Doublet Therapy Shows Better Response Vs Chemotherapy in BRAF V600+ Pediatric Low-Grade Glioma

Eric Bouffet, MD

In pediatric patients with low-grade glioma harboring a BRAF V600 mutation, the combination of dabrafenib (Taflinar) plus trametinib (Mekinist) saw a quadrupling of the overall response rate (ORR) and a tripling of progression-free survival (PFS) compared with standard-of-care chemotherapy, according to results of a phase 2 trial (NCT02684058).¹

In the first-ever randomized clinical trial of targeted treatment for pediatric low-grade glioma, after a median follow-up of 18.9 months, the ORR, defined as the proportion of patients who had a complete or partial response, was 47% (95% CI, 35%-59%) in those assigned to dabrafenib/trametinib vs 11% (95% CI, 3%-25%) in chemotherapy recipients. The median PFS was 20.1 vs 7.4 months, respectively, as reported by Eric Bouffet, MD (HR, 0.31; 95% CI, 0.17-0.55; P <.001).

Liquid formulations of both dabrafenib and trametinib have been developed that may aide in weight-based dosing of pediatric patients, he pointed out. The liquid formulations were available for use in the study and were administered to patients with swallowing disorders, he said.

Treatment of pediatric low-grade glioma has been handled primarily with surgery. In cases of inoperable disease, first-line treatment is chemotherapy. Among the molecular markers that have been identified in this tumor, “the presence of BRAF V600 mutations is associated with a poorer response to chemotherapy and a risk of transformation [to secondary high-grade glioma],” said Bouffet, who is director of the Pediatric Neuro-Oncology Program at The Hospital for Sick Children in Toronto, Canada.

“We see this mutation in 15% to 20% of patients; therefore, we need to develop new treatments,” he said. Dabrafenib monotherapy had already shown clinical benefit in BRAF V600­–mutant pediatric low-grade glioma; the idea to add trametinib came from findings in adult patients with BRAF V600–mutant solid tumors who saw additional benefit and fewer cutaneous adverse events compared with dabrafenib monotherapy. An earlier study of the combination in pediatric patients with pretreated low-grade glioma demonstrated preliminary clinical activity and tolerability.²

In the double-blind trial conducted at 58 centers in 20 countries, 110 patients ages 12 months up to 18 years who had BRAF V600 mutation–positive low-grade gliomas and progressive disease following surgery or nonsurgical candidates were randomly assigned 2:1 to either dabrafenib twice daily plus trametinib once daily, as long as clinical benefit was observed, or to standard-of-care carboplatin plus vincristine for 14 months. Eligible patients had no prior systemic therapy or radiotherapy.

The improvement in ORR per independent assessment, the primary objective, corresponded to an odds ratio of 7.2 (95% CI, 2.3-22.4; P <.001) in favor of targeted treatment. The partial response (PR) rate was 44% and the complete response (CR) rate was 3% in the dabrafenib/trametinib arm compared with 8% and 3%, respectively, for standard of care. The clinical benefit rate, defined as those achieving a CR, PR, or stable disease for at least 24 weeks, was 86% vs 46% in the experimental and chemotherapy arms, respectively.

Overall survival data were immature at the time of analysis.

Patients in the dabrafenib plus trametinib arm had fewer grade 3 or greater adverse events (AEs; 47% vs 94%) and fewer treatment discontinuations due to AEs (4% vs 18%) compared with patients in the carboplatin plus vincristine arm. The most frequent AEs of any grade in the dabrafenib plus trametinib vs carboplatin plus vincristine groups were pyrexia (68% vs 18%), headache (47% vs 27%), and vomiting (34% vs 48%).

“This study demonstrates how important it is to document as early as possible the molecular alterations that are present in this type of tumor,” said Dr. Bouffet.

Availability of liquid formulations will be important, he added, given the potential difficulty in swallowing because of the glioma location, particularly with a BRAF V600 mutation, he added.

“This study shows that a new, oral targeted therapy combination can significantly improve outcomes for the most common type of brain tumor in children over standard-of-care chemotherapy that often requires frequent visits to the hospital or clinic and can result in health problems later in life. It is exciting to see success in developing targeted treatments based on the unique genetic features of a tumor in a young patient,” said Melissa M. Hudson, MD, an ASCO expert in pediatric cancers and a pediatric hematologist-oncologist at St. Jude Children’s Research Hospital in Memphis.

_References

_{1. Bouffet E, Hansford J, Garré ML. Primary analysis of a phase II trial of dabrafenib plus trametinib (dab + tram) in BRAFV600–mutant pediatric low-grade glioma (pLGG). J Clin Oncol. 2022;40(suppl 17):LBA2002. doi:10.1200/JCO.2022.40.17_suppl.LBA2002}

_{2. Geoerger B, Bouffet E, Whitlock JA, et al. Dabrafenib + trametinib combination therapy in pediatric patients with BRAF V600-mutant low-grade glioma: Safety and efficacy results. J Clin Oncol. 2020;38(suppl 15):10506. doi: 10.1200/JCO.2020.38.15_suppl.10506}