Sorafenib in metastatic uveal melanoma: efficacy, toxicity and health-related quality of life in a multicentre phase II study

Abstract

Background:The aim of the study was to analyse efficacy, safety, and health-related quality of life (HRQoL) for sorafenib treatment in patients with metastatic uveal melanoma.Methods:A multicentre, single-arm phase II trial was conducted. The primary objective was to determine the non-progression rate (RECIST) at 24 weeks for patients receiving sorafenib at a dose of 800 mg per day. Secondary endpoints included progression-free survival (PFS), overall survival (OS), toxicity, and HRQoL.Results:Thirty-two patients were included. Ten patients showed non-progression at 24 weeks (31.2%) without objective tumour responses. The estimated 24-week PFS was 31.2% (95% CI: 14.8%–47.6%) and the estimated 24-week OS was 62.5% (95% CI: 45.4%–79.6%). Ten patients (34.3%) had at least one grade 3 or 4 adverse reaction and 12 patients (41.4%) required dose modifications due to toxicity. At 24 weeks, no patient had an improvement in global HRQoL and 87.5% experienced a permanent increase in physical fatigue.Conclusions:Sorafenib demonstrated non-progression at 24 weeks in 31.2% of patients. However, 41.4% of patients required dose modifications due to toxicity and no improvement in HRQoL was demonstrated.

Meta-analysis in metastatic uveal melanoma to determine progression free and overall survival benchmarks: an international rare cancers initiative (IRCI) ocular melanoma study

“…Reasons for data not being available included a lack of investigator response to requests for data and archived data that were no longer available. Of the 29 studies for which data were available, 5 involved immunotherapy [27][28][29][30][31], 7 involved a kinase inhibitor (of which 2 were randomised studies against temozolomide or dacarbazine, respectively) [12,[32][33][34][35][36], 2 used an anti-angiogenic agent [37,38], 8 involved chemotherapy (1 of which was a randomised study of intrahepatic versus intravenous chemotherapy) [39][40][41][42][43][44][45] and 7 studies involved intrahepatic treatment (chemotherapy or immunotherapy) [46][47][48][49][50][51][52] (supplementary Table S1, available at Annals of Oncology online).…”

Oncogenic signaling in uveal melanoma

“…In earlier studies, patients with c‐Kit expressing UM have been trialed with imatinib, a c‐Kit inhibitor (Hofmann, Kauczok‐Vetter, Houben, & Becker, ; Nathan et al., ; Penel et al., ). Multitargeted tyrosine kinase inhibitors such as sunitinib and sorafenib have also been tested in phase II trials (Bhatia et al., ; Mahipal et al., ; Mouriaux et al., ; Sacco et al., ), but none of these inhibitors have shown clinical benefit. Bevacizumab and aflibercept, which inhibit VEGF, have also failed to show any significant clinical benefit (Piperno‐Neumann et al., ; Tarhini et al., ).…”

The bidirectional crosstalk between metastatic uveal melanoma cells and hepatic stellate cells engenders an inflammatory microenvironment

“…Surprisingly, the proliferation of UMC lines was not significantly modified by the paracrine signaling of HSCs. According to clinical experience, some UM patients have metastatic lesions that remain stable during several weeks or months, but then proliferate exponentially and invade the liver (Mouriaux et al, 2016a). Such initial non-proliferation of UMCs may be due to the inhibitory effect of the microenvironment.…”