JS05.6.A EXPLORATORY ANALYSES FROM PHASE 3 INDIGO STUDY SUGGEST POTENTIAL MECHANISM OF SEIZURE CONTROL THROUGH TUMOR VOLUME REDUCTION UNDER TREATMENT WITH VORASIDENIB
Bibliographic record
Abstract
Abstract BACKGROUND Grade 2 isocitrate dehydrogenase 1 or 2 mutant (mIDH1/2) gliomas are slowly progressive, malignant, incurable brain tumors with poor long-term prognosis. Patients may experience tumor-related symptoms (eg seizures) that impact their daily lives. Vorasidenib, an oral, brain-penetrant, dual inhibitor of mIDH1/2, has shown significant clinical benefits, including gradual tumor shrinkage, and a manageable safety profile in the Phase 3 INDIGO study (NCT04164901). Herein, we investigate the potential relationship between vorasidenib and seizure rate and between tumor volume and seizure activity in patients with mIDH1/2 glioma. MATERIAL AND METHODS Patients aged ≥12 years with grade 2 mIDH1/2 oligodendroglioma or astrocytoma, with no prior treatment for glioma other than surgery and no uncontrolled seizures, were randomized 1: 1 to receive vorasidenib 40 mg or placebo daily. Exploratory analyses for the number of on-treatment seizures were conducted in patients with ≥1 seizure in the baseline or on-treatment periods using a negative binomial regression model. The potential association between seizure activity and tumor volume was assessed using the mixed-effect model with repeated measurements. Due to the exploratory nature of these analyses, P-values were not prespecified and should be interpreted with caution. RESULTS This analysis included 168 patients treated with vorasidenib (oligodendroglioma n=88; astrocytoma n=80) and 163 patients treated with placebo (oligodendroglioma n=84; astrocytoma n=79). Patients treated with vorasidenib had lower on-treatment rates of seizures than those treated with placebo (model-estimated rate of on-treatment seizures per person-year: 18.2, 95% confidence interval [CI] 8.4, 39.5 vs 51.2, 95% CI 22.9, 114.8; ratio of rates: 0.36, 95% CI 0.14, 0.89, P=0.0263). There was a highly positive correlation between tumor volume and seizure number (log tumor size estimate of coefficient: 0.7, standard error: 0.26, P=0.007). CONCLUSION Treatment with vorasidenib was associated with lower seizure activity than with placebo in patients with mIDH1/2 glioma. Smaller tumor volume was associated with a lower seizure rate. Since treatment with vorasidenib also leads to gradual tumor shrinkage, these results suggest a potential mechanism of seizure control by tumor size reduction with vorasidenib. Study sponsored by Servier.
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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 | 0.006 | 0.005 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.004 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.008 | 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".