‘Exceptional Response’ to First-Line Vismodegib Reported in Patient With Unresectable/Multifocal Adult Medulloblastoma


Key Points

  • A patient with a history of basal cell carcinoma who was diagnosed with an unresectable/multifocal form of adult medulloblastoma had a response to vismodegib that lasted nearly 3 years at the time of reporting.
  • His tumor showed no alterations in SMO or in other canonical SHH pathway–associated drivers.

In a case report in Cancer Biology & Therapy, Lou et al described an exceptional response to first-line treatment with the hedgehog inhibitor vismodegib (Erivedge) in a 51-year-old patient with a history of basal cell carcinoma who was diagnosed with an unresectable/multifocal form of adult medulloblastoma. The response occurred despite the absence of alterations in SMO or other canonical SHH pathway–associated drivers in the patient’s tumor.

Response to Vismodegib

Radiation therapy following diagnosis showed a marked decrease in size and enhancement of the tumor; due to continued neurologic compromise and a poor performance status, the patient was not a candidate for platinum treatment. Given the preponderance of hedgehog pathway activation in adult medulloblastoma, compassionate use of vismodegib was initiated.

Evidence of abnormal enhancing lesions was absent within 4 months. The patient remained on vismodegib for 22 months with no evidence of disease recurrence before choosing to stop treatment. At the time of reporting, he remained disease free at 7 months after stopping treatment.

Molecular Analysis

Molecular analysis identified mutations in TP53 and the i(17q) cytogenetic abnormality, which is prevalent in and most often associated with subgroup 4 rather than the SHH-activated forms of medulloblastoma. SHH pathway markers SMO, SUFU, PTCH1, and downstream transcription factor GLI2 were all unaffected in the patient’s tumor. The genomic deletion of one copy of TP53 suggests that the tumor was activated via mechanisms also mostly associated with group 4 medulloblastomas. TP53 mutations are associated with pediatric forms of medulloblastoma and considered rare in adults; and loss of 17p is enriched in TP53-mutant cases and mostly observed in childhood cases.

The investigators concluded: “In the case we describe in this report, our patient had a complete and sustained radiologic response over 2 y on vismodegib in the first-line setting after standard craniospinal irradiation. However, this exceptional response occurred in a patient whose tumor did not harbor alterations in SMO or in other canonical SHH pathway-associated drivers; this indicates that vismodegib may inhibit non-canonical alterations that activate the SHH pathway downstream. In light of these findings, further exploration of vismodegib efficacy in other molecular subgroups of medulloblastoma is warranted.”

They noted: “[I]n the burgeoning era of molecularly targeted therapy, vismodegib merits strong consideration and investigation as an appropriate form of first-line treatment, replacing cytotoxic chemotherapies that have traditionally been used to treat adult forms of the disease based on data from trials performed in the pediatric population.”

The research was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health and others.

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