{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T00:23:54Z","timestamp":1791937434550,"version":"4.3.4"},"reference-count":83,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,9,20]],"date-time":"2021-09-20T00:00:00Z","timestamp":1632096000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Rare cancers, as defined by the European Union, occur in fewer than 15 out of 100,000 people each year. The International Rare Cancer Consortium defines rare cancer incidence as less than six per 100,000 per year. There is a growing number of reports of the efficacy of immune checkpoint inhibitor (ICI) therapy in patients with rare tumours, and hence, we conducted a comprehensive review to summarise and analyse the available literature.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A literature search of PubMed was performed on January 31, 2021, using the following ICI names as keywords: ipilimumab, tremelimumab, cemiplimab, nivolumab, pembrolizumab, avelumab, atezolizumab, and durvalumab. Studies on patients with rare tumours who were being treated with ICIs were included. We plotted the overall response rate against the corresponding median survival across a variety of cancer types using linear regression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>From 1,255 publications retrieved during the primary search, 62 publications were selected (with a total of 4,620 patients). Only four were randomised trials. A minority were first-line studies, while the remaining were studies in which ICIs were delivered as salvage therapy in pretreated patients. There was a good correlation between response rate and overall survival (Spearman R<jats:sup>2<\/jats:sup> &amp;gt;0.9) in skin cancers, mesothelioma, and sarcomas.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Treatment of advanced-stage rare tumours with ICI therapy was found to be associated with significant activity in some orphan diseases (e.g., Merkel cell carcinoma) and hepatocellular carcinoma. Several ongoing prospective clinical trials will expand the knowledge on the safety and efficacy of ICI therapy in patients with these rare\u00a0cancers.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2021.720748","type":"journal-article","created":{"date-parts":[[2021,9,20]],"date-time":"2021-09-20T06:41:16Z","timestamp":1632120076000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Efficacy of Immune Checkpoint Inhibitors in Rare Tumours: A Systematic Review"],"prefix":"10.3389","volume":"12","author":[{"given":"Fausto","family":"Petrelli","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Consoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Ghidini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluca","family":"Perego","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Luciani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Mercurio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfredo","family":"Berruti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore","family":"Grisanti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,9,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1200\/JCO.19.01307","article-title":"Pembrolizumab As Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial","volume":"38","author":"Finn","year":"2020","journal-title":"J Clin Oncol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2011.08.008","article-title":"Rare Cancers Are Not So Rare: The Rare Cancer Burden in Europe","volume":"47","author":"Gatta","year":"2011","journal-title":"Eur J Cancer"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(15)00485-4","article-title":"The Promise and Challenges of Rare Cancer Research","volume":"17","author":"Komatsubara","year":"2016","journal-title":"Lancet Oncol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1111\/cas.14148","article-title":"Efficacy and Safety of Nivolumab in Japanese Patients With Uterine Cervical Cancer, Uterine Corpus Cancer, or Soft Tissue Sarcoma: Multicenter, Open-Label Phase 2 Trial","volume":"110","author":"Tamura","year":"2019","journal-title":"Cancer Sci"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2019-000347","article-title":"Phase 2 Study of Pembrolizumab in Patients With Advanced Rare Cancers","volume":"8","author":"Naing","year":"2020","journal-title":"J Immunother Cancer"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdx680","article-title":"Phase II Trial of Pembrolizumab in Patients With Platinum Refractory Germ-Cell Tumors: A Hoosier Cancer Research Network Study GU14-206","volume":"29","author":"Adra","year":"2018","journal-title":"Ann Oncol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.30738","article-title":"Immunotherapy With Single Agent Nivolumab for Advanced Leiomyosarcoma of the Uterus: Results of a Phase 2 Study","volume":"123","author":"Ben-Ami","year":"2017","journal-title":"Cancer"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(18)30420-X","article-title":"Ipilimumab and Nivolumab in the Treatment of Recurrent Malignant Pleural Mesothelioma (INITIATE): Results of a Prospective, Single-Arm, Phase 2 Trial","volume":"7","author":"Disselhorst","year":"2019","journal-title":"Lancet Respir Med"},{"key":"B9","doi-asserted-by":"publisher","first-page":"e000367","DOI":"10.1136\/jitc-2019-000367","article-title":"Efficacy and Biomarker Analysis of Nivolumab Plus Gemcitabine and Cisplatin in Patients With Unresectable or Metastatic Biliary Tract Cancers: Results From a Phase II Study","volume":"8","author":"Feng","year":"2020","journal-title":"J Immunother Cancer"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.32339.Phase","article-title":"Phase 2 Study of Pembrolizumab and Circulating Biomarkers to Predict Anticancer Response in Advanced, Unresectable Hepatocellular Carcinoma","volume":"125","author":"Feun","year":"2019","journal-title":"Cancer"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1915745","article-title":"Atezolizumab Plus Bevacizumab in Unresectable Hepatocellular Carcinoma","volume":"382","author":"Finn","year":"2020","journal-title":"N Engl J Med"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(18)30062-7","article-title":"Pembrolizumab in Patients With Thymic Carcinoma: A Single-Arm, Single-Centre, Phase 2 Study","volume":"19","author":"Giaccone","year":"2018","journal-title":"Lancet Oncol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s40425-019-0722-x","article-title":"Phase II Clinical Trial of Pembrolizumab Efficacy and Safety in Advanced Adrenocortical Carcinoma","volume":"7","author":"Habra","year":"2019","journal-title":"J Immunother Cancer"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/cancers12082307","article-title":"Phase II Clinical Trial of Pembrolizumab in Patients With Progressive Metastatic Pheochromocytomas and Paragangliomas","volume":"12","author":"Jimenez","year":"2020","journal-title":"Cancers (Basel)"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.6004\/jnccn.2018.7070","article-title":"Response to Anti\u2013PD-1 in Uveal Melanoma Without High-Volume Liver Metastasis","volume":"17","author":"Johnson","year":"2019","journal-title":"JNCCN J Natl Compr Cancer Netw"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1097\/CMR.0000000000000175","article-title":"A Phase 2 Study of Tremelimumab in Patients With Advanced Uveal Melanoma","volume":"25","author":"Joshua","year":"2015","journal-title":"Melanoma Res"},{"key":"B17","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.ejca.2020.10.027","article-title":"Triplet Combination of Durvalumab, Tremelimumab, and Paclitaxel in Biliary Tract Carcinomas: Safety Run-in Results of the Randomized IMMUNOBIL PRODIGE 57 Phase II Trial","volume":"143","author":"Boil\u00e8ve","year":"2021","journal-title":"Eur J Cancer"},{"key":"B18","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1016\/j.ejca.2019.03.012","article-title":"Single-Arm, Multicentre, Phase II Trial of Nivolumab for Unresectable or Recurrent Thymic Carcinoma: PRIMER Study","volume":"113","author":"Katsuya","year":"2019","journal-title":"Eur J Cancer"},{"key":"B19","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1186\/s40425-017-0310-x","article-title":"Updated Efficacy of Avelumab in Patients With Previously Treated Metastatic Merkel Cell Carcinoma After \u22651 Year of Follow-Up: JAVELIN Merkel 200, a Phase 2 Clinical Trial","volume":"6","author":"Kaufman","year":"2018","journal-title":"J Immunother Cancer"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1111\/1759-7714.13684","article-title":"Phase II Study of Durvalumab and Tremelimumab in Pulmonary Sarcomatoid Carcinoma: KCSG-LU16-07","volume":"11","author":"Kim","year":"2020","journal-title":"Thorac Cancer"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2020.0930","article-title":"A Phase 2 Multi-Institutional Study of Nivolumab for Patients With Advanced Refractory Biliary Tract Cancer","volume":"6","author":"Kim","year":"2020","journal-title":"JAMA Oncol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2020.2814","article-title":"Evaluation of Combination Nivolumab and Ipilimumab Immunotherapy in Patients With Advanced Biliary Tract Cancers: Subgroup Analysis of a Phase 2 Nonrandomized Clinical Trial","volume":"6","author":"Klein","year":"2020","journal-title":"JAMA Oncol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2019.07.018","article-title":"Programmed Cell Death 1 (PD-1) Targeting in Patients With Advanced Osteosarcomas: Results From the PEMBROSARC Study","volume":"119","author":"Le Cesne","year":"2019","journal-title":"Eur J Cancer"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(17)30446-1","article-title":"Tremelimumab as Second-Line or Third-Line Treatment in Relapsed Malignant Mesothelioma (DETERMINE): A Multicentre, International, Randomised, Double-Blind, Placebo-Controlled Phase 2b Trial","volume":"18","author":"Maio","year":"2017","journal-title":"Lancet Oncol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"168145","DOI":"10.1155\/2013\/168145","article-title":"A Pilot Study of Anti-CTLA4 Antibody Ipilimumab in Patients With Synovial Sarcoma","volume":"2013","author":"Maki","year":"2013","journal-title":"Sarcoma"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.19.03357","article-title":"Phase II Study of Pembrolizumab as First-Line, Single-Drug Therapy for Patients With Unresectable Cutaneous Squamous Cell Carcinomas","volume":"38","author":"Maubec","year":"2020","journal-title":"J Clin Oncol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1007\/s10637-019-00805-4","article-title":"Phase II Study of Avelumab in Multiple Relapsed\/Refractory Germ Cell Cancer","volume":"37","author":"Mego","year":"2019","journal-title":"Invest New Drugs"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(15)00092-2","article-title":"Efficacy and Safety of an Intensified Schedule of Tremelimumab for Chemotherapy-Resistant Malignant Mesothelioma: An Open-Label, Single-Arm, Phase 2 Study","volume":"3","author":"Calabr\u00f2","year":"2015","journal-title":"Lancet Respir Med"},{"key":"B29","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1016\/S1470-2045(19)30728-4","article-title":"Cemiplimab in Locally Advanced Cutaneous Squamous Cell Carcinoma: Results From an Open-Label, Phase 2, Single-Arm Trial","volume":"21","author":"Migden","year":"2020","journal-title":"Lancet Oncol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1805131","article-title":"PD-1 Blockade With Cemiplimab in Advanced Cutaneous Squamous-Cell Carcinoma","volume":"379","author":"Migden","year":"2018","journal-title":"N Engl J Med"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2018.09.010","article-title":"An Open-Label Randomized Phase 2 Study of Durvalumab Alone or in Combination With Tremelimumab in Patients With Advanced Germ Cell Tumors (APACHE): Results From the First Planned Interim Analysis","volume":"75","author":"Necchi","year":"2019","journal-title":"Eur Urol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1200\/JCO.18.01896","article-title":"Durable Tumor Regression and Overall Survival in Patients With Advanced Merkel Cell Carcinoma Receiving Pembrolizumab as First-Line Therapy","volume":"37","author":"Nghiem","year":"2019","journal-title":"J Clin Oncol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1007\/s10147-020-01618-9","article-title":"Multicenter Prospective Phase II Trial of Nivolumab in Patients With Unresectable or Metastatic Mucosal Melanoma","volume":"25","author":"Nomura","year":"2020","journal-title":"Int J Clin Oncol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(20)30462-9","article-title":"Durvalumab With First-Line Chemotherapy in Previously Untreated Malignant Pleural Mesothelioma (DREAM): A Multicentre, Single-Arm, Phase 2 Trial With a Safety Run-in","volume":"21","author":"Nowak","year":"2020","journal-title":"Lancet Oncol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-19-0103","article-title":"Clinical Efficacy and Safety of Nivolumab: Results of a Multicenter, Open-Label, Single-Arm, Japanese Phase II Study in Malignant Pleural Mesothelioma (MERIT)","volume":"25","author":"Okada","year":"2019","journal-title":"Clin Cancer Res"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-19-3356","article-title":"A Phase II Basket Trial of Dual Anti\u2013CTLA-4 and Anti\u2013PD-1 Blockade in Rare Tumors (DART SWOG 1609) in Patients With Nonpancreatic Neuroendocrine Tumors","volume":"26","author":"Patel","year":"2020","journal-title":"Clin Cancer Res"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2018.05.038","article-title":"Programmed Death 1 Blockade With Nivolumab in Patients With Recurrent Malignant Pleural Mesothelioma","volume":"13","author":"Quispel-Janssen","year":"2018","journal-title":"J Thorac Oncol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(18)30151-6","article-title":"Tremelimumab Combined With Durvalumab in Patients With Mesothelioma (NIBIT-MESO-1): An Open-Label, Non-Randomised, Phase 2 Study","volume":"6","author":"Calabr\u00f2","year":"2018","journal-title":"Lancet Respir Med"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)31046-2.Nivolumab","article-title":"\u4e73\u9f20\u5fc3\u808c\u63d0\u53d6 HHS Public Access","volume":"176","author":"Quispe-Tintaya","year":"2017","journal-title":"Physiol Behav"},{"key":"B40","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1200\/JCO.19.01586","article-title":"PD-1 Blockade in Advanced Adrenocortical Carcinoma","volume":"38","author":"Raj","year":"2020","journal-title":"J Clin Oncol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-19-2214","article-title":"A Phase II Trial of Pembrolizumab and Vorinostat in Recurrent Metastatic Head and Neck Squamous Cell Carcinomas and Salivary Gland Cancer","volume":"26","author":"Rodriguez","year":"2020","journal-title":"Clin Cancer Res"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2013.02.022","article-title":"A Clinical Trial of CTLA-4 Blockade With Tremelimumab in Patients With Hepatocellular Carcinoma and Chronic Hepatitis C","volume":"59","author":"Sangro","year":"2013","journal-title":"J Hepatol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(18)30765-4","article-title":"Nivolumab or Nivolumab Plus Ipilimumab in Patients With Relapsed Malignant Pleural Mesothelioma (IFCT-1501 MAPS2): A Multicentre, Open-Label, Randomised, Non-Comparative, Phase 2 Trial","volume":"20","author":"Scherpereel","year":"2019","journal-title":"Lancet Oncol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(17)30624-1","article-title":"Pembrolizumab in Advanced Soft-Tissue Sarcoma and Bone Sarcoma (SARC028): A Multicentre, Two-Cohort, Single-Arm, Open-Label, Phase 2 Trial","volume":"18","author":"Tawbi","year":"2017","journal-title":"Lancet Oncol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2017.1617","article-title":"Use of PD-1 Targeting, Macrophage Infiltration, and IDO Pathway Activation in Sarcomas a Phase 2 Clinical Trial","volume":"4","author":"Toulmonde","year":"2018","journal-title":"JAMA Oncol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-020-0775-0","article-title":"Pembrolizumab Monotherapy in Patients With Previously Treated Metastatic High-Grade Neuroendocrine Neoplasms: Joint Analysis of Two Prospective, non-Randomised Trials","volume":"122","author":"Vijayvergia","year":"2020","journal-title":"Br J Cancer"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(19)30153-6","article-title":"Axitinib Plus Pembrolizumab in Patients With Advanced Sarcomas Including Alveolar Soft-Part Sarcoma: A Single-Centre, Single-Arm, Phase 2 Trial","volume":"20","author":"Wilky","year":"2019","journal-title":"Lancet Oncol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2019.0086","article-title":"A Phase 2 Study of Pembrolizumab Combined With Chemoradiotherapy as Initial Treatment for Anaplastic Thyroid Cancer","volume":"29","author":"Chintakuntlawar","year":"2019","journal-title":"Thyroid"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(18)30351-6","article-title":"Pembrolizumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib (KEYNOTE-224): A Non-Randomised, Open-Label Phase 2 Trial","volume":"19","author":"Zhu","year":"2018","journal-title":"Lancet Oncol"},{"key":"B50","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1371\/journal.pone.0118564","article-title":"Phase II DeCOG-Study of Ipilimumab in Pretreated and Treatment-Na\u00efve Patients With Metastatic Uveal Melanoma","volume":"10","author":"Zimmer","year":"2015","journal-title":"PloS One"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2017.77.3184","article-title":"Pembrolizumab for Patients With Refractory or Relapsed Thymic Epithelial Tumor: An Open-Label Phase II Trial","volume":"37","author":"Cho","year":"2019","journal-title":"J Clin Oncol"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2016.67.9258","article-title":"Efficacy and Safety of Nivolumab Alone or in Combination With Ipilimumab in Patients With Mucosal Melanoma: A Pooled Analysis","volume":"35","author":"D\u2019Angelo","year":"2017","journal-title":"J Clin Oncol"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(18)30006-8","article-title":"Nivolumab With or Without Ipilimumab Treatment for Metastatic Sarcoma (Alliance A091401): Two Open-Label, Non-Comparative, Randomised, Phase 2 Trials","volume":"19","author":"D\u2019Angelo","year":"2018","journal-title":"Lancet Oncol"},{"key":"B54","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1001\/jamaoncol.2018.0077","article-title":"Efficacy and Safety of First-Line Avelumab Treatment in Patients With Stage IV Metastatic Merkel Cell Carcinoma a Preplanned Interim Analysis of a Clinical Trial","volume":"4","author":"D\u2019Angelo","year":"2018","journal-title":"JAMA Oncol"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2019-00600","article-title":"Nivolumab in Metastatic Adrenocortical Carcinoma: Results of a Phase 2 Trial","volume":"104","author":"Carneiro","year":"2019","journal-title":"J Clin Endocrinol Metab"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-20-0621","article-title":"Immunotherapy of Ipilimumab and Nivolumab in Patients With Advanced Neuroendocrine Tumors: A Subgroup Analysis of the CA209-538 Clinical Trial for Rare Cancers","volume":"26","author":"Klein","year":"2020","journal-title":"Clin Cancer Res"},{"key":"B57","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s40425-018-0459-y","article-title":"Avelumab in Patients With Previously Treated Metastatic Melanoma: Phase 1b Results From the JAVELIN Solid Tumor Trial","volume":"7","author":"Keilholz","year":"2019","journal-title":"J Immunother Cancer"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.19.02727","article-title":"PD-1 Blockade in Anaplastic Thyroid Carcinoma","volume":"38","author":"Capdevila","year":"2020","journal-title":"J Clin Oncol"},{"key":"B59","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12885-019-5380-3","article-title":"Safety and Antitumor Activity of the Anti-PD-1 Antibody Pembrolizumab in Patients With Advanced, PD-L1-Positive Papillary or Follicular Thyroid Cancer","volume":"19","author":"Mehnert","year":"2019","journal-title":"BMC Cancer"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2019.6152","article-title":"Objective Response Rate Among Patients With Locally Advanced or Metastatic Sarcoma Treated With Talimogene Laherparepvec in Combination With Pembrolizumab: A Phase 2 Clinical Trial","volume":"6","author":"Kelly","year":"2020","journal-title":"JAMA Oncol"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2019.08.014","article-title":"Safety and Efficacy of Nivolumab in Challenging Subgroups With Advanced Melanoma Who Progressed on or After Ipilimumab Treatment: A Single-Arm, Open-Label, Phase II Study (CheckMate 172)","volume":"121","author":"Schadendorf","year":"2019","journal-title":"Eur J Cancer"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2019.07.010","article-title":"Safety and Efficacy of Nivolumab in Patients With Rare Melanoma Subtypes Who Progressed on or After Ipilimumab Treatment: A Single-Arm, Open-Label, Phase II Study (CheckMate 172)","volume":"119","author":"Nathan","year":"2019","journal-title":"Eur J Cancer"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)32714-8","article-title":"First-Line Nivolumab Plus Ipilimumab in Unresectable Malignant Pleural Mesothelioma (CheckMate 743): A Multicentre, Randomised, Open-Label, Phase 3 Trial","volume":"397","author":"Baas","year":"2021","journal-title":"Lancet"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2020.08.018","article-title":"A Randomized Phase 2 Study of Pembrolizumab With or Without Radiation in Patients With Recurrent or Metastatic Adenoid Cystic Carcinoma","volume":"109","author":"Mahmood","year":"2021","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"B65","doi-asserted-by":"crossref","DOI":"10.1016\/S0140-6736(17)31046-2","article-title":"Nivolumab in Patients With Advanced Hepatocellular Carcinoma (CheckMate 040): An Open-Label, Non-Comparative, Phase 1\/2 Dose Escalation and Expansion Trial","volume":"389","author":"El-Khoueiry","year":"2017","journal-title":"Lancet"},{"key":"B66","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1186\/s40425-018-0424-9","article-title":"Avelumab in Patients With Previously Treated Metastatic Adrenocortical Carcinoma: Phase 1b Results From the JAVELIN Solid Tumor Trial","author":"Le Tourneau","year":"2018","journal-title":"J Immunother Cancer"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2009.26.7609","article-title":"Phase I Study of Single-Agent Anti-Programmed Death-1 (MDX-1106) in Refractory Solid Tumors: Safety, Clinical Activity, Pharmacodynamics, and Immunologic Correlates","volume":"28","author":"Brahmer","year":"2010","journal-title":"J Clin Oncol"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-14-0983","article-title":"PD-L1 Expression as a Predictive Biomarker in Cancer Immunotherapy","volume":"14","author":"Patel","year":"2015","journal-title":"Mol Cancer Ther"},{"key":"B69","doi-asserted-by":"publisher","first-page":"e5","DOI":"10.1038\/bjc.2017.220","article-title":"HYPE or HOPE: The Prognostic Value of Infiltrating Immune Cells in Cancer","volume":"118","author":"Barnes","year":"2017","journal-title":"Br J Cancer"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2018.00027","article-title":"The Expression and Prognostic Impact of Immune Cytolytic Activity-Related Markers in Human Malignancies: A Comprehensive Meta-Analysis","volume":"8","author":"Roufas","year":"2018","journal-title":"Front Oncol"},{"key":"B71","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1186\/s40425-019-0768-9","article-title":"The Role of PD-L1 Expression as a Predictive Biomarker: An Analysis of All US Food and Drug Administration (FDA) Approvals of Immune Checkpoint Inhibitors","volume":"7","author":"Davis","year":"2019","journal-title":"J Immunother Cancer"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-16-0903","article-title":"Mutational Landscape and Sensitivity to Immune Checkpoint Blockers","volume":"22","author":"Chabanon","year":"2016","journal-title":"Clin Cancer Res"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1056\/nejmc1713444","article-title":"Tumor Mutational Burden and Response Rate to PD-1 Inhibition","volume":"377","author":"Yarchoan","year":"2017","journal-title":"N Engl J Med"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2021.02.006","article-title":"High Tumor Mutation Burden Fails to Predict Immune Checkpoint Blockade Response Across All Cancer Types","volume":"32","author":"McGrail","year":"2021","journal-title":"Ann Oncol"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf2834","article-title":"The \u201cCancer Immunogram","volume":"352","author":"Blank","year":"2016","journal-title":"Sci (80- )"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2019.2311","article-title":"Multiomics Prediction of Response Rates to Therapies to Inhibit Programmed Cell Death 1 and Programmed Cell Death 1 Ligand 1","volume":"5","author":"Lee","year":"2019","journal-title":"JAMA Oncol"},{"key":"B77","doi-asserted-by":"publisher","first-page":"e49020","DOI":"10.7554\/eLife.49020","article-title":"Antigen Presentation and Tumor Immunogenicity in Cancer Immunotherapy Response Prediction","volume":"8","author":"Wang","year":"2019","journal-title":"Elife"},{"key":"B78","doi-asserted-by":"publisher","first-page":"e028634","DOI":"10.1136\/bmjopen-2018-028634","article-title":"Application of Orphan Drug Designation to Cancer Treatments (2008-2017): A Comprehensive and Comparative Analysis of the USA and EU","volume":"9","author":"Vokinger","year":"2019","journal-title":"BMJ Open"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2012.08.009","article-title":"Orphan Drugs: The Regulatory Environment","volume":"18","author":"Franco","year":"2013","journal-title":"Drug Discov Today"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(17)30445-X","article-title":"Burden and Centralised Treatment in Europe of Rare Tumours: Results of RARECAREnet\u2014A Population-Based Study","volume":"18","author":"Gatta","year":"2017","journal-title":"Lancet Oncol"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2015.03.001","article-title":"Immune Checkpoint Blockade: A Common Denominator Approach to Cancer Therapy","volume":"27","author":"Topalian","year":"2015","journal-title":"Cancer Cell"},{"key":"B82","doi-asserted-by":"publisher","first-page":"6072863","DOI":"10.1155\/2019\/6072863","article-title":"Molecular Drivers of Potential Immunotherapy Failure in Adrenocortical Carcinoma","volume":"2019","author":"Fiorentini","year":"2019","journal-title":"J Oncol"},{"key":"B83","doi-asserted-by":"publisher","first-page":"3017","DOI":"10.2217\/fon-2020-0686","article-title":"The Long and Winding Road to Effective Immunotherapy in Patients With Adrenocortical Carcinoma","volume":"16","author":"Grisanti","year":"2020","journal-title":"Futur Oncol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.720748\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,20]],"date-time":"2021-09-20T06:41:21Z","timestamp":1632120081000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.720748\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,20]]},"references-count":83,"alternative-id":["10.3389\/fimmu.2021.720748"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.720748","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,20]]},"article-number":"720748"}}