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

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.

Fig 1.

Illustration of sonic hedgehog (SHH) signaling pathway. (1) SHH ligand binds to PTCH1 transmembrane protein. (2) Binding of SHH to PTCH1 relieves inhibition of smoothened (SMO). (3) Activated SMO localizes to cilium. (4) SMO releases suppressor of fused (SUFU) inhibition of GLI proteins. (5) Activated GLI proteins translocate to nucleus and activate transcription of SHH target genes (ie, GLI1, GLI2, PTCH1, and MYCN). In SHH-subgroup medulloblastoma, disruptions to SHH pathway occur through mutation of PTCH1, SMO, or SUFU and/or amplification of GLI2 or MYCN. Vismodegib inhibits SMO.

Fig 2.

Trial schematics and distribution of patients from PBTC-025 (phase I precursor study), PBTC-032 (children), and PBTC-025B (adults). In PBTC-032, strata A and C were closed to accrual before study opening, because no objective responses were seen in 13 patients with non–sonic hedgehog (SHH) medulloblastoma (MB) treated at recommended phase II dose (RP2D) of vismodegib during phase I study PBTC-025. (*) Phase I PBTC-025 patients treated at the RP2D counted toward the phase II (PBTC-032) accrual. Bottom panel shows distribution of available formalin-fixed, paraffin-embedded (FFPE) tumor samples for molecular analysis. BSA, body surface area.

Fig 3.

Clinical and molecular characteristics of patients with sonic hedgehog (SHH) –subgroup medulloblastoma (SHH-MB) enrolled onto PBTC-025B or PBTC-032. Columns arranged in descending order from longest to shortest time to disease progression (PD). Lower panels show mutations in genes (previously described as mutated in SHH-MB) in eight matched tumor and germline biospecimens. Significance assessed using Kolmogorov-Smirnov tests. FISH, fluorescence in situ hybridization; IHC, immunohistochemistry.

Fig 4.

Magnetic resonance images showing responses in five patients with recurrent sonic hedgehog–subgroup medulloblastoma (MB) treated with vismodegib. Images were obtained at start of therapy and at 2, 4, and 6 months after. Gold arrows indicate recurrent lesions. After initial response, MB recurs locally.

Fig 5.

Time to disease progression. (A) Only patients with sonic hedgehog (SHH) - subgroup medulloblastoma (SHH-MB) enrolled onto PBTC-025B (blue shades) or PBTC-032 (light blue shades) remained progression free until second evaluation period. (B) PTCH1 loss of heterozygosity was associated with increased duration of therapy. Patients with P53 diffuse staining were all nonresponders. In all of those patients, disease progressed at or before first evaluation. (★) Patients in whom radiographic response was observed. (†) Patients in whom radiographic response was sustained beyond 8 weeks. SHH-MB patient numbers correlate with those in Figure 3. Adult non-SHH MB (gray) from PBTC-025B are numbered from 025B-22 to 025B-32. Child non-SHH patients from PBTC-025/PBTC-032 (gray) are numbered 032-13 to 032-26.

Fig 6.

Progression-free survival (PFS) of patients enrolled onto (A) PBTC-025B or (B) PBTC-032 and PBTC-025. (A) For PBTC025B, patients in stratum B (blue line) with sonic hedgehog (SHH) –activated tumors had significantly longer PFS than did those in stratum A (gray line) or C (gold line). (B) There was no significant difference between PFS of patients in PBTC032 or PBTC025 who had SHH-subgroup medulloblastoma (SHH-MB; blue line) and those with non-SHH–MB treated at recommended phase II dose of vismodegib (gold line).

Fig. A1.

Progression-free survival of adults with sonic hedgehog (SHH) –subgroup medulloblastoma (SHH-MB; blue line) versus pediatric patients with SHH-MB (gold line). Significance assessed using log-rank test.

Fig. A2.

Progression-free survival of adult and pediatric patients with sonic hedgehog–subgroup medulloblastoma grouped based on status of following molecular characteristics: (A) PTCH1, (B) PTEN, (C) MYCN, (D) GLI2, (E) P53, and (F) 17p. Significance assessed using Kolmogorov-Smirnov tests. AMP, amplification; DS, diffuse staining; gain, imbalanced gain; loss, imbalanced loss; NSA, no significant abnormality; poly, balanced polysomy.