Paxalisib Continues to Provide Survival Benefit Over SOC in Newly Diagnosed Unmethylated Glioblastoma


Key Takeaways

  • Paxalisib improved median OS to 15.54 months in newly diagnosed glioblastoma with unmethylated MGMT, compared to 11.89 months with SOC.
  • No efficacy benefit was observed with paxalisib in recurrent glioblastoma, with median OS of 8.05 months versus 9.69 months with SOC.
John Friend, MD

John Friend, MD

Paxalisib (formerly GDC-0084) demonstrated a clinically meaningful improvement in overall survival (OS) compared with standard of care (SOC) in patients with newly diagnosed glioblastoma and unmethylated MGMT promoter status, according to data from a prespecified secondary analysis of the phase 2/3 GBM AGILE study (NCT03970447).1

The median OS with paxalisib (n = 54) in this population was 15.54 months vs 11.89 with concurrent SOC (n = 46). Findings from the prespecified sensitivity analysis demonstrated a comparable median OS difference between the paxalisib and SOC arms, at 15.54 months and 11.70 months, respectively.

At the time of the primary analysis, the median OS with paxalisib was 14.77 months in patients with newly diagnosed unmethylated disease (n = 54) compared with 13.84 months in cumulative patients with newly diagnosed unmethylated disease who received SOC (n = 75).

No efficacy benefit was achieved with paxalisib (n = 100) over SOC (n = 113) in those with recurrent disease, at a median OS of 8.05 months and 9.69 months, respectively.

“We are excited to have shown a 3.8-month improvement in OS, an approximate 33% improvement, for newly diagnosed unmethylated patients with glioblastoma compared to the concurrent SOC arm,” John Friend, MD, chief executive officer of Kazia Therapeutics, stated in a news release. “Having comparable OS data across two independent studies is a compelling outcome in this difficult-to-treat glioblastoma population. We look forward to discussing possible approaches for an accelerated approval pathway for paxalisib with the FDA.”

The biomarker-based, multi-arm, seamless phase 2/3 response-adaptive, randomization platform trial was launched to examine several therapies in those with newly diagnosed and recurrent glioblastoma to rapidly identify and match effective options to those with different disease subtypes.2

The inclusion criteria for those with newly diagnosed disease included being aged 18 years or older, and having histologically confirmed grade IV glioblastoma, a Karnofsky performance s tatus of at least 60%, and having a tissue sample available.3 They could have methylated or unmethylated disease. Those with recurrent disease needed to be at least 18 years of age, have histologically confirmed grade IV glioblastoma, evidence of progressive disease per slightly modified Response Assessment in Neuro-Oncology criteria, a Karnofsky performance status of at least 70%, and a tumor sample available.

Patients were randomized to receive a multikinase inhibitor in the form of regorafenib (Stivarga); a PI3K/mTOR inhibitor in the form of paxalisib; a cytotoxic DNA alkylator in the form of VAL-083; VT1021, a cyclic peptide derived from PSAP; troriluzole, a glutamate modulator; and ADI-PEG 20.2

For stage 1, the primary objective was to determine what investigative agents improve OS in those with glioblastoma in the screening stage and understand whether certain subsets or those with select biomarkers derive benefit from the options. Based on the performance in stage 1, an experimental arm would be able to graduate to stage 2 if efficacy was demonstrated. Accrual would be stopped if the maximum sample size was reached. Arms could be terminated because of unacceptable safety or dropped for futility. Stage 2 is designed to produce data would support a new drug application.

Secondary objectives include examining progression-free survival and OS by each biomarker or combination, as well as to identify short- and long-term safety signals. Quality of life was also evaluated. The secondary analyses and end points were based on established statistical models in comparison with the control patients enrolled at the same time as the investigational agent, referred to as that concurrent control population.1

A total of 313 patients with newly diagnosed unmethylated disease and recurrent disease were enrolled and underwent randomization in stage 1 of the study. Between January 2021 and May 2022, they received paxalisib at a daily dose of 60 mg or a SOC concurrent control. Patients were enrolled to the cumulative control arm between July 2019 and May 2022.

The agent was found to be well tolerated. No new safety signals were observed in the newly diagnosed unmethylated population.

“Based on the totality of data available from all complete paxalisib clinical studies in newly diagnosed unmethylated glioblastoma patients, Kazia will request a meeting with the US Food & Drug Administration to discuss the results and determine if a potential path to accelerated approval is appropriate for paxalisib,” according to the news release issued by the pharmaceutical company.

Full findings, including secondary end points, will be shared at an upcoming medical meeting.

Previously, the FDA granted a fast track designation to paxalisib for use in patients with newly diagnosed glioblastoma with unmethylated MGMT who have completed initial radiation with concomitant temozolomide.4


  1. Kazia Therapeutics announces phase II/III clinical trial results for paxalisib in glioblastoma. News release. Kazia Therapeutics Limited. July 10, 2024. Accessed July 10, 2024.
  2. Cloughesy TF, Alexander BM, Berry DA, et al. GBM AGILE: A global, phase 2/3 adaptive platform trial to evaluate multiple regimens in newly diagnosed and recurrent glioblastoma. J Clin Oncol. 2022;40(suppl 16):TPS2078. doi:10.200/JCO.2022.40.16_suppl.TPS2078
  3. A trial to evaluate multiple regimens in newly diagnosed and recurrent glioblastoma (GBM AGILE). Updated June 10, 2024. Accessed July 10, 2024.
  4. US FDA awards fast track designation (FTD) to paxalisib for glioblastoma. News release. Kazia Therapeutics Limited. August 20, 2020.
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