Updated findings from the phase 3 INDIGO trial, presented at the 2024 Society for Neuro-Oncology (SNO) Annual Meeting, reinforce the efficacy and manageable safety profile of vorasidenib (Voranigo) in patients with IDH1/2-mutated diffuse glioma. The study's extended follow-up confirms the drug's ability to improve progression-free survival (PFS), reduce tumor volume, and enhance seizure control compared to placebo.
With a median follow-up of 20.1 months (data cutoff March 7, 2023), the median PFS in the vorasidenib arm (n = 168) was not estimable (NE; 95% CI, 22.1-NE) versus 11.4 months (95% CI, 11.1-13.9) in the placebo arm (n = 163). This translated to a 65% reduction in the risk of disease progression or death (HR, 0.35; 95% CI, 0.25-0.49; P = .00000000013). These results confirm the statistically significant PFS improvement seen at the second interim analysis (IA2).
The study also demonstrated a significant improvement in time to next intervention (TTNI) with vorasidenib compared to placebo. The median TTNI with vorasidenib was NE (95% CI, NE-NE) versus 20.1 months (95% CI, 17.5-27.1) with placebo (HR, 0.25; 95% CI, 0.16-0.40; P = .000000000048).
Impact on Seizure Control and Tumor Volume
Patients treated with vorasidenib (n = 167) experienced a lower seizure rate compared to those who received placebo (n = 163), with total on-treatment seizure events of 1541 versus 5124, respectively. The rates of on-treatment seizures per person-year were 18.2% (95% CI, 8.4%-39.5%) and 51.2% (95% CI, 22.9%-114.8%), respectively (ratio of rates, 0.36; 95% CI, 0.14-0.89; 2-sided P = .0263).
Vorasidenib also led to a reduction in tumor volume (-1.3% [95% CI, -3.2% to 0.7%]), while tumor volume increased with placebo (14.4% [95% CI, 12.0%-16.8%]), resulting in a 15.9% difference between the slopes (95% CI, 12.6%-19.3%; P < .001).
Expert Commentary
"In summary, with 6 months of additional follow-up, vorasidenib showed robust efficacy, with greater magnitude of PFS and a reduction in tumor volume [than placebo],” said Ingo K. Mellinghoff, MD, FACP, of Memorial Sloan Kettering Cancer Center (MSKCC). “No additional safety signals [were observed]. Vorasidenib [was also] associated with better seizure control [than placebo].”
Mellinghoff further explained that vorasidenib, an oral inhibitor of mutant IDH1 and IDH2, reduces tumor concentrations of 2-HG by over 90% in resected grade 2 or 3 non-enhancing diffuse glioma. This reduction is linked to lower tumor cell proliferation, reversal of IDH1/2 mutation-associated gene expression programs, and increased DNA 5-hydroxy-methylcytosine as well as tumor-infiltrating lymphocytes.
Trial Design and Patient Population
The INDIGO trial enrolled patients with IDH1/2-mutated grade 2 oligodendroglioma or astrocytoma who had undergone at least one prior surgery for glioma. Eligible patients had measurable non-enhancing disease, defined as at least one target lesion measuring at least 1 cm by 1 cm, confirmed by blinded independent review committee (BIRC). Patients requiring immediate chemotherapy or radiotherapy were excluded.
Participants (n = 331) were randomized 1:1 to receive 40 mg of oral vorasidenib or placebo once daily in 28-day cycles. Centrally confirmed disease progression allowed for unblinding and crossover.
Consistent PFS Benefit Across Subgroups
The PFS benefit with vorasidenib compared to placebo was consistent across all subgroups analyzed. Tumor volume increased before vorasidenib treatment and decreased afterward, with a significant percentage difference of slope change of 8.7% (95% CI, 3.1%-14.6%; P = .002).
Safety Profile
The safety profile of vorasidenib remained consistent with longer follow-up. Any-grade treatment-emergent adverse effects (TEAEs) occurred in 98.8% of patients in the vorasidenib arm versus 95.1% in the placebo arm, with grade 3 or higher effects in 26.9% and 16.0%, respectively. The most common grade 3 or higher TEAEs included increased alanine aminotransferase (10.2% vs 1.2%), increased aspartate aminotransferase (4.8% vs 0%), seizure (4.2% vs 3.1%), and increased gamma-glutamyltransferase (3.0% vs 1.2%). No TEAEs were fatal.
Regulatory Status
Vorasidenib is approved in the United States, Canada, Australia, the Middle East, and Switzerland for grade 2 IDH1/2-mutated astrocytoma and oligodendroglioma. Registrations are ongoing in Europe and other countries.
