Phase II study of bevacizumab and erlotinib in the treatment of advanced hepatocellular carcinoma patients with sorafenib-refractory disease

Abstract

SummaryBackground The combination of bevacizumab (B) and erlotinib (E) has shown promising clinical outcomes as the first-line treatment of advanced HCC patients. We aimed to evaluate the efficacy and safety of using combination of B + E in treating advanced HCC patients who had failed prior sorafenib treatment. Methods Eligible advanced HCC patients with documented radiological evidence of disease progression with sorafenib treatment were recruited. All patients received bevacizumab(B) at 10 mg/kg every 2 weeks with erlotinib(E) at 150 mg daily for a maximum of 6 cycles. Response assessments using both RECIST and modified RECIST criteria were performed after every 6 weeks. The primary endpoint was clinical benefit (CB) rate and a Simon two-stage design was employed. Results The trial was halted in the first stage according to the pre-set statistical criteria with 10 patients recruited. The median age was 47 years (range, 28–61) and all patients were in ECOG performance status 1. Eighty percent of patients were chronic hepatitis B carriers and all patients had Child A cirrhosis. Among these 10 patients, none of the enrolled patients achieved response or stable disease. The median time-to-progression was 1.81 months (95 % confidence interval [C.I.], 1.08–1.74 months) and overall survival was 4.37 months (95 % C.I., 1.08–11.66 months). Rash (70 %), diarrhea (50 %) and malaise (40 %) were the most commonly encountered toxicities. Conclusion The combination of B + E was well tolerated but had no activity in an unselected sorafenib-refractory advanced HCC population. Condensed abstract The combination of bevacizumab and erlotinib had no clinical activity in sorafenib-refractory HCC population.

Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma

“…study with 50 ad- Combinational therapy 5-fluorouracil plus sorafenib [46] Phase Ⅱ 39 SD: 46.2%; median TTP: 8 mo; OS: 13.7 mo Tegafur/uracil plus sorafenib [47] Phase Ⅱ 53 Median PFS: 3.7 mo; median OS: 7.4 mo Octreotide plus sorafenib [48] Phase Ⅱ (So.LAR.) 50 SD: 66%; median TTP: 7.0 mo; median OS: 12 mo Doxorubicin plus sorafenib vs doxorubicin plus placebo [50] Phase Ⅲ 47 vs 49 Median TTP: 6.4 mo vs 2.8 mo; OS: 13.7 mo vs 6.5 mo; PFS: 6.0 mo vs 2.7 mo Erlotinib plus sorafenib vs erlotinib plus placebo [53,54] Phase Ⅲ (SEARCH) 362 Median TTP: 3.2 mo vs 4.0 mo; OS: 9.5 mo vs 8.5 mo Second-line treatments Sunitinib [55] Retrospective analysis 11 SD: 40%; median TTP: 3.2 mo Brivanib [56] Phase Ⅱ 46 SD: 41.3%; RR: 4.3%; DCR: 45.7%; median OS: 9.79 mo Tivantinib vs placebo [6] Phase Ⅱ 71 vs 36 Progressive disease: 65% vs 72%; TTP: 1.6 mo vs 1.4 mo Gemcitabine plus oxaliplatin [59] Retrospective analysis 18 Overall RR: 18.8%; SD: 18.8%; median PFS: 3.2 mo; OS: 4.7 mo Erlotinib plus bevacizumab [61] Phase controlled arm in this trial, the encouraging outcome was unable to justify that the efficacy was from sorafenib alone or the synergism with doxorubicin. Now, a randomized phase Ⅲ trial aiming to evaluate the combinational therapy of doxorubicin plus sorafenib compared with sorafenib alone is recruiting participants (ClinicalTrials.…”

“…To evaluate the effects of erlotinib in combination with bevacizumab as secondline therapy after the failure of sorafenib, a phase Ⅱ trial is ongoing (ClinicalTrials.gov, NCT01180959). However, another similar phase Ⅱ trial executed during the same period showed disappointing interim results [61] . Among the ten recruited patients after first-line sorafenib treatment, no response or SD were achieved and the median TTP and OS was 1.81 and 4.37 mo, respectively.…”

“…Adverse events were common, with rash in 70%, diarrhea in 50% and malaise in 40% of patients. Thus, this trial was halted after the interim analysis [61] . The results of the ongoing similar trial are expected.…”

Human and Mouse VEGFA-Amplified Hepatocellular Carcinomas Are Highly Sensitive to Sorafenib Treatment

“…Although VEGFRs were postulated as mediators of sorafenib response in HCC, testing for VEGF-A serum levels was not found to be predictive of sorafenib treatment success ( 10 ). Moreover, bevacizumab, an antibody against VEGF-A, only shows minimal responses in HCC (17)(18)(19)(20). A possible explanation for this is that the mechanism of action of sorafenib is predominantly independent of VEGF-A inhibition.…”

FGF8 promotes cell proliferation and resistance to EGFR inhibitors via upregulation of EGFR in human hepatocellular carcinoma cells

“…EGFR antagonists were effective in human HCC cells (18). Gefitinib and erlotinib, two clinically approved EGFR chemical inhibitors, are used for the treatment of advanced HCC (20)(21)(22)(23)(24)(25). However, some studies have demonstrated the resistance to EGFR inhibitors in human HCC cells (26)(27)(28)(29).…”