Phase II Study of First-Line Trebananib Plus Sorafenib in Patients with Advanced Hepatocellular Carcinoma

Abstract

Lessons Learned. Trebananib leveraging anti‐angiogenic mechanism that is distinct from the classic sorafenib anti‐vascular endothelial growth factor inhibition did not demonstrate improved progression‐free survival at 4 months in patients with advanced hepatocellular carcinoma (HCC).In support of previously reported high Ang‐2 levels’ association with poor outcome in HCC for patients, trebananib treatment with lower baseline Ang‐2 at study entry was associated with improved overall survival to 22 months and may suggest future studies to be performed within the context of low baseline Ang‐2.Background.Ang‐1 and Ang‐2 are angiopoietins thought to promote neovascularization via activation of the Tie‐2 angiopoietin receptor. Trebananib sequesters Ang‐1 and Ang‐2, preventing interaction with the Tie‐2 receptor. Trebananib plus sorafenib combination has acceptable toxicity. Elevated Ang‐2 levels are associated with poor prognosis in hepatocellular carcinoma (HCC).Methods.Patients with HCC, Eastern Cooperative Oncology Group ≤2, and Childs‐Pugh A received IV trebananib at 10 mg/kg or 15 mg/kg weekly plus sorafenib 400 mg orally twice daily. The study was planned for ≥78% progression‐free survival (PFS) rate at 4 months relative to 62% for sorafenib historical control (power = 80% α = 0.20). Secondary endpoints included safety, tolerability, overall survival (OS), and multiple biomarkers, including serum Ang‐2.Results.Thirty patients were enrolled sequentially in each of the two nonrandomized cohorts. Demographics were comparable between the two arms and the historical controls. PFS rates at 4 months were 57% and 54% on the 10 mg/kg and 15 mg/kg trebananib cohorts, respectively. Median OS was 17 and 11 months, respectively. Grade 3 and above events noted in ≥10% of patients included fatigue, hypertension, diarrhea, liver failure, palmar‐plantar erythrodysesthesia syndrome, dyspnea, and hypophosphatemia. One death was due to hepatic failure. Serum Ang‐2 dichotomized at the median was associated with improved OS in both cohorts.Conclusion.There was no improvement in PFS rate at 4 months in either cohort, when compared with sorafenib historical control.

Tie‐ing Up Angiogenesis to Treat Nonalcoholic Steatohepatitis

“…Those findings are important because high circulating levels of ANG2 are a strong negative predictor of overall patient survival in HCC. (10) However, in a recent study using trebenanib (which sequesters ANG1 and ANG2 and blocks interaction with Tie2) in addition to standard sorafenib treatment, there was no improvement in progression-free survival in patients with advanced HCC. (10) The studies of Lefere and colleagues will hopefully propel further investigation of this important signaling pathway, which could in turn pave the way for clinical trials.…”

“…Among the other intriguing findings from this study is the observation that L1‐10 reduced the tumor burden in a preclinical model of NASH‐associated HCC. Those findings are important because high circulating levels of ANG2 are a strong negative predictor of overall patient survival in HCC . However, in a recent study using trebenanib (which sequesters ANG1 and ANG2 and blocks interaction with Tie2) in addition to standard sorafenib treatment, there was no improvement in progression‐free survival in patients with advanced HCC …”

The Role of Angiogenesis in Hepatocellular Carcinoma

“…Ang2 levels were observed to be increased in cirrhosis, and even more so in HCC, suggesting the angiopoietin pathway may play a role in tumor angiogenesis, potentially in coordination with VEGF ligands (41). Although some agents targeting this pathway alone or combined with sorafenib have been tested in the clinic (43), any potential clinical benefit remains to be proven.…”

“…New agents or combinations of synergizing agents with differing or broader selectivity to inhibit a variety of angiogenic pathways, or targeting agents to specific populations with a sensitizing mutation may potentially overcome initial or acquired resistance to initial antiangiogenic inhibitor treatment. Some agents are already demonstrating encouraging results in the laboratory and clinic (13,36,43,(77)(78)(79).…”

Vascular Targets for the Treatment of Portal Hypertension

“…73 However, additional Ang-1 and Ang-2 inhibition by Trebananib (AMG386) combined with sorafenib did not further improve survival of patients with advanced HCC. 75 Nitric oxide/sGC/cGMP pathway Nitric oxide (NO) is a natural vasodilator 76 with limited bioavailability in a cirrhotic liver as compared to a healthy liver. 77,78 NO deficiency and impaired function of the downstream sGC/cGMP signaling cascade enhance sinusoidal vasoconstriction, and thereby increase IHVR, LSECs capillarization, and HSCs activation in hepatocytes injury (►Fig.…”