髓母细胞瘤(MB)是儿童中最常见的恶性脑肿瘤,但在成人中也很少发生。SonicHedgehog(SHH)驱动的MB与SHH信号通路的异常激活有关。SMO抑制剂,Sonidegib和vismodegib,已被用作通过与SMO结合起作用的刺猬通路的选择性拮抗剂,并抑制下游刺猬靶基因的激活。已经发表了一些研究SMO抑制剂治疗复发MB患者的临床试验。
我们对这些I期和II期临床试验进行了系统综述和荟萃分析。使用ReviewerManager5.3软件分析SMO抑制剂在复发性MB中的汇集效应。通过客观缓解率测量SMO抑制剂对SHH亚型MB的临床疗效。通过比较SHH与非SHH亚型MB之间的ORR来获得风险差异。
五项研究都有明确的患者招募标准,足够的随访时间进行终点评估和明确肿瘤反应的定义.MB患者在试验中有良好的依从性。SMO抑制剂对SHH驱动和其他MBs的合并客观缓解率(ORR)为37%和0。在MBSHH中,sonidegib的合并ORR为55%,在MBnon-SHH亚组中为0。Vismodegib对MB的非SHH亚型也没有疗效。针对SHH驱动的MB的sonidegib产生的ORR比vismodegib高1.87倍(95CI1.23,6.69)。在儿科患者中,Sonidegib的疗效是vismodegib的3.67倍(p<0.05)。共有320例接受SMO抑制剂治疗,36例报告3/4级剂量限制性毒性(DLT)。接受vismodegib和sonidegib的患者之间3/4级DLT的发生率相似(11.6%vs.11.2%)。
Sonidegib和vismodegib具有良好的耐受性,并通过有效抑制Hh信号在SHH驱动的儿科和成人MB中表现出抗肿瘤活性。这些结果支持使用SMO抑制剂与常规化学疗法组合治疗复发性MBSHH的正在进行的临床试验。
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.
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.
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 MBSHH and 0 among MBnon-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%).
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 MBSHH.