Vismodegib exerts targeted efficacy against recurrent sonic hedgehog - Subgroup medulloblastoma: Results from phase II Pediatric Brain Tumor Consortium studies PBTC-025B and PBTC-032

Giles W. Robinson*, Brent A. Orr, Gang Wu, Sridharan Gururangan, Tong Lin, Ibrahim Qaddoumi, Roger J. Packer, Stewart Goldman, Michael D. Prados, Annick Desjardins, Murali Chintagumpala, Naoko Takebe, Sue C. Kaste, Michael Rusch, Sariah J. Allen, Arzu Onar-Thomas, Clinton F. Stewart, Maryam Fouladi, James M. Boyett, Richard J. GilbertsonTom Curran, David W. Ellison, Amar Gajjar

*Corresponding author for this work

Research output: Contribution to journalArticle

180 Scopus citations

Abstract

Purpose: Two phase II studies assessed the efficacy of vismodegib, a sonic hedgehog (SHH) pathway inhibitor that binds smoothened (SMO), in pediatric and adult recurrent medulloblastoma (MB). Patients and Methods: Adult patients enrolled onto PBTC-025B and pediatric patients enrolled onto PBTC-032 were treated with vismodegib (150 to 300 mg/d). Protocol-defined response, which had to be sustained for 8 weeks, was confirmed by central neuroimaging review. Molecular tests to identify patterns of response and insensitivity were performed when tissue was available. Results: A total of 31 patients were enrolled onto PBTC-025B, and 12 were enrolled onto PBTC-032. Three patients in PBTC-025B and one in PBTC-032, all with SHH-subgroup MB (SHH-MB), exhibited protocol-defined responses. Progression-free survival (PFS) was longer in those with SHH-MB than in those with non-SHH-MB, and prolonged disease stabilization occurred in 41% of patient cases of SHH-MB. Among those with SHH-MB, loss of heterozygosity of PTCH1 was associated with prolonged PFS, and diffuse staining of P53 was associated with reduced PFS. Whole-exome sequencing identified mutations in SHH genes downstream from SMO in four of four tissue samples from nonresponders and upstream of SMO in two of four patients with favorable responses. Conclusion: Vismodegib exhibits activity against adult recurrent SHH-MB but not against recurrent non-SHH-MB. Inadequate accrual of pediatric patients precluded conclusions in this population. Molecular analyses support the hypothesis that SMO inhibitor activity depends on the genomic aberrations within the tumor. Such inhibitors should be advanced in SHH-MB studies; however, molecular and genomic work remains imperative to identify target populations that will truly benefit.

Original languageEnglish (US)
Pages (from-to)2646-2654
Number of pages9
JournalJournal of Clinical Oncology
Volume33
Issue number24
DOIs
StatePublished - Aug 20 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Robinson, G. W., Orr, B. A., Wu, G., Gururangan, S., Lin, T., Qaddoumi, I., Packer, R. J., Goldman, S., Prados, M. D., Desjardins, A., Chintagumpala, M., Takebe, N., Kaste, S. C., Rusch, M., Allen, S. J., Onar-Thomas, A., Stewart, C. F., Fouladi, M., Boyett, J. M., ... Gajjar, A. (2015). Vismodegib exerts targeted efficacy against recurrent sonic hedgehog - Subgroup medulloblastoma: Results from phase II Pediatric Brain Tumor Consortium studies PBTC-025B and PBTC-032. Journal of Clinical Oncology, 33(24), 2646-2654. https://doi.org/10.1200/JCO.2014.60.1591