Trials 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.,Trials 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.,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.,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.,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.,In patients with MUM, a combination of bevacizumab plus temozolomide achieved a 6-month PFR of 23%.
Inhibitors of RAF inhibit the MAPK pathway that plays an important role in the development and progression of those melanoma carrying the V600E BRAF mutation, but there’s a subset of such patients who do not respond to the therapy.,Various mechanisms of drug resistance have been proposed which include the clonal heterogeneity of the tumor.,We have studied a population of nodular melanoma to investigate the intratumor and intertumor heterogeneity by Laser Capture Microdissection (LCM) analysis.,Our results showed that BRAF and NRAS mutations were detected in 47% and 33% of nodular melanoma, respectively, and that there is a discrepancy in mutational pattern of tumoral sample because in the 36% of patients a different mutation, in at least 1 area of the tumor, was found by LCM analysis, giving evidence of the presence of different clonal cells populations.,Moreover, we found that mutations in BRAF and NRAS are not mutually exclusive because they were simultaneously present in the same tumor specimens and we observed that when the 2 different mutations were present one is a high-frequency mutation and the other is a low-frequency mutation.,This was more evident in lymphonodal metastasis that resulted from wild type to mutational analysis, but showed different mutations following LCM analysis.,Therefore, we believed that, when primary tumoral sample results negative to mutational analysis, if it is possible, metastases should be investigated to verify the presence of mutations.,Generally, it should be searched for other mutations, in addition to BRAF V600E, so as to better understand the mechanism of drug resistance.