It’s been a long time between positive results for brain cancer.
Brain cancer patients could gain nearly 16 more months of progression-free survival thanks to a new treatment that targets easily identified biomarkers common in young adults.
The treatment may also delay the need for subsequent toxic intervention, according to results presented to great acclaim at the latest ASCO meeting in Chicago.
Professor Ingo Mellinghoff, first author and chair of neuro-oncology at Memorial Sloan Kettering Cancer Center in New York City, announced the INDIGO study findings showing that patients with IDH-mutant grade 2 gliomas who received vorasidenib, an oral brain-penetrant inhibitor of mutant IDH1 and IDH2 enzymes, were 61% less likely than those on placebo to face disease progression or death than those in the placebo group at follow-up of 14 months.
“This is the beginning of much more work to be done. We’ve proven it for this patient population, but it’s very conceivable that this mutant IDH enzyme contributes to the growth of this type of tumour in other settings … and in combination therapies, expanding the patient population,” Professor Mellinghoff told audiences.
Diffuse gliomas with IDH1 or IDH2 mutations are the most common type of brain tumours in adults under 50. Standard adjuvant chemoradiotherapy after surgery can prolong life for these patients, but it does not cure them, and it has neurocognitive and other toxic effects. Researchers have been looking for ways to put off using this treatment as long as possible to preserve quality of life.
“The impacts of the disease and, importantly, its treatments have substantial consequences for patients, families, caregivers and society as a whole,” Associate Professor Rimas Lukas, from Northwestern University in Chicago, told delegates.
Professor Lukas, who was invited by ASCO to speak on the impact of the INDIGO study on the treatment of patients with IDH-mutated gliomas, told audiences the results were “practice changing” for patients with these lower grade tumours, where there was less robust support for what constituted optimal management compared to higher grades.
The phase III multicentre randomised controlled trial initially involved 331 patients around the age of 40 with residual or recurrent grade 2 IDH-mutant glioma, who had had surgery around two-and-half years previously, and were assessed as not needing immediate further treatment. More than 80% of them had tumours measuring at least 2cm. They were randomly assigned to receive vorasidenib (40mg once daily) or a placebo for continuous 28-day cycles. The patients were enrolled from January 2020 to February 2022.
The vorasidenib group had a median progression free survival time of 27.7 months compared with 11.1 months in the control group. At 18 months, those who received vorasidenib had an 86% chance of not requiring further treatment, compared with 48% in the placebo group, and 83% vs 27% at 24 months.
Grade 3 adverse events or higher occurred in 23% of the treatment arm and 22% in the placebo. None were fatal.
The trial was unblinded in March 2023 because of demonstrated efficacy, at which point 52 of the 58 patients whose tumour had progressed opted to switch to vorasidenib.
Professor Lukas said that while overall survival was not yet known, vorasidenib also had benefits for quality of life. The treatment reduced seizure activity (which he said would be reported on in future analyses) and avoided the impact on cognition that radiation had.
He said the overall safety profile provided clinicians with “a lot of flexibility” in terms of using it outside the narrow population group included in the study of oligodendrogliomas and astrocytomas. And it had potential as a good second-line treatment as well, although in those cases, additional mutations could make it difficult for a single targeted therapy to have the same effect.
“This is a really exciting time for the neuro-oncology community. It’s been a really long time between positive studies,” Australian medical oncologist Professor Lucy Gately told Oncology Republic.
Professor Gately said she was happy to see a targeted therapy working for brain cancer patients, with biomarkers that were easily measured, because it had started to appear like these patients were going to miss out on benefits that people with other types of cancer, like melanoma and lung cancer, were seeing.
“For so many years, we haven’t seen good clinical translation of targeted therapies. We tried it with EGFR inhibitors and EGFRvIII therapies. They looked good in the lab, but when we took them to patients, we didn’t see that same success.”
Professor Gately has already had patients contact her about the treatment, just days after the findings were released. Unfortunately, it would be some time before the drug was available here, where it will have to go through the usual TGA approval process and health economics analysis at PBAC.
“If there is an access program, I suspect it will probably follow the same line as the inclusion criteria for the trial. And this is where things get a little difficult, because it’s hard to know which patients exactly are going to benefit,” Professor Gately said.
Would a patient be better off under active observation without treatment, or should they go down the route of daily treatment for over two years? Professor Gately said it would be tricky to gauge without as-yet-unreported quality of life data, and financial toxicity would also be a consideration.
“And can we extrapolate at some point to this higher risk population? It would be really nice to delay chemoradiotherapy for those patients we feel actually need treatment upfront,” said Professor Gately, noting more data was needed on the long-term toxicities and quality of life impacts.
“We might be delaying therapy, but does that improve survival as well? Or are we mainly seeing the improvements in quality of life, potentially? I guess we don’t know those answers yet.”