A Phase I study evaluating the combination of paxalisib and radiation therapy in patients with solid tumor brain metastases or leptomeningeal metastases harboring PI3K pathway mutations has demonstrated promising results. The study, presented at the American Society for Radiation Oncology (ASTRO) 66th Annual Meeting, showed a 67% partial response rate with the combination therapy.
The trial (NCT04192981) investigated the safety and efficacy of concurrent paxalisib and radiation in patients with advanced solid tumors that had metastasized to the brain and harbored PI3K pathway mutations. Part I of the study established the maximum tolerated dose (MTD) of paxalisib in combination with radiation therapy, while Part II further evaluated the safety and efficacy of the MTD (45mg daily) combined with radiation therapy.
Key Findings from the Phase I Study
The study's findings indicate that the concurrent administration of paxalisib, a brain-penetrant PI3K inhibitor, with radiation therapy could be a viable treatment approach for addressing tumor radioresistance in patients with PI3K pathway mutations. At the maximum tolerated dose (MTD) of 45mg paxalisib, over two-thirds of patients achieved intracranial response. This compares favorably to historical response rates of 20-45% typically seen with whole brain radiation therapy (WBRT) alone.
The most commonly reported adverse events were nausea, vomiting, and hyperglycemia, all of which were generally manageable. These findings establish a proof-of-principle for molecularly-selected, rational combination studies in radiation oncology to assess safety and efficacy.
Clinical Significance and Future Directions
"The encouraging response rates observed from this Phase 1 study suggests that the concurrent administration of the investigational brain penetrant PI3K inhibitor, paxalisib, in combination radiation therapy appears to be a viable treatment approach for addressing the tumor radioresistance in patients harboring PI3K pathway mutations," said John Friend, M.D., Chief Executive Officer of Kazia Therapeutics.
With approximately 200,000 cancer patients developing brain metastases each year in the United States, and given the limitations of existing treatments like stereotactic radiosurgery (SRS) or whole brain radiotherapy (WBRT), there is a significant unmet need for new treatment options. The data suggests that paxalisib, in combination with radiation, could offer a more effective approach for patients with PI3K-mutated brain metastases.
Kazia Therapeutics is planning to present additional data, including circulating tumor DNA (ctDNA) results, at an upcoming scientific congress in 2024. Discussions are also underway for a potential pivotal registration study to further evaluate this combination therapy.
