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CHICAGO -- Dual targeted therapy with a BRAF and MEK inhibitor quadrupled responses in pediatric BRAF-mutant low-grade glioma and reduced risk of disease progression or death compared with standard chemotherapy, a phase II study demonstrated.

In children harboring BRAF^V600E mutations with progressive disease following surgery, the overall response rate (ORR) reached a "striking" 47% with dabrafenib (Tafinlar) plus trametinib (Mekinist), versus just 11% with carboplatin plus vincristine (P<0.001), reported Eric Bouffet, MD, of the Hospital for Sick Children in Toronto.

Median progression-free survival nearly tripled with the targeted combination, at 20.1 months compared with 7.4 months (HR 0.31, 95% CI 0.17-0.55, P<0.001), according to findings presented at the American Society of Clinical Oncology (ASCO) annual meeting.

At 1 year, two-thirds of children in the dabrafenib-trametinib arm were alive without disease progression versus 26% of those on chemotherapy.

"These are exciting data because they suggest that there is the possibility to offer a new treatment upfront for these children with low-grade glioma associated with this BRAF^V600E mutation," Bouffet said during a press briefing here. "This study demonstrates how important it is to document, as early as possible, the molecular alterations that are present in this type of tumor."

Bouffet noted that the study used weight-adjusted doses of the targeted agents and employed a novel liquid formulation to treat children who could not otherwise swallow the standard oral formulations. "This is important, because no child was left behind," he said.

"A number of these children have not only difficulty swallowing because of their age, but also difficulty swallowing because of the location of the tumor," he explained. "A number of BRAF-mutated tumors are located in the cervical medulla region."

The targeted combination had a good safety profile, with manageable side effects, said Bouffet. Quality of life outcomes appeared stable among children treated with the targeted agents, whereas there was a gradual decline in the chemotherapy group.

"The difference was not significant, but it was obvious ... that there was an increasing difference in quality of life over time," he said. Children in the targeted-agent group "could continue to go to school, could continue to have a normal life."

Low-grade glioma (grade 1/2) is responsible for the majority of cases in children, and BRAF^V600E mutations are present about 15% to 20% of the time. While surgery is the mainstay of treatment, it is not always possible when tumors penetrate certain parts of the brain, and patients with BRAF-mutant disease tend to have poorer responses to standard chemotherapy.

"These are common pediatric brain tumors," said Melissa Hudson, MD, an ASCO expert in pediatric cancers, during the briefing. "They occur in areas that are often unresectable and are prone to recurrence and progression, requiring multiple lines of therapy."

"Current standard therapy involves cytotoxic agents that cause a need for follow-up in the clinic and are associated with health problems later in life," she said. "Allowing this type of targeted therapy really will enable us to personalize treatment for these children and hopefully improve the quality of their survival long-term."

Study Details

From September 2018 to December 2020, the phase II trial randomized 110 children with low-grade glioma and progressive disease following surgery 2:1 to either oral dabrafenib plus trametinib (given as long as there was evidence of benefit) or carboplatin plus vincristine (given for a fixed period of 14 months). The chemotherapy arm could cross over after disease progression.

Median patient age was 8-10 (range 1-17), and 60% were girls. Patients needed to have a BRAF^V600E mutation, measurable tumor, no prior BRAF- or MEK-inhibitor exposure, and a Karnofsky/Lansky performance status of 50% or greater.

ORR was the primary endpoint, and the median follow-up at data cutoff was 18.9 months. Overall survival results were immature at this point, with one death in the chemotherapy arm.

An equal proportion of patients in each arm had complete responses (3%) and stable disease (41%) with treatment, but children on the chemotherapy arm were three times more likely to have progressive disease as their best response (32% vs 11%).

Higher responses with the targeted combination were seen across a range of histologic subtypes. In ganglioma, for example, eight of 21 patients (38%) in the dabrafenib-trametinib arm experienced a response versus none of nine patients in the chemotherapy arm.

In terms of safety, all patients experienced at least one adverse event (AE), but grade ≥3 AEs were halved with the targeted combination (47% vs 94% with chemotherapy). Common AEs of any grade with the targeted combination included pyrexia (68%), headache (47%), fatigue (32%), dry skin (26%), and nausea (25%) and vomiting (34%).

AEs leading to treatment discontinuation were rare in the targeted-agent group (4% vs 18% with chemotherapy), while dose adjustments/interruptions were common with both treatments (79% in each arm).

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