An investigator-initiated open-label clinical trial of vismodegib as a neoadjuvant to surgery for high-risk basal cell carcinoma

Ally, Mina S.; Aasi, Sumaira Z.; Wysong, Ashley; Teng, Christopher; Anderson, Eric M.; Bailey-Healy, Irene; Oro, Anthony E.; Kim, Jinah; Chang, Anne Lynn S.; Tang, Jean Y.

doi:10.1016/j.jaad.2014.05.020

Cited by 118 publications

(98 citation statements)

References 19 publications

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“…Lower incidences of grade 3/4 AEs, SAEs and AEs leading to discontinuation were observed with 200 mg vs. 800 mg. The majority of the most common AEs were generally grade 1 or 2 and were similar to those reported with other HPIs10, 11, 12, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39; muscle‐related AEs and the increase in CK that can accompany these AEs are thought to be a class effect of HPIs 11, 12, 30, 31, 35, 39. Muscle‐related AEs were effectively managed with dose adjustments or interruptions.…”

Section: Discussionsupporting

confidence: 79%

Long‐term efficacy and safety of sonidegib in patients with locally advanced and metastatic basal cell carcinoma: 30‐month analysis of the randomized phase 2 BOLT study

Lear

Migden

Lewis

et al. 2017

Acad Dermatol Venereol

155

182

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BackgroundPatients with locally advanced basal cell carcinoma (laBCC) or metastatic BCC (mBCC), two difficult‐to‐treat populations, have had limited treatment options. Sonidegib, a hedgehog pathway inhibitor (HPI), was approved in laBCC based on results from the BOLT trial.ObjectiveTo evaluate long‐term efficacy and safety of sonidegib in laBCC and mBCC in the BOLT 18‐ and 30‐month analyses.MethodsBOLT (NCT01327053, ClinicalTrials.gov), a double‐blind phase 2 study, enrolled patients from July 2011 until January 2013. Eligible HPI‐treatment–naïve patients with laBCC not amenable to curative surgery/radiotherapy or mBCC were randomized 1 : 2 to sonidegib 200 mg (laBCC, n = 66; mBCC, n = 13) or 800 mg (laBCC, n = 128; mBCC, n = 23). Tumour response was assessed per central and investigator review.ResultsWith 30 months of follow‐up, among patients treated with sonidegib 200 mg (approved dose), objective response rates were 56.1% (central) and 71.2% (investigator) in laBCC and 7.7% (central) and 23.1% (investigator) in mBCC. Tumour responses were durable as follows: median duration of response was 26.1 months (central) and 15.7 months (investigator) in laBCC and 24.0 months (central) and 18.1 months (investigator) in mBCC. Five patients with laBCC and three with mBCC in the 200‐mg arm died. Median overall survival was not reached in either population; 2‐year overall survival rates were 93.2% (laBCC) and 69.3% (mBCC). In laBCC, efficacy was similar regardless of aggressive or non‐aggressive histology. Sonidegib 200 mg continued to have a better safety profile than 800 mg, with lower rates of grade 3/4 adverse events (43.0% vs. 64.0%) and adverse events leading to discontinuation (30.4% vs. 40.0%).ConclusionSonidegib continued to demonstrate long‐term efficacy and safety in these populations. These data support the use of sonidegib 200 mg per local treatment guidelines.

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Section: Discussionsupporting

confidence: 79%

Long‐term efficacy and safety of sonidegib in patients with locally advanced and metastatic basal cell carcinoma: 30‐month analysis of the randomized phase 2 BOLT study

Lear

Migden

Lewis

et al. 2017

Acad Dermatol Venereol

155

182

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“…Vismodegib (Erivedge), a hedgehog pathway inhibitor approved by for the treatment of metastatic and locally advanced BCC, has been shown to produce either a complete or partial response in 30-60 percent of patients with metastatic or locally advanced BCC, 37 and has also been used as neoadjuvant therapy for patients with orbital invasion to make globe-sparing surgical resection possible. 38,39 For patients with SCC with orbital invasion who are unable or unwilling to undergo exenteration, the prognosis is traditionally quite poor, 40 but various epidermal growth factor receptor (cetuximab) and tyrosine kinase (gefitinib, erlotinib) inhibitors have been studied in small series and shown efficacy in either reducing or stabilizing cutaneous SCC, 41 and may have a neoadjuvant application as well.…”

Section: Discussionmentioning

confidence: 99%

Orbital exenteration for advanced periorbital non-melanoma skin cancer: prognostic factors and survival

Gerring

Ott

Curry

et al. 2016

Eye

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Purpose To describe prognostic factors and survival outcomes in patients who underwent orbital exenteration for periocular nonmelanoma cutaneous malignancies. Methods The authors performed an institutional review board-approved retrospective review of all patients who underwent orbital exenteration for nonmelanoma periocular cutaneous malignancies at a tertiary care hospital system over a 10-year period. Patient demographics, tumor, and treatment data were recorded. Survival outcomes included disease-free survival (DFS) and overall survival (OS). Log-rank tests were used to test for difference in survival curves among various potential prognostic indicators, and multivariate analysis was performed using Cox's proportional hazards model. Results Forty-nine patients with an average age of 70.3 years were followed with a median follow-up of 17.5 months. At 2 years the OS was 78% while the DFS was 61%. The mean DFS for basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and sebaceous gland carcinoma (SGC) were 52.6, 39.2 and 28.1 months, respectively. Multivariate analysis demonstrated that only positive final surgical margin was predictive of worse outcome (P = 0.002). Recurrences were most frequent in the first 2 years. Conclusions Despite the relatively more aggressive nature of periocular malignancies that have invaded the orbit, orbital exenteration offers an overall 2-year DFS of 60%. BCC had the greatest mean survival time, however this was not statistically significant. We found worse prognosis with positive final surgical margins and recommend a multidisciplinary surgical approach to achieve complete resection when indicated.

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“…A number of studies are ongoing to extend or optimize its use in patients with BCC, such as intermittent dosing of the drug to improve tolerability or for its use as a neoadjuvant treatment to decrease the morbidity of surgical procedures (see Table 1). Accordingly, a recent publication reported that vismodegib treatment for 3 months or longer reduces the surgical defect area from baseline, which is of great clinical interest to physicians and patients with lesions located in sensitive locations that require treatment (53).…”

Section: Preclinical Efficacy Modelsmentioning

confidence: 99%

Efficacy of Hedgehog Pathway Inhibitors in Basal Cell Carcinoma

Basset-Séguin

Sharpe

Sauvage

2015

Molecular Cancer Therapeutics

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Basal cell carcinoma (BCC) is the most commonly diagnosed cancer. While most BCCs are amenable to surgery, some tumors can reach a more advanced stage or metastasize, and become ineligible for surgical resection or radiotherapy. Abnormal activation of the Hedgehog (Hh) pathway is a key driver in BCC pathophysiology. Consequently, inhibitors of the Hh pathway have been developed. Molecules that inhibit the receptor protein Smoothened (SMO) are the most advanced in clinical development. Vismodegib is the first-in-class SMO inhibitor and has been approved in a number of countries for the treatment of metastatic or locally advanced BCC. Several molecules have demonstrated antitumoral activity, but treatment may be limited in duration by a number of side effects, and it is not yet established whether these agents are truly curative or whether continued treatment will be required. Resistance to SMO inhibition has been reported in the clinic for which incidence and mechanisms must be elucidated to inform future therapeutic strategies. Intermittent dosing regimens to improve tolerability, as well as neoadjuvant use of Hh pathway inhibitors, are currently under investigation. Here, we review the most recent outcomes obtained with Hh inhibitors under clinical investigation in BCC.

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An investigator-initiated open-label clinical trial of vismodegib as a neoadjuvant to surgery for high-risk basal cell carcinoma

Cited by 118 publications

References 19 publications

Long‐term efficacy and safety of sonidegib in patients with locally advanced and metastatic basal cell carcinoma: 30‐month analysis of the randomized phase 2 BOLT study

Long‐term efficacy and safety of sonidegib in patients with locally advanced and metastatic basal cell carcinoma: 30‐month analysis of the randomized phase 2 BOLT study

Orbital exenteration for advanced periorbital non-melanoma skin cancer: prognostic factors and survival

Efficacy of Hedgehog Pathway Inhibitors in Basal Cell Carcinoma

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