ALK-1是TGF-β的特异性受体，PF-03446962是ALK-1的单克隆抗体。索拉非尼治疗进展或无法耐受的24名患者参与了本项研究。药物的安全性尚可，3-4级的副作用包括血小板减少（12.5%）、脂肪酶升高、AST升高和腹痛（后三者的发病率均为4.2%）。抗ALK-1特异性的副反应毛细血管扩张症的发生率是8.3%。本组患者未观察到肿瘤部分或完全缓解，治疗12周后的肿瘤控制率为29.2%，中位TTP是3.0月。对于其中7名患者，药物治疗与患者肿瘤稳定超过12周相关（？）。作为索拉非尼的二线治疗，这样的数据尚可以接受，故而作者认为这个药物值得进一步研究。
摘要详情：
Abstract:
Background: PF-03446962, a fully human IgG2 mAb against ALK-1 (Activin-Receptor Like Kinase-1, a specific TGF-β receptor) with anti-angiogenesis activity, showed a favourable safety profile and early signs of efficacy in a dose escalation study in patients (pts) with solid tumors. While the interplay between ALK-1 and VEGF-A is not fully elucidated, the clinical benefit observed in VEGF-TKI pre-treated pts supports ALK-1 acting as an escape mechanism after failure of VEGF blockade. Herein we report preliminary efficacy, safety and PK results from an expansion cohort in HCC pts who progressed after receiving at minimum sorafenib.
Methods: Child-Pugh A HCC pts progressed on/intolerant to sorafenib. Tumor specimens (diagnostic and pre-PF-03446962) collected for IHC assessment of CD31, TGF-β, ALK-1 and cMET. Pts treated with 7 mg/kg PF-03446962 on Day 1, 29 and then q2 wks. Efficacy endpoints: Objective Tumor Response (OR) by RECIST, Disease Control Rate (DCR) at 12 wks, and Time To Progression (TTP). Secondary objectives: safety, PK and PD.
Results: 24 pts with advanced HCC pre-treated at minimum with sorafenib (12/24 with ≥ 2 prior therapies) have been enrolled; 19 males and 5 females (median age: 64 y). Pts’ characteristics were: ECOG PS = 0 in 10 and = 1 in 14 pts; Child-Pugh = A5 in 16 and = A6 in 8 pts. The PK profiles from the HCC cohort were consistent with those of the dose escalation cohorts. Safety profile was manageable and mainly characterized by Gr 1-2 events. Gr 3-4 events were represented by thrombocytopenia (12.5%) and lipase increase, AST increase and abdominal pain (4.2% each). Telangiectasia, an anti-ALK-1 mediated toxicity, was also observed (8.3%, Gr 1). There were 3 treatment-related serious AEs (one tumor necrosis and two abdominal pain). No CRs or PRs were reported; DCR was 29.2% and mTTP was 3.0 months. In 7 pts, PF-03446962 was associated with stable disease for ≥ 12 weeks, suggesting that anti-ALK-1 treatment may be an effective strategy in the post-VEGFi setting. Correlation data of target tumor protein expression with efficacy will be presented at the Conference.
Conclusions: PF-03446962 is a first in class mAb anti ALK-1. Preliminary clinical activity observed in this HCC expansion cohort warrants further investigations.
Clinical trial information: NCT00557856.
