PORTER的临床和转化研究结果，一项转移性去势抵抗性前列腺癌联合免疫疗法的多队列I期平台试验。
Clinical and Translational Results from PORTER, a Multicohort Phase I Platform Trial of Combination Immunotherapy in Metastatic Castration-Resistant Prostate Cancer.
作者信息
Galsky Matthew D, Autio Karen A, Cabanski Christopher R, Wentzel Kristopher, Graff Julie N, Friedlander Terence W, Howes Timothy R, Shotts Kristin M, Densmore Julie, Spasic Marko, Da Silva Diane M, Chen Richard O, Lata Jennifer, Skolnik Jeffrey, Keler Tibor, Yellin Michael J, LaVallee Theresa M, Fairchild Justin, Boffo Silvia, O'Donnell-Tormey Jill, Dugan Ute, Bhardwaj Nina, Subudhi Sumit K, Fong Lawrence
机构信息
Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.
出版信息
Clin Cancer Res. 2025 Apr 14;31(8):1463-1475. doi: 10.1158/1078-0432.CCR-24-3693.
PURPOSE
Current immune checkpoint therapies offer limited benefits for metastatic castration-resistant prostate cancer. Novel combinations may enhance immunotherapy efficacy.
PATIENTS AND METHODS
We conducted an open-label, noncomparative platform trial (NCT03835533) in metastatic castration-resistant prostate cancer to assess nivolumab-based combinations. The cohorts were as follows: (A) bempegaldesleukin 0.006 mg/kg and nivolumab 360 mg i.v. every 3 weeks; (B) stereotactic body radiotherapy 30 to 50 Gy, CDX-301 75 μg/kg s.c. for 5 days, poly-ICLC 1 mg intramuscularly weekly twice for 3 weeks, and nivolumab 480 mg every 4 weeks; and (C) CDX-301 75 μg/kg for 10 days, INO-5151 3 mg intramuscularly on lead-in day 8, day 1 of cycles 1 to 3, and then every 12 weeks, and nivolumab 480 mg every 4 weeks. The primary endpoint was safety; secondary endpoints included composite response rate (radiographic, PSA, or circulating tumor cell responses), 6-month disease control rate, progression-free survival, and overall survival. Serial blood and tissue samples were analyzed for pharmacodynamics and association with disease control.
RESULTS
A total of 43 patients were enrolled (n = 14, 15, and 14 in cohorts A, B, and C, respectively). Grade 3 to 4 treatment-related adverse events occurred in 10 (71%), 2 (13%), and 2 (14%) patients, respectively, with one grade 5 treatment-related adverse event in cohort A. Composite response rates were 7% (1/14), 33% (5/15), and 7% (1/14). Across cohorts, 6-month disease control was associated with preexisting memory/regulatory T cells, TNFα, and other inflammatory pathways.
CONCLUSIONS
Cohort B, which combined radiotherapy with CDX-301, poly-ICLC, and nivolumab, demonstrated encouraging clinical activity. Preexisting rather than treatment-induced immune activation was associated with clinical benefit across cohorts, highlighting the importance of baseline immune fitness.
目的
目前的免疫检查点疗法对转移性去势抵抗性前列腺癌的益处有限。新型联合疗法可能会提高免疫治疗效果。
患者与方法
我们在转移性去势抵抗性前列腺癌患者中开展了一项开放标签、非对照的平台试验（NCT03835533），以评估基于纳武利尤单抗的联合疗法。队列如下：（A）贝姆培塞利ukin 0.006 mg/kg，纳武利尤单抗360 mg，静脉注射，每3周一次；（B）立体定向体部放疗30至50 Gy，CDX - 301 75 μg/kg，皮下注射，共5天，聚肌胞苷酸 - 聚左旋赖氨酸 - CpG（poly - ICLC）1 mg，肌肉注射，每周两次，共3周，纳武利尤单抗480 mg，每4周一次；（C）CDX - 301 75 μg/kg，共10天，INO - 5151 3 mg，在导入期第8天、第1周期至第3周期的第1天肌肉注射，然后每12周一次，纳武利尤单抗480 mg，每4周一次。主要终点是安全性；次要终点包括综合缓解率（影像学、前列腺特异性抗原或循环肿瘤细胞反应）、6个月疾病控制率、无进展生存期和总生存期。对系列血液和组织样本进行药效学分析以及与疾病控制的相关性分析。
结果
共纳入43例患者（队列A、B、C分别为14例、15例和14例）。3至4级治疗相关不良事件分别发生在10例（71%）、2例（13%）和2例（14%）患者中，队列A有1例5级治疗相关不良事件。综合缓解率分别为7%（1/14）、33%（5/15）和7%（1/14）。在各个队列中，6个月疾病控制与预先存在的记忆/调节性T细胞、肿瘤坏死因子α及其他炎症途径相关。
结论
将放疗与CDX - 301、poly - ICLC和纳武利尤单抗联合使用的队列B显示出令人鼓舞的临床活性。预先存在而非治疗诱导的免疫激活与各队列的临床获益相关，突出了基线免疫状态的重要性。
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