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Safety and efficacy of vismodegib in patients with basal cell carcinoma nevus syndrome: pooled analysis of two trials.

ABSTRACT: Aberrant activation of the Hedgehog (Hh) pathway is a key driver in the pathogenesis of basal cell carcinomas (BCCs), including patients with BCC nevus syndrome (BCCNS). It is unclear whether BCCs arising in patients with BCCNS respond differently to vismodegib than in patients without BCCNS. We examined the best overall response rate (BORR) and adverse events (AEs) of vismodegib in patients with advanced BCC (aBCC) with and without BCCNS.Patients were treated with vismodegib 150 mg/day in the ERIVANCE BCC trial (ClinicalTrials.gov number, NCT00833417) and the expanded access study (EAS; ClinicalTrials.gov number, NCT01160250). BCCNS diagnosis was based on medical history at the time of enrollment. Metastatic BCC response was evaluated using Response Evaluation Criteria In Solid Tumors, version 1.0 (RECIST v1.0) in both studies. Locally advanced BCC was evaluated by a novel composite end point in ERIVANCE BCC and by RECIST v1.0 in the EAS. Response assessments were performed every 8 weeks in ERIVANCE BCC and every 8-16 weeks in the EAS. Safety assessments (National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0) were performed monthly in both trials. Because of described differences in response assessment/schedule, patients with BCCNS were not pooled across trials. Analytic cohorts for BCCNS and sporadic aBCC were created within each trial for comparison using descriptive statistical methods.Forty-one patients with BCCNS were included in the study: 22 from ERIVANCE BCC and 19 from the EAS. Investigator-assessed BORR in BCCNS groups ranged from 31 to 81 % in patients with locally advanced BCC (n?=?33) and was 50 % in patients with metastatic BCC (n?=?6). These results were comparable with the non-BCCNS groups. Incidence and severity of AEs were also comparable between the BCCNS and non-BCCNS groups. Amenorrhea was observed in both patient cohorts and was reversible in two patients who discontinued treatment.Vismodegib demonstrated comparable efficacy and safety against aBCC in patients with and without BCCNS.

SUBMITTER: Chang AL

PROVIDER: S-EPMC5007799 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Safety and efficacy of vismodegib in patients with basal cell carcinoma nevus syndrome: pooled analysis of two trials.

Chang Anne Lynn S AL Arron Sarah T ST Migden Michael R MR Solomon James A JA Yoo Simon S Day Bann-Mo BM McKenna Edward F EF Sekulic Aleksandar A

Orphanet journal of rare diseases 20160901 1

<h4>Background</h4>Aberrant activation of the Hedgehog (Hh) pathway is a key driver in the pathogenesis of basal cell carcinomas (BCCs), including patients with BCC nevus syndrome (BCCNS). It is unclear whether BCCs arising in patients with BCCNS respond differently to vismodegib than in patients without BCCNS. We examined the best overall response rate (BORR) and adverse events (AEs) of vismodegib in patients with advanced BCC (aBCC) with and without BCCNS.<h4>Methods</h4>Patients were treated ...[more]

PMID: 27581207

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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: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.

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Safety and efficacy of vismodegib in patients with basal cell carcinoma nevus syndrome: pooled analysis of two trials.

Publications

Safety and efficacy of vismodegib in patients with basal cell carcinoma nevus syndrome: pooled analysis of two trials.

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