CHICAGO – Servier's vorasidenib has emerged as an option to delay toxic chemotherapy and radiotherapy in patients with IDH1/2-mutant residual or recurrent grade 2 glioma, based on results from a Phase III trial presented at the American Society of Clinical Oncology's annual meeting on Sunday.
Servier said it will discuss the data from the Phase III INDIGO trial with the US Food and Drug Administration to determine a timeline for a new drug application submission for vorasidenib in this patient population. Mutations in IDH1 or IDH2 occur in 80 percent and 4 percent of grade 2 gliomas, respectively.
The INDIGO trial, results of which were published in the New England Journal of Medicine on Sunday, compared vorasidenib to placebo in a randomized, double-blind study that included 331 patients.
The trial was exploring the addition of a novel treatment at a point in the disease after surgery where patients are usually in a watch-and-wait stage, Ingo Mellinghoff, chair of the department of neurology at Memorial Sloan Kettering Cancer Center, said in a presentation of the INDIGO results at ASCO on Sunday. Glioma is typically a slow-growing disease, he added, that has few treatment options.
"The standard of care for this disease right now is two options: One is to watch and wait, or you commit to radiation for the brain and chemotherapy, which does not cure you and has significant toxicity," Mellinghoff said. "Many patients with grade 2 tumors, who are usually in their 40s, opt to defer this treatment and instead are being monitored with serial MRI scans of the head. This watch-and-wait period represents an opportunity for the evaluation of targeted agents that might delay the need for toxic therapy."
Rimas Lukas, associate professor of neuro-oncology at Northwestern University who was not involved with the INDIGO study, noted that the most robust data supporting the use of chemo and radiation is for more aggressive gliomas, such as grade 4 tumors.
"As we go down in the grade, we have less and less support for what the optimum management is," Lukas said in a discussion of the INDIGO results. "Once we get to a low-risk grade 2 tumor, we drop off rapidly from using radiation [and] chemo to just following clinically and radiographically."
Mellinghoff and his team hoped that vorasidenib could help grade 2 glioma patients further delay the use of chemo or radiation. In the trial, vorasidenib more than doubled their progression-free survival to a median of 27.7 months versus 11.1 months for patients receiving placebo.
That correlates to a 61 percent reduction of the risk of tumor progression, Mellinghoff said, "a significant sign of efficacy that has the potential to change the landscape in this disease."
The researchers also evaluated the time to next intervention in the INDIGO trial, a secondary endpoint of the study. With a median follow-up of 14 months at the data cutoff, the median time to next treatment was not reached for the vorasidenib arm and was 17.8 months for the placebo arm.
"The probability of not receiving another cancer therapy by 24 months was 83 percent in the vorasidenib group and 27 percent in the placebo group," Mellinghoff said. However, these results may have been skewed by the trial allowing for crossover, he added: 52 of 58 patients in the placebo group who received further treatment opted to cross over to the vorasidenib arm.
Vorasidenib is Servier's third IDH enzyme inhibitor in development, all of which the firm acquired from Agios Pharmaceuticals in 2020 in a deal worth $1.8 billion. Servier also owns Idhifa (enasidenib), approved in the US as a treatment for relapsed or refractory IDH2-mutant acute myeloid leukemia (AML), and Tibsovo (ivosidenib), which is approved for newly diagnosed and relapsed IDH1-mutant AML.
While Servier's portfolio of IDH inhibitors is the furthest in development, other firms are studying these drugs in earlier stages for glioma, too. They include Forma Therapeutics' olutasidenib, which is being studied in IDH1-mutated relapsed or refractory gliomas, and Daiichi Sankyo's DS-1001b in IDH1-mutant low grade glioma.
"Vorasidenib improved progression-free survival in IDH-mutated grade 2 gliomas [and] is very well tolerated, and [it] increased time to next intervention in this patient population," Lukas concluded. "From my perspective, it is establishing a new standard of care for these patients."
Going forward, Mellinghoff suggested, vorasidenib could have activity in high-grade gliomas, which are more aggressive cancers, or could be used as part of combination treatments, such as an ongoing study of vorasidenib combined with Merck's Keytruda (pembrolizumab) in IDH1-mutant astrocytomas.
"This is the beginning of much more work to be done," he said. "We've proven [efficacy] for this patient population, but it's very conceivable that the mutant IDH enzyme contributes to the growth of this type of tumor in other settings. We're very excited to take this forward, and in combination therapies, to expand the patient population."