
Version 5.0, 22-SEP-2020 
Contact Addresses 
 
 
 
 
Sponsor 
AIO-Studien-gGmbH 
Kuno-Fischer-Straße 8 
14057 Berlin 
 
 
E-mail: info@aio-studien-ggmbh.de 
Coordinating 
Investigator 
(for Germany: LKP) 
Priv.-Doz. Dr. med. Martin E. Eichhorn 
 
 
  
 
 
 
 
Drug Supply 
MSD 
Protocol Committee  
 
 
 
 
 
 
 


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AIO-Studien-gGmbH 
Approval of the Protocol 
Date (DD Month YYYY) 
SEI' j,!(}) o 
D Month YYYY) 
0316-ASG I NEOMUN 
EudraCT-No. 2017-000105-20 
Version 5.0, 22-SEP-2020 


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AIO-Studien-gGmbH 
lnvestigator's Agreement 
I have read the attached protocol entitled 
"Neoadjuvant anti PD-1 immunotherapy in resectab/e non-sma/1 ce/1/unq · 
cancer CNEOMUNl" 
Version 5.0, 22-SEP-2020 
and agree to abide by all provisions set forth therein. 
I agree to comply with the International Conference on Harmonization Tripartite 
Guideline on Good Clinical Practice all applicable national regulations as weil as the 
requirements of the appropriate lnstitutional Review Boardlindependent Ethics 
Committee and any other institutional requirements. 
I agree to ensure that the confidential information contained in this document will not 
be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of the study sponsor. 
I consent to report every serious clinical adverse event as weil as any other adverse 
event as specified in the safety section of this protocol to the safety desk within 24 
hours after awareness, whether it is related to study medication or not. 
0316-ASG I NEOMUN 
EudraCT-No. 2017-000105-20 
Version 5.0, 22-SEP-2020 


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EudraCT-No. 2017-000105-20 
 
Version 5.0, 22-SEP-2020 
Synopsis 
Protocol No. 
0316-ASG 
Protocol Version 
Final 5.0 
Title 
Neoadjuvant anti PD-1 immunotherapy in resectable non-
small cell lung cancer [NEOMUN] 
EudraCT No. 
2017-000105-20 
National Coordinating 
Investigator 
Priv.-Doz. Dr. med. Martin E. Eichhorn
Thoraxklinik – Universität Heidelberg 
Roentgenstrasse 1 
69126 Heidelberg  
 
 
 
 
Sponsor 
AIO-Studien-gGmbH 
Kuno-Fischer-Straße 8 
14057 Berlin 
 
Study design 
The study is designed as an open-label, single arm, prospective, 
monocenter, phase II study of pembrolizumab in a neoadjuvant 
setting in patients with non-small cell lung cancer of Stage II/IIIA 
suitable for curative intent surgery 
Indication 
Resectable NSCLC stage II/IIIA 
Proposed countries / 
Total number of sites 
Germany 
Number of sites total: 1 
Primary objective 
To assess feasibility and safety of a neoadjuvant application of 
pembrolizumab  
To assess antitumor activity of pembrolizumab with regard to 
clinical and pathologic tumor response  
Secondary objectives 
To assess the impact of neoadjuvant pembrolizumab on patient 
disease free and overall survival. 
Exploratory 
objectives 
To explore potential predictive biomarkers for pembrolizumab 
efficacy 
Immune cell imaging: 
 
immune cell  infiltrates in and around the resected tumor 
 
tumor tissue- and serum cytokine profiles  
 
Hypothesis generation on potential biomarkers predicting 
efficacy of pembrolizumab using multi-OMICS analysis 
Planned sample size 
N=30. 
 


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EudraCT-No. 2017-000105-20 
 
Version 5.0, 22-SEP-2020 
Inclusion criteria 
1. Cooperation and willingness to complete all aspects of the 
study 
2. Signed and dated written informed consent must be given prior 
to study inclusion 
3. Histological or cytological confirmed NSCLC. 
4. Clinical stage II-IIIA according to the TNM classification, 7th 
edition.  
stage IIIa: T1/T2 N2 (IIIa1-3 Robinson classification) 
5. Adequate disease staging by PET/CT performed and 
resectability established. 
6. At least 1 measurable lesion according to RECIST 1.1  
7. Age ≥ 18 years 
8. ECOG performance status 0 - 1  
9. Female subjects of childbearing potential must be willing to use 
an adequate method of contraception as outlined in in the 
protocol, for the course of the study through 120 days after the 
last dose of study medication. 
Note: Abstinence is acceptable if this is the usual lifestyle and 
preferred contraception for the subject.  
Female subject of childbearing potential should have a 
negative urine or serum pregnancy within 72 hours prior to 
receiving the first dose of study medication. If the urine test is 
positive or cannot be confirmed as negative, a serum 
pregnancy test will be required. 
10. Male subjects of childbearing potential must agree to use an 
adequate method of contraception as outlined in protocol, 
starting with the first dose of study therapy through 120 days 
after the last dose of study therapy. 
Note: Abstinence is acceptable if this is the usual lifestyle and 
preferred contraception for the subject. 
11. Adequate bone marrow function, liver and renal function:  
a. Absolute neutrophil count ≥ 1.5 x 109/L  
b. Thrombocytes ≥ 100 x 109/L  
c. Hemoglobin ≥ 9 g/dL without transfusion or EPO 
dependency (within 7 days of assessment) 


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d. INR < 1.4 and PTT < 40 seconds during the last 7 
days before therapy 
e. Bilirubin < 1.5 x upperlimit of normal 
f. AST (GOT) and ALT (GPT) < 2.5 x ULN  
g. Albumin ≥ 2.5 mg/dL 
h. Serum creatinine OR Measured or calculated 
creatinine clearance (GFR can also be used in place 
of creatinine or CrCl):  
 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels  
 
> 1.5 X institutional ULN 
12. adequate lung and cardiac function for intended lung resection 
according to German S3 guideline 
Exclusion criteria 
1. Anticancer treatment during the last 30 days prior to start of 
treatment, including systemic therapy, radiotherapy or major 
surgery 
2. Participation in a clinical trial within the last 30 days prior to 
study treatment 
3. History of allogeneic tissue/solid organ transplant 
4. Has a history of (non-infectious) pneumonitis that required 
steroids or current pneumonitis. 
5. Evidence of interstitial lung disease. 
6. cT4 tumor 
7. Symptomatic acute cardiovascular or cerebrovascular disease 
8. Known active HBV, HCV or HIV infection 
9. Has any other active infection requiring systemic therapy. 
10. Patients with active tuberculosis 
11. Prior therapy with an anti-Programmed cell death protein 1 
(anti-PD-1), anti-Programmed cell death-ligand 1 (anti-PD-L1), 
anti-PD-L2, anti-CD137 (4-1BB ligand, a member of the Tumor 
Necrosis Factor Receptor [TNFR] family), or anti-Cytotoxic T-
lymphocyte-associated antigen-4 (anti-CTLA-4) antibody 
(including ipilimumab or any other antibody or drug specifically 
targeting T-cell co-stimulation or checkpoint pathways) 


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12. A diagnosis of immunodeficiency or patient is receiving chronic 
systemic 
steroid 
therapy 
or 
any 
other 
form 
of 
immunosuppressive therapy within 7 days prior to the first dose 
of trial treatment. 
13. Patient has had a prior monoclonal antibody within 4 weeks 
prior to study Day 1  
14. Patient has had prior chemotherapy, targeted small molecule 
therapy, or radiation therapy within 2 weeks prior to study Day 
1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from 
adverse events due to a previously administered agent. [Note:  
Subjects with ≤ Grade 2 neuropathy are an exception to this 
criterion and may qualify for the study. If subject received major 
surgery, he/she must have recovered adequately from the 
toxicity and/or complications from the intervention prior to 
starting therapy.] 
15. Has an active autoimmune disease requiring systemic 
treatment within the past 3 months or a documented history of 
clinically severe autoimmune disease, or a syndrome that 
requires systemic steroids or immunosuppressive agents. 
Subjects with vitiligo or resolved childhood asthma/atopy 
would be an exception to this rule. Subjects that require 
intermittent use of bronchodilators or local steroid injections 
would not be excluded from the study. Subjects with 
hypothyroidism stable on hormone replacement or Sjorgen’s 
syndrome will not be excluded from the study. 
16. Has received a live vaccine within 30 days prior to the first dose 
of trial treatment. [Seasonal influenza vaccines for injection are 
generally inactivated flu vaccines and are allowed; however 
intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed.] 
17. Has known hypersensitivity to pembrolizumab or any of 
constituents of the product. 
18. Other active malignancy requiring treatment  
Exceptions include basal cell carcinoma of the skin or 
squamous cell carcinoma of the skin that has undergone 
potentially curative therapy or in situ cervical cancer. 


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19. Lactating or pregnant women, women of child-bearing 
potential who do not agree to the usage of highly effective 
contraception methods (allowed methods of contraception, 
meaning methods with a rate of failure of less than 1% per year 
are implants, injectable contraceptives, combined oral 
contraceptives, intrauterine pessars (only hormonal devices), 
sexual abstinence or vasectomy of the partner). Women of 
childbearing potential must have a negative pregnancy test 
(serum β-hCG) at Screening. 
20. Any psychiatric illness that would affect the patient’s ability to 
understand the demands of the clinical trial 
21. Patient has already been recruited in this trial 
22. Patient 
who 
has 
been 
incarcerated 
or 
involuntarily 
institutionalized by court order or by the authorities § 40 Abs. 
1 S. 3 Nr. 4 AMG. 
23. Patients who are unable to consent because they do not 
understand the nature, significance and implications of the 
clinical trial and therefore cannot form a rational intention in the 
light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG]. 
Investigational drug 
Pembrolizumab at fixed dose 
Treatment phase 
Pembrolizumab 200 mg q3w i.v. for 2 cycles
 
After completion of immunotherapy lobectomy/bilobectomy with 
curative intent is scheduled. 
Study rationale 
Survival prognosis in non-small cell lung cancer is strongly disease 
stage dependent. Patients diagnosed with clinical stage IA have a 
5-year survival rate of 82% compared to 6% in patients with stage 
IV disease [1]. Surgery with curative intent is the standard 
treatment approach in stage I and II patients and a subgroup of 
stage III patients. Despite radical tumor resection this treatment 
approach still is associated with a considerable risk of disease 
relapse in particular in stage II and IIIA disease. The overall 5-year 
relapse rate following curative intent surgery is 52% [2]. Standard 
adjuvant therapy was shown to postpone tumor recurrence by 4-5 
month. However, total rate of tumor relapse was not suppressed by 


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adjuvant therapy. Meta-analysis of clinical trial data indicates that 
adjuvant chemotherapy or radio-chemotherapy significantly 
increase overall survival. However, the effect is small and accounts 
for a 4% improvement in the 5-year overall survival rate. 
Neoadjuvant chemotherapy is an alternative standard treatment 
approach and typically consists of 3 cycles of platinum-based 
combination chemotherapy. Comparable to the adjuvant setting a 
neoadjuvant approach confers a 5% increase in the 5-year survival 
rate [3]. In terms of efficacy no difference between a pre- or 
postoperative chemotherapy approach can be determined [4]. 
In the light of the efficacy results it is clear, that improved 
multimodal treatment strategies are direly needed in order to 
improve long term survival following curative intent surgery. 
Immunotherapies made a large impact in the treatment of 
advanced stages of malignant diseases leading to marketing 
approvals for several tumor entities including NSCLC. Neoadjuvant 
immunotherapy by application of anti-PD-1 targeting antibodies is 
a logical conclusion based on the treatment reality described 
above. Clinical data on neoadjuvant treatment is scarce but 
encouraging and several trials investigating anti-PD-1/PD-L1 
checkpoint inhibition (e.g. nivolumab, durvalumab, atezolizumab) 
are ongoing.  
Consequently, the scope of this trial will be the generation of pilot 
data on efficacy, safety and feasibility of neoadjuvant anti-PD-1 
immunotherapy by pembrolizumab. The research endeavor will be 
flanked by a translational research program to elucidate potential 
predictive biomarkers and to investigate the mode of action of anti 
PD-1 treatment in NSCLC patients.  
Rationale for sample 
size and tests to be 
used 
A phase II approach will be used to generate preliminary 
hypothesis generating data. No formal sample size estimation has 
been performed. The scope is to gather information on feasibility, 
safety and efficacy. 
 
Target sample size is N=30. 
 


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The rationale for the sample size of this trial is based on ethical, 
clinical as well as scientific considerations. The neo-adjuvant 
treatment approach with an immune check-point inhibitor is highly 
experimental with only limited data on safety and feasibility 
available. Therefore, only a small number of patients should be 
subjected to this experimental treatment. Nevertheless, the sample 
size should allow the generation of statistically meaningful 
evidence for feasibility and safety to permit the decision to further 
develop this treatment approach.  
 
With a sample size of N=30 and assuming that the number of 
events follows a binomial distribution B(30,p), events with an 
incidence rate p > 9.5% will be observed at least once with a 95% 
probability. 
This 
observation 
limit 
will 
exclude 
individual 
pembrolizumab related SAEs but covers most of the historical 
reference events/rates of the primary endpoints in this trial as well 
as the early stopping rule. 
 
The degree of the potential evidence provided by a sample size of 
N=30 is summarized in the statistics section of the protocol. 
Endpoints / Statistical 
analysis 
The trial design will be a phase II trial, with descriptive outcome 
assessments of:  
Primary endpoints: 
 
frequency and severity of adverse events including peri- 
and post-operative complications (grade 2-4 AEs 
according to NCI-CTCAE V4.03) 
o number of patients treated in compliance with 
protocol 
 
Tumor response evaluation 
Clinical response parameters: 
o response rates (∆ tumor size / lymph node size), 
according to RECIST 1.1 criteria 
o ∆ PET-activity (standardized uptake value [SUV]) 
Pathologic response parameters: 
o Pathologic regression grading according to Junker 
criteria 


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Secondary endpoints:
 
disease free survival 
 
overall survival 
Study plan 
FPI 
 
 
 
 
Q2/2018 
LPI 
 
 
 
 
after approx. 36 month  
 
 
 
 
 
(Q2/2021) 
LPO 
 
 
 
 
after approx. 40 month 
 
 
 
 
 
(Q4/2021) 
EoS (after 24 month FU of LPO) 
after approx. 64 month 
 
 
 
 
 
(Q4/2023) 
 
 


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Schedule of Study Assessments 
Study Phase 
 
Procedure 
Screening
Treatment phase
Pre-
Surgery 
Dis-charge
End of 
treatment 
Follow-up 
Visit 
SCR
V1
V2 
PS
D
EOT
FU1 – FUx 
Time windows 
Day - 28
to 0 
Day 1
Day 21 +/- 3 days
Day 43-50 
Day 60-74 
6 wks. after 
surgery 
every 3 
months 
Informed consent 
X 
 
 
 
 
 
 
Demographics  
(age, gender, race) 
X 
 
 
 
 
 
 
Tumor diagnosis 
X 
 
 
 
 
 
 
Cancer history 
X 
 
 
 
 
 
 
Medical history (incl. smoking status) 
X 
 
 
 
 
 
 
Previous treatments 
X 
 
 
 
 
 
 
Tumor assessments  
(PET)-CT, RECIST 1.1 
X 
 
 
X 
 
 
 
Tumor staging 
(PET-CT, MRI brain) 
X 
 
 
 
 
 
 
Chest X-ray 
X 
 
X 
X 
X 
X 
 
Cardiac evaluation  
(12-lead ECG) 
X 
 
(X)1 
X 
 
X 
 
Physical examination2 
X 
 
X 
X 
X 
X 
 
Body weight and height / BSA3 
X 
 
X 
X 
 
X 
 
Vital signs  
(BP, HR, body temperature) 
X 
(X)8 
X 
X 
X 
X 
 
Lung function test 
blood gas values 
X 
 
X 
X 
 
X 
 
ECOG status 
X 
 
X 
X 
 
X 
 
Pregnancy test (if applicable) 
X 
(X)8 
 
 
 
 
 
Hematology4 
X 
(X)8 
X 
X 
X 
X 
 
Coagulation 
X 
(X)8 
X 
X 
X 
X 
 
Clinical chemistry5 
X 
(X)8 
X 
X 
X 
X 
 
tumor marker 
X 
 
 
X 
 
X 
 
TSH6 
X 
 
X 
X 
X 
X 
 
In- / Exclusion criteria 
X 
 
 
 
 
 
 
Biomarkers (blood sample) 
 
X 
X 
X 
X 
X 
 
Tumor tissue9 
X 
 
 
 
X 
 
 
HR-QoL 
X 
 
 
X 
 
X 
 
Treatment (V1/V2)
 
Pembrolizumab 200 
mg i.v 
Pembrolizumab 200 
mg i.v. . 
 
 
 
 


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Version 5.0, 22-SEP-2020 
Study Phase 
 
Procedure 
Screening
Treatment phase
Pre-
Surgery 
Dis-charge
End of 
treatment 
Follow-up 
Visit 
SCR
V1
V2 
PS
D
EOT
FU1 – FUx 
Time windows 
Day - 28
to 0 
Day 1
Day 21 +/- 3 days
Day 43-50 
Day 60-74 
6 wks. after 
surgery 
every 3 
months 
Concomitant medication 
X 
Continuously 
 
Concomitant procedures 
X 
Continuously 
 
Adverse events 
X 
Continuously 
X7 
Subsequent cancer therapy 
 
 
 
 
 
 
X 
Survival status 
 
 
 
 
 
 
X 
1 if clinically indicated. Consult a specialist if clinically abnormal and exclude any immune-related myocarditis. 
2 Full examination is required at baseline and end of treatment. Focused clinical examination shall prevail throughout the course of treatment. 
3 Body height will only be measured at screening. 
4 Full blood count including blood differential test will be performed at baseline, after start of treatment (V2) and further indicated time points throughout treatment and at end of study. 
5 Sodium, potassium, calcium, magnesium, phosphate, AST, ALT, PTT/INR, LDH, total bilirubin, creatinine, creatinine clearance, albumin, tumor marker CEA, Cyfra 21-1 
6 To be done at baseline and 3 weeks after start of treatment (V2) and further indicated time points throughout treatment and at end of study. If rising TSH is detected, a full assessment of fT3 and fT4 shall be performed and signs of 
hormone depletion shall be monitored clinically. 
7 Follow-up of ongoing SAEs until resolution or stabilization. Serious adverse events are recorded until 90 days after last dose of IMP or for 6 weeks after surgery if the subject initiated new anticancer therapy (e.g. 
radiochemotherapy). Pregnancies occurring in a study subject are recorded from time of signed informed consent until 120 days after last dose of IMP. 
8 Repeat assessment if SCR assessment is older than 7 days. 
9 Post-op. tumor regression grading.  
 
 


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Safety reporting contact information (SAE / Pregnancy) 
 
 
In the case of a serious adverse event (SAE) or pregnancy safety desk must be 
contacted within 24 hours.  
 
Contact details for safety reporting are provided in the Investigator Site File. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The safety desk will inform MSD Germany Pharmacovigilance (Email: 
) and other appropriate 
persons about all SAEs, as well as pregnancy and events of clinical interest, within 1 working 
day of knowledge of the event. 
 


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Glossary of Abbreviations 
ADR 
Adverse drug reaction 
AE 
Adverse event 
AIO 
Arbeitsgemeinschaft Internistische Onkologie 
ALT (SGPT) 
Alanine aminotransferase 
AMG 
Arzneimittelgesetz (German Drug Law) 
ANC 
Absolute neutrophil count 
AST (SGOT) 
Aspartate aminotransferase 
AUC 
Area under the curve 
BP 
Blood pressure 
BSA 
Body Surface Area 
CI 
Confidence interval 
CR 
Complete response 
CRF / eCRF 
Case report form / electronic Case report form 
CSR 
Clinical study report 
CT 
Computed tomography 
CTC 
Common terminology criteria 
CTCAE 
Common terminology criteria of adverse events 
D 
Day 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
e.g. 
For example 
EMA 
European Medicines Agency 
EOT 
End of treatment 
etc 
Et cetera 
FPFV 
First patient first visit 
FU 
Follow up 
g 
Gram 
GCP 
Good Clinical Practice 
GCP-V 
GCP-Verordnung 
HR 
Heart rate 
HR 
Hazard ratio 
IADL 
Instrumental Activities of Daily Living 
IB 
Investigators’ Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee 
i.e. 
That is 
IMP 
Investigational medicinal product 
ITT 
Intent to treat 
i.v. / IV 
Intravenous 
kg 
kilogram 
L 
Liter 
LKP 
Leiter der klinischen Prüfung (Co-ordinating Investigator) 
LPFV 
Last patient first visit 
LPLV 
Last patient last visit 
m² 
Square meter (body surface area) 
mAb 
Monoclonal Antibody 


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mg 
Milligram 
min 
Minute 
mL 
Milliliter 
mm 
Millimeter 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute  
NCT 
National Center for Tumor Diseases 
NOAEL 
no observed adverse effect level 
OP 
Operation 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease 
PD-1 
Programmed death receptor 1 
PD-L1 
Programmed death receptor ligand 1 
PFS 
Progression free survival 
PP 
Per Protocol 
PR 
Partial response 
q3w 
Every 3 weeks 
QoL 
Quality of Life 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RICTOR 
Rapamycin-insensitive companion of mTOR 
SAE 
Serious adverse event 
SADR 
Serious adverse drug reaction 
SCR 
Screening 
SD 
Stable disease 
SOC 
Standard of Care 
SUSAR 
Suspected unexpected serious adverse reaction 
SUV 
Standardized uptake value 
TBD 
To be determined 
TTFS 
Time to Failure of Strategy 
TPS 
Tumor Proportion Score 
V 
Version 
WHO 
World Health Organization 
 
 
 


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Table of Contents 
CONTACT ADDRESSES 
2 
APPROVAL OF THE PROTOCOL 
3 
INVESTIGATOR’S AGREEMENT 
4 
SYNOPSIS  
5 
SCHEDULE OF STUDY ASSESSMENTS 
13 
SAFETY REPORTING CONTACT INFORMATION (SAE / PREGNANCY) 
15 
GLOSSARY OF ABBREVIATIONS 
16 
TABLE OF CONTENTS 
18 
1 
BACKGROUND AND RATIONALE 
23 
1.1 
Disease Background 
23 
1.2 
Pembrolizumab 
23 
1.2.1 
Pembrolizumab Background 
23 
1.2.2 
Mechanism of Action 
24 
1.2.3 
Pembrolizumab Non Clinical Data 
24 
1.1.1.1 
Pharmacology 
24 
1.1.1.2 
Toxicology and Toxicokinetics 
25 
1.2.4 
Pembrolizumab Clinical Safety and Efficacy 
25 
1.3 
Study Rationale 
29 
1.3.1 
Rationale for Dose Selection/Regimen/Modification 
30 
1.4 
Risk-Benefit Analysis 
32 
2 
OBJECTIVES OF THE STUDY 
35 
2.1 
Primary Objective 
35 
2.2 
Secondary Objectives 
35 
2.3 
Exploratory Objectives 
35 
2.4 
Primary endpoint 
35 
2.5 
Secondary endpoints 
36 
2.6 
Exploratory endpoints: 
36 
3 
OVERVIEW OF STUDY DESIGN AND DOSING REGIMEN 
37 
3.1 
Treatment Phase 
37 
3.1.1 
Surgery 
37 
3.2 
End of Treatment 
38 
3.3 
Follow-up Phase 
38 


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3.4 
End of Study 
38 
3.5 
Assignment of Patients to Treatment 
38 
3.6 
Study sites 
38 
3.7 
Study Duration 
38 
4 
SELECTION OF THE STUDY POPULATION 
40 
4.1 
Target Population 
40 
4.2 
Inclusion Criteria 
40 
4.3 
Exclusion Criteria 
41 
5 
SCHEDULE OF ASSESSMENT AND PROCEDURES 
44 
5.1 
Study Assessments 
44 
5.1.1 
Tumor assessments 
44 
5.1.2 
Other Clinical Assessments 
46 
5.1.2.1 
ECOG Performance Status 
46 
5.1.2.2 
Medical history 
46 
5.1.2.3 
ECG 
46 
5.1.2.4 
Chest X-ray 
46 
5.1.2.5 
Quality of life 
46 
5.1.2.6 
Lung function/blood gas analysis 
46 
5.1.2.7 
Physical examination 
47 
5.1.2.8 
Vital signs 
47 
5.1.2.9 
Translational Research 
47 
5.1.3 
Safety Assessments 
47 
5.1.4 
Laboratory Assessments 
47 
5.2 
Study Procedures 
47 
5.2.1 
Screening Procedures (day -28 to 0) 
47 
5.2.2 
Treatment Phase 
49 
5.2.3 
Pre-surgical visit 
50 
5.2.4 
Discharge visit 
50 
5.2.5 
End of Treatment Visit 
51 
5.2.6 
Follow-up 
51 
5.2.7 
End of Study 
52 
5.2.8 
Planned Treatment of the Patient after End of Treatment Phase 
52 
5.3 
Removal of Patients from Treatment 
52 
5.4 
Study discontinuation 
53 
6 
INVESTIGATIONAL PRODUCT 
55 
6.1 
Investigational Medicinal Product (IMP) 
55 
6.1.1 
Supply of pembrolizumab 
55 


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6.1.2 
Documentation 
56 
6.2 
Preparation and Administration of Pembrolizumab 
56 
6.2.1 
Drug Name, Formulation and Storage 
56 
6.2.2 
Route of Administration 
57 
6.2.3 
Infusion reactions – Course of action and premedication 
58 
6.2.4 
Compliance 
58 
6.3 
Dose Modifications 
59 
6.3.1 
Dose Modification and Discontinuation of pembrolizumab for adverse 
reactions 
59 
6.3.2 
Supportive Care Guidelines 
61 
6.4 
Concomitant Medication and Treatment 
64 
7 
ASSESSMENT OF SAFETY 
67 
7.1 
Reference safety documents 
67 
7.2 
Adverse Events definitions 
67 
7.2.1 
Adverse Events 
67 
7.2.2 
Serious Adverse Event 
67 
7.2.3 
AEs of Special Interest (Events of Clinical Interest) 
68 
7.2.4 
Other reportable events 
69 
7.2.5 
Unexpected Adverse Event 
69 
7.2.6 
Overdose 
69 
7.3 
Assessment of relationship - Adverse drug reaction 
70 
7.4 
Assessment of severity 
70 
7.5 
Safety recording and reporting requirements 
71 
7.5.1 
Recording periods 
71 
7.5.2 
Recording and Reporting requirements 
71 
7.5.3 
Sponsor obligations 
74 
7.6 
Handling of Safety Parameters 
75 
7.6.1 
Adverse events 
75 
7.6.2 
Overdose of pembrolizumab 
75 
7.6.3 
Treatment and Follow-up of Adverse Events 
76 
7.6.4 
Treatment and Follow-up of Events of Clinical Interest 
76 
7.6.5 
Follow-up of Abnormal Laboratory Test Values 
76 
7.6.6 
Contraception and Pregnancy 
76 
7.6.7 
Adverse Drug reactions with Concomitant Medication 
78 
8 
STATISTICAL METHODS AND SAMPLE SIZE 
79 
8.1 
Trial design and hypotheses 
79 
8.2 
Sample Size Calculation 
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8.3 
Evaluation categories of the patients 
80 
8.3.1 
Intent-to-Treat population 
80 
8.3.2 
Per-Protocol population 
80 
8.3.3 
Safety population 
81 
8.4 
Methods of Statistical Analysis 
81 
8.4.1 
General statistical considerations 
81 
8.4.2 
Demographics and baseline characteristics 
82 
8.4.3 
Efficacy evaluation 
82 
8.4.4 
Safety evaluation 
83 
9 
INDEPENDENT DATA MONITORING COMMITTEE 
83 
10 
DATA QUALITY ASSURANCE 
84 
11 
ETHICAL ASPECTS 
85 
11.1 
Declaration of Helsinki / Good Clinical Practice 
85 
11.2 
Patient Information and Informed Consent 
85 
11.3 
Independent Ethics Committees and Regulatory Authorities 
86 
11.3.1 
Approval of the study by the Regulatory Authority and Independent 
Ethics Committees 
86 
11.3.2 
Notification of the study 
86 
11.3.3 
Report and documentation obligation 
86 
12 
CONDITIONS FOR MODIFYING THE PROTOCOL 
86 
13 
STUDY DOCUMENTATION, ECRFS AND RECORD-KEEPING 
87 
13.1 
Investigator's Files / Retention of Documents 
87 
13.2 
Source Documents and Background Data 
88 
13.3 
Audits and Inspections 
88 
13.4 
Electronic Case Report Forms (eCRF) 
88 
14 
MONITORING THE STUDY 
90 
15 
CONFIDENTIALITY OF TRIAL DOCUMENTS AND PATIENT RECORDS 
90 
16 
STUDY REPORT AND PUBLICATION POLICY 
90 
17 
REFERENCES 
92 
18 
APPENDICES 
94 
18.1 
Appendix 1 – ECOG Performance Status 
95 
18.2 
Appendix 2 – RECIST 1.1 
96 
18.3 
Appendix 3 - Junker criteria for tumor regression grading 
97 
18.4 
Appendix 4 – Cockcroft-Gault Formula 
98 


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18.5 
Appendix 5 – NCI-CTC Version 4.03 (CTCAE v4.03) 
99 
18.6 
Appendix 6 – Declaration of Helsinki, Republic of South Africa, 
October 1996 
100 
18.7 
Appendix 7 – Summary of Changes 
101 
 
 


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1 Background and Rationale 
1.1 Disease Background 
 
In Germany lung cancer is the most frequent form of cancer death in male and the third 
most frequent malignant disease in women [5]. A steady trend to increasing incidence 
numbers in the female population is observed and the most important risk factor for 
disease remains tobacco smoking. Lung cancer diagnosis is associated with a poor 
prognosis and 5-year survival rates are 16% in male and 21% in female patients [5]. 
Non-small cell lung cancer (NSCLC) is the dominant form comprising 85-90% of all 
lung cancers. NSCLCs are divided into three main subgroups; squamous cell 
carcinoma, large cell carcinoma and adenocarcinomas, the latter of which is generally 
the most frequent (60-70% of NSCLC). Curative intent surgery represents the primary 
treatment modality in approximately 30% of NSCLC patients. However, even in patient 
cohorts of specialized high volume lung cancer centers more than 50% of patients 
develop tumor recurrence within 5 years following curative intend surgery. (see Figure 
1). 
1.2 Pembrolizumab 
1.2.1 Pembrolizumab Background 
 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) 
of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and 
its ligands, PD-L1 and PD-L2. KEYTRUDA® (pembrolizumab) has recently been 
approved in the United Stated and the E.U. for the treatment of patients with 
unresectable or metastatic melanoma and disease progression following ipilimumab 
and, if BRAF V600 mutation positive, a BRAF inhibitor. Additionally, pembrolizumab 
has received marketing approval for the treatment of locally advanced or metastatic 
non-small cell lung carcinoma (NSCLC) in adults whose tumors express PD-L1 and 
who have received at least one prior chemotherapy regimen.  
 
On 05-Aug-2016 the US FDA approved KEYTRUDA®, at a fixed dose of 200 mg Q3W, 
for the treatment of patients with recurrent or metastatic head and neck squamous cell 
carcinoma (HNSCC) with disease progression on or after platinum-containing 


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chemotherapy. Under the FDA’s accelerated approval regulations, this indication for 
KEYTRUDA® is approved based on tumor response rate and durability of response. 
For HNSCC patients, PD-L1 testing is not needed prior to use of KEYTRUDA®. The 
FDA-approved dose of KEYTRUDA® is 200 mg Q3W. 
1.2.2 Mechanism of Action 
 
The PD-L1 and PD-L2 can be found on tumor cells and this receptor-ligand interaction 
is one of the major pathways used by the cancerous cells to suppress the body’s 
immune response to the tumor, as binding of either PD-L1 or PD-L2 to PD-1 inhibits T 
cell activation triggered through the T cell receptor.  
Evidence shows a correlation between tumor-infiltrating lymphocytes in cancer tissue 
and a favorable prognosis in various malignancies. Correspondingly, a high expression 
of PD-L1 (and to a lesser extent PD-L2) on tumor cells has been found to correlate 
with a poor prognosis and survival rate in various types of cancer. Pembrolizumab can 
prevent the binding of PD-L1 and PD-L2 to the PD-1 receptor thus preventing its tumor 
suppressing effects on the immune response. Therefore, it is predicted that 
Pembrolizumab has the potential to improve the prognosis and survival rates of 
patients with various malignancies. For this reason Pembrolizumab is being developed 
to treat patients with various malignancies. 
1.2.3 Pembrolizumab Non Clinical Data 
1.1.1.1 Pharmacology 
 
Pembrolizumab binds to human and Cynomolgus monkey PD-1 with comparable 
affinity and blocks the binding of human and Cynomolgus monkey PD-1 to PD-L1 and 
PD-L2 with comparable potency. Pembrolizumab does not cross-react with dog, rat, or 
mouse PD-1. Pembrolizumab does not bind immunoglobulin (Ig) superfamily members 
cluster of differentiation 28 (CD28), cytotoxic T-lymphocyte-associated protein 4 
(CTLA-4), or inducible T-cell costimulator (ICOS). 
Pembrolizumab strongly enhances T-lymphocyte immune responses in cultured blood 
cells from healthy human donors, cancer subjects, and nonhuman primates. In T-cell 
activation assays using human donor blood cells, the half-maximal effective 
concentration has been approximately 0.1 to 0.3 nanomolar (nM). In addition to 


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interleukin-2 (IL-2), tumor necrosis factor alpha (TNFα), interferon gamma (IFNɣ), and 
levels of other cytokines were found to be modulated by pembrolizumab. The antibody 
potentiates existing immune responses only in the presence of antigen and does not 
nonspecifically activate T-cells. In the in vitro peripheral blood mononuclear cell 
(PBMC) and whole blood cytokine release assays, the cytokine levels induced by 
pembrolizumab were low and comparable to those induced by trastuzumab. 
Pembrolizumab does not induce antibody-dependent cell-mediated cytotoxicity 
(ADCC) or complement-dependent cytotoxicity (CDC). Using anti–murine PD-1 
surrogate antibodies, PD-1 blockade has been shown to significantly inhibit tumor 
growth in a variety of syngeneic murine tumor models. In these experiments in mice, 
anti–PD-1 therapy is synergistic with chemotherapeutic agents such as gemcitabine 
and 5-fluorouracil (5-FU), and combination therapy results in increased complete tumor 
regression rates in vivo. Studies also revealed that immunosuppressive doses of 
dexamethasone included in combination with agents used in standard-of-care 
treatment for NSCLC do not reduce the anti-tumor efficacy of an anti–murine PD-1 
surrogate antibody. 
1.1.1.2 Toxicology and Toxicokinetics 
 
Refer to the current Investigator’s Brochure of pembrolizumab for preclinical data. 
 
1.2.4 Pembrolizumab Clinical Safety and Efficacy  
 
Pharmacokinetics 
PK data are presented in the IB from a total of 1818 PK-evaluable subjects with 
advanced melanoma (KN001 [Parts B and D], KN002), NSCLC (KN001 Parts C and 
F), advanced solid tumors (including triple negative breast cancer [TNBC], head and 
neck squamous cell carcinoma [HNSCC], urothelial carcinoma, gastric cancer 
[KN012]), and hematological cancers (KN013 and KN023). The observed PK profile of 
pembrolizumab was typical when compared with other immunoglobulin G (IgG) mAbs 
with a t1/2 of approximately 3 weeks [6]. 
Safety 


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To date, Pembrolizumab has been generally well tolerated, as expected based on 
preclinical findings and work conducted with other anti-PD-1 monoclonal antibodies. 
No serious infusions reactions have been reported and less than 1% of patients 
assayed so far have tested positive for the presence of Pembrolizumab antibodies 
(anti-drug antibodies - ADA). Where Pembrolizumab antibodies have been detected 
its presence does not appear to have impacted on overall levels of patient exposure. 
The majority of subjects (97.4%) in pembrolizumab monotherapy trials experienced 
one or more AEs, 73.7% experienced one or more AEs reported as drug-related by 
the investigator. The percentage of subjects who experienced SAEs was lower; 37.2% 
of subjects experienced one or more SAEs; and 11.9% of subjects discontinued due 
to an AE. 10.0% of subjects experienced a drug-related SAE, as determined by the 
investigator. 
 
The 5 most frequently reported AEs were: fatigue (37.3%), nausea (24.5%), decreased 
appetite (22.5%), diarrhea (22.3%), and cough (22%). The 5 most frequently reported 
SAEs were pneumonia (3.0%), pleural effusion (1.7%), pneumonitis (1.6%), dyspnea 
(1.6%) and pulmonary embolism (1.5%). 
 
The 5 most frequently reported adverse events considered drug-related by the 
investigator were fatigue (24.2%), pruritus (16.7%), rash (13.8%), diarrhea (12.3%), 
and nausea (10.9%). The 5 most frequently reported serious adverse events 
considered drug related by the investigator were pneumonitis (1.6%), colitis (0.9%), 
diarrhea (0.6%), pyrexia (0.4%) and autoimmune hepatitis (0.3%). 
Full details on pembrolizumab safety can be found in the current Investigator’s 
Brochure [6]. 
 
 
Efficacy 
3 important clinical studies were conducted to evaluate the efficacy of pembrolizumab 
in the treatment of NSCLC: KN001, and KN010 and KN024. 


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KN001 was an open-label, Phase 1, first-in-human study conducted to evaluate clinical 
activity of pembrolizumab as a single agent in 2 cancers, including NSCLC. There were 
several dosing regimens (see IB). Part C and Part F of KN001 enrolled subjects with 
NSCLC.  
KN010 was a randomized, adaptively designed Phase 2/3 trial of pembrolizumab at 2 
dose levels vs docetaxel in subjects with NSCLC with PD-L1 positive tumors who had 
experienced disease progression after platinum-containing systemic therapy. Subjects 
were randomized according to their tumor proportion score (TPS) (extent of PD-L1 
expression) defined as follows: a TPS ≥ 50% was considered strongly positive and a 
TPS°= 1% to 49% was considered weakly positive. 
In KN001 the independently confirmed objective response rate according to RECIST 
1.1 was 41% among all treated subjects (N=61) with strong PD-L1 expression in the 
tumor [6]. 
 
For the KN010 Intent-to-treat (ITT) Population (TPS≥50%), median OS was 14.9 
months in the 2 mg/kg Q3W pembrolizumab arm and 17.3 months in the 10 mg/kg 
Q3W pembrolizumab arm compared with 8.2 months in the docetaxel arm. In the 
TPS≥50% stratum, an HR of 0.54 (p=0.00024, median 14.9 months) was observed for 
OS comparing pembrolizumab 2 mg/kg Q3W to docetaxel [6]. 
For the KN010 ITT population with TPS≥1% (total population), the OS HR for 
pembrolizumab 2 mg/kg vs docetaxel was 0.71 (95% CI: 0.58, 0.88) with a p-value of 
0.00076. The OS HR for pembrolizumab 10 mg/kg vs docetaxel was 0.61 (95% CI: 
0.49, 0.75) with a p-value <0.00001. 
For the KN010 ITT Population (TPS≥50%), median PFS was 5.2 months in the 2 mg/kg 
Q3W and 10 mg/kg Q3W arms compared with 4.1 months in the docetaxel arm. The 
HR for PFS was 0.58 (p=0.00009, median 5.2 months) observed for PFS comparing 
pembrolizumab 2 mg/kg Q3W to docetaxel, and an HR of 0.59 (p=0.00007, median 
5.2 months) was observed for PFS comparing pembrolizumab 10 mg/kg Q3W to 
docetaxel. For the KN010 ITT population with TPS≥1% (total population) PFS results 
did not meet the predefined criteria for statistical significance. 


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Among patients in KN010 with a tumor proportion score of 50% or greater, responses 
occurred in 30% of patients in the pembrolizumab 2 mg/kg group, 29% of patients in 
the pembrolizumab 10 mg/kg group, and 8 % of patients in the docetaxel group 
(p<0.0001 for each pembrolizumab group vs docetaxel). In the total population, 62 
(18%) of 344 patients versus 64 (18%) of 346 patients versus 32 (9%) of 343 had 
responses (p=0.0005 for 2 mg/kg vs docetaxel and p=0.0002 for 10 mg/kg vs 
docetaxel). All responses were partial responses. Median time to response was 9 
weeks in each treatment group [7]. 
Recently the KEYNOTE-024 trial investigating the use of pembrolizumab, in patients 
with previously untreated advanced non-small cell lung cancer (NSCLC) whose tumors 
expressed high levels of PD-L1, met its primary endpoint. In this trial, pembrolizumab 
was superior compared to chemotherapy for both the primary endpoint of progression-
free survival (PFS), and the secondary endpoint of overall survival (OS). Based on 
these results, an independent Data Monitoring Committee (DMC) has recommended 
that the trial be stopped, and that patients receiving chemotherapy in KEYNOTE-024 
be offered the opportunity to receive pembrolizumab. 
 
Conclusion: 
Overall, the results from KN001 and KN010 demonstrated that pembrolizumab 
provided substantial, clinically meaningful benefits in OS, PFS, and ORR in subjects 
with NSCLC who progressed after platinum-containing chemotherapy and whose 
tumor cells expressed PD-L1. The PD-L1 selection employed in KN010 identified 
patients more likely to benefit from pembrolizumab and resulted in favorable HRs in 
OS compared to docetaxel. 
 
 
 


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1.3 Study Rationale 
Survival prognosis in non-small cell lung cancer is strongly disease stage dependent. 
Patients diagnosed with clinical stage IA have a 5-year survival rate of 82% compared 
to 6% in patients with stage IV disease [1]. Surgery with curative intent is the standard 
treatment approach in stage I and II patients and a subgroup of stage III patients. 
Despite radical tumor resection this treatment approach still is associated with a 
considerable risk of disease relapse in particular in stage II and IIIA disease. The 
overall 5-year relapse rate following curative intent surgery is 52% [2]. Standard 
adjuvant therapy was shown to postpone tumor recurrence by 4-5 month. However, 
total rate of tumor relapse was not suppressed by adjuvant therapy. Meta-analysis of 
clinical trial data indicates that adjuvant chemotherapy or radio-chemotherapy 
significantly increase overall survival. However, the effect is small and accounts for a 
4% improvement in the 5-year overall survival rate. Neoadjuvant chemotherapy is an 
alternative standard treatment approach and typically consists of 3 cycles of platinum-
based combination chemotherapy. Comparable to the adjuvant setting a neoadjuvant 
approach confers a 5% increase in the 5-year survival rate [3]. In terms of efficacy no 
difference between a pre- or postoperative chemotherapy approach can be determined 
[4]. 
In the light of the efficacy results it is clear, that improved multimodal treatment 
strategies are direly needed in order to improve long term survival following curative 
intent surgery. Immunotherapies made a large impact in the treatment of advanced 
stages of malignant diseases leading to marketing approvals for several tumor entities 
including NSCLC. Neoadjuvant immunotherapy by application of anti-PD-1 targeting 
antibodies is a logical conclusion based on the treatment reality described above. 
Clinical data on neoadjuvant treatment is scarce but encouraging [8, 9] and trials 
investigating anti-PD-1/PD-L1 checkpoint inhibition (e.g. nivolumab, durvalumab, 
atezolizumab) ongoing.  
First preliminary data on neoadjuvant anti-PD-1 therapy in NSCLC patients presented 
on the ESMO conference 2016. In stage I-III NSCLC patients neoadjuvant nivolumab 
therapy induced pathological tumor response in 80% (12/15) of patients and major 
pathologic response in 40% (6/15) treated with only 2 cycles of nivolumab 
administered  2 and 4 weeks prior to tumor resection [8]. The results were confirmed 


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at final analysis, with a major pathologic response observed in 43% of all treated 
subjects (95% CI 24-63%; 9/21 subjects) [9]. 
Consequently, the scope of this trial will be the generation of pilot data on efficacy, 
safety and feasibility of neoadjuvant anti-PD-1 immunotherapy by pembrolizumab. The 
research endeavor will be flanked by a translational research program to elucidate 
potential predictive biomarkers and to investigate the mode of action of anti PD-1 
treatment in NSCLC patients. 
 
Figure 1- Stage dependent survival in NSCLC. Left panel - The IASLC Lung Cancer Staging 
Project [1] ; right panel - Thoraxklinik Heidelberg 
 
1.3.1 Rationale for Dose Selection/Regimen/Modification 
 
An open-label Phase I trial (Protocol 001) was conducted to evaluate the safety and 
clinical activity of single agent MK-3475. The dose escalation portion of this trial 
evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 
weeks (Q2W) in subjects with advanced solid tumors. All three dose levels were well 
tolerated and no dose-limiting toxicities were observed. This first in human study of 
MK-3475 showed evidence of target engagement and objective evidence of tumor size 
reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W). No MTD has been 
identified to date.  
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic 
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Pharmacodynamic data (IL-2 release assay) suggested that peripheral target 
engagement is durable (>21 days). This early PK and pharmacodynamic data provides 
scientific rationale for testing a Q3W dosing schedule. 
A population pharmacokinetic analysis has been performed using serum concentration 
time data from 476 patients. Within the resulting population PK model, clearance and 
volume parameters of MK-3475 were found to be dependent on body weight. The 
relationship between clearance and body weight, with an allometric exponent of 0.59, 
is within the range observed for other antibodies and would support both body weight 
normalized dosing or a fixed dose across all body weights. MK-3475 has been found 
to have a wide therapeutic range based on the melanoma indication. The differences 
in exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg Q3W body weight 
based regimen are anticipated to remain well within the established exposure margins 
of 0.5 – 5.0 for MK-3475 in the melanoma indication. The exposure margins are based 
on the notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the 
proposed dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The 
population PK evaluation revealed that there was no significant impact of tumor burden 
on exposure. In addition, exposure was similar between the NSCLC and melanoma 
indications. Therefore, there are no anticipated changes in exposure between different 
indication settings. 
The rationale for further exploration of 2 mg/kg and comparable doses of 
pembrolizumab in solid tumors is based on: 1) similar efficacy and safety of 
pembrolizumab when dosed at either 2 mg/kg or 10 mg/kg Q3W in melanoma patients, 
2) the flat exposure-response relationships of pembrolizumab for both efficacy and 
safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg Q3W, 3) the lack of effect of 
tumor burden or indication on distribution behavior of pembrolizumab (as assessed by 
the population PK model) and 4) the assumption that the dynamics of pembrolizumab 
target engagement will not vary meaningfully with tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing 
is based on simulations performed using the population PK model of pembrolizumab 
showing that the fixed dose of 200 mg every 3 weeks will provide exposures that 1) 
are optimally consistent with those obtained with the 2 mg/kg dose every 3 weeks, 2) 
will maintain individual patient exposures in the exposure range established in 


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melanoma as associated with maximal efficacy response and 3) will maintain individual 
patients exposure in the exposure range established in melanoma that are well 
tolerated and safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for 
physicians and to reduce potential for dosing errors. A fixed dosing scheme will also 
reduce complexity in the logistical chain at treatment facilities and reduce wastage. 
Rationale for a 2-cycle treatment regimen 
The rationale for a 2-cycle regimen can be derived from the following three aspects: 
1. Clinical efficacy: Results from a pilot study with nivolumab in a neoadjuvant 
setting in stage I-III NSCLC indicate that 2 cycles of anti-PD-1 inhibition result 
in tumor response and permitted successful tumor resection the majority of 
patients (see also section 1.3)[9]. 
2. Patient safety: Shorter treatment courses (i.e. 2 cycles of neoadjuvant treatment 
vs. 3 cycles or more) are preferable as it would reduce the risk of inoperability 
due to treatment emergent adverse events (e.g. immune-mediated 
pneumonitis) or tumor progression. 
3. Ethical consideration: Patients with resectable lung cancer have the reasonable 
expectation to undergo tumor resection as soon as possible. A waiting period 
of 6 weeks until surgery resulting from the application of 2 doses of neoadjuvant 
immunotherapy still represents a clear and acceptable perspective for the 
patient for tumor removal. 
1.4 Risk-Benefit Analysis 
 
The neoadjuvant treatment approach is an accepted and frequently applied treatment 
strategy in stage II-III lung cancer. The general risk of this strategy is a delay of the 
surgical intervention which may render the tumor unresectable after the completion of 
the pharmaceutical intervention. This potential risk similarly applies to this trial. As a 
measure of risk reduction the extent of the neoadjuvant treatment with pembrolizumab 
will be limited to 2 cycles (i.e. 6 weeks) which corresponds to the typical duration of 
classical chemotherapy regimens and is considered safe. Additional risks arise from 
the insufficient knowledge of the perioperative safety of an immunotherapy such as 


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pembrolizumab. Typically, in pivotal studies extensive temporal safety margins 
between immunotherapies and surgical interventions have been mandated. It will be 
the goal of this pilot study targeting a small patient cohort to generate additional safety 
data in this context. The safety profile of anti-PD-1/PD-L1 antibodies is generally 
favorable compared to classical platinum-combination protocols and no particular 
adverse events (e.g. wound healing disorders) are known which would preclude a use 
of pembrolizumab in the neoadjuvant setting. Additionally, comprehensive AE 
treatment guidelines and dose modification recommendations have been established 
and incorporated in this protocol. 
Pembrolizumab is approved in stage IV NSCLC with a PD-L1 tumor proportion score 
≥50%. However, the predictive role of PD-L1 expression in early stage NSCLC is 
unclear. Pilot data from nivolumab in a neoadjuvant setting in NSCLC did not show a 
correlation between tumor response and resectability and PD-L1 positivity [9]. 
Furthermore, comparative studies between NSCLC biopsies and surgically resected 
specimens revealed major discordance with regard to PD-L1 positivity [10, 11]. Given 
the uncertainty of the temporal and spatial dynamics of PD-L1 expression in early stage 
NSCLC it does not seem justified to exclude patients based on PD-L1 expression 
status. Therefore, an all-comers population will be addressed.  
Neoadjuvant 
immunotherapy 
may 
convey 
a 
number 
of 
benefits: 
Immunotherapeutics/checkpoint-inhibitors 
have 
demonstrated 
significant 
improvements in tumor size reduction, which potentially results in increased 
operability. Reduced toxicities and the simplicity of the treatment protocol may similarly 
increase operability due to increased compliance and efficacy. A neoadjuvant 
approach may be more advantageous compared to an adjuvant treatment since it is 
speculated that an intact blood supply of the tumor is a prerequisite for an efficient 
immune-surveillance and enhances immune-cell-tumor cell interaction and ultimately 
tumor cell killing. Furthermore, immunotherapeutics such as pembrolizumab are 
hypothesized to exert anti-tumor activity through the eradication or prevention of micro-
metastasis, resulting in extended disease free intervals and increased overall survival. 
In summary, we consider the risk-benefit ratio to favor the conduct of this trial. As 
additional safety measure, an independent data monitoring committee will review 
patient safety at a planned interim analysis after 15 study subjects have been treated 


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with preoperative intent and will give recommendations with regard to trial continuation 
or early termination. 


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2 Objectives of the Study 
2.1 Primary Objective 
 
 To assess feasibility and safety of a neoadjuvant application of pembrolizumab. 
 To assess antitumor activity of pembrolizumab with regard to clinical and 
pathologic tumor response 
2.2 Secondary Objectives 
 
To assess the impact of neoadjuvant pembrolizumab on patient disease free and 
overall survival. 
2.3 Exploratory Objectives 
 
To explore potential predictive biomarkers for Pembrolizumab efficacy by 
immune cell and cytokine analysis: 
 Inflammatory infiltrates in and around the resected tumor 
 tumor tissue and serum cytokine profiles  
 Hypothesis generation on potential biomarkers predicting efficacy of 
pembrolizumab using multi-OMICS analysis 
2.4 Primary endpoint 
 
 frequency and severity of adverse events including peri- and post-operative 
complications (grade 2-4 AEs according to NCI-CTCAE V4.03) 
o number of patients treated in compliance with protocol 
 tumor response evaluation 
clinical response parameters: 
o response rates (∆ tumor size / lymph node size), according to RECIST 
1.1 criteria 
o ∆ PET-activity (standardized uptake value [SUV]) 
Pathologic response parameters: 
o Pathologic regression grading according to Junker criteria [12] 


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2.5 Secondary endpoints 
 
 disease free survival  
 overall survival 
 
2.6 Exploratory endpoints:  
 
 prognostic value of tumor shrinkage  
 prognostic value of inflammatory infiltrates in and around the resected tumor 
 serum-  and tumor tissue cytokine concentrations 
 multi-OMICS tissue analysis approach for markers and mechanisms 
 
 


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3 Overview of Study Design and Dosing Regimen 
 
The study is designed as an open-label, single arm, prospective, monocentric, phase 
II study of pembrolizumab in a neoadjuvant setting in patients with non-small cell lung 
cancer of Stage II/IIIA suitable for surgery. 
During the treatment phase, patients will receive intravenous pembrolizumab 200 mg 
q3wks. for 2 cycles or occurrence of non-tolerable toxicity. After completion of 
immunotherapy lobectomy or bilobectomy with curative intent is scheduled. After end 
of protocol treatment, patients will be treated individually according to local standards. 
3.1 Treatment Phase 
 
After screening, patients will be treated with Pembrolizumab every 3 weeks for 2 
cycles. A non-invasive tumor assessment by PET-CT will be performed before 
neoadjuvant treatment and before curative intent surgery. If tumor progression or non-
tolerable toxicity is noted during immunotherapy, an End of Treatment (EOT) visit will 
be performed and the patient will enter the follow-up phase.  
3.1.1 Surgery 
 
Surgery is the standard treatment in the neoadjuvant treatment approach and not a 
study specific procedure. The procedure of standard lobectomy/bilobectomy with 
systematic lymph-node dissection is well described in all manuals of thoracic surgery. 
In brief, patients undergo general anaesthesia and endobronchial double-lumen 
intubation. Blood pressure, heart rate, electrocardiographic trace, respiratory 
frequency and oxygen saturation are monitored continuously throughout the operation 
by an anaesthesiologist. Thoracotomy is usually performed through the fourth or fifth 
intercostal space. Vascular and bronchial structures at the level of the hilum are 
prepared and resected along with the corresponding lobe and lymph node containing 
fatty tissues. A radical systematic lymph node dissection accomplishes a standard 
lobectomy procedure. Vessels can be closed by ligation, suture or stapler. The 
bronchus can be closed by suture or stapler. Depending on the anatomical 
consideration of the interlobar fissure and the different techniques in use, the division 
can be performed at the beginning or the end of the surgery and can be done by 


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stapler, cautery or any other technique. Surgical technique for closure of vessels and 
bronchus, and the different techniques of parenchymal sparing have to be described 
for each patient in the OP-records. In special cases video-assisted thoracic surgery 
(minimal-invasive; small incisions) may replace open thoracotomy (larger incision). 
Two standard chest tubes are placed at the end of the operation. Postoperative 
patients will be monitored on the intensive care unit for at least 12 hours.  
3.2 End of Treatment 
 
End of Treatment is defined as 6 weeks post surgery (approx. 4 weeks post discharge). 
In patients who discontinue during the treatment phase, an End of Treatment (EOT) 
visit will be performed within 28 days after treatment discontinuation. 
3.3 Follow-up Phase 
 
After treatment discontinuation, follow-up evaluations will be performed every 3 months 
in order to collect information on relapse, survival status and subsequent cancer 
treatment until end of study. 
3.4 End of Study 
 
All enrolled patients will be followed up until the end of the study. The study will be 
terminated as soon as the last patient has completed at least 24 months of follow-up. 
3.5 Assignment of Patients to Treatment 
 
A total of 30 patients will be enrolled into the study and will receive neoadjuvant 
treatment of 2 cycles of pembrolizumab.  
3.6 Study sites 
 
The study will be conducted in one center only, which will recruit all required patients. 
3.7 Study Duration 
 
Study duration is approximately 64 months measured from FPI. 
 
 
 


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FPI 
 
 
 
 
 
 
Q2/2018 
LPI 
 
 
 
 
after approx. 36 month 
LPO  
 
 
 
after approx. 40 month 
EoS (after 24 month FU of LPO) after approx. 64 month 


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4 Selection of the Study Population 
4.1 Target Population 
 
Patients with resectable NSCLC stage II/IIIA eligible for immunotherapy and surgery.  
4.2 Inclusion Criteria 
 
1. Cooperation and willingness to complete all aspects of the study 
2. Signed and dated written informed consent must be given prior to study 
inclusion 
3. Histological or cytological confirmed NSCLC 
4. Clinical stage II-IIIA according to the TNM classification, 7th edition: 
stage IIIa: T1/T2 N2 (IIIa1-3 Robinson classification) 
5. Adequate disease staging by PET/CT and brain MRI 
6. At least 1 measurable lesion according to RECIST 1.1  
7. Age ≥ 18 years 
8. ECOG performance status 0 - 1  
9. Female subjects of childbearing potential (Section 7.6.6) must be willing to use 
an adequate method of contraception as outlined in Section 7.6.6 – 
Contraception and Pregnancy, for the course of the study through 120 days 
after the last dose of study medication. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject. 
Female subject of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication. 
If the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required.  
10. Male subjects of childbearing potential (Section 7.6.6) must agree to use an 
adequate method of contraception as outlined in Section 7.6.6 – Contraception 
and Pregnancy, starting with the first dose of study therapy through 120 days 
after the last dose of study therapy. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject. 


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11. Adequate bone marrow function, liver and renal function:  
a. Absolute neutrophil count ≥ 1.5 x 109/L  
b. Thrombocytes ≥ 100 x 109/L  
c. Hemoglobin ≥ 9 g/dL without transfusion or EPO dependency (within 7 
days of assessment) 
d. INR < 1.4 ULN and PTT < 40 seconds during the last 7 days before 
therapy 
e. Bilirubin < 1.5 x upper limit of normal  
f. AST (GOT) and ALT (GPT) < 2.5 x ULN  
g. Albumin >2.5 mg/dL 
h. Serum creatinine OR Measured or calculated creatinine clearance (GFR 
can also be used in place of creatinine or CrCl):  
 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN 
12. Adequate lung and cardiac function for intended lung resection according to 
German S3 guideline 
4.3 Exclusion Criteria 
 
1. Anticancer treatment during the last 30 days prior to start of treatment, 
including systemic therapy, radiotherapy or major surgery 
2. Participation in a clinical trial within the last 30 days prior to study treatment 
3. History of allogeneic tissue/solid organ transplant 
4. Has a history of (non-infectious) pneumonitis that required steroids or 
current pneumonitis. 
5. Evidence of interstitial lung disease. 
6. cT4 tumor 
7. Symptomatic acute cardiovascular or cerebrovascular disease  
8. Known active HBV, HCV or HIV infection 
9. Has any other active infection requiring systemic therapy. 
10. Patients with active tuberculosis 


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11. Prior therapy with an anti-Programmed cell death protein 1 (anti-PD-1), anti-
PD-L1, anti-Programmed cell death-ligand 2 (anti-PD-L2), anti-CD137 (4-
1BB ligand, a member of the Tumor Necrosis Factor Receptor [TNFR] 
family), or anti-Cytotoxic T-lymphocyte-associated antigen-4 (anti-CTLA-4) 
antibody (including ipilimumab or any other antibody or drug specifically 
targeting T-cell co-stimulation or checkpoint pathways) 
12. A diagnosis of immunodeficiency or patient is receiving chronic systemic 
steroid therapy or any other form of immunosuppressive therapy within 7 
days prior to the first dose of trial treatment. 
13. Patient has had a prior monoclonal antibody within 4 weeks prior to study 
Day 1  
14. Patient has had prior chemotherapy, targeted small molecule therapy, or 
radiation therapy in history.  
15. Has an active autoimmune disease requiring systemic treatment within the 
past 3 months or a documented history of clinically severe autoimmune 
disease, 
or 
a 
syndrome 
that 
requires 
systemic 
steroids 
or 
immunosuppressive agents. Subjects with vitiligo or resolved childhood 
asthma/atopy would be an exception to this rule. Subjects that require 
intermittent use of bronchodilators or local steroid injections would not be 
excluded from the study. Subjects with hypothyroidism stable on hormone 
replacement or Sjorgen’s syndrome will not be excluded from the study. 
16. Has received a live vaccine within 30 days prior to the first dose of trial 
treatment. [Seasonal influenza vaccines for injection are generally 
inactivated flu vaccines and are allowed; however, intranasal influenza 
vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.] 
17. Has known hypersensitivity to pembrolizumab or any of the constituents of 
the product. 
18. Other active malignancy requiring treatment  
Exceptions include basal cell carcinoma of the skin or squamous cell 
carcinoma of the skin that has undergone potentially curative therapy or in 
situ cervical cancer. 
19. Lactating or pregnant women, women of child-bearing potential who do not 
agree to the usage of highly effective contraception methods (allowed 


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methods of contraception, meaning methods with a rate of failure of less 
than 1% per year are implants, injectable contraceptives, combined oral 
contraceptives, intrauterine pessars (only hormonal devices), sexual 
abstinence or vasectomy of the partner). Women of childbearing potential 
must have a negative pregnancy test (serum β-hCG) at Screening. 
20. Any psychiatric illness that would affect the patient’s ability to understand 
the demands of the clinical trial 
21. Patient has already been recruited in this trial 
22. Patient who has been incarcerated or involuntarily institutionalized by court 
order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG. 
23. Patients who are unable to consent because they do not understand the 
nature, significance and implications of the clinical trial and therefore 
cannot form a rational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 
3a AMG]. 
 


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5 Schedule of Assessment and Procedures 
 
Please refer to the Schedule of Assessments for an overview. 
Data will be collected via an electronic Case Report Form (eCRF) for each eligible 
patient. The investigator should confirm eligibility of the patient according to the 
inclusion and exclusion criteria of the study. All patients will provide written Informed 
Consent before any study specific assessment is performed. A study specific 
assessment is defined as a procedure that is not part of the routine assessments 
performed for diagnostic purposes or standard care. Screening assessments should 
occur within 28 days of the first administration of study drug. 
Patients not meeting the inclusion/exclusion criteria will not be enrolled into the study. 
Patients should receive their first dose of study treatment as soon as possible after 
they have been intended to be treated with study medication. 
5.1 Study Assessments 
5.1.1 Tumor assessments 
All tumor evaluation is performed according to RECIST (Response Evaluation Criteria 
In Solid Tumors, V. 1.1, 2009, see  Appendix 2 – RECIST 1.1 and table below) using 
CT scan or MRI scan. The baseline tumor assessment must be recorded and 
measured within 28 days prior to treatment start. The imaging technique for baseline 
tumor measurement(s) may be either computed tomography (CT, including spiral CT) 
or MRI according to investigator’s choice and local routine standard of care. However, 
the same imaging technique must be used for all consecutive tumor assessments of 
the same patient. Whenever possible the same personnel should perform the tumor 
image evaluation. 
All lesions identified at screening have to be assessed at each scheduled tumor 
measurement. Patients with measurable lesions will be eligible for inclusion. 
Measurable lesions must have at least one diameter of 20 mm with conventional 
techniques and at least 10 mm with spiral CT scan. Where there are several lesions, 
assessment is based on the sum of the longest diameters of the individual target 
lesions. Lymph nodes with a short axis of ≥ 15 mm are considered measurable and 
assessable as target lesions. The short axis measurement should be included in the 


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sum of lesions in calculation of tumor response. Nodes that shrink to < 10 mm short 
axis are considered normal. All other pathological nodes (those with short axis ≥ 10 
mm but < 15 mm) should be considered non-target lesions. 
In cases where there is suspicion of progression before the next scheduled 
assessment, an unscheduled tumor assessment should be performed. 
 
Response Criteria 
Definitions of the criteria used to determine objective tumor response/ Evaluation of 
target lesions:  
 
Complete response 
Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must 
have reduction in short axis to < 10 mm. 
Partial response 
At least a 30% decrease in the sum of diameters of 
target lesions, taking as reference the baseline sum 
diameters. 
Stable disease 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters on study (this 
includes the baseline sum if that is the smallest on 
study). 
Progressive disease 
At least a 20% increase in the sum of diameters of 
target lesions, taking as reference the smallest sum 
on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. In the absence to clinical 
deterioration, a validation scan shall be performed 
after 4 weeks. Treatment continuation is warranted if 
tumor growth ≤20% of SLD. If PD is confirmed, the 
date of the pervious scan is counted as time point for 
PD. 
or 
Appearance of one or more new lesion. Note that the 
appearance of a single new lesion also requires 
validation of progression by another scan after 4 
weeks.  
 
 
 
 


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5.1.2 Other Clinical Assessments 
5.1.2.1 ECOG Performance Status 
 
To be eligible for study entry, patients must have an ECOG performance score of 0 to 
1. The patients’ ECOG performance status will be assessed at the screening visit, 
during treatment every 3 weeks, before surgery, and at the EOT-visit. 
5.1.2.2 Medical history 
 
Medical history including cancer and treatment history will be reviewed and recorded 
at screening visit (≤ 1 year before enrolment). 
5.1.2.3 ECG  
 
A 12-lead ECG will be performed at screening, pre-surgery and at EOT and during the 
treatment phase if clinically indicated. 
5.1.2.4 Chest X-ray 
 
Routine chest X-ray according to local standard will be performed at screening, during 
neoadjuvant treatment Q3W, pre- and post-surgery and at EoT. 
 
5.1.2.5 Quality of life 
 
Quality of life will be assessed by the EORTC QLQ-C30 questionnaire. 
QoL will be assessed at screening, before surgery and at EoT. 
5.1.2.6 Lung function/blood gas analysis 
 
Lung function test in order to evaluate the operability of a patient should be done prior 
to or at screening. Availability of an adequate lung function test is an inclusion criterion 
and the test should not be older than 4 weeks at screening. The tests include body 
plethysmography, assessment of diffusion capacity and blood gas analysis. Lung 
function tests should be repeated during pembrolizumab treatment Q3W, prior to 
surgery and at EoT.  
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5.1.2.7 Physical examination 
 
A full physical examination will be performed at the screening visit and at EOT. During 
treatment a focused clinical examination at every cycle as well as pre-surgery and at 
discharge is sufficient.  
5.1.2.8 Vital signs 
 
Vital signs (blood pressure, heart rate, body temperature) as well as body weight will 
be measured at the screening visit, at each visit during treatment phase, before 
surgery, at dis-charge and at the EoT-visit. Body height will be measured at screening 
only. 
5.1.2.9 Translational Research 
 
Additional blood and tumor samples will be collected in patients as described in the 
translational research plan which is deposited in the ISF.  
5.1.3 Safety Assessments 
 
See section 7 
5.1.4 Laboratory Assessments 
 
Blood samples will be taken for hematological and serum chemistry monitoring at 
screening and every 3 weeks +/- 3 days during treatment phase, before surgery and 
at EOT. The local laboratory will perform the analyses and provide reference ranges. 
 
5.2 Study Procedures 
5.2.1 Screening Procedures (day -28 to 0) 
NOTE: Any routine procedure which is performed during the screening window may 
be used as a screening assessment in this trial. Documentation of any screening 
procedure in the eCRF can only be performed after informed consent of the patient. 
All patients will be screened and screening procedures performed within 28 days 
prior to start of study treatment include the following: 
Signed Informed Consent 
Obtained prior to any study specific assessment 


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Demographics and medical 
history 
o Age, gender, race 
o Tumor diagnosis 
o Previous and concurrent relevant diseases  
o Previous treatments 
o Tobacco consumption in pack years 
Tumor measurement 
according to RECIST 1.1 
(CT or MRI) 
See section 5.1.1 
Tumor assessments 
 CT or MRI 
Whole body PET-CT and MRI brain scans (or CT 
brain if MRI is not feasible) are required.  
Cardiac evaluation 
12-lead ECG 
Physical examination and 
vital signs 
o Physical examination 
o Body height, weight 
o Vital signs measurements will include body 
temperature, pulse and blood pressure 
ECOG performance status 
See Appendix 1 – ECOG Performance Status 
Serum pregnancy test 
A serum pregnancy test will be performed in pre-
menopausal women and women who are 
menopausal for < 2 years. In case the sampling 
date for serum pregnancy testing exceeds 7 days 
before treatment start, a urine test is required for 
confirmation of the absence of pregnancy. 
Lung function 
Body plethysmography / blood gas analysis, 
diffusion capacity  
Hematology 
Hemoglobin, erythrocytes, platelets, leukocytes, 
absolute neutrophils (ANC), basophils, eosinophils, 
lymphocytes, monocytes 
Clinical chemistry 
Sodium, potassium, calcium, magnesium, albumin 
phosphate, AST, ALT, PTT/INR, LDH, total 
bilirubin, creatinine, creatinine clearance (see 
section 18.4 Appendix 4), TSH 
tumor marker 
CEA, Cyfra 21-1 


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5.2.2 Treatment Phase 
 
For V1 no particular assessments are required. However, the following assessments 
need to be repeated if the Screening assessment is older than 7 days measured from 
first dose of IMP: Hematology, pregnancy test, clinical chemistry, coagulation, vital 
signs. ConMed and AE documentation may need to be updated if required. 
 
During treatment phase the following assessments and procedures will be performed 
for V2 unless a different time point is mentioned specifically: 
Cardiac evaluation 
12-lead ECG, transthoracic echocardiogram (TTE) 
if clinically indicated 
Physical examinations and 
vital signs 
 Physical examination 
 Body weight, BSA 
 Vital signs measurements will include body 
temperature, pulse and blood pressure 
ECOG performance status 
Day 1 of each immunotherapy cycle, see 
Appendix 1 – ECOG Performance Status 
Pregnancy test 
During treatment phase the pregnancy test should 
be repeated if the investigator considers it 
necessary. A serum or urine pregnancy test will be 
performed in pre-menopausal women and women 
who are menopausal for < 2 years. 
Hematology 
 
Hemoglobin, erythrocytes, platelets, leukocytes, 
absolute neutrophils (ANC), basophils, eosinophils, 
lymphocytes, monocytes 
Clinical chemistry + 
coagulation 
Sodium, potassium, calcium, magnesium, 
phosphate, AST, ALT, PTT/INR, LDH, total bilirubin, 
creatinine, creatinine clearance (see section 18.4 
Appendix 4)TSH. If rising TSH is detected, a full 
assessment of fT3 and fT4 shall be performed and 
signs of hormone depletion shall be monitored 
clinically.  
Concomitant medication, 
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Adverse events 
5.2.3 Pre-surgical visit 
 
Tumor measurement 
according to RECIST 1.1 
(CT or MRI) 
See section 5.1.1 
Tumor assessments 
 CT or MRI 
Whole body PET-CT  
Cardiac evaluation 
12-lead ECG 
Physical examination and 
vital signs 
o Physical examination 
o weight 
o Vital signs measurements will include body 
temperature, pulse and blood pressure 
ECOG performance status 
See Appendix 1 – ECOG Performance Status 
Serum pregnancy test 
A serum pregnancy test will be performed in pre-
menopausal women and women who are 
menopausal for < 2 years if clinically indicated.  
Lung function 
Body plethymography / blood gas values 
Hematology 
Hemoglobin, erythrocytes, platelets, leukocytes, 
absolute neutrophils (ANC), basophils, eosinophils, 
lymphocytes, monocytes 
Clinical chemistry + 
coagulation 
Sodium, potassium, calcium, magnesium, 
phosphate, AST, ALT, PTT/INR, LDH, total bilirubin, 
albumin, creatinine, creatinine clearance (see 
section 18.4 Appendix 4), TSH 
Concomitant medication, 
Adverse events 
Assessed on an ongoing basis 
 
5.2.4 Discharge visit 
 


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Hematology 
Hemoglobin, erythrocytes, platelets, leukocytes, 
absolute neutrophils (ANC), basophils, eosinophils, 
lymphocytes, monocytes 
Clinical chemistry + 
coagulation 
Sodium, potassium, calcium, magnesium, 
phosphate, AST, ALT, PTT/INR, LDH, total 
bilirubin, creatinine, creatinine clearance (see 
section 18.4 Appendix 4), TSH 
Concomitant medication, 
Adverse events 
Assessed on an ongoing basis + peri-operative 
complications 
Post-op. tumor tissue 
analysis 
Regression grading accord. to Junker criteria (see 
section 18.3 Appendix 3) 
 
5.2.5 End of Treatment Visit 
Cardiac evaluation 
12-lead ECG 
Physical examination and 
vital signs 
o Physical examination 
o weight 
o Vital signs measurements will include body 
temperature, pulse and blood pressure 
ECOG performance status 
See Appendix 1 – ECOG Performance Status 
Lung function 
Body plethymography / blood gas values 
Hematology 
Hemoglobin, erythrocytes, platelets, leukocytes, 
absolute neutrophils (ANC), basophils, eosinophils, 
lymphocytes, monocytes 
Clinical chemistry + 
coagulation 
Sodium, potassium, calcium, magnesium, 
phosphate, AST, ALT, PTT/INR, LDH, total bilirubin, 
albumin, creatinine, creatinine clearance (see 
section 18.4 Appendix 4), TSH 
Concomitant medication, 
Adverse events 
Including peri-operative complications 
 
5.2.6 Follow-up 
 


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After discontinuation of treatment, all patients will be followed-up for survival every 3 
months. First visit of the follow-up period will take place 3 months after EOT visit. 
Follow-up of the individual patient will continue until death or until study is terminated. 
The following information will be collected during the follow-up: 
 Survival data 
 Subsequent anti-cancer therapy 
 Study drug related adverse events continuing from treatment phase will be 
followed-up until the event has resolved or stabilized 
5.2.7 End of Study 
 
The final statistical analysis will be performed when the last patient has completed at 
least 24 months of follow-up or death occurred, whichever comes first.  
5.2.8 Planned Treatment of the Patient after End of Treatment Phase 
 
After completion of study at the End-of-Treatment-Visit, patients will generally be 
treated at the discretion of the investigator according to medical routine. 
5.3 Removal of Patients from Treatment 
 
Patients will be free to discontinue treatment or withdraw from the study at any time, 
for any reason, or they may be withdrawn/removed if necessary, to protect their health 
(see reasons for withdrawal below). It is understood by all concerned that an excessive 
rate of withdrawals can render the study uninterpretable; therefore, unnecessary 
withdrawal of patients should be avoided. Patients that will be withdrawn from the study 
will not be replaced. 
Patients will be removed from further treatment for the following reasons: 
 Disease progression 
 Continued unacceptable toxicities despite optimal treatment or dose reduction 
 During the treatment a delay of study treatment of more than 6 weeks 
 Delay from screening to start of study treatment of more than 31 days 
 Intercurrent illness, at the investigator’s discretion 
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 Non-compliance / Lost to follow-up 
 Pregnancy 
 Termination of the study by the sponsor 
If there is a medical reason for withdrawal of treatment, the patient will remain under 
the supervision of the investigator until the AEs have been resolved or declined to 
baseline values. 
If a patient has failed to attend scheduled assessments in the study, the investigator 
must determine the reasons and circumstances as completely and accurately as 
possible.  
In case of premature discontinuation of the study treatment, the investigations 
scheduled for the EOT and the Follow-up visits should be performed, if possible. In 
any case, the eCRF section entitled “End of Treatment” must be completed. 
Should a patient decide to withdraw, all efforts will be made to complete and report the 
observations as thoroughly as possible. The investigator should contact the patient to 
determine as completely as possible the reason for the withdrawal. A complete final 
evaluation at the time of the patient’s withdrawal should be made with an explanation 
of why the patient is withdrawing from the study. If the reason for removal of a patient 
from the study is an adverse event or an abnormal laboratory test result, the principal 
specific event or test will be recorded on the eCRF. 
If a patient withdraws consent for further study treatment, the patient should still be 
followed for progression and survival. If a patient withdraws consent for further 
participation in the study, follow-up assessments will be discontinued. 
5.4 Study discontinuation 
 
The whole study will be stopped at the discretion of the sponsor (with or without IDMC 
recommendation) in the event of any of the following: 
 Medical or ethical reasons affecting the continued performance of the study 
 Difficulties in the recruitment of patients 


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 Occurrence of AEs unknown to date in respect of their nature, severity, and 
duration or the unexpected incidence of known AE with a negative impact on 
the risk/benefit assessment 
 Negative benefit/risk assessment due to new information 
 Further external scientific evidence that this regimen might result in a 
suboptimal risk-benefit-assessment for the whole group of patients or for a 
distinct subgroup 
 medically unacceptable risks for the treatment of the patients 
 At the interim analysis, if the rate of unresectability is equal or greater 20%; i.e. 
if 3/15 or more study subjects did not undergo surgery as planned according to 
the protocol (unresectable or excessive delay of surgery). [early stopping rule] 


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6 Investigational Product 
6.1 Investigational Medicinal Product (IMP) 
 
An investigational medicinal product is a pharmaceutical form of an active substance 
or placebo being tested or used as a reference in a clinical trial, including products 
already with a marketing authorization but used or assembled (formulated or 
packaged) in a way different from the authorized form, or when used for an 
unauthorized indication, or when used to gain further information about the authorized 
form. 
The IMP in this study is Pembrolizumab. It will be delivered to the participating center 
free of charge. Details on the distribution will be described in a specific operation 
procedure with appropriate forms attached. All other concomitant medical treatment 
will be prescribed by the treating physician, as this prescription is within the framework 
of standard of care. 
The relevant information on the drug characteristics, storage, application, mode of 
action and adverse reactions is included in the respective and current Investigator's 
Brochure and pharmacy manual provided in the ISF. 
The investigator will ensure that the study medication is used only in accordance with 
the protocol. 
6.1.1 Supply of pembrolizumab 
 
Pembrolizumab will be supplied by MSD and will bear a label with the identification 
required by local law, the protocol number, drug identification and dosage as well as 
the statement "For Clinical Trial Use Only". The packaging and labeling of the study 
medication will be in accordance with MSD standards and local regulations. All the 
requirements of Annex 13 of the Good Manufacturing Practices guideline for labeling 
investigational drug will be fulfilled. 
Upon arrival of study medication the local pharmacy will check the IMP for damage 
and verify proper identity, quantity, integrity of seals and temperature conditions, and 
report any deviations or product complaints to the Sponsor upon discovery. 


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The study medication must be stored according to the details on the product label. The 
drug label indicates the storage temperature. The relevant information on the drug 
characteristics, storage, application, mode of action and adverse reactions is included 
in the respective and current Investigator's Brochure of pembrolizumab. 
The investigator will ensure that the study medication is used only in accordance with 
the protocol. 
6.1.2 Documentation 
The responsible pharmacist will maintain records of the inventory at the site, the use 
for each patient and delivery, storage and destruction. The investigator will also 
maintain records that adequately document that patients were provided the doses 
specified in the protocol and the responsible pharmacist will reconcile all study 
medication received from the central pharmacy. 
The date, time and amount will be documented in the eCRF by the investigator. 
6.2 Preparation and Administration of Pembrolizumab 
6.2.1 Drug Name, Formulation and Storage 
Drug name: 
 
pembrolizumab (MK-3475) CAS number 1374853-91-4 
Dosage:  
 
100 mg/vial 
Formulation: 
 Pembrolizumab Solution for Infusion is provided in Type I glass vials intended 
for single use only. 
 Pembrolizumab Solution for Infusion 100 mg/vial is a liquid DP (manufactured 
using the fully formulated DS with L-histidine as buffering agent, polysorbate 80 
as surfactant, and sucrose as stabilizer/tonicity modifier). 
 
Reconstitution: The liquid drug product can be further diluted with normal saline or 
5%dextrose in the concentration range of 1 to 10 mg/mL in intravenous (IV) containers 
made of polyvinyl chloride (PVC) or non-PVC material. Reconstituted vials should be 
immediately used to prepare the infusion solution in the IV bag and the infusion solution 
should be immediately administered. 
Appearance:  
clear to opalescent solutions, essentially free of visible particles. 


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Labelling: 
Labelling of study drug will be in accordance with German GCP-V § 
5 and other applicable national regulations in the German Drug Law (AMG) and GCP-
V in effect. 
Storage: 
 
 Pembrolizumab (MK-3475) solutions may be stored at room temperature for a 
cumulative time of up to 6 hours. This includes room temperature storage of 
reconstituted drug product solution in vials, room temperature storage of admixture 
solutions in the IV bags and the duration of infusion. 
 In addition, reconstituted vials and/or IV bags may be stored under refrigeration at 
2 °C to 8 °C for up to 18 hours. If refrigerated, allow the vials and/or IV bags to 
come to room temperature prior to use.   
 From a microbiological point of view Pembrolizumab (MK-3475) has to be used 
immediately once the vial has been opened. If not used immediately, the 
responsibility for storage time and storage conditions lie within the handler. 
 
6.2.2 Route of Administration 
Pembrolizumab is administered as an i.v. infusion with 200 mg fixed dose 
corresponding to 2 vials (100 mg/ vial). The treatment interval is q3w (Day 1 of each 
21 day cycle). Pembrolizumab (MK-3475) infusions should be administered in 30 
minutes, with a window of -5 and +10 minutes, using an infusion pump. A central 
catheter is not required for infusion; however if a subject has a central venous catheter 
in place, it is recommended that it be used for the infusion.  
The following infusion set materials are compatible with Pembrolizumab (MK-3475): 
o PVC Infusion set that is plasticized using DEHP 
o PVC and tri-(2-ethylhexyl) trimellitate (TOTM) infusion set 
o Polyethylene lined PVC infusion set 
o PVC Infusion set that is plasticized using Di-2-ethylhexyl Terephthalate 
(DEHT) 
o Polyurethane set 
*Contact Sponsor for materials not listed above 
 A sterile, non-pyrogenic, low-protein binding 0.2 to 5 µm in-line filter made of 
polyethersulfone (PES) must be used during administration to remove any 


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adventitious particles. If the infusion set does not contain 0.2 to 5 µm in-line 
filter, it is recommended to use 0.2 to 5 µm add-on filter which may contain an 
extension line (Note: the materials of the extension line and filter should be as 
mentioned above). 
 Attach the infusion line to the pump and prime the line, either with normal saline 
(at least 25 mL) or with infusion solution as per local SOP, before starting the 
infusion. 
 Infuse Pembrolizumab (MK-3475) over approximately 30 minutes, with a 
window of -5 and +10 minutes, through a peripheral line or indwelling catheter.  
 In case of infusion reactions, infusion rate may differ: 
o Whenever possible, the lowest infusion rate should be used that will allow 
completion of the infusion within the 30 minutes 
o Maximum rate of infusion should not exceed 6.7 mL/min. through a 
peripheral line or indwelling catheter. However, when it is necessary to 
infuse a larger volume (i.e., 250 mL), the flow rate may go as high as 10 
mL/min (maximum) in order to keep the infusion within the window as 
defined above. 
 Ensure the entire contents of the bag are dosed and all remaining drug 
solution in the line is administered according to institutional guidelines for 
saline flushing. 
6.2.3 Infusion reactions – Course of action and premedication 
 
Infusion reactions – although rare – may occur during the administration of 
Pembrolizumab. Patients experiencing infusion reaction need to be treated 
appropriately as detailed in Table 2. 
In case of grade 2 infusion reactions patients may be prophylactically pre-medicated 
upon subsequent study drug applications. Detailed guidelines for handling of infusion 
reactions are provided in Table 2.  
6.2.4 Compliance 
The Investigator or a pharmacist or other appropriate individual, who is designated by 
the local Principal Investigator, should maintain records of the inventory at the site, the 
use for each patient and delivery, storage and destruction. Investigators should 


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maintain records that adequately document that patients were provided the doses 
specified in the protocol and reconcile all investigational product(s) received from the 
sponsor.  
The investigator should ensure that the investigational product(s) are used only in 
accordance with the protocol.  
The investigational product(s) should be stored as specified by the Sponsor and in 
accordance with applicable regulatory requirements. 
6.3 Dose Modifications 
6.3.1 Dose Modification and Discontinuation of pembrolizumab for adverse reactions 
Dose modifications in terms of dose reductions are not allowed in this study. Dose 
modifications in terms of pausing of treatment or discontinuation may be required due 
to AEs. 
Adverse events (both non-serious and serious) associated with pembrolizumab 
exposure may represent an immunologic etiology. These adverse events may occur 
shortly after the first dose or several months after the last dose of treatment. 
Pembrolizumab must be withheld for drug-related toxicities and severe or life-
threatening AEs as per Table 1 below. See Section 6.3.2 for supportive care 
guidelines, including use of corticosteroids. 
Table 1: Dose Modification Guidelines for Drug-Related Adverse Events:  For more details please see 
6.3.2 ‘supportive measure guidelines’. 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Discontinue Treatment Discontinuation 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to Grade 
0-1 
Toxicity does not resolve within 12 weeks of 
last dose or inability to reduce corticosteroid to 
10 mg or less of prednisone or equivalent per 
day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased 
Bilirubin 
2 
Toxicity resolves to Grade 
0-1 
Toxicity does not resolve within 12 weeks of 
last dose 
3-4 
Permanently discontinue 
(see exception below)a 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or  
3-4 
 
Resume pembrolizumab when patients are 
clinically and metabolically stable 


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Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Discontinue Treatment Discontinuation 
Hypophysitis 
2-4 
Toxicity resolves to Grade 
0-1. Therapy with 
pembrolizumab can be 
continued while endocrine 
replacement therapy is 
instituted 
Toxicity does not resolve within 12 weeks of 
last dose or inability to reduce corticosteroid to 
10 mg or less of prednisone or equivalent per 
day within 12 weeks 
Hyperthyroidism  3 
Toxicity resolves to Grade 
0-1 
Toxicity does not resolve within 12 weeks of 
last dose or inability to reduce corticosteroid to 
10 mg or less of prednisone or equivalent per 
day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
2-4 
Therapy with 
pembrolizumab can be 
continued while thyroid 
replacement therapy is 
instituted 
Therapy with pembrolizumab can be continued 
while thyroid replacement therapy is instituted 
 
Infusion 
Reaction 
2b 
Toxicity resolves to Grade 
0-1  
Permanently discontinue if toxicity develops 
despite adequate premedication  
 
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 
0-1 
Toxicity does not resolve within 12 weeks of 
last dose or inability to reduce corticosteroid to 
10 mg or less of prednisone or equivalent per 
day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 
0-1 
Toxicity does not resolve within 12 weeks of 
last dose or inability to reduce corticosteroid to 
10 mg or less of prednisone or equivalent per 
day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related 
Toxicityc 
(e.g. skin 
related AEs, 
such as toxic 
epidermal 
necrolysis) 
3 or 
Severe 
Toxicity resolves to Grade 
0-1 
Toxicity does not resolve within 12 weeks of 
last dose or inability to reduce corticosteroid to 
10 mg or less of prednisone or equivalent per 
day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-
threatening event. 
1a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by 
greater than or equal to 50% relative to baseline and lasts for at least 1 week then patients should be 
discontinued. 
2b If symptoms resolve within one hour of stopping drug infusion, the infusion may be restarted at 50% of the 
original infusion rate   (e.g., from 100 mL/hr to 50 mL/hr).  Otherwise dosing will be held until symptoms resolve 
and the subject should be pre-medicated  for the next scheduled dose; Refer to  
 
 – Infusion Treatment Guidelines for further management details. 
c Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician 
discretion.  Permanently discontinue study drug for persistent Grade 2 adverse reactions for which treatment 
with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose. 
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical 
reasons not related to study therapy (e.g., elective surgery, unrelated medical events, 
patient vacation, and/or holidays). Subjects should be placed back on study therapy 
after not more than 6 weeks after the last dose, unless otherwise discussed with the 


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Sponsor. The reason for interruption should be documented in the patient's study 
record. 
6.3.2 Supportive Care Guidelines 
 
Subjects should receive appropriate supportive care measures as deemed necessary 
by the treating investigator. Suggested supportive care measures for the management 
of adverse events with potential immunologic etiology are outlined below. Where 
appropriate, these guidelines include the use of oral or intravenous treatment with 
corticosteroids as well as additional anti-inflammatory agents if symptoms do not 
improve with administration of corticosteroids.  Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is 
decreased. For each disorder, attempts should be made to rule out other causes such 
as metastatic disease or bacterial or viral infection, which might require additional 
supportive care. The treatment guidelines are intended to be applied when the 
investigator determines the events to be related to pembrolizumab.  
Note: if after the evaluation the event is determined not to be related, the investigator 
does not need to follow the treatment guidance (as outlined below). Refer to Section 
5.2.1 for dose modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, 
endoscopy, or skin photography as part of evaluation of the event.  
 Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When 
symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  
Administer additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
 Diarrhea/Colitis:  


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Subjects should be carefully monitored for signs and symptoms of enterocolitis 
(such as diarrhea, abdominal pain, blood or mucus in stool, with or without 
fever) and of bowel perforation (such as peritoneal signs and ileus).   
o All subjects who experience diarrhea/colitis should be advised to drink 
liberal quantities of clear fluids.  If sufficient oral fluid intake is not feasible, 
fluid and electrolytes should be substituted via IV infusion.  For Grade 2 
or higher diarrhea, consider GI consultation and endoscopy to confirm or 
rule out colitis. 
o For Grade 2 diarrhea/colitis, administer oral corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids 
followed by high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. 
 Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis 
[DKA]) or ≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) 
or metabolic acidosis (DKA) 
 
o For T1DM or Grade 3-4 Hyperglycemia 
 Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with 
metabolic acidosis or ketonuria.  
 Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.  
 Hypophysitis: 
o For Grade 2 events, treat with corticosteroids. When symptoms improve 
to Grade 1 or less, steroid taper should be started and continued over no 
less than 4 weeks. Replacement of appropriate hormones may be 
required as the steroid dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids 
followed by oral corticosteroids. When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over no less than 4 
weeks. Replacement of appropriate hormones may be required as the 
steroid dose is tapered. 


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 Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for 
changes in thyroid function (at the start of treatment, periodically during 
treatment, and as indicated based on clinical evaluation) and for clinical signs 
and symptoms of thyroid disorders. 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) 
are suggested as initial therapy. 
 In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyronine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
 Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, 
steroid taper should be started and continued over no less than 4 
weeks. Replacement of appropriate hormones may be required 
as the steroid dose is tapered. 
 Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until 
returned to baseline values (consider weekly). 
 Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 
hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be 
started and continued over no less than 4 weeks. 
 
 Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks.  


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 Management of Infusion Reactions: Signs and symptoms usually develop 
during or shortly after drug infusion and generally resolve completely within 24 
hours of completion of infusion.  
Table 4 below shows treatment guidelines for subjects who experience an 
infusion reaction associated with administration of pembrolizumab (MK-3475). 
 
Table 2 - Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated 
for < =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator. 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(e.g., from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held until symptoms 
resolve and the subject should be 
premedicated for the next scheduled dose. 
Subjects who develop Grade 2 toxicity 
despite adequate premedication should 
be permanently discontinued from further 
trial treatment administration. 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab (MK-
3475) with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief interruption 
of infusion); recurrence of 
symptoms following initial 
improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further trial treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period 
of drug administration. 
 
 
6.4 Concomitant Medication and Treatment 
 


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Patients may continue their baseline medication(s) according to the recommendations 
of the responsible physician. All concomitant medication(s) must be reported in the 
eCRF. Any therapeutic, or surgical procedure performed during the study period 
should be recorded including the dates, description of the procedure(s) and any clinical 
findings. Patients should receive full supportive care including transfusion of blood and 
products, antibiotics, etc. where applicable. The treatment details have to be recorded 
in the eCRF. 
All concomitant medications received within 28 days before the first dose of trial 
treatment and 21 days after the last dose of trial treatment should be recorded. 
Concomitant medications administered after 21 days after the last dose of trial 
treatment should be recorded for SAEs and events of clinical interest (ECIs). 
Additionally, any diagnostic, therapeutic or surgical procedure performed during the 
study period should be recorded.  
Supportive care for treatment-related symptoms will be offered as needed to all 
patients in this study. 
Prohibited Medications 
Medications or vaccinations specifically prohibited in the exclusion criteria are not 
allowed during the ongoing trial.  If there is a clinical indication for one of these or other 
medications or vaccinations specifically prohibited during the trial, discontinuation from 
trial therapy or vaccination may be required. The investigator should discuss any 
questions regarding this with the Sponsor.  The final decision on any supportive 
therapy or vaccination rests with the investigator and/or the subject's primary 
physician.  
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this 
trial: 
 Antineoplastic systemic chemotherapy or biological therapy  
 Immunotherapy not specified in this protocol 
 Chemotherapy not specified in this protocol 
 Investigational agents other than pembrolizumab 
 Radiation therapy  


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 Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited 
to, the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, 
BCG, and typhoid vaccine.  
 Systemic glucocorticoids for any purpose other than to modulate symptoms 
from an event of clinical interest of suspected immunologic etiology.  The use 
of physiologic doses of corticosteroids may be approved after consultation with 
the Sponsor. 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Subjects may receive other medications that the investigator deems to be medically 
necessary. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 


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7 Assessment of Safety 
 
It is the responsibility of the investigators to report all adverse events in the case report 
form. Any serious adverse event (SAE) must be reported within 24 hours to the safety 
desk who will forward the SAEs to the Coordinating Investigator, sponsor and MSD 
within one working day. 
Contact details for safety reporting are provided in the Investigator Site File.  
 
7.1 Reference safety documents 
The current version of the Investigator’s Brochure of Pembrolizumab will be used as 
reference document and will be provided to the investigators in the Investigator's File. 
7.2 Adverse Events definitions 
 
 
7.2.1 Adverse Events 
 
An adverse event (AE) is defined in the International Conference on Harmonization 
(ICH) Guideline for Good Clinical Practice as “any untoward medical occurrence in a 
patient or clinical investigation subject administered a pharmaceutical product and 
which does not necessarily have a causal relationship with this treatment.” (ICH E6: 
section 1.2). 
An adverse event can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not considered related 
to the medicinal (investigational) product. 
7.2.2 Serious Adverse Event 
 
A serious adverse event (SAE) is defined as any untoward medical occurrence 
(adverse event) that at any dose: 
 results in death, 


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 is life-threatening (subject was at immediate risk of death at the time of 
the event), 
 requires 
in-patient 
hospitalization 
or 
prolongation 
of 
existing 
hospitalization, 
 results in persistent or significant disability/incapacity, 
 is a congenital anomaly / birth defect or, 
 any other significant medical condition. 
A hospitalization meeting the regulatory definition for “serious” is any inpatient hospital 
admission that includes a minimum of an overnight stay in a health care facility. Any 
adverse event that does not meet one of the definitions of serious i.e. important medical 
events that may not be immediately life-threatening or result in death or hospitalization 
but may jeopardize the patient or may require interventions to prevent one of the other 
outcomes listed above (e.g. emergency room visit, outpatient surgery, or requires 
urgent investigation) may be considered by the investigator to meet the “other 
significant medical condition” criterion for classification as a serious adverse event. 
Examples include allergic bronchospasm, convulsions, and blood dyscrasias. 
Hospitalization for performing of protocol-required procedures or administration of 
study treatment or hospitalizations for procedures planned prior to study start and 
elective hospitalizations are not classified as an SAE. 
Progression of the underlying malignant disease and symptoms caused by 
progression of the underlying tumor disease need not to be reported as SAE in 
this protocol, unless progression or symptoms of progression are assessed as 
causally related to study medication. 
7.2.3 AEs of Special Interest (Events of Clinical Interest) 
 
Events of clinical interest for this trial are: 
1. an overdose of pembrolizumab, as defined in Section 7.2.6, that is not associated 
with clinical symptoms or abnormal laboratory results.  
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper 
limit of normal and an elevated total bilirubin lab value that is greater than or 
equal to 2X the upper limit of normal and, at the same time, an alkaline 


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phosphatase lab value that is less than 2X the upper limit of normal, as 
determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology. 
 
7.2.4 Other reportable events 
 
Other reportable events of this trial are: 
 
a new cancer (that is not a condition of the study); 
 
an AE associated with an overdose. 
 
7.2.5 Unexpected Adverse Event 
 
An unexpected adverse event is any adverse drug event, the specificity or severity of 
which is not consistent with the current version of the Investigator’s Brochure of 
Pembrolizumab. Also, reports which add significant information on specificity or 
severity of a known, already documented adverse event constitute unexpected 
adverse events. An event more specific or more severe than described in the reference 
safety document would be considered “unexpected”. 
A suspected unexpected serious adverse reaction (SUSAR) is a serious adverse 
reaction, the nature, or severity of which is not consistent with the applicable reference 
safety document. All suspected adverse reactions related to the IMP which occur in 
the concerned trial and that are both unexpected and serious (SUSARs) are subject to 
expedited reporting. 
7.2.6 Overdose 
 
For subjects treated with pembrolizumab an overdose will be defined as any dose of 
1,000 mg or greater (exceeding 5x the protocol prescribed dose). 
 
 
 


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7.3 Assessment of relationship - Adverse drug reaction 
 
The causal relationship to study drug is determined by a physician and should be 
used to assess all adverse events (AE). The causal relationship can be one of the 
following: 
 Related: There is a reasonable causal relationship between study drug 
administration and the AE. 
 Not related: There is not a reasonable causal relationship between study drug 
administration and the AE.  
The term "reasonable causal relationship" means there is evidence to suggest a 
causal relationship. 
In case of a missing causality assessment in the eCRF or SAE reporting form, the 
event will be regarded as "probably related" unless further specified. 
A serious ADR (SADR) is an adverse drug reaction that meets the definition of a 
serious event (provided below). 
7.4 Assessment of severity 
 
Intensity of adverse events will be graded using the National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE), version 4.03. 
If an adverse event occurs which is not contained in the CTCAE version 4.03, the five-
point scale below will be used. 
Grade 1: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
Grade 2: 
Moderate: minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADL 
Grade 3: 
Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization 
indicated; disabling; limiting self-care ADL 
Grade 4: 
Life-threatening consequences; urgent intervention indicated 


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Grade 5: 
Death related to AE 
7.5 Safety recording and reporting requirements 
 
7.5.1 Recording periods 
 
 Adverse events are recorded from time of signed informed consent until 6 
weeks (EoT visit) after surgery. 
 Serious adverse events are recorded from time of signed informed consent until 
90 days after last dose of IMP or for 6 weeks after surgery if the subject initiated 
new anticancer therapy (e.g. radio-chemotherapy) 
 Pregnancies occurring in a study subject are recorded from time of signed 
informed consent until 120 days after last dose of IMP. 
7.5.2 Recording and Reporting requirements 
 
Adverse events in general: All adverse events are documented by the participating 
site in the patient’s medical records and the eCRF. The investigator is responsible for 
ensuring that all adverse events observed by the investigator or reported by patients 
are properly captured in the patient’s medical records (source data). 
The following adverse event attributes must be assigned by the investigator:  
 adverse event diagnosis or syndrome(s) (if known, signs or symptoms if not 
known),  
 event description (with detail appropriate to the event),  
 dates of onset and resolution,  
 seriousness (yes / no),  
 severity (according to NCI CTCAE V4.03),  
 assessment of relatedness to study treatment (see section 7.3), 
 outcome: 
o recovered / resolved 
o recovered / resolved with sequelae 


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o not recovered / not resolved 
o deteriorating/worsening 
o fatal 
o unknown (only applicable if patient is lost to follow-up); and 
 action taken: 
o none 
o dose reduced (new dose) 
o study drug temporarily interrupted 
o study drug permanently discontinued (stop date) 
o not applicable 
o unknown 
 
Serious adverse events:  
 For each patient any adverse event or abnormal laboratory test value that is 
serious occurring during the course of the study must be reported immediately 
(within 24 hours / GCP-V § 12(4)) after awareness to the safety desk (contact 
details are provided in the Investigator Site File) utilizing a completed SAE 
Report Form. 
 
 Serious Adverse Events that are unexpected and considered related to IMP and 
occur after the completion of the trial should be reported to the sponsor (AIO-
Studien-gGmbH) within one working day [ICH E2A III.E.3]. 
 
Events of clinical interest: Selected non-serious and serious adverse events that are 
also known as Events of Clinical Interest (ECI) are subject to expedited reporting by 
the investigator.  
 For the time period beginning when the consent form is signed (registration) 
until start of treatment, any ECI, or follow up to an ECI, that occurs to any subject 
must be reported within 24 hours of investigators awareness to the safety desk 
if it causes the subject to be excluded from the trial, or is the result of a protocol-


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specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure. 
 For the time period beginning at start of treatment through 6 weeks following 
surgery, any ECI, or follow up to an ECI, whether or not related to IMPs, must 
be reported within 24 hours of investigators awareness to safety desk. 
 
Other reportable events: For each patient any ‘other reportable’ event occurring until 
6 weeks after surgery must be reported immediately (within 24 hours) after 
investigator’s awareness to the safety desk. 
 
Pregnancy: Pregnancies occurring during study treatment and up to 120 days after 
last dose must be reported by the investigator on the Pregnancy Report Form within 
24 hours after awareness to the safety desk.  
Follow up case reports have to be provided as new information becomes available. 
If an SAE is experienced in addition to or related to the pregnancy e.g. an induced or 
spontaneous abortion, also an SAE Report has to be sent to the safety desk within 24 
hours / GCP-V § 12(4) after first knowledge. 
 
Overdose: If an adverse event(s) is associated with (“results from”) the overdose of 
IMP, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met. An SAE Report has to be sent to the safety desk within 
24 hours of investigators awareness. 
If an overdose is administered without any associated clinical symptoms or abnormal 
laboratory results, the overdose is reported as a non-serious Event of Clinical 
Interest (ECI), using the terminology “accidental or intentional overdose without 
adverse effect.” An SAE Report has to be sent to the safety desk within 24 hours of 
investigators awareness. 
 
Abnormal Laboratory results: Abnormal laboratory test results will be recorded on 
the laboratory results pages of the eCRF. Laboratory-test-value abnormalities should 
additionally be considered an AE in case they are: 


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1. Accompanied by clinical symptoms 
2. Leading to a change in study medication (e.g. dose modification, interruption or 
permanent discontinuation) 
3. Requiring a change in concomitant therapy (e.g. addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment) 
In general it is the investigator’s responsibility to review all abnormal laboratory results 
and to determine if a given value represents a clinically significant change compared 
to previously obtained values and results in an Adverse Event or not. 
Any laboratory result abnormality fulfilling the criteria for a serious adverse event (SAE) 
should be reported as such, in addition to being recorded as an adverse event in the 
eCRF. 
 
7.5.3 Sponsor obligations 
 
The Sponsor will ensure compliance with all regulatory reporting requirements 
including the notification of the appropriate Ethics Committees, Competent Authority of 
all serious adverse events occurring at the site in accordance with national law, ICH 
Good Clinical Practice and European / EMA requirements. 
A Sponsor representative will medically review all SAE reports. 
A Sponsor representative will forward SAE, ECI and pregnancy reports within one 
working day to MSD.  
Every SAE, being assessed by either the investigator or the sponsor as suspected to 
be related to IMP und assessed as being either unexpected or unexpected with regard 
to outcome or severity of the event will be reported by the sponsor as SUSAR to the 
competent authority, responsible ethics committee and investigators of the trial in line 
with the national regulations in effect (German drug law [AMG] and GCP-V § 13). 
Fatal or life-threatening SUSARs must be reported as soon as possible, but no later 
than 7 days; further important information to these cases may be reported as follow-
up within additional 8 days. All others SUSARs have to be reported no later than 15 
days. 


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Also all adverse events which can change the benefit-risk ratio of the study drugs or 
otherwise fulfill the criteria outlined in GCP-V §13 Abs.4 have to be handled/reported 
as SUSARs. 
7.6 Handling of Safety Parameters 
7.6.1 Adverse events 
 
Adverse events can be spontaneously reported or elicited during open-ended 
questioning, examination, or evaluation of a subject. (In order to prevent reporting bias, 
subjects should not be questioned regarding the specific occurrence of one or more 
AEs.) 
Medically significant adverse events regardless of causality will be followed until 
resolved or considered stable. All subjects with serious adverse events must be 
followed up for outcome. 
It will be left to the investigator’s clinical judgment to determine whether an adverse 
event is related and of sufficient severity to require the subject’s removal from 
treatment or from the study. A subject may also voluntarily withdraw from treatment 
due to what he or she perceives as an intolerable adverse event. If either of these 
situations arises, the subject should be strongly encouraged to undergo an end-of-
treatment assessment and be under medical supervision until symptoms cease or the 
condition becomes stable. 
 
7.6.2 Overdose of pembrolizumab 
 
No specific information is available on the treatment of overdose of pembrolizumab. In 
the event of overdose, pembrolizumab should be discontinued and the subject should 
be observed closely for signs of toxicity. Appropriate supportive treatment should be 
provided if clinically indicated. If an adverse event(s) is associated with (“results from”) 
the overdose of pembrolizumab, the adverse event(s) is reported as a serious adverse 
event, even if no other seriousness criteria are met. 


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7.6.3 Treatment and Follow-up of Adverse Events 
 
Adverse events, especially those for which the relationship to test drug is not 
"unrelated", should be followed up until they have returned to baseline status or 
stabilized. If a clear explanation is established it should be recorded on the eCRF. All 
subjects with serious adverse events must be followed up for outcome. 
 
7.6.4 Treatment and Follow-up of Events of Clinical Interest 
 
See section 6.3.2 
 
7.6.5 Follow-up of Abnormal Laboratory Test Values 
 
In the event of unexplained abnormal laboratory test values, the tests should be 
repeated immediately and followed up until they have returned to the normal range and 
/ or an adequate explanation of the abnormality is found. If a clear explanation is 
established it should be recorded in the eCRF. 
 
7.6.6 Contraception and Pregnancy 
 
Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not 
known if pembrolizumab has transient adverse effects on the composition of sperm.   
For this trial, male subjects will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying 
medical condition).   
Female subjects will be considered of non-reproductive potential if they are either:  
(1) postmenopausal (defined as at least 12 months with no menses without an 
alternative medical cause; in women < 45 years of age a high follicle stimulating 
hormone (FSH) level in the postmenopausal range may be used to confirm a 
post-menopausal state in women not using hormonal contraception or 


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hormonal replacement therapy. In the absence of 12 months of amenorrhea, a 
single FSH measurement is insufficient.);  
OR  
(2) have 
had 
a 
hysterectomy 
and/or 
bilateral 
oophorectomy, 
bilateral 
salpingectomy or bilateral tubal ligation/occlusion, at least 6 weeks prior to 
screening;  
OR  
(3) has a congenital or acquired condition that prevents childbearing. 
 
Female and male subjects of reproductive potential must agree to avoid becoming 
pregnant or impregnating a partner, respectively, while receiving study drug and for 
120 days after the last dose of study drug by complying with one of the following:   
(1) practice abstinence† from heterosexual activity;  
OR  
(2) use (or have their partner use) acceptable contraception during heterosexual 
activity.   
 
Acceptable methods of contraception are‡: 
 
Single method (one of the following is acceptable): 
• 
intrauterine device (IUD) 
• 
vasectomy of a female subject’s male partner  
• 
contraceptive rod implanted into the skin 
 
Combination method (requires use of two of the following): 
• 
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• 
cervical cap with spermicide (nulliparous women only)   
• 
contraceptive sponge (nulliparous women only)  
• 
male condom or female condom (cannot be used together) 


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• 
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection 
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual lifestyle 
and if considered acceptable by local regulatory agencies and ERCs/IRBs.  Periodic 
abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) 
and withdrawal are not acceptable methods of contraception.  
 
‡If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region. 
 
Subjects should be informed that taking the study medication may involve unknown 
risks to the fetus (unborn baby) if pregnancy were to occur during the study. In order 
to participate in the study subjects of childbearing potential must adhere to the 
contraception requirement (described above) from the day of study medication 
initiation (or 14 days prior to the initiation of study medication for oral contraception) 
throughout the study period up to 120 days after the last dose of trial therapy. If there 
is any question that a subject of childbearing potential will not reliably comply with the 
requirements for contraception, that subject should not be entered into the study. 
 
A female patient must be instructed to immediately inform the investigator if she 
becomes pregnant during the study. The study treatment must immediately be stopped 
and the patient must be withdrawn from the study. The investigator should counsel the 
patient; discuss the risks of continuing the pregnancy, and possible effects on the fetus. 
Monitoring of the patient should continue until conclusion of the pregnancy. 
7.6.7 Adverse Drug reactions with Concomitant Medication 
 
The investigators must be aware that for all concomitant medications the regulations 
of post marketing reporting for suspected adverse drug reactions apply, i.e. reporting 
to the marketing authorization holder or the local regulatory bodies. 


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8 Statistical Methods and Sample Size 
8.1 Trial design and hypotheses 
 
The study is designed as an open-label, single arm, prospective, monocentric, phase 
II study of pembrolizumab in a neoadjuvant setting in patients with non-small cell lung 
cancer of Stage II/IIIA suitable for curative intent surgery. It is formally hypothesized 
that pembrolizumab applied in the neoadjuvant setting is feasible and safe and 
additionally a clinically meaningful pilot data for efficacy can be observed. On a 
preliminary basis, feasibility will be declared if the rate of successfully performed 
resections without extended delays is ≥80% (Feasibility criterion). 
8.2 Sample Size Calculation 
 
A phase II approach will be used to generate preliminary hypothesis generating data. 
No formal sample size estimation has been performed. The scope is to gather 
information on feasibility, safety and efficacy. 
 
Target sample size is N=30 
 
The rationale for the sample size of this trial is based on ethical, clinical as well as 
scientific considerations. The neo-adjuvant treatment approach with an immune check-
point inhibitor is highly experimental with only limited data on safety and feasibility 
available. Therefore, only a small number of patients should be subjected to this 
experimental treatment. Nevertheless, the sample size should allow the generation of 
statistically meaningful evidence for feasibility and safety to permit the decision to 
further develop this treatment approach.  
 
With a sample size of N=30 and assuming that the number of events follows a binomial 
distribution B(30,p), events with an incidence rate p > 9.5% will be observed at least 
once with a 95% probability. This observation limit will exclude individual 
pembrolizumab related SAEs but covers most of the historical reference events/rates 
of the primary endpoints in this trial as well as the early stopping rule. 


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The degree of the potential evidence provided by a sample size of N=30 is summarized 
in Table 3. 
 
Table 3 -- Reported reference data and exact CI under a sample size of N=30 [Clopper Pearson 
method] [13-15] 
Adverse event / endpoint 
Reported Frequency 
95% CI for sample size of N=30 
AE rate in Pembrolizumab monotherapy 
trials 
97.4% 
83.9 – 100.0 
Drug related AE rate in Pembrolizumab 
monotherapy trials * 
73.7% 
54.5 – 88.0 
SAE rate in Pembrolizumab monotherapy 
trials * 
37.2% 
20.4 – 56.7 
Drug related SAE rate in Pembrolizumab 
monotherapy trials * 
10 % 
2.1 – 26.5 
Cumulative rate of the 5 most frequent 
SAEs in Pembrolizumab monotherapy 
trials and potential impact on neo-adjuvant 
treatment approach and/or surgery 
[pneumonia (3.0%), pleural effusion 
(1.7%), pneumonitis (1.6%), dyspnea 
(1.6%) and pulmonary embolism (1.5%)] * 
9.4% 
1.8 – 25.7 
number of patients treated in compliance 
with protocol / Feasibility of resection and 
early stopping rule # 
80 % 
61.4 – 92.3 
Radiologic response (CR or PR) per 
RECIST 1.1 § 
10 % 
2.1 – 26.5 
Pathologic response (grade IIb or higher as 
per Junker criteria) § 
43 % 
25.2 – 62.3 
* See also section 1.2.4 and IB of pembrolizumab 
# Feasibility criterion 
§ Chaft et al. (J Clin Oncol 35, 2017 suppl; abstr 8508) [9] 
 
8.3 Evaluation categories of the patients 
8.3.1 Intent-to-Treat population 
 
The Intent-to-Treat population (ITT) includes all enrolled.  
8.3.2 Per-Protocol population 
 


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The Per-Protocol set (PP) will comprise all patients of the Intent-to-Treat population, if 
the following criteria are additionally met:  
 Administration of at least one study treatment. 
 All of the major inclusion criteria, none of the major exclusion criteria are fulfilled.  
 Documentation of a tumor assessment after start of study treatment. 
 Absence of other major protocol violations such as wrong treatment received. 
Protocol violations resulting in an exclusion from the Per-Protocol population will be 
described in the Clinical Study Report. 
8.3.3 Safety population 
 
The safety population consists of all patients who received at least one dose of 
treatment medication.  
Patients who cannot be included in any of the above mentioned analysis populations 
will be excluded from the statistical analyses. Any recorded data of these patients will 
be listed in the appendix to the Clinical Study Report. 
8.4 Methods of Statistical Analysis 
8.4.1 General statistical considerations 
 
The statistical evaluation will be carried out by sponsor delegate . Statistical analysis 
is based on the International Conference on Harmonization (ICH) Guidelines „Structure 
and Content of Clinical Study Reports“ and “Statistical Principles for Clinical Trials”. 
All data recorded in the eCRF describing the sample, the efficacy and the safety will 
first be analyzed descriptively. Categorical data will be presented in tables with 
frequencies and percentages. 
Continuous data will be summarized with at least the following: frequency (n), median, 
quartiles, mean, standard deviation (standard error), minimum and maximum. 
Descriptive analyses will be summarized. 
Statistical test between changes of parameters over time will be performed for 
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variance, Wilcoxon signed rank test, Fisher`s exact test and other appropriate tests will 
be used where applicable. Further details will be given in the Statistical Analysis Plan. 
Number of patients with protocol deviations during the study and listings describing the 
deviations will be provided. 
For the analysis of Adverse Events, summary tables will be generated for the incidence 
of AEs overall and by severity. This will also be done for Serious Adverse Events. The 
AE summary tables will provide the number and percentage of patients with adverse 
events. All safety analyses will be performed within the safety population. 
For laboratory parameters, the distribution over time (mean values) as well as changes 
from randomization will be computed and reported with descriptive statistics. 
The details of the statistical analysis will be defined in a Statistical Analysis Plan, which 
will be prepared before database closure. 
8.4.2 Demographics and baseline characteristics 
 
All demographic and clinical characteristics recorded at baseline will be submitted to 
descriptive analyses using descriptive statistics by means of listing and tables. 
8.4.3 Efficacy evaluation 
 
Primary efficacy parameter:  
Efficacy of the neoadjuvant treatment approach will be evaluated by radiologic tumor 
response (RECIST 1.1 assessment of base line and pre-surgery CT/MRI), by  changes 
of standardized maximal uptake values (SUVs) of the primary tumor quantified by PET-
scans, as well as a pathologic regression grading of resected tumor material according 
to Junker (see Appendix 18.3).  
 
Secondary efficacy parameters: 
Time-to-event measures (OS, DFS) will be analyzed by means of Kaplan-Meier 
curves. 
 
Details on the analysis of secondary parameters will be given in the Statistical Analysis 
Plan. 
 
 


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8.4.4 Safety evaluation 
 
Adverse events: 
All information recorded such as onset date, stop date, duration, maximum intensity, 
seriousness, relationship to study drug and outcome will be listed. 
Summary tables will be presented. These tables provide the number and percentage 
of patients with adverse events. Associated adverse event tables present the total 
number of patients reporting at least one specific event and the maximum toxicity 
grade. Thus, patients reporting more than one episode of the same event are counted 
only once by the worst grade per patient. 
Tabulations consist of the number and percentages of patients involved per CTC 
category and CTC term, the highest relation to study drug, and the maximum severity. 
Special tables will be displayed for CTC grade III / IV adverse events and for adverse 
events resulting in discontinuation of the trial. Additionally, analysis will be restricted to 
adverse events judged to be at least possibly related to study drug. 
Laboratory parameters: 
Abnormal laboratory parameters will be tabulated according to incidence and severity 
according to NCI CTCAE V4.03 and analyzed descriptively. 
 
9 Independent Data Monitoring Committee 
 
An Independent Data Monitoring Committee (IDMC) has been convened to assess the 
safety data, and provide recommendations to the Sponsor and Coordinating 
Investigator upon the stop or continuation of the study. The members of the IDMC 
serve in their individual capacity and provide their expertise and recommendations. 
The IDMC will review cumulative study data to evaluate subject safety, conduct an 
interim analysis and reassess the risk/benefit of the study. 
 
The role and responsibilities of the IDMC are described in detail in a separate IDMC 
Charter. 
 


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10 Data Quality Assurance 
The overall procedures for quality assurance of clinical study data are described in the 
Standard Operation Procedures of either the Sponsor or Sponsor delegate. Accurate 
and reliable data collection will be assured by verification and cross–check of the 
eCRFs against the investigator’s records by the study monitor (source document 
verification), and the maintenance of the drug accountability log by the investigator. 
Data for this study will be recorded via eCRF by the site from the source documents. 
Data are reviewed and checked for omissions, apparent errors, and values requiring 
further clarifications using computerized (automatic) and manual procedures. Data 
queries requiring clarification are communicated to the site for resolution via the eCRF. 
Only authorized personnel will make corrections to the clinical database and an audit 
trail will document all corrections. 


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11  Ethical Aspects 
11.1 Declaration of Helsinki / Good Clinical Practice 
The Declaration of Helsinki is the accepted basis for clinical study ethics, and must be 
fully followed and respected by all engaged in research on human beings. Any 
exceptions must be justified and stated in the protocol.  
The trial will be performed in accordance with the Declaration of Helsinki, as decided 
upon by the 18th World Medical Assembly, Helsinki, Finland, June 1964 (amended by 
subsequent World Medical Assembly Somerset West, South Africa, October 1996,). 
The declaration is included as appendix. 
Additionally, it is the responsibility of all engaged in research on human beings to 
ensure that the study is performed in accordance with the international Good Clinical 
Practice standards and according to all local laws and regulations concerning clinical 
studies. 
11.2 Patient Information and Informed Consent 
It is the responsibility of the investigator to obtain written informed consent from each 
patient participating in this study, after adequate explanation of aim, importance, 
anticipated benefits, and potential hazards and consequences of the study according 
to applicable local laws. Written informed consent must be obtained before any study 
specific procedures are performed. It must be also explained to the patient that they 
are completely free to refuse to enter the study or to withdraw from it at any time for 
any reason without incurring any penalty or withholding of treatment on the part of the 
investigator. 
With the declaration of consent the patient agrees that data on his disease are 
recorded within the framework of the clinical trial and that they are transferred to the 
sponsor in a pseudonymized way. 
The subject / patient also agrees to allow the monitor / auditor / health authorities to 
verify the collected patient data against the subject's / patient's original medical records 
for the purpose of source data verification. 
The informed consent form personally signed and dated by the patient and the 
investigator and must be kept on file by the investigator(s), and documented in the 


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eCRF and the subject's medical records. The investigator confirms obtaining the 
written informed consent to the sponsor. 
If new safety information results in significant changes in the risk/benefit assessment, 
the consent form should be reviewed and updated if necessary. All patients (including 
those already being treated) should be informed of the new information and must give 
their written informed consent to continue in the study. 
If the family doctors are informed of their patients’ participation in the clinical study, this 
should be mentioned in the consent form. 
11.3 Independent Ethics Committees and Regulatory Authorities 
11.3.1 Approval of the study by the Regulatory Authority and Independent Ethics 
Committees 
It is the responsibility of the sponsor to obtain and maintain independent approval from 
the applicable regulatory authority and a positive opinion from the competent ethics 
committees to conduct the study in accordance with local legal requirements, statutes 
and the European Clinical Trial Directive. 
Indemnity insurance will be contracted for the trial subjects in accordance with the 
applicable local law.  
For Germany, the sponsor names the "Leiter der klinischen Prüfung" (LKP) who has 
to be a physician with at least 2 years’ experience in the conduct of clinical trials of 
drugs according to § 4 (25) and § 40 (1) No. 5 AMG. 
11.3.2 Notification of the study 
The sponsor is responsible to notify competent regional authority about the study and 
all investigators of the participating investigational sites, if applicable to local law. 
11.3.3 Report and documentation obligation  
The sponsor and the investigator are responsible to comply with the report and 
documentation obligations in accordance with local legal requirements, statutes and 
the European Clinical Trial Directive. 
12 Conditions for Modifying the Protocol 
Protocol modifications to ongoing studies must be made via amendment. The sponsor 
is responsible to obtain independent approval for substantial amendments from the 


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applicable regulatory authority and a positive opinion from the competent ethics 
committees in accordance with local legal requirements, statutes and the European 
Clinical Trial Directive. Approval must be awaited before any changes can be 
implemented, except for changes necessary to eliminate an immediate hazard to trial 
subjects or when the changes are non-substantial and involve only logistical or 
administrative aspects of the trial (e.g. change of telephone numbers). 
13 Study Documentation, eCRFs and Record-Keeping 
13.1 Investigator's Files / Retention of Documents 
The investigator must maintain adequate and accurate records to enable the conduct 
of the study to be fully documented and the study data to be subsequently verified. 
These documents should be classified into two different separate categories 
Investigator's Study File, and patient data. 
The Investigator's Study File will contain all essential documents as the protocol / 
amendments, patient information and informed consent form, Ethics Committee and 
regulatory authority approval, notification of the federal regulatory authority and 
competent regional authorities, if applicable, drug records, staff curriculum vitae and 
authorization forms and other appropriate documents / correspondence etc. 
Patient data include patient hospital/clinic records (e.g. medical reports, OP reports 
appointment book, medical records, pathology and laboratory reports, ECG, EEG, X-
ray, etc.) and signed informed consent forms and patient screening and eligibility 
screening forms. 
The investigator must keep these two categories of documents on file for at least 10 
years (or more as legally required) after completion or discontinuation of the study. The 
documents must be archived in a secure place and treated as confidential material. 
Should the investigator wish to assign the study records to another party or move them 
to another location, the sponsor must be notified in advance. 
If the investigator cannot guarantee this archiving requirement at the investigational 
site for any or all of the documents, special arrangements must be made between the 
investigator and the sponsor to store these in a sealed container(s) outside of the site 
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Where source documents are required for the continued care of the patient, 
appropriate copies should be made for storing outside of the site. 
All documents must be archived in a secure place and treated as confidential material. 
13.2 Source Documents and Background Data 
The investigator shall supply the sponsor on request with any required background 
data from the study documentation or clinic records. This is particularly important when 
Case Report Forms are illegible or when errors in data transcription are suspected. In 
case of special problems and / or governmental queries or requests for audit 
inspections, it is also necessary to have access to the complete study records, 
provided that patient confidentiality is protected. According to the standards of the data 
protection law, all data obtained in the course of a clinical study must be treated with 
discretion in order to guarantee the rights of the patient's privacy. 
13.3 Audits and Inspections 
To ensure quality of data, study integrity, and compliance with the protocol and the 
various applicable regulations and guidelines, the sponsor may conduct site visits to 
institutions participating to protocols. The investigator, by accepting to participate to 
this protocol, agrees to co-operate fully with any quality assurance visit undertaken by 
third parties, including representatives from the sponsor, national regulatory authorities 
or company supplying the product under investigation, as well as to allow direct access 
to documentation pertaining to the clinical trial (including eCRFs, source documents, 
hospital subject charts and other study files) to these authorized individuals. The 
investigator must inform the sponsor immediately in case a regulatory authority 
inspection would be scheduled. If inspections will be performed in particular for this 
study by the competent authority, the competent authority / investigator has to send 
the inspection report to the sponsor within 5 working days. 
13.4 Electronic Case Report Forms (eCRF) 
For each patient enrolled, an eCRF must be completed by the principal investigator or 
authorized delegate from the study staff. This also applies to records for those patients 
who fail to complete the study. If a patient withdraws from the study, the reason must 
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limiting adverse event, thorough efforts should be made to clearly document the 
outcome. 
 


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14 Monitoring the Study 
The monitor has the responsibility to familiarize the investigator(s) and the entire center 
staff involved in the study with all study procedures including the administration of study 
drug. 
The  Sponsormust provide a trained monitor to assist the investigator(s) in conducting 
the clinical study. The monitor must visit the clinical study center before the first patient 
has been enrolled (initiation visit); at routine monitoring visits during the course of the 
study at least once if patients were enrolled at the study center; and at study 
completion. The monitor has the responsibility of reviewing the ongoing study with the 
investigator(s) to verify adherence to the protocol and to deal with any problems that 
arise. At all times Sponsor must maintain the confidentiality of the study documents. It 
is the responsibility of the study monitor to verify the study documents against the 
patient’s original medical records. 
The investigator (or his / her deputy) agrees to cooperate with the monitor to ensure 
that any problems detected in the course of these monitoring visits are resolved. 
15 Confidentiality of Trial Documents and Patient Records 
The investigator and the sponsor (or designee) must assure that according to the 
standards of the data protection law, all data obtained in the course of a clinical study 
must be treated with discretion in order to guarantee the rights of the patient's privacy. 
Patient related documents must be submitted to the sponsor in a pseudonymous 
manner. The investigator should keep a patient identification log showing codes and 
names. The investigator should maintain documents not for submission to Sponsor, 
e.g., patients’ written consent forms, in strict confidence. 
16 Study Report and Publication Policy 
This study will be entered into a clinical trial protocol registry and clinical results 
database. The sponsor is responsible for the timely reporting of study data. An 
integrated clinical study report (CSR) has to be completed one year after end of the 
study (whether completed or prematurely terminated). The report has to be approved 
by the responsible specialist chosen by the sponsor the statistician and the 
coordinating investigator / LKP by provision of their signatures. Any publications of the 
results, either in part or in total (abstracts in journals, oral presentations, etc.) by 


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investigators or their representatives will require pre-submission-review by the 
Sponsor and the coordinating investigator / LKP. The coordinating investigator will be 
given the choice to be the first or the last author for the main publication. 


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17 References 
1. 
Goldstraw P, Chansky K, Crowley J, Rami-Porta R, Asamura H, Eberhardt WE, 
Nicholson AG, Groome P, Mitchell A, Bolejack V: The IASLC Lung Cancer Staging 
Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming 
(Eighth) Edition of the TNM Classification for Lung Cancer. Journal of Thoracic 
Oncology 2016, 11(1):39-51. 
2. 
Yamauchi Y, Muley T, Safi S, Rieken S, Bischoff H, Kappes J, Warth A, Herth FJ, 
Dienemann H, Hoffmann H: The dynamic pattern of recurrence in curatively 
resected non-small cell lung cancer patients: Experiences at a single institution. 
Lung cancer 2015, 90(2):224-229. 
3. 
Hanna GG, Siva S, Plumridge N, Solomon B, Ball DL: Preoperative chemotherapy 
for non-small-cell lung cancer. The Lancet 2014, 384(9939):232-233. 
4. 
McElnay P, Lim E: Adjuvant or neoadjuvant chemotherapy for NSCLC. Journal of 
thoracic disease 2014, 6(2):S224-S227. 
5. 
Kaatsch P, Spix C, Hentschel S, Katalinic A, Luttmann S, Stegmaier C, Caspritz S, 
Cernaj J, Ernst A, Folkerts J: Krebs in Deutschland 2009/2010. In., vol. 9. Ausgabe: 
Robert-Koch-Institut und die Gesellschaft der epidemiologischen Krebsregister in 
Deutschland e.V.; 2013. 
6. 
Merck Sharp & Dohme Corp aSoMC, Inc.: Investigator's Brochure MK-3475 
(Pembrolizumab/Keytruda). In., 11 edn; 2016. 
7. 
Herbst RS, Baas P, Kim D-W, Felip E, Pérez-Gracia JL, Han J-Y, Molina J, Kim J-H, 
Arvis CD, Ahn M-J: Pembrolizumab versus docetaxel for previously treated, PD-
L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised 
controlled trial. The Lancet 2016, 387(10027):1540-1550. 
8. 
Forde PM, Smith K, Chaft JE, Hellmann M, Merghoub T, Wolchok JD, Yang SC, 
Battafarano RJ, Gabrielson E, Georgiades C: NSCLC, early stageNeoadjuvant anti-
PD1, nivolumab, in early stage resectable non-small-cell lung cancer. Annals of 
Oncology 2016, 27(suppl_6). 
9. 
Chaft JE, Forde PM, Smith KN, Anagnostou V, Cottrell T, Taube JM, Rekhtman N, 
Merghoub T, Jones DR, Hellmann MD: Neoadjuvant nivolumab in early-stage, 
resectable non-small cell lung cancers. In.: American Society of Clinical Oncology; 
2017. 
10. 
Ilie M, Hofman V, Dietel M, Soria J-C, Hofman P: Assessment of the PD-L1 status 
by immunohistochemistry: challenges and perspectives for therapeutic strategies 
in lung cancer patients. Virchows Archiv 2016, 468(5):511-525. 
11. 
Ilie M, Long-Mira E, Bence C, Butori C, Lassalle S, Bouhlel L, Fazzalari L, Zahaf K, 
Lalvée S, Washetine K: Comparative study of the PD-L1 status between surgically 
resected specimens and matched biopsies of NSCLC patients reveal major 
discordances: a potential issue for anti-PD-L1 therapeutic strategies. Annals of 
Oncology 2015, 27(1):147-153. 
12. 
Junker K, Langner K, Klinke F, Bosse U, Thomas M: Grading of tumor regression in 
non-small cell lung cancer : morphology and prognosis. Chest 2001, 120(5):1584-
1591. 
13. 
PASS 14 Power Analysis and Sample Size Software (2015). NCSS, LLC. In., 14 edn. 
USA: NCSS, LLC. Kaysville, Utah, USA; 2015. 
14. 
Fleiss JL, Levin B, Paik MC: Statistical methods for rates and proportions: John 
Wiley & Sons; 2013. 


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15. 
Newcombe RG: Two‐sided confidence intervals for the single proportion: 
comparison of seven methods. Statistics in medicine 1998, 17(8):857-872. 
 


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18 Appendices 
 


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18.1  Appendix 1 – ECOG Performance Status 
 
GRADE SCALE 
0 
Fully active, able to carry out all pre-disease performance without 
restriction.  
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light housework, office 
work.  
2 
Ambulatory and capable of all self-care, but unable to carry out work 
activities. Up and about more than 50 % of waking hours  
3 
Capable of only limited self-care, confined to bed or chair more than 50 % 
of waking hours.  
4 
Completely disabled. Cannot carry out any self-care. Totally confined to 
bed or chair.  
5 
Dead  
 


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18.2  Appendix 2 – RECIST 1.1 
 
According to: 
 
New response evaluation criteria in solid tumors: 
Revised RECIST guideline (version 1.1) 
 
Eisenhauer EA, Therasse P, Bogaerts J et al. European Journal of Cancer 45 (2009): 
228-247 
 
RECISTGuidelines 
1.1.pdf
 
 
 
 


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18.3  Appendix 3 - Junker criteria for tumor regression grading 
 
Differentiation between spontaneous and therapy induced regression as well as the degree of 
therapy induced regression is critical for assessment of the primary endpoint of this trial. 
Since macroscopic examination of the resection does now allow for unequivocal differentiation 
between vital tumor tissue and therapy induced regression, regions with likely vital tumor tissue 
or former, now regressively altered, tumor tissue as well as all resected mediastinal lymph 
nodes should be embedded in paraffin. 
If macroscopically unequivocally viable tumor tissue is found, representative section through 
the tumor (1 FFPE block per cm) will be sufficient. In all other cases the tumor should be 
embedded fully and all blocks are to be submitted to central review. 
The central review process will look for key histological parameters of therapy induced tumor 
regression: 
 
Type and extent of the vital tumor tissue 
 
Degree of tumor necrosis 
 
Reactive alterations with foam cell reaction 
 
 Fibrosis or scar formation.  
To differentiate between small remaining tumor cell infiltrates from reactive histiocytic 
proliferations and reactive pneumocyte hyperplasia additional immune histochemical analyses 
such as CK7, Ki-67 and P53 may be needed. 
 
The findings will be classified according to the following regression grading: 
Regression grading stages 
Histological observations 
Grade I 
No tumor regression or only spontaneous 
tumor regression in the sections of the 
primary tumor and mediastinal lymph 
nodes.  
Grade IIa 
Morphological signs of therapy-induced 
tumor regression in the sections of the 
primary tumor and/or mediastinal lymph 
nodes in the sections of the primary 
tumor and/or mediastinal lymph nodes: 
More than 10% vital tumor tissue 
Grade IIb 
Morphological signs of therapy-induced 
tumor regression: 
Less than 10% vital tumor tissue 
Grade III 
Complete tumor regression, no evidence 
of vital tumor in the sections of the 
primary tumor and/or mediastinal lymph 
nodes: 
Regression grades IIb and III suggest a good response to neoadjuvant therapy. 
 
Reproduced from Junker et al. 2001 [12]. 


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18.4  Appendix 4 – Cockcroft-Gault Formula 
 
 
 
Calculated CLCR (ml/min) =  
[(140 – subject’s age in years) x subject’s actual body weight in kilograms] * 
 
 
 
 
 
 
 
72 x subject’s serum creatinine (in mg/dL) 
 
*: x 0.85 for females 
 
 
 
 
Calculated CLCR (ml/min) =  
[(140 – subject’s age in years) x subject’s actual body weight in kilograms] x K* 
 
 
 
 
 
 
 
subject’s serum creatinine (in µmol/L) 
 
K*: 1.23 for males, 1.05 for females 
 
 


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18.5  Appendix 5 – NCI-CTC Version 4.03 (CTCAE v4.03) 
 
NCI-CTC Version 
4.03
 
 


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18.6  Appendix 6 – Declaration of Helsinki, Republic of South Africa, 
October 1996 
 
Declaration of 
Helsinki
 
 


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18.7  Appendix 7 – Summary of Changes 
 
The following table provides a summary of changes to the Clinical Study Protocol version 5.0 (02-SEP-2020), which are included in version 4.0 (26-
NOV-2018). Minor editorial changes have also been made but are not included in this summary table. 
 
Summary of changes to previous protocol version 
 
Section 
number  
Section title 
Version 4.0 
Version 5.0 
(Changes / additions in bold 
italic and deletions as 
strikethrough) 
Type of change and 
justification for 
changes 
--- 
Synopsis  
page 7 
Inclusion Criteria 
11. d. INR 1.4 and PTT < 40 
seconds during the last 7 days 
before therapy 
 
11. d. INR < 1.4 and PTT < 40 
seconds during the last 7 days 
before therapy 
Change: non-
substantial 
Justification: 
Alignment with section 
4.2 
--- 
Synopsis  
page 12 
Inclusion Criteria 
Study plan 
FPI Q3/2017 
LPI after approx. 18 month 
LPO after approx. 22 month 
EoS (after 24 month FU of LPO) 
        after approx. 46 month 
Study plan 
FPI Q2/2018 
LPI after approx. 36 month 
(Q2/2021) 
LPO after approx. 40 month 
(Q4/2021) 
EoS (after 24 month FU of LPO) 
after approx. 64 month (Q4/2023) 
Change: non-substantial 
Justification: 
Adjustment, trail 
recruitment 
3.7  
Study 
Inclusion 
Criteria  
Study plan 
FPI Q3/2017 
Study plan 
FPI Q2/2018 
Change: non-substantial 
Justification: 


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Section 
number  
Section title 
Version 4.0 
Version 5.0 
(Changes / additions in bold 
italic and deletions as 
strikethrough) 
Type of change and 
justification for 
changes 
Duration 
page 38 / 39 
 
LPI after approx. 18 month 
LPO after approx. 22 month 
EoS (after 24 month FU of LPO) 
        after approx. 46 month 
LPI after approx. 36 month 
(Q2/2021) 
LPO after approx. 40 month 
(Q4/2021) 
EoS (after 24 month FU of LPO) 
after approx. 64 month (Q4/2023) 
Adjustment, trail 
recruitment 
 

SAP_001.pdf: 
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Adapted from: 
 
Page 1 of 23 
STAT03_A Statistical Analysis Plan 
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Confidential and intellectual property of Assign DMB. No part of this document or its contents may be duplicated, referenced, published or 
otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
 
 
 
Statistical Analysis Plan 
Main Analysis and Addendum Analysis 
 
Neoadjuvant anti PD-1 immunotherapy 
in resectable non-small cell lung cancer 
 
Protocol: NEOMUN 
 
 
Confidential 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor: 
AIO-Studien-gGmbH 
 
 


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Confidential and intellectual property of Assign DMB. No part of this document or its contents may be duplicated, referenced, published or 
otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
Table of Contents 
 
1. 
OVERVIEW 
6 
1.1 
Study Objectives 
6 
1.1.1 
Primary Objective 
6 
1.1.2 
Secondary Objectives 
6 
1.1.3 
Exploratory Objectives 
6 
1.2 
Study Design 
6 
1.3 
Endpoints 
6 
1.3.1 
Primary Endpoint 
6 
1.3.2 
Secondary Endpoints 
6 
1.3.3 
Exploratory Endpoints 
7 
1.4 
Sample Size Calculation 
7 
1.5 
Schedule of Study Assessments 
8 
2. 
GENERAL CONSIDERATIONS 
9 
2.1 
Conduct of Analysis 
9 
2.2 
Statistical Software and Quality Control 
9 
2.3 
Applicable Standard Operating Procedures 
9 
2.4 
Blinding and Randomization 
9 
2.5 
Descriptive Analyses 
10 
2.6 
Inferential Analyses 
10 
2.7 
Center and Country Effect 
10 
2.8 
Handling Missing Data 
10 
2.9 
Protocol Deviations 
10 
2.10 
Medical Coding 
10 
2.11 
Analysis Populations 
11 
2.11.1 
Intent-to-Treat population 
11 
2.11.2 
Per-Protocol population 
11 
2.11.3 
Safety population 
11 
2.12 
Patient Data Listings 
11 
2.13 
Table Columns 
11 
2.14 
Changes in the Conduct of the Study or Planned Analysis 
11 
3. 
OVERALL STUDY INFORMATION 
12 
4. 
BASELINE EVALUATION 
12 
4.1 
Data Points 
12 
5. 
EFFICACY ANALYSIS 
12 
5.1 
Data Points 
12 
5.2 
Definitions 
13 


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otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
5.3 
Inferential Analysis 
14 
6. 
SAFETY ANALYSIS 
14 
6.1 
Extent of Exposure 
14 
6.2 
Adverse Events 
14 
6.2.1 
Data Points 
14 
6.2.2 
Definition 
15 
6.2.3 
Inferential Analysis 
15 
6.3 
Laboratory Parameters 
15 
6.3.1 
Data Points 
15 
6.4 
Other Safety Parameters/ Clinical Assessments 
17 
6.4.1 
Data Points 
17 
7. 
LIST OF TABLES, DATA LISTINGS AND FIGURES 
18 
7.1 
List of Tables 
18 
7.1.1 
Overall Study Information 
18 
7.1.2 
Baseline Evaluation 
18 
7.1.3 
Efficacy Analysis 
18 
7.1.4 
Safety Analysis 
19 
7.2 
List of Data Listings 
20 
7.2.1 
Overall Study Information 
20 
7.2.2 
Baseline Data 
20 
7.2.3 
Efficacy Data 
21 
7.2.4 
Safety Data 
22 
 
 


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otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
List of Abbreviations 
 
AE 
Adverse event 
CEA 
Carcinoembryonic antigen 
CI 
Confidence interval 
CSP 
Clinical study plan 
CTCAE 
Common terminology criteria for adverse events 
Cyfra 21-1 
Cytokeratin-fragment 21-1 
DFS 
Disease-free survival 
DLCO 
Diffusion capacity of lung for CO 
DRM 
Data review meeting 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
FEV 
Forced expiratory volume 
FU 
Follow-up 
IMP 
Investigational medicinal product 
ITT 
Intent-to-treat 
LD 
Least diameter 
NCI 
National Cancer Institute 
NSCLC 
Non-small cell lung cancer 
OA 
Overall 
OS 
Overall survival 
PP 
Per-protocol 
PT 
Preferred term 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SB 
Single breath method 
SD 
Standard deviation 
SOC 
System organ class 
SUV 
Standardized uptake value 
TL 
Target lesion 
TLFs 
Tables, listings and figures 
VA 
Alveolar volume 
VC 
Vital capacity 


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otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
1. 
OVERVIEW 
1.1 
Study Objectives 
1.1.1 
Primary Objective 
 
To assess feasibility and safety of a neoadjuvant application of pembrolizumab. 
 
To assess antitumor activity of pembrolizumab with regard to clinical and pathologic tumor response. 
1.1.2 
Secondary Objectives 
To assess the impact of neoadjuvant pembrolizumab on patient disease free and overall survival. 
1.1.3 
Exploratory Objectives 
To explore potential predictive biomarkers for Pembrolizumab efficacy by immune cell and cytokine analysis: 
 
Inflammatory infiltrates in and around the resected tumor 
 
tumor tissue and serum cytokine profiles 
 
Hypothesis generation on potential biomarkers predicting efficacy of pembrolizumab using multi-OMICS 
analysis 
1.2 
Study Design 
The study is designed as an open-label, single arm, prospective, monocenter, phase II study of pembrolizumab in a 
neoadjuvant setting in patients with non-small cell lung cancer of Stage II/IIIA suitable for curative intent surgery. 
1.3 
Endpoints 
1.3.1 
Primary Endpoint 
 
Frequency and severity of AEs including peri- and post-operative complications (grade 2-4 AEs according to 
NCI-CTCAE V4.03) 
o 
number of patients treated in compliance with protocol 
 
Tumor response evaluation 
clinical response parameters: 
o 
response rates (Δ tumor size / lymph node size), according to RECIST 1.1 criteria 
o 
Δ PET-activity (standardized uptake value [SUV]) (analysis of this end point is not covered in this SAP) 
Pathologic response parameters: 
o 
Pathologic regression grading according to Junker criteria (see Appendix 3 of CSP) 
1.3.2 
Secondary Endpoints 
 
disease free survival 
 
overall survival 
 


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otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
1.3.3 
Exploratory Endpoints 
Following exploratory endpoints were defined for this study, but will not be covered by this SAP: 
 
prognostic value of tumor shrinkage 
 
prognostic value of inflammatory infiltrates in and around the resected tumor 
 
serum- and tumor tissue cytokine concentrations 
 
multi-OMICS tissue analysis approach for markers and mechanisms 
1.4 
Sample Size Calculation 
A phase II approach will be used to generate preliminary hypothesis generating data. No formal sample size 
estimation has been performed. The scope is to gather information on feasibility, safety and efficacy. 
Target sample size is N=30. 
The rationale for the sample size of this trial is based on ethical, clinical as well as scientific considerations. The 
neo-adjuvant treatment approach with an immune check-point inhibitor is highly experimental with only limited data 
on safety and feasibility available. Therefore, only a small number of patients should be subjected to this 
experimental treatment. Nevertheless, the sample size should allow the generation of statistically meaningful 
evidence for feasibility and safety to permit the decision to further develop this treatment approach. 
With a sample size of N=30 and assuming that the number of events follows a binomial distribution B(30,p), events 
with an incidence rate p > 9.5% will be observed at least once with a 95% probability. This observation limit will 
exclude individual pembrolizumab related SAEs but covers most of the historical reference events/rates of the 
primary endpoints in this trial as well as the early stopping rule. 
 
 


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otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
1.5 
Schedule of Study Assessments 
 


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2. 
GENERAL CONSIDERATIONS 
2.1 
Conduct of Analysis 
Two analyses will be performed for this study. 
 
Main analysis will be performed after all patients had their end of treatment, data entry for all visits except 
the follow-up visits is complete, data were cleaned, a Data Review Meeting was performed and database 
snapshot has been completed. 
 
Addendum analysis will be performed after last patient completed the entire study, follow-up data entry and 
cleaning are complete and database was closed. 
 
Main analysis will summarize all data recorded up to the time of the database snapshot. Addendum analysis will 
only present data captured during follow-up. This means, the addendum analysis may only include overall survival, 
end of study details and subsequent cancer therapy. An SAE listing will also be prepared to show possible follow-up 
information of SAEs ongoing after end of treatment. 
2.2 
Statistical Software and Quality Control 
All statistical analyses will be performed using SAS® version 9.3 or higher. Tables, figures and data listings will be 
generated in Microsoft® Word® as well as PDF® format. 
Quality control of SAS® programs will include a review of the whole process of result generation: 
 
Review of all analysis SAS® programs 
 
Review of SAS® log for errors, warnings and other notes that could indicate mistakes in the programs 
 
Review of all tables, listings and figures for completeness and correctness 
2.3 
Applicable Standard Operating Procedures 
The applicable Standard Operating Procedures (SOPs) of Assign DMB for this study are: 
STAT01 Statistical Analysis File 
STAT03 Statistical Analysis Plan 
STAT04 Interim Analysis 
STAT06 Data Review Meeting 
STAT07 Report Writing 
SAS01 SAS General Principles 
SAS04 Handling of Statistical Analyses 
2.4 
Blinding and Randomization 
As it is an open-label and single arm study, principles of blinding and randomization are not applicable. 
 
 


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otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
2.5 
Descriptive Analyses 
 
Descriptive analyses of continuous variables (summary statistics) will be described with the number of non-
missing observations, arithmetic mean, standard deviation (±SD), median, quartiles (Q1 and Q3) and range 
(minimum and maximum). 
 
Categorical variables (frequency statistics) will be described with the number of non-missing observations 
and percentages (%). 
2.6 
Inferential Analyses 
Inferential analysis for efficacy is described in Section 5.3. Inferential analysis for safety is described in Section 
6.2.3. 
2.7 
Center and Country Effect 
Since this study is a one-center pilot study, stratification by country or study site is not applicable. 
2.8 
Handling Missing Data 
In general, missing data will not be imputed and analysis is restricted on available data, with the following 
exceptions: 
 
For time-to-event endpoints (DFS, OS), incomplete dates will be handled as described in Section 5.2. 
 
Response rates will consider missing response assessments as described in Section 5.2. 
 
Missing causality assessment for adverse events will lead to handling of the AE as related (see Section 7.3 
of the CSP) 
2.9 
Protocol Deviations 
Potential protocol deviations will be collected prior to database snapshot for the main analysis. Potential protocol 
deviations will be discussed in a data review meeting (DRM) prior to database snapshot for the main analysis and 
will be classified as relevant or not relevant. A protocol deviation will be considered relevant if it has a potential 
influence on the efficacy analysis. Relevant protocol deviations will lead to exclusion from the PP Population. 
Relevant protocol deviations can be one of the following but are not limited to: 
 
at least one of the major inclusion criteria was not met (criteria with relevant impact on efficacy) 
 
at least one of the major exclusion criteria was fulfilled (criteria with relevant impact on efficacy) 
 
administration of prohibited therapies during the screening and treatment phase as defined in the CSP 
 
administration of no study treatment 
 
no documentation of tumor assessment after start of study treatment 
 
erroneous dose of study medication 
2.10 Medical Coding 
All information regarding the medical coding of medical history and adverse events can be found in the coding 
guideline. 


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otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
2.11 Analysis Populations 
2.11.1 Intent-to-Treat population 
The Intent-to-Treat (ITT) Population includes all enrolled. A patient is regarded as enrolled if considered eligible for 
treatment start at screening (i.e. eCRF question “Have all screening assessments been performed and is patient 
considered eligible for treatment start” is answered with yes by the investigator). 
2.11.2 Per-Protocol population 
The Per-Protocol (PP) Population will comprise all patients of the ITT population who had no protocol deviation 
relevant for efficacy evaluation. PP Population will be defined in the DRM performed before the main analysis. For 
definition of relevant protocol deviations, see Section 2.9. 
2.11.3 Safety population 
The safety population consists of all patients who received at least one dose of study medication. 
If the Safety and ITT Population are identical (i.e. all enrolled patients received at least one dose of treatment 
medication) the analysis will be performed for the Safety Population and the ITT Population together, labelled with 
“Safety/ITT Population”. 
2.12 Patient Data Listings 
All recorded patient data of eligible patients will be included in by-patient data listings. Safety data listings will be 
restricted to the safety population (treated patients). 
Data listings will include the patient number as identifier (and parameter and/or time point if available). A column 
indicating if a patient is in the PP Population will be shown in all baseline and efficacy listings. 
2.13 Table Columns 
All analysis tables will include one column including all patients of the respective analysis population. 
2.14 Changes in the Conduct of the Study or Planned Analysis 
The following changes as compared to descriptions in the CSP are described in this SAP: 
 
According to a sentence in the CSP, all patients' data is included in data listings. During SAP review it was 
decided to not include screening failure data in all data listings. 
 
The CSP planned to include statistical tests between time points. During SAP review it was decided to omit 
such tests due to small sample size. 
 
 


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otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
3. 
OVERALL STUDY INFORMATION 
The following information will be analyzed descriptively and corresponding details on the subject level will be 
provided in data listings: 
 
Patient overview 
o 
Eligible patients 
o 
Study populations 
o 
Screening completion / screening failures incl. reason 
o 
End of treatment incl. reason 
o 
End of study incl. reason for study end 
 
Attended visits 
The following information will be provided only in data listings: 
 
Violated inclusion/ exclusion criteria 
 
Protocol deviations 
4. 
BASELINE EVALUATION 
Baseline characteristics will be summarized for ITT and PP Population, respectively. 
4.1 
Data Points 
 
Demographics and baseline characteristics (Age, gender, race, body weight and height, smoking status) 
 
Disease history 
o 
Cancer history 
o 
Histological type 
o 
Previous cancer treatment (any) 
 
Medical history by SOC and PT 
The following information will be provided only in data listings: 
 
Concomitant medication 
 
Concomitant procedure 
5. 
EFFICACY ANALYSIS 
Efficacy analyses will be performed primarily on the PP Population and will be repeated on the the ITT population. 
5.1 
Data Points 
Following tables and figures will be provided: 
 
Tumor response at pre-surgery visit 
o 
Overall response 
o 
Δ tumor size 
 
Tumor regression grading stage (according to Junker criteria) 
 
Kaplan-Meier statistics for disease free survival (DFS) 


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otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
 
Kaplan-Meier statistics for overall survival (OS) 
 
Tumor staging 
 
Tumor markers (CEA, Cyfra 21-1) 
 
Lung function 
o 
forced expiratory pressure in 1 second (FEV1) 
o 
maximum vital capacity (VC MAX) 
o 
forced vital capacity (FVC) 
o 
inspiratory vital capacity (VC IN) 
o 
diffusion capacity of lung for CO (DLCO SB) 
o 
diffusion capacity of lung for CO / alveolar volume (DLCO/VA) 
o 
DLCOc SB 
o 
DLCOc/VA 
o 
forced expiratory pressure in 1 second / maximum vital capacity (FEV1 % VC MAX) 
o 
partial pressure of O2 (pO2) 
o 
partial pressure of CO2 (pCO2) 
Corresponding details on the patient-level will be listed. 
The following information will be provided only in data listings: 
 
Screening tumor assessment 
 
Target lesions 
 
Non-target lesions 
 
Translational research 
 
Survival status 
5.2 
Definitions 
 
Disease-free survival (DFS) will be defined as the time length from the date of surgery to the date of tumor 
recurrence or death (tumor recurrence as reported on follow-up pages in the eCRF, death as reported in 
the end of study page in the eCRF). Patients that had no tumor recurrence and did not die will be censored 
at the date of last contact when patient was alive (as reported on the end of study page in the eCRF).  
 
Overall survival (OS) will be calculated as the time length from the date of surgery to the date of death. 
Patients that did not die will be censored at the date of last contact when patient was alive (as reported on 
the end of study page in the eCRF).  
 
For both DFS and OS the following rule will be applied for incomplete dates: The date of surgery is assumed 
to always be completely known (day, month and year available), otherwise DFS and OS will not be 
calculated. For the end dates (death, tumor recurrence, last date patient was alive) patients will be secured 
at the earliest possible date. E.g. if the date of death is "UK/05/2019" then the patient is censored at 
01/05/2019 and thus being considered event-free until this date and status is considered unknown after 


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Confidential and intellectual property of Assign DMB. No part of this document or its contents may be duplicated, referenced, published or 
otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
this date. If this rule results in negative survival time, the patient is not considered for Kaplan-Meier 
analysis. 
 
Δ tumor size will be defined as the difference [mm] between "current SUM LD" and "baseline sum LD" on 
the tumor response assessment page of the eCRF. 
5.3 
Inferential Analysis 
No statistical tests are performed due to the small sample size. 
DFS and OS will be described by means of Kaplan-Meier method. Estimates of median DFS and OS rates for specific 
time points (at e.g. 12, 24 and 36 months) will be provided with the associated 95% confidence limits.  
6. 
SAFETY ANALYSIS 
Safety analyses will be performed for the Safety population. 
6.1 
Extent of Exposure 
Detailed information on study drug administration will be provided in data listings. 
6.2 
Adverse Events 
The following information will be analyzed descriptively and corresponding details on the subject level will be 
provided in data listings. 
6.2.1 
Data Points 
 
Adverse Event Overview 
o 
Any AE 
o 
Any AE of clinical interest 
o 
Any related AE 
o 
Any severe AE 
o 
Any AE grade 2-4 
o 
Any related severe AE 
o 
Any related AE grade 2-4 
o 
Any SAE 
o 
Any related SAE 
o 
Any AE requiring study treatment dose modification 
o 
Any AE requiring study treatment discontinuation 
 
Adverse Events by maximum severity 
o 
Any AE 
o 
Any related AE 
 
Adverse Event by highest relationship 
o 
Any AE 
o 
Any AE grade 2-4 


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otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
o 
Any SAE 
 
Adverse Events by SOC and preferred term 
o 
Any AE 
o 
Any related AE 
o 
Any AE grade 2-4 
o 
Any related AE grade 2-4 
o 
Any SAE 
o 
Any related SAE 
o 
Any AE requiring study treatment discontinuation 
6.2.2 
Definition 
 
Severe AE: AEs with severities of Grade 3-5 (severe or medically significant, severe or life threatening, 
death) will be considered as severe AEs 
 
Missing causality assessment for adverse events will lead to handling of the AE as "related", see Section 
7.3 of the CSP. 
6.2.3 
Inferential Analysis 
AE summary tables will provide the number and percentage of patients with AEs and the 95 % confidence intervals 
for the event rates according to Wilson. 
6.3 
Laboratory Parameters 
The following information will be analyzed descriptively and corresponding details on the subject level will be 
provided in data listings. 
6.3.1 
Data Points 
 
Hematology 
o 
basophils absolute 
o 
eosinophils absolute 
o 
erythrocytes 
o 
hemoglobin 
o 
leukocytes 
o 
lymphocytes absolute 
o 
monocytes absolute 
o 
neutrophils absolute 
o 
platelets 
 
Clinical chemistry and coagulation 
o 
ALT 
o 
AST 
o 
activated 
partial 
thromboplastin 
time 
o 
albumin absolute 
o 
calcium 
o 
creatinine 
o 
creatinine clearance 
o 
LDH 
o 
magnesium 
o 
phosphate 
o 
potassium 
o 
prothrombin time relative 
o 
sodium 


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otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
o 
TSH 
o 
total bilirubin 
o 
free T3 
o 
free T4 
The following variables will be analyzed descriptively: 
 
Absolute values by time point 
 
Absolute change from screening values by time point 
 
Values above and below normal range by time point 
 
Conversion of laboratory parameters will be performed from a study site specific laboratory unit into the unit to be 
used in the statistical analysis via the following formula: 
 
Value in analysis unit = value in study site specific unit * conversion factor 
The following units will be used as standard units: 
Parameter 
Unit used for Analysis  
Clinical chemistry and coagulation 
ALT 
U/l 
AST 
U/l 
albumin absolute 
g/l 
calcium 
mmol/l 
creatinine 
mg/dl 
creatinine clearance 
ml/min 
LDH 
U/l 
magnesium 
mmol/l 
phosphate 
mmol/l 
potassium 
mmol/l 
prothrombin time relative 
% 
sodium 
mmol/l 
TSH 
mU/l 
total bilirubin 
mg/dl 
free T3 
ng/l 
free T4 
ng/l 
Tumor marker 
CEA 
µg/l 
Cyfra 21-1 
µg/l 
 


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otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
Parameter 
Unit used for Analysis  
Clinical chemistry and coagulation 
ALT 
U/l 
AST 
U/l 
albumin absolute 
g/l 
calcium 
mmol/l 
creatinine 
mg/dl 
creatinine clearance 
ml/min 
LDH 
U/l 
magnesium 
mmol/l 
phosphate 
mmol/l 
potassium 
mmol/l 
prothrombin time relative 
% 
sodium 
mmol/l 
TSH 
mU/l 
total bilirubin 
mg/dl 
free T3 
ng/l 
free T4 
ng/l 
6.4 
Other Safety Parameters/ Clinical Assessments 
The following information will be analyzed descriptively and corresponding details on the subject level will be 
provided in data listings. 
6.4.1 
Data Points 
 
ECOG status 
 
Vital signs 
o 
blood pressure 
o 
heart rate 
o 
body temperature 
o 
body weight 
The following information will only be provided in data listings: 
 
Pregnancy test (if applicable) 
 
Physical examination 
 
Quality of life 
 
ECG 
 
Chest X-Ray 
 
Subsequent cancer therapy  


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7. 
LIST OF TABLES, DATA LISTINGS AND FIGURES 
Numbering of tables, listings and figures will follow principles as below: 
 
Tables and figures numbering will begin with number 14, listings with number 16.2. 
Numbering of Tables (digits after tables/figures prefix): 
 
First digit will indicate information type shown (1= overall, 2= baseline, 3= efficacy, 4= safety) 
 
Second digit will represent table/listing/figure type. 
7.1 
List of Tables 
7.1.1 
Overall Study Information 
No 
Legend 
Content 
14.1.1 
Patient overview (All patients) 
 
Eligible patients 
 
Study Populations (ITT, PP, Safety) 
 
Screening completion / screening failures 
incl. reason 
 
End of study incl. reason for study end 
14.1.2 
Attended visits (ITT Population) 
 
7.1.2 
Baseline Evaluation 
No 
Legend 
Content 
14.2.1 
Demographics and baseline characteristics 
(ITT Population) 
 
Age at informed consent 
 
Gender 
 
Race 
 
Body weight and height 
 
Smoking status 
14.2.2 
Disease history (ITT Population) 
 
Cancer history 
 
Histological type 
 
Previous cancer treatment (any) 
14.2.3 
Medical history by System Organ Class and 
Preferred Term (ITT Population) 
 
14.2.4-6 
Tables 14.2.1-3 will be repeated for the PP 
Population. 
 
7.1.3 
Efficacy Analysis 
No 
Legend 
Content 
14.3.1 
Tumor Response at Pre-Surgery Visit 
(PP Population) 
 
Overall response 
 
Δ tumor size 
14.3.2 
Tumor Regression Grading Stage (PP 
Population) 
 
14.3.3 
Kaplan-Meier Statistics for Disease-
Free Survival (PP Population) 
 
14.3.4 
Kaplan-Meier Statistics for Overall 
Survival (PP Population) 
 
14.3.5 
Tumor Staging (PP Population) 
 
Tumor stage 
14.3.6 
Tumor Marker Values Over Time (PP 
Population) 
 
CEA 
 
Cyfra 21-1 
14.3.7 
Tumor Marker Value’s Change from 
Baseline (PP Population) 
 
CEA 
 
Cyfra 21-1 


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14.3.8 
Lung function test results (PP 
Population) 
 
VC MAX 
 
FVC 
 
VC IN 
 
FEV1 
 
FEV 1% VC MAX 
 
DLCO SB 
 
DLCO/VA 
 
DLCOc SB 
 
DLCOc/VA 
 
pCO2 
 
pO2 
14.3.9-16 
Tables 14.3.1-8 will be repeated for the 
ITT Population. 
 
7.1.4 
Safety Analysis 
No 
Legend 
Content 
Adverse Events 
14.4.1 
Adverse Events Overview (Safety Population) 
 
Any AE 
 
Any AE of clinical interest 
 
Any related AE 
 
Any severe AE 
 
Any AE grade 2-4 
 
Any related severe AE 
 
Any related AE grade 2-4 
 
Any SAE 
 
Any related SAE 
 
Any AE requiring treatment 
discontinuation 
 
Any AE requiring treatment dose 
modification 
14.4.2 
Adverse Events by Maximum Severity (Safety 
Population) 
 
Any AE 
 
Any related AE 
14.4.3 
Adverse Event by Highest Relationship (Safety 
Population) 
 
Any AE 
 
Any AE grade 2-4 
 
Any SAE 
14.4.4 
Adverse Events by SOC and Preferred Term (Safety 
Population) 
 
Any AE 
 
Any AE grade 2-4 
 
Any related AE 
 
Any related AE grade 2-4 
 
Any SAE 
 
Any related SAE 
 
Any AE requiring study treatment 
discontinuation 
Laboratory Parameters 
14.4.5 
Hematology Values over Time (Safety Population) 
 
14.4.6 
Hematology Value’s Change from Baseline (Safety 
Population) 
 
14.4.7 
Hematology Values above and below Normal 
Range by Time Point (Safety Population) 
 
14.4.8 
Clinical Chemistry and Coagulation Values over 
Time (Safety Population) 
 
14.4.9 
Clinical Chemistry and Coagulation Value’s 
Change from Baseline (Safety Population) 
 


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14.4.10 Clinical Chemistry and Coagulation Values above 
and below Normal Range by Time Point (Safety 
Population) 
 
Other Safety Parameters 
14.4.11 ECOG Status (Safety Population) 
 
14.4.12 Vital Signs (Safety Population) 
 
Blood pressure 
 
Heart rate 
 
Body temperature 
 
Body weight 
 
7.2 
List of Data Listings 
7.2.1 
Overall Study Information 
No 
Legend 
Content 
16.2.1.1 Patient Overview (All patients) 
Patient ID, Date of written informed consent, 
Version of informed consent, Version of informed 
consent form, Patient eligible, Reason not 
eligible, Planned date of treatment start, ITT 
population, PP population, Safety population 
16.2.1.2 Attended visits (ITT Population) 
Patient ID, Visit, Planned date of visit, Actual 
date of visit, Days between planned and actual 
date, Reason outside time window, Days 
between Visit 1 and Discharge 
16.2.1.3 End of study details (ITT Population) 
Patient ID, Date of study end, Date of last 
contact when patient was alive, Reason for study 
end, Specification lost to FU/other reason, Death 
date, Primary cause of death, Date of pregnancy 
noticed, Pregnancy status 
16.2.1.4 Violated 
Inclusion/ 
Exclusion 
Criteria 
(ITT 
Population) 
Patient ID, Criterion category, Criterion, Answer 
16.2.1.5 Protocol violations (All patients) 
Patient ID, Protocol deviation category, Protocol 
deviation description, Classification, Reason for 
classification 
7.2.2 
Baseline Data 
No 
Legend 
Content 
16.2.2.1 Demographics and baseline characteristics (ITT 
Population) 
Patient ID, Gender, Year of birth, Age at informed 
consent, Body height, Body weight, Race, 
Childbearing potential, Reason no childbearing 
potential, Smoking status, Prev. smoker duration 
abstinence [years], Total tobacco consumption 
[pack years] 
16.2.2.2 Cancer history (ITT Population) 
Patient ID, Any cancer history within 5 years prior 
to screening, Specification, Any treatments of 
previous cancer, Number of previous cancer 
treatments 
16.2.2.3 Previous cancer treatment details (ITT Population) Patient ID, Type of prior treatment, Start date of 
prior treatment, Stop date of prior treatment, 
Location/ description 
16.2.2.4 Tumor diagnosis (ITT Population) 
Patient ID, Date of first NSCLC diagnosis, NSCLC 
location, Histologically/ cytologically confirmed 
NSCLC, Date of initial biopsy, Date of 
confirmation, Method, Histological type 


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16.2.2.5 Imaging date and time at screening (ITT 
Population) 
Patient ID, PET/CT performed, Date of PET/CT, 
MRI brain performed, Date of MRI brain 
16.2.2.6 Medical History (ITT Population) 
Patient ID, MH number, Condition, Start date, End 
date/ ongoing, Treated with medications at 
screening, Start date unknown - prior to IC, End 
date unknown - prior to IC 
16.2.2.7 Prior/ Concomitant Medications (ITT Population) 
Patient ID, CM number, Medication (trade name 
preferred), Start Date, Start date unknown but 
prior IC, End Date/ ongoing, Single-dose and unit, 
Frequency, Route of Administration, Indication 
16.2.2.8 Prior/ Concomitant Procedures (ITT Population) 
Patient ID, CP number, Procedure, Start Date, 
Start date unknown but prior IC, End Date/ 
ongoing, End Date unknown but prior IC, 
Indication 
7.2.3 
Efficacy Data 
No 
Legend 
Content 
16.2.3.1 
Screening Tumor Assessment (ITT Population) 
Patient ID, Visit, Date of assessment, Number of 
target lesions, Current sum LD [mm], Current 
sum LD present, Number of non-target lesions,  
16.2.3.2 
Tumor 
Response 
at 
Pre-Surgery 
Visit 
(ITT 
Population) 
Patient ID, date of assessment, Any new 
lesions, New lesion location, New lesion 
present, Date of progression, Current sum LD 
[mm], Current sum LD present, Baseline sum 
LD [mm], Δ tumor size, Target lesion response 
calculated, Target lesion response investigator, 
Reason inconsistent (TL response), Non-target 
lesion response, Non-target lesion response 
present, Overall response calculated, Overall 
response investigator, Reason inconsistent (OA 
response) 
16.2.3.3 
Target Lesion Details (ITT Population) 
Patient ID, Visit, Target lesion, Location, 
Description of location, Method, Diameter [mm], 
Lesion present, Lesion too small to measure, 
Lesion diameter (calculated) [mm] 
16.2.3.4 
Non-Target Lesion Details (ITT Population) 
Patient ID, Visit, Non-Target lesion(s), Location, 
Number of lesion(s), Description of location, 
Method, Lesion(s) still present, Lesion(s) not 
assessed 
16.2.3.5 
Histology (ITT Population) 
Patient ID, Tumor regression grading performed, 
Date tumor regression grading, Regression 
grading stage, Reason regression grading not 
performed, Tumor size (largest diameter) [mm], 
Histologic subtype, Adenocarcinoma subtype 
16.2.3.6 
Overall Response (ITT Population) 
Patient ID, OS [months], OS censored, DFS 
[months], DFS censored 
16.2.3.7 
Tumor Staging (ITT Population) 
Patient ID, Visit, Stage identifier, Stage 
16.2.3.8 
Tumor Markers (ITT Population) 
Patient ID, Visit, Has blood sample been drawn, 
Date of sample drawn, Actual age [years], 
Parameter, Value, Unit, Clinically relevant, 
Causal relationship 
16.2.3.9 
Lung Function (ITT Population) 
Patient ID, Visit, Lung function test, Test 
performed, Date test performed, Method, 
Parameter, (Best) Value, Unit ((Best) value), 
Best/target value [%] 


SAP (NEOMUN Main Analysis and Addendum Analysis, FINAL 1.0, 09-Mar-2022) 
Adapted from: 
 
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STAT03_A Statistical Analysis Plan 
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Confidential and intellectual property of Assign DMB. No part of this document or its contents may be duplicated, referenced, published or 
otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
16.2.3.10 Translational research (ITT Population) 
Patient ID, Visit, Blood sample for biomarkers 
drawn, Date of blood sample drawn 
16.2.3.11 Survival status/ Follow-up (ITT Population) 
Patient ID, Visit, Patient alive, Tumor 
recurrence, Date of diagnosis, CT thorax scan 
performed, X-ray performed 
7.2.4 
Safety Data 
No 
Legend 
Content 
16.2.4.1 
Extent of Exposure (ITT Population) 
Patient ID, Visit, Pembrolizumab administered, 
Reason not administered, Start date, Start time, 
End date, End time, Duration of administration 
[min], Reason duration outside time window, 
Dose according to protocol (200 mg), Dose [mg], 
Reason dose not per protocol 
Adverse Events 
16.2.4.2 
Any Adverse Events (Safety Population) 
Patient ID, AE count, AE term, Event description, 
System organ class, Preferred Term, Start date, 
Stop date, Event of clinical interest, Serious AE, 
Specification of SAE, Date of becoming serious, 
CTCAE grade, Causal relationship to study drug, 
Action taken (IMP), Action taken (other), 
Outcome 
16.2.4.3 
Severe Adverse Events (Safety Population) 
See table 16.2.4.2 
16.2.4.4 
Adverse Events of Grade 2-4 (Safety Population) 
See table 16.2.4.2 
16.2.4.5 
Serious Adverse Events (Safety Population) 
See table 16.2.4.2 
16.2.4.6 
Related Adverse Events (Safety Population) 
See table 16.2.4.2 
16.2.4.7 
Related Severe Adverse Events (Safety 
Population) 
See table 16.2.4.2 
16.2.4.8 
Related Adverse Events of Grade 2-4 (Safety 
Population) 
See table 16.2.4.2 
16.2.4.9 
Related Serious Adverse Events (Safety 
Population) 
See table 16.2.4.2 
16.2.4.10 Adverse Events of Clinical Interest (Safety 
Population) 
See table 16.2.4.2 
16.2.4.11 Adverse Events Requiring Study Treatment Dose 
Modification (Safety Population) 
See table 16.2.4.2 
16.2.4.12 Adverse Events Requiring Study Treatment 
Discontinuation (Safety Population) 
See table 16.2.4.2 
Laboratory Parameters 
16.2.4.13 Laboratory Normal Ranges 
Parameter, Lower Limit Normal (female), Upper 
Limit Normal (female), Lower Limit Normal 
(male), Upper Limit Normal (male), Unit, Valid 
from date (inclusive), Valid from age (inclusive) 
16.2.4.14 Hematology Values (Safety Population) 
Patient ID, Visit, Blood sample drawn, Date 
sample drawn, Parameter, Value, Unit, Change 
from baseline, Lower limit, Upper limit, Outside 
normal range, Clinically relevant, Causal 
relationship 
16.2.4.15 Clinical Chemistry and Coagulation Values (Safety 
Population) 
See Listing 16.2.4.14 
Other Safety Parameters 
16.2.4.16 Surgeries performed (Safety Population) 
Patient ID, Surgery performed, Date of surgery, 
Method, Approach, Extensions, Systematic lymph 
node dissection performed, Intraoperative blood 
loss [ml], Intraoperative blood transfusion 


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STAT03_A Statistical Analysis Plan 
Version 6.0, Effective Date 16-Feb-2018 
Confidential and intellectual property of Assign DMB. No part of this document or its contents may be duplicated, referenced, published or 
otherwise disclosed in any form or by any means without prior written consent of Assign DMB. 
performed, Post-operative complications, Length 
of ICU stay, Re-admission to ICU, Date of re-
admisson 
16.2.4.17 Vital signs (Safety Population) 
Patient ID, Visit, Parameter, Value, Unit 
16.2.4.18 Cardiac evaluation (Safety Population) 
Patient ID, Visit, Evaluation performed, Cardiac 
evaluation, Date, Result, Specification of 
abnormality 
16.2.4.19 ECOG performance status (Safety Population) 
Patient ID, Visit, Date ECOG Score, ECOG Score 
16.2.4.20 Routine Chest X-Ray (Safety Population) 
Patient ID, Visit, Chest X-Ray performed, Date of 
performance, Tumor visible, Comments 
16.2.4.21 Pregnancy test (Safety Population) 
Patient ID, Visit, Pregnancy test performed, Date 
of test, Reason not performed, Method, Result 
16.2.4.22 Quality of Life (Safety Population) 
Patient ID, Visit, Date of assessment, Quality of 
Life question, Answer/Result