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that show promising preliminary results against various tumors&#44; including LC&#44;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">7</span></a> have been developed&#44; but their widespread use&#44; except in metastatic melanoma and renal cell carcinoma&#44; has been limited by lack of specificity and adverse effects&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">3</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">New Pathogenic Concepts of Immunity and Cancer</span><p id="par0020" class="elsevierStylePara elsevierViewall">Recent research<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">6&#8211;8</span></a> has led to a deeper understanding of the complex relationships between the immune system and tumor cells&#44; and of the molecular mechanisms by which tumor cells can avoid destruction by T cells&#46; 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Immune Checkpoint Inhibitors</span><p id="par0030" class="elsevierStylePara elsevierViewall">Cancer cells can be prevented from using these inhibitory pathways by blocking the above-mentioned receptors or the corresponding ligands with specific monoclonal antibodies&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">2&#8211;8</span></a> These agents&#44; by their mechanism of action&#44; neutralize the checkpoints used by the tumor cells&#44; and unblock the ability of the lymphocytes to destroy them &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#44; so they could possibly be called immune checkpoint inhibitors&#44; a neologism that we will provisionally use in this paper&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">Preliminary positive results with immune checkpoint inhibitors in randomized trials were first obtained in metastatic melanoma with ipilimumab&#44; a monoclonal antibody that neutralizes the CTLA-4 receptor which inhibits T cells&#46; A trial published in 2010 showed that ipilimumab in second-line treatment was superior to the comparative regimen based on the gp100 vaccine &#40;median survival 10&#46;1 and 6&#46;4 months&#44; respectively&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">9</span></a> These outcomes helped this drug receive rapid approval by the regulatory authorities in the U&#46;S&#46;&#44; and since then&#44; numerous studies have been performed in other cancers&#46; <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows some of these drugs and their targets&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Preliminary Trials With Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer</span><p id="par0040" class="elsevierStylePara elsevierViewall">The first indications that these agents were effective in LC were obtained in 2 phase I clinical trials that included NSCLC and other tumors&#46; Different doses of the study drugs were tested &#40;anti-PD-1 in 1 trial and anti-PD-L1 in the other&#41;&#46; Favorable outcomes were observed in 18&#37; of NSCLCs&#44; and in up to 36&#37; of PD-L1-positive tumors&#46; Most of these responses lasted more than 1 year&#44; with an acceptable safety profile and a 14&#37; incidence of WHO grade 3&#47;4 adverse events&#46;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">10&#44;11</span></a> These results were quickly followed by initial randomized trials in the second-line treatment of NSCLC patients who had failed or relapsed after a first line of standard chemotherapy &#40;CT&#41; based on platinum doublets&#59; one of the trials included squamous tumors only&#44; and the other non-squamous tumors only&#46; Response rates and overall survival were significantly better with the study drug &#40;nivolumab&#41; than with the control docetaxel-based CT&#46; Moreover&#44; significantly fewer severe side effects were reported in the group treated with nivolumab &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">12&#44;13</span></a> The lack of benefit in progression-free survival &#40;PFS&#41; can be explained by the peculiar effects of these drugs&#44; which sometimes initially produce an apparent increase in tumor volume&#46; This issue is discussed below in the section on evaluation criteria for response&#46; Subsequent trials have confirmed the effectiveness of other immune checkpoint inhibitors in the second-line treatment of NSCLC patients<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">14&#44;15</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#44; and the National Comprehensive Cancer Network &#40;NCCN&#41; &#40;version 6&#46;2017&#41; recommends their use in this setting&#44; citing grade 1 evidence&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">16</span></a> The most recent drugs &#40;durvalumab and avelumab&#41; have shown promising results in phase I-II clinical trials<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">17&#8211;19</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Randomized Trials With Immune Checkpoint Inhibitors in the First-Line Treatment of Lung Cancer</span><p id="par0045" class="elsevierStylePara elsevierViewall">The expectations raised by these drugs has prompted intense research activity&#44; and relevant information is already available on their efficacy in first line&#58; in a phase I trial&#44; nivolumab &#40;at doses of 3<span class="elsevierStyleHsp" style=""></span>mg&#47;kg body weight every 2 weeks&#41;&#44; used as initial monotherapy in 52 patients with NSCLC&#44; yielded objective responses in 23&#37; of the series&#44; and in 28&#37; of the subgroup with PD-L1 biomarker expression&#46; Median overall survival was 19&#46;4 months&#44; and the severe adverse effect rate was 19&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">20</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Numerous first-line phase III trials in NSCLC are currently ongoing&#44;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">21</span></a> and the results of some completed trials have already been published &#40;Keynote-024&#44; <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46; One of these studies compared the anti-PD-1 immune checkpoint inhibitor pembrolizumab with platinum-based CT&#44; although one of the inclusion criteria for the study was PD-L1 expression in over 50&#37; of tumor cells&#44; a criterion met by 20&#37;&#8211;25&#37; of patients with advanced NSCLC&#46; This trial &#40;Keynote-024&#44; <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41; showed pembrolizumab to be superior in terms of overall survival and PFS&#44; and less toxic than CT&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">22</span></a> On the basis of these results&#44; the NCCN &#40;version 3&#46;2017&#41; recommends using this immune checkpoint inhibitor when starting first-line treatment of NSCLC in patients whose tumor expresses the high concentrations of PD-L1 required in the above-mentioned study&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">16</span></a> In the other randomized study &#40;presented at a congress&#44; but not yet published&#41; &#40;CheckMate 026&#41;&#44; nivolumab was compared to standard CT&#59; PD-L1 expression was required in at least 1&#37; of tumor cells&#46; Overall survival was similar in both groups&#44; while the immune checkpoint inhibitor showed less toxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">23</span></a> Although further analysis is required&#44; the failure of nivolumab to show superiority in this trial may be due to the excessively low threshold for PD-L1 expression &#40;1&#37;&#41; required for inclusion in the original design&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Biomarkers Predicting Favorable Response</span><p id="par0055" class="elsevierStylePara elsevierViewall">Immune checkpoint inhibitors sometimes produce remarkable results&#44; including long-term complete remissions&#44; but objective responses are observed in at most 15&#37;&#8211;20&#37; of unselected patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">4&#44;24</span></a> It is of the utmost importance&#44; therefore&#44; to identify some clinical or tumor marker to predict which patients are more likely to benefit&#46; Since some of these drugs are monoclonal antibodies designed to inhibit the PD-1 receptor&#44; as mentioned above&#44; it seems reasonable to expect that the concentration of PD-L1 &#40;ligands that bind to this receptor&#41; expressed in tumor or immune cells would be useful for predicting efficacy&#46; However&#44; the wide range of reagents developed by the different companies and the diverse cut-off points established by different authors have generated conflicting results&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">25&#44;26</span></a> In the CheckMate 017 trial &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#44; conducted in patients with squamous cell carcinoma&#44; PD-L1 concentrations did not affect outcomes<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">12</span></a>&#59; in contrast&#44; in CheckMate 057&#44; patients with non-squamous cell carcinoma and PD-L1 concentrations higher than 10&#37; in tumor biopsies had longer mean overall survival than those with levels lower than 10&#37; &#40;19&#46;4 and 9&#46;9 months&#44; respectively&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">13</span></a> The overall assessment of the findings from these and other studies suggests that this biomarker has a predictive value for response&#44; and cooperative efforts are being made to harmonize&#44; standardize and validate analytical techniques that would simplify the use of this biomarker in clinical practice&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">25</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">In addition to PD-L1&#44; other factors may have predictive value&#46; For example&#44; it seems that the greater the number of mutations in a tumor&#44; the more sensitive it is to these drugs&#44; because the number of antigens that can be recognized by the immune system will also be greater&#46; For this reason&#44; one proposal is to sequence the complete tumor genome or a preselected panel of representative genes to evaluate the mutational load&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">25&#44;26</span></a> This hypothesis is supported by the fact that cancers attributed to excessive exposure to ultraviolet light &#40;skin cancer&#41; or tobacco smoke &#40;lung cancer&#41;&#44; which have a large number of mutations&#44; respond best to these drugs&#46; In NSCLC trials&#44; when responses were analyzed according to different characteristics&#44; smokers were found to respond better than non-smokers&#46;<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">20&#44;22&#44;25</span></a> Although there are still no clear recommendations in this respect&#44; in the absence of available biomarkers&#44; this epidemiological finding may serve to guide difficult therapeutic decisions in clinical practice&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Criteria for the Evaluation of Response</span><p id="par0065" class="elsevierStylePara elsevierViewall">PFS is an essential criterion for assessing the efficacy of a therapeutic regimen in patients with advanced NSCLC&#46; However&#44; these drugs have shown significant discrepancies between PFS and overall survival which can be explained by the specific effects of unblocking the immune reaction&#46; Indeed&#44; an apparent increase in tumor volume can be observed&#44; due to lymphocytes infiltrating the tumor&#44; reflecting the efficacy of the immune checkpoint inhibitory effect of the drug&#46; This paradoxical phenomenon which mimics disease progression&#44; but which in fact is the opposite&#44; is called &#8220;pseudoprogression&#8221;&#44;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">2</span></a> and only after a long period of close monitoring of the patient will the reduction in tumor size become apparent&#46; For this reason&#44; it has been suggested that overall survival&#44; and not PFS&#44; is the criterion that most accurately reflects the real benefits&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">27&#44;28</span></a> This peculiar tumor response also calls for a change in the conventional therapeutic evaluation criteria for solid tumors &#40;RECIST criteria&#41;&#44; which now should take into account the possibility of &#8220;pseudoprogression&#8221;&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">28&#44;29</span></a> It may even be necessary to include different statistical parameters in the evaluation of PFS&#44; since this phenomenon leads to crossing of the Kaplan&#8211;Meier curves that violates the proportional hazards assumption demanded by some tests&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">27</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Combined Immune Checkpoint Inhibitor and Chemotherapy Regimens</span><p id="par0070" class="elsevierStylePara elsevierViewall">Since the antitumor mechanisms of action of immune checkpoint inhibitors and conventional CT differ radically&#44; the idea of testing the combination of both drugs is attractive&#46; This approach has been explored in 2 recent phase I and II trials&#58; &#40;a&#41; CheckMate 012&#44; in which platinum-based CT was combined with different doses of nivolumab&#44; followed by maintenance with nivolumab until disease progression or unacceptable toxicity&#46; Although only 52 patients were included&#44; objective responses &#40;between 33&#37; and 47&#37;&#41; and overall survival at 2 years &#40;between 25&#37; and 62&#37;&#41; are encouraging<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">30</span></a>&#59; and &#40;b&#41; Keynote-021&#44; comparing pembrolizumab plus CT &#40;carboplatin and pemetrexed&#41; with the same CT regimen alone&#59; both arms subsequently received maintenance pemetrexed&#46; Favorable response rates were 55&#37; and 19&#37;&#44; respectively&#44; and adverse effects rates were similar&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">31</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Immune Checkpoint Inhibitors in Small Cell Lung Cancer</span><p id="par0075" class="elsevierStylePara elsevierViewall">Small cell lung cancer is a very aggressive CT-sensitive tumor&#44; closely related to smoking&#44; with the consequent high mutational load&#46; As such&#44; it is in theory an excellent candidate for these new agents&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">32</span></a> Phase II studies combining ipilimumab &#40;anti-CTL4-A&#41; with platinum derivatives and etoposide &#40;the usual regimen in this tumor&#41; showed modest improvements in PFS&#44; but in a large randomized trial the addition of ipilimumab to the standard CT regimen showed no benefit compared to CT alone&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">33</span></a> Recently&#44; a combination of 2 immune checkpoint inhibitors &#40;anti-CTL4-A and anti-PD-1&#41; that act on different targets has produced objective responses in the range of 10&#37;&#8211;19&#37;&#44; with acceptable toxicity&#44; in patients with recurrent small cell lung cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">34</span></a> In view of these results&#44; the NCCN &#40;Version 3&#46;2017&#41; recommends the use of these agents in the event of relapse within 6 months after the first treatment &#40;level of evidence 2A&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">35</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Contraindications&#46; Immune-Related Adverse Effects</span><p id="par0080" class="elsevierStylePara elsevierViewall">In clinical trials&#44; significantly fewer severe adverse effects &#40;WHO grades 3 and 4&#41; were reported with immune checkpoint inhibitors than with standard CT &#40;<a class="elsevierStyleCrossRefs" href="#tbl0010">Tables 2 and 3</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">12&#8211;15&#44;22</span></a> However&#44; the particular mechanism of action of these agents gives them a unique toxicity profile&#46; The PD-1&#47;PD-L1 pathway plays a crucial role in immune homeostasis and the suppression of T cell activity against autoantigens&#46; Thus&#44; if this pathway is blocked&#44; an immune attack can be triggered&#44; not only against the tumor but also against normal tissues&#44; causing autoimmune disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">32&#44;36&#44;37</span></a> In most trials&#44; a clinical history of autoimmune diseases&#44; chronic HIV or hepatitis B or C infection&#44; active interstitial lung disease or other diseases treated with corticosteroids was considered an exclusion criterion&#46; However&#44; although experience is limited&#44; reports of isolated cases and small series in uncontrolled studies suggest that these drugs can even be used in these circumstances if patients are closely monitored&#44; and that toxicities are manageable&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">36&#44;37</span></a></p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">The most common immune-related effects include skin rash&#44; colitis&#44; liver diseases&#44; pneumonitis&#44; and endocrine diseases&#44; such as hypophysitis and thyroiditis &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; If these conditions are suspected&#44; infection or tumor progression should first be ruled out&#44; and topical&#44; oral or intravenous corticosteroids should be administered&#44; depending on severity&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">36&#44;37</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Cost-Effectiveness Analysis</span><p id="par0090" class="elsevierStylePara elsevierViewall">The cost of immune checkpoint inhibitors varies depending on the country and the health system model&#44; but they are generally very high&#58; between &#36;150&#44;000 and &#36;180&#44;000 per quality-adjusted year of life&#46;<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">38&#44;39</span></a> A recent economic analysis conducted in Switzerland concluded that at current prices&#44; nivolumab is not cost-effective compared to docetaxel&#46; Price reduction or a stricter selection of the population according to PD-L1 levels would be necessary&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">39</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Prospects for the Future&#46; Combinations With Chemotherapy and Radiation Therapy</span><p id="par0095" class="elsevierStylePara elsevierViewall">The development of clinical applications of immune checkpoint inhibitors has gained momentum in the USA&#44; because the Food and Drug Administration granted these drugs priority review status&#44; thus speeding up the procedures for the evaluation and approval of new medications&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">25</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Numerous studies are now exploring the use of these drugs in neoadjuvant and adjuvant treatment&#44; and as consolidation therapy after an initial regimen of CT and radiation therapy&#46; Preliminary data have also appeared which suggest that antiangiogenic agents &#40;bevacizumab&#44; nintedanib&#44; etc&#46;&#41; can stimulate the immune system&#44; and trials appear to indicate that the combination with immune checkpoint inhibitors produces synergy without substantially increasing toxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">40</span></a> These combinations are still at an early stage of investigation&#44; and the doses and optimal sequence of administration of each drug remain to be determined&#46; However&#44; research is now focusing primarily on the possible incorporation of these new drugs in first-line therapy and the selection of the right candidates in order to begin this paradigm shift in treatment&#46; The most widely studied biomarker predicting a favorable response to date has been the immunohistochemical expression of PD-L1&#44; although some trials have also shown positive results in patients with low or negative concentrations of PD-L1&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">28</span></a> The use of different antibodies and analytical methods has been an obstacle to the validation of this biomarker&#44;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">25&#44;26</span></a> prompting an international effort to standardize the procedures and to design a common&#44; reliable method&#46; The utility of other markers is also being investigated&#44; and areas of interest range from smoking to the presence of tumor-infiltrating lymphocytes or determination of the mutational load by genomic sequencing of the tumor&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">26</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Data available to date suggest that&#44; in the medium term&#44; it is very unlikely that these drugs will completely substitute platinum-based CT in the treatment of NSCLC&#44; but the development of reliable markers may help us identify patients with a greater chance of benefitting from immune checkpoint inhibitors&#44; whether in monotherapy&#44; or in combination with other similar or different therapeutic modalities&#44; including traditional CT&#46;</p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Conflict of Interests</span><p id="par0110" class="elsevierStylePara elsevierViewall">The authors state that they have no conflict of interests&#46;</p></span></span>"
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          "titulo" => "New Pathogenic Concepts of Immunity and Cancer"
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              "titulo" => "New Therapeutic Concepts&#46; Immune Checkpoint Inhibitors"
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              "titulo" => "Preliminary Trials With Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer"
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              "titulo" => "Randomized Trials With Immune Checkpoint Inhibitors in the First-Line Treatment of Lung Cancer"
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              "titulo" => "Biomarkers Predicting Favorable Response"
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              "titulo" => "Immune Checkpoint Inhibitors in Small Cell Lung Cancer"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Recent research on the relationship between the immune system and cancer has revealed the molecular mechanisms by which cancer cells co-opt certain T cell receptors which block the cytotoxic response to defend themselves from the antitumor immune attack&#46; These findings have helped identify specific targets &#40;T cell receptors or their corresponding ligands&#41; for the design of monoclonal antibodies that can unlock the immune response&#46;</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">These drugs&#44; known as immune checkpoint inhibitors&#44; have shown efficacy in metastatic melanoma and kidney cancer&#44; and have been successfully tested in non-small cell lung cancer in recent trials&#46; Immune checkpoint inhibitors were included in clinical practice as a second-line option after an initial chemotherapy &#40;CT&#41; regimen&#44; and in the last year positive results have been reported from randomized trials in which they were compared in first line with standard CT&#46; Responses have been surprising and durable&#44; but less than 20&#37;&#8211;25&#37; in unselected patients&#44; so it is essential that factors predicting efficacy be identified&#46; One such biomarker is PD-L1&#44; but the different methods used to detect it have produced mixed results&#46;</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">This non-systematic review discusses the results of the latest trials&#44; the possibilities of incorporating these drugs in first-line regimens&#44; the criteria for patient selection&#44; adverse effects&#44; and the prospects of combinations with conventional treatment modalities&#44; such as CT&#44; radiation therapy&#44; and antiangiogenic agents&#46;</p></span>"
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      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Investigaciones recientes sobre la relaci&#243;n entre el sistema inmune y el c&#225;ncer han desvelado los mecanismos moleculares mediante los cuales las c&#233;lulas neopl&#225;sicas aprovechan algunos receptores de los linfocitos T&#44; con funci&#243;n inhibitoria de la respuesta citot&#243;xica&#44; para defenderse del ataque inmune desarrollado frente a ellas&#46; Estos hallazgos han permitido identificar dianas precisas &#40;receptores de los linfocitos T o ligandos que se acoplan a ellos&#41; frente a los que se han dise&#241;ado anticuerpos monoclonales&#44; capaces de desbloquear la respuesta inmunitaria&#46;</p><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Estos f&#225;rmacos <span class="elsevierStyleItalic">&#40;immune check point inhibitors&#41;</span>&#44; de eficacia demostrada en el melanoma metast&#225;sico o el carcinoma renal&#44; han sido probados con &#233;xito frente al carcinoma de pulm&#243;n no microc&#237;tico en ensayos recientes&#46; Tras su aprobaci&#243;n e incorporaci&#243;n a la pr&#225;ctica cl&#237;nica en 2&#46;&#170; l&#237;nea despu&#233;s de una pauta inicial de quimioterapia &#40;QT&#41;&#44; se han comunicado en el &#250;ltimo a&#241;o resultados positivos en ensayos aleatorizados que los comparaban con QT est&#225;ndar en 1&#46;&#170; l&#237;nea&#46; Se han observado respuestas sorprendentes y duraderas&#44; aunque no superan el 20-25&#37; en pacientes no seleccionados&#44; por lo que es crucial detectar rasgos predictivos de eficacia&#44; como el biomarcador PD-L1&#44; si bien los diferentes m&#233;todos para su detecci&#243;n han producido resultados dispares&#46;</p><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">En esta revisi&#243;n no sistem&#225;tica se discuten los resultados de los &#250;ltimos ensayos&#44; las posibilidades de incorporar estos f&#225;rmacos en primera l&#237;nea&#44; los criterios de selecci&#243;n de pacientes&#44; los efectos adversos y las perspectivas de su empleo asociados a modalidades terap&#233;uticas tradicionales como QT&#44; radioterapia o antiangiog&#233;nicos&#46;</p></span>"
      ]
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        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0025">Please cite this article as&#58; S&#225;nchez de Cos Escu&#237;n J&#46; Nueva inmunoterapia y c&#225;ncer de pulm&#243;n&#46; Arch Bronconeumol&#46; 2017&#59;53&#58;682&#8211;687&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Molecular Target&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Immune Checkpoint Inhibitor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Programmed cell death receptor &#40;PD-1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nivolumab&#44; pembrolizumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PD-1 ligand &#40;PD-L1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Atezolizumab&#44; durvalumab&#44; avelumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cytotoxic T lymphocyte antigen-4 &#40;CTLA-4&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr></tbody></table>
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">No&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">ICI vs CT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Strain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Response Rate &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Progression-Free Survival &#40;Months&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Overall Survival &#40;Months&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Severe Adverse Effects<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CheckMate 017&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">272&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nivolumab vs docetaxel&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Squamous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20&#37; nivol&#46; vs 9&#37; docet&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#46;5 nivol&#46; vs 2&#46;8 docet&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9&#46;2 nivol&#46; vs 6&#46;0 docet&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&#37; nivol&#46; vs 55&#37; docet&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CheckMate 057&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">582&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nivolumab vs docetaxel&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Non-squamous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">19&#37; nivol&#46; vs 12&#37; docet&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;3 nivol&#46; vs 4&#46;2 docet&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12&#46;2 nivol&#46; vs 9&#46;4 docet&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#37; nivol&#46; vs 54&#37; docet&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Keynote-010&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">850&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pembrolizumab<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a> vs docetaxel&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Squamous and non-squamous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#46;9 &#38; 4&#46;0 nivol&#46; vs 4&#46;0 docet&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#46;4 &#38; 12&#46;7 vs 8&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">13&#37; &#38; 16&#37; vs 35&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">OAK&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1034&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Atezolizumab vs docetaxel&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Squamous and non-squamous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">18&#37; atezo&#46; vs 16&#37; docet&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;8 atezo&#46; vs 4&#46;0 docet&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">13&#46;8 atezo&#46; vs 9&#46;6 docet&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15&#37; atezo&#46; vs 43&#37; docet&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">This trial included 3 arms&#58; 2 with different doses of pembrolizumab and 1 with docetaxel&#46;</p>"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Immune Checkpoint Inhibitors &#40;ICI&#41; in Advanced NSCLC Randomized Trials After Relapse&#46;</p>"
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          "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Anti-PD-1 agents&#58; pembrolizumab and nivolumab<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">12&#8211;16</span></a>&#59; anti-PD-L1 agent&#58; atezolizumab&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">15</span></a></p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Common toxicity</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Any effect&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">16&#8211;26&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Hyporexia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9&#8211;14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#8211;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Stomatitis&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Nausea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9&#8211;11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#8211;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Vomiting&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Diarrhea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7&#8211;14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#8211;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Anemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Neutropenia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Rash&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&#8211;13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#60;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Pyrexia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&#8211;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#60;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Due to autoimmune mechanism</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Any&nbsp;\t\t\t\t\t\t\n
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New Immunotherapy and Lung Cancer
Nueva inmunoterapia y cáncer de pulmón
Julio Sánchez de Cos Escuín
Servicio de Neumología, Hospital San Pedro de Alcántara, Cáceres, Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Background</span><p id="par0005" class="elsevierStylePara elsevierViewall">The idea of stimulating and enhancing the immune response to cancer was first conceived by Paul Ehrlich more than a century ago&#44;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">1</span></a> and has aroused the interest of many authors&#44; but only in the last few years has the notion taken shape in the form of therapeutic advances that can be used in the clinic&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">2</span></a> For years&#44; the concept map for this line of research was based on introducing a series of generally non-specific antigens that would induce an immune response in the patient that could arrest the growth of neoplastic cells&#46; The aim was to emulate the success of traditional vaccines in the prevention of allergies and infectious diseases&#46; Multiple vaccines derived from inactivated neoplastic cells were tested&#44; and there was even some experimentation involving the introduction of infectious agents into tumors in the hope of activating the immune system&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">3&#44;4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Although lung cancer &#40;LC&#41; has long been considered non-immunogenic&#44; some findings suggest otherwise&#46; For example&#44; the incidence of LC and other cancers is very high in organ transplant recipients with induced immunosuppression and patients with human immunodeficiency virus &#40;HIV&#41; infection&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">5</span></a> The presence of tumor-infiltrating lymphocytes in resected LC specimens has also been associated with better prognosis&#46; Moreover&#44; many non-small cell LCs &#40;NSCLC&#41; are known to produce antigens that can induce an immune response&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">2&#44;5&#44;6</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Anticancer vaccines and immune stimulating substances &#40;interferon and various interleukins&#41; that show promising preliminary results against various tumors&#44; including LC&#44;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">7</span></a> have been developed&#44; but their widespread use&#44; except in metastatic melanoma and renal cell carcinoma&#44; has been limited by lack of specificity and adverse effects&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">3</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">New Pathogenic Concepts of Immunity and Cancer</span><p id="par0020" class="elsevierStylePara elsevierViewall">Recent research<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">6&#8211;8</span></a> has led to a deeper understanding of the complex relationships between the immune system and tumor cells&#44; and of the molecular mechanisms by which tumor cells can avoid destruction by T cells&#46; It has been shown that other stimulatory signals&#44; in addition to the presentation of antigen by dendritic cells&#44; are required to activate cytotoxic T cells&#44; and pathways that block those signals and thus promote tumor growth have been identified&#46; The theory of immune surveillance&#44; referring to the mere recognition by the body of cancer cells as foreign&#44; has been replaced by the concept of immune editing&#44; which hypothesizes that the immune system interacts with the tumor in 3 phases&#58; &#40;1&#41; recently developed cancer cells are eliminated by innate and adaptive immune mechanisms&#59; &#40;2&#41; some cells that can avoid this immune attack enter into a dormant state&#59; and &#40;3&#41; finally&#44; these cells can escape immune control and proliferate&#44; leading to clinically apparent disease&#44; a feature now considered a hallmark of cancer cells&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">6</span></a> In other words&#44; the tumor evades attack by the T cells&#44; taking advantage of certain immune checkpoints&#46; Therapeutic targets of special interest include the programmed cell death-1 &#40;PD-1&#41; receptor&#44; its associated ligands &#40;PD-L1&#41;&#44; and cytotoxic T-lymphocyte antigen-4 &#40;CTL4-A&#41;&#46; Effective therapeutic agents aimed at these targets are already available&#46;<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">6&#8211;8</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">In addition to these regulatory pathways&#44; the immune profile of an individual depends on multiple factors&#44; including the intrinsic properties of the tumor &#40;genetic makeup&#44; cytokine secretion&#44; etc&#46;&#41; and extrinsic circumstances&#44; such as gut microbiome&#44; presence of infections&#44; and exposure to environmental carcinogens&#46; The bottom line of all these influencing factors is a specific anti-cancer immunity status that determines an individual&#39;s potential response to immunotherapy agents&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">8</span></a></p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">New Therapeutic Concepts&#46; Immune Checkpoint Inhibitors</span><p id="par0030" class="elsevierStylePara elsevierViewall">Cancer cells can be prevented from using these inhibitory pathways by blocking the above-mentioned receptors or the corresponding ligands with specific monoclonal antibodies&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">2&#8211;8</span></a> These agents&#44; by their mechanism of action&#44; neutralize the checkpoints used by the tumor cells&#44; and unblock the ability of the lymphocytes to destroy them &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#44; so they could possibly be called immune checkpoint inhibitors&#44; a neologism that we will provisionally use in this paper&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">Preliminary positive results with immune checkpoint inhibitors in randomized trials were first obtained in metastatic melanoma with ipilimumab&#44; a monoclonal antibody that neutralizes the CTLA-4 receptor which inhibits T cells&#46; A trial published in 2010 showed that ipilimumab in second-line treatment was superior to the comparative regimen based on the gp100 vaccine &#40;median survival 10&#46;1 and 6&#46;4 months&#44; respectively&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">9</span></a> These outcomes helped this drug receive rapid approval by the regulatory authorities in the U&#46;S&#46;&#44; and since then&#44; numerous studies have been performed in other cancers&#46; <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows some of these drugs and their targets&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Preliminary Trials With Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer</span><p id="par0040" class="elsevierStylePara elsevierViewall">The first indications that these agents were effective in LC were obtained in 2 phase I clinical trials that included NSCLC and other tumors&#46; Different doses of the study drugs were tested &#40;anti-PD-1 in 1 trial and anti-PD-L1 in the other&#41;&#46; Favorable outcomes were observed in 18&#37; of NSCLCs&#44; and in up to 36&#37; of PD-L1-positive tumors&#46; Most of these responses lasted more than 1 year&#44; with an acceptable safety profile and a 14&#37; incidence of WHO grade 3&#47;4 adverse events&#46;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">10&#44;11</span></a> These results were quickly followed by initial randomized trials in the second-line treatment of NSCLC patients who had failed or relapsed after a first line of standard chemotherapy &#40;CT&#41; based on platinum doublets&#59; one of the trials included squamous tumors only&#44; and the other non-squamous tumors only&#46; Response rates and overall survival were significantly better with the study drug &#40;nivolumab&#41; than with the control docetaxel-based CT&#46; Moreover&#44; significantly fewer severe side effects were reported in the group treated with nivolumab &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">12&#44;13</span></a> The lack of benefit in progression-free survival &#40;PFS&#41; can be explained by the peculiar effects of these drugs&#44; which sometimes initially produce an apparent increase in tumor volume&#46; This issue is discussed below in the section on evaluation criteria for response&#46; Subsequent trials have confirmed the effectiveness of other immune checkpoint inhibitors in the second-line treatment of NSCLC patients<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">14&#44;15</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#44; and the National Comprehensive Cancer Network &#40;NCCN&#41; &#40;version 6&#46;2017&#41; recommends their use in this setting&#44; citing grade 1 evidence&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">16</span></a> The most recent drugs &#40;durvalumab and avelumab&#41; have shown promising results in phase I-II clinical trials<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">17&#8211;19</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Randomized Trials With Immune Checkpoint Inhibitors in the First-Line Treatment of Lung Cancer</span><p id="par0045" class="elsevierStylePara elsevierViewall">The expectations raised by these drugs has prompted intense research activity&#44; and relevant information is already available on their efficacy in first line&#58; in a phase I trial&#44; nivolumab &#40;at doses of 3<span class="elsevierStyleHsp" style=""></span>mg&#47;kg body weight every 2 weeks&#41;&#44; used as initial monotherapy in 52 patients with NSCLC&#44; yielded objective responses in 23&#37; of the series&#44; and in 28&#37; of the subgroup with PD-L1 biomarker expression&#46; Median overall survival was 19&#46;4 months&#44; and the severe adverse effect rate was 19&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">20</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Numerous first-line phase III trials in NSCLC are currently ongoing&#44;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">21</span></a> and the results of some completed trials have already been published &#40;Keynote-024&#44; <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46; One of these studies compared the anti-PD-1 immune checkpoint inhibitor pembrolizumab with platinum-based CT&#44; although one of the inclusion criteria for the study was PD-L1 expression in over 50&#37; of tumor cells&#44; a criterion met by 20&#37;&#8211;25&#37; of patients with advanced NSCLC&#46; This trial &#40;Keynote-024&#44; <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41; showed pembrolizumab to be superior in terms of overall survival and PFS&#44; and less toxic than CT&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">22</span></a> On the basis of these results&#44; the NCCN &#40;version 3&#46;2017&#41; recommends using this immune checkpoint inhibitor when starting first-line treatment of NSCLC in patients whose tumor expresses the high concentrations of PD-L1 required in the above-mentioned study&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">16</span></a> In the other randomized study &#40;presented at a congress&#44; but not yet published&#41; &#40;CheckMate 026&#41;&#44; nivolumab was compared to standard CT&#59; PD-L1 expression was required in at least 1&#37; of tumor cells&#46; Overall survival was similar in both groups&#44; while the immune checkpoint inhibitor showed less toxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">23</span></a> Although further analysis is required&#44; the failure of nivolumab to show superiority in this trial may be due to the excessively low threshold for PD-L1 expression &#40;1&#37;&#41; required for inclusion in the original design&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Biomarkers Predicting Favorable Response</span><p id="par0055" class="elsevierStylePara elsevierViewall">Immune checkpoint inhibitors sometimes produce remarkable results&#44; including long-term complete remissions&#44; but objective responses are observed in at most 15&#37;&#8211;20&#37; of unselected patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">4&#44;24</span></a> It is of the utmost importance&#44; therefore&#44; to identify some clinical or tumor marker to predict which patients are more likely to benefit&#46; Since some of these drugs are monoclonal antibodies designed to inhibit the PD-1 receptor&#44; as mentioned above&#44; it seems reasonable to expect that the concentration of PD-L1 &#40;ligands that bind to this receptor&#41; expressed in tumor or immune cells would be useful for predicting efficacy&#46; However&#44; the wide range of reagents developed by the different companies and the diverse cut-off points established by different authors have generated conflicting results&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">25&#44;26</span></a> In the CheckMate 017 trial &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#44; conducted in patients with squamous cell carcinoma&#44; PD-L1 concentrations did not affect outcomes<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">12</span></a>&#59; in contrast&#44; in CheckMate 057&#44; patients with non-squamous cell carcinoma and PD-L1 concentrations higher than 10&#37; in tumor biopsies had longer mean overall survival than those with levels lower than 10&#37; &#40;19&#46;4 and 9&#46;9 months&#44; respectively&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">13</span></a> The overall assessment of the findings from these and other studies suggests that this biomarker has a predictive value for response&#44; and cooperative efforts are being made to harmonize&#44; standardize and validate analytical techniques that would simplify the use of this biomarker in clinical practice&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">25</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">In addition to PD-L1&#44; other factors may have predictive value&#46; For example&#44; it seems that the greater the number of mutations in a tumor&#44; the more sensitive it is to these drugs&#44; because the number of antigens that can be recognized by the immune system will also be greater&#46; For this reason&#44; one proposal is to sequence the complete tumor genome or a preselected panel of representative genes to evaluate the mutational load&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">25&#44;26</span></a> This hypothesis is supported by the fact that cancers attributed to excessive exposure to ultraviolet light &#40;skin cancer&#41; or tobacco smoke &#40;lung cancer&#41;&#44; which have a large number of mutations&#44; respond best to these drugs&#46; In NSCLC trials&#44; when responses were analyzed according to different characteristics&#44; smokers were found to respond better than non-smokers&#46;<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">20&#44;22&#44;25</span></a> Although there are still no clear recommendations in this respect&#44; in the absence of available biomarkers&#44; this epidemiological finding may serve to guide difficult therapeutic decisions in clinical practice&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Criteria for the Evaluation of Response</span><p id="par0065" class="elsevierStylePara elsevierViewall">PFS is an essential criterion for assessing the efficacy of a therapeutic regimen in patients with advanced NSCLC&#46; However&#44; these drugs have shown significant discrepancies between PFS and overall survival which can be explained by the specific effects of unblocking the immune reaction&#46; Indeed&#44; an apparent increase in tumor volume can be observed&#44; due to lymphocytes infiltrating the tumor&#44; reflecting the efficacy of the immune checkpoint inhibitory effect of the drug&#46; This paradoxical phenomenon which mimics disease progression&#44; but which in fact is the opposite&#44; is called &#8220;pseudoprogression&#8221;&#44;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">2</span></a> and only after a long period of close monitoring of the patient will the reduction in tumor size become apparent&#46; For this reason&#44; it has been suggested that overall survival&#44; and not PFS&#44; is the criterion that most accurately reflects the real benefits&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">27&#44;28</span></a> This peculiar tumor response also calls for a change in the conventional therapeutic evaluation criteria for solid tumors &#40;RECIST criteria&#41;&#44; which now should take into account the possibility of &#8220;pseudoprogression&#8221;&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">28&#44;29</span></a> It may even be necessary to include different statistical parameters in the evaluation of PFS&#44; since this phenomenon leads to crossing of the Kaplan&#8211;Meier curves that violates the proportional hazards assumption demanded by some tests&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">27</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Combined Immune Checkpoint Inhibitor and Chemotherapy Regimens</span><p id="par0070" class="elsevierStylePara elsevierViewall">Since the antitumor mechanisms of action of immune checkpoint inhibitors and conventional CT differ radically&#44; the idea of testing the combination of both drugs is attractive&#46; This approach has been explored in 2 recent phase I and II trials&#58; &#40;a&#41; CheckMate 012&#44; in which platinum-based CT was combined with different doses of nivolumab&#44; followed by maintenance with nivolumab until disease progression or unacceptable toxicity&#46; Although only 52 patients were included&#44; objective responses &#40;between 33&#37; and 47&#37;&#41; and overall survival at 2 years &#40;between 25&#37; and 62&#37;&#41; are encouraging<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">30</span></a>&#59; and &#40;b&#41; Keynote-021&#44; comparing pembrolizumab plus CT &#40;carboplatin and pemetrexed&#41; with the same CT regimen alone&#59; both arms subsequently received maintenance pemetrexed&#46; Favorable response rates were 55&#37; and 19&#37;&#44; respectively&#44; and adverse effects rates were similar&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">31</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Immune Checkpoint Inhibitors in Small Cell Lung Cancer</span><p id="par0075" class="elsevierStylePara elsevierViewall">Small cell lung cancer is a very aggressive CT-sensitive tumor&#44; closely related to smoking&#44; with the consequent high mutational load&#46; As such&#44; it is in theory an excellent candidate for these new agents&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">32</span></a> Phase II studies combining ipilimumab &#40;anti-CTL4-A&#41; with platinum derivatives and etoposide &#40;the usual regimen in this tumor&#41; showed modest improvements in PFS&#44; but in a large randomized trial the addition of ipilimumab to the standard CT regimen showed no benefit compared to CT alone&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">33</span></a> Recently&#44; a combination of 2 immune checkpoint inhibitors &#40;anti-CTL4-A and anti-PD-1&#41; that act on different targets has produced objective responses in the range of 10&#37;&#8211;19&#37;&#44; with acceptable toxicity&#44; in patients with recurrent small cell lung cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">34</span></a> In view of these results&#44; the NCCN &#40;Version 3&#46;2017&#41; recommends the use of these agents in the event of relapse within 6 months after the first treatment &#40;level of evidence 2A&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">35</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Contraindications&#46; Immune-Related Adverse Effects</span><p id="par0080" class="elsevierStylePara elsevierViewall">In clinical trials&#44; significantly fewer severe adverse effects &#40;WHO grades 3 and 4&#41; were reported with immune checkpoint inhibitors than with standard CT &#40;<a class="elsevierStyleCrossRefs" href="#tbl0010">Tables 2 and 3</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">12&#8211;15&#44;22</span></a> However&#44; the particular mechanism of action of these agents gives them a unique toxicity profile&#46; The PD-1&#47;PD-L1 pathway plays a crucial role in immune homeostasis and the suppression of T cell activity against autoantigens&#46; Thus&#44; if this pathway is blocked&#44; an immune attack can be triggered&#44; not only against the tumor but also against normal tissues&#44; causing autoimmune disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">32&#44;36&#44;37</span></a> In most trials&#44; a clinical history of autoimmune diseases&#44; chronic HIV or hepatitis B or C infection&#44; active interstitial lung disease or other diseases treated with corticosteroids was considered an exclusion criterion&#46; However&#44; although experience is limited&#44; reports of isolated cases and small series in uncontrolled studies suggest that these drugs can even be used in these circumstances if patients are closely monitored&#44; and that toxicities are manageable&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">36&#44;37</span></a></p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">The most common immune-related effects include skin rash&#44; colitis&#44; liver diseases&#44; pneumonitis&#44; and endocrine diseases&#44; such as hypophysitis and thyroiditis &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46; If these conditions are suspected&#44; infection or tumor progression should first be ruled out&#44; and topical&#44; oral or intravenous corticosteroids should be administered&#44; depending on severity&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">36&#44;37</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Cost-Effectiveness Analysis</span><p id="par0090" class="elsevierStylePara elsevierViewall">The cost of immune checkpoint inhibitors varies depending on the country and the health system model&#44; but they are generally very high&#58; between &#36;150&#44;000 and &#36;180&#44;000 per quality-adjusted year of life&#46;<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">38&#44;39</span></a> A recent economic analysis conducted in Switzerland concluded that at current prices&#44; nivolumab is not cost-effective compared to docetaxel&#46; Price reduction or a stricter selection of the population according to PD-L1 levels would be necessary&#46;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">39</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Prospects for the Future&#46; Combinations With Chemotherapy and Radiation Therapy</span><p id="par0095" class="elsevierStylePara elsevierViewall">The development of clinical applications of immune checkpoint inhibitors has gained momentum in the USA&#44; because the Food and Drug Administration granted these drugs priority review status&#44; thus speeding up the procedures for the evaluation and approval of new medications&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">25</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Numerous studies are now exploring the use of these drugs in neoadjuvant and adjuvant treatment&#44; and as consolidation therapy after an initial regimen of CT and radiation therapy&#46; Preliminary data have also appeared which suggest that antiangiogenic agents &#40;bevacizumab&#44; nintedanib&#44; etc&#46;&#41; can stimulate the immune system&#44; and trials appear to indicate that the combination with immune checkpoint inhibitors produces synergy without substantially increasing toxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">40</span></a> These combinations are still at an early stage of investigation&#44; and the doses and optimal sequence of administration of each drug remain to be determined&#46; However&#44; research is now focusing primarily on the possible incorporation of these new drugs in first-line therapy and the selection of the right candidates in order to begin this paradigm shift in treatment&#46; The most widely studied biomarker predicting a favorable response to date has been the immunohistochemical expression of PD-L1&#44; although some trials have also shown positive results in patients with low or negative concentrations of PD-L1&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">28</span></a> The use of different antibodies and analytical methods has been an obstacle to the validation of this biomarker&#44;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">25&#44;26</span></a> prompting an international effort to standardize the procedures and to design a common&#44; reliable method&#46; The utility of other markers is also being investigated&#44; and areas of interest range from smoking to the presence of tumor-infiltrating lymphocytes or determination of the mutational load by genomic sequencing of the tumor&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">26</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Data available to date suggest that&#44; in the medium term&#44; it is very unlikely that these drugs will completely substitute platinum-based CT in the treatment of NSCLC&#44; but the development of reliable markers may help us identify patients with a greater chance of benefitting from immune checkpoint inhibitors&#44; whether in monotherapy&#44; or in combination with other similar or different therapeutic modalities&#44; including traditional CT&#46;</p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Conflict of Interests</span><p id="par0110" class="elsevierStylePara elsevierViewall">The authors state that they have no conflict of interests&#46;</p></span></span>"
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          "titulo" => "Background"
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          "identificador" => "sec0010"
          "titulo" => "New Pathogenic Concepts of Immunity and Cancer"
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            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "New Therapeutic Concepts&#46; Immune Checkpoint Inhibitors"
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            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Preliminary Trials With Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer"
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            2 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Randomized Trials With Immune Checkpoint Inhibitors in the First-Line Treatment of Lung Cancer"
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            3 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Biomarkers Predicting Favorable Response"
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            4 => array:2 [
              "identificador" => "sec0035"
              "titulo" => "Criteria for the Evaluation of Response"
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            5 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Combined Immune Checkpoint Inhibitor and Chemotherapy Regimens"
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            6 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "Immune Checkpoint Inhibitors in Small Cell Lung Cancer"
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            7 => array:2 [
              "identificador" => "sec0050"
              "titulo" => "Contraindications&#46; Immune-Related Adverse Effects"
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              "identificador" => "sec0055"
              "titulo" => "Cost-Effectiveness Analysis"
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            9 => array:2 [
              "identificador" => "sec0060"
              "titulo" => "Prospects for the Future&#46; Combinations With Chemotherapy and Radiation Therapy"
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          "identificador" => "sec0065"
          "titulo" => "Conflict of Interests"
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    "fechaRecibido" => "2017-04-13"
    "fechaAceptado" => "2017-06-19"
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            0 => "Immunotherapy"
            1 => "Lung cancer"
            2 => "Immune checkpoint inhibitors"
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
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          "palabras" => array:3 [
            0 => "Inmunoterapia"
            1 => "C&#225;ncer de pulm&#243;n"
            2 => "Inmunodesbloqueadores"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Recent research on the relationship between the immune system and cancer has revealed the molecular mechanisms by which cancer cells co-opt certain T cell receptors which block the cytotoxic response to defend themselves from the antitumor immune attack&#46; These findings have helped identify specific targets &#40;T cell receptors or their corresponding ligands&#41; for the design of monoclonal antibodies that can unlock the immune response&#46;</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">These drugs&#44; known as immune checkpoint inhibitors&#44; have shown efficacy in metastatic melanoma and kidney cancer&#44; and have been successfully tested in non-small cell lung cancer in recent trials&#46; Immune checkpoint inhibitors were included in clinical practice as a second-line option after an initial chemotherapy &#40;CT&#41; regimen&#44; and in the last year positive results have been reported from randomized trials in which they were compared in first line with standard CT&#46; Responses have been surprising and durable&#44; but less than 20&#37;&#8211;25&#37; in unselected patients&#44; so it is essential that factors predicting efficacy be identified&#46; One such biomarker is PD-L1&#44; but the different methods used to detect it have produced mixed results&#46;</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">This non-systematic review discusses the results of the latest trials&#44; the possibilities of incorporating these drugs in first-line regimens&#44; the criteria for patient selection&#44; adverse effects&#44; and the prospects of combinations with conventional treatment modalities&#44; such as CT&#44; radiation therapy&#44; and antiangiogenic agents&#46;</p></span>"
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        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Investigaciones recientes sobre la relaci&#243;n entre el sistema inmune y el c&#225;ncer han desvelado los mecanismos moleculares mediante los cuales las c&#233;lulas neopl&#225;sicas aprovechan algunos receptores de los linfocitos T&#44; con funci&#243;n inhibitoria de la respuesta citot&#243;xica&#44; para defenderse del ataque inmune desarrollado frente a ellas&#46; Estos hallazgos han permitido identificar dianas precisas &#40;receptores de los linfocitos T o ligandos que se acoplan a ellos&#41; frente a los que se han dise&#241;ado anticuerpos monoclonales&#44; capaces de desbloquear la respuesta inmunitaria&#46;</p><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Estos f&#225;rmacos <span class="elsevierStyleItalic">&#40;immune check point inhibitors&#41;</span>&#44; de eficacia demostrada en el melanoma metast&#225;sico o el carcinoma renal&#44; han sido probados con &#233;xito frente al carcinoma de pulm&#243;n no microc&#237;tico en ensayos recientes&#46; Tras su aprobaci&#243;n e incorporaci&#243;n a la pr&#225;ctica cl&#237;nica en 2&#46;&#170; l&#237;nea despu&#233;s de una pauta inicial de quimioterapia &#40;QT&#41;&#44; se han comunicado en el &#250;ltimo a&#241;o resultados positivos en ensayos aleatorizados que los comparaban con QT est&#225;ndar en 1&#46;&#170; l&#237;nea&#46; Se han observado respuestas sorprendentes y duraderas&#44; aunque no superan el 20-25&#37; en pacientes no seleccionados&#44; por lo que es crucial detectar rasgos predictivos de eficacia&#44; como el biomarcador PD-L1&#44; si bien los diferentes m&#233;todos para su detecci&#243;n han producido resultados dispares&#46;</p><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">En esta revisi&#243;n no sistem&#225;tica se discuten los resultados de los &#250;ltimos ensayos&#44; las posibilidades de incorporar estos f&#225;rmacos en primera l&#237;nea&#44; los criterios de selecci&#243;n de pacientes&#44; los efectos adversos y las perspectivas de su empleo asociados a modalidades terap&#233;uticas tradicionales como QT&#44; radioterapia o antiangiog&#233;nicos&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0025">Please cite this article as&#58; S&#225;nchez de Cos Escu&#237;n J&#46; Nueva inmunoterapia y c&#225;ncer de pulm&#243;n&#46; Arch Bronconeumol&#46; 2017&#59;53&#58;682&#8211;687&#46;</p>"
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                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Immune Checkpoint Inhibitor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Programmed cell death receptor &#40;PD-1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nivolumab&#44; pembrolizumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">PD-1 ligand &#40;PD-L1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Atezolizumab&#44; durvalumab&#44; avelumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cytotoxic T lymphocyte antigen-4 &#40;CTLA-4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ipilimumab&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">No&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">ICI vs CT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Strain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Response Rate &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Progression-Free Survival &#40;Months&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Overall Survival &#40;Months&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Severe Adverse Effects<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CheckMate 017&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">272&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nivolumab vs docetaxel&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Squamous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20&#37; nivol&#46; vs 9&#37; docet&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#46;5 nivol&#46; vs 2&#46;8 docet&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9&#46;2 nivol&#46; vs 6&#46;0 docet&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&#37; nivol&#46; vs 55&#37; docet&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CheckMate 057&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">582&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nivolumab vs docetaxel&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Non-squamous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">19&#37; nivol&#46; vs 12&#37; docet&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;3 nivol&#46; vs 4&#46;2 docet&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12&#46;2 nivol&#46; vs 9&#46;4 docet&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#37; nivol&#46; vs 54&#37; docet&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Keynote-010&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">850&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pembrolizumab<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a> vs docetaxel&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Squamous and non-squamous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#46;9 &#38; 4&#46;0 nivol&#46; vs 4&#46;0 docet&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#46;4 &#38; 12&#46;7 vs 8&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">13&#37; &#38; 16&#37; vs 35&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">OAK&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1034&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Atezolizumab vs docetaxel&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Squamous and non-squamous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">18&#37; atezo&#46; vs 16&#37; docet&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;8 atezo&#46; vs 4&#46;0 docet&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">13&#46;8 atezo&#46; vs 9&#46;6 docet&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15&#37; atezo&#46; vs 43&#37; docet&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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            0 => array:3 [
              "identificador" => "tblfn0005"
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Adverse effects WHO grades 3 and 4&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">This trial included 3 arms&#58; 2 with different doses of pembrolizumab and 1 with docetaxel&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Immune Checkpoint Inhibitors &#40;ICI&#41; in Advanced NSCLC Randomized Trials After Relapse&#46;</p>"
        ]
      ]
      3 => array:8 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at3"
            "detalle" => "Table "
            "rol" => "short"
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          "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Anti-PD-1 agents&#58; pembrolizumab and nivolumab<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">12&#8211;16</span></a>&#59; anti-PD-L1 agent&#58; atezolizumab&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">15</span></a></p>"
          "tablatextoimagen" => array:1 [
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              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Intensity of Any Grade &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Intensity WHO Grades 3&#8211;5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Common toxicity</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Any effect&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">63&#8211;73&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">16&#8211;26&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Hyporexia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9&#8211;14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#8211;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Stomatitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#8211;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Nausea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9&#8211;11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#8211;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Vomiting&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Diarrhea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7&#8211;14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#8211;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Anemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Neutropenia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Rash&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&#8211;13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#60;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Pyrexia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&#8211;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#60;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Due to autoimmune mechanism</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Any&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">29&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Hypothyroidism&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&#46;0&#8211;9&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Thyroiditis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Hyperthyroidism&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#60;1&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Pneumonitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&#46;0&#8211;5&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Colitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;0&#8211;2&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#8211;1&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Hypophysitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;0&#8211;0&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#8211;0&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Anti-PD-1 and Anti-PD-L1 Immune Checkpoint Inhibitors Adverse Effects in Randomized Trials in LC Patients&#46;</p>"
        ]
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          0 => array:3 [
            "identificador" => "at4"
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          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">In the 2 first-line trials&#44; only patients selected on the basis of biomarker PD-L1 expression were included&#46;</p>"
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            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">No&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">ICI vs CT<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Strain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Response Rate &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Progression-Free Survival &#40;Months&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Overall Survival at 6 Months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Severe Adverse Effects<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">b</span></a> &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Keynote-024&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">825&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Pembrolizumab vs CT<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Squamous and non-squamous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">44&#46;8&#37; pembro&#46; vs 27&#46;8&#37; CT<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#46;3 pembro&#46; vs 6&#46;0 CT<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">80&#46;2 pembro&#46; vs 72&#46;4 CT<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">26&#46;6&#37; pembro&#46; vs 53&#46;3&#37; CT<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">CheckMate 026&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">541&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nivolumab vs CT<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Squamous and non-squamous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No data available&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&#46;2 nivol&#46; vs 5&#46;9 CT<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">14&#46;4 nivol&#46; vs 13&#46;2 CT<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">18&#37; nivol&#46; vs 51&#37; CT<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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Article information
ISSN: 15792129
Original language: English
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