Immuno-related endocrinopathy in patients treated with immune checkpoint inhibitors

Recently immune checkpoint inhibitors amazingly changed the landscape of cancer therapy worldwide. The number of immune checkpoint molecules in clinical practice is constantly increasing. There are some monoclonal antibodies recently registered in the Russian Federation: anti-PD1 antibodies (nivolumab, pembrolizumab), anti-PD-L1 (atezolizumab, durvalumab), anti-CTLA-4 (ipilimumab). Immune-mediated endocrinopathies are some of the most common complications of immunotherapy. According to the results of clinical studies, the incidence of serious endocrine immuno-mediated adverse events with anti-PD1 monoclonal antibodies is low (3.5–8%). The use of anti-CTLA4 antibodies, combined regimens, and the use of immunotherapy after chemoradiotherapy significantly increase the incidence of serious adverse events to 30%. In clinical practice of N.N. Blokhin Cancer Research Center among 245 non-small cell lung cancer and hepatocellular carcinoma patients treated with immunotherapy, 22 (8,9%) developed an immune-mediated endocrinopathy. Most patients developed adverse events of 1–2 degrees, in two patients – 3 degrees, requiring discontinuation of treatment. The aim of this article was to provide useful information and recommendations regarding the management of common immuno-related endocrine adverse events (including hypothyroidism, hyperthyroidism, pituitary, adrenal insufficiency) for clinical oncologists.

1. Horn L., Gettinger S.N., Gordon M.S., Herbst R.S., Gandhi L., Felip E. et al. Safety and clinical activity of atezolizumab monotherapy in metastatic non-small-cell lung cancer: final results from a phase I study. Eur J Cancer. 2018;101:201–209. doi: 10.1016/j.ejca.2018.06.031.

2. Antonia S.J., Borghaei H., Ramalingam S.S., Horn L., de Castro Carpeño J., Pluzanski A. et al. Four-year survival with nivolumab in patients with previously treated advanced non-small-cell lung cancer: a pooled analysis. Lancet Oncol. 2019;20(10):1395–1408. doi: 10.1016/S1470-2045(19)30407-3.

3. Gettinger S., Horn L., Jackman D., Spigel D., Antonia S., Hellmann M. et al. Five-Year Follow-Up of Nivolumab in Previously Treated Advanced NonSmall-Cell Lung Cancer: Results From the CA209-003 Study. J Clin Oncol. 2018;36(17):1675–1684. doi: 10.1200/JCO.2017.77.0412.

4. Fogt S., Shustova M., Demidov L.V., Moiseyenko V., Tjulandin S., Semiglazova T. et al. Phase II trial (BCD-100-2/MIRACULUM) of the novel PD-1 inhibitor (BCD-100) in patients with advanced melanoma.. J Clin Oncol. 2019;37(15):9549. doi: 10.1200/JCO.2019.37.15_suppl.9549.

5. Vaishampayan U., Schöffski P., Ravaud A., Borel C., Peguero J., Chaves J. et al. Avelumab monotherapy as first-line or second-line treatment in patients with metastatic renal cell carcinoma: phase Ib results from the JAVELIN Solid Tumor trial. J Immunother Cancer. 2019;7(1):275. doi: 10.1186/s40425-019-0746-2.

6. Tan M.H., Iyengar R., Mizokami-Stout K., Yentz S., MacEachern M.P., Shen L.Y. et al. Spectrum of immune checkpoint inhibitors-induced endocrinopathies in cancer patients: a scoping review of case reports. Clin Diabetes Endocrinol. 2019;5:1. doi: 10.1186/s40842-018-0073-4.

7. Pardoll D.M. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–264. doi: 10.1038/nrc3239.

8. Weber J., Mandala M., del Vecchio M., Gogas H.J., Arance A.M., Cowey C.L. et al. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. N Engl J Med. 2017;377(19):1824–1835. doi: 10.1056/NEJMoa1709030.

9. Garon E.B., Hellmann M.D., Rizvi N.A., Carcereny E., Leighl N.B., Ahn M.J. et al. Five-Year Overall Survival for Patients With Advanced Non‒Small-Cell Lung Cancer Treated With Pembrolizumab: Results From the Phase I KEYNOTE-001 Study. J Clin Oncol. 2019;37(28):2518–2527. doi: 10.1200/JCO.19.00934.

10. Hellmann M.D., Ciuleanu T.-E., Pluzanski A., Lee J.S., Otterson G.A., AudigierValette C. et al. Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. N Engl J Med. 2018;378(22):2093–2104. doi: 10.1056/NEJMoa1801946.

11. Mok T.S.K., Wu Y.L., Kudaba I., Kowalski D.M., Cho B.C., Turna H.Z. et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1- expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019;393(10183):1819–1830. doi: doi: 10.1016/S0140-6736(18)32409-7.

12. Socinski M.A., Jotte R.M., Cappuzzo F., Orlandi F., Stroyakovskiy D., Nogami N. et al. Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288–2301. doi: 10.1056/NEJMoa1716948.

13. Antonia S.J., Villegas A., Daniel D., Vicente D., Murakami S., Hui R. et al. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 2017;377(20):1919–1929. doi: 10.1056/NEJMoa1709937.

14. Morganstein D.L., Lai Z., Spain L., Diem S., Levine D., Mace C. et al. Thyroid abnormalities following the use of cytotoxic T-lymphocyte antigen-4 and programmed death receptor protein-1 inhibitors in the treatment of melanoma. Clin Endocrinol (Oxf). 2017;86(4):614–620. doi: 10.1111/cen.13297.

15. Robert C., Joshua A.M., Kefford R., Joseph R.W., Wolchok J.D., Hodi F.S. et al. Association of immune-related thyroid disorders with pembrolizumab (pembro, MK-3475) in patients (pts) with advanced melanoma treated in KEYNOTE-001. Journal of Clinical Oncology. 2015;33(15):9050. doi: 10.1200/jco.2015.33.15_suppl.9050.

16. McMillen B., Dhillon M.S., Yong-Yow S. A rare case of thyroid storm. BMJ Case Rep. 2016;2016:10.1136/bcr-214603. doi: 10.1136/bcr-2016-214603.

17. Win M.A., Thein K.Z., Qdaisat A., Yeung S.J. Acute symptomatic hypocalcemia from immune checkpoint therapy-induced hypoparathyroidism. Am J Emerg Med. 2017;35(7):1039.e5–1039.e7. doi: 10.1016/j.ajem.2017.02.048.

18. Trinh B., Sanchez G.O., Herzig P., Läubli H. Inflammation-induced hypoparathyroidism triggered by combination immune checkpoint blockade for melanoma. J Immunother Cancer. 2019;7(1):52. doi: 10.1186/s40425-019-0528-x.

19. Barroso-Sousa R., Barry W.T., Garrido-Castro A.C., Hodi F.S., Min L., Krop I.E., Tolaney S.M. Incidence of Endocrine Dysfunction Following the Use of Different Immune Checkpoint Inhibitor Regimens: A Systematic Review and Metaanalysis. JAMA Oncol. 2018;4(2):173–182. doi: 10.1001/jamaoncol.2017.3064.

20. Paepegaey A.C., Lheure C., Ratour C., Lethielleux G., Clerc J., Bertherat J. et al. Polyendocrinopathy Resulting From Pembrolizumab in a Patient With a Malignant Melanoma. J Endocr Soc. 2017;1(6):646–649. doi: 10.1210/js.2017-00170.

21. Dillard T., Yedinak C.G., 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(1):29–38. doi: 10.1007/s11102-009-0193-z.

22. Torino F., Barnabei A., De Vecchis L., Salvatori R., Corsello S.M. Hypophysitis induced by monoclonal antibodies to cytotoxic T lymphocyte antigen 4: challenges from a new cause of a rare disease. Oncologist. 2012;17(4):525–535. doi: 10.1634/theoncologist.2011-0404.

23. Corsello S.M., 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(4):1361–1375. doi: 10.1210/jc.2012-4075.

24. Blansfield J.A., Beck K.E., Tran K., Yang J.C., Hughes M.S., Kammula U.S. et al. Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer. J Immunother. 2005;28(6):593–598. doi: 10.1097/01. cji.0000178913.41256.06.

25. Albarel F., Gaudy C., Castinetti F., Carré T., Morange I., Conte-Devolx B. et al. Long-term follow-up of ipilimumab-induced hypophysitis, a common adverse event of the anti-CTLA-4 antibody in melanoma. Eur J Endocrinol. 2015;172(2):195–204. doi: 10.1530/EJE-14-0845.

26. Min L., Hodi F.S., Giobbie-Hurder A., Ott P.A., Luke J.J., Donahue H. et al. Systemic high-dose corticosteroid treatment does not improve the outcome of ipilimumab-related hypophysitis: A retrospective cohort study. Clin Cancer Res. 2015;21(4):749–755. doi: 10.1158/1078-0432.CCR-14-2353.

27. Zhao C., Tella S.H., Del Rivero J., Kommalapati A., Ebenuwa I., Gulley J. et al. Anti-PD-L1 Treatment Induced Central Diabetes Insipidus. J Clin Endocrinol Metab. 2018;103(2):365–369. doi: 10.1210/jc.2017-01905.

28. Barroso-Sousa R., Ott P.A., Hodi F.S., Kaiser U.B., Tolaney S.M., Min L. Endocrine dysfunction induced by immune checkpoint inhibitors: Practical recommendations for diagnosis and clinical management. Cancer. 2018;124(6):1111–1121. doi: 10.1002/cncr.31200.

29. Clotman K., Janssens K., Specenier P., Weets I., De Block C.E.M. Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. J Clin Endocrinol Metab. 2018;103(9):3144–3154. doi: 10.1210/jc.2018-00728.

30. Shamy T.A., Aguasvivas M., Serhan M., Fojas M.M. Diabetic Ketoacidosis Triggered by Pembrolizumab in a Patient with Bladder Cancer. Diabetes. 2018;67(1):219–LB. doi: 10.2337/db18-219-LB.

31. Maamari J., Yeung S.J., Chaftari P.S. Diabetic ketoacidosis induced by a single dose of pembrolizumab. Am J Emerg Med. 2019;37(2):376.e1–376.e2. doi: 10.1016/j.ajem.2018.10.040.