Phase 1b Data Suggest Paxalisib Combo May Suppress CTCs in Metastatic TNBC

Preliminary results from a phase 1b clinical trial suggest that the investigational combination of paxalisib, pembrolizumab (Keytruda), and chemotherapy may rapidly suppress circulating tumor cells (CTCs) and CTC clusters in metastatic triple-negative breast cancer (TNBC), a highly aggressive and treatment-resistant subtype, according to a press release from Kazia Therapeutics Limited.

After completing the first 21-day treatment cycle, the first patient in the trial—a 61-year-old woman with TNBC metastatic to the lung—demonstrated a >50% reduction in total CTC count and a comparable decrease in CTC clusters. The remaining CTCs showed a reduced mesenchymal phenotype, which is strongly associated with metastatic competence and therapy resistance.

These early findings align with mechanistic data from recent preclinical research published in Molecular Cancer Therapeutics, which supports the rationale for combining paxalisib, a dual PI3K–mTOR inhibitor, with immunotherapy to disrupt cancer dissemination and immune evasion.

"It is very exciting to see our extensive preclinical research translate into such positive early data in this first patient receiving a combination of paxalisib and immunotherapy. The degree of reduction in tumor cell dissemination markers in just 21 days gives us strong reason for optimism as we continue this clinical trial," said John Friend, MD, chief executive officer of Kazia Therapeutics, in the press release.

Clinical Significance

CTC clusters are increasingly recognized as highly efficient metastatic precursors, capable of immune evasion, resisting apoptosis, and initiating new tumor sites up to 100 times more effectively than single CTCs. Their presence has been correlated with poor prognosis in multiple malignancies, including TNBC.

Standard chemotherapy regimens can transiently increase CTC and cluster counts during initial treatment cycles, likely due to cytotoxic disruption of primary tumor architecture. Meanwhile, immunotherapy alone often has delayed or inconsistent effects on CTC kinetics. Therefore, the rapid and pronounced decline in both CTCs and clusters following this combination treatment, after only 1 cycle, is particularly noteworthy and supports a potential synergistic mechanism.

In the study, the patient’s response also included a reduction in mesenchymal phenotype among remaining CTCs, suggesting a possible shift toward a less invasive epithelial state. This observation is consistent with paxalisib’s known ability to promote mesenchymal-to-epithelial transition and suppress metastasis-initiating cell signatures.

About Paxalisib

Paxalisib is an orally available, brain-penetrant dual PI3K–mTOR inhibitor. The PI3K and mTOR pathways are frequently upregulated in TNBC and linked to proliferation, migration, metastasis, and drug resistance. Preclinical studies demonstrate that dual inhibition, as opposed to PI3K blockade alone, is required to disrupt aggressive phenotypes in TNBC cells.

The agent also affects multiple resistance-associated transcriptional programs, including p65, FOXQ1, NRF2, and NNMT, and downregulates markers of cancer stemness including ALDH1, SNAIL, and ABCB5. Further, paxalisib influences the tumor immune microenvironment, reducing exhausted T cells, regulatory T cells, and protumor innate populations such as mast cells.

At the epigenetic level, the dual PI3K–mTOR blockade impacts both the repressive (p85β–EZH2–H3K27me3) and active (EZH2–NF-κB) functions of EZH2, a chromatin regulator implicated in metastatic progression and immune resistance. This upstream modulation of EZH2 function may increase tumor visibility to the immune system and enhance the efficacy of checkpoint inhibitors.

Implications and Future Directions

Ongoing enrollment in the phase 1b trial will allow for expansion of the cohort to evaluate safety, tolerability, and pharmacodynamic markers across a broader patient population. Serial monitoring of CTC kinetics and immune microenvironment analyses are planned, with longer-term end points to include radiographic response, progression-free survival, and biomarker correlations.

Paxalisib has been the subject of 10 clinical trials across multiple cancer indications, including glioblastoma, brain metastases, primary central nervous system lymphoma, and various breast cancer subtypes. Paxalisib has received multiple FDA designations, including orphan drug and fast track for glioblastoma and brain metastases harboring PI3K mutations.

Kazia is also developing EVT801, a VEGFR3 inhibitor with preclinical synergy demonstrated alongside immunotherapies. A phase 1 trial of EVT801 has been completed, with initial results presented at the 2024 Ovarian Cancer Research Symposium.

As the current trial advances, these early results position the paxalisib-pembrolizumab-chemotherapy combination as a promising approach to rapidly suppress tumor dissemination in metastatic TNBC, a patient population in critical need of more effective systemic therapies.

"CTC clusters are emerging as key drivers of metastatic spread—they're 20–100X more efficient at seeding than single CTCs—and the sharp decline we're seeing is truly encouraging. We believe this combination may offer a meaningful early intervention against systemic disease progression,” added Friend.

REFERENCE:

Kazia Therapeutics reports early efficacy data from first triple-negative breast cancer patient receiving paxalisib combination regimen achieving >50% reduction in circulating tumor cells in phase 1b trial. News release. Kazia Therapeutics. July 9, 2025. Accessed July 9, 2025. https://tinyurl.com/mr2yb2v5