Phase <scp>II</scp> clinical trial of pazopanib for patients with unresectable or metastatic malignant peripheral nerve sheath tumors

Nishida, Yoshihiro; Urakawa, Hiroshi; Nakayama, Robert; Kobayashi, Eisuke; Ozaki, Toshifumi; Ae, Keisuke; Matsumoto, Yoshihiro; Tsuchiya, Hiroyuki; Goto, Takahiro; Hiraga, Hiroaki; Naka, Norifumi; Takahashi, Shunji; Ando, Yuichi; Ando, Masahiko; Kuwatsuka, Yachiyo; Hamada, Shunsuke; Ueda, Takafumi; Kawai, Akira

doi:10.1002/ijc.33201

Cited by 14 publications

(5 citation statements)

References 53 publications

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“…Given the limited adjuvant treatment options, efforts have been made in targeting pathways regulated by the NF1 protein or other associated mutations. Such targets include tyrosine kinase receptor,[ 19 ] epidermal growth factor receptors,[ 1 ] platelet-derived growth factor receptor,[ 5 ] and Ras/Raf signaling,[ 16 ] among others. Inhibition of mTOR signaling has previously been identified as a transiently effective therapy for delaying tumor growth.…”

Section: Discussionmentioning

confidence: 99%

Cranial nerve and intramedullary spinal malignant peripheral nerve sheath tumor associated with neurofibromatosis-1

Newell

Chalil

Langdon

et al. 2021

Surgical Neurology International

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Background: Malignant peripheral nerve sheath tumors (MPNSTs) are uncommon but aggressive neoplasms associated with radiation exposure and neurofibromatosis Type I (NF1). Their incidence is low compared to other nervous system cancers, and intramedullary spinal lesions are exceedingly rare. Only a few case reports have described intramedullary spinal cord MPNST. Case Description: We describe the clinical findings, management, and outcome of a young patient with NF1 who developed aggressive cranial nerve and spinal MPNST tumors. This 35-year-old patient had familial NF1 and a history of optic glioma treated with radiation therapy (RT). She developed a trigeminal MPNST that was resected and treated with RT. Four years later, she developed bilateral lower extremity deficits related to an intramedullary cervical spine tumor, treated surgically, and found to be a second MPNST. Conclusion: To the best of our knowledge, this is the first report of cranial nerve and intramedullary spinal MPNSTs manifesting in a single patient, and only the third report of a confined intramedullary spinal MPNST. This unusual case is discussed in the context of a contemporary literature review.

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Section: Discussionmentioning

confidence: 99%

Cranial nerve and intramedullary spinal malignant peripheral nerve sheath tumor associated with neurofibromatosis-1

Newell

Chalil

Langdon

et al. 2021

Surgical Neurology International

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“…Median PFS was 7.4 weeks and median OS 2.5 months [146]. A phase II trial with pazopanib found a 50% clinical benefit rate defined by RECIST in MPNST patients; mOS and mPFS were 5.4 and 10.6 months, respectively [147]. Also, the addition of pazopanib to standard chemotherapy with gemcitabine showed prolonged PFS in STS patients.…”

Section: Targeted Treatment and Clinical Trialsmentioning

confidence: 98%

Malignant peripheral nerve sheath tumor — from genetics to multidisciplinary treatment

Czarnecka,

Chmiel,

Sobczuk

et al. 2024

Oncol Clin Pract

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Malignant peripheral nerve sheath tumor (MPNST) is an aggressive soft tissue sarcoma (STS); it originates from nervous tissue and typically develops in proximity to nerve trunks in the limbs and trunk. These tumors, constituting approximately 5% of soft tissue sarcomas, can either form spontaneously or arise from pre-existing neurofibromas. The majority (90%) of cases occur in individuals between the 2 nd and 5 th decades of life. The main risk factor for MPNST is von Recklinghausen disease (type 1 neurofibromatosis). The cornerstone of MPNST management involves radical surgical measures, specifically tumor excision within healthy tissue boundaries (wide local excision), which is complemented by adjuvant radiotherapy. In case of metastatic disease, palliative chemotherapy employing doxorubicin or a combination of doxorubicin and ifosfamide is utilized. Approximately 25-30% of patients experience clinical improvement after chemotherapy. Looking ahead, advancements in research on molecular biology may lead to the development of inhibitors demonstrating greater efficacy than traditional chemotherapy for MPNST patients. At present, ongoing clinical trials of the therapeutic management of MPNST encompass pembrolizumab, the combination of nivolumab with ipilimumab, pexydartinib (an inhibitor targeting KIT, CSF1R, and FLT3) in conjunction with sirolimus, sapanisertib (a TORC1/2 inhibitor), or LOXO-195 (an inhibitor of neurotrophic tyrosine kinase receptors NTRK type 1, 2, and 3).

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“…Pexidartinib, a selective c-KIT inhibitor conjugated with colony-stimulating factor 1 receptor, in association with the mTOR inhibitor sirolimus, has been investigated in a phase 1 trial, and reported a long-lasting (>18 weeks) stable disease in three out of six patients with MPNST [ 196 ], thus leading to further investigation in an ongoing phase 2 trial (NCT02584647). Based on the significant VEGF and PDGFR-alpha protein expression in MPNST, the multi-kinase inhibitor pazopanib was evaluated in a phase 2 trial in 12 patients with advanced MPNST, with a clinical benefit rate of 50% at 12 weeks, a PFS of 5.4 months, and an OS of 10.6 months [ 197 ]. Some biological markers, including EGFR, Aurora kinase A (AURKA), or exportin-1 (XPO1), have been demonstrated to be overexpressed in MPNST, thus representing potential druggable pathways.…”

Section: Medical Treatmentsmentioning

confidence: 99%

Diagnosis and Treatment of Peripheral and Cranial Nerve Tumors with Expert Recommendations: An EUropean Network for RAre CANcers (EURACAN) Initiative

Pellerino

Verdijk

Nichelli

et al. 2023

Cancers

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The 2021 WHO classification of the CNS Tumors identifies as “Peripheral nerve sheath tumors” (PNST) some entities with specific clinical and anatomical characteristics, histological and molecular markers, imaging findings, and aggressiveness. The Task Force has reviewed the evidence of diagnostic and therapeutic interventions, which is particularly low due to the rarity, and drawn recommendations accordingly. Tumor diagnosis is primarily based on hematoxylin and eosin-stained sections and immunohistochemistry. Molecular analysis is not essential to establish the histological nature of these tumors, although genetic analyses on DNA extracted from PNST (neurofibromas/schwannomas) is required to diagnose mosaic forms of NF1 and SPS. MRI is the gold-standard to delineate the extension with respect to adjacent structures. Gross-total resection is the first choice, and can be curative in benign lesions; however, the extent of resection must be balanced with preservation of nerve functioning. Radiotherapy can be omitted in benign tumors after complete resection and in NF-related tumors, due to the theoretic risk of secondary malignancies in a tumor-suppressor syndrome. Systemic therapy should be considered in incomplete resected plexiform neurofibromas/MPNSTs. MEK inhibitor selumetinib can be used in NF1 children ≥2 years with inoperable/symptomatic plexiform neurofibromas, while anthracycline-based treatment is the first choice for unresectable/locally advanced/metastatic MPNST. Clinical trials on other MEK1-2 inhibitors alone or in combination with mTOR inhibitors are under investigation in plexiform neurofibromas and MPNST, respectively.

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Phase II clinical trial of pazopanib for patients with unresectable or metastatic malignant peripheral nerve sheath tumors

Cited by 14 publications

References 53 publications

Cranial nerve and intramedullary spinal malignant peripheral nerve sheath tumor associated with neurofibromatosis-1

Cranial nerve and intramedullary spinal malignant peripheral nerve sheath tumor associated with neurofibromatosis-1

Malignant peripheral nerve sheath tumor — from genetics to multidisciplinary treatment

Diagnosis and Treatment of Peripheral and Cranial Nerve Tumors with Expert Recommendations: An EUropean Network for RAre CANcers (EURACAN) Initiative

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