Purpose: To evaluate linrodostat mesylate, a selective, oral indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, combined with nivolumab ± ipilimumab in advanced solid tumors and hematologic malignancies. Patients and Methods: In this phase 1/2 study, patients received once-daily (QD) linrodostat (part 1 [escalation], 25-400 mg; part 2 [expansion], 100 or 200 mg) plus nivolumab (480 mg every [Q] 4 weeks [W] or 240 mg Q2W) or triplet therapy (part 3, linrodostat 20-100 mg QD; nivolumab 360 mg Q3W or 480 mg Q4W; ipilimumab 1 mg/kg Q6W or Q8W). Endpoints included safety and efficacy (co-primary; parts 2, 3), pharmacokinetics, pharmacodynamics, biomarkers, and efficacy (part 1). Results: Fifty-five, 494, and 41 patients were enrolled in parts 1, 2, and 3, respectively. Linrodostat exposures exceeded predicted therapeutic target concentrations starting at 50 mg. Rates of grade 3/4 adverse events were 50.1%-63.4%. The maximum tolerated linrodostat dose was 200 mg; dose-limiting toxicities were primarily immune related. Responses were observed across different cohorts, study parts, and tumor types, particularly in immunotherapy-naive patients. Kynurenine decreased with linrodostat + nivolumab, regardless of response. In contrast, interferon gamma (IFN-γ) gene expression signature was associated with response; in nonmelanoma patients, a composite of low tryptophan 2,3-dioxygenase (TDO2) gene expression plus high IFN-γ signature was associated with response. Conclusions: Linrodostat + nivolumab ± ipilimumab demonstrated a manageable safety profile. Kynurenine changes supported IDO1 pathway inhibition but did not correlate with response. A composite biomarker of low TDO2 expression plus high IFN-γ gene expression may predict response to linrodostat + nivolumab.

中文翻译：

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吲哚胺 2,3-双加氧酶 1 抑制剂甲磺酸林罗司他联合纳武利尤单抗或纳武利尤单抗和伊匹木单抗治疗晚期实体瘤或血液系统恶性肿瘤的 1/2 期研究


目的：评价甲磺酸林罗司他，一种选择性口服吲哚胺 2,3-双加氧酶 1 （IDO1） 抑制剂，联合纳武利尤单抗±伊匹木单抗治疗晚期实体瘤和血液系统恶性肿瘤。患者和方法：在这项 1/2 期研究中，患者接受每日一次 （QD） linrodostat （第 1 部分 [升级]，25-400 mg;第 2 部分 [扩展]，100 或 200 mg）加纳武利尤单抗 （480 mg 每 [Q] 4 周 [W] 或 240 mg Q2W）或三联疗法 （第 3 部分，linrodostat 20-100 mg QD;纳武利尤单抗 360 mg Q3W 或 480 mg Q4W;伊匹木单抗 1 mg/kg Q6W 或 Q8W）。终点包括安全性和有效性（共同主要;第 2、3 部分）、药代动力学、药效学、生物标志物和疗效（第 1 部分）。结果： 第 1 、 2 和 3 部分分别纳入了 55 例、 494 例和 41 例患者。从 50 mg 开始，Linrodostat 暴露量超过了预测的治疗靶浓度。3/4 级不良事件发生率为 50.1%-63.4%。linrodostat 的最大耐受剂量为 200 mg;剂量限制性毒性主要与免疫有关。在不同的队列、研究部分和肿瘤类型中观察到反应，尤其是在未接受过免疫治疗的患者中。无论反应如何，linrodostat + nivolumab 组犬尿氨酸均降低。相比之下，干扰素 γ （IFN-γ） 基因表达特征与反应相关;在非黑色素瘤患者中，低色氨酸 2,3-双加氧酶 （TDO2） 基因表达加高 IFN-γ 特征的复合与反应相关。结论： Linrodostat + nivolumab ± ipilimumab 显示出可控的安全性。犬尿氨酸变化支持 IDO1 通路抑制，但与反应无关。低 TDO2 表达加高 IFN-γ 基因表达的复合生物标志物可预测对 linrodostat + nivolumab 的反应。