This video and transcript of an interview with Roger Stupp, M.D., were just recently released. The interview was done on January 14, 2019.
It's interesting as he is asked about relevant biomarkers in glioma, and I'd imagine that this will also be something they'll look at in the DCVax-L P3 trial.
He considers the most important biomarker to be IDH. Now I know this was not a biomarker that was initially measured when the trial protocol was initially established, and it certainly wasn't in the protocol by 2014. The trial DID measure MGMT status from the P2 transition to P3 on, as we can see from the recent journal article.
Still, it's good to know what the neuro-oncology community is looking at, and certainly Stupp would be representative of that group. He also makes a slight nod to vaccines, and I wanted to make note of that here. He describes the IDH-mutated tumor as the "one that makes the plateau in the curves when we have long-term survivors" and those are the have mutated from a lower-grad glioma. Which means the IDH wild-type tumor is the primary tumor and it begins as a Grade IV tumor. Now the IDH-mutated type represent 10% of the gliomablastoma population and IDH-wildtype represent 90% - at least according to the quick google I did of it using this phrase - IDH wildtype glioma grade IV.
Dr. Shah: So, we talked in a past conversation about the MGMT promoter and it’s important. What are some of the other important biomarkers in gliomas that have promising clinical implications?
Dr. Stupp: The biomarkers and molecular markers have really changed our understanding of glioma over the last 10-15 years. It has changed and adopted the classification. So the most important marker is IDH, which is an early event, IDH-mutated tumors and IDH-wild-type tumors. IDH mutation most of the time reported by immunohistochemical test, which covers about 85% of the mutations, but if it’s IDH wild type, that still would require that tumor is actually sequenced to look for other IDH1 and IDH2 mutations.
This is a disease entity that is different and that would actually describe very well the IDH-mutated glioblastoma, the so-called previously secondary glioblastoma, tumors that have evolved from a lower-grade glioma. That’s the ones who make the plateau in the curves when we have long-term survivors, these patients are enriched there. So we know that we have to separate those. This may in the future also have therapeutic implication, IDH inhibitors. Maybe these tumors react differently to immunotherapy. That’s on the horizon, nothing that really implies today.
There are vaccines out there in the adjuvant setting, more probably earlier on, and what we know from recent developments is if you want to influence IDH and the IDH pathway, you need to do it before the tumor has transformed as a malignant tumor. Then we have the 1p/19q codeletion, which is not completely new, which actually is a translocation. This defines oligodendroglioma, so while before the pathologists would tell us this looks like X-shaped and so on and that looks like an oligodendroglioma, without the molecule, you cannot give the diagnosis of oligodendroglioma.
Again, the disease entity that had a complete different natural history that responds exquisitely to chemotherapy, but is also the ones who respond exquisitely to radiation, where we have survival times of 20 years and beyond. So late toxicity is a consideration, a complete different way of approaching therapeutically than high-grade glioblastoma.
Dr. Shah: So given sort of the diversity of that, that on the one hand it is critical to identify certain types of gliomas, on the other hand the promise is still not being met. How would you suggest that a practitioner in a medium resource area approach molecular testing or genomic testing in their patients with glioblastoma?
Dr. Stupp: So personally, I would wish that no matter where the patient comes that the pathology is sent out and is reviewed by one of the expert neuropathology centers we have in the country. It’s getting too complex. There may be important implication and consequences, and it takes some expertise, especially with the molecular testing to integrate all of that. There’s other mutations, TERT, ATRX. We have now in the future not any more of the grade 3 tumors, we’re going to have grade 3 tumors with a molecular profile like glioblastoma so we would treat them more aggressively, while if we have an IDH-mutated tumor, we may actually withhold horses and be more gentle because longer survival, so late toxicity and complications is of concern.
Now I've posted this previously, and again, this is what LL said at minute 48:10 of this video.
But some of our data from our immunotherapy trials (note: plural) though, actually have shown immune therapy actually may be more beneficial in the, you know, mesenchymal subgroup of glioblastomas, which actually tend to be IDH1 mutation negative…the IDH1 wild-type tumors. And potentially, these tumors do worse because they have more mutations, and they tend to be more aggressive. That being said, the fact that they have more mutations may actually make them more susceptible to immunotherapy because they have more targets. You know, there are mutations that the immune system can target.
