Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York.
START Madrid-FJD, Hospital Fundación Jiménez Díaz, Madrid, Spain.
Clin Cancer Res. 2021 Apr 15;27(8):2168-2178. doi: 10.1158/1078-0432.CCR-20-4405. Epub 2021 Jan 29.
T-cell immunoglobulin and mucin-domain-containing molecule-3 (TIM-3) blunts anticancer immunity and mediates resistance to programmed death 1 (PD-1) and PD ligand 1 (PD-L1) inhibitors. We assessed a novel, first-in-class, TIM-3 mAb, LY3321367, alone or in combination with the anti-PD-L1 antibody, LY300054 in patients with advanced solid tumor.
This open-label, multicenter, phase Ia/b study aimed to define the safety/tolerability and recommended phase II dose (RP2D) of LY3321367 with or without LY300054. Secondary objectives included pharmacokinetics/pharmacodynamics, immunogenicity, and efficacy. Biomarkers were assessed in exploratory analysis.
No dose-limiting toxicities were observed in the monotherapy ( = 30) or combination ( = 28) dose escalation. LY3321367 treatment-related adverse events (≥2 patients) included pruritus, rash, fatigue, anorexia, and infusion-related reactions. Dose-proportional increase in LY3321367 concentrations was not affected by either LY300054 or antidrug antibodies (observed in 50%-70% of patients). Pharmacokinetic/pharmacodynamic modeling indicated 100% target engagement at doses ≥600 mg. LY3321367 RP2D was 1,200 mg biweekly for four doses followed by 600 mg every 2 weeks thereafter. In the non-small cell lung cancer monotherapy expansion cohort, outcomes varied by prior anti-PD-1 therapy response status: anti-PD-1/L1 refractory patients [ = 23, objective response rate (ORR) 0%, disease control rate (DCR) 35%, progression-free survival (PFS) 1.9 months] versus anti-PD-1/L1 responders ( = 14, ORR 7%, DCR 50%, PFS 7.3 months). In combination expansion cohorts ( = 91), ORR and DCR were 4% and 42%; CD8 infiltration in paired biopsies increased in approximately half these patients.
LY3321367 exhibited acceptable safety profile with favorable pharmacokinetics/pharmacodynamics but only modest antitumor activity. The therapeutic relevance of TIM-3 blockade requires further investigation.
T 细胞免疫球蛋白和粘蛋白结构域蛋白 3（TIM-3）抑制抗肿瘤免疫，并介导对程序性死亡受体 1（PD-1）和 PD 配体 1（PD-L1）抑制剂的耐药性。我们评估了一种新型的、首创的 TIM-3 mAb，LY3321367，单独或联合抗 PD-L1 抗体 LY300054，用于治疗晚期实体瘤患者。
这是一项开放标签、多中心、I/ Ib 期研究，旨在确定 LY3321367 单药或联合 LY300054 的安全性/耐受性和推荐的 II 期剂量（RP2D）。次要目标包括药代动力学/药效学、免疫原性和疗效。在探索性分析中评估了生物标志物。
在单药治疗（n=30）或联合治疗（n=28）剂量递增中未观察到剂量限制毒性。LY3321367 治疗相关不良事件（≥2 例）包括瘙痒、皮疹、疲劳、厌食和输注相关反应。LY300054 或抗药物抗体不会影响 LY3321367 浓度的剂量比例增加（在 50%-70%的患者中观察到）。药代动力学/药效学模型表明，在剂量≥600mg 时，可实现 100%的靶标占有率。LY3321367 的 RP2D 为 1200mg 每 2 周 2 次，共 4 个剂量，随后每 2 周 600mg。在非小细胞肺癌单药扩展队列中，先前抗 PD-1 治疗反应状态决定了结果：抗 PD-1/L1 难治性患者（n=23，客观缓解率（ORR）0%，疾病控制率（DCR）35%，无进展生存期（PFS）1.9 个月）与抗 PD-1/L1 应答者（n=14，ORR 7%，DCR 50%，PFS 7.3 个月）相比。在联合扩展队列中（n=91），ORR 和 DCR 分别为 4%和 42%；大约一半的这些患者的配对活检中 CD8 浸润增加。
LY3321367 具有可接受的安全性和良好的药代动力学/药效学特征，但抗肿瘤活性仅为中等。TIM-3 阻断的治疗相关性需要进一步研究。
