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Real world data in the era of Immune Checkpoint Inhibitors (ICIs): Increasing evidence and future applications in lung cancer

Open AccessPublished:May 15, 2020DOI:https://doi.org/10.1016/j.ctrv.2020.102031

      Highlights

      • Immunotherapy changed treatment paradigm for NSCLC patients.
      • Real-world patients often differ from selected patients enrolled in clinical trials.
      • Some patient subsets are underrepresented in randomized clinical trials (RCTs)
      • Real-world studies may close this gap and overcome the intrinsic limits of RCTs.

      Abstract

      Immune checkpoint inhibitors (ICIs) targeting programmed death 1 (PD-1) and PD-ligand 1 (PD-L1) quickly subverted the standard of treatment in Non-Small Cell Lung Cancer (NSCLC), where they were first introduced in all comers previously treated advanced/metastatic NSCLC patients and subsequently in the first line of PD-L1 selected cases of metastatic and locally advanced disease.
      Treatment algorithm is an evolving landscape, where the introduction of front-line ICIs, with or without chemotherapy, unavoidably influences the following treatment lines. In this context, medical oncologists are currently facing many unclear issues, which have been not clarified so far by available data.
      Effectiveness and safety in special populations underrepresented in clinical trials - such as elderly, poor PS, hepatitis or human immunodeficiency virus-affected patients - are only a part of the unexplored side of ICIs in the real world. Indeed, pivotal randomized clinical trials (RCTs) often lack of external validity because eligibility criteria exclude some patient subgroups commonly treated in real-world clinical practice. Similarly, cost-effectiveness and sustainability of these innovative agents are important issues to be considered in the real-world. Though affected by several limitations, real-world evidence (RWE) studies allow to collect data regarding overall treated patients in clinical practice according to local authority regulations, overcoming the intrinsic limits of RCTs.
      The present review focuses on RWE about ICIs in lung cancer treatment, with particular reference to special patient populations, and discusses potential application of real-world data in a potential innovative drug development model.

      Keywords

      Introduction

      During the course of last five years, the introduction of a new class of drugs, the immune checkpoint inhibitors (ICIs), has dramatically changed the treatment of lung cancer. Anti-PD1 (pembrolizumab and nivolumab) and anti-PD-L1 (atezolizumab and durvalumab) are able to avoid certain tumor immune-escaping mechanisms, thus restoring the antitumor response of patient’s immune system [
      • Raju S.
      • Joseph R.
      • Sehgal S.
      Review of checkpoint immunotherapy for the management of non-small cell lung cancer.
      ]. ICIs were firstly introduced as first or second line treatment of patients with advanced stage disease, both in PD-L1 selected (pembrolizumab) and all comers [
      • Borghaei H.
      • Paz-Ares L.
      • Horn L.
      • Spigel D.R.
      • Steins M.
      • Ready N.E.
      • et al.
      Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer.
      ,
      • Brahmer J.
      • Reckamp K.L.
      • Baas P.
      • Crinò L.
      • Eberhardt W.E.E.
      • Poddubskaya E.
      • et al.
      Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer.
      ,
      • Herbst R.S.
      • Baas P.
      • Kim D.-W.
      • Felip E.
      • Pérez-Gracia J.L.
      • Han J.-Y.
      • et al.
      Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.
      ,
      • Reck M.
      • Rodríguez-Abreu D.
      • Robinson A.G.
      • Hui R.
      • Csőszi T.
      • Fülöp A.
      • et al.
      Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer.
      ]; later on, durvalumab was introduced as consolidation treatment in the algorithm of PD-L1 positive locally-advanced non-small cell lung cancer NSCLC [
      • Antonia S.J.
      • Villegas A.
      • Daniel D.
      • Vicente D.
      • Murakami S.
      • Hui R.
      • et al.
      Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC.
      ]. Currently, several clinical trials in neoadjuvant and adjuvant setting are ongoing [
      • Yi C.
      • He Y.
      • Xia H.
      • Zhang H.
      • Zhang P.
      Review and perspective on adjuvant and neoadjuvant immunotherapies in NSCLC.
      ].
      Different immunotherapeutic agents, with similar indication, target and safety profile, have been approved by regulatory agencies, thus contributing to the proliferation of “me-too drugs” in the current scenario [
      • Greenhalgh J.
      • Dwan K.
      • Boland A.
      • Bates V.
      • Vecchio F.
      • Dundar Y.
      • et al.
      First-line treatment of advanced epidermal growth factor receptor (EGFR) mutation positive non-squamous non-small cell lung cancer.
      ]. In this context, little to no evidence is available to support the selection among available agents.
      It is important to highlight that nowadays the approval process is based on the results of randomized clinical trials (RCTs). The majority of conclusive RCT randomly allocate patients to receive an interventional treatment or the standard of care, thus being able to prove the benefit of the investigational therapeutic agent. Patients’ population is strictly defined by inclusion and exclusion criteria, in order to minimize the bias related to variables other than the interventional treatment itself. As a consequence, RCTs generate the strongest form of evidence and therefore represent the gold standard to evaluate the efficacy of an intervention. However, translating this evidence in the real-life can be challenging, with a significant proportion of patients we deal with in daily practice being under-represented in RCT.
      Since ICIs have become part of the new standard of care for lung cancer, oncologists have had to face the lack of data about subsets of patients usually excluded by pivotal clinical trials. Particularly, it is crucial to gain information about safety and effectiveness of ICIs in patients affected by chronic viral diseases and, more importantly, the ones having brain metastases or an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2 or worse.
      Real world studies are emerging in medical oncology as a useful tool to collect data from daily clinical practice, thus driving clinical choices in special patients population; these studies may be enriched with budget impact analysis data and additional useful information for several stakeholders and possibly might become a part of regulatory agencies approval pathway in the next future.
      The term real-world data (RWD) refers to population-level data gathered from multiple sources, such as existing registries, administrative databases, hospital records, disease-specific databases and insurance claims, in a post-market context. Real-world evidence (RWE) represents the evidence generated from the analysis of RWD, in the setting of pragmatism-oriented studies. RWE might be highly useful, as it could be informative about the features of patients who have access to health care and treatments for a certain disease (i.e. observational studies). On the other hand, it could also assess the efficacy of a certain medical intervention under usual conditions (i.e. pragmatic studies), outside the controlled setting of conventional clinical trials.
      The widespread digitalization of source data is facilitating this kind of studies. Indeed, the advent of so-called electronic health records (EHRs) has simplified both the collection of wide range of data and the integration of patients’ information coming from different data sets.
      The aim of this review is to present a wide picture of RWE available since the advent of ICIs in thoracic oncology, focusing on their application particularly in the clinical management of special populations, and to discuss future application in the drug development process.

      Materials and methods

      We conducted a PRISMA-based systematic review with two systematic PICo searches (Supplementary Appendix). A systematic search of PubMed and Cochrane Library was performed, using the search terms ‘real-world’ and ‘lung cancer’ with all relevant synonyms and the time frame between January 2010 and January 2020.
      A second systematic search of PubMed and Cochrane library was performed, using the search terms ‘real-world’, ‘lung cancer’ and ‘immunotherapy’ or ‘nivolumab’ or ‘pembrolizumab’ or ‘atezolizumab’ or ‘durvalumab’ with all relevant synonyms.
      The first research was meant to evaluate the quantitative impact of ICI introduction in the RW studies in lung cancer. The second one focused on ICIs in particular sub-populations.
      After removal of duplicates, titles and abstracts were screened by two researchers (A.P. and I.A.) independently and split in ‘before’ and ‘after’ ICI introduction, using the July 2015 as split point, and finally focusing on available data between July 2015 and January 2020.
      Only English-language studies published in peer-review journals were considered. Studies that described only case reports, clinical trials, reviews and conference abstracts were excluded. Articles were read in full and a further selection was made based on relevance of these full texts. Discrepancies between the two researchers were discussed and resolved by consensus.

      Results

      Real world data on ICIs in lung cancer

      The first literature search yielded 582 citations in PubMed and 101 citations in Cochrane library. After excluding duplicates and applying the selection criteria, 197 articles were excluded. Among the remaining articles, 60 were published in the 5-year time frame between 2010 and July 2015, whereas 372 in the following 5-year period between July 2015 and January 2020 (Fig. 1, Fig. 2).
      Figure thumbnail gr1
      Fig. 1Amount of real word evidence on ICIs between 2010 and 2020; a) Number of citations/year of real world evidence in lung cancer between January 2010 and January 2020; b) percentage of real world evidence on ICIs in lung cancer before and after July 2015.
      Figure thumbnail gr2
      Fig. 2Flow charts representing results of: a) systematic search of PubMed and Cochrane Library, using the search terms ‘real-world’ and ‘lung cancer’ in the time frame between January 2010 and January 2020; b) systematic search of PubMed and Cochrane library using the search terms ‘real-world’, ‘lung cancer’ and ‘immunotherapy’ or ‘nivolumab’ or ‘pembrolizumab’ or ‘atezolizumab’ or ‘durvalumab’ after July 2015.
      The second combined literature search yielded 157 citations; among them 120 citations were published after July 2015. Five results (4.2%) concern the locally advanced setting of treatment and 115 (95.8%) the treatment of stage IV NSCLC. After applying the selection criteria, nineteen articles were excluded (Fig. 2). Forty-seven final articles were selected according to the relevance of the full-text results.

      Efficacy and safety a of ICIs in the real world

      The vast majority of the real-world data about immunotherapy in lung cancer describes the activity, in terms of objective response rate (ORR), efficacy (in terms of overall survival, OS, and progression free survival, PFS) and the safety profile of the most common ICIs used in clinical practice (Table 1). Studies on pretreated NSCLC patients were all retrospective and showed outcomes comparable with those reported in the pivotal RCTs, with median PFS and median OS ranging from 1.8 to 4.9 months and from 7.9 to 14.6 months, respectively [
      • Morita R.
      • Okishio K.
      • Shimizu J.
      • Saito H.
      • Sakai H.
      • Kim Y.H.
      • et al.
      Real-world effectiveness and safety of nivolumab in patients with non-small cell lung cancer: A multicenter retrospective observational study in Japan.
      ,
      • Kobayashi K.
      • Nakachi I.
      • Naoki K.
      • Satomi R.
      • Nakamura M.
      • Inoue T.
      • et al.
      Real-world efficacy and safety of nivolumab for advanced non–small-cell lung cancer: a retrospective multicenter analysis.
      ,
      • El Karak F.
      • Gh Haddad F.
      • Eid R.
      • Al Ghor M.
      • El Rassy E.
      • Ahmadieh N.
      • et al.
      Lung cancer and immunotherapy: a real-life experience from second line and beyond.
      ,
      • Ahn B.-C.
      • Pyo K.-H.
      • Xin C.-F.
      • Jung D.
      • Shim H.S.
      • Lee C.Y.
      • et al.
      Comprehensive analysis of the characteristics and treatment outcomes of patients with non-small cell lung cancer treated with anti-PD-1 therapy in real-world practice.
      ,
      • Nadler E.
      • Espirito J.L.
      • Pavilack M.
      • Boyd M.
      • Vergara-Silva A.
      • Fernandes A.
      Treatment patterns and clinical outcomes among metastatic non–small-cell lung cancer patients treated in the community practice setting.
      ,
      • Brustugun O.T.
      • Sprauten M.
      • Helland Å.
      Real-world data on nivolumab treatment of non-small cell lung cancer.
      ,
      • Weis T.M.
      • Hough S.
      • Reddy H.G.
      • Daignault-Newton S.
      • Kalemkerian G.P.
      Real-world comparison of immune checkpoint inhibitors in non-small cell lung cancer following platinum-based chemotherapy.
      ,
      • Fujimoto D.
      • Yoshioka H.
      • Kataoka Y.
      • Morimoto T.
      • Kim Y.H.
      • Tomii K.
      • et al.
      Efficacy and safety of nivolumab in previously treated patients with non-small cell lung cancer: A multicenter retrospective cohort study.
      ,
      • Cortinovis D.
      • Chiari R.
      • Catino A.
      • Grossi F.
      • Marinis F.D.E.
      • Sperandi F.
      • et al.
      Italian cohort of the nivolumab EAP in squamous NSCLC: efficacy and safety in patients with CNS metastases.
      ,
      • Crinò L.
      • Bidoli P.
      • Delmonte A.
      • Grossi F.
      • De Marinis F.
      • Ardizzoni A.
      • et al.
      Italian Cohort of nivolumab expanded access program in squamous non-small cell lung cancer: results from a real-world population.
      ,
      • Manrique M.C.A.
      • Martínez J.M.
      • González J.G.
      • Afonso F.J.A.
      • Quintela M.L.
      • Núñez N.F.
      • et al.
      Real world data of nivolumab for previously treated non-small cell lung cancer patients: A Galician lung cancer group clinical experience.
      ,
      • Khozin S.
      • Carson K.R.
      • Zhi J.
      • Tucker M.
      • Lee S.E.
      • Light D.E.
      • et al.
      Real-world outcomes of patients with metastatic non-small cell lung cancer treated with programmed cell death protein 1 inhibitors in the year following U.S. regulatory approval.
      ,
      • Khozin S.
      • Miksad R.A.
      • Adami J.
      • Boyd M.
      • Brown N.R.
      • Gossai A.
      • et al.
      Real-world progression, treatment, and survival outcomes during rapid adoption of immunotherapy for advanced non–small cell lung cancer.
      ,
      • Lin S.-Y.
      • Yang C.-Y.
      • Liao B.-C.
      • Ho C.-C.
      • Liao W.-Y.
      • Chen K.-Y.
      • et al.
      Tumor PD-L1 expression and clinical outcomes in advanced-stage non-small cell lung cancer patients treated with nivolumab or pembrolizumab: real-world data in Taiwan.
      ,
      • Abbas W.
      • Acharya R.
      • Pandit A.
      • Gupta S.
      • Rao R.
      The real-world experience with nivolumab in previously treated patients with advanced non-small cell lung cancer from a cancer center in India.
      ,
      • Figueiredo A.
      • Almeida M.A.
      • Almodovar M.T.
      • Alves P.
      • Araújo A.
      • Araújo D.
      • et al.
      Real-world data from the Portuguese Nivolumab Expanded Access Program (EAP) in previously treated Non Small Cell Lung Cancer (NSCLC).
      ]. Only one study showed a remarkable outcome for patients treated with nivolumab, with a median PFS exceeding 8 months and a median OS of over 15 months; however, this may be due to the small population (n = 11) considered for analysis [
      • Abbas W.
      • Acharya R.
      • Pandit A.
      • Gupta S.
      • Rao R.
      The real-world experience with nivolumab in previously treated patients with advanced non-small cell lung cancer from a cancer center in India.
      ]. There were no particular differences between real world experiences from Asian or non-Asian countries. The presence of EGFR or ALK druggable alterations, whenever tested for impact on outcome of non-squamous NSCLC patients, had a negative predictive role [
      • Morita R.
      • Okishio K.
      • Shimizu J.
      • Saito H.
      • Sakai H.
      • Kim Y.H.
      • et al.
      Real-world effectiveness and safety of nivolumab in patients with non-small cell lung cancer: A multicenter retrospective observational study in Japan.
      ,
      • Kobayashi K.
      • Nakachi I.
      • Naoki K.
      • Satomi R.
      • Nakamura M.
      • Inoue T.
      • et al.
      Real-world efficacy and safety of nivolumab for advanced non–small-cell lung cancer: a retrospective multicenter analysis.
      ,
      • Manrique M.C.A.
      • Martínez J.M.
      • González J.G.
      • Afonso F.J.A.
      • Quintela M.L.
      • Núñez N.F.
      • et al.
      Real world data of nivolumab for previously treated non-small cell lung cancer patients: A Galician lung cancer group clinical experience.
      ,
      • Khozin S.
      • Carson K.R.
      • Zhi J.
      • Tucker M.
      • Lee S.E.
      • Light D.E.
      • et al.
      Real-world outcomes of patients with metastatic non-small cell lung cancer treated with programmed cell death protein 1 inhibitors in the year following U.S. regulatory approval.
      ,
      • Khozin S.
      • Miksad R.A.
      • Adami J.
      • Boyd M.
      • Brown N.R.
      • Gossai A.
      • et al.
      Real-world progression, treatment, and survival outcomes during rapid adoption of immunotherapy for advanced non–small cell lung cancer.
      ,
      • Lin S.-Y.
      • Yang C.-Y.
      • Liao B.-C.
      • Ho C.-C.
      • Liao W.-Y.
      • Chen K.-Y.
      • et al.
      Tumor PD-L1 expression and clinical outcomes in advanced-stage non-small cell lung cancer patients treated with nivolumab or pembrolizumab: real-world data in Taiwan.
      ,
      • Juergens R.A.
      • Mariano C.
      • Jolivet J.
      • Finn N.
      • Rothenstein J.
      • Reaume M.N.
      • et al.
      Real-world benefit of nivolumab in a Canadian non-small-cell lung cancer cohort.
      ]. The rate of EGFR mutant NSCLC patients was consistent with pivotal trials (range: 5–21%), with the exception of the Taiwanese experience (41%) [
      • Lin S.-Y.
      • Yang C.-Y.
      • Liao B.-C.
      • Ho C.-C.
      • Liao W.-Y.
      • Chen K.-Y.
      • et al.
      Tumor PD-L1 expression and clinical outcomes in advanced-stage non-small cell lung cancer patients treated with nivolumab or pembrolizumab: real-world data in Taiwan.
      ]. No new safety signals were observed; however, it is worth mentioning a slightly higher incidence of grade 3–4 treatment related pneumonitis in the Japanese and Portuguese studies (4.3% and 5.7%, respectively) [
      • Morita R.
      • Okishio K.
      • Shimizu J.
      • Saito H.
      • Sakai H.
      • Kim Y.H.
      • et al.
      Real-world effectiveness and safety of nivolumab in patients with non-small cell lung cancer: A multicenter retrospective observational study in Japan.
      ,
      • Figueiredo A.
      • Almeida M.A.
      • Almodovar M.T.
      • Alves P.
      • Araújo A.
      • Araújo D.
      • et al.
      Real-world data from the Portuguese Nivolumab Expanded Access Program (EAP) in previously treated Non Small Cell Lung Cancer (NSCLC).
      ]. Currently there are fewer RW studies in the first line treatment with pembrolizumab, they are retrospective and they deal with efficacy and safety as well [
      • Ksienski D.
      • Wai E.S.
      • Croteau N.
      • Freeman A.T.
      • Chan A.
      • Fiorino L.
      • et al.
      Pembrolizumab for advanced nonsmall cell lung cancer: Efficacy and safety in everyday clinical practice.
      ,
      • Song P.
      • Zhang J.
      • Shang C.
      • Zhang L.
      Real-world evidence and clinical observations of the treatment of advanced non-small cell lung cancer with PD-1/PD-L1 inhibitors.
      ,
      • Tamiya M.
      • Tamiya A.
      • Hosoya K.
      • Taniguchi Y.
      • Yokoyama T.
      • Fukuda Y.
      • et al.
      Efficacy and safety of pembrolizumab as first-line therapy in advanced non-small cell lung cancer with at least 50% PD-L1 positivity: a multicenter retrospective cohort study (HOPE-001).
      ,
      • Velcheti V.
      • Chandwani S.
      • Chen X.
      • Pietanza M.C.
      • Piperdi B.
      • Burke T.
      Outcomes of first-line pembrolizumab monotherapy for PD-L1-positive (TPS ≥50%) metastatic NSCLC at US oncology practices.
      ,
      • Velcheti V.
      • Chandwani S.
      • Chen X.
      • Pietanza M.C.
      • Burke T.
      First-line pembrolizumab monotherapy for metastatic PD-L1-positive NSCLC: real-world analysis of time on treatment.
      ] (Table 1). Results are in line with those obtained in RCTs; of interest however, median OS values in RW studies are closer to that observed in the Keynote 042 subpopulation of patients with PD-L1 TPS ≥ 50%[
      • Mok T.S.K.
      • Wu Y.-L.
      • Kudaba I.
      • Kowalski D.M.
      • Cho B.C.
      • Turna H.Z.
      • et al.
      Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial.
      ], rather than that observed in Keynote 024 [
      • Reck M.
      • Rodríguez-Abreu D.
      • Robinson A.G.
      • Hui R.
      • Csőszi T.
      • Fülöp A.
      • et al.
      Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer.
      ,
      • Reck M.
      • Rodríguez-Abreu D.
      • Robinson A.G.
      • Hui R.
      • Csőszi T.
      • Fülöp A.
      • et al.
      Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non–small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater.
      ]. This may be due to patients characteristics, being the rates of never smokers included in these RW studies (range: 7.4–30.7%) more similar to the one of Keynote 042 (21%) [
      • Mok T.S.K.
      • Wu Y.-L.
      • Kudaba I.
      • Kowalski D.M.
      • Cho B.C.
      • Turna H.Z.
      • et al.
      Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial.
      ]. Whenever clinical variables were tested for their impact on survival, ECOG PS 2 was the only one always affecting outcomes [
      • Ksienski D.
      • Wai E.S.
      • Croteau N.
      • Freeman A.T.
      • Chan A.
      • Fiorino L.
      • et al.
      Pembrolizumab for advanced nonsmall cell lung cancer: Efficacy and safety in everyday clinical practice.
      ,
      • Tamiya M.
      • Tamiya A.
      • Hosoya K.
      • Taniguchi Y.
      • Yokoyama T.
      • Fukuda Y.
      • et al.
      Efficacy and safety of pembrolizumab as first-line therapy in advanced non-small cell lung cancer with at least 50% PD-L1 positivity: a multicenter retrospective cohort study (HOPE-001).
      ]. Safety profile was consistent with literature. Notably, Ksienski and colleagues performed logistic regression analysis in order to determine factors predicting grade 3 or higher immune-related toxicities within 3 months of starting pembrolizumab and found that patients with baseline ECOG PS < 2 had higher risk of developing immune-mediated adverse events [
      • Ksienski D.
      • Wai E.S.
      • Croteau N.
      • Freeman A.T.
      • Chan A.
      • Fiorino L.
      • et al.
      Pembrolizumab for advanced nonsmall cell lung cancer: Efficacy and safety in everyday clinical practice.
      ].
      Table 1Summary of the main studies reporting about efficacy and safety of ICIs in the real world.
      Author (reference)Sample sizeTreatmentMedian PFS (months)Median OS (months)ORR (%)Main factors influencing outcomeSafety profile
      Pre-treated setting
      RMorita R. et al.
      • Morita R.
      • Okishio K.
      • Shimizu J.
      • Saito H.
      • Sakai H.
      • Kim Y.H.
      • et al.
      Real-world effectiveness and safety of nivolumab in patients with non-small cell lung cancer: A multicenter retrospective observational study in Japan.
      901Nivolumab2.1

      (95% CI: 1.9–2.4)
      14.6

      (95% CI: 12.3–15.9)
      20.5Negative impact on PFS and OS:

      • -
        ECOG PS
      • -
        Liver metastasis


      Negative impact on PFS:

      • -
        EGFR sensitizing mutations
      All grade irAE = 45.8%

      G3-4 irAE = 14.0%

      G5 irAE = N.I.

      Pulmonary irAE G3-4 = 4.3%

      ICI discontinuation rate = 17.9%
      RKobayashi K. et al.
      • Kobayashi K.
      • Nakachi I.
      • Naoki K.
      • Satomi R.
      • Nakamura M.
      • Inoue T.
      • et al.
      Real-world efficacy and safety of nivolumab for advanced non–small-cell lung cancer: a retrospective multicenter analysis.
      142Nivolumab1.9

      (95% CI: 1.6–2.2)
      17.0Negative impact on PFS:

      • -
        EGFR sensitizing mutations


      Positive impact on PFS

      • -
        Previous radiotherapy
      All grade irAE = 45.1%

      G3-4 irAE = 13.3%

      G5 irAE = 1.4%

      Pulmonary irAE G3-4 = 2.1%

      Pulmonary irAE G5 = 0.7%

      ICI discontinuation rate = N.I.
      RGrossi F. et al.
      • Grossi F.
      • Crinò L.
      • Logroscino A.
      • Canova S.
      • Delmonte A.
      • Melotti B.
      • et al.
      Use of nivolumab in elderly patients with advanced squamous non–small-cell lung cancer: results from the Italian cohort of an expanded access programme.
      *
      1588Nivolumab3.0

      (95% CI: 2.9–3.1)
      11.3

      (95% CI: 10.2–12.4)
      18.0Negative impact on OS:

      • -
        ECOG PS
      • -
        Liver metastasis
      All grade irAE = 32.0%

      G3-4 irAE = 6.0%

      G5 irAE = 0.0%

      Pulmonary irAE G3-4 = <1%

      ICI discontinuation rate = 5.0%
      RCrinò et al.
      • Crinò L.
      • Bidoli P.
      • Delmonte A.
      • Grossi F.
      • De Marinis F.
      • Ardizzoni A.
      • et al.
      Italian Cohort of nivolumab expanded access program in squamous non-small cell lung cancer: results from a real-world population.
      **
      371Nivolumab4.2

      (95% CI: 3.4–5.0)
      7.9

      (95% CI: 6.2–9.6)
      18.0Negative impact on OS:

      • -
        ECOG PS
      • -
        Liver metastasis
      • -
        Bone metastasis
      All grade irAE = 29.0%

      G3-4 irAE = 6.0%

      G5 irAE = 0.0%

      Pulmonary irAE G3-4 = <1%

      ICI discontinuation rate = 9.0%
      RManrique M. et al.
      • Manrique M.C.A.
      • Martínez J.M.
      • González J.G.
      • Afonso F.J.A.
      • Quintela M.L.
      • Núñez N.F.
      • et al.
      Real world data of nivolumab for previously treated non-small cell lung cancer patients: A Galician lung cancer group clinical experience.
      188Nivolumab4.8

      (95% CI: 3.6–5.9)
      12.8

      (95% CI: 9.1–16.6)
      25.5Negative impact on OS:

      • -
        ECOG PS
      • -
        CNS metastasis
      All grade irAE = 78.0%

      G3-4 irAE = 4.8%

      G5 irAE = 0.0%

      Pulmonary irAE G3-4 = 1.1%

      ICI discontinuation rate = 4.8%
      RKhozin S. et al.
      • Khozin S.
      • Carson K.R.
      • Zhi J.
      • Tucker M.
      • Lee S.E.
      • Light D.E.
      • et al.
      Real-world outcomes of patients with metastatic non-small cell lung cancer treated with programmed cell death protein 1 inhibitors in the year following U.S. regulatory approval.
      1344Nivolumab and pembrolizumab8.0

      (95% CI: 7.4–9.0)
      Negative impact on OS:

      • -
        EGFR sensitizing mutations
      • -
        ALK translocation
      RKhozin S. et al.
      • Khozin S.
      • Miksad R.A.
      • Adami J.
      • Boyd M.
      • Brown N.R.
      • Gossai A.
      • et al.
      Real-world progression, treatment, and survival outcomes during rapid adoption of immunotherapy for advanced non–small cell lung cancer.
      5257Nivolumab, pembrolizumab and atezolizumab3.2

      (95% CI: 3.1–3.3)
      9.3

      (95% CI: 8.9–9.8)
      Negative impact on PFS and OS:

      • -
        EGFR sensitizing mutations
      • -
        ALK translocation
      • -
        Hepatic dysfunction


      Positive impact on PFS and OS:

      • -
        Female sex
      • -
        History of smoking
      RLin S.-Y. et al.
      • Lin S.-Y.
      • Yang C.-Y.
      • Liao B.-C.
      • Ho C.-C.
      • Liao W.-Y.
      • Chen K.-Y.
      • et al.
      Tumor PD-L1 expression and clinical outcomes in advanced-stage non-small cell lung cancer patients treated with nivolumab or pembrolizumab: real-world data in Taiwan.
      74Nivolumab and pembrolizumab1.8

      (95% CI: not indicated)
      7.9

      (95% CI: not indicated)
      32.0Negative impact on PFS and OS:

      • -
        ECOG PS


      Negative impact on PFS
      • -
        EGFR sensitizing mutations


      Positive impact on PFS and OS:

      History of smoking
      All grade irAE = 17.6%

      G3-4 irAE = 4.0

      G5 irAE = 0.0%

      Pulmonary irAE G3-4 = 4.0%

      ICI discontinuation rate = N.I.
      RAbbas W. et al.
      • Abbas W.
      • Acharya R.
      • Pandit A.
      • Gupta S.
      • Rao R.
      The real-world experience with nivolumab in previously treated patients with advanced non-small cell lung cancer from a cancer center in India.
      11Nivolumab8.0

      (95% CI: 1.5–14.5)
      15.0

      (95% CI: 6.9–23.1)
      54.5All grade irAE = 72.7%

      G3-4 irAE = 18.2%

      G5 irAE = 0.0%

      Pulmonary irAE G3-4 = 18.8%

      ICI discontinuation rate = N.I.
      RFigueiredo A. et al.
      • Figueiredo A.
      • Almeida M.A.
      • Almodovar M.T.
      • Alves P.
      • Araújo A.
      • Araújo D.
      • et al.
      Real-world data from the Portuguese Nivolumab Expanded Access Program (EAP) in previously treated Non Small Cell Lung Cancer (NSCLC).
      219Nivolumab4.9

      (95% CI: 3.9–6.1)
      13.2

      (95% CI: 9.9–16.5)
      22.4Negative impact on OS:
      • -
        ECOG PS
      All grade irAE = 76.4%

      G3-4 irAE = 16.0%

      G5 irAE = N.I.

      Pulmonary irAE G3-4 = 5.7%

      ICI discontinuation rate = 12.8%
      RJuergens R.A. et al.
      • Juergens R.A.
      • Mariano C.
      • Jolivet J.
      • Finn N.
      • Rothenstein J.
      • Reaume M.N.
      • et al.
      Real-world benefit of nivolumab in a Canadian non-small-cell lung cancer cohort.
      472Nivolumab3.5

      (95% CI: 3.2–4.0)
      12.0

      (95% CI: 11.0–13.9)
      Negative impact on OS:
      • -
        ECOG PS
      • -
        CNS metastasis
      Negative impact on PFS and OS:
      • -
        EGFR sensitizing mutations
      REl Karak F. et al.
      • El Karak F.
      • Gh Haddad F.
      • Eid R.
      • Al Ghor M.
      • El Rassy E.
      • Ahmadieh N.
      • et al.
      Lung cancer and immunotherapy: a real-life experience from second line and beyond.
      110Nivolumab and pembrolizumab4.0

      (95% CI: 2.6–5.4)
      8.1

      (95% CI: 2.8–13.4)
      25.3All grade irAE = 18.0%

      G3-4 irAE = N.I.

      G5 irAE = 0.0%

      Pulmonary irAE G3-4 = N.I.

      ICI discontinuation rate = N.I.
      RAhn B.-C. et al.
      • Ahn B.-C.
      • Pyo K.-H.
      • Xin C.-F.
      • Jung D.
      • Shim H.S.
      • Lee C.Y.
      • et al.
      Comprehensive analysis of the characteristics and treatment outcomes of patients with non-small cell lung cancer treated with anti-PD-1 therapy in real-world practice.
      155Nivolumab and pembrolizumab3.1

      (95% CI: 1.9–4.2)
      10.2

      (95% CI: 5.4–15.1)
      23.9Negative impact on OS:
      • -
        ECOG PS
      • -
        EGFR sensitizing mutations
      • -
        ALK rearrangement
      • -
        Liver metastasis
      All grade irAE = 61.9%

      G3-4 irAE = 5.3%

      G5 irAE = 0.0%

      Pulmonary irAE G3-4 = 3.2%

      ICI discontinuation rate = N.I.
      RNadler E. et al.
      • Nadler E.
      • Espirito J.L.
      • Pavilack M.
      • Boyd M.
      • Vergara-Silva A.
      • Fernandes A.
      Treatment patterns and clinical outcomes among metastatic non–small-cell lung cancer patients treated in the community practice setting.
      718 (2L)

      302 (3L)
      Nivolumab and pembrolizumab2L: 9.7

      (95% CI: 8.3–13.0)

      3L: 11.3

      (95% CI: 7.8–14.4)
      RBrustugun O. T. et al.
      • Brustugun O.T.
      • Sprauten M.
      • Helland Å.
      Real-world data on nivolumab treatment of non-small cell lung cancer.
      58Nivolumab11.7 (95% CI: not indicated)All grade irAE = 31.0%

      G3-4 irAE = 5.0%

      G5 irAE = 0.0%

      Pulmonary irAE G3-4 = 0.0%

      ICI discontinuation rate = 6.9%
      RWeis T. M. et al.
      • Weis T.M.
      • Hough S.
      • Reddy H.G.
      • Daignault-Newton S.
      • Kalemkerian G.P.
      Real-world comparison of immune checkpoint inhibitors in non-small cell lung cancer following platinum-based chemotherapy.
      124Nivolumab (65.3%) and atezolizumab (34.7%)2.2 (95% CI: 1.7–2.8) for nivolumab

      2.0 (95% CI: 1.8–2.7) for atezolizumab
      8.4 (95% CI: 6.3–11.2) for nivolumab

      6.5 (95% CI: 4.7-NR) for atezolizumab
      14.3Negative impact on PFS and OS:
      • -
        ECOG PS
      Nivolumab

      All grade irAE = 70.4%

      G3-4 irAE = N.I.

      G5 irAE = 0.0%

      Pulmonary irAE G3-4 = N.I.

      ICI discontinuation rate = 19.8%
      Atezolizumab

      All grade irAE = 65.1%

      G3-4 irAE = N.I.

      G5 irAE = 0.0%

      Pulmonary irAE G3-4 = N.I.

      ICI discontinuation rate = 14.0%
      RFujimoto D. et al.
      • Fujimoto D.
      • Yoshioka H.
      • Kataoka Y.
      • Morimoto T.
      • Kim Y.H.
      • Tomii K.
      • et al.
      Efficacy and safety of nivolumab in previously treated patients with non-small cell lung cancer: A multicenter retrospective cohort study.
      613NivolumabND

      1-year PFS = 18%
      20.0Negative impact on PFS:
      • -
        ECOG PS
      • -
        EGFR sensitizing mutations
      • -
        ALK rearrangement
      • -
        Never-smoking status
      All grade irAE = N.I.

      G3-4 irAE = 11.1%

      Pulmonary irAE G3-4 = 4.6%

      G5 irAE = 1.3%

      ICI discontinuation rate = N.I.
      First line setting
      RKsienski D. et al.
      • Ksienski D.
      • Wai E.S.
      • Croteau N.
      • Freeman A.T.
      • Chan A.
      • Fiorino L.
      • et al.
      Pembrolizumab for advanced nonsmall cell lung cancer: Efficacy and safety in everyday clinical practice.
      190Pembrolizumab3.7

      (95% CI: 2.8–4.3)
      24.3

      (95% CI: 9.7-NR)
      Negative impact on OS:
      • -
        ECOG PS
      All grade irAE = 34.7%

      G3-4 irAE = 8.4%

      G5 irAE = 0.0%

      Pulmonary irAE G3-4 = 0.5%

      ICI discontinuation rate = 12.1%
      RTamiya M. et al.
      • Tamiya M.
      • Tamiya A.
      • Hosoya K.
      • Taniguchi Y.
      • Yokoyama T.
      • Fukuda Y.
      • et al.
      Efficacy and safety of pembrolizumab as first-line therapy in advanced non-small cell lung cancer with at least 50% PD-L1 positivity: a multicenter retrospective cohort study (HOPE-001).
      213Pembrolizumab8.3

      (95% CI: 6.0–10.7)
      17.8

      (95% CI: 17.8-NA)
      51.2Negative impact on PFS:
      • -
        ECOG PS
      • -
        Steroid
      • -
        PD-L1 TPS
      All grade irAE = 76.4%

      G3-4 irAE = 18.3%

      G5 irAE = 0.5%

      Pulmonary irAE G3-4 = 0.9%

      ICI discontinuation rate = N.I.
      RVelcheti V. et al.
      • Velcheti V.
      • Chandwani S.
      • Chen X.
      • Pietanza M.C.
      • Piperdi B.
      • Burke T.
      Outcomes of first-line pembrolizumab monotherapy for PD-L1-positive (TPS ≥50%) metastatic NSCLC at US oncology practices.
      611Pembrolizumab6.8

      (95% CI: 5.3–8.1)
      18.9

      (95% CI: 14.9–25.5)
      48.0
      G = grading; irAE = immune-related adverse event; L = line; NI = not indicated; NR = not reached; OS = overall survival; PFS = progression free survival; PS = performance status; R = retrospective study.
      * non-squamous cell advanced NSCLC population; ** squamous cell advanced NSCLC population.

      Budget impact of anti-PD1 and anti-PDL1 agents

      In parallel to these clinical evaluations, the high incremental costs of ICIs have prompted particular attention towards treatment affordability. For the purpose of this review, we have selected studies directly involving real world patients and not cost effectiveness models derived from RCTs. Almazàn and colleagues performed an economical assessment of a retrospective series of patients treated with nivolumab as second line in 15 Spanish hospitals, using the cost per life-year gained (LYG) as variable [
      • Merino Almazán M.
      • Duarte Pérez J.M.
      • Marín Pozo J.F.
      • Ortega Granados A.L.
      • Muros De Fuentes B.
      • Quesada Sanz P.
      • et al.
      A multicentre observational study of the effectiveness, safety and economic impact of nivolumab on non-small-cell lung cancer in real clinical practice.
      ]. LYG was calculated as the rate between the benefit in OS (months) and the incremental cost of nivolumab therapy for all patients and it turned out to be of €110,026.00. The profitability, as defined by WHO, should be lower than three times the gross domestic product of the country per year of life adjusted to disability. In Spain such value is €75,000.00: LYG largely exceeds this threshold, pointing out once more the need of selecting patients with higher potential benefit from ICI. In this context, a more recent study estimated the cost-effectiveness of pembrolizumab according to comorbidities, defined with Charlson scoring system [
      • Ganti A.K.
      • Siedlik E.
      • Marr A.S.
      • Loberiza F.R.
      • Kessinger A.
      Predictive ability of Charlson comorbidity index on outcomes from lung cancer.
      ], using a model that combines clinical trial and real-world patient data [
      • Criss S.D.
      • Palazzo L.
      • Watson T.R.
      • Paquette A.M.
      • Sigel K.
      • Wisnivesky J.
      • et al.
      Cost-effectiveness of pembrolizumab for advanced non-small cell lung cancer patients with varying comorbidity burden.
      ]. Authors evaluated the incremental cost-effectiveness ratios (ICERs) compared to a willingness-to-pay-threshold of $100,000.00/quality-adjusted life-year (QALY). When evaluating pembrolizumab, despite the survival improvement compared to chemotherapy alone, the treatment regimens were not cost-effective in any of the patient populations, mainly due to the shorter OS of real-world patients compared to that observed in clinical trials. ICERs were even higher for patients with relevant comorbidities, suggesting the need of price re-modulation in order to guarantee a fair cost-effectiveness, given the true effectiveness of pembrolizumab reported in the real-world setting [
      • Criss S.D.
      • Palazzo L.
      • Watson T.R.
      • Paquette A.M.
      • Sigel K.
      • Wisnivesky J.
      • et al.
      Cost-effectiveness of pembrolizumab for advanced non-small cell lung cancer patients with varying comorbidity burden.
      ]. In the context of economic evaluation, another interesting study focused on the budget impact of the switch from a weight-based to a fixed dose regimen of anti-PD-1 agents [
      • Bayle A.
      • Besse B.
      • Annereau M.
      • Bonastre J.
      Switch to anti-programmed cell death protein 1 (anti-PD-1) fixed-dose regimen: What is the economic impact?.
      ]. Authors calculated the difference between the costs in these two regimens in patients treated in France from January to April 2018, assuming a constant price for both nivolumab and pembrolizumab. The study reported a mean extra-cost attributable to flat-fixed dosing of €349 per infusion of nivolumab and €1,234 per infusion of pembrolizumab, addressing a new important issue in terms of need of price-adjustment for this innovative class of drug and demonstrate that fixed dosing is likely to have substantial economic impact.

      Real world evidence on special populations

      Elderly

      Median age of lung cancer patients at diagnosis is 70 years [
      • Bray F.
      • Ferlay J.
      • Soerjomataram I.
      • Siegel R.L.
      • Torre L.A.
      • Jemal A.
      Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
      ], however, elderly patients are underrepresented in most RCTs: the over-75 population accounted for about 8% in the CheckMate 017 and 057 trials [
      • Borghaei H.
      • Paz-Ares L.
      • Horn L.
      • Spigel D.R.
      • Steins M.
      • Ready N.E.
      • et al.
      Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer.
      ,
      • Brahmer J.
      • Reckamp K.L.
      • Baas P.
      • Crinò L.
      • Eberhardt W.E.E.
      • Poddubskaya E.
      • et al.
      Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer.
      ] and for about 10–15% in Keynote 042 and 024, respectively [
      • Reck M.
      • Rodríguez-Abreu D.
      • Robinson A.G.
      • Hui R.
      • Csőszi T.
      • Fülöp A.
      • et al.
      Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer.
      ,
      • Mok T.S.K.
      • Wu Y.-L.
      • Kudaba I.
      • Kowalski D.M.
      • Cho B.C.
      • Turna H.Z.
      • et al.
      Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial.
      ,
      • Nosaki K.
      • Saka H.
      • Hosomi Y.
      • Baas P.
      • de Castro G.
      • Reck M.
      • et al.
      Safety and efficacy of pembrolizumab monotherapy in elderly patients with PD-L1–positive advanced non–small-cell lung cancer: Pooled analysis from the KEYNOTE-010, KEYNOTE-024, and KEYNOTE-042 studies.
      ]. With their favorable safety profile, ICIs may represent a good option for elderly patients. On the other hand, immune-senescence might impact on the capability of an aged immune system to properly respond to cancer and to be restored in its antineoplastic response after ICI administration [
      • Ferrara R.
      • Mezquita L.
      • Auclin E.
      • Chaput N.
      • Besse B.
      Immunosenescence and immunecheckpoint inhibitors in non-small cell lung cancer patients: Does age really matter?.
      ]. Several retrospective works tried to shed some light on this topic, evaluating both outcomes (OS, PFS, time to treatment failure, TTF, and ORR) and safety of ICIs in an elderly population. All studies outlined that the benefit from ICI monotherapy was not statistically different between older and younger patients and that also tolerability was not affected by age [
      • Grossi F.
      • Crinò L.
      • Logroscino A.
      • Canova S.
      • Delmonte A.
      • Melotti B.
      • et al.
      Use of nivolumab in elderly patients with advanced squamous non–small-cell lung cancer: results from the Italian cohort of an expanded access programme.
      ,
      • Galli G.
      • De Toma A.
      • Pagani F.
      • Randon G.
      • Trevisan B.
      • Prelaj A.
      • et al.
      Efficacy and safety of immunotherapy in elderly patients with non-small cell lung cancer.
      ,
      • Muchnik E.
      • Loh K.P.
      • Strawderman M.
      • Magnuson A.
      • Mohile S.G.
      • Estrah V.
      • et al.
      Immune checkpoint inhibitors in real-world treatment of older adults with non-small cell lung cancer.
      ,
      • Corbaux P.
      • Maillet D.
      • Boespflug A.
      • Locatelli-Sanchez M.
      • Perier-Muzet M.
      • Duruisseaux M.
      • et al.
      Older and younger patients treated with immune checkpoint inhibitors have similar outcomes in real-life setting.
      ,
      • Youn B.
      • Trikalinos N.A.
      • Mor V.
      • Wilson I.B.
      • Dahabreh I.J.
      Real-world use and survival outcomes of immune checkpoint inhibitors in older adults with non–small cell lung cancer.
      ]. Regarding treatment related adverse events, only Muchnik and colleagues found that the rate of immune-related colitis was higher for patients older than 80 [
      • Muchnik E.
      • Loh K.P.
      • Strawderman M.
      • Magnuson A.
      • Mohile S.G.
      • Estrah V.
      • et al.
      Immune checkpoint inhibitors in real-world treatment of older adults with non-small cell lung cancer.
      ]. This observation was not reported in CheckMate 153, a predominantly community-based phase IIIb/IV study designed to assess primarily the safety, but also the efficacy, of nivolumab monotherapy in previously treated patients with advanced NSCLC [
      • Spigel D.R.
      • McCleod M.
      • Jotte R.M.
      • Einhorn L.
      • Horn L.
      • Waterhouse D.M.
      • et al.
      Safety, efficacy, and patient-reported health-related quality of life and symptom burden with nivolumab in patients with advanced non-small cell lung cancer, including patients aged 70 years or older or with poor performance status (CheckMate 153).
      ]. The setting of this trial more closely reflected the real world, as it used less stringent eligibility criteria, allowing the enrollment of older and ECOG PS 2 patients. Still, results from such studies support the use of ICIs for elderly patients.

      ECOG performance status 2

      The main pivotal trials of ICIs in lung cancer did not include patients with poor PS, limiting inclusion criteria to PS 0 or 1 according to ECOG classification, while PS 2 patients were included in a very limited number of clinical trials [
      • Spigel D.R.
      • McCleod M.
      • Jotte R.M.
      • Einhorn L.
      • Horn L.
      • Waterhouse D.M.
      • et al.
      Safety, efficacy, and patient-reported health-related quality of life and symptom burden with nivolumab in patients with advanced non-small cell lung cancer, including patients aged 70 years or older or with poor performance status (CheckMate 153).
      ,
      • Popat S.
      • Ardizzoni A.
      • Ciuleanu T.
      • Cobo Dols M.
      • Laktionov K.
      • Szilasi M.
      • et al.
      1303PDNivolumab in previously treated patients with metastatic squamous NSCLC: Results of a European single-arm, phase 2 trial (CheckMate 171) including patients aged ≥70 years and with poor performance status.
      ]. Although the proportion of PS 2 patients was very low (about 10% in CheckMate 153 and 12% in CheckMate 171), safety profile seems not to be affected by PS. Survival results suggest a very limited effectiveness of nivolumab in patients with poor PS, with halved OS data compared to PS 0-1 patients [
      • Spigel D.R.
      • McCleod M.
      • Jotte R.M.
      • Einhorn L.
      • Horn L.
      • Waterhouse D.M.
      • et al.
      Safety, efficacy, and patient-reported health-related quality of life and symptom burden with nivolumab in patients with advanced non-small cell lung cancer, including patients aged 70 years or older or with poor performance status (CheckMate 153).
      ,
      • Popat S.
      • Ardizzoni A.
      • Ciuleanu T.
      • Cobo Dols M.
      • Laktionov K.
      • Szilasi M.
      • et al.
      1303PDNivolumab in previously treated patients with metastatic squamous NSCLC: Results of a European single-arm, phase 2 trial (CheckMate 171) including patients aged ≥70 years and with poor performance status.
      ].
      Both the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) approved the four available ICIs, regardless of the PS of patients. Therefore, the use of ICIs in PS 2 patients in clinical practice has been allowed, with subsequent collection of real-world data. Three papers on RWD specifically addressed this population subset, evaluating nivolumab in previously treated NSCLC patients [
      • Fujimoto D.
      • Yoshioka H.
      • Kataoka Y.
      • Morimoto T.
      • Kim Y.H.
      • Tomii K.
      • et al.
      Efficacy and safety of nivolumab in previously treated patients with non-small cell lung cancer: A multicenter retrospective cohort study.
      ,
      • Crinò L.
      • Bidoli P.
      • Delmonte A.
      • Grossi F.
      • De Marinis F.
      • Ardizzoni A.
      • et al.
      Italian Cohort of nivolumab expanded access program in squamous non-small cell lung cancer: results from a real-world population.
      ,
      • Juergens R.A.
      • Mariano C.
      • Jolivet J.
      • Finn N.
      • Rothenstein J.
      • Reaume M.N.
      • et al.
      Real-world benefit of nivolumab in a Canadian non-small-cell lung cancer cohort.
      ]. The largest series included 94 PS 2 pre-treated patients in a retrospective multicenter study in Japan, showing a disease control rate of 26% compared to 50% in patients with PS 0-1 [
      • Fujimoto D.
      • Yoshioka H.
      • Kataoka Y.
      • Morimoto T.
      • Kim Y.H.
      • Tomii K.
      • et al.
      Efficacy and safety of nivolumab in previously treated patients with non-small cell lung cancer: A multicenter retrospective cohort study.
      ]. The Italian experience of nivolumab expanded access program (EAP) included 22 patients with ECOG PS 2, showing worse survival outcome compared to those with PS 0 (HR 2.75, p = 0.0001) [
      • Crinò L.
      • Bidoli P.
      • Delmonte A.
      • Grossi F.
      • De Marinis F.
      • Ardizzoni A.
      • et al.
      Italian Cohort of nivolumab expanded access program in squamous non-small cell lung cancer: results from a real-world population.
      ]. Data from a similar experience in Canada, within the EAP CheckMate 169, included 19% of patients with PS 2, with a 6-month OS rate of 47% compared to 64% in PS 0-1 patients 6. An updated analysis of the same data showed halved OS for PS 2 vs PS 0-1 patients (6.8 vs 12.9 months, p = 0.01) [
      • Juergens R.A.
      • Mariano C.
      • Jolivet J.
      • Finn N.
      • Rothenstein J.
      • Reaume M.N.
      • et al.
      Real-world benefit of nivolumab in a Canadian non-small-cell lung cancer cohort.
      ,
      • Juergens R.
      • Chu Q.
      • Rothenstein J.
      • De Angelis F.
      • Banerji S.
      • Marquis K.
      • et al.
      CheckMate 169: safety/efficacy of nivolumab in canadian pretreated advanced NSCLC (including Elderly and PS 2) patients.
      ]. Similar experience in Spain confirmed PS 2 as an independent prognostic factor for OS with nivolumab [
      • Garde-Noguera J.
      • Martin-Martorell P.
      • De Julián M.
      • Perez-Altozano J.
      • Salvador-Coloma C.
      • García-Sanchez J.
      • et al.
      Predictive and prognostic clinical and pathological factors of nivolumab efficacy in non-small-cell lung cancer patients.
      ]. Curiously, safety data seem not to be affected by PS through all these studies [
      • Fujimoto D.
      • Yoshioka H.
      • Kataoka Y.
      • Morimoto T.
      • Kim Y.H.
      • Tomii K.
      • et al.
      Efficacy and safety of nivolumab in previously treated patients with non-small cell lung cancer: A multicenter retrospective cohort study.
      ,
      • Crinò L.
      • Bidoli P.
      • Delmonte A.
      • Grossi F.
      • De Marinis F.
      • Ardizzoni A.
      • et al.
      Italian Cohort of nivolumab expanded access program in squamous non-small cell lung cancer: results from a real-world population.
      ,
      • Juergens R.A.
      • Mariano C.
      • Jolivet J.
      • Finn N.
      • Rothenstein J.
      • Reaume M.N.
      • et al.
      Real-world benefit of nivolumab in a Canadian non-small-cell lung cancer cohort.
      ].
      In the lack of solid data from RCTs, real world data suggest caution in the use of ICI in patients with poor PS, where the good safety profile may be not sufficient to justify high costs in absence of survival benefit [
      • Passaro A.
      • Spitaleri G.
      • Gyawali B.
      • de Marinis F.
      Immunotherapy in non–small-cell lung cancer patients with performance status 2: Clinical decision making with scant evidence.
      ].
      In this context, trials evaluating efficacy and tolerability of ICIs in this subset of patients are currently ongoing. The first to have some results is the PePS2 trial, a phase II study assessing the safety and tolerability of pembrolizumab for the treatment of NSCLC patients with ECOG PS 2 [
      • Middleton G.
      • Brock K.
      • Summers Y.
      • Connibear J.
      • Shah R.
      • Ottensmeier C.
      • et al.
      1384PDPembrolizumab in performance status 2 patients with non-small cell lung cancer (NSCLC): Results of the PePS2 trial.
      ]. Co-primary outcomes were a durable clinical benefit (DCB, i.e. disease control rate at 18 weeks), ORR and the rate of dose delay or discontinuation due to immune-related adverse event (irAE). Preliminary analyses performed in a subset of 60 patients, showed a DCB of 33%, an ORR of 30%, while the rate of irAE was 8%. These findings are quite encouraging, though survival results (median PFS of 5.4 and an OS of 11.7 months) should be considered carefully, as only 9 out of 60 patients included (15%) received first-line pembrolizumab, with no responses and PFS of 1.9 months.
      Another phase II study (NCT02581943) randomized PS 2 NSCLC patients to receive pembrolizumab alone or combined with weekly carboplatin and paclitaxel. Co-primary objectives were ORR, PFS and OS, and circulating immune markers [
      • Bonomi M.
      • Ahmed T.
      • Addo S.
      • Kooshki M.
      • Palmieri D.
      • Levine B.
      • et al.
      Circulating immune biomarkers as predictors of the response to pembrolizumab and weekly low dose carboplatin and paclitaxel in NSCLC and poor PS: An interim analysis.
      ]. An interim analysis on 20 patients demonstrated a higher ORR was achieved in the combination arm (70% versus 20%), with a good tolerability profile. No grade 3–4 adverse events were recorded, even though it is important to note that four patients had to permanently discontinue carboplatin due to allergic reactions. Another phase II trial (NCT02879617), studying the efficacy and safety of durvalumab in PS 2, treatment-naïve, locally advanced or metastatic NSCLC patients, is currently ongoing. Of note, Facchinetti and colleagues recently published a retrospective study evaluating PS 2 patients treated with first-line pembrolizumab: in this study, median OS was 11.8 months in patients whose PS 2 was related to comorbidity compared to 2.8 months in those with PS 2 driven by lung cancer (HR = 0.5, p = 0.001) [
      • Facchinetti F.
      • Mazzaschi G.
      • Barbieri F.
      • Passiglia F.
      • Mazzoni F.
      • Berardi R.
      • et al.
      First-line pembrolizumab in advanced non–small cell lung cancer patients with poor performance status.
      ].
      Finally, also two phase III trials started their accrual of PS 2 NSCLC patients in first line treatment: the IPSOS trial (NCT03191786), comparing first atezolizumab with a single agent chemotherapy by investigator choice (vinorelbine or gemcitabine), and the eNERGY trial (NCT03351361), comparing nivolumab and ipilimumab and a carboplatin based doublet.

      Central nervous system metastases

      Central nervous system (CNS) is a frequent metastatic site in NSCLC patients, with the rate of brain metastases (BM) being about 40%. Patients with BM are often symptomatic, require treatment with corticosteroids and have a poor PS. For these reasons, this special population is under-represented in clinical trials, where patients with BM are generally included only when CNS disease is under control and does not require active treatment. The proportion of patients with inactive and asymptomatic BM in the main pivotal trials of immunotherapy in lung cancer ranges from six to 17.5% [
      • Borghaei H.
      • Paz-Ares L.
      • Horn L.
      • Spigel D.R.
      • Steins M.
      • Ready N.E.
      • et al.
      Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer.
      ,
      • Brahmer J.
      • Reckamp K.L.
      • Baas P.
      • Crinò L.
      • Eberhardt W.E.E.
      • Poddubskaya E.
      • et al.
      Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer.
      ,
      • Reck M.
      • Rodríguez-Abreu D.
      • Robinson A.G.
      • Hui R.
      • Csőszi T.
      • Fülöp A.
      • et al.
      Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer.
      ,
      • Rittmeyer A.
      • Barlesi F.
      • Waterkamp D.
      • Park K.
      • Ciardiello F.
      • von Pawel J.
      • et al.
      Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial.
      ,
      • Gandhi L.
      • Rodríguez-Abreu D.
      • Gadgeel S.
      • Esteban E.
      • Felip E.
      • De Angelis F.
      • et al.
      Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer.
      ]. Moreover, such trials did not contemplate preplanned analysis of CNS metastasis subgroups.
      With these premises, the data from RCTs showing no differences among chemotherapy and pembrolizumab or nivolumab in a second line setting [
      • Borghaei H.
      • Paz-Ares L.
      • Horn L.
      • Spigel D.R.
      • Steins M.
      • Ready N.E.
      • et al.
      Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer.
      ,
      • Brahmer J.
      • Reckamp K.L.
      • Baas P.
      • Crinò L.
      • Eberhardt W.E.E.
      • Poddubskaya E.
      • et al.
      Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer.
      ,
      • Rittmeyer A.
      • Barlesi F.
      • Waterkamp D.
      • Park K.
      • Ciardiello F.
      • von Pawel J.
      • et al.
      Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial.
      ]. On the other hand, patients with a history of asymptomatic, treated BM, had longer median OS with atezolizumab than with docetaxel [
      • Gadgeel S.M.
      • Lukas R.V.
      • Goldschmidt J.
      • Conkling P.
      • Park K.
      • Cortinovis D.
      • et al.
      Atezolizumab in patients with advanced non-small cell lung cancer and history of asymptomatic, treated brain metastases: Exploratory analyses of the phase III OAK study.
      ] in second line of treatment, while chemotherapy plus pembrolizumab provided clinical benefit also for patients with stable BM, in first line setting [
      • Powell S.F.
      • Abreu D.R.
      • Langer C.J.
      • Tafreshi A.
      • Paz-Ares L.
      • Kopp H.-G.
      • et al.
      1483PDPembrolizumab (pembro) plus platinum-based chemotherapy (chemo) in NSCLC with brain metastases: Pooled analysis of KEYNOTE-021, 189, and 407.
      ]. Such analyses were performed post hoc, therefore they could not be considered conclusive. A non-randomized trial aimed to evaluate the activity of pembrolizumab in untreated brain metastases from melanoma or NSCLC [
      • Goldberg S.B.
      • Gettinger S.N.
      • Mahajan A.
      • Chiang A.C.
      • Herbst R.S.
      • Sznol M.
      • et al.
      Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial.
      ]. A recent update showed BM response rate of 29.7%; all the responses were in the PD-L1 positive cohort [
      • Goldberg S.B.
      • Schalper K.A.
      • Gettinger S.N.
      • Mahajan A.
      • Herbst R.S.
      • Chiang A.C.
      • et al.
      Pembrolizumab for management of patients with NSCLC and brain metastases: long-term results and biomarker analysis from a non-randomised, open-label, phase 2 trial.
      ]. However, it must be stressed that only 42, out of the 71 patients (59.1%) initially screened for the trial, were enrolled; eight of them (19.0%) had already received previous whole brain radiotherapy.
      In this setting, a modest amount of real-world data is available. A recent publication has included 255 patients with BM treated with ICIs in a multi-centric prospective study [
      • Hendriks L.E.L.
      • Henon C.
      • Auclin E.
      • Mezquita L.
      • Ferrara R.
      • Audigier-Valette C.
      • et al.
      Outcome of patients with non-small cell lung cancer and brain metastases treated with checkpoint inhibitors.
      ]. The population in study included about 40% with active BM and 14% were symptomatic. Despite a lower disease control rate, and an increased incidence of brain progressive disease compared to patients without CNS metastasis, the presence of BM was not an independent factor for OS in multivariate analysis, when considering steroid treatment and PS [
      • Hendriks L.E.L.
      • Henon C.
      • Auclin E.
      • Mezquita L.
      • Ferrara R.
      • Audigier-Valette C.
      • et al.
      Outcome of patients with non-small cell lung cancer and brain metastases treated with checkpoint inhibitors.
      ]. Also, the administration of cranial radiotherapy, either whole brain or stereotactic radiotherapy, did not affect survival [
      • Hendriks L.E.L.
      • Henon C.
      • Auclin E.
      • Mezquita L.
      • Ferrara R.
      • Audigier-Valette C.
      • et al.
      Outcome of patients with non-small cell lung cancer and brain metastases treated with checkpoint inhibitors.
      ].
      The Italian EAP with nivolumab included patients with CNS metastasis, showing no differences in OS both in the squamous and non-squamous population, when compared to the overall population OS [
      • Cortinovis D.
      • Chiari R.
      • Catino A.
      • Grossi F.
      • Marinis F.D.E.
      • Sperandi F.
      • et al.
      Italian cohort of the nivolumab EAP in squamous NSCLC: efficacy and safety in patients with CNS metastases.
      ,
      • Crinò L.
      • Bidoli P.
      • Delmonte A.
      • Grossi F.
      • De Marinis F.
      • Ardizzoni A.
      • et al.
      Italian Cohort of nivolumab expanded access program in squamous non-small cell lung cancer: results from a real-world population.
      ,
      • Crinò L.
      • Bronte G.
      • Bidoli P.
      • Cravero P.
      • Minenza E.
      • Cortesi E.
      • et al.
      Nivolumab and brain metastases in patients with advanced non-squamous non-small cell lung cancer.
      ]. Similar results derive from the French EAP with nivolumab, including n = 130 patients with BM [
      • Molinier O.
      • Audigier-Valette C.
      • Cadranel J.
      • Monnet I.
      • Hureaux J.
      • Hilgers W.
      • et al.
      OA 17.05 IFCT-1502 CLINIVO: real-life experience with Nivolumab in 600 patients (Pts) with advanced non-small cell lung cancer (NSCLC).
      ].
      With the exception of three reports including very small number of patients with BM [
      • Juergens R.A.
      • Mariano C.
      • Jolivet J.
      • Finn N.
      • Rothenstein J.
      • Reaume M.N.
      • et al.
      Real-world benefit of nivolumab in a Canadian non-small-cell lung cancer cohort.
      ,

      Watanabe H, Kubo T, Ninomiya T, Ohashi K, Ichihara E, Sato A, et al. The effect of nivolumab treatment for central nervous system metastases in non-small cell lung cancer. J Clin Oncol 2017;35:e20601–e20601. doi: 10.1200/JCO.2017.35.15_suppl.e20601.

      ,
      • Kanai O.
      • Fujita K.
      • Okamura M.
      • Nakatani K.
      • Mio T.
      Severe exacerbation or manifestation of primary disease related to nivolumab in non-small-cell lung cancer patients with poor performance status or brain metastases.
      ], all the real-world published evidence is concordant with the European results described [
      • Garde-Noguera J.
      • Martin-Martorell P.
      • De Julián M.
      • Perez-Altozano J.
      • Salvador-Coloma C.
      • García-Sanchez J.
      • et al.
      Predictive and prognostic clinical and pathological factors of nivolumab efficacy in non-small-cell lung cancer patients.
      ,
      • Henon C.
      • Mezquita L.
      • Auclin E.
      • Ammari S.
      • Caramella C.
      • Le Pechoux C.
      • et al.
      P2.07-005 impact of baseline leptomeningeal and brain metastases on immunotherapy outcomes in advanced non-small cell lung cancer (NSCLC) patients.
      ,
      • Gauvain C.
      • Vauléon E.
      • Chouaid C.
      • Lerhun E.
      • Jabot L.
      • Scherpereel A.
      • et al.
      Intracerebral efficacy and tolerance of nivolumab in non–small-cell lung cancer patients with brain metastases.
      ,
      • Ashinuma H.
      • Shingyoji M.
      • Iuchi T.
      • Yoshida Y.
      • Setoguchi T.
      • Hasegawa Y.
      • et al.
      P2.07-014 Immune Checkpoint Inhibitors for Brain Metastases of Non-Small-Cell Lung.
      ].
      Overall, the amount of real-world data in NSCLC patients with CNS metastasis treated with immunotherapy provide stronger evidence than RCTs on the safety and efficacy of ICIs in this special population.

      Patients with pre-existing autoimmune disorders

      ICIs work acting on molecular pathways physiologically involved with the immune self-tolerance and are characterized by irAEs, which are de facto newly triggered autoimmune disorders. For this reason and for the consequent fear of causing unacceptable immune reactions and severe toxicities, patients with pre-existing autoimmune disease (AIDs), except subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, were excluded from clinical trials testing ICIs. However, patients affected by such disorders are at risk of developing malignancies, including lung cancer [
      • Franks A.L.
      • Slansky J.E.
      Multiple associations between a broad spectrum of autoimmune diseases, chronic inflammatory diseases and cancer.
      ] and almost up to one fifth of all lung cancer patients suffers from an AID [
      • Khan S.A.
      • Pruitt S.L.
      • Xuan L.
      • Gerber D.E.
      Prevalence of autoimmune disease among patients with lung cancer: Implications for immunotherapy treatment options.
      ,
      • Cortellini A.
      • Buti S.
      • Santini D.
      • Perrone F.
      • Giusti R.
      • Tiseo M.
      • et al.
      Clinical outcomes of patients with advanced cancer and pre-existing autoimmune diseases treated with anti-programmed death-1 immunotherapy: a real-world transverse study.
      ]. Given the limited treatment options for advanced stage lung cancer, real world evidence about ICIs treatment in subjects with AIDs under a close clinical monitoring could be clinically useful. Subsequently, several retrospective studies have been conducted in order to investigate the risk and benefit of the use of immunotherapy in this subset of patients. Notably, Leonardi and colleagues studied a group of 56 patients with advanced NSCLC and an AID, treated with an anti-PD-1 or an anti-PD-L1 [
      • Leonardi G.C.
      • Gainor J.F.
      • Altan M.
      • Kravets S.
      • Dahlberg S.E.
      • Gedmintas L.
      • et al.
      Safety of programmed death-1 pathway inhibitors among patients with non-small-cell lung cancer and preexisting autoimmune disorders.
      ]. They reported irAE incidence similar to the one of clinical trials; moreover, AID exacerbation occurred in a minority of patients, especially those who were symptomatic from their AID at the time of ICI initiation. A well-conducted retrospective real-world study has been recently conducted on a large series of patients (n = 751) with advanced solid malignancies treated with anti-PD-1 agents, evaluating safety and efficacy according to the history of pre-existing AIDs [
      • Cortellini A.
      • Buti S.
      • Santini D.
      • Perrone F.
      • Giusti R.
      • Tiseo M.
      • et al.
      Clinical outcomes of patients with advanced cancer and pre-existing autoimmune diseases treated with anti-programmed death-1 immunotherapy: a real-world transverse study.
      ]. Two thirds of cases were represented by NSCLC patients. The incidence of irAEs of any grade was higher in patients with pre-existing AIDs, irrespective of AIDs being symptomatic or not; however no significant difference was observed regarding grade 3–4 irAEs, ORR, PFS or OS. It was also found that almost a half of patients with pre-existing AIDs experienced a flare of the autoimmune disorder, with a wide incidence range according to the subtype of AID: 10% for rheumatologic disorders, up to 100% for gastrointestinal/hepatic diseases [
      • Cortellini A.
      • Buti S.
      • Santini D.
      • Perrone F.
      • Giusti R.
      • Tiseo M.
      • et al.
      Clinical outcomes of patients with advanced cancer and pre-existing autoimmune diseases treated with anti-programmed death-1 immunotherapy: a real-world transverse study.
      ]. According to these real-world findings, pre-existing AIDs should not represent an absolute contraindication to immunotherapy. Patients with an active autoimmune disorder may not represent the best candidates for ICIs, but clinicians should consider this treatment option case by case, in a close collaboration with rheumatologists and immunologists, especially when alternatives are both quantitatively and qualitatively limited.

      Patients with chronic viral diseases

      The majority of clinical trials regarding the use of ICIs in NSCLC treatment excluded patients with chronic viral infections such as human immune-deficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV). The main concerns involve the possibility of viral reactivation, but also the efficacy and the safety of the treatment itself, considering also the antiviral therapy patients must continuatively undergo.
      Real-world evidence about safety of NSCLC treatment with ICI in HIV positive patients comes from retrospective case series. Three case series, accounting for a total of 30 advanced NSCLC patients, showed no viral rebound during the course of therapy and no significant difference in the safety profile [
      • Ostios-Garcia L.
      • Faig J.
      • Leonardi G.C.
      • Adeni A.E.
      • Subegdjo S.J.
      • Lydon C.A.
      • et al.
      Safety and efficacy of PD-1 inhibitors among HIV-positive patients with non-small cell lung cancer.
      ,

      Samri S, Lavolé A, Even S, Lambert-Niclot S, Le Garff G, Cadranel J, et al. PD-1 blockade in 12 HIV-infected patients with lung cancer. Pap Present Int AIDS Soc Conf July 24, 2017 n.d.

      ,
      • Shah N.J.
      • Al-Shbool G.
      • Blackburn M.
      • Cook M.
      • Belouali A.
      • Liu S.V.
      • et al.
      Safety and efficacy of immune checkpoint inhibitors (ICIs) in cancer patients with HIV, hepatitis B, or hepatitis C viral infection.
      ]. In this field, results from a prospective phase I study evaluating the safety of pembrolizumab in people with HIV and advanced cancer (n = 30), including 19 patients with non-AIDS-defining cancers includingNSCLC patients, were recently published [
      • Uldrick T.S.
      • Gonçalves P.H.
      • Abdul-Hay M.
      • Claeys A.J.
      • Emu B.
      • Ernstoff M.S.
      • et al.
      Assessment of the safety of pembrolizumab in patients with HIV and advanced cancer—a phase 1 study.
      ,
      • Frega S.
      • Ferro A.
      • Bonanno L.
      • Guarneri V.
      • Conte P.
      • Pasello G.
      Lung cancer (LC) in HIV positive patients: pathogenic features and implications for treatment.
      ]. Pembrolizumab showed an acceptable safety and no significant alterations in CD4 count were detected. Furthermore, durvalumab was also evaluated in a similar setting, in the phase II trial DURVAST [
      • González-Cao M.
      • Moran T.
      • Dalmau J.
      • Garcia-Corbacho J.
      • Bernabé R.
      • Juan O.
      • et al.
      Phase II study of durvalumab (MEDI4736) in cancer patients HIV-1-infected.
      ]. Twenty patients were enrolled, including 14 NSCLC cases; once again no new safety events were detected and disease control rate reached 50% in the NSCLC cohort.
      Regarding HBV- or HCV-positive NSCLC patients treated with ICI, evidence is scantier. A retrospective work collected 10 HBV-/HCV-positive NSCLC patients treated with immunotherapy and reported toxicity and efficacy rates were similar to those of patients without chronic viral infections [
      • Shah N.J.
      • Al-Shbool G.
      • Blackburn M.
      • Cook M.
      • Belouali A.
      • Liu S.V.
      • et al.
      Safety and efficacy of immune checkpoint inhibitors (ICIs) in cancer patients with HIV, hepatitis B, or hepatitis C viral infection.
      ]. Furthermore, ICI treatment had no repercussions on circulating viral load or on viral replication.

      Discussion

      Since 2013, when anticancer immunotherapy became the breakthrough of the year, a growing body of evidence showed long-term disease control and OS improvement with ICIs compared with standard chemotherapy, in several cancers. In thoracic oncology, anti-PD-1 and anti-PD-L1 drugs subverted the standard of treatment of lung cancer, where some drugs came into clinical practice with different indications, especially in the “unmet medical need” areas.
      Marketing approval by regulatory agencies has recently been based, in some cases, on the evidence raised by early-phase trials, thus making the daily oncology practice a fast-evolving landscape. As a consequence, medical oncologists are currently facing many unclear issues which have been not clarified so far by available data.
      Effectiveness and safety in special populations underrepresented in clinical trials - such as elderly, poor PS, hepatitis or human immunodeficiency virus-affected patients- are only a part of the unexplored side of ICIs in the real world. Activity in oncogene-addicted other than EGFR mutant and ALK rearranged NSCLC, the ideal treatment duration in first line, and the potential role of ICIs rechallenge in previously treated patients are also not yet defined by clinical evidence and may be potential research questions to be addressed by RW studies. Our literature search clearly showed how ICIs introduction in clinical practice raised some clinical issues needed to be solved, with a subsequent outbreak of RWE (Fig. 1). Indeed, between 2010 and 2020 publications on ICIs account for 36% of all RWE in lung cancer, and the ratio of evidence before and after July 2015 was 1–3, with 37 citations before and 120 after the data cut-off.
      While available evidence supports the use of ICIs in elderly patients and in cases with brain metastases, some uncertainties about effectiveness in poor PS patients are still present, and more data about populations with some comorbidities (e.g. autoimmune disorders) is needed (Tables 1, 2).
      Table 2Summary of the main studies reporting about real world efficacy and safety of ICIs in special populations.
      Author (reference)PatientsTreatmentFindings
      Elderly patients
      RGrossi F. et al.
      • Grossi F.
      • Crinò L.
      • Logroscino A.
      • Canova S.
      • Delmonte A.
      • Melotti B.
      • et al.
      Use of nivolumab in elderly patients with advanced squamous non–small-cell lung cancer: results from the Italian cohort of an expanded access programme.
      Over 75: 19%

      (overall population n = 371)
      Nivolumab (100%)Three groups considered: patients aged < 65, 65–75 and ≥ 75 years.

      No differences in terms of ORR.

      Non-significant trend for shorter PFS and OS for the over 75.

      No differences in terms of safety.
      RGalli G. et al.
      • Galli G.
      • De Toma A.
      • Pagani F.
      • Randon G.
      • Trevisan B.
      • Prelaj A.
      • et al.
      Efficacy and safety of immunotherapy in elderly patients with non-small cell lung cancer.
      Over 70: 38%

      (overall population n = 290)
      Anti-PD-1 (66.7%)

      Anti-PD-L1 (29.4%)

      Combo-ICI (3.9%)
      Three groups considered: patients aged < 70, 70–79 and ≥ 80 years.

      No differences in terms of ORR, PFS and OS.

      No differences in terms of safety.
      RMuchnik E. et al.
      • Muchnik E.
      • Loh K.P.
      • Strawderman M.
      • Magnuson A.
      • Mohile S.G.
      • Estrah V.
      • et al.
      Immune checkpoint inhibitors in real-world treatment of older adults with non-small cell lung cancer.
      Over 70: 100%

      (overall population n = 75)
      Nivolumab (86.7%)

      Pembrolizumab (8.0%)

      Other (5.3%)
      Median TTF: 4.2 months. Median OS: 8.2 months.

      Median OS of ECOG PS 0–1 patients (n = 38): 13.7 months.

      Grade 3–4 irAE: 8%.
      RCorbaux P. et al.
      • Corbaux P.
      • Maillet D.
      • Boespflug A.
      • Locatelli-Sanchez M.
      • Perier-Muzet M.
      • Duruisseaux M.
      • et al.
      Older and younger patients treated with immune checkpoint inhibitors have similar outcomes in real-life setting.
      Over 70: 75%

      (overall population n = 304)
      Anti-PD(L)-1 (100%)Absence of statistically significant impact of age on OS and PFS was confirmed after adjustment on prognosis covariates.

      2-year OS rate of older versus younger patients: 29% versus 27%.

      6-month PFS rate of older versus younger patients: 40% versus 29%

      No differences in terms of safety.
      RYoun B. et al.
      • Youn B.
      • Trikalinos N.A.
      • Mor V.
      • Wilson I.B.
      • Dahabreh I.J.
      Real-world use and survival outcomes of immune checkpoint inhibitors in older adults with non–small cell lung cancer.
      Over 75: 43.4%

      (overall population n = 1256)
      Nivolumab (92.0%)

      Pembrolizumab (8.0%)
      Median OS: 9.3 months.

      Age was not significantly associated with the hazard of death.
      RSpigel D.R. et al.
      • Spigel D.R.
      • McCleod M.
      • Jotte R.M.
      • Einhorn L.
      • Horn L.
      • Waterhouse D.M.
      • et al.
      Safety, efficacy, and patient-reported health-related quality of life and symptom burden with nivolumab in patients with advanced non-small cell lung cancer, including patients aged 70 years or older or with poor performance status (CheckMate 153).
      Over 70: 39%

      (overall population n = 1426)
      Nivolumab (100%)Over 70 versus overall study population:
      • -
        Median OS of 9.1 versus 10.3 months.
      No differences in terms of safety.
      RSabatier R. et al.
      • Sabatier R.
      • Nicolas E.
      • Paciencia M.
      • Jonville-Béra A.P.
      • Madroszyk A.
      • Cecile M.
      • et al.
      Nivolumab in routine practice for older patients with advanced or metastatic non-small cell lung cancer.
      Over 70: 100%

      (overall population n = 30)
      Nivolumab (100%)Median PFS 3.3 months. Median OS 7.1 months.

      All grade irAE: 50%. Grade 3–4 irAE: 13.3%
      ECOG PS 2 patients
      RCrinò L. et al
      • Crinò L.
      • Bidoli P.
      • Delmonte A.
      • Grossi F.
      • De Marinis F.
      • Ardizzoni A.
      • et al.
      Italian Cohort of nivolumab expanded access program in squamous non-small cell lung cancer: results from a real-world population.
      ECOG PS 2: 6.0%

      (overall population n = 371)
      NivolumabECOG PS 2 versus PS 0–1 patients:
      • -
        HR for death of 2.75, p < 0.0001.
      RJuergens R.A. et al.
      • Juergens R.
      • Chu Q.
      • Rothenstein J.
      • De Angelis F.
      • Banerji S.
      • Marquis K.
      • et al.
      CheckMate 169: safety/efficacy of nivolumab in canadian pretreated advanced NSCLC (including Elderly and PS 2) patients.
      ECOG PS 2: 19%

      (overall population n = 161)
      NivolumabECOG PS 2 versus PS 0–1 patients:
      • -
        6-month OS rate of 47% versus 64%;
      • -
        Median OS of 5.9 versus 9.1 months.
      Safety profile comparable to overall study population.
      RFujimoto d. et al
      • Fujimoto D.
      • Yoshioka H.
      • Kataoka Y.
      • Morimoto T.
      • Kim Y.H.
      • Tomii K.
      • et al.
      Efficacy and safety of nivolumab in previously treated patients with non-small cell lung cancer: A multicenter retrospective cohort study.
      ECOG PS ≥ 2: 23%

      (overall population n = 613)
      NivolumabECOG PS 2 versus PS 0–1 patients:
      • -
        DCR of 26% versus 50%;
      • -
        1-year PFS of 2.1% versus 11.7%.
      The incidence rates of severe irAEs were similar between those with good PS (0–1) and poor PS scores (2–4).
      RGarde‑Noguera J. et al.
      • Garde-Noguera J.
      • Martin-Martorell P.
      • De Julián M.
      • Perez-Altozano J.
      • Salvador-Coloma C.
      • García-Sanchez J.
      • et al.
      Predictive and prognostic clinical and pathological factors of nivolumab efficacy in non-small-cell lung cancer patients.
      ECOG PS 2: 22.3%

      (overall population n = 175)
      NivolumabECOG PS 2 versus PS 0–1 patients:
      • -
        Median OS of 2.7 versus 7.8 months.
      RFacchinetti F. et al
      • Facchinetti F.
      • Mazzaschi G.
      • Barbieri F.
      • Passiglia F.
      • Mazzoni F.
      • Berardi R.
      • et al.
      First-line pembrolizumab in advanced non–small cell lung cancer patients with poor performance status.
      ECOG PS 2: 100.0%

      (overall population n = 153)
      PembrolizumabMedian OS was 11.8 months in patients whose PS 2 was related to comorbidity compared to 2.8 months in those with PS 2 driven by lung cancer (p = 0.001)
      Patients with brain metastases
      PHendriks L.E.L. et al
      • Hendriks L.E.L.
      • Henon C.
      • Auclin E.
      • Mezquita L.
      • Ferrara R.
      • Audigier-Valette C.
      • et al.
      Outcome of patients with non-small cell lung cancer and brain metastases treated with checkpoint inhibitors.
      BM patients: 22.0%

      (overall population n = 1025)
      Anti-PD-1 (96.3%)

      Anti-PD-L1 (3.7%)
      BM versus without BM patients:
      • -
        ORR of 20.6% versus 22.7%;
      • -
        Median PFS of 1.7 versus 2.1 months;
      • -
        Median OS 8.6 versus 11.4 months.
      RCrinò L. et al
      • Crinò L.
      • Bronte G.
      • Bidoli P.
      • Cravero P.
      • Minenza E.
      • Cortesi E.
      • et al.
      Nivolumab and brain metastases in patients with advanced non-squamous non-small cell lung cancer.
      BM patients: 25.8%

      (overall population n = 1588)
      NivolumabBM patients versus overall study population:
      • -
        DCR of 40% versus 44%;
      • -
        1-year OS 43% versus 48%.
      Safety profile comparable to overall study population.
      RMolinier O. et al.
      • Molinier O.
      • Audigier-Valette C.
      • Cadranel J.
      • Monnet I.
      • Hureaux J.
      • Hilgers W.
      • et al.
      OA 17.05 IFCT-1502 CLINIVO: real-life experience with Nivolumab in 600 patients (Pts) with advanced non-small cell lung cancer (NSCLC).
      BM patients: 22.0%

      (overall population n = 600)
      NivolumabBM patients versus overall study population:
      • -
        ORR 37% versus 37%;
      • -
        Median OS 6.6 versus 9.5 months.
      RHenon C. et al.
      • Henon C.
      • Mezquita L.
      • Auclin E.
      • Ammari S.
      • Caramella C.
      • Le Pechoux C.
      • et al.
      P2.07-005 impact of baseline leptomeningeal and brain metastases on immunotherapy outcomes in advanced non-small cell lung cancer (NSCLC) patients.
      BM patients: 19.0%

      (overall population n = 271)
      Anti-PD(L)-1No difference was observed in terms of ORR and OS between BM versus non-BM population.
      RGauvain C. et al.
      • Gauvain C.
      • Vauléon E.
      • Chouaid C.
      • Lerhun E.
      • Jabot L.
      • Scherpereel A.
      • et al.
      Intracerebral efficacy and tolerance of nivolumab in non–small-cell lung cancer patients with brain metastases.
      BM patients: 100.0%

      (overall population n = 43)
      NivolumabMedian intracerebral PFS: 3.9 months.

      Median PFS: 2.8 months.

      Median OS: 7.5 months.
      Patients with autoimmune disorders
      RCortellini A. et al.
      • Cortellini A.
      • Buti S.
      • Santini D.
      • Perrone F.
      • Giusti R.
      • Tiseo M.
      • et al.
      Clinical outcomes of patients with advanced cancer and pre-existing autoimmune diseases treated with anti-programmed death-1 immunotherapy: a real-world transverse study.
      AID patients: 11.3%

      (overall population n = 751; NSCLC patients n = 492)
      Nivolumab (75.8%)

      Pembrolizumab (24.2%)
      Among patients with pre-existing AIDs, incidence of irAEs of any grade was significantly higher.

      No significant differences were observed regarding grade 3–4 irAEs, ORR, median PFS and OS among subgroups.
      Patients with chronic viral diseases
      RSamri A. et al.

      Samri S, Lavolé A, Even S, Lambert-Niclot S, Le Garff G, Cadranel J, et al. PD-1 blockade in 12 HIV-infected patients with lung cancer. Pap Present Int AIDS Soc Conf July 24, 2017 n.d.

      12 HIV infected advanced NSCLC patientsNivolumabFavorable clinical outcome (3 Partial Response and 4 Disease Stability)

      No significant clinical side effects
      ROstios-Garcia L. et al
      • Ostios-Garcia L.
      • Faig J.
      • Leonardi G.C.
      • Adeni A.E.
      • Subegdjo S.J.
      • Lydon C.A.
      • et al.
      Safety and efficacy of PD-1 inhibitors among HIV-positive patients with non-small cell lung cancer.
      7 HIV infected advanced NSCLC patientsPembrolizumab (71.4%)

      Nivolumab (28.6%)
      Favorable clinical outcome (3 Partial Response and 2 Disease Stability)

      None of the patients experienced grade 3–4 irAE or immune reconstitution

      inflammatory syndrome

      None required dose interruption or discontinuation due to irAE
      RShah N.J. et al
      • Shah N.J.
      • Al-Shbool G.
      • Blackburn M.
      • Cook M.
      • Belouali A.
      • Liu S.V.
      • et al.
      Safety and efficacy of immune checkpoint inhibitors (ICIs) in cancer patients with HIV, hepatitis B, or hepatitis C viral infection.
      12 HIV infected advanced NSCLC patients

      10 HBV/HCV infected advanced NSCLC patients
      HIV patients:
      • -
        8 treated with anti-PD-(L)1
      • -
        4 treated with chemo-immunotherapy
      HBV/HCV patients:
      • -
        7 treated with anti-PD-(L)1
      • -
        3 treated with chemo-immunotherapy
      HIV patients:
      • -
        Any grade irAEs: 25% for both ICI monotherapy and ICI-chemotherapy
      • -
        ORR in ICI monotherapy: 13%
      • -
        ORR in ICI-chemotherapy: 75%
      • -
        No significant changes in HIV viral load and CD4 + T-cell counts
      HBV/HCV patients:
      • -
        Any grade irAEs: 57% for ICI monotherapy and 33% for ICI-chemotherapy
      • -
        ORR in ICI monotherapy: 14%
      • -
        ORR in ICI-chemotherapy: 67%
      • -
        No evidence of viral reactivation
      AID = auto-immune disorder; BM = brain metastasis; ICI = immuno-checkpoint inhibitor; irAE = immune-related adverse event; ORR = overall response rate; OS = overall survival; PFS = progression free survival; PS = performance status; P = prospective study; R = retrospective study.
      There is no question about RCTs being the cornerstone for the best medical knowledge [
      • Collins R.
      • Bowman L.
      • Landray M.
      • Peto R.
      The magic of randomization versus the myth of real-world evidence.
      ], but there is also a strong need to narrow the gap between conventional clinical trial data and the real-world of health care providers. Reliability of RWE depends on the main endpoints in specific settings, because some activity and efficacy data may be impaired by the lack of a control group and of standardized treatment and evaluation methods. Non-randomized observational studies do not allow to assess the benefit of a therapeutic approach considering that treatment choice and subsequent health outcome may be influenced by other concurrent conditions. Strength and limitations of RWE have been recently described [

      Di Maio M, Perrone F, Conte P. Real‐world evidence in oncology: opportunities and limitations. Oncologist 2019:theoncologist.2019-0647. doi: 10.1634/theoncologist.2019-0647.

      ], and should be kept under consideration in real world data applications and study planning. Indeed, we should remark that the application of administrative or clinical datasets or registries without an appropriate study design, planning and conduction does not produce any knowledge. In this context, prior identification of data to be systematically and prospectively collected about a target population from reliable sources may be simplified by electronic health records; however, this should be also integrated with an early definition of specific aims, according to research questions. Though observational RW studies should not be used to inform about efficacy of ICIs, possible aims may be to improve knowledge about toxicity and adverse effects in subgroups not included in RCTs and to get information about modes of use and patterns of care.
      Available RWE is mostly made of retrospective studies making bias minimization more difficult, thus confirming that RW study methodology is still challenging.
      The introduction of innovative high-cost drugs in the clinical practice, such as ICIs in lung cancer management, have risen some social and economical issues with subsequent heterogeneous measures across different countries for sustainability and affordability improvement.
      Available health economics studies are based on efficacy data (e.g. progression free survival according to RECIST criteria) from pivotal clinical trials, while real world post-marketing data could allow a payment by results model construction, which could be extremely useful for a proper budget impact assessment though this could entail a price re-modulation or a reimbursement based on actual results by companies.
      According to our literature review, while safety and efficacy real world data in the main patients population was in line with data from RCTs, some criticism about ICIs cost-effectiveness and sustainability emerged [
      • Criss S.D.
      • Palazzo L.
      • Watson T.R.
      • Paquette A.M.
      • Sigel K.
      • Wisnivesky J.
      • et al.
      Cost-effectiveness of pembrolizumab for advanced non-small cell lung cancer patients with varying comorbidity burden.
      ,
      • Bayle A.
      • Besse B.
      • Annereau M.
      • Bonastre J.
      Switch to anti-programmed cell death protein 1 (anti-PD-1) fixed-dose regimen: What is the economic impact?.
      ].
      Real world datasets and evidence from observational studies may be useful for epidemiological estimation about number of patients suitable for a specific agent and their real treatment duration by investigating time to treatment failure; both of them may be adopted as sources for an accurate place in therapy, and budget impact analyses for resources allocation planning by national and regional health service. Moreover, RWE is useful to depict the whole diagnostic-therapeutic pathway in oncology, enriched with long-term follow-up data about toxicities and treatments sequence.
      Recently, both EMA and FDA have promoted the collection of real world data in the future post-marketing drug monitoring, regulatory and approval flow, thus prospecting a clinical research revolution [
      • Skovlund E.
      • Leufkens H.G.M.
      • Smyth J.F.
      The use of real-world data in cancer drug development.
      ,
      • Burock S.
      • Meunier F.
      • Lacombe D.
      How can innovative forms of clinical research contribute to deliver affordable cancer care in an evolving health care environment?.
      ].
      Finally, in the next future RCT results should be integrated with RWE for a new drug development model where all different stakeholders are actively involved (Fig. 3).
      Figure thumbnail gr3
      Fig. 3A proposed integrated drug development model, where data from RCT and EAP are integrated with RWE in a dynamic process informing different stakeholders.

      Disclosures

      Valentina Guarneri: Eli Lilly & Co. (SAB), Roche (RF), Novartis, AstraZeneca (H). The other authors indicated no financial relationships.
      Giulia Pasello: Astrazeneca (C/A;SAB); BMS (SAB); Boehringer Ing (SAB); MSD (C/A); Roche (C/A;SAB); Eli Lilly & Co. (SAB).
      (C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board.

      Appendix A. Supplementary material

      The following are the Supplementary data to this article:

      References

        • Raju S.
        • Joseph R.
        • Sehgal S.
        Review of checkpoint immunotherapy for the management of non-small cell lung cancer.
        ImmunoTargets Ther. 2018; 7: 63-75https://doi.org/10.2147/ITT.S125070
        • Borghaei H.
        • Paz-Ares L.
        • Horn L.
        • Spigel D.R.
        • Steins M.
        • Ready N.E.
        • et al.
        Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer.
        N Engl J Med. 2015; 373: 1627-1639https://doi.org/10.1056/NEJMoa1507643
        • Brahmer J.
        • Reckamp K.L.
        • Baas P.
        • Crinò L.
        • Eberhardt W.E.E.
        • Poddubskaya E.
        • et al.
        Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer.
        N Engl J Med. 2015; 373: 123-135https://doi.org/10.1056/NEJMoa1504627
        • Herbst R.S.
        • Baas P.
        • Kim D.-W.
        • Felip E.
        • Pérez-Gracia J.L.
        • Han J.-Y.
        • et al.
        Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.
        Lancet. 2016; 387: 1540-1550https://doi.org/10.1016/S0140-6736(15)01281-7
        • Reck M.
        • Rodríguez-Abreu D.
        • Robinson A.G.
        • Hui R.
        • Csőszi T.
        • Fülöp A.
        • et al.
        Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer.
        N Engl J Med. 2016; 375: 1823-1833https://doi.org/10.1056/NEJMoa1606774
        • Antonia S.J.
        • Villegas A.
        • Daniel D.
        • Vicente D.
        • Murakami S.
        • Hui R.
        • et al.
        Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC.
        N Engl J Med. 2018; https://doi.org/10.1056/NEJMoa1809697
        • Yi C.
        • He Y.
        • Xia H.
        • Zhang H.
        • Zhang P.
        Review and perspective on adjuvant and neoadjuvant immunotherapies in NSCLC.
        Onco Targets Ther. 2019; 12: 7329-7336https://doi.org/10.2147/OTT.S218321
        • Greenhalgh J.
        • Dwan K.
        • Boland A.
        • Bates V.
        • Vecchio F.
        • Dundar Y.
        • et al.
        First-line treatment of advanced epidermal growth factor receptor (EGFR) mutation positive non-squamous non-small cell lung cancer.
        Cochrane Database Syst Rev. 2016; https://doi.org/10.1002/14651858.CD010383.pub2
        • Morita R.
        • Okishio K.
        • Shimizu J.
        • Saito H.
        • Sakai H.
        • Kim Y.H.
        • et al.
        Real-world effectiveness and safety of nivolumab in patients with non-small cell lung cancer: A multicenter retrospective observational study in Japan.
        Lung Cancer. 2020; 140: 8-18https://doi.org/10.1016/j.lungcan.2019.11.014
        • Kobayashi K.
        • Nakachi I.
        • Naoki K.
        • Satomi R.
        • Nakamura M.
        • Inoue T.
        • et al.
        Real-world efficacy and safety of nivolumab for advanced non–small-cell lung cancer: a retrospective multicenter analysis.
        Clin Lung Cancer. 2018; 19: e349-e358https://doi.org/10.1016/j.cllc.2018.01.001
        • El Karak F.
        • Gh Haddad F.
        • Eid R.
        • Al Ghor M.
        • El Rassy E.
        • Ahmadieh N.
        • et al.
        Lung cancer and immunotherapy: a real-life experience from second line and beyond.
        Futur Oncol. 2019; 15: 3025-3032https://doi.org/10.2217/fon-2019-0144
        • Ahn B.-C.
        • Pyo K.-H.
        • Xin C.-F.
        • Jung D.
        • Shim H.S.
        • Lee C.Y.
        • et al.
        Comprehensive analysis of the characteristics and treatment outcomes of patients with non-small cell lung cancer treated with anti-PD-1 therapy in real-world practice.
        J Cancer Res Clin Oncol. 2019; 145: 1613-1623https://doi.org/10.1007/s00432-019-02899-y
        • Nadler E.
        • Espirito J.L.
        • Pavilack M.
        • Boyd M.
        • Vergara-Silva A.
        • Fernandes A.
        Treatment patterns and clinical outcomes among metastatic non–small-cell lung cancer patients treated in the community practice setting.
        Clin Lung Cancer. 2018; 19: 360-370https://doi.org/10.1016/j.cllc.2018.02.002
        • Brustugun O.T.
        • Sprauten M.
        • Helland Å.
        Real-world data on nivolumab treatment of non-small cell lung cancer.
        Acta Oncol (Madr). 2017; 56: 438-440https://doi.org/10.1080/0284186X.2016.1253865
        • Weis T.M.
        • Hough S.
        • Reddy H.G.
        • Daignault-Newton S.
        • Kalemkerian G.P.
        Real-world comparison of immune checkpoint inhibitors in non-small cell lung cancer following platinum-based chemotherapy.
        J Oncol Pharm Pract. 2019; (107815521985512)https://doi.org/10.1177/1078155219855127
        • Fujimoto D.
        • Yoshioka H.
        • Kataoka Y.
        • Morimoto T.
        • Kim Y.H.
        • Tomii K.
        • et al.
        Efficacy and safety of nivolumab in previously treated patients with non-small cell lung cancer: A multicenter retrospective cohort study.
        Lung Cancer. 2018; https://doi.org/10.1016/j.lungcan.2018.02.017
        • Cortinovis D.
        • Chiari R.
        • Catino A.
        • Grossi F.
        • Marinis F.D.E.
        • Sperandi F.
        • et al.
        Italian cohort of the nivolumab EAP in squamous NSCLC: efficacy and safety in patients with CNS metastases.
        Anticancer Res. 2019; https://doi.org/10.21873/anticanres.13590
        • Crinò L.
        • Bidoli P.
        • Delmonte A.
        • Grossi F.
        • De Marinis F.
        • Ardizzoni A.
        • et al.
        Italian Cohort of nivolumab expanded access program in squamous non-small cell lung cancer: results from a real-world population.
        Oncologist. 2019; https://doi.org/10.1634/theoncologist.2018-0737
        • Manrique M.C.A.
        • Martínez J.M.
        • González J.G.
        • Afonso F.J.A.
        • Quintela M.L.
        • Núñez N.F.
        • et al.
        Real world data of nivolumab for previously treated non-small cell lung cancer patients: A Galician lung cancer group clinical experience.
        Transl Lung Cancer Res. 2018; https://doi.org/10.21037/tlcr.2018.04.03
        • Khozin S.
        • Carson K.R.
        • Zhi J.
        • Tucker M.
        • Lee S.E.
        • Light D.E.
        • et al.
        Real-world outcomes of patients with metastatic non-small cell lung cancer treated with programmed cell death protein 1 inhibitors in the year following U.S. regulatory approval.
        Oncologist. 2019; 24: 648-656https://doi.org/10.1634/theoncologist.2018-0307
        • Khozin S.
        • Miksad R.A.
        • Adami J.
        • Boyd M.
        • Brown N.R.
        • Gossai A.
        • et al.
        Real-world progression, treatment, and survival outcomes during rapid adoption of immunotherapy for advanced non–small cell lung cancer.
        Cancer. 2019; 125: 4019-4032https://doi.org/10.1002/cncr.32383
        • Lin S.-Y.
        • Yang C.-Y.
        • Liao B.-C.
        • Ho C.-C.
        • Liao W.-Y.
        • Chen K.-Y.
        • et al.
        Tumor PD-L1 expression and clinical outcomes in advanced-stage non-small cell lung cancer patients treated with nivolumab or pembrolizumab: real-world data in Taiwan.
        J Cancer. 2018; 9: 1813-1820https://doi.org/10.7150/jca.24985
        • Abbas W.
        • Acharya R.
        • Pandit A.
        • Gupta S.
        • Rao R.
        The real-world experience with nivolumab in previously treated patients with advanced non-small cell lung cancer from a cancer center in India.
        South Asian J Cancer. 2020; 9: 50https://doi.org/10.4103/sajc.sajc_111_19
        • Figueiredo A.
        • Almeida M.A.
        • Almodovar M.T.
        • Alves P.
        • Araújo A.
        • Araújo D.
        • et al.
        Real-world data from the Portuguese Nivolumab Expanded Access Program (EAP) in previously treated Non Small Cell Lung Cancer (NSCLC).
        Pulmonology. 2020; 26: 10-17https://doi.org/10.1016/j.pulmoe.2019.06.001
        • Juergens R.A.
        • Mariano C.
        • Jolivet J.
        • Finn N.
        • Rothenstein J.
        • Reaume M.N.
        • et al.
        Real-world benefit of nivolumab in a Canadian non-small-cell lung cancer cohort.
        Curr Oncol. 2018; : 25https://doi.org/10.3747/co.25.4287
        • Ksienski D.
        • Wai E.S.
        • Croteau N.
        • Freeman A.T.
        • Chan A.
        • Fiorino L.
        • et al.
        Pembrolizumab for advanced nonsmall cell lung cancer: Efficacy and safety in everyday clinical practice.
        Lung Cancer. 2019; 133: 110-116https://doi.org/10.1016/j.lungcan.2019.05.005
        • Song P.
        • Zhang J.
        • Shang C.
        • Zhang L.
        Real-world evidence and clinical observations of the treatment of advanced non-small cell lung cancer with PD-1/PD-L1 inhibitors.
        Sci Rep. 2019; 9: 4278https://doi.org/10.1038/s41598-019-40748-7
        • Tamiya M.
        • Tamiya A.
        • Hosoya K.
        • Taniguchi Y.
        • Yokoyama T.
        • Fukuda Y.
        • et al.
        Efficacy and safety of pembrolizumab as first-line therapy in advanced non-small cell lung cancer with at least 50% PD-L1 positivity: a multicenter retrospective cohort study (HOPE-001).
        Invest New Drugs. 2019; 37: 1266-1273https://doi.org/10.1007/s10637-019-00843-y
        • Velcheti V.
        • Chandwani S.
        • Chen X.
        • Pietanza M.C.
        • Piperdi B.
        • Burke T.
        Outcomes of first-line pembrolizumab monotherapy for PD-L1-positive (TPS ≥50%) metastatic NSCLC at US oncology practices.
        Immunotherapy. 2019; 11: 1541-1554https://doi.org/10.2217/imt-2019-0177
        • Velcheti V.
        • Chandwani S.
        • Chen X.
        • Pietanza M.C.
        • Burke T.
        First-line pembrolizumab monotherapy for metastatic PD-L1-positive NSCLC: real-world analysis of time on treatment.
        Immunotherapy. 2019; 11: 889-901https://doi.org/10.2217/imt-2019-0061
        • Mok T.S.K.
        • Wu Y.-L.
        • Kudaba I.
        • Kowalski D.M.
        • Cho B.C.
        • Turna H.Z.
        • et al.
        Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial.
        Lancet. 2019; 393: 1819-1830https://doi.org/10.1016/S0140-6736(18)32409-7
        • Reck M.
        • Rodríguez-Abreu D.
        • Robinson A.G.
        • Hui R.
        • Csőszi T.
        • Fülöp A.
        • et al.
        Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non–small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater.
        J Clin Oncol. 2019; 37: 537-546https://doi.org/10.1200/JCO.18.00149
        • Merino Almazán M.
        • Duarte Pérez J.M.
        • Marín Pozo J.F.
        • Ortega Granados A.L.
        • Muros De Fuentes B.
        • Quesada Sanz P.
        • et al.
        A multicentre observational study of the effectiveness, safety and economic impact of nivolumab on non-small-cell lung cancer in real clinical practice.
        Int J Clin Pharm. 2019; 41: 272-279https://doi.org/10.1007/s11096-018-0772-z
        • Ganti A.K.
        • Siedlik E.
        • Marr A.S.
        • Loberiza F.R.
        • Kessinger A.
        Predictive ability of Charlson comorbidity index on outcomes from lung cancer.
        Am J Clin Oncol. 2011; 34: 593-596https://doi.org/10.1097/COC.0b013e3181fe445b
        • Criss S.D.
        • Palazzo L.
        • Watson T.R.
        • Paquette A.M.
        • Sigel K.
        • Wisnivesky J.
        • et al.
        Cost-effectiveness of pembrolizumab for advanced non-small cell lung cancer patients with varying comorbidity burden.
        PLoS ONE. 2020; 15e0228288https://doi.org/10.1371/journal.pone.0228288
        • Bayle A.
        • Besse B.
        • Annereau M.
        • Bonastre J.
        Switch to anti-programmed cell death protein 1 (anti-PD-1) fixed-dose regimen: What is the economic impact?.
        Eur J Cancer. 2019; 113: 28-31https://doi.org/10.1016/j.ejca.2019.02.016
        • Bray F.
        • Ferlay J.
        • Soerjomataram I.
        • Siegel R.L.
        • Torre L.A.
        • Jemal A.
        Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
        CA Cancer J Clin. 2018; 68: 394-424https://doi.org/10.3322/caac.21492
        • Nosaki K.
        • Saka H.
        • Hosomi Y.
        • Baas P.
        • de Castro G.
        • Reck M.
        • et al.
        Safety and efficacy of pembrolizumab monotherapy in elderly patients with PD-L1–positive advanced non–small-cell lung cancer: Pooled analysis from the KEYNOTE-010, KEYNOTE-024, and KEYNOTE-042 studies.
        Lung Cancer. 2019; 135: 188-195https://doi.org/10.1016/j.lungcan.2019.07.004
        • Ferrara R.
        • Mezquita L.
        • Auclin E.
        • Chaput N.
        • Besse B.
        Immunosenescence and immunecheckpoint inhibitors in non-small cell lung cancer patients: Does age really matter?.
        Cancer Treat Rev. 2017; 60: 60-68https://doi.org/10.1016/j.ctrv.2017.08.003
        • Grossi F.
        • Crinò L.
        • Logroscino A.
        • Canova S.
        • Delmonte A.
        • Melotti B.
        • et al.
        Use of nivolumab in elderly patients with advanced squamous non–small-cell lung cancer: results from the Italian cohort of an expanded access programme.
        Eur J Cancer. 2018; https://doi.org/10.1016/j.ejca.2018.05.015
        • Galli G.
        • De Toma A.
        • Pagani F.
        • Randon G.
        • Trevisan B.
        • Prelaj A.
        • et al.
        Efficacy and safety of immunotherapy in elderly patients with non-small cell lung cancer.
        Lung Cancer. 2019; 137: 38-42https://doi.org/10.1016/j.lungcan.2019.08.030
        • Muchnik E.
        • Loh K.P.
        • Strawderman M.
        • Magnuson A.
        • Mohile S.G.
        • Estrah V.
        • et al.
        Immune checkpoint inhibitors in real-world treatment of older adults with non-small cell lung cancer.
        J Am Geriatr Soc. 2019; 67: 905-912https://doi.org/10.1111/jgs.15750
        • Corbaux P.
        • Maillet D.
        • Boespflug A.
        • Locatelli-Sanchez M.
        • Perier-Muzet M.
        • Duruisseaux M.
        • et al.
        Older and younger patients treated with immune checkpoint inhibitors have similar outcomes in real-life setting.
        Eur J Cancer. 2019; 121: 192-201https://doi.org/10.1016/j.ejca.2019.08.027
        • Youn B.
        • Trikalinos N.A.
        • Mor V.
        • Wilson I.B.
        • Dahabreh I.J.
        Real-world use and survival outcomes of immune checkpoint inhibitors in older adults with non–small cell lung cancer.
        Cancer. 2020; (cncr.32624)https://doi.org/10.1002/cncr.32624
        • Spigel D.R.
        • McCleod M.
        • Jotte R.M.
        • Einhorn L.
        • Horn L.
        • Waterhouse D.M.
        • et al.
        Safety, efficacy, and patient-reported health-related quality of life and symptom burden with nivolumab in patients with advanced non-small cell lung cancer, including patients aged 70 years or older or with poor performance status (CheckMate 153).
        J Thorac Oncol. 2019; 14: 1628-1639https://doi.org/10.1016/j.jtho.2019.05.010
        • Popat S.
        • Ardizzoni A.
        • Ciuleanu T.
        • Cobo Dols M.
        • Laktionov K.
        • Szilasi M.
        • et al.
        1303PDNivolumab in previously treated patients with metastatic squamous NSCLC: Results of a European single-arm, phase 2 trial (CheckMate 171) including patients aged ≥70 years and with poor performance status.
        Ann Oncol. 2017; https://doi.org/10.1093/annonc/mdx380.006
        • Juergens R.
        • Chu Q.
        • Rothenstein J.
        • De Angelis F.
        • Banerji S.
        • Marquis K.
        • et al.
        CheckMate 169: safety/efficacy of nivolumab in canadian pretreated advanced NSCLC (including Elderly and PS 2) patients.
        J Thorac Oncol. 2017; : P2.07-029https://doi.org/10.1016/j.jtho.2017.11.088
        • Garde-Noguera J.
        • Martin-Martorell P.
        • De Julián M.
        • Perez-Altozano J.
        • Salvador-Coloma C.
        • García-Sanchez J.
        • et al.
        Predictive and prognostic clinical and pathological factors of nivolumab efficacy in non-small-cell lung cancer patients.
        Clin Transl Oncol. 2018; https://doi.org/10.1007/s12094-017-1829-5
        • Passaro A.
        • Spitaleri G.
        • Gyawali B.
        • de Marinis F.
        Immunotherapy in non–small-cell lung cancer patients with performance status 2: Clinical decision making with scant evidence.
        J Clin Oncol. 2019; https://doi.org/10.1200/JCO.18.02118
        • Middleton G.
        • Brock K.
        • Summers Y.
        • Connibear J.
        • Shah R.
        • Ottensmeier C.
        • et al.
        1384PDPembrolizumab in performance status 2 patients with non-small cell lung cancer (NSCLC): Results of the PePS2 trial.
        Ann Oncol. 2018; : 29https://doi.org/10.1093/annonc/mdy292.007
        • Bonomi M.
        • Ahmed T.
        • Addo S.
        • Kooshki M.
        • Palmieri D.
        • Levine B.
        • et al.
        Circulating immune biomarkers as predictors of the response to pembrolizumab and weekly low dose carboplatin and paclitaxel in NSCLC and poor PS: An interim analysis.
        Oncol Lett. 2018; https://doi.org/10.3892/ol.2018.9724
        • Facchinetti F.
        • Mazzaschi G.
        • Barbieri F.
        • Passiglia F.
        • Mazzoni F.
        • Berardi R.
        • et al.
        First-line pembrolizumab in advanced non–small cell lung cancer patients with poor performance status.
        Eur J Cancer. 2020; 130: 155-167https://doi.org/10.1016/j.ejca.2020.02.023
        • Rittmeyer A.
        • Barlesi F.
        • Waterkamp D.
        • Park K.
        • Ciardiello F.
        • von Pawel J.
        • et al.
        Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial.
        Lancet. 2017; 389: 255-265https://doi.org/10.1016/S0140-6736(16)32517-X
        • Gandhi L.
        • Rodríguez-Abreu D.
        • Gadgeel S.
        • Esteban E.
        • Felip E.
        • De Angelis F.
        • et al.
        Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer.
        N Engl J Med. 2018; 378: 2078-2092https://doi.org/10.1056/NEJMoa1801005
        • Gadgeel S.M.
        • Lukas R.V.
        • Goldschmidt J.
        • Conkling P.
        • Park K.
        • Cortinovis D.
        • et al.
        Atezolizumab in patients with advanced non-small cell lung cancer and history of asymptomatic, treated brain metastases: Exploratory analyses of the phase III OAK study.
        Lung Cancer. 2019; 128: 105-112https://doi.org/10.1016/j.lungcan.2018.12.017
        • Powell S.F.
        • Abreu D.R.
        • Langer C.J.
        • Tafreshi A.
        • Paz-Ares L.
        • Kopp H.-G.
        • et al.
        1483PDPembrolizumab (pembro) plus platinum-based chemotherapy (chemo) in NSCLC with brain metastases: Pooled analysis of KEYNOTE-021, 189, and 407.
        Ann Oncol. 2019; : 30https://doi.org/10.1093/annonc/mdz260.005
        • Goldberg S.B.
        • Gettinger S.N.
        • Mahajan A.
        • Chiang A.C.
        • Herbst R.S.
        • Sznol M.
        • et al.
        Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial.
        Lancet Oncol. 2016; 17: 976-983https://doi.org/10.1016/S1470-2045(16)30053-5
        • Goldberg S.B.
        • Schalper K.A.
        • Gettinger S.N.
        • Mahajan A.
        • Herbst R.S.
        • Chiang A.C.
        • et al.
        Pembrolizumab for management of patients with NSCLC and brain metastases: long-term results and biomarker analysis from a non-randomised, open-label, phase 2 trial.
        Lancet Oncol. 2020; https://doi.org/10.1016/S1470-2045(20)30111-X
        • Hendriks L.E.L.
        • Henon C.
        • Auclin E.
        • Mezquita L.
        • Ferrara R.
        • Audigier-Valette C.
        • et al.
        Outcome of patients with non-small cell lung cancer and brain metastases treated with checkpoint inhibitors.
        J Thorac Oncol. 2019; https://doi.org/10.1016/j.jtho.2019.02.009
        • Crinò L.
        • Bronte G.
        • Bidoli P.
        • Cravero P.
        • Minenza E.
        • Cortesi E.
        • et al.
        Nivolumab and brain metastases in patients with advanced non-squamous non-small cell lung cancer.
        Lung Cancer. 2019; 129: 35-40https://doi.org/10.1016/j.lungcan.2018.12.025
        • Molinier O.
        • Audigier-Valette C.
        • Cadranel J.
        • Monnet I.
        • Hureaux J.
        • Hilgers W.
        • et al.
        OA 17.05 IFCT-1502 CLINIVO: real-life experience with Nivolumab in 600 patients (Pts) with advanced non-small cell lung cancer (NSCLC).
        J Thorac Oncol. 2017; https://doi.org/10.1016/j.jtho.2017.09.430
      1. Watanabe H, Kubo T, Ninomiya T, Ohashi K, Ichihara E, Sato A, et al. The effect of nivolumab treatment for central nervous system metastases in non-small cell lung cancer. J Clin Oncol 2017;35:e20601–e20601. doi: 10.1200/JCO.2017.35.15_suppl.e20601.

        • Kanai O.
        • Fujita K.
        • Okamura M.
        • Nakatani K.
        • Mio T.
        Severe exacerbation or manifestation of primary disease related to nivolumab in non-small-cell lung cancer patients with poor performance status or brain metastases.
        Ann Oncol. 2016; https://doi.org/10.1093/annonc/mdw148
        • Henon C.
        • Mezquita L.
        • Auclin E.
        • Ammari S.
        • Caramella C.
        • Le Pechoux C.
        • et al.
        P2.07-005 impact of baseline leptomeningeal and brain metastases on immunotherapy outcomes in advanced non-small cell lung cancer (NSCLC) patients.
        J Thorac Oncol. 2017; https://doi.org/10.1016/j.jtho.2017.11.064
        • Gauvain C.
        • Vauléon E.
        • Chouaid C.
        • Lerhun E.
        • Jabot L.
        • Scherpereel A.
        • et al.
        Intracerebral efficacy and tolerance of nivolumab in non–small-cell lung cancer patients with brain metastases.
        Lung Cancer. 2018; https://doi.org/10.1016/j.lungcan.2017.12.008
        • Ashinuma H.
        • Shingyoji M.
        • Iuchi T.
        • Yoshida Y.
        • Setoguchi T.
        • Hasegawa Y.
        • et al.
        P2.07-014 Immune Checkpoint Inhibitors for Brain Metastases of Non-Small-Cell Lung.
        Cancer. J Thorac Oncol. 2017; 12: S2420https://doi.org/10.1016/j.jtho.2017.11.073
        • Franks A.L.
        • Slansky J.E.
        Multiple associations between a broad spectrum of autoimmune diseases, chronic inflammatory diseases and cancer.
        Anticancer Res. 2012;
        • Khan S.A.
        • Pruitt S.L.
        • Xuan L.
        • Gerber D.E.
        Prevalence of autoimmune disease among patients with lung cancer: Implications for immunotherapy treatment options.
        JAMA Oncol. 2016; https://doi.org/10.1001/jamaoncol.2016.2238
        • Cortellini A.
        • Buti S.
        • Santini D.
        • Perrone F.
        • Giusti R.
        • Tiseo M.
        • et al.
        Clinical outcomes of patients with advanced cancer and pre-existing autoimmune diseases treated with anti-programmed death-1 immunotherapy: a real-world transverse study.
        Oncologist. 2019; https://doi.org/10.1634/theoncologist.2018-0618
        • Leonardi G.C.
        • Gainor J.F.
        • Altan M.
        • Kravets S.
        • Dahlberg S.E.
        • Gedmintas L.
        • et al.
        Safety of programmed death-1 pathway inhibitors among patients with non-small-cell lung cancer and preexisting autoimmune disorders.
        J Clin Oncol. 2018; https://doi.org/10.1200/JCO.2017.77.0305
        • Ostios-Garcia L.
        • Faig J.
        • Leonardi G.C.
        • Adeni A.E.
        • Subegdjo S.J.
        • Lydon C.A.
        • et al.
        Safety and efficacy of PD-1 inhibitors among HIV-positive patients with non-small cell lung cancer.
        J Thorac Oncol. 2018; 13: 1037-1042https://doi.org/10.1016/j.jtho.2018.03.031
      2. Samri S, Lavolé A, Even S, Lambert-Niclot S, Le Garff G, Cadranel J, et al. PD-1 blockade in 12 HIV-infected patients with lung cancer. Pap Present Int AIDS Soc Conf July 24, 2017 n.d.

        • Shah N.J.
        • Al-Shbool G.
        • Blackburn M.
        • Cook M.
        • Belouali A.
        • Liu S.V.
        • et al.
        Safety and efficacy of immune checkpoint inhibitors (ICIs) in cancer patients with HIV, hepatitis B, or hepatitis C viral infection.
        J Immunother Cancer. 2019; 7: 353https://doi.org/10.1186/s40425-019-0771-1
        • Uldrick T.S.
        • Gonçalves P.H.
        • Abdul-Hay M.
        • Claeys A.J.
        • Emu B.
        • Ernstoff M.S.
        • et al.
        Assessment of the safety of pembrolizumab in patients with HIV and advanced cancer—a phase 1 study.
        JAMA Oncol. 2019; 5: 1332https://doi.org/10.1001/jamaoncol.2019.2244
        • Frega S.
        • Ferro A.
        • Bonanno L.
        • Guarneri V.
        • Conte P.
        • Pasello G.
        Lung cancer (LC) in HIV positive patients: pathogenic features and implications for treatment.
        Int J Mol Sci. 2020; 21: 1601https://doi.org/10.3390/ijms21051601
        • González-Cao M.
        • Moran T.
        • Dalmau J.
        • Garcia-Corbacho J.
        • Bernabé R.
        • Juan O.
        • et al.
        Phase II study of durvalumab (MEDI4736) in cancer patients HIV-1-infected.
        J Clin Oncol. 2019; 37: 2501https://doi.org/10.1200/JCO.2019.37.15_suppl.2501
        • Collins R.
        • Bowman L.
        • Landray M.
        • Peto R.
        The magic of randomization versus the myth of real-world evidence.
        N Engl J Med. 2020; https://doi.org/10.1056/NEJMsb1901642
      3. Di Maio M, Perrone F, Conte P. Real‐world evidence in oncology: opportunities and limitations. Oncologist 2019:theoncologist.2019-0647. doi: 10.1634/theoncologist.2019-0647.

        • Skovlund E.
        • Leufkens H.G.M.
        • Smyth J.F.
        The use of real-world data in cancer drug development.
        Eur J Cancer. 2018; https://doi.org/10.1016/j.ejca.2018.06.036
        • Burock S.
        • Meunier F.
        • Lacombe D.
        How can innovative forms of clinical research contribute to deliver affordable cancer care in an evolving health care environment?.
        Eur J Cancer. 2013; https://doi.org/10.1016/j.ejca.2013.05.016
        • Sabatier R.
        • Nicolas E.
        • Paciencia M.
        • Jonville-Béra A.P.
        • Madroszyk A.
        • Cecile M.
        • et al.
        Nivolumab in routine practice for older patients with advanced or metastatic non-small cell lung cancer.
        J Geriatr Oncol. 2018; https://doi.org/10.1016/j.jgo.2018.02.011