Kazia Therapeutics Limited has presented new clinical and translational data at the 2025 San Antonio Breast Cancer Symposium demonstrating that paxalisib, its investigational brain-penetrant PI3K/mTOR inhibitor, may suppress circulating tumor cell clusters and reverse immune exhaustion in two of the most treatment-resistant breast cancer subtypes—HER2-positive metastatic breast cancer and triple-negative breast cancer. The early evidence, including results from ex vivo liquid biopsy models and the first patient enrolled in a Phase 1b trial, points to paxalisib’s potential as a dual-mechanism therapy capable of disrupting both the metastatic process and the immunologic barriers that limit the effectiveness of current checkpoint inhibitors.
What this reveals about the persistent blind spot in HER2-targeted breast cancer therapy
Despite a decade of progress in HER2-targeted treatments, Kazia Therapeutics’ new data suggests that even patients showing partial or stable response to these therapies often continue to harbor aggressive circulating tumor cell clusters that escape radiographic detection. These clusters are not merely bystanders in the metastatic process. They represent a dynamic and biologically active compartment marked by mesenchymal transformation and epigenetic resistance.
In ex vivo HER2-positive samples, paxalisib reduced single circulating tumor cells by over 40 percent and disrupted clusters by nearly 80 percent, including the most concerning large clusters consisting of five or more cells. These clusters expressed markers such as Vimentin, Snail, and NRF2, indicating a phenotype closely associated with metastasis, immune evasion, and therapeutic resistance. Notably, such clusters persisted even in patients who were otherwise considered to be responding clinically to HER2-targeted agents.
This disconnect between imaging-based response and underlying disease biology underscores a blind spot in the current standard of care. Kazia Therapeutics has now opened a new window of understanding, where circulating tumor cell burden may serve as a critical biomarker of residual disease and therapeutic failure.
Why paxalisib’s immunomodulatory impact matters more than its cytostatic activity
Kazia Therapeutics is not simply positioning paxalisib as another targeted agent against PI3K pathway mutations. The early findings highlight its immunologic reprogramming capabilities, particularly in reversing T-cell exhaustion and restoring cytotoxic function. This attribute is especially relevant in triple-negative breast cancer, where immunotherapy has delivered mixed results and durable responses remain the exception.
In the first patient treated in the PaxPlus-ABC Phase 1b trial, which combines paxalisib with pembrolizumab and chemotherapy, a single cycle of therapy was enough to produce measurable reductions in circulating tumor cell clusters and reinvigoration of cytotoxic immune pathways. The tumor volume shrank significantly from a baseline of 154 square millimeters to just 36 square millimeters on imaging. Concurrently, digital pathology and molecular profiling showed a shift in circulating tumor cells toward less aggressive epigenetic signatures and a reversal of CD8 T-cell exhaustion.
What makes this result more compelling is the clear mechanistic dissociation observed during a temporary treatment pause. When paxalisib was withheld due to a chemotherapy-related adverse event, circulating tumor cell clusters rebounded rapidly. Pembrolizumab monotherapy was unable to maintain suppression. Upon reintroduction of paxalisib, suppression was restored, reinforcing the interpretation that paxalisib—not the checkpoint inhibitor—is directly responsible for modulating both the metastatic burden and the immune environment.
How these findings could redefine patient stratification in future trials
The implications for future trial design are significant. If further validated, circulating tumor cell cluster dynamics could serve as a real-time, non-invasive pharmacodynamic biomarker. Kazia Therapeutics may be able to use this marker to rapidly identify responders, optimize dose timing, and reduce trial duration. Such adaptive strategies are especially valuable in early-stage settings where biomarkers can help select biologically enriched patient subsets.
Moreover, the immune profiling data support a refined understanding of which patients are most likely to benefit from paxalisib combinations. Those with exhausted T-cell populations, impaired granzyme activity, or persistent tumor-associated inflammation may represent an ideal target population. These insights could accelerate the expansion of paxalisib into earlier lines of therapy or into maintenance settings where minimal residual disease is a growing focus.
What clinicians and regulators are likely to monitor next
Clinicians observing the development of paxalisib will likely be focused on three fronts. First, they will want to see durability of the circulating tumor cell and immune effects across a broader patient population beyond the single case reported. Second, there will be close attention to how these biological effects correlate with hard clinical endpoints such as progression-free survival, objective response rate, and duration of response. Third, safety and tolerability will remain under scrutiny, particularly in complex triplet regimens that combine targeted therapy, chemotherapy, and immune checkpoint inhibitors.
Regulators are expected to weigh the novelty of the circulating tumor cell cluster data against the maturity of the clinical evidence. Although surrogate endpoints like circulating tumor cell burden are not yet established surrogates for approval, Kazia Therapeutics’ ability to link this biomarker with clear mechanistic changes and tumor volume shrinkage may increase the credibility of this approach in early dialogues with regulatory agencies.
Where risks remain for Kazia Therapeutics and paxalisib’s clinical trajectory
Despite the enthusiasm generated by the new findings, the clinical program still faces substantial challenges. The HER2-positive dataset is ex vivo and not yet validated in human in vivo studies. The TNBC data, while biologically rich, is based on a single patient. The statistical and clinical reproducibility of these results remains untested in broader cohorts. Until multiple patients demonstrate sustained responses with similar molecular and cellular signatures, the risk of false positives or patient-specific idiosyncrasies remains high.
Another open question concerns long-term dosing feasibility. As with many PI3K/mTOR inhibitors, the risk of immune-related adverse events, metabolic toxicity, and interaction with chemotherapy regimens must be carefully managed. If continuous dosing of paxalisib is required to maintain circulating tumor cell suppression, it could create tolerability hurdles that affect treatment adherence or limit the eligible patient pool.
From a business standpoint, Kazia Therapeutics is still a lean operation. Its clinical strategy is highly reliant on paxalisib’s success. Any delays in trial enrollment, lack of sustained efficacy, or inability to secure partnerships could place pressure on the company’s balance sheet. Commercialization in heavily saturated markets like HER2-positive and triple-negative breast cancer will also depend on securing payer alignment and demonstrating clear value over existing agents and combinations.
What this pivot could signal for Kazia Therapeutics beyond glioblastoma
Historically, Kazia Therapeutics has focused its development efforts on glioblastoma, where paxalisib had shown promise in earlier trials. However, the glioblastoma space is notoriously high-risk, with multiple failed programs and poor commercial viability. The pivot to breast cancer, especially metastatic subtypes with immune dysfunction and mesenchymal transformation, offers a more actionable path to broader utility.
Importantly, the new findings do not suggest a binary shift away from glioblastoma but rather a diversification of clinical opportunity. The dual-action nature of paxalisib—addressing both the metastatic machinery and immune escape—is not tumor-type limited. It could also have potential applications in other cancers characterized by circulating tumor cell cluster formation and immune suppression, such as ovarian cancer, brain metastases from lung or breast origin, or rare central nervous system lymphomas.
Kazia Therapeutics has positioned itself to explore these opportunities without abandoning its core competencies in neuro-oncology. The ex vivo and early patient-level findings in breast cancer may serve as proof points for broader combination strategies with checkpoint inhibitors, radiation, or DNA repair-targeting agents.
Why the breast cancer immunotherapy market is hungry for new mechanism-based adjuncts
Checkpoint inhibition has changed the treatment paradigm for multiple solid tumors, but in breast cancer, particularly triple-negative disease, responses have been inconsistent and often short-lived. One of the most cited reasons for this variability is the presence of immune-cold tumors or the accumulation of exhausted immune cell phenotypes. Paxalisib’s potential to reprogram the immune microenvironment from cold to hot, and to re-energize exhausted T cells, offers a way to revive checkpoint inhibitor efficacy where it otherwise fails.
The combination of direct action on circulating tumor cell clusters and indirect support through immune reinvigoration creates a compelling case for incorporating paxalisib as an adjunct in both checkpoint-naive and checkpoint-experienced settings. Industry analysts watching this space will be particularly attuned to whether Kazia Therapeutics can deliver consistent biomarker-driven outcomes and begin building a regulatory case around these dual endpoints.
Is Kazia’s paxalisib becoming the new backbone for checkpoint combos? added by Venkatesh B on
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