Neoadjuvant Treatment with Angiogenesis-Inhibitor Dovitinib Prior to Local Therapy in Hepatocellular Carcinoma: A Phase II Study

Abstract

Background: Hepatocellular carcinoma (HCC) recurrence rates following locoregional treatment are high. As multireceptor tyrosine kinase inhibitors targeting vascular endothelial growth factor receptors (VEGFRs) are effective in advanced HCC, we assessed the efficacy and safety of neoadjuvant systemic treatment with dovitinib in early- and intermediate-stage HCC.

Materials and methods: Twenty-four patients with modified Child-Pugh class A early- and intermediate-stage HCC received neoadjuvant oral dovitinib 500 mg daily (5 days on/2 days off) for 4 weeks, followed by locoregional therapy. Primary endpoints were objective response rates and intratumoral blood flow changes. Secondary endpoints were safety, pharmacodynamical plasma markers of VEGFR-blockade, time to progression (TTP), and overall survival (OS).

Results: Modified RECIST overall response rate was 48%, including 13% complete remission, and despite dose reduction/interruption in 83% of patients, intratumoral perfusion index decreased significantly. Grade 3-4 adverse events, most frequently (on-target) hypertension (54%), fatigue (25%), and thrombocytopenia (21%), occurred in 88% of patients. Plasma VEGF-A, VEGF-D, and placental growth factor increased significantly, whereas sTie-2 decreased, consistent with VEGFR-blockade. Following neoadjuvant dovitinib, all patients could proceed to their original planned locoregional treatment. No delayed toxicity occurred. Seven patients (three early, four intermediate stage) underwent orthotopic liver transplant after median 11.4 months. Censoring at transplantation, median TTP and OS were 16.8 and 34.8 months respectively; median cancer-specific survival was not reached.

Conclusion: Already after a short 4-week dovitinib treatment period, intratumoral blood flow reduction and modest antitumor responses were observed. Although these results support use of systemic neoadjuvant strategies, the poor tolerability indicates that dovitinib dose adaptations are required in HCC.

Implications for practice: Orthotopic liver transplantation may cure early and intermediate-stage hepatocellular carcinoma. Considering the expected waiting time >6 months because of donor liver scarcity, there is an unmet need for effective neoadjuvant downsizing strategies. Angiogenesis inhibition by dovitinib does not negatively affect subsequent invasive procedures, is safe to administer immediately before locoregional therapy, and may provide a novel treatment approach to improve patient outcomes if tolerability in patients with hepatocellular carcinoma can be improved by therapeutic drug monitoring and personalized dosing.

Keywords: Biomarker; Inflammation; Multireceptor tyrosine kinase inhibitor; Perfusion computed tomography; Quality of life.

Figure 1

Tumor characteristics. (A): Representative HCC specimens, top panel: H&E and CD34 stains, respectively, show well differentiated HCC (×40 magnification) and typical high tumor vascular density (×25 magnification). Bottom panel from left to right: translocation of β‐catenin to the cytoplasm and nucleus in CTNNB1‐mutated HCC versus normal membrane β‐catenin expression in CTNNB1‐wildtype HCC (×100 magnification). (B): Molecular tumor profile by targeted next generation sequencing. Possible and known pathogenic gene mutations were most frequently found in CTNNB1 and TP53. CTNNB1 exon 3 variants: p.G34V, p.I35G38del, p.T41A, p.S45P, p.S45Y, and p.S45F mutations. TP53 exon 5 + 7 variants: p.T155K, p.C238R, p.G245C, and p.R249S mutations. Six tumors did not contain class 3–5 mutations in the evaluated genes or gene fragments. One patient with a CTNNB1 p.T41A and KRAS p.G12D mutation demonstrated aberrant nuclear β‐catenin staining at diagnosis, but wildtype CTNNB1 and membranous β‐catenin expression on the posttreatment sample. Abbreviation: HCC, hepatocellular carcinoma.

Figure 2

Radiologic response according to RECIST 1.1 (A) and mRECIST (B) criteria. No significant Pearson or Spearman correlation was found between mRECIST response and cumulative dovitinib dose, change in intratumoral arterial flow, or development of grade 3–4 on‐target hypertension. *One patient was not evaluable by mRECIST. Abbreviation: mRECIST, modified RECIST.

Figure 3

Changes in tumor density and intratumoral blood flow before (left panel) and after (right panel) dovitinib treatment. After 3 days of dovitinib treatment, one poorly differentiated patient with hepatocellular carcinoma demonstrated (A) massive necrosis on computed tomography (CT) scan and (B) 63% decrease in tumor arterial flow on perfusion CT. Even though 14% increase in tumor size was visible on CT scan, the lesion had become largely necrotic and ruptured. (C): At emergency hemihepatectomy, large fields of necrosis were macroscopically visible.

Figure 4

Treatment‐emergent adverse events from baseline to locoregional therapy. All 24 patients experienced at least one adverse event of any grade during dovitinib treatment. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Figure 5

Plasma levels of pharmacodynamic biomarkers of VEGFR‐blockade. Median and interquartile range on days 0, 12, and 26 of dovitinib treatment are shown. Abbreviations: PlGF, placental growth factor; sTIE2, soluble angiopoietin receptor 2; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.

Figure 6

Survival outcomes of 21 evaluable patients with early to intermediate hepatocellular carcinoma. (A): Cancer‐specific and overall survival. (B): Time to progression. Patients were censored at liver transplant.