CTNI-37. CLINICAL ACTIVITY OF RAF INHIBITOR TOVORAFENIB ACCORDING TO PRIOR MAPK INHIBITOR TREATMENT IN THE REGISTRATIONAL PEDIATRIC LOW-GRADE GLIOMA ARM OF THE PHASE 2 FIREFLY-1 (PNOC026) STUDY
Bibliographic record
Abstract
Abstract BACKGROUND Pediatric low-grade glioma (pLGG) is the most common childhood brain tumor. Genomic alterations of RAF are common oncogenic drivers in pLGG. Tovorafenib is an investigational, selective, CNS-penetrant, type II RAF inhibitor. METHODS FIREFLY-1 (NCT04775485) is a phase 2 study evaluating tovorafenib monotherapy. Registrational arm 1 enrolled patients aged 6 months–25 years of age with recurrent or progressive LGG harboring an activating BRAF alteration. Tovorafenib 420 mg/m2 (600 mg max) was administered weekly (tablet or liquid suspension). Independently assessed overall response rate (ORR), as defined by RANO-HGG and RANO-LGG criteria, are primary and exploratory endpoints. RESULTS As of December 22 2022, 69 (RANO-HGG) and 76 (RANO-LGG) of 77 patients in arm 1 were evaluable at baseline and had ≥9 months of follow-up. Median age at enrollment was 8 years (range 2–21), and 60% (n = 46) patients had received prior MAPK inhibitor (MAPKi) therapy. Among the evaluable patients, the ORR was 62% (RANO-HGG, n = 69) and 45% (RANO-LGG, n = 76), respectively. The ORR in patients previously treated with MAPKis (n = 41 [RANO-HGG]; n = 45 [RANO-LGG]) was 68% (4 CRs; 24 PRs) (RANO-HGG) and 44% (5 PRs; 15 MRs) (RANO-LGG). In MAPKi-naïve patients (28 [RANO-HGG]; 31 [RANO-LGG]), the ORR was 54% (15 PRs) (RANO-HGG) and 45% (7 PRs; 7 MRs) (RANO-LGG). Among 136 patients in arms 1 and 2 of FIREFLY-1, the most common treatment-related adverse events (TRAEs) of any grade were hair color changes (71%), fatigue (40%) and maculopapular rash (38%). Tovorafenib dose modifications occurred in 39 (29%) and discontinuations in 4 (3%) patients due to TRAEs. CONCLUSIONS Tovorafenib provided clinically meaningful tumor responses, including those with a best response reported of SD or PD using another MAPKi, in patients with BRAF-altered pLGG regardless of prior MAPKi therapy, and has a manageable safety profile.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 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, 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".