Abexinostat 联合帕唑帕尼治疗实体瘤恶性肿瘤的 Ib 期临床试验的生存随访更新。

Updated Survival Follow-Up for Phase Ib Trial of the Histone Deacetylase Inhibitor Abexinostat With Pazopanib in Patients With Solid Tumor Malignancies.

机构信息

Division of Hematology and Oncology, University of California San Francisco, San Francisco, CA.

Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.

出版信息

JCO Precis Oncol. 2024 Nov;8:e2400328. doi: 10.1200/PO.24.00328. Epub 2024 Nov 7.

DOI:10.1200/PO.24.00328

PMID:39509670

Abstract

PURPOSE

Histone deacetylase (HDAC) inhibition downregulates hypoxia-inducible factor-1α and modulates multiple metabolomic pathways relevant in cancer. Here we report a potential novel biomarker to predict exceptional responders (>3 years) in patients receiving HDAC and vascular endothelial growth factor (VEGF) inhibition.

PATIENTS AND METHODS

Patients with solid tumor malignancies were enrolled in this phase Ib trial of abexinostat (4/7 ×21 days) and pazopanib (28/28 days), with a dose expansion in renal cell carcinoma (RCC). Plasma was analyzed for metabolomics and peripheral blood mononuclear cells (PBMCs) for VEGF and HDAC2 expression levels.

RESULTS

Fifty-one patients were enrolled: n = 36 patients in dose escalation and n = 15 in dose expansion. After the initial report in 2017, six patients had remained on study: four with RCC and one each with medullary thyroid and thymic neuroendocrine carcinoma. One patient with RCC remains on treatment for >11 years after progression on five systemic therapies. Overall, the median duration of therapy measured 5.6 (1-133) months. The median duration of therapy in exceptional responders measured 44.1 (39.8-133+) months. The median overall survival in patients with high PBMC HDAC2 expression versus low HDAC2 was 32.3 versus 9.2 months ( = .004) for all patients and 43.3 versus 25.1 months for patients with RCC ( = .09). Exceptional responders had lower kynurenine levels both pre- and post-treatment ( = .002, < .001, respectively). HDAC2 and kynurenine expression levels were inversely correlated ( = .02).

CONCLUSION

Abexinostat added to pazopanib shows extended tolerability and long-term responses and survival. PBMC HDAC2 levels, the abexinostat target, are relevant predictors of response. In addition, metabolomic assessment points to kynurenine as a predictor for exceptional response to combined VEGF plus HDAC inhibition.

摘要

目的

组蛋白去乙酰化酶（HDAC）抑制可下调缺氧诱导因子-1α，并调节与癌症相关的多种代谢组学途径。在此，我们报告了一种潜在的新型生物标志物，用于预测接受 HDAC 和血管内皮生长因子（VEGF）抑制治疗的患者中的超长缓解期（>3 年）患者。

患者和方法

本研究纳入了患有实体瘤恶性肿瘤的患者，他们接受了 abexinostat（4/7×21 天）和 pazopanib（28/28 天）的治疗，并且在肾细胞癌（RCC）中进行了剂量扩展。对血浆进行代谢组学分析，对外周血单核细胞（PBMC）进行 VEGF 和 HDAC2 表达水平分析。

结果

共纳入 51 例患者：n=36 例患者进行剂量递增，n=15 例患者进行剂量扩展。2017 年首次报告后，有 6 例患者仍在接受治疗：4 例 RCC 患者，1 例甲状腺髓样癌患者，1 例胸腺神经内分泌癌患者。1 例 RCC 患者在接受五种全身治疗后进展后，仍接受治疗>11 年。总体而言，中位治疗持续时间为 5.6（1-133）个月。超长缓解期患者的中位治疗持续时间为 44.1（39.8-133+）个月。所有患者中，高 PBMC HDAC2 表达患者的中位总生存期为 32.3 个月，低 HDAC2 表达患者为 9.2 个月（=0.004），RCC 患者分别为 43.3 个月和 25.1 个月（=0.09）。超长缓解期患者的预治疗和治疗后均显示出较低的犬尿氨酸水平（=0.002，<0.001）。HDAC2 和犬尿氨酸表达水平呈负相关（=0.02）。