背景：R/M SGCs 是由大唾液腺或小唾液腺引起的一組異質性很大的的惡性腫瘤，沒有標準的治療方法。將PD-1/CTLA-4 免疫檢查點抑製劑的聯合應用在 R/M SGCs 患者中的影響尚不清楚。本研究頭將揭示納武利尤單抗+伊匹單抗在複發性/轉移性唾液腺癌(R/M SGCs)患者中的臨床療效。
Background: R/M SGCs are a diverse group of malignant neoplasms arising from the major or minor salivary glands and have no standard treatment. The impact of combining PD-1/CTLA-4 checkpoint blockade in R/M SGCs is unknown.
方法：在 Simon 兩階段 minimax 的 II 期試驗中，入選 R/M SGCs(除外腺樣囊性癌(ACC))的患者接受每 2 周納武利尤單抗 3mg/kg+每 6 周伊匹利單抗 1mg/kg 的治療(1 個周期=6 周)。同時每 12 周進行一次療效評估。主要終點是根據 RECIST v1.1 標準評估的最佳客觀反應率(BOR=完全緩解[CR]+部分緩解[PR])。受試者可自行決定是否接受疾病進展以外的治療。
Methods: In a Simon's two-stage minimax phase II trial, pts with progressive R/M SGCs (any histology except adenoid cystic carcinoma (ACC)) were enrolled and treated with nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks (1 cycle = 6 weeks). Imaging, using RECIST v1.1 response assessment, was scheduled to be performed approximately every 12 weeks. The primary endpoint was best overall response (BOR = complete response [CR]+partial response [PR]) per RECIST v1.1. To detect a difference between an unacceptable BOR of 5% and a desirable BOR of 20% (one-sided type I error of 10%, power of 90%), at least 1 in the first 18 pts required an observed response. At least 4 responses of 32 total pts were needed to meet the primary endpoint. Treatment beyond progression of disease (PD) was allowed at the discretion of the investigator. A second cohort of pts with ACC was analyzed and reported separately.
結果：2017.7.25 至 2020.7.16 間共 32 例患者納入研究。BOR 率為 16% (5/32)，5 例應答者的目標病灶消退範圍為 66%~100%。7 例患者未達到首次疾病評估標準，被歸為無反應應答者，7 例無反應應答者中 5 例臨床進展，1 例出現不良事件反應，1 例退出試驗。整個試驗有 4 例因不良事件終止:全血細胞減少(1)、視力模糊(1)、心肌病/高血糖症(1)、中性粒細胞減少性敗血症(1)和粘膜炎(1)。治療持續時間 15.7~29.5 個月(截至 2020.6.2,還有 1例正在接受治療)。
Results: From 7/25/2017-7/16/2020, 32 pts were enrolled and evaluable for the primary endpoint. There was 3 confirmed PRs in the first 18 pts, therefore enrollment of the second stage continued. BOR rate was 16% (5/32). Seven pts never reached a first disease assessment and were classified as non-responders: 5 due to clinical PD, 1 due to toxicity, and 1 pt withdrew. Four pts discontinued the trial for toxicities: pancytopenia (1), blurry vision (1), cardiomyopathy/hyperglycemia (1), and neutropenic sepsis (1), and mucositis (1). The 5 confirmed responders had regressions ranging from -66% to -100% in target lesions, with a duration of therapy ranging from 15.7 to 29.5 months (treatment ongoing for one as of 2/6/20).
結論：整個隊列研究觀察到的反應具有戲劇性和持久性。我們將對組織進行活檢和外周血樣本進行分析，以闡明對雙重免疫檢查點抑製劑的反應療效和抵抗機製的見解。
Conclusions: This cohort met its primary endpoint, and the responses observed were dramatic and durable. Paired biopsy and peripheral blood samples will be analyzed to elucidate insights into mechanisms of response and resistance to dual checkpoint blockade.
