非小細胞肺癌病人使用免疫檢查點抑制劑之副作用

Immune-Related Adverse Events Associated with Immune Checkpoint Blockade for Non-small Cell Lung Cancer

李玫萱(Mei-Hsuan Lee) ； 郭家佑(Chia-Yu Kuo) ； 洪仁宇(Jen-Yu Hung)

《內科學誌》 30卷1期 (2019/02) Pp. 19-26

https://doi.org/10.6314/JIMT.201902_30(1).05

摘要

非小細胞肺癌占了所有肺癌近八成，是世界上最常見的惡性腫瘤之一。在過去，鉑金類為基底的化學治療是晚期肺癌的唯一治療選擇，直到上皮細胞生長因素受體酪胺酸酶抑制劑（EGFR TKI）的標靶藥物問世，這樣的狀況因而改變。近年的研究指出，免疫檢查點抑制劑（check point inhibitor）已經證實可以有效控制晚期非小細胞肺癌病情發展的治療方式。其作用機轉是藉由抑制programmed cell death protein 1（PD-1）或programmed cell death ligand-1（PD-L1）來調控T淋巴細胞的功能，以達到抗癌的效果。Nivolumab和Pembrolizumab是對抗PD-1之單株抗體，Atezolizumab和Durvalumab則是對抗PD-L1的單株抗體。無論是在第二線單獨使用，或是搭配傳統化學治療在第一線使用，甚至是第一線單獨使用在癌細胞PD-L1＞50%的病人身上，在療效上都被證實比傳統化療為佳。即使是在無法手術切除的第三期病人且接受同步放射化學治療後，免疫檢查點抑制劑亦有其角色。免疫相關副作用亦是免疫治療上值得關注的議題。其發生機轉可能與免疫檢查點抑制劑活化T淋巴細胞、自體抗體及發炎性細胞因子的血中濃度上升有關。雖然有些過去的研究顯示基因也可能是影響的因子之一，至於影響副作用的預測因子至今仍未可知。一旦發生免疫相關副作用，暫緩使用免疫檢查點抑制劑可以緩解副作用的進展。如副作用嚴重，系統性類固醇的使用是標準的第一線藥物治療。使用時間長度與是否重啟免疫治療則有賴臨床團隊視病人情況判斷。

關鍵字

非小細胞肺癌（Non-small cell lung cancer） ； 免疫檢查點抑制劑（Immune checkpoint blockade） ； 副作用（Adverse effect）

並列摘要

Non-small cell lung cancer (NSCLC) accounts for about 80% of lung cancers, and is one of the most common carcinomas worldwide. Chemotherapy was the standard treatment for advanced NSCLC until the development of the first epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). In recent years, immune checkpoint blockade has been proven to be beneficial in the treatment of advanced NSCLC, through adjusting the function of T lymphocytes by blocking PD-1 or PD-L1 and inducing tumor cell apoptosis. Nivolumab and pembrolizumab are monoclonal antibodies for PD-1; atezolizumab and durvalujmab are monoclonal antibodies for PD-L1. Immune checkpoint blockade has been shown to have better efficacy than chemotherapy as both first-line chemotherapy and second-line treatment for stage IV NSCLC. Even in unresectable stage III NSCLC after concurrent chemoradiotherapy, immune checkpoint inhibitors also play an important role. Immune-related adverse effects (IRAEs) have gained increasing attention with the increased use of immunotherapy. The mechanisms leading to IRAEs have yet to be elucidated, but may include increasing T-cell activity, levels of preexisting autoantibodies, and the level of inflammatory cytokines. Underlying germline genetic factors may also be related to the risk of IRAEs, however larger genome-wide association studies are needed to establish the relationship between genetic factors and the risk of IRAEs. For patients with IRAEs, discontinuing the immune checkpoint blockade therapy can ease the adverse effects. Systemic corticosteroids are the first-line standard therapy for severe IRAEs. The duration of corticosteroid treatment and whether or not to re-start immunotherapy depend on the judgement of the doctor and the condition of the patient.