Efficacy and Safety of Vismodegib in Advanced Basal-Cell Carcinoma

Mayo Clinic, Scottsdale, AZ 85259, USA.
New England Journal of Medicine (Impact Factor: 55.87). 06/2012; 366(23):2171-9. DOI: 10.1056/NEJMoa1113713
Source: PubMed


Alterations in hedgehog signaling are implicated in the pathogenesis of basal-cell carcinoma. Although most basal-cell carcinomas are treated surgically, no effective therapy exists for locally advanced or metastatic basal-cell carcinoma. A phase 1 study of vismodegib (GDC-0449), a first-in-class, small-molecule inhibitor of the hedgehog pathway, showed a 58% response rate among patients with advanced basal-cell carcinoma.
In this multicenter, international, two-cohort, nonrandomized study, we enrolled patients with metastatic basal-cell carcinoma and those with locally advanced basal-cell carcinoma who had inoperable disease or for whom surgery was inappropriate (because of multiple recurrences and a low likelihood of surgical cure, or substantial anticipated disfigurement). All patients received 150 mg of oral vismodegib daily. The primary end point was the independently assessed objective response rate; the primary hypotheses were that the response rate would be greater than 20% for patients with locally advanced basal-cell carcinoma and greater than 10% for those with metastatic basal-cell carcinoma.
In 33 patients with metastatic basal-cell carcinoma, the independently assessed response rate was 30% (95% confidence interval [CI], 16 to 48; P=0.001). In 63 patients with locally advanced basal-cell carcinoma, the independently assessed response rate was 43% (95% CI, 31 to 56; P<0.001), with complete responses in 13 patients (21%). The median duration of response was 7.6 months in both cohorts. Adverse events occurring in more than 30% of patients were muscle spasms, alopecia, dysgeusia (taste disturbance), weight loss, and fatigue. Serious adverse events were reported in 25% of patients; seven deaths due to adverse events were noted.
Vismodegib is associated with tumor responses in patients with locally advanced or metastatic basal-cell carcinoma. (Funded by Genentech; Erivance BCC number, NCT00833417.).

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Available from: Anthony Oro, Apr 02, 2014
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    • "All syndromic BCCs in patients with basal cell nevus syndrome (Gorlin syndrome, caused by inherited PTCH1 loss) respond to vismodegib and have a low rate of acquired resistance (Tang et al., 2012). In contrast, advanced and metastatic BCCs have an overall response rate of 48% (Axelson et al., 2013; Sekulic et al., 2012), with an additional 20% of patients developing resistance during the first year (Chang and Oro, 2012). Vismodegib and other SMO inhibitors have also shown promising results in early clinical trials for medulloblastoma (Gajjar et al., 2013). "
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    ABSTRACT: Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here we identify SMO mutations in 50% (22 of 44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants conferring constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition. In the presence of a SMO inhibitor, tumor cells containing either class of SMO mutants effectively outcompete cells containing the wild-type SMO. Finally, we show that both classes of SMO variants respond to aPKC-ι/λ or GLI2 inhibitors that operate downstream of SMO, setting the stage for the clinical use of GLI antagonists. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Mar 2015 · Cancer Cell
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    • "Remarkably, vismodegib is the first Hh inhibitor to have been clinically approved by the FDA for the treatment of BCC. In a recent multicentre open-label phase II trial, it produced a response rate of 30% in patients with metastatic BCC and of 43% in patients with locally advanced BCC, whereas complete response was seen in 21% of patients with locally advanced BCC (Sekulic et al, 2012). Owing to these encouraging results, it is currently under clinical evaluation for an array of other cancer types including metastatic colorectal cancer, small-cell lung cancer, gastric cancer, pancreatic cancer, medulloblastoma, and chondrosarcoma (Fellner, 2012). "
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    ABSTRACT: Background: Multiple lines of evidence support that the Hedgehog (Hh) signalling has a role in the maintenance and progression of different human cancers. Therefore, inhibition of the Hh pathway represents a valid anticancer therapeutic approach for renal cell carcinoma (RCC) patients. NVP-LDE225 is a Smoothened (Smo) antagonist that induces dose-related inhibition of Hh and Smo-dependent tumour growth. Methods: We assayed the effects of NVP-LDE225 alone or in combination with everolimus or sunitinib on the growth and invasion of human RCC models both in vitro and in vivo. To this aim, we used a panel of human RCC models, comprising cells with acquired resistance to sunitinib - a multiple tyrosine kinase inhibitor approved as a first-line treatment for RCC. Results: NVP-LDE225 cooperated with either everolimus or sunitinib to inhibit proliferation, migration, and invasion of RCC cells even in sunitinib-resistant (SuR) cells. Some major transducers involved in tumour cell motility, including paxillin, were also efficiently inhibited by the combination therapy, as demonstrated by western blot and confocal microscopy assays. Moreover, these combined treatments inhibited tumour growth and increased animal survival in nude mice xenografted with SuR RCC cells. Finally, lung micrometastasis formation was reduced when mice were treated with NVP-LDE225 plus everolimus or sunitinib, as evidenced by artificial metastatic assays. Conclusions: Hedgehog inhibition by NVP-LDE225 plus sunitinib or everolimus bolsters antitumour activity by interfering with tumour growth and metastatic spread, even in SuR cells. Thus, this new evidence puts forward a new promising therapeutic approach for RCC patients.
    Full-text · Article · Aug 2014 · British Journal of Cancer
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    • "In contrast, in sporadic cases only half of patients (19 out of 33) in phase I clinical trials with late advanced or metastatic BCC showed tumor regression with vismodegib treatment despite having a similar histology to BCNS patients (Hoff et al. 2009; LoRusso et al. 2011). In phase II clinical trials, only 30% (10 of 33) of metastatic and 43% (27 of 63) late advanced BCC patients responded to vismodegib (Sekulic et al. 2012). In addition, other HH-driven tumors such as pancreatic or small cell lung cancers showed little to no response to vismodegib despite inhibition of the HH pathway (LoRusso et al. 2011). "
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    ABSTRACT: Basal cell carcinomas (BCCs) are very common epithelial cancers that depend on the Hedgehog pathway for tumor growth. Traditional therapies such as surgical excision are effective for most patients with sporadic BCC; however, better treatment options are needed for cosmetically sensitive or advanced and metastatic BCC. The first approved Hedgehog antagonist targeting the membrane receptor Smoothened, vismodegib, shows remarkable effectiveness on both syndromic and nonsyndromic BCCs. However, drug-resistant tumors frequently develop, illustrating the need for the development of next-generation Hedgehog antagonists targeting pathway components downstream from Smoothened. In this article, we will summarize available BCC treatment options and discuss the development of next-generation antagonists.
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