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

다국어 초록 (Multilingual Abstract)

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.

참고문헌 (Reference)

1 엄고혜, "상급종합병원 암센터에서 Nivolumab 사용평가와 치료성과에 미치는 영향인자" 한국임상약학회 28 (28): 88-94, 2018

2 Duan J, "Use of immunotherapy with programmed cell death 1 vs programmed cell death ligand 1Inhibitors in patients with cancer : A systematic review and metaanalysis" 6 (6): 375-384, 2020

3 Costa R, "Toxicity profile of approved anti-PD-1 monoclonal antibodies in solid tumors : a systematic review and meta-analysis of randomized clinical trials" 8 (8): 8910-8920, 2017

4 Morganstein DL, "Thyroid abnormalities following the use of cytotoxic T-lymphocyte antigen-4 and programmed death receptor protein-1 inhibitors in the treatment of melanoma" 86 (86): 614-620, 2017

5 Health insurance review & assessment service, "Question and answer for medical care application of immune checkpoint inhibitors, nivolumab and pembrolizumab"

6 Kartolo A, "Predictors of immunotherapy-induced immune-related adverse events" 25 (25): e403-e410, 2018

7 Gibney GT, "Predictive biomarkers for checkpoint inhibitor-based immunotherapy" 17 (17): e542-e551, 2016

8 Reck M, "Pembrolizumab versus chemotherapy for PD-L1-Positive non-small-cell lung cancer" 375 (375): 1823-1833, 2016

9 Robert C, "Pembrolizumab versus Ipilimumab in Advanced Melanoma" 372 (372): 2521-2532, 2015

10 Burtness B, "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" 394 (394): 1915-1928, 2019

11 Ministry of Food and Drug Safety, "OPDIVO® Intravenous injection (Nivolumab, recombinant)"

12 Bristol Myers Squibb Corporation, "OPDIVO®"

13 Motzer RJ, "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" 20 (20): 1370-1385, 2019

14 Reck M, "Nivolumab plus ipilimumab versus chemotherapy as first-line treatment in advanced non-smallcell lung cancer with high tumour mutational burden: patientreported outcomes results from the randomised, open-label, phase III CheckMate 227 trial" 116 : 137-147, 2019

15 Hodi FS, "Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial" 19 (19): 1480-1492, 2018

16 Robert C, "Nivolumab in previously untreated melanoma without BRAF mutation" 372 (372): 320-330, 2015

17 Puzanov I, "Managing toxicities associated with immune checkpoint inhibitors : consensus recommendations from the Society for Immunotherapy of Cancer(SITC)Toxicity Management Working Group" 5 (5): 95-, 2017

18 Haanen JBAG, "Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up" 28 (28): iv119-iv142, 2017

19 Thompson JA, "Management of immunotherapy-related toxicities, version 1.2019" 17 (17): 255-289, 2019

20 Brahmer JR, "Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy : American Society of Clinical Oncology Clinical Practice Guideline" 36 (36): 1714-1768, 2018

21 Ministry of Food and Drug Safety, "KEYTRUDA® Intravenous injection (Pembrolizumab, recombinant)"

22 Merck, Sharp & Dohme Corporation, "KEYTRUDA®"

23 de Filette J, "Incidence of thyroid-related adverse events in melanoma patients treated with pembrolizumab" 101 (101): 4431-4439, 2016

24 Patel NS, "Incidence of thyroid function test abnormalities in patients receiving immunecheckpoint inhibitors for cancer treatment" 23 (23): 1236-1241, 2018

25 Baxi S, "Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs : systematic review and meta-analysis" 360 : k793-, 2018

26 González-Rodríguez E, "Immune checkpoint inhibitors : review and management of endocrine adverse events" 21 (21): 804-816, 2016

27 Eigentler TK, "Diagnosis, monitoring and management of immune-related adverse drug reactions of anti-PD-1 antibody therapy" 45 : 7-18, 2016

28 Hofmann L, "Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy" 60 : 190-209, 2016

29 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES, "Common Terminology Criteria for Adverse Events (CTCAE)Version 5.0"

30 Sakakida T, "Clinical features of immune-related thyroid dysfunction and its association with outcomes in patients with advanced malignancies treated by PD-1blockade" 18 (18): 2140-2147, 2019

31 Guaraldi F, "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" 41 (41): 549-556, 2018

32 Osorio JC, "Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with nonsmall-cell lung cancer" 28 (28): 583-589, 2017

33 Eggermont AMM, "Adjuvant pembrolizumab versus placebo in resected stage III melanoma" 378 (378): 1789-1801, 2018

34 Weber J, "Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma" 377 (377): 1824-1835, 2017