In the primary analysis of the ERIVANCE BCC trial, vismodegib, the first US Food and Drug Administration-approved Hedgehog pathway inhibitor, showed objective response rates (ORRs) by independent review facility (IRF) of 30% and 43% in metastatic basal cell carcinoma (mBCC) and locally advanced BCC (laBCC), respectively.,ORRs by investigator review were 45% (mBCC) and 60% (laBCC).,Herein, we present long-term safety and final investigator-assessed efficacy results in patients with mBCC or laBCC.,One hundred four patients with measurable advanced BCC received oral vismodegib 150 mg once daily until disease progression or intolerable toxicity.,The primary end point was IRF-assessed ORR.,Secondary end points included ORR, duration of response (DOR), progression-free survival, overall survival (OS), and safety.,At data cutoff (39 months after completion of accrual), 8 patients were receiving the study drug (69 patients in survival follow-up).,Investigator-assessed ORR was 48.5% in the mBCC group (all partial responses) and 60.3% in the laBCC group (20 patients had complete response and 18 patients had partial response).,ORRs were comparable across patient subgroups, including aggressive histologic subtypes (eg, infiltrative BCC).,Median DOR was 14.8 months (mBCC) and 26.2 months (laBCC).,Median OS was 33.4 months in the mBCC cohort and not estimable in the laBCC cohort.,Adverse events remained consistent with clinical experience.,Thirty-three deaths (31.7%) were reported; none were related to vismodegib.,This long-term update of the ERIVANCE BCC trial demonstrated durability of response, efficacy across patient subgroups, and manageable long-term safety of vismodegib in patients with advanced BCC.,This study was registered prospectively with Clinicaltrials.gov, number NCT00833417 on January 30, 2009.,The online version of this article (doi:10.1186/s12885-017-3286-5) contains supplementary material, which is available to authorized users.
Melanoma is highly resistant to current modalities of therapy, with the extent of pigmentation playing an important role in therapeutic resistance.,Nuclear factor-κB (NF-κB) is constitutively activated in melanoma and can serve as a molecular target for cancer therapy and steroid/secosteroid action.,Cultured melanoma cells were used for mechanistic studies on NF-κB activity, utilising immunofluorescence, western blotting, EMSA, ELISA, gene reporter, and estimated DNA synthesis assays.,Formalin-fixed, paraffin-embedded specimens from melanoma patients were used for immunocytochemical analysis of NF-κB activity in situ.,Novel 20-hydroxyvitamin (20(OH)D3) and classical 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) secosteroids inhibited melanoma cell proliferation.,Active forms of vitamin D were found to inhibit NF-κB activity in nonpigmented cells, while having no effect on pigmented cells.,Treatment of nonpigmented cells with vitamin D3 derivatives inhibited NF-κB DNA binding and NF-κB-dependent reporter assays, as well as inhibited the nuclear translocation of the p65 NF-κB subunit and its accumulation in the cytoplasm.,Moreover, analysis of biopsies of melanoma patients showed that nonpigmented and slightly pigmented melanomas displayed higher nuclear NF-κB p65 expression than highly pigmented melanomas.,Classical 1,25(OH)2D3 and novel 20(OH)D3 hydroxyderivatives of vitamin D3 can target NF-κB and regulate melanoma progression in nonpigmented melanoma cells.,Melanin pigmentation is associated with the resistance of melanomas to 20(OH)D3 and 1,25(OH)2D3 treatment.