Neoadjuvant treatment with angiogenesis-inhibitor dovitinib prior to local therapy in hepatocellular carcinoma: a phase 2 study
Mené sur 24 patients atteints d'un carcinome hépatocellulaire de stade précoce et intermédiaire, cet essai de phase II évalue l'efficacité, du point de vue du taux de réponse objective et des modifications du flux sanguin intratumoral, et la toxicité d'un traitement néoadjuvant par dovitinib (un inhibiteur de VEGFR)
Background : Hepatocellular carcinoma (HCC) recurrence rates following locoregional treatment are high. As multireceptor tyrosine kinase inhibitors (TKI) targeting vascular endothelial growth factor receptors (VEGFR) are effective in advanced HCC, we assessed the efficacy and safety of neoadjuvant systemic treatment with dovitinib in early and intermediate stage HCC. Methods : Twenty-four modified Child-Pugh class A early and intermediate stage HCC patients received neoadjuvant oral dovitinib 500 mg daily (5 days-on/2-days-off) during 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 : mRECIST 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 PlGF increased significantly, while 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 (3 early, 4 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 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 due to 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 HCC patients can be improved by therapeutic drug monitoring and personalized dosing.
The Oncologist 2021