一项联合抗血管生成因子1和2的Peptibody Trebananib与Pembrolizumab治疗晚期卵巢癌和结直肠癌的I期临床试验

A Phase I Trial of Trebananib, an Angiopoietin 1 and 2 Neutralizing Peptibody, Combined with Pembrolizumab in Patients with Advanced Ovarian and Colorectal Cancer

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Cancer Immunology Research

影响因子:8.2

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

DOI: 10.1158/2326-6066.CIR-23-1027

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摘要

卵巢癌和微卫星稳定（MSS）结直肠癌对抗程序性死亡蛋白1（PD-1）免疫疗法不敏感，亟需新的免疫治疗策略。前期数据提示免疫耐药与血管生成因子2（Angiopoietin 2）水平升高有关。我们进行了一项p I剂量递增研究，结合使用Pembrolizumab与血管生成因子1/2抑制剂Trebananib（NCT03239145），对转移性卵巢癌或MSS结直肠癌患者进行治疗。Trebananib每周静脉给药一次，持续12周，联合每3周静脉给药200 mg的Pembrolizumab。该组合的毒性可控，最高耐受剂量（trebananib 30 mg/kg每周加pembrolizumab 200 mg每3周）被确定为最大耐受剂量。所有患者的客观反应率为7.3%（90%置信区间，2.5%-15.9%）。其中三名MSS结直肠癌患者持续反应≥3年。一名反应患者的肠癌携带POLE突变。其他两名反应患者为左侧结直肠癌，且无基础肝转移，基因组分析显示两者均为KRAS野生型、ERBB2扩增肿瘤。耐药后，一名患者的KRAS野生型ERBB2扩增肿瘤活检显示肿瘤相关T细胞显著下降，免疫抑制性肿瘤内巨噬细胞增加。未来研究需仔细评估临床-基因组特征（如缺乏肝转移、ERBB2扩增和左侧肿瘤）是否能预测对PD-1免疫疗法组合的敏感性增强。

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.