In an interview with Targeted Oncology, Arati Desai, MD, co-director of the University of Pennsylvania Brain Tumor Cancer Program Center, assistant professor of clinical medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, discussed the implications of the STELLAR trial, the role of eflornithine, and how IDH1/2 mutational status affects outcomes in patients with anaplastic astrocytomas.
Arati Desai, MD
The combination of eflornithine with lomustine is being compared to lomustine monotherapy for the treatment of patients with a rare brain cancer type, anaplastic astrocytoma (AA), in thephase III STELLAR trial(NCT02796261), The study aims to determine whether the regimen is safe and effective for these patients.
The primary end point of the study is overall survival (OS). STELLAR investigators are also evaluating for 2 secondary end points, which include progression-free survival and objective response rate.
In an interview withTargeted Oncology, Arati Desai, MD, co-director of the University of Pennsylvania Brain Tumor Cancer Program Center, assistant professor of clinical medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, discussed the implications of the STELLAR trial, the role of eflornithine, and howIDH1/2mutational status affects outcomes in patients with anaplastic astrocytomas.
TARGETED ONCOLOGY: What's the rationale for the STELLAR study?
Desai: In terms of thinking about the rationale for the stellar study, the first principle is that anaplastic gliomas, which are grade 3 gliomas, have very limited therapeutic options. So, there have been pre-established standards of care, most recently based on the CATNON data1, which incorporates radiation and temozolomide for patients who have anaplastic gliomas that do not harbor 1p19q codeletion. But beyond that, we need additional therapies desperately in this space. The STELLAR trial uniquely affords an opportunity for these patients with anaplastic astrocytoma to have a trial which is specifically designed for them. And I think it capitalizes on some of the preclinical data and early clinical data that incorporates eflornithine in conjunction with lomustine for these patients.
Where do you think eflornithine and lomustine will fit within the currently available treatment regimen?
We typically wouldn't use this therapeutic approach upfront because there is a better-established therapeutic regimen and therefore one of the integral criteria for entry into the trial require that patients not only have an anaplastic astrocytoma, but also have received temozolomide with radiation up front. With those criteria being met, we think of “what are the appropriate therapies for these patients in the setting of recurrence?" and that would include lomustine therapy. The idea here is to compare lomustine with lomustine plus eflornithine to understand how we might attain better responses with the combination of therapies.
Please discuss the advantage associated with eflornithine specificity.
When we look at [the enzyme] ornithine decarboxylase, there are a couple of things which are important. Number one, that [eflornithine] is a very specific inhibitor. Number two, that it's an irreversible inhibitor, which increases the chance of its potent effect. And number three, that there's rationale which is good to combine this strategy with an alkylating agent. It enhances the vulnerability of the cancer cell when you put these things together.
Can you discuss the relevance ofIDH1/2mutational status and its viability as a target therapy in this disease?
I think that this is a space of important investigation to be thinking about the clinical relevance ofIDHmutations in anaplastic gliomas, as well as the opportunity for therapeutic targeting ofIDHmutations. In brief, this was groundbreaking in terms of the understanding of gliomas writ large, and specifically applies to grade 3 gliomas. When we look at this, this is now integrated in our standard testing. The most common mutation is something that we test for by immunohistochemistry. And then we can validate by next-generation sequencing quite easily. And in so doing, also evaluateIDH1andIDH2more comprehensively to look for other mutations beyond the most common one. Although this is an oncogene, which results in the development of gliomas, until now, there wasn't a clear strategic thought in terms of how we might approach this as a potential therapeutic target. So, number one, data emerged from acute myelogenous leukemia [AML] where there's a similar mutation, the therapeutic targeting of IDH may add significant therapeutic benefit. And that's resulted in the approval of IDH inhibitors in AML. We're looking at a different disease here, and there are two broad schools of thought that are there right now. One is a direct IDH inhibitor, much like the drugs that have been approved in AML. And when we look at IDH inhibition, what we're looking at is how do we diminish production of the [oncometabolite product], which is something called 2HG [2-hydroxyglutarate] that might promote tumor progression?
So, these direct IDH inhibitors bring that down in such a way that they might diminish the chance for tumor progression. These are one school of thought, and there are multiple drugs that have come about in this category. The second school of thought, which is also quite interesting is that IDH inhibition is important in another way that the IDH mutation might confer a DNA damage repair defect, and that if you capitalize on that, you might make the cancer cell more vulnerable to certain drugs such as PARP inhibitors and so there are other trials which are coming about soon that incorporate PARP inhibitors, potentially in conjunction with alkylating agents such as temozolomide in patients who have IDH mutant gliomas, including grade 3 gliomas in the setting of recurrence.
What are you currently evaluating in your lab?
I think the landscape of glioma and glioblastoma therapy is changing quite dramatically, beginning with our molecular understanding of these tumors, and evolving now to include an emphasis on immunotherapy and targeted therapy in a way that is quite unique and selective based on the mutational profile or the immunotherapy profile of the tumor. What we are studying involves immunotherapy quite specifically and a novel kind of immunotherapy called CAR T-cell therapy. The current target that we're evaluating is a specific marker called EGFRvIII, which represents a subset of glioblastoma. But we're hoping to take that forward to include other potential targets in glioblastoma and other grades of recurrent glioma as well.
How has individualized therapy changed the way we treat this disease?
What we recognize, is that there's great diversity beyond a singular headline. These tumors historically have been treated as a broad group and the molecular understanding has evolved faster than the therapeutic understanding has evolved. I think what's really important Is that as we look ahead to the next 5 to 10 years, it's very much about individualized therapy related to a single patient or single patient's mutational profile or immunologic profile that might result in a greater chance that the therapy will work uniquely for that person rather than broadly for that disease.