Department of Medicine, Duke University Medical Center, Durham, North Carolina.
Duke Department of Biostatistics and Bioinformatics, Durham, North Carolina.
Mol Cancer Ther. 2018 Oct;17(10):2248-2256. doi: 10.1158/1535-7163.MCT-17-0916. Epub 2018 Jul 11.
TRC105 is an anti-endoglin antibody currently being tested in combination with VEGF inhibitors. In the phase Ib trial, 38 patients were treated with both TRC105 and bevacizumab (BEV), and improved clinical outcomes were observed, despite the fact that 30 patients (79%) were refractory to prior anti-VEGF therapy. Plasma samples were tested for angiogenic and inflammatory biomarkers at baseline and on-treatment. To provide broader context of this combination biomarker study, direct cross-study comparisons were made to biomarker studies previously conducted in patients treated with either BEV or TRC105 monotherapy. Upon treatment with BEV and TRC105, pharmacodynamic changes in response to both BEV (PlGF increase) and TRC105 (soluble endoglin increase) were noted. In addition, distinct patterns of change were identified (similar, opposing, neutralizing). Similar patterns were observed when the combination elicited similar effects to those observed with monotherapy treatment (i.e., decreases of Ang-2, increases of IL6 and VCAM-1). Opposing patterns were observed when the combination led to opposing effects compared with monotherapy treatment (i.e., TGFβ1, PDGF-AA and PDGF-BB, PAI-1). Lastly, neutralizing patterns were observed when one drug led to increase, whereas the other drug led to decrease, and the combination elicited no overall effect on the marker (i.e., VEGF-A, VEGF-D, and IGFBP-3). Patients achieving partial responses or stable disease from the combination exhibited significantly lower expression of E-Cadherin, HGF, ICAM-1, and TSP-2 at baseline. Taken together, the novel biomarker modulations identified may deepen our understanding of the underlying biology in patients treated with BEV and TRC105 compared with either drug alone. .
TRC105 是一种抗内胚层抗体，目前正在与 VEGF 抑制剂联合进行测试。在 Ib 期试验中，38 名患者接受了 TRC105 和贝伐珠单抗（BEV）联合治疗，观察到了改善的临床结局，尽管 30 名患者（79%）对先前的抗 VEGF 治疗耐药。在基线和治疗时检测了血浆样本中的血管生成和炎症生物标志物。为了提供该联合生物标志物研究的更广泛背景，对先前接受 BEV 或 TRC105 单药治疗的患者的生物标志物研究进行了直接的跨研究比较。在用 BEV 和 TRC105 治疗后，观察到了对 BEV（PlGF 增加）和 TRC105（可溶性内胚层增加）的药效学变化。此外，还确定了不同的变化模式（相似、相反、中和）。当联合治疗产生与单药治疗观察到的相似效果时（即，Ang-2 减少，IL6 和 VCAM-1 增加），观察到相似的模式。当联合治疗与单药治疗相比导致相反的效果时（即，TGFβ1、PDGF-AA 和 PDGF-BB、PAI-1），观察到相反的模式。最后，当一种药物导致增加，而另一种药物导致减少，并且联合治疗对标记物没有总体影响时（即，VEGF-A、VEGF-D 和 IGFBP-3），观察到中和模式。从联合治疗中获得部分缓解或疾病稳定的患者在基线时 E-钙粘蛋白、HGF、ICAM-1 和 TSP-2 的表达明显降低。总之，与单独使用任何一种药物相比，鉴定出的新型生物标志物调节可能会加深我们对接受 BEV 和 TRC105 治疗的患者的基础生物学的理解。
