Pediatric Glioma Trials Test Combination Strategies to Overcome Resistance

At the International Symposium on Pediatric Neuro-Oncology, researchers unveiled results from two studies seeking to counteract resistance to standard BRAF/MEK therapies in children with low-grade gliomas. The studies aimed to assess the effectiveness of adding hydroxychloroquine or everolimus to treatment regimens for patients with recurrent or refractory disease.

Hydroxychloroquine, an autophagy inhibitor, was combined with MEK or MEK and BRAF inhibitors in the first trial. Autophagy has been identified as a potential resistance mechanism in low-grade glioma and has been studied in melanoma. In this phase II trial, hydroxychloroquine was initially given at a high dose to determine the tolerable level, then moved into the phase II stage.

The trial compared patients' responses on the study to their prior treatment progress, allowing it to be conducted with a small participant group. The study found that adding hydroxychloroquine to dabrafenib and trametinib improved responses in patients with V600E-mutant tumors and those with BRAF-altered tumors.

The second study, a phase I trial, examined the combination of mTOR inhibition with everolimus and the MEK inhibitor trametinib. Previously, adult patients with solid tumors experienced toxicity when the combination was studied, limiting the escalation of doses. However, lower doses of the combination proved synergistic and effective in treating low-grade glioma.

The pediatric trial utilized both continuous and intermittent dosing schedules. While the continuous dosing approach did not allow for escalation to standard dosing, it did yield significant responses. The intermittent dosing schedule is still being evaluated, and the trial will progress into a phase II study to assess its effectiveness.

Researchers believe that this combinatorial approach could benefit patients with various mutations, including FGFR mutations and other alterations.