帕博利珠单抗联合恩杂鲁胺用于接受恩杂鲁胺治疗后进展的转移性去势抵抗性前列腺癌：2期KEYNOTE-199研究的队列4和队列5
Pembrolizumab plus enzalutamide for metastatic castration-resistant prostate cancer progressing on enzalutamide: cohorts 4 and 5 of the phase 2 KEYNOTE-199 study.
作者信息
Graff Julie N, Hoimes Christopher J, Gerritsen Winald R, Vaishampayan Ulka N, Elliott Tony, Hwang Clara, Ten Tije Albert J, Omlin Aurelius, McDermott Raymond S, Fradet Yves, Tagawa Scott T, Kilari Deepak, Ferrario Cristiano, Uemura Hiroji, Jones Robert J, Fukasawa Satoshi, Peer Avivit, Niu Cuizhen, Poehlein Christian H, Qiu Ping, Suttner Leah, de Wit Ronald, Schloss Charles, de Bono Johann S, Antonarakis Emmanuel S
机构信息
Oregon Health and Science University, Portland, OR, USA.
Case Comprehensive Cancer Center, University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
出版信息
Prostate Cancer Prostatic Dis. 2025 Jun;28(2):411-418. doi: 10.1038/s41391-024-00865-5. Epub 2024 Aug 12.
BACKGROUND
KEYNOTE-199 (NCT02787005) is a multicohort phase 2 study evaluating pembrolizumab in patients with metastatic castration-resistant prostate cancer (mCRPC). Results from cohorts 4 (C4) and 5 (C5) are presented.
METHODS
Eligible patients had not received chemotherapy for mCRPC and had responded to enzalutamide prior to developing resistance as defined by Prostate Cancer Clinical Trials Working Group 3 guidelines. Patients with RECIST-measurable disease were enrolled in C4, and patients with bone-only or bone-predominant disease were enrolled in C5. All patients received pembrolizumab 200 mg every 3 weeks for ≤35 cycles with ongoing enzalutamide until progression, unacceptable toxicity, or withdrawal. The primary end point was objective response rate (ORR) per RECIST v1.1 by blinded independent central review in C4. Secondary end points included disease control rate (DCR), overall survival, and safety in each cohort and both cohorts combined.
RESULTS
A total of 126 patients were treated (C4, n = 81; C5, n = 45). Median age was 72 years (range 43-92), and 87.3% had received ≥6 months of enzalutamide prior to study entry. Confirmed ORR was 12.3% (95% CI 6.1-21.5%) for C4. Median duration of response in C4 was 8.1 months (range, 2.5+ to 15.2), and 5 of these patients experienced an objective response lasting ≥6 months. DCR was 53.1% (95% CI 41.7-64.3%) in C4 and 51.1% (95% CI 35.8-66.3%) in C5. Median overall survival was 17.6 months (95% CI 14.0-22.6) in C4 and 20.8 months (95% CI 14.1-28.9) in C5. Grade ≥3 treatment-related adverse events occurred in 35 patients (27.8%); 2 patients in C4 died from immune-related adverse events (myasthenic syndrome and Guillain-Barré syndrome).
CONCLUSIONS
The addition of pembrolizumab to ongoing enzalutamide treatment in patients with mCRPC that progressed on enzalutamide after initial response demonstrated modest antitumor activity with a manageable safety profile.
CLINICAL TRIAL REGISTRY AND ID
ClinicalTrials.gov, NCT02787005.
背景
KEYNOTE-199（NCT02787005）是一项多队列2期研究，评估帕博利珠单抗在转移性去势抵抗性前列腺癌（mCRPC）患者中的疗效。本文展示了队列4（C4）和队列5（C5）的研究结果。
方法
符合条件的患者未曾接受过mCRPC化疗，且在出现耐药前对恩杂鲁胺有反应，耐药定义符合前列腺癌临床试验工作组3指南。根据实体瘤疗效评价标准（RECIST）可测量疾病的患者入组C4，仅骨转移或以骨转移为主的疾病患者入组C5。所有患者每3周接受200mg帕博利珠单抗治疗，最多35个周期，同时持续使用恩杂鲁胺直至疾病进展、出现不可接受的毒性或停药。主要终点是C4中由盲态独立中央审查按照RECIST v1.1标准评估的客观缓解率（ORR）。次要终点包括每个队列及两个队列合并后的疾病控制率（DCR）、总生存期和安全性。
结果
共治疗126例患者（C4，n = 81；C5，n = 45）。中位年龄为72岁（范围43 - 92岁），87.3%的患者在入组研究前接受过≥6个月的恩杂鲁胺治疗。C4中确认的ORR为12.3%（95%CI 6.1 - 21.5%）。C4中的中位缓解持续时间为8.1个月（范围，2.5 +至15.2个月），其中5例患者的客观缓解持续≥6个月。C4中的DCR为53.1%（95%CI 41.7 - 64.3%），C5中的DCR为51.1%（95%CI 35.8 - 66.3%）。C4中的中位总生存期为17.6个月（95%CI 14.0 - 22.6），C5中的中位总生存期为20.8个月（95%CI 14.1 - 28.9）。35例患者（27.8%）发生≥3级治疗相关不良事件；C4中有2例患者死于免疫相关不良事件（重症肌无力综合征和吉兰 - 巴雷综合征）。
结论
在初始反应后对恩杂鲁胺产生进展的mCRPC患者中，在持续使用恩杂鲁胺治疗的基础上加用帕博利珠单抗显示出适度的抗肿瘤活性，且安全性可控。
临床试验注册及编号
ClinicalTrials.gov，NCT02787005
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