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。

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。