Calvo Emiliano, Boni Valentina, Dumas Olivier, Shin Sang Joon, Rosen Seth D, Chaudhry Arvind, Debruyne Philip R, He Xiaomin, Vaishampayan Ulka N, McDermott David F
START Madrid-CIOCC, Centro Integral Oncológico Clara Campal, Madrid, Spain
START Madrid-CIOCC, Centro Integral Oncológico Clara Campal, Madrid, Spain.
J Immunother Cancer. 2025 Aug 4;13(8):e010777. doi: 10.1136/jitc-2024-010777.
Despite improved outcomes with immune checkpoint inhibitors (ICIs) and their combinations in advanced solid tumors, a subset of patients remains unresponsive or progresses, highlighting an unmet need for novel treatments with durable benefit. Nemvaleukin alfa (nemvaleukin, ALKS 4230) demonstrated manageable safety and antitumor activity, alone and in combination with pembrolizumab, across heavily pretreated advanced solid tumors in the ARTISTRY-1 study. We report in-depth antitumor activity, safety, pharmacokinetics, and pharmacodynamics of nemvaleukin monotherapy at the recommended phase 2 dose (RP2D) in advanced melanoma and renal cell carcinoma (RCC) cohorts from ARTISTRY-1.
ARTISTRY-1 was a three-part (A, B, and C), multicenter, open-label, phase 1/2 study. Adult patients who had received prior treatment, including ICIs, and had advanced melanoma or RCC were enrolled in Part B. Patients received intravenous nemvaleukin once daily on days 1-5 (21-day cycle) at 6 µg/kg/day (RP2D determined from Part A). Primary endpoints for Part B were overall response rate (ORR) and safety. Secondary endpoints included pharmacokinetic and pharmacodynamic measures.
From July 2016 to March 2023, 74 patients in Part B received nemvaleukin monotherapy (melanoma, n=47; RCC, n=27). ORR in melanoma and RCC cohorts was 9% (95% CI, 2% to 21%; n=4) and 14% (95% CI, 3% to 35%; n=3), respectively; disease control rate was 50% (95% CI, 35% to 65%; n=23) and 50% (95% CI, 28% to 72%, n=11), respectively, with stable disease ≥6 months observed in 3 (7%) and 2 (9%) patients, respectively. The most common nemvaleukin-related treatment-emergent adverse event of grade 3-4 was neutropenia (melanoma, n=27 (57%); RCC, n=9 (33%)). No patients in either cohort experienced grade ≥3 treatment-emergent adverse events (TEAEs) of cytokine release syndrome or infusion-related reaction. There were no reported capillary leak syndrome TEAEs. Pharmacokinetic parameters for extent and duration of nemvaleukin exposure were similar between the two cohorts. Increases in peripheral CD8 T-cell and natural killer cell populations from baseline were similar between the two cohorts, with minimal changes in regulatory T cells observed.
Nemvaleukin demonstrated pharmacodynamic proof of mechanism, with single-agent antitumor activity and manageable safety in patients with advanced melanoma and RCC.
NCT02799095.
尽管免疫检查点抑制剂（ICI）及其联合用药在晚期实体瘤治疗中取得了更好的疗效，但仍有一部分患者无反应或病情进展，这凸显了对具有持久疗效的新型治疗方法的未满足需求。在ARTISTRY-1研究中，纳姆伐利尤金α（纳姆伐利尤金，ALKS 4230）在单独使用以及与帕博利珠单抗联合使用时，在经过大量预处理的晚期实体瘤患者中显示出可控的安全性和抗肿瘤活性。我们报告了在ARTISTRY-1研究中晚期黑色素瘤和肾细胞癌（RCC）队列中，纳姆伐利尤金单药治疗在推荐的2期剂量（RP2D）下的深入抗肿瘤活性、安全性、药代动力学和药效学。
ARTISTRY-1是一项分为三个部分（A、B和C）的多中心、开放标签的1/2期研究。接受过包括ICI在内的先前治疗且患有晚期黑色素瘤或RCC的成年患者被纳入B部分。患者在第1 - 5天每天静脉注射一次纳姆伐利尤金（21天周期），剂量为6 μg/kg/天（RP2D由A部分确定）。B部分的主要终点是总缓解率（ORR）和安全性。次要终点包括药代动力学和药效学指标。
从2016年7月至2023年3月，B部分的74名患者接受了纳姆伐利尤金单药治疗（黑色素瘤，n = 47；RCC，n = 27）。黑色素瘤和RCC队列的ORR分别为9%（95% CI，2%至21%；n = 4）和14%（95% CI，3%至35%；n = 3）；疾病控制率分别为50%（95% CI，35%至65%；n = 23）和50%（95% CI，28%至72%，n = 11），分别有3名（7%）和2名（9%）患者观察到疾病稳定≥6个月。最常见的3 - 4级与纳姆伐利尤金相关的治疗中出现的不良事件是中性粒细胞减少（黑色素瘤，n = 27（57%）；RCC，n = 9（33%））。两个队列中均没有患者经历≥3级的细胞因子释放综合征或输液相关反应的治疗中出现的不良事件（TEAE）。没有报告毛细血管渗漏综合征TEAE。两个队列中纳姆伐利尤金暴露程度和持续时间的药代动力学参数相似。两个队列中，外周血CD8 T细胞和自然杀伤细胞群体相对于基线的增加相似，调节性T细胞的变化最小。
纳姆伐利尤金显示出药效学的作用机制证据，在晚期黑色素瘤和RCC患者中具有单药抗肿瘤活性和可控的安全性。
NCT02799095。
