On December 10, 2025 Kazia Therapeutics Limited ("Kazia" or the "Company") reported new data from two presentations at the 2025 San Antonio Breast Cancer Symposium (SABCS) providing compelling mechanistic and early clinical evidence supporting the activity of paxalisib, the Company’s brain-penetrant dual PI3K/mTOR inhibitor, across both HER2-positive metastatic breast cancer and triple-negative breast cancer (TNBC).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The results, originating from advanced liquid biopsy profiling, immune phenotyping, and early clinical readouts, highlight paxalisib’s potential to disrupt highly aggressive circulating tumor cell (CTC) clusters, reverse epigenetically-driven resistance pathways, and reinvigorate exhausted T- and B-cell populations, thereby enhancing responsiveness to immunotherapy.

Paxalisib Disrupted Drivers of Metastasis: Vim+/Snail+/NRF2+ CTC Clusters in HER2+ Disease Ex Vivo

In HER2-positive metastatic breast cancer, a population in which nearly all patients eventually relapse despite HER2-directed therapies, investigators observed that even patients who were radiographically responding continued to harbor substantial burdens of therapy-resistant CTC clusters—a key driver of metastatic spread.

Poster Presentation: PS2-10-02 : Liquid Biopsy Tracking of PI3K–mTOR Residual Disease Signatures in Metastatic HER2+ Breast Cancer

Key findings:

•
Paxalisib reduced single CTCs by 42% and CTC clusters by 78% ex vivo, including large clusters (≥5 cells), which are strongly associated with metastatic progression.

•
CTC clusters expressed a highly aggressive mesenchymal phenotype marked by Vimentin⁺/Snail⁺/NRF2⁺, which paxalisib significantly disrupted.

•
Patients with poor clinical response demonstrated impaired cytotoxic function (reduced Granzyme B and Perforin) and expanded exhausted T-cell populations, while paxalisib treatment activated cytotoxic, interferon, chemokine, and inflammatory pathways in samples from these patients, supporting a more immunologically "hot" tumor environment.

"These findings reveal an important biological gap left by existing HER2+ directed therapies," said Prof. Sudha Rao, QIMR Berghofer. "CTC clusters persist even in responding patients, and paxalisib is the first agent we have observed that can directly dismantle this highly aggressive and clinically relevant compartment."

TNBC Phase 1b Trial: Early Clinical Data from First Patient Show Robust Suppression of CTC Clusters and Reversal of T-Cell Exhaustion

Early longitudinal biomarker data from the first patient treated in the PaxPlus-ABC Phase 1b study (paxalisib + pembrolizumab + chemotherapy) indicate that paxalisib has had measurable biological activity after only a single cycle.

Poster Presentation: PS5-08-04: A phase 1b, multi-centre, open-label, randomized study to evaluate the safety, tolerability, and clinical activity of combining paxalisib with olaparib or pembrolizumab/chemotherapy in patients with advanced breast cancer

Highlights from first patient include:

•
Marked reduction in CTC clusters following the first cycle of paxalisib.

•
Epigenetic reprogramming of CTCs toward less aggressive phenotypes, confirmed through digital pathology and Nanostring profiling.

•
Significant reduction of exhausted CD8 T cells, with revitalization of cytotoxic and antigen-presentation pathways.

•
CT imaging has demonstrated overall primary tumor volume reduction from baseline 14mm x 11mm (154mm2) to 12mm x 3 mm (36mm2)

•
Notably, a temporary interruption of paxalisib (necessitated by a chemotherapy-related adverse event) resulted in a rapid resurgence of CTC clusters. Resumption of paxalisib after a short 3-week pause restored suppression of CTC clusters, indicating that pembrolizumab alone could not control these metastatic drivers and highlighting paxalisib’s unique mechanistic role.

Pembrolizumab Alone May Not Control CTC Burden; A Mechanistic Opportunity for Paxalisib

Across HER2+ and TNBC ex-vivo datasets, a consistent theme emerges:

•
Pembrolizumab monotherapy does not meaningfully reduce CTC burden, and in TNBC, CTC clusters increased when paxalisib was withheld.

•
Paxalisib directly targets mesenchymal, metastatic, and epigenetically resistant CTC clusters.

•
It also reinvigorates immune effector cells, potentially overcoming the cytotoxic dysfunction and exhaustion that limit checkpoint inhibitor efficacy.

This mechanistic direct suppression of metastasis-initiating cells plus restoration of immune function positions paxalisib as a potentially transformative immunotherapy-enhancing agent.

Expanding Opportunity Across Breast Cancer: HER2+, TNBC, BRCA-Mutated, and Beyond

Because mesenchymal CTC clusters and T-cell exhaustion are shared resistance mechanisms across multiple breast cancer subtypes, paxalisib’s effects are highly relevant beyond TNBC.

Emerging data suggest:

•
In HER2+ patients, despite targeted therapy, residual disease persists in the form of aggressive CTC clusters—a new therapeutic window for paxalisib.

•
In TNBC, paxalisib’s epigenetic and immunologic effects provide a strong rationale for combination with pembrolizumab, PARP inhibitors, and chemotherapy.

•
In BRCA-mutated and homologous recombination–deficient tumors, PI3K/mTOR inhibition may synergize with synthetic lethal strategies such as olaparib.

"Kazia’s recent clinical and translational findings point to a unifying biology across breast cancer subtypes," said Dr. John Friend, CEO of Kazia Therapeutics. "Paxalisib appears capable of disrupting metastatic machinery that is not adequately addressed by current HER2-targeted therapies, checkpoint inhibitors, or chemotherapies. We believe these discoveries meaningfully expand the potential utility of paxalisib beyond our current development programs."

For investor and media, please contact Alex Star, Managing Director LifeSci Advisors LLC, [email protected], +1-201-786-8795.

(Press release, Kazia Therapeutics, DEC 10, 2025, View Source [SID1234661345])