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    Safety and efficacy of apatinib combined with iodine-125 in chemotherapy-refractory advanced lung cancer: A case report. Zhang Yunchao,Yin Shiqiang,Jia Yingjie,Qin Lei Medicine INTRODUCTION:Apatinib is a novel anti-angiogenic agent that targets vascular endothelial growth factor receptor-2, and is effective in patients with advanced lung cancer who are refractory to first-line chemotherapy. However, there are limited reports on concurrent apatinib therapy with iodine-125 radioactive seeds brachytherapy in elderly patients with advanced lung cancer. PATIENT CONCERNS:We describe the first reported case of a 70-year-old woman with advanced lung cancer (T3N3M1, stage IV) who received concurrent apatinib and iodine-125 radioactive seeds brachytherapy after the failure of platinum-based doublet chemotherapy DIAGNOSIS:: The patient was diagnosed with left lower lung cancer with mediastinal lymph node metastasis by chest computed tomography. INTERVENTIONS:Initially, apatinib alone was used as second-line cancer therapy. Subsequently, the patient received concurrent apatinib and iodine-125 radioactive seeds brachytherapy. OUTCOMES:The patient achieved partial response shortly after undergoing treatment with only apatinib. During the treatment, the tumor continued to respond to apatinib therapy, and the lung metastases were diminished eventually. However, a chest computed tomography scan showed a large cavity in the lung tumor. Thereafter, the patient received concurrent apatinib and iodine-125 radioactive seeds brachytherapy. Unfortunately, she died due to pulmonary infection. CONCLUSION:Apatinib alone may be a good second-line therapy for advanced lung cancer patients who are refractory to platinum-based doublet chemotherapy. However, its potential benefits, especially as combination therapy, need further investigation by future prospective clinical studies. Elderly patients with advanced lung cancer may benefit from concurrent apatinib with iodine-125 radioactive seeds brachytherapy when chemotherapy is not tolerated or effective. Further studies are needed to investigate the clinical outcomes and toxicities associated with concurrent apatinib and radiation therapy in patients with advanced lung cancer. 10.1097/MD.0000000000021600
    Combining immunotherapies to treat non-small cell lung cancer. Spagnuolo Alessia,Gridelli Cesare Expert review of respiratory medicine : In recent years, immunotherapy has become an integral part of the treatment of many cancers, including non-small cell lung cancer (NSCLC). Precious therapeutic weapons impacting survival are monoclonal antibodies directed against the programmed death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) immune checkpoint. : Unfortunately, not all patients treated with checkpoint inhibitors have durable clinical responses. However, a better understanding of the complexity of interactions between the immune system and cancer, the latter capable of adopting evasion mechanisms, indicates different opportunities to enhance anti-tumor immunity. : In this paper, we review multiple strategies of combining immunotherapies that exploit not only additional immune checkpoint receptors and ligands but also other synergistic approaches such as vaccines or indoleamine 2,3-dioxygenase (IDO) inhibitors with the potential to extend the number of NSCLC patients achieving successful outcomes. 10.1080/17476348.2019.1623027
    The evolving immuno-oncology landscape in advanced lung cancer: first-line treatment of non-small cell lung cancer. Low Jia Li,Walsh Robert J,Ang Yvonne,Chan Gloria,Soo Ross A Therapeutic advances in medical oncology Lung cancer is the most common cancer and leading cause of cancer death. While targeted therapies have redefined treatment options for non-small cell lung carcinoma (NSCLC) with genetic aberrations such as epidermal growth factor and anaplastic lymphoma kinase, many patients do not harbour these oncogenic drivers. Cancer immunology has enabled the development of immune modulators that has dramatically altered the therapeutic landscape of advanced NSCLC. The success of immune-checkpoint inhibitors in pretreated NSCLC has led to the conduct of multiple studies exploring their role in the first-line setting. This article provides an overview of the evolving landscape of immune-checkpoint inhibitors with a focus on the programmed cell-death 1 (PD-1; pembrolizumab, nivolumab) and programmed cell-death ligand 1 (PD-L1; atezolizumab, durvalumab, avelumab) immune-checkpoint inhibitors as single agent or in combination with either chemotherapy or with another immune-checkpoint inhibitor in the treatment of NSCLC, the challenges faced, as well as future perspectives. 10.1177/1758835919870360
    Systemic Therapy for Locally Advanced and Metastatic Non-Small Cell Lung Cancer: A Review. Arbour Kathryn C,Riely Gregory J JAMA Importance:Non-small cell lung cancer remains the leading cause of cancer death in the United States. Until the last decade, the 5-year overall survival rate for patients with metastatic non-small cell lung cancer was less than 5%. Improved understanding of the biology of lung cancer has resulted in the development of new biomarker-targeted therapies and led to improvements in overall survival for patients with advanced or metastatic disease. Observations:Systemic therapy for metastatic non-small cell lung cancer is selected according to the presence of specific biomarkers. Therefore, all patients with metastatic non-small cell lung cancer should undergo molecular testing for relevant mutations and expression of the protein PD-L1 (programmed death ligand 1). Molecular alterations that predict response to treatment (eg, EGFR mutations, ALK rearrangements, ROS1 rearrangements, and BRAF V600E mutations) are present in approximately 30% of patients with non-small cell lung cancer. Targeted therapy for these alterations improves progression-free survival compared with cytotoxic chemotherapy. For example, somatic activating mutations in the EGFR gene are present in approximately 20% of patients with advanced non-small cell lung cancer. Tyrosine kinase inhibitors such as gefitinib, erlotinib, and afatinib improve progression-free survival in patients with susceptible EGFR mutations. In patients with overexpression of ALK protein, the response rate was significantly better with crizotinib (a tyrosine kinase inhibitor) than with the combination of pemetrexed and either cisplatin or carboplatin (platinum-based chemotherapy) (74% vs 45%, respectively; P < .001) and progression-free survival (median, 10.9 months vs 7.0 months; P < .001). Subsequent generations of tyrosine kinase inhibitors have improved these agents. For patients without biomarkers indicating susceptibility to specific targeted treatments, immune checkpoint inhibitor-containing regimens either as monotherapy or in combination with chemotherapy are superior vs chemotherapy alone. These advances in biomarker-directed therapy have led to improvements in overall survival. For example, the 5-year overall survival rate currently exceeds 25% among patients whose tumors have high PD-L1 expression (tumor proportion score of ≥50%) and 40% among patients with ALK-positive tumors. Conclusions and Relevance:Improved understanding of the biology and molecular subtypes of non-small cell lung cancer have led to more biomarker-directed therapies for patients with metastatic disease. These biomarker-directed therapies and newer empirical treatment regimens have improved overall survival for patients with metastatic non-small cell lung cancer. 10.1001/jama.2019.11058
    NCCN Guidelines Updates: New Immunotherapy Strategies for Improving Outcomes in Non-Small Cell Lung Cancer. Gubens Matthew A,Davies Marianne Journal of the National Comprehensive Cancer Network : JNCCN For the use of immunotherapy in metastatic non-small cell lung cancer (NSCLC), the NCCN Guidelines for NSCLC reflect the importance of assessing levels of PD-L1 expression to determine the best use of PD-1/PD-L1 inhibitors, whether alone or in combination with chemotherapy. Patients who lack a driver mutation and have tumor PD-L1 expression ≥50% are recommended to receive single-agent pembrolizumab, although combining with carboplatin/pemetrexed is also a reasonable choice, especially if there is higher burden of disease. For tumors with PD-L1 expression <50%, it is important to distinguish between nonsquamous and squamous cell carcinoma (SCC). For patients with non-SCC disease, pembrolizumab + carboplatin/pemetrexed is preferred. Alternately, a 4-drug regimen of carboplatin/paclitaxel/bevacizumab/atezolizumab is reasonable, especially for patients ineligible for pemetrexed. In patients with SCC, carboplatin + paclitaxel or nab-paclitaxel with pembrolizumab is a category 1 recommendation. Tumor mutational burden is emerging as a biomarker for efficacy but is not yet ready to be used in patient selection. Optimal management of the unique toxicities associated with immunotherapy, which can be more frequent with these combinations, is also critical for good outcomes. 10.6004/jnccn.2019.5005
    The Potential of Combined Immunotherapy and Antiangiogenesis for the Synergistic Treatment of Advanced NSCLC. Manegold Christian,Dingemans Anne-Marie C,Gray Jhanelle E,Nakagawa Kazuhiko,Nicolson Marianne,Peters Solange,Reck Martin,Wu Yi-Long,Brustugun Odd Terje,Crinò Lucio,Felip Enriqueta,Fennell Dean,Garrido Pilar,Huber Rudolf M,Marabelle Aurélien,Moniuszko Marcin,Mornex Françoise,Novello Silvia,Papotti Mauro,Pérol Maurice,Smit Egbert F,Syrigos Kostas,van Meerbeeck Jan P,van Zandwijk Nico,Yang James Chih-Hsin,Zhou Caicun,Vokes Everett Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Over the past few years, there have been considerable advances in the treatments available to patients with metastatic or locally advanced NSCLC, particularly those who have progressed during first-line treatment. Some of the treatment options available to patients are discussed here, with a focus on checkpoint inhibitor immunotherapies (nivolumab and pembrolizumab) and antiangiogenic agents (bevacizumab, ramucirumab, and nintedanib). It is hypothesized that combining immunotherapy with antiangiogenic treatment may have a synergistic effect and enhance the efficacy of both treatments. In this review, we explore the theory and potential of this novel treatment option for patients with advanced NSCLC. We discuss the growing body of evidence that proangiogenic factors can modulate the immune response (both by reducing T-cell infiltration into the tumor microenvironment and through systemic effects on immune-regulatory cell function), and we examine the preclinical evidence for combining these treatments. Potential challenges are also considered, and we review the preliminary evidence of clinical efficacy and safety with this novel combination in a variety of solid tumor types. 10.1016/j.jtho.2016.10.003
    Engineering patient-specific cancer immunotherapies. Scheetz Lindsay,Park Kyung Soo,Li Qiao,Lowenstein Pedro R,Castro Maria G,Schwendeman Anna,Moon James J Nature biomedical engineering Research into the immunological processes implicated in cancer has yielded a basis for the range of immunotherapies that are now considered the fourth pillar of cancer treatment (alongside surgery, radiotherapy and chemotherapy). For some aggressive cancers, such as advanced non-small-cell lung carcinoma, combination immunotherapies have resulted in unprecedented treatment efficacy for responding patients, and have become frontline therapies. Individualized immunotherapy, enabled by the identification of patient-specific mutations, neoantigens and biomarkers, and facilitated by advances in genomics and proteomics, promises to broaden the responder patient population. In this Perspective, we give an overview of immunotherapies leveraging engineering approaches, including the design of biomaterials, delivery strategies and nanotechnology solutions, for the realization of individualized cancer treatments such as nanoparticle vaccines customized with neoantigens, cell therapies based on patient-derived dendritic cells and T cells, and combinations of theranostic strategies. Developments in precision cancer immunotherapy will increasingly rely on the adoption of engineering principles. 10.1038/s41551-019-0436-x
    Lung cancer: current therapies and new targeted treatments. Hirsch Fred R,Scagliotti Giorgio V,Mulshine James L,Kwon Regina,Curran Walter J,Wu Yi-Long,Paz-Ares Luis Lancet (London, England) Lung cancer is the most frequent cause of cancer-related deaths worldwide. Every year, 1·8 million people are diagnosed with lung cancer, and 1·6 million people die as a result of the disease. 5-year survival rates vary from 4-17% depending on stage and regional differences. In this Seminar, we discuss existing treatment for patients with lung cancer and the promise of precision medicine, with special emphasis on new targeted therapies. Some subgroups, eg-patients with poor performance status and elderly patients-are not specifically addressed, because these groups require special treatment considerations and no frameworks have been established in terms of new targeted therapies. We discuss prevention and early detection of lung cancer with an emphasis on lung cancer screening. Although we acknowledge the importance of smoking prevention and cessation, this is a large topic beyond the scope of this Seminar. 10.1016/S0140-6736(16)30958-8
    Maintenance therapy in advanced non-small cell lung cancer. Coate Linda E,Shepherd Frances A Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Non-small cell lung cancer (NSCLC) is the leading cause of cancer death in the industrialized world, and survival rates for advanced disease remain low with standard platinum-based chemotherapy. One treatment strategy that has been investigated extensively in NSCLC is that of "maintenance" therapy. Options for maintenance include maintaining response to initial therapy by continuing the initial combination chemotherapy regimen, continuing only single agent chemotherapy, or by introducing a new agent. Treatments that have been studied in randomized trials to date include chemotherapy, molecularly targeted agents, and immunotherapy approaches. After the development of multiple new agents that show activity in NSCLC and have a tolerable side effect profile, there has been increasing interest recently in this treatment strategy. In this study, we examine the evolution of this strategy by reviewing trials investigating the main treatment paradigms used in maintenance therapy for NSCLC. 10.1097/JTO.0b013e3181d86e8b
    Current status of immune checkpoint inhibition in early-stage NSCLC. Vansteenkiste J,Wauters E,Reymen B,Ackermann C J,Peters S,De Ruysscher D Annals of oncology : official journal of the European Society for Medical Oncology Immune checkpoint inhibition (ICI) immunotherapy has revolutionized the approach to metastatic non-small-cell lung cancer (NSCLC). In particular, antibodies blocking the inhibitory immune checkpoints programmed death 1 (PD-1) and its ligand (PD-L1) are associated with higher response rates, improved overall survival and better tolerability as compared with conventional cytotoxic chemotherapy. Recently, ICI has moved from the second-line to the first-line setting for many patients with non-oncogene-addicted NSCLC, either alone or in combination with chemotherapy. The next logical step is to examine this therapy in patients with non-metastatic NSCLC to improve long-term overall survival and cure rates. For patients with unresectable stage III NSCLC, ICI with durvalumab after concurrent chemoradiotherapy has brought a major improvement in 2-year progression-free and overall survival, which holds promise for an improved cure rate. As the relapse pattern in patients with completely resected early-stage NSCLC is predominantly systemic, high expectations rest on the integration of ICI therapy in their treatment approach. A large number of studies with adjuvant or neo-adjuvant ICI are ongoing and will be discussed here. The advent of stereotactic ablative radiotherapy has brought a valid alternative treatment of patients unfit for or not willing to undergo surgery. Data on combining systemic therapy and stereotactic ablative radiotherapy are virtually non-existent, but there is a strong biological rationale to combine radiotherapy and ICI therapy. Early findings in small feasibility studies are promising and now need to be explored in well-designed phase III trials. 10.1093/annonc/mdz175
    Lung cancer: potential targets for immunotherapy. Tartour Eric,Zitvogel Laurence The Lancet. Respiratory medicine Lung cancer is the most common cause of cancer-related mortality worldwide and a therapeutic challenge. Recent success with antibodies blocking immune checkpoints in non-small-cell lung cancers (NSCLC) highlights the potential of immunotherapy for lung cancer treatment, and the need for trials of combination regimens of immunotherapy plus chemotherapy that lead to immunogenic cell death. Here, we review the development of immunogenic cytotoxic compounds, vaccines, and antibodies in NSCLC, in view of their integration into personalised oncology. 10.1016/S2213-2600(13)70159-0
    Why has active immunotherapy not worked in lung cancer? Thomas A,Giaccone G Annals of oncology : official journal of the European Society for Medical Oncology Vaccines that rely on active specific stimulation of the host immune system have the potential to trigger durable antitumor responses with minimal toxicity. However, in nonsmall-cell lung cancer (NSCLC), several large phase III trials of vaccines reported within the last year have yielded disappointing results. Compared with placebo, belagenpumatucel-L (an allogenic tumor cell vaccine), tecemotide (a peptide vaccine targeting MUC-1) and melanoma-associated antigen-A3 (a protein-based vaccine) did not improve outcomes in NSCLC. The lack of clinically significant outcomes, despite their ability to prime and expand tumor antigen-specific T cells could at least partly be attributed to the inability of vaccine-induced T-cell responses to overcome the tumoral mechanisms of immune escape which limit the clonal expansion of T cells following vaccination. A number of such mechanisms have been recognized including reduced antigen presentation, antigenic loss, cytokines, immunosuppressive cells and immune checkpoints. Strategies aimed at modulating the immune checkpoints have shown promise and are on the verge of revolutionizing the therapeutic landscape of metastatic NSCLC. Overcoming immune tolerance and improving the activation of antitumor T cells via combinatorial approaches may represent a new and more promising therapeutic application for active immunotherapies in NSCLC. 10.1093/annonc/mdv323
    Comparing and contrasting predictive biomarkers for immunotherapy and targeted therapy of NSCLC. Camidge D Ross,Doebele Robert C,Kerr Keith M Nature reviews. Clinical oncology The era of personalized medicine for advanced-stage non-small-cell lung cancer (NSCLC) began when biomarker-based evidence of molecular pathway and/or oncogene addiction of the tumour became mandatory for the allocation of specific targeted therapies. More recently, the immunotherapy revolution, specifically, the development of immune-checkpoint inhibitors (ICIs), has dramatically altered the NSCLC treatment landscape. Herein, we compare and contrast the clinical development of immunotherapy and oncogene-directed therapy for NSCLC, focusing on the role of predictive biomarkers. Immunotherapy biomarkers are fundamentally different from oncogene biomarkers in that they are continuous rather than categorical (binary), spatially and temporally variable and reliant on multiple complex interactions rather than a single, dominant determinant. The performance of predictive biomarkers for ICIs might be improved by combining different markers to reduce the assumptive risks associated with each one. Novel combinations with chemotherapy and ICIs complicate biomarker discovery but do not decrease the value of the markers identified. Perfectly predictive biomarkers of benefit from immunotherapy are unlikely to be identified, although exclusionary biomarkers of minimal benefit or an unacceptable risk of toxicity might be feasible. The clinical adoption and applicability of such biomarkers might vary depending on line of treatment, the available therapeutic alternatives and health economic considerations. 10.1038/s41571-019-0173-9
    Current and Emergent Therapy Options for Advanced Squamous Cell Lung Cancer. Socinski Mark A,Obasaju Coleman,Gandara David,Hirsch Fred R,Bonomi Philip,Bunn Paul A,Kim Edward S,Langer Corey J,Natale Ronald B,Novello Silvia,Paz-Ares Luis,Pérol Maurice,Reck Martin,Ramalingam Suresh S,Reynolds Craig H,Spigel David R,Wakelee Heather,Thatcher Nick Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Squamous cell lung cancer (SqCLC) is a distinct histologic subtype of NSCLC that is challenging to treat because of specific clinicopathologic characteristics, which include older age, advanced disease at diagnosis, comorbid diseases, and the central location of tumors. These characteristics have a bearing on treatment outcomes in advanced SqCLC, resulting in a median survival approximately 30% shorter than for patients with other NSCLC subtypes. In the context of the specific features of SqCLC, we review challenges of treating SqCLC and the current guideline-recommended treatments for advanced (metastatic) SqCLC in different patient subpopulations. We also evaluate recently approved treatment options, including necitumumab, afatinib, nivolumab, pembrolizumab, and atezolizumab; discuss the survival benefits associated with each agent in the advanced SqCLC population; and propose a treatment algorithm incorporating these agents for this challenging-to-treat disease. Lastly, we review the preliminary clinical evidence for immunotherapy agents in development for advanced NSCLC. 10.1016/j.jtho.2017.11.111
    Challenges in molecular testing in non-small-cell lung cancer patients with advanced disease. Hiley Crispin T,Le Quesne John,Santis George,Sharpe Rowena,de Castro David Gonzalez,Middleton Gary,Swanton Charles Lancet (London, England) Lung cancer diagnostics have progressed greatly in the previous decade. Development of molecular testing to identify an increasing number of potentially clinically actionable genetic variants, using smaller samples obtained via minimally invasive techniques, is a huge challenge. Tumour heterogeneity and cancer evolution in response to therapy means that repeat biopsies or circulating biomarkers are likely to be increasingly useful to adapt treatment as resistance develops. We highlight some of the current challenges faced in clinical practice for molecular testing of EGFR, ALK, and new biomarkers such as PDL1. Implementation of next generation sequencing platforms for molecular diagnostics in non-small-cell lung cancer is increasingly common, allowing testing of multiple genetic variants from a single sample. The use of next generation sequencing to recruit for molecularly stratified clinical trials is discussed in the context of the UK Stratified Medicine Programme and The UK National Lung Matrix Trial. 10.1016/S0140-6736(16)31340-X
    Immunotherapy for non-small cell lung cancer: novel approaches to improve patient outcome. Shepherd Frances A,Douillard Jean-Yves,Blumenschein George R Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer INTRODUCTION:Non-small cell lung cancer (NSCLC) is often diagnosed in advanced stages and is associated with poor outcomes. Existing standards of care for NSCLC result in low overall cure rates, suggesting that novel treatment approaches are needed. In this review, we provide an updated look at the clinical data on immunotherapeutic interventions, which potentiate the immune system's response to lung tumor cells. METHODS:We searched articles on PubMed and abstracts from recent oncology meetings for publications on immunotherapies with clinical applicability to the treatment of NSCLC. RESULTS:Results from phase 2 trials show vaccine therapies, which target either tumor cells themselves or aberrantly expressed tumor markers (mucin 1, melanoma-associated antigen 3, or epidermal growth factor), may be promising immunotherapeutics for NSCLC. Antigen-independent immunotherapies, such as anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibodies, talactoferrin alfa, and toll-like receptor 9 agonists, act on a stimulated immune system regardless of the tumor antigen and may be feasible interventions for metastatic NSCLC. Several immunotherapies are undergoing phase 3 studies to assess optimal treatment settings and to determine clinical benefit compared with current standard treatments for NSCLC. CONCLUSIONS:A growing body of evidence suggests that immune responses to lung tumors are present. Immunotherapeutic interventions, including vaccine therapy and antigen-independent immunomodulatory strategies, may improve outcomes in NSCLC. Furthermore, treatments that enhance antitumor immune responses may prove to be synergistic with chemotherapy. Identification of biomarkers and further elucidation of immunotherapeutic mechanisms of action will be essential in determining which patients will experience the greatest benefit from immunotherapy. 10.1097/JTO.0b013e31822e28fc
    Non-small-cell lung cancer. Gridelli Cesare,Rossi Antonio,Carbone David P,Guarize Juliana,Karachaliou Niki,Mok Tony,Petrella Francesco,Spaggiari Lorenzo,Rosell Rafael Nature reviews. Disease primers Lung cancer is one of the most frequently diagnosed cancers and is the leading cause of cancer-related death worldwide. Non-small-cell lung cancer (NSCLC), a heterogeneous class of tumours, represents approximately 85% of all new lung cancer diagnoses. Tobacco smoking remains the main risk factor for developing this disease, but radon exposure and air pollution also have a role. Most patients are diagnosed with advanced-stage disease owing to inadequate screening programmes and late onset of clinical symptoms; consequently, patients have a very poor prognosis. Several diagnostic approaches can be used for NSCLC, including X-ray, CT and PET imaging, and histological examination of tumour biopsies. Accurate staging of the cancer is required to determine the optimal management strategy, which includes surgery, radiochemotherapy, immunotherapy and targeted approaches with anti-angiogenic monoclonal antibodies or tyrosine kinase inhibitors if tumours harbour oncogene mutations. Several of these driver mutations have been identified (for example, in epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK)), and therapy continues to advance to tackle acquired resistance problems. Also, palliative care has a central role in patient management and greatly improves quality of life. For an illustrated summary of this Primer, visit: http://go.nature.com/rWYFgg. 10.1038/nrdp.2015.9
    The Role of Thoracic Surgery in the Therapeutic Management of Metastatic Non-Small Cell Lung Cancer. David Elizabeth A,Clark James M,Cooke David T,Melnikow Joy,Kelly Karen,Canter Robert J Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer INTRODUCTION:In most patients with NSCLC, the disease is diagnosed in an advanced stage, the prognosis is poor, and survival is typically measured in months. Standard therapeutic treatment regimens for patients with stage IV NSCLC typically include chemotherapy and palliative radiation. Despite newer regimens that may include molecularly targeted therapy and immunotherapy, the overall 5-year survival for stage IV disease remains low at 4% to 6%. Although therapeutic surgery is performed in a minority of cases, accumulating data suggest that thoracic surgery may play several beneficial roles for these patients. METHODS:In this narrative review, we summarize the literature on surgical intervention in the multimodality management of stage IV NSCLC, focusing on the potential evidence for and against therapeutic or curative intent procedures to affect outcomes for patients with oligometastatic disease and pleural metastasis. RESULTS:In selected patients, surgical resection can result in a 5-year survival rate of 30% to 50%, but this is heavily influenced by the presence of mediastinal nodal disease, which should be evaluated before therapeutic surgical procedures are undertaken. Additionally, diagnostic or palliative surgical procedures can play an important role in the personalized management of stage IV disease. These data suggest that for carefully selected patients with advanced stage NSCLC, surgical intervention can be an important component of combined modality treatment. CONCLUSIONS:Given the advances in molecular targeted therapy and immunotherapy, further studies should focus on the possible use of surgery as a strategy of therapeutic "consolidation" for appropriately selected patients with stage IV NSCLC who are receiving combined modality care. 10.1016/j.jtho.2017.08.008
    The non-small cell lung cancer immune contexture. A major determinant of tumor characteristics and patient outcome. Remark Romain,Becker Christian,Gomez Jorge E,Damotte Diane,Dieu-Nosjean Marie-Caroline,Sautès-Fridman Catherine,Fridman Wolf-Herman,Powell Charles A,Altorki Nasser K,Merad Miriam,Gnjatic Sacha American journal of respiratory and critical care medicine Solid tumors, beyond mere accumulation of cancer cells, form a complex ecosystem consisting of normal epithelial cells, fibroblasts, blood and lymphatic vessels, structural components, and infiltrating hematopoietic cells including myeloid and lymphoid elements that impact tumor growth, tumor spreading, and clinical outcome. The composition of the immune microenvironment is diverse, including various populations of T cells, B cells, dendritic cells, natural killer cells, myeloid-derived suppressor cells, neutrophils, or macrophages. The immune contexture describes the density, location, and organization of these immune cells within solid tumors. In lung cancer, which is the deadliest type of cancer, and particularly in non-small cell lung cancer, its most prevalent form, reports have described some of the interactions between the tumor and the host. These data, in addition to articles on various types of tumors, provide a greater understanding of the tumor-host microenvironment interaction and stimulate the development of prognostic and predictive biomarkers, the identification of novel target antigens for therapeutic intervention, and the implementation of tools for long-term management of patients with cancer. 10.1164/rccm.201409-1671PP
    The biology and management of non-small cell lung cancer. Herbst Roy S,Morgensztern Daniel,Boshoff Chris Nature Important advancements in the treatment of non-small cell lung cancer (NSCLC) have been achieved over the past two decades, increasing our understanding of the disease biology and mechanisms of tumour progression, and advancing early detection and multimodal care. The use of small molecule tyrosine kinase inhibitors and immunotherapy has led to unprecedented survival benefits in selected patients. However, the overall cure and survival rates for NSCLC remain low, particularly in metastatic disease. Therefore, continued research into new drugs and combination therapies is required to expand the clinical benefit to a broader patient population and to improve outcomes in NSCLC. 10.1038/nature25183
    Efficacy of Tumor Vaccines and Cellular Immunotherapies in Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis. Dammeijer Floris,Lievense Lysanne A,Veerman G D Marijn,Hoogsteden Henk C,Hegmans Joost P,Arends Lidia R,Aerts Joachim G Journal of clinical oncology : official journal of the American Society of Clinical Oncology PURPOSE:Programmed cell death protein-1- checkpoint blockers have recently been approved as second-line treatment for advanced non-small-cell lung cancer (NSCLC). Unfortunately, only a subgroup of patients responds and shows long-term survival to these therapies. Tumor vaccines and cellular immunotherapies could synergize with checkpoint blockade, but which of these treatments is most efficacious is unknown. In this meta-analysis, we assessed the efficacy of tumor vaccination and cellular immunotherapy in NSCLC. METHODS:We searched for randomized controlled trials (RCTs) investigating cellular immunotherapy or vaccines in NSCLC. We used random effects models to analyze overall survival (OS) and progression-free survival (PFS), expressed as hazard ratios (HRs), and differences in time (months). The effect of immunotherapy type, disease stage, tumor histology, and concurrent chemotherapy was assessed using subgroup analysis and meta-regression. All procedures were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS:We identified 18 RCTs that matched our selection criteria; these included a total of 6,756 patients. Immunotherapy extended NSCLC survival and PFS, expressed as HR (OS: HR, 0.81, 95% CI, 0.70 to 0.94, P = .01; PFS: HR, 0.83, 95% CI, 0.72 to 0.95, P = .006) and month difference (OS: difference, 5.43 months, 95% CI, 3.20 to 7.65, P < .005; PFS: difference, 3.24 months, 95% CI, 1.61 to 4.88, P < .005). Cellular therapies outperformed tumor vaccines (OS as HR: P = .005, month difference: P < .001; PFS as HR: P = .001, month difference: P = .004). There was a benefit of immunotherapy in low-stage compared with high-stage NSCLC and with concurrent administration of chemotherapy only in one of four outcome measures evaluated (PFS in months: P = .01 and PFS as HR: P = .031, respectively). There was no significant effect of tumor histology on survival or PFS. CONCLUSION:Tumor vaccines and cellular immunotherapies enhanced OS and PFS in NSCLC. Cellular immunotherapy was found to be more effective than tumor vaccination. These findings have implications for future studies investigating combination immunotherapy in NSCLC. 10.1200/JCO.2015.66.3955
    Immunological Aspects of Cryoablation of Non-Small Cell Lung Cancer: A Comprehensive Review. Katzman Daniel,Wu Shirley,Sterman Daniel H Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer In cryoimmunotherapy, target tumors are treated with cryoablation to generate antitumor immune responses. Because immune checkpoint inhibitors have demonstrated that lung cancer can be an immunotherapy-responsive disease, there has been renewed interest in the immunological aspects of cryoablation of lung cancer. Herein, we review preclinical and clinical trials of cryoablation of primary lung tumors. We examine the magnitude of cryoablation-induced antitumor immune responses and the synergy between cryoablation and either other immunotherapies or molecular targeted therapies to improve treatment responses in advanced lung cancer. We further discuss a rationale for the addition of cryoablation to immune checkpoint inhibitors for the treatment of advanced lung cancer, which is currently under clinical investigation. 10.1016/j.jtho.2018.01.017
    Clinical Trials Integrating Immunotherapy and Radiation for Non-Small-Cell Lung Cancer. Daly Megan E,Monjazeb Arta M,Kelly Karen Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Methods of harnessing the immune system to treat cancer have been investigated for decades, but yielded little clinical progress. However, in recent years, novel drugs that allow immune recognition and destruction of tumor cells are emerging as potent cancer therapies. Building upon previous immunotherapy strategies that included therapeutic vaccines, recombinant cytokines, and other immunostimulatory agents, newer immunotherapy agents targeting immune checkpoints including programmed cell death 1, programmed cell death ligand-1, and cytotoxic T-lymphocyte-associated protein 4, among others, have garnered substantial enthusiasm after demonstrating clinical activity in a broad spectrum of tumor types. Trials evaluating immune checkpoint inhibitors in metastatic non-small-cell lung cancer (NSCLC) demonstrate robust and durable responses in a subset of patients. However, with overall response rates less than 20%, combinatorial strategies that extend the benefit of these agents to more patients are desirable. The integration of radiotherapy with immunotherapy is a conceptually promising strategy, as radiotherapy has potent immunomodulatory effects and may contribute not only to local control but may also augment systemic antitumor immune response. Preclinical data and case reports suggest the potential for robust clinical responses in metastatic NSCLC patients using this strategy, but prospective clinical trials evaluating the integration of radiation and immunotherapy are limited. The use of immunotherapy in nonmetastatic settings is also intriguing but understudied. We review the potential clinical settings of interest for the partnering of immunotherapy and radiation in NSCLC, including early stage, locally advanced, and metastatic disease, and review completed, accruing, and developing clinical trials. 10.1097/JTO.0000000000000686
    Pembrolizumab in the treatment of metastatic non-small cell lung cancer: a review of current evidence. Rihawi Karim,Gelsomino Francesco,Sperandi Francesca,Melotti Barbara,Fiorentino Michelangelo,Casolari Laura,Ardizzoni Andrea Therapeutic advances in respiratory disease Immune checkpoint inhibitors (ICPIs) are considered one of the most important breakthroughs in cancer treatment of the past decade; notably, different studies of programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors have reported impressive clinical activity and durable responses in patients with advanced non-small cell lung cancer (NSCLC). These findings have led to the changing of the current therapeutic algorithm of advanced NSCLC, adding a new standard first-line treatment option for patients with PD-L1-positive tumors. Pembrolizumab, a highly selective anti-PD-1 humanized monoclonal antibody, was approved by the United States Food and Drug Administration (US FDA) in October 2016 for previously untreated metastatic NSCLC patients whose tumors have high PD-L1 expression, tumor proportion score (TPS) ⩾ 50%, as well as for metastatic NSCLC patients whose tumors express PD-L1 with TPS ⩾ 1% progressing on or after platinum-based chemotherapy. However, many issues remain outstanding, mainly regarding the identification of an optimal biomarker which can help selecting patients more likely to respond to ICPIs. In this review, we discuss the clinical results obtained so far with the anti-PD-1 pembrolizumab in advanced NSCLC, commenting on the role of PD-L1 as a predictive factor and providing an update of the future perspectives. 10.1177/1753465817725486
    Programmed Death Ligand 1 (PD-L1) as a Predictive Biomarker for Pembrolizumab Therapy in Patients with Advanced Non-Small-Cell Lung Cancer (NSCLC). Incorvaia Lorena,Fanale Daniele,Badalamenti Giuseppe,Barraco Nadia,Bono Marco,Corsini Lidia Rita,Galvano Antonio,Gristina Valerio,Listì Angela,Vieni Salvatore,Gori Stefania,Bazan Viviana,Russo Antonio Advances in therapy Recently, immunotherapy has been shown to be an effective and helpful therapeutic option for the treatment of advanced non-small-cell lung cancer (NSCLC). The activity of antitumor T cells may be restored through the checkpoint blockade using anti-programmed death 1 or anti-programmed death ligand 1 (PD-L1) antibodies, showing, in several cancer patients, an increased progression-free survival and overall survival compared with classical chemotherapy. As recently shown by several studies, the PD-L1 expression levels in tumors may offer a selection criterion for patients to predict their immunotherapy response. In particular, NSCLC patients with high tumor PD-L1 levels (proportional score ≥ 50% for first-line therapy and ≥ 1% for second-line treatment, respectively) showed better response rates to immunotherapy and longer survival in first-line therapy compared with conventional chemotherapy. PD-L1, whose expression is evaluated by using immunohistochemistry analysis, is currently the only biomarker approved for clinical use in the first- and second-line monotherapy setting and therefore plays a central role in treatment decision-making for patients with advanced NSCLC. In this review we will discuss the key role of PD-L1 as a predictive biomarker of response to pembrolizumab therapy in NSCLC patients by describing the appropriate techniques and methodologies for immunohistochemical evaluation of PD-L1 expression and providing an overview of the clinical studies supporting its predictive significance. 10.1007/s12325-019-01057-7
    Current status of immune checkpoint inhibitors in treatment of non-small cell lung cancer. Lim Sung Won,Ahn Myung-Ju The Korean journal of internal medicine Lung cancer remains a leading cause of cancer mortality worldwide, including in Korea. Systemic therapy including platinum-based chemotherapy and targeted therapy should be provided to patients with stage IV non-small cell lung cancer (NSCLC). Applications of targeted therapy, such as an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and anaplastic lymphoma kinase (ALK) inhibitors, in patients with NSCLC and an EGFR mutation or ALK gene rearrangement has enabled dramatic improvements in efficacy and tolerability. Despite advances in research and a better understanding of the molecular pathways of NSCLC, few effective therapeutic options are available for most patients with NSCLC without druggable targets, especially for patients with squamous cell NSCLC. Immune checkpoint inhibitors such as anti-cytotoxic T lymphocyte antigen-4 or anti-programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1) have demonstrated durable response rates across a broad range of solid tumors, including NSCLC, which has revolutionized the treatment of solid tumors. Here, we review the current status and future approaches of immune checkpoint inhibitors that are being investigated for NSCLC with a focus on pembrolizumab, nivolumab, atezolizumab, durvalumab, and ipilimumab. 10.3904/kjim.2018.179
    Immunotherapy in the treatment of non-small cell lung cancer. Sundar Raghav,Soong Richie,Cho Byoung-Chul,Brahmer Julie R,Soo Ross A Lung cancer (Amsterdam, Netherlands) Advances in the understanding of the role of the immune system in tumor immunosurveillance have resulted in the recognition that tumors can evade immune destruction via the dysregulation of co-inhibitory or checkpoint signals. This has led to the development of a generation immunotherapeutic agents targeting the immune checkpoint pathway. Recent early phase studies of immune checkpoint modulators, such as CTLA-4, PD-1 and PD-L1 inhibitors in NSCLC have reported promising results with prolonged clinical responses and tolerable toxicity. This article provides an overview of co-stimulatory and inhibitory molecules that regulate the immune response to tumors, recent therapies that have been developed to exploit these interactions and the role of predictive biomarkers in treatment selection. 10.1016/j.lungcan.2014.05.005
    Anti-PD-1/PD-L1 Therapy for Non-Small-Cell Lung Cancer: Toward Personalized Medicine and Combination Strategies. Sui Hongshu,Ma Ningxia,Wang Ying,Li Hui,Liu Xiaoming,Su Yanping,Yang Jiali Journal of immunology research Lung cancer remains a leading cause of cancer-related mortality worldwide with the poor prognosis. Encouragingly, immune checkpoint blockade targeting programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) has dramatically changed the landscape for treatments in patients with non-small-cell lung cancer (NSCLC). However, only a small proportion of NSCLC patients responded to monotherapy of anti-PD-1/PDL1 agents; together, the development of resistance to anti-PD-1/PD-L1 therapy that leads to failure of anti-PD-1/PD-L1 therapy has significantly limited a broad applicability of the findings in clinical practices. Nowadays, several companion diagnostic assays for PDL1 expression have been introduced for identifying patients who may benefit the immunotherapy. In addition, results from clinical trials explored combinatory therapeutic strategies with conventional and/or targeted therapy reported a higher efficacy with an acceptable safety profile in NSCLC treatments, as compared to the monotherapy of these agents alone. In this review article, we summarized several anti-PD-1/PD-L1 agents licensed for NSCLC treatment, with a focus on predictive biomarkers and companion diagnostic assays for identification of NSCLC patients for immunotherapy anti-PD-1/PDL1 antibodies. Of a great interest, potentials of the combinatory therapy of anti-PD-1/PDL1 therapy with a conventional or targeted therapy, or other immunotherapy such as CAR-T cell therapy were emphasized in the article. 10.1155/2018/6984948
    Non-Small-Cell Lung Cancer: Role of the Immune System and Potential for Immunotherapy. Carbone David P,Gandara David R,Antonia Scott J,Zielinski Christoph,Paz-Ares Luis Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer As the leading cause of cancer death worldwide, lung cancer continues to impose a major burden on healthcare systems and cause significant challenges for clinicians and patients. Most patients present with advanced disease at the time of diagnosis and have a poor prognosis, with the vast majority surviving less than 5 years. Although new therapies have been introduced in recent years that target molecular disease drivers present in a subset of patients, there is a significant need for treatments able to improve response and extend survival while minimizing effects on quality of life. Recent evidence of clinical efficacy for immunotherapeutic approaches for lung cancer suggests that they will become the next major therapeutic advance for this disease. Non-small-cell lung cancer, which accounts for approximately 85% of lung cancer cases, has historically been considered a nonimmunogenic disease; however, as with several other malignancies, recent data show that much of this lack of immune responsiveness is functional rather than structural (i.e., possible to overcome therapeutically). This review explores the key elements of the immune system involved in non-small-cell lung cancer and briefly examines immunotherapeutic strategies in development to shift the balance of immune activity away from a tumor-induced immune-suppressive state toward an active antitumor immune response. 10.1097/JTO.0000000000000551
    Acquired resistance to EGFR targeted therapy in non-small cell lung cancer: Mechanisms and therapeutic strategies. Lim Sun Min,Syn Nicholas L,Cho Byoung Chul,Soo Ross A Cancer treatment reviews The tyrosine kinase inhibitors (TKIs) directed at sensitizing mutations in the epidermal growth factor receptor (EGFR) gene represents a critical pillar in non-small cell lung cancer treatment. Despite the excellent disease control with initial EGFR TKI therapy, acquired resistance is ubiquitous and remains a key challenge. Investigations into the mechanisms which foster resistance to EGFR TKIs has led to the discovery of novel biomarkers and drug targets, and in turn has enabled the development of third-generation TKIs and proposals for rational therapeutic combinations. The threonine-to-methionine substitution mutation at position 790 (T790M) is clinically validated to engender refractoriness to first- and second-generation TKIs, and is a standard-of-care predictive biomarker used in therapeutic stratification. Clinical use of liquid biopsy approaches for assessment of T790M mutations continues to increase, with growing advocacy for serial monitoring of tumor evolution. For patients who are T790M-negative, cytotoxic chemotherapy or protracted EGFR TKI treatment are acceptable treatment standards after disease progression, although combinations of targeted therapies and checkpoint blockade immunotherapy may offer promising alternatives in the future. Among T790M-positive patients, the third-generation EGFR TKI, osimertinib, has shown superiority over both platinum-doublet chemotherapy and 1st generation EGFR TKI in randomized clinical trials, and exhibits enhanced in vitro selectivity for mutant EGFR receptors and pharmacokinetics compared to earlier-generation TKIs. This article appraises the key literature on the contemporary management of non-small cell lung cancer patients with acquired resistance to EGFR TKIs, and envisions future directions in translational and clinical research. 10.1016/j.ctrv.2018.02.006
    When to Consider Immune Checkpoint Inhibitors in Oncogene-Driven Non-Small Cell Lung Cancer? Mhanna Laurent,Guibert Nicolas,Milia Julie,Mazieres Julien Current treatment options in oncology OPINION STATEMENT:Targeted therapies and more recently immune checkpoint inhibitors (ICI) have transformed the treatment landscape of advanced NSCLC. Clinical trials investigating immune checkpoint inhibitors (ICI) have usually excluded patients with oncogenic drivers, so that the outcome of these agents in this population is poorly known. In patients with oncogenic addiction, targeted therapy remains clearly the best option, and the place of immunotherapy in this population has not been clearly defined yet.Based on available data, we suggest that (i) immunotherapy single agent should be proposed only after exhaustion of more validated treatments, (ii) combinations of immunotherapy with targeted therapies are of interest provided that we can manage toxicity and find the best sequence, (iii) a combination of immunotherapy with chemotherapy may be appealing in patients pretreated with targeted agents. The best way to opt in for the best strategy will depend upon the identification of adequate biomarkers. New basic and clinical research is awaited in this field. 10.1007/s11864-019-0652-3
    Combination Therapy of Radiotherapy and Anti-PD-1/PD-L1 Treatment in Non-Small-cell Lung Cancer: A Mini-review. Takamori Shinkichi,Toyokawa Gouji,Takada Kazuki,Shoji Fumihiro,Okamoto Tatsuro,Maehara Yoshihiko Clinical lung cancer Immune checkpoint inhibitors against programmed cell death-1 (PD-1) or programmed cell death-ligand 1 (PD-L1) are a standard pharmacologic therapy for patients with non-small-cell lung cancer (NSCLC). Substantial data have accumulated in recent years showing that radiotherapy combined with immunotherapy is more effective than monotherapy alone. Preclinical studies have shown that PD-L1 expression is upregulated on tumor cells after radiotherapy, resulting in the synergistically enhanced antitumor effect of irradiation and PD-L1 blockade. In the clinical setting, patients receiving radiotherapy before anti-PD-1 treatment have had a significantly better prognosis than those who have not undergone radiotherapy. In the present report, we reviewed previous studies of the combination of radiotherapy and anti-PD-1/PD-L1 treatment for NSCLC. In addition, we report our case of a patient whose PD-L1 expression gradually increased in brain metastases from NSCLC after repeated radiotherapy. In the perspectives portion, we focused on the questions of how to integrate radiotherapy into anti-PD-1/PD-L1 agent regimens and described several ongoing clinical trials. 10.1016/j.cllc.2017.06.015
    Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy. Skoulidis Ferdinandos,Heymach John V Nature reviews. Cancer The impressive clinical activity of small-molecule receptor tyrosine kinase inhibitors for oncogene-addicted subgroups of non-small-cell lung cancer (for example, those driven by activating mutations in the gene encoding epidermal growth factor receptor (EGFR) or rearrangements in the genes encoding the receptor tyrosine kinases anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 (ROS1) and rearranged during transfection (RET)) has established an oncogene-centric molecular classification paradigm in this disease. However, recent studies have revealed considerable phenotypic diversity downstream of tumour-initiating oncogenes. Co-occurring genomic alterations, particularly in tumour suppressor genes such as TP53 and LKB1 (also known as STK11), have emerged as core determinants of the molecular and clinical heterogeneity of oncogene-driven lung cancer subgroups through their effects on both tumour cell-intrinsic and non-cell-autonomous cancer hallmarks. In this Review, we discuss the impact of co-mutations on the pathogenesis, biology, microenvironmental interactions and therapeutic vulnerabilities of non-small-cell lung cancer and assess the challenges and opportunities that co-mutations present for personalized anticancer therapy, as well as the expanding field of precision immunotherapy. 10.1038/s41568-019-0179-8
    Mechanisms of immune evasion and current status of checkpoint inhibitors in non-small cell lung cancer. Qin Angel,Coffey David G,Warren Edus H,Ramnath Nithya Cancer medicine In the past several years, immunotherapy has emerged as a viable treatment option for patients with advanced non-small cell lung cancer (NSCLC) without actionable driver mutations that have progressed on standard chemotherapy. We are also beginning to understand the methods of immune evasion employed by NSCLC which likely contribute to the 20% response rate to immunotherapy. It is also yet unclear what tumor or patient factors predict response to immunotherapy. The objectives of this review are (1) review the immunogenicity of NSCLC (2) describe the mechanisms of immune evasion (3) summarize efforts to target the anti-program death-1 (PD-1) and anti-program death-ligand 1(PD-L1) pathway (4) outline determinants of response to PD-1/PD-L1 therapy and (5) discuss potential future areas for research. 10.1002/cam4.819
    Immunotherapeutic strategies in non-small-cell lung cancer: the present and the future. Steendam Christi M,Dammeijer Floris,Aerts Joachim G J V,Cornelissen Robin Immunotherapy Non-small cell lung cancer (NSCLC) is still the leading cause of cancer death worldwide, with a poor prognosis. In the era of immunotherapies, the field is rapidly changing, and the clinician needs to be aware of the current state and future perspectives of immunotherapeutic strategies. In this review, we discuss the current status of immune checkpoint inhibitors, cancer vaccines and cellular therapies specifically in NSCLC. Last but not least, we will discuss rational combination strategies that are promising for the near future. 10.2217/imt-2016-0151
    PD-L1 immunohistochemistry for non-small cell lung carcinoma: which strategy should be adopted? Hofman Paul Expert review of molecular diagnostics INTRODUCTION:PD-L1 detection with immunohistochemistry (IHC) is the only predictive biomarker available to date for PD-L1/PD1 immunotherapy in thoracic oncology. While many studies have been published on this biomarker, they raise a number of questions concerning mainly, (i) the type of antibody for use and its condition of utilization, (ii) the threshold to be used, (iii) the message and information to communicate to the thoracic oncologist and, (iv) the adoption of this methodology as part of the daily practices of a pathology laboratory. Areas covered: This review provides an update on the use of the different PD-L1 antibodies for IHC in the context of metastatic non-small cell lung cancer (NSCLC) and discusses their use as companion or complementary diagnostic tests. The limits of PD-L1 IHC as a predictive test, the precautions to be adopted as well as some perspectives will then be considered. Expert commentary: IHC for PD-L1 can be considered as a theranostic test, which implies providing an extremely reliable result that avoids any false positive and negative results. PD-L1 IHC requires considerable expertise and specific training of pathologists. PD-L1 IHC can be a companion or complementary diagnostic test depending on the clone employed, the molecular therapy prescribed and the indication of use. 10.1080/14737159.2017.1398083
    Immunotherapy in Non-Small Cell Lung Cancer: Facts and Hopes. Doroshow Deborah B,Sanmamed Miguel F,Hastings Katherine,Politi Katerina,Rimm David L,Chen Lieping,Melero Ignacio,Schalper Kurt A,Herbst Roy S Clinical cancer research : an official journal of the American Association for Cancer Research Immune-checkpoint inhibitors (ICI), particularly inhibitors of the PD-1 axis, have altered the management of non-small cell lung cancer (NSCLC) over the last 10 years. First demonstrated to improve outcomes in second-line or later therapy of advanced disease, ICIs were shown to improve overall survival compared with chemotherapy in first-line therapy for patients whose tumors express PD-L1 on at least 50% of cells. More recently, combining ICIs with chemotherapy has been shown to improve survival in patients with both squamous and nonsquamous NSCLC, regardless of PD-L1 expression. However, PD-L1 and, more recently, tumor mutational burden have not proven to be straightforward indicative biomarkers. We describe the advances to date in utilizing these biomarkers, as well as novel markers of tumor inflammation, to ascertain which patients are most likely to benefit from ICIs. Ongoing translational work promises to improve the proportion of patients who benefit from these agents. 10.1158/1078-0432.CCR-18-1538
    Anti-PD-1/PD-L1 antibodies in non-small cell lung cancer: the era of immunotherapy. Valecha Gautam Kishore,Vennepureddy Adarsh,Ibrahim Uroosa,Safa Firas,Samra Bachar,Atallah Jean Paul Expert review of anticancer therapy INTRODUCTION:Advanced non-small cell lung cancer (NSCLC) has been conventionally treated with cytotoxic chemotherapy with short-lived responses and significant toxicities. Monoclonal antibodies to programmed death-1 receptor (PD-1) and programmed death ligand 1 (PD-L1) have shown tremendous promise in the treatment of advanced NSCLC in various clinical trials. Areas covered: In this article, we will review the outcomes of various trials of anti-PD-1/anti-PD-L1 antibodies in the treatment of NSCLC. We will also discuss their mechanism of action and toxicities. Expert commentary: Anti-PD-1/PD-L1 antibodies offer several advantages including significant antitumor activity, induction of long lasting responses, and favorable safety profile. Several trials are now being conducted to evaluate their efficacy as first line agents as well as in combination with other agents. More research is also needed to identify other biomarkers, in addition to PD-L1 expression, that could more reliably predict response to these drugs, and aid in better patient selection. 10.1080/14737140.2017.1259574
    Role of cytokines in combinatorial immunotherapeutics of non-small cell lung cancer through systems perspective. Misra Pragya,Singh Shailza Cancer medicine Lung cancer is the leading cause of deaths related to cancer and accounts for more than a million deaths per year. Various new strategies have been developed and adapted for treatment; still the survival for 5 years is just 16% in patients with non-small cell lung cancer (NSCLC). Most of these strategies to combat NSCLC whether it is a drug molecule or immunotherapy/vaccine candidate require a big cost and time. Integration of computational modeling with systems biology has opened new avenues for understanding complex cancer biology. Resolving the complex interactions of various pathways and their crosstalk leading to oncogenic changes could identify new therapeutic targets with lesser cost and time. Herein, this review provides an overview of various aspects of NSCLC along with available strategies for its cure concluding with our insight into how systems approach could serve as a therapeutic intervention dissecting the immunologic parameters and cross talk between various pathways involved. 10.1002/cam4.2112
    Current WHO guidelines and the critical role of immunohistochemical markers in the subclassification of non-small cell lung carcinoma (NSCLC): Moving from targeted therapy to immunotherapy. Osmani Lais,Askin Frederic,Gabrielson Edward,Li Qing Kay Seminars in cancer biology Recent large scale genomic studies from the Clinical Lung Cancer Genome Project have identified different driver gene mutations in the subtypes of non-small cell lung carcinoma (NSCLC). These findings not only lead to remarkable progress in targeted therapies for lung cancer patients, but also provide fundamental knowledge for the subclassification of NSCLC. More recently, the advancement and clinical application of immunotherapy have reinforced the need for the accurate subclassification of NSCLC. In 2015, the World Health Organization (WHO) and the International Association for the Study of Lung Cancer (IASLC) updated their guidelines for the subclassification of lung cancers. These guidelines emphasize: (1) the subclassification of NSCLC, (2) the critical role of molecular characterization of tumors for targeted therapy, (3) the unique terminology for subclassifying NSCLC using small biopsy specimens, and (4) the utility of IHC biomarkers in the accurate diagnosis and subclassification of lung cancer. The guidelines have significant prognostic impact on oncologic practice and patient care. In this review, we summarize the current WHO guidelines for the classification of lung cancer, discuss advancements of targeted therapy and immunotherapy, and address the utility and limitation of immunomarkers in the subclassification of NSCLC, as well as the prospective future of the field. 10.1016/j.semcancer.2017.11.019
    Feasibility and Safety of Intrathoracic Biopsy and Repeat Biopsy for Evaluation of Programmed Cell Death Ligand-1 Expression for Immunotherapy in Non-Small Cell Lung Cancer. Tsai Emily B,Pomykala Kelsey,Ruchalski Kathleen,Genshaft Scott,Abtin Fereidoun,Gutierrez Antonio,Kim Hyun J,Li Alice,Adame Carlos,Jalalian Ashkan,Wolf Brian,Garon Edward B,Goldman Jonathan W,Suh Robert Radiology Purpose To determine feasibility and safety of biopsy and repeat biopsy for assessment of programmed cell death ligand-1 (PD-L1) status. Materials and Methods This retrospective analysis reviewed 101 patients who underwent transthoracic core needle biopsy for the KEYNOTE-001 (MK-3475) clinical trial of pembrolizumab, an antiprogrammed cell death-1 therapy for non-small cell lung cancer, from May 2012 to September 2014. Sixty-one male patients (mean age, 66.1 years; range 36-83 years) and 40 female patients (mean age, 66.8 years; age range, 36-90 years) were included. Data collected included population characteristics, treatment history, target location, size, and depth from pleura. Adequacy of the tissue sample for diagnostic testing and rates of biopsy-related complications were assessed. Statistical analysis was performed by using univariate and multivariate generalized linear models to determine significant risk factors for biopsy complications. Results A total of 110 intrathoracic biopsies were performed, and 101 (91.8%) were performed as repeat biopsies subsequent to a previous percutaneous or bronchoscopic biopsy or previous surgical biopsy or resection. More than 84.5% (93 of 110) of biopsies were performed in patients who had undergone previous local or systemic therapy. Specimens were adequate for evaluation of PD-L1 expression in 96.4% of biopsies. Procedure-related complications occurred in 28 biopsies (25.4%); pneumothorax was most common (22.7%). Overall mean number of core needle biopsy samples obtained was 7.9 samples. Conclusion Image-guided transthoracic core needle biopsy is an effective method for obtaining tissue for PD-L1 expression analysis. RSNA, 2017. 10.1148/radiol.2017170347
    Immune Checkpoint Immunotherapy for Non-Small Cell Lung Cancer: Benefits and Pulmonary Toxicities. Suresh Karthik,Naidoo Jarushka,Lin Cheng Ting,Danoff Sonye Chest Immune checkpoint inhibitors (ICIs) are newer, immunotherapy-based drugs that have been shown to improve survival in advanced non-small cell lung cancer (NSCLC). Unlike traditional chemotherapeutic agents, ICIs work by boosting the body's natural tumor killing response. However, this unique mechanism of action has also led to the recognition of class-specific side effects. Labeled immune-related adverse events, these toxicities can affect multiple organ systems including the lungs. Immune-mediated lung injury because of ICI use, termed checkpoint inhibitor pneumonitis (CIP), occurs in about 3% to 5% of patients receiving ICIs; however, the real-world incidence of this entity may be higher, especially now that ICIs are being used in nonclinical trial settings. In this review, we briefly introduce the biology of ICIs and the indications for ICI use in NSCLC and then discuss the epidemiology and clinical and radiologic manifestations of CIP. Next, we discuss management strategies for CIP, including the current consensus on management of steroid-refractory CIP. Given the nascent nature of this field, we highlight areas of uncertainty and emerging research questions in the burgeoning field of checkpoint inhibitor pulmonary toxicity. 10.1016/j.chest.2018.08.1048
    Molecular basis and rationale for combining immune checkpoint inhibitors with chemotherapy in non-small cell lung cancer. Leonetti Alessandro,Wever Birgit,Mazzaschi Giulia,Assaraf Yehuda G,Rolfo Christian,Quaini Federico,Tiseo Marcello,Giovannetti Elisa Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy Immunotherapy has prompted a paradigm shift in advanced non-small cell lung cancer (NSCLC) treatment, by demonstrating superior efficacy to chemotherapy alone both in second- and in first-line setting. Novel insights on molecular mechanisms and regimens to enhance the efficacy of immunotherapy are warranted, as only a minority of patients (˜20%) respond to checkpoint blockade. Taking into account the multiple mechanisms adopted by tumor cells to evade the immune system through cancer immunoediting, the frontline combination of immune checkpoint inhibitors with chemotherapy appears to be a successful strategy as: 1) it enhances the recognition and elimination of tumor cells by the host immune system (immunogenic cell-death), and 2) it reduces the immunosuppressive tumor microenvironment. Remarkably, the immune checkpoint inhibitors pembrolizumab and atezolizumab have already been approved by the FDA in combination with chemotherapy for the first-line treatment of advanced NSCLC and many other chemo-immunotherapeutic regimens have been evaluated as an initial therapeutic approach in metastatic NSCLC. Concurrently, several preclinical studies are evaluating the molecular mechanisms underlying immunomodulation by conventional chemotherapeutic agents (platinum salts, antimitotic agents, antimetabolites and anthracyclines), unraveling drug- and dose/schedule-dependent effects on the immune system that should be exploited to achieve synergistic clinical activity. The current review provides a detailed overview of the immunobiological rationale and molecular basis for combining immune checkpoint inhibitors with chemotherapy for the treatment of advanced NSCLC. Moreover, current evidence and future perspectives towards a better selection of patients who are more likely to benefit from chemo-immunotherapy combinations are discussed. 10.1016/j.drup.2019.100644
    PD-1/PD-L1 Blockade Therapy in Advanced Non-Small-Cell Lung Cancer: Current Status and Future Directions. Xia Liliang,Liu Yuanyong,Wang Ying The oncologist The use of immune checkpoint inhibitors (ICIs) has become one of the most promising approaches in the field of cancer therapy. Unlike the current therapies that target tumor cells, such as chemotherapy, radiotherapy, or targeted therapy, ICIs directly restore the exhausted host antitumor immune responses mediated by the tumors. Among multiple immune modulators identified, the programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) axis leading to the exhaustion of T-cell immunity in chronic infections and tumors has been widely investigated. Therefore, blocking antibodies targeting PD-1 or PD-L1 have been developed and approved for the treatment of various advanced cancers, including non-small-cell lung cancer (NSCLC), making them the most successful ICIs. Compared with chemotherapy or radiotherapy, PD-1/PD-L1 blockade therapy significantly improves the durable response rate and prolongs long-term survival with limited adverse effects in both monotherapy and combination therapy for advanced NSCLC. However, extensive challenges exist for further clinical applications, such as a small fraction of benefit population, primary and acquired resistance, the lack of predictive and prognostic biomarkers, and treatment-related adverse effects. In this article, we summarize the latest clinical applications of PD-1/PD-L1 blockade therapy in advanced NSCLC worldwide, as well as in China, and discuss the bottlenecks related to the use of this therapy in clinical practice. An exploration of the underlying mechanism of PD-1/PD-L1 blockade therapy and biomarker identification will maximize the application of ICIs in advanced NSCLC and facilitate bedside-to-bench studies in cancer immunotherapy as well. IMPLICATIONS FOR PRACTICE: Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) and programmed cell death protein ligand 1 (PD-L1) display apparent benefits for the treatment of advanced non-small-cell lung cancer (NSCLC). However, the clinical applications of these therapies are challenged by the limited benefit population with additional high economic burden and adverse events. This review discusses the bottlenecks of ICI therapy in clinical practice and provides appropriate guidance in the development of predictive biomarkers, the establishment of the criteria for combining PD-1/PD-L1 blockade therapy with the existing therapies, and the management of adverse events observed both in monotherapy and combination therapy, which will help maximize the applications of ICIs in advanced NSCLC. 10.1634/theoncologist.2019-IO-S1-s05
    Spatially Resolved and Quantitative Analysis of VISTA/PD-1H as a Novel Immunotherapy Target in Human Non-Small Cell Lung Cancer. Villarroel-Espindola Franz,Yu Xiaoqing,Datar Ila,Mani Nikita,Sanmamed Miguel,Velcheti Vamsidhar,Syrigos Konstantinos,Toki Maria,Zhao Hongyu,Chen Lieping,Herbst Roy S,Schalper Kurt A Clinical cancer research : an official journal of the American Association for Cancer Research Determine the localized expression pattern and clinical significance of VISTA/PD-1H in human non-small cell lung cancer (NSCLC). Using multiplex quantitative immunofluorescence (QIF), we performed localized measurements of VISTA, PD-1, and PD-L1 protein in 758 stage I-IV NSCLCs from 3 independent cohorts represented in tissue microarray format. The targets were selectively measured in cytokeratin tumor epithelial cells, CD3 T cells, CD4 T-helper cells, CD8 cytotoxic T cells, CD20 B lymphocytes and CD68 tumor-associated macrophages. We determined the association between the targets, clinicopathological/molecular variables and survival. Genomic analyses of lung cancer cases from TCGA were also performed. VISTA protein was detected in 99% of NSCLCs with a predominant membranous/cytoplasmic staining pattern. Expression in tumor and stromal cells was seen in 21% and 98% of cases, respectively. The levels of VISTA were positively associated with PD-L1, PD-1, CD8 T cells and CD68 macrophages. VISTA expression was higher in T-lymphocytes than in macrophages; and in cytotoxic T cells than in T-helper cells. Elevated VISTA was associated with absence of EGFR mutations and lower mutational burden in lung adenocarcinomas. Presence of VISTA in tumor compartment predicted longer 5-year survival. VISTA is frequently expressed in human NSCLC and shows association with increased tumor-infiltrating lymphocytes, PD-1 axis markers, specific genomic alterations and outcome. These results support the immunomodulatory role of VISTA in human NSCLC and suggests its potential as therapeutic target. . 10.1158/1078-0432.CCR-17-2542
    Real-world evidenceand clinical observations of the treatment of advanced non-small cell lung cancer with PD-1/PD-L1 inhibitors. Song Peng,Zhang Jingcheng,Shang Congcong,Zhang Li Scientific reports To summarize the therapeutic effects of PD-1/PD-L1 inhibitors on patients with advanced non-small cell lung cancer (NSCLC) in a real-world setting, we attempted to identify potential molecular biomarkers or clinical factors that reflected the therapeutic effect. The medical records of patients with non-small cell lung cancer who were treated with PD-1/PD-L1 inhibitors were obtained from the outpatient department or inpatient department of Peking Union Medical College Hospital from August 1, 2015, to January 1, 2018. Our follow-up continued until May 1,2018. We chose overall survival (OS) as the primary observation endpoint and progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety as the secondary observation endpoints. Efficacy was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The Kaplan-Meier method was used to generate survival curves, and we compared the influence of different factors on PFS and OS by the log-rank test. The median follow-up time was 11 months. At the end of the follow-up, 24 patients (61.5%) were still undergoing immunotherapy, and 7 patients (17.9%) had died. Twenty-six cases (66.7%) employed PD-1/PD-L1 inhibitors as first-line treatment, and 7 cases (17.9%) employed PD-1/PD-L1 inhibitors as second-line treatment. Only 6 cases (15.4%) employed PD-1/PD-L1 inhibitors as third-line treatment. Therapeutic effect evaluation: Complete response (CR): 1 case (2.6%). Partial response (PR): 10 cases (25.6%). Stable disease (SD): 16 cases (41.0%). Progressive disease (PD): 12 cases (30.8%). The ORR was 28.2%, and DCR was 69.2%. The median PFS was 25.5 months (95% CI 6.8-44.1 months), which failed to reach the median OS. PD-1/PD-L1 inhibitor treatment is more effective for advanced non-small cell lung cancer patients in a real-world setting than in clinical trials; PD-1/PD-L1 inhibitor treatment is more effective for people who are over 70 than for people who are under 70. Additionally, patients who are over 75 years old have a higher response rate, suggesting that elderly patients may receive more benefits from immunotherapy; Patients who have an epidermal growth factor receptor (EGFR) mutation (+) may benefit from immunotherapy after treatment with a tyrosine kinase inhibitor (TKI). It is essential to identify these potential patients from the entire patient pool; PD-1 may have a certain curative effect on brain metastases from NSCLC. Local radiotherapy may help to improve PD-1 intracranial efficacy. 10.1038/s41598-019-40748-7
    [Research progress of immune checkpoint inhibitors in clinical diagnosis and treatment of non-small cell lung cancer]. Huang Y,Xu K,Wang W,Cui F,Zeng Y,Hao Z X,Cai W P,He J X,Liu J Zhonghua zhong liu za zhi [Chinese journal of oncology] Lung cancer is currently the malignant tumor with the highest morbidity and mortality in the world, and the main type is non-small cell lung cancer. Immune checkpoint inhibitor is a landmark discovery in the history of cancer treatment, which rewrites the history of cancer treatment, and improves the medical treatment of advanced tumors by a big step forward. The article summarizes the research progress of therapeutic drugs against anti-programmed cell death protein and programmed cell death protein ligand antibodies in the clinical diagnosis and treatment of non-small cell lung cancer. The principle of drug action, the differences in the diagnosis and treatment of non-small cell lung cancer in different clinical stages, and future research directions are discussed to provide the usage guidelines of immune checkpoint inhibitors for clinical oncologists. 10.3760/cma.j.cn112152-20200330-00276
    Successes and failures: what did we learn from recent first-line treatment immunotherapy trials in non-small cell lung cancer? Remon Jordi,Besse Benjamin,Soria Jean-Charles BMC medicine The immune checkpoint inhibitors have significantly modified the therapeutic landscape of advanced non-small cell lung cancer in second-line and, more recently, first-line settings. Because of the superior outcome with pembrolizumab as an upfront strategy, PD-L1 status should now be considered a new reflex biomarker for guiding first-line treatment in patients with advanced non-small cell lung cancer. Improved responses have also been reported with the combination of immune checkpoint inhibitors and chemotherapy as the first-line treatment; however, this strategy has not yet been validated by phase III trial data and its interplay with PD-L1 status still requires clarification.In this manuscript we review the contradictory results of recent phase III trials with immune checkpoint inhibitors in the first-line setting, the potential reasons for discrepancies, and some of the remaining open questions related to the positioning of immune checkpoint inhibitors in the first-line setting of non-small cell lung cancer. 10.1186/s12916-017-0819-3
    [Progress of immune checkpoint inhibitors in neoadjuvant therapy of non-small cell lung cancer]. Chen X Y,Yang F Zhonghua wai ke za zhi [Chinese journal of surgery] Lung cancer carries the highest morbidity and mortality out of all malignancies in the world. About 85% of all cases are non-small cell lung cancer (NSCLC). Surgery is currently the optimal treatment for early-stage NSCLC, however, the postoperative recurrence rate is relatively high and the long-term survival of these patients is still a problem to be overcomed. Previous studies have shown that early-stage NSCLC patients may benefit from preoperative neoadjuvant chemotherapy when compared to surgery alone, although the benefit is only moderate. More recent publications indicate that immune checkpoint blockade may have better potential in neoadjuvant therapy, with reported major pathological response rates at 20% to 85%, compared to chemotherapy alone. Phase Ⅲ random clinical trials are being implemented to confirm the effect of neoadjuvant immunotherapy in NSCLC. Meanwhile, a number of questions remain unanswered, including the time and course of neoadjuvant immunotherapy, the evaluation criteria of immune-related efficacy, the standardization of pathological evaluation, and how to avoid delays in surgery or misjudgment caused by pseudo-progression. 10.3760/cma.j.issn.0529-5815.2019.11.015
    Assessment of Blood Tumor Mutational Burden as a Potential Biomarker for Immunotherapy in Patients With Non-Small Cell Lung Cancer With Use of a Next-Generation Sequencing Cancer Gene Panel. Wang Zhijie,Duan Jianchun,Cai Shangli,Han Miao,Dong Hua,Zhao Jun,Zhu Bo,Wang Shuhang,Zhuo Minglei,Sun Jianguo,Wang Qiming,Bai Hua,Han Jiefei,Tian Yanhua,Lu Jing,Xu Tongfu,Zhao Xiaochen,Wang Guoqiang,Cao Xinkai,Li Fugen,Wang Dalei,Chen Yuejun,Bai Yuezong,Zhao Jing,Zhao Zhengyi,Zhang Yuzi,Xiong Lei,He Jie,Gao Shugeng,Wang Jie JAMA oncology Importance:Tumor mutational burden (TMB), as measured by whole-exome sequencing (WES) or a cancer gene panel (CGP), is associated with immunotherapy responses. However, whether TMB estimated by circulating tumor DNA in blood (bTMB) is associated with clinical outcomes of immunotherapy remains to be explored. Objectives:To explore the optimal gene panel size and algorithm to design a CGP for TMB estimation, evaluate the panel reliability, and further validate the feasibility of bTMB as a clinical actionable biomarker for immunotherapy. Design, Setting, and Participants:In this cohort study, a CGP named NCC-GP150 was designed and virtually validated using The Cancer Genome Atlas database. The correlation between bTMB estimated by NCC-GP150 and tissue TMB (tTMB) measured by WES was evaluated in matched blood and tissue samples from 48 patients with advanced NSCLC. An independent cohort of 50 patients with advanced NSCLC was used to identify the utility of bTMB estimated by NCC-GP150 in distinguishing patients who would benefit from anti-programmed cell death 1 (anti-PD-1) and anti-programmed cell death ligand 1 (anti-PD-L1) therapy. The study was performed from July 19, 2016, to April 20, 2018. Main Outcomes and Measures:Assessment of the Spearman correlation coefficient between bTMB estimated by NCC-GP150 and tTMB calculated by WES. Evaluation of the association of bTMB level with progression-free survival and response to anti-PD-1 and anti-PD-L1 therapy. Results:This study used 2 independent cohorts of patients with NSCLC (cohort 1: 48 patients; mean [SD] age, 60 [13] years; 15 [31.2%] female; cohort 2: 50 patients; mean [SD] age, 58 [8] years; 15 [30.0%] female). A CGP, including 150 genes, demonstrated stable correlations with WES for TMB estimation (median r2 = 0.91; interquartile range, 0.89-0.92), especially when synonymous mutations were included (median r2 = 0.92; interquartile range, 0.91-0.93), whereas TMB estimated by the NCC-GP150 panel found higher correlations with TMB estimated by WES than most of the randomly sampled 150-gene panels. Blood TMB estimated by NCC-GP150 correlated well with the matched tTMB calculated by WES (Spearman correlation = 0.62). In the anti-PD-1 and anti-PD-L1 treatment cohort, a bTMB of 6 or higher was associated with superior progression-free survival (hazard ratio, 0.39; 95% CI, 0.18-0.84; log-rank P = .01) and objective response rates (bTMB ≥6: 39.3%; 95% CI, 23.9%-56.5%; bTMB <6: 9.1%; 95% CI, 1.6%-25.9%; P = .02). Conclusions and Relevance:The findings suggest that established NCC-GP150 with an optimized gene panel size and algorithm is feasible for bTMB estimation, which may serve as a potential biomarker of clinical benefit in patients with NSCLC treated with anti-PD-1 and anti-PD-L1 agents. 10.1001/jamaoncol.2018.7098
    Immune checkpoint-inhibitors and chemoradiation in stage III unresectable non-small cell lung cancer. Melosky Barbara,Juergens Rosalyn,McLeod Deanna,Leighl Natasha,Brade Anthony,Card Paul B,Chu Quincy Lung cancer (Amsterdam, Netherlands) Lung cancer resulted in an estimated 1.8 million deaths worldwide in 2018 and approximately 20% of patients with non-small cell lung cancer (NSCLC) are diagnosed with stage III unresectable disease. Phase III data from the PACIFIC trial show significantly improved progression-free survival for the checkpoint-inhibitor durvalumab given as consolidation following definitive chemoradiotherapy (cCRT). Overall survival results from this study have now been reported, along with outcomes from other phase II trials. A thorough review of the efficacy and safety of checkpoint-inhibitors used in conjunction with cCRT for stage III unresectable NSCLC is needed. Published and presented literature on phase II and III data was identified using the key search terms "non-small cell lung cancer" AND "checkpoint-inhibitors" (OR respective aliases). One randomized phase III clinical trial and three phase II trials reporting outcomes of checkpoint-inhibitors in conjunction with cCRT for stage III unresectable NSCLC were identified. PACIFIC reported significantly improved overall survival for consolidation durvalumab following cCRT compared with placebo. Although discontinuation due to adverse events (AEs) was higher with durvalumab, rates of grade 3/4 pneumonitis or radiation pneumonitis were low and comparable between arms. Results from phase II trials also show promising activity for other checkpoint-inhibitors and alternative sequencing strategies, although these need to be confirmed in a randomized context. Preliminary data suggest differences in the safety profiles between PD-1 and PD-L1 inhibitors. Currently, the role of PD-L1 expression levels for patient selection in this setting remains unclear, and durvalumab should be administered on an individual basis in patients with known driver mutations. Consolidation durvalumab following cCRT significantly improves overall survival with an acceptable safety profile in patients with stage III unresectable NSCLC, now representing a new standard of care. 10.1016/j.lungcan.2019.05.027
    Response to Checkpoint Inhibition in Non-Small Cell Lung Cancer with Molecular Driver Alterations. Kauffmann-Guerrero Diego,Tufman Amanda,Kahnert Kathrin,Bollmann Benjamin Alexander,Reu Simone,Syunyaeva Zulfiya,Schneider Christian,Manapov Farkhad,Huber Rudolf M,Golpon Heiko Oncology research and treatment AIMS:Non-small cell lung cancer (NSCLC) patients with EGFR mutations do not respond well to checkpoint inhibitors. However, little is known about the activity of immunotherapy in NSCLC with other driver mutations. The increasing use of next-generation sequencing (NGS) leads to molecular findings that face the clinician with problems while choosing the best treatment. This study aims at analyzing response of NSCLC with driver mutations to immunotherapy. PATIENTS AND METHODS:We retrospectively included 84 NSCLC patients diagnosed and treated at 2 German tertiary-care lung cancer centers using NGS and treatment with immunotherapy. Response to immunotherapy was analyzed in correlation to molecular findings. RESULTS:51 patients harbored at least 1 driver mutation. PIK3CA, EGFR, and STK11 mutations did not respond to immunotherapy. KRAS, TP53, and MET exon 14 skipping mutations responded well. One patient with NF-1 mutation showed durable response. CONCLUSIONS:Molecular testing may be of use in guiding treatment decision making in NSCLC. 10.1159/000506842
    Genomic Features of Response to Combination Immunotherapy in Patients with Advanced Non-Small-Cell Lung Cancer. Hellmann Matthew D,Nathanson Tavi,Rizvi Hira,Creelan Benjamin C,Sanchez-Vega Francisco,Ahuja Arun,Ni Ai,Novik Jacki B,Mangarin Levi M B,Abu-Akeel Mohsen,Liu Cailian,Sauter Jennifer L,Rekhtman Natasha,Chang Eliza,Callahan Margaret K,Chaft Jamie E,Voss Martin H,Tenet Megan,Li Xue-Mei,Covello Kelly,Renninger Andrea,Vitazka Patrik,Geese William J,Borghaei Hossein,Rudin Charles M,Antonia Scott J,Swanton Charles,Hammerbacher Jeff,Merghoub Taha,McGranahan Nicholas,Snyder Alexandra,Wolchok Jedd D Cancer cell Combination immune checkpoint blockade has demonstrated promising benefit in lung cancer, but predictors of response to combination therapy are unknown. Using whole-exome sequencing to examine non-small-cell lung cancer (NSCLC) treated with PD-1 plus CTLA-4 blockade, we found that high tumor mutation burden (TMB) predicted improved objective response, durable benefit, and progression-free survival. TMB was independent of PD-L1 expression and the strongest feature associated with efficacy in multivariable analysis. The low response rate in TMB low NSCLCs demonstrates that combination immunotherapy does not overcome the negative predictive impact of low TMB. This study demonstrates the association between TMB and benefit to combination immunotherapy in NSCLC. TMB should be incorporated in future trials examining PD-(L)1 with CTLA-4 blockade in NSCLC. 10.1016/j.ccell.2018.03.018
    The Significance of the PD-L1 Expression in Non-Small-Cell Lung Cancer: Trenchant Double Swords as Predictive and Prognostic Markers. Takada Kazuki,Toyokawa Gouji,Shoji Fumihiro,Okamoto Tatsuro,Maehara Yoshihiko Clinical lung cancer Lung cancer is the leading cause of death due to cancer worldwide. Surgery, chemotherapy, and radiotherapy have been the standard treatment for lung cancer, and targeted molecular therapy has greatly improved the clinical course of patients with non-small-cell lung cancer (NSCLC) harboring driver mutations, such as in epidermal growth factor receptor and anaplastic lymphoma kinase genes. Despite advances in such therapies, the prognosis of patients with NSCLC without driver oncogene mutations remains poor. Immunotherapy targeting programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) has recently been shown to improve the survival in advanced NSCLC. The PD-L1 expression on the surface of tumor cells has emerged as a potential biomarker for predicting responses to immunotherapy and prognosis after surgery in NSCLC. However, the utility of PD-L1 expression as a predictive and prognostic biomarker remains controversial because of the existence of various PD-L1 antibodies, scoring systems, and positivity cutoffs. In this review, we summarize the data from representative clinical trials of PD-1/PD-L1 immune checkpoint inhibitors in NSCLC and previous reports on the association between PD-L1 expression and clinical outcomes in patients with NSCLC. Furthermore, we discuss the future perspectives of immunotherapy and immune checkpoint factors. 10.1016/j.cllc.2017.10.014
    Amplifying Outcomes: Checkpoint Inhibitor Combinations in First-Line Non-Small Cell Lung Cancer. Melosky Barbara,Juergens Rosalyn,Hirsh Vera,McLeod Deanna,Leighl Natasha,Tsao Ming-Sound,Card Paul B,Chu Quincy The oncologist PURPOSE:Lung cancer is one of the most common types of cancer, resulting in approximately 1.8 million deaths worldwide. Immunotherapy using checkpoint inhibitors has become standard of care in advanced non-small cell lung cancer (NSCLC), and there is increasing interest in further improving outcomes through combination with other therapeutics. This systematic review evaluates emerging phase III data on the efficacy and safety of checkpoint inhibitor combinations as first-line treatment for advanced NSCLC. MATERIALS AND METHODS:Published and presented literature was searched using the key search terms "non-small cell lung cancer" AND "checkpoint-inhibitors" (OR respective aliases) AND phase III trials. Seven randomized phase III clinical trials reporting outcomes on checkpoint inhibitor combinations in first-line advanced NSCLC were identified. RESULTS:Four first-line trials reported outcomes for checkpoint inhibitor combinations in nonsquamous NSCLC. Pembrolizumab-chemotherapy, atezolizumab-chemotherapy, and atezolizumab-bevacizumab-chemotherapy showed significantly improved overall survival compared with controls in patients with advanced nonsquamous epidermal growth factor receptor-negative (EGFR-)/ anaplastic lymphoma kinase gene (ALK)- NSCLC. Two trials reported outcomes for squamous NSCLC, with pembrolizumab-chemotherapy reporting significantly improved overall survival (OS) compared with chemotherapy. The combination of nivolumab-ipilimumab in all-comer histology failed to improve OS compared with histology appropriate chemotherapy in patients regardless of their tumor mutational burden status. Based on improved survival and safety, either pembrolizumab monotherapy or pembrolizumab-chemotherapy administered based on PD-L1 status and histology is a preferred treatment option. Outcomes for atezolizumab-bevacizumab-chemotherapy in EGFR+/ALK+ patients are promising and require further exploration. CONCLUSION:First-line checkpoint inhibitors added to standard therapies improve overall survival for nonsquamous EGFR-/ALK- and squamous advanced NSCLC. IMPLICATIONS FOR PRACTICE:Single-agent immune checkpoint inhibitors are now standard of care for advanced non-small cell lung cancer (NSCLC), and emerging data show that combining these agents with established chemotherapy further improves outcomes. The phase III KEYNOTE-189 and IMPower-130 trials showed significantly improved survival using this strategy for nonsquamous NSCLC, and the phase III KEYNOTE-407 trial showed similar results in squamous disease. Checkpoint inhibitor combinations are therefore an important new treatment option for first-line NSCLC. Programmed death ligand-1 expression may inform the use of checkpoint inhibitor combination therapy, and overall tumor mutation burden is also an emerging biomarker for this new treatment strategy. 10.1634/theoncologist.2019-0027
    Pneumonitis in Non-Small Cell Lung Cancer Patients Receiving Immune Checkpoint Immunotherapy: Incidence and Risk Factors. Suresh Karthik,Voong Khinh Ranh,Shankar Bairavi,Forde Patrick M,Ettinger David S,Marrone Kristen A,Kelly Ronan J,Hann Christine L,Levy Benjamin,Feliciano Josephine L,Brahmer Julie R,Feller-Kopman David,Lerner Andrew D,Lee Hans,Yarmus Lonny,D'Alessio Franco,Hales Russell K,Lin Cheng Ting,Psoter Kevin J,Danoff Sonye K,Naidoo Jarushka Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Checkpoint inhibitor pneumonitis (CIP) is an immune-related adverse event that can occur after initiation of anti-programmed death 1/programmed death ligand 1 immune checkpoint inhibitor (ICI) therapy for the treatment of multiple malignancies, including NSCLC. However, the incidence of CIP has not been previously examined in a population that included both trial-enrolled and non-trial-enrolled patients with advanced NSCLC. Furthermore, risk factors and other clinical characteristics associated with CIP severity are not known. In this study, we retrospectively examined clinical characteristics, incidence, and risk factors for CIP in a cohort of 205 patients with NSCLC, all of whom received anti-programmed death 1/programmed death ligand 1 ICIs. Our results demonstrate a higher incidence of CIP (19%) than previously reported in clinical trials (3%-5%). Our data also suggest that tumor histologic type may be a risk factor for CIP development. We observed a wide range of time to onset of CIP (median 82 days), with high morbidity and mortality associated with higher-grade CIP regardless of degree of immunosuppression. Our data provide new insight into the epidemiology and clinical characteristics of CIP. Further studies are needed to increase CIP pharmacovigilance, improve risk stratification, and refine diagnostic algorithms for the diagnosis and management of this potential life-threatening complication of ICI therapy. 10.1016/j.jtho.2018.08.2035
    Cost effectiveness of immune checkpoint inhibitors for treatment of non-small cell lung cancer: A systematic review. Ding Haiying,Xin Wenxiu,Tong Yinghui,Sun Jiao,Xu Gaoqi,Ye Ziqi,Rao Yuefeng PloS one BACKGROUND:Immune checkpoint inhibitors (ICIs) for treatment of non-small cell lung cancer (NSCLC) have been rapidly evolving. ICIs are likely to be more effective but also lead to escalating healthcare costs. OBJECTIVES:The aim of this study was to evaluate the cost effectiveness of immune checkpoint inhibitors (ICIs) for treatment of non-small cell lung cancer (NSCLC). METHODS:We searched the PubMed, Web of Science, and Cochrane Library for studies comparing the cost effectiveness of ICIs for NSCLC. Potential studies identified were independently checked for eligibility by two authors, with disagreement resolved by a third reviewer. Quality of the included studies was evaluated using Consolidated Health Economic Evaluation Reporting Standards checklists. RESULTS:A total of 22 economic studies were included. Overall reporting of the identified studies largely met CHEERS recommendations. In the first-line setting, for advanced or metastatic NSCLC patients with PD-L1 ≥ 50%, pembrolizumab appeared cost-effective compared with platinum-based chemotherapy in the US and Hong Kong (China), but not in the UK and China. The cost-effectiveness of pembrolizumab versus chemotherapy for first-line treatment of NSCLC in PD-L1 ≥ 1% patients remained obscure. Regardless of PD-L1 expression status, pembrolizumab in combination with chemotherapy could be a cost-effective first-line therapy in the US. On the contrary, addition of atezolizumab to the combination of bevacizumab and chemotherapy was not cost-effective for patients with metastatic non-squamous NSCLC from the US payer perspective. In the second-line setting compared with docetaxel, pembrolizumab was cost-effective; though nivolumab was not cost-effective in the base case, it could be by increased PD-L1 threshold. Results of the cost-effectiveness of atezolizumab second-line treatment remained inconsistent. In addition, the adoption of durvalumab consolidation therapy after chemoradiotherapy could be cost-effective versus no consolidation therapy for patients with stage III NSCLC. CONCLUSIONS:Immunotherapy can be a cost-effective option for treatment of NSCLC in several scenarios. A discount of the agents or the use of PD-L1 expression as a biomarker improves the cost-effectiveness of immunotherapy. 10.1371/journal.pone.0238536
    Effectiveness of first-line treatments in metastatic squamous non-small-cell lung cancer. Levy B P,Signorovitch J E,Yang H,Patterson-Lomba O,Xiang C Q,Parisi M Current oncology (Toronto, Ont.) Background:Commonly used first-line (1L) chemotherapies for patients with advanced squamous-cell lung cancer (scc) include gemcitabine-platinum (gp), nab-paclitaxel-carboplatin (nabpc), and sb-paclitaxel-carboplatin (sbpc) regimens. However, no head-to-head trials have compared those treatments. In the present study, we compared the efficacy of 1L gp, nabpc, and sbpc in patients with scc and in patients with scc who subsequently received second-line (2L) immunotherapy. Methods:Medical records of patients who initiated the 1L treatments of interest between June 2014 and October 2015 were reviewed by 132 participating physicians. Kaplan-Meier curves were used to evaluate overall survival (os), progression-free survival (pfs), and treatment discontinuation (td), and then Cox proportional hazards regression was used to compare the results between the cohorts. Results:Medical records of 458 patients with scc receiving gp ( = 139), nabpc ( = 159), or sbpc ( = 160) as 1L therapy were reviewed. Median os was longer with nabpc (23.9 months) than with gp (16.9 months; adjusted hazard ratio vs. nabpc: 1.55; < 0.05) and with sbpc (18.3 months; adjusted hazard ratio: 1.42; = 0.10). No differences were observed in pfs (median pfs: 8.8, 8.0, and 7.6 months for gp, nabpc, and sbpc respectively; log-rank = 0.76) or in td (median td: 5.5, 5.7, and 4.6 months respectively; = 0.65). For patients who subsequently received 2L immunotherapy, no differences in os were observed (median os: 27.3, 25.0, and 23.0 months respectively; = 0.59). Conclusions:In a nationwide sample of scc patients, longer median os was associated with 1L nabpc than with gp and sbpc. Median os for all 1L agents considered was similar in the subgroup of patients who sequenced to a 2L immunotherapy. 10.3747/co.26.4485
    The superior efficacy of anti-PD-1/PD-L1 immunotherapy in KRAS-mutant non-small cell lung cancer that correlates with an inflammatory phenotype and increased immunogenicity. Liu Chengming,Zheng Sufei,Jin Runsen,Wang Xinfeng,Wang Feng,Zang Ruochuan,Xu Haiyan,Lu Zhiliang,Huang Jianbing,Lei Yuanyuan,Mao Shuangshuang,Wang Yalong,Feng Xiaoli,Sun Nan,Wang Yan,He Jie Cancer letters Immune checkpoint inhibitors against PD-1/PD-L1 yield improved survival rates of KRAS-mutant NSCLC patients, who conferred a poor prognosis without effective targeted therapy until now. Yet, the underlying association between KRAS mutations and immune responses remains unclear. We performed an integrated analysis of the data from publicly available repositories and from clinical center cohorts to explore the association between KRAS mutation status and tumor immunity-associated features, including PD-L1 expression, CD8 tumor-infiltrating lymphocytes (TILs) and tumor mutational burden (TMB). Our results revealed that KRAS mutations are correlated with an inflammatory tumor microenvironment and tumor immunogenicity, resulting in superior patient response to PD-1/PD-L1 inhibitors. Meanwhile, three-pool analysis further confirmed that KRAS-mutant NSCLC patients show remarkable clinical benefit from anti-PD-1/PD-L1 immunotherapy. In addition, a KRAS-mutant lung adenocarcinoma mouse model was established to estimate the relative efficacy of anti-PD-L1 monoclonal antibody monotherapy or combination treatment with docetaxel versus docetaxel alone. Most surprisingly, we found that PD-L1 blockade combined with docetaxel did not promote an anti-tumor response. These findings uncover that PD-1/PD-L1 blockade monotherapy may be the optimal therapeutic schedule in NSCLC patients harboring KRAS mutations. 10.1016/j.canlet.2019.10.027
    Role of Targeted Therapy and Immune Checkpoint Blockers in Advanced Non-Small Cell Lung Cancer: A Review. Abdel Karim Nagla,Kelly Karen The oncologist Advanced non-small cell lung cancer (NSCLC) is a complex disease comprising molecularly distinct tumor types, each with a unique biology that is becoming increasingly better characterized. The aim of this review is to present an optimized treatment schema and the accompanying diagnostic testing approach for patients with advanced NSCLC. There are a number of therapies currently approved for patients with advanced NSCLC, including agents that target particular oncogenic drivers, as well as immune checkpoint blockers (ICBs) that elicit an antitumor response. Identification of genetic alterations (e.g., epidermal growth factor receptor, anaplastic lymphoma kinase, reactive oxygen species proto-oncogene 1, B-Raf proto-oncogene) or programmed cell death ligand-1 expression levels in NSCLC requires diligent molecular testing at initial diagnosis and, in some cases, at disease progression to ensure the most efficacious treatment is delivered. Accurate molecular diagnostic testing, along with the careful selection of currently approved targeted agents, ICBs, or systemic chemotherapy, provides therapy that is personalized according to patients' needs to achieve the best possible outcome. Enrollment in clinical trials that further the development of tailored therapies is highly recommended at all stages of treatment. IMPLICATIONS FOR PRACTICE: Targeted therapies and immune checkpoint blockers provide effective and tailored options for patients with non-small cell lung cancer. Careful molecular analysis of tumor samples is necessary to identify the genetic alterations that are present, to ensure that each patient receives the most efficacious treatment for their specific tumor type. Personalized therapy provides each patient with the best probability for prolonged survival. Enrolling patients in clinical trials should be the first consideration before making each treatment decision. 10.1634/theoncologist.2018-0112
    Pembrolizumab as first-line therapy for metastatic non-small-cell lung cancer. Reck Martin Immunotherapy This review describes trials evaluating the monoclonal antibody pembrolizumab (an immunotherapy that blocks the interaction between programmed death-1 and programmed death-ligand 1 and 2 [PD-L1/PD-L2]) as first-line therapy for advanced non-small-cell lung cancer (NSCLC). In the Phase III KEYNOTE-024 study, pembrolizumab monotherapy significantly improved progression-free survival (primary end point) and overall survival, and was associated with fewer adverse events compared with platinum-based chemotherapy in patients with NSCLC with PD-L1 expression on ≥50% of tumor cells. In cohort G of the Phase I/II KEYNOTE-021 study, pembrolizumab plus pemetrexed and carboplatin significantly improved objective response rate (primary end point) and progression-free survival versus pemetrexed and carboplatin alone, and had manageable toxicity in patients with nonsquamous NSCLC. These results have changed first-line management of advanced NSCLC. 10.2217/imt-2017-0121
    How to make the best use of immunotherapy as first-line treatment of advanced/metastatic non-small-cell lung cancer. Peters S,Reck M,Smit E F,Mok T,Hellmann M D Annals of oncology : official journal of the European Society for Medical Oncology Antibodies that target programmed death 1 (PD-1) or its ligand [programmed death ligand 1 (PD-L1)] have become a mainstay of first-line treatment of advanced/metastatic non-small-cell lung cancer (NSCLC) without targetable genetic alterations. In this review, we summarize results from recent clinical trials that have evaluated the anti-PD-1 antibodies pembrolizumab and nivolumab and the anti-PD-L1 antibodies atezolizumab and durvalumab as first-line treatment as monotherapy and in combination with chemotherapy, other immunotherapies, and antiangiogenesis agents. We discuss factors that may influence treatment selection, including patient baseline clinical and demographic characteristics, tumor histology, and biomarkers such as PD-L1 expression and tumor mutation burden. While immunotherapy has become a central component of first-line treatment of most patients with advanced NSCLC, important questions remain about how treatment should be managed for individual patients. 10.1093/annonc/mdz109
    The interaction of immune checkpoint inhibitor plus chemotherapy in non-small-cell lung cancer: subadditivity, additivity or synergism? Rassy Elie,Bakouny Ziad,Assi Tarek,Karak Fadi El,Pavlidis Nicholas Immunotherapy The hypothesis that the interaction of chemotherapy and immune checkpoint inhibitors (ICIs) is synergistic has not been formally validated. The frontline ICI Phase II/III trials in advanced non-small-cell lung cancer were reviewed for the objective response rates (ORRs) and grade 3-5 adverse events (AEs) of ICI-chemotherapy combinations and those of each individual drug. The expected ORR and grade 3-5 AE of ICI-chemotherapy combinations were computed as the arithmetic sum of the pooled effects of each drug. Statistical pooling was performed using a double arcsine transformation and a random-effects model. Our findings suggest an enhanced effect that is less than additive for the ICI-chemotherapy combinations since the actual ORR and grade 3-5 AE were found to be less than the expected additive effect. 10.2217/imt-2019-0014
    Immune gene signatures for predicting durable clinical benefit of anti-PD-1 immunotherapy in patients with non-small cell lung cancer. Hwang Sohyun,Kwon Ah-Young,Jeong Ju-Yeon,Kim Sewha,Kang Haeyoun,Park Joonsuk,Kim Joo-Hang,Han Ok Jin,Lim Sun Min,An Hee Jung Scientific reports Immune checkpoint blockade is promising for treating non-small-cell lung cancer (NSCLC). We used multipanel markers to predict the response to immune checkpoint inhibitors (ICIs) by characterizing gene expression signatures or individual genes in patients who showed durable clinical benefit to ICIs. Twenty-one patients with NSCLC treated with single-agent anti-programmed cell death protein (PD)-1 antibody were analyzed and their clinicopathological characteristics and response to ICIs were characterized. Nine (43%) showed a durable clinical benefit (DCB), while the remaining 12 (57%) patients showed non-durable benefit (NDB). The M1 and peripheral T cell signatures showed the best performance for discriminating DCB from NDB (sensitivity, specificity, accuracy = 0.89, 1.0, 0.95, respectively). Progression-free survival (PFS) was significantly longer in patients with high M1 signature or high peripheral T cell signature scores. CD137 and PSMB9 mRNA expression was higher in the DCB group than in the NDB group. Patients with high PSMB9 expression showed longer PFS. M1 signature, peripheral T cell signature and high mRNA expression level of CD137 and PSMB9 showed better predictive performance than known biomarkers, such as PD-L1 immunohistochemistry, tumor mutation burden, or tumor-infiltrating lymphocytes. 10.1038/s41598-019-57218-9
    Choosing wisely first line immunotherapy in non-small cell lung cancer (NSCLC): what to add and what to leave out. Proto C,Ferrara R,Signorelli D,Lo Russo G,Galli G,Imbimbo M,Prelaj A,Zilembo N,Ganzinelli M,Pallavicini L M,De Simone I,Colombo M P,Sica A,Torri V,Garassino M C Cancer treatment reviews Immunotherapy has dramatically changed the therapeutic scenario in treatment naïve advanced non-small cell lung cancer (NSCLC). While single agent pembrolizumab has become the standard therapy in patients with PD-L1 expression on tumor cells ≥ 50%, the combination of pembrolizumab or atezolizumab and platinum-based chemotherapy has emerged as an effective first line treatment regardless of PD-L1 expression both in squamous and non-squamous NSCLC without oncogenic drivers. Furthermore, double immune checkpoint inhibition has shown promising results in treatment naïve patients with high tumor mutational burden (TMB). Of note, the presence of both negative PD-L1 expression and low TMB may identify a subgroup of patients who has little benefit from immunotherapy combinations and for whom the best treatment option may still be platinum-based chemotherapy. To date, first-line single agent immune checkpoint blockade has demonstrated limited activity in EGFR mutated NSCLC and the combination of immunotherapy and targeted agents has raised safety concerns in both EGFR and ALK positive NSCLC patients. Finally, in EGFR mutated or ALK rearranged NSCLC, atezolizumab in combination with platinum-based chemotherapy and bevacizumab is emerging as a potential treatment option upon progression to first line tyrosine kinase inhibitors. 10.1016/j.ctrv.2019.03.004
    Immunotherapy for the First-Line Treatment of Patients with Metastatic Non-Small Cell Lung Cancer. Martinez Pablo,Peters Solange,Stammers Timothy,Soria Jean-Charles Clinical cancer research : an official journal of the American Association for Cancer Research Immunotherapy has fundamentally changed the treatment landscape for many patients with cancer. mAbs targeting programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated antigen-4 immune checkpoints have received regulatory approval across a wide range of tumor types, including non-small cell lung cancer (NSCLC). Indeed, treatment approaches for a majority of patients with newly diagnosed metastatic NSCLC are evolving rapidly. Only for the small proportion of patients with metastatic NSCLC and genomic-driven tumors with EGFR or anaplastic lymphoma kinase (ALK)-sensitizing mutations (5%-15%), and possibly mutations and rearrangements, have initial treatment recommendations remained unchanged, with specific tyrosine kinase inhibitors as the preferred therapy. For the remaining patients, an immunotherapy-based regimen alone or in combination with chemotherapy is now the preferred option based on high-level evidence obtained from randomized controlled trials and in accordance with all available guidelines. Deciding between therapeutic options can be difficult due to the lack of direct cross-comparison studies, differences in chemotherapies and stratification factors, and differences in study populations resulting from inclusion criteria such as histology, PD-L1 expression, or tumor mutational burden (TMB). In an attempt to aid the decision-making process, we discuss and summarize the most recent data from studies using immunotherapies for the treatment of patients with previously untreated metastatic NSCLC. 10.1158/1078-0432.CCR-18-3904
    TCR Repertoire Diversity of Peripheral PD-1CD8 T Cells Predicts Clinical Outcomes after Immunotherapy in Patients with Non-Small Cell Lung Cancer. Han Jiefei,Duan Jianchun,Bai Hua,Wang Yuqi,Wan Rui,Wang Xin,Chen Si,Tian Yanhua,Wang Di,Fei Kailun,Yao Zhuoran,Wang Shuhang,Lu Zhimin,Wang Zhijie,Wang Jie Cancer immunology research T-cell receptor (TCR)-based biomarkers might predict patient response to immune checkpoint blockade (ICB) but need further exploration and validation for that use. We sequenced complementarity-determining region 3 of TCRβ chains isolated from PD-1 CD8 T cells to investigate its value for predicting the response to anti-programmed cell death 1 (PD-1)/PD-ligand 1 (PD-L1) therapy in patients with non-small cell lung cancer (NSCLC). Two independent patient cohorts (cohort A, = 25; cohort B, = 15) were used as discovery and validation sets, respectively. Pre- and post-ICB peripheral blood samples were collected. In cohort A, patients with high PD-1 CD8 TCR diversity before ICB treatment showed better response to ICB and progression-free survival (PFS) compared with patients with low diversity [6.4 months vs. 2.5 months, HR, 0.39; 95% confidence interval (CI), 0.17-0.94; = 0.021]. The results were validated in cohort B. Pre-ICB PD-1 CD8 TCR diversity achieved an optimal Youden's index of 0.81 (sensitivity = 0.87 and specificity = 0.94) for differentiating the ICB response in the merged dataset (cohort A plus cohort B). Patients with increased PD-1 CD8 TCR clonality after ICB treatment had longer PFS (7.3 months vs. 2.6 months, HR, 0.26; 95% CI, 0.08-0.86; = 0.002) than those with decreased clonality. Thus, TCR diversity and clonality in peripheral blood PD-1 CD8 T cells may serve as noninvasive predictors of patient response to ICB and survival outcomes in NSCLC. 10.1158/2326-6066.CIR-19-0398
    Immunotherapy in non-small-cell lung cancer: potential predictors of response and new strategies to assess activity. Rossi Sabrina,Castello Angelo,Toschi Luca,Lopci Egesta Immunotherapy The treatment algorithm of advanced non-small-cell lung cancer is rapidly evolving. This result is mostly related to the availability in clinical practice of checkpoint inhibitors targeting the programmed death-1 (PD-1) and its ligands (PD-Ls) immunosuppressive pathway. Although patient's selection in the first-line setting relies essentially on high levels of PD-L1 tumor expression, treatment choice in pretreated patients is more challenging and, although clinical and biological characteristics might be of help, there is an urgent need for novel tools to better identify sensitive and resistant patients. In this context, the integration of molecular markers and immune-PET imaging might represent a potentially effective strategy to refine patient selection. 10.2217/imt-2017-0187
    Transcriptome-based molecular subtyping of non-small cell lung cancer may predict response to immune checkpoint inhibitors. Jang Hee-Jin,Lee Hyun-Sung,Ramos Daniela,Park In Kyu,Kang Chang Hyun,Burt Bryan M,Kim Young Tae The Journal of thoracic and cardiovascular surgery OBJECTIVES:We set out to investigate whether transcriptome-based molecular subtypes in lung adenocarcinoma and lung squamous cell carcinoma are predictive of the response to programmed cell death 1 blockade. METHODS:Molecular classification of non-small cell lung cancer was performed by unsupervised clustering of mRNA sequencing data from 87 lung adenocarcinoma and 101 lung squamous cell carcinoma specimens, and molecular subtypes were characterized according to their immunogenomic determinants. A prediction algorithm of molecular subtypes was applied to 35 patients with non-small cell lung cancer treated with programmed cell death 1 blockade to test its association with treatment response (GSE93157; the Barcelona cohort). RESULTS:Unsupervised hierarchical clustering of transcriptome sequencing data in lung adenocarcinoma and lung squamous cell carcinoma revealed 3 and 2 distinct clusters, respectively. Cluster 1 in each histology had a higher expression of immune regulatory molecules, increased cytolytic activity, higher interferon-γ signature, and more abundant infiltration of immune cells. Cluster 1 and other cluster(s) in lung adenocarcinoma and lung squamous cell carcinoma had immunologically-hot and immunologically-cold tumor-immune microenvironments, respectively. Immunologically-hot cluster 1 subtype is hereafter referred to as "good-tumor-immune microenvironments" and the other subtypes as "bad-tumor-immune microenvironments." The "good-tumor-immune microenvironments" subtype in lung adenocarcinoma included a high fraction of CD8 T cells and memory B cells, but a low fraction of regulatory CD4 T cells and tumor-associated myeloid cells. Forward and backward application of our molecular subtyping to the Barcelona cohort revealed that transcriptome-based molecular subtyping is significantly associated with response to programmed cell death 1 blockade. CONCLUSIONS:Molecular stratification by transcriptome sequencing data in non-small cell lung cancer identifies distinct immunomolecular subtypes that predict the response to programmed cell death 1 blockade. 10.1016/j.jtcvs.2019.10.123
    The Integration of Radiotherapy with Immunotherapy for the Treatment of Non-Small Cell Lung Cancer. Ko Eric C,Raben David,Formenti Silvia C Clinical cancer research : an official journal of the American Association for Cancer Research Five-year survival rates for non-small cell lung cancer (NSCLC) range from 14% to 49% for stage I to stage IIIA disease, and are <5% for stage IIIB/IV disease. Improvements have been made in the outcomes of patients with NSCLC due to advancements in radiotherapy (RT) techniques, the use of concurrent chemotherapy with RT, and the emergence of immunotherapy as first- and second-line treatment in the metastatic setting. RT remains the mainstay treatment in patients with inoperable early-stage NSCLC and is given concurrently or sequentially with chemotherapy in patients with locally advanced unresectable disease. There is emerging evidence that RT not only provides local tumor control but also may influence systemic control. Multiple preclinical studies have demonstrated that RT induces immunomodulatory effects in the local tumor microenvironment, supporting a synergistic combination approach with immunotherapy to improve systemic control. Immunotherapy options that could be combined with RT include programmed cell death-1/programmed cell death ligand-1 blockers, as well as investigational agents such as OX-40 agonists, toll-like receptor agonists, indoleamine 2,3-dioxygenase-1 inhibitors, and cytokines. Here, we describe the rationale for the integration of RT and immunotherapy in patients with NSCLC, present safety and efficacy data that support this combination strategy, review planned and ongoing studies, and highlight unanswered questions and future research needs. 10.1158/1078-0432.CCR-17-3620
    [Expert consensus on PD-L1 expression testing in non-small-cell lung cancer in China]. , , Zhonghua zhong liu za zhi [Chinese journal of oncology] Cancer immunotherapy, especially the programmed death 1 (PD-1) and (or) programmed death ligand 1 (PD-L1) checkpoint inhibitors, has ushered in the modern oncology era and has achieved impressive success in the treatment of different tumors, including non-small-cell lung cancer (NSCLC). Yet, only a subset of patients achieved clinical benefit. Therefore, how to effectively screen the potential beneficiaries of PD-1 and (or) PD-L1 inhibitors has become a new challenge in the era of cancer immunotherapy. Clinical studies have shown that the expression level of PD-L1 in NSCLC is positively correlated with the efficacy of PD-1 and (or) PD-L1 inhibitors, and is one of the important predictive biomarkers. However, there are many challenges in PD-L1 testing. With the approving of various PD-1 and (or) PD-L1 inhibitors for immunotherapy setting of NSCLC, expert consensus of important issues regarding clinical significance of PD-L1 testing, testing time-point, as well as the standardization of PD-L1 testing procedure, including the PD-L1 testing operation steps, results' interpretation, quality control and so on, is of great significance for improving the accuracy of detection and reducing the difference between laboratories. On account to the practical questions of PD-L1 testing, this consensus was finally reached, which is based on the combination of literature, expert experience and internal discussion among committee members, in the hope of providing the guide for standardizing the PD-L1 testing and providing accurate and reliable result to screen the potential patients and predict clinical efficacy. It must be pointed out that in view of the existence of objective and complex factors of PD-L1 testing and the fact that the clinical application of PD-L1 testing is still at the early stage in China, there are still many issues need to be updated in near future based on further practice experience and research data. 10.3760/cma.j.cn112152-20200313-00202
    The non-small cell lung cancer immune landscape: emerging complexity, prognostic relevance and prospective significance in the context of immunotherapy. Anichini Andrea,Tassi Elena,Grazia Giulia,Mortarini Roberta Cancer immunology, immunotherapy : CII Immunotherapy of non-small cell lung cancer (NSCLC), by immune checkpoint inhibitors, has profoundly improved the clinical management of advanced disease. However, only a fraction of patients respond and no effective predictive factors have been defined. Here, we discuss the prospects for identification of such predictors of response to immunotherapy, by fostering an in-depth analysis of the immune landscape of NSCLC. The emerging picture, from several recent studies, is that the immune contexture of NSCLC lesions is a complex and heterogeneous feature, as documented by analysis for frequency, phenotype and spatial distribution of innate and adaptive immune cells, and by characterization of functional status of inhibitory receptor T cells. The complexity of the immune landscape of NSCLC stems from the interaction of several factors, including tumor histology, molecular subtype, main oncogenic drivers, nonsynonymous mutational load, tumor aneuploidy, clonal heterogeneity and tumor evolution, as well as the process of epithelial-mesenchymal transition. All these factors contribute to shape NSCLC immune profiles that have clear prognostic significance. An integrated analysis of the immune and molecular profile of the neoplastic lesions may allow to define the potential predictive role of the immune landscape for response to immunotherapy. 10.1007/s00262-018-2147-7
    The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of non-small cell lung cancer (NSCLC). Brahmer Julie R,Govindan Ramaswamy,Anders Robert A,Antonia Scott J,Sagorsky Sarah,Davies Marianne J,Dubinett Steven M,Ferris Andrea,Gandhi Leena,Garon Edward B,Hellmann Matthew D,Hirsch Fred R,Malik Shakuntala,Neal Joel W,Papadimitrakopoulou Vassiliki A,Rimm David L,Schwartz Lawrence H,Sepesi Boris,Yeap Beow Yong,Rizvi Naiyer A,Herbst Roy S Journal for immunotherapy of cancer Lung cancer is the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for over 85% of all cases. Until recently, chemotherapy - characterized by some benefit but only rare durable responses - was the only treatment option for patients with NSCLC whose tumors lacked targetable mutations. By contrast, immune checkpoint inhibitors have demonstrated distinctly durable responses and represent the advent of a new treatment approach for patients with NSCLC. Three immune checkpoint inhibitors, pembrolizumab, nivolumab and atezolizumab, are now approved for use in first- and/or second-line settings for selected patients with advanced NSCLC, with promising benefit also seen in patients with stage III NSCLC. Additionally, durvalumab following chemoradiation has been approved for use in patients with locally advanced disease. Due to the distinct features of cancer immunotherapy, and rapid progress in the field, clinical guidance is needed on the use of these agents, including appropriate patient selection, sequencing of therapies, response monitoring, adverse event management, and biomarker testing. The Society for Immunotherapy of Cancer (SITC) convened an expert Task Force charged with developing consensus recommendations on these key issues. Following a systematic process as outlined by the National Academy of Medicine, a literature search and panel voting were used to rate the strength of evidence for each recommendation. This consensus statement provides evidence-based recommendations to help clinicians integrate immune checkpoint inhibitors into the treatment plan for patients with NSCLC. This guidance will be updated following relevant advances in the field. 10.1186/s40425-018-0382-2
    [Advances of the Correlation between Driver Gene Status and Immunotherapy 
in Non-small Cell Lung Cancer]. Chen Jie,Jiang Da,Huang Fang Zhongguo fei ai za zhi = Chinese journal of lung cancer In recent years, the checkpoint inhibitors targeted programmed cell death 1 (PD-1) and its ligand 1 (PD-1 ligand, PD-L1) achieved landmark significance in treating a variety of cancers including non-small cell lung cancer (NSCLC). However, current immunotherapy is not precise enough, only 15%-20% of the unselected patients can benefit from the therapy, and there is a possibility of hyperprogression (HP). Therefore, how to select the dominant population is crucial. Although many studies have emphasized the importance of PD-L1 and tumor mutation burden (TMB) and other indicators to guide immunotherapy, current PD-L1 expression level and mutation load cannot be used as a decisive and excluded predictive marker based on various obstacles. With the deepening of research, we found that there is a close relationship between lung cancer-driver gene mutation and aberrant activation of PD-1/PD-L1 signal pathways, and the correlation between gene mutation and immunotherapy efficacy has broad research value. This article will revolve around the above issues.
. 10.3779/j.issn.1009-3419.2019.04.06
    Combining Immunotherapy with Radiation Therapy in Non-Small Cell Lung Cancer. Fitzgerald Kelly,Simone Charles B Thoracic surgery clinics Immune checkpoint inhibitors have recently been demonstrated to improve survival in metastatic and locally advanced non-small cell lung cancer (NSCLC). Radiation therapy has a well-established role in the treatment of NSCLC and has more recently been shown to be immunostimulatory, with the potential to enhance the efficacy of immunotherapy. This comprehensive review details the current roles of radiation therapy and immune checkpoint inhibitors in NSCLC, discusses the intersection of these two modalities and their potential to have combined synergistic responses, and highlights existing preclinical and clinical data and ongoing clinical trials of combined immunotherapy and radiotherapy across all NSCLC stages. 10.1016/j.thorsurg.2020.01.002
    Chemotherapy-induced immunomodulation in non-small-cell lung cancer: a rationale for combination chemoimmunotherapy. Zheng Hua,Zeltsman Masha,Zauderer Marjorie G,Eguchi Takashi,Vaghjiani Raj G,Adusumilli Prasad S Immunotherapy Spurred by the survival benefits seen with the use of checkpoint blockade in non-small-cell lung cancer (NSCLC), there has been a growing interest in the potential applications of immunotherapy. Despite this, the objective response rate for single-agent immunotherapy remains ≤20% in patients with advanced NSCLC. A combinatorial approach that utilizes both chemotherapy and immunotherapy is a potential strategy to increase antitumor efficacy. Accumulating evidence has shown that the immunomodulatory effects of chemotherapeutic agents can be exploited in a combinational approach. Herein, we review the influence of specific chemotherapeutic agents on the tumor immune microenvironment in preclinical and clinical studies, and establish the rationale for combination chemoimmunotherapy for the treatment of NSCLC. 10.2217/imt-2017-0052
    Dynamics of peripheral T cell clones during PD-1 blockade in non-small cell lung cancer. Zhang Fan,Bai Hua,Gao Ranran,Fei Kailun,Duan Jianchun,Zhang Zemin,Wang Jie,Hu Xueda Cancer immunology, immunotherapy : CII Understanding of the functional states and clonal dynamics of T cells after immune checkpoint blockade (ICB) is valuable for improving these therapeutic strategies. Here we performed Smart-seq2 single-cell RNA sequencing (scRNA-seq) analysis on 3,110 peripheral T cells of non-small cell lung cancer (NSCLC) patients before and after the initiation of programmed cell death protein 1 (PD-1) blockade. We identified individual peripheral T cell clones based on the full-length T cell receptor (TCR) sequences and monitored their dynamics during immunotherapy. We found a higher cytotoxic activity in the tumor-related CD4 T cell clones than in the CD8 T cell clones. Based on a large tumor-related CD4 T cell clone, we observed a dramatically decreased abundance after progression, as well as a reduction in the percentage of PD-1 T cells. We also detected 25 genes, such as CXCR4, DUSP2 and ZFP36, that were noticeably upregulated or downregulated following progression. In addition, the pseudotime trajectory of CD8 T cell clones corresponded to the treatment time points, showing a decreased activity in the "cytokine and cytokine receptor interaction" pathway. These analyses provided an insight into the dynamics of peripheral T cell clones during PD-1 blockade in NSCLC. 10.1007/s00262-020-02642-4
    Current Clinical Progress of PD-1/PD-L1 Immunotherapy and Potential Combination Treatment in Non-Small Cell Lung Cancer. Li Jia-Xin,Huang Ju-Min,Jiang Ze-Bo,Li Run-Ze,Sun Ao,Lai-Han Leung Elaine,Yan Pei-Yu Integrative cancer therapies Conventional methods in treating non-small cell lung cancer contain surgery, chemotherapy, radiotherapy, and targeted therapy, which have various defects. Recently, with the deeper research on tumor immunity, immunotherapy has made the breakthrough in the treatment of cancers. Especially developments of programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors bring the therapy into a new stage. This review mainly focuses on introducing existing monoclonal antibodies containing nivolumab, pembrolizumab, atezolizumab, avelumab, and durvalumab, along with 3 ordinary biomarkers such as PD-L1 expression, tumor mutation burden, and microsatellite instability. By understanding the resistance mechanism of anti-PD-1/L1 blockade, research is further improving the survival benefit and expanding the benefit population. So, PD-1/PD-L1 inhibitors begin to be combined with various therapeutic strategies clinically. Discussion and comparison of their effectiveness and safety are also comprehensively reviewed. Meanwhile, we explore the potential, the impact, and mechanisms of combining traditional Chinese medicine with immunotherapy. 10.1177/1534735419890020
    Sequence of biologic therapies and surgery affects survival in non-small cell lung cancer. Xu Edison,David Elizabeth A,Ding Li,Atay Scott M,McFadden Paul M,Wightman Sean C,Kim Anthony W Journal of surgical oncology BACKGROUND AND OBJECTIVES:Biologic therapy is changing the landscape of lung cancer treatment. The objectives of this study were to compare overall survival (OS) between patients with non-small cell lung cancer (NSCLC) undergoing neoadjuvant and adjuvant biologic therapy in combination with surgery and to evaluate the impact of chemotherapy on survival after combination biologic therapy and surgery. METHODS:The National Cancer Database was queried for cases of NSCLC from 2004 to 2016. Patient treatment was categorized into neoadjuvant and adjuvant biologic therapy in combination with surgery. Kaplan-Meier curves were generated to compare OS between treatment groups and between those who did and did not also undergo chemotherapy. Cox regression was used to identify factors predictive of OS. RESULTS:Six hundred seventy-three patients underwent both biologic therapy and surgery. The unadjusted overall 5-year OS was longer for patients undergoing neoadjuvant biologic therapy than for those undergoing adjuvant biologic therapy (P = .006), with OS being 56.2% and 33.0%, respectively. When comparing OS between those who did and did not undergo additional chemotherapy, no difference was observed. CONCLUSIONS:Neoadjuvant biologic therapy was associated with longer OS than adjuvant biologic therapy. Chemotherapy did not have an effect on OS when combined with biologic therapy and surgery. 10.1002/jso.25937
    Anti-PD-1-Related Exacerbation of Interstitial Lung Disease in a Patient with Non-Small Cell Lung Cancer: A Case Presentation and Review of the Literature. L Gemmill Julie Anne,Sher Amna Cancer investigation Immunotherapy is standard first-line therapy for advanced non-small cell lung cancer (NSCLC) either alone or in combination with chemotherapy. Despite significant benefits, immune checkpoint inhibitors (ICI) can cause toxicities within any organ, termed immune related adverse events. Pneumonitis is a potentially life-threatening complication of ICIs. Currently, there are no established guidelines for use of ICIs in patients with underlying autoimmune or interstitial lung disease (ILD) and few studies have been published. We present a case of first-line ICI-chemotherapy in a patient with metastatic NSCLC and ILD who suffered treatment related lung toxicity and acute worsening ILD, which lead to his death. 10.1080/07357907.2020.1783677
    Immunotherapy as a second-line or later treatment modality for advanced non-small cell lung cancer: A review of safety and efficacy. Geraci Emily,Chablani Lipika Critical reviews in oncology/hematology Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 80-85% of these cases. Surgical resection is the most common conventional treatment of lung cancer. For patients with advanced NSCLC, platinum-based chemotherapy remains the cornerstone of treatment. Although platinum-based chemotherapy demonstrated improved outcomes, the need for the second-line/later therapies is evident. A review was conducted to assess the safety and efficacy of immunotherapies as the second-line/later therapy of advanced NSCLC. Clinical trial data was collected via PubMed and Clinicaltrials.gov. Recent studies were selected based on prespecified inclusion/exclusion criteria. Data on the safety and efficacy of the immunotherapy was subsequently compiled from relevant trials. Monoclonal antibodies targeting PD-1/PD-L1 showed the most promising results as the second-line/later treatment modalities. Immunizations did not produce as robust of an immune response in participants; however, they warrant further research to determine their place in therapy. 10.1016/j.critrevonc.2020.103009
    Bone metastases and immunotherapy in patients with advanced non-small-cell lung cancer. Landi Lorenza,D'Incà Federica,Gelibter Alain,Chiari Rita,Grossi Francesco,Delmonte Angelo,Passaro Antonio,Signorelli Diego,Gelsomino Francesco,Galetta Domenico,Giannarelli Diana,Soto Parra Hector,Minuti Gabriele,Tiseo Marcello,Migliorino Maria Rita,Cognetti Francesco,Toschi Luca,Bidoli Paolo,Piantedosi Francovito,Calabro' Luana,Cappuzzo Federico Journal for immunotherapy of cancer BACKGROUND:Bone metastases (BoM) are a negative prognostic factor in non-small-cell lung cancer (NSCLC). Beyond its supportive role, bone is a hematopoietic organ actively regulating immune system. We hypothesized that BoM may influence sensitivity to immunotherapy. METHODS:Pretreated non-squamous (cohort A) and squamous (cohort B) NSCLCs included in the Italian Expanded Access Program were evaluated for nivolumab efficacy according to BoM. RESULTS:Cohort A accounted for 1588 patients with non-squamous NSCLC, including 626 (39%) with (BoM+) and 962 (61%) without BoM (BoM-). Cohort B accounted for 371 patients with squamous histology including 120 BoM+ (32%) and 251 (68%) BoM- cases. BoM+ had lower overall response rate (ORR; Cohort A: 12% versus 23%, p <  0.0001; Cohort B: 13% versus 22%, p = 0.04), shorter progression free survival (PFS; Cohort A: 3.0 versus 4.0 months, p <  0.0001; Cohort B: 2.7 versus 5.2 months, p <  0.0001) and overall survival (OS; Cohort A: 7.4 versus 15.3 months, p <  0.0001; Cohort B: 5.0 versus 10.9 months, p < 0.0001). Moreover, BoM negatively affected outcome irrespective of performance status (PS; OS in both cohorts: p < 0.0001) and liver metastases (OS cohort A: p < 0.0001; OS Cohort B: p = 0.48). At multivariate analysis, BoM independently associated with higher risk of death (cohort A: HR 1.50; cohort B: HR 1.78). CONCLUSIONS:BoM impairs immunotherapy efficacy. Accurate bone staging should be included in clinical trials with immunotherapy. 10.1186/s40425-019-0793-8
    Curative effect assessment of immunotherapy for non-small cell lung cancer: The "blind area" of Immune Response Evaluation Criteria in Solid Tumors (iRECIST). Song Peng,Zhang Jingcheng,Shang Congcong,Zhang Li Thoracic cancer BACKGROUND:Immunotherapy has considerably changed the treatment of lung cancer. As immunotherapy has a special mechanism of action, the disease remission that it can induce is unique. Recently, Immune Response Evaluation Criteria in Solid Tumors (iRECIST), which focus on assessing the apparent curative effect of immunotherapy, have become widely accepted. Based on iRECIST criteria, if the response to immunotherapy is determined to be immunity-confirmed progressive disease or immunity-unconfirmed progressive disease, and the Eastern Cooperative Oncology Group score is worse than before treatment, immunotherapy should be discontinued. We report two immunity-confirmed progressive disease cases after pembrolizumab treatment and one immunity-unconfirmed progressive disease case after nivolumab treatment. All three patients benefited from continued immunotherapy, which indicates that the iRECIST criteria may have limitations in assessing the efficacy of immunotherapy for non-small cell lung cancer patients. 10.1111/1759-7714.13010
    Impact of Age on Outcomes with Immunotherapy in Patients with Non-Small Cell Lung Cancer. Lichtenstein Morgan R L,Nipp Ryan D,Muzikansky Alona,Goodwin Kelly,Anderson Danyon,Newcomb Richard A,Gainor Justin F Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer INTRODUCTION:Immunotherapy has revolutionized the treatment of NSCLC, but little is known about the activity of programmed cell death 1 and programmed death ligand 1 blockade across age groups. METHODS:We retrospectively evaluated patients with NSCLC who initiated programmed cell death 1 and programmed death ligand 1 inhibitors from January 2013 through July 2017. Medical records and radiographic imaging were reviewed to determine progression-free survival (PFS) and overall survival (OS). We also compared immunotherapy-related toxicities, steroid use, and hospitalizations by age. RESULTS:Of the 245 patients, 26.1% were younger than 60 years, 31.4% were age 60 to 69 years, 31.0% were age 70 to 79 years, and 11.4% were age 80 years or older. The median PFS times by age group were as follows: younger than 60 years, 1.81 months; age 60 to 69 years, 2.53 months; age 70 to 79 years, 3.75 months; and age 80 years or older, 1.64 months (log-rank p value = 0.055). The median OS times by age group were as follows: younger than 60 years, 13.01 months; age 60 to 69 years, 14.56 months; age 70 to 79 years, 12.92 months; and age 80 years or older, 3.62 months (log-rank p value = 0.011). Rates of immunotherapy-related toxicities, steroid use, and hospitalizations did not differ by age. CONCLUSIONS:Although the OS and PFS benefits of immunotherapy differ by age, the rates of toxicity are similar regardless of age. 10.1016/j.jtho.2018.11.011
    Stromal PD-L1-Positive Regulatory T cells and PD-1-Positive CD8-Positive T cells Define the Response of Different Subsets of Non-Small Cell Lung Cancer to PD-1/PD-L1 Blockade Immunotherapy. Wu Si-Pei,Liao Ri-Qiang,Tu Hai-Yan,Wang Wen-Jun,Dong Zhong-Yi,Huang Shu-Mei,Guo Wei-Bang,Gou Lan-Ying,Sun Hui-Wen,Zhang Qi,Xie Zhi,Yan Li-Xu,Su Jian,Yang Jin-Ji,Zhong Wen-Zhao,Zhang Xu-Chao,Wu Yi-Long Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer INTRODUCTION:Inhibition of programmed cell death-1 (PD-1) and its ligand programmed death ligand 1 (PD-L1) by using an immune checkpoint inhibitor has emerged as a promising immunotherapy for NSCLC. The correlation of PD-L1 expression in tumor cells with treatment outcomes has been reported in many pivotal trials; however, the relationship remains unclear. Here, we demonstrate that those patients with both high density of PD-1-positive CD8 and PD-L1-positive CD4-positive CD25-positive (PD-1 PD-L1) regulatory T cells (Tregs) have a better response to PD1/PD-L1 blockade. METHODS:In our study between April 1, 2014, and May 30, 2017, a total of 73 NSCLC peripheral blood samples and fresh tumor specimens were collected for study. Of these, 42 large (10-mm) fresh tumor specimens were obtained from surgical procedures and checked for expression of immunology biomarkers, including PD-L1, PD-1, CD8, CD4, and CD25, in tumor cells and tumor-infiltrating lymphocytes (TILs) by flow cytometry, immunohistochemistry, and immunofluorescence (IF). Moreover, 31 small biopsy specimens from patients who received immunotherapy (pembrolizumab or nivolumab) were analyzed by immunohistochemistry and IF. The correlation between flow cytometry and IF detected for TILs' density was evaluated by Spearman's rank correlation test; the primary end point was progression-free survival. For the PD-1/PD-L1 blockade assay, the TILs and peripheral blood mononuclear CD8 T cells were cultured (1×10 per well) with anti-PD-1 (clone MIH4), anti-PD-L1 (clone MIH1). The cytotoxic activity of TILs in killing NSCLC cells after stimulation by anti-PD-1 and anti-PD-L1 was measured by a conventional Cr release assay. RESULTS:We first identified a population of high-PD-L1-expressing CD25-positive CD4-positive T cells (PD-L1 Tregs) in the tumor microenvironment. The frequency of PD-L1 Tregs was higher in tumor tissue (mean 48.6 ± 14.3% in CD25-positive CD3-positive CD4-positive T cells) than in blood (mean 35.4 ± 10.2% in CD25-positive CD3-positive CD4-positive T cells) and normal tissue (mean 38.6 ± 9.7% in CD25-positive CD3-positive CD4-positive T cells) (p < 0.05), as determined by flow cytometry. The frequency of PD-L1 Tregs was positively correlated with PD-1-positive CD8 in Tregs. In addition, the TILs from these patients (PD-1 PD-L1) showed PD-1/PD-L1 pathway dependence and could induce a greater killing effect of TILs by PD-1/PD-L1 blockade treatment. The patients with PD-L1-positive NSCLC with PD-1 PD-L1 TILs showed a better clinical outcome than those with a low frequency of PD-1 CD8 or PD-L1 Tregs (median progression-free survival not reached versus 2 months). CONCLUSIONS:Our findings suggested that the density of PD-L1-positive CD4-positive CD25-positive Tregs in the tumor microenvironment can serve as a diagnostic factor to supplement PD-L1 expression in tumor cells and predict the response to PD-1/PD-L1 blockade immunotherapy in NSCLC. 10.1016/j.jtho.2017.11.132
    Impact of Treatment-Related Lymphopenia on Immunotherapy for Advanced Non-Small Cell Lung Cancer. Cho Yeona,Park Sangjoon,Byun Hwa Kyung,Lee Chang Geol,Cho Jaeho,Hong Min Hee,Kim Hye Ryun,Cho Byoung Chul,Kim Sinae,Park Juyoung,Yoon Hong In International journal of radiation oncology, biology, physics PURPOSE:The interest in combining radiation therapy (RT) with immunotherapy is increasing. We investigated the significance of lymphopenia in patients receiving immunotherapy for non-small cell lung cancer (NSCLC), and the factors associated with treatment-related lymphopenia, with particular emphasis on RT. METHODS AND METHODS:In this retrospective single institution study, 268 patients with advanced NSCLC received immunotherapy, of whom 146 received RT. Lymphopenia was defined as an absolute lymphocyte count <1000 cells/mm. Patients were divided into 2 groups depending on the presence of peri-immunotherapy lymphopenia at the start of immunotherapy or during immunotherapy. RESULTS:At median 6.4 months of follow-up, patients with peri-immunotherapy lymphopenia (n = 146; 54.5%) showed significantly poorer progression-free survival (PFS) (median PFS: 2.2 vs 5.9 months, P < .001) and overall survival (OS) (median OS: 5.7 vs 12.1 months, P < .001). On multivariate analysis, peri-immunotherapy lymphopenia remained a significant prognostic factor for both PFS and OS. RT significantly increased peri-immunotherapy lymphopenia with an odds ratio (OR) of 1.91 (P = .025). Factors associated with the development of RT-associated lymphopenia included multiple courses (OR, 3.78; P < .001), multiple irradiated sites (OR, 4.77; P = .018), and higher dose (≥50 Gy) (OR, 3.75; P = .004). Conversely, stereotactic body RT/radiosurgery reduced the risk (OR 0.21; P = .002). CONCLUSIONS:Lymphopenia was indicative of poor prognosis in NSCLC patients receiving immunotherapy and was significantly associated with more intensive RT. Choosing appropriate RT regimens and techniques may be essential in reducing lymphopenia. Promising results are expected in the era of precision RT. 10.1016/j.ijrobp.2019.08.047
    Recent Advances in Lung Cancer Immunotherapy: Input of T-Cell Epitopes Associated With Impaired Peptide Processing. Leclerc Marine,Mezquita Laura,Guillebot De Nerville Guillaume,Tihy Isabelle,Malenica Ines,Chouaib Salem,Mami-Chouaib Fathia Frontiers in immunology Recent advances in lung cancer treatment are emerging from new immunotherapies that target T-cell inhibitory receptors, such as programmed cell death-1 (PD-1). However, responses to anti-PD-1 antibodies as single agents are observed in fewer than 20% of non-small-cell lung cancer (NSCLC) patients, and immune mechanisms involved in the response to these therapeutic interventions remain poorly elucidated. Accumulating evidence indicates that effective anti-tumor immunity is associated with the presence of T cells directed toward cancer neoepitopes, a class of major histocompatibility complex (MHC)-bound peptides that arise from tumor-specific mutations. Nevertheless, tumors frequently use multiple pathways to escape T-cell recognition and destruction. In this regard, primary and acquired resistance to immune checkpoint blockade (ICB) therapy was associated with alterations in genes relevant to antigen presentation by MHC-class I/beta-2-microglobulin (MHC-I/β2m) complexes to CD8 T lymphocytes. Among additional known mechanisms involved in tumor resistance to CD8 T-cell immunity, alterations in transporter associated with antigen processing (TAP) play a major role by inducing a sharp decrease in surface expression of MHC-I/β2m-peptide complexes, enabling malignant cells to evade cytotoxic T lymphocyte (CTL)-mediated killing. Therefore, development of novel immunotherapies based on tumor neoantigens, that are selectively presented by cancer cells carrying defects in antigen processing and presentation, and that are capable of inducing destruction of such transformed cells, is a major challenge in translational research for application in treatment of lung cancer. In this context, we previously identified a non-mutant tumor neoepitope, ppCT, derived from the preprocalcitonin (ppCT) leader sequence and processed independently of proteasomes/TAP by a mechanism involving signal peptidase (SP) and signal peptide peptidase (SPP). We also provided and proof of the concept of active immunotherapy based on ppCT-derived peptides capable of controlling growth of immune-escaped tumors expressing low levels of MHC-I molecules. Thus, non-mutant and mutant neoepitopes are promising T-cell targets for therapeutic cancer vaccines in combination with ICB. In this review, we summarize current treatments for lung cancer and discuss the promises that conserved neoantigens offer for more effective immunotherapies targeting immune-escaped tumor variants. 10.3389/fimmu.2019.01505
    Combining Immunotherapy and Chemotherapy for Non-Small Cell Lung Cancer. Judd Julia,Borghaei Hossein Thoracic surgery clinics Over the past year, the combination of platinum-based chemotherapy and immunotherapy has become the standard of care for patients with metastatic non-small-cell lung cancer with any programmed death ligand 1 tumor proportion score. There is preclinical evidence demonstrating potential synergistic immunomodulation with combination therapy by enhancing immune-mediated tumor death and by disrupting the immunosuppressive tumor microenvironment that prevents immune detection. This potential synergy or complementary activity has been demonstrated in clinical trials showing improved and durable responses with chemo-immunotherapy. 10.1016/j.thorsurg.2020.01.006
    Transformation to small cell lung cancer as a mechanism of resistance to immunotherapy in non-small cell lung cancer. Bar Jair,Ofek Efrat,Barshack Iris,Gottfried Teodor,Zadok Oranit,Kamer Iris,Urban Damien,Perelman Marina,Onn Amir Lung cancer (Amsterdam, Netherlands) OBJECTIVES:Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death world-wide. Immune checkpoint inhibitors (ICI) have become the most promising type of treatment in oncology in general, and significantly so in NSCLC. Limited data is available about mechanisms of primary resistance. Data is lacking about mechanisms involved in acquired resistance or mixed responses in NSCLC. We aimed to identify mechanisms of resistance by studying biopsies taken from sites of secondary progression. MATERIALS AND METHODS:We identified all cases of NSCLC that have received ICI for advanced disease in our institute. Of these cases, those that have demonstrated acquired resistance or mixed responses, and have underwent a biopsy from a progressive lesion were analyzed. Selected specimens were subjected to next-generation sequencing (NGS; Oncomine™ Solid Tumour Fusion Transcript Kit). RESULTS:Out of 664 lung cancer cases, 249 were NSCLC that have received ICI. Of these, eight cases matched our search criteria. Two of them demonstrated transformation to small cell lung cancer (SCLC; 2/8, 25%). NGS verified a common origin to a matched pre-treatment NSCLC specimen and an on-treatment progressive SCLC specimen. In two cases no tumor cells were found and in the remaining four the pathology was similar to the initial biopsy. In one of the cases of SCLC transformation platinum-etoposide chemotherapy was administered, with short-term benefit only and further disease progression. CONCLUSION:Mechanisms of acquired resistance to ICI include SCLC transformation. Repeat biopsies of progressing lesions after initial response or in cases of mixed response can shed light on mechanisms of resistance. 10.1016/j.lungcan.2019.09.025
    Immunotherapy causing pneumonitis in a patient with non-small cell lung cancer (NSCLC). Li Rui,Lee Gina,El-Sherief Ahmed BMJ case reports Our patient, who had been previously diagnosed with non-small cell lung cancer, presented with progressive dyspnoea after receiving second-line immunotherapy treatment with atezolizumab. Chest CT scan showed bilateral lung architectural distortion, bronchial dilatation, consolidative opacities, ground-glass opacities and linear opacities concerning for either infectious lung disease or treatment-related lung disease. A diagnostic bronchoscopy was performed and no evidence of malignancy or infection was detected. Discontinuing atezolizumab with the addition of oral corticosteroid improved the patient's respiratory symptoms but the patient required continuous oxygen supplementation. Later, the patient was found to have radiologic findings suggestive of further progression of his pneumonitis after completion of a course of corticosteroid treatment and required another course of oral prednisone. Immune-mediated pneumonitis could present with mild to severe respiratory symptoms with a wide range of clinical and radiologic features and physicians should be aware of this diagnosis of exclusion. Although patients may experience progressive disease with or without immunotherapy rechallenge, most of these cases can be managed successfully with favourable outcomes. 10.1136/bcr-2018-226044
    Co-mutations of TP53 and KRAS serve as potential biomarkers for immune checkpoint blockade in squamous-cell non-small cell lung cancer: a case report. Fang Cheng,Zhang Chu,Zhao Wei-Qing,Hu Wen-Wei,Wu Jun,Ji Mei BMC medical genomics BACKGROUND:Unprecedented durable responses are identified in clinical studies to target the signaling of programmed cell death protein-1 (PD-1) as well as its ligand (PD-L1) in patients with squamous-cell non-small cell lung cancer (NSCLC). However, factors predicting the patient subtypes that are responsive to PD-1/PD-L1inhibitors have not been fully understood yet. Biomarkers, like PD-L1 expression, tumor mutational burden(TMB), DNA mismatch repair deficiency (dMMR), and tumor-infiltrating lymphocytes (TILs), have been utilized to select patients responsive to PD-1/PD-L1inhibitors in the clinic, but each of them has limited use. Lung adenocarcinoma patients with a mutation of TP53 or KRAS, particularly those with co-mutations of TP53 and KRAS, can benefit from anti-PD-1 treatment. CASE PRESENTATION:In this study, the co-mutations of TP53 and KRAS in a 64-year-old non-smoking man with squamous-cell NSCLC patient was described using the next-generation sequencing (NGS) technology. The patient was treated with the pembrolizumab combined with gemcitabine as the salvage therapy, and a marked partial response could be attained, which had persisted for over 7 months. CONCLUSION:In addition to testing common driving genes, like EGFR, ALK, ROS1 and BRAF, both TP53, and KRAS should also be considered in advanced or metastatic squamous-cell NSCLC.TP53 and KRAS co-mutations in squamous-cell NSCLC can be a potential factor to assess possible response to PD-1 blockade immunotherapy, but further studies with more cases are needed to confirm the prediction power. 10.1186/s12920-019-0592-6
    The progress and confusion of anti-PD1/PD-L1 immunotherapy for patients with advanced non-small cell lung cancer. Zhang Shuling,Bai Xueli,Shan Fengping International immunopharmacology Recently, immunotherapy has evolved into a true treatment modality with the approval of PD-1 and PD-L1 inhibitors as the standard care for first-line treatment in patients with non-small cell lung cancer (NSCLC). Until now, for patients with advanced NSCLC, treatment of targeting immune checkpoints reveals a promising survival benefit, and some patients even get long term survive, which creates a paradigm shift in NSCLC treatment. However, many issues or problems are also appearing in clinical practice, such as the lower overall efficacy rate (20-40%), treatment modes, populations choice of immunotherapy, drug resistance, and safety, etc. Thus, in this review, we will mainly summarize and discuss the recent development and confusion of PD-1/PD-L1 inhibitors for advanced NSCLC patients based on current clinical studies. 10.1016/j.intimp.2020.106247
    Immunotherapy with checkpoint inhibitors in non-small cell lung cancer: insights from long-term survivors. Nadal Ernest,Massuti Bartomeu,Dómine Manuel,García-Campelo Rosario,Cobo Manuel,Felip Enriqueta Cancer immunology, immunotherapy : CII Immune checkpoint inhibitors (ICIs) targeting the programmed cell death-1 (PD-1)-programmed cell death ligand-1 (PD-L1) axis have shown promising results in non-small cell lung cancer (NSCLC) patients, some of them with persistent responses to these agents that form a population of long-term survivors. Despite the variable definition of PD-L1 positivity in tumors, an association between expression and response has been reasonably consistent in advanced NSCLC. In addition, the clinical efficacy of ICIs seems to be related to the genomic landscape of the tumor in terms of mutational burden and clonal neoantigens. Furthermore, increasing evidence shows that excessive activation of the immune response elicited by ICIs, leading to immune-related toxicities, might be associated with an improved response to immunotherapy. There are still many unanswered questions about the proper use of these agents to maximize their efficacy, which may be improved through combination with radiation, chemotherapy, targeted therapies, or other immune mediators, including dual checkpoint blockade. To search for clues for addressing these challenges, this review focused on the characteristics and clinical features of long-term NSCLC survivors and the potential biomarkers of response to ICIs. 10.1007/s00262-019-02310-2
    [A Single Center Analysis of Advanced Non-small Cell Lung Cancer Patients Treated with Immunotherapy in Real-world Practice]. Liu Yanxia,Zhang Tongmei,Gao Yuan,Qu Yang,Lu Baohua,Zhang Hongmei,Wang Qunhui,Li Jie,Hu Fanbin,Li Baolan Zhongguo fei ai za zhi = Chinese journal of lung cancer BACKGROUND:In recent years, a number of clinical trials have shown that immunocheckpoint inhibitors (ICI) have brought survival benefits to patients with advanced non-small cell lung cancer (NSCLC), however, such clinical trials comprise cohorts selected based on strict and complex entry and exclusion criteria, and the results cannot fully reflect the real world situation. The purpose of this study was to investigate the clinical efficacy and safety of immunotherapy in the real world, as well as possible prognostic factors. METHODS:Patients with advanced NSCLC receiving immunotherapy in Beijing Chest Hospital from January 2017 to July 2019 were retrospectively collected, and the following information were collected: curative effect, progression-free surival (PFS) and adverse reactions. The occurrence of adverse reactions and clinical curative effect and prognosis factors that may be relevant were explored. RESULTS:34 patients were enrolled in this study, median PFS was 5.66 months (95%CI: 4.48-6.84), grade 1-2 and 3-4 incidence of adverse events was 61.71% (22/34) and 14.71% (5/34), there were 3 patients (8.82%) experienced fatal immune related adverse events (irAE), 2 cases were immune associated pneumonia, 1 case was immune related myocarditis. Univariate analysis showed that tumor-node-metastasis (TNM) stage and metastatic site were correlated with median PFS (P<0.05), and multivariate analysis showed that patients with extrapulmonary metastasis (OR=6.42, P=0.029) and pleural metastasis (OR=14.14, P=0.006) had shorter median PFS. CONCLUSIONS:In the real world, immunotherapy has good efficacy in patients with advanced NSCLC, but the incidence of severe irAE is also higher. Distant metastasis and pleural metastasis are poor prognostic factors for advanced NSCLC patients receiving immunotherapy. 10.3779/j.issn.1009-3419.2019.11.02
    Molecular Mechanisms and Targeted Therapies Including Immunotherapy for Non-Small Cell Lung Cancer. Nagano Tatsuya,Tachihara Motoko,Nishimura Yoshihiro Current cancer drug targets Lung cancer is the leading cause of cancer death worldwide. Molecular targeted therapy has greatly advanced the field of treatment for non-small cell lung cancer (NSCLC), which accounts for the majority of lung cancers. Indeed, gefitinib, which was the first molecular targeted therapeutic agent, has actually doubled the survival time of NSCLC patients. Vigorous efforts of clinicians and researchers have revealed that lung cancer develops through the activating mutations of many driver genes including the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1), v-Raf murine sarcoma viral oncogene homolog B (BRAF), and rearranged during transfection (RET) genes. Although ALK, ROS1, and RET are rare genetic abnormalities, corresponding tyrosine kinase inhibitors (TKIs) can exert dramatic therapeutic effects. In addition to anticancer drugs targeting driver genes, bevacizumab specifically binds to human vascular endothelial growth factor (VEGF) and blocks the VEGF signaling pathway. The VEGF signal blockade suppresses angiogenesis in tumor tissues and inhibits tumor growth. In this review, we also explore immunotherapy, which is a promising new NSCLC treatment approach. In general, antitumor immune responses are suppressed in cancer patients, and cancer cells escape from the immune surveillance mechanism. Immune checkpoint inhibitors (ICIs) are antibodies that target the primary escape mechanisms, immune checkpoints. Patients who respond to ICIs are reported to experience longlasting therapeutic effects. A wide range of clinical approaches, including combination therapy involving chemotherapy or radiation plus adjuvant therapy, are being developed. 10.2174/1568009619666181210114559
    Advances in the Treatment of Non-Small Cell Lung Cancer: Immunotherapy. Patel Shetal A,Weiss Jared Clinics in chest medicine Clinical development of immune checkpoint blockade has dramatically changed the treatment paradigm and prognosis for patients with non-small cell lung cancer. Immune checkpoint blockade with PD-1 and PD-L1 antibodies generates clinically significant, durable responses in patients with advanced non-small cell lung cancer. These agents are approved for first- and second-line treatment, either as single agents or in combination with chemotherapy and angiogenesis inhibitors. Although the toxicity profile of these treatments is favorable, a unique set of immune-mediated adverse events, such as pneumonitis, has been observed. Broader use of these agents is improving survival for patients with advanced lung cancer. 10.1016/j.ccm.2020.02.010
    Prior or concurrent radiotherapy and nivolumab immunotherapy in non-small cell lung cancer. Ratnayake Gishan,Shanker Mihir,Roberts Kate,Mason Robert,Hughes Brett G M,Lwin Zarnie,Jain Vikram,O'Byrne Kenneth,Lehman Margot,Chua Benjamin Asia-Pacific journal of clinical oncology BACKGROUND:Studies suggest that combining radiotherapy (RT) with programmed cell death protein 1 (PD-1) blockade may elicit a synergistic antitumor response. We aimed to assess whether prior or concurrent RT was associated with improved disease control in patients with metastatic non-small cell lung cancer (NSCLC) treated with nivolumab. METHODS:We conducted a retrospective study of patients receiving nivolumab as second or subsequent line therapy for metastatic NSCLC. Patients were categorized into those who received any RT for NSCLC prior to or during nivolumab therapy, and those with no history of RT for NSCLC. RESULTS:A total of 85 patients received nivolumab between July 2015 and December 2016 and were followed up for a median of 15 months. Sixty-five patients (76.4%) received RT prior to or during nivolumab and 20 patients (23.6%) received nivolumab alone. Baseline characteristics of age, performance status, histology, smoking status and previous therapy were similar between the two groups. Prior or concurrent RT was associated with a superior PFS, median 2.8 months with RT versus 1.3 months without RT (Hazard Ratio (HR) = 0.494; 95% Confidence Interval (CI), 0.279-0.873; P = 0.02). The median OS of the group receiving RT was 6.4 months versus 4.2 months for the no RT group (P = 0.20). RT was not associated with an increase in toxicity. CONCLUSION:RT prior to or concurrent with nivolumab for metastatic NSCLC was associated with a modest improvement in PFS over nivolumab alone with no evidence of increase in adverse effects. RT may potentiate the effect of anti-PD-1 immunotherapy in NSCLC. 10.1111/ajco.13242
    Advances in evidence-based medicine for immunotherapy of non-small cell lung cancer. Dong Jingsi,Li Bingjie,Zhou Qinghua,Huang Depei Journal of evidence-based medicine Tumor immunotherapy is praised as "green therapy," which can attack tumor by mobilizing immune system. By removing the inhibition of immune cells, checkpoint inhibitors help T cells to identify and kill tumor cells. In recent years, more and more attention has been paid to its effectiveness as a tumor therapy with a large number of clinical data. Currently, inhibitors of 2 checkpoints, CTLA-4 and PD-1/PD-L1, have been approved to be listed. In particular, the latter has achieved breakthrough progress in non-small cell lung cancer in recent years, bringing about changes in the therapeutic strategy of lung cancer, as well as challenges to the evaluation criteria. This article focuses on the latest immunotherapy methods for lung cancer. The purpose of this article is to summarize the development of evidence-based medicine for lung cancer immunotherapy and to provide help for further understanding of lung cancer immunotherapy. 10.1111/jebm.12322
    Overall survival according to immunotherapy and radiation treatment for metastatic non-small-cell lung cancer: a National Cancer Database analysis. Foster Corey C,Sher David J,Rusthoven Chad G,Verma Vivek,Spiotto Michael T,Weichselbaum Ralph R,Koshy Matthew Radiation oncology (London, England) BACKGROUND:Preclinical studies suggest enhanced anti-tumor activity with combined radioimmunotherapy. We hypothesized that radiation (RT) + immunotherapy would associate with improved overall survival (OS) compared to immunotherapy or chemotherapy alone for patients with newly diagnosed metastatic non-small-cell lung cancer (NSCLC). METHODS:The National Cancer Database was queried for patients with stage IV NSCLC receiving chemotherapy or immunotherapy from 2013 to 2014. RT modality was classified as stereotactic radiotherapy (SRT) to intra- and/or extracranial sites or non-SRT external beam RT (EBRT). OS was analyzed using the Kaplan-Meier method and Cox proportional hazards models. RESULTS:In total, 44,498 patients were included (13% immunotherapy, 46.8% EBRT, and 4.7% SRT). On multivariate analysis, immunotherapy (hazard ratio [HR]:0.81, 95% confidence interval [CI]:0.78-0.83) and SRT (HR:0.78, 95%CI:0.70-0.78) independently associated with improved OS; however, the interaction term for SRT + immunotherapy was insignificant (p = 0.89). For immunotherapy patients, the median OS for no RT, EBRT, and SRT was 14.5, 10.9, and 18.2 months, respectively (p < 0.0001), and EBRT (HR:1.37, 95%CI:1.29-1.46) and SRT (HR:0.78, 95%CI:0.66-0.93) associated with OS on multivariate analysis. In the SRT subset, median OS for immunotherapy and chemotherapy was 18.2 and 14.3 months, respectively (p = 0.004), with immunotherapy (HR:0.82, 95%CI:0.69-0.98) associating with OS on multivariate analysis. Furthermore, for patients receiving SRT, biologically effective dose (BED) > 60 Gy was independently associated with improved OS (HR:0.79, 95%CI:0.70-0.90, p < 0.0001) on multivariate analysis with a significant interaction between BED and systemic treatment (p = 0.008). CONCLUSIONS:Treatment with SRT associated with improved OS for patients with metastatic NSCLC irrespective of systemic treatment. The high survival for patients receiving SRT + immunotherapy strongly argues for evaluation in randomized trials. 10.1186/s13014-019-1222-3
    Association of Survival and Immune-Related Biomarkers With Immunotherapy in Patients With Non-Small Cell Lung Cancer: A Meta-analysis and Individual Patient-Level Analysis. Yu Yunfang,Zeng Dongqiang,Ou Qiyun,Liu Shengbo,Li Anlin,Chen Yongjian,Lin Dagui,Gao Quanlong,Zhou Haiyu,Liao Wangjun,Yao Herui JAMA network open Importance:The beneficial role of immunotherapy and the clinical relevance of current biomarkers in non-small cell lung cancer (NSCLC) remain inconclusive; thus, appropriate strategies and reliable predictors need further definition. Objectives:To evaluate the association of clinical outcomes with immune checkpoint inhibitors, tumor vaccines, and cellular immunotherapy in patients with advanced NSCLC and to explore appropriate strategies, candidates, and predictors. Data Sources:The PubMed, EMBASE, and Cochrane Central Register of Controlled Trials databases were searched from inception to June 2018, using relevant search keywords and Medical Subject Headings (MeSH) terms, including tumor vaccine, cellular immunotherapy, immune checkpoint inhibitor, cytotoxic T-lymphocyte-associated protein 4, programmed death-ligand 1, programmed death receptor 1, and non-small cell lung carcinoma. Systematic reviews, meta-analyses, references, and conference proceedings were manually searched. Study Selection:English-language randomized clinical trials with available data that measured overall survival (OS), progression-free survival (PFS), or objective response rate comparing immune checkpoint inhibitors, tumor vaccines, or cellular immunotherapy with conventional therapy for patients with advanced or metastatic NSCLC were included. Thirty-one immunotherapy randomized clinical trials were included, and multicohort data included next-generation sequencing data from patients with advanced NCSLC. Data Extraction and Synthesis:Hazard ratios and 95% CIs were pooled to estimate the survival increases in OS and PFS. Dichotomous data, such as object response rate data, were analyzed using the risk ratio. Mantel-Haenszel random-effects model was used. I2 was used to assess the heterogeneity between trials; an I2 value exceeding 50% indicated the existence of substantial heterogeneity. Analyses took place from February 1, 2018, to August 31, 2018. Main Outcomes and Measures:Primary outcomes were OS and PFS. Results:In total, 14 395 patients (9500 [66.0%] men) were included in the meta-analysis, and 1833 patients (mean [SD], 65.2 [9.9] years; 1063 [58.0%] men) were included in the individual patient-level study. Compared with conventional therapy, immunotherapy was associated with significantly longer OS (hazard ratio, 0.76; 95% CI, 0.71-0.82; P < .001) and PFS (hazard ratio, 0.76; 95% CI, 0.70-0.83; P < .001). The best checkpoint blockade strategy was first-line pembrolizumab with platinum-based chemotherapy. The combined predictive utility of programmed cell death ligand 1 (PD-L1) expression and tumor mutation burden (TMB) was associated with predictive prognosis (whole-exome sequencing: 1-year PFS area under the receiver operating characteristic curve [AUC], 0.829; 3-year PFS AUC, 0.839; targeted next-generation sequencing: 1-year PFS AUC, 0.826; 3-year PFS AUC, 0.948). Moreover, the addition of CD8+ T-cell tumor-infiltrating lymphocytes was associated with improved prognosis predictions for OS (3-year OS AUC, 0.659; 5-year OS AUC, 0.665). RYR1 or MGAM mutations were significantly associated with concomitantly increased durable clinical benefits (RYR1: durable clinical benefit [DCB], 12 of 51 patients [24%]; no durable benefit [NDB], 2 of 55 patients [4%]; P < .001; MGAM: DCB, 12 of 51 patients [24%]; NDB, 0 patients; P < .001), a higher TMB (RYRI: high TMB, 12 of 53 patients [23%]; low TMB, 2 of 53 patients [38%]; P < .001; MGAM: high TMB, 9 of 53 patients [17%]; low TMB, 0 patients; P < .001), and higher PD-L1 expression (RYRI: high PD-L1 expression, 8 of 30 patients [27%]; low PD-L1 expression, 6 of 85 [7.1%]; P < .001; MGAM: high PD-L1 expression, 6 of 30 patients [20%]; low PD-L1 expression, 5 of 85 patients [6%]; P < .001). Conclusions and Relevance:Immunotherapies showed promising clinical outcomes for patients with NSCLC. Pembrolizumab with platinum-based chemotherapy was found to be the most appropriate first-line immune checkpoint inhibitor regimen for advanced NSCLC, and the combined use of PD-L1 expression and TMB was found to be a promising biomarker to evaluate patients' survival and response to precision immunotherapy. The further combination of CD8+ T-cell tumor-infiltrating lymphocytes, PD-L1 expression, and TMB was associated with reliable prognosis. The predictive value of that combination needs to be prospectively validated in large-scale studies. 10.1001/jamanetworkopen.2019.6879
    Principles of Immunotherapy in Non-Small Cell Lung Cancer. Hsu Melinda L,Naidoo Jarushka Thoracic surgery clinics Immunotherapy has transformed the treatment of many tumors. Robust data demonstrating improved overall survival and progression-free survival in patients treated with monoclonal antibodies have established immune checkpoint inhibitors as standard of care in stages III and IV non-small cell lung cancer. Nivolumab is effective in previously treated patients with metastatic non-small cell lung cancer. Pembrolizumab and atezolizumab are approved as monotherapy and in combination with other therapies. Ongoing trials investigate the potential role of immunotherapy in earlier disease settings. Identifying predictive biomarkers of response will further amplify the impact of immune checkpoint inhibitors in the treatment of non-small cell lung cancer. 10.1016/j.thorsurg.2020.01.009
    Real-world progression, treatment, and survival outcomes during rapid adoption of immunotherapy for advanced non-small cell lung cancer. Khozin Sean,Miksad Rebecca A,Adami Johan,Boyd Mariel,Brown Nicholas R,Gossai Anala,Kaganman Irene,Kuk Deborah,Rockland Jillian M,Pazdur Richard,Torres Aracelis Z,Zhi Jizu,Abernethy Amy P Cancer BACKGROUND:Despite the rapid adoption of immunotherapies in advanced non-small cell lung cancer (advNSCLC), knowledge gaps remain about their real-world (rw) performance. METHODS:This retrospective, observational, multicenter analysis used the Flatiron Health deidentified electronic health record-derived database of rw patients with advNSCLC who received treatment with PD-1 and/or PD-L1 (PD-[L]1) inhibitors before July 1, 2017 (N = 5257) and had ≥6 months of follow-up. The authors investigated PD-(L)1 line of treatment and PD-L1 testing rates and the relationship between overall survival (OS) and rw intermediate endpoints: progression-free survival (rwPFS), rw time to progression (rwTTP), rw time to next treatment (rwTTNT), and rw time to discontinuation (rwTTD). RESULTS:First-line PD-(L)1 inhibitor use increased from 0% (in the third quarter of 2014 [Q3 2014]) to 42% (Q2 2017) over the study period. PD-L1 testing also increased (from 3% in Q3 2015 to 70% in Q2 2017). The estimated median OS was 9.3 months (95% CI, 8.9-9.8 months), and the estimated rwPFS was 3.2 months (95% CI, 3.1-3.3 months). Longer OS and rwPFS were associated with ≥50% PD-L1 percentage staining results. Correlations (⍴) between OS and intermediate endpoints were ⍴ = 0.75 (95% CI, 0.73-0.76) for rwPFS and ⍴ = 0.60 (95% CI, 0.57-0.63) for rwTTP, and, for treatment-based intermediate endpoints, correlations were ⍴ = 0.60 (95% CI, 0.56-0.64) for rwTTNT (N = 856) and ⍴ = 0.81 (95% CI, 0.80-0.82) for rwTTD. CONCLUSIONS:The use of first-line PD-(L)1 inhibitors and PD-L1 testing has substantially increased, with better outcomes for patients who have ≥50% PD-L1 percentage staining. Intermediate rw tumor-dynamics estimates were moderately correlated with OS in patients with advNSCLC who received immunotherapy, highlighting the need for optimizing and standardizing rw endpoints to enhance the understanding of patient outcomes outside clinical trials. 10.1002/cncr.32383
    [Inhibitory effect of endostar on lymphangiogenesis in non-small cell lung cancer and its effect on circulating tumor cells]. Shang Liqun,Zhao Jie,Wang Wei,Xiao Wang,Li Jun,Li Xuechang,Song Weian,Liu Junqiang,Wen Feng,Yue Caiying Zhongguo fei ai za zhi = Chinese journal of lung cancer BACKGROUND AND OBJECTIVE:It is unclear how could endostatin effect tumor lymphangiogenesis? The aim of this study is to explore inhibitory effect of recombinant human endostatin injection (endostar) on lymphangiogenesis in non-small cell lung cancer (NSCLC) tissue and its effect on circulating tumor cells (CTC) in peripheral blood. METHODS:Tumor-bearing model nude mice were divided into eight groups randomly (n=7), including control group, cisplatin group, several concentration endostar groups and endostar plus cisplatin groups. Continuous administration of Endostar for two weeks, observed one week after the end of administration. Using HE staining and immunohistochemical staining to diagnose the tumor tissue and suspect metastasis lymph nodes, detected vascular endothelial growth factor (VEGF)-C, VEGF-D, VEGF receptor (VEGFR)-3 expression level and microlymphatic vessel density (MLVD) of tumor tissue. Enrichment of circulating tumor cells in peripheral blood used immunomagnetic negative selection strategy, used immunofluorescence staining to diagnose and count CTCs. RESULTS:Microlymphatic vessel density and the positive expression rate of VEGF-C, VEGF-D, VEGFR-3 in three endostar groups and three endostar plus cisplatin groups were significantly less than those in control group and cisplatin group. Microlymphatic vessel density and the positive expression rate of VEGF-C, VEGF-D, VEGFR-3 in endostar plus cisplatin group and endostar group with high endostar concentration were significantly less than those with low endostar concentration; There was a significant positive correlation between microlymphatic vessel density and the positive expression rate of VEGF-C, VEGF-D, VEGFR-3. The number of circulating tumor cells in endostar plus cisplatin groups were significantly less than that of endostar or cisplatin alone. CONCLUSIONS:Endostar could inhibit tumor lymphangiogenesis and reduce tumor cells into the bloodstream through the lymphatic. Inhibitory effect concerned with drug concentrationwith a dose-dependant. 10.3779/j.issn.1009-3419.2014.10.03