Phase II Trial of Bevacizumab in Combination With Temozolomide as First-Line Treatment in Patients With Metastatic Uveal Melanoma

Abstract

Lessons LearnedTrials dedicated to metastatic uveal melanoma are needed because of the poor prognosis of this rare cancer and because its biology is distinct from that of cutaneous melanoma.Agents targeting the MEK/ERK/MAP kinase pathways are being tested.Background.In experimental models, bevacizumab suppressed in vitro growth and in vivo hepatic metastasis of ocular melanoma cells. Additional preclinical data suggested a potential benefit when combining bevacizumab with dacarbazine.Methods.This noncomparative phase II study evaluated a combination of bevacizumab (10 mg/kg on days 8 and 22) with temozolomide (150 mg/m2 on days 1–7 and 15–21) in 36 patients with metastatic uveal melanoma (MUM). The primary endpoint was the progression-free rate (PFR) at 6 months. Using a modified 2-step Fleming plan, at least 10 of 35 patients were required to support a predefined PFR at 6 months of 40%. Secondary objectives were progression-free survival (PFS), overall survival (OS), and safety; liver perfusion computed tomography (CT) for response imaging; and impact of VEGF-A gene polymorphisms on bevacizumab pharmacodynamics.Results.First- and second-step analyses revealed nonprogression at 6 months in 3 of 17 and 8 of 35 patients, respectively. Finally, the 6-month PFR was 23% (95% confidence interval [CI]: 10–39), with long-lasting stable disease in 5 patients (14%). Median PFS and OS were 12 weeks and 10 months, respectively. No unexpected toxicity occurred. Liver perfusion CT imaging was not useful in assessing tumor response, and VEGF-A gene polymorphisms were not correlated with toxicity or survival.Conclusion.In patients with MUM, a combination of bevacizumab plus temozolomide achieved a 6-month PFR of 23%.

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).…”

The biology of uveal melanoma

“…Selumetinib is also being tested in combination with temozolomide (NCT01143402), and the maximum tolerated dose of intermittent selumetinib is being investigated (NCT02768766) [69]. Bevacizumab was tested in combination with dacarbazine showing modest activity [70]. A pilot study with the kinase inhibitor sunitinib showed a potential clinical benefit that was independent of the expression level of the target kinase, c-Kit [71].…”

Oncogenic signaling in uveal melanoma

“…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., ). Cabozantinib, a nonspecific MET and tyrosine kinase inhibitor, was tested in a phase II trial, and the UM cohort showed 61% of patients (14/23) achieved stable disease at week 12, with median PFS of 4.8 months and median OS of 12.6 months (Daud et al., ).…”