Sonidegib and vismodegib in the treatment of patients with locally advanced basal cell carcinoma: a joint expert opinion

Abstract

Sonidegib and vismodegib are hedgehog pathway inhibitors (HhIs) approved for the treatment of advanced basal cell carcinoma (BCC). Until recently, vismodegib was the only targeted treatment available for patients with locally advanced BCC (laBCC) in cases where surgery and radiotherapy are inappropriate. Sonidegib has recently been approved and now presents an alternative treatment option. The clinical differences between the two HhIs in patients with laBCC are unclear, as no head‐to‐head randomized controlled trials are or will be initiated. Moreover, there were important differences in the designs of their pivotal studies, BOLT (sonidegib) and ERIVANCE (vismodegib), and these differences complicate evidence‐based analysis of their relative efficacy and safety profiles. In this paper, a group of clinical experts in the management of laBCC summarizes the clinical and pharmacological profiles of sonidegib and vismodegib based on published data and their own clinical experience. One key difference between the two pivotal studies was the criteria used to assess BCC severity. ERIVANCE (a single‐arm phase II trial) used the conventional Response Evaluation Criteria in Solid Tumors (RECIST), while the more recent double‐blind randomized BOLT trial used the stringent modified RECIST. A preplanned analysis adjusted the outcomes from BOLT with RECIST‐like criteria, and this enabled the experts to discuss relative efficacy outcomes for the two treatments. Centrally reviewed objective response rate (ORR) for vismodegib was 47.6% (95% CI: 35.5–60.6) at 21‐month follow‐up using RECIST. After adjusting with RECIST‐like criteria, the ORR for sonidegib according to central review at 18‐month follow‐up was 60.6% (95% CI: 47.8–72.4). Both treatments were associated with similar patterns of adverse events. Sonidegib and vismodegib share the same efficacy and tolerability profiles, but their pharmacokinetic profiles show several differences, such as volume of distribution and half‐life. Further studies are needed to understand how these differences may impact clinical practice.

Tailored Toxicity-Driven Administration of Vismodegib in Patients With Multiple or Locally Advanced Basal Cell Carcinoma: A Pilot Analysis

“…However, this evaluation was performed, in line with our practice, only 2 months after the initiation of therapy, and three patients progressed shortly afterwards. In line with previous literature (16)(17)(18), all the patients in our series with controlled disease showed cramps or dysgeusia over the course of therapy, requiring interruption of the standard therapy. We considered the possibility of switching to an intermittent vismodegib schedule for all these patients, consisting of 4-week courses with 2-week interruptions in between.…”

“…Although vismodegib is widely used for the treatment of advanced BCC, further research has been advocated on its effectiveness and treatment schedules in clinical practice (12,13). In particular, some concerns on the use of vismodegib have been raised due to the frequent onset of AEs associated with this molecule, especially cramps and dysgeusia (16)(17)(18). The onset of these events may lead to treatment interruption and, potentially, to tumor progression.…”

“…In particular, adverse events (AEs) are not uncommon with the chronic use of vismodegib, especially at the gastrointestinal and musculoskeletal level, and often lead to early interruption of treatment (16)(17)(18). This has important clinical consequences because vismodegib, in some cases, does not eradicate the disease, and the tumor may, therefore, regrow when therapy is definitively interrupted.…”

Basal Cell Carcinoma: From Pathophysiology to Novel Therapeutic Approaches

“…Recently the ERIVANCE and BOLT trials were considered appropriate for indirect comparison between sonidegib and vismodegib [ 223 ]. Both trials had similar baseline patient characteristics, and both used ORR by central review as the primary endpoint ( Table 3 ).…”

Sonidegib: Safety and Efficacy in Treatment of Advanced Basal Cell Carcinoma

“…In literature, there are no head-to-head randomized controlled trials comparing sonidegib with vismodegib, the other hedgehog inhibitor firstly approved for the treatment of locally advanced and metastatic basal cell carcinoma. To date, only joint expert opinions summarizing clinical and pharmacological profiles of the two drugs, based on published data and data from clinical experience, have been published [42][43][44].…”