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Vorasidenib (Voranigo) was associated with lower volumetric tumor growth rates (TGR) compared with placebo in patients with grade 2 glioma harboring IDH1/2 mutations, according to data from exploratory analyses from the phase 3 INDIGO trial (NCT04164901) presented at the 2025 Society for Neuro-Oncology (SNO) Annual Meeting.

Across linear, biexponential, and velocity of diametric expansion (VDE) modeling approaches, patients receiving vorasidenib exhibited substantially lower on-treatment TGRs than those receiving placebo, with these differences translating into clinically meaningful improvements in progression-free survival (PFS) and time to next intervention (TTNI).

Using linear TGR, vorasidenib produced a mean on-treatment tumor growth of 0.4 mL per 6 months (95% CI, –0.2 to 1.0) compared with 2.7 mL per 6 months (95% CI, 1.9-3.4) for placebo (difference, –2.3; 95% CI, –3.3 to –1.4; P < .001). Multivariable Cox modeling showed that each 1-mL per 6-month increase in TGR increased the risk of progression by 4.6% and the risk of requiring next intervention by 5.1%. Within this study, vorasidenib significantly reduced the risks of PFS (HR, 0.376; 95% CI, 0.268-0.526) and TTNI (HR, 0.276; 95% CI, 0.177-0.431).

“On-treatment TGR is a strong predictor of PFS and TTNI,” lead study investigator Benjamin M. Ellingson, PhD, MS, and colleagues wrote in a poster presentation of the data. “In patients with IDH1/2[-mutant] glioma enrolled into the INDIGO trial, on-treatment TGR was substantially lower in those receiving vorasidenib than in those receiving placebo, as measured using 3 different approaches.”

Ellingson currently serves as director of MRI Research and a professor of radiology, psychiatry, bioengineering, and neurosurgery within the David Geffen School of Medicine at the University of California, Los Angeles.

What previous data were reported from INDIGO?

In August 2024, the FDA approved vorasidenib for the treatment of adult and pediatric patients 12 years of age and older with grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation, following surgery, including biopsy, sub-total resection, or gross total resection.² This decision was based on prior findings from INDIGO, which showed that patients in the vorasidenib arm achieved a median PFS of 27.7 months (95% CI, 17.0–not estimated) compared with 11.1 months (95% CI, 11.0-13.7) for those given placebo (HR, 0.39; 95% CI, 0.27-0.56; P < .001).

How was the INDIGO TGR analysis conducted?

This analysis utilized volumetric TGR modeling to evaluate whether early tumor growth dynamics could help predict clinical outcomes in patients with grade 2, IDH1/2-mutated diffuse glioma treated in the phase 3 INDIGO trial. The randomized, placebo-controlled study enrolled adults with grade 2 glioma harboring IDH1/2 mutations, and investigators compared vorasidenib, an oral brain-penetrant IDH1/2 inhibitor, with placebo. Tumor volume data from patients assigned to vorasidenib (n = 168) or placebo (n = 163) were analyzed.

Investigators assessed tumor growth using 3 distinct modeling approaches: a linear regression model measuring growth in mL per six months, a biexponential model incorporating a tumor growth parameter, and a velocity of diametric expansion model quantifying millimeters per year^.3 Individual TGRs were derived from volumetric measures obtained during the first 6 months of on-treatment imaging. These TGR metrics were then correlated with PFS and TTNI to determine their predictive relevance for treatment outcomes in this molecularly defined glioma population.

What Did the Biexponential TGR Analyses Reveal About Survival Outcomes?

Consistent findings were observed using biexponential modeling: mean tumor growth (g-value) was lower with vorasidenib (0.00097; 95% CI, 0.00079-0.00114) vs placebo (0.00125; 95% CI, 0.00110-0.00141; P = .0197), and slower-growing tumors were associated with superior PFS and TTNI.¹ VDE analysis similarly demonstrated a marked difference in tumor expansion velocity between treatment arms, with a mean on-treatment VDE of 0.2 mm/year (95% CI, –0.3 to 0.6) for vorasidenib vs 3.1 mm/year (95% CI, 2.6-3.6) for placebo (P < .001).

What Did the VDE Analyses Reveal About Progression Risk in INDIGO?

The VDE analysis further demonstrated that on-treatment tumor growth dynamics strongly correlate with clinical outcomes in the INDIGO trial. Using linear regression modeling to characterize individual tumor expansion rates, vorasidenib markedly reduced on-treatment VDE compared with placebo, with a mean VDE of 0.2 mm per year (95% CI, –0.3 to 0.6) in the vorasidenib arm vs 3.1 mm per year (95% CI, 2.6-3.6) in the placebo, reflecting a significant mean difference of –2.9 mm per year (P < .001).

When VDE values were stratified into clinically relevant categories, slower expansion rates consistently aligned with improved PFS and TTNI. Patients with the lowest VDE (≤ –0.50 mm/year) demonstrated the most favorable outcomes, whereas those with rapid tumor expansion (>3.13 mm/year) experienced markedly shorter PFS (median, 8.4 months) and TTNI (median, 12.0 months). Intermediate ranges (>1.27 to ≤3.13 mm/year) also conveyed reduced benefit, with a median TTNI of 28.8 months.

References

1. Ellingson BM, Wang L, Vangel MG, et al. Volumetric tumor growth rate modeling predicts clinical outcomes in patients with grade 2 IDH1/2–mutant glioma receiving vorasidenib or placebo in the phase 3 INDIGO trial. Presented at: 2025 SNO Annual Meeting; November 19-23, 2025; Honolulu, HI. Abstract IMG-99.
2. FDA approves vorasidenib for Grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation. FDA. August 6, 2024. Accessed November 24, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-vorasidenib-grade-2-astrocytoma-or-oligodendroglioma-susceptible-idh1-or-idh2-mutation
3. Study of vorasidenib (AG-881) in participants with residual or recurrent grade 2 glioma with an IDH1 or IDH2 mutation (INDIGO). Clinicaltrials.gov Updated April 3, 2025. Accessed November 24, 2025. https://clinicaltrials.gov/study/NCT04164901