Endocrine adverse events of immune checkpoint inhibitors: results of a single-center study
Abstract
Immune checkpoint inhibitors (ICPIs) agents can cause endocrine immune-related adverse events (irAEs).
Aim. Determine the incidence, time of onset and risk factors of endocrine irAEs in cancer patients treated with anti-PD1 and anti-CTLA-4 immunotherapy.
Materials and methods. This is a retrospective single-center study that included 61 patients aged 28 to 81 years with diagnosed cancer of the lungs, ovaries, esophagus, stomach, bladder, kidney, and pleural mesothelioma. 44 (72%) patients received anti-PDL1/anti-PD1 monotherapy and 17 (28%) received a combination of anti-PD1 + anti-CTLA-4. Calculated: odds ratio (OR) and 95% confidence interval (CI).
Results. The incidence of endocrine irAEs was 23% (14 patients): thyroiditis (13%), hypophysitis (8%), adrenal insufficiency and diabetes mellitus (2–3%). IrAEs occurred in 9 (20%) patients with monotherapy and in 5 (35%) patients when using a combination of drugs (p=0.318). The average time of onset of irAEs did not differ depending on the applied regimen and amounted to 6 [4–18] weeks. Symptomatic irAEs developed in 2 (13%) patients. Discontinuation of ICPI therapy due to irAE was not required in any case. Risk factors: age younger than 61 years old – OR 4.4 (95% CI 1.198–16.242), female OR 2.4 (95% CI 0.67–8.591), presence of stage IV disease – OR 2.4 (95% CI 0.689–8.362), combination therapy OR 1.855 (95% CI 0.548–6.277), previous endocrine pathology – OR 0.813 (95% CI 0.152–4.356).
Conclusions. The incidence of endocrine irAEs when using ICPI is 23%. Thyroiditis and hypophysitis develop more often. The odds are higher in patients younger than 61 years. In most cases, irAEs are not symptomatic and do not require discontinuation of ICPI therapy.
About the Authors
E. V. Poddubskaya
Sechenov First Moscow State Medical University (Sechenov University)
Russian Federation
Russian Federation
Elena V. Poddubskaya, PhD, Deputy Director of Clinical Center for Oncology
Moscow
M. I. Sekacheva
Sechenov First Moscow State Medical University (Sechenov University)
Russian Federation
Russian Federation
Marina I. Sekacheva, DMSc, Professor, Director of the Institute for Personalized Medicine, Director of the Center for Personalized Oncology Sechenov OncoTarget
Moscow
A. A. Guryanova
Sechenov First Moscow State Medical University (Sechenov University)
Russian Federation
Russian Federation
Anastasia A. Guryanova, 5th year student of the International School "Medicine of the Future" of Biomedical Science & Technology Park
8/2 Trubetskaya st., Moscow, 119991
Tel.: +7 (927) 173-00-35
References
1. Paz-Ares L, Urban L, Audigier-Valette C et al. Safety of flat-dose nivolumab plus weight-based ipilimumab for the first-line (1L) treatment of advanced NSCLC. J Thorac Oncol 2018, 10(13): 493. DOI: 10.1016/j.jtho.2018.08.635
2. Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018, 378(2): 158-168. DOI: 10.1056/NEJMra1703481
3. Kumar V, Chaundary N, Garg M et al. Current diagnosis and management of immune related adverse events (irAEs) induced by immune checkpoint inhibitor therapy. Front Pharmacol 2017, 8(8): 49. DOI: 10.3389/fphar.2017.0004
4. Chang LS, Barroso-Sousa R, Tolaney SM et al. Endocrine toxicity of cancer immunotherapy targeting immune checkpoints. Endocr Rev 2019, 40(1): 17–65. DOI: 10.1210/er.2018-00006
5. Remon J, Mezquita L, Corral J et al. Immune-related adverse events with immune checkpoint inhibitors in thoracic malignancies: focusing on non-small cell lung cancer patients. J Thorac Dis. 2018, 10(Suppl 13): 1516-1533. DOI:10.21037/jtd.2017.12.52
6. 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: 123-135. DOI: 10.1056/NEJMoa1504627
7. 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: 1627-1639. DOI: 10.1056/NEJMoa1507643
8. Weber JS, Dummer R, de Pril V et al. Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: detailed safety analysis from a phase 3 trial in patients with advanced melanoma. Cancer 2013, 119: 1675–1682. DOI: 10.1002/cncr.27969
9. Sznol M, Postow MA, Davies MJ et al. Endocrine-related adverse events associated with immune checkpoint blockade and expert insights on their management. Cancer Treat Rev. 2017, 58: 70-76. DOI: 10.1016/j.ctrv.2017.06.002
10. Presotto EM, Rastrelli G, Desideri I et al. Endocrine toxicity in cancer patients treated with nivolumab or pembrolizumab: results of a large multicentre study. J Endocrinol Invest. 2020, 43(3): 337-345. DOI: 10.1007/s40618-019-01112-8
11. AJCC (American Joint Committee on Cancer) cancer staging manual, eighth edition Published: June 5, 2018 [Electronic resource]. URL: https://cancerstaging.org/references-tools/deskreferences/Documents/AJCC%20Cancer%20Staging%20Form%20Supplement.pdf, free (accessed 20.08.2019)
12. Common Terminology Criteria for Adverse Events (CTCAE) v5.0 Published: November 27, 2017 [Electronic resource]. URL: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf, free (accessed 20.08.2019).
13. Weber JS, Hodi FS, Wolchok JD et al. Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol. 2017, 35(7): 785-792. DOI: 10.1200/JCO.2015.66.1389
14. Larkin J, Chiarion-Sileni V, Gonzalez R et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015, 373: 23–34. DOI: 10.1056/NEJMoa1504030
15. Sampson JH, Vlahovic G, Sahebjam S et al. Preliminary safety and activity of nivolumab and its combination with ipilimumab in recurrent glioblastoma (GBM): CHECKMATE-143. J Clin Oncol 2015, 33(15 suppl): 3010a. DOI: 10.1200/jco.2015.33.15_suppl.3010
16. Wolchok JD, Kluger H, Callahan MK et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013, 369:122–133. DOI: 10.1056/NEJMoa1302369
17. Hammers HJ, Plimack ER, Sternberg C et al. CheckMate 214: A phase III, randomized, open-label study of nivolumab combined with ipilimumab versus sunitinib monotherapy in patients with previously untreated metastatic renal cell carcinoma. J Clin Oncol 2015, 33(15 suppl): TPS4578a. DOI: 10.1200/jco.2015.33.15_suppl.tps4578
18. Larkin J, Chiarion-Sileni V, Gonzalez R et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015, 373: 23–34. DOI: 10.1056/NEJMoa1504030
19. А. Kelly K, Infante JR, Taylor MH et al. Safety profile of avelumab in patients with advanced solid tumors: A pooled analysis of data from the phase 1 JAVELIN solid tumor and phase 2 JAVELIN Merkel 200 clinical trials. Cancer 2018, 124: 2010–2017. DOI:10.1002/cncr.31293
20. Gulley JL, Spigel D, Kelly K et al. Avelumab (MSB0010718C), an anti-PD-L1 antibody, in advanced NSCLC patients: A phase 1b, open-label expansion trial in patients progressing after platinum-based chemotherapy. J Clin Oncol 2015, 33(15 suppl): 8034a. DOI: 10.1200/jco.2015.33.15_suppl.8034
21. Ryder M, Callahan M, Postow M et al. Endocrine-related adverse events following ipilimumab in patients with advanced melanoma: a comprehensive retrospective review from a single institution. Endocr Relat Cancer. 2014, 21(2):371-81. DOI: 10.1530/ERC-13-0499
22. Scott ES, Long GV, Guminski A at al. The spectrum, incidence, kinetics and management of endocrinopathies with immune checkpoint inhibitors for metastatic melanoma. Eur J Endocrinol. 2018, 178(2):173-180. DOI: 10.1530/EJE-17-0810
23. Zhai Y, Ye X, Hu F et al. Endocrine toxicity of immune checkpoint inhibitors: a real-world study leveraging US Food and Drug Administration adverse events reporting system. J Immunother Cancer. 2019, 7(1):286. DOI: 10.1186/s40425-019-0754-2
24. Venetsanaki V, Boutis A, Chrisoulidou A, Papakotoulas P. Diabetes mellitus secondary to treatment with immune checkpoint inhibitors. Curr Oncol. 2019, 26(1): e111–e114. DOI:10.3747/co.26.4151
25. Lin CH, Chen KH, Chen KY et al. Immune checkpoint inhibitor therapy-induced hypophysitis ∼ a case series of Taiwanese patients. J Formos Med Assoc. 2019, 118(1 Pt 3): 524-529. DOI: 10.1016/j.jfma.2018.07.014
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