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

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.