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 (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. The Oncologist 2021;9999:• •

FGFR families: biological functions and therapeutic interventions in tumors

“…The primary target of dovitinib is VEGFR1–3, but it also targets FGFR1–3, PDGFRβ, FMS‐like tyrosine kinase 3 (FLT3), KIT, RET, TrkA, and colony stimulating factor 1 (Csf‐1). Dovitinib has shown therapeutic effects in breast cancer, HCC, prostate cancer, renal cell carcinoma, melanoma, multiple myeloma, and gastrointestinal mesenchymal tumors and its major drug‐related toxicities include nausea, vomiting, fatigue, anorexia, and diarrhea 333–335 . Lucitanib strongly inhibits FGFR1, FGFR2, and VEGFR1–3, and it has antiangiogenic and broad‐spectrum antitumor activity against several cancers, including small cell lung cancer, breast cancer, nasopharyngeal carcinoma, colorectal cancer, ovarian cancer, and kidney cancer 336,337 .…”

Neoadjuvant Dovitinib in Early- and Intermediate-Stage Hepatocellular Carcinoma

“…We read with interest the article published by Woei-A-Jin et al and commend the authors for bringing this interesting report to the field of neoadjuvant systemic treatment in early- and intermediate-stage hepatocellular carcinoma (HCC). 1 Currently, there is an urgent need for active systemic treatment as a preoperative strategy to achieve disease down-staging and expand the proportion of patients who may derive benefit from locoregional therapies. 2 Despite optimal local control, most of patients with HCC recur, and the 5-year survival rate for early- and intermediate-stage HCC ranges between 15% and 50%, with failure to control micro-metastatic disease severely influencing early relapse in this setting.…”

“…In The Oncologist , Woei-A-Jin et al reported the results of a phase II trial including 24 patients with early- and intermediate-stage HCC, treated with neoadjuvant oral dovitinib for 4 weeks, followed by locoregional therapy. 1 Of note, the 48% of patients had an overall response, including 13% complete remission; however, tolerability has represented an important issue, with frequent dose reductions and interruptions. We believe some elements deserve discussion.…”

“…In fact, despite caution should always be exercised when interpreting results from single-arm, phase II trials conducted in a single center, the results of the study published by Woei-A-Jin et al are of great interest. 1 …”

In Reply: Neoadjuvant TKI Study in Early- and Intermediate Stage Hepatocellular Carcinoma

“…We appreciate the letter by Rizzo et al, 1 in which they acknowledged the important pharmacodynamic information obtained from our neoadjuvant phase II study of dovitinib prior to local/locoregional therapy in early- and intermediate-stage hepatocellular carcinoma (HCC). 2 …”