帕博利珠单抗联合多西他赛和泼尼松在转移性去势抵抗性前列腺癌患者中的应用：来自 1b/2 期 KEYNOTE-365 队列 B 研究的长期结果。

Pembrolizumab Plus Docetaxel and Prednisone in Patients with Metastatic Castration-resistant Prostate Cancer: Long-term Results from the Phase 1b/2 KEYNOTE-365 Cohort B Study.

机构信息

Department of Medicine, Division of Oncology, University of Washington and Fred Hutchinson Cancer Research Center, G4-830, Seattle, WA, USA.

Department of Oncology, Cross Cancer Institute, Edmonton, AB, Canada.

出版信息

Eur Urol. 2022 Jul;82(1):22-30. doi: 10.1016/j.eururo.2022.02.023. Epub 2022 Apr 6.

DOI:10.1016/j.eururo.2022.02.023

PMID:35397952

Abstract

BACKGROUND

Patients with metastatic castration-resistant prostate cancer (mCRPC) frequently receive docetaxel after they develop resistance to abiraterone or enzalutamide and need more efficacious treatments.

OBJECTIVE

To evaluate the efficacy and safety of pembrolizumab plus docetaxel and prednisone in patients with mCRPC.

DESIGN, SETTING, AND PARTICIPANTS: The trial included patients with mCRPC in the phase 1b/2 KEYNOTE-365 cohort B study who were chemotherapy naïve and who experienced failure of or were intolerant to ≥4 wk of abiraterone or enzalutamide for mCRPC with progressive disease within 6 mo of screening.

INTERVENTION

Pembrolizumab 200 mg intravenously (IV) every 3 wk (Q3W), docetaxel 75 mg/m IV Q3W, and prednisone 5 mg orally twice daily.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS

The primary endpoints were safety, the prostate-specific antigen (PSA) response rate, and the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by blinded independent central review (BICR). Secondary endpoints included time to PSA progression; the disease control rate (DCR) and duration of response (DOR) according to RECIST v1.1 by BICR; ORR, DCR, DOR, and radiographic progression-free survival (rPFS) according to Prostate Cancer Working Group 3-modified RECIST v1.1 by BICR; and overall survival (OS).

RESULTS AND LIMITATIONS

Among 104 treated patients, 52 had measurable disease. The median time from allocation to data cutoff (July 9, 2020) was 32.4 mo, during which 101 patients discontinued treatment, 81 (78%) for disease progression. The confirmed PSA response rate was 34% and the confirmed ORR (RECIST v1.1) was 23%. Median rPFS and OS were 8.5 mo and 20.2 mo, respectively. Treatment-related adverse events (TRAEs) occurred in 100 patients (96%). Grade 3-5 TRAEs occurred in 46 patients (44%). Seven AE-related deaths (6.7%) occurred (2 due to treatment-related pneumonitis). Limitations of the study include the single-arm design and small sample size.

CONCLUSIONS

Pembrolizumab plus docetaxel and prednisone demonstrated antitumor activity in chemotherapy-naïve patients with mCRPC treated with abiraterone or enzalutamide for mCRPC. Safety was consistent with profiles for the individual agents. Further investigation is warranted.

PATIENT SUMMARY

We evaluated the efficacy and safety of the anti-PD-1 antibody pembrolizumab combined with the chemotherapy drug docetaxel and the steroid prednisone for patients with metastatic prostate cancer resistant to androgen deprivation therapy , and who never received chemotherapy. The combination showed antitumor activity and manageable safety in this patient population. This trial is registered on ClinicalTrials.gov as NCT02861573.

摘要

背景

转移性去势抵抗性前列腺癌（mCRPC）患者在对阿比特龙或恩扎鲁胺产生耐药后经常接受多西他赛治疗，需要更有效的治疗方法。

目的

评估帕博利珠单抗联合多西他赛和泼尼松在 mCRPC 患者中的疗效和安全性。

设计、地点和参与者：该试验包括来自 KEYNOTE-365 队列 B 研究的 mCRPC 患者，这些患者在筛选后 6 个月内疾病进展，且在接受阿比特龙或恩扎鲁胺治疗 mCRPC 期间经历了≥4 周的治疗失败或不耐受，且无化疗史。

干预措施

帕博利珠单抗 200mg 静脉输注（IV），每 3 周（Q3W）一次；多西他赛 75mg/m2 IV，每 3 周一次；泼尼松 5mg 口服，每日两次。

结局测量和统计分析

主要终点为安全性、前列腺特异性抗原（PSA）缓解率和根据实体瘤疗效评价标准 1.1 版（RECIST v1.1）由盲法独立中心评价（BICR）评估的客观缓解率（ORR）。次要终点包括 PSA 进展时间；根据 RECIST v1.1 由 BICR 评估的疾病控制率（DCR）和缓解持续时间（DOR）；根据 BICR 评估的前列腺癌工作组 3 修订版 RECIST v1.1 的 ORR、DCR、DOR 和放射学无进展生存期（rPFS）；以及总生存期（OS）。

结果和局限性

在 104 例接受治疗的患者中，有 52 例有可测量的疾病。截至 2020 年 7 月 9 日数据截止日期的中位时间为 32.4 个月，在此期间 101 例患者停止治疗，81 例（78%）因疾病进展。确认的 PSA 缓解率为 34%，确认的 ORR（RECIST v1.1）为 23%。中位 rPFS 和 OS 分别为 8.5 个月和 20.2 个月。100 例患者（96%）发生与治疗相关的不良事件（TRAEs）。46 例患者（44%）发生 3-5 级 TRAEs。7 例 AE 相关死亡（6.7%）发生（2 例与治疗相关的肺炎有关）。该研究的局限性包括单臂设计和样本量小。