Pre-Conference Coverage: Miami Brain Symposium 2021 - Molecular...

Pre-Conference Coverage: Miami Brain Symposium 2021 - Molecular Markers, Part 1
Published in Brain Cancer - Expert Opinion / Interview · November 29, 2021

Dr. McDermott: Minesh, one of the things that I thought was interesting in the last few years was the shift away from the classification of low grade gliomas, for example, based on the phenotype to a purely molecular profile. Then again we have other primary brain, more malignant grades of astrocytoma where we don't do that but the markers as you say might predict the response to temozolomide for example. I think the low grade gliomas are the perfect example of how molecular markers have changed our practice. What do you think?

Dr. Mehta: I think you're absolutely right. It was very easy at one point in time to put gliomas into a single classification system and have either three or four tiers of histopathologic definitions associated with prognostic outcomes. But I think the story really started taking place in two parallel developments. First, the identification that temozolomide as a chemotherapy agent is effective, but not in all patients with gliomas. It turns out that perhaps the presence of methylation of the MGMT gene is the driving mechanism imparting sensitivity to the effectiveness of temozolomide.

That allowed us for a glioblastoma at least to very broadly categorize these into MGMT methylated versus MGMT unmethylated, and this has now become a very routine common standard in clinic. What's intriguing though is that we do recognize that the methylated glioblastoma population categorically derives a survival benefit, but the unmethylated population, it is actually questionable, whether there is genuine benefit from the use of temozolomide. Yet in the absence of other therapeutics, the continued utilization of temozolomide in this group persists even today. There are however newer clinical trials where this is being dispensed with.

"There is in fact a trial known as GBM AGILE, that is in fact interrogating patients, took tissue from patients for various targetable mutations and then assigning patients to a specific therapeutic arm, whether this will be successful remains to be defined".

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NCT03970447 - A Trial to Evaluate Multiple Regimens in Newly Diagnosed and Recurrent Glioblastoma (GBM AGILE)
Experimental: Paxalisib Treatment Arm

Newly Diagnosed MGMT Unmethylated GBM: XRT 60 Gy for 6 weeks. Temozolomide 75 mg/m2 orally daily during radiation therapy. Rest Period 4 weeks from the last day of radiation. Maintenance period: Paxalisib (Dosage Form: Tablet for oral administration; Strength: 15 mg per tablet) 45 mg orally (PO) every day for 28 days for the first cycle. If tolerated, increase dose to 60 mg orally (PO) every day for 28 days for all subsequent cycles.

Recurrent GBM: Paxalisib (Dosage Form: Tablet for oral administration; Strength: 15 mg per tablet) 45 mg orally (PO) every day for 21 days for the first cycle. If tolerated, increase dose to 60 mg orally (PO) every day for 21 days for all subsequent cycles


IMO Kazia's paxalisib FDA registration approval target is the MGMT unmethylated glioblastoma patients, where it is actually questionable, whether there is genuine benefit from the use of temozolomide.

Investigators will also test paxalisib for recurrent GBM patients.

Good paxalisib results achieved against the GBM AGILE control arm will lead investigators to test the benefit of paxalisib in combination with other drugs.

Regards.