Opportunities for the treatment of NF1-associated low-grade gliomas: how to decide on the best treatment options for patients?

See the article by Ullrich et al in this issue, pp. 1527–1535.

Within pediatric low-grade glioma (PLGG) populations, children and adolescents with neurofibromatosis type 1 (NF1)–associated tumors are among the largest and most vulnerable group of patients. Despite carrying a low risk of progression and being associated with a favorable outcome overall, some patients require multiple lines of therapy during childhood, until tumor senescence is achieved. Bridging those crucial years in the child’s development and treating progressive/recurrent disease are challenging. On one hand, NF1 patients show increased toxicity to most conventional PLGG therapies, and due to the tumors’ typical location in midline structures (optic pathway, brainstem), surgical resection is generally not an option. Moreover, despite an indolent growth, symptomatic tumors can have a permanent impact on the patient’s life (eg, visual loss in optic pathway gliomas), and preservation of function is one of the main treatment priorities. Given the complexity of the issues affecting these patients, having therapeutic options suitable for chronic use, with good efficacy and low toxicity profile, is key.

In this issue of Neuro-Oncology, Ullrich et al report on a phase II clinical trial evaluating the use of everolimus as a single agent in pediatric patients with progressive low-grade gliomas.¹ This is a study focusing on NF1 patients, who often represent only a minority group in larger PLGG studies, with recurrent tumors post carboplatin containing chemotherapy. As an oral agent targeting the phosphatidylinositol-3 kinase/mammalian target of rapamycin (PI3K/mTOR) pathway—with evidence of good blood–brain barrier penetration—the rationale for using everolimus to treat pediatric NF1-associated LGG patients is strong. With encouraging toxicity profiles and the majority of patients showing tumor stability or shrinkage upon treatment, this study consolidates everolimus as an important therapy alternative for NF1-associated PLGG. Importantly, each patient was discussed with the study team prior to enrollment to ensure that progression was identified on MRI.

Recent reports have emerged showing high rates of partial responses to the MEK inhibitor selumetinib in a similar population of NF1 patients with recurrent PLGG.² It is important to note that a direct comparison of the response rates between everolimus and selumetinib is challenging to be undertaken, given that the selumetinib study also enrolled refractory disease, whereas the study by Ullrich et al mandated progressive disease for all patients. Given the coactivation of the Ras/MEK/mitogen-activated protein kinase and PI3K/mTOR pathways in NF1 and PLGG, treatment strategies co-targeting both pathways are likely to show increased antitumor activity and will be explored in future clinical trials (PNOC021, NCT04485559).

One of the main challenges of studies assessing therapy efficacy in PLGG is how to best define and measure response. In the study by Ullrich et al, pre- and posttherapy MRIs were centrally reviewed by a neuroradiologist blinded for outcome. Radiological responses, however, do not necessarily correlate with clinical/functional outcomes, and given that patients rarely succumb to their disease, assessing impact in overall survival is of limited use. Though complex to assess and quantify, functional outcomes and quality-of-life measures will be crucial moving forward. Therefore, it is exciting to see the development that upfront studies for this disease group include functional endpoints (NCT03871257)—a critical aspect when deciding between therapy options for a vulnerable patient population such as NF1-associated gliomas.

Biomarkers of response can further aid therapy guidance and patient stratification. In this study, the authors seek to provide mechanistic insights into drug response by monitoring drug levels and assessing overall PI3K/mTOR pathway inhibition within peripheral blood mononuclear cells. Though no correlation was found between response and degree of pathway inhibition, correlative biomarkers should continue to be developed and included as standard of care in clinical trials. It will be critical for future biomarker development to assess these in tumor tissue directly, as measurement in peripheral blood mononuclear cells has rarely proven to be valuable for brain tumors.

Lastly, a central missing piece of the puzzle is the information on the tumors’ molecular characteristics and their impact on patient outcome. Tumor biopsy was not mandatory in this study and one may in fact argue against performing a biopsy in these patients, given that NF1 is likely the main and sole driver in the majority of NF1-associated PLGG.³ However, though rarely biopsied and largely uncharacterized thus far, PLGGs in NF1 patients may harbor additional alterations—for example, at the level of BRAF, FGFR1, or H3F3A, which dictates outcome and response to therapy.⁴ Moreover, the presence of additional mutations cooperating with NF1 in glioma development increases with age, and malignant NF1-associated gliomas occur in adulthood. The mechanisms underlying malignant transformation are yet poorly characterized. Particularly in the adolescent and young adult population, the presence of alterations associated with malignant NF1-associated gliomas (eg, TP53, ATRX, CDKN2A) should be screened for at progression whenever possible.³ To best care for these patients and optimize therapies, especially at tumor recurrence after cytotoxic therapy, tumor biopsy should be considered.

Building on this and other studies, optimized treatment strategies for NF1-associated PLGG, including combination therapies, are under way. Despite the many challenges in the field, it is encouraging to have an increasing arsenal of targeted agents for NF1-associated PLGG in advanced stages of clinical development and better treatment options for these patients.

Funding/Conflict of interest statement. No funding. No conflicts of interest are reported for any author.

Authorship statement. Ana Stücklin participated in the conception and final editing of the editorial. Sabine Mueller participated in the conception and final editing and approval of the editorial.

This material has not been previously published or presented in any venue.