Phase I and phase II sonidegib and vismodegib clinical trials for the treatment of paediatric and adult MB patients: a systemic review and meta-analysis

Abstract

Background: Medulloblastoma (MB) is the most common malignant brain tumour in children but also rarely occur in adults. Sonic Hedgehog (SHH) driven MB is associated with aberrant activation of the SHH signalling pathway. SMO inhibitors, sonidegib and vismodegib, have been used as selective antagonist of the hedgehog pathway that acts by binding to SMO, and inhibits activation of the downstream hedgehog target genes. Several clinical trials investigating SMO inhibitors for the treatment of relapsed MB patients have been published.

Methods: We conducted a systemic review and meta-analysis among these Phase I and II clinical trials. The pooled effect of SMO inhibitors in relapsed MB were analysed using Reviewer Manager 5.3 software. The clinical efficacy of SMO inhibitors on SHH subtype of MB were measured by the objective response rate. The risk difference was obtained by comparing the ORR between SHH and non-SHH subtypes of MB.

Results: The five studies all had clear criteria for patient recruitment, adequate follow-up time for endpoint assessment and clear definition of tumour responses. MB patients had good compliance in the trials. The pooled objective response rate (ORR) of SMO inhibitor was 37% and 0 against SHH-driven and other MBs. The pooled ORR of sonidegib was 55% among MB^SHH and 0 among MB^non-SHH subgroup. Vismodegib also had no efficacy on non-SHH subtype of MB. The sonidegib against SHH-driven MB produced the ORR 1.87-fold higher than that of vismodegib (95%CI 1.23, 6.69). Among paediatric patients, the efficacy of sonidegib was 3.67-fold higher than vismodegib (p < 0.05). A total of 320 cases received SMO inhibitor therapy and 36 cases reported grade 3/4 dose-limiting toxicity (DLT). The rate of grade 3/4 DLT was similar between patients receiving vismodegib and sonidegib (11.6% vs. 11.2%).

Conclusion: Sonidegib and vismodegib were well tolerated and demonstrated anti-tumour activity in SHH-driven paediatric and adult MB by effectively inhibiting Hh signalling. These results support the ongoing clinical trials using SMO inhibitors in combination with conventional chemotherapies for the treatment of relapsed MB^SHH.

Keywords: And vismodegib; Medulloblastoma; SMO inhibitor; Sonic hedgehog pathway; Sonidegib.

Fig. 1

Flow diagram of study search and inclusion

Fig. 2

The objective response rate of sonidegib and vismodegib in MB patients. SMO inhibitors in relapsed MB were analysed using Reviewer Manager 5.3 software. No efficacy in non-SHH subtype of MB for either agent was detected. While the pooled ORR of sonidegib and vismodegib was 55 and 17% among MB^SHH patients, respectively

Fig. 3

The pooled clinical efficacy of sonidegib and vismodegib in paediatric versus adult SHH-driven MB. Efficacy was analysed using Reviewer Manager 5.3 software. In adult patients, sonidegib had a 1.45-fold higher effect, but the difference was not significant. In contrast, the efficacy of sonidegib was significant showing a 3.67-fold higher effect than vismodegib in paediatric patients (p < 0.05)

Fig. 4

Hedgehog signalling and SMO inhibitors action in MB. a. Hedgehog (Hh) proteins (Sonic, Indian, or Desert Hedgehog) bind to PTCH1 transmembrane protein. Binding to PTCH1 relieves inhibition of smoothened (SMO). Active SMO moves to cilium and promotes to release suppressor of fused (SUFU) inhibition of glioma-associated oncogene (GLI) proteins. Activated GLI proteins then translocate to the nucleus to affect transcription of SHH target genes (ie, GLI1, GLI2, PTCH1, PTCH2, and MYCN). Vismodegib and sonidegib bind to the extracellular domain of SMO, inhibiting downstream signalling. Most commonly mutations in MB associated with Hh pathway includes, mutations in PTCH1 (red star, favourable prognostic mutation), SMO and SUFU (brown star, worse prognostic mutations). b. SMO inhibitors inhibit Hh pathway signalling by preventing activation of SMO