A phase II trial of bevacizumab with dacarbazine and daily low-dose interferon-α2a as first line treatment in metastatic melanoma

Abstract

Metastatic melanomas are hypervascular tumours with poor prognosis. We hypothesized that treatment of metastatic melanoma with a combination of bevacizumab, a monoclonal antibody against vascular endothelial growth factor, dacarbazine (DTIC) and low-dose interferon alpha-2a (IFN-alpha2a) might lead to a synergistic inhibition of angiogenesis and regression of tumours. Patients with metastatic melanoma were treated with bevacizumab (5 mg/kg every 2 weeks), DTIC (200 mg/m days 1-5 every 4 weeks) and IFN-alpha2a (three MIU subcutaneously daily from day 15 onwards). Patients exhibiting response or stable disease after 6 months were treated with bevacizumab+/-IFN-alpha2a until disease progression. The primary study objectives were progression-free survival (PFS), overall survival and safety. Twenty-six patients were accrued. Response rate was 23% (two complete responses, four partial responses), and six patients showed stable disease. The median PFS for all patients was 2.3 months and for responders 8.1 months. The median overall survival for all patients was 11.5 months. Four life-threatening adverse events were seen: two pulmonary thromboembolisms, an intracerebral haemorrhage, and one grade 4 hypertension. One of the pulmonary emboli and the intracerebral haemorrhage were observed > or =3 months after the last bevacizumab-DTIC dose. Serum matrix metalloproteinase-9 and vascular endothelial growth factor levels changed during therapy. There was a trend towards favourable PFS among patients with only minimal or moderate change in these marker expression levels. The present regimen was active in this patient group but was also associated with remarkable vascular events.

Comparison of Immunosuppressive and Immunomodulatory Cells in Keratoacanthoma and Cutaneous Squamous Cell Carcinoma

“…Because it remodels the extracellular .4cta Derm Ï enereot 93 matrix and promotes the sprouting and growth of new blood vessels by making vascular endothelial growth factor (VEGF) available to the VEGFR-2/flk receptor on endothelial cells, MMP-9 is a linchpin in tumour progression (29). Actually, several reports revealed that the expression of MMP-9 on tumours was correlated with the progression or prognosis of several skin tumours, such as malignant melanoma, SCC, basal cell carcinoma, mycosis fungoides, extrammamary Paget's disease and angiosarcoma (20,(29)(30)(31)(32)(33)(34). In addition, other reports indicate that the expression of MMP-9 on immunosuppressive macrophages in the tumour microenvironment contributes to tumour invasion and metastasis (10,11,20,34,35).…”

Circulating levels of VEGFR-1 and VEGFR-2 in patients with metastatic melanoma treated with chemoimmunotherapy alone or combined with bevacizumab

“…If there was no progression after six cycles, the treatment was continued with maintenance therapy with bevacizumab (5 mg/kg) on days 1 and 15 with or without continuous IFN-a2a 3 million international units subcutaneously daily. The treatment schedule has been published in detail recently ( [20]; ML 18580/www. clinicaltrials.gov).…”

“…Eligibility criteria also included the following: age greater than or equal to 18 years, life expectancy greater than or equal to 3 months, Eastern Cooperative Oncology Group performance status less than or equal to 2, normal organ and bone marrow function, no previous treatment for metastatic disease [bevacizumab-dacarbazine (DTIC)-interferon-a2a (IFN-a2a) trial] or progressing melanoma irrespective of previous treatments [carboplatin, vinorelbine, and subcutaneous interleukin-2 (IL-2) trial], and no central nervous system metastases. The study protocols were approved by the local ethics committees and each patient provided a written informed consent to participate in the trials [20,21]. The key clinical characteristics of the patients are shown in Table 1.…”

“…In our recent study on patients with melanoma, treated with bevacizumab, we found that therapy-induced decrease in s-VEGF levels was unexpectedly associated with worse progression-free survival [20]. In this study, we analyzed VEGFR-1 and VEGFR-2 in serum samples of 48 patients with metastatic melanoma, of whom 22 had chemoimmunotherapy and 26 received bevacizumab plus chemoimmunotherapy.…”

Chinese Guidelines on the Diagnosis and Treatment of Melanoma (2015 Edition)

“…Bevacizumab is a monoclonal antibody that can selectively bind VEGF and block its binding with receptors. It has been widely applied in the treatment of metastatic melanoma (182)(183)(184)(185). In a randomized, double-blind phase II study (BEAM study), 214 metastatic melanoma patients were randomized into carboplatin + paclitaxel + bevacizumab (CPB) group or placebo group (CP) at a proportion of 2:1.…”