Neil Osterweil
June 04, 2023
UPDATED June 9, 2023 // Editor’s note: This story has been updated with additional comments from Dr Rimas Vincas Lukas of Northwestern University.
CHICAGO — Patients with a certain type of brain tumor could soon be treated with an oral targeted drug instead of undergoing more toxic chemotherapy and radiation, say researchers reporting new results that could potentially change the treatment landscape.
The investigational drug vorasidenib (Servier) is awaiting approval for use in gliomas bearing mutations in isocitrate dehydrogenase 1 and 2 (IDH1, IDH2).
Results from the pivotal phase 3 INDIGO trial show that the drug was associated with a significant delay in time to disease progression when compared with placebo.
The median progression-free survival (PFS) was 27.7 months for patients on vorasidenib, compared with 11.1 months for patients assigned to placebo (hazard ratio (HR) for progression or death with vorasidenib of 0.39 (P < .0001).
Vorasidenib was also associated with significantly longer time to the next treatment, and patients generally tolerated the drug well, reported first author Ingo K. Mellinghoff, MD, from Memorial Sloan Kettering Cancer Center, New York City.
The results show that “treatment with an oral precision medicine therapy can produce a reduction in the risk of tumor progression by 61%, so that is, we think, a significant sign of efficacy that has potential to change the landscape in this disease,” he commented.
Mellinghoff was speaking at a media briefing prior to presenting the data at a plenary session here at the American Society of Clinical Oncology annual meeting.
The study was published online today in The New England Journal of Medicine to coincide with the presentation.
“What you just heard is a trial that was well done and well thought out: to use an oral, targeted, well-tolerated therapy to see if we could delay the use of our standard chemotherapy and radiation,” commented ASCO expert Glenn Lesser, MD, from Wake Forest Baptist Health in Winston-Salem, North Carolina, the invited discussant at the briefing.
“The results are quite striking and they’re statistically highly significant, and more importantly, they’re clinically very, very significant,” he continued.
“The results of this study really suggest that in selected patients with IDH mutant low-grade gliomas we can potentially delay the use of these toxic chemotherapies and radiation, maybe for years if not many years, and as a result delay the long-term toxicities of those therapies in a group of patients who typically are experiencing long-term survival,” Lesser added.
At the plenary session, invited discussant Rimas Vincas Lukas, MD, of the Malnati Brain Tumor Institute at Northwestern University in Chicago, said the data were “practice changing.”
He illustrated the importance of the treatment using the clinical case of a 21-year-old female who presented with new-onset seizure and was found to have an IDH-mutated grade 2 oligodendroglioma.
Lukas said that in addition to the significant improvements in PFS and time to the next intervention for such patients, the use of vorasidenib can help to reduce the incidence of seizures associated with IDH-mutated tumors and can delay the use of brain irradiation.
“IDH-mutated tumors have a very high incidence of seizure activity, and if we look at preclinical models we can see that vorasidenib can help decrease that seizure activity, and if we’re thinking about our 21-year-old college student, this can have a significant impact on the quality of life,” he said.
In addition, considering the care of patients such as the 21-year-old, “radiation therapy has a number of negative long-term consequences, particularly with respect to cognitive impairment — speed of processing information,” he continued. “And what we end up seeing from a practical perspective is when these patients with low-grade tumors are treated with radiation therapy, as they live for a number of years we can see that there is diffuse atrophy and wear and tear on the white matter tract in the brain, and that’s something we desperately want to prevent in this patient.”
Brain-Penetrating Oral Drug
Vorasidenib is an oral inhibitor of the IDH1 and IDH2 enzymes, with the ability to cross the blood–brain barrier. Mutations in IDH1 are found in about 80% of grade 2 gliomas, and IDH2 mutations occur in about 4%.
Adjuvant chemoradiotherapy has become the standard of care for patients with IDH-mutant grade 3 gliomas and patients with IDH-mutant grade 2 tumors who are thought to be a high risk for early progression.
Many patients with IDH-mutant grade 2 gliomas are initially followed with serial MRI scans, with toxic therapies reserved for use after disease progression, Mellinghoff noted.
Voradisenib offers the potential for delaying the use of more toxic therapies and the potential to alter the natural history of diffuse glioma while helping patients to maintain a good quality of life, he said.
Study Details
The INDIGO trial involved 331 patients with grade 2 gliomas with IDH mutations, who were enrolled across 77 centers in 10 countries in North America, Europe, and the Middle East.
Patients were aged 12-80 years and had residual or recurrent grade 2 IDH1 or IDH2 mutated oligodendroglioma or astrocytoma, with measurable non-enhancing disease and no prior treatment for glioma (with the most recent surgery 1 to 5 years before randomization). They were eligible for the study if they were not in immediate need of chemotherapy and/or radiation.
After stratification by 1p/19q status and baseline tumor size, they were randomly assigned to receive either vorasidenib 40 mg daily or placebo in 28-day cycles.
At the second planned interim analysis data cutoff in September 2022, at a median follow-up of 14.2 months, 226 (68.3%) of the 331 patients remained on treatment.
The primary endpoint was median PFS by blinded independent central review, which as noted above was 16.6 months longer in those on the drug compared with placebo.
The time to next therapy was also significantly longer with vorasidenib, with a median not yet reached, compared to 17.4 months for placebo (hazard ratio, 0.26, P < .001).
Adverse events of any grade occurring in more than 20% of those receiving vorasidenib were elevated liver enzymes, fatigue, headache, diarrhea, and nausea. Grade 3 or 4 alanine aminotransferase elevations occurred in 9.6% of patients assigned to vorasidenib, but not in the placebo group.
Vorasidenib received fast-track status from the US Food and Drug Administration in March. It is currently being studied in a phase I trial in combination with pembrolizumab (Keytruda) in patients with grade 2/3 gliomas, and further exploration of the drug in combination with other agents is being considered.
The study was funded by Servier Pharmaceuticals, manufacturer of vorasidenib. Mellinghoff disclosed honoraria from Roche, a consulting or advisory role with Agios, Black Diamond Therapeutics, Debiopharm Group, Puma Biotechnology, Voyager Therapeutics, research funding from Amgen, General Electric, Lilly, and travel expenses from Agios, AstraZeneca, Puma Biotechnology, Roche, and Voyager Therapeutics. Lesser disclosed honoraria from SDP Oncology, consulting/advising for Cancer Expert Now, Agio, IN8bio, and Ono Pharmaceutical.
American Society of Clinical Oncology (ASCO) 2023: Abstract LBA1. Presented June 4. 2023
N Engl J Med. Published June 4, 2023.
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