Dordaviprone (Modeyso) has received accelerated approval from the FDA for the treatment of H3 K27M-mutant diffuse midline glioma (DMG) in adult and pediatric patients aged 1 year and older with progressive disease following prior therapy.1 This marks a significant milestone as it is the first FDA-approved systemic therapy for this aggressive and rare brain tumor, which primarily affects children and young adults and has historically had limited and often hazardous treatment options.
Microscopic, photorealistic image of glioma cells – Generated with Adobe Firefly
The approval is based on efficacy data from an integrated analysis of 50 patients across 5 open-label clinical trials, showing an overall response rate (ORR) of 22% and a median duration of response (DOR) of 10.3 months. While promising, this accelerated approval requires confirmatory trials, with the phase 3 ACTION study (NCT05580562) currently underway to further evaluate dordaviprone in newly diagnosed H3 K27M-mutant diffuse glioma patients after radiotherapy.
Diffuse midline gliomas are aggressive grade IV brain tumors that are fast-growing, likely to spread, and difficult to remove surgically due to their diffuse nature. The H3 K27M mutation is a molecular driver of the disease, preventing methylation at a specific site and altering gene expression. It is found in up to 80% of pediatric and 15% to 58% of adult patients with DMG. Survival is exceptionally poor for patients with H3 K27M-mutant tumors, with a median overall survival of 0.73 years, significantly lower than 4.59 years for H3 K27M wild-type tumors.2
In an interview with Targeted Oncology, Patrick Wen, MD, director of the Center for Neuro-Oncology at Dana-Farber Cancer Center and professor of neurology at Harvard Medical School, discusses the research that led to dordaviprone’s approval as well the clinical implications and benefits of having this option available for patients.
Targeted Oncology: Could you provide some background on dordaviprone and what gap it fills in the treatment landscape?
Patrick Wen, MD: Diffuse midline gliomas with H3 K27M mutation are probably the hardest to treat of all gliomas because they’re in the midline. You can’t resect them surgically, so the best you can do is a biopsy, and they usually have an unmethylated MGMT, so they’re not usually responsive to the standard chemotherapies. The only treatment that has been available up until now is radiation, and that helps for a number of months, but usually the tumor recurs within a year, and most patients die around a year or so.
There has been a huge need for better treatments, but it’s also been very difficult to figure out if treatments are actually efficacious, because one of the challenges is that it’s very hard to look at response rates. Following [patients] for progression-free survival and overall survival is pretty unreliable. You really need a randomized study to do that.
This study that was done was different from most studies in that it’s not a standard trial with a fixed end point. It was the accumulation of patients from 5 different trials who had measurable disease, so there was a way to see if the drug did something or not to the tumor. There has been some criticism that it’s not just 1 trial with a fixed end point, but there was no way to do that. This [study] was done in conjunction with the FDA to have 50 patients that you could evaluate and see if the drug did anything or not.
Overall response rate and duration of response data
The other challenge in this area is that the response criteria are complicated. In the past, we used RANO high-grade glioma [criteria] that that we developed, and the response rate based on enhancing tumor was only 20%. But a lot of these patients have nonenhancing tumors. If you look at the RANO low-grade glioma criteria that looks at nonenhancing tumors, the response rate was 26%. If you looked at any kind of response, whether it’s enhancing or nonenhancing, it was 30%. That makes a difference. Twenty percent is at the low end of what’s likely to be approved. Thirty percent is not unreasonable. Understanding these challenges, we actually developed the RANO 2.0 which was published a couple of years ago that incorporated both enhancing and nonenhancing tumors. They actually reanalyzed the data using RANO 2.0, and that was part of the basis of approval. The numbers don’t match up, so the response rate is low, but once you get a response, it is somewhat durable.
In the initial paper, it was just over 11%, but it takes about 8 months to get a response, and then once you get a response, you have another 11 months. So, it’s almost 20 months, basically, of stability.
What would be your considerations when prescribing this agent to patients? Are there any notable toxicities or idiosyncrasies with the drug?
I think with any treatment, there’s always a balance of the risks and benefits. I think one of the nice things about this drug is that, unlike most targeted drugs, it’s relatively easy for patients to tolerate. You only take it once a week. There is a level of fatigue, headaches, nausea, but it’s really pretty mild, so most patients don’t feel bad on the drug. In a lot of drugs for breast cancer and colon cancer and others, even though they’re supposed to be targeted, patients don’t feel good on it. So that’s where it also helps, because even though the response rate is not as high as some of the cancers, [dordaviprone] is also very well tolerated, better than most targeted drugs.
In terms of who to use for, the study was done mainly in patients with tumors that had measurable disease. So there a lot of them were thalamic gliomas in in young adults. That’s where most of the danger is. I think the controversy is whether you can extrapolate and use the drug also for diffuse intrinsic pontine glioma or spinal cord tumors. We don’t have very strong data for that.
What do you see as the next line of research with this agent?
I think while this agent was helpful for some patients, it’s a small subset of patients, so we’d still need much better treatments. I think having this option does allow that subset to have some benefit and hopefully a longer survival. But also, by it becoming available, potentially, there could be more trials combining other agents with dordaviprone.
We we need to see if the phase 3 [confirmatory] trial confirms the results. Hopefully it does. I think there there’s a lot of interest in using combination therapies, but then there are also other treatments that are shown some promise, like CAR T-cell therapy. I think it there’s still a lot of work to be done, but at least for the small subset of patients, there’s a treatment that’s not very toxic that may be helpful.