Randomized, open‐label phase 2 study comparing frontline dovitinib versus sorafenib in patients with advanced hepatocellular carcinoma

Abstract

Angiogenesis inhibition by the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) inhibitor sorafenib provides survival benefit in hepatocellular carcinoma (HCC); however, angiogenic escape from sorafenib may occur due to angiogenesis-associated fibroblast growth factor receptor (FGFR) pathway activation. In addition to VEGFR and PDGFR, dovitinib inhibits FGFR. Frontline oral dovitinib (500 mg/day, 5 days on, 2 days off; n 5 82) versus sorafenib (400 mg twice daily; n 5 83) was evaluated in an open-label, randomized phase 2 study of Asian-Pacific patients with advanced HCC. The primary and key secondary endpoints were overall survival (OS) and time to tumor progression (TTP) as determined by a local investigator, respectively. Patients included in the study were ineligible for surgical and/or locoregional therapies or had disease progression after receiving these therapies. The median OS (95% confidence interval [CI]) was 8.0 (6.6-9.1) months for dovitinib and 8.4 (5.4-11.3) months for sorafenib. The median TTP (95% CI) per investigator assessment was 4.1 (2.8-4.2) months and 4.1 (2.8-4.3) months for dovitinib and sorafenib, respectively. Common any-cause adverse events included diarrhea (62%), decreased appetite (43%), nausea (41%), vomiting (41%), fatigue (35%), rash (34%), and pyrexia (30%) for dovitinib and palmar-plantar erythrodysesthesia syndrome (66%) and decreased appetite (31%) for sorafenib. Subgroup analysis revealed a significantly higher median OS for patients in the dovitinib arm who had baseline plasma soluble VEGFR1 (sVEGFR1) and hepatocyte growth factor (HGF) below median levels versus at or above the median levels (median OS [95% CI]: sVEGFR1,.0] months, respectively [P 5 .0002]; HGF,] months, respectively [P 5 0.0002]). Conclusion: Dovitinib was well tolerated, but activity was not greater than sorafenib as a frontline systemic therapy for HCC. Based on these data, no subsequent phase 3 study has been planned. (HEPATOLOGY 2016;64:774-784)

FGFR a promising druggable target in cancer: Molecular biology and new drugs

“…The recommended phase II dose was 300 mg (Schäfer, 2016). A phase II trial tested Dovitinib against Sorafenib in Hepatocellular carcinoma but the activity of Dovitinib was not superior than Sorafenib (Cheng et al, 2016).…”

Treatment of high-burden hepatocellular carcinoma: an oncologist perspective

“…Unfortunately, none of the trials in the past decade was able to identify a better targeted agent in treating advanced HCC [112][113][114][115][116] . Only recently in 2017, Bruix et al [117] in the RESORCE trial has found regorafenib, an oral multikinase inhibitor that blocks angiogenesis, oncogenesis, metastasis and tumor immunity, to be an effective second line treatment for patients who have failed sorafenib.…”

Management of advanced hepatocellular carcinoma: review of current and potential therapies

“…[10] Sorafenib improves survival compared to placebo, with median OS of 6.5-10.7 months, with significant benefit in time to progression (TTP). Many molecular agents have been studied, but only the sorafenib showed efficacy in terms of OS and TTP, based on results of two phase III, randomized controlled studies [2,11] and confirmed in other clinical trials comparing sorafenib to other molecules, [12][13][14][15][16] as well as in real life clinical practice. [17,18] Despite the approval of sorafenib in advanced-stage HCC, several issues remain not known.…”

“…None of the other targeted agents: the anti-angiogenic tyrosine kinase inhibitors (TKI) sunitinib, [12] linifanib, [15] brivanib, [13] dovitinib [16] or the combination of sorafenib with erlotinib [14] were found superior compared to sorafenib in phase II and III trials as first line therapies in patients with advanced HCC, and none have exceeded the benefits of sorafenib [ Figure 1, Supplementary Table 1].…”