A Phase II Open Label Study of Atezolizumab in Combination With Bevacizumab as First Line Treatment for Locally Advanced or Metastasic High-intermediate Tumor Mutation Burden Selected Non-squamous Non-small Cell Lung Cancer Patients.
Phase: PHASE2
Conditions: Non Small Cell Lung Cancer
Sponsor: Fundación GECP

 
Protocol_TELMA_GECP 18/03_ML40237_v.5.1_01Jul2024 
 
 
 
 
 
O昀昀icial Title: <A PHASE II OPEN LABEL STUDY OF ATEZOLIZUMAB IN 
COMBINATION WITH BEVACIZUMAB AS FIRST LINE TREATMENT FOR LOCALLY 
ADVANCED OR METASTASIC HIGH-INTERMEDIATE TUMOR MUTATION BURDEN 
(TMB) SELECTED NON-SQUAMOUS NON-SMALL CELL LUNG CANCER (NSCLC) 
PATIENTS= TELMA 
 
 
 
 
       NCT Number:  NCT03836066 
 
 
Document Dates:  
Protocol Version v.5.1_01Jul2024 
 
 

 
 
 
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A PHASE II OPEN LABEL STUDY OF ATEZOLIZUMAB IN 
COMBINATION WITH BEVACIZUMAB AS FIRST LINE 
TREATMENT FOR LOCALLY ADVANCED OR METASTASIC 
HIGH-INTERMEDIATE TUMOR MUTATION BURDEN (TMB) 
SELECTED NON-SQUAMOUS NON-SMALL CELL LUNG 
CANCER (NSCLC) PATIENTS 
 
 
TELMA: Atezolizumab plus bevacizumab in first line NSCLC patients 
 
 
 
Study Sponsor: Fundación GECP 
 
EudraCT Number: 2018-004654-17  
Sponsor code: GECP 18/03 
Roche code: ML40237 
 
Version 5.1 
 
 
 
 
 
 
 

 
 
 
 
 
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Contacts 
 
Trial Chair  
 
 
Dr. Mariano Provencio, 
MD, PhD 
Fundación GECP 
President 
Oncology Service 
Hospital Univ. Puerta de Hierro, 
Majadahonda, Madrid,  
Tel. 93 430 20 06 
Fax. 993 419 17 68 
Email: secretaria@gecp.org 
Safety and Regulatory 
Affairs 
Coordinating office of 
the Fundación GECP 
Beatriz García  
Avenida Meridiana 358, 6ª planta 
08027 Barcelona 
Tel. +34 93 430 20 06 
Fax. +34 93 419 17 68 
Email: pharmacovigilance.slcg@gecp.org 
Coordinating office of the 
Fundación GECP 
Monitoring team 
Monitor/CRA 
 
 
 
 
 
 
Lead CRA 
 
 
 
 
 
 
Clinical Operations 
Manager: 
 
 
Miriam BaladaAvenida Meridiana 358, 
6ª planta 
08027 Barcelona 
Tel. +34 93 430 20 06 
Fax. +34 93 419 17 68 
Email: mbalada@gecp.org  
Ana Verdú 
Avenida Meridiana 358, 6ª planta 
08027 Barcelona 
Tel. +34 93 430 20 06 
Fax. +34 93 419 17 68 
Email: averdu@gecp.org 
Eva Pereira 
Avenida Meridiana 358, 6ª planta 
08027 Barcelona 
Tel. +34 93 430 20 06 
Fax. +34 93 419 17 68 
Email: epereira@gecp.org 

 
 
 
 
 
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 Protocol Signature Page 
 
A PHASE II OPEN LABEL STUDY OF ATEZOLIZUMAB IN COMBINATION 
WITH BEVACIZUMAB AS FIRST LINE TREATMENT FOR LOCALLY 
ADVANCED OR METASTATIC HIGH-INTERMEDIATE TUMOR MUTATION 
BURDEN (TMB) SELECTED NON-SQUAMOUS NON-SMALL CELL LUNG 
CANCER (NSCLC) PATIENTS 
 
TELMA: Atezolizumab plus bevacizumab in first line NSCLC patients 
 
 
Sponsor code: GECP 18/03 
 
 
Approved by: 
 
Signature 
 
 
_____________________________ 
Dr. Mariano Provencio 
Trial Chair 
 
 
Signature 
 
 
 
 __________________________ 
Dr. Bartomeu Massutí 
Fundación GECP Secretary 
 
 
 
Signature 
 
 
_____________________________ 
Dr. Mariano Provencio 
Fundación GECP President 

 
 
 
 
 
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Principal Investigator Protocol Signature Page 
 
 
Study Title: <A phase II open-label study of Atezolizumab in combination with bevacizumab as first 
line treatment for locally advanced or metastatic high-intermediate tumor mutation burden (TMB) 
selected non-squamous non-small cell lung cancer (NSCLC) patients= TELMA 
 
Sponsor protocol code: GECP 18/03 
EudraCT Number: 2018-004654-17  
Protocol version: v 5.1,21th July 2024 
 
 
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. 
 
 
Name of Principal Investigator: ___________________________________ 
 
 
 
Institution9s name and place: _____________________________________ 
 
 
 
 
 
 
 
Signature                                                                              Date 

 
 
 
 
 
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TABLE OF CONTENTS  
Section 
Page 
 
1. 
Protocol summary ............................................................................................................ 7 
2. 
Trial schedule ................................................................................................................. 20 
3. 
Background and rationale ............................................................................................... 23 
3.1. 
Disease background and treatments in advanced NSCLC patients............................... 23 
3.2. 
Immunotherapy ......................................................................................................... 26 
3.3. 
Background on Atezolizumab ..................................................................................... 26 
3.4. 
Background on Bevacizumab ...................................................................................... 30 
3.5. 
Rationale for trial design ............................................................................................ 31 
3.6. 
Rationale for additional translational research (stool and blood samples) .................. 32 
4. 
Objectives and endpoints ............................................................................................... 33 
4.1. 
Primary objective and endpoint ................................................................................. 33 
4.2. 
Secondary objectives and endpoint ............................................................................ 34 
4.3. 
Exploratory objectives ................................................................................................ 35 
5. 
Trial design, duration and termination ............................................................................ 35 
6. 
Patient selection ............................................................................................................. 37 
6.1. 
Inclusion criteria ......................................................................................................... 37 
6.2. 
Exclusion criteria ........................................................................................................ 39 
7. 
Patient pre-screening and enrollment............................................................................. 43 
8. 
Trial procedures ............................................................................................................. 44 
8.1. 
Overview of treatment sequence ............................................................................... 44 
9. 
Investigational Medicinal Product ................................................................................... 52 
9.1. 
Packaging and labelling .............................................................................................. 53 
9.2. 
Receipt and storage of the IMP .................................................................................. 53 
9.3. 
Unused trial drug supplies .......................................................................................... 53 
10. 
Trial treatments description ........................................................................................... 54 
10.1. 
ATEZOLIZUMAB .......................................................................................................... 54 
10.2. 
BEVACIZUMAB ........................................................................................................... 55 
11. 
Dose modifications criteria ............................................................................................. 56 
11.1. 
General Notes Regarding Dose Modification .............................................................. 56 
11.2. 
ATEZOLIZUMAB dose delay criteria ............................................................................ 56 
11.3. 
BEVACIZUMAB dose delay/reduction criteria ............................................................. 57 
12. 
Prohibited and permitted concomitant treatments......................................................... 61 
13. 
Adverse events and reporting ......................................................................................... 64 
13.1. 
Definition of an Adverse Event (AE) and AE9s reporting .............................................. 64 
13.2. 
Definition of Serious Adverse Event (SAE) and Suspected Unexpected Serious Adverse 
Reaction (SUSAR) ....................................................................................................... 66 
13.3. 
Adverse events of Special Interest for Atezolizumab (Immediately reportable to the 
Sponsor) .................................................................................................................... 69 
13.4. 
Overdose and secondary malignancies ....................................................................... 70 
13.5. 
SAEs and SUSARs reporting ........................................................................................ 70 
13.6. 
Pregnancy .................................................................................................................. 71 
13.1. 
Other safety considerations ....................................................................................... 72 
13.2. 
Adverse events related to the treatment and associated risks .................................... 72 
14. 
Biological material and translational research ................................................................. 73 

 
 
 
 
 
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15. 
Case report forms and documentation ........................................................................... 75 
16. 
Statistical considerations ................................................................................................ 75 
17. 
Criteria for termination of the trial ................................................................................. 76 
17.1. 
General criteria for termination of the trial ................................................................ 76 
17.2. 
Discontinuation of protocol treatment and from the study for individual patients ...... 77 
18. 
Ethics aspects, regulatory approval, and Patient Informed Consent ................................ 78 
18.1. 
Ethical Review Board/Ethics Committee/Health Authority .......................................... 78 
18.2. 
Informed consent ....................................................................................................... 78 
19. 
Governance and administrative issues ............................................................................ 79 
19.1. 
Study documentation ................................................................................................. 79 
19.2. 
Protocol non-compliances/deviations ........................................................................ 79 
19.3. 
Protocol amendment ................................................................................................. 79 
19.4. 
Final report ................................................................................................................ 80 
19.5. 
Independent Data Monitoring Committee .................................................................. 80 
19.6. 
Publication ................................................................................................................. 80 
19.7. 
Financial disclosure .................................................................................................... 80 
19.8. 
Clinical trial insurance ................................................................................................ 80 
19.9. 
Quality assurance ....................................................................................................... 80 
19.10. 
Data protection .......................................................................................................... 81 
19.11. 
Study monitoring team............................................................................................... 81 
19.12. 
Record retention ........................................................................................................ 82 
20. 
References ..................................................................................................................... 82 
20.1. 
References for translational research ......................................................................... 86 
 
Appendices: 
1. Common Terminology criteria for Adverse Events (CTCAE)  
2. RECIST criteria v1.1  
3. SAE Form  
4. Pregnancy Form 
5. Health-related Quality of life questionnaire: EORTC C30 (QLQ-C30) and submodule LC13 
6. System of classification for non-microcytic lung cancer (NSCLC) and definition of lymph node 
maps, 8th edition 
7. Risks associated with Atezolizumab and guidelines for management of adverse events 
associated with Atezolizumab 
8. Patient pre-screening form TELMA 
9. Foundation one CDx Specimen Instructions 
10.  Foundation one Liquid technical sheet 
11. Foundation one CDx technical sheet 
 
Tables: 
Table 1. Administration of First and Subsequent Infusions of Atezolizumab 

 
 
 
 
 
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1. 
Protocol summary 
 
A PHASE II OPEN LABEL STUDY OF ATEZOLIZUMAB IN COMBINATION WITH 
BEVACIZUMAB AS FIRST LINE TREATMENT FOR LOCALLY ADVANCED OR 
METASTATIC HIGH-INTERMEDIATE TUMOR MUTATION BURDEN (TMB) 
SELECTED NON-SQUAMOUS NON-SMALL CELL LUNG CANCER (NSCLC) 
PATIENTS 
 
TELMA: Atezolizumab plus bevacizumab in first line NSCLC patients 
 
Sponsor: Fundación GECP 
Trial Chair: Mariano Provencio Pulla (MD, PhD) 
Pharma Partner: Hoffmann-La Roche 
Protocol code: GECP 18/03 (ML40237) 
Population: stage IIIB - IV non-squamous selected high-intermediate tumor mutation burden (TMB) 
non-small cell lung cancer patients 
Design: Open-label, non-randomized, phase II multi-centre clinical trial  
 
   
 

 
 
 
 
 
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Sample size: 40 patients  
 
Rationale: 
Despite recent improvements in treatment, the prognosis for patients with advanced NSCLC remains 
dismal, with a median OS of approximately 12.5 months3.  
 
Inhibition of programmed cell death protein-ligand 1/programmed cell death protein 1 (PD-L1/PD-
1) signalling has been shown to induce durable responses in some patients with different tumors, 
and expression of PD-L1 by tumor cells (TCs) in several tumor types (including NSCLC) correlates with 
response to therapy4. Immunotherapy has demonstrated that therapies focused on enhancing T-cell 
responses against cancer may result in a significant survival benefit in patients with Stage IV 
cancer5,6,7. 
 
Immunotherapeutic targeting of PD-L1 or PD-1 is revolutionizing the treatment of metastatic NSCLC. 
Currently, two anti-PD-1 therapeutic antibodies (Pembrolizumab and Nivolumab) and one anti-PD-
L1 (Atezolizumab) have been approved for NSCLC treatment. Both agents are recommended as 
second-line agents in advanced NSCLC after prior progression on platinum-containing 
chemotherapy. 
 
Atezolizumab is a humanized anti-PD-L1 monoclonal antibody that inhibits its interaction with its 
receptors, PD-1 and B7.1 (CD80, B7-1), reinvigorating anticancer immunity. The OAK study evaluated 
the efficacy of Atezolizumab compared to Docetaxel in 1.225 patients previously treated with locally-
advanced or metastatic NSCLC. The PD-L1 targeted therapy by Atezolizumab resulted in a clinically 
relevant improvement of overall survival versus Docetaxel regardless of PD-L1 expression or 
histology, with a favourable safety profile. The median OS in this study was 13.8 months (95% CI 
11.8-15.7) in the Atezolizumab arm compared to 9.6 months (95% CI 8.6-11.2) in the Docetaxel arm 
(HR=0.73, 95% CI 0.62-0.87; p=0.0003)8. 
 
The GO28625 (NCT01846416, FIR) phase 2 study enrolled 137 PD-L1-selected NSCLC patients 
regardless previous treatments. The primary analysis for efficacy-evaluable patients, confirmed ORR 
after the first-line treatment with Atezolizumab was 28.6% (95% CI: 3.7-71.0) in IHC TC3 or IC3 
patients and 25.8% (95% CI: 11.9-44.6) in IHC TC2/3 or IC2/3 patients9. 
 
The efficacy and safety of Atezolizumab was also evaluated in another phase 2 single-arm study 
where 142 PD-L1-selected advanced NSCLC patients (NCT02031458, BIRCH) were treated with 
Atezolizumab monotherapy. The primary endpoint ORR in the ITT population was 25%, in TC3 or IC3 
subgroup was 34% and 18% in TC2 and IC2. Median PFS and OS for the entire population were 7.3 
and 23.5 months respectively. These results indicate that Atezolizumab monotherapy has durable 
efficacy in the first line setting10. 
 
Currently, first-line treatment for advanced NSCLC without presence of genetic aberrations, such as 
sensitizing mutations of epidermal growth factor receptor (EGFR) or translocations of anaplastic 
lymphoma kinase (ALK), are chemotherapy and Pembrolizumab, approved based on KEYNOTE-024 
study. This study randomized patients with advanced NSCLC and PD-L1 expression (at least 50% of 

 
 
 
 
 
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tumor cells), showing median progression-free survival (PFS) of 10.3 months (95% CI 6.7-not reached) 
versus 6.0 months (95% CI 4.2-6.2) (HR 0.50; 95% CI 0.37-0.68; P<0.001) for the Pembrolizumab and 
chemotherapy groups respectively11. 
 
Currently there is a clinical trial (NCT02409342, IMpower110) of Atezolizumab as first line 
monotherapy in PD-L1 selected NSCLC patients that is expected to add the first line approval to 
Roche´s portfolio. Thus, all the above data support the rational of cancer immunotherapy in first line 
PD-L1 positive NSCLC12. In addition, there is a growing body of evidence that suggests that pro-
angiogenic factors can modulate the immune response and may serve as mechanisms of scape. 
Therefore, the combination of cancer immunotherapy with antiangiogenic agents makes sense. 
 
The vascular endothelial growth factor (VEGF) is the most important pro-angiogenic protein and a 
key regulator of physiological angiogenesis. It is also implicated in pathological angiogenesis 
associated with tumor growth. Indeed, increased levels of VEGF have been found in lung cancer; 
moreover, the overexpression of VEGF is associated with a poor prognosis13,14. Actually, VEGF plays 
a role in cancer immune evasion through modification of the endothelial cells in the tumor 
microenvironment, where VEGF may reduce lymphocyte adhesion and migration from vessels to the 
tumor site contributing to decreased immune cell recruitment15.  Given the immunosuppressive role 
of VEGF and angiogenesis within tumors, it is not surprising that there is evidence supporting how 
antiangiogenic agents stimulate the immune response and enhance the efficacy of 
immunotherapies16. 
 
Recent findings indicating an intertwined regulation of VEGF signalling and immunosuppression in 
the tumor microenvironment suggest that the combination of anti-VEGF agents and immune 
checkpoint blockade could have synergistic antitumor activity, along with favourable tolerability16. 
 
Bevacizumab is a recombinant, humanized therapeutic anti-VEGF antibody that inhibits tumor 
angiogenesis which may correct the immunosuppressive function exerted by VEGF, increasing the 
infiltration of T effector cells in cancer17. 
 
So far, the more advanced studies to address the combination of cancer immunotherapy (CIT)-
antiangiogenic agents such as Bevacizumab, there is a phase 3 study of Paclitaxel, Carboplatin 
Bevacizumab and Atezolizumab (NCT02366143, IMpower150). IMpower150 is the first phase III 
immunotherapy-based combination study to demonstrate a statistically significant and clinically 
meaningful improvement in PFS in all-comer 1L NSQ mNSCLC, providing a potential new standard of 
care for patients, showing a median PFS of 8.3 moths vs 6.8 moths (HR 0.62; 95% CI: 0.52, 0.74; P < 
0.0001) for the Atezolizumab, chemotherapy and Bevacizumab arm (ABCP) and Carboplatin, 
Paclitaxel and Bevacizumab arm (BCP) respectively. In terms of PFS 12 months the results were 37% 
in the Atezolizumab arm vs 18% un the CT + Bevacizumab arm. Median overall survival among the 
patients was longer in the ABCP group than in the BCP group (19.2 months vs. 14.7 months; hazard 
ratio for death, 0.78; 95% CI, 0.64 to 0.96; P = 0.02)18. 
 
The phase 3 study of Atezolizumab in combination with Bevacizumab compared to Sunitinib single 
agent (IMmotion151), as first-line therapy in untreated metastatic Renal Cell Carcinoma (RCC) 
patients. This clinical trial showed a significant benefit of 3.5 months in the PFS favouring the CIT-
Bevacizumab combination (11.2 m vs. 7.7 m) with a tolerable safety profile in PD-L1+ patients19.  
 

 
 
 
 
 
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These data confirm the role of Bevacizumab as an immune modulating agent that may provide a 
successful combination strategy in different tumor types. 
 
Increased mutation rate is a well-characterized feature of human cancer. Abnormal activity in several 
cellular pathways, including DNA damage repair and DNA replication, can increase the overall rate 
of somatic mutations in tumors, as can exposure to mutagens such as ultraviolet light and tobacco 
smoke20. Defects in DNA damage repair lead to the accumulation of mutations caused by replicative 
errors and environmental damage21. 
 
The core DNA mismatch repair protein complex is composed of two cooperative dimers: the PMS2 
protein dimerizes with MLH1 to form the complex MutL-alpha, which cooperates with the MSH2-
MSH6 dimer, MutS-alpha, to repair single base pair mismatches and small insertion–deletion loops22. 
PMS2 promoter mutations are present in ~10% of melanoma samples and ~8% of squamous cell 
carcinomas23. 
 
Perturbations in mismatch repair gene expression, both loss and overexpression, can be deleterious 
to genomic stability, and loss of function mutations in mismatch repair pathway genes are known to 
correlate with high Tumor Mutational Burden (TMB) in tumors, overall mutations in these genes 
accounted for less than 10% of cases with high TMB23. 
 
As such, tumors with defective DNA repair mechanisms are more likely to benefit from 
immunotherapy. DNA replication is another key pathway in which defects can lead to increased 
somatic mutation rate. 
 
Loss of function mutations in TP53 are very common in cancer and are a somatic marker of elevated 
mutation rate24. Mutations in a number of other genes have also been linked to increase TMB. KRAS-
mutant lung cancers account for approximately 25% of non-small cell lung carcinomas, thus 
representing an enormous burden of cancer worldwide. KRAS mutations are clear drivers 
of tumor growth and are characterized by a complex biology involving the interaction between 
mutant KRAS, various growth factor pathways, and tumor suppressor genes. KRAS mutations are 
classically associated with a significant smoking history25. Then, it is an emerging biomarker for 
response to immunotherapy. The CheckMate 026 trial is a randomized trial comparing the treatment 
efficacy of Nivolumab versus chemotherapy in first line therapy of advanced non-small cell lung 
cancer based on the programmed death-ligand 1 expression. However, there was no strong 
correlation between treatment response and PD-L1 expression. Therefore, researchers performed a 
subanalysis to assess if the TMB could determine Nivolumab treatment response in 312 patients with 
evaluable TMB data. The results demonstrated that patients with a high mutation burden had a 
better progression free survival (9.7 vs 5.8 months; HR, 0.62) and objective response rate (46.8% vs 
28.3%) compared with the control arm. These findings imply that tumor mutation burden may be 
considered as a biomarker for immunotherapy26. 
 
Regarding TMB data, the CheckMate227 study is an open-label, phase 3 trial, that examined 
progression-free survival with nivolumab plus ipilimumab versus chemotherapy among patients with 
stage IV or recurrent NSCLC that was not previously treated with chemotherapy with a high tumor 
mutational burden (g10 mutations per megabase). Median PFS among patients with a high tumor 
mutational burden was significantly longer with nivolumab plus ipilimumab than with chemotherapy, 
7.2 months (95% confidence interval [CI], 5.5 to 13.2) versus 5.5 months (95% CI, 4.4 to 5.8) (HR, 
0.58; 97.5% CI, 0.41 to 0.81; P<0.001)27. 

 
 
 
 
 
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Further understanding the factors associated with increased TMB is important for better 
understanding this key driver of cancer progression and for understanding the molecular 
mechanisms which lead to TMB. 
 
Unlike the majority of genetic panels used within the standard of practice in oncology, even those 
using Next Generation Sequencing (NGS), Foundation Medicine ® (FMI) is a <Comprehensive 
Genomic Profiling= test, able to detect all cancer-relevant genes with all classes of alterations across 
the entire coding region, being also a validated performance36. Moreover, is a hybridization capture-
based NGS method which, contrary to the more common Hot Spot Multi-gene panels, do not miss 
any relevant gene or genetic alteration37. Besides, FMI has two formats, both of them validated in 
top tier peer-reviewed journal: <FoundationOne ®= for solid tumors37. Finally, current service has 
been implemented for detection of Microsatellite Instability (MSI) and Tumor Mutational Burden 
(TMB). 
 
Based on the above synergistic effects, Atezolizumab plus Bevacizumab might provide significant 
TMB selected NSCLC patients. For this reason, the Fundación GECP finds of great interest the 
following protocol: A phase 2 study evaluating the efficacy of Atezolizumab in combination with 
Bevacizumab as first line therapy for advanced or metastatic high-intermediate TMB (TMBg10 
mutations/MB analyzed in tumor or TMBg16 analyzed in blood) non-squamous NSCLC patients. 
Objectives and endpoints:  
Primary objective: 
 
• 
To evaluate the efficacy of Atezolizumab in combination with Bevacizumab as measured by 
Progression Free Survival (PFS) at 12 months according to Response Evaluation Criteria in 
Solid Tumors (RECIST) Version 1.1.  
 
Secondary objectives: 
 
 
• 
To evaluate the ORR of Atezolizumab in combination with Bevacizumab as measured by 
investigator-assessed overall response rate (ORR) according to RECIST v1.1. 
• 
To evaluate the efficacy of Atezolizumab in combination with Bevacizumab as measured by 
investigator-assessed duration of response (DOR) according to RECIST v1.1. 
• 
To evaluate the efficacy of Atezolizumab in combination with Bevacizumab as measured by 
investigator-assessed time to response (TTR) according to RECIST v1.1. 
• 
To evaluate the efficacy of Atezolizumab in combination with Bevacizumab as measured by 
investigator-assessed ORR, PFS and DOR according to immune-related response criteria; 
irRC. 
• 
To evaluate the efficacy of Atezolizumab in combination with Bevacizumab as measured by 
investigator ORR, PFS and DOR according to immune-related response criteria (irRC) in 
patients with TMB g16 mutations/MB. 
• 
To evaluate the PFS rate at 1 and 2 years of Atezolizumab in combination with Bevacizumab. 
• 
To evaluate the OS rate at 1 and 2 years of Atezolizumab in combination with Bevacizumab. 

 
 
 
 
 
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• 
To evaluate ORR and PFS according PD-L1 expression of Atezolizumab in combination with 
Bevacizumab. 
• 
To evaluate the safety and tolerability of Atezolizumab in combination with Bevacizumab. 
• 
To evaluate patient-reported outcomes (PROs) of lung cancer symptoms, patient 
functioning, and health-related quality of life (HRQoL) as measured by the European 
Organisation for Research and treatment of Cancer (EORTC) Quality-of-life Questionnaire 
Core 30 (QLQ C30) and its Lung Cancer Module (QLQ LC13) of Atezolizumab in combination 
with Bevacizumab. 
 
Exploratory Objectives 
 
Foundation one: 
 
• 
To determine the tumor mutational burden (TMB) and determine its association with all 4 
types of genomic alteration (Indels, mutation, CNV, rearrangement) in 324 tumor related 
genes, MSI and determine by FoundationOne CDx# (F1CDx), and other biomarkers such as 
tumor PD-L1 expression. 
• 
To investigate genomics alteration change measure in blood after progression measured 
with FoundationOne®Liquid, in respect with genomics alteration measure by FoundationOne 
CDx# (F1CDx) in tissue including genomics signatures (MSI and TMB) at progression. 
• 
To evaluate the clinical utility of the TMB results/reports in patients with TMB<10, 
mutations/MB describing druggable alterations or driver mutation that influence treatment 
selection. 
• 
To evaluate overall survival (OS) and ORR of atezolizumab in combination with bevacizumab 
based on the TMB analysis in blood and in tumor)  
 
Additional pharmacogenomic exploratory analysis: 
• 
To evaluate the basal peripheral blood TCR and BCR repertoire and their changes during 
treatment, as well as, their correlation with clinical variables associated with treatment 
efficacy (ORR, PFS, OS, DOR).   
• 
To study the levels of peripheral blood immune cells and soluble factors from plasma 
samples considering their changes during treatment, as well as, their correlation with clinical 
variables associated with treatment efficacy (ORR, PFS, OS, DOR).   
• 
To determine the pre-treatment fecal microbiome of all patients included in the study and 
its predictive value in terms of ORR, PFS, OS and DOR. 
  
 
Eligibility criteria:  
Inclusion criteria: 
1. Male or female, aged g 18 years old 
2. ECOG performance status of 0 or 1. 

 
 
 
 
 
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3. Histologically or cytologically confirmed, Stage IIIB - IV non-squamous NSCLC according to 8th 
version of the International Association for the Study of Lung Cancer Staging Manual in 
Thoracic Oncology 
4. No prior treatment for Stage IIIB - IV non-squamous NSCLC. 
5. Patients who have received prior neo-adjuvant, adjuvant chemotherapy, radiotherapy, or 
chemo-radiotherapy with curative intent for non-metastatic disease must have experienced 
a treatment-free interval of at least 6 months from enrollment since the last chemotherapy, 
radiotherapy, or chemo-radiotherapy. 
6. Patients with a treated asymptomatic CNS metastasis are eligible, provided they meet all of 
the following criteria: 
a. Only supratentorial and cerebellar metastases allowed (i.e., no metastases to 
midbrain, pons, medulla or spinal cord). 
b. No ongoing requirement for corticosteroids as therapy for CNS disease. 
c. No stereotactic radiation within 7 days or whole-brain radiation within 14 days prior 
to enrollment. 
d. No evidence of interim progression between the completion of CNS-directed 
therapy and the screening radiographic study. 
Patients with new asymptomatic CNS metastases detected at the screening scan must 
receive radiation therapy and/or surgery for CNS metastases. Following treatment, these 
patients may then be eligible without the need for an additional brain scan prior to inclusion, 
if all other criteria are met. 
7. Patients with high-intermediate Tumor Mutational Burden analyzed by Foundation Medicine 
(g10 mutations/ MB) performed by a Foundation Medicine laboratory on previously 
obtained archival tumor tissue or tissue obtained from a biopsy at pre-screening (sample 
must fulfil minimal sample requirements of 20% tumor cellularity and a minimum surface of 
25mm2). TMBg16 mutations/ MB is required if the analysis is performed in blood sample. 
8. Measurable disease, as defined by RECIST v1.1. 
Previously irradiated lesions can only be considered as measurable disease if disease 
progression has been unequivocally documented at that site since radiation and the 
previously irradiated lesion is not the only site of disease. 
9. Adequate hematologic and organ function defined by the following laboratory results 
obtained within 14 days prior to enrollment: 
• 
Neutrophils g 1500 cells/μL without granulocyte colony-stimulating factor support. 
• 
Lymphocyte count g 500/μL. 
• 
Platelet count g 100,000/μL without transfusion. 
• 
Haemoglobin g 9.0 g/dL. Patients may be transfused to meet this criterion. 
• 
INR or aPTT f 1.5 × upper limit of normal (ULN). This applies only to patients who are 
not receiving therapeutic anticoagulation; patients receiving therapeutic 
anticoagulation should be on a stable dose. 
• 
AST, ALT, and alkaline phosphatase f 2.5 × ULN, with the following exceptions: 
Patients with documented liver metastases: AST and/or ALT f 5 × ULN. 
Patients with documented liver or bone metastases: alkaline phosphatase f 
5 × ULN. 
• 
Serum bilirubin f 1.25 × ULN. Patients with known Gilbert disease who have serum 
bilirubin level f 3 × ULN may be enrolled. 
• 
Serum creatinine f 1.5 × ULN or creatinine clearance of g45ml/min (based on the 
Cockcroft Gault formula). 
 

 
 
 
 
 
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10. 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. 
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 (oestrogen 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 (g 12 months of non2therapy-induced amenorrhea) 
or surgically sterile must have a negative serum pregnancy test result within 8 days prior to 
initiation of study drug. 
 
Exclusion criteria: 
Cancer-Specific Exclusions: 
 
1. Patients with a sensitizing mutation or an amplification in the epidermal growth factor 
receptor (EGFR) gene. 
2. Patients with an anaplastic lymphoma kinase (ALK) fusion oncogene. 
3. Patients with an STK-11 Ligand alteration. 
4. Patients with MDM2 amplification. 
5. Patients with ROS1 translocations. 
6. Active or untreated CNS metastases as determined by CT or magnetic resonance imaging 
(MRI) evaluation during screening and prior radiographic assessments. 
7. Spinal cord compression not definitively treated with surgery and/or radiation or previously 
diagnosed and treated spinal cord compression without evidence that disease has been 
clinically stable for > 2 weeks prior to enrollment. 
8. Leptomeningeal disease. 
9. Uncontrolled tumor-related pain. 
Patients requiring pain medication must be on a stable regimen at study entry. 
Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or 
metastases causing nerve impingement) should be treated prior to initiation of study 
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Patients should be recovered from the effects of radiation. There is no required 
minimum recovery period. 
Asymptomatic metastatic lesions whose further growth would likely cause 
functional deficits or intractable pain (e.g., epidural metastasis that is not currently 
associated with spinal cord compression) should be considered for locoregional 
therapy, if appropriate, prior to initiation of study drug. 
10. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once monthly or more frequently). 
Patients with indwelling catheters (e.g., PleurX®) are allowed. 
11. Uncontrolled or symptomatic hypercalcemia (> 1.5 mmol/L ionized calcium or Ca > 12 mg/dL 
or corrected serum calcium > ULN). 
12. Malignancies other than NSCLC within 5 years prior to enrollment, with the exception of 
those with a negligible risk of metastasis or death (e.g., expected 5-year OS > 90%) treated 
with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, 
basal or squamous-cell skin cancer, localized prostate cancer treated with radiotherapy or 
surgically with curative intent, ductal carcinoma in situ treated surgically with curative 
intent). 
 
 
General Medical Exclusions: 
 
13. Women who are pregnant, lactating, or intending to become pregnant during the study. 
14. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins. 
15. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary 
cells or any component of the Atezolizumab formulation. 
16. History of autoimmune disease, including but not limited to myasthenia gravis, myositis, 
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory 
bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener9s 
granulomatosis, Sjögren9s 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). 
17. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active 
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History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
18. Positive test for HIV. All patients will be tested for HIV prior to inclusion into the study; 
patients who test positive for HIV will be excluded from the clinical study. 
19. Patients with active hepatitis B (chronic or acute; defined as having a positive hepatitis B 
surface antigen [HBsAg] test at screening) or hepatitis C. 
Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined 
as the presence of hepatitis B core antibody [HBcAb] and absence of HBsAg) are 
eligible only if they are negative for HBV DNA (vaccinated patients are excluded). 
Patients positive for hepatitis C virus (HCV) antibody are eligible only if PCR is 
negative for HCV RNA. 
20. Active tuberculosis. 
21. Severe infections within 4 weeks prior to be included in the study, including but not limited 
to hospitalization for complications of infection, bacteraemia, or severe pneumonia. 
22. Received therapeutic oral or IV antibiotics within 2 weeks prior to be included in the study. 
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract 
infection or to prevent chronic obstructive pulmonary disease exacerbation) are 
eligible. 
23. Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class 
II or greater), myocardial infarction, or cerebrovascular accident within 3 months prior to 
inclusion, unstable arrhythmias, or unstable angina. 
Patients with known coronary artery disease, congestive heart failure not meeting 
the above criteria, or left ventricular ejection fraction < 50% must be on a stable 
medical regimen that is optimized in the opinion of the treating physician, in 
consultation with a cardiologist if appropriate. 
24. Major surgical procedure other than for diagnosis within 28 days prior to inclusion or 
anticipation of need for a major surgical procedure during the course of the study. 
25. Prior allogeneic bone marrow transplantation or solid organ transplant. 
26. 
Administration of a live, attenuated vaccine within 4 weeks before inclusion 
or anticipation that such a live attenuated vaccine will be required during 
the study. 
27. Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that contraindicates 
the use of an investigational drug or that may affect the interpretation of the results or 
renders the patient at high risk from treatment complications. 
28. Patients with illnesses or conditions that interfere with their capacity to understand follow 
and/or comply with study procedures. 
 
Exclusion Criteria Related to Medications: 
 
29. Any approved anti-cancer therapy, including hormonal therapy, within 3 weeks prior to 
initiation of study treatment. 
30. Treatment with any other investigational agent with therapeutic intent within 28 days prior 
to initiation of study treatment. 
31. Treatment with systemic immunosuppressive medications (including but not limited to 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
anti2tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to inclusion. 
Patients who have received acute, low-dose (f 10 mg oral prednisone or equivalent), 
systemic immunosuppressant medications may be enrolled in the study. 

 
 
 
 
 
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The use of corticosteroids (f 10 mg oral prednisone or equivalent) for chronic 
obstructive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for 
patients with orthostatic hypotension, and low-dose supplemental corticosteroids 
for adrenocortical insufficiency is allowed. 
 
Exclusions Related to Bevacizumab: 
 
32. 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. 
33. Prior history of hypertensive crisis or hypertensive encephalopathy. 
34. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent 
peripheral arterial thrombosis) within 6 months prior to inclusion. 
35. History of haemoptysis (g one-half teaspoon of bright red blood per episode) within 1 month 
prior to inclusion. 
36. Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic 
anticoagulation). 
37. Current or recent (within 10 days of inclusion) use of aspirin (> 325 mg/day) or treatment 
with dipyramidole, ticlopidine, clopidogrel, and cilostazol. 
38. 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. 
39. Core biopsy or other minor surgical procedure, excluding placement of a vascular access 
device, within 7 days prior to the first dose of Bevacizumab. 
40. History of abdominal or tracheoesophageal fistula or gastrointestinal perforation within 6 
months prior to inclusion. 
41. Clinical signs of gastrointestinal obstruction or requirement for routine parenteral hydration, 
parenteral nutrition, or tube feeding. 
42. Evidence of abdominal free air not explained by paracentesis or recent surgical procedure. 
43. Serious, non-healing wound, active ulcer, or untreated bone fracture. 
44. Proteinuria, as demonstrated by urine dipstick or > 1.0 g of protein in a 24-hour urine 
collection. 
All patients with g 2+ protein on dipstick urinalysis at baseline must undergo a 24-
hour urine collection and must demonstrate f 1 g of protein in 24 hours. 
45. Known sensitivity to any component of Bevacizumab. 
46. Clear tumor infiltration into the thoracic great vessels is seen on imaging. 
47. Clear cavitation of pulmonary lesions is seen on imaging. 
 
 
 

 
 
 
 
 
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Treatment: 
Atezolizumab: 1200mg, IV infusion 
Bevacizumab: 15 mg/kg, IV infusion 
 
The treatment will start within 1-5 days from enrollment. The treatment will be administered at 21-
day intervals (3 weeks ±3days). On Day 1 of each cycle, all eligible patients will receive drug infusions 
in the following order: 
Atezolizumab → Bevacizumab 
 
Atezolizumab may continue beyond disease progression per RECIST v1.1 until loss of clinical benefit, 
unacceptable toxicity, patient or physician decision to discontinue, or death. If the principal 
investigator would like to continue beyond progression a permission from the trial chair/sponsor 
have to be granted. For all patients, tumor response data collection will continue until disease 
progression, even if the patient stops study treatment prior to disease progression.  
 
Bevacizumab will be administered until progression disease, unacceptable toxicity, patient or 
physician decision to discontinue or death. 
 
Statistical considerations:  
The primary endpoint is Progression Free Survival (PFS) at 12 months according to Response 
Evaluation Criteria in Solid tumors (RECIST) v1.1. 
 
For one arm, we estimate to achieve a PFS at 12 months of 40% (vs 18% from Chemotherapy, 
previous published studies), with a 90% power and alpha 5%, one-sided test. The test statistic for 
survival probability is based on the non-parametric estimate of the survival distribution. Additionally, 
estimating a 10% of errors, withdrawals or others, it will be necessary to recruit 40 patients in order 
to get the study objectives 
 
 
If the withdrawals are higher than 5%, so that in order to reach the proposed sample size, if a patient 
initially enrolled in the study does not fulfil the inclusion criteria, they will be replaced by a new one 
subject that fulfil them, this replacement will ensure that the sample size will be the one calculated 
initially.  
 
Data analysis and statistical methods 
A descriptive analysis will be made of the variables calculating absolute and relative frequencies of 
qualitative variables and mean (standard deviation) or median (25 and 75 percentiles), minimum and 
maximum values for quantitative variables.  
 
For the primary endpoint analysis, survivor function estimated by Kaplan-Meier method will be used, 
as well as the survival curves. The 95% confidence interval will be estimated. 
 

 
 
 
 
 
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For the bivariate analysis, appropriate parametric and nonparametric tests will be used depending 
on whether the data are normally or non-normally distributed. For comparison of quantitative 
variables, Student9s t test for independent data, the Mann-Whitney U test, analysis of variance or 
the Kruskal-Wallis H test will be used. 
 
 
Total trial duration:  4.5 years (1.5 years of recruitment, approximately 1.5 years of treatment and 
1.5 years of follow up) 
 
Translational research:  
Before enrollment, tissue samples will be analyzed by different methods as IHC and FoundationOne 
CDx# (F1CDx). These exploratory analyses aim to study tumor-associated alterations to further 
understand disease pathobiology (including but not limited to mechanisms of disease progression, 
pseudo-progression, acquired resistance), to evaluate surrogate biomarkers and to potentially allow 
for the development of tissue-based diagnostic tests to help predict which patients may benefit from 
Atezolizumab in combination with Bevacizumab vs Atezolizumab alone. If the submitted tumor 
sample is insufficient or not valid and a biopsy is not feasible to be performed to evaluate the TMB, 
a blood sample can be sent instead.  
A permission from the trial chair/sponsor must be requested in case no tumor sample is available for 
a possible patient and blood sample want to be sent to analyze the TMB. 
 
 
After enrollment, blood and stool samples will be send to the central laboratory at Hospital Puerta 
de Hierro de Majadahonda to perform additional pharmacogenomic exploratory analysis (see 
section 3.6) 
 
 

 
 
 
 
 
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2. 
Trial schedule 
 
Pre-Screening 
 
Screening/ 
Baseline 
(-28 days before 
enrollment) 
Bevacizumab and 
Atezolizumab 
Cycles16 
Atezolizumab 
Cycles (beyond 
progression 
disease)17 
End of 
Treatment18 
Follow up19 
Informed consent1 
X 
X 
 
 
 
 
Medical history and 
demographic data 
 
X 
 
 
 
 
Physical examination: 
 
 
 
 
 
 
Height 
 
X 
 
 
 
 
Performance status 
(ECOG) 
 
X 
X 
X 
 
X 
Weight, Temperature, 
Blood pressure 
 
X 
X16 
X 
 
X 
First follow up 
Hematology2, 3 
 
X 
X 
X 
 
X 
First follow up 
Biochemistry2, 4 
(Including renal and 
hepatic function) 
 
X 
X 
X 
 
X 
First follow up 
Coagulation2, 5 
 
X 
X 
X 
 
X 
First follow up 
Thyroid function2, 6 
 
X 
X 
At day 1 of Cycle 2 
and every 2 cycles 
X 
Every 2 cycles 
 
X 
First follow up 
HIV / Hepatitis B/C7 
 
X 
 
 
 
 
Pregnancy test8 
 
X 
X 
At day 1 of Cycle 2 
and every 2 cycles 
X 
Every 2 cycles 
 
X8 
First follow up 
Urine dipstick9 
 
X 
X 
 
 
X 
First follow up 
12-lead ECG 
 
X 
 
 
 
X 
First follow up 
Adverse events10 
(Toxicity evaluation) 
 
X 
To evaluate 
baseline status 
Continuous 
Continuous 
Continuous 
X 
First follow up10 
Concomitant 
medications11 
 
X 
Continuous 
Continuous 
Continuous 
X 
First follow up 
Tumor assessment12 
 
X 
X 
X 
 
X12 
Patient Reported 
Outcomes (PROs): 
QLQ30-LC1313 
 
X 
X 
At day 1 of Cycle 3 
and every 3 cycles 
 
X13 
X13 
Blood sample 
(Foundation one) 
X15 
 
 
 
X14 
X14 
FFPE tumor material 
(Foundation one)15 
X 
 
 
 
 
 
Blood samples 
(pharmacogenomic 
exploratory analysis)20 
 
X 
X 
 
 
X  
Stool sample 
collection21 
 
X 
 
 
 
 

 
 
 
 
 
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1 Before any trial specific evaluations or interventions. The patient has to sign a specific pre-screening informed 
consent to send the tumor block for pre-screening. If the patient has a TMB g10 analyzed in tumor or TMB g16 
analyzed in blood, then the patient will sign the Informed consent (IC) of the study 
2 Laboratory testing prior to each dose administration: within 14 days in baseline visit and within 3 days prior 
to day 1 administration of each cycle. If baseline testing is performed more than 3 days before first study dose, 
they must be repeated on day 1 cycle 1. 
3Hematology: WBC count, neutrophils, haemoglobin, platelet count   
4Biochemistry: Ca, Mg, Na, K, Glucose, ALT, AST, LDH, total bilirubin, alkaline phosphatase, creatinine and 
clearance of creatinine calculated by Cockcroft-Gault formula, total protein, albumin, amylase, lipase. 
5Coagulation: PT, INR and APTT  
6Thyroid function: thyroid-stimulating hormone (TSH). Total or free T3 and total or free T4 must be analyzed if 
TSH result is out of ULN or LLN.  
7 HIV / Hepatitis B/C: The following baseline local laboratory assessments should be done within 28 days prior 
to first dose: Hepatitis B and C testing (HBV sAg, HBV Ab and HCV Ab) and HIV test. In patients with positive 
hepatitis B/C results, HBV DNA/HCV RNA must be performed (Hepatitis B vaccinated patients are excluded). 
8 Pregnancy Tests: A serum or urine pregnancy testing is required within 3 days prior to study enrollment, then 
every 6 weeks and within 30 days of last treatment dose (more frequently if required by local standard). 
9Urine test: A urine testing is required for proteinuria within 3 days prior to study enrollment and at day 1 of 
each cycle of Bevacizumab and Atezolizumab (+/- 3 days). 
10 Adverse events must be recorded and followed from the day of the signs the patient Informed consent for 
the study to 30 days from last dose of administration. SAEs and AESIs must be recorded and followed from the 
subject written consent to 30 days from last dose of administration. 
11 Concomitant medications must be recorded and followed from 7 days prior to day 1 cycle 1 to 30 days from 
last dose of administration. 
12 Tumor assessment: 
• 
Chest and abdomen CT SCAN with oral/IV contrast (unless contraindicated) must be done at baseline 
within 28 days before enrollment (+ 12 days). During treatment the tumor assessments will be done 
every 12 weeks (+/- 7 days) from cycle 1 day 1. CT SCAN must be performed until progression disease 
or until last dose of Atezolizumab in case of continuing beyond progression. The CT SCAN schedule will 
be maintained even if a delay in administration occurs.  
• 
An MRI or CT brain with oral/IV contrast (unless contraindicated) must be done at baseline within 28 
days before enrollment (+ 12 days).  
• 
A full-body PET-TAC, pelvis or the neck CT scan and Bone scans should be performed if clinically 
indicated at baseline and at subsequent response evaluations.  
Note that it is not mandatory to perform the tumor assessment in first follow up visit if the end of treatment 
reason is other than progression disease and a tumor assessment is been performed in the previous 12 weeks. 
During follow up, tumor assessment will be maintained every 12 weeks (+/- 7 days) in case end of treatment 
reason is other than disease progression. Tumor assessments must be performed until progression disease. 
13 PROs (QLQ30-LC13) must be performed at: 
• 
Baseline 
• 
Day 1 of Cycle 3 and every 3 cycles until discontinuation of treatment  

 
 
 
 
 
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• 
At progression disease, when it occurs.  
In the event of a delay in administration, the PROs schedule will be also delayed to be performed on day 1 
of the specified cycles. 
Even if the progression disease occurs within 9 weeks after of the last completed PRO, the progression PRO 
must be performed. 
14 Foundation one blood samples will be drawn at progression (two 10 ml tubes).  
15 Tumor sample is required for pre-screening before enrollment. A minimum of 10 slides 4-5 um thick, with at 
least 20% tumor cellularity will be necessary for FoundationOne CDx# (F1CDx) Panel. If the submitted tumor 
sample is insufficient or not valid and a biopsy is not feasible to be performed to evaluate the TMB, a blood 
sample can be sent instead. A permission from the trial chair/sponsor must be requested in case no tumor 
sample is available for a possible patient, and blood sample want to be sent to analyze the TMB. 
16 Cycles will be administered every 3 weeks (±3 days) until progression or other reason to discontinue. Day 1 
of cycle 1 treatment will start within 1-5 days from enrollment. If a patient must stop one of the two drugs due 
to toxicity it is allowed to continue treatment with the other drug as long as patient does not present 
progression disease. If progression disease is shown is only permitted continue treatment beyond progression 
with atezolizumab. 
Blood pressure must be taken always before the drug administration. Blood pressure should be routinely 
measured before every infusion after a resting period of 10 min. If baseline record is performed more than 3 
days before first study dose, they must be repeated on day 1 cycle 1  
17 Atezolizumab may continue beyond disease progression per RECIST v1.1 until loss of clinical benefit, 
unacceptable toxicity, patient or physician decision to discontinue, or death. If the principal investigator would 
like to continue beyond progression a permission from the trial chair/sponsor have to be granted. 
18 End of treatment is defined as the day of discontinuation of the treatment.  
19 A first follow up visit must be done 30 days (±3 days) after the last dose of treatment (Bevacizumab 
+Atezolizumab or Atezolizumab beyond progression) or immediately before the initiation of any other 
anticancer therapy.  
The subsequent follow up visits can be matched at least with the CT SCAN schedule or more frequently as per 
local standard.  
20 Pharmacogenomic exploratory analysis blood samples will be drawn at: 
- 
Baseline or before day 1 of cycle 1 treatment 
- 
First CT-scan evaluation (cycle 5 if there is no delay in treatment administration) 
- 
Second CT-scan evaluation (cycle 9 if there is no delay in treatment administration) 
- 
Fourth CT-scan evaluation (cycle 17 if there is no delay in treatment administration) 
- 
Sixth CT-scan evaluation (cycle 25 if there is no delay in treatment administration) 
- 
Progression disease, either if it occurs during the bevacizumab + atezolizumab treatment or in follow 
up phase 
 21 Stool samples will be collected at baseline. 

 
 
 
 
 
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3. 
Background and rationale 
3.1. 
Disease background and treatments in advanced NSCLC patients 
 
Lung cancer is the leading cause of cancer-related death in industrialized countries1. Non-small cell 
lung cancer (NSCLC) accounts for 85% of cases of lung cancer and is categorized into a variety of 
histological subtypes being non-squamous tumors the most common subtype2. 
 
Despite recent improvements in treatment, the prognosis for patients with advanced NSCLC remains 
dismal, with a median OS of approximately 12.5 months3.  
 
Inhibition of programmed cell death protein-ligand 1/programmed cell death protein 1 (PD-L1/PD-
1) signalling has been shown to induce durable responses in some patients with different tumors, 
and expression of PD-L1 by tumor cells (TCs) in several tumor types (including NSCLC) correlates with 
response to therapy4. Immunotherapy has demonstrated that therapies focused on enhancing T-cell 
responses against cancer may result in a significant survival benefit in patients with Stage IV 
cancer5,6,7. 
 
Immunotherapeutic targeting of PD-L1 or PD-1 is revolutionizing the treatment of metastatic NSCLC. 
Currently, two anti-PD-1 therapeutic antibodies (Pembrolizumab and Nivolumab) and one anti-PD-
L1 (Atezolizumab) have been approved for NSCLC treatment. Both agents are recommended as 
second-line agents in advanced NSCLC after prior progression on platinum-containing 
chemotherapy. 
 
Atezolizumab is a humanized anti-PD-L1 monoclonal antibody that inhibits its interaction with its 
receptors, PD-1 and B7.1 (CD80, B7-1), reinvigorating anticancer immunity. The OAK study evaluated 
the efficacy of Atezolizumab compared to Docetaxel in 1.225 patients previously treated with locally-
advanced or metastatic NSCLC. The PD-L1 targeted therapy by Atezolizumab resulted in a clinically 
relevant improvement of overall survival versus Docetaxel regardless of PD-L1 expression or 
histology, with a favourable safety profile. The median OS in this study was 13.8 months (95% CI 
11.8-15.7) in the Atezolizumab arm compared to 9.6 months (95% CI 8.6-11.2) in the Docetaxel arm 
(HR=0.73, 95% CI 0.62-0.87; p=0.0003)8. 
 
The GO28625 (NCT01846416, FIR) phase 2 study enrolled 137 PD-L1-selected NSCLC patients 
regardless previous treatments. The primary analysis for efficacy-evaluable patients, confirmed ORR 
after the first-line treatment with Atezolizumab was 28.6% (95% CI: 3.7-71.0) in IHC TC3 or IC3 
patients and 25.8% (95% CI: 11.9-44.6) in IHC TC2/3 or IC2/3 patients9. 
 
The efficacy and safety of Atezolizumab was also evaluated in another phase 2 single-arm study 
where 142 PD-L1-selected advanced NSCLC patients (NCT02031458, BIRCH) were treated with 
Atezolizumab monotherapy. The primary endpoint ORR in the ITT population was 25%, in TC3 or IC3 
subgroup was 34% and 18% in TC2 and IC2. Median PFS and OS for the entire population were 7.3 
and 23.5 months respectively. These results indicate that Atezolizumab monotherapy has durable 
efficacy in the first line setting10. 
 

 
 
 
 
 
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Currently, first-line treatment for advanced NSCLC without presence of genetic aberrations, such as 
sensitizing mutations of epidermal growth factor receptor (EGFR) or translocations of anaplastic 
lymphoma kinase (ALK), are chemotherapy and Pembrolizumab, approved based on KEYNOTE-024 
study. This study randomized patients with advanced NSCLC and PD-L1 expression (at least 50% of 
tumor cells), showing median progression-free survival (PFS) of 10.3 months (95% CI 6.7-not reached) 
versus 6.0 months (95% CI 4.2-6.2) (HR 0.50; 95% CI 0.37-0.68; P<0.001) for the Pembrolizumab and 
chemotherapy groups respectively11 . 
 
Currently there is a clinical trial (NCT02409342, IMpower110) of Atezolizumab as first line 
monotherapy in PD-L1 selected NSCLC patients that is expected to add the first line approval to 
Roche´s portfolio. Thus, all the above data support the rational of cancer immunotherapy in first line 
PD-L1 positive NSCLC12. In addition, there is a growing body of evidence that suggests that pro-
angiogenic factors can modulate the immune response and may serve as mechanisms of scape. 
Therefore, the combination of cancer immunotherapy with antiangiogenic agents makes sense. 
 
The vascular endothelial growth factor (VEGF) is the most important pro-angiogenic protein and a 
key regulator of physiological angiogenesis. It is also implicated in pathological angiogenesis 
associated with tumor growth. Indeed, increased levels of VEGF have been found in lung cancer; 
moreover, the overexpression of VEGF is associated with a poor prognosis13,14. Actually, VEGF plays 
a role in cancer immune evasion through modification of the endothelial cells in the tumor 
microenvironment, where VEGF may reduce lymphocyte adhesion and migration from vessels to the 
tumor site contributing to decreased immune cell recruitment15.  Given the immunosuppressive role 
of VEGF and angiogenesis within tumors, it is not surprising that there is evidence supporting how 
antiangiogenic agents stimulate the immune response and enhance the efficacy of 
immunotherapies16. 
 
Recent findings indicating an intertwined regulation of VEGF signalling and immunosuppression in 
the tumor microenvironment suggest that the combination of anti-VEGF agents and immune 
checkpoint blockade could have synergistic antitumor activity, along with favourable tolerability16. 
 
Bevacizumab is a recombinant, humanized therapeutic anti-VEGF antibody that inhibits tumor 
angiogenesis which may correct the immunosuppressive function exerted by VEGF, increasing the 
infiltration of T effector cells in cancer17. 
 
So far, the more advanced studies to address the combination of cancer immunotherapy (CIT)-
antiangiogenic agents such as Bevacizumab, there is a phase 3 study of Paclitaxel, Carboplatin, 
Bevacizumab and Atezolizumab (NCT02366143, IMpower150). IMpower150 is the first phase III 
immunotherapy-based combination study to demonstrate a statistically significant and clinically 
meaningful improvement in PFS in all-comer 1L NSQ mNSCLC, providing a potential new standard of 
care for patients, showing a median PFS of 8.3 moths vs 6.8 moths (HR 0.62; 95% CI: 0.52, 0.74; P < 
0.0001) for the Atezolizumab, chemotherapy and Bevacizumab arm (ABCP) and Carboplatin, 
Paclitaxel and Bevacizumab arm (BCP) respectively. In terms of PFS 12 months the results were 37% 
in the Atezolizumab arm vs 18% un the CT + Bevacizumab arm. Median overall survival among the 
patients was longer in the ABCP group than in the BCP group (19.2 months vs. 14.7 months; hazard 
ratio for death, 0.78; 95% CI, 0.64 to 0.96; P = 0.02)18. 
 

 
 
 
 
 
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The phase 3 study of Atezolizumab in combination with Bevacizumab compared to Sunitinib single 
agent (IMmotion151), as first-line therapy in untreated metastatic Renal Cell Carcinoma (RCC) 
patients. This clinical trial showed a significant benefit of 3.5 months in the PFS favouring the CIT-
Bevacizumab combination (11.2 m vs. 7.7 m) with a tolerable safety profile in PD-L1+ patients19.  
 
These data confirm the role of Bevacizumab as an immune modulating agent that may provide a 
successful combination strategy in different tumor types. 
 
Increased mutation rate is a well-characterized feature of human cancer. Abnormal activity in several 
cellular pathways, including DNA damage repair and DNA replication, can increase the overall rate 
of somatic mutations in tumors, as can exposure to mutagens such as ultraviolet light and tobacco 
smoke20. Defects in DNA damage repair lead to the accumulation of mutations caused by replicative 
errors and environmental damage21. 
 
The core DNA mismatch repair protein complex is composed of two cooperative dimers: the PMS2 
protein dimerizes with MLH1 to form the complex MutL-alpha, which cooperates with the MSH2-
MSH6 dimer, MutS-alpha, to repair single base pair mismatches and small insertion–deletion loops22. 
PMS2 promoter mutations are present in ~10% of melanoma samples and ~8% of squamous cell 
carcinomas23. 
 
Perturbations in mismatch repair gene expression, both loss and overexpression, can be deleterious 
to genomic stability, and loss of function mutations in mismatch repair pathway genes are known to 
correlate with high Tumor Mutational Burden (TMB) in tumors, overall mutations in these genes 
accounted for less than 10% of cases with high TMB23. 
 
As such, tumors with defective DNA repair mechanisms are more likely to benefit from 
immunotherapy. DNA replication is another key pathway in which defects can lead to increased 
somatic mutation rate. 
 
Loss of function mutations in TP53 are very common in cancer and are a somatic marker of elevated 
mutation rate24. Mutations in a number of other genes have also been linked to increase TMB. KRAS-
mutant lung cancers account for approximately 25% of non-small cell lung carcinomas, thus 
representing an enormous burden of cancer worldwide. KRAS mutations are clear drivers 
of tumor growth and are characterized by a complex biology involving the interaction between 
mutant KRAS, various growth factor pathways, and tumor suppressor genes. KRAS mutations are 
classically associated with a significant smoking history25. Then, it is an emerging biomarker for 
response to immunotherapy. The CheckMate 026 trial is a randomized trial comparing the treatment 
efficacy of Nivolumab versus chemotherapy in first line therapy of advanced non-small cell lung 
cancer based on the programmed death-ligand 1 expression. However, there was no strong 
correlation between treatment response and PD-L1 expression. Therefore, researchers performed a 
sub analysis to assess if the TMB could determine Nivolumab treatment response in 312 patients 
with evaluable TMB data. The results demonstrated that patients with a high mutation burden had 
a better progression free survival (9.7 vs 5.8 months; HR, 0.62) and objective response rate (46.8% 
vs 28.3%) compared with the control arm. These findings imply that tumor mutation burden may be 
considered as a biomarker for immunotherapy26. 
 
Regarding TMB data, the CheckMate227 study is an open-label, phase 3 trial, that examined 

 
 
 
 
 
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progression-free survival with nivolumab plus ipilimumab versus chemotherapy among patients with 
stage IV or recurrent NSCLC that was not previously treated with chemotherapy with a high tumor 
mutational burden (g10 mutations per megabase). Median PFS among patients with a high tumor 
mutational burden was significantly longer with nivolumab plus ipilimumab than with chemotherapy, 
7.2 months (95% confidence interval [CI], 5.5 to 13.2) versus 5.5 months (95% CI, 4.4 to 5.8) (HR, 
0.58; 97.5% CI, 0.41 to 0.81; P<0.001)27. 
 
Unlike the majority of genetic panels used within the standard of practice in oncology, even those 
using Next Generation Sequencing (NGS), Foundation Medicine ® (FMI) is a <Comprehensive 
Genomic Profiling= test, able to detect all cancer-relevant genes with all classes of alterations across 
the entire coding region, being also a validated performance36. Moreover, is a hybridization capture-
based NGS method which, contrary to the more common Hot Spot Multi-gene panels, do not miss 
any relevant gene or genetic alteration37. Besides, FMI has two formats, both of them validated in 
top tier peer-reviewed journal: <FoundationOne ®= for solid tumors37. Finally, current service has 
been implemented for detection of Microsatellite Instability (MSI) and Tumor Mutational Burden 
(TMB). 
3.2. 
Immunotherapy 
Several studies in patients with NSCLC suggested an association of increased immune cell infiltration 
into tumors 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 NSCLC28.  
3.3. 
Background on Atezolizumab 
Atezolizumab (MPDL3280A) is a humanized immunoglobulin (Ig) G1 monoclonal antibody consisting 
of two heavy chains (448 amino acids) and two light chains (214 amino acids) and is produced in 
Chinese hamster ovary cells. Atezolizumab was engineered to eliminate Fc-effector function via a 
single amino acid substitution on position 298 of the heavy chain, which results in a non-glycosylated 
antibody that has minimal binding to Fc receptors and prevents Fc-effector function at expected 
concentrations in humans.  
Atezolizumab blocks the interaction between Programmed death-ligand 1 (PD-L1 or B7-H1) and 
Programmed death-1 (PD-1) and B7.1 (CD80), both of which are negative regulators of T-lymphocyte 
activation29. Binding of PD-L1 to its receptors suppresses T-cell migration, proliferation and secretion 
of cytotoxic mediators and restricts tumor cell killing. Blocking PD-L1 enhances anticancer immunity 
by restoring antitumor T-cell activity and T-cell priming.  
 
Clinical Pharmacokinetics and Immunogenicity 
On the basis of available preliminary PL data (0.03-20 mg/kg), atezolizumab appeared to show linear 
pharmacokinetics at doses g 1mg/kg. For the 1-mg/kg and 20-mg/kg dose groups, the mean apparent 
clearance and the mean volume of distribution under steady-state conditions had a range of 3.11 to 
4.14 mL/kg and 48.1 to 67.0 mL/kg, respectively, which is consistent with the expected profile of an 
IgG1 antibody in humans. 

 
 
 
 
 
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The development of anti-therapeutic antibodies (ATAs) has been observed in patients in all dose 
cohorts and was associated with changes in pharmacokinetics for some patients in the lower dose 
cohorts (0.3, 1, and 3 mg/kg). The development of detectable ATAs has not had a significant impact 
on pharmacokinetics for doses from 10 to 20 mg/kg. Patients dosed at the 10-, 15- and 20-mg/kg 
dose levels have maintained the expected target trough levels of drug despite detection of ATAs. To 
date, no clear relationship among ATAs detection and adverse events or infusion reactions or efficacy 
has been observed. 
 
Summary of Nonclinical Studies 
The nonclinical strategy of the atezolizumab program was to demonstrate in vitro and in vivo activity, 
to determine in vivo pharmacokinetic (PK) behaviour, to demonstrate an acceptable safety profile 
and to identify a Phase I starting dose. The safety, pharmacokinetics and toxicokinetics of 
atezolizumab were investigated in mice and cynomolgus monkeys to support intravenous (IV) 
administration and to aid in defining the appropriate starting dose in humans. The nonclinical 
pharmacokinetics and toxicokinetics observed for atezolizumab supported entry into clinical studies 
and were consistent with the anticipated pharmacologic activity of down-modulating the PD-L1/PD-
1 pathway.  
 
Summary of Clinical Studies 
Safety and efficacy data are summarized below from the following studies: 
• 
Study PCD4989g: A Phase Ia, multicentre, first-in-human, open-label, dose-escalation study 
evaluating the safety, tolerability, immunogenicity, PK, exploratory pharmacodynamics and 
preliminary evidence of biologic activity of atezolizumab administered as a single agent by 
IV infusion every 3 weeks (q3w) to patients with locally advanced or metastatic solid 
malignancies or hematologic malignancies. 
• 
Study GO28753 (POPLAR): A randomized, Phase II, open-label study assessing the clinical 
benefit of atezolizumab as a single agent versus docetaxel in PD-L1 unselected patients with 
locally advanced or metastatic NSCLC that has progressed during or following treatment with 
a platinum-containing regimen. 
• 
Study OAK: A randomized, Phase III, open-label study assessing the clinical benefit of 
atezolizumab as a single agent versus docetaxel in PD-L1 unselected patients with previously 
treated advanced NSCLC that has progressed during or following treatment with a platinum-
containing regimen. 
• 
Study GP28328:  A Phase Ib study of the safety and pharmacology of atezolizumab 
administered with bevacizumab and/or with chemotherapy in patients with advanced solid 
tumors. 
Currently atezolizumab is approved by FDA and EMA in patients with advanced NSCLC who 
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Atezolizumab Single-Agent Safety Data on Patients with Advanced NSCLC 
In the Phase I PCD4989g, in which atezolizumab was used as a single agent in patients with locally 
advanced or metastatic solid tumors or hematologic malignancies no maximum tolerated (MTD), no 
dose-limiting toxicities (DLTs) and no clear dose-related trends in the incidence of adverse events 
was determined. In this study, 520 out of 558 (93%) safety-evaluable patients experienced at least 
one adverse event, including 376 (67%) patients who experienced one treatment-related adverse 
event. Commonly reported events (g10% of all patients) included fatigue, decreased appetite, 
nausea, pyrexia, constipation and cough.  Grade 3-4 adverse events based on the National Cancer 
Institute Common Terminology Criteria for Adverse Events version 4.0 [NCI CTCAE v4.0] were 
reported in 239 (43%) patients, of which 66 (12%) were considered related. Grade 3 and 4 adverse 
events considered related by the investigator included dyspnoea, pneumonitis, increased ALT, 
increase AST, increased GGT, lymphocyte count decreased, cardiac tamponade, asthenia, 
autoimmune hepatitis, pneumonia, influenza and hypoxia. 
In the randomized Phase II POPLAR Study (GO28753), the frequency of patients who reported any 
adverse events regardless of attribution was 96% for both arms30. A higher number of Grade g 3 
adverse events were observed in the docetaxel arm (53% vs 40%), explained mainly by the difference 
in adverse events due to bone marrow suppression. This difference was more evident in Grade 3-4 
treatment-related adverse events (39% vs 11%). The most common atezolizumab Grade 3 adverse 
events were pneumonia (2%) and increased AST (2%). No atezolizumab-related Grade 4 adverse 
events were reported.  Immune-related adverse events of any grade with atezolizumab were 
increased AST (4%), increased ALT (4%), pneumonitis (3%), colitis (1%) and hepatitis (1%). Fewer 
patients discontinued treatment with atezolizumab than with docetaxel (8% vs 22% respectively). 
There were six (4%) Grade 5 adverse events in atezolizumab were cardiac failure, pneumonia, ulcer 
haemorrhage, pneumothorax, pulmonary embolism and embolism.  
 
In the randomized Phase III OAK Study, the frequency of patients who reported any adverse event 
regardless of attribution was similar in both arms: 94% in atezolizumab arm and 96% in docetaxel 
arm31. A higher number of Grade g 3 adverse events were observed in the docetaxel arm (54%) 
compared with atezolizumab arm (37%). This difference was greater in Grade 3-4 treatment-related 
adverse events (43% vs 15%). The most common atezolizumab-related adverse events were fatigue 
(14%), nausea (9%), decreased appetite (9%) and asthenia (8%). Immune-related adverse events 
reported with atezolizumab included pneumonitis (1%), hepatitis (<1%) and colitis (<1%). 
 
A pooled safety analysis conducted in 843 patients who received atezolizumab in 4 studies 
(PCD4989g [N = 76]; BIRCH [N = 520]; FIR [N = 105]; POPLAR [N = 142]) (Lukas et al. WCLC 2016). 
Twenty-seven (3%) of 843 patients had asymptomatic untreated brain metastases or stable 
previously treated brain metastases at baseline. The incidence of treatment-related neurological AEs 
was 4 (15%) in patients with baseline brain metastases, including the most common treatment-
related AE of headache in 2 (7%) and 27 (3%) patients, respectively. The most common all-cause AEs 

 
 
 
 
 
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in patients with baseline brain metastases were fatigue, nausea, and vomiting (7 [26%] each). No 
treatment discontinuations occurred due to AEs. 
 
Atezolizumab in Combination with Platinum-Based Chemotherapy Safety Data on patients with 
Advanced NSCLC 
The Study GP28328 is a Phase Ib study of atezolizumab in combination with bevacizumab or cytotoxic 
chemotherapy in patients with multiple tumor types including NSCLC, triple-negative breast cancer 
and colorectal cancer. Patients with advanced NSCLC were included in the following arms: Arm C 
(atezolizumab + carboplatin + paclitaxel), Arm E (atezolizumab + carboplatin + pemetrexed) and Arm 
E (atezolizumab + carboplatin + nab-paclitaxel). These combinations have been generally well 
tolerated and no DLTs have been reported during the dose-escalation stage in any study arm. A total 
of 141 of 144 (98%) patients reported at least one adverse event while receiving study drug. Most of 
these events were Grade 2 and 3 in severity. The five most commonly adverse events across the 
study arms (g10%) included fatigue, nausea, diarrhoea, decreased appetite and pyrexia. The adverse 
events were consistent with the known safety profile of each agent and no additive effects were 
observed when atezolizumab was administered with chemotherapy. 
 
Atezolizumab Single-Agent Efficacy Data on Patients with Advanced NSCLC 
In the Phase I PCD4989g Study, the efficacy evaluable population included 88 patients with locally 
advanced or metastatic NSCLC and represented a heavily pre-treated patient population (97% of the 
patients had received g 2 prior systemic therapies and 77% had received g 4 prior systemic 
therapies). Overall, responses were observed in 20 out of 88 (23%) patients with NSCLC and included 
responses in patients with squamous and non-squamous NSCLC (4 in 21 and 16 in 67 patients 
respectively).  
In the POPLAR Study, the primary OS analysis was conducted when 173 deaths had occurred. Most 
patients had received one prior therapy (65%), had non-squamous histology (66%) and ECOG 
performance status of 1 (68%). Atezolizumab showed significant improvement in OS compared with 
docetaxel (12.6 vs 9.7 months; HR = 0.73, 95% CI 0.53-0.99; p = 0.04). OS benefit was associated with 
tumor PD-L1 overexpression. PFS was similar among both arms (2.7 vs 3 months respectively) and 
objective responses with atezolizumab were durable, with a median duration of 14.3 months 
compared with 7.2 months for docetaxel. 
 
In the OAK Study, the primary efficacy analysis population comprised the first 850 patients. Most 
patients had received one prior therapy (75%), had non-squamous histology (74%) and ECOG 
performance status of 1 (63%). Atezolizumab showed significant improvement in OS compared with 
docetaxel (13.8 vs 9.6 months; HR = 0.73, 95% CI 0.62-0.87; p = 0.003). Based on the last data cut off 
with a minimum follow-up of 26 months, the 2-year OS rate in patients who received atezolizumab 
was 31% versus 21% in patients treated with docetaxel (Satouchi et al. WCLC 2017). Although the 
benefit in terms of OS was associated with tumor PD-L1 overexpression, patients with low or 
undetectable PD-L1 expression (IC0/TC0) also had improved OS with atezolizumab.  A post-hoc 

 
 
 
 
 
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subgroup analysis showed that patients with stable previously treated BM also had significant benefit 
in OS and PFS from atezolizumab (Gadgeel et al. WCLC 2016).  
 
Atezolizumab in Combination with Platinum-Based Chemotherapy Efficacy Data on patients with 
Advanced NSCLC 
In the Study GP28328, patients with advanced NSCLC received atezolizumab q3w in combination 
with platinum-based chemotherapy: carboplatin + paclitaxel (Arm C), carboplatin + pemetrexed (Arm 
D) and carboplatin + nab-paclitaxel (Arm E).  All patients had histologically or cytologically 
documented Stage IIIB or IV or recurrent NSCLC and had not received prior chemotherapy for 
advanced disease. The median age was 65 years and 79% had non-squamous histology. In the first 
data cut off (February 10th 2015), 41 patients were evaluable for efficacy and the ORR in all three 
arms was 63%. In the last update of the study, 76 patients were evaluable for efficacy and the ORR 
according to the three arms was: Arm C (n=25) 46%; Arm D (n=25) 68%; Arm E (n=26) 36% (Liu et al. 
ASCO 2017). For patients treated with carboplatin + pemetrexed (Arm D), median PFS was 8.4 
months (4.7-11) and OS rate at 12 months was 68%. 
Refer to the local prescribing information for additional details on nonclinical and clinical studies. 
Rationale for Atezolizumab dose  
The fixed dose of 1200 mg (equivalent to an average body weight-base dose of 15mg/kg) 
intravenously was selected on the basis of both nonclinical studies and available clinical data from 
Study PCD4989g. The target exposure for atezolizumab was projected on the basis of nonclinical 
tissue distribution data in tumor-bearing mice, target-receptor occupancy in the tumor, the observed 
atezolizumab interim pharmacokinetics and other factors. 
Antitumor activity has been observed across doses from 1 mg/kg to 20 mg/kg. The MTD of 
atezolizumab was not reached and DLTs have been observed at any dose in Study PCD4989g. 
Currently available PK and ATA data suggest that the 15-mg/kg atezolizumab q3w regimen (or fixed-
dose equivalent) for Phase II and Phase III studies would be sufficient to both maintain Ctrough g 6 
μg/mL and further safeguard against both interpatient variability and the potential effect of ATAs 
that may lead to subtherapeutic levels of atezolizumab relative to the 10-mg/kg atezolizumab q3w 
regimen. 
In this trial, atezolizumab will be given as an intravenous fixed dose of 1200 mg every 3 weeks (q3w) 
until unacceptable toxicity or disease progression, as assessed by the investigator. Atezolizumab 
treatment could continue beyond disease progression if the investigator deems the patient to have 
clinical benefit. 
3.4. 
Background on Bevacizumab 
 
Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that blinds to and inhibits the 
interaction of VEGF-A to its receptors (Flt-1 and KDR) on the surface of endothelial cells. The 

 
 
 
 
 
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interaction of VEGF with its receptors leads to endothelial cell proliferation and new blood vessel 
formation in in vitro models of angiogenesis. 
Neutralising the biological activity of VEGF regresses the vascularisation of tumors, normalises 
remaining tumor vasculature, and inhibits the formation of new tumor vasculature, thereby 
inhibiting tumor growth. 
Administration of Bevacizumab to xenotransplant models of colon in nude mice caused reduction of 
microvascular growth and inhibition of metastatic disease progression32,33.  
Bevacizumab is indicated for the first line treatment of unresectable, locally advanced, recurrent or 
metastatic non-squamous non-small cell lung cancer. The recommended dose of bevacizumab is 
15mg/Kg by IV infusion once every 3 weeks (21 days). 
3.5. 
Rationale for trial design 
 
Further understanding the factors associated with increased TMB is important for better 
understanding this key driver of cancer progression and for understanding the molecular 
mechanisms which lead to TMB. 
FoundationOne CDx# (F1CDx) is performed exclusively as a laboratory service using DNA extracted 
from formalin-fixed, paraffin-embedded (FFPE) tumor samples. The assay employs a single DNA 
extraction method from routine FFPE biopsy or surgical resection specimens, 50-1000 ng of which 
will undergo whole-genome shotgun library construction and hybridization-based capture of all 
coding exons from 309 cancer-related genes, one promoter region, one non-coding (ncRNA), and 
select intronic regions from 34 commonly rearranged genes, 21 of which also include the coding 
exons. In total, the assay detects alterations in a total of 324 genes. Using the Illumina® HiSeq 4000 
platform, hybrid capture–selected libraries are sequenced to high uniform depth (targeting >500X 
median coverage with >99% of exons at coverage >100X). Sequence data is then processed using a 
customized analysis pipeline designed to detect all classes of genomic alterations, including base 
substitutions, indels, copy number alterations (amplifications and homozygous gene deletions), and 
selected genomic rearrangements (e.g., gene fusions). Additionally, genomic signatures including 
microsatellite instability (MSI) and tumor mutational burden (TMB) are reported. 
FoundationOne®Liquid, its next-generation liquid biopsy test for solid tumors. Using a blood sample, 
FoundationOne Liquid analyses 70 genes known to drive cancer growth, and reports the genomic 
biomarker for microsatellite instability (MSI),1 to help inform the use of checkpoint inhibitor 
immunotherapies and multiple targeted therapies, as well as clinical trials for patients with advanced 
cancer. 
FoundationOne Liquid is a hybrid capture-based, next-generation sequencing in vitro diagnostic 
device for the detection of substitutions, insertion and deletion alterations (indels), copy number 
alterations (CNAs) and select gene rearrangements using circulating cell-free DNA (cfDNA) isolated 
from plasma derived from peripheral whole blood. The FoundationOne Liquid test expands upon the 
previous version of the Company9s liquid biopsy test, FoundationACT®, which has been analytically 
validated across the four main classes of genomic alterations. Evaluation of the platform using 

 
 
 
 
 
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multiple validation methods across a broad range of tumor types demonstrated high sensitivity2 and 
positive predictive value3, even at the low allele frequencies often observed in clinical samples 
 Based on the above synergistic effects, Atezolizumab plus Bevacizumab might provide significant 
TMB selected NSCLC patients. For this reason, the Fundación GECP finds of great interest the 
following protocol: A phase 2 study evaluating the efficacy of Atezolizumab in combination with 
Bevacizumab as first line therapy for advanced or metastatic high-intermediate TMB (TMBg10 
mutations/MB analyzed in tumor or TMBg16 analyzed in blood) non-squamous NSCLC patients. 
At the European Congress of Medical Oncology (ESMO) of this year 2020, the results of the 
WJOG @Be38 -A phase II study of Atezolizumab with Bevacizumab for Non-Squamous Non-small-cell 
lung cancer with high PD-L1 expression by Seto et al. In this study, in a population with PD-L1 positive 
of more than 50%, not TMB, but with the same treatment as the TELMA study, they found an ORR 
of 64.1% (95% CI, 47.18-78.80), with a median PFS of 15.9 months (95% CI, 5.65-15.93), being the 
PFS at one year of 54.9% (95% CI, 35.65-70.60) and an overall survival at one year of 70.6% (95% CI, 
50.5-83.4) and a median duration of response 10.4 months. 
There are few studies on this population and no others with this treatment combination. From the 
date of the design of the TELMA study, we have known data from the study of the Ipilimumab-
Nivolumab combination for patients with TMB> 10mut / megabase in which they found a PFS at one 
year of 43% compared to 13% for the control arm. 
The same study in a subsequent analysis and in that population PDL1> 50% obtained a PFS at one 
year of 41% for the combination vs 15% for the control arm with chemotherapy. 
At this point, it was considered that primary objective must be modified to 12 months PFS because 
current data on the efficacy of immunotherapy in populations with a high probability of response, 
either by identification by TMB or by PDL1 expression, inform us of a greater benefit than expected 
at the time of design. On the other hand, the selection of patients based on the latest generation 
NGS technology and the identification of concomitant mutations, makes recruitment very slow and 
difficult to achieve in adequate time. 
 
3.6. 
Rationale for additional pharmacogenomic exploratory research 
(stool and blood samples) 
 
An interesting way to assess the status of the antitumor immune response is the deep sequencing of 
the TCR and BCR locus. During T cell maturation, their TCR locus suffer somatic rearrangements 
allowing T cells to recognize different antigens including tumor antigens. Cha et al., showed on 
melanoma and prostate patients treated with ipilimumab that massive sequencing on TCR locus from 
PBMCs allow them to correlate T cell repertoire with response to immunotherapy treatment [a]. 
Later on, Akyüz et al., on another study with 18 patients treated with anti-PD1 found a clear pattern 
of diversification of T cell clones correlated with the control of the disease [b]. Recently, on 9 patients 
with NSCLC, Forde et al. have described that the number of T cells clones in tumor or in peripheral 

 
 
 
 
 
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blood increased after anti PD-1 treatment [c]. Importantly, Casarrubios et. al. have shown that the 
baseline tissue TCR repertoire evenness and top 1% clonal space are associated to pathological 
complete responses after chemo-immunotherapy (d).  
In addition to T cells, B cells play a key role in the antitumor immune response accounting for 20% of 
TILs in NSCLC and participating in both antigenic presentation and the production of specific 
antitumor antibodies (e). Recently, several authors have addressed the study of tertiary lymphoid 
structures (TLS), associating their presence with antitumor immunity and increased overall survival 
in patients with lung cancer and melanoma (f. Although detailed study is needed to elucidate their 
role in this context, it has been suggested that B cells present in tertiary structures of solid tumors 
suffer somatic hypermutation and proliferation in germinal centers acting as antigen presenting cells 
that favor the expansion of memory T cells, contributing positively to the antitumor response (g. 
Therefore, the massive sequencing of the TCR and BCR locus is positioned as an interesting technique 
for the evaluation of the antitumor immune response. 
Besides the characterization of TCR and BCR repertoires, it is interesting to immunophenotype and 
study the peripheral blood mononuclear cells to determine the levels and activation of distinct 
regulatory, memory, cytotoxic and helper subpopulations. The impact of the anti-PD-L1 + anti-VEGF 
combination on PBMCs immunophenotype and its capacity as a source of predictive biomarkers is 
currently unknown. However, different groups have demonstrated the value of lymphocyte 
populations in the treatment with immunotherapy in advanced stages (h). 
Human gut microbes outnumber host eukariotic cells by 10-fold. These a priori commensal cells 
modify human health through several mechanisms, being the alteration of systemic immune 
responses one of the most relevant. Recently, some studies have shown that gut microbiota could 
mediate diverse responses to immunotherapy and might serve as a potential predictive biomarker. 
In patients with melanoma receiving anti–PD-1 therapy, significant difference in the diversity and 
composition of gut microbiome was observed between the responders and nonresponders to the 
therapy [i]. The relationship between fecal microbiome and response to ICI therapy has been 
observed also for NSCLC in different cohorts [j] [k]. 
4. 
Objectives and endpoints 
4.1. 
Primary objective and endpoint 
 
• 
To evaluate the efficacy of Atezolizumab in combination with Bevacizumab as measured by 
Progression Free Survival (PFS) at 12 months according to Response Evaluation Criteria in 
Solid Tumors (RECIST) Version 1.1. 
PFS after enrollment is defined as the time from enrollment to the first occurrence of disease 
progression or death from any cause, whichever occurs first.  

 
 
 
 
 
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4.2. 
Secondary objectives and endpoint 
 
• 
To evaluate the Overall response rate (ORR) of Atezolizumab in combination with 
Bevacizumab as measured by investigator-assessed overall response rate (ORR) according to 
RECIST v1.1. 
ORR defined as percentage of patients reaching complete or partial response. 
• 
To evaluate the efficacy of Atezolizumab in combination with Bevacizumab as measured by 
investigator-assessed duration of response (DOR) according to RECIST v1.1. 
DOR defined as the time from the first occurrence of a documented objective response to 
disease progression or death from any cause, whichever occurs first. 
• 
To evaluate the efficacy of Atezolizumab in combination with Bevacizumab as measured by 
investigator-assessed time to response (TTR) according to RECIST v1.1. 
TTR defined as the time from the start of the treatment to the first objective tumor response 
observed for patients who achieved CR or PR. 
• 
To evaluate the efficacy of Atezolizumab in combination with Bevacizumab as measured by 
investigator-assessed ORR, PFS and DOR according to immune-related response criteria; 
irRC. 
• 
To evaluate the efficacy of Atezolizumab in combination with Bevacizumab as measured by 
investigator ORR, PFS and DOR according to immune-related response criteria (irRC) in 
patients with TMB g16. 
• 
To evaluate the PFS rate at 1 and 2 years of Atezolizumab in combination with Bevacizumab. 
• 
To evaluate the Overall Survival (OS) rate at 1 and 2 years of Atezolizumab in combination 
with Bevacizumab. 
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. 
• 
To evaluate ORR and PFS according PD-L1 expression of Atezolizumab in combination with 
Bevacizumab. 
• 
To evaluate the safety and tolerability of Atezolizumab in combination with Bevacizumab. 
Occurrence and severity of adverse events, with severity determined by NCI CTCAE v5.0 
criteria. 
• 
To evaluate patient-reported outcomes (PROs) of lung cancer symptoms, patient 
functioning, and health-related quality of life (HRQoL) as measured by the European 
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Core 30 (QLQ C30) and its Lung Cancer Module (QLQ LC13) of Atezolizumab in combination 
with Bevacizumab. 
Change from baseline in quality of life, as assessed through use of the EORTC C30 and LC13 
at baseline, at cycle 3, every 3 cycles until progression and at progression. 
4.3. 
Exploratory objectives  
Foundation one: 
• 
To determine the tumor mutational burden (TMB) and determine its association with all 4 
types of genomic alteration (Indels, mutation, CNV, rearrangement) in 324 tumor related 
genes, MSI and determine by FoundationOne CDx# (F1CDx), and other biomarkers such 
as tumor PD-L1 expression. 
• 
To investigate genomics alteration change measure in blood after progression measured 
with FoundationOne®Liquid, in respect with genomics alteration measure by FoundationOne 
CDx# (F1CDx) in tissue including genomics signatures (MSI and TMB) at progression. 
• 
To evaluate the clinical utility of the TMB results/reports in patients with TMB<10, 
mutations/MB describing druggable alterations or driver mutation that influence treatment 
selection. 
• 
To evaluate overall survival (OS) and ORR of atezolizumab in combination with bevacizumab 
based on the TMB analysis in blood and in tumor) 
Additional pharmacogenomic exploratory analysis: 
• 
To evaluate the basal peripheral blood TCR and BCR repertoire and their changes during 
treatment, as well as, their correlation with clinical variables associated with treatment 
efficacy (ORR, PFS, OS, DOR).   
• 
To study the levels of peripheral blood immune cells and soluble factors from plasma 
samples considering their changes during treatment, as well as, their correlation with clinical 
variables associated with treatment efficacy (ORR, PFS, OS, DOR).   
• 
To determine the pre-treatment fecal microbiome of all patients included in the study and 
its predictive value in terms of ORR, PFS, OS and DOR. 
5. 
Trial design, duration and termination  
 
This is an open-label, non-randomized, phase II, multi-centre clinical trial. Chemotherapy-naïve 
patients high-intermediate TMB (TMBg10 mutations/MB analyzed in tumor or TMBg16 
mutations/MB analyzed in blood) and with locally advanced or metastatic non-squamous non-small 
cell lung cancer patients will be selected. 

 
 
 
 
 
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Patients enrolled in the study will receive Atezolizumab 1200mg + Bevacizumab 15mg/Kg every 21 
days (3 weeks ±3days). 
Atezolizumab may continue beyond disease progression per RECIST v1.1 until loss of clinical benefit, 
unacceptable toxicity, patient or physician decision to discontinue, or death. If the principal 
investigator would like to continue beyond progression a permission from the trial chair/sponsor 
have to be granted. For all patients, tumor response data collection will continue until disease 
progression, even if the patient stops study treatment prior to disease progression.  
 
Bevacizumab will be administered until progression disease, unacceptable toxicity, patient or 
physician decision to discontinue or death. 
 
Patient accrual is expected to be completed within 1.5 years excluding a run-in-period of 4-6 months. 
Treatment and follow-up are expected to extend the study duration to a total of 4.5 years. Patients 
will be followed 1.5 years after the end of treatment independently of the cause of end of treatment. 
The study will end once survival follow-up has concluded. 
The trial will end with the preparation of the final report, scheduled for 5.5 years after the inclusion 
of the first patient approximately. 
Rationale for Atezolizumab treatment Beyond progression (TBP) 
Cancer immunotherapy in second- or third-line setting of treatment can have a positive impact on 
OS that exceeds response rate or PFS effects, termed post progression prolongation of survival 
(PPPS). This effect can also result from unconventional response due to tumor immune infiltration 
or delayed response, reducing reliability of RECIST v1.1 (RECIST) progression as an indicator of 
treatment failure. A posthoc analysis evaluated clinical benefit from TBP, defined by post PD tumor 
regression, OS and safety (Gandara et al. ASCO 2017). Among 332 patients who received 
atezolizumab and experienced progression, 51% (n = 168) continued atezolizumab TBP; 7% (12/168) 
achieved subsequent response in target lesions and 49% (83/168) had stable target. Median OS was 
12.7 months (95% CI 9.3 - 14.9) post PD for pts on atezolizumab TBP. TBP with atezolizumab was not 
associated with increased safety risk. 
In this clinical trial, patients will be fully informed of the risk of continuing study treatment in spite 
of apparent radiographic progression when they maintain clinical benefit, and investigators should 
make a careful assessment of the potential benefit of doing so, considering radiographic data, biopsy 
results and the clinical status of the patient. 
 
  

 
 
 
 
 
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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 enrollment if they fulfil the following criteria: 
6.1. 
Inclusion criteria   
 
1. Male or female, aged g 18 years old. 
2. ECOG performance status of 0 or 1. 
3. Histologically or cytologically confirmed, Stage IIIB - IV non-squamous NSCLC according to 8th 
version of the International Association for the Study of Lung Cancer Staging Manual in 
Thoracic Oncology. 
4. No prior treatment for Stage IIIB - IV non-squamous NSCLC. 
5. Patients who have received prior neo-adjuvant, adjuvant chemotherapy, radiotherapy, or 
chemo-radiotherapy with curative intent for non-metastatic disease must have experienced 
a treatment-free interval of at least 6 months from enrollment since the last chemotherapy, 
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6. Patients with a treated asymptomatic CNS metastasis are eligible, provided they meet all of 
the following criteria: 
a. Only supratentorial and cerebellar metastases allowed (i.e. no metastases to 
midbrain, pons, medulla or spinal cord). 
b. No ongoing requirement for corticosteroids as therapy for CNS disease. 
c. No stereotactic radiation within 7 days or whole-brain radiation within 14 days prior 
to enrollment. 
d. No evidence of interim progression between the completion of CNS-directed 
therapy and the screening radiographic study. 
Patients with new asymptomatic CNS metastases detected at the screening scan must 
receive radiation therapy and/or surgery for CNS metastases. Following treatment, these 
patients may then be eligible without the need for an additional brain scan prior to inclusion, 
if all other criteria are met. 
7. Patients with high-intermediate Tumor Mutational Burden analyzed by Foundation Medicine 
(g10 mutations/ MB) performed by a Foundation Medicine laboratory on previously 
obtained archival tumor tissue or tissue obtained from a biopsy at pre-screening (sample 
must fulfil minimal sample requirements of 20% tumor cellularity and a minimum surface of 
25mm2). TMBg16 mutations/ MB is required if the analysis is performed in blood sample. 
8. Measurable disease, as defined by RECIST v1.1. 
Previously irradiated lesions can only be considered as measurable disease if disease 
progression has been unequivocally documented at that site since radiation and the 
previously irradiated lesion is not the only site of disease. 
9. Adequate hematologic and organ function defined by the following laboratory. results 
obtained within 14 days prior to enrollment: 
• 
Neutrophils g 1500 cells/μL without granulocyte colony-stimulating factor support. 
• 
Lymphocyte count g 500/μL. 
• 
Platelet count g 100,000/μL without transfusion. 
• 
Haemoglobin g 9.0 g/dL. Patients may be transfused to meet this criterion. 
• 
INR or aPTT f 1.5 × upper limit of normal (ULN). This applies only to patients who are 
not receiving therapeutic anticoagulation; patients receiving therapeutic 
anticoagulation should be on a stable dose. 
• 
AST, ALT, and alkaline phosphatase f 2.5 × ULN, with the following exceptions: 
Patients with documented liver metastases: AST and/or ALT f 5 × ULN. 
Patients with documented liver or bone metastases: alkaline phosphatase f 
5 × ULN. 
• 
Serum bilirubin f 1.25 × ULN. Patients with known Gilbert disease who have serum 
bilirubin level f 3 × ULN may be enrolled. 
• 
Serum creatinine f 1.5 × ULN or creatinine clearance of g45ml/min (based on the 
Cockcroft Gault formula). 
 
10. All patients are notified of the investigational nature of this study and signed a written 

 
 
 
 
 
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informed consent in accordance with institutional and national guidelines, including the 
Declaration of Helsinki prior to any trial-related intervention. 
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 (oestrogen 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 (g 12 months of non2therapy-induced amenorrhea) 
or surgically sterile must have a negative serum pregnancy test result within 8 days prior to 
initiation of study drug. 
 
6.2. 
Exclusion criteria  
 
Cancer-Specific Exclusions: 
 
1. Patients with a sensitizing mutation or an amplification in the epidermal growth factor 
receptor (EGFR) gene. 
2. Patients with an anaplastic lymphoma kinase (ALK) fusion oncogene. 
3. Patients with an STK-11 Ligand alteration. 
4. Patients with MDM2 amplification. 
5. Patients with ROS1 translocations. 
6. Active or untreated CNS metastases as determined by CT or magnetic resonance imaging 
(MRI) evaluation during screening and prior radiographic assessments. 
7. Spinal cord compression not definitively treated with surgery and/or radiation or previously 
diagnosed and treated spinal cord compression without evidence that disease has been 
clinically stable for > 2 weeks prior to enrollment. 

 
 
 
 
 
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8. Leptomeningeal disease. 
9. Uncontrolled tumor-related pain. 
Patients requiring pain medication must be on a stable regimen at study entry. 
Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or 
metastases causing nerve impingement) should be treated prior to initiation of study 
drug. 
Patients should be recovered from the effects of radiation. There is no required 
minimum recovery period. 
Asymptomatic metastatic lesions whose further growth would likely cause 
functional deficits or intractable pain (e.g., epidural metastasis that is not currently 
associated with spinal cord compression) should be considered for locoregional 
therapy, if appropriate, prior to initiation of study drug. 
10. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once monthly or more frequently). 
Patients with indwelling catheters (e.g., PleurX®) are allowed. 
11. Uncontrolled or symptomatic hypercalcemia (> 1.5 mmol/L ionized calcium or Ca > 12 mg/dL 
or corrected serum calcium > ULN). 
12. Malignancies other than NSCLC within 5 years prior to enrollment, with the exception of 
those with a negligible risk of metastasis or death (e.g., expected 5-year OS > 90%) treated 
with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, 
basal or squamous-cell skin cancer, localized prostate cancer treated with radiotherapy or 
surgically with curative intent, ductal carcinoma in situ treated surgically with curative 
intent). 
 
 
General Medical Exclusions: 
 
13. Women who are pregnant, lactating, or intending to become pregnant during the study. 
14. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins. 
15. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary 
cells or any component of the Atezolizumab formulation. 
16. History of autoimmune disease, including but not limited to myasthenia gravis, myositis, 
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory 
bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener9s 
granulomatosis, Sjögren9s 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 
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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). 
17. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest CT scan. 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
18. Positive test for HIV. All patients will be tested for HIV prior to inclusion into the study; 
patients who test positive for HIV will be excluded from the clinical study. 
19. Patients with active hepatitis B (chronic or acute; defined as having a positive hepatitis B 
surface antigen [HBsAg] test at screening) or hepatitis C. 
Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined 
as the presence of hepatitis B core antibody [HBcAb] and absence of HBsAg) are 
eligible only if they are negative for HBV DNA (vaccinated patients are excluded). 
Patients positive for hepatitis C virus (HCV) antibody are eligible only if PCR is 
negative for HCV RNA. 
20. Active tuberculosis. 
21. Severe infections within 4 weeks prior to be included in the study, including but not limited 
to hospitalization for complications of infection, bacteraemia, or severe pneumonia. 
22. Received therapeutic oral or IV antibiotics within 2 weeks prior to be included in the study. 
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract 
infection or to prevent chronic obstructive pulmonary disease exacerbation) are 
eligible. 
23. Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class 
II or greater), myocardial infarction, or cerebrovascular accident within 3 months prior to 
inclusion, unstable arrhythmias, or unstable angina. 
Patients with known coronary artery disease, congestive heart failure not meeting 
the above criteria, or left ventricular ejection fraction < 50% must be on a stable 
medical regimen that is optimized in the opinion of the treating physician, in 
consultation with a cardiologist if appropriate. 
24. Major surgical procedure other than for diagnosis within 28 days prior to inclusion or 
anticipation of need for a major surgical procedure during the course of the study. 
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26. Administration of a live, attenuated vaccine within 4 weeks before inclusion or anticipation 
that such a live attenuated vaccine will be required during the study. 
27. Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that contraindicates 
the use of an investigational drug or that may affect the interpretation of the results or 
renders the patient at high risk from treatment complications. 
28. Patients with illnesses or conditions that interfere with their capacity to understand follow 
and/or comply with study procedures. 
 
Exclusion Criteria Related to Medications: 
 
29. Any approved anti-cancer therapy, including hormonal therapy, within 3 weeks prior to 
initiation of study treatment. 
30. Treatment with any other investigational agent with therapeutic intent within 28 days prior 
to initiation of study treatment. 
31. Treatment with systemic immunosuppressive medications (including but not limited to 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
anti2tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to inclusion. 
Patients who have received acute, low-dose (f 10 mg oral prednisone or equivalent), 
systemic immunosuppressant medications may be enrolled in the study. 
The use of corticosteroids (f 10 mg oral prednisone or equivalent) for chronic 
obstructive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for 
patients with orthostatic hypotension, and low-dose supplemental corticosteroids 
for adrenocortical insufficiency is allowed. 
 
Exclusions Related to Bevacizumab: 
 
32. 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. 
33. Prior history of hypertensive crisis or hypertensive encephalopathy. 
34. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent 
peripheral arterial thrombosis) within 6 months prior to inclusion. 
35. History of haemoptysis (g one-half teaspoon of bright red blood per episode) within 1 month 
prior to inclusion. 
36. Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic 
anticoagulation). 
37. Current or recent (within 10 days of inclusion) use of aspirin (> 325 mg/day) or treatment 
with dipyramidole, ticlopidine, clopidogrel, and cilostazol. 
38. Current use of full-dose oral or parenteral anticoagulants or thrombolytic agents for 
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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. 
39. Core biopsy or other minor surgical procedure, excluding placement of a vascular access 
device, within 7 days prior to the first dose of Bevacizumab. 
40. History of abdominal or tracheoesophageal fistula or gastrointestinal perforation within 6 
months prior to inclusion. 
41. Clinical signs of gastrointestinal obstruction or requirement for routine parenteral hydration, 
parenteral nutrition, or tube feeding. 
42. Evidence of abdominal free air not explained by paracentesis or recent surgical procedure. 
43. Serious, non-healing wound, active ulcer, or untreated bone fracture. 
44. Proteinuria, as demonstrated by urine dipstick or > 1.0 g of protein in a 24-hour urine 
collection. 
All patients with g 2+ protein on dipstick urinalysis at baseline must undergo a 24-
hour urine collection and must demonstrate f 1 g of protein in 24 hours. 
45. Known sensitivity to any component of Bevacizumab. 
46. Clear tumor infiltration into the thoracic great vessels is seen on imaging. 
47. Clear cavitation of pulmonary lesions is seen on imaging. 
7. 
Patient pre-screening and enrollment  
The patients will be eligible for the study after the tumor mutation burden (TMB) determination. This 
analysis will be done at the pre-screening phase of the study. The patient pre-screening form 
(appendix 8) has to be sent to the Fundación GECP headquarters scanned by email to the clinical 
monitor or by fax (+34 93 419 17 68). A pre-screening number will be assigned and returned to the 
participating hospital by fax or email. After the TMB determination if the patient has a TMBg10 
mut/MB analyzed in tumor or TMBg16 analyzed in blood and fulfil all the eligibility criteria, the 
patient will be enrolled in the study. 
Note that written informed consent has to be obtained from the patient prior to any trial-specific 
intervention. The patient has to sign a specific pre-screening informed consent to send the tumor 
block for pre-screening (TMB analysis). If the submitted tumor sample is insufficient or not valid and 
a biopsy is not feasible to be performed to evaluate the TMB, a blood sample can be sent instead.  
A permission from the trial chair/sponsor must be requested in case no tumor sample is available for 
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If the patient has a TMB g10 analyzed in tumor TMBg16 analyzed in blood then the patient will sign 
the Informed consent of the study. 
This trial will use a web-based enrollment system (eCRF-Electronic Case Report Form). Each 
participating centre will access the system directly to enrol the patients.  
Patient eligibility needs to be checked before enrollment of the patient in the Fundación GECP web-
based system (eCRF). The dates of the patient signature of the Informed Consent of the study and 
the specific informed consent to pathology material submission for pre-screening are required to be 
filled in the eligibility checklist of the eCRF. 
The treatment has to start preferably the date of enrollment or within 1-5 days from the date of 
enrollment. 
8. 
Trial procedures 
8.1. 
Overview of treatment sequence 
8.1.1. 
Pre-screening phase 
 
During pre-screening phase, the following procedures must be done: 
 
1. Sign the specific pre-screening informed consent. 
 
2. Sent patient pre-screening form to Fundación GECP to obtain pre-screening 
number for the patient. 
 
3. Foundation one: the tumor sample must be shipped to central laboratory. Sample 
must fulfil minimal sample requirements of 20% tumor cellularity and a minimum 
surface of 25mm2. 
 
4. If the submitted tumor sample is insufficient or not valid and a biopsy is not 
feasible to be performed to evaluate the TMB, a blood sample can be sent instead. 
A permission from the trial chair/sponsor must be requested in case no tumor 
sample is available for a possible patient and blood sample want to be sent to analyze 
the TMB. 
 
Once the central lab has the TMB analysis results, the Fundación GECP staff will send back 
the patient pre-screening form with the outcome for the enrollment. 
8.1.2. 
Screening/Baseline visit:  
 

 
 
 
 
 
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Once a patient pre-screening form is received with a positive enrollment outcome (TMB g10 mut/MB 
analyzed in tumor or TMBg16 analyzed in blood), the patient must sign the informed consent of the 
study, the eligibility criteria must be reviewed, and the following procedures must be performed 28 
days before enrollment: 
1. Demographic data including age and gender and medical relevant history, 
including comorbidities and allergies, surgeries, cancer history (including prior 
cancer therapies and procedures), reproductive status and smoking history.  
2.  Complete physical examination including: Height, weight, ECOG, Temperature 
and blood pressure.  
3. Laboratory testing must be performed within 14 days before the enrollment and 
includes: 
• 
Hematology and coagulation: WBC count, neutrophils, 
haemoglobin, platelet count, PT, INR and APTT. 
• 
Biochemistry: Ca, Mg, Na, K, Glucose, ALT, AST, LDH, total 
bilirubin, alkaline phosphatase, creatinine and clearance of 
creatinine calculated by Cockcroft-Gault formula, total protein, 
albumin, amylase, lipase. 
• 
Thyroid function: thyroid-stimulating hormone (TSH). Total or 
free T3 and total or free T4 must be analyzed if TSH result is out 
of ULN or LLN. 
• 
HIV / Hepatitis B/C test: The following local laboratory 
assessments should be done within 28 days prior to first dose: 
Hepatitis B and C testing (HBV sAg, HBV Ab and HCV Ab) and HIV 
test. In patients with positive hepatitis B/C results, HBV DNA/HCV 
RNA must be performed (Hepatitis B vaccinated patients are 
excluded). 
• 
Pregnancy Tests: A serum or urine pregnancy testing is required 
within 3 days prior to study enrollment. 
• 
Urine test: A urine testing (dipstick is allowed) is required for 
proteinuria within 3 days prior to study enrollment. 
4. Electrocardiograms: A 12-lead ECG is required at screening and as clinically 
indicated. ECGs should be obtained on the same machine whenever possible. 
Lead placement should be as consistent as possible. ECG recordings should be 
performed after the patient has been resting in a supine position for at least 10 
minutes. For safety monitoring purposes, the investigator must review, sign, and 
date all ECG tracings. Paper copies of ECG tracings will be kept as part of the 
patient's permanent study file at the site. Any morphologic waveform changes or 
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5. Baseline symptoms within the sign of study9s Informed Consent will be recorded. 
6. Medications (e.g. prescription drugs, over-the-counter drugs, vaccines, herbal or 
homeopathic remedies, nutritional supplements) from 7 days prior to initiation 
of study treatment (day 1 cycle 1) will be recorded. 
7. Tumor assessment must be done within 28 days before enrollment (+ 12 days): 
• 
Chest and abdomen CT SCAN with oral/IV contrast (unless contraindicated) 
to determine measurable disease according to RECIST v1.1 (at least one 
lesion outside of irradiated areas that can be measured in at least one 
dimension as g 10 mm, or g 15 mm in case of lymph nodes).  
• 
An MRI or CT brain with oral/IV contrast (unless contraindicated) must be 
done at baseline within 28 days before enrollment (+ 12 days).  
• 
A full-body PET-TAC, pelvis or the neck CT scan and bone scans should be 
performed if clinically indicated.  
8. Patient Reported Outcomes (PRO): QLQ30-LC13 (see appendix 5).  
9. Pharmacogenomic exploratory analysis: blood samples will be drawn before day 
1 of cycle 1 treatment 
10. Stool sample will be collected 
8.1.3. 
Bevacizumab and Atezolizumab cycles 
 
Day 1 of cycle 1 treatment will start within 1-5 days from enrollment. Cycles will be administered 
every 3 weeks (±3 days) until progression or other reason to discontinue. If a patient must stop one 
of the two drugs due to toxicity it is allowed to continue treatment with the other drug as long as 
patient does not present progression disease. If progression disease is shown is only permitted 
continue treatment beyond progression with atezolizumab. 
 
On Day 1 of each cycle, all eligible patients will receive drug infusions in the following order:  
 
1. Atezolizumab: 1200mg, IV infusion 
2. Bevacizumab: 15 mg/kg, IV infusion 
 
Patients should receive treatments according to the local standard of care and manufacturer9s 
instruction. A suggested infusion times for treatment administration:  
 
Atezolizumab 
Bevacizumab 
Infusion rate 
Over 60 (±15) min 
(for the first 
Over 90 (±15) min (for 
the first infusion); 

 
 
 
 
 
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infusion); 
30 (± 10) min for 
subsequent 
infusions if tolerated 
shortening to 
60 (± 10) then 
30 (± 10) min for 
subsequent infusions if 
tolerated 
 
The following procedures must be performed on day 1 of each cycle (±3 days): 
 
1. Physical examination, including: weight, ECOG, Temperature and blood 
pressure.  
2. Blood pressure must be taken always before the drug administration. Blood 
pressure should be routinely measured before every infusion after a resting 
period of 10 min. If baseline record is performed more than 3 days before first 
study dose, they must be repeated on day 1 cycle 1. 
3. Laboratory testing prior to each dose administration within 3 days prior to day 1 
administration of each cycle. If baseline testing is performed more than 3 days 
before first study dose, they must be repeated on day 1 cycle 1: 
• 
Hematology and coagulation: WBC count, neutrophils, 
haemoglobin, platelet count, PT, INR and APTT. 
• 
Biochemistry: Ca, Mg, Na, K, Glucose, ALT, AST, LDH, total 
bilirubin, alkaline phosphatase, creatinine and clearance of 
creatinine calculated by Cockcroft-Gault formula, total protein, 
albumin, amylase, lipase. 
• 
Thyroid function: thyroid-stimulating hormone (TSH). Total or 
free T3 and total or free T4 must be analyzed if TSH result is out 
of ULN or LLN. It is required at cycle 2 and then every 2 cycles 
(more frequently if clinical indicated). 
• 
Pregnancy Tests: A serum or urine pregnancy testing is required 
at cycle 2 and then every 2 cycles (more frequently if required by 
local standard). 
• 
Urine test: A urine testing (dipstick is allowed) is required for 
proteinuria. 
4. Adverse events: Changes from baseline symptoms (new or worsened clinically 
significant ones) should be recorded as adverse events on the Adverse Event 
form of the eCRF. For laboratory parameters, only grade 2 events will be 
reported as an AE. All the other events not related to laboratory values will be 
reported from grade 1. 

 
 
 
 
 
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5. Concomitant medications: Changes from baseline should be recorded on the 
eCRF. 
6. Tumor assessment will be done every 12 weeks (± 7 days) from cycle 1 day 1. CT 
SCAN must be performed until progression disease or until last dose of 
Atezolizumab in case of continuing beyond progression. The CT SCAN schedule 
will be maintained even if a delay in administration occurs. 
• 
Chest and abdomen CT SCAN with oral/IV contrast (unless contraindicated) 
to determine measurable disease according to RECIST v1.1 (at least one 
lesion outside of irradiated areas that can be measured in at least one 
dimension as g 10 mm, or g 15 mm in case of lymph nodes).  
• 
A full-body PET-TAC, pelvis or the neck CT scan, MRI or CT brain and bone 
scans should be performed if clinically indicated.  
7. PRO (QLQ30-LC13) must be performed always before dose administration, 
starting on day 1 of cycle 3 and then every 3 cycles. In the event of a delay in 
administration, the PROs schedule will be also delayed to be performed on day 
1 of the specified cycles. 
8. Pharmacogenomic exploratory analysis: blood samples will be drawn at: 
• 
First CT-scan evaluation (cycle 5 if there is no delay in treatment 
administration) 
• 
Second CT-scan evaluation (cycle 9 if there is no delay in treatment 
administration) 
• 
Fourth CT-scan evaluation (cycle 17 if there is no delay in treatment 
administration) 
• 
Sixth CT-scan evaluation (cycle 25 if there is no delay in treatment 
administration) 
• 
Progression disease, if it occurs during the bevacizumab + atezolizumab 
treatment  
8.1.4. 
 Atezolizumab cycles (beyond progression):  
Atezolizumab may continue beyond disease progression per RECIST v1.1 until loss of clinical benefit, 
unacceptable toxicity, patient or physician decision to discontinue, or death. If the principal 
investigator would like to continue beyond progression a permission from the trial chair/sponsor 
have to be granted. 
Cycles will be administered every 3 weeks (±3 days). Patient will receive:  
   
Atezolizumab: 1200mg, IV infusion 

 
 
 
 
 
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The following procedures must be performed on day 1 of each cycle (±3 days): 
1. Physical examination, including: weight, ECOG, Temperature and blood 
pressure (always before the drug administration).  
2. Laboratory testing prior to each dose administration within 72 hours prior to 
day 1 administration of each cycle: 
 
• 
Hematology and coagulation: WBC count, neutrophils, 
hemoglobin, platelet count, PT, INR and APTT. 
• 
Biochemistry: Ca, Mg, Na, K, Glucose, ALT, AST, LDH, total 
bilirubin, alkaline phosphatase, creatinine and clearance of 
creatinine calculated by Cockcroft-Gault formula, total protein, 
albumin, amylase, lipase. 
• 
Thyroid function: thyroid-stimulating hormone (TSH). Total or 
free T3 and total or free T4 must be analyzed if TSH result is out 
of ULN or LLN. It is required at cycle 2 and then every 2 cycles 
(more frequently if clinical indicated). 
• 
Pregnancy Tests: A serum or urine pregnancy testing is required 
at cycle 2 and then every 2 cycles (more frequently if required 
by local standard). 
3. Adverse events: Changes from baseline symptoms (new or worsened clinically 
significant ones) should be recorded as adverse events on the Adverse Event 
form of the eCRF. For laboratory parameters, only grade 2 events will be reported 
as an AE. All the other events not related to laboratory values will be reported 
from grade 1. 
4. Concomitant medications: Changes from baseline should be recorded on the 
eCRF. 
5. Tumor assessment will be done every 12 weeks (± 7 days) from cycle 1 day 1. The 
CT SCAN schedule will be maintained even if a delay in administration occurs: 
a. Chest and abdomen CT SCAN with oral/IV contrast (unless contraindicated) 
to determine measurable disease according to RECIST v1.1 (at least one 
lesion outside of irradiated areas that can be measured in at least one 
dimension as g 10 mm, or g 15 mm in case of lymph nodes).  
b. A full-body PET-TAC, pelvis or the neck CT scan, MRI or CT brain and Bone 
scans should be performed if clinically indicated.  
8.1.5. 
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End of treatment is defined as the day of discontinuation of the treatment. If the reason for the end 
of treatment is progression the following procedures must be performed between the end of 
treatment and the first follow up visit: 
1. Patient Reported Outcomes (PRO): QLQ30-LC13 (see appendix 5). Even if the 
progression disease occurs within 9 weeks after of the last completed PRO, the 
progression PRO must be performed. 
2. Blood samples for translational research must be drawn and shipped to central 
lab. 
A first follow up visit must be done 30 days (±3 days) after the last dose of treatment 
(Bevacizumab+Atezolizumab or Atezolizumab beyond progression) or immediately before the 
initiation of any other anticancer therapy.  
The following procedures must be performed: 
1. Physical examination, including: weight, ECOG, Temperature and blood 
pressure.  
2. Laboratory testing: 
• 
Hematology and coagulation: WBC count, neutrophils, hemoglobin, platelet 
count, PT, INR and APTT. 
• 
Biochemistry: Ca, Mg, Na, K, Glucose, ALT, AST, LDH, total bilirubin, alkaline 
phosphatase, creatinine and clearance of creatinine calculated by Cockcroft-
Gault formula , total protein, albumin, amylase, lipase. 
• 
Thyroid function: thyroid-stimulating hormone (TSH). Total or free T3 and 
total or free T4 must be analyzed if TSH result is out of ULN or LLN.  
• 
Pregnancy Tests: A serum or urine pregnancy testing is required. 
• 
Urine test: A urine testing (dipstick is allowed) is required for proteinuria. 
3. Electrocardiograms: A 12-lead ECG is required at screening and as clinically 
indicated. ECGs should be obtained on the same machine whenever possible. 
Lead placement should be as consistent as possible. ECG recordings should be 
performed after the patient has been resting in a supine position for at least 10 
minutes. For safety monitoring purposes, the investigator must review, sign, and 
date all ECG tracings. Paper copies of ECG tracings will be kept as part of the 
patient's permanent study file at the site. Any morphologic waveform changes or 
other ECG abnormalities must be documented on the eCRF. 
4. Adverse events: Changes from baseline abnormalities (new or worsened clinically 
significant ones) should be recorded as adverse events on the Adverse Event eCRF 
until this visit. For laboratory parameters, only grade 2 events will be reported as 
an AE. All the other events not related to laboratory values will be reported from 

 
 
 
 
 
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grade 1. SAEs and AESIs must be recorded and followed from the subject written 
informed consent signature to 30 days from last dose of treatment. 
5. Concomitant medications: Changes from baseline should be recorded on the eCRF 
until this visit (30 days from last dose of treatment). 
6. Tumor assessment will be done every 12 weeks (± 7 days) from cycle 1 day 1. In 
case end of treatment reason is other than disease progression the CT SCAN schedule 
will be maintained every 12 weeks.: 
• 
Chest and abdomen CT SCAN with oral/IV contrast (unless contraindicated) 
to determine measurable disease according to RECIST v1.1 (at least one 
lesion outside of irradiated areas that can be measured in at least one 
dimension as g 10 mm, or g 15 mm in case of lymph nodes).  
• 
A full-body PET-TAC, pelvis or the neck CT scan, MRI or CT brain and Bone 
scans should be performed if clinically indicated.  
It is not mandatory to perform the tumor assessment in first follow up visit if the 
end of treatment reason is other than progression disease and a tumor 
assessment is been performed in the previous 12 weeks. 
8.1.6. 
Follow up visits 
The subsequent follow up visits can be matched at least with the CT SCAN schedule or more 
frequently as per local standard. 
The following procedures must be performed: 
1. Physical examination, including ECOG. 
2. Tumor assessment will be done every 12 weeks (± 7 days) from cycle 1 day 1 
until progression. In case end of treatment reason is other than disease 
progression the CT SCAN schedule will be maintained every 12 weeks.  
• 
Chest and abdomen CT SCAN with oral/IV contrast (unless contraindicated) 
to determine measurable disease according to RECIST v1.1 (at least one 
lesion outside of irradiated areas that can be measured in at least one 
dimension as g 10 mm, or g 15 mm in case of lymph nodes).  
• 
A full-body PET-TAC, pelvis or the neck CT scan, MRI or CT brain and Bone 
scans should be performed if clinically indicated.  
If the patient withdraws the study due to progression the subsequent follow up 
visits can be matched at least with the CT SCAN schedule planned as per local 
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3. At the moment of progression (if applicable):  
• 
Patient Reported Outcomes (PRO): QLQ30-LC13 (appendix 5). Even if the 
progression disease occurs within 9 weeks after of the last completed PRO, 
the progression PRO must be performed. 
• 
Foundation one: Blood samples for translational research must be drawn 
and shipped to the central laboratory.  
4. Pharmacogenomic exploratory analysis_ blood samples will be drawn at: 
• 
Progression disease, if it occurs during the follow up phase 
8.1.7. 
Quality of Life (QoL) 
The quality of life (QoL) of patients will be assessed using EORTC QLQ-C3034 and the lung cancer 
module (QLQ-LC13) questionnaires. The EORTC QLQ-C3034 is a self-administered cancer specific 
questionnaire with multi-dimensional scales. It consists of both multi-item scales and single item 
measures, including five functioning domains, a global quality of life domain, three symptom 
domains and six single items. For each domain or single item measure a linear transformation will be 
applied to standardize the raw score to range between 0 and 100.  
The QLQ-LC13 lung cancer module35 includes questions assessing lung cancer-associated symptoms 
(cough, hemoptysis, dyspnea, and site-specific pain), treatment-related side effects (sore mouth, 
dysphagia, peripheral neuropathy and alopecia) and pain medication. The validity and reliability have 
been studied by the EORTC Study Group on Quality of Life. The EORTC QLQ-C30 and module will be 
scored according to the EORTC QLQ-C30 Scoring Manual and analyzed accordingly. 
Changes of the quality of life scores while on treatment versus baseline will be examined using 
analysis and descriptive statistics. Specific time points will be checked to explore treatment side 
effect on patients QoL, and the longtime benefit of the study treatment.  
Please see Sections 8.1.2, 8.1.3, 8.1.4, 8.1.5 and 8.1.6 to know the QoL tests schedules. 
9. 
Investigational Medicinal Product 
Atezolizumab and Bevacizumab are the Investigational Medicinal Products (IMP) used in this trial. 
Roche will provide the IMPs 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 TELMA drug supply manual that will be provided in the 
Pharmacy site file to all the participant sites.  
Description of the Investigational Medicinal Products 
Atezolizumab (MPDL3280A) is a humanized immunoglobulin (Ig) G1 monoclonal antibody consisting 
of two heavy chains (448 amino acids) and two light chains (214 amino acids) and is produced in 

 
 
 
 
 
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Chinese hamster ovary cells. Atezolizumab was engineered to eliminate Fc-effector function via a 
single amino acid substitution on position 298 of the heavy chain, which results in a non-glycosylated 
antibody that has minimal binding to Fc receptors and prevents Fc-effector function at expected 
concentrations in humans. 
Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that blinds to and inhibits the 
interaction of VEGF-A to its receptors (Flt-1 and KDR) on the surface of endothelial cells. The 
interaction of VEGF with its receptors leads to endothelial cell proliferation and new blood vessel 
formation in in vitro models of angiogenesis. Neutralizing the biological activity of VEGF regresses 
the vascularization of tumors, normalizes remaining tumor vasculature, and inhibits the formation 
of new tumor vasculature, thereby inhibiting tumor growth. 
9.1. 
Packaging and labelling 
Roche will provide the IMP (Atezolizumab and Bevacizumab) at no cost for this study. Clinical supplies 
will be affixed with a clinical label in accordance with regulatory requirements.  
The atezolizumab (MPDL3280A) drug product is provided as a sterile liquid in 20-mL glass vials.  The 
vial is designed to deliver 20 mL (1200 mg) of atezolizumab solution but may contain more than the 
stated volume to enable delivery of the entire 20 mL volume. For further details on the formulation 
and handling of atezolizumab, see the Pharmacy Manual and Investigator9s Brochure. 
The Avastin® (bevacizumab) drug product is provided as a concentrate for solution for infusion 
(400mg/16ml) per vial. For further details on the formulation and handling of bevacizumab, see the 
summary of product characteristics (SmPC). 
9.2. 
Receipt and storage of the IMP 
Accurate records of the IMP received at, dispensed from, returned to, and disposed of by the study 
site should be recorded on the Drug Accountability Log. In the event that the IMPs are destroyed a 
certification of destruction form should be generated and retained in the Pharmacy Site File. 
The IMPs must be stored in a secure area according to local regulations. The investigator must ensure 
that the IMPs are stored refrigerated at 2-8⁰C, protected from light and freezing, see the TELMA drug 
supply manual for details. 
9.3. 
Unused trial drug supplies 
If the IMPs are to be destroyed, it is the investigator9s responsibility to ensure that arrangements 
have been made for disposal and that procedures for proper disposal have been established 
according to applicable regulations, guidelines, and institutional procedures. Appropriate records of 
the disposal must be maintained. Provide a certificate of destruction to Fundación GECP upon 
disposal. See the TELMA drug supply manual for details. 

 
 
 
 
 
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9.4. 
Treatment beyond trial closure  
The Fundación GECP, the Sponsor of the TELMA trial, will offer continued access to the two Roche 
IMPs atezolizumab and bevacizumab free of charge to eligible participants in accordance with the 
Roche Global Policy on Continued Access to Investigational Medicinal Product.  
9.4.1. 
Eligibility to receive atezolizumab and/or bevacizumab 
after study completion.  
A participant will be eligible to receive Roche IMPs atezolizumab and/or bevacizumab after 
completing the study if all of the following conditions are met:  
• 
The patient has received Roche IMPs atezolizumab and bevacizumab during 
study conduct, and  
• 
The patient is still experiencing clinical benefit from Roche IMPs atezolizumab 
and/or bevacizumab at the time of study closure, and  
• 
The patient has a life-threatening or severe medical condition and requires 
continued treatment with Roche IMPs atezolizumab and/or bevacizumab for 
their well-being, and  
• 
There are no appropriate alternative treatments available to the participant, 
and  
• 
The participant and their doctor comply with and satisfy any legal or regulatory 
requirements that apply to them.  
9.4.2. 
Safety reporting requirements beyond trial closure  
The last dose of IMP administered before study closure shall be considered the last per protocol 
treatment administration. Any adverse events related to this last IMP dose and occurring within the 
time until the first off-study IMP administration (e.g. approximately 3 weeks) should be reported as 
described in Section 13. Adverse Events and Reporting. Beyond this timeline, any adverse events 
related to the IMP more than 30 days after the last administration of on-study IMP,  should be 
reported by the treating physician to Roche and/or the appropriate body in accordance with local 
rules and regulations. 
10. 
Trial treatments description 
10.1. ATEZOLIZUMAB 
Patients will receive 1200 mg of atezolizumab administered by IV infusion every 21 days (+/- 3 days) 
in a monitored setting where there is immediate access to trained personnel and adequate 

 
 
 
 
 
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equipment/medicine to manage potentially serious reactions. Guidelines for treatment interruption 
or discontinuation and the management of specific adverse events are provided in Appendix 7.  
Atezolizumab infusions will be administered per the instructions outlined in Table 1. 
Table 1 
Administration of First and Subsequent Infusions of Atezolizumab 
First Infusion 
Subsequent Infusions 
• No premedication administered for atezolizumab 
specifically is permitted  
• Record patient9s vital signs within 60 minutes before 
starting infusion. 
• Infuse atezolizumab (1200 mg in a 250 mL 0.9% NaCl IV 
bag) over 60 ( 15) minutes. 
• If clinically indicated, record patient9s vital signs during 
the infusion at 15, 30, 45, and 60 minutes ( 5-minute 
windows are allowed for all timepoints). 
• If clinically indicated, record patient9s vital signs at 30 
( 10) minutes after the infusion. 
• Patients will be informed about the possibility of 
delayed post-infusion symptoms and instructed to 
contact their study physician if they develop such 
symptoms. 
• If patient experienced infusion-related reaction 
during any previous infusion, premedication with 
antihistamines may be administered for Cycles ó 2 at 
the discretion of the treating physician. 
• Record patient9s vital signs within 60 minutes before 
starting infusion. 
• If the patient tolerated the first infusion well without 
infusion-associated adverse events, the second 
infusion may be delivered over 30 ( 10) minutes. 
• If no reaction occurs, subsequent infusions may be 
delivered over 30 ( 10) minutes. 
Continue to record vital signs within 60 minutes 
before starting infusion.  Record vital signs during 
and after the infusion, if clinically indicated. 
• If the patient had an infusion-related reaction during 
the previous infusion, the subsequent infusion must 
be delivered over 60 ( 15) minutes. 
Record patient9s vital signs every 15 ( 5) minutes 
during the infusion if clinically indicated or patient 
experienced symptoms during the previous infusion. 
NaCl = sodium chloride; Vital signs: heart rate, respiratory rate, blood pressure, and temperature. 
 
Refer to TELMA drug supply manual for detailed instructions on drug preparation, storage, and 
administration. 
10.2. BEVACIZUMAB 
Patients will receive 15mg/Kg of Avastin® (bevacizumab) administered by IV infusion every 21 days 
in a monitored setting where there is immediate access to trained personnel and adequate 
equipment/medicine to manage potentially serious reactions (see Section 11.2). 
Refer to TELMA drug supply manual for detailed instructions on drug preparation, storage, and 
administration. 

 
 
 
 
 
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11. 
Dose modifications criteria 
Reasons for dose modifications, 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. 
 
- If, in the opinion of the investigator, a toxicity is considered to be due solely to one component of 
the study treatment (i.e., atezolizumab or bevacizumab) and the dose of that component is delayed 
or modified in accordance with the guidelines below, other components may be administered if 
there is no contraindication. 
 
- When treatment is temporarily interrupted because of toxicity caused by bevacizumab or 
atezolizumab, the treatment cycles will be restarted such that the atezolizumab and bevacizumab 
infusions remain synchronized. 
 
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. 
11.2. ATEZOLIZUMAB dose delay criteria 
There will be no dose reduction for atezolizumab in this study. Patients may temporarily suspend 
study treatment for up to 105 days beyond the last dose if they experience an adverse event that 
requires a dose to be withheld.  If atezolizumab is withheld because of adverse events for more than 
105 days beyond the last dose, then the patient will be discontinued from atezolizumab treatment 
and will be followed for safety and efficacy.  
If, in the judgment of the investigator, the patient is likely to derive clinical benefit from atezolizumab 
after a hold beyond 105 days, study drug may be restarted with the approval of trial chair/sponsor. 
If a patient must be tapered off steroids used to treat adverse events, atezolizumab may be withheld 
for additional time beyond 105 days from the last dose until steroids are discontinued or reduced to 
prednisone dose (or dose equivalent)  10 mg/day.  The acceptable length of interruption will 
depend on agreement between the investigator and the trial chair/sponsor. 
Dose interruptions for reason(s) other than adverse events, such as surgical procedures, may be 
allowed with trial chair/sponsor approval. The acceptable length of interruption will depend on 
agreement between the investigator and the trial chair/sponsor. Given the mechanism of action of 
atezolizumab, events associated with inflammation and/or immune-related adverse events (irAEs) 
have been closely monitored during the atezolizumab clinical program.  Guidelines for the 
management of patients who experience specific adverse events associated with atezolizumab (i.e., 
pulmonary, hepatic, gastrointestinal, endocrine, ocular, infusion-related [IRR], pancreatic, 

 
 
 
 
 
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dermatologic, neurologic, or autoimmune events) are provided in Section 6 (Guidance for the 
Investigator) of the Atezolizumab Investigator's Brochure. 
Systemic Immune Activation 
Systemic immune activation is a rare condition characterized by an excessive immune response.  
Given the mechanism of action of atezolizumab, systemic immune activation is considered a 
potential risk when given in combination with other immunomodulating agents.  Systemic immune 
activation should be included in the differential diagnosis for patients who, in the absence of an 
alternate etiology, develop a sepsis-like syndrome after administration of atezolizumab, and the 
initial evaluation should include the following: 
CBC with peripheral smear 
PT, PTT, fibrinogen, and D-dimer 
Ferritin 
Triglycerides 
AST, ALT, and total bilirubin 
LDH 
Complete neurologic and abdominal examination (assess for hepatosplenomegaly) 
If systemic immune activation is still suspected after the initial evaluation, contact the trial 
chair/sponsor for additional recommendations. 
11.3. BEVACIZUMAB dose delay/reduction criteria 
 
The dose of bevacizumab is calculated based on the body weight of the patient [kg]. If the 
body weight changes by 10% or more in the course of the treatment, dose adjustment is 
recommended for further infusions. If the body weight changes by less than 10%, no dose 
adjustment is needed. 
• 
 Blood pressure should be routinely measured before every infusion after a 
resting period of 10 min. 
• 
Proteinuria should be routinely measured before every infusion of bevacizumab 
using dipstick. 
• 
No routine premedication (e.g. to prevent infusion reaction) is recommended 
for bevacizumab. 
 
The initial infusion of bevacizumab should be given over 90 minutes. If the initial infusion is well 
tolerated, the second infusion can be given over 60 minutes. If the second infusion is again well 
tolerated, all subsequent infusions can be given over 30 minutes. 
In case of relevant toxicity, bevacizumab should be paused or discontinued.  
 
Bevacizumab should be given every 3 weeks +/-3 days. If the administration was pre- or postponed 
up to 3 days the patient should (if possible) return to schedule and the next dose. 

 
 
 
 
 
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should be given 21 days after the last administration. 
 
Management of bevacizumab related toxicities 
 
No reductions in bevacizumab dose are allowed in this study.  
 
Treatment with bevacizumab should be temporarily interrupted if one of the following adverse 
events occurs despite optimal supportive care, when not attributable to the disease under 
investigation, where the investigator considers the AE of concern to be specifically associated with 
bevacizumab: 
 
• 
Any intolerable adverse event regardless of grade 
 
• 
Any adverse events CTCAE V 5.0 grade g3 (despite optimal supportive care) 
 
If toxicity resolves or reverts to CTCAE V5.0 grade f1 within 21 days of onset and the patient is 
showing clinical benefit, treatment with bevacizumab may be restarted using the rules below for 
dose modifications.  
 
If toxicity does not resolve to CTCAE V 5.0 grade f1 after 42 days, then the patient must be 
permanently discontinued from bevacizumab. 
 
The bevacizumab-related AEs hypertension, proteinuria, thromboembolism and hemorrhage 
including any CNS bleeding, as well as any grade 3 or 4 bevacizumab related AEs, should be managed 
as described below. 
 
Event 
CTCAE Version 5.0 
Grade 
Action to be Taken 
Allergic reactions  
or  
Infusion-related reactions 
Or  
Anaphylaxis 
Grade 1 
 
Systemic intervention not indicated – continue 
bevacizumab 
Grade 2 
Oral intervention indicated – slow infusion to 
50% or interrupt if clinically indicated (re-
start infusion at 50% and increase in 50% 
increments if well tolerated). Infusion can be 
re-started at the full rate for subsequent 
infusions. 
Grade 3 
Bronchospasm (allergy-related 
oedema/angioedema; hypotension); 
hospitalization for clinical sequelae; 
intravenous intervention indicated – 
discontinue bevacizumab 
Grade 4 
Life-threatening consequences; urgent 
intervention indicated - discontinue 
bevacizumab 
Thromboembolic Event 
(arterial) 
Any Grade 
Discontinue bevacizumab 

 
 
 
 
 
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Thromboembolic Event 
(Venous) 
Grade 3 
 
Hold bevacizumab treatment.  If the planned 
duration of full-dose anticoagulation is 
<2weeks, bevacizumab should be held until 
the full-dose anticoagulation period is over. 
The use of direct oral anticoagulants is not 
recommended. 
If the planned duration of full-dose 
anticoagulation is >2 weeks, bevacizumab 
may be resumed during full-dose 
anticoagulation IF all of the criteria below are 
met: 
- The patient must not have pathological 
conditions that carry high risk of 
bleeding (e.g. tumor involving major 
vessels or other conditions) 
- The patient must not have had 
hemorrhagic events > grade 2 while on 
study 
- The patient must be on stable dose of 
heparin, low molecular weight heparin, 
or have an in-range INR (usually 2-3) on 
a stable dose of warfarin prior to 
restarting bevacizumab. 
If thromboemboli worsen/recur upon resumption 
of study therapy, discontinue bevacizumab 
Grade 4  
Discontinue bevacizumab 
Hypertension 
 
[Treat with anti-hypertensive medication as needed.  The goal of BP 
control should be consistent with general medical practice] 
 
Grade 1 
(SBP 120-139 
mmHg or DBP80-89 
mm Hg) 
Consider increased BP monitoring; start anti-
hypertensive medication if appropriate 
 
Grade 2 
asymptomatic 
(SBP 140-159 
mmHg or DBP 90-
99 mm Hg) 
Begin (or modify baseline anti-HTN therapy) anti-
hypertensive therapy and continue bevacizumab 
 
• Grade 2 
symptomatic 
(SBP 140-159 
mmHg or DBP 90-
99 mm Hg) 
 
• 
Start or adjust anti-hypertensive 
medication 
 
 
• Grade 3 
• (g SBP 160 mmHg 
or g DBP 100 
mmHg 
• 
Modify existing anti-HTN therapy (more 
than one drug or more intensive therapy 
than previously indicated. 
• 
Hold bevacizumab until symptoms resolve 
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Grade 4 
(e.g. Hypertensive 
crisis or malignant 
hypertension) 
Discontinue bevacizumab 
Heart Failure or left ventricular 
dysfunction 
Grade 3 
Discontinue bevacizumab 
Grade 4  
Discontinue bevacizumab 
Proteinuria* 
1+ proteinuria 
(g ULN - <1.0g/24h) 
Continue bevacizumab 
2+ and 3+ 
proteinuria 
(1.0 - <3.5g/24h) 
2+ - administer bevacizumab and obtain 24-hour 
urine protein before next administration 
3+ - obtain 24-hour urine protein and administer 
bevacizumab if <2.0 g/24h 
4+ proteinuria 
(g 3.5g/24h) 
Obtain 24-hour urine protein and administer 
bevacizumab only when <2.0 g/24h 
Nephrotic syndrome 
 
Grade 3 or 4 Discontinue bevacizumab 
Haemorrhage (CNS) 
Any grade 
Discontinue bevacizumab 
Haemorrhage (haemoptysis) 
Grade 1 
Trace haemoptysis; continue bevacizumab 
Grade 2 - 4 
ó 2.5 mL bright red blood per episode; discontinue 
bevacizumab 
Haemorrhage (other) 
Grade 3 - 4 
Discontinue bevacizumab 
RPLS (Reversible Posterior Leukoencephalopathy 
syndrome or PRES (Posterior Reversible 
Encephalopathy Syndrome) 
Discontinue bevacizumab 
Wound dehiscence requiring medical or surgical 
intervention 
Discontinue bevacizumab 
Perforation (GI, or any other organ) 
Discontinue bevacizumab 
Fistula (GI, pulmonary or any other organ) 
Discontinue bevacizumab 
Obstruction of GI tract 
G2 requiring 
medical intervention 
Hold bevacizumab until complete resolution  
 
G3-4 
Hold bevacizumab until complete resolution 
If surgery is required, patient may restart 
bevacizumab after full recovery from surgery, 
and at investigator’s discretion 
Febrile neutropenia 
Grade 3 
Continue bevacizumab 
Grade 4 
Hold bevacizumab until resolution or return to 
baseline 
Platelet count decreased 
Grades 1 - 3 
Continue bevacizumab 
Grade 4 
Hold bevacizumab until resolution or return to 
baseline 
Other Unspecified 
bevacizumab-related AEs 
Grade 3 
Hold bevacizumab until symptoms resolve to  
f grade 1 or baseline 

 
 
 
 
 
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(except controlled 
nausea/vomiting). 
Grade 4 
Discontinue bevacizumab 
Upon consultation with the study chair/medical 
monitor, resumption of bevacizumab may be 
considered if a patient is benefiting from 
therapy, and the G4 toxicity is transient, has 
recovered to  
f grade 1 (or baseline) and unlikely to recur 
with retreatment. 
*Institutional protocols acceptable 
 
Infusion of bevacizumab should be interrupted in patients who develop dyspnea or clinically 
significant hypotension. Patients who experience an NCI CTCAE Grade 3 or 4 allergic 
reaction/hypersensitivity, adult respiratory distress syndrome, or bronchospasm (regardless of 
grade) will be discontinued from bevacizumab treatment. 
 
Bevacizumab infusion should be slowed to f 50% or interrupted for patients who experience any 
infusion-associated symptoms not specified above. If the infusion is interrupted, it may be resumed 
at f 50% of the rate prior to the reaction after the patient9s symptoms have adequately resolved and 
increased in 50% increments up to the full rate if well tolerated. Infusions may be restarted at the 
full rate during the next cycle. 
 
Surgery and wound healing complications 
 
The appropriate interval between the last dose of bevacizumab and major surgery is unknown. 
Because bevacizumab has a half-life of approximately 21 days, elective surgery should be delayed 
whenever possible, but if necessary, bevacizumab should be withheld for g 28 days prior to the 
procedure. 
 
Bevacizumab may adversely affect the wound healing process. Bevacizumab therapy should not be 
initiated for at least 28 days following major surgery or until the surgical wound is fully healed. In 
patients who experience wound healing complications during bevacizumab treatment, bevacizumab 
should be withheld until the wound is fully healed. Bevacizumab therapy should be withheld 4 weeks 
prior to elective surgery. 
Necrotising fasciitis, including fatal cases, has rarely been reported in patients treated with 
bevacizumab. This condition is usually secondary to wound healing complications, gastrointestinal 
perforation or fistula formation. Bevacizumab therapy should be discontinued in patients who 
develop necrotising fasciitis, and appropriate treatment should be promptly initiated. 
 
12. 
Prohibited and permitted concomitant treatments 
 
Concomitant therapy consists of any medication (e.g., prescription drugs, over-the-counter drugs, 
vaccines, herbal or homeopathic remedies, nutritional supplements) used by a patient in addition to 
protocol-mandated treatment from 7 days prior to initiation of study drug to the study 

 
 
 
 
 
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completion/discontinuation visit. All such medications should be reported to the investigator and 
recorded on the Concomitant Medications form in the eCRF.  
Prohibited Concomitant Therapy  
 Any concomitant therapy intended for the treatment of cancer, whether health authority−approved 
or experimental, is prohibited for various time periods prior to starting study treatment, depending 
on the anti-cancer agent, and during study treatment until disease progression is documented and 
patient has discontinued study treatment. This includes, but is not limited to, chemotherapy, 
hormonal therapy, immunotherapy, radiotherapy, investigational agents, or herbal therapy (unless 
otherwise noted). 
The following medications are prohibited while on study, unless otherwise noted: 
- Denosumab; patients who are receiving denosumab prior to enrollment must be willing and 
eligible to receive a bisphosphonate instead while in the study.  
- Any live or attenuated vaccine (e.g., FluMist®) within 4 weeks prior to enrollment or during 
treatment or within 30 days following the last atezolizumab dose  
- Use of steroids to premedicate patients for whom CT scans with contrast are contraindicated (i.e., 
patients with contrast allergy or impaired renal clearance); in such patients, non-contrast CT 
scans of the chest and non-contrast CT scans or MRIs of the abdomen and pelvis should be 
performed. 
- Metamizole (dipyrone) is prohibited in treating atezolizumab-associated IRRs because of its 
potential for causing agranulocytosis. 
 
The concomitant use of herbal therapies is not recommended because their pharmacokinetics, 
safety profiles, and potential drug-drug interactions are generally unknown. However, their use for 
patients on study is allowed at the discretion of the investigator provided that there are no known 
interactions with any study treatment. As noted above, herbal therapies intended for the treatment 
of cancer are prohibited. 
Permitted Concomitant Therapy 
Premedication with antihistamines may be administered for any atezolizumab infusions after Cycle 1. 
The following therapies should continue while patients are on study: 
- Oral contraceptives. 
- Hormone-replacement therapy. 
- Prophylactic or therapeutic anticoagulation therapy, such as low molecular weight heparin 
(preferred) or warfarin at a stable dose level. 
- Palliative radiotherapy (e.g., treatment of known bony metastases) provided it does not interfere 
with the assessment of tumor target lesions (e.g., the lesion being irradiated is not the only site 
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according to RECIST v1.1). It is not a requirement to withhold atezolizumab during palliative 
radiotherapy. 
- Local therapy (e.g., surgery, stereotactic radiosurgery, whole brain radiotherapy) as outlined 
below: 
Patients experiencing a mixed response requiring local therapy for control may still be 
eligible to continue study treatment after Medical Monitor approval has been obtained.  
Patients who receive local therapy directed at a target lesion will no longer be evaluable 
for radiographic response but will remain evaluable for progression. 
- Inactive influenza vaccinations.  
- Megestrol administered as an appetite stimulant.  
- Inhaled corticosteroids for chronic obstructive pulmonary disease. 
- Mineralocorticoids (e.g., fludrocortisone).  
- Low-dose corticosteroids for patients with orthostatic hypotension or adrenocortical insufficiency  
(e.g oral hidroaltesona 20 mg per day). 
- G-CSF is allowed as per local standard. 
 
In general, investigators should manage a patient9s care with supportive therapies as 
clinically indicated per local standards.  Patients who experience infusion-associated symptoms may 
be treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or famotidine 
or another H2-receptor antagonist per standard practice. Serious infusion-associated events 
manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen 
saturation, or respiratory distress should be managed with supportive therapies as 
clinically indicated (e.g., supplemental oxygen and ò2-adrenergic agonists). 
 
 
Cautionary Concomitant Therapy 
Systemic corticosteroids and TNF-ñ inhibitors may attenuate potential beneficial immunologic 
effects of treatment with atezolizumab.  Therefore, in situations where systemic corticosteroids or 
TNF-ñ inhibitors would be routinely administered, alternatives, including antihistamines, should be 
considered first by the treating physician. If the alternatives are not feasible, systemic corticosteroids 
and TNF-ñ inhibitors may be administered at the discretion of the treating physician except in the 
case of patients for whom CT scans with contrast are contraindicated (i.e., patients with contrast 
allergy or impaired renal clearance).  
Systemic corticosteroids are recommended, with caution at the discretion of the treating physician, 
for the treatment of specific adverse events when associated with atezolizumab therapy.  Guidelines 
for the management of immune-mediated adverse events are described in Appendix 7. 

 
 
 
 
 
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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 AE is 
defined as any untoward medical occurrence that occurs from the subject9s written consent to 
participate in the study through 30 days after the final administration of the IMP, regardless of 
whether it is considered related or not to the study drug. 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. 
An adverse event can therefore be any of the following: 
Any unfavourable 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 
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: 

 
 
 
 
 
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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 hypokalaemia) or a change in 
concomitant therapy, 
Is clinically significant in the investigator9s 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 investigator9s judgment. 
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 (þ 3 ô baseline value) in combination with either an elevated 
total bilirubin (þ 2 ô 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 þ 3 ô baseline value in combination with total bilirubin þ 2 ô ULN 
(of which ó 35% is direct bilirubin), 
Treatment-emergent ALT or AST þ 3 ô 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). 

 
 
 
 
 
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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.  
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 

 
 
 
 
 
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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 subject9s written consent to participate in the study through 
30 days after the final administration of the IMP, regardless of whether it is considered related or 
not to the study drug and that, at any dose, 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. 
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, 

 
 
 
 
 
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− 
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). 
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 

 
 
 
 
 
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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. Also, 
the autonomous regions will be informed about all SUSARs according to the current Spanish clinical 
trial regulation. 
13.3. Adverse events of Special Interest for Atezolizumab (Immediately 
reportable to the Sponsor)  
Adverse events of special interest are required to be reported by the investigator to the Fundación 
GECP (SLCG/GECP) immediately) (no more than 24 hours after learning of the event; see Section 13.5 
for reporting instructions), despite not being serious.  Adverse events of special interest for this study 
include the following: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's Law,  
• 
Suspected transmission of an infectious agent by the study treatment, as defined below, 
• 
Any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible 
spongiform encephalopathy), pathogenic or non-pathogenic, is considered an infectious 
agent.  A transmission of an infectious agent may be suspected from clinical symptoms or 
laboratory findings that indicate an infection in a patient exposed to a medicinal product.  
This term applies only when a contamination of study treatment is suspected. 
• 
Pneumonitis, 
• 
Colitis, 
• 
Endocrinopathies:  diabetes mellitus, pancreatitis, adrenal insufficiency, hyperthyroidism, 
and hypophysitis, 
• 
Hepatitis, including AST or ALT þ 10 ô ULN, 
• 
Systemic lupus erythematosus, 
• 
Neurological disorders:  Guillain-Barré syndrome, myasthenic syndrome or myasthenia 
gravis, and meningoencephalitis, 
• 
Events suggestive of hypersensitivity, infusion-related reactions, cytokine-release syndrome, 
influenza-like illness, systemic inflammatory response syndrome, and systemic immune 
activation, 
• 
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• 
Ocular inflammatory toxicity (e.g., uveitis, retinitis, optic neuritis), 
• 
Myositis, 
• 
Myopathies, including rhabdomyolysis, 
• 
Grade ó 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis), 
• 
Vasculitis, 
• 
Autoimmune haemolytic anaemia, 
• 
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, toxic 
epidermal necrolysis). 
13.4. Overdose and secondary malignancies 
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. All occurrences of overdose must be reported 
as a SAE, indicating <life-threatening= as the seriousness. 
Secondary malignancies are not always serious by regulatory definition, these events must be 
handled as SAEs. 
13.5. SAEs and SUSARs reporting 
All SAEs that occur within 30 days of the last administered study medication must be collected. 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 pharmacovigilance.slcg@gecp.org or by fax to the Fundación GECP (SLCG/GECP) 
Pharmacovigilance Office: +34 93 419 17 68. 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. 
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 

 
 
 
 
 
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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. 
 
For any doubt please contact Fundation GECP (SLCG/GECP) pharmacovigilance office by this email: 
pharmacovigilance.slcg@gecp.org or by the telephone: +(34) 93 430 20 06. 
Also, Fundación GECP (SLCG/GECP) will ensure that all SAEs, SUSARs, AESIs and pregnancy reports in 
the clinical database (eCRF) are reported to the authorization holder y during the conduct of the 
study including periodic reconciliation. 
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.  
In both cases, the investigator must immediately notify to the Fundación GECP (SLCG/GECP) 
Pharmacovigilance Office by sending the Pregnancy form (see appendix 4) preferably by email to 
pharmacovigilance.slcg@gecp.org or by fax to the Fundación GECP (SLCG/GECP) Pharmacovigilance 
Office: +34 93 419 17 68.  
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. 

 
 
 
 
 
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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.  
13.8. Adverse events related to the treatment and associated risks 
ATEZOLIZUMAB 
The PD-L1/PD-1 pathway is involved in peripheral tolerance; therefore, such therapy may increase 
the risk of immune-mediated adverse events (ir-AE), specifically the induction or enhancement of 
autoimmune conditions. Adverse events with potentially immune-mediated causes, including rash, 
hypothyroidism, hepatitis/transaminitis, colitis, pneumonitis, myositis, and myasthenia gravis, have 
been observed in the Phase Ia study PCD4989g.   
Although most immune-mediated adverse events observed with immunomodulatory agents have 
been mild and self-limiting, such events should be recognized early and treated promptly to avoid 
potential major complications.  
Given the mechanism of action of atezolizumab, events associated with inflammation and/or 
immune-related adverse events (irAEs) have been closely monitored during the atezolizumab clinical 
program.  These include potential dermatologic, hepatic, endocrine, gastrointestinal and respiratory 
events.  Refer to the Atezolizumab Investigator9s Brochure for details on irAEs that were observed in 
patients treated with atezolizumab.  
BEVACIZUMAB 
Warnings and precautious for bevacizumab include perforation or fistula; surgery and wound healing 
complications; hemorrhage; arterial thromboembolic events; venous thromboembolic events; 
hypertension; posterior reversible encephalopathy syndrome (PRES); proteinuria; infusion reactions; 
ovarian failure. The most common adverse reactions observed in bevacizumab patients at a rate 
>10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, 
proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and 
exfoliative dermatitis (see SPC for details). 
 
In a phase II study of erlotinib in combination with bevacizumab as first line therapy for EGFRm NSCLC 
patients, no new safety signals were identified between erlotinib plus bevacizumab group and 
erlotinib alone group, with hypertension (60% vs 10%) and proteinuria (8% vs 0%) being the more 
frequently observed grade 3 AEs in the combination group compared against erlotinib alone group. 

 
 
 
 
 
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Based on the identified and potential risks associated with bevacizumab, this trial protocol 
incorporates mandatory safety monitoring procedures and guidance to assist with early diagnosis 
and rapid management of potential drug-related symptoms. 
The following NCI CTC grade 3 - 5 adverse reactions have been reported: 
Very common (g10%): Febrile neutropenia, leucopenia, thrombocytopenia, neutropenia, anorexia, 
peripheral sensory neuropathy, dysarthria, headache, dysguesia, eye disorder, lacrimeation 
increased, hypertension, thromboembolism, dyspnoea, rhinitis, rectal haemorrhage, stomatitis, 
constipation, diarrhoea, nausea, vomiting, abdominal pain, wound healing complications, exfoliative 
dermatitis, dry skin, skin discoloration, arthralgia, proteinuria, ovarian failure, asthenia, fatigue, 
pyrexia, pain, mucosal inflammation, weight decreased. 
Common (1 – <10%): Sepsis, abscess, cellulitis, infection, urinary tract infection, anaemia, 
lymphopenia, hypersensitivity, infusion reaction, dehydration, cerebrovascular accident, syncope, 
somnolence, headache, congestive heart failure, supraventricular tachycardia, arterial 
thromboembolism, deep vein thrombosis, haemorrhage, pulmonary haemorrhage, haemoptysis, 
pulmonary embolism, dysphonia, hypoxia, epistaxis, gastrointestinal perforation, intestinal 
perforation, ileus, intestinal obstruction, recto-vaginal fistulae, gastrointestinal disorder, proctalgia, 
palmar-plantar erythrodysaesthesia syndrome, fistula, muscular weakness, myalgia, back pain, pelvic 
pain, lethargy. 
14. 
Biological material and translational research 
 
Biological Sample Collection (Foundation one): 

 
 
 
 
 
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1. FFPE tumor tissue: At pre-screening. Primary tumor and/or the recurrence/metastatic 
biopsy will be obtained from a primary tumor or metastatic site. A minimum of 10 slides 4-5 
um thick, with at least 20% tumor cellularity will be necessary for FoundationOne CDx# 
(F1CDx).  
Tissue samples will be analyzed by different methods as IHC and Hybrid-capture NGS based 
comprehensive genome sequencing by Foundation Medicine. These exploratory analyses 
aim to study tumor-associated alterations to further understand disease pathobiology 
(including but not limited to mechanisms of disease progression, pseudo-progression, 
acquired resistance), to evaluate surrogate biomarkers and to potentially allow for the 
development of tissue-based diagnostic tests to help predict which patients may benefit 
from Atezolizumab in combination with Bevacizumab vs Atezolizumab alone. 
• 
Comprehensive genomic profile (CGP):  High-intermediate tumor mutational burden 
(TMB) is an emerging biomarker of sensitivity to immune checkpoint inhibitors and 
has been shown to be significantly associated with response to PD-1 and PD-L1 
blockade immunotherapy. CGP assay targeting ~0.8 Mb of coding genome measure 
with F1CDx (Foundation Medicine) can accurately assess TMB compared with 
sequencing the whole exome. F1CDx® is a comprehensive genomic profile that applies 
next- generation sequencing in a unique manner to identify all 4 types of genomic 
alterations across all genes known to be unambiguous drivers of solid tumous with 
high accuracy. The test simultaneously sequences the coding region of 324 cancer-
related genes plus introns from 29 genes often rearranged or altered in cancer to a 
typical median depth of coverage of greater than 500X. 
If the submitted tumor sample is insufficient or not valid and a biopsy is not feasible to be 
performed to evaluate the TMB, a blood sample can be sent instead.  A permission from the 
trial chair/sponsor must be requested in case no tumor sample is available for a possible 
patient and blood sample want to be sent to analyze the TMB. 
2. Blood samples for ctDNA: At progression, two 10 ml tubes of blood sample will be needed, 
to perform ctDNA analysis with Foundation One Liquid panel. 
FoundationACT is a blood-based circulating tumor DNA (ctDNA) assay for solid tumors that 
identifies clinically relevant genomic alterations driving the growth of a patient's cancer. Test 
results provide information about potential targeted therapies. Foundation One Liquid is 
validated to detect all 4 classes of genomic alterations and to analyse more than 70 of the 
most commonly mutated genes in solid tumors using a blood sample. 
In a retrospective analysis suggest that Nivolumab improves ORR and PFS compared with 
platinum doublet chemotherapy in patients with high TMB (Peters et al. Abs CTMS02 AACR 
2017). 

 
 
 
 
 
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CGP of lung cancer to simultaneously determine TMB, MSI status, PD-L1 amplification, and 
the presence of driver alterations may provide clinically useful predictors of response to ICPI 
and other targeted therapies (Chalmers et al. Genome Medicine 2017; Spigel et al. J Clin 
Oncol 2016). 
Biological Sample Collection (Pharmacogenomic exploratory analysis): 
Blood samples for the pharmacogenomic exploratory analysis will be drawn at: 
- 
Baseline or before day 1 of cycle 1 treatment 
- 
First CT-scan evaluation (cycle 5 if there is no delay in treatment administration) 
- 
Second CT-scan evaluation (cycle 9 if there is no delay in treatment administration) 
- 
Fourth CT-scan evaluation (cycle 17 if there is no delay in treatment administration) 
- 
Sixth CT-scan evaluation (cycle 25 if there is no delay in treatment administration) 
- 
Progression disease, either if it occurs during the bevacizumab + atezolizumab treatment 
or in follow up phase 21  
Also, stool samples will be collected at baseline. Also, data at baseline of PDL1 status provided by the 
sites will be analyzed. 
Please, refer to the TELMA Samples Manual for more information. 
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 enrollment. 
Only the patient pre-screening form will be used in a paper form and will be send scanned by email 
or by fax (+34 93 419 17 68) to obtain the pre-screening number. 
 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 
Three populations will be considered for different analyses: 
• 
Per protocol population (PP): Per protocol population will consider patients that will receive a 
minimum of two cycles of atezolizumab and Bevacizumab or that have at least the first tumor 
response evaluation carried out. Patients without any radiological evaluation who may die during 
the first 12 weeks will also be considered PP population. Patients without the first tumor 
response evaluation carried out but with a progression disease (also clinical progression) at 6 
weeks will also be considered into PP population.  

 
 
 
 
 
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• 
Intention to treat analysis (ITT): Intention to treat analysis will include all patients that will be 
registered into the clinical trial. 
• 
Safety population (SFP): Safety population will include all patients that will be exposed to study 
treatment (atezolizumab + bevacizumab), whatever will be the quantity received 
 
The primary endpoint is Progression Free Survival  at 12 months (PFS) according to Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1. 
 
For one arm, we estimate to achieve a PFS at 12 months of 40% (vs 18% from Chemotherapy, 
previous published studies), with a 90% power and alpha 5%, one-sided test. The test statistic for 
survival probability is based on the non-parametric estimate of the survival distribution. 
Additionally, estimating a 10% of errors, withdrawals or others, it will be necessary to recruit 40 
patients in order to get the study objectives. 
 
If the withdrawals are higher than 5%, so that in order to reach the proposed sample size, if a patient 
initially enrolled in the study does not fulfil the inclusion criteria, they will be replaced by a new one 
subject that fulfil them, this replacement will ensure that the sample size will be the one calculated 
initially.  
 
Data analysis and statistical methods 
 
A descriptive analysis will be made of the variables calculating absolute and relative frequencies of 
qualitative variables and mean(standard deviation) or median (25 and 75 percentiles), minimum and 
maximum values for quantitative variables.  
 
For the primary endpoint analysis, survivor function estimated by Kaplan-Meier method will be used, 
as well as the survival curves.. The 95% confidence interval will be estimated. 
 
For the bivariate analysis, appropriate parametric and nonparametric tests will be used depending 
on whether the data are normally or non-normally distributed. For comparison of quantitative 
variables, Student9s t test for independent data, the Mann-Whitney U test, analysis of variance or 
the Kruskal-Wallis H test will be used. 
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 of Fundación GECP or Trial Steering Committee, or at 
the suggestion of the IDMC. 

 
 
 
 
 
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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 and loss of 
clinical benefit 
• 
Symptomatic deterioration attributed to clinical disease progression 
• 
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 patient9s 
individual situation. 
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. 

 
 
 
 
 
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The primary reason for the treatment and study discontinuation should be documented on the 
appropriate 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 if it affords greater protection to the patient. For studies conducted in the 
EU/EEA countries, the Investigator will ensure compliance with the EU Clinical Trial Directive 
(2001/20/EC). 
18.1. Ethical Review Board/Ethics Committee/Health Authority 
All protocols and the patient informed consent forms must have the approval of a properly 
constituted committee or committees responsible for approving clinical trials. The 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  
Both Informed consent (pre-screening IC and IC for the study) for each patient will be obtained prior 
to initiating any trial procedures in accordance with the <Patient Information and Informed Consent".  
Once signed and dated, a copy of the informed consent must be given to each patient and the original 
copy must be retained in the investigator9s site file.  The informed consent form must be available in 
the case of data audits.  

 
 
 
 
 
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The <Declaration of Helsinki= recommends that consent be obtained from each potential patient in 
biomedical research trials after the aims, methods, anticipated benefits, and potential hazards of the 
trial, and discomfort it may entail, are explained to the individual by the physician.  The potential 
patient should also be informed of her/his right to not participate or to withdraw from the trial at 
any time.  The patient should be told that material from her/his tumor and blood and serum 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=.  
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, Informed 
Consent Forms, and documentation of IRB/EC and governmental approval. 
19.2. Protocol non-compliances/deviations 
The investigator should document and explain any protocol non-compliances/deviations. The 
investigator should promptly report any non-compliances/deviations that might have an impact on 
patient safety and data integrity to the Sponsor and to the IRB/EC in accordance with established 
IRB/EC policies and procedures.  The Sponsor will review all protocol non-compliances/deviations 
and assess whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities. All protocol non-compliances/deviations will be recorded by the 
monitoring team. 
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 

 
 
 
 
 
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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 BICR (blinded independent 
central review).  
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 centre 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 
Spanish legislation demands cover with a civil responsibility policy for subjects participating in a 
clinical trial. 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.  
19.9. Quality assurance 
Fundación GECP conducts trials according to the ICH Good Clinical Practice (GCP) guidelines.  The 
Trial Data Manager reviews 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. 

 
 
 
 
 
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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 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 and serum 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 repositories in the 
central laboratories. 
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. 
In Spain 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). 
19.11. Study monitoring team 
The Fundación GECP will be responsible for monitoring the trial at Spanish 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 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: 
 

 
 
 
 
 
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Miriam Balada 
Fundación GECP CRA 
Meridiana 358, 6ª planta 
08027 Barcelona 
Tel. 93 430 20 06 
Fax. 93 419 17 68 
Email:  mbalada@gecp.org  
 
 
Ana Verdú 
Fundación GECP Lead CRA 
Meridiana 358, 6ª planta 
08027 Barcelona 
Tel. 93 430 20 06 
Fax. 93 419 17 68 
Email: averdu@gecp.org 
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. 
20. 
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Suarez, Sergio Bracarda, Walter M. Stadler, Frede Donskov, Jae Lyun Lee, Robert Hawkins, 
Alain Ravaud, Boris Alekseev, Michael Staehler, Motohide Uemura, Francis Donaldson, Shi Li, 
Mahrukh Huseni, Christina Schiff, Brian Rini. IMmotion151: A Randomized Phase III Study of 
Atezolizumab Plus Bevacizumab vs Sunitinib in Untreated Metastatic Renal Cell Carcinoma. 
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Campbell, Paolo Vineis, David H. Phillips, Michael R. Stratton. Science VOL 354 ISSUE 6312. 
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Andrew V. Biankin, Graham R. Bignell, Niccolo` Bolli, Ake Borg, Anne-Lise Børresen-Dale, 
Sandrine Boyault, Birgit Burkhardt, Adam P. Butler, Carlos Caldas, Helen R. Davies, Christine 
Desmedt, Roland Eils, Jo´runn Erla Eyfjo¨rd, John A. Foekens, Mel Greaves, Fumie Hosoda, 
Barbara Hutter, Tomislav Ilicic, Sandrine Imbeaud, Marcin Imielinski, Natalie Ja¨ger, David T. 
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Campo, Tatsuhiro Shibata, Stefan M. Pfister, Peter J. Campbell & Michael R. Stratton. Nature 
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Otto, Jeffrey S. Ross, Levi Garraway, Vincent A. Miller, Phillip J. Stephens and Garrett M. 
Frampton. Genome Medicine (2017) 9:34. 
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Hainaut, and Magali Olivier. HUMAN MUTATION 28(6),622-629, 2007. 
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Peters. Mutational burden determines sensitivity to PD-1 blockade in NSCLC .AACR 2017, Oral. 
27. 
M.D. Hellmann, T.-E. Ciuleanu, A. Pluzanski, J.S. Lee, G.A. Otterson, C. Audigier-Valette, E. 
Minenza, H. Linardou, S. Burgers, P. Salman, H. Borghaei, S.S. Ramalingam, J. Brahmer, M. 
Reck, K.J. O9Byrne, W.J. Geese, G. Green, H. Chang, J. Szustakowski, P. Bhagavatheeswaran, D. 
Healey, Y. Fu, F. Nathan, and L. Paz-Ares. This article was published on April 16, 2018, at 
NEJM.org. DOI: 10.1056/NEJMoa1801946. 
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review of agents in phase III development. Ann Oncol 2012; 23: 1387-1393 
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of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014 Nov 

 
 
 
 
 
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27;515(7528):563–7.  
30. 
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(POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016 Apr 
30;387(10030):1837–46.  
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3, open-label, multicentre randomised controlled trial. Lancet. 2017 Jan 21;389(10066):255–
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Satouchi, N. Yamamoto, K. Nakagawa. LBA55. ESMO 2020 
20.1. References for translational research 
 
[a] 
E. Cha, M. Klinger, Y. Hou, C. Cummings, A. Ribas, M. Faham, et al., Improved Survival with T 
Cell Clonotype Stability After Anti – CTLA-4 Treatment in Cancer Patients, Sci. Transl. Med. 6 
(2014) 238ra70. doi:10.1126/scitranslmed.3008211. 
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N. Akyüz, A. Brandt, A. Stein, S. Schliffke, T. Mährle, J. Quidde, et al., T-cell diversification 
reflects antigen selection in the blood of patients on immune checkpoint inhibition and may 
be exploited as liquid biopsy biomarker, Int. J. Cancer. 140 (2017) 2535–2544. 

 
 
 
 
 
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doi:10.1002/ijc.30549. 
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Neoadjuvant PD-1 Blockade in Resectable Lung Cancer, N. Engl. J. Med. (2018) 
NEJMoa1716078. doi:10.1056/NEJMoa1716078. 
 
[d] Casarrubios, M. et al. Pretreatment Tissue TCR Repertoire Evenness Is Associated with Complete 
Pathologic Response in Patients with NSCLC Receiving Neoadjuvant Chemoimmunotherapy. 
Clin. Cancer Res. 27, 5878–5890 (2021). 
[e] 
Stankovic, B. et al. Immune Cell Composition in Human Non-small Cell Lung Cancer. Front. 
Immunol. 9, 3101 (2018). 
 
[f] 
Cabrita, Rita, Martin Lauss, Adriana Sanna, Marco Donia, Mathilde Skaarup Larsen, Shamik 
Mitra, Iva Johansson, et al. 2020. <Tertiary Lymphoid Structures Improve Immunotherapy and 
Survival in Melanoma.= Nature 577 (7791): 561–65. https://doi.org/10.1038/s41586-019-
1914-8. 
 
[g] 
Helmink BA, Reddy SM, Gao J, Zhang S, Basar R, Thakur R, et al. B cells and tertiary 
lymphoid structures promote immunotherapy response. Nature. 2020;577:549–55. 
 
[h]  Hernandez C, Arasanz H, Chocarro L, Bocanegra A, Zuazo M, Fernandez-Hinojal G, et al. 
Systemic blood immune cell populations as biomarkers for the outcome of immune checkpoint 
inhibitor therapies. Int J Mol Sci. 2020;21:1–13. 
 
[i] V. Gopalakrishnan, C.N. Spencer, L. Nezi, A. Reuben, M.C. Andrews, T. V. Karpinets, et al., Gut 
microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients, Science 
(80-. ). 359 (2018) 97–103. doi:10.1126/science.aan4236. 
[j] B. Routy, E. Le Chatelier, L. Derosa, C.P.M. Duong, M.T. Alou, R. Daillère, et al., Gut microbiome 
influences efficacy of PD-1-based immunotherapy against epithelial tumors, Science (80-. ). 
359 (2018) 91–97. doi:10.1126/science.aan3706. 
 
[k] Y. Jin, H. Dong, L. Xia, Y. Yang, Y. Zhu, Y. Shen, et al., The Diversity of Gut Microbiome is Associated 
With Favorable Responses to Anti–Programmed Death 1 Immunotherapy in Chinese Patients 
With NSCLC, J. Thorac. Oncol. 14 (2019) 1378–1389. doi:10.1016/j.jtho.2019.04.007. 
 
 

 
 
 
 
 
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Appendices: 
1. Common Terminology criteria for Adverse Events (CTCAE)  
2. RECIST criteria v1.1  
3. SAE Form  
4. Pregnancy Form 
5. Health-related Quality of life questionnaire: EORTC C30 (QLQ-C30) and submodule 
LC13 
6. System of classification for non-microcytic lung cancer (NSCLC) and definition of 
lymph node maps, 8th edition 
7. Risks associated with Atezolizumab and guidelines for management of adverse 
events associated with Atezolizumab 
8. Patients pre-screening form TELMA 
9. Foundation one CDx Specimen Instructions 
10. Foundation one Liquid technical sheet 
11. Foundation one CDx technical sheet 
 
 
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_Quick_Reference_8.5x11.pdf 
 
 
 
 
 
 

 
 
 
 
 
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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 f 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 
g10 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. 
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) 

 
 
 
 
 
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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 g 15mm in short axis when assessed by CT scan, assuming the slice thickness 
is f 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 g 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 reference to further characterize the objective tumor response of the measurable dimension 
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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 
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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 

 
 
 
 
 
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SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE  
(unless the sum of 
diam. Of evaluated 
lesions indicates 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 
 

 
 
 
 
 
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APPENDIX 4. Pregnancy Form 
 

 
 
 
 
 
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APPENDIX 5. Health-related Quality of life questionnaire: EORTC C30 (QLQ-C30) and 
submodule LC13 
 
Please see documents attached to the protocol 
 
 
APPENDIX 6. System of classification for non-microcytic lung cancer (NSCLC) and definition 
of lymph node maps, 8th edition 
 
 

 
 
 
 
 
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APPENDIX 7. Risks associated with Atezolizumab and guidelines for management of 
adverse events associated with Atezolizumab 
 
Toxicities associated or possibly associated with atezolizumab treatment should be managed 
according to standard medical practice. Additional tests, such as autoimmune serology or biopsies, 
should be used to evaluate for a possible immunogenic etiology, when clinically indicated.  
Although most immune-mediated adverse events observed with immunomodulatory agents have 
been mild and self-limiting, such events should be recognized early and treated promptly to avoid 
potential major complications. Discontinuation of atezolizumab may not have an immediate 
therapeutic effect, and in severe cases, immune-mediated toxicities may require acute management 
with topical corticosteroids, systemic corticosteroids, or other immunosuppressive agents. 
The investigator should consider the benefit-risk balance a given patient may be experiencing prior 
to further administration of atezolizumab. In patients who have met the criteria for permanent 
discontinuation, resumption of atezolizumab may be considered if the patient is deriving benefit and 
has fully recovered from the immune-mediated event. The decision to rechallenge patients with 
atezolizumab should be based on investigator9s assessment of benefit-risk and documented by the 
investigator (or an appropriate delegate). Medical Monitor is available to advise as needed. 
Guidelines for managing patients who experience selected adverse events are provided in the 
following sections. Management guidelines are presented by adverse event severity based on the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). 
 
PULMONARY EVENTS 
 
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been associated with 
the administration of atezolizumab. Patients will be assessed for pulmonary signs and symptoms 
throughout the study and will have computed tomography (CT) scans of the chest performed at every 
tumor assessment. 
All pulmonary events should be thoroughly evaluated for other commonly reported etiologies such 
as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary embolism, heart failure, 
chronic obstructive pulmonary disease, or pulmonary hypertension. Management guidelines for 
pulmonary events are provided in Table 1. 
 
 
 

 
 
 
 
 
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Table 1 Management Guidelines for Pulmonary Events, Including Pneumonitis 
 
HEPATIC EVENTS 
 
Immune-mediated hepatitis has been associated with the administration of atezolizumab. Eligible 
patients must have adequate liver function, as manifested by measurements of total bilirubin and 
hepatic transaminases, and liver function will be monitored throughout study treatment. 
Management guidelines for hepatic events are provided in Table 2. 

 
 
 
 
 
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Patients with right upper-quadrant abdominal pain and/or unexplained nausea or vomiting should 
have liver function tests (LFTs) performed immediately and reviewed before administration of the 
next dose of study drug.  
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or neoplastic 
etiologies should be considered and addressed, as appropriate. 
 
Table 2 Management Guidelines for Hepatic Events 
  
 

 
 
 
 
 
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GASTROINTESTINAL EVENTS 
 
Immune-mediated colitis has been associated with the administration of atezolizumab. Management 
guidelines for diarrhea or colitis are provided in Table 3. 
All events of diarrhea or colitis should be thoroughly evaluated for other more common etiologies. 
For events of significant duration or magnitude or associated with signs of systemic inflammation or 
acute-phase reactants (e.g., increased C-reactive protein, platelet count, or bandemia): Perform 
sigmoidoscopy (or colonoscopy, if appropriate) with colonic biopsy, with three to five specimens for 
standard paraffin block to check for inflammation and lymphocytic infiltrates to confirm colitis 
diagnosis. 
 
Table 3 Management Guidelines for Gastrointestinal Events (Diarrhea or Colitis) 
 

 
 
 
 
 
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ENDOCRINE EVENTS 
 
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders have been 
associated with the administration of atezolizumab. Management guidelines for endocrine events 
are provided in Table 4. 
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, constipation, 
or mental status changes should be investigated for the presence of thyroid, pituitary, or adrenal 
endocrinopathies. The patient should be referred to an endocrinologist if an endocrinopathy is 
suspected. Thyroid-stimulating hormone (TSH) and free triiodothyronine and thyroxine levels should 
be measured to determine whether thyroid abnormalities are present. Pituitary hormone levels and 
function tests (e.g., TSH, growth hormone, luteinizing hormone, follicle-stimulating hormone, 
testosterone, prolactin, adrenocorticotropic hormone [ACTH] levels, and ACTH stimulation test) and 
magnetic resonance imaging (MRI) of the brain (with detailed pituitary sections) may help to 
differentiate primary pituitary insufficiency from primary adrenal insufficiency. 

 
 
 
 
 
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Table 4 Management Guidelines for Endocrine Events 
 
 
 
 

 
 
 
 
 
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OCULAR EVENTS 
 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events). Management 
guidelines for ocular events are provided inTable 5. 
 

 
 
 
 
 
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Table 5 Management Guidelines for Ocular Events 
 
 
 
IMMUNE-MEDIATED MYOCARDITIS 
 
Immune-mediated myocarditis has been associated with the administration of atezolizumab. 
Immune-mediated myocarditis should be suspected in any patient presenting with signs or 
symptoms suggestive of myocarditis, including, but not limited to, laboratory (e.g., BNP [B-
Natriuretic Peptide]) or cardiac imaging abnormalities, dyspnea, chest pain, palpitations, fatigue, 
decreased exercise tolerance, or syncope. Myocarditis may also be a clinical manifestation of 
myositis and should be managed accordingly Immune-mediated myocarditis needs to be 

 
 
 
 
 
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distinguished from myocarditis resulting from infection (commonly viral, e.g., in a patient who 
reports a recent history of gastrointestinal illness), ischemic events, underlying arrhythmias, 
exacerbation of preexisting cardiac conditions, or progression of malignancy. 
All patients with possible myocarditis should be urgently evaluated by performing cardiac enzyme 
assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as appropriate per 
institutional guidelines. A cardiologist should be consulted. An endomyocardial biopsy may be 
considered to enable a definitive diagnosis and appropriate treatment, if clinically indicated. 
Patients with signs and symptoms of myocarditis, in the absence of an identified alternate etiology, 
should be treated according to the guidelines inTable 6. 
 
Table 6 Management Guidelines for Immune-Related Myocarditis 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
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INFUSION-RELATED REACTIONS AND CYTOKINE-RELEASE SYNDROME 
 
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  However, patients 
who experience an infusion-related reaction (IRR) or cytokine-release syndrome (CRS) with 
atezolizumab may receive premedication with antihistamines, anti-pyretics, and/or analgesics (e.g., 
acetaminophen) for subsequent infusions.  Metamizole (dipyrone) is prohibited in treating 
atezolizumab-associated IRRs because of its potential for causing agranulocytosis. 
IRRs are known to occur with the administration of monoclonal antibodies and have been reported 
with atezolizumab.  These reactions, which are thought to be due to release of cytokines and/or 
other chemical mediators, occur within 24 hours of atezolizumab administration and are generally 
mild to moderate in severity. 
CRS is defined as a supraphysiologic response following administration of any immune therapy that 
results in activation or engagement of endogenous or infused T cells and/or other immune effector 
cells.  Symptoms can be progressive, always include fever at the onset, and may include 
hypotension, capillary leak (hypoxia), and end-organ dysfunction (Lee et al. 2019).  CRS has been 
well documented with chimeric antigen receptor T-cell therapies and bispecific T-cell engager 
antibody therapies but has also been reported with immunotherapies that target PD-1 or PD-L1 
(Rotz et al. 2017; Adashek and Feldman 2019), including atezolizumab. 
There may be significant overlap in signs and symptoms of IRRs and CRS, and in recognition of the 
challenges in clinically distinguishing between the two, consolidated guidelines for medical 
management of IRRs and CRS are provided in table 7. 
Severe COVID-19 appears to be associated with a cytokine-release syndrome (CRS) involving the 
inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and interferon-γ (Merad and Martin 2020). If a 
patient develops suspected CRS during the study, a differential diagnosis should include COVID-19, 
which should be confirmed or refuted through assessment of exposure history, appropriate 
laboratory testing, and clinical or radiologic evaluations per investigator judgment. If a diagnosis of 
COVID-19 is confirmed, the disease should be managed as per local or institutional guidelines.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
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Table 7 Management Guidelines for Infusion-Related Reactions and Cytokine-Release Syndrome 
 
 
 
 

 
 
 
 
 
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PANCREATIC EVENTS 
 
Symptoms of abdominal pain associated with elevations of amylase and lipase, suggestive of 
pancreatitis, have been associated with the administration of atezolizumab. 
The differential diagnosis of acute abdominal pain should include pancreatitis. Appropriate workup 
should include an evaluation for ductal obstruction, as well as serum amylase and lipase tests. 
Management guidelines for pancreatic events, including pancreatitis, are provided in Table 8. 
 
 
 

 
 
 
 
 
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Table 8 Management Guidelines for Pancreatic Events, Including Pancreatitis 
 

 
 
 
 
 
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DERMATOLOGIC EVENTS 
 
Treatment-emergent rash has been associated with atezolizumab. The majority of 
cases of rash were mild in severity and self limited, with or without pruritus. Although 
uncommon, cases of severe cutaneous adverse reactions such as Stevens-Johnson 
syndrome and toxic epidermal necrolysis have been reported with atezolizumab. A 
dermatologist should evaluate persistent and/or severe rash or pruritus. A biopsy should 
be considered unless contraindicated. Management guidelines for dermatologic events 
are provided in Table 9. 
 
Table 9 Management Guidelines for Dermatologic Events 
 

 
 
 
 
 
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NEUROLOGIC DISORDERS 
 
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent atezolizumab. 
Patients may present with signs and symptoms of sensory and/or motor neuropathy. Diagnostic 
work-up is essential for an accurate characterization to differentiate between alternative etiologies. 
Management guidelines for neurologic disorders are provided in Table 10. 
 
Table 10 Management Guidelines for Neurologic Disorders 
 
IMMUNE-MEDIATED MENINGOENCEPHALITIS 
 
Immune-mediated meningoencephalitis is an identified risk associated with the administration of 
atezolizumab. Immune-mediated meningoencephalitis should be suspected in any patient 

 
 
 
 
 
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presenting with signs or symptoms suggestive of meningitis or encephalitis, including, but not limited 
to, headache, neck pain, confusion, seizure, motor or sensory dysfunction, and altered or depressed 
level of consciousness. 
Encephalopathy from metabolic or electrolyte imbalances needs to be distinguished from potential 
meningoencephalitis resulting from infection (bacterial, viral, or fungal) or progression of 
malignancy, or secondary to a paraneoplastic process.  
All patients being considered for meningoencephalitis should be urgently evaluated with a CT scan 
and/or MRI scan of the brain to evaluate for metastasis, inflammation, or edema. If deemed safe by 
the treating physician, a lumbar puncture should be performed and a neurologist should be 
consulted. 
Patients with signs and symptoms of meningoencephalitis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 11. 
 
Table 11 Management Guidelines for Immune-Mediated Meningoencephalitis 
 
 
RENAL EVENTS 
 
Immune-mediated nephritis has been associated with the administration of atezolizumab. Eligible 
patients must have adequate renal function. Renal function, including serum creatinine, should be 
monitored throughout study treatment. Patients with abnormal renal function should be evaluated 
and treated for other more common etiologies (including prerenal and postrenal causes, and 
concomitant medications such as non-steroidal anti-inflammatory drugs). Refer the patient to a renal 
specialist if clinically indicated. A renal biopsy may be required to enable a definitive diagnosis and 
appropriate treatment. 
Patients with signs and symptoms of nephritis, in the absence of an identified alternate etiology, 
should be treated according to the guidelines in Table 12. 

 
 
 
 
 
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Table 12 Management Guidelines for Renal Events 
 
 
 
IMMUNE-MEDIATED MYOSITIS 
 
Myositis or inflammatory myopathies are a group of disorders sharing the common feature of 
inflammatory muscle injury; dermatomyositis and polymyositis are among the most common 
disorders. Initial diagnosis is based on clinical (muscle weakness, muscle pain, skin rash in 
dermatomyositis), biochemical (serum creatine kinase increase), and imaging 
(electromyography/MRI) features, and is confirmed with a muscle biopsy. Patients with possible 
myositis should be referred to a rheumatologist or neurologist. Patients with possible myositis 
should be monitored for signs of miocarditis. 

 
 
 
 
 
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Patients with signs and symptoms of myositis, in the absence of an identified alternate etiology, 
should be treated according to the guidelines in Table 13. 
 
 
Table 13 Management Guidelines for Immune-Mediated Myositis 
 
 
 
 

 
 
 
 
 
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HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND MACROPHAGE ACTIVATION SYNDROME 
Immune-mediated reactions may involve any organ system and may lead to hemophagocytic 
lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS).  
Clinical and laboratory features of severe CRS overlap with HLH, and HLH should be considered 
when CRS presentation is atypical or prolonged.   
Patients with suspected HLH should be diagnosed according to published criteria by McClain and 
Eckstein (2014).  A patient should be classified as having HLH if five of the following eight criteria 
are met: 
Fever ó 38.5°C 
Splenomegaly 
Peripheral blood cytopenia consisting of at least two of the following: 
– 
Hemoglobin ü 90 g/L (9 g/dL) (ü 100 g/L [10 g/dL] for infants ü 4 weeks old) 
– 
Platelet count ü 100 ô 109/L (100,000/L) 

 
 
 
 
 
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– 
ANC ü 1.0 ô 109/L (1000/L) 
Fasting triglycerides þ 2.992 mmol/L (265 mg/dL) and/or fibrinogen ü 1.5 g/L (150 mg/dL) 
Hemophagocytosis in bone marrow, spleen, lymph node, or liver 
Low or absent natural killer cell activity 
Ferritin þ 500 mg/L (500 ng/mL) 
Soluble IL-2 receptor (soluble CD25) elevated ó 2 standard deviations above age-adjusted 
laboratory-specific norms 
 
Patients with suspected MAS should be diagnosed according to published criteria for systemic 
juvenile idiopathic arthritis by Ravelli et al. (2016).  A febrile patient should be classified as having 
MAS if the following criteria are met: 
Ferritin þ 684 mg/L (684 ng/mL) 
At least two of the following: 
– 
Platelet count  181 ô 109/L (181,000/L) 
– 
AST ó 48 U/L 
– 
Triglycerides þ 1.761 mmol/L (156 mg/dL) 
– 
Fibrinogen  3.6 g/L (360 mg/dL) 
 
Patients with suspected HLH or MAS should be treated according to the guidelines in Table 14.  
Table 14 
Management Guidelines for Suspected Hemophagocytic Lymphohistiocytosis or 
Macrophage Activation Syndrome 
 
 
 
 
 

 
 
 
 
 
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APPENDIX 8: Patient pre-screening form TELMA 
 

 
 
 
 
 
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APPENDIX 9: Foundation one CDx Specimen Instructions 
 

 
 
 
 
 
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APPENDIX 10: Foundation one Liguid technical sheet 
 

 
 
 
 
 
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APPENDIX 11: Foundation one CDx technical sheet 
 
Please see documents attached to the protocol