Dabrafenib + trametinib combination therapy in pediatric patients with BRAF V600-mutant low-grade glioma: Safety and efficacy results.
Bibliographic record
Abstract
10506 Background: Low-grade gliomas (LGGs) are the most common brain tumors among children. Pediatric LGGs are often not surgically resectable and tend to demonstrate relapsed/remitting courses with current standard chemotherapy regimens. Moreover, radiation is often avoided due to its associated neurocognitive and endocrinologic sequelae. However, in pediatric patients (pts) with BRAF V600-mutant LGG, dabrafenib monotherapy has demonstrated meaningful clinical activity and acceptable tolerability (Hargrave et al, Clin Cancer Res. 2019; NCT01677741). Here we report the efficacy and safety of dabrafenib + trametinib (D+T) combination therapy in pediatric pts with previously treated BRAF V600-mutant LGG. Methods: This is a 4-part, open-label, multicenter, phase I/II study (NCT02124772). The limited dose-escalation (ESC) portion evaluated the D+T combination in pediatric pts ( < 18 y) with recurrent/refractory BRAF V600-mutated solid tumors that were naive to MAPK pathway–targeted therapy. This was followed by a tumor cohort expansion (EXP), and the D+T combination was evaluated in BRAF V600-mutant LGG pts at recommended dose levels. Efficacy was determined by both investigator and independent review using the RANO criteria (for gliomas). Adverse events (AEs) were assessed per NCI-CTCAE v4.03. Results: Overall, 36 pediatric pts with LGG received D+T combination therapy (ESC, n = 16; EXP, n = 20); pooled efficacy data were available for both ESC and EXP, while LGG-specific safety data were available for EXP. At interim analysis (Aug 2019), 17 of the 20 pts in EXP remained on protocol therapy. Three pts withdrew/discontinued treatment because of AEs. Skin toxicity (95%) and pyrexia (75%) were the frequent AEs reported. No on-treatment deaths were reported. Across both ESC and EXP, the objective response rate (ORR) was 25% (95% CI, 12%–42%) per independent review (1 complete response [CR], 8 partial response [PR], 24 stable disease [SD], 2 progressive disease [PD], 1 unknown [UNK]) and 50% (95% CI, 33%–67%) per investigator review (2 CR, 16 PR, 17 SD, 1 UNK). However, ORR + SD was similar, with 92% and 97% of pts having SD or better per independent and investigator review, respectively. Conclusions: In pediatric pts with pretreated BRAF V600-mutant LGG, D+T combination therapy demonstrated clinical activity, with 92% of pts having SD or better by independent review using the RANO criteria. Pyrexia and skin toxicity were the common AEs; majority of these were low-grade and manageable. Clinical trial information: NCT02124772.
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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
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".