Trebananib（血管生成素1和2中和肽）的I期试验与晚期卵巢癌和大肠癌患者的pembrolizumab结合
A Phase I Trial of Trebananib, an Angiopoietin 1 and 2 Neutralizing Peptibody, Combined with Pembrolizumab in Patients with Advanced Ovarian and Colorectal Cancer
影响因子:8.20000
分区:医学1区 Top / 免疫学2区 肿瘤学2区
发表日期:2025 Jan 09
作者:
Brandon M Huffman, Osama E Rahma, Kevin Tyan, Yvonne Y Li, Anita Giobbie-Hurder, Benjamin L Schlechter, Bruno Bockorny, Michael P Manos, Andrew D Cherniack, Joanna Baginska, Adrián Mariño-Enríquez, Katrina Z Kao, Anna K Maloney, Allison Ferro, Sarah Kelland, Kimmie Ng, Harshabad Singh, Emma L Welsh, Kathleen L Pfaff, Marios Giannakis, Scott J Rodig, F Stephen Hodi, James M Cleary
摘要
卵巢癌和微卫星稳定（MSS）结直肠癌对抗编程细胞死亡1（PD-1）免疫疗法不敏感，需要新的免疫治疗方法。临床前数据表明，免疫疗法抗性与血管生成素2水平之间存在关系。我们对pembrolizumab和Angiopoietin 1/2抑制剂Trebananib进行了I期剂量升级研究（NCT03239145）。该多中心试验招募了转移性卵巢癌或MSS结直肠癌的患者。每周静脉注射静脉注射12周，每3周静脉注射200毫克pembrolizumab。该组合的毒性特征是可以控制的，方案定义的最高剂量水平（每周30 mg/kg每周30 mg/kg，每3周pembrolizumab 200 mg）宣布最大耐受剂量。所有患者的客观反应率为7.3％（90％置信区间，2.5％-15.9％）。三名MSS SS结直肠癌患者的耐用反应≥3年。一个反应患者的结直肠癌具有杆突变。其他两个反应的患者患有左侧结直肠癌，没有基线肝转移，基因组分析表明，他们均具有KRAS野生型ERBB2扩增的肿瘤。产生获得的耐药性后，一名患者的KRAS野生型ERBB2放大肿瘤的活检显示肿瘤相关的T细胞大幅下降，并增加了免疫抑制性肿瘤内巨噬细胞。需要进行未来的研究来仔细评估临床基因组学特征（例如缺乏肝转移，ERBB2扩增和左侧肿瘤）是否可以预测对PD-1免疫疗法组合的敏感性增加。
Abstract
Ovarian cancers and microsatellite stable (MSS) colorectal cancers are insensitive to anti-programmed cell death 1 (PD-1) immunotherapy, and new immunotherapeutic approaches are needed. Preclinical data suggest a relationship between immunotherapy resistance and elevated angiopoietin 2 levels. We performed a phase I dose escalation study of pembrolizumab and the angiopoietin 1/2 inhibitor trebananib (NCT03239145). This multicenter trial enrolled patients with metastatic ovarian cancer or MSS colorectal cancer. Trebananib was administered intravenously weekly for 12 weeks with 200 mg intravenous pembrolizumab every 3 weeks. The toxicity profile of this combination was manageable, and the protocol-defined highest dose level (trebananib 30 mg/kg weekly plus pembrolizumab 200 mg every 3 weeks) was declared the maximum tolerated dose. The objective response rate for all patients was 7.3% (90% confidence interval, 2.5%-15.9%). Three patients with MSS colorectal cancer had durable responses for ≥3 years. One responding patient's colorectal cancer harbored a POLE mutation. The other two responding patients had left-sided colorectal cancers, with no baseline liver metastases, and genomic analysis revealed that they both had KRAS wild-type, ERBB2-amplified tumors. After development of acquired resistance, biopsy of one patient's KRAS wild-type ERBB2-amplified tumor showed a substantial decline in tumor-associated T cells and an increase in immunosuppressive intratumoral macrophages. Future studies are needed to carefully assess whether clinicogenomic features, such as lack of liver metastases, ERBB2 amplification, and left-sided tumors, can predict increased sensitivity to PD-1 immunotherapy combinations.