Department of GI Medical Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University, Tianjin, China.
Department of Medical Oncology, Department of Cancer Center, Peking Union Medical College Hospital, Beijing, China.
Cancer Immunol Immunother. 2024 Jun 4;73(8):154. doi: 10.1007/s00262-024-03743-0.
Alpha-fetoprotein elevated gastric cancer (AFPGC) got growing interests for its aggressive nature and unfavorable prognosis. Here, a phase 1 dose escalation study was conducted to evaluate safety and efficacy of zimberelimab (GLS-010, anti-PD-1) plus lenvatinib and chemotherapy (XELOX) as the first-line treatment for AFPGC.
Histologically confirmed HER2-negative, advanced GC patients with elevated serum AFP level (≥ 20 ng/ml) were screened. Using a 3 + 3 dose escalation design, patients were administered varying doses of lenvatinib (12, 16, 20 mg) with GLS-010 and XELOX. The primary endpoints were safety and determination of recommended phase II dose (RP2D). Secondary endpoints included overall response rate (ORR), progression-free survival (PFS) and disease control rate.
Nine patients were enrolled with no dose-limiting toxicities observed. Most frequent treatment-related AEs were fatigue (55.6%), hand-foot syndrome (55.6%) and rash (55.6%), and no grade ≥ 4 AEs were reported. All patients exhibited disease control with ORR reaching 33.3%. The median PFS and OS reached 7.67 months (95% CI 4.07-11.27) and 13.17 months (95% CI 2.78-23.56), respectively. Serum AFP level was found correlated with therapeutic responses. Further 16s rRNA sequencing analysis demonstrated altered gut microbiota with elevated abundance of Lachnospiraceae bacterium-GAM79 and Roseburia hominis A2-183.
GLS-010 plus lenvatinib and XELOX demonstrated a manageable safety profile with promising efficacy for AFPGC. With RP2D of lenvatinib determined as 16 mg, further expansion cohort is now ongoing. Translational investigation suggested that serum AFP can be indictive for therapeutic responses and certain microbiota species indicating favorable responses to immunotherapy was elevated after the combinational treatment.
甲胎蛋白升高型胃癌（AFPGC）因其侵袭性和不良预后而受到越来越多的关注。在这里，进行了一项 1 期剂量递增研究，以评估 zimberelimab（GLS-010，抗 PD-1）联合 lenvatinib 和化疗（XELOX）作为 AFPGC 一线治疗的安全性和疗效。
筛选出组织学证实的 HER2 阴性、血清 AFP 水平升高（≥20ng/ml）的晚期 GC 患者。采用 3+3 剂量递增设计，给予不同剂量的 lenvatinib（12、16、20mg）联合 GLS-010 和 XELOX。主要终点是安全性和确定推荐的 II 期剂量（RP2D）。次要终点包括总缓解率（ORR）、无进展生存期（PFS）和疾病控制率。
共纳入 9 例患者，未观察到剂量限制毒性。最常见的治疗相关不良事件是乏力（55.6%）、手足综合征（55.6%）和皮疹（55.6%），无≥4 级不良事件报告。所有患者均表现出疾病控制，ORR 达到 33.3%。中位 PFS 和 OS 分别达到 7.67 个月（95%CI 4.07-11.27）和 13.17 个月（95%CI 2.78-23.56）。血清 AFP 水平与治疗反应相关。进一步的 16s rRNA 测序分析显示，治疗后肠道微生物群发生改变，lachnospiraceae 菌-GAM79 和 Roseburia hominis A2-183 的丰度增加。
GLS-010 联合 lenvatinib 和 XELOX 治疗 AFPGC 具有良好的安全性和有希望的疗效。确定 lenvatinib 的 RP2D 为 16mg，目前正在进行扩大队列研究。转化研究表明，血清 AFP 可作为治疗反应的指示物，某些对免疫治疗有良好反应的微生物物种在联合治疗后升高。
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