Dabrafenib Plus Trametinib for Relapsed/Refractory BRAF V600–Mutant Pediatric High-Grade Glioma

The authors present the results of a phase II trial that evaluated dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor) as combination therapy in pediatric patients with relapsed/refractory high-grade glioma who harbor the BRAF V600E mutation. More than 90% of patients had received prior radiotherapy, and 80% had received prior antineoplastic therapy. The authors report an overall response rate (the primary objective) of 56.0% (95% CI, 40–72), with an encouraging median duration of response of 22.2 months (95% CI, 7.6 months to not reached [NR]) and a median survival of 32.8 months (95% CI, 19.2 months to NR). Their results suggest that BRAF-targeted treatment may prolong survival, and the treatment compares favorably in both efficacy and tolerability with conventional cytotoxic chemotherapy. The single-arm design and lack of molecularly characterized controls limit the data applicability to some degree.

The study demonstrates the importance and impact of systematic molecular characterization of primary brain tumors, which will allow the identification of approximately 3% to 5% of tumors that could be successfully treated by molecularly targeted agents. Yet, the presence of a BRAF V600E mutation does not necessarily mean that this is the driving mutation in all tumor subtypes. Almost half of the tumors do not respond to this treatment. In future studies, cohort stratification is warranted. As an example, diffuse midline gliomas are not BRAF- or MAPK-driven tumors despite the presence of the V600E mutation. Data from patients with truly MAPK-driven tumors (such as pediatric low-grade gliomas) will add additional insight and may inform other indications.

The protocol also included a second cohort of patients with newly diagnosed, previously untreated, low-grade pediatric glioma (grade 1, ~80%; grade 2, ~20%) harboring a BRAF V600E mutation. Patients were randomized 2:1 to the same dabrafenib/trametinib regimen versus standard carboplatin/vincristine chemotherapy. BRAF-targeted therapy led to a response rate of 47% compared with only 11% with chemotherapy. Median progression-free survival was prolonged with the targeted treatment, 20.1 months versus 7.4 months (HR, 0.31; 95% CI, 0.17–0.55; P < .001), demonstrating that this strategy is ready as a first-line treatment. These trial results were published in The New England Journal of Medicine on September 21, 2023.¹

These results demonstrate the unequivocal efficacy of targeted therapy in both molecularly selected patients with recurrent and newly diagnosed pediatric glioma. Implementation in daily practice and integration into an overall therapeutic strategy aiming at long-term and sustained tumor control are warranted. We need to further identify the patients likely to respond (and also the ones for whom other strategies should be pursued). It appears that, in this industry-sponsored trial, no central tissue collection and pathological review of tumor tissue was performed, a missed opportunity.

Reference

1. Bouffet E, Hansford JR, Garrè ML, et al. Dabrafenib plus Trametinib in Pediatric Glioma with BRAF V600 Mutations. N Engl J Med. 2023;389(12):1108-1120. https://www.nejm.org/doi/

Pediatric high-grade gliomas (pHGG) account for 11% of all childhood brain tumors, and patient survival remains poor despite treatment with surgery, radiation, and chemotherapy.¹ There is currently no standard of care at the time of relapse. However, molecular profiling has revealed that 5% to 10% of pHGG have BRAF-V600 mutations and may be therapeutically targeted with RAF (RAFi) and MEK inhibitors (MEKi).² In a recent study, Hargrave and colleagues evaluated the efficacy and safety of a combination of RAFi and MEKi, dabrafenib and trametinib, respectively, in a phase II trial involving 41 pediatric patients with relapsed/refractory pHGG. Hargrave et al report an impressive overall response rate of 56% among children and adolescents as well as prolonged progression-free survival and overall survival compared with previous reports on relapsed/refractory pHGG. The reported outcomes in children and adolescents are notably superior to those noted in a similar phase II trial involving adults.³

Targeted therapy with a combination of RAFi and MEKi can benefit patients with pHGG when molecular profiling is routinely performed. The promising findings of this study, in addition to case reports of the upfront use of RAFi and MEKi, highlight the importance of an ongoing clinical trial evaluating the combination of dabrafenib and trametinib in newly diagnosed children, adolescents, and young adults with pHGG (NCT03919071).² Two areas of active investigation are the brain distribution of RAFi and MEKi and therapeutic resistance to these agents. Dabrafenib and trametinib both have limited brain distribution in models with an intact blood–brain barrier, which may have implications in the treatment of pHGG.^4,5 Patients can have various mechanisms underlying resistance to treatment with RAFi/MEKi that make them unresponsive or only temporarily sensitive to therapy.⁶ Clinical development of RAFi and MEKi has dramatically changed the management of BRAF V600–driven tumors, and next-generation inhibitors may overcome current limitations, leading to more effective treatments.

References

1. Udaka YT, Packer RJ. Pediatric Brain Tumors. Neurol Clin. 2018;36(3):533-556. https://www.sciencedirect.com/science/article/abs/pii/S0733861918312064
2. Arbour G, Ellezam B, Weil AG, et al. Upfront BRAF/MEK Inhibitors for Treatment of High-Grade Glioma: A Case Report and Review of the Literature. Neurooncol Adv. 2022;4(1):vdac174. https://academic.oup.com/noa/article/4/1/vdac174/6834111
3. 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 Trial. Lancet Oncol. 2022;23(1):53-64. https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(21)00578-7/fulltext
4. Mittapalli RK, Vaidhyanathan S, Dudek AZ, et al. Mechanisms Limiting Distribution of the Threonine-Protein Kinase B-RaF(V600E) Inhibitor Dabrafenib to the Brain: Implications for the Treatment of Melanoma Brain Metastases. J Pharmacol Exp Ther. 2013;344(3):655-664. https://jpet.aspetjournals.org/content/344/3/655.short
5. Vaidhyanathan S, Mittapalli RK, Sarkaria JN, et al. Factors Influencing the CNS Distribution of a Novel MEK-1/2 Inhibitor: Implications for Combination Therapy for Melanoma Brain Metastases. Drug Metab Dispos. 2014;42(8):1292-1300. https://dmd.aspetjournals.org/content/42/8/1292.long
6. Schreck KC, Morin A, Zhao G, et al. Deconvoluting Mechanisms of Acquired Resistance to RAF Inhibitors in BRAFV600E-Mutant Human Glioma. Clin Cancer Res. 2021;27(22):6197-6208. https://aacrjournals.org/clincancerres/article/27/22/6197/671737/Deconvoluting-Mechanisms-of-Acquired-Resistance-to