Inhibiting the Hedgehog Pathway in Patients with the Basal-Cell Nevus Syndrome

Abstract

BACKGROUND Dysregulated hedgehog signaling is the pivotal molecular abnormality underlying basal-cell carcinomas. Vismodegib is a new orally administered hedgehog-pathway inhibitor that produces objective responses in locally advanced and metastatic basal-cell carcinomas. METHODS We tested the anti–basal-cell carcinoma efficacy of vismodegib in a randomized, double-blind, placebo-controlled trial in patients with the basal-cell nevus syndrome at three clinical centers from September 2009 through January 2011. The primary end point was reduction in the incidence of new basal-cell carcinomas that were eligible for surgical resection (surgically eligible) with vismodegib versus placebo after 3 months; secondary end points included reduction in the size of existing basal-cell carcinomas. RESULTS In 41 patients followed for a mean of 8 months (range, 1 to 15) after enrollment, the per-patient rate of new surgically eligible basal-cell carcinomas was lower with vismodegib than with placebo (2 vs. 29 cases per group per year, P<0.001), as was the size (percent change from baseline in the sum of the longest diameter) of existing clinically significant basal-cell carcinomas (−65% vs. −11%, P = 0.003). In some patients, all basal-cell carcinomas clinically regressed. No tumors progressed during treatment with vismodegib. Patients receiving vismodegib routinely had grade 1 or 2 adverse events of loss of taste, muscle cramps, hair loss, and weight loss. Overall, 54% of patients (14 of 26) receiving vismodegib discontinued drug treatment owing to adverse events. At 1 month, vismodegib use had reduced the hedgehog target-gene expression by basal-cell carcinoma by 90% (P<0.001) and diminished tumor-cell proliferation, but apoptosis was not affected. No residual basal-cell carcinoma was detectable in 83% of biopsy samples taken from sites of clinically regressed basal-cell carcinomas. CONCLUSIONS Vismodegib reduces the basal-cell carcinoma tumor burden and blocks growth of new basal-cell carcinomas in patients with the basal-cell nevus syndrome. The adverse events associated with treatment led to discontinuation in over half of treated patients. (Funded by Genentech and others; ClinicalTrials.gov number, NCT00957229.)

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

“…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.…”

Synergistic cross‐talk of hedgehog and interleukin‐6 signaling drives growth of basal cell carcinoma

“…Despite the remarkable therapeutic benefits of SMOi in BCC, development of resistance, severe adverse effects and recurrence after cessation of drug treatment9, 42, 43, 44 highlight the need for novel strategies that not only focus on HH inhibition but also take into account interacting pathways modulating the oncogenicity of HH signaling.…”

Guidelines of care for the management of basal cell carcinoma

“…The recommendations for the treatment of metastatic BCC are shown in Table XI, and the level of evidence/ strength of the recommendations are in Table XII. [106][107][108][109][110][111][113][114][115] …”