Stein Mark N, Vinceneux Armelle, Robbrecht Debbie, Doger Bernard, Autio Karen A, Schweizer Michael T, Calvo Emiliano, Medina Laura, Van Dongen Marloes, Deville Jean-Laurent, Bernard-Tessier Alice, Ghosh Debopriya, Shotts Kristin, Shen Fei, Jaiprasart Pharavee, Chaudhary Ruchi, Wu Shujian, Cartee Leanne, Schnepp Robert, Gaut Daria, Lauring Josh, Wang Sherry C, Villalobos Victor M, Baldini Capucine
Columbia University Medical Center, New York, NY.
Centre Léon Bérard, Lyon, France.
J Clin Oncol. 2025 Aug;43(22):2515-2526. doi: 10.1200/JCO-25-00678. Epub 2025 Jun 1.
We report phase I trial results for pasritamig, a first-in-class, T-cell-engaging bispecific antibody targeting human kallikrein 2 (KLK2) expressed on the surface of prostate cancer (PC) cells.
Participants had metastatic castration-resistant PC and ≥1 prior therapy. Pasritamig was escalated from 0.5 mg to 2,000 mg for subcutaneous administration and from 150 mg to 900 mg for intravenous (IV) administration at dosing frequencies ranging from once every week to once every 6 weeks with different step-up dosing schedules. The primary objectives were to determine safety and the recommended phase II dose (RP2D) of pasritamig. Secondary objectives included preliminary assessment of antitumor activity.
One hundred seventy-four participants received pasritamig, with a median of 4 prior lines of systemic therapy. Treatment-related adverse events (TRAEs) occurred in 144 of 174 (82.8%) participants, with 17 of 174 (9.8%) experiencing grade ≥3 TRAEs. The RP2D was determined to be 3.5 mg (day 1), 18 mg (day 8), 300 mg (day 15), and then 300 mg IV once every 6 weeks. In the RP2D safety population (n = 45), infusion-related reactions (11/45, 24.4%), fatigue (7/45, 15.6%), cytokine release syndrome (CRS; 4/45, 8.9%, all grade 1), and lipase increase (4/45, 8.9%) were the most frequent TRAEs; all were grade 1 or 2. In the RP2D efficacy population (n = 33), median radiographic progression-free survival was 7.85 (95% CI, 2.89 to not estimable) months, and 14 of 33 (42.4%) participants achieved a ≥50% decrease from baseline in prostate-specific antigen.
Pasritamig demonstrated a favorable safety profile with very low rates of CRS and could be safely administered in an outpatient setting. Preliminary antitumor activity demonstrated proof of concept for KLK2 as a target in PC, warranting further development of pasritamig.
我们报告了帕斯里他米（pasritamig）的I期试验结果，这是一种一流的、靶向前列腺癌细胞表面表达的人激肽释放酶2（KLK2）的T细胞接合双特异性抗体。
参与者患有转移性去势抵抗性前列腺癌且接受过≥1线先前治疗。帕斯里他米皮下给药剂量从0.5毫克递增至2000毫克，静脉注射剂量从150毫克递增至900毫克，给药频率为每周一次至每6周一次，采用不同的逐步递增给药方案。主要目标是确定帕斯里他米的安全性和推荐的II期剂量（RP2D）。次要目标包括对抗肿瘤活性的初步评估。
174名参与者接受了帕斯里他米治疗，既往全身治疗的中位数为4线。174名参与者中有144名（82.8%）发生了与治疗相关的不良事件（TRAEs），174名中有17名（9.8%）经历了≥3级TRAEs。RP2D确定为3.5毫克（第1天）、18毫克（第8天）、300毫克（第15天），然后每6周静脉注射300毫克一次。在RP2D安全性人群（n = 45）中，与输注相关的反应（11/45，24.4%）、疲劳（7/45，15.6%）、细胞因子释放综合征（CRS；4/45，8.9%，均为1级）和脂肪酶升高（4/45，8.9%）是最常见的TRAEs；均为1级或2级。在RP2D疗效人群（n = 33）中，中位影像学无进展生存期为7.85（95%CI，2.89至不可估计）个月，33名参与者中有14名（42.4%）前列腺特异性抗原较基线水平下降≥50%。
帕斯里他米显示出良好的安全性，CRS发生率极低，可在门诊环境中安全给药。初步的抗肿瘤活性证明了KLK2作为前列腺癌靶点的概念，值得对帕斯里他米进行进一步开发。
