肿瘤细胞治疗研究
英文原题：Nemvaleukin alfa monotherapy in patients with advanced melanoma and renal cell carcinoma: results from the phase 1/2 non-randomized ARTISTRY-1 trial.
Nemvaleukin 展示了药效学机制验证，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。
尽管免疫检查点抑制剂（ICI）及其联合方案在晚期实体瘤中的疗效不断改善，但仍有部分患者无应答或出现疾病进展，凸显了对具有持久获益的新型治疗的未满足需求。Nemvaleukin alfa（nemvaleukin，ALKS 4230）在ARTISTRY-1研究中，单药及与pembrolizumab联合，在经重度治疗的晚期实体瘤中均显示出可控的安全性和抗肿瘤活性。我们报告ARTISTRY-1研究中晚期黑色素瘤和肾细胞癌（RCC）队列中，nemvaleukin单药在推荐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是一项分为三部分（A、B和C）的多中心、开放标签、1/2期研究。既往接受过治疗（包括ICIs）且患有晚期黑色素瘤或RCC的成年患者被纳入B部分。患者接受静脉注射nemvaleukin，每日一次，第1-5天给药（21天为一个周期），剂量为6 µg/kg/天（RP2D由A部分确定）。B部分的主要终点为总缓解率（ORR）和安全性。次要终点包括药代动力学和药效学指标。
2016年7月至2023年3月，Part B中74例患者接受了nemvaleukin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例（7%）和2例（9%）患者观察到疾病稳定≥6个月。最常见的nemvaleukin相关3-4级治疗中出现的不良事件为中性粒细胞减少症（黑色素瘤，n=27（57%）；RCC，n=9（33%））。两个队列中均无患者发生≥3级治疗中出现的细胞因子释放综合征或输注相关反应不良事件（TEAEs）。未报告毛细血管渗漏综合征TEAEs。两个队列之间nemvaleukin暴露程度和持续时间的药代动力学参数相似。两个队列之间外周CD8+ T细胞和NK 细胞群体较基线的增加相似，观察到调节性T细胞变化极小。
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Nemvaleukin demonstrated pharmacodynamic proof of mechanism, with single-agent antitumor activity and manageable safety in patients with advanced melanoma and RCC. TRIAL REGISTRATION NUMBER: NCT02799095.
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