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HHYYPPEERRIIOONN

ML39885

THE EFFECTIVENESS OF ATEZOLIZUMAB UNDER REAL-WORLD CONDITIONS IN PATIENTS

WITH LOCALLY-ADVANCED OR METASTATIC NON-SMALL CELL LUNG CANCER AFTER PRIOR

CHEMOTHERAPY

NIS PROTOCOL

TITLE: NON-INTERVENTIONAL STUDY TO ASSESS THE EFFECTIVENESS OF ATEZOLIZUMAB UNDER REAL-WORLD CONDITIONS IN PATIENTS WITH LOCALLY-ADVANCED OR METASTATIC NON-SMALL CELL LUNG CANCER AFTER PRIOR CHEMOTHERAPY [HYPERION]

PROTOCOL NUMBER: ML39885

VERSION NUMBER: 8.0 Datum

STUDIED MEDICINAL PRODUCT

Atezolizumab (TECENTRIQ®)

MARKETING AUTHORIZATION HOLDER{S} (MAH

Roche Registration GmbH Emil-Barell-Str. 1 79639 Grenzach-Wyhlen Germany

DATE FINAL: Protocol version 1.2 – 22 June2016 Protocol version 2.0 – 08 August 2017 Protocol version 3.0 – 13 September 2017 Protocol version 4.0 – 17 November 2017 Protocol version 5.0 – 01 December 2017 Protocol version 6.0 – 01 February 2018 Protocol version 7.0 – 26 March 2018 Protocol version 8.0 – 26 July 2019

CONFIDENTIAL

The information contained in this document, especially any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore is provided to you in confidence as a

treating physician, or consultant, for review by you, your staff, and an applicable Ethics Committee or Institutional Review Board. It is understood that this information will not be disclosed to others without

written authorization from Roche except to the extent necessary to obtain informed consent from persons who will participate.

Atezolizumab (TECENTRIQ®) - F. Hoffmann-La Roche Ltd Protocol ML39885 Version 8.0 Based on protocol template Version 6.0 released on 10-May-2019 3

PROTOCOL FINALIZATION SIGNATURE PAGE TITLE: NON-INTERVENTIONAL STUDY TO ASSESS THE

EFFECTIVENESS OF ATEZOLIZUMAB UNDER REAL-WORLD CONDITIONS IN PATIENTS WITH LOCALLY-ADVANCED OR METASTATIC NON-SMALL CELL LUNG CANCER AFTER PRIOR CHEMOTHERAPY [HYPERION]

PROTOCOL NUMBER: ML39885

VERSION NUMBER: 8.0

STUDIED MEDICINAL PRODUCT


MARKETING AUTHORIZATION HOLDER (MAH):


DATE FINAL: Protocol version 1.2 – 22 June2016 Protocol version 2.0 – 08 August 2017 Protocol version 3.0 – 13 September 2017 Protocol version 4.0 – 17 November 2017 Protocol version 5.0 – 01 December 2017 Protocol version 6.0 – 01 February 2018 Protocol version 7.0 – 26 March 2018 Protocol version 8.0 – 26 July 2019

Atezolizumab (TECENTRIQ®) - F. Hoffmann-La Roche Ltd Protocol ML39885 Version 780 Based on protocol template Version 6.0 released on 10-May-2019 5

TABLE OF CONTENTS

PROTOCOL FINALIZATION SIGNATURE PAGE ............................................... 3

PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 10

1. LIST OF ABBREVIATIONS ......................................................................... 11

2. SYNOPSIS .................................................................................................. 13

2.1 Background ........................................................................... 13

2.2 Research Question and Objectives ....................................... 14

2.2.1 Effectiveness Objectives........................................................ 15

2.2.2 Safety Objectives ................................................................... 16

2.2.3 Other Objectives .................................................................... 16

2.3 Study Design ......................................................................... 17

2.3.1 Target Population .................................................................. 19

2.4 Studied Medicinal Product ..................................................... 20

2.4.1.1 Variables .............................................................................. 20

2.4.1.2 Primary Effectiveness Variables ........................................... 20

2.4.1.3 Secondary Effectiveness Variable ........................................ 21

2.4.1.4 Safety Variables ................................................................... 21

2.4.1.5 Other Variables of Interest ................................................... 21

2.4.2 Data Sources ......................................................................... 23

2.4.3 Data Analysis ......................................................................... 23

2.4.4 Study Size/Determination of Sample Size ............................. 24

3. PROTOCOL AMENDMENTS AND UPDATES ........................................... 26

4. RATIONALE AND BACKGROUND............................................................. 31

4.1 Study Rationale ..................................................................... 33

5. RESEARCH QUESTION AND OBJECTIVES ............................................. 37

5.1 Research Question ................................................................ 37

5.2 Objectives .............................................................................. 38

5.2.1 Effectiveness Objectives........................................................ 38

5.2.2 Safety Objectives ................................................................... 38

5.2.3 Other Objectives .................................................................... 38


6. RESEARCH METHODS ............................................................................. 40

6.1 Study Design ......................................................................... 40

6.1.1 Overview of Study Design ..................................................... 41

6.1.2 Number of Patients Observed in the Study ............................ 42

6.1.3 Sites....................................................................................... 42

6.1.4 Rationale for Study Design .................................................... 43

6.2 Population .............................................................................. 43

6.2.1 Rationale for Patient Population ............................................ 44

6.2.2 Concomitant Medication and Treatment ................................ 45

6.2.3 Dosage, Administration, and Compliance .............................. 45

6.3 Variables ................................................................................ 45

6.3.1 Primary Effectiveness Variable .............................................. 45

6.3.2 Secondary Effectiveness Variable ......................................... 45

6.3.3 Safety Variables .................................................................... 46

6.3.4 Other Variables of Interest ..................................................... 46

6.4 Data Sources ......................................................................... 48

6.4.1 Data Collected during the Observation Period ....................... 48

6.4.2 Data Collected at Study Completion ...................................... 50

6.4.3 Safety Data Collection ........................................................... 51

6.5 Patient, Study and Site Discontinuation ................................. 51

6.5.1 Patient Discontinuation .......................................................... 51

6.5.2 Discontinuation from Treatment with Studied Medicinal Product .................................................................................... 51

6.5.3 Withdrawal from Study........................................................... 51

6.5.4 Study and Site Discontinuation .............................................. 52

6.6 Data Management ................................................................. 52

6.6.1 Data Quality Assurance ......................................................... 52

6.6.2 Electronic Case Report Forms ............................................... 53

6.6.3 Source Data Documentation .................................................. 53

6.7 Statistical Considerations ...................................................... 54

6.7.1 Effectiveness Analyses .......................................................... 54

6.7.2 Safety Analyses ..................................................................... 55

6.7.3 Other Analyses ...................................................................... 55


6.7.4 Interim and Final Analyses and Timing of Analyses 57

6.7.5 Determination of Sample size ................................................ 58

6.8 Study Documentation, Monitoring, and Administration ........................................................................ 59

6.8.1 Study Documentation ............................................................ 59

6.8.2 Site Audits and Inspections ................................................... 59

6.8.3 Use of Site Computerized Systems ....................................... 59

6.8.4 Retention of Records ............................................................. 60

6.8.5 Administrative Structure......................................................... 60

6.9 Limitations of the Research Method ...................................... 60

7. PROTECTION OF HUMAN SUBJECTS ..................................................... 62

7.1 Compliance with Laws and Regulations ................................ 62

7.2 Informed Consent .................................................................. 62

7.3 Institutional Review Board or Ethics Committee .................... 62

7.4 Confidentiality ........................................................................ 63

8. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ ADVERSE REACTIONS ............................................................................. 64

8.1 Safety Reporting Requirements for Studied Medicinal Products ................................................................ 64

8.1.1 Safety Parameters and Definitions ........................................ 64

8.1.1.1 Adverse Events .................................................................... 64

8.1.1.2 Assessment of Serious Adverse Events ............................... 65

8.1.2 Methods and Timing for Capturing and Assessing Safety Parameters .................................................................. 67

8.1.2.1 Adverse Event Reporting Period .......................................... 67

8.1.2.2 Procedures for Recording Adverse Events .......................... 67

8.1.3 Reporting Requirements from Physician to Marketing Authorization Holder ................................................................ 68

8.1.3.1 Immediate Reporting Requirements from Physician to Marketing Authorization Holder ...................................... 68

8.1.3.2 Reporting Requirements for Non-Serious Adverse Events .................................................................................. 69

8.1.3.3 If EDC System is Temporarily Unavailable ........................... 69


8.1.3.4 Reporting Requirements for Pregnancies/Breastfeeding ................................................................ 70

8.1.3.5 Reporting Requirements for Adverse Events originating from Patient Reported Outcomes ...................................... 70

8.1.3.6 Reporting Requirements for Adverse Events originating from previous (non-atezolizumab) therapies (before first atezolizumab treatment) .................................................. 71

8.1.4 Follow-Up of Patients after Adverse Events .......................... 71

8.1.4.1 HCP Follow-Up..................................................................... 71

8.1.4.2 Marketing Authorization Holder Follow-Up ........................... 71

8.2 Safety REPORTING Requirements for non-Studied Medicinal products .................................................... 71

8.3 Reporting of product complaints without adverse events .................................................................................... 72

9. PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS ................................................................................................... 73

10. REFERENCES ........................................................................................... 74

APPENDIX 1 LIST OF STAND-ALONE DOCUMENTS NOT INCLUDED IN THE PROTOCOL ................................................................ 77

Appendix 1.1 List of contact details ......................................................... 77

APPENDIX 2 Data Collection Overview (as per Standard of Care) 78

APPENDIX 3 Methods for Assessing and Recording Adverse Events 80

Appendix 3.1 Assessment of Severity of Adverse Events ...................... 80

Appendix 3.2 Assessment of Causality of Adverse Events ..................... 81

Appendix 3.3 Procedures for recording Adverse Events ........................ 82

Appendix 3.3.1 Infusion-Related Reactions .................................... 82

Appendix 3.3.2 Diagnosis versus Signs and Symptoms ................. 82

Appendix 3.3.3 Adverse Events Occurring Secondary to Other Events 82

Appendix 3.3.4 Persistent or Recurrent Adverse Events ................ 83

Appendix 3.3.5 Abnormal Laboratory Values .................................. 83

Appendix 3.3.6 Abnormal Vital Sign Values .................................... 84

Appendix 3.3.7 Abnormal Liver Function Tests ............................... 85


Appendix 3.3.8 Deaths .................................................................... 85

Appendix 3.3.9 Preexisting Medical Conditions .............................. 86

Appendix 3.3.10 Lack of Therapeutic Efficacy ................................ 86

Appendix 3.3.11 Hospitalization or Prolonged Hospitalization 86

Appendix 3.3.12 Overdoses, Misuses, Abuses, Off-Label Use, Occupational Exposure, or Medication Error .................... 87

Appendix 3.3.13 Quality Defects and Falsified Products and Product Complaints ..................................................................... 87

Appendix 3.3.14 Drug Interactions ................................................... 87

Appendix 3.3.15 Patient-reported outcome ...................................... 87

Appendix 3.4 List of AESIs ...................................................................... 89


1. LIST OF ABBREVIATIONS

Abbreviation Definition AE Adverse event AESI Adverse event of special interest ALK Anaplastic lymphoma kinase ALT Alanine aminotransferase ASCO American Society of Clinical Oncology AST Aspartate aminotransferase BOR Best overall response CI Confidence interval CIT Cancer immunotherapy Coh2 Cohort 2 CNS Central nervous system CR Complete response CRO Contract research organization CTCAE Common Terminology Criteria for Adverse Events DCR Disease control rate DOR Duration of response EC Ethics Committee ECG Electrocardiogram ECOG Eastern Cooperative Oncology Group eCRF Electronic Case Report Form EGFR Epidermal growth factor receptor EDC Electronic data capture EMA European Medicines Agency FACT-L Functional Assessment of Cancer Therapy - Lung FDA Food and Drug Administration GEKID Gesellschaft der epidemiologischen Krebsregister in

Deutschland GPP Good Pharmacoepidemiological Practice GVP EU Guideline on Good Pharmacovigilance Practices HR Hazard ratio HCP Healthcare Professional IC Immune cells ICH International Conference of Harmonisation IgG Immunoglobulin G IHC Immunohistochemistry irAEs Immune-related adverse events irRC Immune-related response criteria ISPE International Society of Pharmacoepidemiology ITT Intention to treat KRAS Kirsten rat sarcoma


Abbreviation Definition LCS Lung cancer subscale LPLV Last patient, last visit MAH Marketing authorization holder MedDRA Medical Dictionary for Regulatory Activities mRECIST Modified response evaluation criteria in solid tumors NCI National Cancer Institute NIS Non-interventional study NGS Next-generation sequencing NSCLC Non-small cell lung cancer ORR Overall response rate OS Overall survival PD Progressive disease PD-1 Programmed cell death protein 1 PD-L1 Programmed cell death ligand-1 PD-L2 Programmed cell death ligand-2 PFS Progression-free survival PR Partial response PRO Patient reported outcomes QoL Quality of Life RECIST Response evaluation criteria in solid tumors ROS1 ROS proto-oncogene 1 receptor tyrosine kinase SAE Serious adverse event SD Stable disease or standard deviation SDV Source data verification SMT Study management team SmPC Summary of Product Characteristics SOC System organ class TC Tumor cells TKI Tyrosine kinase inhibitor TOI Trial Outcome Index TTR Time to response TTLCB Time to loss of clinical benefit ULN Upper limit of normal


2. SYNOPSIS

TITLE: NON-INTERVENTIONAL STUDY TO ASSESS THE EFFECTIVENESS OF ATEZOLIZUMAB UNDER REAL-WORLD CONDITIONS IN PATIENTS WITH LOCALLY-ADVANCED OR METASTATIC NON-SMALL CELL LUNG CANCER AFTER PRIOR CHEMOTHERAPY [HYPERION ]

PROTOCOL NUMBER: ML39885 VERSION NUMBER: Final 7.0 – corresponding to Protocol Version 8.0 DATE OF SYNOPSIS: 26.07.2019 STUDIED MEDICINAL PRODUCT


MAIN AUTHOR:

INDICATION: Locally advanced or metastatic non-small cell lung cancer (NSCLC)

MARKETING AUTHORIZATION HOLDER


2.1 BACKGROUND

Lung cancer is the most frequent cause of cancer-related death in men and the second most common in women in Germany. Despite improvements in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC) that have resulted in longer survival times and reduced disease-related symptoms, nearly all patients experience disease progression. Chemotherapy, particularly docetaxel, has been the most common choice for second-line patients for over a decade.

In recent years, checkpoint blockade has become an increasingly important factor in the therapy of lung carcinomas and relevant classes are antibodies that are directed against the surface-bound proteins programmed cell death protein 1 (PD-1) and programmed cell death ligand-1 (PD-L1).


Atezolizumab is a humanized engineered immunoglobulin G1 (IgG1) monoclonal antibody that selectively targets human PD-L1, blocking its interactions with receptors PD-1 and B7.1, which reinvigorates and enhances anti-cancer activity. Atezolizumab preserves the potential for PD-L2 to bind PD-1, potentially preserving immune homeostasis in normal tissues.

In pivotal trials of anti-PDL1/anti-PD1-antibodies different tests (antibodies, scoring algorithm, cell types etc.) have been used to evaluate PD-L1 expression on tumor cells (TC) and, in case of the atezolizumab pivotal trial OAK, also on tumor-infiltrating immune cells (IC).

The Food and Drug Administration (FDA) as well as the European Medicines Agency (EMA) approval of atezolizumab in pretreated NSCLC is based on results from the randomized Phase III OAK and Phase II POPLAR studies. Both studies evaluate the efficacy and safety of atezolizumab compared with docetaxel in patients with locally advanced or metastatic NSCLC whose disease had progressed following or during previous treatment with platinum-containing chemotherapy. Patients who had a detectable epidermal growth factor receptor (EGFR)-mutation or anaplastic lymphoma kinase (ALK)-rearrangement had to be treated with an appropriate tyrosine kinase inhibitor (TKI)-based therapy. In the preliminary analysis of the phase III-study OAK a 27% improvement in overall survival was observed in the intention-to-treat (ITT) population for patients receiving atezolizumab compared to those treated with docetaxel. Overall survival hazard ratios (HRs) favored atezolizumab across predefined histology subgroups (squamous or non-squamous disease; both HR 0.73). The subgroup of patients with the highest PD-L1 expression (TC3/IC3) derived the greatest benefit from atezolizumab treatment (HR 0.41), however even in patients with no PD-L1 expression (TC0/IC0), the risk of death was still statistically reduced by 25% with atezolizumab compared to those treated with docetaxel. Furthermore, responses appear durable in this PD-L1-negative subgroup with the median duration of response (DoR) not reached for atezolizumab versus 6.2 months with docetaxel at the time of analysis. Median DoR for the ITT population was 16.3 months for atezolizumab compared to 6.2 months for docetaxel.

The median time to response for patients with second-line NSCLC under treatment with anti-PDL1/PD1-checkpoint inhibitors varies from two to three months.

Clinical responses and possible associations with patient-related factors in the real-world setting are of great interest.

2.2 RESEARCH QUESTION AND OBJECTIVES

To date there is a lack of understanding why some lung cancer patients do or do not respond to checkpoint inhibitors. Previous therapies (e.g. chemotherapeutic agents,


TKIs) as well as other patient-related factors (e.g. smoking history, biomarkers) can influence the composition of the tumor stroma and/or the immunogenicity of the tumor.

The objective of the present non-interventional study is to observe the duration of clinical benefit from atezolizumab treatment in patients with locally-advanced or metastatic NSCLC of squamous or non-squamous histology after prior chemotherapy under real-world conditions. Furthermore, this NIS aims at investigating the association of previous therapies and patients’ baseline characteristics with the clinical benefit in atezolizumab-treated patients under real-world conditions.

In this NIS patients will be assigned to one of two cohorts, to observe potential correlating factors in prior therapies or patient characteristics and

• lack of clinical benefit from atezolizumab (cohort 1), or

• durability of clinical benefit from and tumor response to atezolizumab (cohort 2)

under real-world conditions, respectively (see 2.3 study design for details).

Further objectives include the collection of data concerning the observed effectiveness, safety and quality of life (QoL) for atezolizumab in pre-treated NSCLC patients in a routine clinical practice setting.

PD-L1 testing results from routine histological work-up as opposed to pivotal trial conditions and the association of PD-L1-status with benefit from atezolizumab will be analyzed.

2.2.1 Effectiveness Objectives

Please note that the “effectiveness” in this protocol is defined as the observed beneficial effects of a drug – atezolizumab in this case – in a real-world setting, under everyday practice conditions. It should not be confused with the term “efficacy”, which can only be stringently assessed in randomized controlled clinical trials. Therefore, effectiveness should, for all intents and purposes, not be translated into German – this being a study conducted in Germany – with the term “Wirksamkeit”; rather, it may be translated using the terms “Auswirkungen” or “Beobachtungen zu (Aus)wirkungen” (see also Godwin et al., 2003; Gartlehner et al., 2006)


The co-primary effectiveness objectives for this study are as follows:

To evaluate/observe:

• Time to loss of clinical benefit (TTLCB) from atezolizumab treatment as assessed by the treating physician under real-world conditions (Overall population and cohort 2 (“Coh 2 TTCLB”); for details please see study design below).

• Duration of response (DOR) to atezolizumab treatment as assessed by the treating physician under real-world conditions (patients with CR and PR in cohort 2 only; for details please see study design below).

The secondary effectiveness objectives for this study are as follows:


• Disease control rate (DCR) (overall population)

• Progression-free survival (PFS) (overall population)

• Time to response (TTR) (in patients with documented PR/CR)

• Overall response rate (ORR) (overall population)

• Best overall response (BOR) (overall population)

• Best overall response of patients in cohort 2 (“Coh2 BOR”) (cohort 2 only)

• Overall survival of cohort 2 (“Coh2 OS”) (cohort 2 only)

2.2.2 Safety Objectives

The safety objectives for this study are as follows:


• Incidence of all adverse events (AEs), serious adverse events (SAEs) and AEs of Special Interest (AESIs) in atezolizumab treated patients per cohorts and overall study population (see Appendix 3.4)

• Duration of withholding atezolizumab & management of AEs, SAEs and AESIs

2.2.3 Other Objectives


• Health-related quality of life (HRQoL) prior to first atezolizumab infusion, during, atezolizumab treatment and after atezolizumab discontinuation, using the Functional Assessment of Cancer Therapy - Lung (FACT-L) instrument (and a


modified questionnaire for patients being enrolled retrospectively), and association of QoL with disease progression

• Type and lines of cancer-related therapies used before initiation of atezolizumab, and their relationship to outcome measures (TTLCB, Coh 2 TTCLB, DOR, and Coh2 OS)

• Time between completion of the prior treatment and the start of the treatment with atezolizumab

• Patients’ characteristics (subgroups of interest) and their relationship to outcome measures (TTLCB, Coh 2 TTCLB, DOR, and Coh2 OS)

• Outcome of follow-up measurement of patients with suspected pseudoprogression within first 12 weeks of treatment (subsequent disease control – yes/no)

• Occurrence and patterns of radiotherapy during treatment with atezolizumab

• Characteristics of PD-L1 testing in real-world clinical practice, including rates of PD-L1 (re-)testing, methodology (diagnostic antibody used), test results (PD-L1 status)

• Main reason for decision for treatment with atezolizumab

2.3 STUDY DESIGN

HYPERION is a prospective, multicenter, non-interventional, two-cohort study collecting primary data in patients with locally advanced or metastatic NSCLC of squamous or non-squamous histology after prior chemotherapy treated with atezolizumab in routine clinical practice.

No specific treatments are mandated in this observational study. Instead, choice of treatments, including atezolizumab (use according to SmPC), will be at the discretion of the treating physician per local guidelines.

In eligible patients who have been chosen by their treating physicians to receive atezolizumab and who consent to participate in this non-interventional study, atezolizumab will be administered as described in the TECENTRIQ® Summary of Product Characteristics (SmPC) from the European Medicines Agency (EMA).

Depending on their benefit from atezolizumab patients included in this non-interventional study will be grouped in the following two cohorts 12 weeks after their first atezolizumab infusion (or after 18 weeks if pseudoprogression suspected (please refer to section 4.1 page 31 for details on pseudoprogression)), which should coincide with the first re-staging in most patients:


o Cohort 1:

Patients who, prior to their next planned infusion of atezolizumab at week 12 (counted from the day of their first infusion), were withdrawn from atezolizumab therapy due to loss of clinical benefit (e.g. disease progression at critical anatomical sites, etc. as assessed by the treating physician), patient’s or physician’s decision to withdraw, or death. o Cohort 2:

Patients who, at week 12 (counted from the day of their first infusion) , show or have shown disease control (i.e. complete response (CR), partial response (PR) or stable disease (SD)) or clinical benefit as assessed by the treating physician.

Patients with clinical benefit but unacceptable toxicity will be also assigned to cohort 2 but will not continue to receive atezolizumab.

Patients who display clinical benefit without radiographic disease control as assessed by the treating physician (e.g. in the absence of symptoms and signs indicating unequivocal progression of disease; no decline in ECOG performance status that can be attributed to disease progression; absence of tumor progression at critical anatomical sites) may be included in cohort 2 for additional 2 cycles of atezolizumab treatment to account for the possibility of pseudoprogression. If after this time radiographic disease progression is confirmed AND treatment with atezolizumab is discontinued, patients will be included in cohort 1 and documentation for this patient will be halted after post-treatment visit documentation, collection of QoL as well as AE reporting for 90 days followed by end of study documentation. Patients who continue to receive atezolizumab will be included in cohort 2. Also patients with clinical benefit but treatment discontinuation due to toxicity will be assigned to cohort 2.

The usage of PROs is considered non-interventional according to local regulation.

As after 12 weeks most patients will have received at least one staging to determine response and/or clinical benefit from treatment with atezolizumab, this time point has been chosen as a time point to help guiding the assignment of patients to cohort 1 or 2.

Start Date of Study:

The study start date will be the date of the first data collection: the date from which information on the first study patient is recorded in the study database.

First data collection: Q2 2018


End of Study

The end of the study will be the date from which the last information of the last patient is recorded in the study database.

Last data collection: The study will end 3 years after first dose of the last patient (~Q2 2023)

Length of Study

The expected length of study is calculated to be 5 years. This includes approximately 2 years of recruitment and a minimum of 3 years treatment and follow-up phase after the last patient has started on the first dose with atezolizumab.

2.3.1 Target Population

Patients must meet the following inclusion criteria for study entry:

• Adult patients (at least 18 years of age at time of treatment decision)

• Diagnosis of locally advanced or metastatic NSCLC (histologically or cytologically confirmed stage IIIB/stage IV) and prior chemotherapy

• Decision to be treated with atezolizumab according to SmPC by treating physician, independent of this non-interventional study (where a patient is evaluated/discussed by a tumor board, the decision to treat with atezolizumab should be documented)

• Patients for whom signed informed consent is available

• No contraindication to treatment with atezolizumab

Inclusion after (neo)adiuvant treatment:

Patients, having solely received chemotherapy in the (neo)adiuvant setting can only be included, if they have progressed within 6 months after finishing the last course of (neo)adjuvant therapy. If the first progression after (neo)adiuvant chemotherapy has occurred later than 6 months after the start of this therapy, these patients are considered to be eligible for first-line therapy and should therefore not be included into the study.

Patients who have received first-line pembrolizumab monotherapy are not eligible for participation, if they have not received any chemotherapy before the start of the atezolizumab treatment.


Retrospective Inclusion:

• Patients may be included retrospectively. Retrospective inclusion and documentation is limited to up to 9 weeks after initial start of therapy with atezolizumab, corresponding to a maximum of 9 weeks prior to date of informed consent. Quality of life for this population will be captured and assessed retrospectively with a modified questionnaire for the period immediately prior to treatment start until study inclusion. Patients who started atezolizumab therapy more than 9 weeks prior to ICF being obtained may not be included in the study.

• Patients who give consent to be retrospectively enrolled but have already discontinued atezolizumab for reasons such as loss of clinical benefit or toxicity may also take part in the study, given their first administration of atezolizumab is within 9 weeks of consenting to take part, and they meet all other eligibility criteria.

2.4 STUDIED MEDICINAL PRODUCT

The studied medicinal product will be atezolizumab, administered as described in the TECENTRIQ® SmPC.

Prior to administration, the treating physician should refer to the SmPC for a summary of contraindications, special warnings, precautions for use, interactions with other medicinal products, and side effects.

All other treatments should be at the discretion of the treating physician and conform to standard of care per local practice.

2.4.1.1 Variables

Only variables, obtained according to routine clinical practice and follow objectives can and should be documented in this study. Please see definition of effectiveness in section 2.2.1.

2.4.1.2 Primary Effectiveness Variables • TTLCB, defined as the time from first dose to loss of clinical benefit as assessed

by the treating physician (single or multiple reasons possible: e.g. disease progression, deterioration in ECOG performance status, patient preference, death, etc.) (Overall population and cohort 2)

• DoR, defined as the time from first documentation of CR or PR (whichever occurs first) until progressive disease (PD), as evaluated by the physician according to routine practice or death (patients with CR and PR in cohort 2 only)


2.4.1.3 Secondary Effectiveness Variable • DCR, percentage of patients who achieved a CR, a PR, or SD as evaluated by

the physician according to clinical practice 12 weeks after their first atezolizumab infusion (or after 18 weeks if pseudoprogression suspected

• PFS, defined as the time from initiation of study treatment to the first occurrence of PD or death from any cause, whichever occurs first, as evaluated by the physician according to clinical practice

• TTR, defined as the time from first dose to first response as assessed in clinical routine

• ORR, defined as rate of CR and PR in patients as assessed in clinical routine

• BOR, defined as the best response achieved within 12 weeks as assessed in clinical routine

• Coh2 BOR, defined as the best response achieved over the study period (cohort 2 only)

• Coh2 OS, defined as the time from initiation of atezolizumab treatment to death from any cause (cohort 2 only)

2.4.1.4 Safety Variables • Incidence, severity, seriousness and treatment-relatedness of AEs, SAEs and

AEs of Special Interest (AESIs) (see Appendix 3.4)


2.4.1.5 Other Variables of Interest • FACT-L scores, their association with disease progression, and factors

influencing capturing of QoL in real-world

• Type of prior cancer-related therapies for NSCLC, and their relationship to outcome measures (TTLCB, Coh 2 TTCLB, DOR, and Coh2 OS). Prior cancer therapies of interests including details (type, dose, treatment intent, etc.) are the following:

o Chemotherapy

o Thoracic radiotherapy

o Treatment of CNS metastases (if applicable)

o Targeted therapy (EGFR, ALK inhibitors etc.)

o Surgery

o Cancer immunotherapy


• Lines of prior cancer-related therapies, and their relationship to observed outcome measures (TTLCB, Coh 2 TTCLB, DOR, and Coh2 OS)

• Start and end date (if available) of the prior treatment(s) and the start date of the treatment with atezolizumab

• Best response to prior treatment regimens for metastatic disease (if available)

• Patients’ characteristics and their relationship to observed outcome measures (TTLCB, Coh 2 TTCLB, DOR, and Coh2 OS). Patients’ characteristics of interest are

o Stage of disease at first diagnosis

o Stage of disease at treatment start (TNM status)

o Performance status at baseline

o Age

o Gender

o Smoker status

o Presence of asymptomatic or symptomatic CNS metastasis

o Sites and number of metastases

o Biomarker status

PD-L1

EGFR

ALK

KRAS

Others (e.g. markers from next-generation sequencing (NGS) panel analysis)

o LDH

o Histologies

squamous

non-squamous (e.g. Adenocarcinoma)

• Outcome of radiological follow-up measurement of patients with suspected pseudoprogression within first 12 weeks of treatment (subsequent disease control – yes/no)

• Method(s) used for response assessment (assessed by physician, RECIST 1.1 vs. modified RECIST (mRECIST), other)


• Parameters leading to loss of clinical benefit (single or multiple reasons possible: e.g. disease progression, deterioration in ECOG performance status, patient preference, death, etc.)

• Patterns of radiotherapy performed during treatment with atezolizumab

• Length of treatment and reasons for discontinuation of atezolizumab

• Dose interruptions and delays

• Rate and timing of PD-L1 (re-)testing

• PD-L1 testing on tumor cells (yes vs. no)

• PD-L1 status on tumor cells (%)

• PD-L1 testing on immune cells (yes vs. no)

• PD-L1 status on immune cells (%)

• Identity of the anti-PDL1 antibody used for PD-L1 testing

• Rationale for treatment decision

2.4.2 Data Sources

Patients’ data will be recorded on electronic Case Report Forms (eCRFs). The degree of detail and completeness of data collected is dependent on local clinical practice. Data from patient notes should be entered on the eCRF as soon as they become available. Patient-reported outcomes (PROs) and questionnaire data for prospectively enrolled patients will be recorded using the paper-based FACT-L questionnaire, which will be completed by the patients. PROs and questionnaire data for retrospectively enrolled patients will be recorded using a paper-based modified questionnaire for the period immediately prior to treatment start until study inclusion. PROs and questionnaire data thereafter will be recorded using the same FACT-L questionnaire as for prospectively enrolled patients.

2.4.3 Data Analysis

The analysis of this study will be exploratory and will primarily use descriptive statistical methods. Inferential methods (e.g. confidence intervals) will be used in selected analyses to highlight interesting aspects of the data, but will be interpreted in an exploratory manner.

For the statistical analysis of time-to-event endpoints, Kaplan-Meier methods will be used for the estimation of the median overall survival. Its corresponding 95% CI will be calculated according to Brookmeyer & Crowley, 1982.


Effectiveness variables will be summarized by cohort and/or overall population. For continuous data the mean, standard deviation (SD), median, range (min, max), interquartile range (Q1, Q3). Categorical data will be displayed by absolute and relative frequencies (percentages). In addition, the number of missing values will be presented for all analyses.

The incidence of serious and non-serious AEs will be summarized according to the primary system organ class (SOC), and within each SOC by the Medical Dictionary for Regulatory Activities (MedDRA) preferred term by cohort and overall. All AEs will further be divided in treatment-related and non-treatment-related. AE data will be presented in frequency tables (overall and by NCI CTCAE grading) by body system. Listing of deaths and cause of deaths will be provided.

Final analyses will include all patients enrolled in this study meeting the eligibility criteria and being treated at least once with atezolizumab according to SmPC.

2.4.4 Study Size/Determination of Sample Size

The co-primary objectives are the estimation of time to loss of clinical benefit (TTLCB) for the overall population and for cohort 2 as well as the estimation of duration of response (DOR) for patients with CR and PR in cohort 2 under real-world conditions in patients with locally-advanced or metastatic NSCLC after prior chemotherapy and who subsequently receive atezolizumab. There is no common sample size calculation for all three co-primary objectives. As the expected rates of CR, PR are very small and the expected median DOR is much larger than the expected median TTLCB in the overall population or in cohort 2, the sample size calculation is based only on the co-primary effectiveness objective DOR and on this basis calculation for TTLCB are done.

In this study approximately 450 patients will be enrolled across 120 sites throughout Germany.

Assuming a median DOR of 18.5 months, a one-sample non-parametric survival analysis would yield in a confidence interval of [14.3 months; 24.9 months], given the sample size was 61 (10% dropout rate not included). Assuming a rate of 15% of patients achieving PR or CR under treatment, 450 patients have to be enrolled in this study.

The sample size of 207 patients with a response (CR or PR) is based on the following assumptions:

• Median DOR is expected to be18.5 months (Smith DA et al. ASCO 2016). Data from POPLAR was chosen as a reference since it has the most mature DOR data.


• The precision will be within the range of ± 4.5 months. Higher precision than ± 4.5 months would not result in more clinically relevant information but would need significant more patient numbers. A precision of ± 4.5 months secures a clear distance to confidence interval (CI) of standard therapy

• A two-sided alpha-level of 5% (i.e. 95% CI)

• Loss to follow-up is expected to be 10% Given the number of enrolled patients (N=450) and an expected median TTLCB of 3.4 months for the overall population, a one-sample non-parametric survival analysis with the sample size of 405 (10% dropout rate not included) would yield in a confidence interval of [3.1 months; 3.8 months].

As there is too little information to estimate the expected median TTLCB for cohort 2, an overview for different conceivable scenarios is given below. Given the number of enrolled patients and a proportion of 50% of patients achieving PR, CR or SD a one-sample non-parametric survival analysis with the sample size of 202 (10% dropout rate not included) would yield in the following confidence intervals.

Median TTLCB (cohort 2) Confidence Interval

5 [4.3 months ; 5.9 months ]

7 [6.0 months ; 8.2 months]




3. PROTOCOL AMENDMENTS AND UPDATES

Any protocol amendments will be prepared by the Marketing Authorization Holder (MAH) or designee.

The Scientific Responsible will seek Counsel / Consultancy for the Protocol and succeeding amendments with his/her competent Ethics Committee (EC).

Substantial protocol amendments/updates so far: see table below


Amendment/ Update Number Date

Section of Study Protocol

Amendment or Update Reason

1/ New version: Version 2.0

08-Aug-2017

8.1.3.4 Reporting Requirements for

Pregnancies/Breastfeeding

Deletion of section “Pregnancies in

Female Partners of Male Patients”

There were no effects on the male reproductive organ as stated in the SmPC..


13-Sep-2017

2.3 and 6.1 Study design; 2.2.3

and 5.2.3 Other Objectives, 2.3.2.2 and 6.3.1 Primary

Effectiveness Variables,

2.3.2.5 and 6.3.4. Other Variables of

Interest

Discontinuation of treatment due to unacceptable toxicity has been removed as criterion for assignment to cohort 1

Occurrence of irAEs can lead to permanent treatment discontinuation, but can still be accompanied by benefits from efficacy of atezolizumab.


17-Nov-2017

2.1 and 4 Background

2.3.1 and 6.2 Population;

2.3 and 6.1 Study design;

Update of approval status

Inclusion criteria for study entry: deleted “male and female” changed to “Adult patients”; Replaced “after having received prior chemotherapy” with “and prior chemotherapy”;

Adaption of study timelines.

A safety reporting period of 90 days was added for cohort 1 after treatment discontinuation and spontaneous safety reporting until end of

Atezolizumab has been approved by the

EMA in Sep 2017;

Allow “undifferentiated” sex

for patients; Clarification of eligible study population;

Study start has been postponed to Q4 2017.

AEs can occur after treatment

discontinuation and should be captured in the eCRF for cohort 1 for a wash out period

of 90 days and should be reported

spontaneously to the






8.1 Safety Reporting

Requirements for Studied Medicinal

Products

study;

Addition of cross-references to details on pseudoprogression;

Changed “Management of AEs, SAEs and AESIs (duration of withholding atezolizumab (all AEs), medication used to manage AEs)” to “Duration of withholding atezolizumab & management of AEs, SAEs and AESIs”

Addition of “Events that are clearly consistent with the expected pattern of the course of the underlying disease should not be recorded as AEs.”

Addition of section 8.1.3.6 Reporting Requirements for Adverse Events originating from previous therapies (before patient was

appropriate MAH thereafter until end of

study;

Supporting cross-references to find

information on pseudoprogression;

Medication used to manage AE was

deleted from safety objectives. However,

we are collecting these data on AE

reporting forms within the study

Clarification of scope and procedures for

adverse event recording





Appendix 3.3 PROCEDURES

FOR RECORDING ADVERSE EVENTS

enrolled in the study)

Addition of Appendix 3.3.15 Patient-reported outcome

Additional minor changes have been made to improve clarity and consistency.


01-Dec-2017

2.3.1 and 6.2 Population

Amendment of retrospective inclusion

To avoid selection bias and support

independent treatment decision


01-Feb-2018

2.2.1 and throughout

Addition of definition of effectiveness vs. efficacy and note regarding translation into German in 2.2.1 and minor semantic changes throughout

To ensure effectiveness is

clearly differentiated from efficacy and to

clarify that safety outcomes in a NIS are understood as

being observed effects under non-

controlled conditions


26-Mar-2018

Synopsis

8.1.1 and 8.1.2

8.1.3.6

Study start and end date

AE/AESI reporting period for retrospectively enrolled patients and inclusion of hypothyroidism in AESIs

Clarification of AE reporting period

Reflect delayed study start date and ensure that all relevant AEs

and AESIs are captured correctly in

eCRF





7/ New

Protocol version:

8.0

XX-XXX-2019

Synopsis 2.3

2.3.1 2.4.4

Protocol

6.1 6.2

6.7.4 6.7.5 6.8.4 8.3

App 3.1.15

Study design – q2w/q3w/q4w

Study Size/determination of

sample size 450 patients, 120 sites

Clarification of inclusion criteria

Definition of cohorts

Adapted Timing of Interims Analyses

Adaptions to NIS Template Version 6.0 - Changed Retention

time - Reporting of Complaints

Reflecting actual patient recruitment, clarifying inclusion

criteria and including new dosing regimen

for Atezolizumab


4. RATIONALE AND BACKGROUND

Lung Cancer

In Germany, lung cancer is the third most common cancer diagnosis in both, men and women - about 17,000 women and 33,000 men are diagnosed with lung cancer every year. With 45,000 deaths per year in 2015, lung cancer was also the most common cause of death from cancer in Germany (GEKID 2013; Statistisches Bundesamt 2017).

NSCLC is one of the two major types of lung cancer, accounting for approximately 75% of all lung cancer cases (Bundesweite Onkologische Qualitätskonferenz 2016). The two predominant histologic types of NSCLC are adenocarcinoma, which accounts for more than half of cases, and squamous cell carcinoma, which accounts for approximately 25% of cases (Langer et al. 2010; Travis et al. 2011).

The overall 5-year survival rate for stage IV non−small cell lung cancer (NSCLC) is 2%−4%, depending on geographic location (Cetin et al. 2011). Poor prognostic factors for survival in patients with NSCLC include advanced stage of disease at the time of initial diagnosis, poor Eastern Cooperative Oncology Group (ECOG) performance status, and a history of unintentional weight loss. More than half of the patients with NSCLC present with distant metastatic disease at the time of initial diagnosis, which directly contributes to poor survival prospects.

Management of patients with advanced (stage IIIB/IV) NSCLC is individualized on the basis of molecular and histologic features of the tumor. The presence of somatic activating mutations in the epidermal growth factor receptor (EGFR) gene and rearrangements in the anaplastic lymphoma kinase (ALK) gene or in the ROS proto-oncogene 1 receptor tyrosine kinase (ROS1) are strongly predictive of sensitivity to EGFR tyrosine kinase inhibitors (TKIs) or specific ALK TKIs, respectively. The rates of these mutations differ depending on patients’ characteristics, particularly between squamous cell carcinoma and adenocarcinoma. (Herbst et al. 2008; Langer et al. 2010, Travis et al. 2011).

Recently, PD-L1 is emerging as another biomarker in NSCLC for the use of cancer immunotherapy (CIT) in patients with locally advanced or metastatic NSCLC. Pivotal trials of therapies targeting PD-1 or PD-L1 show differences regarding the association between PD-L1 expression in the tumor and magnitude of clinical benefit from these checkpoint inhibitors (Rittmeyer et al. 2016, Brahmer et al. 2015, Borghaei et al. 2015, Herbst et al. 2016, Reck et al. 2016).


Second-Line Treatment for Non−Small Cell Lung Cancer

Despite improvements in the first-line treatment of patients with advanced NSCLC that have resulted in longer survival times and reduced disease-related symptoms, nearly all patients experience disease progression. To date there is still an unmet need for more effective and better tolerable therapeutic options for 2nd and further line treatment of patients with NSCLC. The most commonly used agents in the second-line setting of NSCLC without somatic mutations are docetaxel (plus nintedanib or ramucirumab), pemetrexed, erlotinib, and recently nivolumab and pembrolizumab (Onkopedia 2016). The choice of agents depends upon a number of factors, including tumor histology, the patient’s comorbidities, toxicity from previous treatments, risk of neutropenia, smoking history, and patient’s preference. Patients with a good performance status in second-line trials have a median survival duration of approximately 8 to 9 months with chemotherapy or about 10 to 14 months with checkpoint inhibitors, respectively, and may receive two salvage therapies during the course of their treatment (Stinchcombe et al. 2008; Rittmeyer et al. 2016, Brahmer et al. 2015, Borghaei et al. 2015, Herbst et al. 2016).

In September 2017 Atezolizumab has been approved by the European Medical Agency (EMA) as monotherapy for the treatment of patients with locally advanced or metastatic NSCLC after prior therapy. Patients with EGFR activating mutations or ALK-positive tumour mutations should also have received targeted therapy before receiving atezolizumab (TECENTRIQ SmPC). Approval was based on results from the randomized Phase III OAK and Phase II POPLAR studies, both evaluating the efficacy and safety of atezolizumab compared with docetaxel in patients with locally advanced or metastatic NSCLC whose disease had progressed following or during previous treatment with platinum-containing chemotherapy. Patients who had a detectable EGFR-mutation or ALK-rearrangement were additionally required to have received previous tyrosine kinase inhibitor therapy. In the preliminary analysis of the phase III-study OAK, a 27% reduced risk of death was observed in the ITT population for patients receiving atezolizumab compared to those treated with docetaxel after a median follow-up of 21 months. Overall survival HRs favored atezolizumab across predefined histology subgroups (squamous or non-squamous disease; both HR 0.73; 95% CI, 0.60, 0.89 and 95% CI, 0.54, 0.98, respectively). Median DoR for the ITT population was 16.3 month for atezolizumab compared to 6.2 month for docetaxel.

The phase II POPLAR study enrolled 287 patients with previously treated advanced NSCLC. The primary endpoint was OS; secondary endpoints included PFS, ORR and safety. Atezolizumab showed a median OS of 12.6 month (95% CI: 9.7, 16.0) compared to 9.7 month (95% CI: 8.6, 12.0) for docetaxel with a minimal follow-up time of 21 months. The median duration of response was 18.6 month for atezolizumab vs 7.2 month for docetaxel (Smith et al. 2016).


For further information on the condition under observation and on Atezolizumab (TECENTRIQ®) please refer to the most recent version of the SmPC.

4.1 STUDY RATIONALE Thorough knowledge of the treatment reality regarding clinical characteristics, diagnostics, treatment regimens and outcome of patients treated with atezolizumab in real-life practice is crucial to understand the effectiveness of atezolizumab and observe safety signals and parameters in patients outside of interventional clinical trials. Currently the knowledge and experience around treatment with atezolizumab in patients with NSCLC is solely based on clinical trials.

Cancer immunotherapy is an innovative therapy and atezolizumab will be the first approved PD-L1 inhibitor as treatment option for patients with advanced NSCLC in Germany. Data on atezolizumab in clinical routine is needed to generate real-world evidence to complement clinical data obtained from randomized trials and to gain additional information around the effectiveness and observed safety in overall populations and in relevant subgroups.

Various factors are currently being discussed to potentially have an effect on the tumor micro-environment and as a result on response to cancer immunotherapy. Several studies have indicated that the antitumor activity of chemotherapy does not only happen through direct killing of tumor cells, but also relies on several off-target effects, especially directed to the host immune system (Bracci et al. 2014). Prior chemotherapy regimens therefore might influence response to treatment with atezolizumab and other checkpoint inhibitors. Carcinogens in tobacco smoke are largely responsible for the mutagenesis in NSCLC and smoking-related lung cancers are generally characterized by a greater mutation burden than those that occur in never smokers (Pfeifer et al. 2002, Govindan et al. 2012). It has been hypothesized that a higher mutational burden in smokers conferring increased immunogenicity might represent a predictive marker of response to cancer immunotherapy. Some pivotal trials of immune checkpoints inhibitors hint at a potential relationship between efficacy of PD-1/PD-L1 therapy and smoking history, however the observed better efficacy in smoking patients’ needs to be further confirmed (Gettinger et al. 2016, Rizvi et al. 2015). Never smokers appear to be a patient population historically less responsive to these agents, however with atezolizumab an overall survival benefit was also observed in this subgroup (Rittmeyer et al. 2016).

Due to potential age-related impairment of adaptive and innate immunity, which could impair effective checkpoint inhibition, analysis of effectiveness and also observed safety outcomes in different age groups is also a topic of interest. To date, little is known about the effectiveness and the toxicity of immune-checkpoint inhibitors in elderly, due to a lower inclusion rate of these patients in pivotal clinical trials. In the OAK trial survival


benefit was consistent across age subgroups. The median OS for a total of 397 patients aged ≥65 years was 14.1 and 9.2 months for patients treated with atezolizumab and docetaxel respectively (HR 0.66) (Rittmeyer et al. 2016).

To date, the favored biomarker for anti-PDL1 as well as anti-PD1 therapies seems to be the expression of PD-L1 assessed by immunohistochemistry (IHC). However, distinct approaches have been taken to PD-L1 IHC evaluation (different diagnostic antibodies, technical staining platforms, definitions of a “positive” predictive IHC stain, and analyzed cell types (immune cells as opposed to, or in combination with, tumor cells; Table 1) (Kerr et al. 2015, Scheel et al. 2016).

Table 1. Overview PD-L1 assays and scoring-criteria in pivotal trials

Assay,

antibody Cell type Negative Low/weak Medium High/strong

Nivolumab (anti-PD1; Bristol-Myers Squibb)

Dako 28-8 Tumor 0–1% 1–5% 5–10% ≥10%

Pembrolizumab (anti-PD1; Merck Sharp & Dohme)

Dako 22C3 Tumor 0–1% 1–50% ≥50%

Atezolizumab (anti-PDL1; Roche)

Ventana SP142

Tumor 0–1% 1–5% 5–50% ≥50%

Immune 0–1% 1–5% 5–10% ≥10%

Durvalumab (anti-PDL1; AstraZeneca)

Ventana SP263 Tumor 1–25% ≥25%

Modifiziert nach Scheel et al. Modern Pathology, 2016

In pivotal trials of anti-PDL1 and anti-PD1 checkpoint inhibitors the association of PD-L1 status and clinical benefit derived from the respective therapy seems to vary (Kerr et al. 2015). In the OAK trial the subgroup of patients with the highest PD-L1 expression (TC3/IC3) derived the greatest benefit from atezolizumab treatment (HR 0.41), however even in patients with no PD-L1 expression (TC0/IC0), the risk of death was still reduced by 25% with atezolizumab compared to those treated with docetaxel. Furthermore, responses appear durable in this PD-L1-negative subgroup with the median duration of response (DoR) not reached for atezolizumab versus 6.2 months with docetaxel at the time of primary analysis. Pivotal trials of nivolumab in advanced NSCLC (Checkmate 017 and 057) have shown distinct results for the association of benefit from nivolumab treatment with the level of PD-L1 expression depending on the histology (non-squamous vs. squamous NSCLC) (Brahmer et al. 2015, Borghaei et al. 2015). In the phase II/III


trial of pembrolizumab in advanced NSCLC (KEYNOTE-010) only patients with PD-L1 expression of at least 1% of tumor cells were eligible for the trial (Herbst et al. 2016). Therefore, pembrolizumab is currently the only checkpoint inhibitor that requires a positive PD-L1 expression for use in second-line NSCLC patients. To date, there is no data available on PD-L1 testing results and methodology from routine histological work-up and the association of PD-L1-status with benefit from atezolizumab. The median time to response for patients with second-line NSCLC under treatment with anti-PDL1/PD1-checkpoint inhibitors varies from two to three months. In patients treated with checkpoint inhibitors, unconventional radiographic response patterns have been observed, such as a response after an initial increase of tumor burden or a reduction in tumor burden during or after the appearance of new lesions, which would otherwise be classified as PD by RECIST1.1. These unconventional response patterns are termed “pseudoprogression” (Nishino et al. 2016). To take these response patterns into account a novel approach for the evaluation of response, immune-related response criteria (irRC), was proposed in 2009 (Wolchok et al. 2009). The key features of irRC are 1) inclusion of new lesion measurements to the total tumor burden and 2) requirement of confirmation of PD on two consecutive scans at least 4 weeks apart. irRC, in some trials also termed “modified RECIST”, has been applied in trials of PD-1 and PD-L1 inhibitors in NSCLC to define trial endpoints (Nishino et al. 2016; Fehrenbacher et al. 2016). However, pseudoprogression is generally rare in NSCLC patients treated with PD-1 or PD-L1 inhibitors (3-5% of patients), and for patients with clear clinical progression (declining performance status, tumor progression at critical anatomical sites, and/or worsening clinical symptoms) therapy should be switched (Patel 2015). For patients with advanced NSCLC after prior chemotherapy treatment with atezolizumab is recommended until loss of clinical benefit or unmanageable toxicity. This is in line with pivotal studies where treatment with atezolizumab was permitted until loss of clinical benefit as defined by the following criteria:

• Absence of symptoms and signs (including worsening of laboratory values [e.g., new or worsening hypercalcemia]) indicating unequivocal progression of disease

• No decline in ECOG performance status

• Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal disease) that cannot be readily managed and stabilized by medical interventions prior to repeat dosing

• Evidence of clinical benefit as assessed by the investigator

In the OAK trial, 39% of patients receiving atezolizumab were treated beyond disease progression assessed by RECIST 1.1. No data on treatment duration and time to loss of clinical benefit in a real-world setting are currently available.


Rates as well as duration of displaying clinical benefit and possible associations with patient-related factors (e.g. age, smoker status etc.) in the real-world setting are of great interest in order to help identifying patients most likely to benefit from treatment with atezolizumab.

In addition to effectiveness analyses also the observation of the safety profile of atezolizumab under real-world conditions is of interest. In the POPLAR as well as the OAK trial atezolizumab showed a consistent favorable safety profile compared with docetaxel (Fehrenbacher et al. 2016, Rittmeyer et al. 2016). The majority of common chemotherapy-associated adverse effects are due to off-target cytotoxicity by killing cells that are dividing rapidly, irrespective of whether they are cancerous or healthy cells. The development of cancer immunotherapies presents new challenges in recognizing and managing treatment-related adverse effects. Cancer immunotherapies, although showing a favorable toxicity profile compared to chemotherapy, are associated with side effect profiles that are distinct from those well-known when administering chemotherapy or targeted therapies (Gangadhar and Vonderheide 2014). Most of these immune-related adverse events (irAEs) of CIT can be managed by counteracting lymphocyte activation with steroids (Michot et al. 2016). So far there is no data on atezolizumab-related irAEs and their management in clinical routine.

There is increasing recognition of the importance of evaluating quality of life (QOL) as part of clinical trials and clinical practice in patients with thoracic malignancies (Gralla et al. 2004). Current guidelines recommend to regularly assess the quality of life of in the course of the disease, which may include appropriate standardized questionnaires reflecting patient-assessed quality of life (Goeckenjan et al. 2010). There are several aspects that cause difficulties in the collection of QoL data (e.g. deterioration of PS, response burden etc.) and might also affect questionnaire response rates. The problem of “missing data” again causes difficulties in drawing conclusions from QoL studies (Anant et al. 2005; Rolstad et al. 2011). The literature suggests that the event of disease recurrence/radiological disease progression causes psychological distress in patients (Mahon et al. 1990). Furthermore, there are non-patient-related barriers to capture QoL data in clinical routine (e.g. management/time, education, tool specific, financing, illness-related, clinician’s beliefs; Antunes et al. 2014; Donaldson MS 2004). There is a need to understand the current practice and hurdles of collecting QoL data as well the potential effects of disease progression on the QoL of lung cancer patients in real-world.

There are so far no data available for atezolizumab and its effect on quality of life in a real-world setting.


5. RESEARCH QUESTION AND OBJECTIVES

5.1 RESEARCH QUESTION

To date there is a lack of deep understanding why some lung cancer patients do or do not respond to checkpoint inhibitors. Previous therapies (e.g. chemotherapeutic agents, TKIs) as well as other patient-related factors (e.g. smoking history, biomarkers) can influence the composition of the tumor stroma and/or the immunogenicity of the tumor.

The following research questions should be addressed in this non-interventional study:

• What is the effectiveness of atezolizumab under real-world-conditions?

• What is the duration of clinical benefit and response of patients treated with atezolizumab under real-world conditions?

• Which parameters (e.g. previous therapies and baseline characteristics (patient and tumor characteristics)) appear to be associated with clinical outcome in patients treated with atezolizumab under real-world conditions?

• What is the observed safety profile of atezolizumab under real-world conditions?

• What is the quality of life of patients treated with atezolizumab under real-world conditions and how does it correlate with OS?

• What is the relationship of disease progression and patients‘ QoL (symptoms and emotional well-being)?

• How frequently are QoL data collected under real-world conditions? What parameters impact capturing QoL data?

• What are the characteristics of PD-L1 testing results gained in routine clinical practice as opposed to clinical trial conditions?

• What is the occurrence of radiotherapy during treatment with atezolizumab in routine clinical practice?

In this NIS, patients will be assigned to one of two cohorts depending on their clinical benefit from atezolizumab, to address the question of potential correlating factors in prior therapies or patient characteristics and

• lack of benefit from atezolizumab (cohort 1) or

• durability of clinical benefit and tumor response to atezolizumab (cohort 2)

under real-world conditions, respectively.


5.2 OBJECTIVES

5.2.1 Effectiveness Objectives

The primary effectiveness objective of this study is as follows:

• To evaluate the time to loss of clinical benefit (TTLCB) to atezolizumab treatment as assessed by the treating physician under real-world conditions (Overall population and cohort 2; for details please see study design section 6.0)

• To evaluate duration of response (DoR) to atezolizumab treatment under real-world conditions (patients with CR and PR in cohort 2 only; for details please see study design below).

• The secondary effectiveness objectives of this study are as follows:

To evaluate

• Disease control rate (DCR) (overall population)

• Progression-free survival (PFS) (overall population)

• Time to response (TTR) (in patients with documented PR/CR)

• Overall response rate (ORR) (overall population)

• Best overall response (BOR) (overall population)

• Best overall response of patients in cohort 2 (“Coh2 BOR”)

• Overall survival of patients in cohort 2 (“Coh2 OS”)


The safety objectives of this study are as follows:


• Incidence of all adverse events (AEs), serious adverse events (SAEs) and AEs of Special Interest (AESIs) in atezolizumab treated patients per cohort and overall study population – see Appendix 3.4


5.2.3 Other Objectives


• Health-related quality of life (HRQoL) prior to first atezolizumab infusion, during, atezolizumab treatment and after atezolizumab discontinuation, using the FACT-


L instrument and a modified questionnaire where applicable, and association of QoL with disease progression

• Type and lines of cancer-related therapies used before initiation of atezolizumab, and their relationship to outcome measures (TTLCB, Coh 2 TTCLB, DOR, and Coh2 OS)

• Time between completion of the prior treatment and the start of the treatment with atezolizumab

• Patients’ characteristics (subgroups of interest) and their relationship to outcome measures (TTLCB, Coh 2 TTCLB, DOR, and Coh2 OS)

• Outcome of follow-up measurement of patients with suspected pseudoprogression within first 12 weeks of treatment (subsequent disease control – yes/no)

• Occurrence and patterns of radiotherapy during treatment with atezolizumab

• Characteristics of PD-L1 testing in real-world clinical practice, including rates of PD-L1 (re-)testing, methodology (diagnostic antibody used), and test result (PD-L1 status)

• Main reason for decision for treatment with atezolizumab


6. RESEARCH METHODS

6.1 STUDY DESIGN

HYPERION is a prospective, multicenter, non-interventional, two-cohort study collecting primary data in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) of squamous or non-squamous histology after prior chemotherapy treated with atezolizumab in routine clinical practice.

Depending on their clinical benefit from atezolizumab patients included in this non-interventional study will be assigned to one of the two following cohorts 12 weeks after their first atezolizumab infusion (or after 18 weeks if pseudoprogression suspected):

Cohort 1:

Patients who, prior to their next planned infusion of atezolizumab at week 12 (counted from the day of their first infusion),, were withdrawn from atezolizumab therapy due to loss of clinical benefit (e.g. disease progression at critical anatomical sites, etc.), patient’s or physician’s decision to withdraw, or death.

Cohort 2:

Patients who, at week 12 (counted from the day of their first infusion) show or have shown disease control (i.e. complete response (CR), partial response (PR) or stable disease (SD)) or clinical benefit.

Patients who display clinical benefit without radiographic disease control as assessed by the treating physician (e.g. in the absence of symptoms and signs indicating unequivocal progression of disease; no decline in ECOG performance status that can be attributed to disease progression; absence of tumor progression at critical anatomical sites) may be included in cohort 2 for additional 2 cycles of atezolizumab treatment to account for the possibility of pseudoprogression. If after this time radiographic disease progression is confirmed AND treatment with atezolizumab is discontinued, patients will be included in cohort 1 and documentation for this patient will be halted after post-treatment visit documentation, collection of QoL as well as AE reporting for 90 days followed by end of study documentation. Patients who continue to receive atezolizumab will be included in cohort 2. Also patients with clinical benefit but treatment discontinuation prior to week 12 due to toxicity will be assigned to cohort 2.


6.1.1 Overview of Study Design

The study will be conducted in approximately 120 centers across Germany and will enroll approximately 450 eligible patients. The overall study duration is planned to be approximately 5 years including a 2-year recruitment period and 3-year time period after the last patient has started the treatment with atezolizumab. Eligible are patients with locally advanced or metastatic NSCLC after prior chemotherapy, who have been chosen by their treating physicians to receive atezolizumab according to the current SmPC of TECENTRIQ®, and who consent to participate in this non-interventional study. No specific treatments are mandated. Instead, choice of treatments, including atezolizumab, will be at the discretion of the treating physician per local guidelines.

Patients are to be enrolled in the study no earlier than the decision to initiate treatment with atezolizumab, and no later than 9 weeks after the first administration of atezolizumab . The treating physician’s decision to start patients’ treatment with atezolizumab has to be taken independently of participation in the study and the rationale for choice of treatment will be captured. Where a patient is evaluated/discussed by a tumor board, the decision to treat with atezolizumab should be documented.

An overview of the study design is shown in Figure 1.

* after 18 weeks if pseudoprogression is suspected #Patients with clinical benefit but unacceptable toxicity will be

assigned to cohort 2 but will not continue to receive atezolizumab; $AEs and QoL should be documented for 90 days after

treatment discontinuation. General clinical documentation will be halted.

Figure 1 Study Design

For patients assigned to cohort 1, following the post-treatment visit general documentation of clinical data will be halted. AEs and QoL should be documented for 90 days after treatment discontinuation followed by end of study documentation. After this period AEs should be sent spontaneously to the MAH of the suspected medicinal


product, or to the concerned competent authorities via the national spontaneous reporting system.

Patients assigned to cohort 2 will continue on atezolizumab until physician-assessed loss of clinical benefit, unacceptable toxicity, physician or patient decision to withdraw from therapy, or death, whichever occurs first. Patients’ survival from cohort 2 will be followed for a maximum of 5 years from study start date until death, withdrawal of consent, loss of follow-up/record, or to end of study, whichever comes first. During the follow-up period, assessment schedules will be performed according to routine local clinical practice.

Following atezolizumab discontinuation, QoL assessments should be conducted according to clinical practice (recommendation: QoL assessments around the time of progression and at 6, 12, and if applicable 24 weeks following disease progression).

As this is a non-interventional study, no visits or measurements are mandatory by the protocol and data collection at pre-specified time-points are only recommendations and will only take place if the patient visits the site.

New anti-cancer therapies will be documented at the next patient-physician contact for cohort 1 and 2, and if applicable during the follow-up period for cohort 2. Information on AEs, SAEs, AESIs and Pregnancies will be collected until the end of the study. A data collection overview is provided in Appendix 2.

Start Date of Study:

The start date will be the date of the first data collection: the date from which information on the first patient is recorded in the database. The planned start date is Q2/2018.

End of Study:

The end date will be the date from which the last information of the last patient is recorded in the database. The planned end of study date is Q2/2023.

6.1.2 Number of Patients Observed in the Study

According to the sample size calculation specified in chapter 6.7.5 approximately 450 patients should be enrolled.

6.1.3 Sites

This non-interventional study will collect data from both office-based and hospital-based oncology care facilities in Germany. This national study will be conducted at


approximately 120 sites across all of Germany. Additional centers may be added or substituted if underperforming.

6.1.4 Rationale for Study Design

The objective of the present non-interventional study is to observe the clinical outcome of patients with locally-advanced or metastatic NSCLC of squamous or non-squamous histology after prior chemotherapy and treated with atezolizumab under real-world conditions. To date, no data on effectiveness, or observations around the safety and utilization of atezolizumab in a real-world setting are available.

In this NIS patients will be assigned to one of two cohorts, to address the question of potential correlating factors in prior therapies or patient characteristics, and either

• lack of clinical benefit from atezolizumab (cohort 1) or

• durability of clinical benefit from and tumor response to atezolizumab (cohort 2)

under real-world conditions, respectively.

After informed consent is obtained, data on patients’ demographic and clinical characteristics, biomarker testing, and prior anti-cancer therapies will be documented. During the treatment period and follow-up period, data on all treatments, course of disease and outcome will be collected.

Interims analyses for early response and safety evaluation will be performed after 80% of patients have been enrolled (expected Q4 2019).

6.2 POPULATION

Patients receiving treatment for locally-advanced or metastatic NSCLC with atezolizumab after prior chemotherapy according to standard of care and in line with the current summary of product characteristics (SmPC)/local labeling are eligible for observation in this non interventional study.

Patients must meet the following inclusion criteria for study entry:

• Adult patients (≥18 years of age at time of treatment decision)

• Diagnosis of locally advanced or metastatic NSCLC (histologically or cytologically confirmed stage IIIB/stage IV) and prior chemotherapy

• Decision to be treated with atezolizumab according to SmPC by treating physician, independent of this non-interventional study (where a patient is evaluated/discussed by a tumor board, the decision to treat with atezolizumab should be documented)


• Patients for whom signed informed consent is available

• No contraindication to treatment with atezolizumab

Inclusion after (neo)adiuvant treatment:

Patients, having solely received chemotherapy in the (neo)adiuvant setting can only be included, if they have progressed within 6 months after finishing the last course of (neo)adjuvant therapy. If the first progression after (neo)adiuvant chemotherapy has occurred later than 6 months after the start of this therapy, these patients are considered to be eligible for first-line therapy and should therefore not be included into the study.

Patients who have received first-line pembrolizumab monotherapy are not eligible for participation, if they have not received any chemotherapy before the start of the atezolizumab treatment.

Retrospective Inclusion:

• Patients may be included retrospectively. Retrospective documentation is limited to up to 9 weeks after initial start of therapy with atezolizumab,corresponding to up to a maximum of 9 weeks prior to date of informed consent. Quality of life for this population will be captured and assessed retrospectively with a modified questionnaire for the period immediately prior to treatment start until study inclusion. Patients who started atezolizumab therapy more than 9 weeks prior to ICF being obtained may not be included in the study.

• Patients who give consent to be retrospectively enrolled, but have already discontinued atezolizumab for reasons such as loss of clinical benefit or toxicity, may also take part in the study, given their first administration of atezolizumab is within 9 weeks of consenting to take part, and they meet all other eligibility criteria.

6.2.1 Rationale for Patient Population

Real-world data on observed effectiveness, safety and quality of life of atezolizumab will be collected in pre-treated patients with squamous or non-squamous, locally-advanced or metastatic NSCLC according to market authorization.


6.2.2 Concomitant Medication and Treatment

Concomitant medication prescribed for concomitant diseases and treatment for locally advanced or metastatic NSCLC at the beginning of the observation period or introduced during the observation period will be documented in the eCRF from start of therapy with atezolizumab until discontinuation of the treatment, if applicable.

Information on medication used for management of all AEs, SAEs and AESIs will be collected.

6.2.3 Dosage, Administration, and Compliance

Dosing and treatment duration of any studied medicinal products collected as parts of this non-interventional study are at the discretion of the physician in accordance with local clinical practice and local labeling.

6.3 VARIABLES

Only variables obtained according to routine clinical practice and which follow objectives can and should be documented in this study.

Potential confounding variables and effect modifiers are baseline characteristic of patients (e.g. histology subtype (squamous versus non-squamous), age, PS, tumor mutation status, PD-L1 expression status, prior therapies, etc.). Baseline documentation of quality of life collected after first administration of atezolizumab might impact change of scores from baseline.

6.3.1 Primary Effectiveness Variable • TTLCB, defined as the time from first dose to treatment discontinuation due to

loss of clinical benefit as assessed by the treating physician (single or multiple reasons possible: e.g. disease progression, deterioration in ECOG performance status, patient preference, death, etc.) (Overall population and cohort 2)

• Duration of response (DoR), defined as the time from first documentation of partial or complete response (whichever occurs first) until progressive disease, as evaluated by the physician according to routine practice (patients with CR and PR in cohort 2 only)

6.3.2 Secondary Effectiveness Variable • DCR, percentage of patients who achieved a complete response, a partial

response, or stable disease as evaluated by the physician according to clinical


practice 12 weeks after their first atezolizumab infusion (or after 18 weeks if pseudoprogression suspected):

• PFS, defined as the time from initiation of study treatment to the first occurrence of disease progression or death from any cause, whichever occurs first, as evaluated by the physician according to clinical practice

• TTR, defined as the time from first dose to first response as assessed in clinical routine

• ORR, defined as rate of complete (CR) and partial responses (PR) in patients as assessed in clinical routine

• BOR, defined as the best response achieved within 12 weeks as assessed in clinical routine

• Coh2 BOR, defined as the best response achieved over the study period, (cohort 2 only)

• Coh2 OS, defined as the time from initiation of atezolizumab treatment to death from any cause (cohort 2 only)

6.3.3 Safety Variables • Incidence, time of onset, severity, seriousness and treatment-relatedness of AEs

and SAEs


6.3.4 Other Variables of Interest • FACT-L scores, their association with disease progression, and factors

influencing capturing of QoL in real-world

• Type of prior cancer-related therapies for NSCLC, and their relationship to outcome measures (TTLCB, Coh 2 TTCLB, DOR, and Coh2 OS). Prior cancer therapies of interests including details (type, dose, treatment intent, etc.) are the following:

o Chemotherapy

o Thoracic radiotherapy

o Treatment of CNS metastases (if applicable)

o Targeted therapy (EGFR, ALK inhibitors etc.)

o Surgery

o Cancer immunotherapy


• Lines of prior cancer-related therapies, and their relationship to outcome measures (TTLCB, Coh 2 TTCLB, DOR, and Coh2 OS)

• Start and end date (if available) of the prior treatment(s) and the start date of the treatment with atezolizumab

• Best response to prior treatment regimens for metastatic disease (if available)

• Patients’ characteristics and their relationship to outcome measures (TTLCB, Coh 2 TTCLB, DOR, and Coh2 OS). Patients’ characteristics of interest are

o Stage of disease at first diagnosis

o Stage of disease at treatment start (TNM status)

o Performance status at baseline

o Age

o Gender

o Smoker status

o Presence of asymptomatic or symptomatic CNS metastasis

o Sites and number of metastases

o Biomarker status

PD-L1

EGFR

ALK

KRAS

Others (e.g. markers from next-generation sequencing (NGS) panel analysis)

LDH

o Histologies

squamous

non-squamous (e.g. Adenocarcionoma)

• Outcome of radiological follow-up measurement of patients with suspected pseudoprogression within first 12 weeks of treatment (subsequent disease control – yes/no)

• Method(s) used for response assessment (assessed by physician, RECIST 1.1 vs. modified RECIST (mRECIST), other)


• Parameters leading to loss of clinical benefit (single or multiple reasons possible: e.g. disease progression, deterioration in ECOG performance status, death, etc.)

• Patterns of radiotherapy performed during treatment with atezolizumab

• Length of treatment and reasons for discontinuation of atezolizumab

• Dose interruptions and delays

• Rate and timing of PD-L1 (re-)testing

• PD-L1 testing on tumor cells (yes vs. no)

• PD-L1 status on tumor cells (%)

• PD-L1 testing on immune cells (yes vs. no)

• PD-L1 status on immune cells (%)

• Identity of the anti-PDL1 antibody used for PD-L1 testing


6.4 DATA SOURCES

Patients’ data will be recorded in eCRFs. The degree of detail and completeness of data collected is dependent on local clinical practice. Data from patient notes should be entered in the eCRF as soon as they become available.

Patient-reported outcomes (PRO) and questionnaire data for prospectively enrolled patients will be recorded using the paper-based FACT-L questionnaire in accordance with current guidelines (e.g. S3 guidelines NSCLC). PROs and questionnaire data for retrospectively enrolled patients will be recorded using a paper-based modified questionnaire for the retrospective period, followed by the paper-based FACT-L questionnaire. Questionnaires completed by patients will remain at the sites, and will be sent to the CRO via fax or email for entering of data in the eCRF.

6.4.1 Data Collected during the Observation Period

During therapy with atezolizumab laboratory assessments are routinely performed in accordance with current guidelines and local standard of care. Available results from the range of assessments described below will be documented in the eCRF. Most data will be documented around point in time or period during the treatment period when the respective assessments are usually performed according to standard of careThe proposed assessments and suggested timings for assessments in the protocol/observational plan are not mandatory. It is up to the treating physician to perform and document the assessments as performed in the real clinical setting.


For retrospectively included patients, baseline measures should be available and are to be documented and entered on the eCRF at or shortly after obtaining patient consent in the same fashion as for prospectively included patients.

At baseline, the following items should be documented:

• Acceptance of inclusion / exclusion criteria


• Demographic data including age, sex, height, weight, and self-reported race / ethnicity

• ECOG performance status

• Smoker status

• NSCLC history (including information on date of diagnosis, histologic type, stage at diagnosis of advanced disease, number and location of metastases at baseline, presence of asymptomatic or symptomatic brain metastasis at baseline)

• Prior anticancer therapies (type, number of lines, number of cycles, dose, start and end date (if available), best response (if available), for surgery: intent of treatment, for radiotherapy: field of radiation)

• Medical history including significant diseases within the previous 3 years, major surgeries

• Conduct, methodology, timing, and outcome of PD-L1 (re-)testing

• Biomarker status: EGFR, ALK, KRAS, other, LDH

• Concomitant medication (e.g. systemic immunosuppressants) and comorbidities (e.g. COPD, autoimmune diseases)

• Start date of therapy with atezolizumab

During treatment period the following items should be documented (if applicable):

• Performance status

• Information on dosage and dosing schedule of atezolizumab

• Start and end date of treatment interruption or delays

• Reasons for and lengths of treatment interruptions and delays

• Concomitant medication

• Tumor Response (CR, PR, SD, PD) according to clinical practice

• Method of response evaluation


• Assessment of response and clinical benefit

• Location of disease progression

• Location and number of metastases

• Occurrence of secondary cancer

• Date and cause of death

• Stop date of therapy with atezolizumab

• AEs, SAE, AESIs, pregnancies

• AE management

• FACT-L questionnaire according to clinical routine (Recommendations: baseline on day 1 before start of treatment with atezolizumab; after 6 weeks, 12 weeks, and every 12 weeks thereafter; for details see 6.7.3)

At the post-treatment visit and/or during follow-up period the following items should be documented:

• Performance status (post-treatment visit)

• Reason(s) for Discontinuation (multiple answers possible): Loss of clinical benefit, PD, deterioration of PS, toxicity (AE/SAE/AESI), patient’s wish, physician’s decision, other

• Subsequent therapies for NSCLC (type, start and end date (if available), best response (if available))

• AEs, SAE, AESI, Pregnancies

• FACT-L questionnaire (according to clinical routine; around the time of progression and after 6, 12 and 24 weeks after progression; for details see 6.7.3)

• Date and cause of death

In the routine care setting, patients are seen regularly by their treating physicians either for treatment or for regular assessment after treatment. Thus, no study-specific visits or evaluations are required by this protocol.

Please see Appendix 2 for the data collection overview (as per routine practice).

6.4.2 Data Collected at Study Completion

For patients who complete the study, the study completion visit should be documented, which collects information on survival status (e.g. death date, reason for death) and reasons for study discontinuation if applicable.


Please see Appendix 2 for the data collection overview at the study completion visit.

6.4.3 Safety Data Collection

Clinical AEs, serious and non-serious, will be recorded in the eCRF during the total observation period, with physician’s assessment of severity (mild, moderate, severe or in oncology studies using the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE]) and relationship to therapy (i.e., related or unrelated) as described in Appendix 3. As health-related quality of life is a secondary endpoint of this study all AEs reported within the patient-reported outcome using the FACT-L questionnaire should be documented within the eCRF if the physician becomes aware of a potential AE. The CRO screens the provided questionnaires for additional potential safety information out of scope of the questionnaire and will inform the site treating physician for immediate appropriate documentation in the eCRF.

6.5 PATIENT, STUDY AND SITE DISCONTINUATION

6.5.1 Patient Discontinuation

Patients have the right at any time and for any reason to withdraw their consent that their data are collected and used for the study. Reasons for discontinuation of treatment with the medicinal product or withdrawal from the study may include, but are not limited to, the following:

• Patient withdrawal of consent at any time

• Patient is lost to follow-up.

6.5.2 Discontinuation from Treatment with Studied Medicinal Product

The decision for discontinuation from treatment lies with the treating physician in agreement with the patient’s decision and is not regulated by this protocol. The reason(s) for treatment discontinuation as assessed by the treating physician should be documented on the appropriate eCRF page. Every effort should be made to obtain information on patients who discontinue treatment.

6.5.3 Withdrawal from Study

Every effort should be made to obtain information on patients who withdraw from the study. The primary reason for withdrawal from the study should be documented on the


appropriate eCRF page. Patients will not be followed for any reason after consent has been withdrawn. Patients who withdraw from the study will not be replaced.

6.5.4 Study and Site Discontinuation

The MAH has the right to terminate this study at any time. Reasons for terminating the study may include, but are not limited to, the following:

• Patient enrollment is unsatisfactory

• The incidence or severity of adverse events in this or other studies investigating atezolizumab indicates a potential health hazard to patients

The MAH will notify the physician if the study is placed on hold, or if the MAH decides to discontinue the study.

The MAH has the right to replace a site at any time. Reasons for replacing a site may include, but are not limited to, the following:

• Excessively slow recruitment

• Poor protocol adherence

• Inaccurate or incomplete data recording

• Non-compliance with the Guidelines for Good Pharmacoepidemiological Practices (GPP) or any other pertinent local law or guideline

6.6 DATA MANAGEMENT

6.6.1 Data Quality Assurance

A contract research organization (CRO) will be responsible for the data management of this study, including quality checking of the data. Data entered manually will be collected via Electronic data capture (EDC) using eCRFs. Sites will be responsible for data entry into the EDC system. In the event of discrepant data, the CRO will request data clarification from the sites, which the sites will resolve electronically in the EDC system.

AMS GmbH will produce a Data Quality Review Plan that describes the quality checking to be performed on the data.

The MAH will perform oversight of the data management of this study, including approval of the CRO data management plans and guidance (including Data Quality Review Plan). Data will be periodically transferred electronically from the CRO to the marketing authorization holder, and the CRO’s standard procedures will be used to handle and process the electronic transfer of these data.


CRFs and correction documentation will be maintained in the EDC system audit trail. System backups for data stored at the CRO will be consistent with the CRO standard procedures. The CRO will comply with the MAH’s procedures regarding archiving and record management

6.6.2 Electronic Case Report Forms

CRFs are to be completed using a MAH designated EDC system. Sites will receive training and have access to a manual for appropriate eCRF completion. CRFs will be submitted electronically to the MAH and should be handled in accordance with instructions from the MAH.

All CRFs should be completed by designated trained site staff. CRFs should be reviewed and electronically signed and dated by the physician or a designee.

At the end of the study, the physician will receive the data related to patients from his or her site in an electronically readable format (e.g., on a compact disc). Data must be kept with the study records. Acknowledgement of receipt of the data is required.

6.6.3 Source Data Documentation

Site Operations Representative will perform ongoing SDV as defined in the Clinical Monitoring Plan to confirm that critical protocol data (i.e., source data) entered in the eCRF by authorized site personnel are accurate, complete, and verifiable from source documents.

Source documents (paper or electronic) are those in which patient data are recorded and documented for the first time. They include, but are not limited to, hospital records, clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies of transcriptions that are certified after verification as being accurate and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, and records kept at pharmacies, laboratories, and medico-technical departments involved in a clinical study.

Before study initiation, the types of source documents that contain study-relevant information will be clearly defined in the Trial Monitoring Plan. The Trial Monitoring Plan defines which kind of source data – if available from clinical routine - can be used for documentation into eCRF. No additional source data creation beyond routine is allowed.

Source documents that are required to verify the validity and completeness of data entered in the eCRF must not be obliterated or destroyed and must be retained per the policy for retention of records described in Section 6.8.4


To facilitate SDV, the physicians and institutions must provide the MAH direct access to applicable source documents and reports for trial-related monitoring, MAH audits, and EC review. The participating sites must also allow inspection by applicable health authorities.

6.7 STATISTICAL CONSIDERATIONS

All effectiveness and safety variables documented in this study will be analyzed by means of descriptive analyses; no comparative analyses assessing the effectiveness of other treatments will be undertaken. No formal hypothesis testing is planned. Inferential methods (e.g. confidence intervals) will be used in selected analyses to highlight interesting aspects of the data, but will be interpreted in an exploratory manner.

Baseline characteristics will be described in order to provide context for the observed outcomes of patients treated with atezolizumab. Patients with a history of another primary malignancy should also be analyzed separately.

Specific analyses as outlined in the objectives will be performed for overall population, cohort 1 and/or cohort 2.

As this study is a non-interventional trial with only one treatment arm all analyses will be performed only for the overall population, cohort 1 and/or cohort 2. This analysis population consists of all eligible patients included in the study who received at least one dose of atezolizumab. Patients with ‘off-label’ use of atezolizumab during study will only be included in these analysis populations, if intake of atezolizumab was ‘in-label’ at their study start. Patients with ‘off-label’ use of atezolizumab at study start will be excluded from these analysis populations, but adverse events data will be listed.

6.7.1 Effectiveness Analyses

For the statistical analysis of time-to-event endpoints, Kaplan-Meier methods will be used for the estimation of the median overall survival. Its corresponding 95% CI will be calculated according to Brookmeyer & Crowley, 1982.

Effectiveness variables will be summarized by cohort and/or overall population. For continuous data the mean, standard deviation (SD), median, range (min, max), interquartile range (Q1, Q3). Categorical data will be displayed by absolute and relative frequencies (percentages). In addition, the number of missing values will be presented for all analyses.

The time to endpoint will be defined as an interval between the date of enrolment (date of first visit) and date of first occurrence of the event. For patients who are event free, the censoring time will be calculated as a time interval between date of enrolment and


the patient`s final contact with available data concerning the event. The estimates and graphical presentation will be performed via Kaplan-Meier approach.

Logistic regression will be performed on the rate of endpoints in order to observe and assess the impact of covariates, i.e. different risk factors.

Exploratory analysis subgroup analysis will be performed using Cox regression model and including relevant risk factors, where risk factors are defined as patient and tumor characteristics, particularly PD-L1 expression level, number of lines of prior therapy, histology.

For all statistical estimates 95% confidence intervals will be provided.

6.7.2 Safety Analyses

Safety Analysis Population: All enrolled patients who have received at least one dose of atezolizumab.

The analysis of safety outcomes/variables is based on the incidence, seriousness, and severity of all AEs, SAEs, AESIs with NCI CTCAE. The incidence of serious and non-serious AEs will be summarized according to the primary system organ class (SOC), and within each SOC by the most recent version (at the time point of database lock) of Medical Dictionary for Regulatory Activities (MedDRA) preferred term by cohort and overall. All AEs will further be divided in treatment-related and non-treatment-related. AE data will be presented in frequency tables (overall and by intensity) by body system. Listings of deaths and cause of death will be provided.

Listings of procedures (medications, (length of) treatment discontinuations) to manage adverse events according to standard medical practice will be provided.

6.7.3 Other Analyses Patient-reported outcomes (PRO) and questionnaire data recorded using FACT-L questionnaires will be self-administered and completed by patients.

Questionnaires will be handed out to the patients as paper copies. Questionnaires should be completed by the patient on site prior to any assessment and are collected by site personnel following completion (see also 2.3.3). The patients shall take no questionnaires home. As it is preferable to reduce all sources of potential bias it is recommended that questionnaires are completed prior to seeing the physician.

PROs will be evaluated according to scoring manual.


FACT-L scores: FACT-L is a combination of a generic cancer scale, the Functional Assessment of Cancer Therapy-Generic (FACT-G) and a lung cancer subscale (LCS), and consists of 37 questions (Cella et al. 1993, 1995). Generic subscales and the item compositions of FACT-G are as follows: Physical Well-Being (seven items), Social/Family Well-Being (seven items), Emotional Well-Being (six items), and Functional Well-Being (seven items). The 10-item LCS assesses LC symptoms. The Trial Outcome Index (TOI) is a 21-item single-score scale that sums the PWB, EWB, and LCS subscales of the FACT-L, proposed to assess the physical components of HRQOL. Total possible scores range between 0 and 84, with higher scores indicating a better QOL (Cella et al. 1995).

The modified questionnaire to be used for retrospectively included patients and covering the period from immediately prior to the first atezolizumab dose up the time point of providing informed consent will be based on the FACIT FACT-L questionnaire. The only modification to the FACT-L questionnaire will concern the time period the patient has to take into consideration for providing outcomes. The questions and scoring criteria of the modified questionnaire are identical to that of the FACT-L questionnaire.

If there are missing items, subscale scores can be prorated. This is done by multiplying the sum of the subscale by the number of items in the subscale, then dividing by the number of items actually answered. This can be done on the scoring guide or by using the formula below:

Prorated subscale score = [Sum of item scores] x [N of items in subscale] [N of items answered]

When there are missing data, prorating by subscale in this way is acceptable as long as more than 50% of the items were answered (e.g., a minimum of 4 of 7 items, 4 of 6 items, etc). The total score is then calculated as the sum of the un-weighted subscale scores. The FACT scale is considered to be an acceptable indicator of patient quality of life as long as overall item response rate is greater than 80% (e.g., at least 22 of 27 FACT-G items completed). This is not to be confused with individual subscale item response rate, which allows a subscale score to be prorated for missing items if greater than 50% of items are answered. In addition, a total score should only be calculated if ALL of the component subscales have valid scores. For more details, see FACIT Administration and Scoring Guidelines.

Collection of PROs will be done according to clinical routine. For suggested timelines for PRO assessments see Figure 2. The concurrence of disease progression with worsening of patient-reported symptoms and emotional well-being compared to baseline will be analyzed descriptively.


Figure 2a Suggested timeline (in weeks) PRO assessments for prospectively enrolled patients

Figure 2b Suggested timeline (in weeks) PRO assessments for retrospectively enrolled patients

* Earliest PRO assessment for retrospectively enrolled patients must be after informed consent and can be anytime between 0 to 9 weeks after first atezolizumab administration; first (modified) PRO questionnaire will assess situation prior to first atezolizumab administration

Parameters impacting capturing of QoL in clinical practice will be presented descriptively according to barriers described in the literature (e.g. management/time, education, tool specific, financing, illness-related, clinician’s beliefs; patient-related barriers; Antunes et al. 2014; Donaldson MS 2004).

6.7.4 Interim and Final Analyses and Timing of Analyses

One interim analyses is planned to assess observed response and safety results:

• After 80% of patients enrolled (~ October 2019)

Analyzing interim data will use descriptive statistics only; therefore, there is no adjustment for multiplicity planned.


Final Analysis: At the end of study. All patients enrolled in this study meeting the eligibility criteria and treated according to the SmPC will be included in the final analysis.

6.7.5 Determination of Sample size

The co-primary objectives are the estimation of time to loss of clinical benefit (TTLCB) for the overall population and for cohort 2 as well as the estimation of duration of response (DOR) for patients with PR or CR in cohort 2 under real-world conditions in patients with locally-advanced or metastatic NSCLC after prior chemotherapy and who subsequently receive atezolizumab. There is no common sample size calculation for all three co-primary objectives. As the expected rates of CR, PR are very small and the expected median DOR is much larger than the expected median TTLCB in the overall population or in cohort 2, the sample size calculation is based on only on the co-primary effectiveness objective DOR and on this basis calculation for TTLCB are done.

Assuming a median DOR of 18.5 months, a one-sample non-parametric survival analysis would yield in a confidence interval of [14.3 months; 24.9 months], given the sample size was 61 (10% dropout rate not included). Assuming a rate of 15% of patients achieving PR or CR under treatment, 450 patients have to be enrolled in this study.

The sample size of 207 patients with a response (CR or PR) is based on the following assumptions:

• Median DOR is expected to be18.5 months (Smith DA et al. ASCO 2016). Data from POPLAR was chosen as a reference since it has the most mature DOR data.

• The precision will be within the range of ± 4.5 months. Higher precision than ± 4.5 months would not result in more clinically relevant information but would need significant more patient numbers. A precision of ± 4.5 months secures a clear distance to confidence interval (CI) of standard therapy

• A two-sided alpha-level of 5% (i.e. 95% CI)

• Loss to follow-up is expected to be 10% Given the number of enrolled patients (N=450) and an expected median TTLCB of 3.4 months for the overall population, a one-sample non-parametric survival analysis with the sample size of 405 (10% dropout rate not included) would yield in a confidence interval of [3.1 months; 3.8 months].

As there is too little information to estimate the expected median TTLCB for cohort 2, an overview for different conceivable scenarios is given below. Given the number of enrolled patients and a proportion of 50% of patients achieving PR, CR or SD a one-


sample non-parametric survival analysis with the sample size of 202 (10% dropout rate not included) would yield in the following confidence intervals.

Median TTLCB (cohort 2) Confidence Interval

5 [4.3 months ; 5.9 months ]




6.8 STUDY DOCUMENTATION, MONITORING, AND ADMINISTRATION

6.8.1 Study Documentation

The physician 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 EC and governmental notification. In addition, at the end of the study, the physician will receive the patient data, which include an audit trail containing a complete record of all changes to data.

The MAH shall ensure that the dataset and statistical programs used for generating the data included in the final study report are kept in electronic format and are available for auditing and inspection.

6.8.2 Site Audits and Inspections

Site visits will be conducted by the MAH or an authorized representative for audit of study data, patients’ medical records, and CRFs.

The physician will also permit national and local health authorities to inspect facilities and records relevant to this study.

6.8.3 Use of Site Computerized Systems

When clinical observations are entered directly into a participating site's computerized medical record system (i.e., in lieu of original hardcopy records), the electronic record can serve as the source document if the system has been validated in accordance with


health authority requirements pertaining to computerized systems used in clinical research. An acceptable computerized data collection system allows preservation of the original entry of data. If original data are modified, the system should maintain a viewable audit trail that shows the original data as well as the reason for the change, name of the person making the change, and date of the change.

6.8.4 Retention of Records

Archiving at the study site has to be for at least five years after final study report or first publication of study results, whichever comes later; or according to local regulation.

Records and documents pertaining to the conduct of this study must be retained by the sponsor for at least 25 years after completion or discontinuation of the study, or for the length of time required by relevant national or local health authorities, whichever is longer. After that period of time, the documents may be destroyed, subject to local regulations.

No records may be disposed of without the written approval of the MAH. Written notification should be provided to the MAH prior to transferring any records to another party or moving them to another location.

All supporting functional parties will comply with the MAH procedures regarding archiving and record management.

6.8.5 Administrative Structure

For this non-interventional study, the Sponsor liaises with a contract research organization for site management and data management. The responsibility of the CRO includes:

• Preparation or preparation support of study documents and data repositories (including but not limited to case report form, electronic data base)

• Initiation of participating sites, support of physicians throughout the study and site inspections

• Data analysis

• Reporting of results

No steering committee or expert advisory committee is involved in this study.

6.9 LIMITATIONS OF THE RESEARCH METHOD

As any observational research this study is subject to a series of risks of bias. The potential major ones have been taken into account as much as possible in the design and analysis of the non-interventional study.


The target population of this study is the population of patients treated with atezolizumab for locally advanced or metastatic non-small cell lung cancer after prior chemotherapy in a real-life setting in Germany. A representative sample of the target population will be drawn from 120 selected sites, both office-based and hospital-based oncology care facilities in Germany, with an estimated average of 4 to 5 patients per site and a total of about 450 patients. Physicians from hospitals are to identify and recruit the patients. Sample representativeness may be compromised by selection biases. Due to the observational nature of this study, some data might not be available in patient notes and will be missing in the study database.

Additionally, the following limitations need to be considered:

• Patient representativeness

• Care facility representativeness

• Information bias

• Measurement errors

• Missing data

• Confounding

• Risk of underrecruiting or overrecruiting

To minimize the risk for the above mentioned biases, certain measurements will be performed, including balancing the site selection according to geography and demographics of NSCLC patients in Germany. Minimization of patients lost to follow up will be attempted by increasing efforts of physicians to contact such patients. Sensitivity analysis will be carried out to investigate bias if appropriate.

As this is a non-interventional study, no assessments are defined as mandatory. Nevertheless, data reporting / collection will be conducted in a consistent way to avoid bias in the data collection process.

Unbalance between the two cohorts is expected as a result of the main research questions addressed in this NIS. The two cohorts will be analyzed separately in addition to the overall population.


7. PROTECTION OF HUMAN SUBJECTS

7.1 COMPLIANCE WITH LAWS AND REGULATIONS

This study will be conducted in full conformance with the Guidelines for GPP published by the International Society of Pharmacoepidemiology (ISPE) and the laws and regulations of the country in which the research is conducted.

7.2 INFORMED CONSENT

The marketing authorization holder’s sample Informed Consent Form (and ancillary sample Informed Consent Forms such as Caregiver's Informed Consent Form, if applicable) will be provided to each site. The MAH must review and approve any proposed deviations from the marketing authorization holder's sample Informed Consent Forms or any alternate Consent Forms proposed by the site (collectively, the “Consent Forms”) before EC submission. The final Consent Forms approved by the EC must be provided to the MAH for health authority submission purposes according to local requirements.

The Consent Forms must be signed and dated by the patient or the patient’s legally authorized representative before start of documentation of his or her data in the eCRF. The case history or clinical records for each patient shall document the informed consent process and that written informed consent was obtained prior to first documentation of this patient’s data in the eCRF.

By signing the form, the patient confirms that he/she has been informed about the study and agrees to pseudonymous data collection, pooling of data with similar scientific data (if applicable), and the possibility of monitoring activities. It is the responsibility of the physician to obtain written informed consent from each patient participating in the study, after adequate explanation of the aims, methods, anticipated benefits, and potential hazards of the study. The physician must also explain that the patient is completely free to refuse to enter the study or to withdraw from it at any time, for any reason and without losing the benefit of any medical care to which the patient is entitled or is presently receiving.

A copy of each signed Consent Form must be provided to the patient or the patient’s legally authorized representative. All signed and dated Consent Forms must remain in each patient’s study file or in the site file and must be available for verification by Site Operations Representative at any time.

7.3 INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE

This protocol, the Informed Consent Forms, any information to be given to the patient, and relevant supporting information must be submitted to the IRB/EC by the Site Operations Representative in consultation with the Scientific Responsible and reviewed


and approved by the IRB/EC before the study is initiated. In addition, any patient recruitment materials must be approved by the IRB/EC.

In addition to the requirements for collecting and reporting all AEs, adverse events of special interest (AESI), and SAEs to the MAH, physicians must comply with requirements for AE reporting to the local health authority and IRB/EC.

7.4 CONFIDENTIALITY

The MAH maintains confidentiality standards by coding each patient enrolled in the study through assignment of a unique patient identification number. This means that patient names are not included in datasets that are transmitted to any MAH location.

Patient medical information obtained by this study is confidential and may be disclosed to third parties only as permitted by the Informed Consent Form (or separate authorization for use and disclosure of personal health information) signed by the patient, unless permitted or required by law.

Medical information may be given to a patient’s personal physician or other appropriate medical personnel responsible for the patient’s welfare, for treatment purposes.

Data generated by this study must be available for inspection upon request by representatives of national and local health authorities, MAH monitors, representatives, and collaborators, and the EC for each study site, as appropriate.


8. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ ADVERSE REACTIONS

8.1 SAFETY REPORTING REQUIREMENTS FOR STUDIED MEDICINAL PRODUCTS

8.1.1 Safety Parameters and Definitions

The reporting requirements in this section apply to all studied medicinal products (observational products of interest, as specifically stated in the study objectives). For safety reporting requirements for non-studied medicinal products, see Section 8.2.

Safety assessments will consist of monitoring and recording SAEs and non-serious AEs (including AEs of special interest (see appendix 3.4.) and special situations (see appendix 3.3)), performing safety laboratory assessments, measuring vital signs, and conducting other tests that are deemed critical to the safety evaluation of the study as per standard medical practice.

For both prospectively and retrospectively included patients all AEs, SAEs and AESIs should be captured in the AE section of the eCRF from the first atezolizumab treatment onwards.

8.1.1.1 Adverse Events

According to the International Conference of Harmonisation (ICH), an AE is any untoward medical occurrence in a patient or clinical investigation patient administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any of the following:

• Any unfavorable and unintended sign (including an abnormal laboratory finding), 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 as described in Appendix 3

• 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., electrocardiogram [ECG], X-ray) that is associated with symptoms or leads to a change in study treatment or concomitant treatment or discontinuation from study medicine.


8.1.1.2 Assessment of Serious Adverse Events

(Immediately Reportable to the Marketing Authorization Holder), Non-serious Adverse Events of Special Interest (AESI) and Other Non-serious Adverse Events

Serious Adverse Events

An SAE is any AE that meets any of the following criteria:

• Is fatal (i.e., the AE actually causes or leads to death)

• Is life-threatening (NOTE: The term “life-threatening” refers to an event in which the patient was at immediate risk of death at the time of the event; it does not refer to an event that hypothetically might have caused death if it were more severe.)

• Requires or prolongs inpatient hospitalization (see Appendix 3.3.11)

• Results in persistent or significant disability/incapacity (i.e., the AE results in substantial disruption of the patient’s ability to conduct normal life functions)

• Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to study medicine

• Is a significant medical event in the physician’s judgment (e.g., may jeopardize the patient or may require medical/surgical intervention to prevent one of the outcomes listed above)

• All NCI CTCAE Grade 4 events have to be reported as an SAE

The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of an AE (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE criteria; see Appendix 3.1); the event itself may be of relatively minor medical significance (such as severe headache without any further findings).

Severity and seriousness need to be independently assessed for each AE recorded on the eCRF (for detailed instructions, see Appendix 3).

Non-Serious Adverse Events of Special Interest

Adverse events of special interest are required to be reported by the investigator to the Sponsor immediately (i.e., no more than 24 hours after learning of the event; see Section 8.1.3 for reporting instructions). 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 and based on the following observations:

o Treatment-emergent ALT or AST > 3 × baseline value in combination with total bilirubin > 2 × ULN (of which ≥ 35% is direct bilirubin)

o Treatment-emergent ALT or AST > 3 × baseline value in combination with clinical jaundice

• 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 > 10 × 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

• Nephritis

• Ocular toxicities (e.g., uveitis, retinitis)

• Myositis

• Myopathies, including rhabdomyolysis

• Grade ≥ 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis)

• Vasculitis


Non-Serious Adverse Events other than Adverse Events of Special Interest

All non-serious AEs in addition to AEs of special interest must be collected for this study.

8.1.2 Methods and Timing for Capturing and Assessing Safety Parameters

The physician is responsible for ensuring that all AEs collected as per protocol (see Section 8.1.1.1 for definition) are recorded in the AE section of the eCRF and reported to the MAH in accordance with instructions provided in this section and in Section 8.1.3.

For each AE recorded in the AE section of the eCRF, the physician will make an assessment of seriousness (see Section 8.1.1.2), severity (see Appendix 3.1), and causality (see Appendix 3.2).

8.1.2.1 Adverse Event Reporting Period Qualified HCPs will seek information on AEs at each patient contact. All AEs subject to the collecting and reporting requirements outlined in this protocol, whether reported by the patient or noted by study personnel, will be recorded in the patient’s medical record and in the AE section of the CRF.

For all patients AEs will be collected from the first atezolizumab treatment onward until the end of his or her observation period. After this period, the HCP is not required to actively monitor patients for AEs but if the treating HCP becomes aware of any related AEs to any medicinal product they should be notified to the competent authority in the Member State where the reactions occurred or to the marketing authorization holder of the suspected medicinal product, but not to both (to avoid duplicate reporting).

8.1.2.2 Procedures for Recording Adverse Events

HCPs should use correct medical terminology/concepts when recording AEs in the AE section of the eCRF. Colloquialisms and abbreviations should be avoided.

Only one AE term should be recorded in the event field of the eCRF.

See Appendix 3.3 for further specific instruction regarding:

• Infusion-Related Reactions

• Diagnosis versus signs and symptoms

• Adverse Events occurring secondary to other Adverse Events

• Persistent or recurrent Adverse Events


• Abnormal Laboratory Values

• Abnormal Vital Sign Values

• Abnormal Liver Function Tests

• Deaths: All events with an outcome or consequence of death should be classified as serious adverse events (SAEs) and reported to the MAH immediately. All deaths that occur during the protocol-specified AE reporting period, regardless of relationship to study medicine, must be recorded in the AE section of the eCRF and immediately reported to the MAH. Events that are clearly consistent with the expected pattern of the course of the underlying disease should not be recorded as AEs.

• Pre-existing Medical Conditions

• Lack of Therapeutic Efficacy. Events that are clearly consistent with the expected pattern of progression of the underlying disease should not be recorded as AEs.

• Hospitalization or Prolonged Hospitalization

• Overdoses, Misuses, Abuses, Off-Label Use, Occupational Exposure, or Medication Error

• Quality Defects and Falsified Medicinal Products

• Drug Interactions

8.1.3 Reporting Requirements from Physician to Marketing Authorization Holder

8.1.3.1 Immediate Reporting Requirements from Physician to Marketing Authorization Holder

Certain events require immediate reporting to allow the MAH and the regulatory authorities to take appropriate measures to address potential new risks associated with the use of the medicine. The HCP must report such events to the MAH immediately; under no circumstances should reporting take place more than 24 hours after the HCP learns of the event. The following is a list of events that the HCP must report to the MAH within 24 hours after learning of the event, regardless of relationship to study medicine:

• SAEs

• Non-serious AEs of special interest – see 8.1.1.2Pregnancies

The HCP must report new significant follow-up information for these events to the MAH immediately (i.e., no more than 24 hours after becoming aware of the information). New significant information includes the following:


• New signs or symptoms or a change in the diagnosis

• Significant new diagnostic test results

• Change in causality based on new information

• Change in the event’s outcome, including recovery

• Additional narrative information on the clinical course of the event

For reports of SAEs and non-serious AESIs, including follow-up, HCPs should record all case details that can be gathered immediately (i.e., within 24 hours) in the AE page of the eCRF and submit the report via the EDC system. A report will be generated and sent to Roche Drug Safety by the EDC system.

In the event that the EDC system is temporarily unavailable, please refer to Section 8.1.3.3.

HCPs must also comply with local requirements for reporting SAEs to the local health authority and IRB/EC.

8.1.3.2 Reporting Requirements for Non-Serious Adverse Events

For all non-serious AEs, including follow-up reports, HCPs must record all case details that can be gathered within 30 calendar days of learning of the event on the AE section of the eCRF and submit the report via the EDC system. A report will be generated and sent to Roche Drug Safety to allow appropriate reporting to relevant competent authorities.

In the event that the EDC system is temporarily unavailable, please refer to Section 8.1.3.3.

8.1.3.3 If EDC System is Temporarily Unavailable

In the event that the EDC system is temporarily unavailable, a completed paper reporting form and fax coversheet should be faxed/scanned immediately and submitted to the CRO (i.e., no more than 24 hours after learning of the event) or within 30 days for non-serious AEs if not AEs of special interest, using the fax number or preferably email address provided to physicians.

Once the system is available again, all information should additionally be entered and submitted via the EDC system.


8.1.3.4 Reporting Requirements for Pregnancies/Breastfeeding

Pregnancy: This refers to situation where the embryo or fetus may have been exposed to Roche medicinal product(s) through maternal exposure

Breastfeeding: This refers to a situation in infants following exposure to a Roche medicinal product from breast milk

Pregnancy and Breastfeeding should be reported if occurring during the protocol-specified AE reporting period, even in the absence of adverse events.

Female patients of childbearing potential will be instructed to immediately inform the physician if they become pregnant during the study or within 5 months after the last dose of medicine. A Pregnancy Report should be completed by the physician immediately (i.e., no more than 24 hours after learning of the pregnancy and sent to Roche designee. Pregnancy should be recorded in the AE section of the eCRF and a Pregnancy Reporting form provided by ROCHE in paper form should be sent to ROCHE designee preferably via email, in exceptions information can be send via fax. The physician should counsel the patient, discussing the risks of the pregnancy and the possible effects on the fetus. Monitoring of the patient should continue until conclusion of the pregnancy. Any SAEs 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) should be reported on the AE section of the eCRF.

Suspected adverse reactions that occur in infants following exposure to a medicinal product from breast milk should be reported to Roche designee.

Abortions

Any abortion should be classified as an SAE (as the MAH considers abortions to be medically significant), recorded in the AE section of the eCRF, and reported to the MAH immediately (i.e., no more than 24 hours after learning of the event; see Section 8.1.3.1).

Congenital Anomalies/Birth Defects

Any congenital anomaly/birth defect in a child born to a female patient exposed to the medicine or the female partner of a male patient exposed to the medicine should be classified as an SAE, recorded in the AE section of the eCRF, and reported to the MAH immediately (i.e., no more than 24 hours after learning of the event; see Section 8.1.3.1).

8.1.3.5 Reporting Requirements for Adverse Events originating from Patient Reported Outcomes

Although physicians are not expected to review the PRO data, if HCP/study personnel become aware of a potential adverse event during site review of the PRO questionnaire


data, he/she will determine whether the criteria for an adverse event have been met and, if so, these must be reported using the Adverse Event eCRF.

8.1.3.6 Reporting Requirements for Adverse Events originating from previous (non-atezolizumab) therapies (before first atezolizumab treatment)

Any AEs which occurred before the patient was treated with atezolizumab as part of this study are assumed to already have been reported spontaneously according to local regulations or within a previous study. Therefore, there will be no AE reporting on a single case basis for any previous therapies before the first atezolizumab treatment within the scope of this non-interventional study. However; there will be an appropriate presentation of the structured data collection in the clinical study report.

8.1.4 Follow-Up of Patients after Adverse Events

8.1.4.1 HCP Follow-Up

The HCP should follow each AE until the event has resolved to baseline grade or better, the event is assessed as stable by the HCP, the patient is lost to follow-up, or the patient withdraws consent. Every effort should be made to follow all SAEs considered to be related to studied medicinal product until a final outcome can be reported.

During the study period, resolution of AEs (with dates) should be documented in the AE section of the eCRF and in the patient’s medical record to facilitate SDV.

All pregnancies reported during the study should be followed until pregnancy outcome.

8.1.4.2 Marketing Authorization Holder Follow-Up

For all AEs, the MAH or a designee may follow up by telephone, fax, electronic mail, and/or a monitoring visit to obtain additional case details and outcome information (e.g., from hospital discharge summaries, consultant reports, autopsy reports) in order to perform an independent medical assessment of the reported case.

8.2 SAFETY REPORTING REQUIREMENTS FOR NON-STUDIED MEDICINAL PRODUCTS

Although adverse event information is not being actively solicited for non-studied medicinal products, the physician/consumers are reminded to report any adverse reactions (for which they suspect a causal role of a medicinal product) that come to their attention to the MAH of the suspected medicinal product, or to the concerned competent authorities via the national spontaneous reporting system.


In addition, the following should also be reported if occurring during exposure to a marketed medicinal product, even in the absence of adverse events:

• Pregnancy

• Breastfeeding

• Abnormal laboratory findings

• Overdose, abuse, misuse, off-label use, medication error or occupational exposure

• Reports of lack of efficacy

• Product quality defects and falsified medicinal products

• Data related to a suspected transmission of an infectious agent via a medicinal product

• Drug interactions (including drug/drug, drug/food, drug/device and drug/alcohol)

When a patient is not exposed to a marketed medicinal product, but the HCP/consumer becomes aware of the potential for a medication error, or an intercepted medication error, this should also be reported.

8.3 REPORTING OF PRODUCT COMPLAINTS WITHOUT ADVERSE EVENTS

Report Roche product complaints without Adverse Events, where Product Complaint is any written or oral information received from a complainant that alleges deficiencies related to Identity, Quality, Safety, Strength, Purity, Reliability, Durability, Effectiveness, or Performance of a product after it has been released and distributed to the commercial market, to [email protected]. Report non-Roche-product complaints as per local regulation.

mailto:[email protected]


9. PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS

Regardless of the outcome of a study, the MAH is dedicated to openly providing information on the study to healthcare professionals and to the public, both at scientific congresses and in peer-reviewed journals. The MAH will comply with all requirements for publication of study results

The results of this study may be published or presented at scientific meetings. If this is foreseen, the physician must agree to submit all manuscripts or abstracts to the MAH prior to submission for publication or presentation. This allows the MAH to protect proprietary information and to provide comments based on information from other studies that may not yet be available to the physician.

In accordance with standard editorial and ethical practice, the MAH will generally support publication of multicenter studies only in their entirety and not as individual center data. In this case, a coordinating physician will be designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with International Committee of Medical Journal Editors’ authorship requirements. Any formal publication of the study in which contribution of MAH personnel exceeded that of conventional monitoring will be considered as a joint publication by the physician and the appropriate MAH personnel.

Any inventions and resulting patents, improvements, and/or know-how originating from the use of data from this study will become and remain the exclusive and unburdened property of the marketing authorization holder, except where agreed otherwise.

Publication will be done after the planned interim analyses and the final analysis of the non-interventional study.


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Atezolizumab (TECENTRIQ®) - F. Hoffmann-La Roche Ltd Protocol ML39885 Version 5.0 Based on protocol template Version 3.0 released on 31-Dec-2016 77

APPENDIX 1 LIST OF STAND-ALONE DOCUMENTS NOT INCLUDED IN THE PROTOCOL

APPENDIX 1.1 LIST OF CONTACT DETAILS

Roche Contacts

Activity Person Responsible

General Queries [email protected]

Individual Case Safety Reports

Roche Pharma AG Abteilung Arzneimittelsicherheit Emil-Barell-Straße 1 79639 Grenzach-Wyhlen Germany Fax: +49 7624 14 3183 Email: [email protected]

mailto:[email protected]

Atezolizumab (TECENTRIQ®) - F. Hoffmann-La Roche Ltd Protocol ML39885 Version 5.0 Based on protocol template Version 3.0 released on 31-Dec-2016 78

APPENDIX 2 Data Collection Overview (as per Standard of Care)

Data Collection (available data will be

collected; no additional diagnostic

or monitoring procedures shall be

applied to the patients outside of

routine clinical practice)

Baseline (f)

Data collected during the treatment

period (until loss of

clinical benefit per

atezolizumab SmPC)

Post treatment visit

(first patient-physician

contact after atezolizumab

discontinuation)

Cohort 1: Post-

progression QoL

assessment & AE

collection (90 days)

Cohort 2: Follow-up

Study completion

visit

Informed consent a X

Inclusion/exclusion criteria X

Baseline characteristics (incl. biomarkers etc.)

X

ECOG Performance Status X X X

Prior anti-cancer therapies (type, lines, dose, start/end date, best response)

X

Radiotherapy during atezolizumab therapy (type, dose, start/end date)

X

Height and weight X b

Comorbidities and comedication X X

Occurrence, methodology, and outcome of PD-L1 (re-)testing

X

Treatment with atezolizumab (start/end date, schedule, delays, interruptions, etc.)

X


Reason(s) for discontinuation of atezolizumab

X

AEs, SAEs, AESIs X X Xe Xe

Management of AEs, SAEs and AESIs X X Xe Xe

Outcome assessments (loss of clinical benefit, progression, objective response)

X X

Method of response evaluation (e.g. assessed by physician, RECIST 1.1, mRECIST)

X X

Post atezolizumab anti-cancer therapies (type, start/end date, best response)

X X

Survival X X X X X

QoL (FACT-L) (according to clinical routine)

X

Xc

Xd

Xd

Xd

AE, adverse event; ECOG, Eastern Cooperative Oncology Group; FACT-L, Functional Assessment of Cancer Therapy - Lung; SmPC, European Medicines Agency Summary of Product Characteristics. a. Written informed consent must be obtained before any data collection. b. Height and weight should be recorded only once. c. According to clinical practice; Recommendation: week 6, week 12, and thereafter every 12 weeks (see Figure 2) d. According to clinical practice; Recommendation: around the time of progression, and 6, 12 weeks and if applicable

24 weeks after progression (see also Figure 2) e. Solicited AE reporting applies to study drug (atezolizumab), for all non-study-drug- AEs spontaneous reporting

regulations apply. f. Retrospective documentation up to 9 weeks allowed


APPENDIX 3 Methods for Assessing and Recording Adverse Events

3.1 Assessment of Severity of Adverse Events 3.2 Assessment of Causality of Adverse Events 3.3 Procedures for Recording Adverse Events

APPENDIX 3.1 ASSESSMENT OF SEVERITY OF ADVERSE EVENTS The AE severity grading scale for the NCI CTCAE will be used for assessing AE severity. The table below will be used for assessing severity for AEs that are not specifically listed in the NCI CTCAE.

Adverse Event Severity Grading Scale

Grade Severity

1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated

2 Moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living a

3 Severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living b, c

4 Life-threatening consequences or urgent intervention indicated d

5 Death related to AE d Note: Based on the NCI CTCAE, which can be found at: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm a Instrumental activities of daily living refer to preparing meals, shopping for groceries or

clothes, using the telephone, managing money, etc. b Examples of self-care activities of daily living include bathing, dressing and undressing,

feeding oneself, using the toilet, and taking medications, as performed by patients who are not bedridden.

c If an event is assessed as a “significant medical event,” it must be reported as an SAE (see Section 8.1.3.1 for reporting instructions), per the definition of SAE in Section 8.1.1.2.

d Grade 4 and 5 events must be reported as SAEs (see Section 8.1.3.1 for reporting instructions), per the definition of SAE in Section 8.1.1.2.

http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm


APPENDIX 3.2 ASSESSMENT OF CAUSALITY OF ADVERSE EVENTS

Physicians should use their knowledge of the patient, the circumstances surrounding the event, and an evaluation of any potential alternative causes to determine whether or not an AE is considered to be related to the study medicine, indicating “yes” or “no” accordingly. The following guidance should be taken into consideration:

• Temporal relationship of event onset to the initiation of study medicine

• Course of the event, considering especially the effects of dose reduction, discontinuation of study medicine, or reintroduction of study medicine (when applicable)

• Known association of the event with the study medicine or with similar treatments

• Known association of the event with the disease under study

• Presence of risk factors in the patient or use of concomitant medications known to increase the occurrence of the event

• Presence of non-treatment-related factors that are known to be associated with the occurrence of the event

• For patients receiving combination therapy, causality will be assessed individually for each of the medicinal product.


APPENDIX 3.3 PROCEDURES FOR RECORDING ADVERSE EVENTS

Appendix 3.3.1 Infusion-Related Reactions

AEs that occur during or within 24 hours after study medicine administration and are judged to be related to studied medicinal product infusion should be captured as a diagnosis (e.g., infusion-related reaction, anaphylactic reaction) in the AE section of the eCRF. If possible, avoid ambiguous terms such as "systemic reaction." Associated signs and symptoms should be also recorded in the AE section of the eCRF in the “additional relevant information” field. If a patient experiences both a local and systemic reaction to the same dose of studied medicinal product, each reaction should be recorded separately in the AE section of the eCRF, with signs and symptoms also recorded separately in the ‘additional relevant information’ field.

Appendix 3.3.2 Diagnosis versus Signs and Symptoms

For AEs, other than infusion-related reactions (see Section 3.3.1) a diagnosis (if known) should be recorded in the AE section of the eCRF rather than individual signs and symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and elevated transaminases). However, if a constellation of signs and/or symptoms cannot be medically characterized as a single diagnosis or syndrome at the time of reporting, each individual event should be recorded in the AE section of the eCRF. If a diagnosis is subsequently established, all previously reported AEs based on signs and symptoms should be nullified and replaced by one AE report based on the single diagnosis, with a starting date that corresponds to the starting date of the first symptom of the eventual diagnosis.

Appendix 3.3.3 Adverse Events Occurring Secondary to Other Events

In general, AEs that are secondary to other events (e.g., cascade events or clinical sequelae) should be identified by their primary cause, with the exception of severe or serious secondary events. A medically significant secondary AE that is separated in time from the initiating event should be recorded as an independent event in the AE section of the eCRF. For example:

• If vomiting results in mild dehydration with no additional treatment in a healthy adult, only vomiting should be reported on the eCRF.

• If vomiting results in severe dehydration, both events should be reported separately on the eCRF.

• If a severe gastrointestinal hemorrhage leads to renal failure, both events should be reported separately on the eCRF.


• If dizziness leads to a fall and subsequent fracture, all three events should be reported separately on the eCRF.

• If neutropenia is accompanied by an infection, both events should be reported separately on the eCRF.

All AEs should be recorded separately in the AE section of the eCRF if it is unclear as to whether the events are associated.

Appendix 3.3.4 Persistent or Recurrent Adverse Events

A persistent AE is one that extends continuously, without resolution, between patient evaluation timepoints. Such events should only be recorded once in the AE section of the eCRF. The initial severity (intensity or grade) of the event will be recorded at the time the event is first reported. If a persistent AE becomes more severe, the most extreme severity should also be recorded in the AE section of the eCRF. If the event becomes serious, it should be reported to the MAH immediately (i.e., no more than 24 hours after learning that the event became serious; see Section 8.1.3.1 for reporting instructions). The AE section of the eCRF should be updated by changing the event from "non-serious" to "serious," providing the date that the event became serious, and completing all data fields related to SAEs.

A recurrent AE is one that resolves between patient’s evaluation timepoints and subsequently recurs. Each recurrence of an AE should be recorded separately in the AE section of the eCRF.

Appendix 3.3.5 Abnormal Laboratory Values

Not every laboratory abnormality qualifies as an AE. A laboratory test result must be reported as an AE if it meets any of the following criteria:

• Is accompanied by clinical symptoms

• Results in a change in study treatment (e.g., dosage modification, treatment interruption, or treatment discontinuation)

• Results in a medical intervention (e.g., potassium supplementation for hypokalemia) or a change in concomitant therapy

• Is clinically significant in the physician’s judgment

Note: For oncology studies, certain abnormal values may not qualify as AEs.


It is the physician’s responsibility to review all laboratory findings. Medical and scientific judgment should be exercised in deciding whether an isolated laboratory abnormality should be classified as an AE.

If a clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g., alkaline phosphatase and bilirubin 5 × the upper limit of normal [ULN] associated with cholestasis), only the diagnosis (i.e., cholestasis) should be recorded in the AE section of the eCRF.

If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, the abnormality itself should be recorded in the AE section of the eCRF, along with a descriptor indicating if the test result is above or below the normal range (e.g., “elevated potassium,” as opposed to “abnormal potassium”). If the laboratory abnormality can be characterized by a precise clinical term per standard definitions, the clinical term should be recorded as the AE. For example, an elevated serum potassium level of 7.0 mEq/L should be recorded as “hyperkalemia.”

Abnormal LDH values associated with disease progression should not reported as single AE reports. However, there will be an appropriate presentation of the structured data collection in the clinical study report.

Observations of the same clinically significant laboratory abnormality from visit to visit should only be recorded once in the AE section of the eCRF (see Appendix 3.3.4 for details on recording persistent AEs).

Appendix 3.3.6 Abnormal Vital Sign Values

Not every vital sign abnormality qualifies as an AE. A vital sign result must be reported as an AE if it 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 physician’s judgment

• It is the physician’s responsibility to review all vital sign findings. Medical and scientific judgment should be exercised in deciding whether an isolated vital sign abnormality should be classified as an AE.


• 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 in the AE section of the eCRF.

Observations of the same clinically significant vital sign abnormality from visit to visit should only be recorded once in the AE section of the eCRF (see Appendix 3.3.4 for details on recording persistent AEs).

Appendix 3.3.7 Abnormal Liver Function Tests

The finding of an elevated ALT or AST (> 3 × the ULN) in combination with either an elevated total bilirubin (> 2 × the 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, physicians must report as an AE the occurrence of either of the following:

• Treatment-emergent ALT or AST > 3 × ULN in combination with total bilirubin > 2 × the ULN

• Treatment-emergent ALT or AST > 3 × ULN in combination with clinical jaundice The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal laboratory values should be recorded in the AE section of the eCRF (see Appendix 3.3.5) and reported to the MAH immediately (i.e., no more than 24 hours after learning of the event) either as an SAE or a non-serious AE of special interest.

Appendix 3.3.8 Deaths

All deaths that occur during the protocol-specified AE reporting period, regardless of relationship to study medicine, must be recorded in the AE section of the eCRF and immediately reported to the MAH. Events that are clearly consistent with the expected pattern of the course of the underlying disease should not be recorded as AEs.

Death should be considered an outcome and not a distinct event. The event or condition that caused or contributed to the fatal outcome should be recorded as the single medical concept on the AE section of the eCRF. Generally, only one such event should be reported. The term “sudden death” should only be used for the occurrence of an abrupt and unexpected death due to presumed cardiac causes in a patient with or without preexisting heart disease, within 1 hour after the onset of acute symptoms or, in the case of an unwitnessed death, within 24 hours after the patient was last seen alive and stable. If the cause of death is unknown and cannot be ascertained at the time of reporting, “unexplained death” should be recorded on the AE section of the eCRF. If the cause of death later becomes available (e.g., after autopsy), “unexplained death” should be replaced by the established cause of death.


Appendix 3.3.9 Preexisting Medical Conditions

A preexisting medical condition is one that is present at the screening visit for this study. Such conditions should be recorded on the General Medical History and Baseline Conditions in the eCRF.

A preexisting medical condition should be recorded as an AE only if the frequency, severity, or character of the condition worsens during the study. When recording such events in the AE section of the eCRF, it is important to convey the concept that the preexisting condition has changed by including applicable descriptors (e.g., “more frequent headaches”).

Appendix 3.3.10 Lack of Therapeutic Efficacy

Events that are clearly consistent with the expected pattern of progression of the underlying disease should not be recorded as AEs. These data will be captured as effectiveness assessment data only. In most cases, the expected pattern of progression will be based on clinical criteria. In rare cases, the determination of clinical progression will be based on symptomatic deterioration. However, every effort should be made to document progression through use of objective criteria. If there is any uncertainty as to whether an event is due to disease progression, it should be reported as an AE. This exception from reporting includes events of disease progression with a fatal outcome which are clearly attributable to disease progression.

Appendix 3.3.11 Hospitalization or Prolonged Hospitalization

Any AE that results in hospitalization or prolonged hospitalization should be documented and reported as an SAE (per the definition of SAE in Section 8.1.1.2), except as outlined below.

The following hospitalization scenarios are not considered to be SAEs:

• Hospitalization for respite care

• Hospitalization for a preexisting condition, provided that all of the following criteria are met:

o The hospitalization was planned prior to the study or was scheduled during the study when elective surgery became necessary because of the expected normal progression of the disease.

o The patient has not suffered an AE.

• Hospitalization due solely to progression of the underlying cancer:


• The following hospitalization scenarios are not considered to be SAEs but should be reported as AEs instead:

• Hospitalization that was necessary because of patient requirement for outpatient care outside of normal outpatient clinic operating hours

Appendix 3.3.12 Overdoses, Misuses, Abuses, Off-Label Use, Occupational Exposure, or Medication Error Any overdose, misuse, abuse, off-label use, occupational exposure, medication error (including intercepted or potential), or any other incorrect administration of medicine under observation should be noted in the Drug Administration section of the CRF. Any overdose, abuse, misuse, off-label use, inadvertent/erroneous administration, medication error (including intercepted or potential), or occupational exposure reports must be forwarded to the marketing authorization holder with or without an AE.

Reports with or without an AE should be forwarded to the marketing authorization holder as per non-serious timelines. If the associated AE fulfills the seriousness criteria, the event should be reported to the marketing authorization holder immediately (i.e., no more than 24 hours after learning of the event. For the purpose of reporting cases of suspected adverse reactions, an occupational exposure to a medicine means an exposure to a medicine as a result of one’s professional or non-professional occupation.

Appendix 3.3.13 Quality Defects and Falsified Products and Product Complaints

Reports of suspected or confirmed falsified medicinal product or quality defect of a product, with or without an associated AE, should be forwarded to the MAH as per non-serious timelines. If the associated AE fulfills the seriousness criteria, the event should be reported to the MAH immediately (i.e., no more than 24 hours after learning of the event.

Appendix 3.3.14 Drug Interactions

Reports of suspected or confirmed drug interactions, including drug/drug, drug/food, drug/device and drug/alcohol, should be forwarded to the MAH as per non-serious timelines. If the associated AE fulfills the seriousness criteria, the event should be reported to the MAH immediately (i.e., no more than 24 hours after learning of the event.

Appendix 3.3.15 Patient-reported outcome

As health-related quality of life is a secondary endpoint of this study all AEs reported within the patient-reported outcome using the FACT-L questionnaire should be


documented within the eCRF if the physician becomes aware of a potential AE. The CRO screens the provided questionnaires for additional potential safety information out of scope of the questionnaire and will inform the site treating physician for immediate appropriate documentation in the eCRF.


APPENDIX 3.4 LIST OF AESIS

Adverse events of special interest are required to be reported by the investigator to the Sponsor immediately (i.e., no more than 24 hours after learning of the event; see Section 8.1.3.1 for reporting instructions). 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 and based on the following observations:

o Treatment-emergent ALT or AST > 3 × baseline value in combination with total bilirubin > 2 × ULN (of which ≥ 35% is direct bilirubin)

o Treatment-emergent ALT or AST > 3 × baseline value in combination with clinical jaundice

• 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 > 10 × 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

• Nephritis

• Ocular toxicities (e.g., uveitis, retinitis)

• Myositis

• Myopathies, including rhabdomyolysis


• Grade ≥ 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis)

• Vasculitis

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