DOI QR코드

DOI QR Code

PD-1 억제제의 사용패턴 및 갑상선 관련 유해사례 발현 양상 분석

Usage Patterns and Incidence of Thyroid-related Adverse Events in Patients Treated with PD-1 Inhibitors

  • 황서영 (중앙대학교 대학원 약학과) ;
  • 김희재 (중앙대학교 대학원 약학과) ;
  • 정선영 (삼성서울병원 약제부) ;
  • 민명숙 (삼성서울병원 약제부) ;
  • 서동철 (중앙대학교 대학원 약학과)
  • 투고 : 2021.05.10
  • 심사 : 2021.07.30
  • 발행 : 2021.09.30

초록

Objective: PD-1 inhibitors have demonstrated improved health outcomes in cancer patients. PD-1 inhibitors are well-tolerated and associated with immune-related adverse events. The objectives of this study are to analyze use patterns of PD-1 inhibitors in patients with cancer and to investigate the incidence of thyroid-related adverse reactions in patients treated with PD-1 inhibitors. Methods: The study included patients who had been administered PD-1 inhibitors (either nivolumab or pembrolizumab) at the Samsung Medical Center between October 1, 2016 and June 30, 2017. Data was collected from electronic medical records and tested using Mann-Whitney tests and Chi-Square tests for statistical significance. Associations between PD-1 inhibitors and incidence of adverse events were tested using Cox regression for age, gender, BMI, ECOG PS and medication. Results: Two hundred fifteen patients were identified as eligible for analyses. Thyroid-related adverse events occurred in 20% of patients (n=43). Thyroid function tests (TFTs) was performed in 109 patients (50.7%). Positive results of PD-L1 testing were found in 53.2% of the 94 patients who had the test. Approved doses of nivolumab (3 m/kg) and pembrolizumab (200 mg) were administered in 70.4% and 53% of patients, respectively. The analysis of risk factor of thyroid-related adverse reaction did not show statistically significant differences (Cox regression). Conclusion: Thyroid-related adverse events are common in patients treated with PD-1 inhibitors and hypothyroidism is the most frequent adverse reaction. Routine TFTs monitoring is strongly recommended to evaluate thyroid function in real-world clinical practice.

키워드

참고문헌

  1. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015;372(4):320-30. https://doi.org/10.1056/NEJMoa1412082
  2. Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol 2019;20(10):1370-85. https://doi.org/10.1016/s1470-2045(19)30413-9
  3. Duan J, Cui L, Zhao X, et al. Use of immunotherapy with programmed cell death 1 vs programmed cell death ligand 1 Inhibitors in patients with cancer: A systematic review and metaanalysis. JAMA Oncol 2020;6(3):375-84. https://doi.org/10.1001/jamaoncol.2019.5367
  4. Merck, Sharp & Dohme Corporation. KEYTRUDA® [package insert on the Internet]. Available from https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf. Accessed December 11, 2020.
  5. Bristol Myers Squibb Corporation. OPDIVO® [package insert on the Internet]. Available from https://packageinserts.bms.com/pi/pi_opdivo.pdf. Accessed December 11, 2020.
  6. Weber J, Mandala M, Del Vecchio M, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med 2017;377(19):1824-35. https://doi.org/10.1056/NEJMoa1709030
  7. Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-Positive non-small-cell lung cancer. N Engl J Med 2016;375(19):1823-33. https://doi.org/10.1056/NEJMoa1606774
  8. Baxi S, Yang A, Gennarelli RL, et al. Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis. BMJ 2018;360:k793. https://doi.org/10.1136/bmj.k793
  9. Eigentler TK, Hassel JC, Berking C, et al. Diagnosis, monitoring and management of immune-related adverse drug reactions of anti-PD-1 antibody therapy. Cancer Treat Rev 2016;45:7-18. https://doi.org/10.1016/j.ctrv.2016.02.003
  10. Costa R, Carneiro BA, Agulnik M, et al. Toxicity profile of approved anti-PD-1 monoclonal antibodies in solid tumors: a systematic review and meta-analysis of randomized clinical trials. Oncotarget 2017;8(5):8910-20. https://doi.org/10.18632/oncotarget.13315
  11. Sakakida T, Ishikawa T, Uchino J, et al. Clinical features of immune-related thyroid dysfunction and its association with outcomes in patients with advanced malignancies treated by PD-1 blockade. Oncol Lett 2019;18(2):2140-7.
  12. Morganstein DL, Lai Z, Diem S, 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):614-20. https://doi.org/10.1111/cen.13297
  13. Guaraldi F, Selva RL, Sama MT, et al. Characterization and implications of thyroid dysfunction induced by immune checkpoint inhibitors in real-life clinical practice: a long-term prospective study from a referral institution. J Endocrinol Invest 2018;41(5):549-56. https://doi.org/10.1007/s40618-017-0772-1
  14. 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):1480-92. https://doi.org/10.1016/S1470-2045(18)30700-9
  15. Reck M, Schenker M, Lee KH, et al. Nivolumab plus ipilimumab versus chemotherapy as first-line treatment in advanced non-small-cell lung cancer with high tumour mutational burden: patient-reported outcomes results from the randomised, open-label, phase III CheckMate 227 trial. Eur J Cancer 2019;116:137-47. https://doi.org/10.1016/j.ejca.2019.05.008
  16. Burtness B, Harrington KJ, Greil R, et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet 2019;394(10212):1915-28. https://doi.org/10.1016/s0140-6736(19)32591-7
  17. Patel NS, Oury A, Daniels GA, Bazhenova L, Patel SP. Incidence of thyroid function test abnormalities in patients receiving immunecheckpoint inhibitors for cancer treatment. Oncologist 2018;23(10):1236-41. https://doi.org/10.1634/theoncologist.2017-0375
  18. Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med 2018;378(19):1789-801. https://doi.org/10.1056/NEJMoa1802357
  19. de Filette J, Jansen Y, Schreuer M, et al. Incidence of thyroid-related adverse events in melanoma patients treated with pembrolizumab. J Clin Endocrinol Metab 2016;101(11):4431-9. https://doi.org/10.1210/jc.2016-2300
  20. Gonzalez-Rodriguez E, Rodriguez-Abreu D. Immune checkpoint inhibitors: review and management of endocrine adverse events. Oncologist 2016;21(7):804-16. https://doi.org/10.1634/theoncologist.2015-0509
  21. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med 2015;372(26):2521-32. https://doi.org/10.1056/NEJMoa1503093
  22. Kartolo A, Sattar J, Sahai V, Baetz T, Lakoff JM. Predictors of immunotherapy-induced immune-related adverse events. Curr Oncol 2018;25(5):e403-e410.
  23. Gibney GT, Weiner LM, Atkins MB. Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol 2016;17(12):e542-e551. https://doi.org/10.1016/S1470-2045(16)30406-5
  24. Health insurance review & assessment service. Question and answer for medical care application of immune checkpoint inhibitors, nivolumab and pembrolizumab. Available from https://www.hira.or.kr/bbsDummy.do?pgmid=HIRAA030023080000&brdScnBltNo=4&brdBltNo=45624#none. Accessed December 11, 2020.
  25. Gohye Eoum, Yoonsook Cho, Sandy Jeong Rhie. Evaluation of nivolumab use and factors related to treatment outcomes in a cancer center of a top tier general hospital. Korean J Clin Pharm 2018;28(2):88-94. https://doi.org/10.24304/kjcp.2018.28.2.88
  26. Hofmann L, Forschner A, Loquai C, et al. Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy. Eur J Cancer 2016;60:190-209. https://doi.org/10.1016/j.ejca.2016.02.025
  27. Osorio JC, Ni A, Chaft JE, et al. Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer. Ann Oncol 2017;28(3):583-9. https://doi.org/10.1093/annonc/mdw640
  28. 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(17):1714-68. https://doi.org/10.1200/JCO.2017.77.6385
  29. Thompson JA, Schneider BJ, Brahmer J, et al. Management of immunotherapy-related toxicities, version 1.2019. J Natl Compr Canc Netw 2019;17(3):255-89. https://doi.org/10.6004/jnccn.2019.0013
  30. Ministry of Food and Drug Safety. OPDIVO® Intravenous injection (Nivolumab, recombinant). Available from https://nedrug.mfds.go.kr/pbp/CCBBB01/getItemDetail?itemSeq=201501485. Accessed December 11, 2020.
  31. Ministry of Food and Drug Safety. KEYTRUDA® Intravenous injection (Pembrolizumab, recombinant). Available from https://nedrug.mfds.go.kr/pbp/CCBBB01/getItemDetail?itemSeq=201501487. Accessed December 11, 2020.
  32. Puzanov I, Diab A, Abdallah K, et al. 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(1):95. https://doi.org/10.1186/s40425-017-0300-z
  33. Haanen JBAG, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017;28(suppl_4):iv119-iv142. https://doi.org/10.1093/annonc/mdx225
  34. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. Available from https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_reference_5x7.pdf. Accessed December 11, 2020.