Dabrafenib + trametinib (dab + tram) in relapsed/refractory (r/r) <i>BRAF</i> V600–mutant pediatric high-grade glioma (pHGG): Primary analysis of a phase II trial.
Bibliographic record
Abstract
2009 Background: HGGs comprise ≈10% of pediatric central nervous system tumors and are a leading cause of childhood cancer-related death. Overall response rates (ORRs) with current standards of care are low, particularly in the second line, and 2-y overall survival (OS) rates are ≤35%. BRAF V600 mutation is infrequent (≈5% of pHGGs) but associated with improved survival from time of initial diagnosis. In previous trials, dab monotherapy and dab + tram yielded encouraging outcomes in BRAF V600–mutant HGG in pediatric and adult patients (pts), respectively. We describe the results of a Phase II study (NCT02684058) of dab + tram in r/r BRAF V600–mutant pHGG. Methods: Pts aged 1 to <18 y with BRAF V600–mutant HGGs and Karnofsky/Lansky performance status ≥50% who had failed first-line therapy were enrolled in a single-arm cohort. Pts received 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). The primary endpoint was ORR (independent review; HGG-RANO criteria); secondary endpoints included ORR (investigator review), duration of response (DOR), progression-free survival (PFS), OS, and safety. Results: A total of 41 pts with diverse WHO Grade III/IV gliomas were enrolled; median time since diagnosis was 17.4 mo (range, 2.7-174.3 mo), and most had prior surgery (97.6%), radiotherapy (90.2%), and/or systemic antineoplastic therapy (80.5%). At data cutoff (August 23, 2021; median follow-up, 25.1 mo), 21 pts (51.2%) remained on treatment; most discontinuations (16 of 20) were due to progressive disease. Median exposure was 72.7 wk (range, 1.3-172.1 wk). The primary endpoint was met, with an independently assessed ORR of 56.1% (95% CI, 39.7%-71.5%). Median DOR was 22.2 mo (95% CI, 7.6 mo-not estimable [NE]; 12-mo Kaplan-Meier [KM] DOR rate, 62.2%), and median PFS was 9.0 mo (95% CI, 5.3-24.0 mo; 12-mo KM PFS rate, 44.1%). There were 14 deaths (34.1%), with 12 due to HGG and 2 due to serious adverse events (AEs; encephalomyelitis and intracranial pressure increased [n = 1 each], not treatment related per investigators); median OS was 32.8 mo (95% CI, 19.2 mo-NE; 12-mo KM OS rate, 76.3%). The most common all-cause AEs were pyrexia (51.2%), headache (34.1%), dry skin (31.7%), vomiting (29.3%), and diarrhea (24.4%). Two pts (4.9%) had AEs leading to discontinuation (both rash), and 26 (63.4%) had AEs leading to dose modification. Conclusions: Treatment with dab + tram demonstrated an improvement in ORR, response durability, and survival compared with estimates based on historical observations with current treatment approaches in r/r BRAF V600–mutant pHGG. Safety was consistent with the established profile of dab + tram in other indications. Thus, dab + tram may represent a critical treatment advance for this pt population with high unmet need. Clinical trial information: NCT02684058.
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How this classification was reachedexpand
Direct model labels (unvalidated)
Per-model category and study-design labels from the labeling rounds. They are machine output, unvalidated, and the disagreement between models ships as data. No study design here is MEDLINE-validated yet.
| Model arm | Categories | Study design | Confidence |
|---|---|---|---|
| gemma | no category Domain: not available · Genre: Empirical About the Canadian research system: no · About a Canadian topic: no | Randomized trial | low |
| gpt | no category Domain: not available · Genre: Empirical About the Canadian research system: no · About a Canadian topic: no | Non-randomized trial | medium |
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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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, unvalidatedLabeled directly by 2 models reading the full record.
The models disagree on parts of this classification; every voice is preserved in the section at the end of the page.
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".