Advances in the Immunobiological Therapies for Advanced Melanoma

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Activation of T lymphocyte after interaction between TCR and HLA and between costimulatory molecules B7 and CD28 (left). Inhibition of response following binding of CTLA-4 to B7 (right). TCR indicates T-cell receptor; CD28, cluster of differentiation 28; MHC, major histocompatibility complex; CTLA-4, cytoxic T-lymphocyte associated protein 4." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "I. Escandell, J.M. Martín, E. Jordá" "autores" => array:3 [ 0 => array:2 [ "nombre" => "I." "apellidos" => "Escandell" ] 1 => array:2 [ "nombre" => "J.M." "apellidos" => "Martín" ] 2 => array:2 [ "nombre" => "E." 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Pérez Gago, O. Saavedra Santa Gadea, L. de la Cruz-Merino" "autores" => array:3 [ 0 => array:2 [ "nombre" => "M.C. Pérez" "apellidos" => "Gago" ] 1 => array:2 [ "nombre" => "O. Saavedra Santa" "apellidos" => "Gadea" ] 2 => array:4 [ "nombre" => "L." "apellidos" => "de la Cruz-Merino" "email" => array:1 [ 0 => "ldelacruzmerino@gmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Oncología Médica, Hospital Universitario Virgen Macarena, Sevilla, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Nuevos avances de tratamiento inmunobiológico en el melanoma avanzado" ] ] "textoCompleto" => "IntroductionMelanoma is the type of skin cancer with the highest mortality rate<a class="elsevierStyleCrossRef" href="#bib0210">1</a> because, even though most tumors are diagnosed in their early stages, a significant proportion (19%-25%) recur and/or are detected with advanced locoregional and/or distant disease.Until recently, systemic treatment of metastatic melanoma was mainly chemotherapy-based, although outcomes were in general disappointing, with mean survival ranging from 6 to 9 months.<a class="elsevierStyleCrossRef" href="#bib0215">2</a> However, in recent years, a revolution has occurred in systemic melanoma therapy, driven by targeted therapies and modern immunotherapy.The increased understanding of the molecular biology of skin tumors and the successful development of molecules targeting specific molecular aberrations are based on molecular biology studies indicating that activation of the RAS-RAF kinase signaling pathway is implicated in the development of certain melanomas. It has been shown that RAF kinases are components of the mitogen-activated protein (MAP) kinase pathway, which is its only substrate. Between 40% and 60% of melanomas have a mutation in the gene that codes for BRAF kinase, conferring on it constitutive activation independently of external stimulae.<a class="elsevierStyleCrossRefs" href="#bib0220">3,4</a> Between 70% and 80% of these mutations correspond to substitution of glutamic acid with valine at amino acid 600 (V600E); other mutations at the V600 site correspond to substitutions of alternative amino acids (V600K, V600D, V600R). BRAF inhibitors (vemurafenib, dabrafenib) have shown a clear impact on response rate, progression-free survival, and overall survival in patients with advanced melanoma with a V600 mutation compared with standard chemotherapy.<a class="elsevierStyleCrossRefs" href="#bib0230">5,6</a>In addition, in the MAP kinase pathway, inhibition of MEK, the only substrate phosphorylated by BRAF, has been considered an effective target for treatment of melanomas with a BRAF or NRAS mutation. Mature data from phase iii studies show that combination treatment with a BRAF inhibitor and a MEK inhibitor such as dabrafenib in combination with trametinib or vemurafenib and cobimetinib in patients with the V600 mutation of the BRAF gene have improved survival compared with any of the agents used in monotherapy.<a class="elsevierStyleCrossRefs" href="#bib0240">7,8</a>In parallel with the development of targeted therapy in melanoma, advances in new immunotherapy have been made and clinical development has blossomed, with a large number of potential immunomodulatory monoclonal antibodies. These antibodies are directed against proteins that control immune response (immune checkpoints) present in the virtual space denominated immune synapse established between T lymphocyte effectors and antigen presenting cells and/or tumor cells. Currently, solid scientific evidence attests to clinical benefit; there is an impact on response rates, disease control, and survival with this immunotherapy approach compared with conventional therapies for melanoma.<a class="elsevierStyleCrossRefs" href="#bib0250">9,10</a>This aim of this article is to provide an update on the main clinical data obtained with immunomodulatory antibodies in advanced melanoma.Costimulatory Molecules and CoinhibitorsThe interaction between antigen-presenting cells, tumor cells, and T lymphocytes, as well as between T lymphocytes and other cells in the organism occurs through a series of costimulatory molecules and coinhibitors. These molecules regulate T lymphocyte activation. Immune response is a finely tuned dynamic process that is often governed by inducible molecules with a tendency to maintain what is known as immune homeostasis. Cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and programmed death-1 (PD1) are 2 of the main inhibitory molecules. Activation of these molecules dampens T lymphocyte activity, thereby decreasing immune response to tumor cells.The first of the immunotherapeutic drugs to be approved by the FDA in metastatic melanoma was ipilimumab (anti-CTLA-4). The molecules currently approved in Spain and reimbursed by the Spanish National Health System are ipilimumab, nivolumab, and pembrolizumab (the latter 2 agents are anti-PD1 agents).Anti-CTLA-4 AntibodiesT-lymphocyte-associated protein-4 belongs to the immunoglobulin superfamily of coinhibitory receptors. It is expressed both on the surface of T cells (CD4+, CD8+) and on the surface of regulatory T cells (CD25+, FOXP3+).<a class="elsevierStyleCrossRef" href="#bib0260">11</a> In the first phase of immune response, antigen-presenting cells expose their tumor antigens to T lymphocytes. The T lymphocyte receptors, CTLA-4 (inhibitory molecule) and CD28 (stimulatory molecule) compete to bind with B7-1 (CD80) and B7-2 (CD86) molecules of the antigen-presenting cells. Stimulation of CTLA-4, on binding to its B7 ligand, triggers an inhibitory signal that blocks T lymphocyte response.The first anti-CTLA-4 agent approved by the FDA in 2011 in metastatic melanoma was the humanized IgG1 monoclonal antibody known as ipilimumab. On the basis of results obtained in early-phase dose-finding studies,<a class="elsevierStyleCrossRefs" href="#bib0265">12,13</a> 2 phase III studies were initiated in first- and second-line locally advanced, unresectable and/or metastatic melanoma.The first trial included 676 patients with unresectable stage iii or stage iv melanoma who had progressed after treatment for metastatic disease. Patients were randomized 3:1:1 to receive 4 doses of ipilimumab 3mg/kg every 3 weeks along with the gp100 peptide vaccine (403 patients); ipilimumab as monotherapy at the same dose (137 patients); and the gp100 vaccine as monotherapy (136 patients). This trial found a median overall survival of 10.1 months for the ipilimumab arm in monotherapy, 10 months for the ipilimumab/gp100 arm, and 6.4 months for the arm who received gp100 alone (HR, 0.8; P<.001).<a class="elsevierStyleCrossRef" href="#bib0275">14</a>The second trial included 502 patients with advanced melanoma who had not received prior treatment for metastatic disease. Patients were randomized 1:1 to receive ipilimumab 10mg/kg plus dacarbazine 850mg/m2 every 3 weeks or placebo plus dacarbazine at the same dose. The trial found a median overall survival of 11.2 months for the ipilimumab plus dacarbazine arm compared with 9.1 months for the dacarbazine arm. Likewise, a higher survival rate was observed in the combination group: 47.3% vs 36.3% at 1 year, 28.5% vs 17.9% at 2 years, and 20.8% vs 12.2% at 3 years (HR, 0.72; P<.001). The median duration of response was 19.3 months in the combination therapy arm and 8.1 months in the dacarbazine arm.<a class="elsevierStyleCrossRef" href="#bib0280">15</a> Recently reported data after minimum follow-up of 5 years showed 5-year survival with dacarbazine plus ipilimumab of 18.2% versus 8.8% in the dacarbazine monotherapy arm. The survival curves start to flatten and enter a plateau from the third year onwards, such that overall survival in the arm that includes ipilimumab is 21.3% at 3 years and and 18.2% at 5 years.<a class="elsevierStyleCrossRef" href="#bib0285">16</a>Further support for the survival data of the phase 3 trials came from the meta-analysis by Schadendorf et al.<a class="elsevierStyleCrossRef" href="#bib0290">17</a> That analysis included 1861 patients from the phase 2 and 3 trials with ipilimumab (at different dose levels and lines of treatment) as well as 4486 patients from the expanded use program. Overall survival at 3 years was 22% and 21%, respectively, once again showing flattening of the overall survival curve from the third year on.Another anti-CTLA-4 compound investigated in melanoma is the humanized IgG2 monoclonal antibody known as tremelimumab. The efficacy of this drug was assessed as first-line treatment in a phase ii clinical trial that included 655 patients with unresectable stage iiic or stage iv melanoma. The study was negative as no statistically significant differences were detected in overall survival, although the median duration of response in those patients who responded was 35.8 months with tremelimumab and 13.7 months in the chemotherapy arm (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRef" href="#bib0295">18</a><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Between 40% and 50% of patients with advanced melanoma have the BRAF V600 mutation. In this subgroup of patients, treatment with an anti-CTLA-4 agent has been shown to have a similar efficacy to that obtained in patients with the wild-type BRAF mutation.<a class="elsevierStyleCrossRef" href="#bib0300">19</a>Anti-PD1 AntibodiesAnti-PD1 antibodies are directed against PD1 (CD279), which are proteins located on the membrane of T and B lymphocytes and monocytes. Their ligands, PDL1 and PDL2 are expressed on the membrane of antigen-presenting cells, in tumor cells, and in other cells in the organism.<a class="elsevierStyleCrossRef" href="#bib0305">20</a>These molecules therefore appear to act in the second phase of immune response (effector phase) when the activated T lymphocyte (PD1) binds to its ligand (PDL1) expressed on tumor cells, leading to T lymphocyte deactivation. Different types of tumors overexpress PDL1 on their surface and on cells of the tumor microenvironment in an attempt to evade antitumor immune response.NivolumabOne of the first anti-PD1 antibodies assessed in the clinic in advanced melanoma was the humanized IgG4 antibody known as nivolumab. In different phase I studies, nivolumab was able to demonstrate promising efficacy (objective response rate of 30% to 40%) with a favorable safety profile,<a class="elsevierStyleCrossRef" href="#bib0310">21</a> encouraging pivotal phase 3 studies for approval.One of the phase 3 studies included patients with metastatic melanoma refractory to ipilimumab or targeted anti-BRAF therapy. An objective response rate of 32% was reported in the nivolumab arm compared with 11% in the chemotherapy arm,<a class="elsevierStyleCrossRef" href="#bib0315">22</a> with lower toxicity in the experimental arm compared with the chemotherapy one.Efficacy data of first-line use of nivolumab are also available thanks to the results of a phase 3 study of 418 patients (unmutated BRAF) who had not received prior treatment for metastatic melanoma. Patients were randomized 1:1 to receive ipilimumab 3mg/kg every 2 weeks or dacarbazine 1000mg/m2 every 3 weeks. After 1 year of follow-up, overall survival was 72.9% (95% CI, 65.5%-78.9%) in the nivolumab arm and 42.1% (95% CI, 33%-50.9%) with dacarbazine (HR, 0.42; 95% CI, 0.25-0.73; P<.001). The median progression-free survival was 5.1 months in nivolumab arm and 2.2 months in the dacarbazine arm (HR, 0.43; 95% CI, 0.34-0.56; P<.001). The objective response rate was 40% (95% CI, 33.3%-47%) in the nivolumab arm and 13.9% (95% CI, 9.5%-19.4%) with dacarbazine (odds ratio, 4.06; P<.001). It was also concluded that the favorable nivolumab response rates were independent of PDL1 expression.<a class="elsevierStyleCrossRef" href="#bib0320">23</a> In addition, in a clinical trial performed subsequently, patients with the BRAF V600 mutation were also found to benefit from anti-PD1 treatment.<a class="elsevierStyleCrossRef" href="#bib0325">24</a>PembrolizumabPembrolizumab is another human monoclonal antibody of the IgG4 type (HuMab) that also binds to the negative regulator of lymphocyte activity (PD-1), thus blocking its interaction with PD-L1 and PD-L2.A phase 2 clinical trial included 540 patients with metastatic melanoma refractory to ipilimumab. These patients were randomized 1:1:1 to receive pembrolizumab 2mg/kg every 3 weeks, 10mg/kg every 3 weeks, or chemotherapy chosen by the investigator (carboplatin+paclitaxel, carboplatin, paclitaxel, dacarbazine, or temozolomide). After 6 months of follow-up, the progression-free survival rate was 34% (95% CI, 27% to 41%) and 38% (95% CI, 31% to 45%) for pembrolizumab at 2mg/kg and 10mg/kg, respectively, compared with 16% (95% CI, 10% to 22%) for the chemotherapy arm. The objective response rate was 21% at doses of 2mg/kg; 25% at doses of 10mg/kg; and 4% in the chemotherapy arm.<a class="elsevierStyleCrossRef" href="#bib0330">25</a>After this phase 2 study, pembrolizumab was compared with the anti-CTLA-4 antibody ipilimumab in the KEYNOTE-006 phase 3 trial (analyzed in the following section).Anti-CTLA-4 Antibodies versus Anti-PD1 AntibodiesAs explained above, CTLA-4 and PD1 are expressed and act at different immune checkpoints. Clinical trial results are now available that compare the efficacy of monoclonal antibodies specifically targeting these molecules.<a class="elsevierStyleCrossRefs" href="#bib0325">24,26</a>The KEYNOTE-006 trial compared the efficacy of pembrolizumab (anti-PD1) and ipilimumab (anti-CTLA-4).<a class="elsevierStyleCrossRef" href="#bib0325">24</a> This trial included 834 patients with advanced melanoma, the majority of whom had not received prior treatment for metastatic disease. Patients were randomized 1:1:1 to receive pembrolizumab 10mg/kg every 2 or 3 weeks, or 4 doses of ipilimumab 3mg/kg every 3 weeks. The progression-free survival rate estimated at 6 months was 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (HR, 0.58; P<.001 for both pembrolizumab regimens versus ipilimumab; 95% CI, 0.46-0.72 and 0.47-0.72, respectively). The estimated survival rate at 12 months in each case was 74.1%, 68.4%, and 58.2%, respectively (for pembrolizumab every 2 weeks HR, 0.63; 95% CI, 0.47-0.83; P=.0005; for pembrolizumab every 3 weeks HR, 0.69; 95% CI, 0.52-0.90; P=.0036). Likewise, a higher response rate was obtained with pembrolizumab—33.7% and 32.9%—compared with ipilimumab—11.9% (P<.001 for both comparisons).The CheckMate 067 trial (analyzed in the next section) also supported the superiority of anti-PD1 therapy in monotherapy versus ipilimumab.<a class="elsevierStyleCrossRef" href="#bib0335">26</a>Anti-PD1 and Anti-CTLA-4 CombinationsThe combination of ipilimumab and nivolumab was assessed in a phase 1 clinical trial in patients with metastatic melanoma. A notable decrease in tumor load was observed, usually occurring early (at 12 weeks). This decrease was profound and sustained. Although the frequency of grade 3 and 4 adverse effects was high,<a class="elsevierStyleCrossRef" href="#bib0245">8</a> the efficacy observed was sufficiently large to justify clinical development of the combination.A phase 2 clinical trial was designed with 142 patients with advanced melanoma who had not received any prior treatment. Patients were randomized 2:1 to receive ipilimumab 3mg/kg in combination with nivolumab 1mg/kg or placebo every 3 weeks (4 doses) followed by nivolumab 3mg/kg or placebo every 2 weeks until progression or toxicity, or ipilimumab at standard dose.<a class="elsevierStyleCrossRef" href="#bib0340">27</a> In this study, the objective response rate in patients without the BRAF mutation was 61% (44 of 72 patients) in the combination group versus 11% (4 of 37 patients) in the group who received ipilimumab and placebo (P<.001). There was documented complete response in 16 patients (22%) in the group who received combination therapy. No complete response was observed in patients who received ipilimumab as monotherapy. The results were similar in the 33 patients with a BRAF V600 mutation. Grade 3 or 4 adverse effects were reported in 54% of the patients who received combination therapy, compared with 24% in the group who received only ipilimumab.Finally, the phase 3 CheckMate 067 study was a double-blind study that randomized 945 patients with unresectable or metastatic stage iii melanoma (with no previous treatment) to receive nivolumab monotherapy, ipilimumab monotherapy, or a combination of the 2 drugs. The median progression-free survival was 11.5 months in the combination group (95% CI, 8.9-16.7 months) compared with 2.9 months (95% CI, 2.8-3.4 months) with ipilimumab and 6.9 months (95% CI, 4.3-9.5 months) with nivolumab. The objective response rates were 57.6% for patients treated with combination, 43.7% for nivolumab, and 19% for ipilimumab.A subgroup analysis was undertaken and it was found that patients positive for PDL1 had a progression-free survival of 14 months in both arms that included nivolumab (both in monotherapy and for the combination) and of 3.9 months in the ipilimumab group used as a single agent. However, PDL1-negative patients appear to benefit more from the 2 drugs in combination, with a progression-free survival of 11.2 months compared with 5.3 months and 2.8 months for the nivolumab and ipilimumab arms, respectively.Data from the CheckMate 067 trial therefore support the use of nivolumab as a first-line therapy in patients with metastatic melanoma (regardless of BRAF mutation status) and the authors concluded that combination of nivolumab and ipilimumab is a promising line of investigation for treatment of melanoma.<a class="elsevierStyleCrossRef" href="#bib0335">26</a>Another combination of anti-CTLA-4 and anti-PD1 antibodies under study is ipilimumab at low doses (1mg/kg) in combination with pembrolizumab, with the aim of maintaining the improved efficacy while improving the toxicity profile.<a class="elsevierStyleCrossRef" href="#bib0345">28</a> Preliminary data reported to date suggest that tolerability with this regimen is probably better than the combination of nivolumab and ipilimumab at a dose of 3mg/kg, although these data should be confirmed with longer follow-up in new studies.Toxicity Associated with Monoclonal AntibodiesThe adverse effects are associated with inflammatory infiltration of T lymphocytes in solid organs and increased cytokine concentrations in patient serum.<a class="elsevierStyleCrossRef" href="#bib0350">29</a>The adverse effects observed with ipilimumab appear to be dose dependent, and may have immediate onset or appear in the long term. Onset usually occurs late, at 8 to 10 weeks after start of treatment.<a class="elsevierStyleCrossRef" href="#bib0355">30</a> Adverse effects commonly observed with the anti-CTLA-4 antibodies ipilimumab or tremelimumab are dermatitis (pruritus, rash), enterocolitis, endocrine disorders (hypophysitis, thyroiditis), elevated liver enzymes, and uveitis.<a class="elsevierStyleCrossRef" href="#bib0360">31</a>Adverse effects associated with the use of anti-PD1 agents are fatigue, rash, diarrhea, colitis, and endocrine disorders (hypo- or hyperthyroidism). However, these effects appear less frequently than with anti-CTLA-4 agents.<a class="elsevierStyleCrossRef" href="#bib0365">32</a>The phase 3 KEYNOTE-006 trial assessed the safety and efficacy of 2 regimens of pembrolizumab in comparison with ipilimumab.<a class="elsevierStyleCrossRef" href="#bib0325">24</a> In general, the group that received pembrolizumab had a more favorable safety profile than ipilimumab (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>The combination of anti-CTLA-4 and anti-PD1 agents has been shown to be notably more toxic than the components of the combination separately.With regards the management of adverse effects, mild toxicities usually resolve spontaneously or with the use of corticosteroids. Endocrine disorders may require permanent hormone replacement therapy. In more serious situations, high-dose corticosteroids and even immunosuppressants such as anti-TNF agents may be necessary (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Response BiomarkersAn extensive program to study biomarkers predictive of response is underway with the aim of selecting patients who stand to benefit from immunotherapy.Absolute lymphocyte counts and absolute and differential eosinophil counts are potential pharmacodynamic biomarkers in patients treated with ipilimumab.<a class="elsevierStyleCrossRefs" href="#bib0370">33–38</a>In addition, in a study with patients treated with ipilimumab, exome sequencing was performed for tumor and peripheral blood samples and, after identifying somatic mutations specific to each tumor, it was possible to characterize the neoepitopes resulting from these mutations.<a class="elsevierStyleCrossRef" href="#bib0400">39</a> With this method, the relationship between a high number of missense mutations (total mutational load) and a significant increase in clinical benefit was demonstrated. After analysis of the neoantigen characteristics, along with the histocompatibility molecules (HLA) specific to each patient, a representative pattern of tumors that respond to treatment with anti-CTLA-4 agents was established. This supports the hypothesis that some mutations represent immune determinants on which the efficacy of the treatment may depend.<a class="elsevierStyleCrossRef" href="#bib0400">39</a>The presence of PDL1 may also play a role as a response biomarker. However, its expression is probably heterogeneous and may vary from sample to sample taken from the same tumor. Other limitations of PDL1 as a reliable biomarker include the instability of PDL1 epitopes detected by some antibodies, possible different affinities between antibodies (nonstandard techniques), and the fact that expression of PDL1 could be membrane or cytoplasmic and ubiquitous (detectable in tumor cells, natural killer T cells, T and B lymphocytes, etc).<a class="elsevierStyleCrossRef" href="#bib0405">40</a> From the above, it follows that we are still far from considering PDL1 as a valid and reliable predictive marker.Finally, a recent study has shown that the presence of a high density of CD8+ T cells in the invasive tumor margin, as well as colocalization of PD1 and PDL1 may predict a favorable response in patients treated with anti-PD1.<a class="elsevierStyleCrossRef" href="#bib0410">41</a>Future Perspectives and ConclusionsSystemic therapy for advanced melanoma has been transformed in the past decade by targeted therapies and modern immunotherapy. The available data from the coBRIM, Combi-d, and Combi-v studies show that in patients with unresectable locally advanced and metastatic melanoma with the V600 BRAF mutation, the combination of a BRAF inhibitor with a MEK inhibitor is overall superior in efficacy to monotherapy with a BRAF inhibitor and should become the standard of first-line care in this subpopulation of patients, particularly in subgroups of patients with rapidly progressing disease, visceral involvement, and/or elevated lactate dehydrogenase (M1c stages) and a high tumor load. In the remaining cases, first-line treatment with immunotherapy (anti-CTLA-4 or anti-PDL) may be a reasonable alternative although the scientific evidence in this setting is weaker with immunotherapy than with targeted therapy. The introduction of immunomodulatory monoclonal antibodies in the treatment of metastatic melanoma has become a reality. These therapies have displaced the previously available standards of care. Anti-CTLA-4 and anti-PD1 therapy have notably extended overall survival with respect to standard chemotherapy, and compared with each other, anti-PD1 antibodies show a better overall benefit-risk in terms of efficacy and toxicity and so should be considered the standard of care for first-line treatment in all cases of unresectable BRAF wild-type metastatic melanoma. The role of the anti-CTLA-4 and anti-PD1 combination has yet to be determined. Although it appears more effective than anti-CTLA-4 therapy and, perhaps, perhaps not clearly demonstrated, also more effective than anti-PD1 agents in monotherapy, it is notably more toxic.Although advances in targeted therapy and immunotherapy in melanoma have been notable in recent years, with median overall survival in excess of 24 months in recently reported studies, additional effort is still required to improve on the current results. New lines of investigation focusing on combination strategies with immunomodulatory monoclonal antibodies and targeted therapy, in association with an in depth study of predictive biomarkers and monitoring of response, would probably enable the efficacy of these new therapies in advanced melanoma to be optimized and increased.Ethical ResponsibilitiesProtection of human and animal subjectsThe authors declare that no experiments were performed on humans or animals for this investigation.Confidentiality of dataThe authors declare that they have followed their hospital's protocol on the publication of data concerning patients.Right to privacy and informed consentThe authors declare that patient data do not appear in this article.Conflicts of InterestThe authors declare that they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:16 [ 0 => array:3 [ "identificador" => "xres908288" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec888213" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres908289" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec888212" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Costimulatory Molecules and Coinhibitors" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Anti-CTLA-4 Antibodies" ] 7 => array:3 [ "identificador" => "sec0020" "titulo" => "Anti-PD1 Antibodies" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0025" "titulo" => "Nivolumab" ] 1 => array:2 [ "identificador" => "sec0030" "titulo" => "Pembrolizumab" ] ] ] 8 => array:2 [ "identificador" => "sec0035" "titulo" => "Anti-CTLA-4 Antibodies versus Anti-PD1 Antibodies" ] 9 => array:2 [ "identificador" => "sec0040" "titulo" => "Anti-PD1 and Anti-CTLA-4 Combinations" ] 10 => array:2 [ "identificador" => "sec0045" "titulo" => "Toxicity Associated with Monoclonal Antibodies" ] 11 => array:2 [ "identificador" => "sec0050" "titulo" => "Response Biomarkers" ] 12 => array:2 [ "identificador" => "sec0055" "titulo" => "Future Perspectives and Conclusions" ] 13 => array:3 [ "identificador" => "sec0060" "titulo" => "Ethical Responsibilities" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0065" "titulo" => "Protection of human and animal subjects" ] 1 => array:2 [ "identificador" => "sec0070" "titulo" => "Confidentiality of data" ] 2 => array:2 [ "identificador" => "sec0075" "titulo" => "Right to privacy and informed consent" ] ] ] 14 => array:2 [ "identificador" => "sec0080" "titulo" => "Conflicts of Interest" ] 15 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-04-24" "fechaAceptado" => "2017-01-09" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec888213" "palabras" => array:5 [ 0 => "Melanoma" 1 => "Antibodies" 2 => "Immunomodulators" 3 => "Anti-CTLA4" 4 => "Anti-PD1" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec888212" "palabras" => array:5 [ 0 => "Melanoma" 1 => "Anticuerpos" 2 => "Inmunomoduladores" 3 => "Anti-CTLA4" 4 => "Anti-PD1" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Metastatic or locally advanced unresectable melanoma carries a high morbidity and mortality. However, notable advances have been made in recent years in the systemic treatment of this disease, with the appearance of targeted therapy using tyrosine kinase inhibitors that block the mitogen activated protein kinase pathway, and of modern immunotherapy with immune-modulating monoclonal antibodies. In this paper, we provide an update of available data on new immune therapies and we review the clinical development that led to their approval for use in routine clinical practice." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "El melanoma irresecable localmente avanzado y metastásico es una situación clínica asociada a una elevada tasa de morbimortalidad. En los últimos años, sin embargo, han acontecido notables avances en el ámbito del tratamiento sistémico de esta enfermedad, con la irrupción de la terapia dirigida con inhibidores tirosincinasa que actúan bloqueando la vía de las MAPKinasas, y de la moderna inmunoterapia con anticuerpos monoclonales inmunomoduladores. En la presente revisión se realiza una actualización sobre los datos disponibles con los nuevos inmunoterápicos, así como un repaso del desarrollo clínico que ha permitido la aprobación para su uso en la práctica clínica habitual." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Gago MCP, Gadea OSS, de la Cruz-Merino L. Nuevos avances de tratamiento inmunobiológico en el melanoma avanzado. Actas Dermosifiliogr. 2017;108:721–728." ] ] "multimedia" => array:3 [ 0 => 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:2 [ "leyenda" => "Abbreviations: DTIC, dacarbazine; HR, hazard ratio; LDH, lactate dehydrogenase, OS, overall survival; TMZ, temozolomide." "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">Tremelimumab \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">Ipilimumab \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 " align="char" valign="top">N \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">655 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">502 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">Experimental Group \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">Tremelimumab \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">Ipilimumab+DTIC \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">Treatment Group \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">DTIC or TMZ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">DTIC \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">Median follow-up \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">--- \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">>37months \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">Median OS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12.6 vs 10.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11.2 vs 9.1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">Difference Median OS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.9m \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.1m \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">HR \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.88 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.72 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">P \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">.127 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top"><.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">ECOG 1 (% of patients) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">29 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">29 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">M1b/M1c (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">22/58 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">24/56 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">Elevated LDH (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">32 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">40 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1527651.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Key Data on Phase 3 Clinical Trials of First-Line Ipilimumab and Tremelimumab in Metastatic Melanoma." ] ] 1 => 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: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">Grade 3-4 Immune Adverse Effects (%) \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">Pembrolizumab \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">Nivolumab \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">Ipilimumab \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">Nivolumab+Ipilimumab \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">Pembrolizumab+ Ipilimumab \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 " align="char" 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">14.4-16.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">11.2-19.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">22.7-33.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">44.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" 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">1.8-3.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1-1.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8.2-11.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">Hepatitis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.1-1.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3.4-6.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.2-7.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">30 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" 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">8.7-10.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4.4-8.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.0-4.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">15.0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">17 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" 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">3.2-6.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.9-4.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.0-2.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" 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"><1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.3-3.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" 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"><1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1.9-1.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.4-1.6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">7 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" 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">13.4-14.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">9.3-21.7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">14.5-20.9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">28.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">53 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">Pruritus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">14.1-14.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">16-18.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">24.4-35.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">33.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">28 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1527653.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Immune-Related Toxicity with Immunomodulatory Antibodies." ] ] 2 => 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: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">CTCAE Toxicity \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">Management \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">Grade 1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Support measures Close monitoring of symptoms Rule out infections Education of patient \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">Grade 2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Suspend immunotherapy until reduction of toxicity to grade 1 Assess administering oral corticosteroids if symptoms last >5 days (prednisone 1mg/Kg/d) \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">Grade 3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Support measures Begin intravenous corticosteroids (1-2mg/kg methylprednisolone) If not resolved in 48h, consider adding other immunosuppressants (infliximab, micophenolate) Consult with other specialists Suspend immunotherapy and assess reinitiation if toxicity grade 1 or lower Corticosteroids will be necessary for 3-6 weeks \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">Grade 4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">As for grade 3 but with permanent discontinuation of immunotherapy \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1527652.png" ] ] ] ] "descripcion" => array:1 [ "en" => "General Recommendations for Management of Immune-Related Toxicities." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:41 [ 0 => array:3 [ "identificador" => "bib0210" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC." ] ] ] 1 => array:3 [ "identificador" => "bib0215" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advance metastatic malignant melanoma" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M.R. Middleton" 1 => "J.J. Grob" 2 => "N. Aaronson" 3 => "G. Fierlbeck" 4 => "W. Tilgen" 5 => "S. Seiter" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.2000.18.1.158" "Revista" => array:6 [ "tituloSerie" => "J Clin Oncol" "fecha" => "2000" "volumen" => "18" "paginaInicial" => "158" "paginaFinal" => "166" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10623706" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0220" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mutations of the BRAF gene in human cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "H. Davies" 1 => "G.R. Bignell" 2 => "C. Cox" 3 => "P. Stephens" 4 => "P. Edkins" 5 => "S. Clegg" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/nature00766" "Revista" => array:6 [ "tituloSerie" => "Nature" "fecha" => "2002" "volumen" => "417" "paginaInicial" => "949" "paginaFinal" => "954" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12068308" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0225" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Distinct sets of genetic alterations in melanoma" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.A. Curtin" 1 => "J. Fridlyand" 2 => "T. Kageshita" 3 => "H.N. Patel" 4 => "K.J. Busam" 5 => "H. Kutzner" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa050092" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2005" "volumen" => "353" "paginaInicial" => "2135" "paginaFinal" => "2147" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16291983" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0230" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Combined vemurafenib and combimetinib in BRAF-mutated melanoma" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J. Larkin" 1 => "P.A. Ascierto" 2 => "B. Dréno" 3 => "V. Atkinson" 4 => "G. Liszkay" 5 => "M. Maio" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1408868" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med." "fecha" => "2014" "volumen" => "371" "paginaInicial" => "1867" "paginaFinal" => "1876" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25265494" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0235" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Combined BRAF and MEK inhibition versus BRAF inhibition along in melanoma" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G.V. Long" 1 => "D. Stroyakovskiy" 2 => "H. Gogas" 3 => "E. Levchenko" 4 => "F. de Braud" 5 => "J. Larkin" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1406037" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med." "fecha" => "2014" "volumen" => "371" "paginaInicial" => "1877" "paginaFinal" => "1888" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25265492" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0240" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R.V. Parry" 1 => "J.M. Chemnitz" 2 => "K.A. Frauwirth" 3 => "A.R. Lanfranco" 4 => "I. Braunstein" 5 => "S.V. Kobayashi" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1128/MCB.25.21.9543-9553.2005" "Revista" => array:6 [ "tituloSerie" => "Mol Cell Biol." "fecha" => "2005" "volumen" => "25" "paginaInicial" => "9543" "paginaFinal" => "9553" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16227604" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0245" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Nivolumab plus ipilimumab in advanced melanoma" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.D. Wolchok" 1 => "H. Kluger" 2 => "M.K. Callahan" 3 => "M.A. Postow" 4 => "N.A. Rizvi" 5 => "A.M. Lesokhin" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1302369" "Revista" => array:7 [ "tituloSerie" => "N Engl J Med" "fecha" => "2013" "volumen" => "369" "paginaInicial" => "122" "paginaFinal" => "133" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23724867" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0939475314002051" "estado" => "S300" "issn" => "09394753" ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0250" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cellular and Molecular Immunology" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "A.K. Abbas" 1 => "A.H. Lichtman" 2 => "S. Pillai" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:4 [ "edicion" => "6th ed" "fecha" => "2010" "editorial" => "Saunders Elsevier" "editorialLocalizacion" => "Philadelphia" ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0255" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Trial Watch: Immunostimulatory monoclonal antibodies in cancer therapy" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "F. Aranda" 1 => "E. Vacchelli" 2 => "A. Eggermont" 3 => "J. Galon" 4 => "W.H. Fridman" 5 => "L. Zitvogel" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.4161/onci.27297" "Revista" => array:5 [ "tituloSerie" => "Oncoimmunology." "fecha" => "2014" "volumen" => "3" "paginaInicial" => "e27297" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24701370" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0260" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Modulation of CTLA-4 and GITR for cancer immunotherapy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "F. Avogadri" 1 => "J. Yuan" 2 => "A. Yang" 3 => "D. Schaer" 4 => "J.D. Wolchok" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/82_2010_49" "Revista" => array:6 [ "tituloSerie" => "Curr Top Microbiol Immunol" "fecha" => "2011" "volumen" => "344" "paginaInicial" => "211" "paginaFinal" => "244" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20563707" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0265" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:1 [ "host" => array:1 [ 0 => array:1 [ "LibroEditado" => array:2 [ "titulo" => "MDX-010 (human anti-CTLA4): A phase I trial in malignant melanoma. The American Society of Clinical Oncology Annual Meeting" "serieFecha" => "2002" ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0270" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Ipilimumab monotherapy in patients with pretreated advanced melanoma: A randomised, double-blind, multicentre, phase 2, dose ranging study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.D. Wolchok" 1 => "B. Neyns" 2 => "G. Linette" 3 => "S. Negrier" 4 => "J. Lutzky" 5 => "L. Thomas" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S1470-2045(09)70334-1" "Revista" => array:6 [ "tituloSerie" => "Lancet Oncol" "fecha" => "2010" "volumen" => "11" "paginaInicial" => "155" "paginaFinal" => "164" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20004617" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0275" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Improved survival with ipilimumab in patients with metastatic melanoma" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "F.S. Hodi" 1 => "S.J. O’Day" 2 => "D.F. McDermott" 3 => "R.W. Weber" 4 => "J.A. Sosman" 5 => "J.B. Haanen" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1003466" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2010" "volumen" => "363" "paginaInicial" => "711" "paginaFinal" => "723" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20525992" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0280" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Ipilimumab plus dacarbazine for previously untreated metastatic melanoma" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C. Robert" 1 => "L. Thomas" 2 => "I. Bondarenko" 3 => "S. O’Day" 4 => "J. Weber" 5 => "C. Garbe" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1104621" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med." "fecha" => "2011" "volumen" => "364" "paginaInicial" => "2517" "paginaFinal" => "2526" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21639810" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0285" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. Maio" 1 => "J.J. Grob" 2 => "S. Aamdal" 3 => "I. Bondarenko" 4 => "C. Robert" 5 => "L. Thomas" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.2014.56.6018" "Revista" => array:6 [ "tituloSerie" => "J Clin Oncol" "fecha" => "2015" "volumen" => "33" "paginaInicial" => "1191" "paginaFinal" => "1196" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25713437" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0290" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "D. Schadendorf" 1 => "F.S. Hodi" 2 => "C. Robert" 3 => "J.S. Weber" 4 => "K. Margolin" 5 => "O. Hamid" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.2014.56.2736" "Revista" => array:6 [ "tituloSerie" => "J Clin Oncol" "fecha" => "2015" "volumen" => "33" "paginaInicial" => "1889" "paginaFinal" => "1894" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25667295" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0295" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A. Ribas" 1 => "R. Kefford" 2 => "M.A. Marshall" 3 => "C.J. Punt" 4 => "J.B. Haanen" 5 => "M. Marmol" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.2012.44.6112" "Revista" => array:6 [ "tituloSerie" => "J Clin Oncol" "fecha" => "2013" "volumen" => "31" "paginaInicial" => "616" "paginaFinal" => "622" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23295794" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0300" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical experience with ipilimumab 3mg/kg: Real-world efficacy and safety data from an expanded access programme cohort" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P.A. Ascierto" 1 => "E. Simeone" 2 => "V.C. Sileni" 3 => "J. Pigozzo" 4 => "M. Maio" 5 => "M. Altomonte" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1186/1479-5876-12-116" "Revista" => array:6 [ "tituloSerie" => "J Transl Med." "fecha" => "2014" "volumen" => "12" "paginaInicial" => "116" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24885479" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0735109714023067" "estado" => "S300" "issn" => "07351097" ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0305" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "PD-1 and its ligands in tolerance and immunity" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "M.E. Keir" 1 => "M.J. Butte" 2 => "G.J. Freeman" 3 => "A.H. Sharpe" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1146/annurev.immunol.26.021607.090331" "Revista" => array:6 [ "tituloSerie" => "Annu Rev Immunol" "fecha" => "2008" "volumen" => "26" "paginaInicial" => "677" "paginaFinal" => "704" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18173375" "web" => "Medline" ] ] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0310" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Safety, activity, and immune correlates of anti-PD-1 antibody in cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S.L. Topalian" 1 => "F.S. Hodi" 2 => "J.R. Brahmer" 3 => "S.N. Gettinger" 4 => "D.C. Smith" 5 => "D.F. McDermott" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1200690" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2012" "volumen" => "366" "paginaInicial" => "2443" "paginaFinal" => "2454" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22658127" "web" => "Medline" ] ] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0315" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Weber JS, Minor DR, D’Angelo SP, Hodi FS, Gutzmer R, Neyns B, et al. A phase 3 randomized, open-label study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) versus investigator's choice chemotherapy (ICC) in patients with advanced melanoma with prior anti-CTLA-4 therapy. Presented at the European Society for Medical Oncology 2014 Congress, Madrid, September 26-30, 2014. Abstract." ] ] ] 22 => array:3 [ "identificador" => "bib0320" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Nivolumab in previously untreated melanoma without BRAF mutation" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C. Robert" 1 => "G.V. Long" 2 => "B. Brady" 3 => "C. Dutriaux" 4 => "M. Maio" 5 => "L. Mortier" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1412082" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2015" "volumen" => "372" "paginaInicial" => "320" "paginaFinal" => "330" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25399552" "web" => "Medline" ] ] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0325" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pembrolizumab versus ipilimumab in advanced melanoma" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C. Robert" 1 => "J. Schachter" 2 => "G.V. Long" 3 => "A. Arance" 4 => "J.J. Grob" 5 => "L. Mortier" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1503093" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2015" "volumen" => "372" "paginaInicial" => "2521" "paginaFinal" => "2532" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25891173" "web" => "Medline" ] ] ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0330" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Keytruda (pembrolizumab) prescribing information. Whitehouse Station, NJ: Merck. Disponible en: http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf." ] ] ] 25 => array:3 [ "identificador" => "bib0335" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Combined nivolumab and ipilimumab or monotherapy in untreated melanoma" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J. Larkin" 1 => "V. Chiarion-Sileni" 2 => "R. Gonzalez" 3 => "J.J. Grob" 4 => "C.L. Cowey" 5 => "C.D. Lao" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1504030" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2015" "volumen" => "373" "paginaInicial" => "23" "paginaFinal" => "34" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26027431" "web" => "Medline" ] ] ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib0340" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Nivolumab and ipilimumab versus ipilimumab in untreated melanoma" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M.A. Postow" 1 => "J. Chesney" 2 => "A.C. Pavlick" 3 => "C. Robert" 4 => "K. Grossmann" 5 => "D. McDermott" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1414428" "Revista" => array:7 [ "tituloSerie" => "N Engl J Med" "fecha" => "2015" "volumen" => "372" "paginaInicial" => "2006" "paginaFinal" => "2017" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25891304" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0735109715046215" "estado" => "S300" "issn" => "07351097" ] ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib0345" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "(Suppl; abstr 3009)" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pembrolizumab (MK-3475) plus low-dose ipilimumab (IPI) in patients (pts) with advanced melanoma (MEL) or renal cell carcinoma (RCC): Data from the KEYNOTE-029 phase 1 study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M.B. Atkins" 1 => "T.K. Choueiri" 2 => "F.S. Hodi" 3 => "J.A. Thompson" 4 => "W.J. Hwu" 5 => "D.F. McDermott" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "J Clin Oncol." "fecha" => "2015" "paginaInicial" => "33" ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib0350" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Safety and activity of anti-PD-L1 antibody in patients with advanced cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.R. Brahmer" 1 => "S.S. Tykodi" 2 => "L.Q. Chow" 3 => "W.J. Hwu" 4 => "S.L. Topalian" 5 => "P. Hwu" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1200694" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2012" "volumen" => "366" "paginaInicial" => "2455" "paginaFinal" => "2465" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22658128" "web" => "Medline" ] ] ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib0355" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "abstr 9010" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical activity, safety, and biomarkers with MPDL32801A, an engineered anti-PD2 antibody in patients with locally advanced or metastatic malignant melanoma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "O.S.J. Hamid" 1 => "D.P. Lawrence" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.2013.49.0219" "Revista" => array:5 [ "tituloSerie" => "J Clin Oncol" "fecha" => "2012" "volumen" => "31" "numero" => "Suppl." "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23897962" "web" => "Medline" ] ] ] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib0360" "etiqueta" => "31" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Ipilimumab and its toxicities: A multidisciplinary approach" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "L.A. Fecher" 1 => "S.S. Agarwala" 2 => "F.S. Hodi" 3 => "J.S. Weber" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1634/theoncologist.2012-0483" "Revista" => array:6 [ "tituloSerie" => "Oncologist" "fecha" => "2013" "volumen" => "18" "paginaInicial" => "733" "paginaFinal" => "743" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23774827" "web" => "Medline" ] ] ] ] ] ] ] ] 31 => array:3 [ "identificador" => "bib0365" "etiqueta" => "32" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Management of immune-related adverse events and kinetics of response with ipilimumab" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "J.S. Weber" 1 => "K.C. Kahler" 2 => "A. Hauschild" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.2012.41.6750" "Revista" => array:6 [ "tituloSerie" => "J Clin Oncol" "fecha" => "2012" "volumen" => "30" "paginaInicial" => "2691" "paginaFinal" => "2697" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22614989" "web" => "Medline" ] ] ] ] ] ] ] ] 32 => array:3 [ "identificador" => "bib0370" "etiqueta" => "33" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Immune modulation in cancer with antibodies" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "D.B. Page" 1 => "M.A. Postow" 2 => "M.K. Callahan" 3 => "J.P. Allison" 4 => "J.D. Wolchok" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Annu Rev Immunol" "fecha" => "2014" "volumen" => "65" "paginaInicial" => "185" "paginaFinal" => "202" ] ] ] ] ] ] 33 => array:3 [ "identificador" => "bib0375" "etiqueta" => "34" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mitigating the toxic effects of anticancer immunotherapy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "T.C. Gangadhar" 1 => "R.H. Vonderheide" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/nrclinonc.2013.245" "Revista" => array:6 [ "tituloSerie" => "Nat Rev Clin Oncol" "fecha" => "2014" "volumen" => "11" "paginaInicial" => "91" "paginaFinal" => "99" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24445516" "web" => "Medline" ] ] ] ] ] ] ] ] 34 => array:3 [ "identificador" => "bib0380" "etiqueta" => "35" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting: Lymphocyte count after 2 doses correlates with survival" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G.Y. Ku" 1 => "J. Yuan" 2 => "D.B. Page" 3 => "S.E. Schroeder" 4 => "K.S. Panageas" 5 => "R.D. Carvajal" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/cncr.24951" "Revista" => array:6 [ "tituloSerie" => "Cancer" "fecha" => "2010" "volumen" => "116" "paginaInicial" => "1767" "paginaFinal" => "1775" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20143434" "web" => "Medline" ] ] ] ] ] ] ] ] 35 => array:3 [ "identificador" => "bib0385" "etiqueta" => "36" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "abstr 8595" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Evaluation of the absolute lymphocyte count as a biomarker for melanoma patients treated with the commercially available dose of ipilimumab (3mg/kg). The American Society of Clinical Oncology Annual Meeting, Chicago, USA" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M.A. Postow" 1 => "J. Yuan" 2 => "K. Panageas" 3 => "K. Bogatch" 4 => "M. Callahan" 5 => "M. Cheng" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "J Clin Oncol." "fecha" => "2012" "volumen" => "30" "numero" => "Suppl." ] ] ] ] ] ] 36 => array:3 [ "identificador" => "bib0390" "etiqueta" => "37" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Experience in daily practice with ipilimumab for the treatment of patients with metastatic melanoma: An early increase in lymphocyte and eosinophil counts is associated with improved survival" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J. Delyon" 1 => "C. Mateus" 2 => "D. Lefeuvre" 3 => "E. Lanoy" 4 => "L. Zitvogel" 5 => "N. Chaput" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/annonc/mdt027" "Revista" => array:6 [ "tituloSerie" => "Ann Oncol" "fecha" => "2013" "volumen" => "24" "paginaInicial" => "1697" "paginaFinal" => "1703" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23439861" "web" => "Medline" ] ] ] ] ] ] ] ] 37 => array:3 [ "identificador" => "bib0395" "etiqueta" => "38" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "abstr 9024" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pretreatment levels of absolute and relative eosinophil count to improve overall survival (OS) in patients with metastatic melanoma under treatment with ipilimumab, an anti-CTLA-4 antibody. The Annual Meeting of the American Society of Clinical Oncology. Chicago, USA" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "K. Schindler" 1 => "K. Harmankaya" 2 => "M.A. Postow" 3 => "S. Frantal" 4 => "D. Bello" 5 => "C.E. Ariyan" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.2013.49.0219" "Revista" => array:5 [ "tituloSerie" => "J Clin Oncol." "fecha" => "2013" "volumen" => "31" "numero" => "Suppl" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23897962" "web" => "Medline" ] ] ] ] ] ] ] ] 38 => array:3 [ "identificador" => "bib0400" "etiqueta" => "39" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Genetic basis for clinical response to CTLA-4 blockade in melanoma" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A. Snyder" 1 => "V. Makarov" 2 => "T. Merghoub" 3 => "J. Yuan" 4 => "J.M. Zaretsky" 5 => "A. Desrichard" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1406498" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2014" "volumen" => "371" "paginaInicial" => "2189" "paginaFinal" => "2199" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25409260" "web" => "Medline" ] ] ] ] ] ] ] ] 39 => array:3 [ "identificador" => "bib0405" "etiqueta" => "40" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "abstr 3003" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Peripheral and tumor immune correlates in patients with advanced melanoma treated with combination nivolumab (anti-PD-1, BMS-936558, ONO-4358) and ipilimumab. The Annual Meeting of the American Society of Clinical Oncology, Chicago, USA" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "M.K. Callahan" 1 => "C.E. Horak" 2 => "M.A. Curran" 3 => "T. Hollman" 4 => "D.A. Schaer" 5 => "J. Yan" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1200/JCO.2013.49.0219" "Revista" => array:6 [ "tituloSerie" => "J Clin Oncol." "fecha" => "2013" "volumen" => "31" "numero" => "Suppl." "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23897962" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0735109715070965" "estado" => "S300" "issn" => "07351097" ] ] ] ] ] ] ] 40 => array:3 [ "identificador" => "bib0410" "etiqueta" => "41" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "PD-1 blockade induces responses by inhibiting adaptive immune resistance" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P.C. Tumeh" 1 => "C.L. Harview" 2 => "J.H. Yearley" 3 => "I.P. Shintaku" 4 => "E.J. Taylor" 5 => "L. 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Estadísticas

Review

Advances in the Immunobiological Therapies for Advanced Melanoma

Nuevos avances de tratamiento inmunobiológico en el melanoma avanzado

M.C. Pérez Gago, O. Saavedra Santa Gadea, L. de la Cruz-Merino

Autor para correspondencia

ldelacruzmerino@gmail.com

Corresponding author.

Servicio de Oncología Médica, Hospital Universitario Virgen Macarena, Sevilla, Spain

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in recent years&#44; a revolution has occurred in systemic melanoma therapy&#44; driven by targeted therapies and modern immunotherapy&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">The increased understanding of the molecular biology of skin tumors and the successful development of molecules targeting specific molecular aberrations are based on molecular biology studies indicating that activation of the RAS-RAF kinase signaling pathway is implicated in the development of certain melanomas&#46; It has been shown that RAF kinases are components of the mitogen-activated protein &#40;MAP&#41; kinase pathway&#44; which is its only substrate&#46; Between 40&#37; and 60&#37; of melanomas have a mutation in the gene that codes for BRAF kinase&#44; conferring on it constitutive activation independently of external stimulae&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">3&#44;4</span></a> Between 70&#37; and 80&#37; of these mutations correspond to substitution of glutamic acid with valine at amino acid 600 &#40;V600E&#41;&#59; other mutations at the V600 site correspond to substitutions of alternative amino acids &#40;V600<span class="elsevierStyleHsp" style=""></span>K&#44; V600D&#44; V600R&#41;&#46; BRAF inhibitors &#40;vemurafenib&#44; dabrafenib&#41; have shown a clear impact on response rate&#44; progression-free survival&#44; and overall survival in patients with advanced melanoma with a V600 mutation compared with standard chemotherapy&#46;<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">5&#44;6</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">In addition&#44; in the MAP kinase pathway&#44; inhibition of MEK&#44; the only substrate phosphorylated by BRAF&#44; has been considered an effective target for treatment of melanomas with a BRAF or NRAS mutation&#46; Mature data from phase <span class="elsevierStyleSmallCaps">iii</span> studies show that combination treatment with a BRAF inhibitor and a MEK inhibitor such as dabrafenib in combination with trametinib or vemurafenib and cobimetinib in patients with the V600 mutation of the BRAF gene have improved survival compared with any of the agents used in monotherapy&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">7&#44;8</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">In parallel with the development of targeted therapy in melanoma&#44; advances in new immunotherapy have been made and clinical development has blossomed&#44; with a large number of potential immunomodulatory monoclonal antibodies&#46; These antibodies are directed against proteins that control immune response &#40;immune checkpoints&#41; present in the virtual space denominated immune synapse established between T lymphocyte effectors and antigen presenting cells and&#47;or tumor cells&#46; Currently&#44; solid scientific evidence attests to clinical benefit&#59; there is an impact on response rates&#44; disease control&#44; and survival with this immunotherapy approach compared with conventional therapies for melanoma&#46;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">9&#44;10</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">This aim of this article is to provide an update on the main clinical data obtained with immunomodulatory antibodies in advanced melanoma&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Costimulatory Molecules and Coinhibitors</span><p id="par0035" class="elsevierStylePara elsevierViewall">The interaction between antigen-presenting cells&#44; tumor cells&#44; and T lymphocytes&#44; as well as between T lymphocytes and other cells in the organism occurs through a series of costimulatory molecules and coinhibitors&#46; These molecules regulate T lymphocyte activation&#46; Immune response is a finely tuned dynamic process that is often governed by inducible molecules with a tendency to maintain what is known as immune homeostasis&#46; Cytotoxic T-lymphocyte-associated protein-4 &#40;CTLA-4&#41; and programmed death-1 &#40;PD1&#41; are 2 of the main inhibitory molecules&#46; Activation of these molecules dampens T lymphocyte activity&#44; thereby decreasing immune response to tumor cells&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">The first of the immunotherapeutic drugs to be approved by the FDA in metastatic melanoma was ipilimumab &#40;anti-CTLA-4&#41;&#46; The molecules currently approved in Spain and reimbursed by the Spanish National Health System are ipilimumab&#44; nivolumab&#44; and pembrolizumab &#40;the latter 2 agents are anti-PD1 agents&#41;&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Anti-CTLA-4 Antibodies</span><p id="par0045" class="elsevierStylePara elsevierViewall">T-lymphocyte-associated protein-4 belongs to the immunoglobulin superfamily of coinhibitory receptors&#46; It is expressed both on the surface of T cells &#40;CD4&#43;&#44; CD8&#43;&#41; and on the surface of regulatory T cells &#40;CD25&#43;&#44; FOXP3&#43;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">11</span></a> In the first phase of immune response&#44; antigen-presenting cells expose their tumor antigens to T lymphocytes&#46; The T lymphocyte receptors&#44; CTLA-4 &#40;inhibitory molecule&#41; and CD28 &#40;stimulatory molecule&#41; compete to bind with B7-1 &#40;CD80&#41; and B7-2 &#40;CD86&#41; molecules of the antigen-presenting cells&#46; Stimulation of CTLA-4&#44; on binding to its B7 ligand&#44; triggers an inhibitory signal that blocks T lymphocyte response&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">The first anti-CTLA-4 agent approved by the FDA in 2011 in metastatic melanoma was the humanized IgG1 monoclonal antibody known as ipilimumab&#46; On the basis of results obtained in early-phase dose-finding studies&#44;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">12&#44;13</span></a> 2 phase III studies were initiated in first- and second-line locally advanced&#44; unresectable and&#47;or metastatic melanoma&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">The first trial included 676 patients with unresectable stage <span class="elsevierStyleSmallCaps">iii</span> or stage <span class="elsevierStyleSmallCaps">iv</span> melanoma who had progressed after treatment for metastatic disease&#46; Patients were randomized 3&#58;1&#58;1 to receive 4 doses of ipilimumab 3<span class="elsevierStyleHsp" style=""></span>mg&#47;kg every 3 weeks along with the gp100 peptide vaccine &#40;403 patients&#41;&#59; ipilimumab as monotherapy at the same dose &#40;137 patients&#41;&#59; and the gp100 vaccine as monotherapy &#40;136 patients&#41;&#46; This trial found a median overall survival of 10&#46;1 months for the ipilimumab arm in monotherapy&#44; 10 months for the ipilimumab&#47;gp100 arm&#44; and 6&#46;4 months for the arm who received gp100 alone &#40;HR&#44; 0&#46;8&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">14</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">The second trial included 502 patients with advanced melanoma who had not received prior treatment for metastatic disease&#46; Patients were randomized 1&#58;1 to receive ipilimumab 10<span class="elsevierStyleHsp" style=""></span>mg&#47;kg plus dacarbazine 850<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span> every 3 weeks or placebo plus dacarbazine at the same dose&#46; The trial found a median overall survival of 11&#46;2 months for the ipilimumab plus dacarbazine arm compared with 9&#46;1 months for the dacarbazine arm&#46; Likewise&#44; a higher survival rate was observed in the combination group&#58; 47&#46;3&#37; vs 36&#46;3&#37; at 1 year&#44; 28&#46;5&#37; vs 17&#46;9&#37; at 2 years&#44; and 20&#46;8&#37; vs 12&#46;2&#37; at 3 years &#40;HR&#44; 0&#46;72&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46; The median duration of response was 19&#46;3 months in the combination therapy arm and 8&#46;1 months in the dacarbazine arm&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">15</span></a> Recently reported data after minimum follow-up of 5 years showed 5-year survival with dacarbazine plus ipilimumab of 18&#46;2&#37; versus 8&#46;8&#37; in the dacarbazine monotherapy arm&#46; The survival curves start to flatten and enter a plateau from the third year onwards&#44; such that overall survival in the arm that includes ipilimumab is 21&#46;3&#37; at 3 years and and 18&#46;2&#37; at 5 years&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">16</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Further support for the survival data of the phase 3 trials came from the meta-analysis by Schadendorf et al&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">17</span></a> That analysis included 1861 patients from the phase 2 and 3 trials with ipilimumab &#40;at different dose levels and lines of treatment&#41; as well as 4486 patients from the expanded use program&#46; Overall survival at 3 years was 22&#37; and 21&#37;&#44; respectively&#44; once again showing flattening of the overall survival curve from the third year on&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Another anti-CTLA-4 compound investigated in melanoma is the humanized IgG2 monoclonal antibody known as tremelimumab&#46; The efficacy of this drug was assessed as first-line treatment in a phase <span class="elsevierStyleSmallCaps">ii</span> clinical trial that included 655 patients with unresectable stage <span class="elsevierStyleSmallCaps">iiic</span> or stage <span class="elsevierStyleSmallCaps">iv</span> melanoma&#46; The study was negative as no statistically significant differences were detected in overall survival&#44; although the median duration of response in those patients who responded was 35&#46;8 months with tremelimumab and 13&#46;7 months in the chemotherapy arm &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">18</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">Between 40&#37; and 50&#37; of patients with advanced melanoma have the BRAF V600 mutation&#46; In this subgroup of patients&#44; treatment with an anti-CTLA-4 agent has been shown to have a similar efficacy to that obtained in patients with the wild-type BRAF mutation&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">19</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Anti-PD1 Antibodies</span><p id="par0080" class="elsevierStylePara elsevierViewall">Anti-PD1 antibodies are directed against PD1 &#40;CD279&#41;&#44; which are proteins located on the membrane of T and B lymphocytes and monocytes&#46; Their ligands&#44; PDL1 and PDL2 are expressed on the membrane of antigen-presenting cells&#44; in tumor cells&#44; and in other cells in the organism&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">20</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">These molecules therefore appear to act in the second phase of immune response &#40;effector phase&#41; when the activated T lymphocyte &#40;PD1&#41; binds to its ligand &#40;PDL1&#41; expressed on tumor cells&#44; leading to T lymphocyte deactivation&#46; Different types of tumors overexpress PDL1 on their surface and on cells of the tumor microenvironment in an attempt to evade antitumor immune response&#46;</p><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Nivolumab</span><p id="par0090" class="elsevierStylePara elsevierViewall">One of the first anti-PD1 antibodies assessed in the clinic in advanced melanoma was the humanized IgG4 antibody known as nivolumab&#46; In different phase I studies&#44; nivolumab was able to demonstrate promising efficacy &#40;objective response rate of 30&#37; to 40&#37;&#41; with a favorable safety profile&#44;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">21</span></a> encouraging pivotal phase 3 studies for approval&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">One of the phase 3 studies included patients with metastatic melanoma refractory to ipilimumab or targeted anti-BRAF therapy&#46; An objective response rate of 32&#37; was reported in the nivolumab arm compared with 11&#37; in the chemotherapy arm&#44;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">22</span></a> with lower toxicity in the experimental arm compared with the chemotherapy one&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Efficacy data of first-line use of nivolumab are also available thanks to the results of a phase 3 study of 418 patients &#40;unmutated BRAF&#41; who had not received prior treatment for metastatic melanoma&#46; Patients were randomized 1&#58;1 to receive ipilimumab 3<span class="elsevierStyleHsp" style=""></span>mg&#47;kg every 2 weeks or dacarbazine 1000<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span> every 3 weeks&#46; After 1 year of follow-up&#44; overall survival was 72&#46;9&#37; &#40;95&#37; CI&#44; 65&#46;5&#37;-78&#46;9&#37;&#41; in the nivolumab arm and 42&#46;1&#37; &#40;95&#37; CI&#44; 33&#37;-50&#46;9&#37;&#41; with dacarbazine &#40;HR&#44; 0&#46;42&#59; 95&#37; CI&#44; 0&#46;25-0&#46;73&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46; The median progression-free survival was 5&#46;1 months in nivolumab arm and 2&#46;2 months in the dacarbazine arm &#40;HR&#44; 0&#46;43&#59; 95&#37; CI&#44; 0&#46;34-0&#46;56&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46; The objective response rate was 40&#37; &#40;95&#37; CI&#44; 33&#46;3&#37;-47&#37;&#41; in the nivolumab arm and 13&#46;9&#37; &#40;95&#37; CI&#44; 9&#46;5&#37;-19&#46;4&#37;&#41; with dacarbazine &#40;odds ratio&#44; 4&#46;06&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46; It was also concluded that the favorable nivolumab response rates were independent of PDL1 expression&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">23</span></a> In addition&#44; in a clinical trial performed subsequently&#44; patients with the BRAF V600 mutation were also found to benefit from anti-PD1 treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">24</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Pembrolizumab</span><p id="par0105" class="elsevierStylePara elsevierViewall">Pembrolizumab is another human monoclonal antibody of the IgG4 type &#40;HuMab&#41; that also binds to the negative regulator of lymphocyte activity &#40;PD-1&#41;&#44; thus blocking its interaction with PD-L1 and PD-L2&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">A phase 2 clinical trial included 540 patients with metastatic melanoma refractory to ipilimumab&#46; These patients were randomized 1&#58;1&#58;1 to receive pembrolizumab 2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg every 3 weeks&#44; 10<span class="elsevierStyleHsp" style=""></span>mg&#47;kg every 3 weeks&#44; or chemotherapy chosen by the investigator &#40;carboplatin<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>paclitaxel&#44; carboplatin&#44; paclitaxel&#44; dacarbazine&#44; or temozolomide&#41;&#46; After 6 months of follow-up&#44; the progression-free survival rate was 34&#37; &#40;95&#37; CI&#44; 27&#37; to 41&#37;&#41; and 38&#37; &#40;95&#37; CI&#44; 31&#37; to 45&#37;&#41; for pembrolizumab at 2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg and 10<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#44; respectively&#44; compared with 16&#37; &#40;95&#37; CI&#44; 10&#37; to 22&#37;&#41; for the chemotherapy arm&#46; The objective response rate was 21&#37; at doses of 2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#59; 25&#37; at doses of 10<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#59; and 4&#37; in the chemotherapy arm&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">25</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">After this phase 2 study&#44; pembrolizumab was compared with the anti-CTLA-4 antibody ipilimumab in the KEYNOTE-006 phase 3 trial &#40;analyzed in the following section&#41;&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Anti-CTLA-4 Antibodies versus Anti-PD1 Antibodies</span><p id="par0120" class="elsevierStylePara elsevierViewall">As explained above&#44; CTLA-4 and PD1 are expressed and act at different immune checkpoints&#46; Clinical trial results are now available that compare the efficacy of monoclonal antibodies specifically targeting these molecules&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">24&#44;26</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">The KEYNOTE-006 trial compared the efficacy of pembrolizumab &#40;anti-PD1&#41; and ipilimumab &#40;anti-CTLA-4&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">24</span></a> This trial included 834 patients with advanced melanoma&#44; the majority of whom had not received prior treatment for metastatic disease&#46; Patients were randomized 1&#58;1&#58;1 to receive pembrolizumab 10<span class="elsevierStyleHsp" style=""></span>mg&#47;kg every 2 or 3 weeks&#44; or 4 doses of ipilimumab 3<span class="elsevierStyleHsp" style=""></span>mg&#47;kg every 3 weeks&#46; The progression-free survival rate estimated at 6 months was 47&#46;3&#37; for pembrolizumab every 2 weeks&#44; 46&#46;4&#37; for pembrolizumab every 3 weeks&#44; and 26&#46;5&#37; for ipilimumab &#40;HR&#44; 0&#46;58&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001 for both pembrolizumab regimens versus ipilimumab&#59; 95&#37; CI&#44; 0&#46;46-0&#46;72 and 0&#46;47-0&#46;72&#44; respectively&#41;&#46; The estimated survival rate at 12 months in each case was 74&#46;1&#37;&#44; 68&#46;4&#37;&#44; and 58&#46;2&#37;&#44; respectively &#40;for pembrolizumab every 2 weeks HR&#44; 0&#46;63&#59; 95&#37; CI&#44; 0&#46;47-0&#46;83&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0005&#59; for pembrolizumab every 3 weeks HR&#44; 0&#46;69&#59; 95&#37; CI&#44; 0&#46;52-0&#46;90&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0036&#41;&#46; Likewise&#44; a higher response rate was obtained with pembrolizumab&#8212;33&#46;7&#37; and 32&#46;9&#37;&#8212;compared with ipilimumab&#8212;11&#46;9&#37; &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001 for both comparisons&#41;&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">The CheckMate 067 trial &#40;analyzed in the next section&#41; also supported the superiority of anti-PD1 therapy in monotherapy versus ipilimumab&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">26</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Anti-PD1 and Anti-CTLA-4 Combinations</span><p id="par0135" class="elsevierStylePara elsevierViewall">The combination of ipilimumab and nivolumab was assessed in a phase 1 clinical trial in patients with metastatic melanoma&#46; A notable decrease in tumor load was observed&#44; usually occurring early &#40;at 12 weeks&#41;&#46; This decrease was profound and sustained&#46; Although the frequency of grade 3 and 4 adverse effects was high&#44;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">8</span></a> the efficacy observed was sufficiently large to justify clinical development of the combination&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">A phase 2 clinical trial was designed with 142 patients with advanced melanoma who had not received any prior treatment&#46; Patients were randomized 2&#58;1 to receive ipilimumab 3<span class="elsevierStyleHsp" style=""></span>mg&#47;kg in combination with nivolumab 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg or placebo every 3 weeks &#40;4 doses&#41; followed by nivolumab 3<span class="elsevierStyleHsp" style=""></span>mg&#47;kg or placebo every 2 weeks until progression or toxicity&#44; or ipilimumab at standard dose&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">27</span></a> In this study&#44; the objective response rate in patients without the BRAF mutation was 61&#37; &#40;44 of 72 patients&#41; in the combination group versus 11&#37; &#40;4 of 37 patients&#41; in the group who received ipilimumab and placebo &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46; There was documented complete response in 16 patients &#40;22&#37;&#41; in the group who received combination therapy&#46; No complete response was observed in patients who received ipilimumab as monotherapy&#46; The results were similar in the 33 patients with a BRAF V600 mutation&#46; Grade 3 or 4 adverse effects were reported in 54&#37; of the patients who received combination therapy&#44; compared with 24&#37; in the group who received only ipilimumab&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Finally&#44; the phase 3 CheckMate 067 study was a double-blind study that randomized 945 patients with unresectable or metastatic stage <span class="elsevierStyleSmallCaps">iii</span> melanoma &#40;with no previous treatment&#41; to receive nivolumab monotherapy&#44; ipilimumab monotherapy&#44; or a combination of the 2 drugs&#46; The median progression-free survival was 11&#46;5 months in the combination group &#40;95&#37; CI&#44; 8&#46;9-16&#46;7 months&#41; compared with 2&#46;9 months &#40;95&#37; CI&#44; 2&#46;8-3&#46;4 months&#41; with ipilimumab and 6&#46;9 months &#40;95&#37; CI&#44; 4&#46;3-9&#46;5 months&#41; with nivolumab&#46; The objective response rates were 57&#46;6&#37; for patients treated with combination&#44; 43&#46;7&#37; for nivolumab&#44; and 19&#37; for ipilimumab&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">A subgroup analysis was undertaken and it was found that patients positive for PDL1 had a progression-free survival of 14 months in both arms that included nivolumab &#40;both in monotherapy and for the combination&#41; and of 3&#46;9 months in the ipilimumab group used as a single agent&#46; However&#44; PDL1-negative patients appear to benefit more from the 2 drugs in combination&#44; with a progression-free survival of 11&#46;2 months compared with 5&#46;3 months and 2&#46;8 months for the nivolumab and ipilimumab arms&#44; respectively&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Data from the CheckMate 067 trial therefore support the use of nivolumab as a first-line therapy in patients with metastatic melanoma &#40;regardless of BRAF mutation status&#41; and the authors concluded that combination of nivolumab and ipilimumab is a promising line of investigation for treatment of melanoma&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">26</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">Another combination of anti-CTLA-4 and anti-PD1 antibodies under study is ipilimumab at low doses &#40;1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41; in combination with pembrolizumab&#44; with the aim of maintaining the improved efficacy while improving the toxicity profile&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">28</span></a> Preliminary data reported to date suggest that tolerability with this regimen is probably better than the combination of nivolumab and ipilimumab at a dose of 3<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#44; although these data should be confirmed with longer follow-up in new studies&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Toxicity Associated with Monoclonal Antibodies</span><p id="par0165" class="elsevierStylePara elsevierViewall">The adverse effects are associated with inflammatory infiltration of T lymphocytes in solid organs and increased cytokine concentrations in patient serum&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">29</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">The adverse effects observed with ipilimumab appear to be dose dependent&#44; and may have immediate onset or appear in the long term&#46; Onset usually occurs late&#44; at 8 to 10 weeks after start of treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">30</span></a> Adverse effects commonly observed with the anti-CTLA-4 antibodies ipilimumab or tremelimumab are dermatitis &#40;pruritus&#44; rash&#41;&#44; enterocolitis&#44; endocrine disorders &#40;hypophysitis&#44; thyroiditis&#41;&#44; elevated liver enzymes&#44; and uveitis&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">31</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">Adverse effects associated with the use of anti-PD1 agents are fatigue&#44; rash&#44; diarrhea&#44; colitis&#44; and endocrine disorders &#40;hypo- or hyperthyroidism&#41;&#46; However&#44; these effects appear less frequently than with anti-CTLA-4 agents&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">32</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">The phase 3 KEYNOTE-006 trial assessed the safety and efficacy of 2 regimens of pembrolizumab in comparison with ipilimumab&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">24</span></a> In general&#44; the group that received pembrolizumab had a more favorable safety profile than ipilimumab &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0185" class="elsevierStylePara elsevierViewall">The combination of anti-CTLA-4 and anti-PD1 agents has been shown to be notably more toxic than the components of the combination separately&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">With regards the management of adverse effects&#44; mild toxicities usually resolve spontaneously or with the use of corticosteroids&#46; Endocrine disorders may require permanent hormone replacement therapy&#46; In more serious situations&#44; high-dose corticosteroids and even immunosuppressants such as anti-TNF agents may be necessary &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Response Biomarkers</span><p id="par0195" class="elsevierStylePara elsevierViewall">An extensive program to study biomarkers predictive of response is underway with the aim of selecting patients who stand to benefit from immunotherapy&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">Absolute lymphocyte counts and absolute and differential eosinophil counts are potential pharmacodynamic biomarkers in patients treated with ipilimumab&#46;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">33&#8211;38</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">In addition&#44; in a study with patients treated with ipilimumab&#44; exome sequencing was performed for tumor and peripheral blood samples and&#44; after identifying somatic mutations specific to each tumor&#44; it was possible to characterize the neoepitopes resulting from these mutations&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">39</span></a> With this method&#44; the relationship between a high number of missense mutations &#40;total mutational load&#41; and a significant increase in clinical benefit was demonstrated&#46; After analysis of the neoantigen characteristics&#44; along with the histocompatibility molecules &#40;HLA&#41; specific to each patient&#44; a representative pattern of tumors that respond to treatment with anti-CTLA-4 agents was established&#46; This supports the hypothesis that some mutations represent immune determinants on which the efficacy of the treatment may depend&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">39</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">The presence of PDL1 may also play a role as a response biomarker&#46; However&#44; its expression is probably heterogeneous and may vary from sample to sample taken from the same tumor&#46; Other limitations of PDL1 as a reliable biomarker include the instability of PDL1 epitopes detected by some antibodies&#44; possible different affinities between antibodies &#40;nonstandard techniques&#41;&#44; and the fact that expression of PDL1 could be membrane or cytoplasmic and ubiquitous &#40;detectable in tumor cells&#44; natural killer T cells&#44; T and B lymphocytes&#44; etc&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">40</span></a> From the above&#44; it follows that we are still far from considering PDL1 as a valid and reliable predictive marker&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">Finally&#44; a recent study has shown that the presence of a high density of CD8&#43; T cells in the invasive tumor margin&#44; as well as colocalization of PD1 and PDL1 may predict a favorable response in patients treated with anti-PD1&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">41</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Future Perspectives and Conclusions</span><p id="par0220" class="elsevierStylePara elsevierViewall">Systemic therapy for advanced melanoma has been transformed in the past decade by targeted therapies and modern immunotherapy&#46; The available data from the coBRIM&#44; Combi-d&#44; and Combi-v studies show that in patients with unresectable locally advanced and metastatic melanoma with the V600 BRAF mutation&#44; the combination of a BRAF inhibitor with a MEK inhibitor is overall superior in efficacy to monotherapy with a BRAF inhibitor and should become the standard of first-line care in this subpopulation of patients&#44; particularly in subgroups of patients with rapidly progressing disease&#44; visceral involvement&#44; and&#47;or elevated lactate dehydrogenase &#40;M1c stages&#41; and a high tumor load&#46; In the remaining cases&#44; first-line treatment with immunotherapy &#40;anti-CTLA-4 or anti-PDL&#41; may be a reasonable alternative although the scientific evidence in this setting is weaker with immunotherapy than with targeted therapy&#46; The introduction of immunomodulatory monoclonal antibodies in the treatment of metastatic melanoma has become a reality&#46; These therapies have displaced the previously available standards of care&#46; Anti-CTLA-4 and anti-PD1 therapy have notably extended overall survival with respect to standard chemotherapy&#44; and compared with each other&#44; anti-PD1 antibodies show a better overall benefit-risk in terms of efficacy and toxicity and so should be considered the standard of care for first-line treatment in all cases of unresectable BRAF wild-type metastatic melanoma&#46; The role of the anti-CTLA-4 and anti-PD1 combination has yet to be determined&#46; Although it appears more effective than anti-CTLA-4 therapy and&#44; perhaps&#44; perhaps not clearly demonstrated&#44; also more effective than anti-PD1 agents in monotherapy&#44; it is notably more toxic&#46;</p><p id="par0225" class="elsevierStylePara elsevierViewall">Although advances in targeted therapy and immunotherapy in melanoma have been notable in recent years&#44; with median overall survival in excess of 24 months in recently reported studies&#44; additional effort is still required to improve on the current results&#46; New lines of investigation focusing on combination strategies with immunomodulatory monoclonal antibodies and targeted therapy&#44; in association with an in depth study of predictive biomarkers and monitoring of response&#44; would probably enable the efficacy of these new therapies in advanced melanoma to be optimized and increased&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Ethical Responsibilities</span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Protection of human and animal subjects</span><p id="par0230" class="elsevierStylePara elsevierViewall">The authors declare that no experiments were performed on humans or animals for this investigation&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Confidentiality of data</span><p id="par0235" class="elsevierStylePara elsevierViewall">The authors declare that they have followed their hospital&#39;s protocol on the publication of data concerning patients&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Right to privacy and informed consent</span><p id="par0240" class="elsevierStylePara elsevierViewall">The authors declare that patient data do not appear in this article&#46;</p></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Conflicts of Interest</span><p id="par0245" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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          "identificador" => "xpalclavsec888213"
          "titulo" => "Keywords"
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          "identificador" => "xres908289"
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          "identificador" => "sec0005"
          "titulo" => "Introduction"
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          "identificador" => "sec0010"
          "titulo" => "Costimulatory Molecules and Coinhibitors"
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        6 => array:2 [
          "identificador" => "sec0015"
          "titulo" => "Anti-CTLA-4 Antibodies"
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          "titulo" => "Anti-PD1 Antibodies"
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              "titulo" => "Nivolumab"
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              "identificador" => "sec0030"
              "titulo" => "Pembrolizumab"
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        8 => array:2 [
          "identificador" => "sec0035"
          "titulo" => "Anti-CTLA-4 Antibodies versus Anti-PD1 Antibodies"
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          "identificador" => "sec0040"
          "titulo" => "Anti-PD1 and Anti-CTLA-4 Combinations"
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          "identificador" => "sec0045"
          "titulo" => "Toxicity Associated with Monoclonal Antibodies"
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          "identificador" => "sec0050"
          "titulo" => "Response Biomarkers"
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        12 => array:2 [
          "identificador" => "sec0055"
          "titulo" => "Future Perspectives and Conclusions"
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              "titulo" => "Protection of human and animal subjects"
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              "identificador" => "sec0075"
              "titulo" => "Right to privacy and informed consent"
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          "identificador" => "sec0080"
          "titulo" => "Conflicts of Interest"
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          "titulo" => "References"
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    "fechaRecibido" => "2016-04-24"
    "fechaAceptado" => "2017-01-09"
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          "clase" => "keyword"
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            0 => "Melanoma"
            1 => "Antibodies"
            2 => "Immunomodulators"
            3 => "Anti-CTLA4"
            4 => "Anti-PD1"
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      ]
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          "palabras" => array:5 [
            0 => "Melanoma"
            1 => "Anticuerpos"
            2 => "Inmunomoduladores"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Metastatic or locally advanced unresectable melanoma carries a high morbidity and mortality&#46; However&#44; notable advances have been made in recent years in the systemic treatment of this disease&#44; with the appearance of targeted therapy using tyrosine kinase inhibitors that block the mitogen activated protein kinase pathway&#44; and of modern immunotherapy with immune-modulating monoclonal antibodies&#46; In this paper&#44; we provide an update of available data on new immune therapies and we review the clinical development that led to their approval for use in routine clinical practice&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">El melanoma irresecable localmente avanzado y metast&#225;sico es una situaci&#243;n cl&#237;nica asociada a una elevada tasa de morbimortalidad&#46; En los &#250;ltimos a&#241;os&#44; sin embargo&#44; han acontecido notables avances en el &#225;mbito del tratamiento sist&#233;mico de esta enfermedad&#44; con la irrupci&#243;n de la terapia dirigida con inhibidores tirosincinasa que act&#250;an bloqueando la v&#237;a de las MAPKinasas&#44; y de la moderna inmunoterapia con anticuerpos monoclonales inmunomoduladores&#46; En la presente revisi&#243;n se realiza una actualizaci&#243;n sobre los datos disponibles con los nuevos inmunoter&#225;picos&#44; as&#237; como un repaso del desarrollo cl&#237;nico que ha permitido la aprobaci&#243;n para su uso en la pr&#225;ctica cl&#237;nica habitual&#46;</p></span>"
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      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Gago MCP&#44; Gadea OSS&#44; de la Cruz-Merino L&#46; Nuevos avances de tratamiento inmunobiol&#243;gico en el melanoma avanzado&#46; Actas Dermosifiliogr&#46; 2017&#59;108&#58;721&#8211;728&#46;</p>"
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          "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; DTIC&#44; dacarbazine&#59; HR&#44; hazard ratio&#59; LDH&#44; lactate dehydrogenase&#44; OS&#44; overall survival&#59; TMZ&#44; temozolomide&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" 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">Tremelimumab&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">Ipilimumab&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  " align="char" valign="top">N&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">655&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">502&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">Experimental Group&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">Tremelimumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">Ipilimumab<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>DTIC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">Treatment Group&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">DTIC or TMZ&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">DTIC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">Median follow-up&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">---&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#62;<span class="elsevierStyleHsp" style=""></span>37<span class="elsevierStyleHsp" style=""></span>months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">Median OS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">12&#46;6 vs 10&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">11&#46;2 vs 9&#46;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  " align="char" valign="top">Difference Median OS&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;9<span class="elsevierStyleHsp" style=""></span>m&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;1<span class="elsevierStyleHsp" style=""></span>m&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">HR&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;88&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;72&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top"><span class="elsevierStyleItalic">P</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#46;127&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#60;&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">ECOG 1 &#40;&#37; of patients&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">29&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">29&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">M1b&#47;M1c &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">22&#47;58&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">24&#47;56&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">Elevated LDH &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">32&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">40&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Key Data on Phase 3 Clinical Trials of First-Line Ipilimumab and Tremelimumab in Metastatic Melanoma&#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">Grade 3-4 Immune Adverse Effects &#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">Pembrolizumab&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">Nivolumab&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">Ipilimumab&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">Nivolumab<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>Ipilimumab&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">Pembrolizumab<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span> Ipilimumab&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  " align="char" valign="top">Diarrhea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">14&#46;4-16&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11&#46;2-19&#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">22&#46;7-33&#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">44&#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">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">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;8-3&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1-1&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8&#46;2-11&#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">11&#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">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">Hepatitis&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;1-1&#46;8&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;4-6&#46;4&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;2-7&#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">30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">Hypothyroidism&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8&#46;7-10&#46;1&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;4-8&#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">2&#46;0-4&#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">15&#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">17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">Hyperthyroidism&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&#46;2-6&#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">1&#46;9-4&#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">1&#46;0-2&#46;3&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;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">Hypophysitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#60;<span class="elsevierStyleHsp" style=""></span>1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#60;<span class="elsevierStyleHsp" style=""></span>1&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;3-3&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">Pneumonitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">&#60;<span class="elsevierStyleHsp" style=""></span>1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;9-1&#46;3&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;4-1&#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">6&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">Rash&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">13&#46;4-14&#46;7&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;3-21&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">14&#46;5-20&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">28&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">53&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">Pruritus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">14&#46;1-14&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">16-18&#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">24&#46;4-35&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">33&#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">28&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Immune-Related Toxicity with Immunomodulatory Antibodies&#46;</p>"
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        "tipo" => "MULTIMEDIATABLA"
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                  \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">CTCAE Toxicity&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">Management&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">Grade 1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Support measures<br>Close monitoring of symptoms<br>Rule out infections<br>Education of patient&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">Grade 2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Suspend immunotherapy until reduction of toxicity to grade 1<br>Assess administering oral corticosteroids if symptoms last <span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>5 days &#40;prednisone 1<span class="elsevierStyleHsp" style=""></span>mg&#47;Kg&#47;d&#41;&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">Grade 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Support measures<br>Begin intravenous corticosteroids &#40;1-2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg methylprednisolone&#41;<br>If not resolved in 48<span class="elsevierStyleHsp" style=""></span>h&#44; consider adding other immunosuppressants &#40;infliximab&#44; micophenolate&#41;<br>Consult with other specialists<br>Suspend immunotherapy and assess reinitiation if toxicity grade 1 or lower<br>Corticosteroids will be necessary for 3-6 weeks&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">Grade 4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">As for grade 3 but with permanent discontinuation of immunotherapy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">General Recommendations for Management of Immune-Related Toxicities&#46;</p>"
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      "titulo" => "References"
      "seccion" => array:1 [
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          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:41 [
            0 => array:3 [
              "identificador" => "bib0210"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "Ferlay J&#44; Soerjomataram I&#44; Ervik M&#44; Dikshit R&#44; Eser S&#44; Mathers C&#44; et al&#46; GLOBOCAN 2012 v1&#46;0&#44; Cancer Incidence and Mortality Worldwide&#58; IARC&#46;"
                ]
              ]
            ]
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              "identificador" => "bib0215"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advance metastatic malignant melanoma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46;R&#46; Middleton"
                            1 => "J&#46;J&#46; Grob"
                            2 => "N&#46; Aaronson"
                            3 => "G&#46; Fierlbeck"
                            4 => "W&#46; Tilgen"
                            5 => "S&#46; Seiter"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1200/JCO.2000.18.1.158"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Oncol"
                        "fecha" => "2000"
                        "volumen" => "18"
                        "paginaInicial" => "158"
                        "paginaFinal" => "166"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10623706"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0220"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mutations of the BRAF gene in human cancer"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "H&#46; Davies"
                            1 => "G&#46;R&#46; Bignell"
                            2 => "C&#46; Cox"
                            3 => "P&#46; Stephens"
                            4 => "P&#46; Edkins"
                            5 => "S&#46; Clegg"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/nature00766"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nature"
                        "fecha" => "2002"
                        "volumen" => "417"
                        "paginaInicial" => "949"
                        "paginaFinal" => "954"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12068308"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0225"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Distinct sets of genetic alterations in melanoma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46;A&#46; Curtin"
                            1 => "J&#46; Fridlyand"
                            2 => "T&#46; Kageshita"
                            3 => "H&#46;N&#46; Patel"
                            4 => "K&#46;J&#46; Busam"
                            5 => "H&#46; Kutzner"
                          ]
                        ]
                      ]
                    ]
                  ]
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                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa050092"
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                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2005"
                        "volumen" => "353"
                        "paginaInicial" => "2135"
                        "paginaFinal" => "2147"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16291983"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0230"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Combined vemurafenib and combimetinib in BRAF-mutated melanoma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46; Larkin"
                            1 => "P&#46;A&#46; Ascierto"
                            2 => "B&#46; Dr&#233;no"
                            3 => "V&#46; Atkinson"
                            4 => "G&#46; Liszkay"
                            5 => "M&#46; Maio"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa1408868"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med&#46;"
                        "fecha" => "2014"
                        "volumen" => "371"
                        "paginaInicial" => "1867"
                        "paginaFinal" => "1876"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25265494"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0235"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Combined BRAF and MEK inhibition versus BRAF inhibition along in melanoma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "G&#46;V&#46; Long"
                            1 => "D&#46; Stroyakovskiy"
                            2 => "H&#46; Gogas"
                            3 => "E&#46; Levchenko"
                            4 => "F&#46; de Braud"
                            5 => "J&#46; Larkin"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa1406037"
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                        "tituloSerie" => "N Engl J Med&#46;"
                        "fecha" => "2014"
                        "volumen" => "371"
                        "paginaInicial" => "1877"
                        "paginaFinal" => "1888"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25265492"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "R&#46;V&#46; Parry"
                            1 => "J&#46;M&#46; Chemnitz"
                            2 => "K&#46;A&#46; Frauwirth"
                            3 => "A&#46;R&#46; Lanfranco"
                            4 => "I&#46; Braunstein"
                            5 => "S&#46;V&#46; Kobayashi"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1128/MCB.25.21.9543-9553.2005"
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                        "tituloSerie" => "Mol Cell Biol&#46;"
                        "fecha" => "2005"
                        "volumen" => "25"
                        "paginaInicial" => "9543"
                        "paginaFinal" => "9553"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16227604"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0245"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Nivolumab plus ipilimumab in advanced melanoma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46;D&#46; Wolchok"
                            1 => "H&#46; Kluger"
                            2 => "M&#46;K&#46; Callahan"
                            3 => "M&#46;A&#46; Postow"
                            4 => "N&#46;A&#46; Rizvi"
                            5 => "A&#46;M&#46; Lesokhin"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa1302369"
                      "Revista" => array:7 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2013"
                        "volumen" => "369"
                        "paginaInicial" => "122"
                        "paginaFinal" => "133"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23724867"
                            "web" => "Medline"
                          ]
                        ]
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                      "titulo" => "Cellular and Molecular Immunology"
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                            0 => "A&#46;K&#46; Abbas"
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              "referencia" => array:1 [
                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Trial Watch&#58; Immunostimulatory monoclonal antibodies in cancer therapy"
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                          "autores" => array:6 [
                            0 => "F&#46; Aranda"
                            1 => "E&#46; Vacchelli"
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                            3 => "J&#46; Galon"
                            4 => "W&#46;H&#46; Fridman"
                            5 => "L&#46; Zitvogel"
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                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24701370"
                            "web" => "Medline"
                          ]
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              "identificador" => "bib0260"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Modulation of CTLA-4 and GITR for cancer immunotherapy"
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                          "autores" => array:5 [
                            0 => "F&#46; Avogadri"
                            1 => "J&#46; Yuan"
                            2 => "A&#46; Yang"
                            3 => "D&#46; Schaer"
                            4 => "J&#46;D&#46; Wolchok"
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                        "tituloSerie" => "Curr Top Microbiol Immunol"
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                        "paginaInicial" => "211"
                        "paginaFinal" => "244"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20563707"
                            "web" => "Medline"
                          ]
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                      ]
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                  ]
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              ]
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              "identificador" => "bib0270"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Ipilimumab monotherapy in patients with pretreated advanced melanoma&#58; A randomised&#44; double-blind&#44; multicentre&#44; phase 2&#44; dose ranging study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
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                            1 => "B&#46; Neyns"
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                            3 => "S&#46; Negrier"
                            4 => "J&#46; Lutzky"
                            5 => "L&#46; Thomas"
                          ]
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                    ]
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                    0 => array:2 [
                      "doi" => "10.1016/S1470-2045(09)70334-1"
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                        "tituloSerie" => "Lancet Oncol"
                        "fecha" => "2010"
                        "volumen" => "11"
                        "paginaInicial" => "155"
                        "paginaFinal" => "164"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20004617"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Improved survival with ipilimumab in patients with metastatic melanoma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "F&#46;S&#46; Hodi"
                            1 => "S&#46;J&#46; O&#8217;Day"
                            2 => "D&#46;F&#46; McDermott"
                            3 => "R&#46;W&#46; Weber"
                            4 => "J&#46;A&#46; Sosman"
                            5 => "J&#46;B&#46; Haanen"
                          ]
                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
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                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2010"
                        "volumen" => "363"
                        "paginaInicial" => "711"
                        "paginaFinal" => "723"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20525992"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0280"
              "etiqueta" => "15"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Ipilimumab plus dacarbazine for previously untreated metastatic melanoma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46; Robert"
                            1 => "L&#46; Thomas"
                            2 => "I&#46; Bondarenko"
                            3 => "S&#46; O&#8217;Day"
                            4 => "J&#46; Weber"
                            5 => "C&#46; Garbe"
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                        ]
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                        "fecha" => "2011"
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                        "paginaInicial" => "2517"
                        "paginaFinal" => "2526"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21639810"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0285"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46; Maio"
                            1 => "J&#46;J&#46; Grob"
                            2 => "S&#46; Aamdal"
                            3 => "I&#46; Bondarenko"
                            4 => "C&#46; Robert"
                            5 => "L&#46; Thomas"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1200/JCO.2014.56.6018"
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                        "tituloSerie" => "J Clin Oncol"
                        "fecha" => "2015"
                        "volumen" => "33"
                        "paginaInicial" => "1191"
                        "paginaFinal" => "1196"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25713437"
                            "web" => "Medline"
                          ]
                        ]
                      ]
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              ]
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              "identificador" => "bib0290"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
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                            1 => "F&#46;S&#46; Hodi"
                            2 => "C&#46; Robert"
                            3 => "J&#46;S&#46; Weber"
                            4 => "K&#46; Margolin"
                            5 => "O&#46; Hamid"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1200/JCO.2014.56.2736"
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                        "tituloSerie" => "J Clin Oncol"
                        "fecha" => "2015"
                        "volumen" => "33"
                        "paginaInicial" => "1889"
                        "paginaFinal" => "1894"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25667295"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46; Ribas"
                            1 => "R&#46; Kefford"
                            2 => "M&#46;A&#46; Marshall"
                            3 => "C&#46;J&#46; Punt"
                            4 => "J&#46;B&#46; Haanen"
                            5 => "M&#46; Marmol"
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                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1200/JCO.2012.44.6112"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Oncol"
                        "fecha" => "2013"
                        "volumen" => "31"
                        "paginaInicial" => "616"
                        "paginaFinal" => "622"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23295794"
                            "web" => "Medline"
                          ]
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                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0300"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Clinical experience with ipilimumab 3<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#58; Real-world efficacy and safety data from an expanded access programme cohort"
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                        0 => array:2 [
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                            0 => "P&#46;A&#46; Ascierto"
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                            3 => "J&#46; Pigozzo"
                            4 => "M&#46; Maio"
                            5 => "M&#46; Altomonte"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/1479-5876-12-116"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Transl Med&#46;"
                        "fecha" => "2014"
                        "volumen" => "12"
                        "paginaInicial" => "116"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24885479"
                            "web" => "Medline"
                          ]
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                          "pii" => "S0735109714023067"
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                          "issn" => "07351097"
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                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0305"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "PD-1 and its ligands in tolerance and immunity"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "M&#46;E&#46; Keir"
                            1 => "M&#46;J&#46; Butte"
                            2 => "G&#46;J&#46; Freeman"
                            3 => "A&#46;H&#46; Sharpe"
                          ]
                        ]
                      ]
                    ]
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                    0 => array:2 [
                      "doi" => "10.1146/annurev.immunol.26.021607.090331"
                      "Revista" => array:6 [
                        "tituloSerie" => "Annu Rev Immunol"
                        "fecha" => "2008"
                        "volumen" => "26"
                        "paginaInicial" => "677"
                        "paginaFinal" => "704"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18173375"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0310"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Safety&#44; activity&#44; and immune correlates of anti-PD-1 antibody in cancer"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "S&#46;L&#46; Topalian"
                            1 => "F&#46;S&#46; Hodi"
                            2 => "J&#46;R&#46; Brahmer"
                            3 => "S&#46;N&#46; Gettinger"
                            4 => "D&#46;C&#46; Smith"
                            5 => "D&#46;F&#46; McDermott"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa1200690"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2012"
                        "volumen" => "366"
                        "paginaInicial" => "2443"
                        "paginaFinal" => "2454"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22658127"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0315"
              "etiqueta" => "22"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "Weber JS&#44; Minor DR&#44; D&#8217;Angelo SP&#44; Hodi FS&#44; Gutzmer R&#44; Neyns B&#44; et al&#46; A phase 3 randomized&#44; open-label study of nivolumab &#40;anti-PD-1&#59; BMS-936558&#59; ONO-4538&#41; versus investigator&#39;s choice chemotherapy &#40;ICC&#41; in patients with advanced melanoma with prior anti-CTLA-4 therapy&#46; Presented at the European Society for Medical Oncology 2014 Congress&#44; Madrid&#44; September 26-30&#44; 2014&#46; Abstract&#46;"
                ]
              ]
            ]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Nivolumab in previously untreated melanoma without BRAF mutation"
                      "autores" => array:1 [
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                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46; Robert"
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                            4 => "M&#46; Maio"
                            5 => "L&#46; Mortier"
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                        ]
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                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa1412082"
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                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2015"
                        "volumen" => "372"
                        "paginaInicial" => "320"
                        "paginaFinal" => "330"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25399552"
                            "web" => "Medline"
                          ]
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                      ]
                    ]
                  ]
                ]
              ]
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              "identificador" => "bib0325"
              "etiqueta" => "24"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pembrolizumab versus ipilimumab in advanced melanoma"
                      "autores" => array:1 [
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                          "autores" => array:6 [
                            0 => "C&#46; Robert"
                            1 => "J&#46; Schachter"
                            2 => "G&#46;V&#46; Long"
                            3 => "A&#46; Arance"
                            4 => "J&#46;J&#46; Grob"
                            5 => "L&#46; Mortier"
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                        ]
                      ]
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                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa1503093"
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                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2015"
                        "volumen" => "372"
                        "paginaInicial" => "2521"
                        "paginaFinal" => "2532"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25891173"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0330"
              "etiqueta" => "25"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "Keytruda &#40;pembrolizumab&#41; prescribing information&#46; Whitehouse Station&#44; NJ&#58; Merck&#46; Disponible en&#58; http&#58;&#47;&#47;www&#46;merck&#46;com&#47;product&#47;usa&#47;pi&#95;circulars&#47;k&#47;keytruda&#47;keytruda&#95;pi&#46;pdf&#46;"
                ]
              ]
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Combined nivolumab and ipilimumab or monotherapy in untreated melanoma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46; Larkin"
                            1 => "V&#46; Chiarion-Sileni"
                            2 => "R&#46; Gonzalez"
                            3 => "J&#46;J&#46; Grob"
                            4 => "C&#46;L&#46; Cowey"
                            5 => "C&#46;D&#46; Lao"
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                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa1504030"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2015"
                        "volumen" => "373"
                        "paginaInicial" => "23"
                        "paginaFinal" => "34"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26027431"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0340"
              "etiqueta" => "27"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Nivolumab and ipilimumab versus ipilimumab in untreated melanoma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46;A&#46; Postow"
                            1 => "J&#46; Chesney"
                            2 => "A&#46;C&#46; Pavlick"
                            3 => "C&#46; Robert"
                            4 => "K&#46; Grossmann"
                            5 => "D&#46; McDermott"
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                      ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa1414428"
                      "Revista" => array:7 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2015"
                        "volumen" => "372"
                        "paginaInicial" => "2006"
                        "paginaFinal" => "2017"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25891304"
                            "web" => "Medline"
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                  "comentario" => "&#40;Suppl&#59; abstr 3009&#41;"
                  "contribucion" => array:1 [
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                          "autores" => array:6 [
                            0 => "M&#46;B&#46; Atkins"
                            1 => "T&#46;K&#46; Choueiri"
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                            5 => "D&#46;F&#46; McDermott"
                          ]
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                    ]
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                        "paginaInicial" => "33"
                      ]
                    ]
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                ]
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              "identificador" => "bib0350"
              "etiqueta" => "29"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Safety and activity of anti-PD-L1 antibody in patients with advanced cancer"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46;R&#46; Brahmer"
                            1 => "S&#46;S&#46; Tykodi"
                            2 => "L&#46;Q&#46; Chow"
                            3 => "W&#46;J&#46; Hwu"
                            4 => "S&#46;L&#46; Topalian"
                            5 => "P&#46; Hwu"
                          ]
                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa1200694"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2012"
                        "volumen" => "366"
                        "paginaInicial" => "2455"
                        "paginaFinal" => "2465"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22658128"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0355"
              "etiqueta" => "30"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "abstr 9010"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Clinical activity&#44; safety&#44; and biomarkers with MPDL32801A&#44; an engineered anti-PD2 antibody in patients with locally advanced or metastatic malignant melanoma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "O&#46;S&#46;J&#46; Hamid"
                            1 => "D&#46;P&#46; Lawrence"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1200/JCO.2013.49.0219"
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                        "tituloSerie" => "J Clin Oncol"
                        "fecha" => "2012"
                        "volumen" => "31"
                        "numero" => "Suppl&#46;"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23897962"
                            "web" => "Medline"
                          ]
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                  ]
                ]
              ]
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              "identificador" => "bib0360"
              "etiqueta" => "31"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Ipilimumab and its toxicities&#58; A multidisciplinary approach"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "L&#46;A&#46; Fecher"
                            1 => "S&#46;S&#46; Agarwala"
                            2 => "F&#46;S&#46; Hodi"
                            3 => "J&#46;S&#46; Weber"
                          ]
                        ]
                      ]
                    ]
                  ]
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                    0 => array:2 [
                      "doi" => "10.1634/theoncologist.2012-0483"
                      "Revista" => array:6 [
                        "tituloSerie" => "Oncologist"
                        "fecha" => "2013"
                        "volumen" => "18"
                        "paginaInicial" => "733"
                        "paginaFinal" => "743"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23774827"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0365"
              "etiqueta" => "32"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Management of immune-related adverse events and kinetics of response with ipilimumab"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "J&#46;S&#46; Weber"
                            1 => "K&#46;C&#46; Kahler"
                            2 => "A&#46; Hauschild"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1200/JCO.2012.41.6750"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Oncol"
                        "fecha" => "2012"
                        "volumen" => "30"
                        "paginaInicial" => "2691"
                        "paginaFinal" => "2697"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22614989"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0370"
              "etiqueta" => "33"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Immune modulation in cancer with antibodies"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "D&#46;B&#46; Page"
                            1 => "M&#46;A&#46; Postow"
                            2 => "M&#46;K&#46; Callahan"
                            3 => "J&#46;P&#46; Allison"
                            4 => "J&#46;D&#46; Wolchok"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Annu Rev Immunol"
                        "fecha" => "2014"
                        "volumen" => "65"
                        "paginaInicial" => "185"
                        "paginaFinal" => "202"
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0375"
              "etiqueta" => "34"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mitigating the toxic effects of anticancer immunotherapy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "T&#46;C&#46; Gangadhar"
                            1 => "R&#46;H&#46; Vonderheide"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/nrclinonc.2013.245"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nat Rev Clin Oncol"
                        "fecha" => "2014"
                        "volumen" => "11"
                        "paginaInicial" => "91"
                        "paginaFinal" => "99"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24445516"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            34 => array:3 [
              "identificador" => "bib0380"
              "etiqueta" => "35"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting&#58; Lymphocyte count after 2 doses correlates with survival"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "G&#46;Y&#46; Ku"
                            1 => "J&#46; Yuan"
                            2 => "D&#46;B&#46; Page"
                            3 => "S&#46;E&#46; Schroeder"
                            4 => "K&#46;S&#46; Panageas"
                            5 => "R&#46;D&#46; Carvajal"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/cncr.24951"
                      "Revista" => array:6 [
                        "tituloSerie" => "Cancer"
                        "fecha" => "2010"
                        "volumen" => "116"
                        "paginaInicial" => "1767"
                        "paginaFinal" => "1775"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20143434"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            35 => array:3 [
              "identificador" => "bib0385"
              "etiqueta" => "36"
              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "abstr 8595"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Evaluation of the absolute lymphocyte count as a biomarker for melanoma patients treated with the commercially available dose of ipilimumab &#40;3<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41;&#46; The American Society of Clinical Oncology Annual Meeting&#44; Chicago&#44; USA"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46;A&#46; Postow"
                            1 => "J&#46; Yuan"
                            2 => "K&#46; Panageas"
                            3 => "K&#46; Bogatch"
                            4 => "M&#46; Callahan"
                            5 => "M&#46; Cheng"
                          ]
                        ]
                      ]
                    ]
                  ]
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                    0 => array:1 [
                      "Revista" => array:4 [
                        "tituloSerie" => "J Clin Oncol&#46;"
                        "fecha" => "2012"
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                        "numero" => "Suppl&#46;"
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "etiqueta" => "37"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Experience in daily practice with ipilimumab for the treatment of patients with metastatic melanoma&#58; An early increase in lymphocyte and eosinophil counts is associated with improved survival"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
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                            1 => "C&#46; Mateus"
                            2 => "D&#46; Lefeuvre"
                            3 => "E&#46; Lanoy"
                            4 => "L&#46; Zitvogel"
                            5 => "N&#46; Chaput"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/annonc/mdt027"
                      "Revista" => array:6 [
                        "tituloSerie" => "Ann Oncol"
                        "fecha" => "2013"
                        "volumen" => "24"
                        "paginaInicial" => "1697"
                        "paginaFinal" => "1703"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23439861"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "etiqueta" => "38"
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                0 => array:3 [
                  "comentario" => "abstr 9024"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pretreatment levels of absolute and relative eosinophil count to improve overall survival &#40;OS&#41; in patients with metastatic melanoma under treatment with ipilimumab&#44; an anti-CTLA-4 antibody&#46; The Annual Meeting of the American Society of Clinical Oncology&#46; Chicago&#44; USA"
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                          "autores" => array:6 [
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                            2 => "M&#46;A&#46; Postow"
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              "etiqueta" => "39"
              "referencia" => array:1 [
                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Genetic basis for clinical response to CTLA-4 blockade in melanoma"
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                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46; Snyder"
                            1 => "V&#46; Makarov"
                            2 => "T&#46; Merghoub"
                            3 => "J&#46; Yuan"
                            4 => "J&#46;M&#46; Zaretsky"
                            5 => "A&#46; Desrichard"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa1406498"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2014"
                        "volumen" => "371"
                        "paginaInicial" => "2189"
                        "paginaFinal" => "2199"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25409260"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "referencia" => array:1 [
                0 => array:3 [
                  "comentario" => "abstr 3003"
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Peripheral and tumor immune correlates in patients with advanced melanoma treated with combination nivolumab &#40;anti-PD-1&#44; BMS-936558&#44; ONO-4358&#41; and ipilimumab&#46; The Annual Meeting of the American Society of Clinical Oncology&#44; Chicago&#44; USA"
                      "autores" => array:1 [
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                          "etal" => false
                          "autores" => array:6 [
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                            2 => "M&#46;A&#46; Curran"
                            3 => "T&#46; Hollman"
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                            5 => "J&#46; Yan"
                          ]
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                  ]
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              "etiqueta" => "41"
              "referencia" => array:1 [
                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "PD-1 blockade induces responses by inhibiting adaptive immune resistance"
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                          "autores" => array:6 [
                            0 => "P&#46;C&#46; Tumeh"
                            1 => "C&#46;L&#46; Harview"
                            2 => "J&#46;H&#46; Yearley"
                            3 => "I&#46;P&#46; Shintaku"
                            4 => "E&#46;J&#46; Taylor"
                            5 => "L&#46; Robert"
                          ]
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                        "tituloSerie" => "Nature"
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                        "volumen" => "515"
                        "paginaInicial" => "568"
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                        "link" => array:1 [
                          0 => array:2 [
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                ]
              ]
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Información del artículo

ISSN: 15782190
Idioma original: Inglés

DOI:10.1016/j.adengl.2017.01.005

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