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| Ref Type | Abstract | ||||||||||||
| PMID | |||||||||||||
| Authors | Ingo K. Mellinghoff, Martin J. Van Den Bent, Deborah T. Blumenthal, Mehdi Touat, Katherine B. Peters, Jennifer Leigh Clarke, Joe Sammy Mendez, Liam Welsh, Warren P. Mason, Andreas Felix Hottinger, Juan Manuel Sepulveda Sanchez, Wolfgang Wick, Riccardo Soffietti, Steven Schoenfeld, Dan Zhao, Shuchi Sumant Pandya, Lori Steelman, Islam Hassan, Patrick Y. Wen, Timothy Francis Cloughesy | ||||||||||||
| Title | 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. | ||||||||||||
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| URL | https://ascopubs.org/doi/10.1200/JCO.2023.41.17_suppl.LBA1 | ||||||||||||
| Abstract Text | 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 (2nd 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 | ||||||||||||
| Molecular Profile | Treatment Approach |
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| Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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| Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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| Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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| Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| IDH1 mutant | oligodendroglioma | predicted - sensitive | Vorasidenib | Phase III | Actionable | In a Phase III trial, Vorasidenib (AG-881) treatment improved progression-free survival (27.7 months vs 11.1 months, HR=0.39, p=0.000000067) and time to next intervention (not reached vs 17.8 months, HR=0.26, p=000000019) in patients with oligodendroglioma or astrocytoma harboring IDH1/2 mutations compared to placebo (J Clin Oncol 41, 2023 (suppl 17; abstr LBA1); NCT04164901). | detail... |
| IDH1 mutant | malignant astrocytoma | predicted - sensitive | Vorasidenib | Phase III | Actionable | In a Phase III trial (INDIGO), Vorasidenib (AG-881) treatment improved progression-free survival (27.7 months vs 11.1 months; HR=0.39, p=0.000000067) and time to next intervention (not reached vs 17.8 months; HR=0.26, p=0.000000019) compared to placebo in patients with astrocytoma or oligodendroglioma harboring IDH1/2 mutations (J Clin Oncol 41, 2023 (suppl 17; abstr LBA1); NCT04164901). | detail... |
| IDH2 mutant | malignant astrocytoma | predicted - sensitive | Vorasidenib | Phase III | Actionable | In a Phase III trial (INDIGO), Vorasidenib (AG-881) treatment improved progression-free survival (27.7 months vs 11.1 months; HR=0.39, p=0.000000067) and time to next intervention (not reached vs 17.8 months; HR=0.26, p=0.000000019) compared to placebo in patients with astrocytoma or oligodendroglioma harboring IDH1/2 mutations (J Clin Oncol 41, 2023 (suppl 17; abstr LBA1); NCT04164901). | detail... |
| IDH2 mutant | oligodendroglioma | predicted - sensitive | Vorasidenib | Phase III | Actionable | In a Phase III trial (INDIGO), Vorasidenib (AG-881) treatment improved progression-free survival (27.7 months vs 11.1 months; HR=0.39, p=0.000000067) and time to next intervention (not reached vs 17.8 months, HR=0.26; p=0.000000019) compared to placebo in patients with oligodendroglioma or astrocytoma harboring IDH1/2 mutations (J Clin Oncol 41, 2023 (suppl 17; abstr LBA1); NCT04164901). | detail... |