Memorial Sloan Kettering Cancer Center, New York, New York, USA
Weill Cornell Medical College, New York, New York, USA.
Oncologist. 2019 Feb;24(2):161-e70. doi: 10.1634/theoncologist.2018-0654. Epub 2018 Oct 23.
Patients with hepatocellular carcinoma (HCC) often have limited therapeutic responses to the vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor sorafenib, which is standard of care in advanced HCC. Targeting the activin receptor-like kinase 1 (ALK1) and VEGF pathways simultaneously by combining the ALK1 ligand trap dalantercept with sorafenib may result in more effective angiogenic blockade and delay tumor progression in patients with advanced HCC.Although the combination was generally well tolerated, there was no additive antitumor activity with the combination of dalantercept plus sorafenib in patients with advanced HCC. No complete or partial responses were observed, and overall survival ranged from 1.9 to 23.3 months.These results suggest that, in this patient population, further development of the possible limited benefits of combination therapy with dalantercept plus sorafenib is not warranted.
Targeting the activin receptor-like kinase 1 (ALK1) and vascular endothelial growth factor (VEGF) pathways may result in more effective angiogenic blockade in patients with hepatocellular carcinoma (HCC).
In this phase Ib study, patients with advanced HCC were enrolled to dose-escalation cohorts, starting at 0.6 mg/kg dalantercept subcutaneously every 3 weeks plus 400 mg sorafenib orally once daily, or to a dose expansion cohort. The primary objective was to determine the safety and tolerability and the dalantercept maximum tolerated dose (MTD) level. Secondary objectives were to assess the preliminary activity and the association of pharmacodynamic biomarkers with tumor response.
A total of 21 patients were enrolled in the study. Five patients received 0.6 mg/kg dalantercept in the first dose escalation cohort. Based on the initial safety results, the dose level was de-escalated to 0.4 mg/kg in the second cohort ( = 6). The MTD was identified as 0.4 mg/kg and used for the dose expansion cohort ( = 10). At this dose level, the combination was generally well tolerated. Overall survival ranged from 1.9 to 23.3 months, and the best overall response was stable disease.
The addition of dalantercept to sorafenib did not improve antitumor activity in patients with HCC. The dalantercept program in this population was discontinued.
肝细胞癌 (HCC) 患者对血管内皮生长因子 (VEGF) 酪氨酸激酶抑制剂索拉非尼的治疗反应往往有限，而索拉非尼是晚期 HCC 的标准治疗方法。通过将 ALK1 配体陷阱 dalantercept 与索拉非尼联合靶向激活素受体样激酶 1 (ALK1) 和 VEGF 通路，可能会导致更有效的血管生成阻断，并延迟晚期 HCC 患者的肿瘤进展。虽然联合治疗通常耐受性良好，但在晚期 HCC 患者中，dalantercept 加索拉非尼联合治疗没有附加的抗肿瘤活性。未观察到完全或部分缓解，总生存期为 1.9 至 23.3 个月。这些结果表明，在该患者人群中，进一步开发 dalantercept 加索拉非尼联合治疗的可能有限益处是没有必要的。
靶向激活素受体样激酶 1 (ALK1) 和血管内皮生长因子 (VEGF) 通路可能会导致肝细胞癌 (HCC) 患者更有效的血管生成阻断。
在这项 Ib 期研究中，招募了晚期 HCC 患者进入剂量递增队列，起始剂量为皮下每 3 周给予 0.6mg/kg dalantercept，每日口服一次 400mg 索拉非尼，或进入剂量扩展队列。主要目的是确定安全性和耐受性以及 dalantercept 的最大耐受剂量 (MTD) 水平。次要目的是评估初步活性和药效学生物标志物与肿瘤反应的相关性。
共有 21 名患者入组研究。第一剂量递增队列中有 5 名患者接受了 0.6mg/kg 的 dalantercept。基于最初的安全性结果，在第二队列中剂量下调至 0.4mg/kg(=6)。确定 MTD 为 0.4mg/kg，并用于剂量扩展队列(=10)。在该剂量水平下，联合治疗通常耐受性良好。总生存期为 1.9 至 23.3 个月，最佳总体反应为疾病稳定。
在 HCC 患者中，添加 dalantercept 并未提高抗肿瘤活性。该人群中的 dalantercept 项目已停止。
