Phase II study of front-line dovitinib (TKI258) versus sorafenib in patients (Pts) with advanced hepatocellular carcinoma (HCC).

Abstract

237 Background: HCC is a highly vascularized tumor, and inhibition of angiogenesis by sorafenib (Sor)—a VEGFR and PDGFR inhibitor—delays tumor progression. However, angiogenic escape from Sor may result from activation of the FGFR pathway, which also plays an important role in angiogenesis. Dovitinib (Dov) inhibits FGFR as well as VEGFR and PDGFR. Here, we study frontline Dov vs Sor in pts with advanced HCC. Methods: Eligible pts in this open-label study had ≥ 1 measurable lesion at baseline. All pts were ineligible for or had disease progression after surgical and/or locoregional therapies. Prior systemic HCC therapy was not allowed. Pts were randomized to receive Dov (500 mg/day, 5 days on/2 days off) or Sor (400 mg twice daily) until disease progression, unacceptable toxicity, or death. No treatment crossover was allowed. The primary endpoint was overall survival (OS). The key secondary endpoint was time to tumor progression (TTP) by local investigator’s assessment (per RECIST v1.1). Results: Pts received Dov (n = 82) or Sor (n = 83). Most pts—43 (52.4%) in the Dov arm and 60 (72.3%) in the Sor arm—discontinued treatment due to progressive disease. Median OS (95% CI) was 34.6 wk (28.6-39.4 wk) for Dov and 36.7 wk (23.3-49.3 wk) for Sor; Kaplan-Meier HR, 1.27; 95% CI, 0.89-1.80. Median TTP (95% CI) was 17.6 wk (12.3-18.4 wk) and 17.9 wk (12.3-18.9 wk), respectively. In pts who received ≥ 1 dose of study drug, median duration of exposure was 2.5 mo for Dov (n = 79) and 3.2 mo for Sor (n = 83). The most common adverse events, regardless of cause, were diarrhea (62.0%), decreased appetite (43.0%), nausea and vomiting (40.5% each), fatigue (35.4%), rash (34.2%), and pyrexia (30.4%) in the Dov arm and palmar-plantar erythrodysesthesia syndrome (66.3%), diarrhea (42.2%), and decreased appetite (31.3%) in the Sor arm. VEGFR1 and HGF baseline plasma levels appear to be associated with OS only in the Dov arm. Median OS in the lower biomarker group for both VEGFR1 and HGF was 11 mo while it was 5.6 and 5.9 mo for VEGFR1 and HGF, respectively, in the higher biomarker group. Conclusions: Activity of Dov was not greater than that of Sor in frontline HCC. The safety profile was similar to that observed in other single-agent Dov trials. Clinical trial information: NCT01232296.

Tracking the 2015 Gastrointestinal Cancers Symposium: bridging cancer biology to clinical gastrointestinal oncology

“…Nonetheless, dovitinib failed to prove superior to sorafenib in the first-line treatment of HCC. In the Phase II trial presented by Cheng et al 24 OS was 34.6 weeks for dovitinib and 36.7 weeks (23.3 weeks–49.3 weeks) for sorafenib (HR: 1.27; 95% CI: 0.89–1.80). Palmer et al 25 presented disappointing results for the triple angiokinase inhibitor nintedanib.…”

“…Two Phase II randomized studies with novel antitumor agents were presented. 24 , 25 Dovitinib was tested in patients with advanced HCC in an attempt to overcome the fibroblast growth factor receptors (FGFRs)-activated mechanism of resistance, which is considered an escape pathway for sorafenib activity. Nonetheless, dovitinib failed to prove superior to sorafenib in the first-line treatment of HCC.…”

Targeting FGF19/FGFR4 Pathway: A Novel Therapeutic Strategy for Hepatocellular Carcinoma

“…Despite promising results in II studies [ 14 ] it failed to meet its primary endpoints in phase III studies of patients with advanced HCC compared to sorafenib in the first line [ 15 ] and placebo in the second line setting [ 16 ]. Another multikinase inhibitor that has been tested was dovitinib with activity against VEGFR1-3, FGFR1-3 and PDGFR-β and similarly failed to show superiority against sorafenib in a phase II study of patients with advanced HCC [ 17 ]. Nintedanib which has activity VEGFR1-3, FGFR1-3 and PDGFRα and PDGFRβ has been approved for the treatment of non-small cell lung cancer and idiopathic pulmonary fibrosis [ 18 ].…”

Systemic Chemotherapy for Advanced Hepatocellular Carcinoma: Past, Present, and Future

“…After the introduction of sorafenib, a number of phase III trials of various molecular-targeted agents vs. sorafenib as first-line treatment have been conducted to determine if any could offer a longer overall survival than sorafenib [ 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ], however, none of the agents examined so far have been demonstrated to offer survival benefit over sorafenib. Furthermore, some phase III trials of various molecular-targeted agents vs. placebo have been conducted in HCC patients who were refractory or intolerant to sorafenib [ 52 , 53 , 54 , 55 , 56 , 57 ], to determine if any could offer a longer overall survival than placebo, however, none of the agents examined so far have been demonstrated to offer survival benefit over placebo.…”

“…Dovitinib inhibits FGFR as well as VEGFR and PDGFR. A phase II trial of dovitinib vs. sorafenib as first-line therapy in patients with advanced HCC revealed no significant benefit of the drug on either the survival or the time to progression as compared to sorafenib [ 50 ]. In addition, some adverse events, including diarrhea, decreased appetite, nausea and vomiting, fatigue, rash, and pyrexia occurred at significantly high frequencies (more than 30%) in the dovitinib arm.…”