Dabrafenib plus Trametinib in Pediatric Glioma with
            <i>BRAF</i>
            V600 Mutations

Bouffet, Eric; Hansford, Jordan R.; Garrè, Maria Luisa; Hara, Junichi; Plant-Fox, Ashley; Aerts, Isabelle; Locatelli, Franco; van der Lugt, Jasper; Papusha, Ludmila; Sahm, Felix; Tabori, Uri; Cohen, Kenneth J.; Packer, Roger J.; Witt, Olaf; Sandalic, Larissa; Bento Pereira da Silva, Ana; Russo, Mark; Hargrave, Darren R.

doi:10.1056/nejmoa2303815

Cited by 93 publications

(29 citation statements)

References 32 publications

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“…Median PFS was significantly longer with D + T (20.1 vs. 7.4 months), with higher 12-month Kaplan−Meier PFS rates (67% vs. 26%). 14 In terms of safety, no deaths related to LGG occurred in the D + T group, while one death was reported in the C + T group. Patients receiving D + T had lower rates of discontinuation due to adverse events (4% vs. 18%) compared to those in the C + V group.…”

Section: Discussionmentioning

confidence: 86%

“…The most common (>2%) Grade 3 or 4 laboratory abnormalities were decreased neutrophil count (20%), increased alanine aminotransferase (3.1%), and aspartate aminotransferase increased (3.1%). 14 Notably, an ongoing Phase III trial is investigating the efficacy of selumetinib, a MEK inhibitor, comparing its performance to the…”

Section: Discussionmentioning

confidence: 99%

“…The independently assessed ORR was higher with D + T (47% vs. 11%), as was the CBR (86% vs. 46%). Median PFS was significantly longer with D + T (20.1 vs. 7.4 months), with higher 12‐month Kaplan−Meier PFS rates (67% vs. 26%) 14 …”

mentioning

confidence: 95%

“…The most common adverse events observed with D + T were pyrexia (68%), rash (54%), headache (40%), vomiting (34%), musculoskeletal pain (36%), fatigue (31%), dry skin (31%), diarrhea (30%), nausea (26%), epistaxis and other bleeding events (25%), abdominal pain (24%), and dermatitis acneiform (23%). The most common (>2%) Grade 3 or 4 laboratory abnormalities were decreased neutrophil count (20%), increased alanine aminotransferase (3.1%), and aspartate aminotransferase increased (3.1%) 14 …”

mentioning

confidence: 99%

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Dabrafenib plus Trametinib: A breakthrough in pediatric low‐grade glioma therapy

Dar,

Shahid,

Waqas

et al. 2024

Health Science Reports

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Background and AimsPediatric‐type low‐grade gliomas (pLGGs) are the most common solid tumors in children, with v‐raf murine sarcoma viral oncogene homolog B (BRAF) mutations playing a significant role in their development. Dabrafenib and trametinib are targeted therapies that are recently approved by Food and Drug Administration for pediatric patients with pLGG harboring a BRAF V600E mutation.BodyThis study emphasizes the role of Dabrafenib and Trametinib in pLGG. A multicenter Phase I/II trial demonstrated the superior efficacy of dabrafenib plus trametinib (D+T) compared to carboplatin plus vincristine (C+T), with higher overall response rates, clinical benefit rates, and longer progression‐free survival. The safety profile of dabrafenib plus trametinib (D+T) was favorable, with fewer discontinuations and adverse events compared to the control group.ConclusionThe introduction of D+T as a targeted therapy represents a significant advancement in the management of pLGG, necessitating further investigations to understand its long‐term consequences and optimize patient care.

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 95%

mentioning

confidence: 99%

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Dabrafenib plus Trametinib: A breakthrough in pediatric low‐grade glioma therapy

Dar,

Shahid,

Waqas

et al. 2024

Health Science Reports

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“…BRAF inhibitors (BRAFi), including vemurafenib and dabrafenib, have shown significant clinical benefits in human patients with BRAF V600E mutant cancer and have been approved by the FDA. 40,41 with BRAF mutant UC. 42 Treatment led to partial remission in 9 out of 24 dogs, with a median progression-free interval of 181 days.…”

Section: Discussionmentioning

confidence: 99%

Effective detection of BRAF^V595E mutation in canine urothelial and prostate carcinomas using immunohistochemistry

Aeschlimann,

Kehl,

Guscetti

et al. 2024

Vet Comparative Oncology

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Canine urothelial carcinoma (UC) and prostate carcinoma (PC) frequently exhibit the BRAFV595E mutation, akin to the BRAFV600E mutation common in various human cancers. Since the initial discovery of the BRAF mutation in canine cancers in 2015, PCR has been the standard method for its detection in both liquid and tissue biopsies. Considering the similarity between the canine BRAFV595E and human BRAFV600E mutations, we hypothesized that immunohistochemistry (IHC) using a BRAFV600E‐specific antibody could effectively identify the canine mutant BRAFV595E protein. We tested 122 canine UC (bladder n = 108, urethra n = 14), 21 PC, and benign tissue using IHC and performed digital droplet PCR (ddPCR) on all 122 UC and on 14 IHC positive PC cases. The results from ddPCR and IHC were concordant in 99% (135/136) of the tumours. Using IHC, BRAFV595E was detected in 72/122 (59%) UC and 14/21 (65%) PC. Staining of all benign bladder and prostate tissues was negative. If present, mutant BRAF staining was homogenous, with rare intratumour heterogeneity in three (4%) cases of UC. Additionally, the BRAFV595E mutation was more prevalent in tumours with urothelial morphology, and less common in glandular PC or UC with divergent differentiation. This study establishes that BRAFV600‐specific IHC is a reliable and accurate method for detecting the mutant BRAFV595E protein in canine UC and PC. Moreover, the use of IHC, especially with tissue microarrays, provides a cost‐efficient test for large‐scale screening of canine cancers for the presence of BRAF mutations. This advancement paves the way for further research to define the prognostic and predictive role of this tumour marker in dogs and use IHC to stratify dogs for the treatment with BRAF inhibitors.

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BRAF/MEK inhibitors use to treat ventriculoperitoneal shunt‐associated ascites in pediatric low‐grade gliomas

Amayiri,

Obeidat,

Laban

et al. 2024

Pediatric Blood & Cancer

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Dabrafenib plus Trametinib in Pediatric Glioma with BRAF V600 Mutations

Cited by 93 publications

References 32 publications

Dabrafenib plus Trametinib: A breakthrough in pediatric low‐grade glioma therapy

Dabrafenib plus Trametinib: A breakthrough in pediatric low‐grade glioma therapy

Effective detection of BRAF^V595E mutation in canine urothelial and prostate carcinomas using immunohistochemistry

BRAF/MEK inhibitors use to treat ventriculoperitoneal shunt‐associated ascites in pediatric low‐grade gliomas

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Dabrafenib plus Trametinib in Pediatric Glioma with BRAF V600 Mutations

Cited by 93 publications

References 32 publications

Dabrafenib plus Trametinib: A breakthrough in pediatric low‐grade glioma therapy

Dabrafenib plus Trametinib: A breakthrough in pediatric low‐grade glioma therapy

Effective detection of BRAFV595E mutation in canine urothelial and prostate carcinomas using immunohistochemistry

BRAF/MEK inhibitors use to treat ventriculoperitoneal shunt‐associated ascites in pediatric low‐grade gliomas

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Effective detection of BRAF^V595E mutation in canine urothelial and prostate carcinomas using immunohistochemistry