Improving Outcomes for IDH1/2-Mutant Glioma in the INDIGO Study With Timothy Cloughesy, MD

Oncology Data Advisor: Welcome to Oncology Data Advisor. Today, we're here at the ASCO Annual Meeting, and I'm joined by Dr. Timothy Cloughesy. Thank you so much for coming on today.

Timothy Cloughesy, MD: You're welcome. It's great to be here.

Oncology Data Advisor: Would you like to introduce yourself and share what your research focus is on?

Dr. Cloughesy: I'm a Neuro-Oncologist and I work at UCLA. I'm the Director of the Neuro-Oncology Program, and really my research focuses on primary brain tumors, predominantly gliomas.

Oncology Data Advisor: Great. So, you're the senior author of the INDIGO study, which is being presented here, about vorasidenib for residual grade 2 glioma with an IDH1/2 mutation. Would you like to give some background about the trial?

Dr. Cloughesy: First, it was really not that long ago that we even knew that IDH mutations existed. In 2008, there was a study that was done that looked at a bunch of gliomas, and they did a genome-wide evaluation, and they found that there were these IDH mutations that were present. Digging in a little deeper, one thing that they found is that the location of the mutation was always on the same codon. There could be different substitutions of amino acids, different for IDH1 versus IDH2, the codon, but still consistent throughout.

It was then later found that this mutation causes a change in the way that we metabolize glucose through the Krebs cycle. So, there are two alleles; one allele is wild type, the other one is mutated. The first allele takes isocitrate and metabolizes it to alpha ketoglutarate. And the second one, now the mutated form, takes alpha-ketoglutarate and metabolizes it into 2-hydroxyglutarate (2-HG), and 2-hydroxyglutarate ends up just accumulating in the cell because we don't have a way to metabolize it. By doing that, it causes changes in the genes—the epigenetic features of the genes—and that leads to a decrease in differentiation, and a precursor to tumors forming.

It turns out then that, when we go and we look, we see that these tumors that are IDH-mutated are predominantly low-grade tumors, or lower-grade tumors, not the most aggressive type of glioblastoma. As a matter of fact, as we go through this entire process, we find out that the IDH mutation is disease-defining. It really helped us understand what the different tumor subtypes were, and these tumor subtypes had different prognosis. So, it was all the things that you'd want to look for identifying unique tumor types.

With that, all of the treatments to date for these types of tumors, it was shown that if you give radiation and you add chemotherapy, patients live longer compared to just giving radiation alone. Some of these were even lower-grade, like grade 2, and in that setting, there was an opportunity that was found, that you could just watch the tumor for a period of time before radiating. The reason that people wanted to consider doing that was because radiation and chemotherapy could damage the normal brain over time, causing cognitive changes, and those cognitive changes could manifest themselves in a way that patients wouldn't be able to function, may not be independent, and may not be able to be employed. The population that gets this disease ends up being in their 30s and 40s, so it's really people in the prime of their lives. That's the baseline for this tumor and the mutations that we found.

Oncology Data Advisor: Great, thank you. That was a really great overview of it. So, what has the efficacy of vorasidenib been in this population so far?

Dr. Cloughesy: So, then, the idea was, "Okay, if these mutations seem to be so important, why don't we then try to target them?" And that's where the inhibitors were developed, and vorasidenib is one of them. One of the important things, there are IDH1 and IDH2 mutations that occur, so vorasidenib was made to inhibit mutant IDH1 and mutant IDH2. As I was going through that Krebs cycle discussion, the idea is to block the formation of 2-HG and that would then hopefully cause some changes—either it would take longer for the cell to divide, maybe the cells would die, and there would be some ability to see some effect. In phase 1 studies, when we looked across the board, there was grade 1, 2, 3, and 4 oligodendroglioma and astrocytoma. Iit was a little hard to see if there was a signal coming out, but eventually, it was clear that there was tumor shrinkage occurring in the populations that had non-enhancing tumor.

First time I'm talking about non-enhancing tumor, but this is a tumor that's usually slower-growing, whereas enhancing tumor means that there are new blood vessels—the tumor's growing fast. We didn't quite see anything there, but we saw it in this earlier stage. So, it made sense to think about, how are we now going to define a potential opportunity to seek clinical benefit? And that's where using it as early as possible in the disease made sense. I told you about this watchful waiting timeframe, and watchful waiting is where we just monitor the patients, and when the tumor gets to a certain size, we start radiation. If we could use it during this time, prevent the tumors from growing, maybe even shrink them, maybe prevent and prolong the time before one would need radiation, or even decrease the opportunity for malignant transformation that can occur from the chemotherapies because of DNA-damage and mutations that have formed, there would be a potential benefit.

But it would be really important to make sure that there weren't toxicities associated with it if you're going to have patients on this therapy, who are young, for this long period of time. It turned out that these IDH inhibitors that were developed, vorasidenib in particular, have very few side effects. People really are going about their lives in a normal way without interruptions of any major source. So, that set it all up for, "Okay, this makes sense to study this population, where no one's had any other treatment than surgery, there's some residual tumor there, and we could just try to prolong the time till they need some other intervention." We also are able to actually measure to see if the tumor got to a certain size that we arbitrarily call progression, when it reaches that threshold.

So, it was a study with the primary end point would be progression-free survival. It's a randomized study, so two arms. One gets the drug, the other one gets a placebo; nobody knows, it's double-blind, there are no biases anywhere. And they just evaluated two things. How long did it take until the tumor reached a 25% increase in the bidirectional area? And the second thing was, how long did it take for the patients to start another therapy? That's how it was developed, and those were the end points that were chosen.

Oncology Data Advisor: That's a really exciting new avenue of treatment.

Dr. Cloughesy: Yes, and it's like a new indication for a therapy, nothing that has ever been used before.

Oncology Data Advisor: What are some of the results that are being presented here at ASCO this week?

Dr. Cloughesy: First, it's a great opportunity to understand toxicity and side effects, and nicely, you have a control group to understand what are real effects from the therapy and what is just present in the disease. And there are very limited effects. One of them is that some of the liver enzymes could increase, but very few people had to come off-study or lower their dose in this setting, so that part was great; it confirmed that.

The second thing that was great—these studies are set up to have different interim looks, so they start the study, and maybe they would look initially and say, "Is it futile? Should we even continue this study?" That would be the first look. And then the second look would be, "Are we seeing some obvious benefit that's happening? Should we just continue, or should we stop the study because there's enough here?" When the Data and Safety Monitoring Board evaluated in the second interim, the first time that they were looking for efficacy, they said, "This is a big effect, we're stopping. We're even saying that the people who are on placebo should be put on study drug."

There was a clear prolongation of progression-free survival when comparing the two groups. The data at this point show that the progression-free survival for the placebo group was 11 months, and 27 months for the treatment group, so that's a good prolongation. I think at this point though, only 28% of the patients were actually off study drug and progressed in the treatment arm.

There's still 78% of the patients where data is still going to come out, and those data might change somewhat, because there's a lot censoring that occurs in these data, so that looks very promising. I think we're going to learn a lot more about populations that get a long benefit from this therapy, holding off on next treatment interventions.

I said that there was a second end point that was time to the next treatment intervention, and that was even a greater difference. There was a very small percentage of patients in the treatment arm that went on to a second intervention, whereas in the placebo arm, they were able to cross over so they could get the study drug when they were able to.

So, all of that points to a very positive outcome. It validates that this is a good tumor target to go after. The drug being created specifically for brain cancer was great, and we don't get a lot of opportunities for positive results in brain cancer. Blood-brain barrier, is this the right target—all these things that come up. This was really a great clinical development path that was very clear in the end that it was going to have a high likelihood of benefit.

For us, I think, in our field, it's just been really great to see something come out positive for our patients.

Oncology Data Advisor: Anything else about either the INDIGO trial or about other glioma research here that you'd like to mention?

Dr. Cloughesy: I think we need to follow this paradigm that was created in the way that this study was, and not the study, but the way that the clinical development path went—the opportunity to make drugs that are specific for the disease, which doesn't happen a lot in brain tumors, and then the ability to study it and show the benefits. There were even some of these unique approaches—we call them perioperative or window of opportunity—where you could give drug for a period of time, take the tumor out, and then look to see if you've affected the biology of the tumor. Did 2-HG drop down? Did all these things occur that we would like to see?

And that just gives you, again, more confidence that it's doing what we think it's doing, we're seeing some imaging changes, and this has a high likelihood of success. We just need to rinse and repeat for other types of brain tumors and hope that that can happen.

Oncology Data Advisor: Absolutely. Well, this is really exciting to hear about, so thank you so much for stopping by to talk about it.

Dr. Cloughesy: You're welcome. It's my pleasure.

About Dr. Cloughesy

Timothy Cloughesy is the Director of the Neuro-Oncology Program at UCLA, as well as the Co-Director of UCLA's Brain Tumor Center. His research encompasses brain tumors, with a special focus on gliomas and discovering novel therapy options in the field. Dr. Cloughesy avidly participates in phase 1, 2, and 3 studies, often taking on a leadership or senior role.

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Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of Oncology Data Advisor.