New Immunotherapy and Lung Cancer | Archivos de Bronconeumología

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Highly metabolic nodule of the right lower lobe, without mediastinal lymphadenopathy." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Maria Kipourou, Ioannis Papachristos, Konstantinos Katsoulis" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Maria" "apellidos" => "Kipourou" ] 1 => array:2 [ "nombre" => "Ioannis" "apellidos" => "Papachristos" ] 2 => array:2 [ "nombre" => "Konstantinos" "apellidos" => "Katsoulis" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S0300289617301382" "doi" => "10.1016/j.arbres.2017.05.002" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0300289617301382?idApp=UINPBA00003Z" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1579212917303609?idApp=UINPBA00003Z" "url" => "/15792129/0000005300000012/v1_201711290721/S1579212917303609/v1_201711290721/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S1579212917303506" "issn" => "15792129" "doi" => "10.1016/j.arbr.2017.10.011" "estado" => "S300" "fechaPublicacion" => "2017-12-01" "aid" => "1626" "copyright" => "SEPAR" "documento" => "article" "crossmark" => 1 "subdocumento" => "fla" "cita" => "Arch Bronconeumol. 2017;53:675-81" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 2207 "formatos" => array:3 [ "EPUB" => 159 "HTML" => 1497 "PDF" => 551 ] ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "Original Article" "titulo" => "Small Cell Lung Cancer. 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The aim was to emulate the success of traditional vaccines in the prevention of allergies and infectious diseases. Multiple vaccines derived from inactivated neoplastic cells were tested, and there was even some experimentation involving the introduction of infectious agents into tumors in the hope of activating the immune system.<a class="elsevierStyleCrossRefs" href="#bib0215">3,4</a>Although lung cancer (LC) has long been considered non-immunogenic, some findings suggest otherwise. For example, the incidence of LC and other cancers is very high in organ transplant recipients with induced immunosuppression and patients with human immunodeficiency virus (HIV) infection.<a class="elsevierStyleCrossRef" href="#bib0225">5</a> The presence of tumor-infiltrating lymphocytes in resected LC specimens has also been associated with better prognosis. Moreover, many non-small cell LCs (NSCLC) are known to produce antigens that can induce an immune response.<a class="elsevierStyleCrossRefs" href="#bib0210">2,5,6</a>Anticancer vaccines and immune stimulating substances (interferon and various interleukins) that show promising preliminary results against various tumors, including LC,<a class="elsevierStyleCrossRef" href="#bib0235">7</a> have been developed, but their widespread use, except in metastatic melanoma and renal cell carcinoma, has been limited by lack of specificity and adverse effects.<a class="elsevierStyleCrossRef" href="#bib0215">3</a>New Pathogenic Concepts of Immunity and CancerRecent research<a class="elsevierStyleCrossRefs" href="#bib0230">6–8</a> has led to a deeper understanding of the complex relationships between the immune system and tumor cells, and of the molecular mechanisms by which tumor cells can avoid destruction by T cells. It has been shown that other stimulatory signals, in addition to the presentation of antigen by dendritic cells, are required to activate cytotoxic T cells, and pathways that block those signals and thus promote tumor growth have been identified. The theory of immune surveillance, referring to the mere recognition by the body of cancer cells as foreign, has been replaced by the concept of immune editing, which hypothesizes that the immune system interacts with the tumor in 3 phases: (1) recently developed cancer cells are eliminated by innate and adaptive immune mechanisms; (2) some cells that can avoid this immune attack enter into a dormant state; and (3) finally, these cells can escape immune control and proliferate, leading to clinically apparent disease, a feature now considered a hallmark of cancer cells.<a class="elsevierStyleCrossRef" href="#bib0230">6</a> In other words, the tumor evades attack by the T cells, taking advantage of certain immune checkpoints. Therapeutic targets of special interest include the programmed cell death-1 (PD-1) receptor, its associated ligands (PD-L1), and cytotoxic T-lymphocyte antigen-4 (CTL4-A). Effective therapeutic agents aimed at these targets are already available.<a class="elsevierStyleCrossRefs" href="#bib0230">6–8</a>In addition to these regulatory pathways, the immune profile of an individual depends on multiple factors, including the intrinsic properties of the tumor (genetic makeup, cytokine secretion, etc.) and extrinsic circumstances, such as gut microbiome, presence of infections, and exposure to environmental carcinogens. The bottom line of all these influencing factors is a specific anti-cancer immunity status that determines an individual's potential response to immunotherapy agents.<a class="elsevierStyleCrossRef" href="#bib0240">8</a>New Therapeutic Concepts. Immune Checkpoint InhibitorsCancer cells can be prevented from using these inhibitory pathways by blocking the above-mentioned receptors or the corresponding ligands with specific monoclonal antibodies.<a class="elsevierStyleCrossRefs" href="#bib0210">2–8</a> These agents, by their mechanism of action, neutralize the checkpoints used by the tumor cells, and unblock the ability of the lymphocytes to destroy them (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>), so they could possibly be called immune checkpoint inhibitors, a neologism that we will provisionally use in this paper.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Preliminary positive results with immune checkpoint inhibitors in randomized trials were first obtained in metastatic melanoma with ipilimumab, a monoclonal antibody that neutralizes the CTLA-4 receptor which inhibits T cells. A trial published in 2010 showed that ipilimumab in second-line treatment was superior to the comparative regimen based on the gp100 vaccine (median survival 10.1 and 6.4 months, respectively).<a class="elsevierStyleCrossRef" href="#bib0245">9</a> These outcomes helped this drug receive rapid approval by the regulatory authorities in the U.S., and since then, numerous studies have been performed in other cancers. <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows some of these drugs and their targets.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Preliminary Trials With Immune Checkpoint Inhibitors in Non-Small Cell Lung CancerThe first indications that these agents were effective in LC were obtained in 2 phase I clinical trials that included NSCLC and other tumors. Different doses of the study drugs were tested (anti-PD-1 in 1 trial and anti-PD-L1 in the other). Favorable outcomes were observed in 18% of NSCLCs, and in up to 36% of PD-L1-positive tumors. Most of these responses lasted more than 1 year, with an acceptable safety profile and a 14% incidence of WHO grade 3/4 adverse events.<a class="elsevierStyleCrossRefs" href="#bib0250">10,11</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 (CT) based on platinum doublets; one of the trials included squamous tumors only, and the other non-squamous tumors only. Response rates and overall survival were significantly better with the study drug (nivolumab) than with the control docetaxel-based CT. Moreover, significantly fewer severe side effects were reported in the group treated with nivolumab (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).<a class="elsevierStyleCrossRefs" href="#bib0260">12,13</a> The lack of benefit in progression-free survival (PFS) can be explained by the peculiar effects of these drugs, which sometimes initially produce an apparent increase in tumor volume. This issue is discussed below in the section on evaluation criteria for response. Subsequent trials have confirmed the effectiveness of other immune checkpoint inhibitors in the second-line treatment of NSCLC patients<a class="elsevierStyleCrossRefs" href="#bib0270">14,15</a> (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>), and the National Comprehensive Cancer Network (NCCN) (version 6.2017) recommends their use in this setting, citing grade 1 evidence.<a class="elsevierStyleCrossRef" href="#bib0280">16</a> The most recent drugs (durvalumab and avelumab) have shown promising results in phase I-II clinical trials<a class="elsevierStyleCrossRefs" href="#bib0285">17–19</a> (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Randomized Trials With Immune Checkpoint Inhibitors in the First-Line Treatment of Lung CancerThe expectations raised by these drugs has prompted intense research activity, and relevant information is already available on their efficacy in first line: in a phase I trial, nivolumab (at doses of 3mg/kg body weight every 2 weeks), used as initial monotherapy in 52 patients with NSCLC, yielded objective responses in 23% of the series, and in 28% of the subgroup with PD-L1 biomarker expression. Median overall survival was 19.4 months, and the severe adverse effect rate was 19%.<a class="elsevierStyleCrossRef" href="#bib0300">20</a>Numerous first-line phase III trials in NSCLC are currently ongoing,<a class="elsevierStyleCrossRef" href="#bib0305">21</a> and the results of some completed trials have already been published (Keynote-024, <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>). One of these studies compared the anti-PD-1 immune checkpoint inhibitor pembrolizumab with platinum-based CT, although one of the inclusion criteria for the study was PD-L1 expression in over 50% of tumor cells, a criterion met by 20%–25% of patients with advanced NSCLC. This trial (Keynote-024, <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>) showed pembrolizumab to be superior in terms of overall survival and PFS, and less toxic than CT.<a class="elsevierStyleCrossRef" href="#bib0310">22</a> On the basis of these results, the NCCN (version 3.2017) 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.<a class="elsevierStyleCrossRef" href="#bib0280">16</a> In the other randomized study (presented at a congress, but not yet published) (CheckMate 026), nivolumab was compared to standard CT; PD-L1 expression was required in at least 1% of tumor cells. Overall survival was similar in both groups, while the immune checkpoint inhibitor showed less toxicity.<a class="elsevierStyleCrossRef" href="#bib0315">23</a> Although further analysis is required, the failure of nivolumab to show superiority in this trial may be due to the excessively low threshold for PD-L1 expression (1%) required for inclusion in the original design.Biomarkers Predicting Favorable ResponseImmune checkpoint inhibitors sometimes produce remarkable results, including long-term complete remissions, but objective responses are observed in at most 15%–20% of unselected patients.<a class="elsevierStyleCrossRefs" href="#bib0220">4,24</a> It is of the utmost importance, therefore, to identify some clinical or tumor marker to predict which patients are more likely to benefit. Since some of these drugs are monoclonal antibodies designed to inhibit the PD-1 receptor, as mentioned above, it seems reasonable to expect that the concentration of PD-L1 (ligands that bind to this receptor) expressed in tumor or immune cells would be useful for predicting efficacy. However, the wide range of reagents developed by the different companies and the diverse cut-off points established by different authors have generated conflicting results.<a class="elsevierStyleCrossRefs" href="#bib0325">25,26</a> In the CheckMate 017 trial (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>), conducted in patients with squamous cell carcinoma, PD-L1 concentrations did not affect outcomes<a class="elsevierStyleCrossRef" href="#bib0260">12</a>; in contrast, in CheckMate 057, patients with non-squamous cell carcinoma and PD-L1 concentrations higher than 10% in tumor biopsies had longer mean overall survival than those with levels lower than 10% (19.4 and 9.9 months, respectively).<a class="elsevierStyleCrossRef" href="#bib0265">13</a> The overall assessment of the findings from these and other studies suggests that this biomarker has a predictive value for response, and cooperative efforts are being made to harmonize, standardize and validate analytical techniques that would simplify the use of this biomarker in clinical practice.<a class="elsevierStyleCrossRef" href="#bib0325">25</a>In addition to PD-L1, other factors may have predictive value. For example, it seems that the greater the number of mutations in a tumor, the more sensitive it is to these drugs, because the number of antigens that can be recognized by the immune system will also be greater. For this reason, one proposal is to sequence the complete tumor genome or a preselected panel of representative genes to evaluate the mutational load.<a class="elsevierStyleCrossRefs" href="#bib0325">25,26</a> This hypothesis is supported by the fact that cancers attributed to excessive exposure to ultraviolet light (skin cancer) or tobacco smoke (lung cancer), which have a large number of mutations, respond best to these drugs. In NSCLC trials, when responses were analyzed according to different characteristics, smokers were found to respond better than non-smokers.<a class="elsevierStyleCrossRefs" href="#bib0300">20,22,25</a> Although there are still no clear recommendations in this respect, in the absence of available biomarkers, this epidemiological finding may serve to guide difficult therapeutic decisions in clinical practice.Criteria for the Evaluation of ResponsePFS is an essential criterion for assessing the efficacy of a therapeutic regimen in patients with advanced NSCLC. However, these drugs have shown significant discrepancies between PFS and overall survival which can be explained by the specific effects of unblocking the immune reaction. Indeed, an apparent increase in tumor volume can be observed, due to lymphocytes infiltrating the tumor, reflecting the efficacy of the immune checkpoint inhibitory effect of the drug. This paradoxical phenomenon which mimics disease progression, but which in fact is the opposite, is called “pseudoprogression”,<a class="elsevierStyleCrossRef" href="#bib0210">2</a> and only after a long period of close monitoring of the patient will the reduction in tumor size become apparent. For this reason, it has been suggested that overall survival, and not PFS, is the criterion that most accurately reflects the real benefits.<a class="elsevierStyleCrossRefs" href="#bib0335">27,28</a> This peculiar tumor response also calls for a change in the conventional therapeutic evaluation criteria for solid tumors (RECIST criteria), which now should take into account the possibility of “pseudoprogression”.<a class="elsevierStyleCrossRefs" href="#bib0340">28,29</a> It may even be necessary to include different statistical parameters in the evaluation of PFS, since this phenomenon leads to crossing of the Kaplan–Meier curves that violates the proportional hazards assumption demanded by some tests.<a class="elsevierStyleCrossRef" href="#bib0335">27</a>Combined Immune Checkpoint Inhibitor and Chemotherapy RegimensSince the antitumor mechanisms of action of immune checkpoint inhibitors and conventional CT differ radically, the idea of testing the combination of both drugs is attractive. This approach has been explored in 2 recent phase I and II trials: (a) CheckMate 012, in which platinum-based CT was combined with different doses of nivolumab, followed by maintenance with nivolumab until disease progression or unacceptable toxicity. Although only 52 patients were included, objective responses (between 33% and 47%) and overall survival at 2 years (between 25% and 62%) are encouraging<a class="elsevierStyleCrossRef" href="#bib0350">30</a>; and (b) Keynote-021, comparing pembrolizumab plus CT (carboplatin and pemetrexed) with the same CT regimen alone; both arms subsequently received maintenance pemetrexed. Favorable response rates were 55% and 19%, respectively, and adverse effects rates were similar.<a class="elsevierStyleCrossRef" href="#bib0355">31</a>Immune Checkpoint Inhibitors in Small Cell Lung CancerSmall cell lung cancer is a very aggressive CT-sensitive tumor, closely related to smoking, with the consequent high mutational load. As such, it is in theory an excellent candidate for these new agents.<a class="elsevierStyleCrossRef" href="#bib0360">32</a> Phase II studies combining ipilimumab (anti-CTL4-A) with platinum derivatives and etoposide (the usual regimen in this tumor) showed modest improvements in PFS, but in a large randomized trial the addition of ipilimumab to the standard CT regimen showed no benefit compared to CT alone.<a class="elsevierStyleCrossRef" href="#bib0365">33</a> Recently, a combination of 2 immune checkpoint inhibitors (anti-CTL4-A and anti-PD-1) that act on different targets has produced objective responses in the range of 10%–19%, with acceptable toxicity, in patients with recurrent small cell lung cancer.<a class="elsevierStyleCrossRef" href="#bib0370">34</a> In view of these results, the NCCN (Version 3.2017) recommends the use of these agents in the event of relapse within 6 months after the first treatment (level of evidence 2A).<a class="elsevierStyleCrossRef" href="#bib0375">35</a>Contraindications. Immune-Related Adverse EffectsIn clinical trials, significantly fewer severe adverse effects (WHO grades 3 and 4) were reported with immune checkpoint inhibitors than with standard CT (<a class="elsevierStyleCrossRefs" href="#tbl0010">Tables 2 and 3</a>).<a class="elsevierStyleCrossRefs" href="#bib0260">12–15,22</a> However, the particular mechanism of action of these agents gives them a unique toxicity profile. The PD-1/PD-L1 pathway plays a crucial role in immune homeostasis and the suppression of T cell activity against autoantigens. Thus, if this pathway is blocked, an immune attack can be triggered, not only against the tumor but also against normal tissues, causing autoimmune disease.<a class="elsevierStyleCrossRefs" href="#bib0360">32,36,37</a> In most trials, a clinical history of autoimmune diseases, chronic HIV or hepatitis B or C infection, active interstitial lung disease or other diseases treated with corticosteroids was considered an exclusion criterion. However, although experience is limited, 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, and that toxicities are manageable.<a class="elsevierStyleCrossRefs" href="#bib0380">36,37</a><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="tbl0020"></elsevierMultimedia>The most common immune-related effects include skin rash, colitis, liver diseases, pneumonitis, and endocrine diseases, such as hypophysitis and thyroiditis (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>). If these conditions are suspected, infection or tumor progression should first be ruled out, and topical, oral or intravenous corticosteroids should be administered, depending on severity.<a class="elsevierStyleCrossRefs" href="#bib0380">36,37</a>Cost-Effectiveness AnalysisThe cost of immune checkpoint inhibitors varies depending on the country and the health system model, but they are generally very high: between $150,000 and $180,000 per quality-adjusted year of life.<a class="elsevierStyleCrossRefs" href="#bib0390">38,39</a> A recent economic analysis conducted in Switzerland concluded that at current prices, nivolumab is not cost-effective compared to docetaxel. Price reduction or a stricter selection of the population according to PD-L1 levels would be necessary.<a class="elsevierStyleCrossRef" href="#bib0395">39</a>Prospects for the Future. Combinations With Chemotherapy and Radiation TherapyThe development of clinical applications of immune checkpoint inhibitors has gained momentum in the USA, because the Food and Drug Administration granted these drugs priority review status, thus speeding up the procedures for the evaluation and approval of new medications.<a class="elsevierStyleCrossRef" href="#bib0325">25</a>Numerous studies are now exploring the use of these drugs in neoadjuvant and adjuvant treatment, and as consolidation therapy after an initial regimen of CT and radiation therapy. Preliminary data have also appeared which suggest that antiangiogenic agents (bevacizumab, nintedanib, etc.) can stimulate the immune system, and trials appear to indicate that the combination with immune checkpoint inhibitors produces synergy without substantially increasing toxicity.<a class="elsevierStyleCrossRef" href="#bib0400">40</a> These combinations are still at an early stage of investigation, and the doses and optimal sequence of administration of each drug remain to be determined. However, 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. The most widely studied biomarker predicting a favorable response to date has been the immunohistochemical expression of PD-L1, although some trials have also shown positive results in patients with low or negative concentrations of PD-L1.<a class="elsevierStyleCrossRef" href="#bib0340">28</a> The use of different antibodies and analytical methods has been an obstacle to the validation of this biomarker,<a class="elsevierStyleCrossRefs" href="#bib0325">25,26</a> prompting an international effort to standardize the procedures and to design a common, reliable method. The utility of other markers is also being investigated, 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.<a class="elsevierStyleCrossRef" href="#bib0330">26</a>Data available to date suggest that, in the medium term, it is very unlikely that these drugs will completely substitute platinum-based CT in the treatment of NSCLC, but the development of reliable markers may help us identify patients with a greater chance of benefitting from immune checkpoint inhibitors, whether in monotherapy, or in combination with other similar or different therapeutic modalities, including traditional CT.Conflict of InterestsThe authors state that they have no conflict of interests." "textoCompletoSecciones" => array:1 [ "secciones" => array:8 [ 0 => array:3 [ "identificador" => "xres948192" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec920527" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres948193" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec920526" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Background" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "New Pathogenic Concepts of Immunity and Cancer" "secciones" => array:10 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "New Therapeutic Concepts. Immune Checkpoint Inhibitors" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Preliminary Trials With Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Randomized Trials With Immune Checkpoint Inhibitors in the First-Line Treatment of Lung Cancer" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Biomarkers Predicting Favorable Response" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Criteria for the Evaluation of Response" ] 5 => array:2 [ "identificador" => "sec0040" "titulo" => "Combined Immune Checkpoint Inhibitor and Chemotherapy Regimens" ] 6 => array:2 [ "identificador" => "sec0045" "titulo" => "Immune Checkpoint Inhibitors in Small Cell Lung Cancer" ] 7 => array:2 [ "identificador" => "sec0050" "titulo" => "Contraindications. Immune-Related Adverse Effects" ] 8 => array:2 [ "identificador" => "sec0055" "titulo" => "Cost-Effectiveness Analysis" ] 9 => array:2 [ "identificador" => "sec0060" "titulo" => "Prospects for the Future. Combinations With Chemotherapy and Radiation Therapy" ] ] ] 6 => array:2 [ "identificador" => "sec0065" "titulo" => "Conflict of Interests" ] 7 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2017-04-13" "fechaAceptado" => "2017-06-19" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec920527" "palabras" => array:3 [ 0 => "Immunotherapy" 1 => "Lung cancer" 2 => "Immune checkpoint inhibitors" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec920526" "palabras" => array:3 [ 0 => "Inmunoterapia" 1 => "Cáncer de pulmón" 2 => "Inmunodesbloqueadores" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "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. These findings have helped identify specific targets (T cell receptors or their corresponding ligands) for the design of monoclonal antibodies that can unlock the immune response.These drugs, known as immune checkpoint inhibitors, have shown efficacy in metastatic melanoma and kidney cancer, and have been successfully tested in non-small cell lung cancer in recent trials. Immune checkpoint inhibitors were included in clinical practice as a second-line option after an initial chemotherapy (CT) regimen, and in the last year positive results have been reported from randomized trials in which they were compared in first line with standard CT. Responses have been surprising and durable, but less than 20%–25% in unselected patients, so it is essential that factors predicting efficacy be identified. One such biomarker is PD-L1, but the different methods used to detect it have produced mixed results.This non-systematic review discusses the results of the latest trials, the possibilities of incorporating these drugs in first-line regimens, the criteria for patient selection, adverse effects, and the prospects of combinations with conventional treatment modalities, such as CT, radiation therapy, and antiangiogenic agents." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "Investigaciones recientes sobre la relación entre el sistema inmune y el cáncer han desvelado los mecanismos moleculares mediante los cuales las células neoplásicas aprovechan algunos receptores de los linfocitos T, con función inhibitoria de la respuesta citotóxica, para defenderse del ataque inmune desarrollado frente a ellas. Estos hallazgos han permitido identificar dianas precisas (receptores de los linfocitos T o ligandos que se acoplan a ellos) frente a los que se han diseñado anticuerpos monoclonales, capaces de desbloquear la respuesta inmunitaria.Estos fármacos (immune check point inhibitors), de eficacia demostrada en el melanoma metastásico o el carcinoma renal, han sido probados con éxito frente al carcinoma de pulmón no microcítico en ensayos recientes. Tras su aprobación e incorporación a la práctica clínica en 2.ª línea después de una pauta inicial de quimioterapia (QT), se han comunicado en el último año resultados positivos en ensayos aleatorizados que los comparaban con QT estándar en 1.ª línea. Se han observado respuestas sorprendentes y duraderas, aunque no superan el 20-25% en pacientes no seleccionados, por lo que es crucial detectar rasgos predictivos de eficacia, como el biomarcador PD-L1, si bien los diferentes métodos para su detección han producido resultados dispares.En esta revisión no sistemática se discuten los resultados de los últimos ensayos, las posibilidades de incorporar estos fármacos en primera línea, los criterios de selección de pacientes, los efectos adversos y las perspectivas de su empleo asociados a modalidades terapéuticas tradicionales como QT, radioterapia o antiangiogénicos." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Sánchez de Cos Escuín J. Nueva inmunoterapia y cáncer de pulmón. Arch Bronconeumol. 2017;53:682–687." ] ] "multimedia" => array:5 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2250 "Ancho" => 2062 "Tamanyo" => 273345 ] ] "descripcion" => array:1 [ "en" => "Immune checkpoint inhibitor mechanisms of action." ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 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="left" valign="top" scope="col" style="border-bottom: 2px solid black">Molecular Target \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 \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 (PD-1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Nivolumab, pembrolizumab \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 (PD-L1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Atezolizumab, durvalumab, avelumab \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 (CTLA-4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Ipilimumab \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1605798.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Immune Checkpoint Inhibitors Used in LC and Their Specific Targets." ] ] 2 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 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"> \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. \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 \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 \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 (%) \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 (Months) \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 (Months) \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">a</a> (%) \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">272 \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Squamous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">20% nivol. vs 9% docet. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3.5 nivol. vs 2.8 docet. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9.2 nivol. vs 6.0 docet. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">7% nivol. vs 55% docet. \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">582 \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Non-squamous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">19% nivol. vs 12% docet. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.3 nivol. vs 4.2 docet. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12.2 nivol. vs 9.4 docet. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10% nivol. vs 54% docet. \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">850 \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">b</a> vs docetaxel \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3.9 & 4.0 nivol. vs 4.0 docet. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10.4 & 12.7 vs 8.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">13% & 16% vs 35% \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1034 \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 \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">18% atezo. vs 16% docet. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2.8 atezo. vs 4.0 docet. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">13.8 atezo. vs 9.6 docet. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">15% atezo. vs 43% docet. \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1605801.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "Adverse effects WHO grades 3 and 4." ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "This trial included 3 arms: 2 with different doses of pembrolizumab and 1 with docetaxel." ] ] ] "descripcion" => array:1 [ "en" => "Immune Checkpoint Inhibitors (ICI) in Advanced NSCLC Randomized Trials After Relapse." ] ] 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" ] ] "tabla" => array:2 [ "leyenda" => "Anti-PD-1 agents: pembrolizumab and nivolumab<a class="elsevierStyleCrossRefs" href="#bib0260">12–16</a>; anti-PD-L1 agent: atezolizumab.<a class="elsevierStyleCrossRef" href="#bib0275">15</a>" "tablatextoimagen" => array:1 [ 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"> \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 % \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 3–5% \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">Common toxicity</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Any effect \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">63–73 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">16–26 \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">Hyporexia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9–14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0–1 \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">Stomatitis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2–4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \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">Nausea \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9–11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0–1 \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">Vomiting \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.6 \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">Diarrhea \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7–14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1–4 \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">Anemia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \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">Neutropenia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \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">Rash \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4–13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top"><1 \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">Pyrexia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5–10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top"><1 \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"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">Due to autoimmune mechanism</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Any \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">29.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9.7 \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">Hypothyroidism \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4.0–9.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.0 \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">Thyroiditis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.0 \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">Hyperthyroidism \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4.0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top"><1.0 \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">Pneumonitis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4.0–5.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.6 \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">Colitis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.0–2.0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0–1.0 \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">Hypophysitis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.0–0.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0–0.6 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1605799.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Anti-PD-1 and Anti-PD-L1 Immune Checkpoint Inhibitors Adverse Effects in Randomized Trials in LC Patients." ] ] 4 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at4" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "In the 2 first-line trials, only patients selected on the basis of biomarker PD-L1 expression were included." "tablatextoimagen" => array:1 [ 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"> \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. \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">a</a> \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 \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 (%) \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 (Months) \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 \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">b</a> (%) \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">825 \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">a</a> \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">44.8% pembro. vs 27.8% CT<a class="elsevierStyleCrossRef" href="#tblfn0015">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10.3 pembro. vs 6.0 CT<a class="elsevierStyleCrossRef" href="#tblfn0015">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">80.2 pembro. vs 72.4 CT<a class="elsevierStyleCrossRef" href="#tblfn0015">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">26.6% pembro. vs 53.3% CT<a class="elsevierStyleCrossRef" href="#tblfn0015">a</a> \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">541 \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">a</a> \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 \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 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4.2 nivol. vs 5.9 CT<a class="elsevierStyleCrossRef" href="#tblfn0015">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">14.4 nivol. vs 13.2 CT<a class="elsevierStyleCrossRef" href="#tblfn0015">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">18% nivol. vs 51% CT<a class="elsevierStyleCrossRef" href="#tblfn0015">a</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1605800.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "a" "nota" => "Several platinum-based CT regimens were included." ] 1 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "b" "nota" => "Adverse effects WHO grades 3 and 4." ] ] ] "descripcion" => array:1 [ "en" => "Randomized First-Line Trials With Immune Checkpoint Inhibitors (ICI) in Advanced NSCLC Patients Positive for PD-L1." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:40 [ 0 => array:3 [ "identificador" => "bib0205" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Ueber den jetzingen stand der karzinomforschung" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "P. 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Chow" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1634/theoncologist.2014-0490" "Revista" => array:6 [ "tituloSerie" => "Oncologist" "fecha" => "2015" "volumen" => "20" "paginaInicial" => "1" "paginaFinal" => "11" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25589499" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0215" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Releasing the brakes on cancer inmunotherapy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "A. 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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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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Immune checkpoint inhibitor mechanisms of action&#46;</p>"
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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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        1 => array:2 [
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          "titulo" => "Keywords"
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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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              "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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          "titulo" => "References"
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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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        "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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                  \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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                  <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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              "identificador" => "tblfn0010"
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              "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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          ]
        ]
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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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        "tipo" => "MULTIMEDIATABLA"
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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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                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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          "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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              "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Several platinum-based CT regimens were included&#46;</p>"
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              "identificador" => "tblfn0020"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Adverse effects WHO grades 3 and 4&#46;</p>"
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          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Randomized First-Line Trials With Immune Checkpoint Inhibitors &#40;ICI&#41; in Advanced NSCLC Patients Positive for PD-L1&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:40 [
            0 => array:3 [
              "identificador" => "bib0205"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Ueber den jetzingen stand der karzinomforschung"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "P&#46; Ehrlich"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Ned Tijdschr Geneeeskd"
                        "fecha" => "1909"
                        "volumen" => "5"
                        "paginaInicial" => "273"
                        "paginaFinal" => "290"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0210"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The evolving role of immune checkpoint inhibitors in cancer treatment"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "G&#46;K&#46; Pennock"
                            1 => "L&#46;Q&#46;M&#46; Chow"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1634/theoncologist.2014-0490"
                      "Revista" => array:6 [
                        "tituloSerie" => "Oncologist"
                        "fecha" => "2015"
                        "volumen" => "20"
                        "paginaInicial" => "1"
                        "paginaFinal" => "11"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25589499"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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Article information

ISSN: 15792129
Original language: English

DOI:10.1016/j.arbr.2017.10.014

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	4	2	6
2024 October	82	20	102
2024 September	60	16	76
2024 August	82	40	122
2024 July	59	20	79
2024 June	111	30	141
2024 May	85	26	111
2024 April	66	30	96
2024 March	54	19	73
2024 February	52	26	78
2023 March	25	3	28
2023 February	81	22	103
2023 January	42	29	71
2022 December	85	32	117
2022 November	78	30	108
2022 October	92	45	137
2022 September	107	36	143
2022 August	131	52	183
2022 July	150	59	209
2022 June	69	43	112
2022 May	135	71	206
2022 April	143	35	178
2022 March	173	48	221
2022 February	208	40	248
2022 January	217	43	260
2021 December	119	52	171
2021 November	181	53	234
2021 October	141	89	230
2021 September	103	71	174
2021 August	72	50	122
2021 July	68	49	117
2021 June	200	76	276
2021 May	77	76	153
2021 April	134	160	294
2021 March	99	38	137
2021 February	62	38	100
2021 January	77	27	104
2020 December	41	54	95
2020 November	44	39	83
2020 October	58	49	107
2020 September	47	34	81
2020 August	43	35	78
2020 July	57	48	105
2020 June	55	36	91
2020 May	74	47	121
2020 April	92	51	143
2020 March	113	48	161
2020 February	78	49	127
2020 January	73	41	114
2019 December	104	74	178
2019 November	86	65	151
2019 October	66	68	134
2019 September	72	55	127
2019 August	81	55	136
2019 July	67	42	109
2019 June	61	33	94
2019 May	134	94	228
2019 April	83	93	176
2019 March	116	41	157
2019 February	142	83	225
2019 January	203	97	300
2018 December	189	84	273
2018 November	298	111	409
2018 October	146	40	186
2018 September	75	17	92
2018 May	0	2	2
2018 April	35	20	55
2018 March	46	19	65
2018 January	0	2	2
2017 December	1	1	2

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