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.
Oncogenic BRAF mutation had been considered to be a founder event in the formation of melanocytic tumours; however, we recently argued against this notion by showing marked polyclonality of BRAF mutations in acquired melanocytic nevi (Lin et al, J Natl Cancer Inst., 2009; 101:1423-7).,Here, we tested whether similar heterogeneity of BRAF mutations exists in primary melanomas.,We isolated and sequenced single melanoma cells from five primary melanoma tissues using antibodies against human high-molecular-weight melanoma-associated antigen.,We also examined 10 primary melanomas by the sensitive Mutector assay detecting the BRAFV600E mutation, as well as by cloning and sequencing of separated alleles.,Furthermore, we estimated the frequency of BRAF mutant alleles in paired samples of primary tumour and recurrence or metastasis in three patients.,Single-cell mutation analyses revealed that four of five primary melanomas contained both BRAF-wild-type and BRAF-mutant tumour cells.,Tumour heterogeneity in terms of BRAF mutations was also shown in 8 of 10 primary melanomas.,Selection of BRAF mutant alleles during progression was demonstrated in all the three patients.,Acquisition of a BRAF mutation is not a founder event, but may be one of the multiple clonal events in melanoma development, which is selected for during the progression.