Significant Clinical Findings in TNBC and HER2+ Populations

The latest research indicates a substantial impact of paxalisib in inhibiting circulating tumor cells (CTCs) and reactivating immune responses. Early data from a TNBC trial revealed that the first patient experienced a remarkable 76% reduction in tumor volume, alongside significant decreases in CTCs and their clusters.

• Preliminary findings suggest paxalisib disrupts aggressive CTC clusters and reverses resistance pathways.
• The treatment appears to rekindle exhausted T- and B-cell populations, which may enhance the efficacy of immunotherapy.

Paxalisib’s Mechanism Against Metastasis in HER2+ Disease

In patients with HER2-positive breast cancer, a comprehensive analysis revealed that even those showing treatment responses continued to harbor substantial therapy-resistant CTC clusters. These CTC clusters are known to drive metastatic spread and pose significant challenges in achieving lasting remission.

Key findings from the research include:

• Reduction of single CTCs by 42% and CTC clusters by 78%.
• Presence of an aggressive mesenchymal phenotype marked by Vimentin⁺/Snail⁺/NRF2⁺ was significantly disrupted by paxalisib.
• The treatment was linked with the activation of cytotoxic and inflammatory immune pathways, suggesting a transition to a more immunologically conducive tumor environment.

According to Prof. Sudha Rao from QIMR Berghofer, “These findings reveal an important biological gap left by existing HER2+ directed therapies." This highlights paxalisib's potential in bridging these gaps.

Initial Results from the TNBC Phase 1b Trial

The PaxPlus-ABC Phase 1b study, which combines paxalisib with pembrolizumab and chemotherapy, has also yielded promising early results. Notably, longitudinal biomarker data from the first patient opened new avenues in treatment approaches.

Highlights include:

• Marked decrease in CTC clusters following the initial cycle of paxalisib.
• Evidence of epigenetic reprogramming of CTCs towards less aggressive forms.
• Reported reduction of exhausted CD8 T cells and revitalization of critical immune pathways.
• CT imaging displayed primary tumor volume reduction from baseline measurements of 154 mm² to 36 mm².

Paxalisib's Unique Role in Combination Therapy

Analysis of data indicates that reliance solely on pembrolizumab may not adequately control CTC burden in either HER2+ or TNBC patients. Withdrawals of paxalisib resulted in increased CTC clusters, revealing its critical role in managing metastatic drivers.

It appears that paxalisib not only suppresses these clusters but also rejuvenates the immune system, thus offering a potentially transformative approach to enhancing immunotherapy efficacy.

Future Implications and Broader Applications

There’s growing evidence that paxalisib’s benefits are relevant beyond TNBC. Its ability to address shared resistance mechanisms in various breast cancer subtypes opens new therapeutic opportunities, particularly in:

• HER2+ patients, where aggressive CTC clusters remain even after targeted therapy.
• Combination therapies with pembrolizumab, PARP inhibitors, and chemotherapy in TNBC.
• BRCA-mutated and homologous recombination-deficient tumors, where synergistic effects with PI3K/mTOR inhibition may be observed.

Dr. John Friend, CEO of Kazia Therapeutics, stated, “Paxalisib appears capable of disrupting metastatic machinery that is not adequately addressed by current HER2-targeted therapies." This underscores the expansive potential of paxalisib (NASDAQ: KZIA) in cancer treatment strategies.

About Kazia Therapeutics

Kazia Therapeutics Limited (NASDAQ: KZIA) is an oncology-focused drug development firm based in Sydney, Australia. The company is advancing paxalisib, an investigational drug targeting the PI3K/Akt/mTOR pathway, which is undergoing development for various cancer types, including advanced breast cancer, glioblastoma, and others. Kazia is committed to expanding its portfolio to address unmet medical needs in oncology.