In the brain cancer known as a diffuse glioma, the disease infiltrates the central nervous system causing cognitive and physical disability. But the limited treatment options available bring about cognitive problems too. An experimental drug from Servier Pharmaceuticals has Phase 3 results showing it can keep this cancer from progressing, suggesting it has the potential to offer patients another treatment choice.
Right now, the first option is watching and waiting—monitoring the cancer to see if it worsens, said Ingo Mellinghoff, chair of the department of neurology at Memorial Sloan Kettering Cancer Center, speaking during a briefing with journalists Saturday at the annual meeting of the American Society of Clinical Oncology (ASCO). If the tumor grows, radiation and chemotherapies are possible next steps. But those treatments won’t cure the cancer and they introduce many toxic effects.
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“That is not a great choice you have to make, and many patients of course prefer to push that decision out because a therapy doesn’t cure you,” said Mellinghoff, who presented the results from the study Sunday at the ASCO meeting in Chicago.
Servier’s drug, vorasidenib, reduced the risk of tumor progression or death by 61%. Those results, alongside the drug’s manageable safety profile, mean that the once-daily pill may delay the need for more therapies, such as radiation and chemo. Mellinghoff said the France-based company’s drug has the potential to change the landscape in this type of brain cancer. Results from the study were published Sunday in the New England Journal of Medicine.
Diffuse gliomas make up about 80% of malignant primary brain cancer in adults who have brain cancers, Mellinghoff said. Vorasidenib is designed to address tumors with mutations to isocitrate dehydrogenases (IDH), enzymes that are important in cellular metabolism. Mutated versions of these enzymes produce metabolites that accumulate and contribute to the formation and progression of gliomas, according to published research. The Servier drug specifically targets mutated IDH1 and IDH2, binding to those enzymes and stopping them. While drugs are already available that address each of those mutations separately, vorasidenib is able to target both of them, Mellinghoff said. Another key feature is the small molecule’s ability to penetrate the blood-brain barrier.
The Phase 3 test of vorasidenib enrolled 331 patients randomly assigned to receive the study drug or a placebo. The main goal was to measure progression-free survival—how long patients lived without their disease worsening. On this measure, the median was 27.7 months for vorasidenib compared with 11.1 months for those given a placebo. One of the secondary goals was to measure the amount of time until the patient needed another treatment option. The median time on that measure has not yet been reached in the vorasidenib arm but it was 17.4 months in the placebo group. Patients in the placebo arm were permitted to cross over to vorasidenib upon confirmation of disease progression.
Mellinghoff said the Servier drug was well tolerated by study participants. Adverse effects included fatigue, headache, and nausea. The most common serious adverse effect was higher levels of liver enzymes, which can be a sign of drug toxicity. This complication was observed in 9.6% of patients who received the study drug. Mellinghoff said the toxicities were manageable.
Glenn Lesser, professor of hematology and oncology and an ASCO expert, said low-grade gliomas are diagnosed in about 4,000 patients every year in the U.S. These cancers typically affect people when they’re in their 40s. Only those who have IDH mutations will benefit from the Servier therapy. But Lesser added that the vorasidenib study results are important because radiation treatment for these brain cancers leads to long-term problems such as memory loss and cognitive decline. That’s significant for patients in their 40s, who are in the prime of their lives.
“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 said.
Vorasidenib came from the research of Agios Pharmaceuticals. Two years ago, the Cambridge, Massachusetts-based biotech sold its cancer drug portfolio to Servier for $1.8 billion as part of a strategy shift to focus on rare diseases. If vorasidenib wins FDA approval, the deal calls for Servier to pay Agios a $200 million milestone payment and a 15% royalty on U.S. sales of the drug. But Agios may choose to sell that royalty as a way of financing its rare disease drug research. Last fall, Agios sold its royalty rights to the approved cancer drug Tibsovo for $132 million.
Servier said it is still working on the timeline for submitting an application seeking FDA approval. But research continues to further explore vorasidenib’s potential. A Phase 1 study is testing the drug in combination with Merck immunotherapy Keytruda as a treatment for grade 2/3 glioma.
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