Dabrafenib plus trametinib in patients with BRAF V600E-mutant low-grade and high-grade glioma (ROAR): a multicentre, open-label, single-arm, phase 2, basket trial
Mené dans 13 pays sur 45 patients atteints d'un gliome de haut grade et sur 15 patients atteints d'un gliome de bas grade, tous récidivants ou en progression et présentant la mutation V600E du gène BRAF, cet essai de phase II évalue l'efficacité, du point de vue du taux de réponse objective, et la toxicité d'un traitement combinant dabrafénib et tramétinib
Background : Effective treatments are needed to improve outcomes for high-grade glioma and low-grade glioma. The activity and safety of dabrafenib plus trametinib were evaluated in adult patients with recurrent or progressive BRAFV600E mutation-positive high-grade glioma and low-grade glioma. Methods : This study is part of an ongoing open-label, single-arm, phase 2 Rare Oncology AgnosticResearch (ROAR) basket trial at 27 community and academic cancer centres in 13 countries(Austria, Belgium, Canada, France, Germany, Italy, Japan, the Netherlands, Norway,South Korea, Spain, Sweden, and the USA). The study enrolled patients aged 18 yearsor older with an Eastern Cooperative Oncology Group performance status of 0, 1, or2. Patients with BRAFV600E mutation-positive high-grade glioma and low-grade glioma received dabrafenib 150mg twice daily plus trametinib 2 mg once daily orally until unacceptable toxicity,disease progression, or death. In the high-grade glioma cohort, patients were requiredto have measurable disease at baseline using the Response Assessment in Neuro-Oncologyhigh-grade glioma response criteria and have been treated previously with radiotherapyand first-line chemotherapy or concurrent chemoradiotherapy. Patients with low-gradeglioma were required to have measurable non-enhancing disease (except pilocytic astrocytoma)at baseline using the Response Assessment in Neuro-Oncology low-grade glioma criteria.The primary endpoint, in the evaluable intention-to-treat population, was investigator-assessed objective response rate (complete response plus partial response for high-grade gliomaand complete response plus partial response plus minor response for low-grade glioma).This trial is ongoing, but is closed for enrolment, NCT02034110. Findings : Between April 17, 2014, and July 25, 2018, 45 patients (31 with glioblastoma) were enrolled into the high-grade glioma cohort and 13 patients were enrolled into the low-grade glioma cohort. The results presented here are based on interim analysis16 (data cutoff Sept 14, 2020). In the high-grade glioma cohort, median follow-upwas 12·7 months (IQR 5·4–32·3) and 15 (33%; 95% CI 20–49) of 45 patients had an objectiveresponse by investigator assessment, including three complete responses and 12 partialresponses. In the low-grade glioma cohort, median follow-up was 32·2 months (IQR 25·1–47·8).Nine (69%; 95% CI 39–91) of 13 patients had an objective response by investigatorassessment, including one complete response, six partial responses, and two minorresponses. Grade 3 or worse adverse events were reported in 31 (53%) patients, themost common being fatigue (five [9%]), decreased neutrophil count (five [9%]), headache(three [5%]), and neutropenia (three [5%]). Interpretation : Dabrafenib plus trametinib showed clinically meaningful activity in patients with BRAFV600E mutation-positive recurrent or refractory high-grade glioma and low-grade glioma,with a safety profile consistent with that in other indications. BRAFV600E testing could potentially be adopted in clinical practice for patients with glioma.
The Lancet Oncology 2021