卵巢癌和微卫星稳定 (MSS) 结直肠癌 (CRC) 对抗 PD1 免疫治疗不敏感，需要新的免疫治疗方法。临床前数据表明免疫治疗耐药性与血管生成素 2 水平升高之间存在关系。我们对 pembrolizumab 和血管生成素 1/2 抑制剂 trebananib 进行了 1 期剂量递增研究 (NCT03239145)。这项多中心试验招募了转移性卵巢癌或 MSS CRC 患者。 Trebananib 每周静脉注射一次，持续 12 周，每 3 周静脉注射 200 mg 派姆单抗。该组合的毒性特征是可控的，并且方案规定的最高剂量水平（曲巴那尼每周 30 mg/kg 加派姆单抗每 3 周 200 mg）被宣布为最大耐受剂量。所有患者的客观缓解率为 7.3%（90% 置信区间：2.5-15.9%）。三名 MSS CRC 患者的持久缓解时间≥3 年。一名有反应的患者的 CRC 含有 POLE 突变。另外两名有反应的患者患有左侧 CRC，没有基线肝转移，基因组分析显示他们都患有 KRAS 野生型、ERBB2 扩增肿瘤。出现获得性耐药后，对一名患者的 KRAS 野生型、ERBB2 扩增肿瘤进行活检，结果显示肿瘤相关 T 细胞大幅下降，而肿瘤内免疫抑制性巨噬细胞则增加。未来的研究需要仔细评估临床基因组特征（例如缺乏肝转移、ERBB2 扩增和左侧肿瘤）是否可以预测对 PD1 免疫治疗组合的敏感性增加。

Ovarian cancers and microsatellite stable (MSS) colorectal cancers (CRC) are insensitive to anti-PD1 immunotherapy, and new immunotherapeutic approaches are needed. Preclinical data suggests a relationship between immunotherapy resistance and elevated angiopoietin 2 levels. We performed a phase 1 dose-escalation study of pembrolizumab and the angiopoietin 1/2 inhibitor trebananib (NCT03239145). This multicenter trial enrolled patients with metastatic ovarian cancer or MSS CRC. 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 CRC had durable responses for ≥3 years. One responding patient's CRC harbored a POLE mutation. The other two responding patients had left-sided CRCs 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 PD1 immunotherapy combinations.