Crafting Targeted Treatments in Pediatric Low-Grade Glioma Improves Results

Killmurray,Conor;

Crafting Targeted Treatments in Pediatric Low-Grade Glioma Improves Results

August 4, 2023

Conor Killmurray

Publication

Article

Targeted Therapies in OncologyJuly 1, 2023

Volume 12

Issue 9

Pages: 43

Identifying alterations to tailor treatment is important for patients with pediatric low-grade glioma as it accounts for one-third of all pediatric central nervous system tumors.

Jason Fangusaro, MD

Professor Department of Pediatrics

The Carter S. Martin Endowed Chair

Emory University School of Medicine

Director and Medical Director of the Clinical Research Office

Aflac Cancer and Blood Disorders Center

Atlanta, GA

The use of targeted therapies focusing on protein pathways in patients with pediatric low-grade gliomas (pLGG) has resulted in several impactful treatments and ongoing trials that have shown effectiveness and tolerability in a real-world setting. According to a recent collection of research, most of these cases are driven by gene alterations within the MAPK/ mTOR pathways, and molecular diagnostics and new targeted therapies have led to positive outcomes in these patients.¹

Among the notable gene alterations found in these patients, most common is the BRAF-KIAA1549 fusion compared with the less common BRAF V600E, followed by MYB, FGFR, and other BRAF mutations or fusions.¹ Identifying these alterations to tailor treatment to these patients is important as pLGG has been identified among researchers as accounting for one-third of all pediatric central nervous system tumors,² but new advancements in targeted treatment have allowed for quick responses to some therapies.

“mTOR activity appears to be very important in [pLGG] biology, and there may be actually different mechanisms of action and variable activation in individual tumors,” explained Jason Fangusaro, MD, in a presentation of pertinent data in this landscape at the 2023 American Society of Pediatric Hematology/Oncology Conference. “In the pathway, we go from PI3K to AKT to mTOR, and then cell proliferation and survival. And so, propagation down this pathway obviously leads to tumor formation.”

Pathway Inhibitions

One of the earlier mTOR inhibitors to be considered for these patients with radiographically progressive pLGG was everolimus (Afinitor) based on results of the phase 2 POETIC study (NCT00782626).³ Researchers gave 23 eligible patients previously treated with chemotherapy, with a median age of 9 years, a 5-mg/m² daily dose of the inhibitor and observed that by week 48 of treatment, 2 patients had a partial response (PR), 10 were at stable disease (SD), and 11 had clinical or radiographic progression. Further, the researchers had a median follow-up of 1.8 years (range, 0.2-6.7 years) for patients who remained on the drug and saw promising progression-free survival (PFS) at 2, 3, and 5 years (39 ± 11%, 26 ± 11%, and 26 ± 11%, respectively).

Overall survival (OS) trended favorably for patients in this study, with OS at 2, 3, and 5 years all being the same (93 ± 6%). According to Fangusaro, grade 1 and 2 adverse events (AEs) made up most toxicities. Of note, 2 grade 3 cases of mucositis and neutropenia were observed and a grade 4 elevation of liver enzymes was seen in another case, with 2 patients dying due to disease progression during treatment. Still, daily use of this drug provided physicians with an alternative treatment for patients with progressive pLGG, making a case for inhibiting the mTOR pathway.

Further research was then done to target alterations within this pathway, such as use of the MEK-1/-2 inhibitor selumetinib (Koselugo) in the phase 2 PBTC-029B trial (NCT01089101) conducted by Fangusaro.⁴ Among 25 evaluable patients, including those with neurofi bromatosis type 1 (NF1)-associated pLGG, results showed 9 PRs, 9 patients with SD, and 7 with partial disease (PD) during treatment; among the 9 patients with PRs, 7 had a BRAF alteration duplication and 2 had a BRAF V600E mutation. According to Fangusaro, patients with a BRAF V600E mutation in their disease are more likely to have worse outcomes; therefore, this study led to further analysis of selumetinib for these patients.

In a fourth stratum of patients on the PBTC029B trial, patients with sporadic recurrent or progressive disease with a known BRAF mutation were given 25 mg/m² of selumetinib twice daily.⁵ Patients had a median of 4 prior therapies, including MEK inhibition, with 14 of the 25 patients completing all 26 courses of treatment.

Bouffet E, Geoerger B, Moertel C, et al. Efficacy and safety of trametinib monotherapy or in combination with dabrafenib in pediatric BRAF V600-mutant low-grade glioma. J Clin Oncol. 2023;41(3):664-674. doi:10.1200/JCO.22.01000

They observed 6 patients had a PR, 14 had SD, and 5 had PD through the course of treatment (the 2-year PFS rate was 78 ± 8.5%). Again, the most common toxicities were grade 1/2, but notable grade 3 AEs included creatine kinase elevation (5%) with 3% of cases being grade 4, emesis (2%), weight gain (2%), and hyponatremia (2%). Visual outcomes also improved in 4 of 19 evaluable patients, whereas it was stable in 13 patients but worsened in 2; one had SD and the other had PD.

These results led to the approval of twice-daily selumetinib for patients with NF1 pLGG,⁶but for patients specifically with a BRAF V600E mutation, further research was needed.

Targeting BRAF V600E

To address patients with BRAF V600E mutation in their disease, researchers looked to the monotherapy of trametinib (Mekinist) in a phase 1/2 study (NCT02124772) that found no dose-limiting toxicities in a recommended dosage of 0.032 mg/kg daily for patients younger than 6 years and 0.025 mg/kg daily for patients older than 6 years.⁷ With the monotherapy, a majority of patients had responses or stable disease, similar to other trials with selumetinib, Fangusaro explained. However, what pushed the treatment to an eventual approval was the addition of dabrafenib (Tafinlar).

“What we saw was dabrafenib plus trametinib monotherapy [is] another effective strategy for treating recurrent low-grade glioma, and specifically in this study [shows positive results] with BRAF V600E-mutant low-grade glioma,” said Fangusaro, director of the Aflac Cancer and Blood Disorders Center and professor in the Department of Pediatrics at Emory University School of Medicine in Atlanta, Georgia, in his presentation.

Toxicity with this combination was proven tolerable in the phase 1/2 study as well, with the most common toxicities of any grade being diarrhea (30.6%), dry skin (41.7%), fatigue (38.9%), acneiform dermatitis (38.9%), pyrexia (50%), and rash (36.1%).⁸ According to Fangusaro, it is important to take rash and skin AEs seriously, as these can be mitigated by new methods that require continuing education among physicians.

Further, objective response rates (ORR) among these patients were 25% (95% CI, 12.1%-42.2%) in the combination arm compared with 15% (95% CI, 1.9%-45.4%) in the monotherapy arm. Moreover, AE-related discontinuations were observed more frequently in the monotherapy arm compared with the combination arm, at 54% vs 22%, respectively.

Earlier comparisons were done with this combination against standard-of-care (SOC) carboplatin plus vincristine; patients under 18 years with pLGG that harbored a BRAF V600E mutation had stronger results with the combination. For instance, ORR in the initial study compared with chemotherapy was 47% on the combination vs 11% on SOC, with an 86% clinical benefit compared with 46%. Further, high-grade AEs were observed in 86% of patients on SOC compared with 47% on the inhibitor combination.

These results led to approval of the dabrafenib and trametinib combination, along with a new oral formulation of these drugs in pediatric patients unable to swallow pills.⁹ According to Fangusaro, this continues the trend of targeted treatments being more impactful than historical chemotherapies, meaning physicians must research why these tumors with mostly similar histology are reacting differently.

“Why are some of them responding to molecularly targeted agents and some of them not? And this is an important finding that we need to answer as best we can,” he concluded. “It’s also important to follow these patients for many years to make sure we don’t see secondary late effects many years later, which will lead to increase morbidity and mortality."