Efficacy of sonic hedgehog inhibitors rechallenge, after initial complete response in recurrent advanced basal cell carcinoma: a retrospective study from the CARADERM database

Abstract

Background: Smoothened (SMO) inhibitors, blocking the sonic hedgehog pathway, have been approved for advanced basal cell carcinoma (aBCC). Safety analyses reveal a high rate of adverse events (AEs) and, most of the time, vismodegib is most commonly stopped when the best overall response is reached. The long-term evolution of aBCC after vismodegib discontinuation is poorly described. The aim of this study is to evaluate the efficacy and safety of the SMO inhibitors (SMOis) available (vismodegib and sonidegib) following rechallenge after complete response (CR) following an initial treatment by vismodegib. Materials and methods: This real-life, retrospective, multicenter and descriptive study is based on an extraction from the CARADERM accredited database, including 40 French regional hospitals, of patients requiring BCC systemic treatment. Results: Of 303 patients treated with vismodegib, 110 achieved an initial CR. The vast majority of these patients (98.2%) stopped vismodegib, notably due to poorly tolerated AEs. The CARADERM database provided a median follow-up of 21 months (13.5-36.0 months) after CR. Of the 110 patients, 48.1% relapsed after a median relapse-free survival of 24 months (13.0-38.0 months). Among them, 35 patients were retreated by an SMOi and the overall response rate was 65.7% (34.3% of CR and 31.4% of partial response). The median duration of retreatment was 6.0 months (4.0-9.5 months). Conclusion: Our real-life study, carried out on patients with complex clinical pictures, shows that after treatment discontinuation, 48.1% of patients achieved CR relapse within an average of 24 months (13.0-38.0 months). It emphasized that even though rechallenge can be considered as a therapeutic option, efficacy seems to decrease, suggesting the development of resistance mechanisms.

Sonidegib in the Treatment of Locally Advanced Basal Cell Carcinoma: A Retrospective Study

“…Only when patients develop secondary resistance under HHI therapy, they may avail the approved second-line treatment with cemiplimab ( 23 ), with a lower response rate of 30%. If there is a relapse after discontinuation of a HHI, re-challenge with HHI-therapy seems to be the most effective approach, with response rates of 85% ( 24 , 25 ).…”

Clinical activity of PD-1 inhibition in the treatment of locally advanced or metastatic basal cell carcinoma

“…In a retrospective study of 110 BCC patients who achieved CR to HHI but then discontinued treatment, nearly half of the patients (48.1%) experienced a relapse while off treatment. 40 It has been shown that patients with advanced melanoma who experience CR following 2 years of treatment with PD-1 therapy can safely discontinue treatment. 25 Meanwhile, patients with Merkel cell carcinoma who discontinue PD-1 therapy after CR appear to have higher risk of relapse, 41 suggesting these outcomes may differ with tumor type.…”

Reinduction of Hedgehog Inhibitors after Checkpoint Inhibition in Advanced Basal Cell Carcinoma: A Series of 12 Patients

“…Two French studies investigated efficacy of HHI rechallenge [ 10 , 11 ]. Both studies recorded CR in about a third of the respective patient cohorts with aBCC under initial HHI treatment with vismodegib, which was then discontinued.…”