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Targeted Therapies Produce Durable Responses in BRAF V600E-Mutated Pediatric Low-Grade Gliomas

NEW YORK – In a study published in JCO Precision Oncology last week, researchers found that pediatric low-grade glioma patients who had a BRAF V600E mutation tended to experience durable responses to BRAF inhibition. Additionally, after some patients became resistant to BRAF inhibitors, the study showed that these patients could be successfully rechallenged with a BRAF inhibitor alone or in combination with a MEK inhibitor.

Low-grade gliomas are the most common type of brain tumors found in children, and for the most part these slow-growing tumors are curable. The standard of care is chemotherapy and radiotherapy, and the 20-year survival rate is greater than 90 percent.

However, survival outcomes are poor for the between 15 percent and 20 percent of patients with BRAF V600E mutations, especially when they also harbor a homozygous CDKN2A deletion. In this subset, standard therapies can control tumor growth in fewer than 30 percent of patients but can increase the risk of secondary malignancies and other adverse effects. In contrast to low-grade gliomas, BRAF V600E-mutated pediatric high-grade gliomas have even worse prognosis, with a five-year survival rate of 10 percent on chemotherapy and radiotherapy.

Since BRAF inhibitors have been successfully used to treat BRAF V600E-mutated colon cancer and melanoma, a team of researchers, led by Cynthia Hawkins at the Hospital for Sick Children in Toronto, Canada, investigated if targeted therapies could be effective in these molecularly defined subsets of glioma patients. For their study, the researchers collected clinical, imaging, molecular, and outcomes data on BRAF V600E-mutated glioma pediatric patients who were treated with a BRAF inhibitor from 29 neuro-oncology centers around the world.

They gathered data on 67 pediatric patients — 56 patients with BRAF V600E-mutated, low-grade gliomas and 11 with BRAF V600E-mutated high-grade gliomas. All patients had their BRAF V600E mutation status confirmed by immunohistochemistry or sequencing. Among low-grade glioma patients, 15 percent also had a co-occurring CDKNA deletion, and one patient had a co-occurring H3.3 K27M mutation.

Response to treatment was evaluated by measuring reductions in tumor size. A minor response was defined as a reduction in tumor size of between 25 percent and 49 percent, a partial response was defined as a tumor reduction of between 50 percent and 99 percent, and a complete response was defined as the disappearance of tumors on imaging scans.

Hawkins and colleagues reported that 80 percent of patients with low-grade gliomas saw their tumors shrink on BRAF inhibitors, with 15 patients having a minor response, 28 patients having a partial response, and two patients having a complete response. All patients with a CDKN2A-deleted tumor responded to treatment, and there was no difference in response rates between BRAF V600E-mutated tumors with and without a CDKN2A deletion.

For comparison, the researchers then looked at how 50 low-grade glioma patients with BRAF V600E mutations fared on standard chemotherapy and noted a 28 percent response rate.

Out of 56 low-grade glioma patients, there were eight who experienced tumor progression after BRAF inhibitor treatment likely due to acquired resistance. Five patients then received a combination of a BRAF inhibitor with a MEK inhibitor, and at a median follow up of eight months, their tumors had not yet progressed.

Seventeen low-grade glioma patients stopped BRAF inhibitor treatment based on their own or their doctors' decision, or due to toxicity. Thirteen of these patients experienced rapid disease progression within an average of 2.3 months. Eight patients were re-challenged with a BRAF inhibitor alone and one patient was given a combination of a BRAF inhibitor and MEK inhibitor. Eight of these patients experienced tumor regression. One patient who had to stop treatment due to toxicity started progressing again and died.

The patient who had a co-occurring H3 K27M mutation experienced progression after discontinuing therapy but had stable disease after being re-challenged with BRAF and MEK inhibitor after nearly 23 months of follow-up.

"Previous reports have identified both CDKN2A deletion and H3.3 K27M mutation as poor prognostic markers in [pediatric low-grade gliomas] with concomitant BRAF V600E mutation. … Our data suggest that CDKN2A-deleted tumors still respond to BRAF inhibition in a manner similar to that of other BRAF V600E-mutated tumors," the authors wrote. "Additional studies in larger cohorts are required to verify these outcomes."

In this analysis, there were 28 low-grade glioma patients who received continuous treatment with a BRAF inhibitor for more than 10 months. The two-year progression-free survival rate was 81.6 percent in these patients, and some didn't experience progression after up to five years of treatment. Comparatively, only 26.7 percent of patients who discontinued therapy after 10 months experienced progression-free survival one year after stopping BRAF inhibitor treatment.

"Chronic long-term use of BRAF inhibition may be needed, as is commonly done with mTOR inhibitors in patients with tuberous sclerosis and [subependymal giant cell astrocytoma]. If so, studies of long-term adverse effects and potential developmental issues unique to children are required," the authors stated. On average, BRAF V600E-mutated patients treated with BRAF inhibition had a three-year progression-free survival of 49.6 percent.

For further comparison, Hawkins and colleagues also considered if the efficacy of BRAF inhibitors seen in BRAF-mutated, low-grade gliomas would extend to high-grade pediatric glioma patients with the same mutations. In the 11 BRAF V600E-mutated high-grade glioma patients treated with BRAF inhibitors, the overall response rate was 36 percent, with 10 patients experiencing progression within 18 months.

Three patients also had a co-occurring H3.3 K27M mutation, and although they initially responded to treatment, all died as a result of their disease. Progression-free survival at one-year in this group was 27 percent. These results suggested to the researchers that "resistance in [high-grade gliomas] occur in most cases, and new strategies beyond BRAF inhibitor monotherapy are needed."

The authors noted that BRAF inhibition is currently reserved for recurrent tumors, but these results may suggest utility in earlier lines of treatment for low-grade gliomas.

"Despite the majority of our cohort comprising patients with relapsed disease treated with BRAF inhibition, the responses of BRAF V600E-mutated [low-grade gliomas] to BRAF inhibition was remarkable," the authors wrote. "Notably, these responses were usually achieved within three months, contrasting the slow responses and mostly stabilization observed with chemotherapy and/or radiotherapy approaches."