One of the most important questions regarding Kazia's participation in GBM Agile is whether or not paxalisib will eventually show a statistically significant improvement in overall survival once the final results are revealed. Showing a statistically significant benefit is almost certainly necessary for FDA approval. In terms of statistical significance, this is usually shown in terms of a "p value", and in general, the p value must be less than 0.05 to have a chance at FDA approval, and the lower the better.
From Kazia's previously completed Phase 2 trial in glioblastoma, we know that (in that group of patients) the median overall survival came out to be 15.7 months. Although this number has been shown to be better than overall survival for any other trial with a reasonably matched patient population (i.e., patients of similar average age, racial makeup, etc.), we still don't know if it's "good enough" to show statistical significance. Given the large drop in price since the announcement of staying with a maximum of 150 patients in GBM Agile, instead of recruiting an extra 50, it seems many are speculating that it will not end up being a statistically significant finding and have thus sold off. Some have speculated that overall survival in general (without medication) has increased over the years in GBM, and therefore comparing to past studies is not valid.
Therefore, I found it very interesting when I found the following study abstract for the recent SNO/ASCO 2022 Brain Metastasis Conference (
https://academic.oup.com/noa/article/4/Supplement_1/i21/6654217):
" SYST-02 PHASE ⅡB CLINICAL TRIAL OF NEOADJUVANT CHEMOTHERAPY REVERSING GLIOMA STEM CELLS CHEMORESISTANCE IN NEWLY DIAGNOSED GBM WITH MGMT PROMOTER UNMETHYLATION Jun Dong, Liping Wang, Yanming Chen Neuro-Oncology Advances, Volume 4, Issue Supplement_1, August 2022, Page i21, https://doi.org/10.1093/noajnl/vdac078.081 Published: 05 August 2022 PDF Split View Cite Permissions Icon Permissions Share AbstractPURPOSETo evaluate clinical efficacy and safety of combination of nicardipine and valproic acid on temozolomide (TMZ) neoadjuvant chemotherapy targeting on glioma stem cells (GSCs) in newly diagnosed glioblastoma multiforme (GBM) patients with O6-methylguanine-DNA-methyltransferase (MGMT) promoter unmethylation. METHODS
From June 2018 to April 2021, newly diagnosed GBM patients after tumor surgical removal and concurrent radio-chemotherapy with TMZ, with
MGMT promoter unmethylation were randomly assigned to two groups. The control group was applied standard TMZ regimen. The trial group was administered standard TMZ regimen, plus nicardipine(20mg/d) and valproic acid (1.2g/d) as neoadjuvant treatment against GSCs chemoresistance. The relevant treatment data and adverse reactions of the patients were collected, Karnofsky performance status (KPS) score, progression-free survival (PFS) and overall survival (OS) were evaluated during patient follow-up. RESULTS33 patients were enrolled in this study, eighteen patients were randomly assigned in the trial group and 15 patients were in the control group. There was no statistical difference in gender composition, age, degree of surgical resection, or KPS score before treatment between the two groups. The median progression-free survival (mPFS) in the trial group was 10.8 months (95%CI 5.81-15.79 month), and the mPFS in the control group was 7.1 months (95%CI 5.12-9.08 month), which was a statistically difference (Log-Rank test P=0.033). The
median overall survival (mOS) increased from 12.1 months (95%CI 9.18-15.00 month) in the control group to
15.7 months (95%CI 7.67-23.73 month) in the trial group (Log-Rank test
P=0.015). There was no statistically significant difference in the incidence of adverse reactions between the two groups, and there were no treatment regimen related deaths. CONCLUSIONSTMZ combined with neoadjuvant of nicardipine and valproic acid against GSCs chemoresistance can prolong the survival time of patients who was newly diagnosed glioblastoma with MGMT promoter unmethylation. The preferred regimen can be applied safely without serious adverse events, which deserved further multi-center clinical investigations."
Statistical significance could not be calculated in Kazia's Phase 2 study because you need two groups of patients to calculate this, but
the aforementioned recent study shows that 15.7 months for median overall survival can indeed be statistically significant (p = 0.015, which is less than 0.05).
