Paxalisib Achieves 100% Clinical Benefit Rate in Metastatic TNBC

The investigational PI3K/Akt/mTOR inhibitor paxalisib produced a 100% clinical benefit rate among 6 evaluable patients with stage IV triple-negative breast cancer (TNBC), according to a news release from the developer, Kazia Therapeutics.¹

Five of the 6 patients achieved an objective response, defined as a 30% or greater reduction in tumor burden, including 1 complete response and 4 partial responses, for an objective response rate of 83%. Of note, the remaining patient achieved stable disease. No paxalisib-related serious adverse events were reported, and investigators observed no grade 3 or higher hyperglycemia, stomatitis, or mucositis, toxicities that are commonly associated with PI3K/mTOR pathway inhibition.

These findings build on earlier data from the same ongoing phase 1b trial, which CancerNetwork previously reported showed meaningful clinical activity with paxalisib plus pembrolizumab (Keytruda) and chemotherapy in patients with metastatic TNBC.²

Main Paxalisib Data

Clinical responses were observed across a broad range of metastatic disease sites, including the lung, liver, bone, lymph nodes, and central nervous system. Responses emerged as early as approximately 3 months after treatment began. The press release highlighted that a 44-year-old woman with stage IV TNBC achieved a complete metabolic response that has remained durable since November 2025. Her response has been accompanied by sustained and complete abolishment of circulating tumor cell (CTC) clusters and a significant reduction in terminally exhausted CD8-positive T cells, alongside an overall improvement in markers of immune function.

“Metastatic triple-negative breast cancer is one of the toughest cancers to treat. Historically, only 12% of patients are alive 5 years after diagnosis. Once a patient’s disease progresses on immunotherapy, options run out quickly,” said John Friend, MD, chief executive officer of Kazia Therapeutics, in the news release.¹ “Across the 6 evaluable patients treated, every one of them has benefited, and we haven’t seen a single serious adverse event tied to paxalisib.”

Translational Findings

Across all 6 patients, translational analyses showed reductions in terminally exhausted CD8-positive T cells, a dysfunctional population of cytotoxic T cells that has lost the ability to recognize and kill cancer cells, with a median reduction of 51% within approximately 3 weeks of treatment. Total CD8-positive T cell counts remained unchanged, suggesting paxalisib may be restoring function in existing exhausted cells rather than eliminating or replacing them. Blood-based multi-modal protein, RNA, and plasma profiling supported this finding, showing increases in immune cell populations associated with antitumor activity, reductions in markers of immune exhaustion, and evidence of PI3K-AKT pathway target engagement.

All 6 patients also demonstrated reductions in metastasis-associated CTC clusters, aggressive groupings of tumor cells in the bloodstream associated with metastatic spread, with a median reduction of 83% within 6 to 7 weeks of treatment.

“Two of the biggest challenges in treating triple-negative breast cancer are the dormant cancer cells that spread through the bloodstream, and an immune system too exhausted to fight them,” said Sudha Rao, PhD, chief scientific officer of Kazia Therapeutics, in the release.¹ “The circulating tumor cell clusters that seed new metastases are being suppressed, while the exhausted T cells needed to fight the cancer are recovering function and showing signs of immune memory, which may translate to more durable responses.”

Phae 1b Trial Details

The ongoing phase 1b trial is evaluating paxalisib in combination with pembrolizumab and chemotherapy in patients with advanced metastatic TNBC. Paxalisib is administered orally, once daily. Enrollment in the study is expected to be completed by July 2027, and the company anticipates interim clinical updates throughout 2026 and 2027.

Kazia's release noted that these early biological findings may reflect a first-in-class effect, suggesting paxalisib’s activity may extend beyond direct PI3K/mTOR pathway inhibition by simultaneously restoring antitumor immune function and reducing metastatic dissemination, 2 processes considered fundamental drivers of disease progression in TNBC.

References

1. Kazia Therapeutics reports 100% clinical benefit rate in initial six patients treated for advanced triple-negative breast cancer. News release. Kazia Therapeutics Limited. August 28, 2026. Accessed August 28, 2026. https://tinyurl.com/bd3tf2e

2. Kazia Therapeutics reports encouraging preliminary clinical responses in ongoing phase 1b study of paxalisib in late-stage metastatic triple-negative breast cancer. News release. Kazia Therapeutics Limited. January 27, 2026. Accessed August 28, 2026. https://tinyurl.com/3246wtdr