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J Clin Oncol. 2015 Aug 20;33(24):2646-54. doi: 10.1200/JCO.2014.60.1591. Epub 2015 Jul 13.

Vismodegib Exerts Targeted Efficacy Against Recurrent Sonic Hedgehog-Subgroup Medulloblastoma: Results From Phase II Pediatric Brain Tumor Consortium Studies PBTC-025B and PBTC-032.

Author information

1
Giles W. Robinson, Brent A. Orr, Gang Wu, Tong Lin, Ibrahim Qaddoumi, Sue C. Kaste, Michael Rusch, Sariah J. Allen, Arzu Onar-Thomas, Clinton F. Stewart, James M. Boyett, Richard J. Gilbertson, David W. Ellison, and Amar Gajjar, St Jude Children's Research Hospital, Memphis, TN; Sridharan Gururangan and Annick Desjardins, Duke University Medical Center, Durham, NC; Roger J. Packer, Children's National Medical Center, Washington, DC; Stewart Goldman, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL; Michael D. Prados, University of California San Francisco, San Francisco, CA; Murali Chintagumpala, Texas Children's Cancer Center, Houston, TX; Naoko Takebe, National Cancer Institute, Bethesda, MD; Maryam Fouladi, Cincinnati Children's Hospital, Cincinnati, OH; and Tom Curran, Children's Hospital of Philadelphia, Philadelphia, PA. giles.robinson@stjude.org.
2
Giles W. Robinson, Brent A. Orr, Gang Wu, Tong Lin, Ibrahim Qaddoumi, Sue C. Kaste, Michael Rusch, Sariah J. Allen, Arzu Onar-Thomas, Clinton F. Stewart, James M. Boyett, Richard J. Gilbertson, David W. Ellison, and Amar Gajjar, St Jude Children's Research Hospital, Memphis, TN; Sridharan Gururangan and Annick Desjardins, Duke University Medical Center, Durham, NC; Roger J. Packer, Children's National Medical Center, Washington, DC; Stewart Goldman, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL; Michael D. Prados, University of California San Francisco, San Francisco, CA; Murali Chintagumpala, Texas Children's Cancer Center, Houston, TX; Naoko Takebe, National Cancer Institute, Bethesda, MD; Maryam Fouladi, Cincinnati Children's Hospital, Cincinnati, OH; and Tom Curran, Children's Hospital of Philadelphia, Philadelphia, PA.

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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00939484 NCT01239316.

PMID:
26169613
PMCID:
PMC4534527
DOI:
10.1200/JCO.2014.60.1591
[Indexed for MEDLINE]
Free PMC Article

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