Primary analysis of a phase II trial of dabrafenib plus trametinib (dab + tram) in <i>BRAF</i> V600–mutant pediatric low-grade glioma (pLGG).
Bibliographic record
Abstract
LBA2002 Background: LGG is the most common pediatric brain cancer, and BRAF V600 mutation has been detected in ≈17% of cases. Most patients (pts) with pLGG have disease progression and require post-surgical therapy. The standard of care is chemotherapy, such as carboplatin + vincristine (C+V), which may be less effective in BRAF V600–mutant disease; thus, alternative treatment options are needed. Dab + tram showed encouraging efficacy in a Phase I/II study (NCT02124772) in pts with previously treated BRAF V600–mutant pLGG. We describe the results of a randomized Phase II study (NCT02684058) of first-line dab + tram vs C+V in BRAF V600–mutant pLGG. Methods: Pts aged 1 to <18 y with BRAF V600 mutation–positive gliomas and Karnofsky/Lansky performance status ≥50% were enrolled. In the pLGG cohort, pts with progressive disease after surgery or nonsurgical pts requiring systemic treatment were randomized (2:1) to receive either dab twice daily (<12 y, 5.25 mg/kg/d; ≥12 y, 4.5 mg/kg/d) + tram once daily (<6 y, 0.032 mg/kg/d; ≥6 y, 0.025 mg/kg/d) or C+V (standard dosing). The primary endpoint was overall response rate (ORR; independent review, RANO criteria). Secondary endpoints included investigator-assessed ORR, clinical benefit rate (CBR), duration of response, time to response, progression-free survival (PFS), overall survival, and safety. Results: A total of 110 pts were randomized to receive dab + tram (n=73) or C+V (n=37); 4 pts in the C+V arm withdrew before treatment. Baseline characteristics were well balanced between treatment arms. At data cutoff (August 23, 2021; median follow-up, 18.9 mo), 61 pts (84%) in the dab + tram arm and 8 (22%) in the C+V arm remained on treatment; in the C+V arm, 9 completed planned treatment and 16 discontinued before completion. The primary endpoint was met: the independently assessed ORR (CR+PR) was 47% (95% CI, 35%-59%) with dab + tram vs 11% (95% CI, 3%-25%) with C+V ( P<.001; odds ratio, 7.2 [95% CI, 2.3-22.4]), and the clinical benefit rate (CR+PR+SD ≥24 wk) was 86% (95% CI, 76%-93%) vs 46% (95% CI, 30%-63%). Median PFS was 20.1 mo (95% CI, 12.8 mo-not estimable) with dab + tram vs 7.4 mo (95% CI, 3.6-11.8 mo) with C+V ( P<.001; HR, 0.31 [95% CI, 0.17-0.55]); 12-mo Kaplan-Meier PFS rates were 67% vs 26%. There were no deaths in the dab + tram arm and 1 in the C+V arm due to LGG. Pts in the dab + tram arm had fewer grade ≥3 adverse events (AEs; 47% vs 94%) and fewer discontinuations due to AEs (4% vs 18%) than pts in the C+V arm. The most frequent AEs in the dab + tram vs chemotherapy arms were pyrexia (68% vs 18%), headache (47% vs 27%), and vomiting (34% vs 48%). Conclusions: Dab + tram significantly increased ORR and CBR and prolonged PFS compared with C+V in pts with BRAF V600 mutation–positive pLGG. These encouraging results and the tolerable safety profile suggest that dab + tram may be a promising first-line systemic treatment option for this pt population. Clinical trial information: NCT02684058.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.002 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.008 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".