INDIGO: A global, randomized, double-blinded, phase 3 study of vorasidenib versus placebo in patients with residual or recurrent grade 2 glioma with an IDH1/2 mutation.
Bibliographic record
Abstract
LBA1 Background: Grade 2 gliomas are slowly progressive, malignant brain tumors with a poor long-term prognosis. Current treatments (surgery followed by observation or adjuvant radiation and chemotherapy) are not curative and can be associated with short- and long-term toxicities. Mutations in isocitrate dehydrogenase (IDH) 1 or 2 occur in approximately 80% and 4% of grade 2 gliomas, respectively, and are a disease defining characteristic in the World Health Organization (WHO) 2021 definition. Vorasidenib (VOR) – an oral, brain-penetrant, dual inhibitor of mutant (m)IDH1/2 enzymes has shown a tolerable safety profile and preliminary clinical activity in phase 1 studies. Methods: In this randomized, double-blind, placebo-controlled phase 3 study (NCT04164901) patients (pts) were randomized 1:1 to receive VOR 40 mg daily or placebo (PBO) daily in 28-day cycles. Patients were stratified by 1p19q status and baseline tumor size. Key eligibility criteria included: age ≥12; KPS >80; residual or recurrent grade 2 IDH1m or IDH2m oligodendroglioma or astrocytoma; measurable non-enhancing disease; no prior treatment for glioma with most recent surgery 1-5 years from randomization; and not in immediate need of chemotherapy/radiation. Primary endpoint: radiographic progression-free survival (PFS) by blinded independent radiology committee (BIRC). Key secondary endpoint: time to next intervention (TTNI). Results: As of 6Sep2022 (2 nd planned interim analysis data cutoff), 331 pts were randomized across 10 countries: 168 to VOR and 163 to PBO. Of the 331 pts: median age: 40.4 years (range, 16 to 71); KPS =100: 53.5%; histological subtype: oligodendroglioma: 172 and astrocytoma: 159; median time from last surgery until randomization: 2.4 years. Two hundred twenty-six (68.3%) pts remained on treatment (131VOR; 95PBO). PFS by BIRC was statistically significant in favor of the VOR arm (HR, 0.39; 95% CI, (0.27, 0.56); P=0.000000067). Median PFS: VOR: 27.7 mos; PBO: 11.1 mos. TTNI was statistically significant in favor of the VOR arm (HR, 0.26; 95% CI, (0.15, 0.43); P=0.000000019). Median TTNI: PBO: 17.8 mos; VOR: not reached. All reported P values are one-sided. All-grade adverse events (AEs) occurring in >20% pts receiving VOR vs PBO were alanine aminotransferase increased (38.9% vs 14.7%), COVID-19 (32.9% vs 28.8%), fatigue (32.3% vs 31.9%), aspartate aminotransferase increase (28.7% vs 8.0%), headache (26.9% vs 27.0%), diarrhea (24.6% vs 16.6%), nausea (21.6% vs 22.7%). Common grade ≥3 AEs (>5%): ALT increased (9.6% vs 0%). Conclusions: This is the first prospective, randomized phase 3 study of a targeted therapy in grade 2 mIDH glioma. VOR significantly improved PFS by BIRC compared with PBO with a manageable safety profile. These data demonstrate the clinical benefit of VOR in this pt population for whom chemotherapy and radiotherapy are being delayed. Clinical trial information: NCT04164901 .
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.006 | 0.006 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| 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) | 0.000 | 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 teacher head, 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".