Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY, USA.
Hospital Universitario 12 de Octubre (CiberOnc), Madrid, Spain.
Lancet Oncol. 2017 Nov;18(11):1483-1492. doi: 10.1016/S1470-2045(17)30616-2. Epub 2017 Sep 26.
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.
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.
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).
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).
Merck & Co.
超过一半的晚期尿路上皮癌患者由于肾功能障碍、身体状况不佳或其他合并症而无法接受标准的一线含顺铂化疗。我们评估了一线帕博利珠单抗在不适合顺铂治疗的局部晚期和不可切除或转移性尿路上皮癌患者中的活性和安全性。
在这项多中心、单臂、2 期 KEYNOTE-052 研究中，从 20 个国家的 91 个学术医疗中心招募了既往未接受过全身化疗的晚期尿路上皮癌且不适合顺铂治疗的患者。入组患者接受静脉注射帕博利珠单抗 200mg，每 3 周一次。主要终点是所有患者和根据实体瘤反应评估标准 1.1（由独立中心审查评估）的 PD-L1 表达状态的客观缓解率（完全或部分缓解患者的比例）。在研究入组时，通过肿瘤活检评估肿瘤和炎症细胞中的 PD-L1 表达。在至少接受一剂帕博利珠单抗的所有患者（所有患者治疗人群）中分析了活性和安全性。这项研究在 ClinicalTrials.gov 上注册，编号为 NCT02335424，随访正在进行中。
在 2015 年 2 月 24 日至 2016 年 8 月 8 日期间，共纳入 374 例患者，370 例患者至少接受了一剂帕博利珠单抗治疗。370 例患者中有 89 例（24%，95%CI 20-29）经中心评估有客观缓解，截至 2016 年 9 月 1 日（数据截止日期），89 例缓解中的 74 例（83%）仍在持续。中位随访时间为 5 个月（IQR 3.0-8.6）。PD-L1 表达截断值为 10%与帕博利珠单抗反应频率更高相关；在 110 例联合阳性评分≥10%的患者中，有 42 例（38%，95%CI 29-48）经中心评估有客观缓解。最常见的 3 级或 4 级治疗相关不良事件是疲劳（370 例患者中有 8 例[2%]）、碱性磷酸酶升高（5 例[1%]）、结肠炎和肌肉无力（均为 4 例[1%]）。370 例患者中有 36 例（10%）发生严重治疗相关不良事件。17 例（5%）患者因与死亡相关的非治疗相关不良事件死亡，1 例患者因治疗相关不良事件死亡（除 3 级甲状腺炎、3 级肝炎、3 级肺炎和 4 级心肌炎外，还出现肌炎）。
在不适合顺铂治疗的尿路上皮癌患者中，一线帕博利珠单抗具有抗肿瘤活性和可接受的耐受性，其中大多数患者年龄较大，预后因素较差，或存在严重的合并症。鉴于这一结果，帕博利珠单抗已成为不适合顺铂治疗或不适合化疗的患者的新治疗选择。帕博利珠单抗在一线治疗中的疗效正在 3 期 KEYNOTE-361 试验中进一步评估（ClinicalTrials.gov，NCT02335424）。
默克公司。
