背景:我们进行了一项试验,以评估纳武单抗和紫杉醇作为富含免疫相关生物标志物的晚期胃癌(AGC)的二线治疗的有效性和安全性。
方法:这个开放标签,单臂,Ib/II期研究是多机构研究的一部分,在韩国进行的生物标志物综合伞式研究。在Ib阶段,患者在第1天和第15天接受nivolumab(3mg/kg),在第1,8,15天接受紫杉醇(剂量水平1,70mg/m2或剂量水平2,80mg/m2).在第二阶段,EB病毒相关患者,纳入了错配修复缺陷或程序性细胞死亡-配体-1阳性AGC。主要终点是推荐的II期剂量(RP2D,Ib期)和无进展生存期(PFS,第二阶段)。次要终点包括客观反应率(ORR),总生存期(OS),安全,和探索性生物标志物分析。
结果:选择剂量水平2作为RP2D。在第二阶段,纳入48例患者。中位PFS和OS分别为3.9和11.2个月,分别。ORR为23.3%,中位缓解持续时间为16.7个月.3级或更高级别治疗相关不良事件,主要是中性粒细胞减少症,发生在20例患者中(41.7%)。靶向测序显示具有RTK/RAS途径改变或HLA-A02超型的患者具有更好的存活率。基线白细胞介素-1受体拮抗剂水平升高的患者生存率较差。
结论:虽然研究未达到主要终点,nivolumab和紫杉醇用于AGC表现出持久的反应,毒性可控制.基因组分析或血浆细胞因子分析可以为选择将从免疫疗法结合化学疗法中受益更多的患者提供信息。
We conducted a
trial to evaluate the efficacy and safety of nivolumab and paclitaxel as second-line therapy for immune-related biomarker-enriched advanced gastric cancer (AGC).
This open-label, single-arm, phase Ib/II
study was a part of multi-institutional, biomarker-integrated umbrella
study conducted in Korea. In phase Ib, patients received nivolumab (3 mg/kg) on Days 1 and 15 and paclitaxel (dose level 1, 70 mg/m2 or dose level 2, 80 mg/m2) on Days 1, 8, 15 every four weeks. In phase II, patients with Epstein-Barr virus-related, deficient mismatch repair or programmed cell death-ligand-1-positive AGC were enrolled. The primary endpoints were recommended phase II dose (RP2D, phase Ib) and progression-free survival (PFS, phase II). Secondary endpoints included objective response rate (ORR), overall survival (OS), safety, and exploratory biomarker analysis.
Dose level 2 was selected as RP2D. In phase II, 48 patients were enrolled. The median PFS and OS were 3.9 and 11.2 months, respectively. The ORR was 23.3%, and the median response duration was 16.7 months. Grade 3 or higher treatment-related adverse events, mainly neutropenia, occurred in 20 patients (41.7%). Targeted sequencing revealed that patients with RTK/RAS pathway alterations or the HLA-A02 supertype had better survival. Patients with elevated baseline interleukin-1 receptor antagonist levels had worse survival.
Although the
study did not meet its primary end point, nivolumab and paclitaxel for AGC demonstrated a durable response with manageable toxicity profiles. Genomic analysis or plasma cytokine analysis may provide information for the selection of patients who would benefit more from immunotherapy combined with chemotherapy.