ABBV-428（一种间皮素-CD40 双特异性药物）在晚期实体瘤患者中的 I 期研究。,Journal for ImmunoTherapy of Cancer

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ABBV-428（一种间皮素-CD40 双特异性药物）在晚期实体瘤患者中的 I 期研究。
Journal for ImmunoTherapy of Cancer ( IF 10.3 ) Pub Date : 2021-02-01 , DOI: 10.1136/jitc-2020-002015
Jason J Luke ₁ , Fabrice Barlesi ₂ , Ki Chung ₃ , Anthony W Tolcher ₄ , Karen Kelly ₅ , Antoine Hollebecque ₆ , Christophe Le Tourneau _{7,

8,

9} , Vivek Subbiah ₁₀ , Frank Tsai ₁₁ , Steven Kao ₁₂ , Philippe A Cassier ₁₃ , Mustafa Khasraw ₁₄ , Hedy L Kindler ₁₅ , Hua Fang ₁₆ , Frances Fan ₁₇ , Kathryn Allaire ₁₇ , Maulik Patel ₁₈ , Shiming Ye ₁₉ , Debra T Chao ₂₀ , William R Henner ₂₁ , Joel S Hayflick ₂₂ , Michael A McDevitt ₂₂ , Lawrence Fong ₁₇

Affiliation

Cancer Immunotherapeutics Center, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
Multidisciplinary Oncology & Therapeutic Innovations Department, Aix-Marseille University, Assistance Publique Hôpitaux de Marseille, CNRS, INSERM, CRCM, CEPCM CLIP2, Marseille, France.
Hematology and Oncology, PRISMA Health System, Greenville, South Carolina, USA.
Clinical Research, NEXT Oncology, San Antonio, Texas, USA.
UC Davis Comprehensive Cancer Center, University of California, Sacramento, California, USA.
Drug Development Department (DITEP), Gustave Roussy Cancer Campus, Villejuif, France.
Department of Drug Development and Innovation (D3i), Curie Institute, Paris and Saint-Cloud, France.
INSERM U900 Research Unit, Saint-Cloud, France.
Paris-Saclay University, Paris, France.
Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Hematology/Oncology, HonorHealth Research Institute, Scottsdale, Arizona, USA.
Medical Oncology, Chris O'Brien Lifehouse, Camperdown, New South Wales, Australia.
Department of Medical Oncology, Centre Léon Bérard, Lyon, France.
Department of Neurosurgery, Duke University, Durham, North Carolina, USA.
Section of Hematology/Oncology, University of Chicago Medicine, Chicago, Illinois, USA.
Precision Medicine, AbbVie Inc, Redwood City, California, USA.
Department of Medicine, University of California San Francisco, San Francisco, California, USA.
Clinical Pharmacology, AbbVie Inc, Redwood City, California, USA.
Oncology Discovery, AbbVie Inc, Redwood City, California, USA.
Search & Evaluation, Oncology, AbbVie Inc, Redwood City, California, USA.
Statistics, AbbVie Inc, Redwood City, California, USA.
Oncology Early Development, AbbVie Inc, Redwood City, California, USA.

背景 CD40 激动剂免疫疗法可能会允许抗原呈递细胞促进抗肿瘤 T 细胞活化并重新培养巨噬细胞以破坏肿瘤间质。CD40 激动剂的全身给药历来与相当大的毒性有关，这为开发肿瘤靶向免疫调节剂以提高临床安全性和有效性提供了理论基础。该 I 期研究评估了 ABBV-428 的安全性、耐受性、初步抗肿瘤活性和初步生物标志物，ABBV-428 是一流的间皮素靶向双特异性抗体，专为肿瘤微环境依赖性 CD40 激活而设计，具有有限的全身毒性。方法每 2 周对晚期实体瘤患者进行一次 ABBV-428 静脉内给药。加速滴定（从 0. 01 mg/kg 剂量）和 3+3 剂量递增方案，随后在卵巢癌和间皮瘤（与高间皮素表达相关的肿瘤类型）中推荐的 II 期剂量队列扩展。结果 59 名患者接受了 0.01 至 3.6 mg/kg 之间的剂量治疗。未达到最大耐受剂量，选择3.6 mg/kg作为II期推荐剂量。七名患者 (12%) 报告了输液相关反应。与治疗相关的 ≥ 3 级治疗紧急不良事件为心包积液、结肠炎、输液相关反应和胸腔积液（各 n = 1，2%），没有细胞因子释放综合征的报道。药代动力学概况表明暴露量大致呈剂量比例增加，从 0.4 到 3.6 mg/kg。在推荐的 II 期剂量下，9/25 (36%) 患者的最佳反应是疾病稳定。从 0.8 mg/kg 开始，在外周 B 细胞上观察到 CD40 受体占据 >90%；然而，在 ABBV-428 治疗后（第 2 周期，第 1 天），未检测到肿瘤内 CD8+ T 细胞、程序性死亡配体-1 (PD-L1+) 细胞或免疫相关基因表达相对于基线的一致变化。与更广泛的剂量递增人群相比，间皮素膜染色显示与卵巢癌和间皮瘤的无进展生存期有更大的相关性。结论 ABBV-428 单一疗法表现出与剂量成比例的药代动力学和可接受的安全性，特别是对于 CD40 激动作用的毒性特征，说明利用肿瘤靶向、双特异性抗体可以提高CD40激动作为一种治疗方法的安全性。ABBV-428 单一疗法在剂量递增和晚期间皮瘤或卵巢癌患者的小型扩展队列中具有最小的临床活性。试用注册号 NCT02955251。

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Phase I study of ABBV-428, a mesothelin-CD40 bispecific, in patients with advanced solid tumors.

BACKGROUND CD40 agonist immunotherapy can potentially license antigen-presenting cells to promote antitumor T-cell activation and re-educate macrophages to destroy tumor stroma. Systemic administration of CD40 agonists has historically been associated with considerable toxicity, providing the rationale for development of tumor-targeted immunomodulators to improve clinical safety and efficacy. This phase I study assessed the safety, tolerability, preliminary antitumor activity, and preliminary biomarkers of ABBV-428, a first-in-class, mesothelin-targeted, bispecific antibody designed for tumor microenvironment-dependent CD40 activation with limited systemic toxicity. METHODS ABBV-428 was administered intravenously every 2 weeks to patients with advanced solid tumors. An accelerated titration (starting at a 0.01 mg/kg dose) and a 3+3 dose escalation scheme were used, followed by recommended phase II dose cohort expansions in ovarian cancer and mesothelioma, tumor types associated with high mesothelin expression. RESULTS Fifty-nine patients were treated at doses between 0.01 and 3.6 mg/kg. The maximum tolerated dose was not reached, and 3.6 mg/kg was selected as the recommended phase II dose. Seven patients (12%) reported infusion-related reactions. Treatment-related grade ≥3 treatment-emergent adverse events were pericardial effusion, colitis, infusion-related reaction, and pleural effusion (n=1 each, 2%), with no cytokine release syndrome reported. The pharmacokinetic profile demonstrated roughly dose-proportional increases in exposure from 0.4 to 3.6 mg/kg. Best response was stable disease in 9/25 patients (36%) treated at the recommended phase II dose. CD40 receptor occupancy >90% was observed on peripheral B-cells starting from 0.8 mg/kg; however, no consistent changes from baseline in intratumoral CD8+ T-cells, programmed death ligand-1 (PD-L1+) cells, or immune-related gene expression were detected post-ABBV-428 treatment (cycle 2, day 1). Mesothelin membrane staining showed greater correlation with progression-free survival in ovarian cancer and mesothelioma than in the broader dose escalation population. CONCLUSIONS ABBV-428 monotherapy exhibited dose-proportional pharmacokinetics and an acceptable safety profile, particularly for toxicities characteristic of CD40 agonism, illustrating that utilization of a tumor-targeted, bispecific antibody can improve the safety of CD40 agonism as a therapeutic approach. ABBV-428 monotherapy had minimal clinical activity in dose escalation and in a small expansion cohort of patients with advanced mesothelioma or ovarian cancer. TRIAL REGISTRATION NUMBER NCT02955251.

更新日期：2021-02-01

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