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BRAF–MEK Inhibition May Offer ‘Notable Activity’ Against BRAF-Mutated Glioma

Early findings indicate dabrafenib plus trametinib may be active against high- and low-grade glioma carrying the BRAFV600E mutation
02 Dec 2021
Anticancer Agents;  Central Nervous System Malignancies;  Personalised/Precision Medicine

Author: By Lynda Williams, Senior medwireNews Reporter 

 

medwireNews: Interim results from the ROAR trial indicate that dabrafenib plus trametinib may have efficacy in patients with BRAF-mutated high- or low-grade glioma. 

“[T]his study is the first time that a combination of a BRAF inhibitor (dabrafenib) and a MEK inhibitor (trametinib) have shown notable activity in these difficult-to-treat gliomas, including glioblastomas, which have historically shown resistance to therapies”, say Patrick Wen, from the Dana-Farber Cancer Institute in Boston, Massachusetts, USA, and co-workers. 

The international phase II basket trial included 45 patients (31 with glioblastoma) with high-grade glioma who had previously been treated with radiotherapy and chemotherapy, and 13 patients with symptomatic low-grade glioma, all of whom had either grade I symptomatic disease, or had grade II disease and were ineligible for chemotherapy. All participants had tumours positive for the BRAFV600E mutation.  

After a median 12.7 months of follow-up, 33% of the high-grade glioma patients had achieved an investigator-assessed objective response to dabrafenib 150 mg twice daily plus trametinib 2 mg/day, including three complete and 12 partial responses, and stable disease in 10 patients. 

And after a median 32.2 months, 69% of the low-grade patients had achieved an investigator-assessed objective response to the same regimen, with one complete, six partial and two minor responses, and stable disease in a further three patients. 

Median duration of response in the high-grade glioma arm was 36.9 months, with a median progression-free survival of 3.8 months and overall survival of 17.6 months. In the low-grade glioma arm, the median values of these three endpoints were unreached. 

The researchers also report the outcomes of the 31 patients with high-grade glioblastoma in a post-hoc analysis, finding that 32% responded to treatment, including two complete and eight partial responses, as well as stable disease in six patients. The median progression-free and overall survival durations in this subgroup were 2.8 and 13.7 months, respectively. 

Overall, 47% of the high-grade glioma and 61% of the low-grade glioma patients reported adverse events (AEs) such as fatigue, headache, nausea and pyrexia. The most common AEs of grade 3 or worse in the overall population were fatigue (9%), decreased neutrophil counts (9%) and neutropenia (5%). Serious AEs occurred in 33% of high-grade and 23% of low-grade glioma patients. 

Dose reductions, interruptions and discontinuations related to AEs were required in 38%, 41% and 9% of the patients, respectively. 

Patrick Wen and co-authors conclude in The Lancet Oncology that “[t]he clinically meaningful and durable anti-tumour activity suggests that dabrafenib plus trametinib is a promising treatment option for patients with BRAFV600E-mutant recurrent high-grade glioma and low-grade glioma.” 

They therefore recommend that routine testing for this mutation “should be considered in clinical practice”. 

In a comment accompanying the article, Katherine Peters, from Duke University in Durham, North Carolina, USA, says that the ROAR findings “support the updated WHO recommendations for the classification of [central nervous system] tumours”, recognising that disease histology and grade alone are no longer adequate for patient management. 

Describing the study’s results as a “paradigm shift in thoughtfully integrating targeted therapies into care of patients with glioma”, the commentator recommends future research should determine the optimal timing of BRAF and MEK inhibitors and include patient-reported outcomes to improve management of toxicities and maintain quality of life. 

References  

Wen PY, Stein A, van den Bent M, et al. Dabrafenib plus trametinib in patients with BRAFV600E-mutant low-grade and high-grade glioma (ROAR): a multicentre, open-label, single-arm, phase 2, basket trialLancet Oncol; Advance online publication 24 November 2021. https://doi.org/10.1016/S1470-2045(21)00578-7

Peters KB. Targeting BRAF-mutant glioma: reflections on the ROAR trialLancet Oncol; Advance online publication 24 November 2021. https://doi.org/10.1016/S1470-2045(21)00662-8

medwireNews (www.medwireNews.com) is an independent medical news service provided by Springer Healthcare. © 2021 Springer Healthcare part of the Springer Nature group

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