, by Edward Winstead
Treatment with the targeted cancer drug vorasidenib slowed the growth of tumors in some people with brain cancers called low-grade gliomas.
Credit: iStock
The first targeted drug developed specifically for people with brain cancer has shown promise as a treatment for tumors called low-grade gliomas.
In a large clinical trial, treatment with the investigational drug vorasidenib slowed the growth of tumors in some people with low-grade gliomas that had mutations in the IDH1 or IDH2 genes.
Gliomas are the most common malignant primary brain tumors in adults. When the tumors are diagnosed, they are graded from 1 to 4, with the higher numbers indicating a worse prognosis.
Many people with low-grade gliomas are in their 30s and 40s and are otherwise healthy. Their tumors tend to grow slowly at first and may be treated with surgery. But the cancers eventually develop into high-grade tumors and may require radiation and/or chemotherapy.
The new research suggests that vorasidenib can delay the progression of some low-grade gliomas with IDH1 or IDH2 mutations and postpone the need for additional therapies.
In the international clinical trial, called INDIGO, patients with grade 2 gliomas and IDH1 or IDH2 mutations who received vorasidenib lived much longer without the disease worsening than participants who received a placebo, researchers reported at the American Society of Clinical Oncology (ASCO) annual meeting in Chicago on June 4.
The median time until the disease worsened or death from any cause—a measure called progression-free survival—was estimated to be 27.7 months for people in the vorasidenib group versus 11.1 months for those in the placebo group, the researchers found.
“This targeted drug potentially puts a new tool in our toolbox for patients with this disease,” said study co-leader Ingo Mellinghoff, M.D., of Memorial Sloan Kettering Cancer Center, who presented the findings at the ASCO meeting. The results were concurrently published in the New England Journal of Medicine.
Servier, the maker of vorasidenib, sponsored the phase 3 INDIGO trial.
Vorasidenib, a tablet that patients take by mouth, blocks the activity of abnormal IDH1 and IDH2 proteins in cancer cells, largely sparing healthy cells. Unlike other drugs that target mutant IDH proteins, this one can cross the blood-brain barrier.
The study’s ability to recruit more than 300 patients from 10 countries during the peak of the coronavirus pandemic is a measure of the unmet need for new treatments for these patients, noted Dr. Mellinghoff.
“We call these tumors ‘low-grade’ gliomas, but they cause significant disabilities and death,” he said. “Our current therapies cannot cure the disease.”
Trying to delay the inevitable progression of tumors
After surgery for brain cancer, some people with grade 2 gliomas decide to delay additional treatment until the cancer progresses—an approach known as watchful waiting or active surveillance.
“All patients with these tumors eventually get to the point where they need radiation and chemotherapy,” said study co-leader Timothy Cloughesy, M.D., who directs the UCLA Neuro-Oncology Program. “But watchful waiting is a way to put off doing radiation for a while.”
That delay can be important for patients’ quality of life, Dr. Cloughesy explained. The cognitive changes that can result from radiation and chemotherapy, such as difficulty concentrating, learning, and remembering new things, can be debilitating.
“Patients with these tumors are young and could live for many years with the disease,” he said. “At this stage of their lives, they are active and working hard at their jobs and may be starting families.”
With the INDIGO trial, the researchers wanted to see if vorasidenib could postpone the inevitable progression of these gliomas in patients aged 12 or older who had undergone brain tumor surgery. The median age of the 331 study participants was about 40.
After being randomly assigned to receive vorasidenib or a placebo, they underwent regular imaging tests to check for signs that the cancer had worsened.
Participants in the placebo group were allowed to switch to vorasidenib if imaging tests showed that the cancer had worsened during the trial.
In addition to improving progression-free survival, vorasidenib lengthened the amount of time until a patient’s next cancer treatment. For participants who received the placebo, the median time to the next cancer treatment was 17.4 months, whereas longer follow-up is needed to determine the median time to the next treatment for those who received vorasidenib.
“This treatment is generally very well tolerated by patients,” said Dr. Mellinghoff. The most common side effects include fatigue, headache, and diarrhea. Some patients develop increased levels of liver enzymes that are an indication of liver damage, but the changes were reversible, according to the researchers.
A possible new standard treatment for low-grade gliomas
The researchers also determined that the chances of not needing another cancer therapy after 2 years were much higher in the vorasidenib group than in the placebo group (83% versus 27%).
The trial was stopped early after a planned analysis of the results showed that the trial had met its goal of demonstrating a benefit for the vorasidenib group. All participants in the placebo group were offered access to vorasidenib.
If the Food and Drug Administration (FDA) approves vorasidenib, it would become a new treatment option for this disease, Dr. Mellinghoff predicted. Experts at the ASCO meeting agreed.
The findings establish “a new standard of care for these patients,” said Rimas Lukas, M.D., who specializes in treating brain cancer at the Robert H. Lurie Comprehensive Cancer Center at the Northwestern University Feinberg School of Medicine, at the ASCO meeting.
Mark Gilbert, M.D., chief of the Neuro-Oncology Branch in NCI’s Center for Cancer Research, also expects the new findings to change cancer care. The INDIGO trial could be “transformative for the management of patients with low-grade glioma and the field of neuro-oncology,” said Dr. Gilbert, who was not involved in the study.
The positive results from a brain cancer study are likely to spur new studies. Researchers can now explore a range of questions about the treatment, Dr. Lukas noted. These include learning which patients might benefit most from the drug and determining whether gliomas might develop resistance to the therapy.
Vorasidenib also could be tested against higher-grade gliomas with IDH1 or IDH2 mutations and in combination with other therapies. Vorasidenib is currently being studied in combination with pembrolizumab (Keytruda) for the treatment of some gliomas.
The FDA granted a fast-track designation for vorasidenib in March. Servier is working to establish a timeline for submission of an application for approval to the agency, the company said in a news release.
“Watching history being made!”
Good news travels fast, especially when it’s about treating brain cancer. Almost as soon as the vorasidenib results were presented in Chicago, people living with low-grade gliomas began to discuss the results online and with their doctors.
“The INDIGO trial has been a hot topic in our community and has caused a great deal of hope and excitement,” said Nestelynn Gay, who founded a Facebook group for people with low-grade gliomas that has grown to about 4,000 members. She was diagnosed with the disease a decade ago, at age 37.
“Having a new study that focuses on low-grade glioma is huge for our community, because little to no pharmaceutical research has been done specifically for us,” Ms. Gay said. She is working to change that by participating in a research advisory group for an NCI-supported study of low-grade gliomas called OPTIMUM.
Ashley Sumrall, M.D., who treats patients with gliomas at the Levine Cancer Institute in North Carolina, attended the presentation of the INDIGO trial results in Chicago. As Dr. Mellinghoff wrapped up his presentation, she tweeted, “Watching history be[ing] made!”
“Over the last 30 years, there have been very few positive trials for patients with brain tumors,” Dr. Sumrall said after the meeting. “But we are finally seeing some encouraging news for patients with brain tumors.”
A recent study found that some gliomas may respond to a combination of targeted drugs. “Now, with vorasidenib, we have a targeted therapy that is tolerated well and could potentially be used by thousands of patients,” she said.
On her first day back in her office after the ASCO meeting, Dr. Sumrall fielded phone calls and emails from patients and colleagues who had read news reports about vorasidenib and wanted to learn more.
“It’s exciting to have a new drug to discuss with my patients,” said Dr. Sumrall. “Many were thrilled by the news even if they were not eligible for this treatment. Patients with brain tumors cheer for each other.”
Potential model for future brain tumor studies
Researchers first identified mutations in IDH1 and IDH2 in gliomas in 2008. Fifteen years later, these mutations are known to occur in about 80% of low-grade gliomas. The mutant IDH1 and IDH2 proteins in gliomas produce a molecule, called 2-HG, that can affect cells in various ways, including altering the behavior of genes.
The research team that developed vorasidenib took steps to increase the likelihood that the phase 3 study would yield positive results. The investigators started by confirming in the laboratory that IDH1 and IDH2 were promising drug targets.
They then designed a drug that would likely cross the blood-brain barrier and inactivate mutant IDH proteins. And before launching a large randomized trial, they conducted a study to confirm that the drug does in fact penetrate the brain and has the ability to affect mutant IDH1 and IDH2.
“We hope this approach might help other people think about how to develop drugs for glioblastoma and other brain tumors,” said Dr. Cloughesy. “These findings are just the beginning. We need to take the research forward, because this drug is not a cure for the disease.”
People living with low-grade gliomas will be following the progress. “This work is so important to us,” said Ms. Gay. “The promise of another tool in the toolbox offers hope.”
