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Targeted therapy for advanced Basal-cell carcinoma: vismodegib and beyond.

ABSTRACT: Basal-cell carcinoma is a commonly occurring skin malignancy that has the potential to progress into locally invasive or resistant disease, as well as spread distantly. Due to advances in the molecular understanding of the disease over the last two decades, it has been discovered that the Hedgehog pathway plays an important role in the pathogenesis of this disease and can be exploited as a treatment target. Several agents that inhibit the Hedgehog pathway have reached clinical studies and one drug, vismodegib, has recently been US Food and Drug Administration (FDA) approved based on clinical activity and tolerability in patients with advanced basal-cell carcinoma. This review will describe the clinical development of vismodegib, as well as the proper application of the drug in clinical practice. Other important clinical questions, such as mechanisms of resistance to vismodegib and the role of other Hedgehog pathway inhibitors currently in development will also be discussed.

SUBMITTER: Cowey CL

PROVIDER: S-EPMC3680638 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Targeted therapy for advanced Basal-cell carcinoma: vismodegib and beyond.

Cowey C Lance CL

Dermatology and therapy 20130302 1

Basal-cell carcinoma is a commonly occurring skin malignancy that has the potential to progress into locally invasive or resistant disease, as well as spread distantly. Due to advances in the molecular understanding of the disease over the last two decades, it has been discovered that the Hedgehog pathway plays an important role in the pathogenesis of this disease and can be exploited as a treatment target. Several agents that inhibit the Hedgehog pathway have reached clinical studies and one dr ...[more]

PMID: 23888252

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Project description:BackgroundAlterations 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.MethodsIn 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.ResultsIn 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.ConclusionsVismodegib is associated with tumor responses in patients with locally advanced or metastatic basal-cell carcinoma. (Funded by Genentech; Erivance BCC ClinicalTrials.gov number, NCT00833417.).

Project description:BackgroundSurgery is the primary treatment for basal cell carcinoma (BCC). In locally advanced basal cell carcinoma (laBCC), surgery may cause functional or aesthetic damage. In laBCC, neoadjuvant administration of vismodegib, an inhibitor of the Hedgehog signaling pathway, may reduce tumor size, facilitate resection, and reduce functional and aesthetic consequences of surgery. The VISMONEO study assessed efficacy and safety of vismodegib in neoadjuvant treatment of laBCC.MethodsVISMONEO (NCT02667574) is an open-label, noncomparative, multicenter, phase 2 study. Patients with ≥1 histologically confirmed facial BCC, inoperable or operable with functional or major aesthetic sequelae risk, were included. Oral vismodegib 150 mg was administered once daily for 4 to 10 months before planned surgery, which was performed once the best response under vismodegib was observed. Primary endpoint was percentage of patients with BCC with tumor downstaging following surgical resection after neoadjuvant vismodegib. Downstaging was defined according to a 6-stage surgical classification related to the aesthetic and functional consequences of surgery.Findings55 patients (median age: 73 years) with laBCC were included from November 2014 to June 2015. At inclusion, 4 patients were inoperable, 15 were operable with a major functional risk, and 36 were operable with a minor functional risk or a major aesthetic risk. Mean size of target lesion was 47.3 mm (SD: 27.2 mm). 44 patients presented with downstaging after vismodegib treatment (80%; 95% confidence interval [CI], 67 to 90). Of these 44 patients, 27 had a complete response (25 proved by biopsy). Mean treatment duration was 6.0 months. Overall Response Rate according to RECIST 1.1 criteria was 71% (95% CI, 59 to 88). At 3-years of follow-up, 16/44 patients had known recurrence (36%; 95%CI, 22 to 51).InterpretationNeoadjuvant vismodegib allows for a downstaging of the surgical procedure for laBCCs in functionally sensitive locations.FundingVISMONEO was funded by F. Hoffmann-La Roche Ltd.

Project description:INTRODUCTION:Locally advanced basal cell carcinoma (laBCC) has always represented an uncommon, difficult-to-treat form of skin cancer, but approval of the Hedgehog inhibitor (HHI) vismodegib has provided an effective, well-tolerated therapy. While this drug has been shown to be a safe and effective during treatment, to date the effect of its prolonged use at a low dose after complete remission (CR) of laBCC has not been described. The aim of this study was to report our experience regarding the long-term efficacy of low-dose vismodegib as maintenance therapy in patients with CR of the disease during a 1-year follow-up period. METHODS:An observational retrospective study was conducted at the Non-Melanoma Skin Cancer Unit of the University of Federico II (Naples). Patients who reported complete regression of their advanced BCC after vismodegib treatment were included in the study and subsequently separated into two groups. One group of patients continued with the "drug holiday" regimen consisting of a once-weekly maintenance dosage of 150 mg vismodegib for 1 year after CR of their BCC; the second group comprised patients who decided not to take a maintenance dosage following complete regression of their BCC. RESULTS:A total of 42 patients (35 males, 7 females) with a median age of 75.2 years and complete regression of their advanced BCC after treatment with vismodegib were included in the study. Of these, 27 (64%) patients continued with the "drug holiday" regimen, receiving a once-weekly maintenance dosage of 150 mg vismodegib for 1 year after CR of their BCC, and 15 (36%) patients decided not to take the maintenance dosage. Patients who continued to receive the low-dose vismodegib treatment did not present any BCC recurrence during 1-year follow-up period, while those who discontinued vismodegib treatment reported a BCC recurrence rate of 26.6% (4/15 patients) during the 1-year follow-up period. CONCLUSIONS:Our retrospective analysis focused on the use of a novel therapeutic scheme based on prolonged use of vismodegib after CR of the laBCC. The results demonstrate that the maintenance dose of vismodegib described herein effectively eliminated skin tumor recurrence and reduced the severity of common adverse events, thus increasing patient compliance.

Project description:ImportanceThe outcomes of vismodegib treatment in a relatively large cohort of study participants with periocular locally advanced basal cell carcinoma (POLA-BCC) may guide physicians when considering this treatment.ObjectiveTo report the outcomes of vismodegib treatment in patients with POLA-BCC in the Safety Events in Vismodegib (STEVIE) study.Design, setting, and participantsThis post hoc subgroup analysis from the STEVIE single-arm, multicenter, open-label cohort study screened all 1215 participants for ocular or periocular involvement and identified 244 participants with POLA-BCC or metastatic BCC. Data for the first STEVIE trial were collected from 167 treatment locations in 36 countries from June 30, 2011, to June 14, 2017. This post hoc analysis was performed from April 1 to August 31, 2019.Main outcomes and measuresResponse to treatment and adverse events.ResultsOcular or periocular involvement was found in 244 of 1215 STEVIE participants (20.1%), who constituted the analytic sample. The median age of the study participants was 72.0 (interquartile range [IQR], 60.0-82.0]) years, and they included 143 men (58.6%). Locally advanced BCC was diagnosed in 238 of the 244 participants (97.5%) and metastatic BCC, in 6 (2.5%). The median duration of exposure to vismodegib was 40.0 (IQR, 20.0-78.0) weeks, specifically 39.7 (IQR, 19.9-76.0) weeks for POLA-BCC and 92.4 (IQR, 53.2-163.0) weeks for metastatic BCC. Sixty-nine participants (28.3%) sustained serious adverse events (alopecia, muscle spasms, dysgeusia, weight loss, decreased appetite, asthenia, ageusia, nausea, fatigue, and diarrhea). Two hundred thirty-two study participants (95.1%) sustained more than 1 adverse effect. The overall mean (SD) number of drug-related adverse effects per study participant by first adverse event, regardless of the severity, was 5.48 (3.84). Discontinuation of vismodegib treatment owing to an adverse event was recorded in 58 participants (23.8%). During the study, 22 participants (9.0%) died, 70 (28.7%) achieved complete response, and 94 (38.5%) achieved partial response.Conclusions and relevanceVismodegib was well tolerated by the study participants with POLA-BCC. The safety of vismodegib treatment according to the STEVIE trial findings is consistent with that reported in previous studies. These data may be helpful when considering vismodegib for patients with POLA-BCC.

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Targeted therapy for advanced Basal-cell carcinoma: vismodegib and beyond.

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Targeted therapy for advanced Basal-cell carcinoma: vismodegib and beyond.

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