September 10, 2015
2 min read

Vismodegib appears effective in medulloblastoma subtype

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Vismodegib appeared efficacious for the treatment of some patients with the most common subtype of medulloblastoma, according to results of a multi-institutional study.

Vismodegib (Erivedge, Genentech) — typically used to treat advanced skin cancer — inhibits the sonic hedgehog pathway, which is often active during fetal development.

The pathway is switched on in approximately 30% of medulloblastoma tumors, which most frequently affect children aged younger than 5 years, as well as those aged between 16 years and adulthood.

Medulloblastoma has four different subtypes, the most common of which is the sonic hedgehog subtype.

Five-year OS is approximately 70% for patients with sonic hedgehog medulloblastoma, although outcomes are poor for those with recurrent disease. Additionally, current treatments are often are associated with severe morbidity.

“The great hope is that targeted therapies will help more patients survive with fewer long-term side effects,” Giles Robinson, MD, assistant member of the department of oncology at St. Jude Children’s Research Hospital, said in a press release.

Robinson and colleagues conducted two prospective phase 2 studies to assess the efficacy of vismodegib in adult and pediatric patients with recurrent medulloblastoma. The researchers also evaluated genomic responses to vismodegib.

The investigators enrolled 31 adults (age range, 22.4 to 51.9 years) in one trial and 12 pediatric patients (age range, 3.9 to 20 years) in the second trial.

Patients received 150 mg to 300 mg vismodegib per day.  Sustained objective response served as the primary endpoint for both trials.

Treatment led to a reduction in size or disappearance of tumors for 8 weeks or longer in four patients (three adults and one pediatric patient). Forty-one percent of all patients experienced stable disease and tumor control for as long as 17 months.

Adults with the sonic hedgehog subtype of medulloblastoma experienced significantly longer PFS than adults with other subtypes (P = .0279). Pediatric patients with the sonic hedgehog subtype of medulloblastoma experienced significantly longer PFS than pediatric patients with other subtypes, but the difference did not reach statistical significance.

Among patients with the sonic hedgehog subtype, researchers observed an association between loss of heterozygosity of PTCH1 and longer PFS, whereas they observed an association between diffuse staining of the tumor suppressing gene P53 and shorter PFS.

“While it was disappointing that not all medulloblastoma patients with the sonic hedgehog subtype will benefit, for the right patients these results mark the beginning of a new era of targeted therapy for the treatment of this tumor,” Robinson said in the press release. “The findings also highlight the importance of ongoing research to identify the genetic alterations that define who the right patients are and help identify those most likely to benefit from this drug, as well as those for whom different therapy is needed.”

Additionally, the researchers identified sonic hedgehog gene mutations downstream from smoothened in all four tissue samples from non-responders and upstream of smoothened in two of the four patients who had favorable responses.

This suggested that the location of the mutations in the pathway assisted in identifying vismodegib sensitivity. This also will help researchers with the development of combination therapies to overcome vismodegib resistance.

“This means complete genetic profiling of all sonic hedgehog medulloblastoma is needed to identify the patients who will benefit from vismodegib and those who are candidates for another therapy,” Robinson said in the press release. “Tumor response to vismodegib in this study was transient, probably due to the development of drug resistance.”

The findings from these studies have led to another clinical trial in which St. Jude researchers are evaluating vismodegib as maintenance therapy in patients aged 3 to 22 years with newly-diagnosed medulloblastoma. – by Anthony SanFilippo

Disclosure: Robinson reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.