What are the characteristics of relapsed IDH mutant high-grade gliomas?
Tumors of the central nervous system (CNS) are rare: around 2,000 new cases per year in France; gliomas, which develop from glial cells, make up the majority. Within these gliomas, two large groups can be distinguished depending on the mutational status of the IDH protein, involved in cellular metabolism.
“IDH mutant” gliomas, the subject of our study, are often diagnosed in patients aged 25 to 50 years. These tumors have a better prognosis and respond better to initial treatments, generally surgery followed by radiochemotherapy. However, these patients suffer from serious symptoms and significant after-effects: epileptic seizures, motor disability, visual loss, language or cognition disorders, which are often irreversible due to the location of the tumor and edema. which surrounds it. Treatments allow, at best, to stabilize these signs.
Remission after treatment can last several years, but patients always end up relapsing. Upon relapse, there is no standard treatment: when surgery or new irradiation are no longer possible, therapeutic options are limited. We therefore resort to clinical trials. In this context, we designed and carried out REVOLUMAB, a trial intended for patients with grade 3 or 4 “IDH mutant” glioma, relapsed after treatment with radio- and/or chemotherapy.
What were the objectives of the REVOLUMAB study and how was it carried out?
The REVOLUMAB study, a phase 2 trial funded by PHRC-K in 2016, aimed to evaluate the effectiveness of nivolumaban immunotherapy with checkpoint inhibitors, hoping that the hypermutation of the treated gliomas [c’est-à-dire les nombreuses modifications génétiques qui apparaissent dans les gliomes après les traitements, NDLR] can elicit an immune response. Indeed, when these tumors have already been subjected to chemotherapy, they mutate more, which causes the appearance of antigens and can allow the immune system to react.
This multicenter project involved seven centers from the POLA/RENOCLIP-LOC network (the first “rare cancers” network in neuro-oncology certified by the INCa in 2009) and included 42 patients, 39 of whom ultimately received the treatment. These patients, with a median age of 43 years, had previously received radiotherapy and at least two lines of chemotherapy. The protocol consisted of bimonthly infusions for four months, then monthly for patients responding to treatment, for a total treatment duration of 1 year. The progression-free survival criterion was estimated with clinical and MRI monitoring every two months.
What are the results of this study and what follow-up could be given to it?
Of the 39 patients treated, more than half of whom were already progressing at the time of their inclusion, our study did not achieve its main objective of progression-free survival at six months: only 28% of patients were stable or in response. However, 17 patients (44%) presented stabilization (13) or a partial response (4), with a median progression-free duration of eight months: this is not better, but no worse than the standard treatment. We have tried to find simple markers to distinguish these patients from others, without success so far. Another important point: good tolerance to treatment, without notable alteration in quality of life, which is crucial in this population of young patients who are often very disabled by their cancer.
Ultimately, even if the main criterion used for REVOLUMAB, namely progression-free survival, is negative, this treatment made it possible to maintain stabilization of the tumor for a few months in 44% of the patients included, which is not negligible. in view of the poor prognosis of relapsed IDH-mutated gliomas. Our results, published in particular in theEuropean Journal of Cancer in May 2024, confirm the complexity of the immune environment of gliomas. Future studies of combining checkpoint inhibitors with other targeted therapies, such as IDH mutation inhibitors, may represent a promising avenue to further stimulate the immune response.
“I would also like to salute the remarkable dynamics of the French structuring of the rare cancer networks labeled and financed by the INCa, which allowed us to quickly and easily identify the participating centers, to motivate the laboratory to give us the product and to include patients in less than a year, faster than expected, even though we did it in the middle of the COVID pandemic! The structuring of these networks by the National Cancer Institute is proving decisive in accelerating research and development of new therapeutic approaches. »
Dr Caroline DEHAIS
Zoom: understand the REVOLUMAB study
The REVOLUMAB study aimed to evaluate the effectiveness of nivolumab in patients with a brain tumor called “high-grade glioma with IDH protein mutation”, in relapse, knowing that there is no standard treatment after recurrence and that these cancers have a poor prognosis. This clinical trial was carried out on 42 patients in 7 centers of the POLA/RENOCLIP-LOC network.
Nivolumab is an immunotherapy, that is to say it is a monoclonal antibody acting on the immune system to destroy the production of cancer cells.
Although the study did not meet its primary goal of extending progression-free survival to 24 weeks (6 months), it showed that this treatment was well tolerated overall. Additionally, a group of participants (17 out of 39, or 44%) experienced a partial response or stabilization of their tumor, which is encouraging for the future.
This research paves the way for further studies to improve treatment options for recurrent IDH mutant gliomas, bringing hope to affected patients.
