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Bevacizumab plus fotemustine may be first-line option for advanced melanoma patients
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Significant inhibition of pro-angiogenic activity in serum was observed in patients with advanced melanoma who were treated with bevacizumab-fotemustine combination therapy, according to study results.
Researchers from several sites in Italy aimed to assess the clinical and biological activity of the association of bevacizumab (Avastin, Genentech) and fotemustine as a first-line regimen for patients with advanced melanoma.
Eligible patients had a histologically or cytologically confirmed measurable diagnosis of metastatic, inoperable nonchoroidal melanoma; an ECOG performance status of 0 to 1; had been previously untreated for metastatic disease; and had normal hematologic, hepatic and renal function, no brain metastases and a life expectancy of at least 3 months.
Twenty patients were administered bevacizumab at 15 mg/kg every 3 weeks and IV fotemustine at 100 mg/m² on days 1, 8 and 15; the IV fotemustine regimen was repeated after 4 weeks. The phase 2, open-label study involved a single arm.
The primary outcome measure was the best overall response rate. Secondary endpoints included toxicity, time to progression and OS.
The treatment yielded one complete response, two partial responses and 10 patients with stable disease. The average time to progression was 8.3 months, and the average OS was 20.5 months.
Eighteen patients experienced one or more adverse events, and grade 3 to 4 toxicity was reported in 14 patients. Neutropenia was the most frequently observed grade 3 to 4 hematologic toxicity.
Significant inhibition of serum VEGF-A and overall serum pro-angiogenic activity were reported in 15 patients who were evaluated within 1 hour of the first administration of therapy. Sixty-six of 67 post-therapy serum samples of VEGF-A remained significantly lower compared with samples tested before therapy.
“These results indicate that administration of bevacizumab plus fotemustine was associated with profound and durable inhibition of systemic levels of VEGF-A in all assessed patients,” the researchers wrote.
VEGF-C levels were significantly reduced in several post- vs. pre-therapy serum samples. In vitro results indicated that fotemustine inhibited the release of VEGF-C by melanoma cells but did not induce significant cell death.
Patients who demonstrated a partial response had the highest serum levels of interleukin-10 and IL-12p70 compared with patients with stable or progressive disease. The opposite pattern was true for IL-23.
The researchers monitored serum cytokines, angiogenesis and lymphangiogenesis factors by multiplex arrays and by in vitro angiogenesis assays. An enzyme-linked immunosorbent assay was used to measure the effects of fotemustine on melanoma cells, in vitro, and on VEGF-C release. Apoptosis was assessed by flow cytometry.
For more information:
- Del Vecchio M. Clin Cancer Res. 2010;doi:10.1158/1078-0432.CCR-10-2363.