Comparative safety of immune checkpoint inhibitors in cancer: Systematic review and network meta-analysis

BMJ (Online)

Volumn 363, Issue , 2018, Pages

  Xu, Cheng ^a   Chen, Yu Pei ^a   Du, Xiao Jing ^a   Liu, Jin Qi ^a   Huang, Cheng Long ^a   Chen, Lei ^a   Zhou, Guan Qun ^a   Li, Wen Fei ^a   Mao, Yan Ping ^a   Hsu, Chiun ^b   Liu, Qing ^c   Lin, Ai Hua ^c   Tang, Ling Long ^a   Sun, Ying ^a   Ma, Jun ^a  

^a SUN YAT SEN UNIVERSITY CANCER CENTER   (China)

^b NATIONAL TAIWAN UNIVERSITY HOSPITAL   (Taiwan)

^c SUN YAT SEN UNIVERSITY   (China)

Author keywords

[No Author keywords available]

Indexed keywords

ALANINE AMINOTRANSFERASE; ASPARTATE AMINOTRANSFERASE; ATEZOLIZUMAB; IMMUNE CHECKPOINT INHIBITOR; IMMUNOLOGICAL ANTINEOPLASTIC AGENT; IPILIMUMAB; NIVOLUMAB; PEMBROLIZUMAB; PLACEBO; TICILIMUMAB; UNCLASSIFIED DRUG; ANTINEOPLASTIC AGENT; MONOCLONAL ANTIBODY;

ARTHRALGIA; ARTICLE; COLITIS; DIARRHEA; DRUG EFFICACY; DRUG SAFETY; ENDOCRINE DISEASE; EVIDENCE BASED MEDICINE; FATIGUE; GASTROINTESTINAL SYMPTOM; HUMAN; HYPERTHYROIDISM; HYPERTRANSAMINASEMIA; HYPOTHYROIDISM; LIVER DISEASE; LIVER TOXICITY; LUNG CANCER; LUNG DISEASE; MALIGNANT NEOPLASM; META ANALYSIS; NAUSEA; NEPHROTOXICITY; NETWORK META ANALYSIS; OUTCOME ASSESSMENT; PNEUMONIA; PRIORITY JOURNAL; PRURITUS; RASH; SKIN DISEASE; STUDY DESIGN; SYSTEMATIC REVIEW; VALIDATION PROCESS; VOMITING; ADVERSE DRUG REACTION; IMMUNOLOGY; NEOPLASM; NETWORK META-ANALYSIS; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); RANDOMIZED CONTROLLED TRIAL (TOPIC);

ANTIBODIES, MONOCLONAL; ANTIBODIES, MONOCLONAL, HUMANIZED; ANTINEOPLASTIC AGENTS, IMMUNOLOGICAL; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; CLINICAL TRIALS, PHASE II AS TOPIC; CLINICAL TRIALS, PHASE III AS TOPIC; DRUG-RELATED SIDE EFFECTS AND ADVERSE REACTIONS; HUMANS; IPILIMUMAB; NEOPLASMS; NETWORK META-ANALYSIS; NIVOLUMAB; RANDOMIZED CONTROLLED TRIALS AS TOPIC;

EID: 85056330383     PISSN: 09598146     EISSN: 17561833     Source Type: Journal    
DOI: 10.1136/bmj.k4226     Document Type: Article

References (78)

1. Sharon E, Streicher H, Goncalves P, Chen HX. Immune checkpoint inhibitors in clinical trials. Chin J Cancer2014;33:434-44. doi:10.5732/cjc.014.10122
2. Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: moving beyond current vaccines. Nat Med2004;10:909-15. doi:10.1038/ nm1100
3. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer2012;12:252-64. doi:10.1038/ nrc3239
4. Friedman CF, Proverbs-Singh TA, Postow MA. Treatment of the Immune-Related Adverse Effects of Immune Checkpoint Inhibitors: A Review. JAMA Oncol2016;2:1346-53. doi:10.1001/ jamaoncol.2016.1051
5. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. version 2. 2018. https://www.nccn.org/professionals/ physician-gls/default.aspx.
6. Gangadhar TC, Vonderheide RH. Mitigating the toxic effects of anticancer immunotherapy. Nat Rev Clin Oncol2014;11:91-9. doi:10.1038/nrclinonc.2013.245
7. 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 Med2017;377:1824-35. doi:10.1056/NEJMoa1709030
8. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med2017;377:1345-56. doi:10.1056/ NEJMoa1709684
9. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med2015;373:23-34. doi:10.1056/ NEJMoa1504030
10. Robert C, Schachter J, Long GV, et al, KEYNOTE-006 investigators. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med2015;372:2521-32. doi:10.1056/ NEJMoa1503093
11. Schachter J, Ribas A, Long GV, et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet2017;390:1853-62. doi:10.1016/S0140-6736(17)31601-X
12. Rittmeyer A, Barlesi F, Waterkamp D, et al, OAK Study Group. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet2017;389:255-65. doi:10.1016/ S0140-6736(16)32517-X
13. Larkin J, Minor D, D'Angelo S, et al. Overall Survival in Patients With Advanced Melanoma Who Received Nivolumab Versus Investigator's Choice Chemotherapy in CheckMate 037: A Randomized, Controlled, Open-Label Phase III Trial. J Clin Oncol2018;36:383-90. doi:10.1200/JCO.2016.71.8023
14. Weber JS, D'Angelo SP, Minor D, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol2015;16:375-84. doi:10.1016/S1470-2045(15)70076-8
15. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med2011;364:2517-26. doi:10.1056/NEJMoa1104621
16. Maio M, Grob JJ, Aamdal S, et al. Five-year survival rates for treatmentnaive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. J Clin Oncol2015;33:1191-6. doi:10.1200/JCO.2014.56.6018
17. Ferris RL, Blumenschein GJr, Fayette J, et al. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med2016;375:1856-67. doi:10.1056/NEJMoa1602252
18. Govindan R, Szczesna A, Ahn MJ, et al. Phase III Trial of Ipilimumab Combined With Paclitaxel and Carboplatin in Advanced Squamous Non-Small-Cell Lung Cancer. J Clin Oncol2017;35:3449-57. doi:10.1200/JCO.2016.71.7629
19. Motzer RJ, Escudier B, McDermott DF, et al, CheckMate 025 Investigators. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med2015;373:1803-13. doi:10.1056/ NEJMoa1510665
20. Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial. J Clin Oncol2015;33:1430-7. doi:10.1200/JCO.2014.59.0703
21. Carbone DP, Reck M, Paz-Ares L, et al, CheckMate 026 Investigators. First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer. N Engl J Med2017;376:2415-26. doi:10.1056/ NEJMoa1613493
22. Bellmunt J, de Wit R, Vaughn DJ, et al, KEYNOTE-045 Investigators. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med2017;376:1015-26. doi:10.1056/ NEJMoa1613683
23. Bang YJ, Cho JY, Kim YH, et al. Efficacy of Sequential Ipilimumab Monotherapy versus Best Supportive Care for Unresectable Locally Advanced/Metastatic Gastric or Gastroesophageal Junction Cancer. Clin Cancer Res2017;23:5671-8. doi:10.1158/1078-0432.CCR-17-0025
24. Ascierto PA, Del Vecchio M, Robert C, et al. Ipilimumab 10 mg/ kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol2017;18:611-22. doi:10.1016/S1470- 2045(17)30231-0
25. 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 Med2016;375:1823- 33. doi:10.1056/NEJMoa1606774
26. Reck M, Luft A, Szczesna A, et al. Phase III Randomized Trial of Ipilimumab Plus Etoposide and Platinum Versus Placebo Plus Etoposide and Platinum in Extensive-Stage Small-Cell Lung Cancer. J Clin Oncol2016;34:3740-8. doi:10.1200/JCO.2016.67.6601
27. Langer CJ, Gadgeel SM, Borghaei H, et al, KEYNOTE-021 investigators. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the openlabel KEYNOTE-021 study. Lancet Oncol2016;17:1497-508. doi:10.1016/S1470-2045(16)30498-3
28. Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med2015;372:2006-17. doi:10.1056/NEJMoa1414428
29. Hodi FS, Chesney J, Pavlick AC, et al. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol2016;17:1558-68. doi:10.1016/S1470-2045(16)30366-7
30. 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. Lancet2016;387:1540-50. doi:10.1016/ S0140-6736(15)01281-7
31. Fehrenbacher L, Spira A, Ballinger M, et al, POPLAR Study Group. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet2016;387:1837-46. doi:10.1016/S0140-6736(16)00587-0
32. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med2015;372:320-30. doi:10.1056/NEJMoa1412082
33. Ribas A, Puzanov I, Dummer R, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol2015;16:908-18. doi:10.1016/S1470- 2045(15)00083-2
34. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med2015;373:123-35. doi:10.1056/NEJMoa1504627
35. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med2015;373:1627-39. doi:10.1056/NEJMoa1507643
36. Powles T, Durán I, van der Heijden MS, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, openlabel, phase 3 randomised controlled trial. Lancet2018;391:748-57. doi:10.1016/S0140-6736(17)33297-X
37. 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 Oncol2013;31:616-22. doi:10.1200/JCO.2012.44.6112
38. Reck M, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-diseasesmall- cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial. Ann Oncol2013;24:75-83. doi:10.1093/ annonc/mds213
39. Lynch TJ, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/ IV non-small-cell lung cancer: results from a randomized, doubleblind, multicenter phase II study. J Clin Oncol2012;30:2046-54. doi:10.1200/JCO.2011.38.4032
40. Hersh EM, O'Day SJ, Powderly J, et al. A phase II multicenter study of ipilimumab with or without dacarbazine in chemotherapynaïve patients with advanced melanoma. Invest New Drugs2011;29:489-98. doi:10.1007/s10637-009-9376-8
41. Hamid O, Schmidt H, Nissan A, et al. A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J Transl Med2011;9:204. doi:10.1186/1479-5876-9-204
42. 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 Oncol2010;11:155-64. doi:10.1016/S1470-2045(09)70334-1
43. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med2012;366:2443-54. doi:10.1056/NEJMoa1200690
44. Nishino M, Sholl LM, Hodi FS, Hatabu H, Ramaiya NH. Anti-PD- 1-Related Pneumonitis during Cancer Immunotherapy. N Engl J Med2015;373:288-90. doi:10.1056/NEJMc1505197
45. Zou T, Awad MM. More valuable than platinum: first-line pembrolizumab in advanced stage non-small-cell lung cancer. Ann Oncol2017;28:685-7. doi:10.1093/annonc/mdx083
46. Wu J, Hong D, Zhang X, Lu X, Miao J. PD-1 inhibitors increase the incidence and risk of pneumonitis in cancer patients in a doseindependent manner: a meta-analysis. Sci Rep2017;7:44173. doi:10.1038/srep44173
47. 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 Cancer2017;141:1018-28. doi:10.1002/ijc.30678
48. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ2009;339:b2700. doi:10.1136/bmj.b2700
49. Hutton B, Salanti G, Caldwell DM, et al. The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann Intern Med2015;162:777-84. doi:10.7326/M14-2385
50. Common terminology criteria for adverse events ver.4.0. http:// www.eortc.be/services/doc/ctc/CTCAE-4.03-2010-06-14- QuickReference-5x7.pdf.
51. Higgins J, Green S. Cochrane handbook of systematic reviews of interventions.Cochrane Collaboration, John Wiley & Sons, 2008. doi:10.1002/9780470712184.
52. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials1996;17:1-12. doi:10.1016/0197-2456(95)00134-4
53. Chaimani A, Higgins JP, Mavridis D, Spyridonos P, Salanti G. Graphical tools for network meta-analysis in STATA. PLoS One2013;8:e76654. doi:10.1371/journal.pone.0076654
54. Sutton AJ, Abrams KR. Bayesian methods in meta-analysis and evidence synthesis. Stat Methods Med Res2001;10:277-303. doi:10.1177/096228020101000404
55. Mills EJ, Thorlund K, Ioannidis JP. Demystifying trial networks and network meta-analysis. BMJ2013;346:f2914. doi:10.1136/bmj.f2914
56. Brooks SP, Gelman A. General methods for monitoring convergence of iterative simulations. J Comput Graph Stat1998;7:434-55.
57. Lu G, Ades AE. Assessing evidence inconsistency in mixed treatment comparisons. J Am Stat Assoc2006;101:447-59. doi:10.1198/016214505000001302.
58. Dias S, Welton NJ, Caldwell DM, Ades AE. Checking consistency in mixed treatment comparison meta-analysis. Stat Med2010;29:932-44. doi:10.1002/sim.3767
59. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ2003;327:557-60. doi:10.1136/bmj.327.7414.557
60. Wallace BC, Schmid CH, Lau J, Trikalinos TA. Meta-Analyst: software for meta-analysis of binary, continuous and diagnostic data. BMC Med Res Methodol2009;9:80. doi:10.1186/1471-2288-9-80
61. 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 Oncol2014;15:700-12. doi:10.1016/S1470-2045(14)70189-5
62. 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, placebocontrolled, phase 3 trial. Lancet2017;390:2461-71. doi:10.1016/ S0140-6736(17)31827-5
63. Balar AV, Galsky MD, Rosenberg JE, et al, IMvigor210 Study Group. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet2017;389:67-76. doi:10.1016/S0140-6736(16)32455-2
64. Bauml J, Seiwert TY, Pfister DG, et al. Pembrolizumab for Platinumand Cetuximab-Refractory Head and Neck Cancer: Results From a Single-Arm, Phase II Study. J Clin Oncol2017;35:1542-9. doi:10.1200/JCO.2016.70.1524
65. Peters S, Gettinger S, Johnson ML, et al. Phase II Trial of Atezolizumab As First-Line or Subsequent Therapy for Patients With Programmed Death-Ligand 1-Selected Advanced Non-Small-Cell Lung Cancer (BIRCH). J Clin Oncol2017;35:2781-9. doi:10.1200/ JCO.2016.71.9476
66. Rizvi NA, Mazières J, Planchard D, et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol2015;16:257-65. doi:10.1016/S1470-2045(15)70054-9
67. Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinumbased chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet2016;387:1909-20. doi:10.1016/S0140-6736(16)00561-4
68. O'Day SJ, Maio M, Chiarion-Sileni V, et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol2010;21:1712-7. doi:10.1093/annonc/mdq013
69. Donegan S, Williamson P, D'Alessandro U, Tudur Smith C. Assessing key assumptions of network meta-analysis: a review of methods. Res Synth Methods2013;4:291-323. doi:10.1002/jrsm.1085
70. Abdel-Rahman O, Helbling D, Schmidt J, et al. Treatment-related Death in Cancer Patients Treated with Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis. Clin Oncol (R Coll Radiol)2017;29:218-30. doi:10.1016/j.clon.2016.11.007
71. Khoja L, Day D, Wei-Wu Chen T, Siu LL, Hansen AR. Tumourand class-specific patterns of immune-related adverse events of immune checkpoint inhibitors: a systematic review. Ann Oncol2017;28:2377-85. doi:10.1093/annonc/mdx286
72. Nishino M, Giobbie-Hurder A, Hatabu H, Ramaiya NH, Hodi FS. Incidence of Programmed Cell Death 1 Inhibitor-Related Pneumonitis in Patients With Advanced Cancer: A Systematic Review and Meta-analysis. JAMA Oncol2016;2:1607-16. doi:10.1001/ jamaoncol.2016.2453
73. Kirsch I, Moncrieff J. Clinical trials and the response rate illusion. Contemp Clin Trials2007;28:348-51. doi:10.1016/j.cct.2006. doi:10.012
74. Wu Y, Shi H, Jiang M, et al. The clinical value of combination of immune checkpoint inhibitors in cancer patients: A meta-analysis of efficacy and safety. Int J Cancer2017;141:2562-70. doi:10.1002/ ijc.31012
75. Sznol M, Ferrucci PF, Hogg D, et al. Pooled Analysis Safety Profile of Nivolumab and Ipilimumab Combination Therapy in Patients With Advanced Melanoma. J Clin Oncol2017;35:3815-22. doi:10.1200/ JCO.2016.72.1167
76. Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature2014;515:568-71. doi:10.1038/nature13954
77. Tan PS, Aguiar PJr, Haaland B, Lopes G. Comparative effectiveness of immune-checkpoint inhibitors for previously treated advanced non-small cell lung cancer - A systematic review and network meta-analysis of 3024 participants. Lung Cancer2018;115:84-8. doi:10.1016/j.lungcan.2017.11.017
78. Ma C, Armstrong AW. Severe adverse events from the treatment of advanced melanoma: a systematic review of severe side effects associated with ipilimumab, vemurafenib, interferon alfa-2b, dacarbazine and interleukin-2. J Dermatolog Treat2014;25:401-8. doi:10.3109/09546634. 2013.813897