Immune Checkpoint Inhibitor-Induced Liver Injury

Cathrin L.C. Gudd; Roosey Sheth; Mark R. Thursz; Evangelos Triantafyllou; Lucia A. Possamai

doi:10.1055/s-0043-1776761

Seminars in Liver Disease, Inhaltsverzeichnis

Semin Liver Dis 2023; 43(04): 402-417
DOI: 10.1055/s-0043-1776761

Review Article

Immune Checkpoint Inhibitor-Induced Liver Injury

Cathrin L.C. Gudd‡^*

¹Section of Hepatology and Gastroenterology, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom

,

Roosey Sheth‡^*

²Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, King's College London, London, United Kingdom

,

Mark R. Thursz

¹Section of Hepatology and Gastroenterology, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom

³Liver and Antiviral Unit, St Mary's Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom

,

Evangelos Triantafyllou

¹Section of Hepatology and Gastroenterology, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom

,

Lucia A. Possamai

¹Section of Hepatology and Gastroenterology, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom

³Liver and Antiviral Unit, St Mary's Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom

› Institutsangaben

Abstract

In recent years cancer treatment has been revolutionized by the development and wide application of checkpoint inhibitor (CPI) drugs, which are a form of immunotherapy. CPI treatment is associated with immune-related adverse events, off-target tissue destructive inflammatory complications, which may affect a range of organs, with liver inflammation (hepatitis) being one of the more commonly noted events. This is a novel form of drug-induced liver injury and a rapidly evolving field, as our understanding of both the basic immunopathology of CPI hepatitis (CPI-H) and optimal clinical management, races to catch up with the increasing application of this form of immunotherapy in clinical practice. In this review, we summarize current evidence and understanding of CPI-H, from fundamental immunology to practical patient management.

Keywords

checkpoint inhibitor - immunotherapy - liver injury - hepatotoxicity

Volltext

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References
1 Kraehenbuehl L, Weng CH, Eghbali S, Wolchok JD, Merghoub T. Enhancing immunotherapy in cancer by targeting emerging immunomodulatory pathways. Nat Rev Clin Oncol 2022; 19 (01) 37-50
2 Gudd CLC, Possamai LA. The role of myeloid cells in hepatotoxicity related to cancer immunotherapy. Cancers (Basel) 2022; 14 (08) 1913
3 Shojaie L, Ali M, Iorga A, Dara L. Mechanisms of immune checkpoint inhibitor-mediated liver injury. Acta Pharm Sin B 2021; 11 (12) 3727-3739
4 Urwyler P, Earnshaw I, Bermudez M. et al. Mechanisms of checkpoint inhibition-induced adverse events. Clin Exp Immunol 2020; 200 (02) 141-154
5 Zhao M, Huang H, He F, Fu X. Current insights into the hepatic microenvironment and advances in immunotherapy for hepatocellular carcinoma. Front Immunol 2023; 14: 1188277
6 Fessas P, Possamai LA, Clark J. et al. Immunotoxicity from checkpoint inhibitor therapy: clinical features and underlying mechanisms. Immunology 2020; 159 (02) 167-177
7 Boussiotis VA, Patsoukis N. Effects of PD-1 signaling on immunometabolic reprogramming. Immunometabolism 2022; 4 (02) 1-17
8 Strauss L, Mahmoud MAA, Weaver JD. et al. Targeted deletion of PD-1 in myeloid cells induces antitumor immunity. Sci Immunol 2020; 5 (43) 1863
9 Jiang X, Shapiro DJ. The immune system and inflammation in breast cancer. Mol Cell Endocrinol 2014; 382 (01) 673-682
10 Yang H, Yao Z, Zhou X, Zhang W, Zhang X, Zhang F. Immune-related adverse events of checkpoint inhibitors: insights into immunological dysregulation. Clin Immunol 2020; 213: 108377
11 Triantafyllou E, Gudd CLC, Mawhin MA. et al. PD-1 blockade improves Kupffer cell bacterial clearance in acute liver injury. J Clin Invest 2021; 131 (04) e140196
12 Singanayagam A, Triantafyllou E. Macrophages in chronic liver failure: diversity, plasticity and therapeutic targeting. Front Immunol 2021; 12: 661182
13 De Martin E, Michot JM, Papouin B. et al. Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors. J Hepatol 2018; 68 (06) 1181-1190
14 De Martin E, Michot JM, Rosmorduc O, Guettier C, Samuel D. Liver toxicity as a limiting factor to the increasing use of immune checkpoint inhibitors. JHEP Rep Innov Hepatol 2020; 2 (06) 100170
15 Johncilla M, Misdraji J, Pratt DS. et al. Ipilimumab-associated hepatitis: clinicopathologic characterization in a series of 11 cases. Am J Surg Pathol 2015; 39 (08) 1075-1084
16 Bhave P, Buckle A, Sandhu S, Sood S. Mortality due to immunotherapy related hepatitis. J Hepatol 2018; 69 (04) 976-978
17 Sarmen S, Tara S. Acute liver failure from anti-PD-1 antibody nivolumab in a patient with metastatic lung squamous cell carcinoma. Austin Oncol 2016; 1 (02) 2-4
18 Zen Y, Yeh MM. Hepatotoxicity of immune checkpoint inhibitors: a histology study of seven cases in comparison with autoimmune hepatitis and idiosyncratic drug-induced liver injury. Mod Pathol 2018; 31 (06) 965-973
19 Karamchandani DM, Chetty R. Immune checkpoint inhibitor-induced gastrointestinal and hepatic injury: pathologists' perspective. J Clin Pathol 2018; 71 (08) 665-671
20 Fujimura T, Sato Y, Tanita K. et al. Serum levels of soluble CD163 and CXCL5 may be predictive markers for immune-related adverse events in patients with advanced melanoma treated with nivolumab: a pilot study. Oncotarget 2018; 9 (21) 15542-15551
21 Taherian M, Chatterjee D, Wang H. Immune checkpoint inhibitor-induced hepatic injury: a clinicopathologic review. J Clin Transl Pathol 2022; 2 (03) 83-90
22 Gudd CLC, Au L, Triantafyllou E. et al. Activation and transcriptional profile of monocytes and CD8⁺ T cells are altered in checkpoint inhibitor-related hepatitis. J Hepatol 2021; 75 (01) 177-189
23 McElroy AK, Shrivastava-Ranjan P, Harmon JR. et al. Macrophage activation marker soluble CD163 associated with fatal and severe Ebola virus disease in humans. Emerg Infect Dis 2019; 25 (02) 290-298
24 Adam K, Iuga A, Tocheva AS, Mor A. A novel mouse model for checkpoint inhibitor-induced adverse events. PLoS One 2021; 16 (02) e0246168
25 Affolter T, Llewellyn HP, Bartlett DW. et al. Inhibition of immune checkpoints PD-1, CTLA-4, and IDO1 coordinately induces immune-mediated liver injury in mice. PLoS One 2019; 14 (05) e0217276
26 Llewellyn HP, Arat S, Gao J. et al. T cells and monocyte-derived myeloid cells mediate immunotherapy-related hepatitis in a mouse model. J Hepatol 2021; 75 (05) 1083-1095
27 Ramos-Casals M, Brahmer JR, Callahan MK. et al. Immune-related adverse events of checkpoint inhibitors. Nat Rev Dis Primers 2020; 6 (01) 38
28 Hoofnagle JH, Björnsson ES. Drug-induced liver injury - types and phenotypes. N Engl J Med 2019; 381 (03) 264-273
29 Liu Z, Zhu Y, Xie H, Zou Z. Immune-mediated hepatitis induced by immune checkpoint inhibitors: current updates and future perspectives. Front Pharmacol 2023; 13: 1077468
30 Cunningham M, Gupta R, Butler M. Checkpoint inhibitor hepatotoxicity: pathogenesis and management. Hepatology 2022
31 Suzman DL, Pelosof L, Rosenberg A, Avigan MI. Hepatotoxicity of immune checkpoint inhibitors: an evolving picture of risk associated with a vital class of immunotherapy agents. Liver Int 2018; 38 (06) 976-987
32 Brown LJ, Weppler A, Bhave P. et al. Combination anti-PD1 and ipilimumab therapy in patients with advanced melanoma and pre-existing autoimmune disorders. J Immunother Cancer 2021; 9 (05) e002121
33 Menzies AM, Johnson DB, Ramanujam S. et al. Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab. Ann Oncol 2017; 28 (02) 368-376
34 Atallah E, Welsh SJ, O'Carrigan B. et al. Incidence, risk factors and outcomes of checkpoint inhibitor-induced liver injury: a 10-year real-world retrospective cohort study. JHEP Rep 2023; 5 (10) 100851
35 Wang W, Lie P, Guo M, He J. Risk of hepatotoxicity in cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis of published data. Int J Cancer 2017; 141 (05) 1018-1028
36 Rose LM, DeBerg HA, Vishnu P. et al. Incidence of skin and respiratory immune-related adverse events correlates with specific tumor types in patients treated with checkpoint inhibitors. Front Oncol 2021; 10: 570752
37 El-Khoueiry AB, Sangro B, Yau T. et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 2017; 389 (10088): 2492-2502
38 Peeraphatdit TB, Wang J, Odenwald MA, Hu S, Hart J, Charlton MR. Hepatotoxicity from immune checkpoint inhibitors: a systematic review and management recommendation. Hepatology 2020; 72 (01) 315-329
39 Arnaud-Coffin P, Maillet D, Gan HK. et al. A systematic review of adverse events in randomized trials assessing immune checkpoint inhibitors. Int J Cancer 2019; 145 (03) 639-648
40 D'Alessio A, Fulgenzi CAM, Nishida N. et al. Preliminary evidence of safety and tolerability of atezolizumab plus bevacizumab in patients with hepatocellular carcinoma and Child-Pugh A and B cirrhosis: a real-world study. Hepatology 2022; 76 (04) 1000-1012
41 Finn RS, Qin S, Ikeda M. et al; IMbrave150 Investigators. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 2020; 382 (20) 1894-1905
42 Cheng AL, Qin S, Ikeda M. et al. Updated efficacy and safety data from IMbrave150: atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J Hepatol 2022; 76 (04) 862-873
43 Sangro B, Chan SL, Meyer T, Reig M, El-Khoueiry A, Galle PR. Diagnosis and management of toxicities of immune checkpoint inhibitors in hepatocellular carcinoma. J Hepatol 2020; 72 (02) 320-341
44 Papatheodoridis GV, Lekakis V, Voulgaris T. et al. Hepatitis B virus reactivation associated with new classes of immunosuppressants and immunomodulators: a systematic review, meta-analysis, and expert opinion. J Hepatol 2022; 77 (06) 1670-1689
45 Cho YA, Han JM, Kang SY. et al. Analysis of risk factors for hepatotoxicity induced by immune checkpoint inhibitors. J Immunother 2021; 44 (01) 16-21
46 Schoenfeld AJ, Arbour KC, Rizvi H. et al. Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib. Ann Oncol 2019; 30 (05) 839-844
47 Yamaguchi O, Kaira K, Shinomiya S. et al. Pre-existing interstitial lung disease does not affect prognosis in non-small cell lung cancer patients with PD-L1 expression ≥50% on first-line pembrolizumab. Thorac Cancer 2021; 12 (03) 304-313
48 Da Cunha T, Wu GY, Vaziri H. Immunotherapy-induced hepatotoxicity: a review. J Clin Transl Hepatol 2022; 10 (06) 1194-1204
49 Riveiro-Barciela M, Muñoz-Couselo E, Fernandez-Sojo J, Diaz-Mejia N, Parra-López R, Buti M. Acute liver failure due to immune-mediated hepatitis successfully managed with plasma exchange: new settings call for new treatment strategies?. J Hepatol 2019; 70 (03) 564-566
50 Brahmer JR, Lacchetti C, Schneider BJ. et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2018; 36: 1714-1768
51 Hountondji L, De Matos CF, Lebossé F. et al. Clinical pattern of checkpoint inhibitor-induced liver injury in a multicenter cohort. JHEP Rep 2023; 39 (36) 100719
52 Imoto K, Kohjima M, Hioki T. et al. Clinical features of liver injury induced by immune checkpoint inhibitors in Japanese patients. Can J Gastroenterol Hepatol 2019;
53 Schneider BJ, Naidoo J, Santomasso BD. et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO Guideline Update. J Clin Oncol 2021; 5 (06) 4073-4126
54 Haanen JBAG, Carbonnel F, Robert C. et al; ESMO Guidelines Committee. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017; 28 (Suppl. 04) iv119-iv142
55 Dougan M, Wang Y, Rubio-Tapia A, Lim JK. AGA clinical practice update on diagnosis and management of immune checkpoint inhibitor colitis and hepatitis: expert review. Gastroenterology 2021; 160 (04) 1384-1393
56 Tsung I, Dolan R, Lao CD. et al. Liver injury is most commonly due to hepatic metastases rather than drug hepatotoxicity during pembrolizumab immunotherapy. Aliment Pharmacol Ther 2019; 50 (07) 800-808
57 Shroff GS, Shroff S, Ahuja J, Truong MT, Vlahos I. Imaging spectrum of adverse events of immune checkpoint inhibitors. Clin Radiol 2021; 76 (04) 262-272
58 Tirumani SH, Ramaiya NH, Keraliya A. et al. Radiographic profiling of immune-related adverse events in advanced melanoma patients treated with ipilimumab. Cancer Immunol Res 2015; 3 (10) 1185-1192
59 Li M, Sack JS, Bell P. et al. Utility of liver biopsy in diagnosis and management of high-grade immune checkpoint inhibitor hepatitis in patients with cancer. JAMA Oncol 2021; 7 (11) 1711-1714
60 Cohen JV, Dougan M, Zubiri L, Reynolds KL, Sullivan RJ, Misdraji J. Liver biopsy findings in patients on immune checkpoint inhibitors. Mod Pathol 2021; 34 (02) 426-437
61 Bessone F, Bjornsson ES. Checkpoint inhibitor-induced hepatotoxicity: role of liver biopsy and management approach. World J Hepatol 2022; 14 (07) 1269-1276
62 Puzanov I, Diab A, Abdallah K. et al; Society for Immunotherapy of Cancer Toxicity Management Working Group. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer 2017; 5 (01) 95
63 European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu, Clinical Practice Guideline Panel: Chair, Panel members, EASL Governing Board representative. EASL Clinical Practice Guidelines: drug-induced liver injury. J Hepatol 2019; 70 (06) 1222-1261
64 Li M, Wong D, Vogel AS. et al. Effect of corticosteroid dosing on outcomes in high-grade immune checkpoint inhibitor hepatitis. Hepatology 2022; 75 (03) 531-540
65 Del Castillo M, Romero FA, Argüello E, Kyi C, Postow MA, Redelman-Sidi G. The spectrum of serious infections among patients receiving immune checkpoint blockade for the treatment of melanoma. Clin Infect Dis 2016; 63 (11) 1490-1493
66 Miller ED, Abu-Sbeih H, Styskel B. et al. Clinical characteristics and adverse impact of hepatotoxicity due to immune checkpoint inhibitors. Am J Gastroenterol 2020; 115 (02) 251-261
67 Gauci ML, Baroudjian B, Zeboulon C. et al; PATIO group. Immune-related hepatitis with immunotherapy: are corticosteroids always needed?. J Hepatol 2018; 69 (02) 548-550
68 Cheung V, Gupta T, Payne M. et al. Immunotherapy-related hepatitis: real-world experience from a tertiary centre. Frontline Gastroenterol 2019; 10 (04) 364-371
69 Ziogas DC, Gkoufa A, Cholongitas E. et al. When steroids are not enough in immune-related hepatitis: current clinical challenges discussed on the basis of a case report. J Immunother Cancer 2020; 8 (02) e001322
70 Xing H, Wang Y, Qu B. et al. The current status of steroid-refractory immune-checkpoint-inhibitor-related hepatotoxicity. Transl Oncol 2023; 28: 101619
71 Corrigan M, Haydon G, Thompson F. et al. Infliximab for the treatment of refractory immune-related hepatitis secondary to checkpoint inhibitors: a case report. JHEP Rep Innov Hepatol 2019; 1 (01) 66-69
72 Reddy HG, Schneider BJ, Tai AW. Immune checkpoint inhibitor-associated colitis and hepatitis. Clin Transl Gastroenterol 2018; 9 (09) 180
73 Moi L, Bouchaab H, Mederos N. et al. Personalized cytokine-directed therapy with tocilizumab for refractory immune checkpoint inhibitor-related cholangiohepatitis. J Thorac Oncol 2021; 16 (02) 318-326
74 Onishi S, Tajika M, Bando H. et al. Ursodeoxycholic acid and bezafibrate were useful for steroid-refractory, immune-related hepatitis: a case report. J Med Case Rep 2020; 14 (01) 230
75 Katsumoto TR, Wilson KL, Giri VK. et al. Plasma exchange for severe immune-related adverse events from checkpoint inhibitors: an early window of opportunity?. Immunother Adv 2022; 2 (01) ltac012
76 Riveiro-Barciela M, Barreira-Díaz A, Callejo-Pérez A. et al. Retreatment with immune checkpoint inhibitors after a severe immune-related hepatitis: results from a prospective multicenter study. Clin Gastroenterol Hepatol 2023; 21 (03) 732-740
77 Li M, Sack JS, Rahma OE, Hodi FS, Zucker SD, Grover S. Outcomes after resumption of immune checkpoint inhibitor therapy after high-grade immune-mediated hepatitis. Cancer 2020; 126 (23) 5088-5097
78 Malnick SDH, Abdullah A, Neuman MG. Checkpoint inhibitors and hepatotoxicity. Biomedicines 2021; 9 (02) 1-18
79 Ziemer M, Koukoulioti E, Beyer S, Simon JC, Berg T. Managing immune checkpoint-inhibitor-induced severe autoimmune-like hepatitis by liver-directed topical steroids. J Hepatol 2017; 66 (03) 657-659
80 Wang DY, Salem JE, Cohen JV. et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol 2018; 4 (12) 1721-1728
81 Weber J, Thompson JA, Hamid O. et al. A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res 2009; 15 (17) 5591-5598
82 Hodi FS, O'Day SJ, McDermott DF. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363 (08) 711-723
83 Wolchok JD, Neyns B, Linette G. et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol 2010; 11 (02) 155-164
84 Ribas A, Kefford R, Marshall MA. et al. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol 2013; 31 (05) 616-622
85 Kwon ED, Drake CG, Scher HI. et al; CA184-043 Investigators. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol 2014; 15 (07) 700-712
86 Robert C, Schachter J, Long GV. et al; KEYNOTE-006 investigators. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 2015; 372 (26) 2521-2532
87 Larkin J, Chiarion-Sileni V, Gonzalez R. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015; 373 (01) 23-34
88 Eggermont AMM, Chiarion-Sileni V, Grob JJ. et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med 2016; 375 (19) 1845-1855
89 Weber J, Mandala M, Del Vecchio M. et al; CheckMate 238 Collaborators. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med 2017; 377 (19) 1824-1835
90 Hodi FS, Chiarion-Sileni V, Gonzalez R. et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol 2018; 19 (11) 1480-1492
91 Aamdal E, Jacobsen KD, Straume O. et al. Ipilimumab in a real-world population: a prospective phase IV trial with long-term follow-up. Int J Cancer 2022; 150 (01) 100-111
92 Wolchok JD, Chiarion-Sileni V, Gonzalez R. et al. Long-term outcomes with nivolumab plus ipilimumab or nivolumab alone versus ipilimumab in patients with advanced melanoma. J Clin Oncol 2022; 40 (02) 127-137
93 Brahmer J, Reckamp KL, Baas P. et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015; 373 (02) 123-135
94 Borghaei H, Paz-Ares L, Horn L. et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015; 373 (17) 1627-1639
95 Kang YK, Boku N, Satoh T. et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017; 390 (10111): 2461-2471
96 Kelly RJ, Ajani JA, Kuzdzal J. et al; CheckMate 577 Investigators. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer. N Engl J Med 2021; 384 (13) 1191-1203
97 Bajorin DF, Witjes JA, Gschwend JE. et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N Engl J Med 2021; 384 (22) 2102-2114
98 Janjigian YY, Shitara K, Moehler M. et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet 2021; 398 (10294): 27-40
99 Tawbi HA, Schadendorf D, Lipson EJ. et al; RELATIVITY-047 Investigators. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med 2022; 386 (01) 24-34
100 Paz-Ares LG, Ramalingam SS, Ciuleanu TE. et al. First-line nivolumab plus ipilimumab in advanced NSCLC: 4-year outcomes from the randomized, open-label, phase 3 CheckMate 227 part 1 trial. J Thorac Oncol 2022; 17 (02) 289-308
101 Garon EB, Rizvi NA, Hui R. et al; KEYNOTE-001 Investigators. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015; 372 (21) 2018-2028
102 Herbst RS, Baas P, Kim DW. et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 2016; 387 (10027): 1540-1550
103 Reck M, Rodríguez-Abreu D, Robinson AG. et al; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 2016; 375 (19) 1823-1833
104 Eggermont AMM, Blank CU, Mandala M. et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med 2018; 378 (19) 1789-1801
105 Zhu AX, Finn RS, Edeline J. et al; KEYNOTE-224 investigators. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol 2018; 19 (07) 940-952
106 Finn RS, Ryoo BY, Merle P. et al; KEYNOTE-240 investigators. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III trial. J Clin Oncol 2020; 38 (03) 193-202
107 André T, Shiu KK, Kim TW. et al; KEYNOTE-177 Investigators. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med 2020; 383 (23) 2207-2218
108 Choueiri TK, Larkin J, Oya M. et al. Preliminary results for avelumab plus axitinib as first-line therapy in patients with advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100): an open-label, dose-finding and dose-expansion, phase 1b trial. Lancet Oncol 2018; 19 (04) 451-460
109 Powles T, van der Heijden MS, Castellano D. et al; DANUBE study investigators. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol 2020; 21 (12) 1574-1588
110 Jotte R, Cappuzzo F, Vynnychenko I. et al. Atezolizumab in combination with carboplatin and nab-paclitaxel in advanced squamous NSCLC (IMpower131): results from a randomized phase III trial. J Thorac Oncol 2020; 15 (08) 1351-1360
111 Bellmunt J, Hussain M, Gschwend JE. et al; IMvigor010 Study Group. Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2021; 22 (04) 525-537
112 Cho BC, Abreu DR, Hussein M. et al. Tiragolumab plus atezolizumab versus placebo plus atezolizumab as a first-line treatment for PD-L1-selected non-small-cell lung cancer (CITYSCAPE): primary and follow-up analyses of a randomised, double-blind, phase 2 study. Lancet Oncol 2022; 23 (06) 781-792
113 Postow MA, Chesney J, Pavlick AC. et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 2015; 372 (21) 2006-2017
114 Long GV, Atkinson V, Cebon JS. et al. Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial. Lancet Oncol 2017; 18 (09) 1202-1210
115 Yau T, Kang YK, Kim TY. et al. Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib: the CheckMate 040 randomized clinical trial. JAMA Oncol 2020; 6 (11) e204564
116 Boyer M, Şendur MAN, Rodríguez-Abreu D. et al; KEYNOTE-598 Investigators. Pembrolizumab plus ipilimumab or placebo for metastatic non-small-cell lung cancer with PD-L1 tumor proportion score ≥ 50%: randomized, double-blind phase III KEYNOTE-598 study. J Clin Oncol 2021; 39 (21) 2327-2338