Traitement médical des carcinomes basocellulaires avancés: Medical treatment of advanced basal cell carcinoma.

Until recently, advanced BCC were only accessible to a highly morbid surgery not necessarily proving to be carcinologic, and leaving terrible dysmorphic sequelae hard to accept by the patient. Another possibility, the only one in case of metastatic BCC, was chemotherapy which efficacy has never been proven in a clinical trial. Radiotherapy is most often not accessible because of previous radiotherapy or because of the localization or the extension of the lesion. The discovery of the importance of the sonic hedgehog pathway in the physiopathology of BCC has opened a new strategy with the development of targeted anti SMO drugs inactivating the pathway. Two molecules have become available following Phase I and II studies: vismodegib (Erivedge®) the first in class indicated for locally advanced and metastatic BCC and sonidegib (Odomzo®) indicated only for locally advanced BCC. The pharmacokinetic profiles of sonidegib and vismodegib showed several differences. No head to head comparative studies are available between these two drugs. Their pivotal phase II studies had similar study designs and endpoints. The objective response rate (ORR) by central review for vismodegib was 47.6% (95% CI 35.5-60.6) at 21 months follow-up. The ORR for sonidegib according to central review at 18 months follow-up is 56.1% (95% CI 43.3-68.3). Although both treatments share a similar adverse event profile with possible numerically differences in incidence, most patients will discontinue hedgehog inhibitors treatment in the long term because of side effects. Some resistant cases to these drugs have been described but are rather rare. In case of resistance or bad tolerability to the drug future hopes rely on immunotherapy currently under investigation. © 2018. Published by Elsevier Masson SAS. All rights reserved. Cet article fait partie du numéro supplément Prise en charge des carcinomes basocellulaires difficiles à traiter réalisé avec le soutien institutionnel de Sun Pharma.

Basset-Seguin N 《ANNALES DE DERMATOLOGIE ET DE VENEREOLOGIE》

A Review of Hedgehog Inhibitors Sonidegib and Vismodegib for Treatment of Advanced Basal Cell Carcinoma.

Migden M ，Farberg AS ，Dummer R ，Squittieri N ，Hanke CW ... -  《Journal of Drugs in Dermatology》

Efficacy, safety, and comparison of sonic hedgehog inhibitors in basal cell carcinomas: A systematic review and meta-analysis.

Sonic hedgehog inhibitors (SHHis) provide an additional treatment option for basal cell carcinomas (BCCs), especially for metastatic or locally advanced BCC. However, studies have been heterogeneous and lacked direct comparisons between molecules. To determine the efficacy and safety of the class of molecules SHHi for treating BCC and to compare them individually. We performed a PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses)-compliant systematic review of studies followed by a meta-analysis. Eighteen articles were included in our meta-analysis; 16 articles were combined for efficacy and 16 for safety. In locally advanced BCC, overall response rates (ORRs) were similar for vismodegib and sonidegib (69% vs 57%, respectively) but not complete response rates (31% vs 3%, respectively). In metastatic disease, the ORR of vismodegib was 2.7-fold higher than the ORR of sonidegib (39% vs 15%, respectively). For side effects affecting a majority of patients, prevalences for muscle spasms (67.1%), dysgeusia (54.1%), and alopecia (57.7%) were in similar proportions for sonidegib and vismodegib. Patients receiving sonidegib experienced more upper gastrointestinal distress than patients receiving vismodegib. SHHis induce a partial response to locally advanced BCC disease. Side effects are common, similar across molecules, associated with high discontinuation rates, and warrant discussion beforehand.

Xie P ，Lefrançois P 《-》

Hedgehog Pathway Inhibitor Therapy for Locally Advanced and Metastatic Basal Cell Carcinoma: A Systematic Review and Pooled Analysis of Interventional Studies.

Jacobsen AA ，Aldahan AS ，Hughes OB ，Shah VV ，Strasswimmer J ... -  《-》

Expanded access study of patients with advanced basal cell carcinoma treated with the Hedgehog pathway inhibitor, vismodegib.

Vismodegib, a first-in-class Hedgehog pathway inhibitor, was US Food and Drug Administration (FDA) approved for advanced basal cell carcinomas (BCCs) based on a single, nonrandomized, phase-II trial. Consequently, additional clinical data are critical to confirm the efficacy and safety of vismodegib. We sought to assess efficacy and safety of vismodegib, while providing early drug access to patients with advanced BCC and limited treatment options. This was an open-label, multicenter study in patients with advanced BCC inappropriate for radiotherapy or surgery. Patients received 150 mg vismodegib daily until disease progression or intolerable toxicity. Tumor response was assessed via Response Evaluation Criteria in Solid Tumors version 1.0. A total of 119 patients with advanced BCC took vismodegib for a median of 5.5 months. Objective responses occurred in 46.4% of locally advanced BCC and 30.8% of patients with metastatic BCC. Response was negatively associated with prior systemic therapy in patients with locally advanced BCC (P = .002). Mean follow-up for safety was 6.5 months, with muscle spasms (70.6%), dysgeusia (70.6%), alopecia (58.0%), and diarrhea (25.2%) as the most common adverse events. Abbreviated follow-up time because of study termination upon FDA approval was a limitation. This study provides important clinical data supporting the efficacy and safety of vismodegib. Larger studies are underway to assess predictors of response and long-term outcomes.

Chang AL ，Solomon JA ，Hainsworth JD ，Goldberg L ，McKenna E ，Day BM ，Chen DM ，Weiss GJ ... -  《-》