Immune-related Adverse Events: Overview and Management Strategies for the Use of Immune Checkpoint Inhibitors

Hei-Cheul Jeung; Se Eung Oh; Jee Hung Kim

doi:10.4078/jrd.2019.26.4.221

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Jeung, Oh, and Kim: Immune-related Adverse Events: Overview and Management Strategies for the Use of Immune Checkpoint Inhibitors

Review Article

J Rheum Dis 2019;26(4):221-234.

Published online: 31 October 2019

DOI: https://doi.org/10.4078/jrd.2019.26.4.221

Immune-related Adverse Events: Overview and Management Strategies for the Use of Immune Checkpoint Inhibitors

Hei-Cheul Jeung, Se Eung Oh, Jee Hung Kim

Division of Medical Oncology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea

Corresponding to: Hei-Cheul Jeung http://orcid.org/0000-0003-0952-3679 Division of Medical Oncology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul 06237, Korea. E-mail: jeunghc1123@yuhs.ac

Received 15 April 20194 July 2019 Accepted 6 July 2019

This is a Open Access article, which permits unrestricted non-commerical use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Recent studies on T cell immunology have been instrumental in developing therapies to overcome cancer immune escape, and immune checkpoint inhibitors have emerged as one of the most promising therapeutic tools in advanced cancer patients. Immune checkpoint inhibitors (ICPIs) are monoclonal antibodies that modulate the effects of immune checkpoints. These include cytotoxic T lymphocyte antigen 4 and programmed cell death protein 1, which are co-inhibitory signals responsible for immune suppression. Despite their clinical benefits, ICPIs behave as general immune activators, exerting to several toxic effects called immune-related adverse events attributed to organ-specific inflammation. Here, we review ICPI toxicities, highlighting the importance of their early identification and proper management.

Keywords: Immune checkpoint inhibitors, Immune-related adverse events, Adrenal cortex hormones, Programmed cell death protein 1, CTLA-4 antigen

REFERENCES

1. Lesterhuis WJ, Haanen JB, Punt CJ. Cancer immunotherapy– revisited. Nat Rev Drug Discov. 2011; 10:591–600.

2. Dolan DE, Gupta S. PD-1 pathway inhibitors: changing the landscape of cancer immunotherapy. Cancer Control. 2014; 21:231–7.

3. Sharma P, Allison JP. The future of immune checkpoint therapy. Science. 2015; 348:56–61.

4. Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015; 27:450–61.

5. Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol. 2004; 22:329–60.

6. Linsley PS, Brady W, Urnes M, Grosmaire LS, Damle NK, Ledbetter JA. CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med. 1991; 174:561–9.

7. Sznol M, Chen L. Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer– response. Clin Cancer Res. 2013; 19:5542.

8. Xu C, Chen YP, Du XJ, Liu JQ, Huang CL, Chen L, et al. Comparative safety of immune checkpoint inhibitors in cancer: systematic review and network meta-analysis. BMJ. 2018; 363:k4226.

9. Weber JS, Antonia SJ, Topalian SL, Schadendorf D, Larkin JMG, Sznol M, et al. Safety profile of nivolumab (NIVO) in patients (pts) with advanced melanoma (MEL): a pooled analysis. J Clin Oncol. 2015; 33(15 Suppl):9018.

10. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010; 363:711–23.

11. Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012; 30:2691–7.

12. O'Day SJ, Maio M, Chiarion-Sileni V, Gajewski TF, Pehamberger H, Bondarenko IN, et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol. 2010; 21:1712–7.

13. Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015; 372:320–30.

14. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012; 366:2443–54.

15. Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYN OTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015; 16:908–18.

16. Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014; 384:1109–17.

17. Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol. 2014; 32:1020–30.

18. Immunemediated adverse reactions management guide [Internet]. Princeton (NJ): Bristol-Myers Squibb;2013. [cited 2019 Mar 20]. Available from:. http://www.hcp.yervoy.com/servlet/servlet.FileDownload?file=00Pi000000PI1ZVEA1.

19. Haanen JBAG, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, 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_4):iv119–42.

20. ESMO Guidelines Methodology [Internet]. Lugano: ESMO;2019. [cited 2019 Mar 20]. Available from:. https://www.esmo.org/Guidelines/ESMO-Guidelines-Methodology.

21. Michot JM, Bigenwald C, Champiat S, Collins M, Carbonnel F, Postel-Vinay S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer. 2016; 54:139–48.

22. Curry JL, Tetzlaff MT, Nagarajan P, Drucker C, Diab A, Hymes SR, et al. Diverse types of dermatologic toxicities from immune checkpoint blockade therapy. J Cutan Pathol. 2017; 44:158–76.

23. Villadolid J, Amin A. Immune checkpoint inhibitors in clinical practice: update on management of immune-related toxicities. Transl Lung Cancer Res. 2015; 4:560–75.

24. Hodi FS, Mihm MC, Soiffer RJ, Haluska FG, Butler M, Seiden MV, et al. Biologic activity of cytotoxic T lympho-cyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci U S A. 2003; 100:4712–7.

25. Bristol-Myers Squibb. Yervoy (Ipilimumab) injection [Internet]. Princeton (NJ): Bristol-Myers Squibb;2015. [cited 2019 Feb 20]. Available from:. http://packageinserts.bms.com/pi/pi_yervoy.xml.

26. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015; 373:23–34.

27. Naidoo J, Page DB, Li BT, Connell LC, Schindler K, Lacouture ME, et al. Toxicities of the anti-PD-1 and an-ti-PD-L1 immune checkpoint antibodies. Ann Oncol. 2015; 26:2375–91.

28. Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015; 373:123–35.

29. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015; 373:1803–13.

30. Hua C, Boussemart L, Mateus C, Routier E, Boutros C, Cazenave H, et al. Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab. JAMA Dermatol. 2016; 152:45–51.

31. Merck Sharp & Dohme Corp. Highlights of prescribing information [Internet]. County Cork: Merck Sharp & Dohme Corp;2015. [cited 2019 Feb 20]. Available from:. http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.xml.

32. Berman D, Parker SM, Siegel J, Chasalow SD, Weber J, Galbraith S, et al. Blockade of cytotoxic T-lymphocyte antigen-4 by ipilimumab results in dysregulation of gastrointestinal immunity in patients with advanced melanoma. Cancer Immun. 2010; 10:11.

33. Kim KW, Ramaiya NH, Krajewski KM, Shinagare AB, Howard SA, Jagannathan JP, et al. Ipilimumab-associated colitis: CT findings. AJR Am J Roentgenol. 2013; 200:W468–74.

34. Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after an-ti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015; 16:375–84.

35. Weber JS, Kudchadkar RR, Yu B, Gallenstein D, Horak CE, Inzunza HD, et al. Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. J Clin Oncol. 2013; 31:4311–8.

36. Fecher LA, Agarwala SS, Hodi FS, Weber JS. Ipilimumab and its toxicities: a multidisciplinary approach. Oncologist. 2013; 18:733–43.

37. Minor DR, Chin K, Kashani-Sabet M. Infliximab in the treatment of anti-CTLA4 antibody (ipilimumab) induced immune-related colitis. Cancer Biother Radiopharm. 2009; 24:321–5.

38. Spain L, Diem S, Larkin J. Management of toxicities of immune checkpoint inhibitors. Cancer Treat Rev. 2016; 44:51–60.

39. Corsello SM, Barnabei A, Marchetti P, De Vecchis L, Salvatori R, Torino F. Endocrine side effects induced by immune checkpoint inhibitors. J Clin Endocrinol Metab. 2013; 98:1361–75.

40. Corsello SM, Salvatori R, Barnabei A, De Vecchis L, Marchetti P, Torino F. Ipilimumab-induced endocrinopathies: when to start corticosteroids (or not). Cancer Chemother Pharmacol. 2013; 72:489–90.

41. Torino F, Corsello SM, Salvatori R. Endocrinological side-effects of immune checkpoint inhibitors. Curr Opin Oncol. 2016; 28:278–87.

42. Ribas A, Kefford R, Marshall MA, Punt CJ, Haanen JB, Marmol M, et al. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol. 2013; 31:616–22.

43. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015; 372:2521–32.

44. Weber JS, Yang JC, Atkins MB, Disis ML. Toxicities of immunotherapy for the practitioner. J Clin Oncol. 2015; 33:2092–9.

45. Ryder M, Callahan M, Postow MA, Wolchok J, Fagin JA. Endocrine-related adverse events following ipilimumab in patients with advanced melanoma: a comprehensive retrospective review from a single institution. Endocr Relat Cancer. 2014; 21:371–81.

46. Iwama S, De Remigis A, Callahan MK, Slovin SF, Wolchok JD, Caturegli P. Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody. Sci Transl Med. 2014; 6:230ra45.

47. Dillard T, Yedinak CG, Alumkal J, Fleseriu M. Anti-CTLA-4 antibody therapy associated autoimmune hypophysitis: serious immune related adverse events across a spectrum of cancer subtypes. Pituitary. 2010; 13:29–38.

48. Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015; 16:522–30.

49. Tabchi S, Messier C, Blais N. Immunemediated respiratory adverse events of checkpoint inhibitors. Curr Opin Oncol. 2016; 28:269–77.

50. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus docetaxel in advanced non-squamous non-small-cell lung cancer. N Engl J Med. 2015; 373:1627–39.

51. Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, 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; 387:1540–50.

52. Nishino M, Sholl LM, Hodi FS, Hatabu H, Ramaiya NH. Anti-PD-1-related pneumonitis during cancer immunotherapy. N Engl J Med. 2015; 373:288–90.

53. Vogel WV, Guislain A, Kvistborg P, Schumacher TN, Haanen JB, Blank CU. Ipilimumab-induced sarcoidosis in a patient with metastatic melanoma undergoing complete remission. J Clin Oncol. 2012; 30:e7–10.

54. Eckert A, Schoeffler A, Dalle S, Phan A, Kiakouama L, Thomas L. Anti-CTLA4 monoclonal antibody induced sarcoidosis in a metastatic melanoma patient. Dermatology. 2009; 218:69–70.

55. Wilgenhof S, Morlion V, Seghers AC, Du Four S, Vanderlinden E, Hanon S, et al. Sarcoidosis in a patient with metastatic melanoma sequentially treated with anti-CTLA-4 monoclonal antibody and selective BRAF inhibitor. Anticancer Res. 2012; 32:1355–9.

56. Rizvi NA, Mazières J, Planchard D, Stinchcombe TE, Dy GK, Antonia SJ, et al. Activity and safety of nivolumab, an an-ti-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 Oncol. 2015; 16:257–65.

57. Izzedine H, Gueutin V, Gharbi C, Mateus C, Robert C, Routier E, et al. Kidney injuries related to ipilimumab. Invest New Drugs. 2014; 32:769–73.

58. Fadel F, El Karoui K, Knebelmann B. Anti-CTLA4 anti-body-induced lupus nephritis. N Engl J Med. 2009; 361:211–2.

59. Bristol-Myers Squibb. Highlights of prescribing information [Internet]. Princeton (NJ): Bristol-Myers Squibb;2015. [cited 2019 Feb 20]. Available from:. http://packageinserts.bms.com/pi/pi_opdivo.xml.

60. Wilgenhof S, Neyns B. Anti-CTLA-4 antibody-induced Guillain-Barré syndrome in a melanoma patient. Ann Oncol. 2011; 22:991–3.

61. Cappelli LC, Gutierrez AK, Bingham CO 3rd, Shah AA. Rheumatic and musculoskeletal immune-related adverse events due to immune checkpoint inhibitors: a systematic review of the literature. Arthritis Care Res (Hoboken). 2017; 69:1751–63.

62. Goldstein BL, Gedmintas L, Todd DJ. Drug-associated polymyalgia rheumatica/giant cell arteritis occurring in two patients after treatment with ipilimumab, an antagonist of ctla-4. Arthritis Rheumatol. 2014; 66:768–9.

63. Belkhir R, Burel SL, Dunogeant L, Marabelle A, Hollebecque A, Besse B, et al. Rheumatoid arthritis and polymyalgia rheumatica occurring after immune checkpoint inhibitor treatment. Ann Rheum Dis. 2017; 76:1747–50.

64. Benfaremo D, Manfredi L, Luchetti MM, Gabrielli A. Musculoskeletal and rheumatic diseases induced by immune checkpoint inhibitors: a review of the literature. Curr Drug Saf. 2018; 13:150–64.

65. Calabrese LH, Calabrese C, Cappelli LC. Rheumatic immune-related adverse events from cancer immunotherapy. Nat Rev Rheumatol. 2018; 14:569–79.

66. Simeone E, Grimaldi AM, Esposito A, Curvietto M, Palla M, Paone M, et al. Serious haematological toxicity during and after ipilimumab treatment: a case series. J Med Case Rep. 2014; 8:240.

67. Delyon J, Mateus C, Lambert T. Hemophilia A induced by ipilimumab. N Engl J Med. 2011; 365:1747–8.

68. Vogel WV, Guislain A, Kvistborg P, Schumacher TN, Haanen JB, Blank CU. Ipilimumab-induced sarcoidosis in a patient with metastatic melanoma undergoing complete remission. J Clin Oncol. 2012; 30:e7–10.

69. Tissot C, Carsin A, Freymond N, Pacheco Y, Devouassoux G. Sarcoidosis complicating anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody biotherapy. Eur Respir J. 2013; 41:246–7.

70. Andersen R, Nørgaard P, Al-Jailawi MK, Svane IM. Late development of splenic sarcoidosis-like lesions in a patient with metastatic melanoma and long-lasting clinical response to ipilimumab. Oncoimmunology. 2014; 3:e954506.

Table 1.

General management guideline of immune-related adverse events

Severity CTCAE grade	Type of patient care	Use of steroid	Use of additional immunosuppressive agents	Continuation of next cycle immunotherapy	Other medication
1	Outpatient	Generally, not necessary	Not recommended	Continue	Not recommended
2	Outpatient	Topical steroids or oral steroids: Prednisone 0.5∼1 mg/kg/d	Not recommended	Suspend temporarily: outside skin or endocrine disorders, where immunotherapy can be maintained	Not recommended
3∼4	Consider hospitalization according to the specific case	IV or oral steroids; prednisone or methylprednisolone 1∼2 mg/kg/d for 48∼72 hours, then reduce to 1 mg/kg/d; course of generally 2∼4 weeks; steroids must be reduced gradually over a period of at least 1 month	Considered administration of infliximab (5 mg/Kg) and eventually repeat after 14 days; Consider mycophenolate mofetil (500 mg every 12 h)	Skipping a dose of immunotherapy or discontinuing the immunotherapy can be considered, depending on the benefit/risk ratio of each given situation; If grade 4 toxicity occurs, discontinue permanently r	If a dose equivalent to 20 mg of prednisone is administered for over 4 weeks, consider prophylaxis for pneumocystis infections with trimethoprim/ sulfamethoxazole (80+40 mg/d or 160/800 mg TIW)

CTCAE: common terminology criteria for adverse events, TIW: 3 times a week.

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