Efficacy of Bevacizumab plus Erlotinib for Advanced Hepatocellular Carcinoma and Predictors of Outcome: Final Results of a Phase II Trial

Abstract

Objective: A phase II study was performed to evaluate the efficacy and tolerability of bevacizumab and erlotinib in advanced hepatocellular carcinoma (HCC) patients, and to investigate clinical and molecular predictors of outcome. Methods: 59 patients with advanced HCC received 10 mg/kg i.v. of bevacizumab every 14 days and 150 mg p.o. of erlotinib daily. The primary endpoint was progression-free survival (PFS) at 16 weeks. Clinical characteristics and plasma biomarkers expression levels were analyzed. Results: PFS at 16 weeks was 64% (95% CI 51–76): 14 patients achieved partial response (24%), 33 had stable disease (56%), 6 progressed (10%), and 6 were not evaluable (10%). Median overall survival was 13.7 months (95% CI 9.6–19.7), and median PFS was 7.2 months (95% CI 5.6–8.3). Grade 3–4 adverse events included fatigue (30%), diarrhea (17%), hypertension (14%), elevated transaminases (12%), and gastrointestinal hemorrhage (10%). High plasma angiopoietin-2, epidermal growth factor receptor, and endothelin-1, and lack of acneiform rash were associated with poor outcome. Conclusions: The combination of bevacizumab with erlotinib achieved encouraging results in patients with advanced HCC. Current correlatives may help to guide future HCC studies.

Angiogenesis- and Hypoxia-Associated Proteins as Early Indicators of the Outcome in Patients with Metastatic Breast Cancer Given First-Line Bevacizumab-Based Therapy

“…Coexistence of high baseline levels of proangiogenic proteins may therefore be indicative of a subset of carcinomas with a particularly aggressive nature. High baseline levels of ANG2 have been associated earlier with a poor clinical outcome in patients receiving a bevacizumabcontaining regime (23)(24)(25). Daly and colleagues (26) have shown in a human tumor xenograft model that ANG2 is a TIE2 agonist and may thereby limit the antivascular effects of VEGF inhibition.…”

Optimal combination of antiangiogenic therapy for hepatocellular carcinoma

“…VEGF2578AA genotype was associated with a superior overall survival in the combination arm [45] . [108] Bevacizumab Advanced 59 High Ang2, EGFR, endothelin 1, no acneiform rash correlate with poor outcome Kaseb et al [109] Thalidomide Advanced 47 No predictive value of VEGF, bFGF, PlGF Hsu et al [110] Thalidomide/tegafur/uracil Advanced 43 High IL-6, IL-8 correlate with short survival…”

Management of Hepatocellular Carcinoma: An Update at the Start of 2014

“…Good results were also achieved with capecitabine and oxaliplatin[PR: 11%; DS: 78%] [57,58]. A recent study by Kaseb et al evaluated the use of bevacizumab in combination with erlotinib in patients with advanced HCC and achieved encouraging results [59]. However, apart from more contraindications [cardiovascular and renal impairment] compared with other targetedagents, the risk of hemorrhagic and thromboembolic events needs further evaluation [55,59].…”

“…A recent study by Kaseb et al evaluated the use of bevacizumab in combination with erlotinib in patients with advanced HCC and achieved encouraging results [59]. However, apart from more contraindications [cardiovascular and renal impairment] compared with other targetedagents, the risk of hemorrhagic and thromboembolic events needs further evaluation [55,59]. In addition, due to the small sample size, the non-randomized nature and the single-arm setting in these studies, the relative contribution from the chemotherapy regimen remains unknown and no recommendation for routine clinical use of bevacizumab can be recommended.…”