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Dabrafenib shows promise for BRAF V600–mutated pediatric low-grade gliomas
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COPENHAGEN, Denmark — Targeted treatment with dabrafenib induced a high rate of response and appeared safe in pediatric patients with BRAF V600–mutated relapsed or refractory low-grade glioma, according to the final results of a phase 1/phase 2 study presented at the European Society for Medical Oncology Congress.
“Low-grade gliomas are the most common brain tumors in children,” Mark W. Kieran, MD, PhD, director of pediatric medical neuro-oncology at Dana-Farber Boston Children’s Hospital, said during his presentation. “Unlike their adult counterparts, although they often recur and relapse, the long-term survival in this patient population is excellent. It’s exceedingly rare to have a patient die of low-grade pediatric glioma. The need for repeated therapies, however, can frequently cause significant long-term morbidity these patients suffer with their entire lives.”
Researchers are now beginning to understand more about the characteristics about low-grade gliomas, particularly those with BRAF mutations, that provide information about the likelihood of recurrence and long-term prognosis, Kieran added.
Ten to twenty percent of children with low-grade gliomas harbor a BRAF V600 mutation. Compared with patients with wild-type disease, patients with this mutation have poorer survival and lower objective response rates to chemotherapy.
“With the identification of BRAF mutations in this disease, the question emerged about whether there was a possibility for targeted therapy to provide better efficacy than our current standards, chemotherapy and radiation, and with less toxicity,” Kieran said.
This study is the first to evaluate dabrafenib (Tafinlar, Novartis) — a selective inhibitor of the V600–mutant form of the BRAF kinase — in pediatric patients with relapsed or refractory low-grade gliomas. The study included data from 32 patients aged 2 to 17 years (median age, 9 years), 15 of whom were treated on the phase 1 trial. Results of that portion of the study — presented at the ASCO Annual Meeting in 2015 — defined the recommended phase 2 dosing as 4.5 mg/kg a day for patients aged 12 years and older and 5.25 mg/kg a day for patients aged younger than 12 years.
The other 17 patients were treated on the phase 2 trial. The current analysis includes data from all patients treated on the phase 1 and phase 2 portions, including 24 children who received the recommended phase 2 dosing.
Twenty-two patients remained on study as of April 2016. Median duration of exposure to study drug was 55 weeks (range, 1-109).
Overall, the investigator-confirmed objective response rate was 72% (95% CI, 53-86), and the overall response rate using Response Assessment in Neuro-Oncology criteria was 41% (95% CI, 24-59).
Two patients achieved a complete response and 11 achieved a partial response — of those 13 responding patients, eight were still on therapy at the time of the analysis.
Thirteen patients achieved stable disease for at least 6 months, eight of whom were still on therapy.
Eighteen patients had adverse events that led to dose interruptions; of these, five led to dose reductions. Two patients discontinued treatment due to adverse events.
Common adverse events were similar to those observed among adults treated with dabrafenib and included low-grade pyrexia, vomiting, fatigue, headache and rash. Researchers observed no cases of cutaneous squamous cell carcinoma, which has been reported among adults.
Three patients experienced grade 3 or grade 4 pneumonia and one patient experienced a significant allergic reaction on day 2 of dosing, leading to study discontinuation.
Because BRAF inhibitors have demonstrated long-term activity when combined with MEK inhibitors in adults, research is now underway evaluating dabrafenib in combination with a MEK inhibitor in phase 1 and phase 2 studies of children with low-grade gliomas.
“We want to make the response rate with dabrafenib even higher by combining it with a MEK inhibitor since that works in adults,” Kieran said in a press release. “Adding two drugs together normally produces twice as much toxicity. But, much of the toxicity from the BRAF drug is inhibited by the MEK drug, so the combination is less toxic than either drug alone, which is unusual.
“This combined therapy may completely change the way we treat low-grade gliomas in children with this mutation,” Kieran added. “The caveat is that these targeted personalized drugs are relatively new so we need to make sure that they don’t have any long-term developmental toxicities in children.” – by Alexandra Todak
Reference:
Kieran MW, et al. Abstract LBA19_PR. Presented at: European Society for Medical Oncology Congress; Oct. 7-11, 2016; Copenhagen, Denmark.
Disclosure: Kieran reports an advisory board role with Novartis. Other researchers report consultant roles with, equity ownership in and research funding from Bayer, Bristol-Myers Squibb, Eisai, GlaxoSmithKline, Novartis and Pfizer.