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Immune checkpoint inhibitors plus chemotherapy versus chemotherapy or immunotherapy for first-line treatment of advanced non-small cell lung cancer: a generic protocol (Protocol) Syn NLX, Roudi R, Wang LZ, Wang L, Loh M, Huang Y, Ou SHI, Soong R, Drilon A, Wee I

Syn NLX, Roudi R, Wang LZ, Wang L, Loh M, Huang Y, Ou SHI, Soong R, Drilon A, Wee I. Immune checkpoint inhibitors plus chemotherapy versus chemotherapy or immunotherapy for first-line treatment of advanced non-small cell lung cancer: a generic protocol. Cochrane Database of Systematic Reviews 2018, Issue 4. Art. No.: CD013009. DOI: 10.1002/14651858.CD013009.

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Immune checkpoint inhibitors plus chemotherapy versus chemotherapy or immunotherapy for first-line treatment of advanced nonsmall cell lung cancer: a generic protocol (Protocol) Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

TABLE OF CONTENTS HEADER . . . . . . . . . . ABSTRACT . . . . . . . . . BACKGROUND . . . . . . . Figure 1. . . . . . . . . OBJECTIVES . . . . . . . . METHODS . . . . . . . . . ACKNOWLEDGEMENTS . . . REFERENCES . . . . . . . . APPENDICES . . . . . . . . CONTRIBUTIONS OF AUTHORS DECLARATIONS OF INTEREST .

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[Intervention Protocol]

Immune checkpoint inhibitors plus chemotherapy versus chemotherapy or immunotherapy for first-line treatment of advanced non-small cell lung cancer: a generic protocol Nicholas LX Syn1 , Raheleh Roudi2 , Louis Zizhao Wang3 , Lingzhi Wang4 , Marie Loh5 , Yiqing Huang1 , Sai-Hong Ignatius Ou6 , Richie Soong7 , Alexander Drilon8 , Ian Wee1 1 Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore. 2 Oncopathology Research Center, Iran University of Medical Sciences, Teheran, Iran. 3 Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. 4 Cancer Science Institute of Singapore, Singapore, Singapore. 5 Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore, Singapore. 6 Division of Hematology-Oncology, Chao Family Comprehensive Cancer Center, University of California Irvine, Medical Center, Irvine, USA. 7 Department of Pathology, National University of Singapore, Singapore, Singapore. 8 Early Drug Development Service, Memorial Sloan-Kettering Cancer Center, New York, USA

Contact address: Nicholas LX Syn, Department of Haematology-Oncology, National University Cancer Institute, 1E Kent Ridge Road, NUHS Tower Block, Level 7, Singapore, 119228, Singapore. [email protected]. Editorial group: Cochrane Lung Cancer Group. Publication status and date: New, published in Issue 4, 2018. Citation: Syn NLX, Roudi R, Wang LZ, Wang L, Loh M, Huang Y, Ou SHI, Soong R, Drilon A, Wee I. Immune checkpoint inhibitors plus chemotherapy versus chemotherapy or immunotherapy for first-line treatment of advanced non-small cell lung cancer: a generic protocol. Cochrane Database of Systematic Reviews 2018, Issue 4. Art. No.: CD013009. DOI: 10.1002/14651858.CD013009. Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To determine the effectiveness and toxicity of immune checkpoint inhibitors plus chemotherapy versus chemotherapy or immunotherapy alone as first-line treatment of advanced non-small cell lung cancer (NSCLC).

BACKGROUND

Description of the condition Lung cancer is the most common cause of cancer-related mortality worldwide (Ferlay 2013; GBDCC 2017). Approximately 1.8 million new cases are diagnosed annually, and 85% to 90% of all primary lung malignancies are non-small cell lung cancers (NSCLCs) (Ferlay 2013; Jemal 2011). Cigarette smoking is by far the leading cause of lung carcinogenesis in most people, accounting for 80%

of lung cancer deaths in men and 50% in women worldwide (ACS 2015). Other risk factors include exposure to secondhand smoke, urban air pollution, alcohol, viral infections, occupational carcinogens, and genetic inheritance (Baan 2009; Besaratinia 2008; Molina 2008). A person’s prognosis is determined by the type and extent of their cancer, established during staging. Lung cancer staging takes into consideration the size and anatomic subsite of the primary tumour, lymph node involvement, and the presence of distant metastases and malignant pleural or pericardial effusions (AJCC 2010). Up to 70% of people have locally advanced or metastatic disease when


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they first present (Molina 2008). Therapeutic decisions for NSCLC are based not only on disease stage, comorbidities, performance status and histology, but also the mutational and immunological profile of the tumour, and patient’s preferences. The chemotherapy standard for advanced disease generally consists of a platinum agent in combination with a second drug, such as paclitaxel, nab-paclitaxel, vinorelbine, pemetrexed, gemcitabine, irinotecan, or docetaxel (Novello 2016). In select cases, chemotherapy may be combined with local treatment (surgery or radiation) or the angiogenesis inhibitor, bevacizumab, for further symptom control. People with molecularlydefined subsets of NSCLC - specifically those whose tumours harbour sensitising mutations in the epidermal growth factor receptor (EGFR) gene or translocations affecting the anaplastic lymphoma kinase (ALK) and proto-oncogene tyrosine-protein kinase (ROS1) genes - are currently considered candidates for selective molecular inhibitors known as ’targeted therapies’ (Heong 2017; Kumarakulasinghe 2015; Martínez 2017; Ou 2017; Piotrowska 2016; Syn 2016; West 2017). In addition, immune checkpoint blockers (ICBs), exemplified by the humanised monoclonal antibodies pembrolizumab, nivolumab, and atezolizumab, have also recently obtained approval for first- or subsequent-line treatment of advanced NSCLC (Huang 2017; Kazandjian 2016; Soo 2017).

Description of the intervention

Chemotherapy for advanced NSCLC The combination of a platinum compound (cisplatin or carboplatin) with a third-generation chemotherapy agent, with or without bevacizumab, represents the current treatment standard for advanced NSCLC in people who are ineligible for immunotherapy and targeted therapies. In historic trials, platinum-based chemotherapy doublets exhibit response rates (objective response rates (ORRs)) ranging from 12% to 37%, and median progressionfree and overall survival durations of four to seven months and eight to 13 months, respectively (Burdett 2008; Schiller 2002). People with non-squamous, advanced NSCLC may benefit more from the addition of pemetrexed or bevacizumab, or both, to platinum-based chemotherapy compared to people with squamous cell histology (Hanna 2004; Sandler 2006; Scagliotti 2008). Cisplatin may have a slight advantage over carboplatin in terms of ORR (30% versus 24%), and in certain subgroups (non-squamous histology and people treated with third-generation chemotherapy) may be associated with marginally longer overall survival (Ardizzoni 2007). However, cisplatin is associated with more severe vomiting, nephrotoxicity, and ototoxicity, whereas carboplatin causes a higher rate of alopecia and severe thrombocytopenia. Overall, platinum doublets are considered to be similarly efficacious, with differences in antitumour activity between major trials testing different regimens mostly attributable to disparities

in trial populations (e.g. the proportion of participants with stage IIIB disease, age > 65 years, and performance status 2). Despite that, single agent chemotherapy still has its place for a select group of people, especially the elderly with multiple comorbidities. Non-platinum combination therapies were not associated with improved overall survival as compared to single agent treatments (Santos 2015). Although platinum-based combination therapies confer a slight advantage over single-agent treatments, this should be balanced with clinical judgement of the person’s tolerence to such therapies given the higher risk of grade 3 and 4 adverse events (Santos 2015).

Immunotherapy for advanced NSCLC When used as monotherapy in people with advanced NSCLC, immune checkpoint inhibitors which neutralise programmed death 1 (PD-1) and its ligand, PD-L1, have demonstrated robust efficacy and tolerable safety profiles compared with standard firstor second-line chemotherapy regimens. One of these therapies is pembrolizumab, an anti-PD-1 monoclonal antibody which is approved as a single-agent for first-line treatment of people whose tumours have high PD-L1 expression (tumour proportion score (TPS) ≥ 50%) (Garon 2015; Reck 2016), and for second-line treatment (after disease progression on platinum-based chemotherapy or targeted therapies) of people whose tumours express PD-L1 (TPS ≥ 1%) (Garon 2015; Herbst 2016). Another antiPD-1 drug, nivolumab, is approved for second-line treatment of unselected metastatic NSCLC (Borghaei 2015; Brahmer 2015; Rizvi 2015a), but is currently not indicated for use in the firstline setting among people with ≥ 5% PD-L1 expression (Socinski 2016). The anti-PD-L1 antibody, atezolizumab, was recently approved for second-line therapy based on the international, randomised OAK study (Rittmeyer 2017), in which atezolizumab yielded superior overall survival compared with docetaxel in participants with stage IIIB or IV NSCLC independent of PD-L1 expression status and tumour histology. Further trials are ongoing to address the role of nivolumab, atezolizumab and other PD-1/ PD-L1 inhibitors, either as single-agents or in combination with other immune checkpoint blockers (e.g. treatments targeting the cytoxtoic T-lymphocyte-associated protein 4 (CTLA-4) receptor or indoleamine 2,3-dioxygenase (IDO)) in the front-line setting (Antonia 2016; Hellmann 2017). A significant proportion of people treated with checkpoint protein inhibition develop autoimmune-like syndromes, the spectrum and frequency of which appear to vary depending on the class of inhibitors used. CTLA-4 blockers appear to be associated with a broader set of immunerelated adverse events compared to PD-1/PD-L1 inhibitors, affecting diverse organ systems including skin, gastrointestinal tract, hepatic, renal, nervous and endocrine systems, perhaps owing to their different modes of action: CTLA-4 acts early in inhibiting Tcell activation in secondary lymphoid organs, whereas PD-1 suppresses the execution of effector T-cell responses within the tu-


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mour microenvironment and in tissues (Friedman 2016; Pardoll 2012; Topalian 2015). PD-1 inhibitors are distinctly associated with pneumonitis, which occurs in 1.8% to 4.1% of people with NSCLC (Nishino 2016), but other immune-related adverse events include colitis, hypophysitis and thyroid disorders in 10% to 13% of patients (Michot 2016; Weber 2012; Weber 2015).

Immunotherapy plus chemotherapy for advanced NSCLC Among the recent highlights in research, the role of immunotherapy plus chemotherapy (chemo-immunotherapy) combinations in advanced NSCLC warrant discussion. In the KEYNOTE-021 study involving chemotherapy-naive, stage IIIB or IV, non-squamous NSCLC without targetable or ALK genetic aberrations, the addition of pembrolizumab to carboplatin and pemetrexed was found to confer significant progression-free survival (median progression-free survival, 13.0 months versus 8.9 months; hazard ratio (HR) 0.53, 95% confidence interval (CI) 0.31 to 0.91) and objective response rate (ORR) (55% versus 29%; estimated treatment difference 26%, 95% CI 9% to 42%) benefits, however no statistical difference in overall survival was detected over the reported median follow-up of 10.6 months (Langer 2016). These benefits extended to participants with PD-L1 TPS < 1%. The incidence of grade 3 or worse adverse events (39% versus 26%) and rate of treatment discontinuation owing to toxicity (10% versus 13%) were comparable between the chemo-immunotherapy group and chemotherapy (Langer 2016). A randomised, double-blind, multicentre phase II trial reported an improvement in progression-

free survival (per both immune-related response criteria and modified World Health Organization (WHO) criteria) of phased ipilimumab (two doses of paclitaxel and carboplatin followed by four doses of ipilimumab plus paclitaxel and carboplatin) compared to carboplatin plus paclitaxel alone (Lynch 2012). Of note, the study by Lynch 2012 justifies the scientific relevance of including studies with CTLA-4 antibodies. The CheckMate 012 trial, which investigated the combination of nivolumab plus platinum-based doublet chemotherapy in a nonrandomised setting, provided encouraging efficacy signals, especially for the nivolumab 5 mg/kg plus paclitaxel-carboplatin regimen which demonstrated a twoyear overall survival rate of 62% in all NSCLC histologies (Rizvi 2016). As such, the results of several ongoing randomised trials (e.g. CheckMate 227, CheckMate 722, IMpower 130, IMpower 131, IMpower 150, KEYNOTE-189, KEYNOTE-407) of frontline chemo-immunotherapy are eagerly awaited.

How the intervention might work Preclinical evidence has accumulated that chemotherapeutic agents may exert immune-potentiating effects under certain conditions, and increase the sensitivity of cancer cells to CD8+ Tcell dependent immunosurveillance and rejection. Notably, platinum agents, which are used as the chemotherapy backbone in NSCLC, are recognised for their immune-adjuvant properties (de Biasi 2014; Hato 2014; Lam 2018; Syn 2017b). Some of the mechanisms by which chemotherapy helps to prime robust antitumour immune responses are summarised in Figure 1 (Syn 2017b), and include but are not limited to the following.


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Figure 1. Mechanisms by which chemotherapy synergises with immunotherapy. Figure drawn by Nicholas Syn.

1. Increasing the mutational load in cancer cells (Szikriszt 2016), which results in a higher chance that a neoepitope is presented on a major histocompatilibity complex molecule. This is crucial as neoantigens are required to drive productive antitumour immunity (McGranahan 2016; Pardoll 2012; Rizvi 2015; Snyder 2014; Syn 2017a; Van Allen 2015). 2. Modulating the immune contexture, specifically depleting or reducing the activity of immune-suppressive regulatory T-cells and myeloid-derived cell subsets, as well as revitalising exhausted antigen-specific CD8+ T-cells in the tumour microenvironment (Kodumudi 2010; Nowak 2002; Pol 2015; Zitvogel 2008). 3. Normalising the tumour neovasculature by exerting antiangiogenic and anti-vasculogenic effects (Schwartz 2009), thus allowing for greater CD8+ T-cell infiltration. This is because the neovasculature poses a selective barrier against CD8+ T-cell extravasation, even inducing effector CD8+ T-cells to undergo apoptosis upon contact with the neovascular endothelium (Motz 2014). 4. Augmenting major histocompatilibity complex class I expression and various components of the antigen presentation machinery in tumour cells (de Biasi 2014; Galluzzi 2012). 5. Enhancing the cross presentation of neoantigens through

inducing immunogenic forms of tumour cell death (Galluzzi 2017; Pfirschke 2016; Pol 2015). 6. Increasing the sensitivity of tumour cells to interferon-γ , a T-cell effector cytokine which can restrain tumour growth and induce cancer cell apoptosis, by modulating signal transducers and activators of transcription (STAT) signalling (Hato 2014).

Why it is important to do this review Despite extensive studies of targeted and cytotoxic therapies, until recently, few agents with the exception of bevacizumab and cetuximab have shown potential to improve survival or progression-free survival when added as a third drug to standard first-line platinum doublet chemotherapy (Soria 2013; Yang 2014). Immune checkpoint inhibitors hold potential for filling this therapeutic void, as evidenced by the approval of pembrolizumab in combination with carboplatin and pemetrexed in the front-line treatment of advanced non-squamous NSCLC (Langer 2016). Furthermore, despite the acceptance of chemo-immunotherapy as a new therapeutic benchmark, several unanswered questions remain. Will the chemo-immunotherapy regimen lead to a tradeoff between higher efficacy at the expense of increased toxicity?


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Based on the relatively limited published data that are currently available, the incidence of serious (grade 3 or worse) treatmentrelated adverse events was numerically, but not statistically, higher in the pembrolizumab plus chemotherapy group (23 of 59 participants (39%)) compared to the chemotherapy group (16 of 62 participants (26%)) in the KEYNOTE-021 trial (Langer 2016). In CheckMate 012, adverse events led to a higher rate of treatment discontinuation (21%) with nivolumab plus platinum-based firstline therapy as compared with historical controls (Rizvi 2016). In the study by Lynch 2012, rates of grade 3 and 4 adverse events were 15% to 20% with ipilimumab plus carboplatin and paclitaxel regimens compared to 6% with placebo. In addition, will the magnitude of treatment effects vary across different contexts (eg. whether trials were conducted in Asia or outside of Asia) and participant subgroups (eg. whether the efficacy of immunotherapy may be higher in high PD-L1-expressing tumours - a claim which remains debatable (Dijkstra 2016; Gaule 2016; McLaughlin 2016; Sacher 2016)) (see Subgroup analysis and investigation of heterogeneity), or might it be influenced by the design aspects of individual trials (see Sensitivity analysis)? We will therefore undertake this review to clarify outstanding questions by drawing together the available evidence, which will hopefully benefit physicians and people with advanced NSCLC, as well as inform policy.

OBJECTIVES To determine the effectiveness and toxicity of immune checkpoint inhibitors plus chemotherapy versus chemotherapy or immunotherapy alone as first-line treatment of advanced non-small cell lung cancer (NSCLC).

METHODS

Criteria for considering studies for this review

Types of studies Randomised controlled trials, with or without blinding. We will not include quasi-randomised or cluster-randomised trials. To limit publication bias, we will consider including meeting abstracts and unpublished online data if there are sufficient results to analyse.

(NSCLC). We will include participants regardless of their histology (e.g. squamous, non-squamous) and molecular pathology (e.g. PD-L1 expression, epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) or ROS1 rearrangements, microsatellite instability status). Studies of mixed solid tumours are eligible only if results on NSCLC partipants are provided separately in stratified analyses. Types of interventions 1. Intervention arm: immune checkpoint blockade plus chemotherapy. 2. Comparison arm A: chemotherapy (without immune checkpoint blockade). 3. Comparison arm B: immune checkpoint blockade (without chemotherapy). Immune checkpoint blockade therapy is defined as the administration of drug(s) which target T-cell suppressive pathways and can include, but is not limited to: pembrolizumab and nivolumab (anti-PD-1), atezolizumab, durvalumab and avelumab (anti-PDL1), and ipilimumab (anti-CTLA-4) given as single-agents or in combination. Chemotherapy is defined as the administration of cytotoxic drug(s), and can include, but is not limited to: carboplatin, cisplatin, paclitaxel, nab-paclitaxel, vinorelbine, premetrexed, gemcitabine, irinotecan, or docetaxel given as single-agents or in combination. Other active antitumour treatment modalities, such as the targeted therapy bevacizumab, and radiotherapy are permitted, and we will group such trials together under relevant subgroups (see Subgroup analysis and investigation of heterogeneity). To address concerns regarding the mixing of CTLA-4 plus chemotherapy and PD-1 plus chemotherapy studies together, we will address the role of anti-CTLA-4 plus chemotherapy combinations and anti-PD-1/anti-PD-L1 plus chemotherapy combinations in separate reviews. Furthermore, although we acknowledge a few ongoing clinical trials investigating the potential benefit of nivolumab + ipilimumab combination immunotherapies (CheckMate 227 NCT02477826 and CheckMate 772 - NCT02864251), double immunotherapy without chemotherapy extends beyond the scope of our review. Thus, this generic protocol will address the following two interventions. 1. Anti-PD-1/anti-PD-L1 plus chemotherapy versus chemotherapy or anti-PD-1/anti-PD-L1 alone. 2. Anti-CTLA-4 plus chemotherapy versus chemotherapy or anti-CTLA-4 alone. Types of outcome measures

Types of participants Participants aged 18 years and older who have not received previous chemotherapy or immunotherapy for histologically or cytologically confirmed, stage IIIB or IV non-small cell lung cancer

Primary outcomes

1. Overall survival: time from randomisation until death.


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2. Toxicity.

Secondary outcomes

1. Progression-free survival: time from randomisation until disease progression or death from any cause. If progression-free survival is not provided, we will extract the time-to-progression, time-to-treatment failure, or relapse-free survival. 2. Objective response rate (according to Response Evaluation Criteria in Solid Tumours (RECIST) or immune-related RECIST (Wolchok 2009)). 3. Health-related quality of life. 4. Duration of response. 5. Time to response.

Search methods for identification of studies

Electronic searches The Cochrane Lung Cancer Group Information Specialists will conduct bibliographic searches in the following databases for randomised controlled trials from 2005 based on the review authors’ prior knowledge that immune checkpoint inhibitors were not available (even in clinical trials) prior to 2005. 1. Cochrane Lung Cancer Review Group Specialised Register. 2. Cochrane Central Register of Controlled Trials (CENTRAL). 3. MEDLINE. 4. Embase. 5. Ovid CAB abstracts. The review authors (NS, IW) will conduct searches in the following clinical trial registries to identify unpublished and ongoing trials. 1. ClinicalTrials.gov. 2. WHO International Clinical Trials Registry Platform (ICTRP). 3. ISRCTN. We will model the subject strategies for databases on the search strategies designed for Cochrane Register of Studies Online (CRSO) and MEDLINE (Appendix 1). Where appropriate, we will combine these with subject strategy adaptations of the highly sensitive search strategy designed by Cochrane for identifying randomised controlled trials and controlled clinical trials (as described in the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0, Box 6.4.b. (Higgins 2011). Search strategies for Embase and CENTRAL can be found in Appendix 2 and Appendix 3, respectively.

Searching other resources We will search the meeting abstracts of conferences in the following sources from 2014 onwards. 1. International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer (WCLC). 2. European Society for Medical Oncology (ESMO). 3. European Lung Cancer Conference (ELCC). 4. American Society of Clinical Oncology (ASCO). We will also retrieve the clinical study reports about the checkpoint inhibitors on the European Medicines Agency (EMA) website.

Data collection and analysis To prevent duplication of data, we have listed the immunotherapy plus chemotherapy interventions in a specific order. Each review will include comparisons between one of the interventions with only those interventions listed above it. For instance, the review of chemotherapy plus immunotherapy (3) will only include comparisons with immunotherapy (2) or chemotherapy (1). Given that this generic protocol covers only two specific immunotherapies (anti-PD-1/anti-PD-L1 and anti-CTLA-4), the type of immunotherapy used in the chemotherapy plus immunotherapy arm must be similar to that in the comparison immunotherapy arm. The current list stands as: 1. chemotherapy; 2. immunotherapy (anti-PD-1/anti-PD-L1/anti-CTLA-4); 3. chemotherapy plus immunotherapy (anti-PD-1/anti-PDL1/anti-CTLA-4). Selection of studies We will download all titles and abstracts retrieved by electronic searching to a reference management database (e.g. Mendeley) and remove duplicates. Two review authors (NLS, IW) will examine the remaining references independently. We will exclude those studies that clearly do not meet the inclusion criteria and obtain copies of the full text of potentially relevant references. Two review authors (NLS, IW) will independently assess the eligibility of retrieved papers and resolve disagreements through discussion or, if necessary, by referral to a third review author (SIO or RAS). We will document the reasons for exclusion.

Selection of studies We will download all titles and abstracts retrieved by electronic searching to a reference management database (e.g. Mendeley) and remove duplicates. Two review authors (NLS, IW) will examine the remaining references independently. We will exclude those studies that clearly do not meet the inclusion criteria and obtain copies of the full text of potentially relevant references. Two


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review authors (NLS, IW) will independently assess the eligibility of retrieved papers and resolve disagreements through discussion or, if necessary, by referral to a third review author (SIO or RAS). We will document the reasons for exclusion.

Data extraction and management Two review authors (NLS, IW) will independently extract study characteristics and outcome data from included studies onto a prepiloted data collection form. We will note in the ’Characteristics of included studies’ table if outcome data were not reported in a usable way. We will resolve disagreements by consensus or by appeal to a third review author (YH or AD). One review author (NLS) will transfer data into the Cochrane Review Manager 5 software (Review Manager 2014). A second review author (IW) will double-check that data are entered correctly by comparing the data presented in the review with the study reports. For included studies, we will extract the following data. 1. Author, year of publication and journal citation. 2. Methods i) random sequence generation ii) allocation concealment iii) type of analysis eg. intention-to-treat (ITT), modified ITT, or per-protocol; including potential sources of attrition bias, i.e. incomplete efficacy or safety data. If adjusted analyses were performed, we will record the adjustment variables used iv) primary, secondary, and exploratory endpoints v) whether computed tomography (CT)/magnetic resonance imaging (MRI) scans were reviewed by investigators or by independent radiologists, and whether the latter were blinded vi) duration of follow-up for each outcome. 3. Partipants i) total number enrolled in each group ii) country iii) inclusion and exclusion criteria, and key baseline characteristics of participants, e.g. percentage of adenocarcinoma histology, stage, age, proportion of males/females PD-L1 expression, tumour mutation burden, CTLA-4 expression. 4. Interventions i) details of intervention, e.g. choice and dosing schedule of immune checkpoint inhibitors and cytotoxic agents. We will extract results as follows. 1. For time-to-event data (survival and disease progression), we will extract the log of the hazard ratio (log(HR)) and its standard error from the study reports. If these are not reported, we will attempt to estimate the log(HR) and its standard error using the methods of Parmar 1998 and Tierney 2007. 2. For dichotomous outcomes (e.g. adverse events or deaths), if it is not possible to use a HR we will extract the number of participants in each treatment arm who experienced the outcome of interest and the number of participants assessed at endpoint, in order to estimate a risk ratio (RR) or odds ratio (OR).

3. For continuous outcomes (e.g. quality of life measures), we will extract the final value and standard deviation (SD) of the outcome of interest and the number of participants assessed at endpoint in each treatment arm at the end of follow-up, in order to estimate the mean difference (MD) between treatment arms and its standard error. 4. For ordinal outcomes (e.g. quality of life measures), as per the recommendations in the Cochrane Handbook for Systematic Reviews of Interventions (Section 7.7.4) (Higgins 2011), we will either dichotomise the scale for analysis (for shorter scales) or treat the ordinal scale as a continuous outcome (for longer scales where the data appear to be approximately normally distributed or if the analysis that the investigators performed suggests parametric tests were appropriate). We will not prespecify the method of data extraction, but we will extract data in all forms in which they are reported, as it will not be clear which is the most common method used for analysing data until all studies have been reviewed. We may undertake more than one form of analysis if applicable. If dichotomisation is performed, we may investigate the choice of the cut-off point in a sensitivity analysis. If reported, we will extract both unadjusted and adjusted statistics, as well as data relevant to an intention-to-treat and per-protocol analysis. For meta-analysis, we will use the estimates from intention-to-treat analyses, if available.

Assessment of risk of bias in included studies We will assess and report on the methodological risk of bias of the included studies using the Cochrane ’Risk of bias’ tool (Higgins 2011), which assesses the explicit reporting of the following individual elements. 1. Selection bias: random sequence generation and allocation concealment. 2. Performance bias: blinding of participants and personnel (participants and treatment providers). 3. Detection bias: blinding of outcome assessment. 4. Attrition bias: incomplete outcome data pertaining to efficacy and toxicity. 5. Reporting bias: selective reporting of outcomes. 6. Other potential sources of bias, for example i) was sample size predefined and was target accrual met? ii) was there unplanned interim analyses? iii) was tumour response assessment performed by trial investigators or by independent/blinded radiologists? iv) were baseline characteristics balanced?

Measures of treatment effect We will use the following measures of the effect of treatment. 1. For time-to-event data, we will use the HR, if possible. 2. For dichotomous outcomes, we will use the OR or RR, if possible.


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3. For continuous outcomes, we will use the MD, if possible. We will undertake meta-analyses only where this is meaningful, i.e. if the treatments, participants and the underlying clinical question are similar enough for pooling to make sense.

Unit of analysis issues For studies with more than one intervention arm, we will combine groups to create a single pairwise comparison. For instance, assuming a trial with three arms (arm A: immunotherapy plus chemotherapy; arm B: chemotherapy regimen 1; arm C: chemotherapy regimen 2), we will statistically combine the results of arms B + C, and compare arm A against the pooled results of arms B + C.

Dealing with missing data If data are missing, we will attempt to contact the study authors to obtain necessary results. Where necessary, unreported hazard ratios and their variances can be approximated from log-rank Chi² or P values, ratios of median time-to-events, observed-to-expected event ratios, and survival rates at given time points using the methods of Parmar 1998 and Tierney 2007. Furthermore, unreported median time-to-event outcomes and survival rates can be read from the Kaplan-Meier survival curves, if provided. We will attempt to run ITT analyses in such a scenario.

Assessment of heterogeneity Where studies are considered similar enough (in terms of participants, settings, intervention and outcome measures) to allow pooling of data using meta-analysis, we will assess the degree of heterogeneity by visual inspection of forest plots, by estimation of the percentage of heterogeneity (I² statistic) between studies that cannot be ascribed to sampling variation (Higgins 2003), by a formal statistical test of the significance of the heterogeneity (Chi² test) (Deeks 2001) and, if possible, by subgroup analyses. We will regard heterogeneity as substantial if the I² value is greater than 30% or there is a low P value (< 0.10) in the Chi² test for heterogeneity.

Data synthesis If sufficient and clinically similar studies are available to ensure meaningful conclusions, and if statistical heterogeneity is low (I² < 30%), we will pool the results in meta-analyses using the fixedeffect model. If there is variability in the participants, settings and interventions in the included studies, or if statistical heterogeneity is substantial (I² > 30%), we will use the random-effects model for meta-analysis (DerSimonian 1986). We will apply the inversevariance model in all cases regardless of model and effect measure. 1. For time-to-event data, we will pool HRs using the generic inverse variance. 2. For any dichotomous outcomes, we will calculate the RR as appropriate for each study and then pool these. We may analyse data based on the number of events and the number of people assessed in the intervention and comparison groups, and use these to calculate the RR and 95% confidence interval (CI). 3. For continuous outcomes, we will pool the MDs between the treatment arms at the end of follow-up, if all studies measure the outcome on the same scale; otherwise we will pool standardised mean differences (SMDs). We will analyse data based on the mean, SD and number of people assessed for both the intervention and comparison groups to calculate the MD between treatment arms with a 95% CI. If the MD is reported without individual group data, we will use this to report the study results. If more than one study measures the same outcome using different tools, we will calculate the SMD and 95% CI using the inverse variance method If any studies have multiple treatment groups, we will divide the ’shared’ comparison group into the number of treatment groups and comparisons between each treatment group and treat the split comparison group as independent comparisons. If we are unable to pool the data statistically using meta-analysis, we will conduct a narrative synthesis of results. We will present the major outcomes and results, organised by intervention categories according to the major types, or aims, or both, of the identified interventions. Depending on the assembled research, we may also explore the possibility of organising the data by population. Within the data categories we will explore the main comparisons of the review. We will also consider conducting a narrative synthesis in the event of high clinical variability (treatment types, population) between studies, where pooling of data is not advised.

Grade and ’Summary of findings’ table Assessment of reporting biases We will examine funnel plots corresponding to meta-analysis of the primary outcome to assess the potential for small study effects such as publication bias if more than 10 studies are identified. We will assess funnel plot asymmetry visually and, if asymmetry is suggested by this visual assessment, we will perform exploratory analyses to investigate it (Sterne 2011).

We will use the GRADEprofiler (GRADEpro) software to assist with the preparation of a ’Summary of findings’ table (GRADEpro GDT 2015). ’Summary of findings’ tables present the review’s main findings in a table format and provide key information about the best estimate of the magnitude of the effect, in relative terms, and the absolute differences for each relevant comparison of alternative management strategies, the number of participants and studies addressing each important outcome and the rating of the


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overall confidence in the effect estimates for the comparisons in a outcome specific manner. The outcomes we will include in the ’Summary of findings’ table are: 1. overall survival 2. toxicity 3. progression-free survival; and/or time-to-progression; and/ or time-to-treatment failure; and/or relapse-free survival 4. objective response rates 5. health-related quality of life We acknowledge that it may not be possible to address all important outcomes within the constraints of results reported in randomised controlled trials only.

Subgroup analysis and investigation of heterogeneity We consider the following factors as possible sources of heterogeneity, and will attempt to investigate them through subgroup analysis. • Squamous versus non-squamous NSCLC • PD-L1 expression and tumour proportion score cut-off

• Choice of chemo-immunotherapeutic regimen in the experimental arm • Studies conducted in Asia versus studies conducted outside of Asia • Age < 65 years or > 65 years Sensitivity analysis We will perform sensitivity analyses by excluding studies with unclear or high risk of bias in terms of allocation concealment. For the endpoint of overall survival, we will assess if the pooled HR and statistical heterogeneity changes considerably with the exclusion of studies with a large proportion (> 20%) of participants who cross over from the chemotherapy arm to the immunotherapy or chemo-immunotherapy arms.

ACKNOWLEDGEMENTS We thank the Cochrane Lung Cancer Group, especially Corynne Marchal for editorial support, and Francois Calais and Giorgio Maria Agazzi for developing and executing the search strategy.

• CLTA-4 expression • Tumour mutational burden and genomic statuses • Choice of chemotherapeutic regimen in the reference arm • Choice of immunotherapeutic regimen in the reference arm

We also thank the following individuals for feedback on the review protocol: Fergus Macbeth, Jean-Paul Sculier, Kwun Fong, Cheryl Ho and Nicolas Girard, as well as sign-off editor Virginie Westeel.

REFERENCES

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APPENDICES

Appendix 1. MEDLINE search strategy


13

Search

Query

1

Search Carcinoma, Non-Small-Cell Lung[MeSH Terms]

2

Search nsclc

3

Search lung cancer*

4

Search lung carcinom*

5

Search lung neoplasm*

6

Search lung tumor*

7

Search lung tumour*

8

Search non small cell*

9

Search nonsmall cell*

10

Search (#3 OR #4 OR #5 OR #6 OR #7) AND (#8 OR #9)

11

Search #1 OR #2 OR #10

12

Search (checkpoint) OR ICB

13

Search (((pembrolizumab) OR lambrolizumab) OR Keytruda) OR MK-3475

14

Search ((((nivolumab) OR MDX-1106) OR ONO-4538) OR BMS-936558) OR Opdivo

15

Search (((((atezolizumab) OR anti-PDL1) OR MPDL3280A) OR Tecentriq) OR RG7446) OR RG-7446

16

Search ((((ipilimumab) OR MDX-CTLA-4) OR Yervoy) OR MDX-010) OR MDX010

17

Search Durvalumab

18

Search (((((CTLA-4 Antigen[MeSH Terms]) OR CTLA-4) OR CTLA4) OR CD152) OR Cytotoxic T-LymphocyteAssociated Antigen 4) OR Cytotoxic T-Lymphocyte Antigen 4

19

Search #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18

20

Search antineoplastic agents[MeSH Terms]

21

Search Drug Therapy[MeSH Terms]

22

Search ((antineoplas*) OR drug therap*) OR chemotherap*


14

(Continued)

23

Search (((((((cisplatin[MeSH Terms]) OR platin*) OR Diamminedichloroplatinum) OR Platinum Diamminodichloride) OR cis Platin*) OR NSC-119875) OR Biocisplatinum) OR Platidiam

24

Search ((((((((((((((((carboplatin[MeSH Terms]) OR carboplatin) OR CBDCA) OR Carbosin) OR Carbotec) OR Ercar) OR JM 8) OR JM8) OR Neocarbo) OR NSC 241240) OR NSC241240) OR Paraplatin*) OR Carboplat) OR Platinwas) OR Ribocarbo) OR Blastocarb) OR Nealorin

25

Search ((Bevacizumab[MeSH Terms]) OR Bevacizumab) OR Avastin

26

Search (((((Pemetrexed[MeSH Terms]) OR Pemetrexed) OR MTA) OR LY 231514) OR LY231514) OR Alimta

27

Search #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26

28

Search #11 AND #19 AND #27

Appendix 2. Embase search strategy

No.

Query

1

’non small cell lung cancer’/exp

2

’nsclc’:ti,ab

3

’lung cancer*’:ti,ab

4

’lung carcinom*’:ti,ab

5

’lung neoplasm*’:ti,ab

6

’lung tumor*’:ti,ab

7

’lung tumour*’:ti,ab

8

’non small cell*’:ti,ab

9

’nonsmall cell*’:ti,ab

10

(#3 OR #4 OR #5 OR #6 OR #7) AND (#8 OR #9)

11

#1 OR #2 OR #10

12

checkpoint OR icb

13

pembrolizumab OR lambrolizumab OR keytruda OR ’mk 3475’


15

(Continued)

14

nivolumab OR ’mdx 1106’ OR ’ono 4538’ OR ’bms 936558’ OR opdivo

15

atezolizumab OR ’anti pdl1’ OR mpdl3280a OR tecentriq OR rg7446 OR ’rg 7446’

16

ipilimumab OR ’mdx ctla 4’ OR yervoy OR ’mdx 010’ OR mdx010

17

durvalumab

18

’cytotoxic t lymphocyte antigen 4’/exp OR ’ctla 4’ OR ctla4 OR cd152 OR ’cytotoxic t-lymphocyte-associated antigen 4’ OR ’cytotoxic t-lymphocyte antigen 4’

19

#12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18

20

’antineoplastic agent’/exp

21

’drug therapy’/exp

22

antineoplas* OR ’drug therap*’ OR chemotherap*

23

’cisplatin’/exp OR platin* OR diamminedichloroplatinum OR ’platinum diamminodichloride’ OR ’cis platin*’ OR ’nsc 119875’ OR biocisplatinum OR platidiam

24

’carboplatin’/exp OR carboplatin OR cbdca OR carbosin OR carbotec OR ercar OR ’jm 8’ OR jm8 OR neocarbo OR ’nsc 241240’ OR nsc241240 OR paraplatin* OR carboplat

25

’bevacizumab’/exp OR bevacizumab OR avastin

26

’pemetrexed’/exp OR pemetrexed OR mta OR ’ly 231514’ OR ly231514 OR alimta

27

#20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26

28

#11 AND #19 AND #27

Appendix 3. CENTRAL search strategy

#1

MeSH descriptor: [Carcinoma, Non-Small-Cell Lung] explode all trees

#2

nsclc

#3

lung cancer*

#4

lung carcinom*

#5

lung neoplasm*


16

(Continued)

#6

lung tumor*

#7

lung tumour*

#8

non small cell*

#9

nonsmall cell*

#10

(#3 or #4 or #5 or #6 or #7) and (#8 or #9)

#11

#1 or #2 or #10

#12

checkpoint or ICB

#13

pembrolizumab or lambrolizumab or Keytruda or MK-3475

#14

nivolumab or MDX-1106 or ONO-4538 or BMS-936558 or Opdivo

#15

atezolizumab or anti-PDL1 or MPDL3280A or Tecentriq or RG7446 or RG-7446

#16

ipilimumab or MDX-CTLA-4 or Yervoy or MDX-010 or MDX010

#17

Durvalumab

#18

MeSH descriptor: [CTLA-4 Antigen] explode all trees

#19

CTLA-4 or CTLA4 or CD152 or Cytotoxic T-Lymphocyte-Associated Antigen 4 or Cytotoxic T-Lymphocyte Antigen 4

#20

#12 or #13 or #14 or #15 or #16 or #17 or #18 or #19

#21

MeSH descriptor: [Antineoplastic Agents] explode all trees

#22

MeSH descriptor: [Drug Therapy] explode all trees

#23

antineoplas* or drug therap* or chemotherap*

#24

MeSH descriptor: [Cisplatin] explode all trees

#25

platin* or Diamminedichloroplatinum or Platinum Diamminodichloride or cis Platin* or NSC-119875 or Biocisplatinum or Platidiam

#26

MeSH descriptor: [Carboplatin] explode all trees

#27

carboplatin or CBDCA or Carbosin or Carbotec or Ercar or JM 8 or JM8 or Neocarbo or NSC 241240 or NSC241240 or Paraplatin* or Carboplat or Platinwas or Ribocarbo or Blastocarb or Nealorin

#28

MeSH descriptor: [Bevacizumab] explode all trees


17

(Continued)

#29

Bevacizumab or Avastin

#30

MeSH descriptor: [Pemetrexed] explode all trees

#31

Pemetrexed or MTA or LY 231514 or LY231514 or Alimta

#32

#21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30 or #31

#33

#11 and #20 and #32

CONTRIBUTIONS OF AUTHORS Drafting the protocol: Nicholas Syn, Sai-Hong Ignatius Ou, Marie Loh, Ian Wee, Louis Zizhao Wang, Lingzhi Wang, Yiqing Huang, Richie Soong, Alexander Drilon. Developing and running the search strategy: Cochrane Lung Cancer Group Information Specialists (Francois Calais and Giorgio Maria Agazzi). Obtaining copies of studies: Louis Zizhao Wang. Selecting which studies to include: Nicholas Syn, Raheleh Roudi, Ian Wee, Sai-Hong Ignatius Ou, Yiqing Huang, Richie Soong, Alexander Drilon. Extracting data from studies: Nicholas Syn, Raheleh Roudi, Ian Wee. Entering data into RevMan: Nicholas Syn, Raheleh Roudi. Carrying out the analysis: Nicholas Syn, Ian Wee Interpreting the analysis: Nicholas Syn, Sai-Hong Ignatius Ou, Marie Loh, Ian Wee, Louis Zizhao Wang, Lingzhi Wang, Yiqing Huang, Richie Soong, Alexander Drilon. Drafting the final review: Nicholas Syn, Sai-Hong Ignatius Ou, Marie Loh, Ian Wee, Louis Zizhao Wang, Lingzhi Wang, Yiqing Huang, Richie Soong, Alexander Drilon. Updating the review: Nicholas Syn, Sai-Hong Ignatius Ou, Marie Loh, Ian Wee, Louis Zizhao Wang, Lingzhi Wang, Yiqing Huang, Richie Soong, Alexander Drilon.

DECLARATIONS OF INTEREST Nicholas Syn: none known. Raheleh Roudi: none known. Louis Zizhao Wang: none known. Lingzhi Wang: none known. Marie Loh: none known. Yiqing Huang: none known. Sai-Hong Ignatius Ou: none known. Richie Soong: none known. Immune checkpoint inhibitors plus chemotherapy versus chemotherapy or immunotherapy for first-line treatment of advanced nonsmall cell lung cancer: a generic protocol (Protocol) Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Alexander Drilon has received consulting fees/honoraria from AstraZeneca and Roche/Genetech. He has also received consulting fees/ honoraria from Loxo Oncology/Bayer, Beigene, Ignyta, TP Therapeutics, and Blueprint Medicines, and royalties from Lippincott. Ian Wee: none known.


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