Pediatric PK/PD Phase I Trial of Pexidartinib in Relapsed and Refractory Leukemias and Solid Tumors Including Neurofibromatosis Type I–Related Plexiform Neurofibromas

Neurofibromatosis type 1 (NF1) is a genetic disorder that carries a higher risk of tumor development. Plexiform neurofibromas (PNs) are present in 50% of NF1 and cause significant morbidity when surgery is not feasible. Systemic therapies had not succeeded to reduce PN tumor volume until 2016 when the first trial with an MAPK/extracellular-signal-regulated kinase (MEK) inhibitor was published. We performed a systematic research on novel targeted therapies for patients with NF1 and PNs in PubMed, EMBASE, and conference abstracts with the last update in February 2021. Since 2016, seven trials have reported positive results with MEK inhibitors and other molecular targeted therapies (cabozantinib). Selumetinib has shown an overall response rate of 68% in children with NF1 and symptomatic inoperable PNs, and was associated with pain improvement and a manageable adverse events profile. This led to Food and Drug Administration (FDA) approval of selumetinib in May 2020. Recently, cabozantinib and mirdametinib have also proven their efficacy in adult population. Other MEK inhibitors such as trametinib and binimetinib have also communicated promising preliminary results. Ongoing trials in different populations and with intermittent dosing strategies are underway.

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“…Three children with NF1 and PNs received pexidartinib in the context of a phase I trial and had stable disease without DLT. 52 …”

Section: Resultsmentioning

confidence: 99%

Novel molecular targeted therapies for patients with neurofibromatosis type 1 with inoperable plexiform neurofibromas: a comprehensive review

et al. 2021

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“…In a phase 1 study of Pexidartinib in pediatric and young adult patients with relapsed and refractory solid tumors, target inhibition was observed as evidenced by decreased absolute monocyte count and increased M-CSF (CSF-1) levels correlating with dose. Preliminary clinical activity was also seen, with three patients having stable disease for four or more cycles and one patient with peritoneal mesothelioma having a deep partial response [42].…”

Section: Key Pointsmentioning

confidence: 96%

Targeting tumor microenvironment and metastasis in children with solid tumors

Wessel

Kaplan

2021

Current Opinion in Pediatrics

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Purpose of reviewThe prognosis of pediatric patients with metastatic solid tumors remains poor, necessitating development of novel therapeutic strategies. The biology of the pediatric tumor microenvironment (TME) presents obstacles for the efficacy of current therapeutic approaches including immunotherapies. Targeting various aspects of the TME in pediatric patients with solid tumors represents a therapeutic opportunity that may improve outcomes. Here we will discuss recent advances in characterization of the TME, and clinical advances in targeting the immune, vascular, and stromal aspects of the TME. Recent findingsAlthough immunotherapies have shown limited success in the treatment of pediatric solid tumor patients thus far, optimization of these approaches to overcome the TME shows promise. In addition, there is increasing focus on the myeloid compartment as a therapeutic target. Vascular endothelial growth factor (VEGF) targeting has resulted in responses in some refractory pediatric solid tumors. There has been relatively little focus on stromal targeting; however, emerging preclinical data are improving our understanding of underlying biology, paving the way for future therapies.

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“…Everolimus, another mTOR inhibitor, and pexidartinib, an inhibitor of a tyrosine kinase in the mTOR signaling pathway, have also been studied without much success [ 51 , 52 ]. Everolimus, in particular, was associated with significant adverse effects [ 53 ].…”

Section: Neurofibromatosis Typementioning

confidence: 99%

Targeted Therapies for the Neurofibromatoses

Sanchez

Bui

Klesse

2021

Cancers

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Over the past several years, management of the tumors associated with the neurofibromatoses has been recognized to often require approaches that are distinct from their spontaneous counterparts. Focus has shifted to therapy aimed at minimizing symptoms given the risks of persistent, multiple tumors and new tumor growth. In this review, we will highlight the translation of preclinical data to therapeutic trials for patients with neurofibromatosis, particularly neurofibromatosis type 1 and neurofibromatosis type 2. Successful inhibition of MEK for patients with neurofibromatosis type 1 and progressive optic pathway gliomas or plexiform neurofibromas has been a significant advancement in patient care. Similar success for the malignant NF1 tumors, such as high-grade gliomas and malignant peripheral nerve sheath tumors, has not yet been achieved; nor has significant progress been made for patients with either neurofibromatosis type 2 or schwannomatosis, although efforts are ongoing.

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Pediatric PK/PD Phase I Trial of Pexidartinib in Relapsed and Refractory Leukemias and Solid Tumors Including Neurofibromatosis Type I–Related Plexiform Neurofibromas

Cited by 19 publications

References 56 publications

Novel molecular targeted therapies for patients with neurofibromatosis type 1 with inoperable plexiform neurofibromas: a comprehensive review

Novel molecular targeted therapies for patients with neurofibromatosis type 1 with inoperable plexiform neurofibromas: a comprehensive review

Targeting tumor microenvironment and metastasis in children with solid tumors

Targeted Therapies for the Neurofibromatoses

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