Paxalisib Plus Radiotherapy Reveals Promising ORR in Patients With Brain Metastases


The combination of paxalisib and radiotherapy exhibited complete or partial responses in all patients with brain metastases, according to interim data from an ongoing phase I clinical trial.

Paxalisib (GDC-0084) in combination with radiotherapy for the treatment of brain metastases elicited an overall response rate (ORR) of 100%, according to interim data from the first stage of an ongoing phase I clinical trial (NCT04192981).1

In this initial stage of the trial, 9 of 12 patients were evaluable for efficacy and all patients exhibited complete or partial response. When compared with published studies, this showed a major improvement as the typical ORR associated with whole brain radiotherapy alone ranges from 20-45%.

Furthermore, the safety profile of paxalisib in combination with radiotherapy was consistent with monotherapy experience in other clinical trials. The maximum tolerated dose (MTD) of 45 mg daily in combination with radiotherapy was confirmed as a result.

“We are encouraged by these data and by the potential benefit it may indicate to this substantial and high-need group of patients. Radiotherapy is a ubiquitous component of the treatment paradigm for brain metastases, but resistance is common. said James Garner, MD, chief executive officer of Kazia, in the press release. “Dr. Yang's study has shown a promising signal that paxalisib may help to potentiate the effect of radiotherapy. We also learned recently that the ongoing Alliance study in brain metastases had graduated to an expansion stage in the breast cancer cohort, so this now represents the second positive signal for paxalisib in brain metastases, which we increasingly believe represents a promising opportunity for the product candidate.”

In the single-arm, prospective phase 1 study, patients with brain metastases or leptomeningeal metastases from any primary tumor are being examined to determine the safety of paxalisib in combination with radiation therapy in this patient population. All of those enrolled have PI3K pathway mutations at baseline.2

Within the first stage of the study, investigators aimed to establish the MTD of paxalisib in combination with whole-brain radiotherapy and to characterize its safety and tolerability. The second stage of the trial will look at the confirmatory signals of efficacy and intends to recruit another 12 patients.

Enrollment is open to patients aged 18 years and older with a range of primary tumors. Breast cancer is the most common, representing a third of patients enrolled. Patients are required to have a Karnofsky performance score of 70 or more, and their last systemic therapy was 1 or more weeks from initiation of protocol therapy. Patients must also have adequate organ, bone marrow, liver, and renal function, be able to swallow and retain oral medication, and if the patient is at reproductive potential then they must agree to practice an effective contraceptive method.

Further, patients with prior SRS are eligible for enrollment and patients with a history of seizures related to brain metastases or leptomeningeal metastases are eligible if controlled on antiepileptic medications.

The primary end point of the study is safety and tolerability, including MTD and a secondary end point of local recurrence rate.

Recruitment to the expansion stage has already begun and preliminary data from the second part should be available in 2023. Discussion of the emerging data from this study, along with other research in brain metastases, is expected along with a potential FDA consultation at a future date, according to the press release. The data has already been accepted for an oral presentation at the upcoming 2022 Annual Conference on CNS Clinical Trials and Brain Metastases and the American Society for Clinical Oncology (ASCO), which will be held in Toronto, Canada from 12-13 August 2022.

Kazia therapeutics reports promising interim data from combination study of paxalisib with radiotherapy in treatment of brain metastases. News release. Kazia Therapeutics Limited. August 5, 2022. Accessed August 8, 2022.
GDC-0084 with radiation therapy for people with PIK3CA-mutated solid tumor brain metastases or leptomeningeal metastases. Updated July 27, 2022. Accessed August 8, 2022.
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