"WHO Grade 2 gliomas are frequently diagnosed in patients in their 30s or 40s in the prime of their lives," noted Patrick Wen, MD, Director of the Center for Neuro-Oncology at Dana-Farber Cancer Institute. During ASCO 2023, he presented a plenary session that revealed results for the Phase III INDIGO trial (NCT04164901) prior to publication in the New England Journal of Medicine (2023; doi: 10.1056/NEJMoa2304194).
In an interview with Oncology Times, Wen discussed their findings from the INDIGO study, which evaluated the isocitrate dehydrogenase (IDH) 1 and 2 inhibitor vorasidenib in patients with Grade 2 glioma. "This is the first prospective, randomized, Phase III study of a targeted therapy in Grade 2 IDH-mutant glioma," he stated.
When asked about the clinical needs of glioma patients, Wen replied, "There is a significant unmet need for these patients regarding their treatment. Many patients are diagnosed in young adulthood, and treatment usually entails surgical removal of the tumor followed by radiation therapy and chemotherapy. Since these patients are fairly young, with a median age of about 40 years when treated with longer survival times, we have seen increased levels of cognitive decline over time as a result of their radiation therapy."
When queried about the relevance of using vorasidenib in this patient population, Wen noted, "Approximately 80 percent of patients with Grade 2 glioma have disease driven by mutant IDH1, while another 4 percent have mutated IDH2."
Vorasidenib is an orally bioavailable selective inhibitor of IDH1/2. "Importantly," Wen noted, "this compound is able to pass the blood-brain barrier. Many compounds are not able to enter the brain to be effective therapies, so this ability was crucial." Another relevant point is that there are currently no curative therapies for these patients.
INDIGO Study
This Phase III study compared oral vorasidenib with placebo in patients 12 years or older with IDH-mutant Grade 2 astrocytoma or oligodendroglioma (WHO 2016 guidelines). The only permitted therapy prior to participation was surgical removal of the tumor. Patients were randomized in a 1:1 ratio to either vorasidenib or placebo. Vorasidenib was dosed at 40 mg once daily in 28-day cycles. Patients receiving placebo were allowed to crossover and receive vorasidenib upon disease progression.
"The primary endpoint was imaging-based blinded independent review committee-assessed progression-free survival," Wen stated. "The key secondary endpoint was the time to next intervention."
Patients were enrolled from 77 cancer treatment centers across 10 countries between January 2020 and February 2022. A total of 163 patients were randomized to and received placebo; correspondingly, 168 were randomized to vorasidenib and 167 received the investigational compound. One patient withdrew their consent from study treatment and subsequently from the overall study.
"There was a significant advantage for vorasidenib over placebo for the primary endpoint of progression-free survival," Wen observed. For the vorasidenib patients, the median progression-free survival was 27.7 months (95% CI: 17.0 months-not estimable); while for those receiving placebo, this figure was 11.1 months (95% CI: 11.0-13.7). These data afforded a hazard ratio of 0.39 (95% CI: 0.27-0.56; p=0.000000067) favoring vorasidenib.
For the key secondary endpoint, time-to-next intervention, the median value for the placebo arm was 17.8 months (95% CI: 15.0 months-not estimable); in the vorasidenib arm, the median value had not yet been attained. These data gave a hazard ratio of 0.26 (95% CI: 0.15-0.43; p=0.000000019). At 18 months and 24 months, 85.6 percent and 83.4 percent of the patients in the vorasidenib arm had not required an additional anti-cancer intervention for their disease. In contrast, for those in the placebo arm, at 18 months and 24 months, 47.4 percent and 27.0 percent of patients did not require another treatment for their glioma.
"The safety profile was generally good with only minor issues with hepatotoxicity," Wen stated, regarding the safety results for vorasidenib. In the vorasidenib arm, 29.9 percent of patients had a treatment interruption due to a treatment-emergent adverse event, while 22.7 percent of the placebo patients had a similar interruption. Dose reductions arising from treatment-emergent adverse events were noted in 10.8 percent and 3.1 percent of the patients in the vorasidenib and placebo arms, respectively. A greater number of patients in the placebo arm discontinued study treatment (68) compared to the vorasidenib arm (36). Study unblinding occurred in March 2023.
As of September 6, 2022, patients in the vorasidenib arm had a median follow-up of 14.0 months, while those in the placebo arm the median value was 14.3 months. Importantly, there were no deaths in the study and no patients were lost to follow-up for the primary study outcome.
"The success in this study allows the use of vorasidenib as the first new treatment for patients with low-grade gliomas in more than 20 years," Wen stated. "Also, these results show the validity for using this targeted agent in this patient population. This provides another treatment option for these patients after surgical removal of their tumors."
Noting potential future directions of research for this IDH1/2 inhibitor, Wen commented, "In the future, as we have done with many other cancer therapies, we will evaluate vorasidenib in combinations with other therapeutic agents."
Richard Simoneaux is a contributing writer.