Clinical trial NCT04512430
Conditions: Non Small Cell Lung Cancer EGFR Gene Mutation
Keywords: Lung Neoplasms Respiratory Tract Neoplasms Thoracic Neoplasms Lung Diseases Carcinoma, Bronchogenic Carcinoma, Non-Small-Cell Lung Bronchial Neoplasms Atezolizumab Bevacizumab Carboplatin Pemetrexed Neoadjuvant treatment Adjuvant treatment Antineoplastic Agents, Immunological EGFR Mutation Chemotherapy
Sponsor: Fundación GECP
Start date: 2020-12-02; Completion date: 2024-07-19
Enrollment: 4 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label, non-randomised, phase II, multi-centre clinical trial

26 patients will be enrolled in this trial to evaluate the major pathologic response in patients with neoadjuvant treatment with Carboplatin Pemetrexed Bevacizumab plus Atezolizumab in patients with non-small cell lung carcinoma locally advanced mutated in EGFR

Detailed description:
This is an open-label, non-randomised, phase II, multi-centre clinical trial. Patients enrolled will receive Atezolizumab 1200mg + Bevacizumab 15mg/Kg + Carboplatin AUC6 + Pemetrexed 500mg/m2 for 3 cycles every 21 days (+/- 3 days) as neoadjuvant treatment followed by surgery and 6 months of adjuvant treatment with Atezolizumab 1200 mg Q4W (+/- 3 days).

The primary objective is to evaluate the major pathologic response defined as 10 percent or fewer viable cancer cells detectable in the resected tumor and in lymph nodes in stage IIIA EGFR mutated patients treated in neoadjuvant setting with atezolizumab- bevacizumab- carboplatin and pemetrexed.

Patient accrual is expected to be completed within 2 years excluding a run-in-period of 3-6 months. Treatment and follow-up are expected to extend the study duration to a total of 6 years. Patients will be followed 3 years after adjuvant treatment. The study will end once survival follow-up has concluded. This will be followed by a close out period of 4 months.

Arms: arm 1: * Neoadjuvant treatment: (Atezolizumab: 1200 mg, IV infusion+Bevacizumab: 15mg/Kg mg, IV infusion+Carboplatin: AUC6, IV infusion+Pemetrexed: 500 mg/m2, IV infusion) will start within 1-3 days from enrollment. 3 cycles will be administered at 21-day (+/- 3 days) intervals (QW3) prior to surgery.Before surgery a tumor assessment will be done. Patients must leave the study if there is evidence of progression. Patients with stable disease or partial response may be considered for surgery.
* Surgery: Surgery must be done within the 4th week (+7 days) from day 21 cycle 3 of neoadjuvant treatment (day 42-49 after day 1 of cycle 3).
* Adjuvant treatment: Atezolizumab: 1200 mg, IV infusion Q4W (+/- 3 days) for 6 months (6 cycles) Patients that are R0 confirmed by surgical pathology evaluation will receive the first adjuvant administration within the 3rd to 8th week (+7 days) from surgery and for 6 months (6 cycles).
Interventions: intervention 1: Atezolizumab intervention 2: Bevacizumab intervention 3: Carboplatin intervention 4: Pemetrexed
Intervention descriptions: intervention 1: Patients will receive 1200 mg of Atezolizumab every 21 days (QW3) (+/- 3 days) during neoadjuvant phase and every 28 days (QW4) (+/- 3 days) at adjuvant phase in a monitored setting where there is immediate access to trained personnel and adequate equipment/medicine to manage potentially serious reactions.

First Infusion

* No premedication administered for atezolizumab specifically is permitted
* Infuse atezolizumab (1200 mg in a 250 mL 0.9% NaCl IV bag) over 60 (+/- 15) minutes.

Subsequent Infusions:

* If patient experienced infusion-related reaction during any previous infusion, premedication with antihistamines may be administered for Cycles \> 2 at the discretion of the treating physician.
* If the patient tolerated the first infusion well without infusion-associated adverse events, the successive infusion may be delivered over 30 (+/- 10) minutes. intervention 2: Patients will receive 15mg/Kg of Avastin® (bevacizumab) administered by IV infusion every 21 days, for 3 cycles during neoadjuvant phase, in a monitored setting where there is immediate access to trained personnel and adequate equipment/medicine to manage potentially serious reactions. intervention 3: Structure: The cis-diamino (cyclobutan-1, 1 dicarboxilate) platin. Stability: 24 hours at ambient temperature in 5% glucose, glucosaline or physiologic saline. It is recommended not to dilute with chlorinated solutions since this could affect the carboplatin.

Route of administration: Intravenous infusion Patients will receive Carboplatin AUC6 administered by IV infusion every 21 days, for 3 cycles during neoadjuvant phase.

Guidelines of Carboplatin administration: According to the standard of each center intervention 4: Patients will receive Pemetrexed 500mg/m2 administered by IV infusion every 21 days, for 3 cycles during neoadjuvant phase.

Pemetrexed disodium (ALIMTA®, pemetrexed) is a novel pyrrolo\[2,3 d\]pyrimidine-based folic acid analogue.

Route of administration: Intravenous infusion. Guidelines of Pemetrexed administration: According to the standard of each center

Protocol documents:
Prot_SAP_000.pdf: 
Protocol_Neo-DIANA_GECP 20/01_ML42249_v.3.0_16Feb2022 
 
 
 
 
 
Official Title: “A phase II trial of neoadjuvant treatment with carboplatin-
pemetrexed-bevacizumab plus atezolizumab for the treatment of locally 
advanced and potentially resectable NSCLC patients with EGFR mutations” 
Neo-DIANA 
 
 
 
       NCT Number: NCT04512430 
 
 
Document Dates:  
Summary of Protocol Amendment Version v.3.0_16Feb2022 
 
 


 
Confidential 
 
 
 
A PHASE II TRIAL OF NEOADJUVANT TREATMENT 
CARBOPLATIN-PEMETREXED-BEVACIZUMAB PLUS 
ATEZOLIZUMAB FOR THE TREATMENT OF LOCALLY 
ADVANCED AND POTENTIALLY RESECTABLE NSCLC 
PATIENTS WITH EGFR MUTATIONS 
 
 
 
 
Neo-DIANA: Neoadjuvant treatment for EGFR mutated patients 
 
 
  
 
 
 
 
Sponsor: Fundación GECP 
EudraCT Number: 2020-000642-33 
Sponsor code: GECP 20/01 
 
Version 3.0 
 
 
 
 
 


 
 
 
 
 
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Contacts 
Trial Chair  
Dr. Mariano Provencio, 
MD, PhD 
Fundación GECP President 
Oncology Service 
Hospital Univ. Puerta de Hierro, 
Majadahonda, Madrid,  
 
 
Email: secretaria@gecp.org   
Safety and 
Regulatory Affairs 
Coordinating office of the 
Fundación GECP 
 
Avenida Meridiana 358, 6ª planta 
08027 Barcelona 
 
 
 
Coordinating office 
of the Fundación 
GECP 
Monitoring team 
Monitor/CRA 
 
Avenida Meridiana 358, 6ª planta 
08027 Barcelona 
 
 
 
Lead CRA 
 
Avenida Meridiana 358, 6ª planta 
08027 Barcelona 
 
 
  
Clinical Operations 
Manager: 
 
Avenida Meridiana 358, 6ª planta 
08027 Barcelona 
 
 
  
 


 
 
 
 
 
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Protocol Signature Page 
A PHASE II TRIAL OF NEOADJUVANT TREATMENT CARBOPLATIN-
PEMETREXED-BEVACIZUMAB PLUS ATEZOLIZUMAB FOR THE 
TREATMENT OF LOCALLY ADVANCED AND POTENTIALLY RESECTABLE 
NSCLC PATIENTS WITH EGFR MUTATIONS 
Neo-DIANA: Neoadjuvant treatment for EGFR mutated patients 
Sponsor code: GECP 20/01 
Approved by: 
Signature 
 
 
 
_____________________________ 
 
Trial Chair 
 
 
 
Signature 
 
 
 
 __________________________ 
 
 
 
 
 
Signature 
 
 
 
_____________________________ 
 
Fundación GECP President  
 


 
 
 
 
 
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Principal Investigator’s protocol signature page 
Study Title: “A phase II trial of neoadjuvant treatment with carboplatin-pemetrexed-bevacizumab plus 
atezolizumab for the treatment of locally advanced and potentially resectable NSCLC patients with 
EGFR mutations” 
Sponsor protocol code: GECP 20/01 
EudraCT Number: 2020-000642-33 
Protocol version: v.3.0, 16th February 2022 
Name of Principal Investigator: Dr. ________________________________________________ 
 
Institution’s name: Hospital ______________________________________________________ 
As principal investigator of this site, I hereby confirm that: 
I have read the protocol and agree that it contains all necessary details for conducting this trial. I will 
conduct the trial as outlined in the following protocol and in compliance with GCP and will apply due 
diligence to avoid protocol deviations.  
I will provide copies of the protocol and all drug information relating to pre-clinical and prior clinical 
experience furnished to me by the Fundación GECP, to all physicians responsible to me who participate 
in this trial. I will discuss this material with them to assure that they are fully informed regarding the 
drug and the conduct of the trial.  
I agree to keep accurate records on all patient information including patient's informed consent 
statement, drug shipment and return forms, and all other information collected during the trial for a 
minimum period of 25 years according to the new Royal Decree 1090/2015 approved in Spain. 
Signed in ______________________________________ (place), 
 
 
 
 
_____________________________________________________ 
________________________ 
Signature  
Date 
 
 


 
 
 
 
 
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TABLE OF CONTENTS 
1. 
Protocol summary .......................................................................................................................... 8 
2. 
Trial schedule ................................................................................................................................ 18 
3. 
Background and rationale ............................................................................................................ 21 
3.1. 
Disease background .............................................................................................................. 21 
3.2. 
Prognostic factors after neoadjuvant treatment ................................................................ 22 
3.3. 
Immunotherapy .................................................................................................................... 24 
3.4. 
Immune checkpoint receptors ............................................................................................. 24 
3.5. 
Rationale for trial design ...................................................................................................... 25 
4. 
Objectives and endpoints ............................................................................................................. 27 
4.1. 
Primary objective and endpoint .......................................................................................... 27 
4.2. 
Secondary objectives and endpoint ..................................................................................... 27 
5. 
Trial design, duration and termination ........................................................................................ 28 
6. 
Patient selection ........................................................................................................................... 29 
6.1. 
Inclusion criteria ................................................................................................................... 29 
6.2. 
Exclusion criteria ................................................................................................................... 30 
7. 
Patient enrolment ........................................................................................................................ 32 
8. 
Trial procedures ............................................................................................................................ 33 
8.1. 
Overview of treatment sequence ........................................................................................ 33 
8.1.1. 
Screening/Baseline visit: .............................................................................................. 33 
8.1.2. 
Neoadjuvant treatment ................................................................................................ 33 
8.1.3. 
Surgery .......................................................................................................................... 35 
8.1.4. 
Adjuvant treatment ...................................................................................................... 36 
8.1.5. 
End of treatment .......................................................................................................... 37 
8.1.6. 
Follow up visits ............................................................................................................. 37 
9. 
Investigational Medicinal Product ............................................................................................... 37 
9.1. 
Packaging and labelling ........................................................................................................ 38 
9.2. 
Receipt and storage of the IMP ............................................................................................ 38 
9.3. 
Unused trial drug supplies .................................................................................................... 38 
10. 
Trial treatments description..................................................................................................... 39 
10.1. ATEZOLIZUMAB .................................................................................................................... 39 
10.2. BEVACIZUMAB ...................................................................................................................... 40 
10.3. CARBOPLATIN ....................................................................................................................... 40 
10.4. PEMETREXED ........................................................................................................................ 40 


 
 
 
 
 
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10.5. 10.5 PACLITAXEL ................................................................................................................... 41 
11. 
Dose modifications criteria ...................................................................................................... 42 
11.1. General Notes Regarding Dose Modification ...................................................................... 42 
11.2. ATEZOLIZUMAB dose modifications .................................................................................... 42 
11.3. BEVACIZUMAB dose modifications ...................................................................................... 43 
11.4. CARBOPLATIN and PACLITAXEL dose modifications ........................................................... 48 
11.5. PEMETREXED dose modification .......................................................................................... 52 
12. 
Prohibited and permitted concomitant treatments ............................................................... 53 
13. 
Adverse events and reporting .................................................................................................. 55 
13.1. Definition of an Adverse Event (AE) and AE’s reporting ..................................................... 55 
13.2. Definition of Serious Adverse Event (SAE) and Suspected Unexpected Serious Adverse 
Reaction (SUSAR) .............................................................................................................................. 58 
13.3. Adverse events of Special Interest for Atezolizumab (Immediately reportable to the 
Sponsor) ............................................................................................................................................ 60 
13.4. Overdose and secondary malignancies ............................................................................... 61 
13.5. SAEs and SUSARs reporting .................................................................................................. 61 
13.6. Pregnancy.............................................................................................................................. 62 
13.7. Other safety considerations ................................................................................................. 63 
13.8. Adverse events related to the treatment and associated risks .......................................... 63 
14. 
Biological material and translational research ........................................................................ 66 
15. 
Case report forms and documentation .................................................................................... 67 
16. 
Statistical considerations ......................................................................................................... 67 
17. 
Criteria for termination of the trial .......................................................................................... 68 
17.1. General criteria for termination of the trial ........................................................................ 68 
17.2. Discontinuation of protocol treatment and from the study for individual patients ......... 68 
18. 
Ethics aspects, regulatory approval, and Patient Informed Consent ..................................... 69 
18.1. Ethical Review Board/Ethics Committee/Health Authority ................................................ 69 
18.2. Informed consent ................................................................................................................. 69 
19. 
Governance and administrative issues .................................................................................... 70 
19.1. Study documentation ........................................................................................................... 70 
19.2. Protocol non-compliances/deviations ................................................................................. 70 
19.3. Protocol amendment ............................................................................................................ 71 
19.4. Final report ........................................................................................................................... 71 
19.5. Independent Data Monitoring Committee .......................................................................... 71 


 
 
 
 
 
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19.6. Publication ............................................................................................................................ 71 
19.7. Financial disclosure............................................................................................................... 71 
19.8. Clinical trial insurance .......................................................................................................... 71 
19.9. Quality assurance ................................................................................................................. 72 
19.10. Data protection ..................................................................................................................... 72 
19.11. Study monitoring team ........................................................................................................ 72 
19.12. Record retention ................................................................................................................... 73 
20. 
References ................................................................................................................................ 74 
 
 
Appendices: 
1. Common Terminology criteria for Adverse Events (CTCAE)  
2. RECIST criteria v1.1  
3. SAE Form  
4. Pregnancy Form 
5. System of classification for non-microcytic lung cancer (NSCLC) and definition of lymph node 
maps, 8th edition 
6. Risks associated with Atezolizumab and guidelines for management of adverse events 
associated with Atezolizumab 
Tables: 
Table 1. Administration of First and subsequent infusions of Atezolizumab 
Table 2. Premedication for Pemetrexed 
Table 3. Carboplatin Dose Modification for Hematologic Toxicities 
Table 4. Carboplatin Dose Modification on the Basis of Non-Hematologic Toxicities in the preceding 
cycle 
Table 5. Pemetrexed Dose Modification for Hematologic Toxicities 
Table 6.  Pemetrexed Dose Modification for Non-Hematologic Toxicities 
Figures: 
Figure 1. Study schema 
 
 
 


 
 
 
 
 
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1. Protocol summary 
A PHASE II TRIAL OF NEOADJUVANT TREATMENT CARBOPLATIN-
PEMETREXED-BEVACIZUMAB PLUS ATEZOLIZUMAB FOR THE 
TREATMENT OF LOCALLY ADVANCED AND POTENTIALLY RESECTABLE 
NSCLC PATIENTS WITH EGFR MUTATIONS 
Neo-DIANA: Neoadjuvant treatment for EGFR mutated patients 
Sponsor: Fundación GECP 
Trial Chair: Mariano Provencio Pulla (MD, PhD) 
Pharma Partner: Roche Farma S.A 
Protocol code: GECP 20/01 (Neo-DIANA). 
 
Population: stage IIIA or IIIB with T3N2 disease potentially resectable EGFR mutated non-small cell 
lung cancer patients 
Design: Open-label, non-randomised, phase II, multi-centre clinical trial  
Figure 1. Study schema 
 


 
 
 
 
 
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Sample size: 26 patients  
Rationale: 
The cure is unlikely in patients with NSCLC and locally advanced stage who are not surgical candidates, 
with a 3-year survival rate of 27% in those patients receiving chemotherapy and concomitant 
radiotherapy.  
At diagnosis, at least 40% of patients are diagnosed at an advanced stage and a third locally advanced 
disease (stage III). Only 25-30% of the NSCLC are candidates for curative-intent surgery. The results of 
stage IIIA with induction treatment of clinical practice outside the clinical trial show a median survival 
of 22 months and a 3-year survival rate of 34%.  
Complete surgical resection, tumor downstaging and pathologic complete response are predictors of 
long-term survival following neoadjuvant therapy. 
Locally advanced NSCLC is one of the most heterogeneous conditions, with multidimensional 
treatments involved.  
Neoadjuvant therapy had been commonly considered an optimal management strategy for patients 
with operable locally advanced. Pre-operative therapy in early stage in has many advantages: better 
treatment delivery, early treatment of micro-metastatic disease, ability to study biological impact 
treatment intervention and identify sensitive vs resistant disease. 
However, as targeted therapy has been widely applied in advanced NSCLC, neoadjuvant targeted 
therapy has remained poorly explored in locally advanced disease. 
Patients with stage IIIA-N2 NSCLC have a poor prognosis, especially those with EGFR mutations35.  
EGFR TKI therapy has shown good efficacy and favorable tolerability in patients with EGFR mutation-
positive NSCLC in stage IV.  The efficacy and tolerability of preoperative EGFR TKI therapy, although 
promising36, requires further research. 
There is a clinical trial recently published37  with erlotinib in 19 patients, radical resection was 68%, with 
21% rate of pathologic downstaging. The objective response rate was 42% and 89% of patients 
achieved disease control.  
CTONG 1103 is an ongoing trial comparing erlotinib vs gemcitabine plus cisplatin as neoadjuvant 
treatment for stage IIIA EGFR mutation (EMERGING trial)38 with 72 patients included, PFS favored 
erlotinib (HR: 0.42), nodal downstaging 11% erlotinib vs 3% in chemotherapy arm, safety results are 
consistent with prior studies, but no pathological complete response was observed with erlotinib.  
Neoadjuvant studies are difficult to execute because requires multidisciplinary setting, need for 
additional biopsy, patient inclination to undergo surgery right away and competing priorities and 
surgical considerations.  
Previously, IMpower150 showed significant improvements in PFS and OS with atezolizumab plus 
bevacizumab plus carboplatin plus paclitaxel (ABCP) vs the standard-of-care bevacizumab plus 
carboplatin plus paclitaxel (BCP) in chemotherapy-naive patients with non-squamous NSCLC. The 
addition of atezolizumab to standard-of-care bevacizumab and carboplatin-paclitaxel chemotherapy 


 
 
 
 
 
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appears to improve survival outcomes in an all-comer population of chemotherapy-naive patients with 
metastatic non-squamous NSCLC. 
This randomized phase 3 study is the first to show promising results with the combination of 
atezolizumab plus bevacizumab and chemotherapy in patients with EGFR mutations. PFS at 12 
months= 22.2% chemotherapy arm vs 42% in mutated arm. HR= 0.61 (0.36-1.03). 
The ABCP regimen represents a new therapy option for these key patient subgroups, especially those 
with sensitizing EGFR mutations and it could useful in neoadjuvant setting. 
 
NADIM Study (CA209-547) is a Phase II, single-arm, open-label multicentre study aimed to assess the 
feasibility, safety and efficacy of combined neoadjuvant chemotherapy and immunotherapy with 
Nivolumab 360 mg IV Q3W + Paclitaxel 200mg/m2 + Carboplatin AUC 6 IV Q3W in locally advanced 
resectable stage IIIA NSCLC adult patients followed by adjuvant treatment during 1 year (4 months 
with Nivolumab 240mg IV Q2W and 8 months with Nivolumab 480 mg IV Q4W). The primary endpoint 
is the progression-free survival (PFS) at 24 months from diagnosis. The PFS was defined as the time 
from diagnosis to relapse, progression or death, whichever occurred first. Secondary endpoints include 
overall survival at 3 years, response rate (RR), toxicity profile of the combination, the down-staging 
rate and complete resection rate. A total of 46 patients were to be included from 25 participating sites 
in Spain.  
NADIM Study results: (cut-off date 30th June 2018), 80% are N2 IIIA. Available efficacy results for this 
subset of 30 out of 46 patients: Tumor responses after neoadjuvant therapy (100% compliance rate), 
according to RECIST criteria v1.1 assessed per CT-SCAN: ORR= 21/30 (70%), including 3 CR (10%) and 
18 PR (60%), SD was reported for the remaining 9/30 (30%) patients. Pathological responses after 
surgery: The high total MPR defined as <10% of tumor viable cells in the resection specimen (pCR+ 
MPR) = 24/30 (80%), including 18 pCR (60%) and 6 MPR (20%). Pathological response <90%= 6 (20%). 
pCR rates observed are unprecedented and highly promising in the context of neoadjuvant therapy of 
NSCLC.  
Current study results are considered an acceptable evidence to support the hypothesis of efficacy of 
the proposed Chemo Immunotherapy (Ch-IO) combination in the setting of neoadjuvant treatment in 
NSCLC. 
We can use the screening that is going to be performed for the NADIM II stage IIIA clinical trial to 
identify all patients EGFR mutated for the Neo-DIANA trial. 
Objectives and endpoints:  
Primary objective: 
• 
To evaluate the major pathologic response (MPR) defined as 10 percent or fewer viable cancer 
cells detectable in the resected tumor and in lymph nodes in stage IIIA EGFR mutated patients 
treated in neoadjuvant setting with atezolizumab- bevacizumab- carboplatin and pemetrexed 
 


 
 
 
 
 
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Secondary objectives: 
• 
Overall survival 
• 
Progression-free survival at 12 months 
• 
Complete response rate 
• 
Downstaging 
• 
Major pathological response 
• 
Safety and tolerability: Adverse events graded according to CTCAE v5.0 
• 
Biomarker endpoints 
Eligibility criteria:  
Inclusion criteria: 
1. Previously untreated patients with histologically- or cytologically- documented NSCLC who 
present stage IIIA disease (according to 8th version of the International Association for the Study 
of Lung Cancer Staging Manual in Thoracic Oncology) and also, potentially resectable locally 
advanced NSCLC patients’ stage IIIB with T3N2 disease according to 8th edition can be included. 
- 
PET/CT including IV contrast (CT of diagnostic quality) will be performed at 
baseline (28 days +10 before inclusion) 
2. Tumor should be considered resectable before study entry by a multidisciplinary team 
3. Sensitizing EGFR mutation (Del Exon 19 and mut Exon 21) 
4. ECOG (Performance status) 0-1 
5. Screening laboratory values must meet the following criteria and should be obtained within 14 
days prior to inclusion 
i. Neutrophils  
≥ 1500×109/L 
ii. Platelets 
 ≥ 100 ×109/L 
iii. Hemoglobin  
> 9.0 g/dL 
iv. Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if 
using the Cockcroft-Gault formula below): 
a. Female CrCl = (140 - age in years) x weight in kg x 0.85/ 
72 x serum creatinine in mg/dL 
b. Male CrCl = (140 - age in years) x weight in kg x 1.00/  
 
 
 
 
 
 
 
 
72 x serum creatinine in mg/dL 
v. AST/ALT ≤ 3 x ULN  
vi. Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can 
have total bilirubin < 3.0 mg/dL)  
vii. PT/APTT/INR within normal limits 
6. Measurable or evaluable disease according to RECIST v1.1 
7. The patients need to have a forced expiratory volume (FEV1)≥ 1.2 liters or >40% predicted value 
8. All patients are notified of the investigational nature of this study and signed a written informed 


 
 
 
 
 
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consent in accordance with institutional and national guidelines, including the Declaration of 
Helsinki prior to any trial-related intervention 
9. Patients aged > 18 years 
10. Patient capable of proper therapeutic compliance and accessible for correct follow-up 
11. For female patients of childbearing potential, agreement (by patient and/or partner) to use a 
highly effective form(s) of contraception that results in a low failure rate (< 1% per year) when 
used consistently and correctly, and to continue its use for 5 months after the last dose of 
Atezolizumab and/or 6 months after the last dose of Bevacizumab, whichever is later. Such 
methods include: combined (estrogen and progestogen containing) hormonal contraception, 
progestogen-only hormonal contraception associated with inhibition of ovulation together 
with another additional barrier method always containing a spermicide, intrauterine device 
(IUD): intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized 
partner (on the understanding that this is the only one partner during the whole study 
duration), and sexual abstinence. 
12. For male patients with female partners of childbearing potential, agreement (by patient and/or 
partner) to use a highly effective form(s) of contraception that results in a low failure rate [< 
1% per year] when used consistently and correctly, and to continue its use for 6 months after 
the last dose of Bevacizumab. Male patients should not donate sperm during this study and for 
at least 6 months after the last dose of Bevacizumab. 
13. Oral contraception should always be combined with an additional contraceptive method 
because of a potential interaction with the study drugs. The same rules are valid for male 
patients involved in this clinical study if they have a partner of childbirth potential. Male 
patients must always use a condom. 
14. Women who are not postmenopausal (≥ 12 months of non−therapy-induced amenorrhea) or 
surgically sterile must have a negative serum pregnancy test result within 14 days prior to 
initiation of study drug 
Exclusion criteria: 
1. All patients carrying other EGFR mutations. 
2. Patients with known anaplastic lymphoma kinase (ALK) fusion oncogene, STK11 ligand 
alteration or ROS1 translocations. 
3. Clinically significant comorbidities that impaired administration of platinum-based 
chemotherapy  
4. Patients with a condition requiring systemic treatment with either corticosteroids (>10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
inclusion. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily 
prednisone equivalent, are permitted in the absence of active autoimmune disease. 
5. Patients with a history of interstitial lung disease cannot be included if they have symptomatic 
ILD (Grade 3-4) and/or poor lung function. In case of doubt please contact trial team. 
6. Patients with other active malignancy requiring concurrent intervention and/or concurrent 
treatment with other investigational drugs or anti-cancer therapy. 
7. Patients with previous malignancies (except non-melanoma skin cancers, and the following in 
situ cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, melanoma, or breast) are 
excluded unless a complete remission was achieved at least 2 years prior to study entry AND 


 
 
 
 
 
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no additional therapy is required during the study period. 
8. Any medical, mental or psychological condition which in the opinion of the investigator would 
not permit the patient to complete the study or understand the patient information  
9. Patients with positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus 
ribonucleic acid (HCV antibody) indicating acute or chronic infection 
10. Patients with known history of testing positive for human immunodeficiency virus (HIV) or 
known acquired immunodeficiency syndrome (AIDS) 
11. Active tuberculosis 
12. Severe infections within 4 weeks prior to be included in the study, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia 
13. Patients with history of allergy to study drug components excipients 
14. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins 
15. Women who are pregnant or in the period of breastfeeding 
16. Sexually active men and women of childbearing potential who are not willing to use an 
effective contraceptive method during the study 
17. Patients with active, known or suspected autoimmune disease, including but not limited to 
myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, 
rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with 
antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré 
syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. 
Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid 
replacement hormone are eligible for this study. 
Patients with controlled Type 1 diabetes mellitus on a stable dose of insulin regimen are 
eligible for this study. 
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted 
provided that they meet the following conditions: 
- 
Rash must cover less than 10% of body surface area (BSA). 
- 
Disease is well controlled at baseline and only requiring low-potency topical 
steroids. 
- 
No acute exacerbations of underlying condition within the previous 12 months 
(not requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate, 
retinoids, biologic agents, oral calcineurin inhibitors, high-potency or oral 
steroids). 
18. Patients with any contraindication for bevacizumab administration:  
- 
Inadequately controlled hypertension (defined as systolic blood pressure > 150 
mmHg and/or diastolic blood pressure > 100 mmHg). 


 
 
 
 
 
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Anti-hypertensive therapy to achieve these parameters is allowable. 
- 
Prior history of hypertensive crisis or hypertensive encephalopathy. 
- 
Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or 
recent peripheral arterial thrombosis) within 6 months prior to inclusion. 
- 
History of hemoptysis (≥ one-half teaspoon of bright red blood per episode) within 
1 month prior to inclusion. 
- 
Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic 
anticoagulation). 
- 
Current or recent (within 10 days of inclusion) use of aspirin (> 325 mg/day) or 
treatment with dipyramidole, ticlopidine, clopidogrel, and clostazol. 
- 
Current use of full-dose oral or parenteral anticoagulants or thrombolytic agents 
for therapeutic purposes that has not been stable for > 2 weeks prior to inclusion. 
The use of full-dose oral or parenteral anticoagulants is permitted as long as the 
INR or aPTT is within therapeutic limits (according to the medical standard of the 
enrolling institution) and the patient has been on a stable dose of anticoagulants 
for at least 2 weeks prior to inclusion. 
Prophylactic anticoagulation for the patency of venous access devices is allowed, 
provided the activity of the agent results in an INR < 1.5 × ULN and aPTT is within 
normal limits within 14 days prior to inclusion. 
Prophylactic use of low-molecular-weight heparin (i.e., enoxaparin 40 mg/day) is 
permitted. 
- 
Core biopsy or other minor surgical procedure, excluding placement of a vascular 
access device, within 7 days prior to the first dose of Bevacizumab. 
- 
History of abdominal or tracheoesophageal fistula or gastrointestinal perforation 
within 6 months prior to inclusion. 
- 
Clinical signs of gastrointestinal obstruction or requirement for routine parenteral 
hydration, parenteral nutrition, or tube feeding. 
- 
Evidence of abdominal free air not explained by paracentesis or recent surgical 
procedure. 
- 
Serious, non-healing wound, active ulcer, or untreated bone fracture. 
- 
Proteinuria, as demonstrated by urine dipstick or > 1.0 g of protein in a 24-hour 
urine collection. 
All patients with ≥ 2+ protein on dipstick urinalysis at baseline must undergo a 24-
hour urine collection and must demonstrate ≤ 1 g of protein in 24 hours. 
- 
Known sensitivity to any component of Bevacizumab. 
 
 
 
 
 
 


 
 
 
 
 
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Treatment:  
 
Neoadjuvant treatment: 
 
Atezolizumab: 1200 mg, IV infusion 
Bevacizumab: 15mg/Kg mg, IV infusion   
Carboplatin: AUC6, IV infusion  
Pemetrexed: 500 mg/m2, IV infusion 
Treatment sequence: 
Atezolizumab              Bevacizumab             Carboplatin             Pemetrexed    
  
 
 
NOTE:  
for squamous or adenosquamous patients, neodjuvant treatment must switch to: 
 
Atezolizumab: 1200 mg, IV infusion 
Carboplatin: AUC6, IV infusion  
Paclitaxel: 200 mg/m2, IV infusion 
Treatment sequence: 
Atezolizumab              Paclitaxel            Carboplatin  
 
Surgery: 
 
 
 
Adjuvant treatment 
 
Atezolizumab: 1200 mg, IV infusion Q4W (+/- 3 days) for 6 months (6 cycles) 
 
 


 
 
 
 
 
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Statistical considerations: 
 
To find a 40% of MPR vs a theorical reference equals to 10.7% in patients with EGFR mutation NSCLC 
stage IIIA, with a 80% of power and alpha level of 0.05, 22 patients are needed. If we expect a 15% of 
losses of follow-up, 26 patients with EGFR mutation and NSCLC stage IIIA will be necessary. Thus, 
considering a prevalence of EGFR mutation of 15% in patients with NSCLC stage IIIA, 174 patients 
NSCLC stage IIIA should perform the test to check the presence of EGFR mutation. 
It is expected that approximately the 15% of the patients initially enrolled should be discarded because 
they do not meet the inclusion criteria; so that in order to reach the proposed sample size, if the 15% 
is exceeded because a patient initially enrolled in the study does not fulfil the inclusion criteria, it will 
be replaced by a new subject that fulfil them, this replacement will ensure that the sample size will be 
the one calculated initially.  
The analysis will be conducted according to the intention-to-treat (ITT) principle. Descriptive analysis 
will be performed by means of absolute and relative frequencies for categorical variables and mean 
and standard deviation, or median and percentiles 25 and 75 for numerical variables.  
The main analysis asses the response rate after the neoadjuvant therapy plus surgery. Response rates 
will be estimated along with their corresponding 95% confidence interval and then compared with 
other variables through a chi-square test or Fisher exact test if expected frequencies are less than or 
equal to 5. Effect size will be estimated by means of logistic regression analysis through the Odds Ratio 
(OR) as well as their corresponding confidence interval (95%CI).  
Progression free survival (PFS) is set as a secondary outcome. Survival function will be estimated by 
the Kaplan-Meier method. Cox proportional hazards model, will be used to estimate potential risk 
factors, along with the Hazard Ratios (HR) and 95% confidence intervals.  
Reported p values will be two-sided, and the significance level will be set at 5% (0.05) for all analyses 
unless otherwise noted. Stata v15.1 software (StataCorp. 2017. Stata Statistical Software: Release 15. 
College Station, TX: StataCorp LLC) will be used for statistical analyses. 
Total trial duration: 
6 years: 2 years of recruitment, 1 year of treatment and 3 years of follow up (excluding a run-in period 
of 3-6 months and a close out period of at least 4 months) 
Translational research: 
 
 
  
 


 
 
 
 
 
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2. Trial schedule 
 
 
Baseline 
(-28 days before 
inclusion) 
Neoadjuvant 
treatment 
Surgery15 
Adjuvant 
treatment16 
(Atezolizumab) 
End of 
Treatment17 
Follow up18 


 
 
 
 
 
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Baseline 
(-28 days before 
inclusion) 
Neoadjuvant 
treatment 
Surgery15 
Adjuvant 
treatment16 
(Atezolizumab) 
End of 
Treatment17 
Follow up18 


 
 
 
 
 
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3. Background and rationale 
3.1. Disease background  
Lung cancer is the primary cause of cancer mortality in western countries. Approximately 80% of lung 
cancers are non-small-cell lung cancer (NSCLC).  
In Spain occur about 18,800 new cases per year1 and has been responsible for 19,513 deaths in 2006, 
twice the mortality of colon cancer (the most common tumor in absolute terms in Spain) 2 and NSCLC 
accounts for 85% of newly diagnosed cases. Most patients are diagnosed with unresectable disease 
and around 40% advanced3 disease. The cure is unlikely in patients with NSCLC and locally advanced 
stage who are not surgical candidates, with a 3-year survival rate of 27% in those patients receiving 
chemotherapy and concomitant radiotherapy4. On the contrary, in localized stages (stage I, II, IIIA) with 
surgical resection and cytostatic therapy, a survival of 5 years of 51% 5 is achieved and those with an 
absolute benefit in survival at 5 years of 5.4%, especially in patients with good performance status 
(PS)6. 
 
At diagnosis, at least 40% of patients are diagnosed at an advanced stage and a third locally advanced 
disease (stage III). We understand as locally advanced disease when the tumor exceeds the lung 
structures, but without clinical evidence of distant spread, and are a very heterogeneous group of 
patients with a controversial treatment based on a combination of surgery, chemotherapy and 
radiotherapy. 
In the past, radiation therapy was considered standard therapy for patients with stage IIIA and IIIB but 
presented poor survival with poor local control and early development of distant disease. Patients with 
inoperable stage III treated with chest radiation therapy alone, had a median survival of 11.9 months, 
survival at 2 years of 10-20% and 3 years 5-10% 7. 
Currently, there is no consensus on the best standard treatment, and it has been demonstrated that 
the experience of the therapeutic team plays an important role in the decisions to take. 
 
Only 25-30% of the NSCLC are candidates for curative-intent surgery. The rest are advanced local 
tumors or widespread metastases. Survival at 5 years depends, among other factors, on the size of the 
tumor and lymph node involvement. But even without mediastinal involvement, less than half of the 
patients survive more than 5 years and the majority dies of disseminated metastases. 
  
Patients with stage IIIA disease with clinically evident N2 nodal spread have an overall 5-year survival 
rate of only 10%-15%, although this fall to 2%-5% in those with bulky mediastinal N2 involvement. The 
surgical management of stage IIIA NSCLC remains highly controversial and most patients with stage 
IIIB disease are generally considered inoperable. The aims of therapy in stage III NSCLC are to increase 
both locoregional and systemic control of the disease. As a matter of fact, it is reported that at least 
80% of patients treated with local modalities alone will have micrometastases and will relapse.  These 
aims could in some way be in conflict and may require different combined modality therapy 
sequencing strategies. Success in achieving them is measured in time of progression, survival and cure 
rate. Strategies that have been investigated include induction chemotherapy, concomitant 
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remain the major site of failure, it is likely that more effective cytotoxic or other anti-tumor agents will 
be required further to improve current levels of response and survival8. Meta-analysis has suggested 
that cisplatin-based induction chemotherapy prior to surgery reduces risk of death by 13 % and 
increased absolute 5-year survival rates by 5%9. Neoadjuvant therapy has theoretical advantages: in 
vivo assessment of response to chemotherapy helps identify patients who will potentially benefit from 
adjuvant chemotherapy, early treatment of micrometastatic disease, reduction in drug resistance by 
early exposure to treatment and downstaging with improved resectability. Potential disadvantages 
include: delay in local therapy secondary to toxicity, risk progression in chemo-resistant patients and 
pre-operative complications. 
Several newly available chemotherapeutic agents are both highly active against NSCLC and potent 
radiosensitizers. 
The results of stage IIIA with induction treatment of clinical practice outside the clinical trial show a 
median survival of 22 months and a 3-year survival rate of 34%10. An EORTC study11  with  carboplatin 
and paclitaxel used as induction regimen in patients with biopsy-proven stage N2 non-small cell lung 
cancer of the 52 eligible patients, 33 patients responded, one CR and 32 PR, for an overall response 
rate of 64% (95% CI, 48%- 76%). In addition, there were 10 patients with no changes (10%) and 9 with 
progressive disease (17%). The median duration of survival was 20.5 months (95% CI, 16.1-31.2 
months) with an estimated 1-year survival rate of 68.5% (95% CI, 55.2-81.7). Furthermore, phase II 
neoadjuvant studies of docetaxel alone, in combination with cisplatin or carboplatin, or in combination 
with platinum and gemcitabine have produced promising results, with more recently reported RRs 
ranging from 44 to 82% and rates of complete resection ranging from 67 to 79%12 
3.2. Prognostic factors after neoadjuvant treatment 
Complete surgical resection13,14, tumor downstaging and pathologic complete response are predictors 
of long-term survival following neoadjuvant therapy.  
Pathologic complete response after induction chemotherapy generally ranges from 0% to 9.5%. Others 
higher complete response: one Martini15 with 16.7% and one Kumar with 15%16 are rare.  
Andre analyzed a cohort of 702 patients with resected N2 disease and identified four negative factors: 
preoperative clinical N2 status, involvement of multiple lymph node levels, pathological T3 or T4 
disease, and absence of preoperative chemotherapy17. Choi et al18, reviewed cases of pathologic 
proven N2 disease, complete resection rate was 83,2% and overall 5-year was 23,3%. Five-year 
recurrence –free survival was 19,6%. Among 19 clinicopathological prognostic factors, incomplete 
resection and non-downstaging after neoadjuvant therapy were unfavorable prognostic factors in 
univariate analyses. Clinical N2 status, multiple N2 nodes, and cell type of adenocarcinoma showed 
poor prognosis but were not statistically significant. Postoperative chemotherapy showed good 
prognosis but was not statistically significant. Multivariate analysis showed that significant favorable 
prognostic factors were complete resection and adjuvant chemotherapy19. Experience of Memorial 
Sloan-Kettering Cancer Center confirms survival is significantly influenced by patient age, the median 
survival for complete resection 27.8 months compared with 11.4 months for incomplete resection, 
pathologic stage with 3-year survival for N0/N1 was 43.3% and 25.5% for N2 patients20. 


 
 
 
 
 
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An emerging hallmark of cancer is immunoevasion—the cancer cell’s ability to avoid destruction by 
the immune system. The three general categories of immunoevasive mechanisms include: (A) an 
insufficient number of T cells generated within the lymphoid compartment; (B) an insufficient number 
of T cells extravasating into the tumor; and (C) inhibition of T cells in the tumor microenvironment. The 
tumor microenvironment, in turn, offers three main immunoevasive tools: (1) surface membrane 
proteins that function as immune checkpoints, including PD-1, CTLA-4, lymphocyte-activation gene 3 
(LAG-3) protein, T-cell immunoglobulin and mucin domain–containing protein 3 (TIM-3), B- and T-
lymphocyte attenuator (BTLA), and the adenosine A2a receptor (A2aR); (2) the relationship between 
selected soluble factors and metabolic alterations, such as IL-10, transforming growth factor beta, 
adenosine, indoleamine 2,3-dioxygenase (IDO), and arginase; and (3) inhibitory cells, including cancer-
associated fibroblasts (CAFs), regulatory T cells, myeloid-derived suppressor cells (MDSCs), and tumor-
associated macrophages.  
The immune response and the use of strategies to upregulate surface proteins, including programmed 
death 1 (PD-1), is a new approach for the treatment of tumors. PD-L1 overexpression has been 
observed in 40% - 50% of all NSCLC tumors, on the set of all stages and histologies21. Targeted therapy 
to PD-1 receptor and to PD-L1 ligands is intended to inhibit their intervention and is an attractive 
therapeutic option in the locally advanced NSCLC stage, which can reactivate the host immune 
responses and allow good long-term control of the tumor22.  
In lung cancer, inhibition of the Check Point PD-1 pathway with antibodies directed against PD-1 or 
against its ligand, PD-L1, has showed preliminary and encouraged results that suggest a "class effect" 
and validate this pathway as a therapeutic target in NSCLC.  
Results from cohorts of heavily pretreated NSCLC patients in phase I studies showed objective 
responses dose dependent, ranging from 10% to 32%23. 
Inhibition of the Checkpoint PD-1 pathway with antibodies against PD-1 or PD-L1 produces long lasting 
tumor response and stable disease as well, for more than 6 months.  
Exploratory analysis of PD-L1 tumor expression and treatment response have confirmed the 
prevalence of > 40% of PD-L1 expression in NSCLC. Some studies suggest an association between 
treatment response and PD-L1 tumor expression before treatment.  
However, PD-L1 expression role as a biomarker for response has not yet been validated. 
Immunotherapy with antibodies anti-PD-1 and anti-PD-L1 in many different tumors types has been, in 
general, well tolerated.  Frequent adverse events related to the drug are limited episodes of grade 1 
or 2 fatigue, diarrhea, rash, pruritus, nausea and decreased appetite.  
In clinical trials, grade 3 or 4 adverse events related to the treatment occur in < 15% of patients. 
Immune-related adverse events treatment related are infrequent (<2%) and include pneumonitis, 
vitiligo, colitis, hepatitis, thyroiditis and hypophysitis24  
Numerous ongoing trials are evaluating the combination of chemotherapy and checkpoint blockade in 
solid tumors, including melanoma, NSCLC, and SCLC. In untreated metastatic melanoma, a phase III 
study showed that ipilimumab (at 10 mg/kg) plus dacarbazine improved OS compared with 
dacarbazine alone (11.2 vs 9.1 months, respectively), but this was at the expense of higher toxicity and 
there was no ipilimumab-alone comparator arm.  A phase II study showed that phased but not 
simultaneous ipilimumab plus platinum doublet chemotherapy (carboplatin/paclitaxel) improved 
immune-related PFS in patients with stage IIIB or IV NSCLC and extensive-stage SCLC, when compared 


 
 
 
 
 
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with chemotherapy alone25,26 The choice of chemotherapy and dosing schedule are thus critical to 
optimizing outcomes of checkpoint blockade and chemotherapy combinations. With this in mind, a 
phase I four-cohort study evaluated first-line nivolumab at 10 mg/kg (N10) vs 5 mg/kg (N5) in 
combination 
with 
gemcitabine/cisplatin 
(N10) 
in 
advanced 
squamous-cell 
NSCLC, 
pemetrexed/cisplatin (N10) in advanced non-squamous NSCLC, and paclitaxel/carboplatin (N5 vs N10) 
in combined cohorts of squamous and non-squamous NSCLC27.The toxicity profile was additive, 
representing effects of both nivolumab and chemotherapy. The ORR, PFS, and 1-year OS outcomes 
were acceptable. In particular the 1-year OS rate was 85% for the N5 paclitaxel/carboplatin group and 
87% for the N10 pemetrexed/cisplatin group, which may reflect a positive signal. 
A phase Ib study enrolled untreated patients with locally advanced or metastatic NSCLC to three 
treatment arms of atezolizumab plus chemotherapy, including carboplatin/pemetrexed, 
carboplatin/paclitaxel, and carboplatin/nab-paclitaxel28. Atezolizumab at 15 mg/kg every 3 weeks was 
administered with standard chemotherapy for 4 to 6 cycles followed by atezolizumab maintenance or 
atezolizumab/pemetrexed maintenance in the carboplatin/pemetrexed arm. A preliminary analysis on 
41 patients showed that the ORR was 64% (95% CI, 46.9–77.9) by RECIST, with the 
carboplatin/pemetrexed arm having the highest response rate at 75% (95% CI, 45–93). The four 
complete responses occurred in the carboplatin/nab-paclitaxel arm. The toxicity profile was as 
expected for chemotherapy, and no pneumonitis was observed. There was one grade 5 adverse event 
in a patient in the carboplatin/nab-paclitaxel arm who developed candidemia after prolonged 
neutropenia. Overall, the combination therapy response rates exceeded the 30% traditionally 
expected with platinum doublet chemotherapy; more mature data are forthcoming. 
In this study, prospective tissue and blood samples will be obtained from all patients to increase our 
knowledge of the predictive value of molecular variables. Determining mutational profiles is crucial in 
NSCLC. The relationship between known promoters or other mutations and PD-L1 status and clinical 
outcomes will be studied29. 
Other markers, such as IFN-γ, TNF-α (tumor necrosis factor), and IL-2, IL-6, IL-10, IL-8 and IL-12 may 
have a correlation with clinical outcomes and response to treatment. In addition to these correlation 
studies that are planned prospectively, it will be preserved in tissue banks. 
3.3. Immunotherapy 
Several studies in patients with NSCLC suggested an association of increased immune cell infiltration 
into tumours with improved survival. In recent years, improved identification of antigenic targets, the 
addition of immunoadjuvants, and the production of more efficient delivery systems have resulted in 
more efficient vaccines, able to elicit a potent immune response, leading to the development of 
immunotherapy for the treatment of NSCLC30. 
3.4. Immune checkpoint receptors 
 
 
 


 
 
 
 
 
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3.5. Rationale for trial design 
 
 
  
 


 
 
 
 
 
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. 
4. Objectives and endpoints 
4.1. Primary objective and endpoint 
• 
To evaluate the major pathologic response (MPR)  
MPR defined as 10 percent or fewer viable cancer cells detectable in the resected tumor and 
in lymph nodes in stage IIIA EGFR mutated patients treated in neoadjuvant setting with 
atezolizumab- bevacizumab- carboplatin and pemetrexed.  
4.2. Secondary objectives and endpoint 
• 
To evaluate the PFS rate at 1 year of treatment  
PFS defined as the length of time from the date of diagnosis to the date of the first documented 
progression of disease 
• 
To evaluate the Overall Survival (OS) rate at 1 year, 2 and 3 years  
OS defined as the length of time from either the date of diagnosis or the start of the treatment 
that patients diagnosed with the disease are still alive. 


 
 
 
 
 
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• 
To assess the complete response rate and major pathological response 
• 
To evaluate the downstaging after surgery 
• 
To evaluate the safety and tolerability of the combination. 
Occurrence and severity of adverse events, with severity determined by NCI CTCAE v5.0 
criteria. 
5. Trial design, duration and termination  
 
This is an open-label, non-randomised, phase II, multi-centre clinical trial. 
Patients enrolled will receive Atezolizumab 1200mg + Bevacizumab 15mg/Kg + Carboplatin AUC6 + 
Pemetrexed 500mg/m2 for 3 cycles every 21 days (+/- 3 days) as neoadjuvant treatment followed by 
surgery and 6 months of adjuvant treatment with Atezolizumab 1200 mg Q4W (+/- 3 days). Note: 
squamous or adenosquamous patients neodjuvant treatment must switch to Atezolizumab 1200mg + 
Carboplatin AUC6 + Paclitaxel 200mg/m2.  
 
Patient accrual is expected to be completed within 2 years excluding a run-in-period of 3-6 months. 
Treatment and follow-up are expected to extend the study duration to a total of 6 years. Patients will 
be followed 3 years after adjuvant treatment. The study will end once survival follow-up has 
concluded. This will be followed by a close out period of 4 months. 
The trial will end with the preparation of the final report, scheduled for 7 years after the inclusion of 
the first patient approximately. 
Figure 1. Study schema 
 


 
 
 
 
 
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6. Patient selection 
Written Informed Consent (IC) must be signed and dated by the patient and the investigator prior to 
any trial-related intervention for trial treatment and biomaterial submission to the central laboratory.  
Patients should only be selected and consented for enrolment if they fulfil the following criteria: 
6.1. Inclusion criteria  
1. Previously untreated patients with histologically- or cytologically- documented NSCLC who 
present stage IIIA disease (according to 8th version of the International Association for the Study 
of Lung Cancer Staging Manual in Thoracic Oncology) and also, potentially resectable locally 
advanced NSCLC patients’ stage IIIB with T3N2 disease according to 8th edition can be included. 
- 
PET/CT including IV contrast (CT of diagnostic quality) will be performed at 
baseline (28 days +10 before inclusion) 
2. Tumor should be considered resectable before study entry by a multidisciplinary team 
3. Sensitizing EGFR mutation (Del Exon 19 and mut Exon 21) 
4. ECOG (Performance status) 0-1 
5. Screening laboratory values must meet the following criteria and should be obtained within 14 
days prior to inclusion 
i. Neutrophils  
≥ 1500×109/L 
ii. Platelets 
 ≥ 100 ×109/L 
iii. Hemoglobin  
> 9.0 g/dL 
iv. Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if 
using the Cockcroft-Gault formula below): 
a. Female CrCl = (140 - age in years) x weight in kg x 0.85/ 
72 x serum creatinine in mg/dL 
b. Male CrCl = (140 - age in years) x weight in kg x 1.00/  
 
 
 
 
 
 
 
 
72 x serum creatinine in mg/dL 
v. AST/ALT ≤ 3 x ULN  
vi. Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can 
have total bilirubin < 3.0 mg/dL)  
vii. PT/APTT/INR within normal limits 
6. Measurable or evaluable disease according to RECIST v1.1 
7. The patients need to have a forced expiratory volume (FEV1) ≥ 1.2 liters or >40% predicted 
value 
8. All patients are notified of the investigational nature of this study and signed a written informed 
consent in accordance with institutional and national guidelines, including the Declaration of 
Helsinki prior to any trial-related intervention 
9. Patients aged > 18 years 
10. Patient capable of proper therapeutic compliance and accessible for correct follow-up 


 
 
 
 
 
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11. For female patients of childbearing potential, agreement (by patient and/or partner) to use a 
highly effective form(s) of contraception that results in a low failure rate (< 1% per year) when 
used consistently and correctly, and to continue its use for 5 months after the last dose of 
Atezolizumab and/or 6 months after the last dose of Bevacizumab, whichever is later. Such 
methods include: combined (estrogen and progestogen containing) hormonal contraception, 
progestogen-only hormonal contraception associated with inhibition of ovulation together 
with another additional barrier method always containing a spermicide, intrauterine device 
(IUD): intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized 
partner (on the understanding that this is the only one partner during the whole study 
duration), and sexual abstinence. 
12. For male patients with female partners of childbearing potential, agreement (by patient and/or 
partner) to use a highly effective form(s) of contraception that results in a low failure rate [< 
1% per year] when used consistently and correctly, and to continue its use for 6 months after 
the last dose of Bevacizumab. Male patients should not donate sperm during this study and for 
at least 6 months after the last dose of Bevacizumab. 
13. Oral contraception should always be combined with an additional contraceptive method 
because of a potential interaction with the study drugs. The same rules are valid for male 
patients involved in this clinical study if they have a partner of childbirth potential. Male 
patients must always use a condom. 
14. Women who are not postmenopausal (≥ 12 months of non−therapy-induced amenorrhea) or 
surgically sterile must have a negative serum pregnancy test result within 14 days prior to 
initiation of study drug 
 
6.2. Exclusion criteria  
1. All patients carrying other EGFR mutations. 
2. Patients with known anaplastic lymphoma kinase (ALK) fusion oncogene, STK11 ligand 
alteration or ROS1 translocations. 
3. Clinically significant comorbidities that impaired administration of platinum-based 
chemotherapy  
4. Patients with a condition requiring systemic treatment with either corticosteroids (>10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
inclusion. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily 
prednisone equivalent, are permitted in the absence of active autoimmune disease. 
5. Patients with a history of interstitial lung disease cannot be included if they have symptomatic 
ILD (Grade 3-4) and/or poor lung function. In case of doubt please contact trial team. 
6. Patients with other active malignancy requiring concurrent intervention and/or concurrent 
treatment with other investigational drugs or anti-cancer therapy. 
7. Patients with previous malignancies (except non-melanoma skin cancers, and the following in 
situ cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, melanoma, or breast) are 
excluded unless a complete remission was achieved at least 2 years prior to study entry AND 
no additional therapy is required during the study period. 
8. Any medical, mental or psychological condition which in the opinion of the investigator would 
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9. Patients with positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus 
ribonucleic acid (HCV antibody) indicating acute or chronic infection 
10. Patients with known history of testing positive for human immunodeficiency virus (HIV) or 
known acquired immunodeficiency syndrome (AIDS) 
11. Active tuberculosis 
12. Severe infections within 4 weeks prior to be included in the study, including but not limited to 
hospitalization for complications of infection, bacteremia, or severe pneumonia 
13. Patients with history of allergy to study drug components excipients 
14. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins 
15. Women who are pregnant or in the period of breastfeeding 
16. Sexually active men and women of childbearing potential who are not willing to use an 
effective contraceptive method during the study 
17. Patients with active, known or suspected autoimmune disease, including but not limited to 
myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, 
rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with 
antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré 
syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. 
Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid 
replacement hormone are eligible for this study. 
Patients with controlled Type 1 diabetes mellitus on a stable dose of insulin regimen are 
eligible for this study. 
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted 
provided that they meet the following conditions: 
- 
Rash must cover less than 10% of body surface area (BSA). 
- 
Disease is well controlled at baseline and only requiring low-potency topical 
steroids. 
- 
No acute exacerbations of underlying condition within the previous 12 months 
(not requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate, 
retinoids, biologic agents, oral calcineurin inhibitors, high-potency or oral 
steroids). 
18. Patients with any contraindication for bevacizumab administration:  
- 
Inadequately controlled hypertension (defined as systolic blood pressure > 150 
mmHg and/or diastolic blood pressure > 100 mmHg). 
Anti-hypertensive therapy to achieve these parameters is allowable. 
- 
Prior history of hypertensive crisis or hypertensive encephalopathy. 


 
 
 
 
 
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- 
Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or 
recent peripheral arterial thrombosis) within 6 months prior to inclusion. 
- 
History of hemoptysis (≥ one-half teaspoon of bright red blood per episode) within 
1 month prior to inclusion. 
- 
Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic 
anticoagulation). 
- 
Current or recent (within 10 days of inclusion) use of aspirin (> 325 mg/day) or 
treatment with dipyramidole, ticlopidine, clopidogrel, and clostazol. 
- 
Current use of full-dose oral or parenteral anticoagulants or thrombolytic agents 
for therapeutic purposes that has not been stable for > 2 weeks prior to inclusion. 
The use of full-dose oral or parenteral anticoagulants is permitted as long as the 
INR or aPTT is within therapeutic limits (according to the medical standard of the 
enrolling institution) and the patient has been on a stable dose of anticoagulants 
for at least 2 weeks prior to inclusion. 
Prophylactic anticoagulation for the patency of venous access devices is allowed, 
provided the activity of the agent results in an INR < 1.5 × ULN and aPTT is within 
normal limits within 14 days prior to inclusion. 
Prophylactic use of low-molecular-weight heparin (i.e., enoxaparin 40 mg/day) is 
permitted. 
- 
Core biopsy or other minor surgical procedure, excluding placement of a vascular 
access device, within 7 days prior to the first dose of Bevacizumab. 
- 
History of abdominal or tracheoesophageal fistula or gastrointestinal perforation 
within 6 months prior to inclusion. 
- 
Clinical signs of gastrointestinal obstruction or requirement for routine parenteral 
hydration, parenteral nutrition, or tube feeding. 
- 
Evidence of abdominal free air not explained by paracentesis or recent surgical 
procedure. 
- 
Serious, non-healing wound, active ulcer, or untreated bone fracture. 
- 
Proteinuria, as demonstrated by urine dipstick or > 1.0 g of protein in a 24-hour 
urine collection. 
All patients with ≥ 2+ protein on dipstick urinalysis at baseline must undergo a 24-
hour urine collection and must demonstrate ≤ 1 g of protein in 24 hours. 
- 
Known sensitivity to any component of Bevacizumab 
7. Patient enrolment  
 
This trial will use a web-based registration and enrolment system (eCRF-Electronic Case Report Form). 
Each participating centre will access the system directly to enrol patients.  
Note that written informed consent has to be obtained from the patient prior to any trial-specific 
intervention. 
Patient eligibility needs to be checked before enrolment of the patient in the Fundación GECP web-
based system (eCRF). The dates of the patient signature of the Informed Consent Form and the consent 


 
 
 
 
 
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to pathology material submission section are required to be filled in the eligibility checklist of the eCRF. 
Neoadjuvant treatment has to start within 1-3 days from inclusion.  
8. Trial procedures 
8.1. Overview of treatment sequence 
8.1.1. Screening/Baseline visit:  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
8.1.2. Neoadjuvant treatment 
 
 
 
Neoadjuvant treatment: 
 
Atezolizumab: 1200 mg, IV infusion 
Bevacizumab: 15mg/Kg mg, IV infusion   


 
 
 
 
 
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Carboplatin: AUC6, IV infusion  
Pemetrexed: 500 mg/m2, IV infusion 
 
 
Treatment sequence: 
Atezolizumab              Bevacizumab             Carboplatin             Pemetrexed    
 
 
  
NOTE: for squamous or adenosquamous patients, neodjuvant treatment must switch to: 
Atezolizumab: 1200 mg, IV infusion 
Carboplatin: AUC6, IV infusion  
Paclitaxel: 200 mg/m2, IV infusion 
Treatment sequence: 
Atezolizumab              Paclitaxel             Carboplatin  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
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8.1.3. Surgery 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


 
 
 
 
 
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8.1.4. Adjuvant treatment  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
  
 
 
 
 


 
 
 
 
 
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8.1.5. End of treatment  
  
  
 
 
 
 
 
 
 
 
 
8.1.6. Follow up visits 
 
 
  
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
  
 
9. Investigational Medicinal Product 
Atezolizumab and Bevacizumab are the Investigational Medicinal Products (IMP) used in this trial. 
Roche will provide the IMP at no cost for this trial. 
Complete details of the trial drug logistics, distribution, packaging, labelling, storage and handling as 
well as accountability are described in the Neo-DIANA drug supply manual that will be provided in the 
Pharmacy site file to all the participant sites.  


 
 
 
 
 
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Description of the Investigational Medicinal Products 
 
 
 
 
 
 
 
 
 
 
 
 
9.1. Packaging and labelling 
 
  
 
 
 
 
 
 
 
9.2. Receipt and storage of the IMP 
 
 
 
 
 
9.3. Unused trial drug supplies 
 
 
 


 
 
 
 
 
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10. Trial treatments description 
10.1. ATEZOLIZUMAB 
 
 
 
 
  
 
 


 
 
 
 
 
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10.2. BEVACIZUMAB 
 
 
 
 
 
 
10.3. CARBOPLATIN 
Structure: The cis-diamino (cyclobutan-1, 1 dicarboxilate) platin. 
Stability: 24 hours at ambient temperature in 5% glucose, glucosaline or physiologic saline. It is 
recommended not to dilute with chlorinated solutions since this could affect the 
carboplatin. 
Route of administration: Intravenous infusion 
 
 
 
 
  
  
  
 
 
Guidelines of Carboplatin administration: According to the standard of each center 
10.4. PEMETREXED 
 
 
 
Pemetrexed disodium (ALIMTA®, pemetrexed) is a novel pyrrolo[2,3 d]pyrimidine−based folic acid 
analogue. 
Route of administration: Intravenous infusion. 
Guidelines of Pemetrexed administration: According to the standard of each center 
 
 
 
 


 
 
 
 
 
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10.5.  PACLITAXEL 
Patients will receive Paclitaxel 200mg/m2 administered by IV infusion every 21 days, for 3 cycles during 
neoadjuvant phase. 
Structure: 
A diterpene whose composition is: 5b, 20-epoxi-1, 2a, 4,7b, 10b, 13a-hexahidroxytax-
11-en 9 one 4,10-diacetato 2-benzoate 13-ester with (2R,3S)- N-benzoyl-3-
phenylisoserine. 
Stability: 
Concentrations of 0.3-1.2 mg/ml in 5% dextrose or normal saline have demonstrated 
chemical and physical stability for more that 27 hours at ambient temperature (25ºC 
approximately). The intact vial must be stored between 15º and 25ºC.  
Guidelines of Paclitaxel administration: Paclitaxel must be administered by infusion over 3 hours in 
dextrose (D5W) or normal saline (NS). The concentration must not exceed 1.2 mg/ml. 
 
  
 
 
  
 
 


 
 
 
 
 
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11. Dose modifications criteria 
Reasons for dose modifications (delays/reductions), the supportive measures taken, and the outcomes 
will be documented in the patient's chart and recorded on the eCRF. 
11.1. General Notes Regarding Dose Modification 
When several toxicities with different grades of severity occur at the same time, the dose modifications 
should be according to the highest grade observed. 
The investigator may use discretion in modifying or accelerating the dose modification guidelines 
described below depending on the severity of toxicity and an assessment of the risk versus benefit for 
the patient, with the goal of maximizing patient compliance and access to supportive care. 
Treatment should not be delayed or interrupted for more than 2 weeks during neoadjuvant treatment 
or more than 6 weeks during the adjuvant treatment. In the event that longer interruptions or delays 
are required, please contact trial team for assessment of the case. 
11.2. ATEZOLIZUMAB dose modifications 
  
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
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. 
11.3. BEVACIZUMAB dose modifications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
Management of bevacizumab related toxicities 
  
 
  
 
 
 
 
  
 
 
 
 
 
  
 
  


 
 
 
 
 
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Surgery and wound healing complications 
 
 
 
 
  
 
 
 
 
11.4. CARBOPLATIN and PACLITAXEL dose modifications 
 
 


 
 
 
 
 
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DOSE MODIFICATION BASED ON NON-HEMATOLOGICAL TOXICITY CRITERIA 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
  
 
   
 
  
  
 
 


 
 
 
 
 
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• 
 
 
  
   
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bilirubin Grade 4 (>10.0 x UNL) 
Withdraw the patient from the protocol 
OTHER TOXICITIES 
 
 
 
 
 
HYPERSENSITIVITY REACTIONS 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
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If
 
 
 
 
 
  
Guidelines for the re-initiation of treatment following hypersensitivity reactions 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
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. 
11.5. PEMETREXED dose modification  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 


 
 
 
 
 
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Non-Hematologic Toxicity 
  
 
 
 
 
 
 
 
 
 
 
 
Treatment Delays Caused by Insufficient Folic Acid or Vitamin B12 Supplementation 
 
 
  
 
 
 
12. Prohibited and permitted concomitant treatments 
 
 
 
 
  


 
 
 
 
 
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Prohibited Concomitant Therapy  
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
Permitted Concomitant Therapy 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 


 
 
 
 
 
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Cautionary Concomitant Therapy 
 
 
 
 
 
 
 
 
  
 
 
 
13. Adverse events and reporting 
13.1. Definition of an Adverse Event (AE) and AE’s reporting 
The main criterion for tolerability is the occurrence of toxicities and Adverse Events (AEs). 
 
 
 
 
 
 
 
 
An adverse event can therefore be any of the following: 
Any unfavorable and unintended sign (including an abnormal laboratory finding) (see NOTE 1 
below), symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product. 
Any new disease or exacerbation of an existing disease (a worsening in the character, frequency, or 
severity of a known condition), except events that are clearly consistent with the expected 
pattern of the disease progression. These data will be captured as efficacy assessment data 


 
 
 
 
 
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only. If there is any uncertainty as to whether an event is due to disease progression, it should be 
reported as an adverse event. 
Recurrence of an intermittent medical condition (e.g., headache) not present at baseline. 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is associated with 
symptoms or leads to a change in study treatment or concomitant treatment or discontinuation 
from study drug. 
Adverse events that are related to a protocol-mandated intervention, including those that occur prior 
to assignment of study treatment (e.g., screening invasive procedures such as biopsies). 
Adverse events that occur during or within 24 hours after study drug administration and are judged to 
be related to study drug infusion should be captured as a diagnosis (e.g., "infusion-related 
reaction" or "anaphylactic reaction") on the Adverse Event eCRF. If a patient experiences both a 
local and systemic reaction to the same dose of study drug, each reaction should be recorded 
separately on the Adverse Event eCRF. Associated signs and symptoms should be recorded on the 
dedicated Infusion-Related Reaction eCRF. 
A pre-existing medical condition should be recorded as an adverse event only if the frequency, 
severity, or character of the condition worsens during the study (e.g., “more frequent 
headaches”).   
NOTE 1: Abnormal laboratory and vital signs values: 
A laboratory test result must be reported as an adverse event if it is a change from baseline and meets 
any of the following criteria: 
Is accompanied by clinical symptoms, 
Results in a change in study treatment (e.g., dosage modification, treatment interruption, or treatment 
discontinuation), 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) or a change in 
concomitant therapy, 
Is clinically significant in the investigator’s judgment. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, the abnormality 
itself should be recorded on the Adverse Event eCRF, along with a descriptor indicating if the test result 
is above or below the normal range (e.g., "elevated potassium"). 
A vital sign result must be reported as an adverse event if it is a change from baseline and meets any 
of the following criteria: 
Is accompanied by clinical symptoms, 
Results in a change in study treatment (e.g., dosage modification, treatment interruption, or treatment 
discontinuation), 
Results in a medical intervention or a change in concomitant therapy, 
Is clinically significant in the investigator’s judgment. 


 
 
 
 
 
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If a clinically significant vital sign abnormality is a sign of a disease or syndrome (e.g., high blood 
pressure), only the diagnosis (i.e., hypertension) should be recorded on the Adverse Event eCRF. 
The finding of an elevated ALT or AST ( 3  baseline value) in combination with either an elevated 
total bilirubin ( 2  ULN) or clinical jaundice in the absence of cholestasis or other causes of 
hyperbilirubinemia is considered to be an indicator of severe liver injury. Therefore, investigators must 
report as an adverse event the occurrence of either of the following: 
Treatment-emergent ALT or AST  3  baseline value in combination with total bilirubin  2  ULN (of 
which  35% is direct bilirubin), 
Treatment-emergent ALT or AST  3  baseline value in combination with clinical jaundice. 
This abnormal laboratory values related to the liver function should be recorded on the Adverse Event 
eCRF and reported immediately as a SAE (AESI). 
The severity will be classified according to the NCI CTCAE Version 5.0. The CTCAE is available for 
downloading on the internet (see appendix 1). 
The AE severity grade provides a qualitative assessment of the extent or intensity of an AE, as 
determined by the investigator or as reported by the patients.  The severity grade does not reflect 
the clinical seriousness of the event, only the degree or extent of the affliction or occurrence (e.g., 
severe nausea, mild seizure), and does not reflect the relationship to study drug. 
Severity grade for other adverse events not covered in the toxicity grading scale: 
 
1 = Grade 1 
Mild 
2 = Grade 2 
Moderate 
3 = Grade 3 
Severe 
4 = Grade 4 
Life-threatening 
5 = Grade 5 
Fatal 
 
However, depending on the SAE term, there is some AE that do not have all the grades (e.g., the SAE 
term Alopecia only has the Grade 1 and 2). 
The causal relationship to study drug is determined by the physician and should be used to assess all 
AE. The casual 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.  


 
 
 
 
 
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About the AEs that have to be recorded in the eCRF note that: 
• Baseline symptoms will be recorded on the eCRF and changes and updates in grade as well 
as resolution of an AE during treatment have to be reported, 
• An AE has to be reported for each SAE notified, 
• AEs should not be reported in a narrative description. 
AEs 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). 
Any AE must be reported by an entry in the eCRF within 5 days of awareness, even if they do not meet 
the whole information. The diagnosis of the event should be recorded as AE term. If there is a 
secondary AE separated in time from the initiating event, it should be recorded as an independent 
event (e.g., if vomiting results in severe dehydration, both events should be reported separately). 
13.2. Definition of Serious Adverse Event (SAE) and Suspected Unexpected 
Serious Adverse Reaction (SUSAR) 
A Serious Adverse Event (SAE) is defined in general as any undesirable medical occurrence/adverse 
drug experience that occurs from the subject’s written consent to participate in the study through 
100 days after the final administration of the IMP, regardless of whether it is considered related or 
not to the study drug and that, or immediately before initiation of any other anticancer therapy, 
whichever comes first, and results in any of the following: 
• 
results in death (fatal), 
• 
is life-threatening (defined as an event in which the participant was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it was 
more severe), 
• 
requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE 2 
below), 
• 
results in persistent or significant disability/incapacity, 
• 
is a congenital anomaly/birth defect,  
• 
is an important medical event. Defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention (e.g., medical, 
surgical, laboratory abnormal parameters…) to prevent one of the other serious outcomes listed 
in the definition above (see NOTE 3 below), 
After informed consent has been obtained, but prior to initiation of study drug, only serious adverse 
events caused by a protocol-mandated intervention (e.g., invasive procedures such as biopsies, 
discontinuation of medications) should be reported. 


 
 
 
 
 
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Seriousness is based on patient/event outcome or action criteria usually associated with events that 
pose a threat to a patient's life or functioning. Seriousness (not severity) serves as a guide for defining 
regulatory reporting obligations 
NOTE 2: The following hospitalizations are not considered SAEs:  
− 
A visit to the emergency room or other hospital department < 24 hours, that does not result in 
admission, except if it is considered as an important medical event or life- threatening,  
− 
elective surgery, planned prior to signing consent, 
− 
routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy), 
− 
admissions as per protocol for a planned medical/surgical procedure, 
− 
admission for administration of anticancer therapy in the absence of any other SAEs, 
− 
admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason), 
− 
progression of disease. By convention, clinical events related to the primary cancer being studied 
or to the primary cancer progression are not to be reported as SAEs, even if they meet any of 
the seriousness criteria from the standard SAE definition, unless the event is more severe than 
expected and therefore the investigator considers that their clinical significance deserves 
reporting. 
NOTE 3: Any laboratory abnormalities should be documented as a SAE if: 
− 
Intensive treatment in an emergency room or at home for allergic bronchospasm is needed, 
− 
Blood dyscrasias or convulsions that do not result in hospitalization, 
− 
Any untoward event related, and unexpected, to the protocol procedures,  
− 
The laboratory test result is clinically significant or meets the definition of a SAE, 
− 
The laboratory abnormality required the participant to have study drug discontinued or 
interrupted, 
− 
The laboratory abnormality required the subject to receive specific corrective therapy. 
A SAE report should be completed for any event where doubt exists regarding its seriousness. Although 
overdose, pregnancy, AESI (e.g., potential drug-induced liver injury (DILI)), important medical event, 
and cancer (secondary malignancy) are not always serious by regulatory definition, these events must 
be handled as SAEs. If applicable, SAEs must be collected that relate to any later protocol-specified 
procedure (e.g., a follow-up skin biopsy). 


 
 
 
 
 
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If the investigator believes that a SAE is not related to study drug but is potentially related to the 
conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form and 
an important medical event would be the seriousness. 
All deaths that occur during the reporting period that are clearly the result of disease progression 
should not be reported as a SAE, but they should be collected as an AE. All deaths where it is not due 
to disease progression and deaths with an unknown cause should always be reported as a SAE.  
Death should be considered as an outcome and not the event, the AE causing the death must be 
reported as the SAE term. The term "sudden death" should be used only for the occurrence of an 
abrupt and unexpected death due to presumed cardiac causes in a patient with or without preexisting 
heart disease, within 1 hour after the onset of acute symptoms or, in the case of an unwitnessed death, 
within 24 hours after the patient was last seen alive and stable.  If the cause of death is unknown and 
cannot be ascertained at the time of reporting, "Death due to Unknown Cause" should be recorded on 
the Adverse Event eCRF. If the cause of death later becomes available (e.g., after autopsy), the event 
should be replaced by the established cause of death. 
If the SAE is considered as related to the study drug by the Principal Investigator, it is a Serious Adverse 
Reaction. The SAR is assessed by the Fundación GECP (SLCG/GECP) to know if it is expected. A SAR that 
is not listed as a known toxicity of the investigational drug in the summary of product characteristics 
(Investigator Brochure or Data Sheet) will be considered as a Suspected Unexpected Serious Adverse 
Reaction (SUSAR). The sponsor will inform to the Principal Investigator that this SAE has been 
considered as a SUSAR. In Spain, Health authority (AEMPS: Agencia Española del Medicamento y 
Productos Sanitarios) will also be informed about all SUSARs via EudraVigilance.  
13.3. Adverse events of Special Interest for Atezolizumab (Immediately 
reportable to the Sponsor)  
 
 
   
 
 
   
 
   
 
 


 
 
 
 
 
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13.4. Overdose and secondary malignancies 
 
 
 
 
 
13.5. SAEs and SUSARs reporting 
 
 Any SAE must be 
reported by submitting the completed Initial SAE Form in the online eCRF within 24 hours of 
awareness, even if they do not meet any of the seriousness criteria. 
In case of the eCRF is unavailability, the submission could be done by sending the SAE form preferably 
by email to 
 
 An appropriate SAE form (see appendix 3) should be used 
to report SAEs to Fundación GECP (SLCG/GECP). The paper SAE form has to be sent within the timeline 
period for reporting of 24 hours of awareness. Once the eCRF system is available again, the SAE has 
to be completed and submitted by the site into the eCRF. 


 
 
 
 
 
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If only limited information is initially available, a follow-up report is required to complete the 
information as soon as possible. (Note: Follow-up SAE reports should include the same SAE term(s) 
initially reported.)  
The SAE outcome must be reported within 14 days after initial reporting by submitting the Follow up 
SAE Form in the online eCRF. In case the SAE is reported as ongoing after 14 days, a follow-up report 
has to be submitted again with the final outcome. 
If an ongoing SAE changes in its grade, relationship to study drug, seriousness, SAE term or if new 
information becomes available, a new follow-up SAE report should be sent within 24 hours to the 
Fundación GECP (SLCG/GECP) using the same procedure after described.  
Any SUSAR occurred during the trial will be notified under Spanish clinical regulation to the principal 
investigators, to the Health Authority (AEMPS) via Eudravigilance within the timelines specified in the 
Royal Decree 1090/2015 on clinical trials regarding the recording, evaluation and reporting of adverse 
events. Also, the autonomous regions will be informed about all SUSARs according to the current 
Spanish clinical trial regulation. 
 
 
 
 
 
13.6. Pregnancy 
If, following initiation of the investigational product, it is subsequently discovered that a study 
participant is pregnant or may have been pregnant at the time of investigational product exposure, 
within 5 months after the last dose of atezolizumab and/or bevacizumab, or within 6 months after the 
last dose of atezolizumab and/or bevacizumab, the investigational product will be permanently 
discontinued in an appropriate manner (e.g., dose tapering if necessary for participant).  
Any pregnancy that occurs in a female partner of a male study participant should also be reported to 
the Fundación GECP (SLCG/GECP). Male patients will be instructed through the Informed Consent Form 
to immediately inform the investigator if his partner becomes pregnant during the chemotherapy 
treatment period or within 6 months after the last dose of chemotherapy. In order for Fundación GECP 
(SLCG/GECP) or designee to collect any pregnancy surveillance information from the female partner, 
the female partner must sign an informed consent form for disclosure of this information.  
 
 
 
  


 
 
 
 
 
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Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information, study discontinuation must be reported 
following the before procedure described during at least 1 year after child-bearing. 
  Any serious adverse events associated with the pregnancy (e.g., an event in the fetus, an event in the 
mother during or after the pregnancy, or a congenital anomaly/birth defect in the child) or abortion 
should be reported as a SAE.   
13.7. Other safety considerations 
Any significant worsening noted during interim or final physical examinations, electrocardiograms, X-
rays, and any other potential safety assessments, whether or not these procedures are required by the 
protocol, should also be recorded as a non-serious or serious AE, as appropriate, and reported 
accordingly. 
Reference Safety information: 
- 
Atezolizumab: Investigator Brochure 
- 
Bevacizumab: Investigator Brochure 
- 
Carboplatin: SmPC 
- 
Pemetrexed: SmPC 
- 
Paclitaxel: SmPC 
13.8. Adverse events related to the treatment and associated risks 
ATEZOLIZUMAB 
 
 


 
 
 
 
 
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BEVACIZUMAB 
 
 


 
 
 
 
 
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CARBOPLATIN 
 
  
 
 
PEMETREXED 
 
 


 
 
 
 
 
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PACLITAXEL 
 
 
 
 
 
  
14. Biological material and translational research 
Figure 1. Study schema 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
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15. Case report forms and documentation 
eCRFs will only be available on-line at the Remote Data Entry (RDE) facility of Fundación GECP for 
patient enrolment. 
Also, another exception will be a paper SAE form and pregnancy form that will be used only in case of 
eCRF system unavailability. 
16. Statistical considerations 
 
To find a 40% of MPR vs a theorical reference equals to 10.7% in patients with EGFR mutation NSCLC 
stage IIIA, with an 80% of power and alpha level of 0.05, 22 patients are needed. If we expect a 15% of 
losses of follow-up, 26 patients with EGFR mutation and NSCLC stage IIIA will be necessary. Thus, 
considering a prevalence of EGFR mutation of 15% in patients with NSCLC stage IIIA, 174 patients 
NSCLC stage IIIA should perform the test to check the presence of EGFR mutation. 
It is expected that approximately the 15% of the patients initially enrolled should be discarded because 
they do not meet the inclusion criteria; so that in order to reach the proposed sample size, if the 15% 
is exceeded because a patient initially enrolled in the study does not fulfil the inclusion criteria, it will 
be replaced by a new subject that fulfil them, this replacement will ensure that the sample size will be 
the one calculated initially.  
The analysis will be conducted according to the intention-to-treat (ITT) principle. Descriptive analysis 
will be performed by means of absolute and relative frequencies for categorical variables and mean 
and standard deviation, or median and percentiles 25 and 75 for numerical variables.  
The main analysis asses the response rate after the neoadjuvant therapy plus surgery. Response rates 
will be estimated along with their corresponding 95% confidence interval and then compared with 
other variables through a chi-square test or Fisher exact test if expected frequencies are less than or 
equal to 5. Effect size will be estimated by means of logistic regression analysis through the Odds Ratio 
(OR) as well as their corresponding confidence interval (95%CI).  
Progression free survival (PFS) is set as a secondary outcome. Survival function will be estimated by 
the Kaplan-Meier method. Cox proportional hazards model, will be used to estimate potential risk 
factors, along with the Hazard Ratios (HR) and 95% confidence intervals.  


 
 
 
 
 
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Reported p values will be two-sided, and the significance level will be set at 5% (0.05) for all analyses 
unless otherwise noted. Stata v15.1 software (StataCorp. 2017. Stata Statistical Software: Release 15. 
College Station, TX: StataCorp LLC) will be used for statistical analyses. 
17. Criteria for termination of the trial 
17.1. General criteria for termination of the trial 
The trial may be discontinued early in parts or completely if the information on the product leads to 
doubt as to the benefit/risk ratio, by decision Trial Steering Committee of Fundación GECP, or at the 
suggestion of the IDMC/DSMB. 
The trial can be terminated at any time if the authorization and approval to conduct the study is 
withdrawn by ethics committee or regulatory authority decision, insufficient accrual, emerging new 
data impacting the scientific value of the trial or on ethical grounds. 
17.2. Discontinuation of protocol treatment and from the study for individual 
patients  
Patients may be withdrawn from the protocol treatment and from the study in the following situations: 
• 
Occurrence of unacceptable toxicities. Stopping protocol treatment is determined by 
medical judgment of the treating physician. 
• 
Disease progression per investigator assessment according to RECIST v1.1  
• 
Inter-current severe illnesses which would in the judgment of the investigator affect 
assessments of the clinical status to a significant degree and require discontinuation of 
protocol therapy 
• 
Request by the patient. Patients have the right to refuse further trial treatment at any 
time during the trial. Such patients will remain in the trial and will be transferred to the 
follow-up phase. 
• 
If a patient refuses to have follow-up examinations and tests needed to determine 
whether the treatment is safe and effective 
• 
Protocol non-compliance or study termination by sponsor or site closure by the sponsor 
(poor protocol adherence, inaccurate or incomplete data recording…) 
• 
Pregnancy 
• 
Patient non-compliance, defined as a failure to comply with the protocol requirements as 
determined by the protocol 
The decision for discontinuation of protocol treatment and the study of individual patients is taken by 
the treating physician based on his medical evaluation and taking into account the patient’s individual 
situation. 


 
 
 
 
 
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Specific reasons for trial discontinuation where further collection of data is not allowed are:  
withdrawal of consent, patient lost to follow up, death. 
All possible measures will be undertaken to maintain the investigation program and to continue the 
follow-up even if the treatment was prematurely concluded and/or if the patient did not attend the 
follow-up visits at the participating institution. 
The primary reason for the treatment and study discontinuation should be documented on the 
appropriate form of the eCRF. 
18. Ethics aspects, regulatory approval, and Patient Informed Consent 
The Investigator will ensure that this study is conducted in full conformance with the principles of the 
“Declaration of Helsinki” or with the laws and regulations of the country in which the research is 
conducted, whichever affords the greater protection to the individual. The study must fully adhere to 
the principles outlined in “Guideline for Good Clinical Practice” ICH6 Tripartite Guideline (January 
1997) or local Spanish law. For studies conducted in the EU/EEA countries, the Investigator will ensure 
compliance with the EU Clinical Trial Directive (2001/20/EC). 
18.1. Ethical Review Board/Ethics Committee/Health Authority 
All protocols and the patient informed consent form must have the approval of a properly constituted 
committee or committees responsible for approving clinical trials. The Ethic Committee decision must 
contain approval of the designated investigator, the protocol (identifying protocol title and version 
number), and of the patient informed consent. 
The Ethic Committee written, signed approval letter/form must contain approval of the designated 
investigator, the protocol (identifying protocol title and version number), and of the patient informed 
consent.  
Any modifications made to the protocol must be submitted to the appropriate Ethic Committee for 
information or approval in accordance with local procedures and regulatory requirements and to 
Health Authorities if required.  
Once approved or acknowledged by the appropriate ERB/IRB and by the Health Authorities (if 
required), the investigator shall implement the protocol modifications.  
If applicable, in addition to the approval of the Ethics Committee according to national legislation, the 
protocol, other protocol related documents including patient information and informed consent and 
other documents as required locally must be submitted to and be approved by the health authority.  
18.2. Informed consent  
The Informed consent will be obtained prior to initiating any trial procedures in each patient.  Once 
signed and dated, a copy of the informed consent must be given to the patient and the original copy 


 
 
 
 
 
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must be retained in the investigator’s site file.  The informed consent form must be available in case 
of audits.  
The “Declaration of Helsinki” recommends that consent be obtained from each potential patient in 
biomedical research trials after the aims, methods, anticipated benefits, and potential hazards of the 
trial, and discomfort it may entail, are explained to the individual by the physician.  The potential 
patient should also be informed of her/his right to not participate or to withdraw from the trial at any 
time.  The patient should be told that material from her/his tumor and blood samples will be stored 
and potentially used for additional studies not described in this protocol.  
If the patient is in a dependent relationship to the physician or gives consent under duress, the 
informed consent should be obtained by an independent physician. It is preferable that the patient 
who gives the consent signs the form but if it is not possible or if the patient is legally incompetent 
(i.e., a minor, or mentally incompetent), informed consent must be obtained from the parent, legal 
guardian, or legal representative in accordance with the law of the country in which the trial is to take 
place.   
By signing this protocol, the investigator agrees to conduct the trial in accordance with Good Clinical 
Practice and the "Declaration of Helsinki".  
The template Patient Information Sheet and Informed Consent has been written according to ICH 
guidelines which state the Informed Consent should adhere to GCP and to the ethical principles that 
have origin in the “Declaration of Helsinki” and also, according to the Spanish Health Authority 
recommendations. 
19. Governance and administrative issues 
19.1. Study documentation 
The investigator must maintain adequate and accurate records to enable the conduct of the study to 
be fully documented, including, but not limited to, the protocol, protocol amendments, Patient 
Information Sheet and Informed Consent Forms, and documentation of IRB/EC and Health Authority 
approval. 
19.2. Protocol non-compliances/deviations 
The investigator should document and explain any protocol non-compliances/deviations. 
 
 
 
 
 
 
 


 
 
 
 
 
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19.3. Protocol amendment 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will be submitted 
to the IRB/EC and to regulatory authorities in accordance with local regulatory requirements. Approval 
must be obtained from the IRB/EC and regulatory authorities (as locally required) before 
implementation of any changes, except for changes necessary to eliminate an immediate hazard to 
patients or changes that involve logistical or administrative aspects only (e.g., change in Medical 
Monitor or contact information). 
19.4. Final report 
A final clinical trial report will be written and distributed to the Ethic committees and Health 
Authorities as required by applicable regulatory requirements. 
19.5. Independent Data Monitoring Committee 
The trial will be presented periodically for review to the Fundación GECP Independent Data Monitoring 
Committee (IDMC/DSMB).  
19.6. Publication 
Authorship on the final manuscript or publications or provisional extracts will be decided in accordance 
with the Fundación GECP publication and authorship guidelines (SOP GECP:  Política de publicaciones 
y auditorías). 
None of the participants will present data to his center in isolation from the rest of the results of the 
study and will need to seek approval from the sponsor. 
19.7. Financial disclosure 
Investigators will provide the sponsor with enough, accurate financial information in accordance with 
local regulations to allow the Sponsor to submit complete and accurate financial certification or 
disclosure statements to the appropriate health authorities.  Investigators are responsible for 
providing information on financial interests during the course of the study and for 1 year after 
completion of the study. 
19.8. Clinical trial insurance 
A civil responsibility policy for subjects participating in a clinical trial has to be contracted. Fundación 
GECP will contract the appropriate liability insurance for this trial. Patients who suffer injuries due to 
the trial should report them immediately to their physician.  


 
 
 
 
 
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19.9. Quality assurance 
Fundación GECP conducts trials according to the ICH Good Clinical Practice (GCP) guidelines.  The Trial 
Data Manager and the monitors (CRA) review each eCRF as per monitoring plan schedule. 
Fundación GECP will conduct periodic triggered visits to the participating sites to ensure proper trial 
conduct, verify compliance with GCP, and perform source data verification. 
The Investigator should ensure that source documents are made available to appropriately qualified 
personnel from Fundación GECP, or to ethics committee and health authority inspectors if needed, 
after appropriate notification. 
At regular intervals during the clinical trial, the centre will be contacted, through monitoring visits, 
letters or telephone calls, by a representative of the Monitoring Team to review study progress, 
investigator and patient compliance with clinical trial protocol requirements and any emergent 
problems. These monitoring visits will include but not be limited to review of the following aspects: 
patient informed consent, patient recruitment and follow-up, SAE documentation and reporting, AEs 
with pre-specified monitoring documentation and reporting, AE documentation, dispensing IMP, 
compliance with protocol, drug accountability, concomitant therapy use, quality of data and storage 
of blood samples. 
19.10. Data protection 
The samples and data collected will be coded to protect patient confidentiality. Each patient will have 
a pre-screening number at the pre-screening phase to identify the biological material and a unique 
identifier assigned by the eCRF of the study once enrolled. Sites are responsible to keep a patient log 
locally in order to be able to link the pre-screening number and the unique identifier to the record of 
the patient.  
No identifiable / personal data will be stored in the trial database or the tissue and blood repositories 
in the central laboratory. 
Regulatory authorities and pertinent Ethics Committees (IRB/ERB) may have access to patient data on-
site. Fundación GECP audit or monitoring personnel will also have access to such data on-site. 
To ensure the patient confidentiality of data applies from the 25th of May 2018 the Reglamento (UE) 
2016/679 del Parlamento europeo y del Consejo de 27 de abril de 2016 de Protección de Datos (RGPD) 
and in Spain it is regulated by the Organic Law 3/2018, 5th of December, on Personal data protection 
and digital rights guarantee. 
19.11. Study monitoring team 
The Fundación GECP will be responsible for monitoring the trial at all the participant sites. 
The clinical monitor is obliged to rigorously follow the study. For this, the clinical monitor will regularly 
visit the study centers and the investigators as well as maintain necessary written and telephone 


 
 
 
 
 
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communications.  
The clinical monitor will assess the data collected in the acquisition forms and compare them with the 
original data of the clinical history and other original documents in conjunction with the study 
investigator.  
The contact persons will be: 
 
Fundación GECP CRA 
Meridiana 358, 6ª planta 
08027 Barcelona 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
19.12. Record retention 
The centre must retain all essential documents according to ICH GCP. This includes copies of the patient 
trial records, which are considered as source data, patient informed consent statement, laboratory 
printouts, drug inventory and destruction logs, and all other information collected during the trial. 
These documents are to be stored until at least 25 years after the termination of the trial.  
In the event that the Principal Investigator retires or changes employment, custody of the records may 
be transferred to another competent person who will accept responsibility for those records. Written 
notice of such transfer must be given to the Fundación GECP and the local Ethics Committee at least 
1 month in advance. 


 
 
 
 
 
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20. References  
 
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2. López-Abente G, Pollán M, Aragonés N et al. Situación del cáncer en España: incidencia. An Sist 
Sanit Navar 2004; 27 (2): 165-173. 
3. Ramalingam S, Belani C. Systemic chemotherapy for advanced non-small cell lung cancer: recent 
advances and future directions. The Oncologist 2008;1: 5-13 
4. Hanna N, Neubauer M, Yiannoutsos et al. Phase III study of cisplatin, etoposide and concurrent 
chest radiation with or without consolidation with docetaxel in patients with inoperable stage III 
NSCLC: The Hoosier Oncology Group and U.S. Oncology. J Clin Oncol 2008; 26: 5755-60 
5. Douillard JY, Rosell R, De Lena M et al. Adjuvant vinorelbine plus cisplatin versus observation in 
patients with completely resected satge IB-IIIA NSCLC (Adjuvant Navelbine International Trialist  
Association (ANITA): A randomised controlled trial. Lancet Oncol 2006 ; 7 : 719-27. 
6. Pignon JP, Tribodet H, Scagliotti GV et al. Lung adjuvant cisplatin evaluation: A pooled analysis by 
LACE Collaborative Group.  J Clin Oncol 2008; 26: 3552-9 
7. Perez CA, Pajak TF, Rubin P, et al. Long-term observations of the patterns of failure in patients with 
unresectable non oat cell carcinoma of the lung treated with definitive radiotherapy. Report by 
the Radiation Therapy Oncology Group. Cancer 1987; 59:1874–81. 
8. Langer CJ, Leighton JC, Comis RL, O'Dwyer PJ, McAleer CA, Bonjo CA, Engstrom PF, Litwin S, Ozols 
RF.  Paclitaxel and carboplatin in combination in the treatment of advanced non-small-cell lung 
cancer (NSCLC): A phase II toxicity, response, and survival analysis (FCCC 93-024). J Clin Oncol 1995; 
13: 1860-1870.  
9. Non-Small Cell Lung Cancer Co-operative Group. Chemotherapy in non-small cell lung cancer: a 
meta-analysis using updated data on individual patients from 52 randomized clinical trials. Br Med 
J 1995;311:899-909. 
10. Martin J, Ginsberg RJ, Ennapadam S, et al. Long-term results of combined-modality therapy in 
resectable non-small cell lung cancer. J Clin Oncol 2002;20:1989-1995.  
11. O´Brien MER, Splinter T, Smit EF, et al. Carboplatin and paclitaxel (Taxol) as an induction regimen 
for patients with biopsy-proven stage IIIA N2 non-small cell lung cancer : an EORTC phase II study 
(EORTC 08958). Eur J Cancer 2003; 39:1416-1422. 
12. Zaragoulidis K, Kontakiotis T, Hatziapostolou P, et al. A phase II study of docetaxel and carboplatin 
in the treatment of non-small cell lung cancer. Lung Cancer 2001;32:281-287. 
13. Sugarbaker DJ, Herdon J, Kohman LJ, et al. Results of cancer and leukemia group B protocol 8935: 
A multi-institutional phase II trimodality trial for stage IIIA (N2) non-small-cell lung cancer-Cancer 
and Leukemia Group B Thoracic Surgery Group. J Thorc Cardiovasc Surg 1995; 109:473-485. 
14. Kirn DH, Lynch TJ, Mentzer SJ, et al. Multimodality therapy of patients with satge IIIA, N2 non-small 
–cell lung cancer: Impact of preoperative chemotherapy on resectability and downstaging,. J 
Thorac Cardiovasc Surg 1993; 106: 696-702. 
15. Martini N, Kris MG, Flehinger BJ, eta al. Preoperative chemotherapy for stage IIIa (N2) lung cancer: 
The Sloan-Kettering experience with 136 patients. Ann Thorc Surg 1993; 55:1365-1374.                                          
16. Martín N. Mediatinal lymph node dissection for lung cancer: The Memorial experience. Chest Surg 


 
 
 
 
 
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Clin N Am 1995; 5: 189-203. 
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Cancer and Leucemia Group B Phase III Protocol 9134. Int J Radiat Oncol Biol Phys 1997; 39: 195. 
18. Choi Y S, shim Y M, Kim J, Kim K. Recurrence-free survival and prognostic factors in resected pN2 
non-small cell lung cancer. European Journal of Cardiothoracic Surgery 2002; 22: 695-700. 
19. Miller AB, Hoogstraten B, Staquet M, et al. Reporting results of cancer treatment.Cancer 1981; 47: 
207-214. 
20. Martín N. Mediatinal lymph node dissection for lung cancer: The Memorial experience. Chest Surg 
Clin N Am 1995; 5: 189-203. 
21. Johnson DH, Paul DM, Hande KR, Shyr Y, Bianke C, Murphy B, Lewis M, DeVore RF.  Paclitaxel plus 
carboplatin in advanced non-small-cell lung cancer - a phase II trial.  J Clin Oncol 1996; 14: 2054-
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22. Rowinsky EK, Flood WA, Sartorius SE, Bowling MK, Wagner J, Ettinger DS.  Phase I study of paclitaxel 
as a 3-hour infusion followed by carboplatin in untreated patients with stage IV non-small-cell lung 
cancer.  Semin Oncol 1995; 22 (Suppl 9): 48-54.  
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small-cell lung cancer (NSCLC).  ProcAm Soc Clin Oncol 1995; 14: A352. 
24. Klastersky J, Sculier JP, Lacroix H, Dabouis G, Bureau G, Libert P, Richez M, Ravez P, Vandermoten 
G, Thiriaux J, et al. A randomized study comparing cisplatin or carboplatin with etoposide in 
patients with advanced non-small-cell lung cancer:EORTC Protocol 07861. J. Clin. Oncol. 1990 Sep; 
8(9): 1556-1562. 
25. Bonomi P, Finkelstein D, Ruckdeschel J, et al. Combination Chemotherapy versus single agents 
followed by combination in stage IV non-small-cell lung cancer: astudy of the ECOG. J. Clin. Oncol. 
1989; 7: 1602.  
26. Greco FA y Hainsworth JD. Paclitaxel (1-hour infusion) plus carboplatin in the treatment of 
advanced NSCLC. Semin Oncol 1997; 24: S12-17. 
27. DeVore RF, Jagasia M y Johnson D. Paclitaxel by either 1-hour or 24h infusion in combination with 
carboplatin in advanced NSCLC. Semin Oncol 1997;24: S27-29. 
28. Palackdharry CS, Durham SJ, Durzinsky DS, et al: Preliminary results of neoadjuvant paclitaxel and 
carboplatin in the treatment of early stage NSCLC. Semin Oncol 1997; 24: S12-34-S12-36. 
29. Stroun M et al. Neoplastic  characateristics  of the DNA found  in the plasma of cancer patients. 
Oncology  1989; 46:318-322. 
30. Decoster L, Wauters I, Vansteenkiste JF. Vaccination therapy for non-small-cell lung cancer: review 
of agents in phase III development. Ann Oncol 2012; 23: 1387-1393. 
31. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. 
Science 1996; 271: 1734-1736. 
32. Wing K, Sakaguchi S. Regulatory T cells exert checks and balances on self tolerance and 
autoimmunity. Nat Immunol 2010; 11: 7-13. 
33. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 
12: 252-264. 
34. Sharma P, Allison JP. The future of immune checkpoint therapy. Science 2015; 348: 56-61. 


 
 
 
 
 
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35. Ahn HK, Choi YL, Han JH, et al. Epidermal growth factor recpetor mutation and treatment 
outcome of mediastinoscopic N2 positive non-small cell lung cancer patients treated with 
neoadjuvant chemoradiotherapy followed by surgery. Lung Cancer 2013, 79: 300-306.  
36. López-González A, Almagro E, Salas C, Varela A, Provencio M. Use of a tyrosine kinase inhibitor 
as neoadjuvant therapy for non-small cell lung cancer: A case report. Respir Med Case Rep. 2013 
Apr 24; 9: 8-10.  
37. Xiong L, et al. Erlotinib as neoadjuvant therapy in stage IIIA (N2) EGFR mutation-positive non-
small cell lung cancer: A prospective single-arm, phase II study. The Oncologist. 24: 157-e64. 
2019. 
38. Zhong et al. EMERGIG trial. ESMO 2018. 
Appendices: 
1. Common Terminology criteria for Adverse Events (CTCAE)  
2. RECIST criteria v1.1  
3. SAE Form  
4. Pregnancy Form 
5. System of classification for non-microcytic lung cancer (NSCLC) and definition of lymph node 
maps, 8th edition 
6. Risks associated with Atezolizumab and guidelines for management of adverse events 
associated with Atezolizumab 
 
 


 
 
 
 
 
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APPENDIX 1. Common Terminology criteria for Adverse Events (CTCAE)  
 
Version 5.0: November 27, 2017 is available from the internet at:  
 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Qu
ick_Reference_8.5x11.pdf 
 
APPENDIX 2. RECIST criteria v1.1 
1. Introduction 
All included patients will be evaluated for response according to the revised Response Evaluation 
Criteria In Solid Tumors (RECIST version 1.1) [1]. This appendix defines all criteria applied in this trial. 
2. Methods of assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred 
to evaluation by clinical examination when both methods have been used to assess the antitumor 
effect of a treatment. 
CT is the best currently available and reproducible method to measure lesions selected for response 
assessment. CT should generally be performed using a ≤ 5 mm contiguous reconstruction algorithm. 
MRI is acceptable for certain situations, e.g. body scans. 
Clinical lesions will only be considered measurable when they are superficial (e.g. skin nodules) and 
≥10 mm. In the case of skin lesions, documentation by color photography including a ruler to estimate 
the size of the lesion is recommended.  
Lesions on chest X-ray are acceptable as measurable lesions when they are clearly defined and 
surrounded by aerated lung. However, CT is preferable. 
Ultrasound is not useful in assessment of lesion size and is not accepted as method of assessment. 
FDG-PET is not foreseen for regular response assessments. It may, however, be used to detect or 
confirm the appearance of new lesions. Attenuation correction CT scans performed as part of a PET/CT 
scan frequently show lower resolution; therefore, dedicated CT scans are preferred. However, if the 
site can demonstrate that the CT performed as part of a PET/CT is of the same diagnostic quality as a 
diagnostic CT (with IV and oral contrast), then the CT portion of the PET/CT can be used for RECIST 
measurements. 
3. Measurability of tumor at baseline 
Measurable disease is defined as the presence of at least one measurable lesion. 


 
 
 
 
 
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Measurable lesions: 
• 
Tumor lesions must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of 
o 10 mm by CT scan (CT scan slice thickness no greater than 5mm) 
o 10mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable) 
o 20 mm by chest X-ray 
• 
Malignant lymph nodes: to be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15mm in short axis when assessed by CT scan, assuming the slice thickness is 
≤ 5 mm. At baseline and in follow-up, only the short axis will be measured. 
Non-measurable lesions: all other lesions, i.e.: 
• 
Small non-nodal lesions (longest diameter < 10 mm in CT scan) 
• 
Small lymph nodes (short axis ≥ 10 and < 15 mm). Lymph nodes that have a short axis < 10 mm 
are considered non-pathological and should not be recorded or followedBone lesions. Lytic 
bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. Blastic bone lesions are non-measurable. 
• 
Leptomeningeal disease 
• 
Ascites 
• 
Pleural or pericardial effusion 
• 
Inflammatory breast disease 
• 
Lymphangitic involvement of skin or lung 
• 
Cystic lesions. Cystic lesions thought to represent cystic metastases may be considered as 
measurable lesions. However, if non-cystic lesions are present, these are preferred as target 
lesions 
• 
Tumor lesions situated in a previously irradiated area, or subjected to other locoregional 
therapy. Such lesions may be considered measurable if there has been demonstrated 
progression in the lesion 
• 
abdominal masses/abdominal organomegaly identified by physical exam that are not 
measurable by reproducible imaging techniques 
4. Selection of lesions 
4.1. Selection of target lesions 
At baseline, measurable lesions up to a maximum of 5 lesions representative of all involved organs, 
and up to 2 per organ, should be identified as target lesions and measured and recorded. Target lesions 
(TL) should be selected on the basis of their size and their suitability for accurate repetitive 
measurements. A sum of diameters for all target lesions will be calculated and reported as the baseline 
sum of diameters. Lymph nodes selected as TL should always have the short axis recorded. All other 
lesions should always have their longest diameters recorded. The sum of diameters will be used as 


 
 
 
 
 
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reference to further characterize the objective tumor response of the measurable dimension of the 
disease. 
4.2. Selection of non-target lesions 
All other lesions (or sites of disease) should be identified as non-target lesions and should also be 
recorded at baseline. Measurements are not required, but the presence or absence of each should be 
noted throughout follow-up. It is possible to record multiple non-target lesions as a single item on the 
CRF (e.g. "multiple liver metastases"). 
5. Evaluation of Lesions 
5.1. Evaluation of Target Lesions 
All target lesions will be measured at each tumor assessment, and the sum of their diameters will be 
compared to previous assessments in order to assign the response status as specified below. 
• 
Complete Response (CR): Disappearance of all target lesions. Lymph nodes selected as target 
lesions must each have reduction in the short axis to < 10 mm in order for the response to be 
considered complete. In this case, the sum of diameters may be > 0. 
• 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking 
as reference the baseline sum of diameters. 
• 
Progression (PD): At least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum recorded on study. In addition to the relative increase of 20%, the 
sum must also demonstrate an absolute increase of at least 5 mm. 
• 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD taking as reference the smallest sum of diameters recorded on study. 
• 
Inevaluable for response: specify reasons (for example: early death due to malignant disease 
or toxicity; tumor assessment not repeated/incomplete; other, specify). 
Note: All target lesions, including lymph nodes, should have their actual measurements recorded at 
each subsequent evaluation, even when very small (e.g. 2 mm). If the radiologist does not feel 
comfortable assigning an exact measure and reports a lesion as "too small to measure", a default value 
of 5 mm should be recorded. If a TL is thought likely to have disappeared, "0 mm" is noted. 
5.2. Evaluation of Non-Target Lesions 
• 
Complete Response (CR): Disappearance of all non-target lesions; lymph nodes selected as 
non-target lesions must be non-pathological in size (< 10 mm). 
• 
Non-CR/non-PD: Persistence of one or more non-target lesions (non-CR). 
• 
Progression (PD): unequivocal progression of existing non-target lesions. Unequivocal means: 
comparable in magnitude to the increase that would be required to declare PD for measurable 
disease, or an overall substantial increase in tumor burden that merits treatment 
discontinuation. 
 


 
 
 
 
 
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5.3. Determination of new lesions 
The appearance of any new malignant lesions denotes disease progression. The finding of a new lesion 
should be unequivocal, i.e. not attributable to differences in scanning technique or findings thought to 
represent something other than tumor. If a new lesion is equivocal, e.g. because of its small size, the 
patient will stay on treatment (if the decision on PD is based on this lesion only). If the repeat scans 
confirm there is definitely a new lesion, then progression should be declared using the date of the 
previous scan. 
Lesions found in a new location not included in the baseline scan (e.g. brain metastases) are considered 
new lesions. 
Note: the "re-appearance" of a previously "disappeared" target or non-target lesion does not in itself 
necessarily qualify as PD; this is the case only if the overall evaluation meets the PD criteria, or if the 
patient was previously in CR. 
5.4. Additional considerations 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. When the 
evaluation of complete response depends upon this determination, it is recommended that the 
residual lesion be investigated (fine needle aspirate/biopsy) before confirming the complete response 
status. 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment when the measurable tumor has met criteria for response or stable disease is mandatory to 
differentiate between response or stable disease (an effusion may be a side effect of the treatment) 
and progressive disease. 
6. Determination of time point response 
Based on the responses of Target Lesions, Non-Target Lesions, and the presence or absence of new 
lesions, the overall response will be determined at each tumor assessment time point, according to 
the table below: 
 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR / non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD 
or 
not 
all 
evaluated 
No 
PR 
SD 
Non-PD 
or 
not 
all 
evaluated 
No 
SD 


 
 
 
 
 
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Not all evaluated 
Non-PD 
No 
NE  
(unless the sum of 
diam. Of evaluated 
lesions indicates PD1) 
PD 
Any 
Yes or no 
PD 
Any  
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
1 From ref. 1 p.234: When no imaging/measurement is done at all at a particular time point, the patient is not evaluable (NE) 
at that time point. If only a subset of lesion measurements are made at an assessment, usually the case is also considered NE 
at that time point, unless a convincing argument can be made that the contribution of the individual missing lesion(s) would 
not change the assigned time point response. This would be most likely to happen in the case of PD. For example, if a patient 
had a baseline sum of 50mm with three measured lesions and at follow-up only two lesions were assessed, but those gave a 
sum of 80 mm, the patient will have achieved PD status, regardless of the contribution of the missing lesion. 
7. Determination of best overall response 
Best overall response is defined as best response across all time points. Confirmation of partial or 
complete response by an additional scan is not requested in this trial. Best overall response will be 
determined by central review. 
8. References 
1. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther 
S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). EurJ Cancer 2009;45(2):228-
47. 
 
 


 
 
 
 
 
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APPENDIX 3. SAE Form 
SAEs will be reported in the eCRF. Only in the case that it is not working the paper form will be used. 
See the form attached 
APPENDIX 4. Pregnancy Form 
Pregnancies will be reported in the eCRF. Only in the case that it is not working the paper form will be 
used. 
See the form attached 
 
 


 
 
 
 
 
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APPENDIX 5. System of classification for non-microcytic lung cancer (NSCLC) and definition 
of lymph node maps, 8th edition 
 


 
 
 
 
 
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APPENDIX 6. Risks associated with Atezolizumab and guidelines for management of adverse 
events associated with Atezolizumab 
 
Please see current version of the Atezolizumab’s IB.