Two targeted therapies, dabrafenib (Taflinar®; Novartis Pharmaceuticals) plus trametinib (Mekinst®; Novartis Pharmaceuticals), significantly increased the overall response rate compared to the standard-of-care chemotherapy combination of carboplatin (Paraplatin®; Bristol-Myers Squibb) plus vincristine (Oncovin®; Hospira/Pfizer) in pediatric patients with BRAF V600 mutation-positive low-grade gliomas. [1]

The secondary findings of the trial showed an improved clinical benefit rate and prolonged progression-free survival for dabrafenib plus trametinib compared to carboplatin plus vincristine, according to new research that will be presented at the annual meeting of the American Society of Clinical Oncology (ASCO), held June 3-7, 2022 in Chicago, Il.

Key Findings
The primary trial endpoint was met with an ORR (CR+PR) 47% (95% CI, 35%-59%) for dabrafenib plus trametinib compared to 11% (95% CI, 3%-25%) for carboplatin plus vincristine (P<.001; odds ratio, 7.2 [95% CI, 2.3-22.4]). For secondary endpoints, the clinical benefit rate (CR+PR+SD ≥24 wk) was 86% (95% CI, 76%-93%) for dabrafenib plus trametinib vs 46% (95% CI, 30%-63%) for carboplatin plus vincristine. The median PFS was 20.1 mo (95% CI, 12.8 mo-not estimable) with dabrafenib plus trametinib vs 7.4 mo (95% CI, 3.6-11.8 mo) with carboplatin plus vincristine (P<.001; HR, 0.31 [95% CI, 0.17-0.55]); 12-mo Kaplan-Meier PFS rates were 67% vs 26%. These findings were assessed independently by a central medical imaging vendor.

Adverse events
There were no deaths in the dabrafenib plus trametinib arm and 1 in the carboplatin plus vincristine arm due to LGG . Furthermore, the dabrafenib plus trametinib arm had fewer high-grade adverse events (47% vs. 94%) and fewer discontinuations of treatment due to adverse events (4% vs. 18%) than patients in the carboplatin plus vincristine group. The most frequent adverse events in the dabrafenib plus trametinib vs. carboplatin plus vincristine groups were fever (68% vs. 18%), headache (47% vs. 27%) and vomiting (34% vs. 48%).

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“For pediatric patients with BRAF V600-mutant low-grade glioma, dabrafenib plus trametinib may offer an improved standard of care. This represents an important advance for the youngest patients with brain cancer, as this is the first combination of targeted therapies developed for patients as young as one year of age,” said lead author Eric Bouffet, MD, FRCPC, Director of the Pediatric Neuro-Oncology Program at The Hospital for Sick Children in Toronto, Canada.

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In the treatment arm, patients received the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib. Dabrafenib targets the V600-mutant form of BRAF, which is found at varying prevalence in many types of cancer, while trametinib targets the kinase MEK within the same signaling pathway. When combined, both medicines can inhibit the effect of the BRAF V600 mutation and thereby inhibit the growth of cancer cells with this mutation. Patients assigned to the comparison arm received the chemotherapy drugs carboplatin and vincristine, two standard-of-care agents that have been used for decades.

Central nervous system tumors are the most common solid tumors in children. An estimated 4,170 new cases of childhood brain tumors are expected to be diagnosed in the United States in 2022, with gliomas accounting for up to 50% of those cases.[2]

Depending on their location, pediatric low-grade gliomas may not be able to be completely removed surgically, and patients with residual, progressive, or recurrent disease frequently require systemic therapy. With current approaches to treatment, 5-year survival rates are approximately 95%. However, there is a continued risk of tumor progression and most patients require multiple lines of treatment.

The BRAF V600 mutation has been detected in about 15-20% of low-grade gliomas cases and may be associated with an increased risk of progression to high-grade glioma. At the time this study was initiated, it was also noted, but not confirmed, that patients with BRAF V600-mutant disease may have worse outcomes than patients with non-mutated disease treated with the current standard of care.

About the Study
Dabrafenib was shown to be clinically meaningful as a standalone therapy in a phase I/II trial in patients with previously treated BRAF V600–mutant low-grade glioma. Data from the first pediatric study of dabrafenib plus trametinib demonstrated tolerability and preliminary clinical activity of the combination in those patients.

The study was a double-blind clinical trial conducted at 57 investigative centers in 20 countries. The trial randomly assigned 110 patients from the age of 1 to 17 who had BRAF V600 mutation-positive low-grade gliomas to either dabrafenib twice daily plus trametinib once daily or to standard-of-care doses of carboplatin plus vincristine. The primary endpoint was the ORR. Secondary endpoints included the clinical benefit rate, duration of response, time to response, PFS, OS, and safety.

Next Steps
This study is ongoing and is still collecting long-term safety data. Safety data will also be collected in a companion study. Researchers hope to learn more about the optimal duration of treatment.

The researchers hope to determine if this treatment fits into the World Health Organization (WHO) global initiative for childhood cancer. Pediatric low-grade glioma is one of six diseases that comprise the WHO initiative and targeted therapies may have a potential impact as part of this initiative.

Clinical trials
Study to Investigate Safety, Pharmacokinetic (PK), Pharmacodynamic (PD) and Clinical Activity of Trametinib in Subjects With Cancer or Plexiform Neurofibromas and Trametinib in Combination With Dabrafenib in Subjects With Cancers Harboring V600 Mutations – NCT02124772
Phase II Pediatric Study With Dabrafenib in Combination With Trametinib in Patients With HGG and LGG – NCT02684058

Highlights f prescribing information
Dabrafenib (Taflinar®; Novartis Pharmaceuticals)(Prescription Information)
Trametinib (Mekinst®; Novartis Pharmaceuticals)(Prescription Information)
Carboplatin (Paraplatin®; Bristol-Myers Squibb)(Prescription Information)
Vincristine. (Oncovin®; Hospira/Pfizer)(Prescription Information)

Reference
[1] Bouffet E, Hansford J, Garré ML, Hara J, Plant-Fox A, Aerts I, Locatelli F, et al. Primary analysis of a phase II trial of dabrafenib plus trametinib (dab + tram) in BRAF V600–mutant pediatric low-grade glioma (pLGG). J Clin Oncol 40, 2022 (suppl 17; abstr LBA2002) | DOI 10.1200/JCO.2022.40.17_suppl.LBA2002
[2] Cancer Stat Facts: Childhood Brain and Other Nervous System Cancer (Ages 0–19). Online. Last accessed on June 6, 2022.

Featured image: ASCO 2019. Novartis.  Photo courtesy: © 2019 – 2022. Sunvalley Communication/Evan Wendt. Used with permission.

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