MEVITEM—a phase I/II trial of vismodegib + temozolomide vs temozolomide in patients with recurrent/refractory medulloblastoma with Sonic Hedgehog pathway activation

Frappaz, Didier; Barritault, Marc; Montané, Laure; Laigle‐Donadey, Florence; Chinot, Olivier; Rhun, Émilie Le; Bonneville-Levard, Alice; Hottinger, Andreas F.; Meyronnet, David; Bidaux, Anne-Sophie; Garin, Gwenaële; Pérol, David

doi:10.1093/neuonc/noab087

Cited by 23 publications

(19 citation statements)

References 48 publications

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“… 44 A phase II randomized clinical trial combining temozolomide with vismodegib against temozolomide alone was conducted in adults patients with SHH medulloblastoma and did not report any improvement of 6-m PFS with the combination. 45 Patients were not distributed in the different arms based on the molecular alteration. Only 11 patients with a proven PTCH1 mutation were randomized between arm A (combination of vismodegib and temozolomide, n = 4), arm B (temozolomide alone, n = 2), and arm C (vismodegib alone for patients previously treated by temozolomide, n = 5).…”

Section: Discussionmentioning

confidence: 99%

Clinical and molecular analysis of smoothened inhibitors in Sonic Hedgehog medulloblastoma

Pereira

Torrejón

Kariyawasam

et al. 2021

Neuro-Oncology Advances

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Background Smoothened inhibitors (SMOi) have shown activity in Sonic Hedgehog (SHH) medulloblastoma, however this therapeutic class was not developed in children due to severe effects reported on growth. We hereby report long-term follow up of young patients treated with SMOi for recurrent medulloblastoma. Methods Clinical data on response and toxicity from patients treated with vismodegib or sonidegib from 2011 to 2019 for a SHH medulloblastoma were retrospectively reviewed. Methylation analysis and whole exome sequencing were performed whenever possible. Results All patients with a somatic PTCH1 mutation responded to SMOi (6/8), including two prolonged complete responses. One patient was free of disease 8.2 years after treatment. SMOi was challenged again for three patients. Two of them had a response, one with SMOi alone, the other one in combination with temozolomide despite previous progression under monotherapy. SMO resistance mutations were found in patients from biopsy at relapse. Combination with temozolomide or surgery plus radiotherapy was associated with very long disease control in two patients. The most severe adverse events were myalgia and growth plate fusion with metaphyseal sclerosis. Normal growth velocity was recovered for one patient although her final height was below estimated target height. Conclusion Targeting SMO in mutated PTCH1 is an interesting strategy for long-term responses. Combination of SMOi with chemotherapy or surgery and local radiotherapy is an appealing strategy to prevent early resistance and diminish SMOi exposure, especially in young patients. Inhibition of SHH pathway causes growth and development impairment but partial recovery of the growth velocity is possible.

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Section: Discussionmentioning

confidence: 99%

Clinical and molecular analysis of smoothened inhibitors in Sonic Hedgehog medulloblastoma

Pereira

Torrejón

Kariyawasam

et al. 2021

Neuro-Oncology Advances

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“…Recently, Frappaz et al have reported the final results of the phase I/II MEVITEM study evaluating vismodegib + temozolomide vs. temozolomide alone in patients affected by recurrent/refractory SHH-activated MB [ 40 ] ( Table 1 ). At the end of stage I, the study was prematurely terminated.…”

Section: Treatment Of Shh Subgroupmentioning

confidence: 99%

Molecular Targeted Therapies: Time for a Paradigm Shift in Medulloblastoma Treatment?

Gatto¹,

Franceschi

Tosoni

et al. 2022

Cancers

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Medulloblastoma is a rare malignancy of the posterior cranial fossa. Although until now considered a single disease, according to the current WHO classification, it is a heterogeneous tumor that comprises multiple molecularly defined subgroups, with distinct gene expression profiles, pathogenetic driver alterations, clinical behaviors and age at onset. Adult medulloblastoma, in particular, is considered a rarer “orphan” entity in neuro-oncology practice because while treatments have progressively evolved for the pediatric population, no practice-changing prospective, randomized clinical trials have been performed in adults. In this scenario, the toughest challenge is to transfer the advances in cancer genomics into new molecularly targeted therapeutics, to improve the prognosis of this neoplasm and the treatment-related toxicities. Herein, we focus on the recent advances in targeted therapy of medulloblastoma based on the new and deeper knowledge of disease biology.

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“…The rate of grade 3/4 drug-related toxicity was similar between patients receiving vismodegib and sonidegib (11.6% vs. 11.2%) [ 76 ]. Recently, a phase 1/2 trial comparing the association of vismodegib and temozolomide versus temozolomide alone in recurrent or refractory SHH-activated medulloblastoma failed to demonstrate a significant improvement of six months progression-free survival for the combined treatment [ 77 ].…”

Section: Reviewmentioning

confidence: 99%

Targeted Therapies in Rare Brain Tumours

Bruno

Pellerino

Bertero³

et al. 2021

IJMS

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Rare central nervous system (CNS) tumours represent a unique challenge. Given the difficulty of conducting dedicated clinical trials, there is a lack of therapies for these tumours supported by high quality evidence, and knowledge regarding the impact of standard treatments (i.e., surgery, radiotherapy or chemotherapy) is commonly based on retrospective studies. Recently, new molecular techniques have led to the discovery of actionable molecular alterations. The aim of this article is to review recent progress in the molecular understanding of and therapeutic options for rare brain tumours, both in children and adults. We will discuss options such as targeting the mechanistic target of rapamycin (mTOR) pathway in subependymal giant cells astrocytomas (SEGAs) of tuberous sclerosis and BRAF V600E mutation in rare glial (pleomorphic xanthoastrocytomas) or glioneuronal (gangliogliomas) tumours, which are a model of how specific molecular treatments can also favourably impact neurological symptoms (such as seizures) and quality of life. Moreover, we will discuss initial experiences in targeting new molecular alterations in gliomas, such as isocitrate dehydrogenase (IDH) mutations and neurotrophic tyrosine receptor kinase (NTRK) fusions, and in medulloblastomas such as the sonic hedgehog (SHH) pathway.

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MEVITEM—a phase I/II trial of vismodegib + temozolomide vs temozolomide in patients with recurrent/refractory medulloblastoma with Sonic Hedgehog pathway activation

Cited by 23 publications

References 48 publications

Clinical and molecular analysis of smoothened inhibitors in Sonic Hedgehog medulloblastoma

Clinical and molecular analysis of smoothened inhibitors in Sonic Hedgehog medulloblastoma

Molecular Targeted Therapies: Time for a Paradigm Shift in Medulloblastoma Treatment?

Targeted Therapies in Rare Brain Tumours

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