Kazia Therapeutics Discusses Shift for Paxalisib Into Triple-Negative Breast Cancer

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Key Takeaways

Paxalisib has been administered to >550 patients historically, leveraging blood-brain barrier penetration, and is now being tested in a phase 1b advanced breast cancer program initiated June 2025.
Lower-dose administration (15–30 mg daily) is associated with putative epigenetic effects, including mesenchymal-to-epithelial shifting of cancer stem cells and reduced invasiveness.
Mechanistically, paxalisib is positioned as an “immunotherapy sensitizer,” increasing tumor immune visibility and enabling checkpoint inhibitor activity in historically refractory settings.
In early metastatic TNBC experience (n=3), two partial responses and one confirmed complete metabolic response on PET/CT were reported with predominantly mild-to-moderate AEs.
Enrollment expanded from 12 to 36 patients with topline readout expected early 2027, alongside exploration in earlier TNBC, HR+/HER2− disease, colorectal cancer, and liquid biopsy monitoring.

Kazia Therapeutics advances paxalisib, a dual PI3K/mTOR inhibitor, into triple-negative breast cancer, boosting immunotherapy responses with early promising data.

For Kazia Therapeutics, the past year has been one of changing direction, with the hope that a strategic pivot from one hard-to-treat cancer to another will bear fruit.

CEO John Friend II, MD, and Chief Scientific Officer Sudha Rao, PhD, described the journey for their company’s lead agent, paxalisib, in an interview with The American Journal of Managed Care. Paxalisib, an oral, once-daily dual PI3K/mTOR inhibitor originally licensed from Genentech, was designed to cross the blood-brain barrier, and Kazia has dosed more than 550 patients with paxalisib, primarily in glioblastoma and pediatric brain cancers.

Then, in June 2025, the company initiated a phase 1b trial in advanced breast cancer, including triple-negative breast cancer (TNBC).¹

What makes the breast cancer program scientifically distinctive, Rao explained, is paxalisib’s downstream epigenetic effects at doses well below those used in brain cancer, which are 15 mg and 30 mg daily vs the 45 mg/kg used in glioblastoma studies. At these lower doses, the drug appears to reprogram cancer stem cells, shifting them from an aggressive mesenchymal phenotype to a less invasive epithelial phenotype.

Friend said paxalisib removes the “invisibility cloak,” acting as a sensitizer for checkpoint inhibitors in tumors where immunotherapy has historically failed.

Thus, Rao explained, the combination is bringing responses in patients who did not respond to a single immunotherapy, because paxalisib “rewires the cancer cells, it makes them immune visible, allowing immunotherapy now to work.”

As of a January 2026 update, 3 patients with stage IV metastatic TNBC have been treated with paxalisib in combination with pembrolizumab and chemotherapy. Two trial participants achieved partial responses, including 1 patient with complete resolution of a target lung lesion after 3 cycles.² A third patient, treated under compassionate use after progressing on prior therapy, achieved a confirmed complete metabolic response on PET/CT, an outcome Friend noted is exceedingly rare in this setting. Adverse events have been predominantly mild to moderate, with approximately 75% deemed unrelated to paxalisib.²

The trial has since expanded its target enrollment from 12 to 36 patients, Friend said, with topline data anticipated in early 2027. Kazia is also exploring paxalisib in earlier-stage TNBC, hormone receptor–positive/HER2-negative breast cancer, and colorectal cancer, while developing a liquid biopsy platform to identify patients at metastatic risk and track real-time treatment response.

References

Kazia Therapeutics announces first patient dosed in phase 1b trial of paxalisib in advanced breast cancer. 1stOncology. June 5, 2025. Accessed June 24, 2026. https://bit.ly/4aljBEW
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. January 27, 2026. Accessed June 24, 2026. https://bit.ly/43TnsFK