Kazia's Paxalisib Shows Promise in Advanced Breast Cancer with 76% Tumor Reduction and Immune System Reinvigoration
核心洞察
Kazia Therapeutics (搜索) reported new clinical data from the 2025 San Antonio Breast Cancer Symposium showing paxalisib's dual PI3K (搜索)/mTOR (搜索) inhibitor demonstrated significant anti-tumor activity across multiple breast cancer subtypes.
The first patient in the TNBC Phase 1b trial achieved 76% tumor volume reduction with corresponding decreases in circulating tumor cells and clusters after just one treatment cycle.
Ex-vivo studies in HER2 (搜索)-positive patients showed paxalisib reduced single circulating tumor cells by 42% and CTC clusters by 78%, while reinvigorating exhausted immune cells.
Kazia Therapeutics (搜索) announced compelling new clinical and translational data at the 2025 San Antonio Breast Cancer Symposium demonstrating the potential of paxalisib, its brain-penetrant dual PI3K (搜索)/mTOR (搜索) inhibitor, to reinvigorate anti-tumor immunity across multiple advanced breast cancer populations. The findings highlight the drug's ability to disrupt highly aggressive circulating tumor cell clusters and reverse immune exhaustion in both HER2-positive metastatic breast cancer (搜索) and triple-negative breast cancer (搜索) (TNBC).
Breakthrough Results in TNBC Phase 1b Trial
Early longitudinal biomarker data from the first patient treated in the PaxPlus-ABC Phase 1b study revealed remarkable biological activity after just a single cycle of treatment. The patient, receiving paxalisib in combination with pembrolizumab and chemotherapy, demonstrated a 76% reduction in primary tumor volume, with CT imaging showing shrinkage from baseline measurements of 14mm x 11mm (154mm²) to 12mm x 3mm (36mm²).
The clinical response was accompanied by significant biological changes, including marked reduction in circulating tumor cell clusters and epigenetic reprogramming of CTCs toward less aggressive phenotypes. Digital pathology and Nanostring profiling confirmed these molecular changes, while immune monitoring revealed a significant reduction of exhausted CD8 T cells with revitalization of cytotoxic and antigen-presentation pathways.
A temporary interruption of paxalisib due to a chemotherapy-related adverse event provided crucial mechanistic insights. During the 3-week pause, CTC clusters rapidly resurged, but their suppression was restored upon resumption of paxalisib treatment. This observation indicated that pembrolizumab alone could not control these metastatic drivers, highlighting paxalisib's unique mechanistic role.
Targeting Metastatic Drivers in HER2-Positive Disease
In HER2-positive metastatic breast cancer (搜索), where nearly all patients eventually relapse despite HER2 (搜索)-directed therapies, investigators observed that even radiographically responding patients continued to harbor substantial burdens of therapy-resistant CTC clusters. Ex-vivo studies demonstrated paxalisib's ability to directly target these aggressive cellular populations.
The drug reduced single CTCs by 42% and CTC clusters by 78% ex vivo, including large clusters of five or more cells that are strongly associated with metastatic progression. These CTC clusters expressed a highly aggressive mesenchymal phenotype marked by Vimentin⁺/Snail⁺/NRF2⁺, which paxalisib significantly disrupted.
"These findings reveal an important biological gap left by existing HER2 (搜索)+ directed therapies," said Prof. Sudha Rao from QIMR Berghofer (搜索). "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."
Immune System Reinvigoration Mechanism
The research revealed that patients with poor clinical response demonstrated impaired cytotoxic function, characterized by reduced Granzyme B and Perforin levels, along with expanded exhausted T-cell populations. Paxalisib treatment activated cytotoxic, interferon, chemokine, and inflammatory pathways in samples from these patients, supporting the creation of a more immunologically "hot" tumor environment.
Across both HER2 (搜索)-positive and TNBC datasets, a consistent pattern emerged showing that pembrolizumab monotherapy does not meaningfully reduce CTC burden. In TNBC specifically, CTC clusters increased when paxalisib was withheld, demonstrating the drug's direct targeting of mesenchymal, metastatic, and epigenetically resistant CTC clusters while simultaneously reinvigorating immune effector cells.
Expanding Therapeutic Opportunities
The mechanistic findings suggest broad applicability across breast cancer subtypes, as mesenchymal CTC clusters and T-cell exhaustion represent shared resistance mechanisms. In HER2 (搜索)-positive patients, despite targeted therapy, residual disease persists in the form of aggressive CTC clusters, creating a new therapeutic window for paxalisib intervention.
For TNBC patients, paxalisib's epigenetic and immunologic effects provide strong rationale for combination approaches with pembrolizumab, PARP inhibitors, and chemotherapy. In BRCA (搜索)-mutated and homologous recombination-deficient tumors, PI3K (搜索)/mTOR (搜索) 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 (搜索). "Paxalisib appears capable of disrupting metastatic machinery that is not adequately addressed by current HER2 (搜索)-targeted therapies, checkpoint inhibitors, or chemotherapies. We believe these discoveries meaningfully expand the potential utility of paxalisib beyond our current development programs."
Clinical Development Context
Paxalisib, licensed from Genentech in late 2016, has been the subject of ten clinical trials and has received multiple FDA designations, including Orphan Drug Designation for glioblastoma (搜索) and Fast Track Designation for both glioblastoma and solid tumor brain metastases harboring PI3K (搜索) pathway mutations. The drug is currently being evaluated in ongoing clinical trials across advanced breast cancer, brain metastases, diffuse midline gliomas (搜索), and primary central nervous system lymphoma (搜索), with several trials reporting encouraging interim data.