贝博利珠单抗联合纳武利尤单抗治疗未经治晚期黑色素瘤的 III 期开放标签、PIVOT IO 001 研究结果。
Bempegaldesleukin Plus Nivolumab in Untreated Advanced Melanoma: The Open-Label, Phase III PIVOT IO 001 Trial Results.
机构信息
Melanoma Medical Oncology Department, The University of Texas MD Anderson Cancer Center, Houston, TX.
First Department of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
出版信息
J Clin Oncol. 2023 Oct 20;41(30):4756-4767. doi: 10.1200/JCO.23.00172. Epub 2023 Aug 31.
PURPOSE
Despite marked advances in the treatment of unresectable or metastatic melanoma, the need for novel therapies remains. Bempegaldesleukin (BEMPEG), a pegylated interleukin-2 (IL-2) cytokine prodrug, demonstrated efficacy in the phase II PIVOT-02 trial. PIVOT IO 001 (ClinicalTrials.gov identifier: NCT03635983) is a phase III, randomized, open-label study that builds on the PIVOT-02 results in first-line melanoma.
METHODS
Patients with previously untreated, unresectable, or metastatic melanoma were randomly assigned 1:1 to receive BEMPEG plus nivolumab (NIVO) or NIVO monotherapy. Primary end points were objective response rate (ORR) and progression-free survival (PFS) by blinded independent central review and overall survival (OS). Secondary and exploratory end points included additional efficacy measures, safety, and pharmacokinetics (PKs) and pharmacodynamics analyses.
RESULTS
In 783 patients (n = 391, BEMPEG plus NIVO; n = 392, NIVO monotherapy), the median follow-up was 11.6 months in the intent-to-treat population. The ORR with BEMPEG plus NIVO was 27.7% versus 36.0% with NIVO (two-sided = .0311). The median PFS with BEMPEG plus NIVO was 4.17 months (95% CI, 3.52 to 5.55) versus 4.99 months (95% CI, 4.14 to 7.82) with NIVO (hazard ratio [HR], 1.09; 97% CI, 0.88 to 1.35; = .3988). The median OS was 29.67 months (95% CI, 22.14 to not reached [NR]) with BEMPEG plus NIVO versus 28.88 months (95% CI, 21.32 to NR) with NIVO (HR, 0.94; 99.929% CI, 0.59 to 1.48; = .6361). Grade 3-4 treatment-related adverse events (AEs) and serious AE rates were higher with the combination (21.7% and 10.1%, respectively) versus NIVO (11.5% and 5.5%, respectively). BEMPEG PK exposure and absolute lymphocyte count changes after BEMPEG plus NIVO were comparable between PIVOT IO 001 and PIVOT-02.
CONCLUSION
The PIVOT IO 001 study did not meet its primary end points of ORR, PFS, and OS. Increased toxicity was observed with BEMPEG plus NIVO versus NIVO.
目的
尽管在治疗不可切除或转移性黑色素瘤方面取得了显著进展，但仍需要新的治疗方法。贝美格利单抗（BEMPEG）是一种聚乙二醇化的白细胞介素-2（IL-2）细胞因子前药，在 II 期 PIVOT-02 试验中显示出疗效。PIVOT IO 001（临床试验.gov 标识符：NCT03635983）是一项基于 PIVOT-02 结果的一线黑色素瘤的 III 期、随机、开放标签研究。
方法
先前未经治疗、不可切除或转移性黑色素瘤患者被随机分配 1:1 接受 BEMPEG 联合纳武利尤单抗（NIVO）或 NIVO 单药治疗。主要终点是盲法独立中心审查的客观缓解率（ORR）和无进展生存期（PFS）以及总生存期（OS）。次要和探索性终点包括其他疗效指标、安全性以及药代动力学（PK）和药效学分析。
结果
在 783 名患者（n=391，BEMPEG 联合 NIVO；n=392，NIVO 单药）中，意向治疗人群的中位随访时间为 11.6 个月。BEMPEG 联合 NIVO 的 ORR 为 27.7%，NIVO 为 36.0%（双侧=.0311）。BEMPEG 联合 NIVO 的中位 PFS 为 4.17 个月（95%CI，3.52 至 5.55），NIVO 为 4.99 个月（95%CI，4.14 至 7.82）（HR，1.09；97%CI，0.88 至 1.35；=.3988）。BEMPEG 联合 NIVO 的中位 OS 为 29.67 个月（95%CI，22.14 至未达到[NR]），NIVO 为 28.88 个月（95%CI，21.32 至 NR）（HR，0.94；99.929%CI，0.59 至 1.48；=.6361）。联合用药（分别为 21.7%和 10.1%）与 NIVO（分别为 11.5%和 5.5%）相比，治疗相关不良事件（AE）和严重 AE 发生率更高。与 PIVOT-02 相比，BEMPEG 联合 NIVO 后的 BEMPEG PK 暴露和绝对淋巴细胞计数变化在 PIVOT IO 001 中相似。
结论
PIVOT IO 001 研究未达到其主要终点，包括 ORR、PFS 和 OS。与 NIVO 相比，BEMPEG 联合 NIVO 观察到毒性增加。
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