柳葉刀腫瘤分冊：尿路上皮癌患者派姆單抗一線治療療效佳可耐受

分類＼健康
時間＼2017-10-20

《柳葉刀腫瘤分冊》2017年9月26日線上先發

在不適合順鉑治療、局部晚期、不能切除或轉移性尿路上皮癌患者中派姆單抗一線治療(KEYNOTE-052試驗):一項多中心、單臂、II期研究

背景

由於腎功能不全、體能狀態不佳或其它並存疾病，半數以上的晚期尿路上皮癌患者不能接受順鉑為基礎的一線化療。我們在不適合順鉑治療的、局部晚期、不能切除或轉移性尿路上皮癌患者中，評估了派姆單抗一線治療的安全性及有效性。

方法

在這項多中心、單臂、II期研究（KEYNOTE-052試驗）中，

我們在20個國家的91家學術性醫療中心招募了不適合順鉑治療且既往未進行過全身化療的晚期尿路上皮癌患者。入組患者靜脈輸注派姆單抗200mg，每三周1次。主要研究終點為在所有患者中的客觀緩解率（患者達到完全緩解或部分緩解的比例）以及按PD-L1表達狀態分組的客觀緩解率，由獨立的中心審查委員按照“實體瘤療效評價標準1.1版”來評判客觀緩解率。

在研究開始時所提供的腫瘤活檢標本中評價腫瘤細胞和炎性細胞中的PD-L1表達情況。在接受至少一個劑量的派姆單抗的所有患者（全部治療人群）中評估有效性及安全性。該研究已在ClinicalTrials.gov網站註冊，註冊號NCT02335424，仍在進行隨訪。

結果

2015年2月24日至2016年8月8日，入組了374例患者，370例患者接受了至少1個劑量的派姆單抗治療。370例患者中有89例（24%,95%CI，20–29）中心評價為客觀緩解，截至2016年9月1日（資料鎖定日），89例緩解患者中有74例仍在緩解中。

中位隨訪5個月（四分位距3.0-8.6）。以10%的PD-L1表達為界，PD-L1表達越多，對派姆單抗的緩解率越高；（腫瘤細胞和炎性細胞）組合陽性評分≥10%的110例患者中有42例（38%，95%CI，29-48）中心評價為客觀緩解。最常見的3、4級治療相關性不良反應為乏力（370例中有8例[2%]）、鹼性磷酸酶升高（5例[1%]）、結腸炎和肌無力（各4例[1%]）。370例患者中有36例（10%）有治療相關的嚴重不良反應。370例患者中有17例（5%）死於非治療相關性不良反應，1例患者死于治療相關性不良反應（除了3級甲狀腺炎以外還有肌炎、3級肝炎、3級肺炎、4級心肌炎）。

解釋

在不適合順鉑治療的尿路上皮癌患者中，大部分為老年人、預後差、或有嚴重並存疾病，派姆單抗一線治療具有抗腫瘤活性和可耐受性，鑒於此，派姆單抗已成為不適合順鉑治療或不適合化療患者的一種新的治療選擇。派姆單抗一線治療正在KEYNOTE-361這項III期臨床試驗（ClinicalTrials.gov網站註冊，註冊號NCT02335424）中進行進一步評估。

First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study

Background

More than half of all patients with advanced urothelial cancer cannot receive standard, first-line cisplatin-based chemotherapy because of renal dysfunction, poor performance status, or other comorbidities. We assessed the activity and safety of first-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer.

Methods

In this multicentre, single-arm, phase 2 study (KEYNOTE-052), cisplatin-ineligible patients with advanced urothelial cancer who had not been previously treated with systemic chemotherapy were recruited from 91 academic medical centres in 20 countries. Enrolled patients received intravenous pembrolizumab 200 mg every 3 weeks. The primary endpoint was objective response (the proportion of patients who achieved complete or partial response) in all patients and by PD-L1 expression status according to the Response Evaluation Criteria in Solid Tumors, version 1.1, as assessed by independent central review. PD-L1 expression was assessed in tumour and inflammatory cells from tumour biopsies provided at study entry. Activity and safety were analysed in all patients who received at least one dose of pembrolizumab (all-patients-treated population). This study is registered with ClinicalTrials.gov, number NCT02335424, and follow-up is ongoing.

Findings

Between Feb 24, 2015, and Aug 8, 2016, 374 patients were enrolled and 370 patients received at least one dose of pembrolizumab. 89 (24%, 95% CI 20–29) of 370 patients had a centrally assessed objective response, and as of Sept 1, 2016 (data cutoff), 74 (83%) of 89 responses were ongoing. Median follow-up was 5 months (IQR 3·0–8·6). A PD-L1-expression cutoff of 10% was associated with a higher frequency of response to pembrolizumab; 42 (38%, 95% CI 29–48) of 110 patients with a combined positive score of 10% or more had a centrally assessed objective response. The most common grade 3 or 4 treatment-related adverse events were fatigue (eight [2%] of 370 patients), alkaline phosphatase increase (five [1%]), colitis, and muscle weakness (both four [1%]). 36 (10%) of 370 patients had a serious treatment-related adverse event. 17 (5%) of 370 patients died from non-treatment-related adverse events associated with death, and one patient died from treatment-related adverse events (myositis in addition to grade 3 thyroiditis, grade 3 hepatitis, grade 3 pneumonia, and grade 4 myocarditis).

Interpretation

First-line pembrolizumab has antitumour activity and acceptable tolerability in cisplatin-ineligible patients with urothelial cancer, most of whom were elderly, had poor prognostic factors, or had serious comorbidities. In view of this result, pembrolizumab has become a new treatment option for patients who are cisplatin-ineligible or not suitable candidates for chemotherapy. Pembrolizumab in the first-line setting is being further assessed in the phase 3 KEYNOTE-361 trial (ClinicalTrials.gov, NCT02335424).

責任編輯：腫瘤資訊-Ruby