Kazia Therapeutics Limited (NASDAQ: KZIA), the Sydney-based oncology drug developer, delivered new translational and early clinical data at the 2025 San Antonio Breast Cancer Symposium (SABCS) that could redefine how advanced breast cancers—especially HER2-positive and triple-negative breast cancer (TNBC)—are treated when it comes to immune resistance and metastatic spread. In a move that generated a flurry of interest among clinical researchers and investors alike, Kazia Therapeutics unveiled evidence that its investigational PI3K/mTOR inhibitor, paxalisib, is showing robust activity in breaking down therapy-resistant circulating tumor cell (CTC) clusters while also reversing immune exhaustion, a well-known stumbling block for current checkpoint inhibitor regimens like pembrolizumab.
In the triple-negative breast cancer (TNBC) setting, early clinical signals from the ongoing Phase 1b PaxPlus-ABC trial were particularly eye-catching: the very first patient treated with a paxalisib–pembrolizumab–chemotherapy combination experienced a striking 76% reduction in primary tumor volume, accompanied by dramatic drops in both single CTCs and highly aggressive clusters. Crucially, researchers observed that interrupting paxalisib—even briefly—led to a resurgence of CTC clusters, which pembrolizumab alone could not control, highlighting the compound’s unique role in targeting metastatic drivers.
This mechanistic double punch—disrupting the metastatic machinery and reinvigorating exhausted immune cells—puts Kazia Therapeutics on the radar of those watching for the next wave of immunotherapy enhancers. Early ex-vivo work in HER2-positive disease has also shown that paxalisib can dismantle stubborn Vim+/Snail+/NRF2+ CTC clusters, shifting the tumor microenvironment from immunologically “cold” to “hot”—a transition that often predicts better outcomes with immunotherapy.
What new mechanisms of action did Kazia Therapeutics’ presentations at SABCS 2025 reveal about paxalisib’s impact on tumor biology and immune response?
Presentations at the symposium provided a rare deep dive into the cellular and molecular impact of paxalisib. In HER2-positive metastatic breast cancer, where nearly all patients eventually relapse despite targeted therapies, Kazia’s research spotlighted an underappreciated gap: persistent, highly aggressive CTC clusters remain in circulation even among radiographically responding patients. By leveraging advanced liquid biopsy profiling, investigators revealed that paxalisib, when applied ex vivo, slashed the number of single CTCs by 42% and CTC clusters by 78%, including large clusters associated with rapid disease spread.
Moreover, these clusters were not just any tumor cells—they were enriched for a mesenchymal phenotype (Vimentin+, Snail+, NRF2+), long recognized as drivers of metastasis and therapeutic resistance. Paxalisib not only disrupted these clusters but also appeared to reverse some of the “epigenetically locked” resistance pathways that typically fuel disease progression.
On the immune side, samples from patients with poor clinical response had increased populations of exhausted T-cells and dampened cytotoxic activity. Paxalisib exposure, however, led to a resurgence of cytotoxic, interferon, and inflammatory pathways—classic hallmarks of an immune system ready to attack tumors. This ability to “reheat” cold tumors is what gives paxalisib such compelling potential as an immunotherapy adjuvant.
How does early clinical data from the PaxPlus-ABC Phase 1b study inform expectations for paxalisib in TNBC and other subtypes?
The first clinical signals from the PaxPlus-ABC Phase 1b trial combine the best of bench and bedside. The lead patient not only saw a rapid and marked decrease in CTC clusters and exhausted CD8 T cells but also experienced epigenetic reprogramming of tumor cells toward less aggressive phenotypes, as confirmed by digital pathology and gene expression profiling. Imaging corroborated these findings, with tumor area shrinking from 154 mm² to just 36 mm² after a single treatment cycle.
Notably, when paxalisib was paused due to a chemotherapy side effect, CTC clusters resurged—despite the continued use of pembrolizumab. Once paxalisib was restarted, cluster suppression resumed. This on–off–on dynamic offers clear, real-world evidence that pembrolizumab monotherapy may be insufficient to control metastatic progression in this setting, and that paxalisib’s addition addresses a critical therapeutic gap.
Why do experts believe paxalisib may expand its relevance beyond triple-negative and HER2-positive breast cancer?
Kazia Therapeutics is making the case that paxalisib’s unique biology is not limited to a single tumor type. Both HER2-positive and TNBC tumors share two hallmarks: therapy-resistant mesenchymal CTC clusters and T-cell exhaustion. By directly targeting both, paxalisib could offer a powerful strategy across a spectrum of breast cancer subtypes—including BRCA-mutated and homologous recombination-deficient tumors, where synergy with synthetic lethal agents like olaparib is a promising next step.
Kazia’s CEO, Dr. John Friend, said in comments attributed by the company that these findings hint at a “unifying biology across breast cancer subtypes” and suggest that paxalisib’s impact could be far broader than initially envisioned. Investors, naturally, are watching to see how quickly these data can translate into registrational studies and, ultimately, regulatory approval.
How does Kazia Therapeutics’ broader clinical development program for paxalisib reflect its ambition to redefine cancer therapy, and what milestones should investors watch for next?
Paxalisib, originally licensed from Genentech in 2016, has steadily expanded its clinical reach. Beyond breast cancer, the molecule has moved through trials in glioblastoma, brain metastases, and rare pediatric brain tumors—securing multiple Orphan Drug, Fast Track, and Rare Pediatric Disease designations from the U.S. Food and Drug Administration in the process. A pivotal study in glioblastoma is under discussion after completion of a Phase 2/3 program in 2024, and a growing slate of breast cancer and brain metastasis trials is generating encouraging interim signals.
Kazia Therapeutics is also developing EVT801, an inhibitor of VEGFR3 acquired from Evotec SE, which has shown promise in preclinical models and is now entering early clinical testing. Taken together, these programs reflect Kazia Therapeutics’ ambition to tackle solid tumors from multiple biological angles, using precision-targeted drugs that work in concert with immunotherapy.
What is the current investor sentiment on Kazia Therapeutics (NASDAQ: KZIA) following these updates, and what could drive future stock movement?
As of this data release, Kazia Therapeutics’ shares (NASDAQ: KZIA) have seen modest movement, typical for early-stage clinical readouts, with institutional attention likely to increase as further data mature. Sentiment among biotech analysts tracking Kazia Therapeutics is cautiously optimistic, reflecting the need for larger, more definitive studies to confirm these early signals but also acknowledging that the underlying science addresses urgent gaps in breast cancer care. Market watchers expect that tangible progress toward pivotal trials, partnership announcements, or accelerated regulatory pathways—especially if accompanied by stronger financials or institutional buy-in—could be catalysts for renewed upward momentum.
Key takeaways: What the new paxalisib data from Kazia Therapeutics means for breast cancer treatment
- Kazia Therapeutics presented new clinical and translational findings at SABCS 2025 showing that paxalisib, a brain-penetrant PI3K/mTOR inhibitor, can reinvigorate anti-tumor immunity and dismantle therapy-resistant circulating tumor cell (CTC) clusters in both HER2-positive and triple-negative breast cancer.
- In HER2-positive metastatic breast cancer, ex-vivo studies revealed that paxalisib reduced single CTCs by 42% and CTC clusters by 78%, directly disrupting highly aggressive clusters associated with metastatic spread—something current HER2-targeted therapies often fail to address.
- Early Phase 1b data in triple-negative breast cancer (TNBC) indicated that the first patient treated with a paxalisib combination experienced a 76% reduction in tumor volume and significant drops in CTC clusters. Interruption of paxalisib led to a resurgence of clusters, underscoring its unique role in controlling metastatic drivers.
- Mechanistically, paxalisib appears to reverse T-cell exhaustion and activate immune pathways, shifting the tumor microenvironment from immunologically “cold” to “hot” and potentially boosting the effectiveness of immunotherapies like pembrolizumab.
- Kazia Therapeutics’ data suggest that pembrolizumab alone may not sufficiently suppress CTC burden, highlighting a new opportunity for combination strategies that include paxalisib.
- The company believes paxalisib’s ability to address mesenchymal CTC clusters and immune dysfunction may extend its relevance to BRCA-mutated, homologous recombination–deficient, and other breast cancer subtypes where current options fall short.
- Paxalisib is being developed for multiple cancer indications beyond breast cancer, including glioblastoma, brain metastases, and rare pediatric brain tumors. It has received Orphan Drug and Fast Track designations from the U.S. Food and Drug Administration in several indications.
- Biotech analysts and investors are watching for upcoming registrational studies and pivotal trial designs, with institutional sentiment tilting positive but measured pending more mature data.
- Kazia Therapeutics’ broader pipeline includes EVT801, a VEGFR3 inhibitor also moving through early-stage development, signaling an ambition to expand its presence in the oncology field.
- The latest data position Kazia Therapeutics and paxalisib as innovators aiming to redefine the metastatic breast cancer treatment roadmap by combining targeted inhibition of tumor spread with restoration of anti-tumor immunity.
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