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Immune Checkpoint Inhibitors in Thoracic Malignancies: Review of the Existing Evidence by an IASLC Expert Panel and Recommendations

Open ArchivePublished:March 13, 2020DOI:https://doi.org/10.1016/j.jtho.2020.03.006

      Abstract

      In the past 10 years, a deeper understanding of the immune landscape of cancers, including immune evasion processes, has allowed the development of a new class of agents. The reactivation of host antitumor immune response offers the potential for long-term survival benefit in a portion of patients with thoracic malignancies.
      The advent of programmed cell death protein 1/programmed death ligand-1 immune checkpoint inhibitors (ICIs), both as single agents and in combination with chemotherapy, and more recently, the combination of ICI, anti–programmed cell death protein 1, and anticytotoxic T-lymphocyte antigen 4 antibody, have led to breakthrough therapeutic advances for patients with advanced NSCLC, and to a lesser extent, patients with SCLC. Encouraging activity has recently emerged in pretreated patients with thymic carcinoma (TC). Conversely, in malignant pleural mesothelioma, pivotal positive signs of activity have not been fully confirmed in randomized trials. The additive effects of chemoradiation and immunotherapy suggested intriguing potential for therapeutic synergy with combination strategies. This has led to the introduction of ICI consolidation therapy in stage III NSCLC, creating a platform for future therapeutic developments in earlier-stage disease. Despite the definitive clinical benefit observed with ICI, primary and acquired resistance represent well-known biological phenomena, which may affect the therapeutic efficacy of these agents.
      The development of innovative strategies to overcome ICI resistance, standardization of new patterns of ICI progression, identification of predictive biomarkers of response, optimal treatment duration, and characterization of ICI efficacy in special populations, represent crucial issues to be adequately addressed, with the aim of improving the therapeutic benefit of ICI in patients with thoracic malignancies.
      In this article, an international panel of experts in the field of thoracic malignancies discussed these topics, evaluating currently available scientific evidence, with the final aim of providing clinical recommendations, which may guide oncologists in their current practice and elucidate future treatment strategies and research priorities.

      Keywords

      Introduction

      Immunotherapeutic strategy has recently transformed the therapeutic landscape of many thoracic malignancies. The immune checkpoint inhibitors (ICIs), antibodies targeting programmed cell death protein 1 (PD-1) receptor or its ligand programmed death ligand 1 (PD-L1), as monotherapy or in combination with chemotherapy (CT) have become a mainstay of first-line treatment of both patients with metastatic NSCLC and, more recently, in patients with SCLC.
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      This is based on significant improvement in overall survival (OS) when compared with standard CT. We are now witnessing unprecedented 5-year OS rates associated with the upfront use of these agents with long-term survivors in patients with NSCLC, particularly those who achieved a radiologic response and whose tumors express PD-L1.
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      Literature Search and Study Selection

      The literature search was conducted using MEDLINE/PubMed, EMBASE databases, and Cochrane Library, up to October 2019. Keywords used as literature search terms included the following: lung cancer, non-small cell lung cancer, small cell lung cancer, mesothelioma, thymic, immunotherapy, PD-1/PD-L1, CTLA4, ICIs, and chemotherapy. The literature search was limited to human studies in English language, and expert members of the International Association for the Study of Lung Cancer (IASLC) panel selected relevant trials. Relevant abstracts presented during 2018 and 2019 at the American Society of Clinical Oncology and European Society of Medical Oncology congress, the World Conference on Lung Cancer, and the European Society of Medical Oncology Immuno Oncology Congress were also included as scientific support to published evidence. Expert perspectives, based on current scientific evidence, have been provided by the IASLC panel.

      Immunolandscape and Tumor Inflammation in Thoracic Malignancies

      Generally, NSCLCs have been found to have higher immune infiltration than their normal counterpart. Prominent adaptive antitumor immune responses have been documented by direct analysis of immune cell populations and indirectly by measuring tumor PD-L1 expression, interferon gamma–related signatures, or multimarker transcriptomic profiles.
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      Using immunohistochemistry (IHC), PD-L1 expression in greater than or equal to 1% of tumor cells has been reported in approximately 60% of advanced NSCLC and with high levels (e.g., ≥50% of tumor cells) in 25% to 30% of cases.
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      Nevertheless, there is prominent variation across the studies owing to, at least in part, the use of multiple IHC assays/platforms with divergent performance. Analysis of specific T-cell populations reveals that NSCLC tumors contain higher CD3+ tumor-infiltrating lymphocytes (TILs), CD8+ cytotoxic cells, and CD8+/CD45R0+ effector memory cells than nontumor lung.
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      Progressive changes in composition of lymphocytes in lung tissues from patients with non-small-cell lung cancer.
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      Neutrophils dominate the immune cell composition in non-small cell lung cancer.
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      Multiparametric profiling of non-small-cell lung cancers reveals distinct immunophenotypes.
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      Immune cell composition in human non-small cell lung cancer.
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      Innate immune landscape in early lung adenocarcinoma by paired single-cell analyses.
      Elevated levels of these T-cell subsets have been consistently associated with better outcomes, confirming their antitumor nature.
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      The role of tumor-infiltrating lymphocytes in development, progression, and prognosis of non-small cell lung cancer.
      High levels of CD4+ helper cells, CD4+/FOXP3+ regulatory T cells (Tregs), and CD8+ T cells expressing immune inhibitory receptors, such as PD-1, LAG-3, and TIM-3, are also present and support potent immune regulation.
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      Progressive changes in composition of lymphocytes in lung tissues from patients with non-small-cell lung cancer.
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      Neutrophils dominate the immune cell composition in non-small cell lung cancer.
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      Multiparametric profiling of non-small-cell lung cancers reveals distinct immunophenotypes.
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      Dysfunctional CD8 T cells form a proliferative, dynamically regulated compartment within human melanoma.
      The fraction of CD19+/CD20+ B-lymphocytes is smaller than that of T cells, and the overall B-cell content is higher in NSCLC than in nontumor tissues.
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      Progressive changes in composition of lymphocytes in lung tissues from patients with non-small-cell lung cancer.
      ,
      • Kargl J.
      • Busch S.E.
      • Yang G.H.
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      Neutrophils dominate the immune cell composition in non-small cell lung cancer.
      Notably, the B cells are often located at the periphery of tumor nests within tertiary lymphoid structures.
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      Immune cell composition in human non-small cell lung cancer.
      ,
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      Innate immune landscape in early lung adenocarcinoma by paired single-cell analyses.
      Numerous studies have proposed a prominent immunologic and proinflammatory role of tertiary lymphoid structures in lung malignancies, which is supported by their positive association with T-cell content, T-cell receptor clonality, and a favorable prognostic effect.
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      A high density of tertiary lymphoid structure B cells in lung tumors is associated with increased CD4+ T cell receptor repertoire clonality.
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      Innate immune cells are also differentially expressed in NSCLC relative to normal lung, with lower levels of CD68+ or CD14+/HLA-DR+ macrophages, CD11c+ dendritic cells (DCs), and CD3−/CD16+/CD56+ natural killer (NK) cells.
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      • Busch S.E.
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      Neutrophils dominate the immune cell composition in non-small cell lung cancer.
      • Lizotte P.H.
      • Ivanova E.V.
      • Awad M.M.
      • et al.
      Multiparametric profiling of non-small-cell lung cancers reveals distinct immunophenotypes.
      • Stankovic B.
      • Bjørhovde H.A.K.
      • Skarshaug R.
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      Immune cell composition in human non-small cell lung cancer.
      • Lavin Y.
      • Kobayashi S.
      • Leader A.
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      Innate immune landscape in early lung adenocarcinoma by paired single-cell analyses.
      Interestingly, granulocytes comprise a prominent fraction of immune infiltrates, but the content of neutrophils is similar between paired tumor and nontumor specimens.
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      • Skarshaug R.
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      Immune cell composition in human non-small cell lung cancer.
      ,
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      • Kobayashi S.
      • Leader A.
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      Innate immune landscape in early lung adenocarcinoma by paired single-cell analyses.
      The influence of tumor-associated macrophages and other myeloid- and innate immune cell subsets on the prognosis of patients with NSCLC is not fully elucidated, and studies report variable results.
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      Prognostic significance of tumor-associated macrophages in solid tumor: a meta-analysis of the literature.
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      Macrophages, inflammation, and lung cancer.
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      Tumour-associated macrophages as treatment targets in oncology.
      Although immunologic differences among major histology variants have been described, variations in the immune composition between adenocarcinomas (ADCs) and squamous cell carcinomas (SCCs) have revealed inconsistent results.
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      • Brown J.
      • Carvajal-Hausdorf D.
      • et al.
      Objective measurement and clinical significance of TILs in non-small cell lung cancer.
      ,
      • Velcheti V.
      • Schalper K.A.
      • Carvajal D.E.
      • et al.
      Programmed death ligand-1 expression in non-small cell lung cancer.
      ,
      • Del Mar Valenzuela-Membrives M.
      • Perea-García F.
      • Sanchez-Palencia A.
      • et al.
      Progressive changes in composition of lymphocytes in lung tissues from patients with non-small-cell lung cancer.
      • Kargl J.
      • Busch S.E.
      • Yang G.H.
      • et al.
      Neutrophils dominate the immune cell composition in non-small cell lung cancer.
      • Lizotte P.H.
      • Ivanova E.V.
      • Awad M.M.
      • et al.
      Multiparametric profiling of non-small-cell lung cancers reveals distinct immunophenotypes.
      • Stankovic B.
      • Bjørhovde H.A.K.
      • Skarshaug R.
      • et al.
      Immune cell composition in human non-small cell lung cancer.
      ,
      • Parra E.R.
      • Behrens C.
      • Rodriguez-Canales J.
      • et al.
      Image analysis-based assessment of PD-L1 and tumor-associated immune cells density supports distinct intratumoral microenvironment groups in non-small cell lung carcinoma patients.
      ,
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      • Madeddu D.
      • Falco A.
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      Low PD-1 expression in cytotoxic CD8+ tumor-infiltrating lymphocytes confers an immune-privileged tissue microenvironment in NSCLC with a prognostic and predictive value.
      Differences in the immune composition among lung ADCs harboring distinct oncogenic driver mutations have also been reported
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      Low PD-1 expression in cytotoxic CD8+ tumor-infiltrating lymphocytes confers an immune-privileged tissue microenvironment in NSCLC with a prognostic and predictive value.
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      (see the next section). Studies assessing the immunologic spectrum across multiple tumor types using RNA sequencing data from The Cancer Genome Atlas found that NSCLCs have a relatively high calculated leukocyte fraction
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      The immune landscape of cancer.
      and one of the highest proportion of cases with elevated coexpression of CD8A and PD-L1 transcripts,
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      Pan-cancer immunogenomic perspective on the tumor microenvironment based on PD-L1 and CD8 T-cell infiltration.
      supporting the designation as an immunologically active or “T-cell inflamed” tumor type.
      Conversely, fewer studies have addressed the immune composition of SCLC, possibly reflecting its lower prevalence and limitations to access adequate tumor specimens. In retrospective cohorts, PD-L1 expression by IHC has been detected in 0% to 71.6% of cases with predominance of signal in immune/stromal cells.
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      PD-L1 expression in small cell neuroendocrine carcinomas.
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      Significance of programmed cell death-ligand 1 expression and its association with survival in patients with small cell lung cancer.
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      PD-L1 expression in neuroendocrine tumors of the lung.
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      • Pavan A.
      • Dieci M.V.
      • et al.
      The role of immune microenvironment in small-cell lung cancer: distribution of PD-L1 expression and prognostic role of FOXP3-positive tumour infiltrating lymphocytes.
      • Carvajal-Hausdorf D.
      • Altan M.
      • Velcheti V.
      • et al.
      Expression and clinical significance of PD-L1, B7-H3, B7-H4 and TILs in human small cell lung cancer (SCLC).
      • Wang H.
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      • Dong B.
      • et al.
      Prognostic significance of PD-L1 expression and CD8+ T cell infiltration in pulmonary neuroendocrine tumors.
      Prospective clinical trials using complementary IHC diagnostics have revealed similarly variable results, with one study reporting 17% of cases with greater than or equal to 1% tumor cell PD-L1
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      Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial.
      and another revealing 31.7% of cases with greater than or equal to 1% in either tumor or stromal-cell staining.
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      • Elez E.
      • Hiret S.
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      Pembrolizumab in patients with extensive-stage small-cell lung cancer: results from the phase Ib KEYNOTE-028 study.
      Notably, very high PD-L1 (≥50% positive cells) is a rare event in SCLC. As in other tumor types, PD-L1 expression is associated with increased adaptive immune responses reflected as elevated CD3ε and CD68 mRNA transcripts
      • Schultheis A.M.
      • Scheel A.H.
      • Ozretić L.
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      PD-L1 expression in small cell neuroendocrine carcinomas.
      and high CD8+ TILs.
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      • Pavan A.
      • Dieci M.V.
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      The role of immune microenvironment in small-cell lung cancer: distribution of PD-L1 expression and prognostic role of FOXP3-positive tumour infiltrating lymphocytes.
      In qualitative analysis, 13% of SCLCs had detectable CD8+ TILs and 72.1% FOXP3+ Tregs.
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      • Pavan A.
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      The role of immune microenvironment in small-cell lung cancer: distribution of PD-L1 expression and prognostic role of FOXP3-positive tumour infiltrating lymphocytes.
      The IHC quantification of 94 SCLCs revealed a median of 264.6 CD8+ cells/mm2,
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      • Li Z.
      • Dong B.
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      Prognostic significance of PD-L1 expression and CD8+ T cell infiltration in pulmonary neuroendocrine tumors.
      which is prominently lower than the 1040.8 CD8+ cells/mm2 reported in the peritumoral compartment of lung ADCs (n = 146) and 1365.6 CD8+ cells/mm2 in SCCs (n = 108).
      • Parra E.R.
      • Behrens C.
      • Rodriguez-Canales J.
      • et al.
      Image analysis-based assessment of PD-L1 and tumor-associated immune cells density supports distinct intratumoral microenvironment groups in non-small cell lung carcinoma patients.
      Consistent with this, multiplex immunofluorescence analysis identified 5.4-fold lower CD8+ cells in SCLC than in ADCs and 6-fold lower CD8+ cells than in SCCs.
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      • Altan M.
      • Velcheti V.
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      Expression and clinical significance of PD-L1, B7-H3, B7-H4 and TILs in human small cell lung cancer (SCLC).
      The level of CD3+ and CD20+ cells and the CD3/CD8 signal ratio were also lower in SCLC, supporting a less cytotoxic T-cell profile. Associations between TILs and survival in SCLC reveal inconsistent results, further supporting the presence of limited adaptive responses in this disease. Higher levels of CD14+ monocytes and CD68+ macrophages have been found in patients with longer survival (>2 y), suggesting a role of myeloid cells in SCLC immune rejection.
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      Immune cell infiltration may be a key determinant of long-term survival in small cell lung cancer.
      Finally, a marked down-regulation of HLA antigens in SCLC tumor cells may have a negative influence on the antitumor immune response.
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      Defective HLA class I antigen processing machinery in cancer.
      Malignant pleural mesotheliomas (MPMs) are characterized by an aggressive clinical course, multiple histology patterns, and molecular/immunophenotypes. Using a 1% tumor cell positivity threshold, PD-L1 expression has been recognized in 14% to 72.4% of MPMs and reveals consistent association with nonepithelioid histology (e.g., sarcomatoid/biphasic) and elevated TILs.
      • Thapa B.
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      The immune microenvironment, genome-wide copy number aberrations, and survival in mesothelioma.
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      Tumor PD-L1 expression in malignant pleural and peritoneal mesothelioma by Dako PD-L1 22C3 pharmDx and Dako PD-L1 28-8 pharmDx assays.
      • Brosseau S.
      • Danel C.
      • Scherpereel A.
      • et al.
      Shorter survival in malignant pleural mesothelioma patients with high PD-L1 expression associated with sarcomatoid or biphasic histology subtype: a series of 214 cases from the Bio-MAPS cohort.
      • Cedrés S.
      • Ponce-Aix S.
      • Zugazagoitia J.
      • et al.
      Analysis of expression of programmed cell death 1 ligand 1 (PD-L1) in malignant pleural mesothelioma (MPM).
      • Nguyen B.H.
      • Montgomery R.
      • Fadia M.
      • Wang J.
      • Ali S.
      PD-L1 expression associated with worse survival outcome in malignant pleural mesothelioma.
      • Patil N.S.
      • Righi L.
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      • et al.
      Molecular and histopathological characterization of the tumor immune microenvironment in advanced stage of malignant pleural mesothelioma.
      • Awad M.M.
      • Jones R.E.
      • Liu H.
      • et al.
      Cytotoxic T cells in PD-L1-positive malignant pleural mesotheliomas are counterbalanced by distinct immunosuppressive factors.
      Detailed analysis using flow cytometry revealed a highly variable distribution of immune cells with an overall higher proportion of CD3+ T cells and CD33+ monocytes and a relatively lower presence of CD19+ B cells, CD56+ NK cells, CD66b+ neutrophils, and CD123+ DCs.
      • Awad M.M.
      • Jones R.E.
      • Liu H.
      • et al.
      Cytotoxic T cells in PD-L1-positive malignant pleural mesotheliomas are counterbalanced by distinct immunosuppressive factors.
      Cases with PD-L1 expression revealed a higher fraction of Tregs and effector T cells positive for immune inhibitory receptors. MPMs also contain abundant CD68+ and CD163+ macrophages with comparable levels across histology subtypes and association with shorter survival, suggesting a negative effect of these myeloid cells.
      • Burt B.M.
      • Rodig S.J.
      • Tilleman T.R.
      • Elbardissi A.W.
      • Bueno R.
      • Sugarbaker D.J.
      Circulating and tumor-infiltrating myeloid cells predict survival in human pleural mesothelioma.
      Studies on the prognostic role of T cells reveal variable results, probably reflecting the biological diversity of MPMs and the use of different methods. Using unsupervised clustering of targeted immune gene expression analysis, MPMs were classified into three molecularly distinct subgroups. Forty percent of cases in one cluster had low levels of inflammatory transcripts and enrichment of nonepithelioid tumors. Nearly 60% of cases in the other two clusters had higher PD-L1 expression and transcripts associated with adaptive B-/T-cell responses, suggesting active immune responses and therapeutic potential using immune checkpoint blockers.
      • Patil N.S.
      • Righi L.
      • Koeppen H.
      • et al.
      Molecular and histopathological characterization of the tumor immune microenvironment in advanced stage of malignant pleural mesothelioma.

      Expert Perspective

      Because of the complexity of the interaction between cancer and the immune microenviroment, novel cutting-edge technologies for comprehensive molecular and cellular characterization of cancer immunity, including single-cell sequencing, mass cytometry, and multiplexed spatial cellular phenotyping, are needed in association with computational methods and software tools. Interrogating cancer immunity through these different approaches will likely increase our current knowledge on the immune composition of thoracic tumors and improve physicians’ ability to select appropriate treatments in the coming few years.

      Genotype and Immunophenotype in Thoracic Tumors

      Tumor-cell–intrinsic oncogenic pathways that are initiated and sustained by both oncogenic driver events and the compendium of co-occurring genomic alterations in key tumor suppressor genes can shape the lung cancer immune microenvironment.
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      Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy.
      • Spranger S.
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      Impact of oncogenic pathways on evasion of antitumour immune responses.
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      • Carter J.
      • Cañadas I.
      • Barbie D.A.
      Molecular and genomic determinants of response to immune checkpoint inhibition in cancer.
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      • de Visser K.E.
      Cancer-cell-intrinsic mechanisms shaping the tumor immune landscape.
      In nonsquamous NSCLC, inactivating somatic genomic alterations in STK11/LKB1 represent a prominent mediator of T-cell exclusion. Deleterious STK11/LKB1 alterations are prevalent (approximately 18% of lung ADCs), frequently co-occuring with mutations in KRAS, and are associated with low density of CD3+, CD8+, and CD4+ TILs and reduced expression of PD-L1 on the surface of tumor cells, despite the presence of intermediate to high tumor mutational burden (TMB).
      • Skoulidis F.
      • Goldberg M.E.
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      STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma.
      • Rizvi H.
      • Sanchez-Vega F.
      • La K.
      • et al.
      Molecular determinants of response to anti-programmed cell death (PD)-1 and anti-programmed death-ligand 1 (PD-L1) blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing.
      • Cristescu R.
      • Mogg R.
      • Ayers M.
      • et al.
      Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy.
      • Kadara H.
      • Choi M.
      • Zhang J.
      • et al.
      Whole-exome sequencing and immune profiling of early-stage lung adenocarcinoma with fully annotated clinical follow-up.
      • Skoulidis F.
      • Arbour K.C.
      • Hellmann M.D.
      • et al.
      Association of STK11/LKB1 genomic alterations with lack of benefit from the addition of pembrolizumab to platinum doublet chemotherapy in non-squamous non-small cell lung cancer.
      • Jordan E.J.
      • Kim H.R.
      • Arcila M.E.
      • et al.
      Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies.
      • Gao J.
      • Aksoy B.A.
      • Dogrusoz U.
      • et al.
      Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal.
      • Cerami E.
      • Gao J.
      • Dogrusoz U.
      • et al.
      The cBio Cancer Genomics Portal: an open platform for exploring multidimensional cancer genomics data.
      The impact of Stk11/Lkb1 loss on the NSCLC immune contexture is further recapitulated in immunocompetent murine models of Stk11/Lkb1 loss, thus supporting a direct and causative role.
      • Skoulidis F.
      • Goldberg M.E.
      • Greenawalt D.M.
      • et al.
      STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma.
      ,
      • Koyama S.
      • Akbay E.A.
      • Li Y.Y.
      • et al.
      STK11/LKB1 deficiency promotes neutrophil recruitment and proinflammatory cytokine production to suppress T-cell activity in the lung tumor microenvironment.
      ,
      • Scheel A.H.
      • Ansén S.
      • Schultheis A.M.
      • et al.
      PD-L1 expression in non-small cell lung cancer: correlations with genetic alterations.
      In the KrasLSL-G12D/+;Stk11/Lkb1Fl/Fl genetically engineered mouse model, loss of Stk11/Lkb1 promotes recruitment of immunosuppressive myeloid cells (predominantly neutrophils) that may account for both reduced T-cell abundance and increased expression of T-cell exhaustion markers.
      • Koyama S.
      • Akbay E.A.
      • Li Y.Y.
      • et al.
      STK11/LKB1 deficiency promotes neutrophil recruitment and proinflammatory cytokine production to suppress T-cell activity in the lung tumor microenvironment.
      Although the precise mechanisms and pathways through which STK11/LKB1 loss promotes immune exclusion have not yet been fully elucidated, it was recently reported that STK11/LKB1 inactivation impairs innate immune signaling through epigenetic repression of STING.
      • Kitajima S.
      • Ivanova E.
      • Guo S.
      • et al.
      Suppression of STING associated with LKB1 loss in KRAS-driven lung cancer.
      The negative prognostic role of STK11 has been clearly reported in different studies. All reported inferior survival in patients with STK11-mutated versus those with STK11-wild-type metastatic NSCLC regardless of the treatment received (CT or immunotherapy alone, chemo-immunotherapy or anti–PD-L1 plus anti-CTLA4 combinations); however, its predictive value still remains debatable.
      • Skoulidis F.
      • Arbour K.C.
      • Hellmann M.D.
      • et al.
      Association of STK11/LKB1 genomic alterations with lack of benefit from the addition of pembrolizumab to platinum doublet chemotherapy in non-squamous non-small cell lung cancer.
      ,
      • Golozar A.
      • Collins J.
      • Fraeman K.
      • et al.
      OA07.02 LKB1 mutations in metastatic non-small cell lung cancer (mNSCLC): prognostic value in the real world.
      ,
      • Rizvi N.
      • Cho B.C.
      • Reinmuth N.
      • et al.
      OA04.07 mutations associated with sensitivity or resistance to immunotherapy in mNSCLC: analysis from the MYSTIC trial.
      Somatic mutations in KEAP1, encoding an adaptor protein critical for the ubiquitination and subsequent proteosomal degradation of NRF2 (encoded by NFE2L2)—a master regulator of cellular antioxidant and cytoprotective transcriptional programs—have also emerged as a key modifier of the NSCLC immune microenvironment. KEAP1 mutations are common in both lung ADC (approximately 17%, wherein they co-occur with STK11/LKB1 mutations in approximately 11%) and SCC (approximately 10%–12%) and are negatively associated with a T-cell inflammation signature among TMB-high tumors in both tumor types.
      • Cristescu R.
      • Mogg R.
      • Ayers M.
      • et al.
      Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy.
      ,
      • Skoulidis F.
      • Arbour K.C.
      • Hellmann M.D.
      • et al.
      Association of STK11/LKB1 genomic alterations with lack of benefit from the addition of pembrolizumab to platinum doublet chemotherapy in non-squamous non-small cell lung cancer.
      ,
      • Gao J.
      • Aksoy B.A.
      • Dogrusoz U.
      • et al.
      Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal.
      ,
      • Cerami E.
      • Gao J.
      • Dogrusoz U.
      • et al.
      The cBio Cancer Genomics Portal: an open platform for exploring multidimensional cancer genomics data.
      ,
      • Sanchez-Vega F.
      • Mina M.
      • Armenia J.
      • et al.
      Oncogenic signaling pathways in The Cancer Genome Atlas.
      ,
      Cancer Genome Atlas Research Network
      Comprehensive genomic characterization of squamous cell lung cancers.
      In genetically engineered mouse model models, concurrent inactivation of Keap1 and Pten (Keap1Fl/Fl;PtenFl/Fl) supported the emergence of immunologically cold tumors, whereas depletion of KEAP1 in the context of endogenous oncogenic KRASG12D expression (KrasLSL–G12D/+;Keap1Fl/FL) resulted in paucity of protumorigenic M2 macrophages.
      • Best S.A.
      • De Souza D.P.
      • Kersbergen A.
      • et al.
      Synergy between the KEAP1/NRF2 and PI3K pathways drives non-small-cell lung cancer with an altered immune microenvironment.
      ,
      • Best S.A.
      • Ding S.
      • Kersbergen A.
      • et al.
      Distinct initiating events underpin the immune and metabolic heterogeneity of KRAS-mutant lung adenocarcinoma.
      Intriguingly, a link between NRF2 expression and innate immune sensing through negative effects on STING mRNA stability was recently reported, thus providing a plausible mechanistic link that further underscores the functional association between STK11/LKB1 and KEAP1.
      • Olagnier D.
      • Brandtoft A.M.
      • Gunderstofte C.
      • et al.
      Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming.
      Furthermore, KEAP1 loss may affect the recruitment and function of additional immune cell types, including NK cells, and these associations warrant further study in independent data sets.
      • Kadara H.
      • Choi M.
      • Zhang J.
      • et al.
      Whole-exome sequencing and immune profiling of early-stage lung adenocarcinoma with fully annotated clinical follow-up.
      Oncogenic mutations in PIK3CA represent an additional genomic alteration that has been linked with reduced tumor cell PD-L1 expression in both lung ADC and SCC,
      • Kadara H.
      • Choi M.
      • Zhang J.
      • et al.
      Whole-exome sequencing and immune profiling of early-stage lung adenocarcinoma with fully annotated clinical follow-up.
      ,
      • Choi M.
      • Kadara H.
      • Zhang J.
      • et al.
      Mutation profiles in early-stage lung squamous cell carcinoma with clinical follow-up and correlation with markers of immune function.
      whereas loss of the PTEN tumor suppressor has been associated with reduced CD8+ T-cell infiltration,
      • Zhang X.C.
      • Wang J.
      • Shao G.G.
      • et al.
      Comprehensive genomic and immunological characterization of Chinese non-small cell lung cancer patients.
      in agreement with its role as the driver of immune evasion in melanoma and other tumor types.
      • Peng W.
      • Chen J.Q.
      • Liu C.
      • et al.
      Loss of PTEN promotes resistance to T cell-mediated immunotherapy.
      Mutational inactivation of TP53, a guardian of genome integrity, is associated with higher TMB and an inflamed tumor immune microenvironment with increased tumor cell PD-L1 expression in both KRAS-mutant lung ADC
      • Skoulidis F.
      • Goldberg M.E.
      • Greenawalt D.M.
      • et al.
      STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma.
      and across nonsquamous NSCLC regardless of KRAS status.
      • Rizvi H.
      • Sanchez-Vega F.
      • La K.
      • et al.
      Molecular determinants of response to anti-programmed cell death (PD)-1 and anti-programmed death-ligand 1 (PD-L1) blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing.
      Both tolerance of an increased load of putative neoantigens and direct effects of p53 inactivation on inflammatory pathways (e.g., potentiation of nuclear factor κB signaling) may underpin this association.
      • Petitjean A.
      • Mathe E.
      • Kato S.
      • et al.
      Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database.
      • Chalmers Z.R.
      • Connelly C.F.
      • Fabrizio D.
      • et al.
      Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden.
      • Cha Y.J.
      • Kim H.R.
      • Lee C.Y.
      • Cho B.C.
      • Shim H.S.
      Clinicopathological and prognostic significance of programmed cell death ligand-1 expression in lung adenocarcinoma and its relationship with p53 status.
      • Meylan E.
      • Dooley A.L.
      • Feldser D.M.
      • et al.
      Requirement for NF-kappaB signalling in a mouse model of lung adenocarcinoma.
      Beyond TP53 mutations in components of DNA repair pathways, including mismatch-repair genes,
      • Maby P.
      • Tougeron D.
      • Hamieh M.
      • et al.
      Correlation between density of CD8+ T-cell infiltrate in microsatellite unstable colorectal cancers and frameshift mutations: a rationale for personalized immunotherapy.
      POLE
      • Mehnert J.M.
      • Panda A.
      • Zhong H.
      • et al.
      Immune activation and response to pembrolizumab in POLE-mutant endometrial cancer.
      and BRCA2
      • Wen W.X.
      • Leong C.O.
      Association of BRCA1- and BRCA2-deficiency with mutation burden, expression of PD-L1/PD-1, immune infiltrates, and T cell-inflamed signature in breast cancer.
      have also been linked with increased CD8+ T-cell infiltrate in distinct tumor types, although their impact on the microenvironment of NSCLC has not yet been examined systematically. Interestingly, inactivating mutations in ARID1A, a component of the SWI/SNF chromatin remodeling complex that was identified as a MSH2 interacting partner, were reported to promote tumor hypermutation owing to impaired mismatch repair
      • Shen J.
      • Ju Z.
      • Zhao W.
      • et al.
      ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade.
      and were recently identified as a candidate biomarker of favorable clinical outcomes with durvalumab and tremelimumab in NSCLC.
      • Rizvi N.
      • Cho B.C.
      • Reinmuth N.
      • et al.
      OA04.07 mutations associated with sensitivity or resistance to immunotherapy in mNSCLC: analysis from the MYSTIC trial.
      Among distinct oncogenic driver-defined subsets of lung ADC, activating mutations in EGFR and ALK rearrangements are generally characterized by high PD-L1 expression levels as a result of the oncogenic signaling activation.
      • Akbay E.A.
      • Koyama S.
      • Carretero J.
      • et al.
      Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors.
      ,
      • Koh J.
      • Jang J.Y.
      • Keam B.
      • et al.
      EML4-ALK enhances programmed cell death-ligand 1 expression in pulmonary adenocarcinoma via hypoxia-inducible factor (HIF)-1α and STAT3.
      Nevertheless, both low TMB and neoantigen load,
      • Offin M.
      • Rizvi H.
      • Tenet M.
      • et al.
      Tumor mutation burden and efficacy of EGFR-tyrosine kinase inhibitors in patients with EGFR-mutant lung cancers.
      ,
      • Spigel D.R.
      • Schrock A.B.
      • Fabrizio D.
      • et al.
      Total mutation burden (TMB) in lung cancer (LC) and relationship with response to PD-1/PD-L1 targeted therapies.
      along with an inert tumor immune microenvironment with a reduced T-cell infiltration, likely as a result of an impaired tumor antigenicity,
      • Gainor J.F.
      • Shaw A.T.
      • Sequist L.V.
      • et al.
      EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: a retrospective analysis.
      ,
      • Busch S.E.
      • Hanke M.L.
      • Kargl J.
      • Metz H.E.
      • MacPherson D.
      • Houghton A.M.
      Lung cancer subtypes generate unique immune responses.
      limiting the immunotherapy activity in these subgroups of patients. Low levels of tumor cell PD-L1 expression were recently reported for RET-rearranged
      • Offin M.
      • Guo R.
      • Wu S.L.
      • et al.
      Immunophenotype and response to immunotherapy of RET-rearranged lung cancers.
      and ERBB2-mutant NSCLC,
      • Mazières J.
      • Drilon A.
      • Lusque A.
      • et al.
      Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET Registry.
      ,
      • Lai W.-C.V.
      • Feldman D.L.
      • Buonocore D.J.
      • et al.
      PD-L1 expression, tumor mutation burden and response to immune checkpoint blockade in patients with HER2-mutant lung cancers.
      in keeping with the poor clinical responses of these oncogenotypes to PD-1 axis inhibitor monotherapy. Lung ADCs harboring MET exon 14 skipping mutations and ROS1 rearrangements frequently express high levels of PD-L1 on tumor cells, but this did not seem to translate into improved clinical outcomes with PD-1/PD-L1 inhibitors, and more detailed assessment of their immune contexture is thus far lacking.
      • Mazières J.
      • Drilon A.
      • Lusque A.
      • et al.
      Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET Registry.
      ,
      • Sabari J.K.
      • Leonardi G.C.
      • Shu C.A.
      • et al.
      PD-L1 expression, tumor mutational burden, and response to immunotherapy in patients with MET exon 14 altered lung cancers.
      In contrast, BRAF-mutant lung ADCs (both V600E and non-V600E) exhibit high tumor cell PD-L1 expression and are characterized by more favorable response to ICIs than other oncogenic driver-defined subsets.
      • Mazières J.
      • Drilon A.
      • Lusque A.
      • et al.
      Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET Registry.
      ,
      • Dudnik E.
      • Peled N.
      • Nechushtan H.
      • et al.
      BRAF mutant lung cancer: programmed death ligand 1 expression, tumor mutational burden, microsatellite instability status, and response to immune check-point inhibitors.
      ,
      • Negrao M.V.
      • Lam V.K.
      • Reuben A.
      • et al.
      PD-L1 expression, tumor mutational burden, and cancer gene mutations are stronger Predictors of benefit from immune checkpoint blockade than HLA class I genotype in non-small cell lung cancer.

      Expert Perspective

      Retrospective studies identified tumor-cell-intrinsic oncogenic pathways or co-mutations, including STK11, KEAP1, EGFR, and ALK, being generally associated with a “cold” immune tumor microenvironment, thus substantially impairing clinical responses to ICIs in patients with lung cancer. The genomics of response and resistance to ICIs remains largely unknown, and only prospective investigations may clarify the predictive role of these biomakers.

      Maximum Biological Effective Dose or Maximum Tolerated Dose for Immune Checkpoint Agents

      Nivolumab was evaluated in a dose-escalation study across multiple tumor types escalating doses between 0.1 and 10 mg/kg every 2 weeks (Q2W).
      • Agrawal S.
      • Feng Y.
      • Roy A.
      • Kollia G.
      • Lestini B.
      Nivolumab dose selection: challenges, opportunities, and lessons learned for cancer immunotherapy.
      Receptor occupancy was similar across all dose levels, and minimal peripheral chemokine/cytokine changes were observed. Peripheral receptor occupancy was saturated at doses greater than or equal to 0.3 mg/kg, and contrary to CT or targeted agents, neither was maximum tolerated dose identified nor was a relationship identified between dose and selected grade greater than or equal to 3 treatment-related adverse events (AEs). Across the dose levels, a dose-dependent overall response rate (RR) trend was observed, plateauing at greater than or equal to 3 mg/kg for NSCLC, which was chosen as a unified recommended phase 2/3 dose across all tumors. Subsequent population pharmacokinetic (PK) data identified dose-proportional exposures between 0.1 and 10 mg/kg and flat exposure-response (E-R) relationships for efficacy and safety, with a comparable risk-benefit profile for 240 mg Q2W to 3 mg/kg Q2W, leading to the approvals by the Food and Drug Administration (FDA) and the European Medicines Agency.
      • Zhao X.
      • Suryawanshi S.
      • Hruska M.
      • et al.
      Assessment of nivolumab benefit-risk profile of a 240-mg flat dose relative to a 3-mg/kg dosing regimen in patients with advanced tumors.
      Most recently, additional PK exposure simulation and patient data across multiple tumor types revealed exposure and safety for 480 mg every 4 weeks (Q4W) with 240 mg and 3 mg/kg Q2W dosing.
      • Long G.V.
      • Tykodi S.S.
      • Schneider J.G.
      • et al.
      Assessment of nivolumab exposure and clinical safety of 480 mg every 4 weeks flat-dosing schedule in patients with cancer.
      Similarly to nivolumab, the maximum tolerated dose for pembrolizumab was not reached by adaptive dose escalation, evaluating 0.005 to 10 mg/kg Q2W or every 3 weeks (Q3W),
      • Patnaik A.
      • Kang S.P.
      • Rasco D.
      • et al.
      Phase I study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in patients with advanced solid tumors.
      with E-R analysis revealing similar shrinkage at 2 or 10 mg/kg Q3W. Biological activity models confirmed activity at the lowest dose, but a strong quantitative pharmacodynamic E-R relationship could not be unequivocally reported in the models. Specified AE rates were not associated with dose escalation or exposure.
      European Medicines Agency
      Assessment report. Keytruda. International non-proprietary name: pembrolizumab.
      Population PK modeling from three trials, from trials of fixed-dose pembrolizumab and E-R results revealed similar exposures for 200 mg and 2 mg/kg 3QW dosing, leading to regulatory approvals,
      • Freshwater T.
      • Kondic A.
      • Ahamadi M.
      • et al.
      Evaluation of dosing strategy for pembrolizumab for oncology indications.
      and most recently for 400 mg every 6 week dosing.
      • Lala M.
      • Li M.
      • Sinha V.
      • de Alwis D.
      • Chartash E.
      • Jain L.
      A six-weekly (Q6W) dosing schedule for pembrolizumab based on an exposure-response (E-R) evaluation using modeling and simulation.
      For atezolizumab, doses of 0.01 to 20 mg/kg were evaluated Q3W, again with no dose-limiting toxicities, with responses at all doses.
      • Herbst R.S.
      • Soria J.-C.
      • Kowanetz M.
      • et al.
      Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients.
      A dedicated dose-finding study was not performed, but instead a target optimal serum drug level was achieved at doses of greater than or equal to 10 mg/kg, with no additional safety concerns, leading to the selection of a flat dose of 1200 mg (15 mg/kg-equivalent) being selected for further development, after identifying no meaningful differences with weight-based or flat dosing. Again, no meaningful relationship between dose, exposure, or AE rate was identified.
      European Medicines Agency
      Assessment report. Tecentriq. International non-proprietary name: atezolizumab.
      For durvalumab, dosages of 0.1 to 10 mg/kg Q2W, 15 mg/kg Q3W, and 20 mg/kg Q4W were evaluated, and again, no dose-limiting toxicities were identified.
      • Massard C.
      • Gordon M.S.
      • Sharma S.
      • et al.
      Safety and efficacy of durvalumab (MEDI4736), an anti-programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer.
      ,
      • Baverel P.G.
      • Dubois V.F.S.
      • Jin C.Y.
      • et al.
      Population pharmacokinetics of durvalumab in cancer patients and association with longitudinal biomarkers of disease status.
      No dose-response study was performed. PK simulations revealed that 10 mg/kg Q2W resulted in target levels maintaining greater than 99% target saturation. As discussed previously, no meaningful relationship between dose, exposure, or AE rate was identified. A flat dose of durvalumab of 1500 mg Q4W is also explored.
      Ipilimumab was evaluated over a 0.3 to 10 mg/kg dose range with no difference in increase in activated HLA-DR+ CD4+ and CD8+T cells with 3 mg/kg or 10 mg/kg, with a terminal half-life of approximately 15 days.
      • Feng Y.
      • Masson E.
      • Dai D.
      • Parker S.M.
      • Berman D.
      • Roy A.
      Model-based clinical pharmacology profiling of ipilimumab in patients with advanced melanoma.
      Nevertheless, a dose-dependent RR and immune-related (ir)-AE increase was observed from the CA184-022 melanoma trial.
      • Wolchok J.D.
      • Neyns B.
      • Linette G.
      • et al.
      Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study.
      Therefore, in phase 3 clinical trials in NSCLC, the dosage of 1 mg/kg every 6 weeks has been adopted as the standard.
      • Hellmann M.D.
      • Paz-Ares L.
      • Bernabe Caro R.
      • et al.
      Nivolumab plus ipilimumab in advanced non-small-cell lung cancer.

      Expert Perspective

      PK data and flat E-R relationships for efficacy and safety reported comparable risk-benefit profile with ICIs for flat dose and dose by mg/kg leading to FDA and European Medicines Agency approvals. Nevertheless, it should be noted that using a flat dose of ICIs instead of personalizing the dose to the patient’s body weight results in an excess of 25% to 40% in drug dose, and hence a 25% increase in drug costs.
      • 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?.
      Accurate well-designed pharmacoeconomic studies are clearly warranted in the setting of well-recognized variables.

      Clinical Studies With ICIs in First-Line Setting

      Clinical Trials With Prospective Biomarker Selection

      With the exception of the CheckMate 227 and NEPTUNE trials, which implemented an additional primary efficacy end point on the basis of tissue TMB (tTMB) or blood TMB (bTMB), so far, PD-L1 expression has been used as the main selection marker in the first-line setting. As different IHC assays can be used for assessing PD-L1 expression, an industrial-academic collaborative partnership was launched to provide information on the analytical and clinical comparability of four PD-L1 IHC assays used in clinical trials. The Blueprint phase 2 PD-L1 IHC Assay Comparison Project revealed that three of the five IHC assays for assessing PD-L1 expression were closely aligned on tumor cell staining (22C3, 28-8, and SP263 assays), whereas the SP142 assay exhibited fewer stained tumor cells overall and higher sensitivity with the 73-10 assay to detect PD-L1 expression on TCs.
      • Tsao M.S.
      • Kerr K.M.
      • Kockx M.
      • et al.
      PD-L1 immunohistochemistry comparability study in real-life clinical samples: results of blueprint phase 2 project.
      For patients with PD-L1–positive tumors, no survival benefit with upfront nivolumab or atezolizumab compared with CT has been reported in the CheckMate 026
      • Carbone D.P.
      • Reck M.
      • Paz-Ares L.
      • et al.
      First-line nivolumab in stage IV or recurrent non-small-cell lung cancer.
      or IMpower 110 trials,
      • Spigel D.
      • de Marinis F.
      • Giaccone G.
      • et al.
      IMpower110: interim overall survival (OS) analysis of a phase III study of atezolizumab (atezo) vs platinum-based chemotherapy (chemo) as first-line (1L) treatment (TX) in PD-L1–selected NSCLC.
      respectively, with only a significant survival improvement with atezolizumab limited to tumors with high PD-L1 expression.
      • Spigel D.
      • de Marinis F.
      • Giaccone G.
      • et al.
      IMpower110: interim overall survival (OS) analysis of a phase III study of atezolizumab (atezo) vs platinum-based chemotherapy (chemo) as first-line (1L) treatment (TX) in PD-L1–selected NSCLC.
      Conversely, the KEYNOTE 042 trial reported a significant improvement in OS for pembrolizumab monotherapy in an equally selected population, mostly generated in the subgroup of patients with high PD-L1 expression (≥50%).
      • Mok T.S.K.
      • Wu Y.L.
      • Kudaba I.
      • 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.
      In the KEYNOTE 024 trial, a significant benefit with first-line pembrolizumab compared with CT was revealed by using a higher selection threshold, PD-L1 greater than or equal to 50%
      • Reck M.
      • Rodríguez-Abreu D.
      • Robinson A.G.
      • 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.
      ,
      • Reck M.
      • Rodríguez-Abreu D.
      • Robinson A.G.
      • et al.
      Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer.
      (Table 1). Of note, in an additional retrospective analysis, the outcome with first-line treatment with pembrolizumab is higher with higher PD-L1 expression, especially among tumors with PD-L1 expression greater than or equal to  90%, suggesting that PD-L1 expression level has implications for treatment selection and clinical trial interpretation.
      • Aguilar E.J.
      • Ricciuti B.
      • Gainor J.F.
      • et al.
      Outcomes to first-line pembrolizumab in patients with non-small cell lung cancer and very high PD-L1 expression.
      Table 1Clinical Trials Testing Immune Checkpoint Inhibitors in the First-Line Setting in Patients With Advanced NSCLC
      TrialNTreatment ArmsRR (%)Median PFS (mo)

      HR; 95% CI
      Median OS (mo)

      HR; 95% CI
      KEYNOTE 024
      • Reck M.
      • Rodríguez-Abreu D.
      • Robinson A.G.
      • 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.


      PD-L1 ≥ 50%
      350Pembrolizumab

      Chemotherapy
      45 vs. 2810.3 vs. 6.0

      HR 0.5; 0.37–0.68
      30.0 vs. 14.2

      HR 0.63; 0.47–0.86
      KEYNOTE 042
      • Mok T.S.K.
      • Wu Y.L.
      • Kudaba I.
      • 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.


      PD-L1 ≥ 1%
      1274Pembrolizumab

      Chemotherapy
      27 vs. 275.4 vs. 6.5

      HR 1.07; 0.94–1.21
      16.7 vs. 12.1

      HR 0.81; 0.71–0.93
      CheckMate 026
      • Carbone D.P.
      • Reck M.
      • Paz-Ares L.
      • et al.
      First-line nivolumab in stage IV or recurrent non-small-cell lung cancer.


      PD-L1 ≥ 5%
      423Nivolumab

      Chemotherapy
      26 vs. 334.2 vs. 5.9

      HR 1.15; 0.91–1.45
      14.4 vs. 13.2

      HR 1.02; 0.80–1.30
      IMPOWER 110
      • Spigel D.
      • de Marinis F.
      • Giaccone G.
      • et al.
      IMpower110: interim overall survival (OS) analysis of a phase III study of atezolizumab (atezo) vs platinum-based chemotherapy (chemo) as first-line (1L) treatment (TX) in PD-L1–selected NSCLC.


      PD-L1 ≥ 1% TC or IC
      554Atezolizumab

      Chemotherapy
      29 vs. 325.7 vs. 5.5

      HR 0.77; 0.63–0.94
      17.5 vs. 14.1

      HR 0.83; 0.65–1.07
      MYSTIC
      • Rizvi N.A.
      • Cho B.C.
      • Reinmuth N.
      • et al.
      Durvalumab with or without tremelimumab vs platinum-based chemotherapy as first-line treatment for metastatic non-small cell lung cancer: MYSTIC.


      PD-L1 ≥ 25%
      488Durvalumab

      Durvalumab + Tremelimumab

      Chemotherapy
      36 vs. 34 vs. 384.7

      HR 0.87; 0.59–1.3

      3.9

      HR 1.05; 0.72–1.53

      5.4
      16.3

      HR 0.76; 0.56–1.02

      11.9

      HR 0.85; 0.61–1.17

      12.9
      CheckMate 227
      • Hellmann M.D.
      • Paz-Ares L.
      • Bernabe Caro R.
      • et al.
      Nivolumab plus ipilimumab in advanced non-small-cell lung cancer.


      PD-L1 ≥ 1%
      1189Nivolumab + Ipilimumab

      Chemotherapy

      Nivolumab
      36 vs. 30 vs. 285.1

      HR 0.82; 0.69–0.97

      5.6

      4.2, HR 0.84; 0.75–1.17
      17.1

      HR 0.79; 0.65–0.96

      14.9

      15.7, HR 0.88; 0.75–1.04
      CheckMate 227
      • Hellmann M.D.
      • Ciuleanu T.E.
      • Pluzanski A.
      • et al.
      Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden.


      TMB-High
      10 Mut/Mb.
      399Nivolumab + Ipilimumab

      Chemotherapy
      45 vs. 277.2 vs. 5.5

      HR 0.58; 0.41–0.81
      23.03 vs. 16.72

      HR 0.77; 0.56–1.06
      B-F1RST
      • Socinski M.
      • Velcheti V.
      • Mekhail T.
      • et al.
      Final efficacy results from B-F1RST, a prospective phase II trial evaluating blood-based tumour mutational burden (bTMB) as a predictive biomarker for atezolizumab (atezo) in 1L non-small cell lung cancer (NSCLC).
      bTMB high vs. low
      High: >16 Mut/Mb and Low: <16 Mut/Mb.
      28 vs. 91Atezolizumab28.6 vs. 4.45.0 vs. 3.5

      HR 0.80; 0.54–1.18
      23.9 vs. 13.40

      HR 0.66; 0.40–1.10
      KEYNOTE189
      • Gandhi L.
      • Rodríguez-Abreu D.
      • Gadgeel S.
      • et al.
      Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer.
      ,
      • Gadgeel S.M.
      • Rodríguez-Abreu D.
      • Speranza G.
      • et al.
      Updated analysis from KEYNOTE-189: pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic nonsquamous non-small-cell lung cancer.


      All comers
      616Pembrolizumab + Platinum + Pem

      Platinum + Pem
      48 vs. 199.0 vs. 4.9

      HR 0.48; 0.40–0.58
      22 vs. 10.7

      HR 0.56 0.45–0.70
      IMPOWER 150
      • Socinski M.A.
      • Jotte R.M.
      • Cappuzzo F.
      • et al.
      Overall survival (OS) analysis of IMpower150, a randomized Ph 3 study of atezolizumab (atezo) + chemotherapy (chemo) ± bevacizumab (bev) vs chemo + bev in 1L nonsquamous (NSQ) NSCLC.


      All comers/ITT-WT
      Only reported arm B vs .arm C.
      696BVZ + Atezolizumab + Carbo + P

      BVZ + Carbo + P
      56 vs. 418.3 vs. 6.8

      HR 0.59; 0.50–0.70
      19.2 vs. 14.7

      HR 0.78; 0.69–0.96
      IMPOWER 130
      • West H.
      • McCleod M.
      • Hussein M.
      • et al.
      Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial.


      All comers/ITT-WT
      679Atezolizumab + Carbo + nP

      Carbo + nabP
      49 vs. 327.0 vs. 5.5

      HR 0.64; 0.54–0.77
      18.6 vs. 13.9

      HR 0.79; 0.64–0.98
      IMPOWER 132
      • Barlesi F.
      • Nishio M.
      • Cobo M.
      • et al.
      IMpower132: efficacy of atezolizumab (atezo) + carboplatin (carbo)/cisplatin (cis) + pemetrexed (pem) as 1L treatment in key subgroups with stage IV non-squamous non-small cell lung cancer (NSCLC).


      All comers
      578Atezolizumab + Platinum + Pem

      Platinum + Pem
      --7.6 vs. 5.2

      HR 0.60; 0.49–0.72
      18.1 vs. 13.6

      HR 0.84; 0.64–1.03
      KEYNOTE 407
      • Paz-Ares L.
      • Luft A.
      • Vicente D.
      • et al.
      Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer.


      All comers
      559Pembrolizumab + Carbo + P/nP

      Carbo + P/nP
      58 vs. 386.4 vs. 4.8

      HR 0.56; 0.45–0.70
      15.9 vs. 11.3

      HR 0.64; 0.49–0.85
      IMPOWER 131
      • Jotte R.
      • Cappuzzo F.
      • Vynnychenko I.
      • et al.
      OA14.02 IMpower131: final OS results of carboplatin + nab-paclitaxel ± atezolizumab in advanced squamous NSCLC.


      All comers
      Intention to treat population.
      683Atezolizumab + Carbo + nP

      Carbo + nP
      49.7 vs. 416.5 vs. 5.6

      HR 0.75; 0.64–0.88
      14.2 vs. 13.5

      HR 0.88; 0.73–1.05
      PD-L1, programmed death ligand-1; RR, response rate; PFS, progression-free survival; CI, confidence interval; HR, hazard ratio; OS, overall survival; TMB, tumor mutation burden; bTMB, blood TMB; TC, thymic carcinomas; pem, pemetrexed; Carbo; carboplatin; ITT, intention to treat; BVZ, bevacizumab; P, paclitaxel; nP, nab-paclitaxel; ITT-WT, intention to treat wild-type population.
      a 10 Mut/Mb.
      b High: >16 Mut/Mb and Low: <16 Mut/Mb.
      c Only reported arm B vs .arm C.
      d Intention to treat population.
      In the MYSTIC trial, no significant survival improvement was found for the combination of durvalumab plus tremelimumab compared with that for CT, and, for durvalumab compared with that for CT, in a PD-L1–positive population (PD-L1 ≥ 25%). Nevertheless, a retrospective exploratory revealed a survival benefit for the immunotherapy combination, not with durvalumab monotherapy, only for patients with high bTMB (defined by both >16 mutations per megabase [Mut/Mb]
      • Rizvi N.A.
      • Cho B.C.
      • Reinmuth N.
      • et al.
      Durvalumab with or without tremelimumab vs platinum-based chemotherapy as first-line treatment for metastatic non-small cell lung cancer: MYSTIC.
      or ≥20 Mut/Mb
      • Peters S.
      • Cho B.C.
      • Reinmuth N.
      • et al.
      Tumor mutational burden (TMB) as a biomarker of survival in metastatic non-small cell lung cancer (mNSCLC): blood and tissue TMB analysis from MYSTIC, a phase III study of first-line durvalumab ± tremelimumab vs chemotherapy.
      ).
      The tTMB has been used as a prospective biomarker for progression-free survival (PFS), one of the two coprimary end points in the CheckMate 227 study, which compared the combination of nivolumab and ipilimumab with platinum-based CT.
      • Hellmann M.D.
      • Ciuleanu T.E.
      • Pluzanski A.
      • et al.
      Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden.
      In the group of patients with high tTMB (defined by ≥10 Mut/Mb, which counted for 44.2% of evaluable patients), the combination arm compared with CT had a significant PFS benefit (7.2 mo versus 5.5 mo; hazard ratio [HR] 0.58, 75% confidence interval [CI]: 0.41–0.81) and an improvement in overall RR (ORR) (45.3% versus 26.9%), whereas no PFS difference was reported in patients with low TMB < 10 mut/Mb (HR 1.07, 95% CI: 0.84–1.35).
      • Hellmann M.D.
      • Ciuleanu T.E.
      • Pluzanski A.
      • et al.
      Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden.
      Recently, the coprimary end point of the study (OS in PD-L1 ≥ 1%) has been met, with nivolumab plus ipilimumab combination associated with a significant improvement in OS compared with that in CT (17.2 mo versus 12.2 mo; HR 0.62, 95% CI: 0.48–0.78). This benefit occurred for populations with PD-L1 greater than or equal to 1% (HR 0.79, 95% CI: 0.65–0.96) and PD-L1 less than 1% (HR 0.62, 95% CI: 0.49–0.79). There were no differences in HR between both tTMB cutoffs assessed (high: HR 0.68, 95% CI: 0.51–0.91; or low: HR 0.75, 95% CI: 0.59–0.94), thus questioning the predictive role for tTMB as a biomarker.
      • Hellmann M.D.
      • Paz-Ares L.
      • Bernabe Caro R.
      • et al.
      Nivolumab plus ipilimumab in advanced non-small-cell lung cancer.
      The prospective B-F1RST trial reported higher ORR and longer PFS and OS with atezolizumab in tumors with high (≥16 Mut/Mb) versus low bTMB (Table 1).
      • Socinski M.
      • Velcheti V.
      • Mekhail T.
      • et al.
      Final efficacy results from B-F1RST, a prospective phase II trial evaluating blood-based tumour mutational burden (bTMB) as a predictive biomarker for atezolizumab (atezo) in 1L non-small cell lung cancer (NSCLC).
      A confirmatory phase 3 study (BFAST, NCT03178552) is currently ongoing and recruiting patients. The phase III NEPTUNE trial compared the combination of durvalumab and tremelimumab versus CT in the first-line treatment, including patients with a high bTMB (≥20 Mut/Mb) in the primary analysis population. Nevertheless, the trial did not meet the OS primary end point. The predictive biomarker role of TMB remains a challenge in the absence of prospective validation for survival. In contrast to these difficulties, high TMB has been recently reported as a potential biomarker for assessing patients’ risk of ir-AEs during anti–PD-1 therapy.
      • Bomze D.
      • Hasan Ali O.
      • Bate A.
      • Flatz L.
      Association between immune-related adverse events during anti-PD-1 therapy and tumor mutational burden.
      Nevertheless, a potential bias may exist as high TMB correlates with RR, and these patients may have been under treatment for longer time, potentially increasing the ir-AE rates.

      Expert Perspective

      Currently, a high level of PD-L1 expression (≥50% or above) is the only standard predictive marker for ICI efficacy as monotherapy in the first-line setting. There is a clear need for prospective well-defined studies to assess the predictive role of PD-L1, tTMB, bTMB, or any other proposed biomarker of ICI combination efficacy once a solid definition and reproducibility of selected cutoff points has been established.

      Clinical Trials Without Any Biomarker Selection

      The KEYNOTE 021 trial was the first phase II randomized study reporting improved outcome (ORR: 56.7% versus 30.2%; PFS: 24.0 mo versus 9.3 mo; and OS: not reported versus 21.0 mo) with upfront pembrolizumab-CT combinations in unselected patients with nonsquamous advanced NSCLC compared with CT alone (carboplatin plus pemetrexed).
      • Borghaei H.
      • Langer C.J.
      • Gadgeel S.
      • et al.
      24-month overall survival from KEYNOTE-021 cohort G: pemetrexed and carboplatin with or without pembrolizumab as first-line therapy for advanced nonsquamous non-small cell lung cancer.
      These results were confirmed by the phase III KEYNOTE 189 trial
      • Gandhi L.
      • Rodríguez-Abreu D.
      • Gadgeel S.
      • et al.
      Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer.
      in all PD-L1 subsets, even PD-L1–negative tumors
      • Gadgeel S.M.
      • Rodríguez-Abreu D.
      • Speranza G.
      • et al.
      Updated analysis from KEYNOTE-189: pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic nonsquamous non-small-cell lung cancer.
      (Table 1), and regardless of tTMB.
      • Paz-Ares L.
      • Langer C.J.
      • Novello S.
      • et al.
      Pembrolizumab (pembro) plus platinum-based chemotherapy (chemo) for metastatic NSCLC: tissue TMB (TTMB) and outcomes in KEYNOTE-021, 189, and 407.
      Other phase III trials in a similar patient population are IMpower 132
      • Barlesi F.
      • Nishio M.
      • Cobo M.
      • et al.
      IMpower132: efficacy of atezolizumab (atezo) + carboplatin (carbo)/cisplatin (cis) + pemetrexed (pem) as 1L treatment in key subgroups with stage IV non-squamous non-small cell lung cancer (NSCLC).
      and IMpower 130
      • West H.
      • McCleod M.
      • Hussein M.
      • et al.
      Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial.
      with atezolizumab combined with platinum-pemetrexed or nab-paclitaxel, respectively, and the three-arm IMpower 150 phase III trial comparing carboplatin, paclitaxel, and bevacizumab (BCP) to carboplatin, paclitaxel, and atezolizumab (ACP) or carboplatin, paclitaxel, bevacizumab, and atezolizumab (ABCP).
      • Socinski M.A.
      • Jotte R.M.
      • Cappuzzo F.
      • et al.
      Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC.
      ,
      • Socinski M.A.
      • Jotte R.M.
      • Cappuzzo F.
      • et al.
      Overall survival (OS) analysis of IMpower150, a randomized Ph 3 study of atezolizumab (atezo) + chemotherapy (chemo) ± bevacizumab (bev) vs chemo + bev in 1L nonsquamous (NSQ) NSCLC.
      The ABCP arm significantly improved the PFS and OS compared with the BCP arm (Table 1), but the ACP arm did not reach significant survival benefit compared with the BCP arm (HR: 0.88; 95% CI: 0.78–1.08; p = 0.2041).
      • Socinski M.A.
      • Jotte R.M.
      • Cappuzzo F.
      • et al.
      Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC.
      ,
      • Socinski M.A.
      • Jotte R.M.
      • Cappuzzo F.
      • et al.
      Overall survival (OS) analysis of IMpower150, a randomized Ph 3 study of atezolizumab (atezo) + chemotherapy (chemo) ± bevacizumab (bev) vs chemo + bev in 1L nonsquamous (NSQ) NSCLC.
      In squamous histology, the addition of atezolizumab to CT did not improve OS of patients enrolled in the IMpower 131 trial, except for those with high tumor PD-L1 expression.
      • Jotte R.M.
      • Cappuzzo F.
      • Vynnychenko I.
      • et al.
      IMpower131: primary PFS and safety analysis of a randomized phase III study of atezolizumab + carboplatin + paclitaxel or nab-paclitaxel vs carboplatin + nab-paclitaxel as 1L therapy in advanced squamous NSCLC.
      ,
      • Jotte R.
      • Cappuzzo F.
      • Vynnychenko I.
      • et al.
      OA14.02 IMpower131: final OS results of carboplatin + nab-paclitaxel ± atezolizumab in advanced squamous NSCLC.
      Conversely, in the KEYNOTE 407 study,
      • Paz-Ares L.
      • Luft A.
      • Vicente D.
      • et al.
      Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer.
      the addition of pembrolizumab significantly improved the outcome compared with CT alone (Table 1) regardless of PD-L1 expression, and this combination is the only combination approved in the first-line setting for advanced squamous NSCLC. The CheckMate 227 trial (part 2), assessing the addition of nivolumab to first-line platinum-based CT, did not meet the primary end point of OS benefit in treatment-naive patients with nonsquamous histology.
      • Paz-Ares L.
      • Ciuleanu T.E.
      • Yu X.
      • et al.
      LBA3 nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo as first-line (1L) treatment (tx) for advanced non-small cell lung cancer (aNSCLC): CheckMate 227 - part 2 final analysis.
      Finally, press releases about two phase III clinical trials in all histologies and full range of PD-L1 expression level have reported to achieve the primary end point, the CheckMate 9LA trial (NCT03215706, assessing nivolumab plus ipilimumab and platinum-based CT versus CT) and the POSEIDON trial (NCT03164616, assessing CT plus durvalumab with and without ipilimumab versus CT).

      Expert Perspective

      Although there is evidence indicating that immunotherapy in combination with CT is superior to CT alone in the first-line treatment for patients with advanced NSCLC, regardless of PD-L1 expression, there is no current evidence of the superiority of CT and ICI combination over ICI alone in patients with high PD-L1 expression (≥50%). Upfront use of ICIs in druggable oncogene-driven tumors must be discouraged, and in patients with advanced-stage disease, ICI should not be initiated without complete information about routine genomic alterations (at least EGFR, ALK, ROS1, and BRAF status).

      Long-Term Survival With ICIs

      Early success with PD-1 axis inhibitors has translated into long-term survival in approximately 15% of patients with advanced NSCLC. Five-year OS data are now available for four trials that evaluated PD-1 axis inhibitors.
      • Garon E.B.
      • Hellmann M.D.
      • Rizvi N.A.
      • et al.
      Five-year overall survival for patients with advanced non‒small-cell lung cancer treated with pembrolizumab: results from the phase I KEYNOTE-001 study.
      • Antonia S.J.
      • Borghaei H.
      • Ramalingam S.S.
      • et al.
      Four-year survival with nivolumab in patients with previously treated advanced non-small-cell lung cancer: a pooled analysis.
      ,
      • Gettinger S.
      • Horn L.
      • Jackman D.
      • et al.
      Five-year follow-up of nivolumab in previously treated advanced non-small-cell lung cancer: results from the CA209-003 study.
      ,
      • Gettinger S.
      • Borghaei H.
      • Brahmer J.
      • et al.
      OA14.04 five-year outcomes from the randomized, phase 3 trials CheckMate 017/057: nivolumab vs docetaxel in previously treated NSCLC.
      The CheckMate 003 trial evaluated a 2-year administration of nivolumab monotherapy in patients with pretreated advanced NSCLC. With a minimum follow-up of 75 months, the 6-year survival rate among 129 patients was 15%, whereas the 5-year PFS rate was 5.3%. Of the 22 patients with response by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1 criteria (17.1%), median duration of response was 19.1 months, and 50% of these patients had ongoing response at 5 years.
      • Topalian S.L.
      • Hodi F.S.
      • Brahmer J.R.
      • et al.
      Five-year survival and correlates among patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer treated with nivolumab.
      ,
      • Gettinger S.
      • Horn L.
      • Jackman D.
      • et al.
      Five-year follow-up of nivolumab in previously treated advanced non-small-cell lung cancer: results from the CA209-003 study.
      In the CheckMate 057 and 017, with minimum follow-up of 50 months, pooled 5-year survival rate among 427 patients treated with nivolumab was 13.4%,
      • Gettinger S.
      • Borghaei H.
      • Brahmer J.
      • et al.
      OA14.04 five-year outcomes from the randomized, phase 3 trials CheckMate 017/057: nivolumab vs docetaxel in previously treated NSCLC.
      and 5-year PFS rate was 8%. Of the 84 patients with response by the RECIST version 1.1, median duration of response was 19.9 months, with 32.2% of responders experiencing ongoing response at 5 years. Among 101 previously untreated and 449 pretreated patients who received pembrolizumab until progression in the phase 1 KEYNOTE 001 trial, 5-year survival rates were 23.2% and 15.5%, respectively, with minimum follow-up of 60.6 months.
      • Garon E.B.
      • Hellmann M.D.
      • Rizvi N.A.
      • et al.
      Five-year overall survival for patients with advanced non‒small-cell lung cancer treated with pembrolizumab: results from the phase I KEYNOTE-001 study.
      Of the 42 previously untreated and 103 treated responders (as assessed by immune-related response criteria, irRC), median duration of response was 16.8 months and 38.9 months, with 43% and 59% of responders alive and in response at 5 years, respectively. Late-onset toxicities associated with PD-1 axis inhibitor therapy were rare in those trials, with one report of grade 3 to 4 treatment-related AEs (tr-AEs) among the CheckMate 057 and 017 trials
      • Gettinger S.
      • Borghaei H.
      • Brahmer J.
      • et al.
      OA14.04 five-year outcomes from the randomized, phase 3 trials CheckMate 017/057: nivolumab vs docetaxel in previously treated NSCLC.
      and three grade of 3 or higher positive tr-AEs after 3 years in the KEYNOTE 001 trial (hypertension, glucose intolerance, and hypersensitivity reaction; all grade 3 and resolved). Achievement of response by the RECIST criteria on ICI and PD-L1 expression was associated with greatly improved OS.
      • Antonia S.J.
      • Borghaei H.
      • Ramalingam S.S.
      • et al.
      Four-year survival with nivolumab in patients with previously treated advanced non-small-cell lung cancer: a pooled analysis.
      ,
      • Gettinger S.
      • Borghaei H.
      • Brahmer J.
      • et al.
      OA14.04 five-year outcomes from the randomized, phase 3 trials CheckMate 017/057: nivolumab vs docetaxel in previously treated NSCLC.

      Expert Perspective

      ICIs have reported 5-year OS of 15% and 23% as second- and first-line treatment, respectively, in PD-L1 unselected populations. PD-L1 expression and response to ICI are prognostic factors for improved outcome. Well-curated, real-world data are needed to confirm those figures in the context of efficacy-toxicity assessment.

      Immunologic Cell Death Agents

      Immunologic cell death (ICD) is a type of regulated cell death that can activate an adaptive immune response stimulating recruitment of CD8+ T cells to the tumor.
      • Rapoport B.L.
      • Anderson R.
      Realizing the clinical potential of immunogenic cell death in cancer chemotherapy and radiotherapy.
      • Gerber H.P.
      • Sapra P.
      • Loganzo F.
      • May C.
      Combining antibody-drug conjugates and immune-mediated cancer therapy: what to expect?.
      • Kroemer G.
      • Galluzzi L.
      • Kepp O.
      • Zitvogel L.
      Immunogenic cell death in cancer therapy.
      • Krysko D.V.
      • Garg A.D.
      • Kaczmarek A.
      • Krysko O.
      • Agostinis P.
      • Vandenabeele P.
      Immunogenic cell death and DAMPs in cancer therapy.
      • Bezu L.
      • Gomes-de-Silva L.C.
      • Dewitte H.
      • et al.
      Combinatorial strategies for the induction of immunogenic cell death.
      Data suggest that patients who respond better to ICI therapy have higher levels of CD8+ T cells in the tumor before treatment.
      • Gerber H.P.
      • Sapra P.
      • Loganzo F.
      • May C.
      Combining antibody-drug conjugates and immune-mediated cancer therapy: what to expect?.
      Therefore, the development of ICIs has increased interest in ICD because of the potential of improved patient outcomes when combining ICI therapy with agents that induce ICD.
      Agents that trigger ICD generally induce endoplasmic reticulum (ER) stress, which leads to release of damage-associated molecular patterns (DAMPs) that initiate antitumor immune responses.
      • Rapoport B.L.
      • Anderson R.
      Realizing the clinical potential of immunogenic cell death in cancer chemotherapy and radiotherapy.
      Type I inducers, including many anticancer drugs and radiotherapy, lead to ER stress indirectly by generating intracellular oxidative stress.
      • Rapoport B.L.
      • Anderson R.
      Realizing the clinical potential of immunogenic cell death in cancer chemotherapy and radiotherapy.
      Some chemotherapeutic agents, such as cyclophosphamide, mitoxantrone, anthracyclines, oxaliplatin, and the proteasome inhibitor bortezomib, use the combined action of reactive oxygen species (ROS) generation and ER stress to trigger the release of DAMPs, such as calreticulin (CRT), secreted adenosine triphosphate (ATP), high-mobility group box 1 protein (HMGB1), and heat-shock proteins. These DAMPs, through interactions with various receptors, trigger innate host defense mechanisms by recruiting and activating antigen-presenting cells, which drive antitumor CD8+ cytotoxic T-cell reactivity resulting from ICD.
      • Rapoport B.L.
      • Anderson R.
      Realizing the clinical potential of immunogenic cell death in cancer chemotherapy and radiotherapy.
      Many recent clinical trials have reported synergistic effects of immunogenic CT and/or radiation in combination with immunotherapy.
      • Wang Y.J.
      • Fletcher R.
      • Yu J.
      • Zhang L.
      Immunogenic effects of chemotherapy-induced tumor cell death.
      • Serrano-Del Valle A.
      • Anel A.
      • Naval J.
      • Marzo I.
      Immunogenic cell death and immunotherapy of multiple myeloma.
      • Mathew M.
      • Enzler T.
      • Shu C.A.
      • Rizvi N.A.
      Combining chemotherapy with PD-1 blockade in NSCLC.
      Oncolytic viruses and hypericin-based photodynamic therapy target the ER directly through ROS-mediated damage,
      • Rapoport B.L.
      • Anderson R.
      Realizing the clinical potential of immunogenic cell death in cancer chemotherapy and radiotherapy.
      and there is also evidence for the combination of these ICD inducers with immunotherapy. A phase Ib clinical trial using oncolytic virotherapy, specifically talimogene laherparepvec, combined with pembrolizumab improved the efficacy of anti–PD-1 therapy in patients with advanced melanoma.
      • Ribas A.
      • Dummer R.
      • Puzanov I.
      • et al.
      Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy.
      Intratumoral injection of talimogene laherparepvec led to a systemic increase in circulating CD4+ and CD8+ T cells and increased CD8+ T-cell tumor infiltration. The PD-1 and PD-L1 interactions between these T cells and tumors were blocked by pembrolizumab, resulting in increased antitumor activity and leading patients to have high overall and complete RRs.
      • Ribas A.
      • Dummer R.
      • Puzanov I.
      • et al.
      Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy.
      The ongoing phase I MASTERKEY-318 (NCT02509507) trial assesses the intratumoral injection of talimogene laherparepvec in combination with pembrolizumab in patients with primary and metastatic (including NSCLC) liver tumors.
      Ongoing and recently completed trials will help to better understand the efficacy and safety of combining agents that induce ICD along with ICIs in the clinical setting. Several factors limit our current understanding of the relevance of ICD in the clinical setting including challenges in determining dosing, frequency, and combinations of ICD agents, ICIs that are safe and effective, and the lack of appropriate systemic biomarkers to predict ICD efficacy.
      • Rapoport B.L.
      • Anderson R.
      Realizing the clinical potential of immunogenic cell death in cancer chemotherapy and radiotherapy.
      ,
      • Mathew M.
      • Enzler T.
      • Shu C.A.
      • Rizvi N.A.
      Combining chemotherapy with PD-1 blockade in NSCLC.

      Expert Perspective

      Although ICD is a well-defined phenomenon, its contribution in harnessing the human immune system remains unclear. Nowadays, the addition of CT to ICIs is the only combination strategy proven to increase survival in patients with NSCLC in the clinical setting. A deeper understanding of potential benefit/risk ratio derived from ICD-inducing agents and ICI combinations is needed along with a careful immunologic characterization of currently approved anticancer drugs.

      Radiotherapy and ICIs

      Radiation promotes the release of danger signals and chemokines that recruit inflammatory cells into the tumor microenvironment, including antigen-presenting cells that activate cytotoxic T-cell function. By contrast, radiation can also attract immunosuppressive cells into the tumor microenvironment. In rare circumstances, the antitumor effect of radiotherapy has been observed outside of the radiation field, known as the abscopal effect.
      • Weichselbaum R.R.
      • Liang H.
      • Deng L.
      • Fu Y.-X.
      Radiotherapy and immunotherapy: a beneficial liaison?.
      The PACIFIC study is a pivotal randomized phase III study conducted in unresectable stage III NSCLC for assessing the consolidative role of durvalumab administered for 1 year compared with placebo after concurrent radio-CT. This trial randomized 713 patients and reported a significant improvement of both PFS (17.3 mo versus 5.6 mo; HR 0.51, 95% CI: 0.41–0.63) and OS (not reached versus 28.7 mo; HR 0.68, 99.73% CI: 0.47–0.997) in the durvalumab arm compared with placebo. The benefit was particularly pronounced among those patients who started durvalumab less than 14 days from previous radiation dose, suggesting better baseline prognostic patients. The OS benefit was observed across almost all of the prespecified subgroups. Nevertheless, in 292 patients with PD-L1 status less than or equal to 25%, the HR for death was 0.92 (95% CI: 0.63–1.34), whereas in 301 patients who had received carboplatin as the previous CT, the HR for death was 0.86 (95% CI: 0.60–1.23). In a post hoc, exploratory subgroup analysis, HR for progression or death was 0.73 (95% CI: 0.48–1.11) and 1.36 (95%CI: 0.79–2.34) in 148 (21% of randomized patients) patients whose tumors did not express PD-L1 (≤1%). To date, the clinical benefit of durvalumab in patients with PD-L1–negative NSCLC is controversial.
      • Antonia S.J.
      • Villegas A.
      • Daniel D.
      • et al.
      Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC.
      ,
      • Peters S.
      • Dafni U.
      • Boyer M.
      • et al.
      Position of a panel of international lung cancer experts on the approval decision for use of durvalumab in stage III non-small-cell lung cancer (NSCLC) by the Committee for Medicinal Products for Human Use (CHMP).
      Further studies are needed to evaluate the role of ICIs in tumors with PD-L1 of less than 1%.
      The next step involves evaluating the concurrent administration of ICIs with radiotherapy. Different studies are currently assessing this approach, and results from the NICOLAS trial investigating the safety of nivolumab concurrent with chemoradiation has reported no grade of 3 or higher pneumonitis by the end of the 3-month postradiotherapy follow-up period in the first 21 patients, and no unexpected AEs or increased toxicities were observed.
      • Peters S.
      • Felip E.
      • Dafni U.
      • et al.
      Safety evaluation of nivolumab added concurrently to radiotherapy in a standard first line chemo-radiotherapy regimen in stage III non-small cell lung cancer-the ETOP NICOLAS trial.
      Radiotherapy may have positive immune effects including tumor antigen release followed by presentation to DCs that activate the immune system and modulate the tumor microenvironment. Several retrospective and prospective studies of radiotherapy and ICI suggested increased distant response in sites other than the irradiated field.
      • Chicas-Sett R.
      • Morales-Orue I.
      • Castilla-Martinez J.
      • et al.
      Stereotactic ablative radiotherapy combined with immune checkpoint inhibitors reboots the immune response assisted by immunotherapy in metastatic lung cancer: a systematic review.
      A phase II trial of pembrolizumab after local ablative therapy (LAT), including operation or stereotactic radiotherapy in patients with oligometastatic NSCLC (≤4 metastatic sites), resulted in encouraging PFS of 19.1 months after LAT, with acceptable toxicities and no reduction in quality of life.
      • Bauml J.M.
      • Mick R.
      • Ciunci C.
      • et al.
      Pembrolizumab after completion of locally ablative therapy for oligometastatic non-small cell lung cancer: a phase 2 trial.
      Randomized phase II trial of pembrolizumab with or without stereotactic body radiotherapy in patients with advanced NSCLC failed to meet predefined end point criteria (ORR: 50% versus 20%) and reported encouraging results of overall response (18% versus 36%), median PFS (1.9 mo versus 6.6 mo), and median OS (7.6 mo versus 15.9 mo).
      • Theelen W.S.M.E.
      • Peulen H.M.U.
      • Lalezari F.
      • et al.
      Effect of pembrolizumab after stereotactic body radiotherapy vs pembrolizumab alone on tumor response in patients with advanced non-small cell lung cancer: results of the PEMBRO-RT phase 2 randomized clinical trial.
      Randomized phase III trials of ICI with or without RT are warranted in patients with stage IV NSCLC. Optimal treatment sequence, field, volume, dose, and fractionation of radiotherapy should also be evaluated in prospective clinical trials. Further prospective studies are needed to prove clinical meaningful abscopal effect in stage IV NSCLC.

      Expert Perspective

      Durvalumab is a standard of care in the treatment of locally advanced NSCLCs after concurrent chemoradiation. The role of concomitant RT-CT is being evaluated, but further clinical trials with robust hypothesis testing are required to determine the appropriate approach to integrate these modalities for the vast majority of patients with unresectable stage IIIA/B NSCLC. Enhancing innate and adaptive immunities by combining radiotherapy and immunotherapy is a crucial strategy to improve patient survival. Integration of ICI with LAT merits further clinical investigation.

      Treatment Duration

      In phase III clinical trials, the treatment duration varied, ranging from 2 years to until disease progression, and in some of them, until loss of clinical benefit.
      • Reck M.
      • Rodríguez-Abreu D.
      • Robinson A.G.
      • 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.
      • Mok T.S.K.
      • Wu Y.L.
      • Kudaba I.
      • 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.
      • Gandhi L.
      • Rodríguez-Abreu D.
      • Gadgeel S.
      • et al.
      Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer.
      ,
      • West H.
      • McCleod M.
      • Hussein M.
      • et al.
      Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial.
      ,
      • Socinski M.A.
      • Jotte R.M.
      • Cappuzzo F.
      • et al.
      Overall survival (OS) analysis of IMpower150, a randomized Ph 3 study of atezolizumab (atezo) + chemotherapy (chemo) ± bevacizumab (bev) vs chemo + bev in 1L nonsquamous (NSQ) NSCLC.
      Data from phase I clinical trials have reported no differences in long-term survival benefit regardless of treatment duration for a maximum of 2 years with nivolumab
      • Topalian S.L.
      • Hodi F.S.
      • Brahmer J.R.
      • et al.
      Five-year survival and correlates among patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer treated with nivolumab.
      or with pembrolizumab until disease progression,
      • Garon E.B.
      • Hellmann M.D.
      • Rizvi N.A.
      • et al.
      Five-year overall survival for patients with advanced non‒small-cell lung cancer treated with pembrolizumab: results from the phase I KEYNOTE-001 study.
      reaching a 5-year OS of 15% in both trials. Nevertheless, in the exploratory survival data from the CheckMate 153 trial, continuous nivolumab versus 1-year fixed duration in patients without progression prolonged the PFS (HR 0.42, 95% CI: 0.25–0.71) and OS (HR 0.63, 95% CI: 0.33–1.20). This benefit occurred regardless of the best response on treatment.
      • Spigel D.R.
      • McLeod M.
      • Hussein M.A.
      • et al.
      Randomized results of fixed-duration (1-yr) vs continuous nivolumab in patients (pts) with advanced non-small cell lung cancer (NSCLC).
      Although the study design was not adequately powered to address efficacy outcomes (primary end point was safety), these results suggest that stopping treatment after 1 year, regardless of the clinical and radiologic benefits, increases the risk of relapse. Furthermore, a maximum of 2 years on treatment with pembrolizumab was allowed in patients with metastatic NSCLC in the KEYNOTE 024 trial.
      • Reck M.
      • Rodríguez-Abreu D.
      • Robinson A.G.
      • et al.
      OA14.01 KEYNOTE-024 3-year survival update: pembrolizumab vs platinum-based chemotherapy for advanced non–small-cell lung cancer.
      Conversely, in patients with locally advanced NSCLC, the PACIFIC trial reported survival benefit with just 1 year of treatment with durvalumab.
      • Antonia S.J.
      • Villegas A.
      • Daniel D.
      • et al.
      Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC.
      One of the major risks of stopping treatment is disease relapse and the lack of the ability to rescue those patients. Nevertheless, in the advanced setting, rechallenge at PD after completing the maximum number of cycles per protocol revealed a clinical benefit in 70% of patients, but this benefit seems mainly restricted to patients who progress 1 year after stopping previous treatment with ICI and among those previously responsive to ICI.
      • Reck M.
      • Rodríguez-Abreu D.
      • Robinson A.G.
      • et al.
      OA14.01 KEYNOTE-024 3-year survival update: pembrolizumab vs platinum-based chemotherapy for advanced non–small-cell lung cancer.
      ,
      • Herbst R.S.
      • Garon E.B.
      • Kim D.W.
      • et al.
      Long-term survival in patients (pts) with advanced NSCLC in the KEYNOTE-010 study overall and in pts who completed two years of pembrolizumab (pembro).
      Evidence of rechallenge efficacy in other clinical situations remains scarce.
      The lack of knowledge from phase III clinical trials regarding the survivorship of patients undergoing prolonged ICI treatment and the high ICI costs that pose a problem to the sustainability of health care systems present a new challenge in daily clinical practice as physicians decide when to stop ICI and what tools (radiologic, pathologic) should be applied in making this treatment decision.

      Expert Perspective

      The optimal duration of ICI therapy in daily clinical practice remains an open challenge to be addressed. The ideal time to stop ICI and what tools (radiologic, pathologic) could support physicians in this treatment decision are unknown. For patients with metastatic NSCLC who received clinical benefit from ICI, current evidence suggests 2 years as the most robustly recommended treatment duration, whereas IO consolidation for 1 year after chemoradiation is currently recommended as standard of care in locally advanced disease.

      Integration of Immunotherapy Agents in the Early Stage Strategy

      Neoadjuvant Immunotherapy Trials With or Without CT

      In preclinical models, neoadjuvant ICI improved survival and reduced the occurrence of lung metastases compared with adjuvant administration.
      • Cascone T.
      • Hamdi H.
      • Zhang F.
      • et al.
      Superior efficacy of neoadjuvant compared to adjuvant immune checkpoint blockade in non-small cell lung cancer.
      Several studies have assessed the feasibility and safety of neoadjuvant ICI in NSCLC, including the pivotal study by Forde et al.
      • Forde P.M.
      • Chaft J.E.
      • Smith K.N.
      • et al.
      Neoadjuvant PD-1 blockade in resectable lung cancer.
      that assessed single-agent nivolumab, the phase I MK3475-223, the phase II LCMC3, and the IONESCO (NCT03030131) trials, which evaluated pembrolizumab,
      • Bar J.
      • Urban D.
      • Ofek E.
      • et al.
      Neoadjuvant pembrolizumab (pembro) for early stage non-small cell lung cancer (NSCLC): updated report of a phase I study, MK3475-223.
      atezolizumab,
      • Kwiatkowski D.J.
      • Rusch V.W.
      • Chaft J.E.
      • et al.
      Neoadjuvant atezolizumab in resectable non-small cell lung cancer (NSCLC): interim analysis and biomarker data from a multicenter study (LCMC3).
      and durvalumab, respectively. The NEOSTAR phase II study
      • Cascone T.
      • William W.N.
      • Weissferdt A.
      • et al.
      Neoadjuvant nivolumab (N) or nivolumab plus ipilimumab (NI) for resectable non-small cell lung cancer (NSCLC): clinical and correlative results from the NEOSTAR study.
      investigated nivolumab or the combination of nivolumab and ipilimumab as neoadjuvant strategy in early stage NSCLC. More recently, the anti–PD-1 antibody sintilimab was evaluated in the same population

      Gao S, Li N, Gao S, et al. Neoadjuvant PD-1 inhibitor (Sintilimab) in NSCLC [e-pub ahead of print]. J Thorac Oncol. https://doi.org/10.1016/j.jtho.2020.01.017. Accessed April 6, 2020.

      (Table 2). One of the challenging findings of these trials was the use of major pathologic response (MPR), defined as less than or equal to 10% of residual viable tumor after neoadjuvant treatment, as a potential surrogate of efficacy. MPR was previously defined with neoadjuvant CT, but its value as a surrogate marker of immunotherapy efficacy remains uncertain. Recently, pathologic response criteria have been developed to standardize pathologic assessment of immunotherapy activity.
      • Cottrell T.R.
      • Thompson E.D.
      • Forde P.M.
      • et al.
      Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC).
      In tumors with MPR after PD-1 blockade, new infiltration with PD-1–positive CD8+ T cells was reported, a finding that was consistent with an adaptive PD-L1 up-regulation mechanism.
      • Forde P.M.
      • Chaft J.E.
      • Smith K.N.
      • et al.
      Neoadjuvant PD-1 blockade in resectable lung cancer.
      Table 2Clinical Trials With Neoadjuvant Immune Checkpoint Inhibitors With or Without Chemotherapy in Early Stage NSCLC
      TrialStagesNDrugSq. (%)Non-Sq. (%)Surgery (%)RECIST ORR (%)MPR (%)pCR (%)
      Forde et al.
      • Forde P.M.
      • Chaft J.E.
      • Smith K.N.
      • et al.
      Neoadjuvant PD-1 blockade in resectable lung cancer.
      IB–IIIA21Nivolumab 3 mg/kg Q2W two cycles296295104515
      MK3475-223
      • Bar J.
      • Urban D.
      • Ofek E.
      • et al.
      Neoadjuvant pembrolizumab (pembro) for early stage non-small cell lung cancer (NSCLC): updated report of a phase I study, MK3475-223.
      I–II15Pembrolizumab 200 mg Q3W464687NR3115
      LCMC3
      • Kwiatkowski D.J.
      • Rusch V.W.
      • Chaft J.E.
      • et al.
      Neoadjuvant atezolizumab in resectable non-small cell lung cancer (NSCLC): interim analysis and biomarker data from a multicenter study (LCMC3).
      IB–IIIB101/180
      Recruitment ongoing.
      Atezolizumab 1200 mg Q3W two cycles3565897195
      NEOSTAR
      MPR and pCR reported in NEOSTAR trial are intention to treat.
      ,
      • Cascone T.
      • William W.N.
      • Weissferdt A.
      • et al.
      Neoadjuvant nivolumab (N) or nivolumab plus ipilimumab (NI) for resectable non-small cell lung cancer (NSCLC): clinical and correlative results from the NEOSTAR study.
      I–IIIA (N2 single)23Nivolumab 3 mg/kg Q2W three cycles43579622179
      21Nivolumab 3 mg/kg Q2W three cycles

      Ipilimumab 1 mg/kg D1
      336281193329
      Gao

      Gao S, Li N, Gao S, et al. Neoadjuvant PD-1 inhibitor (Sintilimab) in NSCLC [e-pub ahead of print]. J Thorac Oncol. https://doi.org/10.1016/j.jtho.2020.01.017. Accessed April 6, 2020.

      IB–IIIA40Sintilimab 200 mg Q3W two cycles821593204116
      NADIM
      • Provencio M.
      • Nadal E.
      • Insa A.
      • et al.
      OA13.05 NADIM study: updated clinical researc-h and outcomes.
      IIIA (N2 or T4)46Nivolumab (360 mg) + CT
      Platinum-paclitaxel. Adjuvant nivolumab was administered (37 patients received adjuvant nivolumab).
      Q3W three cycles
      356189748359
      Shu et al.
      • Shu C.A.
      • Grigg C.
      • Chiuzan C.
      • et al.
      Neoadjuvant atezolizumab + chemotherapy in resectable non-small cell lung cancer (NSCLC).
      IB–IIIA14/30Atezolizumab 1200 mg + CT
      Platinum-paclitaxel. Adjuvant nivolumab was administered (37 patients received adjuvant nivolumab).
      two cycles
      435779575021
      Sq., squamous; RECIST ORR, Response Evaluation Criteria in Solid Tumors Overall Response Rate (complete response plus partial response); MPR, major pathologic response; pCR, pathologic complete response; CT, chemotherapy; NR, not reported; Q2W every 2 weeks; Q3W, every 3 weeks.
      a Recruitment ongoing.
      b MPR and pCR reported in NEOSTAR trial are intention to treat.
      c Platinum-paclitaxel. Adjuvant nivolumab was administered (37 patients received adjuvant nivolumab).
      Neoadjuvant ICI studies reported MPR ranging from 17% to 45% with a pathologic complete response (pCR) in 5% to 29% of samples (Table 2 and Fig. 1), but response by the RECIST criteria does not capture the ICI effect because the objective responses occur in 7% to 22% of cases. Of note, the risk of progression on ICI was less than 10%, and 90% of tumors were resected.
      • Forde P.M.
      • Chaft J.E.
      • Smith K.N.
      • et al.
      Neoadjuvant PD-1 blockade in resectable lung cancer.
      ,
      • Kwiatkowski D.J.
      • Rusch V.W.
      • Chaft J.E.
      • et al.
      Neoadjuvant atezolizumab in resectable non-small cell lung cancer (NSCLC): interim analysis and biomarker data from a multicenter study (LCMC3).
      ,
      • Cascone T.
      • William W.N.
      • Weissferdt A.
      • et al.
      Neoadjuvant nivolumab (N) or nivolumab plus ipilimumab (NI) for resectable non-small cell lung cancer (NSCLC): clinical and correlative results from the NEOSTAR study.
      Nevertheless, the unpublished IONESCO trial has been recently halted owing to an excess of postoperative deaths.
      Figure thumbnail gr1
      Figure 1Efficacy of neoadjuvant immune checkpoint inhibitors (ICIs) with or without chemotherapy (CT). Ipi, ipilimumab; MPR, major pathologic response; Nivo, nivolumab; NR, not reported; pCR, pathologic complete response; RR, response rate by RECIST.
      Figure thumbnail gr2
      Figure 2Ongoing phase III trials with adjuvant immune checkpoint inhibitor (ICI). ACT, adjuvant chemotherapy; DFS, disease-free survival; ITT, intention to treat; OS, overall survival; PD-L1, programmed death ligand-1; PS, performance status; Q2W, every 2 weeks; Q3W, every 3 weeks; 1 y, 1 year.
      The role of PD-L1 or TMB as predictive biomarkers remains controversial, as in some studies, MPR was observed irrespective of PD-L1 expression
      • Forde P.M.
      • Chaft J.E.
      • Smith K.N.
      • et al.
      Neoadjuvant PD-1 blockade in resectable lung cancer.
      ,
      • Kwiatkowski D.J.
      • Rusch V.W.
      • Chaft J.E.
      • et al.
      Neoadjuvant atezolizumab in resectable non-small cell lung cancer (NSCLC): interim analysis and biomarker data from a multicenter study (LCMC3).
      and TMB
      • Kwiatkowski D.J.
      • Rusch V.W.
      • Chaft J.E.
      • et al.
      Neoadjuvant atezolizumab in resectable non-small cell lung cancer (NSCLC): interim analysis and biomarker data from a multicenter study (LCMC3).
      ; but not in others.
      • Forde P.M.
      • Chaft J.E.
      • Smith K.N.
      • et al.
      Neoadjuvant PD-1 blockade in resectable lung cancer.
      ,
      • Cascone T.
      • William W.N.
      • Weissferdt A.
      • et al.
      Neoadjuvant nivolumab (N) or nivolumab plus ipilimumab (NI) for resectable non-small cell lung cancer (NSCLC): clinical and correlative results from the NEOSTAR study.
      Finally, the role of the combination of ICI (e.g., nivolumab plus ipilimumab) over monotherapy remains unresolved, although the NEOSTAR study suggested higher MPR and pCR with combination compared withmonotherapy.
      • Cascone T.
      • William W.N.
      • Weissferdt A.
      • et al.
      Neoadjuvant nivolumab (N) or nivolumab plus ipilimumab (NI) for resectable non-small cell lung cancer (NSCLC): clinical and correlative results from the NEOSTAR study.
      On the basis of the synergism of ICI with CT in the metastatic setting,
      • Gandhi L.
      • Rodríguez-Abreu D.
      • Gadgeel S.
      • et al.
      Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer.
      ,
      • Paz-Ares L.
      • Luft A.
      • Vicente D.
      • et al.
      Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer.
      this strategy has been also tested as neoadjuvant treatment in early stage NSCLC (Table 2).
      • Provencio M.
      • Nadal E.
      • Insa A.
      • et al.
      OA13.05 NADIM study: updated clinical researc-h and outcomes.
      ,
      • Shu C.A.
      • Grigg C.
      • Chiuzan C.
      • et al.
      Neoadjuvant atezolizumab + chemotherapy in resectable non-small cell lung cancer (NSCLC).
      Despite the limited number of patients enrolled, current data from the NADIM trial (preoperative nivolumab plus CT–paclitaxel/carboplatin for three cycles followed by surgery and postoperative nivolumab for 1 year)
      • Provencio M.
      • Nadal E.
      • Insa A.
      • et al.
      OA13.05 NADIM study: updated clinical researc-h and outcomes.
      and the trial by Shu et al.
      • Shu C.A.
      • Grigg C.
      • Chiuzan C.
      • et al.
      Neoadjuvant atezolizumab + chemotherapy in resectable non-small cell lung cancer (NSCLC).
      (four cycles of neoadjuvant atezolizumab plus CT–nab-paclitaxel/carboplatin followed by surgery) suggest that immune-CT combinations have substantially higher activity in terms of MPR (up to 83%) and pCR (up to 59%)
      • Provencio M.
      • Nadal E.
      • Insa A.
      • et al.
      OA13.05 NADIM study: updated clinical researc-h and outcomes.
      than that in immunotherapy alone (Fig. 1). Of note, MPR with combination strategies was observed regardless of PD-L1 expression.
      • Shu C.A.
      • Grigg C.
      • Chiuzan C.
      • et al.
      Neoadjuvant atezolizumab + chemotherapy in resectable non-small cell lung cancer (NSCLC).
      With a median follow-up of 17 months in the intention-to-treat population, the NADIM trial reported 18-month PFS and OS of 81% and 91%, respectively.
      • Provencio M.
      • Nadal E.
      • Insa A.
      • et al.
      OA13.05 NADIM study: updated clinical researc-h and outcomes.
      Ongoing phase III clinical trials assessing ICI and different platinum-based doublets will validate the role of immune-CT neoadjuvant strategy (Table 3).
      Table 3Ongoing Clinical Trials With Neoadjuvant Immune Checkpoint Inhibitors With or Without Chemotherapy
      TrialNCTDrugStageTarget AccrualPhaseEnd Point
      MK3475-223NCT02938624Pembrolizumab different dose/regimens → SI–II28IToxicity, MPR
      TOP 1501NCT02818920Pembrolizumab (200 mg) × two cycles → S → Pembrolizumab (200 mg) × four cyclesIB–IIIA32IISurgical feasibility
      PRICNEPSNCT02994576Atezolizumab (1200 mg) × one cycle → SIA–IIIA (no N2)60IIToxicity
      SAKK 16/14NCT02572843CT × 2 → Durvalumab (750 mg) × two cycles → Durvalumab (750 mg) × 1 yIIIA (N2)68IIEFS
      IONESCONCT03030131Durvalumab (750 mg) Q2W × three cycles → SIB–II81IIR0 resection
      CANOPY NNCT03968419Canakinumab +/– Pembrolizumab × two cycles → SIB–IIIA110IIMPR
      KEYNOTE 617NCT03425643CT + Pembrolizumab (200 mg)/placebo × four cycles → S → Pembrolizumab/Placebo × 13 cyclesIIB–IIIA786IIIEFS, OS
      CheckMate 816
      The third arm of the trial, nivolumab plus ipilimumab, was withdrawn after results from NADIM trial.
      NCT02998528CT + Nivolumab (360 mg) × three cycles → S vs. CT × three cycles → SIB–IIIA350IIIEFS, MPR
      IMpower 030NCT03456063CT + Atezolizumab (1200 mg)/placebo × four cycles → S → Atezolizumab/Placebo × 16 cyclesII–IIIB (cT3N2)374IIIMPR
      AEGEANNCT03800134CT + Durvalumab (1500 mg)/placebo Q3W × four cycles → S → Durvalumab/Placebo Q4W × 12 cyclesIIA–IIIB300IIIMPR
      CANOPY-ANCT03447769Canakinumab (200 mg sc)/placebo Q3W × 18 cyclesII–IIIB1500IIIinvDFS
      CT, chemotherapy; EFS, event-free survival; MPR, major pathologic response; S, surgery; Adj., adjuvant; Inv, investigator; OS, overall survival; DFS, disease-free survival; Q2W, every 2 weeks; Q3W, every 3 weeks; Q4W, every 4 weeks; NCT, national clinical trial.
      a The third arm of the trial, nivolumab plus ipilimumab, was withdrawn after results from NADIM trial.
      Unresolved challenges in this field include how to assess radiologic response, as false progression may exist, such as nodal immune flares, which account for approximately 22% of patients in the NEOSTAR study, requiring pathologic evaluation before excluding potentially curative surgery.
      • Cascone T.
      • William W.N.
      • Weissferdt A.
      • et al.
      Neoadjuvant nivolumab (N) or nivolumab plus ipilimumab (NI) for resectable non-small cell lung cancer (NSCLC): clinical and correlative results from the NEOSTAR study.
      The identification of optimal biomarkers for personalizing neoadjuvant treatment approaches presents another challenge. Finally, the role of the addition of postoperative ICI after neoadjuvant ICI plus CT may be questioned, especially among those patients with limited or no tumor regression.

      Adjuvant Immunotherapy Trials

      Cancer vaccines have been the most studied immune-based therapeutic strategies in early stage NSCLC. Unlike advanced-stage tumors, in which the potent immune-evasive microenvironment is thought to suppress T-cell–mediated immune response after vaccination, curative surgery could eventually lead to a decrease in the systemic release of immunosuppressive molecules, thus enabling the generation of more effective immune responses against residual disease on vaccination.
      • Melero I.
      • Gaudernack G.
      • Gerritsen W.
      • et al.
      Therapeutic vaccines for cancer: an overview of clinical trials.
      Despite this rationale, the clinical efficacy of cancer vaccines, even in early stage NSCLC, such as the MAGRIT trial,
      • Vansteenkiste J.F.
      • Cho B.C.
      • Vanakesa T.
      • et al.
      Efficacy of the MAGE-A3 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small-cell lung cancer (MAGRIT): a randomised, double-blind, placebo-controlled, phase 3 trial.
      has been disappointing, suggesting that immune responses elicited by currently tested vaccine formulations are too weak to be translated into meaningful clinical benefits in NSCLC. Other immunologic pathways may be disrupted by oncologic surgical stress inducing an immunosuppressive state,
      • Bakos O.
      • Lawson C.
      • Rouleau S.
      • Tai L.H.
      Combining surgery and immunotherapy: turning an immunosuppressive effect into a therapeutic opportunity.
      which provides evidence for assessing the efficacy of novel vaccination strategies and ICI after surgery.
      No clinical data on the safety and efficacy of ICI in patients with completely resected NSCLC are currently available. Nevertheless, adjuvant ICI in resected melanoma is tolerable and has improved DFS.
      • Weber J.
      • Mandala M.
      • Del Vecchio M.
      • et al.
      Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma.
      Ongoing phase III clinical trials are assessing adjuvant ICI in patients with completely resected NSCLC (Fig. 2). More than 4500 patients with resected stage IB–IIIA NSCLC will be randomized to receive ICI for 1 year, placebo (PEARLS and BR31 trials), or observation (ANVIL and IMpower-010 trials), regardless of PD-L1 status, after adjuvant CT (if clinically indicated). The most common primary end point across these trials is DFS. Treatment compliance, lack of predictive biomarker, and DFS as primary end point instead of OS are potential concerns of these trials. Finally, the optimal treatment duration of adjuvant ICI related to the treatment compliance and financial toxicity also represent relevant challenges.

      Expert Perspective

      Currently, there is no established guidance on how to process and evaluate resected lung cancer specimens after neoadjuvant therapy in the setting of clinical trials and clinical practice. There is also a lack of precise definitions on the degree of pathologic response, including MPR or pCR. The IASLC will be delivering recommendations for pathologic assessment of resection specimens after neoadjuvant therapies.
      Ongoing neoadjuvant studies with targeted therapies and immunotherapies in resectable NSCLC represent a unique source of information, and the IASLC strongly recommends and promotes the design and implementation of an international database to collect uniformly clinical and pathologic information with the ultimate goals of fostering collaboration and facilitating the identification of surrogate end points of long-term survival.

      Hyperprogressive Disease

      Hyperprogressive disease (HPD) is a rapid and aggressive pattern of progression (PD) in patients with advanced solid tumors after immunotherapy initiation.
      • Champiat S.
      • Ferrara R.
      • Massard C.
      • et al.
      Hyperprogressive disease: recognizing a novel pattern to improve patient management.
      HPD was first described in 2016
      • Borcoman E.
      • Kanjanapan Y.
      • Champiat S.
      • et al.
      Novel patterns of response under immunotherapy.
      ,
      • Champiat S.
      • Dercle L.
      • Ammari S.
      • et al.
      Hyperprogressive disease is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1.
      and was later reported in several tumor types with varying frequencies (3.8%–37.3%).
      • Champiat S.
      • Dercle L.
      • Ammari S.
      • et al.
      Hyperprogressive disease is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1.
      • Kato S.
      • Goodman A.
      • Walavalkar V.
      • Barkauskas D.A.
      • Sharabi A.
      • Kurzrock R.
      Hyperprogressors after immunotherapy: analysis of genomic alterations associated with accelerated growth rate.
      • Kanjanapan Y.
      • Day D.
      • Wang L.
      • et al.
      Hyperprogressive disease in early-phase immunotherapy trials: clinical predictors and association with immune-related toxicities.
      • Ferrara R.
      • Mezquita L.
      • Texier M.
      • et al.
      Hyperprogressive disease in patients with advanced non-small cell lung cancer treated with PD-1/PD-L1 inhibitors or with single-agent chemotherapy.
      • Kim C.G.
      • Kim K.H.
      • Pyo K.H.
      • et al.
      Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer.
      • Sasaki A.
      • Nakamura Y.
      • Mishima S.
      • et al.
      Predictive factors for hyperprogressive disease during nivolumab as anti-PD1 treatment in patients with advanced gastric cancer.
      • Aoki M.
      • Shoji H.
      • Nagashima K.
      • et al.
      Hyperprogressive disease during nivolumab or irinotecan treatment in patients with advanced gastric cancer.
      • Matos I.
      • Martin-Liberal J.
      • Hierro C.
      • et al.
      Incidence and clinical implications of a new definition of hyperprogression (HPD) with immune checkpoint inhibitors (ICIs) in patients treated in phase 1 (Ph1) trials.
      Even though there is no consensus on the HPD definition, across the studies, the main criteria used to define HPD include variations in tumor growth rate (TGR)
      • Champiat S.
      • Dercle L.
      • Ammari S.
      • et al.
      Hyperprogressive disease is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1.
      ,
      • Kanjanapan Y.
      • Day D.
      • Wang L.
      • et al.
      Hyperprogressive disease in early-phase immunotherapy trials: clinical predictors and association with immune-related toxicities.
      • Ferrara R.
      • Mezquita L.
      • Texier M.
      • et al.
      Hyperprogressive disease in patients with advanced non-small cell lung cancer treated with PD-1/PD-L1 inhibitors or with single-agent chemotherapy.
      • Kim C.G.
      • Kim K.H.
      • Pyo K.H.
      • et al.
      Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer.
      and tumor growth kinetics (TGK).
      • Kim C.G.
      • Kim K.H.
      • Pyo K.H.
      • et al.
      Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer.
      ,
      • Saâda-Bouzid E.
      • Defaucheux C.
      • Karabajakian A.
      • et al.
      Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma.
      Clinical parameters, such as time-to-treatment failure (TTF),
      • Kato S.
      • Goodman A.
      • Walavalkar V.
      • Barkauskas D.A.
      • Sharabi A.
      • Kurzrock R.
      Hyperprogressors after immunotherapy: analysis of genomic alterations associated with accelerated growth rate.
      ,
      • Kim C.G.
      • Kim K.H.
      • Pyo K.H.
      • et al.
      Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer.
      ,
      • Matos I.
      • Martin-Liberal J.
      • Hierro C.
      • et al.
      Incidence and clinical implications of a new definition of hyperprogression (HPD) with immune checkpoint inhibitors (ICIs) in patients treated in phase 1 (Ph1) trials.
      tumor burden, or appearance of new lesions,
      • Matos I.
      • Martin-Liberal J.
      • Hierro C.
      • et al.
      Incidence and clinical implications of a new definition of hyperprogression (HPD) with immune checkpoint inhibitors (ICIs) in patients treated in phase 1 (Ph1) trials.
      have also been used. Retrospective and heterogeneous studies have identified a subset of patients with an aggressive PD linked to poor outcomes, raising the hypothesis of an accelerated PD after ICI initiation.
      Ferrara et al.
      • Ferrara R.
      • Mezquita L.
      • Texier M.
      • et al.
      Hyperprogressive disease in patients with advanced non-small cell lung cancer treated with PD-1/PD-L1 inhibitors or with single-agent chemotherapy.
      reported for first time the occurrence of HPD in 406 NSCLC under ICI, with HPD defined as PD with greater than or equal to 50%ΔTGR. HPD occurred in 13.8% of patients, and it was associated with poorer prognosis. Notably, in a control cohort under CT, HPD occurred in 5% of the patients, suggesting that this phenomenon could be more frequent under ICI. Kim et al.
      • Kim C.G.
      • Kim K.H.
      • Pyo K.H.
      • et al.
      Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer.
      reported the unique comparison of definitions (TGR, TGK, TTF) in 263 patients with NSCLC.
      • Kim C.G.
      • Kim K.H.
      • Pyo K.H.
      • et al.
      Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer.
      HPD was seen in 21% using the TGR/TGK criteria, which also correlated with worse outcomes. Of note, HPD rate increased to 37% according to a TTF-based definition.
      The identification of the causes and mechanisms of HPD may be crucial to identify vulnerable populations before ICI initiation and while under treatment to distinguish HPD from other atypical clinical responses. Unfortunately, evidence is lacking. The first immunologic hypothesis has been published by Lo Russo et al.
      • Lo Russo G.
      • Moro M.
      • Sommariva M.
      • et al.