Kazia Therapeutics Expands Paxalisib Clinical Trial into HR+/HER2- Breast Cancer, Supported by Preclinical Data Showing Strong Clinical Activity and Safety in HR+ Breast Cancer
Rhea-AI Summary
Kazia Therapeutics (NASDAQ: KZIA) reported new preclinical data showing that its PI3K/mTOR inhibitor paxalisib, in combination with standard-of-care therapy, was well tolerated and produced statistically significant antitumor activity in HR+/HER2- breast cancer models, including resensitizing CDK4/6 inhibitor‑resistant tumors.
Based on these findings, Kazia is expanding its ongoing TNBC clinical trial to include a three‑arm cohort in pre‑treated HR+/HER2- metastatic breast cancer, evaluating paxalisib plus fulvestrant with palbociclib at 15 mg and 30 mg versus fulvestrant alone. The company has filed a provisional patent and identified a high‑risk subset defined by a novel PI3K/mTOR biomarker with tissue‑ and blood‑based tests. Sites for the expansion are expected to activate and enroll the first patient before year‑end 2026, with full enrollment anticipated by end of 2027 and a full data readout in 2028. According to Kazia, recent financing is expected to fund this program through completion.
Positive
- Preclinical models showed statistically significant reductions in tumor volume with paxalisib combinations in HR+/HER2- breast cancer
- Trial expansion adds three arms testing paxalisib 15 mg and 30 mg plus fulvestrant and palbociclib versus fulvestrant alone
- Company expects funding from recent financing to support the HR+/HER2- trial expansion program through completion
Negative
- None.
News Explained
The planned expansion adds two paxalisib dose combinations and a fulvestrant-only comparator; enrollment has not yet begun.
Kazia Therapeutics is amending its ongoing TNBC trial to add an HR+/HER2- metastatic breast-cancer expansion, so the disclosed change is a new clinical-development cohort rather than an expansion already enrolling patients.
The three-arm design will compare paxalisib at
Safety and tolerability are the primary endpoints; progression-free survival, overall response rate, and overall survival are secondary endpoints.
Key Figures
Previous Clinical trial Reports
| Date | Event | Sentiment | 24h Move | Catalyst |
|---|---|---|---|---|
| Oct 27 | FDA meeting request | Positive | +4.6% | Planned FDA discussion of overall survival data and potential NDA pathway |
| Jul 09 | Phase 1b efficacy data | Positive | +39.6% | First patient showed greater than 50% circulating tumor-cell reduction |
| Jun 11 | Preclinical trial data | Positive | +81.5% | Paxalisib demonstrated antitumor activity in immunotherapy-resistance models |
| Jun 05 | Phase 1b initiation | Positive | -0.2% | First patient was dosed in advanced breast cancer combination trial |
| Oct 02 | Phase I clinical data | Positive | +1.3% | Paxalisib plus radiation produced partial responses in brain metastases |
24h Move is the share-price change in the day after each event; other market factors may also have contributed.
Clinical-trial announcements were generally aligned with positive price reactions, with one divergence.
Key Terms
cdk4/6 inhibitor medical
pi3k/mTOR biomarker medical
xenograft model medical
progression-free survival medical
overall response rate medical
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Preclinical Data Show Paxalisib Combined With Standard-of-Care Therapy Is Well Tolerated and Produces Statistically Significant Antitumor Activity
Three-Arm Expansion of the Ongoing TNBC Trial Will Evaluate Paxalisib Plus Fulvestrant, With Palbociclib, Versus Standard-of-Care
First Patient Expected By Year-End 2026 and Full Enrollment by End of 2027
"HR+/HER2- breast cancer accounts for approximately 60–
In addition to these findings, paxalisib in combination with fulvestrant, and paxalisib in combination with fulvestrant and palbociclib, showed consistent safety and resulted in statistically significant reductions in tumor volume across preclinical models. Kazia has filed a patent that is supported by the Company's preclinical findings and has identified a high-risk subset of metastatic HR+/HER2- breast cancer defined by a novel PI3K/mTOR biomarker, with tissue- and blood-based tests associated with poor survival. Extensive benchmarking studies show that paxalisib can resensitize treatment-resistant tumors to combination therapy through a distinct epigenetic mechanism, an effect not observed with gedatolisib, an FDA-approved intravenous PI3K/mTOR inhibitor, indicating a paxalisib-specific effect rather than a class effect. In a HR+ xenograft model, paxalisib in combination with fulvestrant and palbociclib reduced tumor burden without added toxicity and showed primary tumor growth inhibition comparable to gedatolisib in combination with the same regimen.
"Our extensive benchmarking shows that paxalisib is differentiated in targeting the PI3K/mTOR–epigenetic resistance axis and importantly, this is not a class effect," said Dr. Sudha Rao, Chief Scientific Officer, Kazia Therapeutics. "Paxalisib's unique attributes are uncovering a broader role for PI3K/mTOR beyond conventional cytoplasmic signalling, with alternative pathways that may drive metastatic disease and resistance. In HR+ breast cancer, we have identified a novel epigenetic PI3K/mTOR biomarker, with both liquid and tissue tests, that is enriched in patients with poor prognosis. This gives us the opportunity to enrich for the patients where this biology matters most and brings precision medicine to HR+ breast cancer."
This benchmarking work is ongoing, and Kazia expects to present additional data later this year, including further cellular, molecular and epigenetic characterization of paxalisib relative to other PI3K/mTOR inhibitors.
Current development strategies in this setting have primarily focused on sequencing additional lines of endocrine therapy, targeted agents or antibody-drug conjugates after resistance emerges. Kazia's preclinical findings suggest that paxalisib may address resistance mechanisms at an earlier biological level through epigenetic and transcriptional effects that extend beyond conventional PI3K/mTOR pathway inhibition.
Alongside its IP filing, Kazia is amending the protocol of its ongoing TNBC clinical trial to add a three-arm expansion evaluating paxalisib in patients with pre-treated HR+/HER2- metastatic breast cancer. Patients will be randomized to one of three arms: paxalisib at 15mg plus fulvestrant (hormone therapy), with CDK4/6 inhibitor palbociclib; paxalisib at 30mg plus fulvestrant, with palbociclib; or a standard-of-care comparator arm of fulvestrant. The primary endpoint is safety and tolerability, with progression-free survival, overall response rate and overall survival as secondary endpoints.
The Company expects sites for this expansion to be activated and the first patient enrolled before the end of 2026, with full enrollment anticipated by the end of 2027. Clinical updates are anticipated throughout 2027, with a full readout anticipated in 2028.
About Kazia Therapeutics
Kazia Therapeutics (NASDAQ: KZIA) is an oncology-focused drug development company, based in Sydney, Australia. The Company's lead asset, paxalisib, is an investigational brain-penetrant inhibitor of the PI3K/Akt/mTOR pathway, which is being developed to treat multiple forms of cancer. Licensed from Genentech in late 2016, paxalisib is or has been the subject of over 15 clinical trials. A completed Phase 2/3 study in glioblastoma (GBM AGILE) was reported in 2024, and discussions are ongoing for designing and executing a pivotal registrational study in pursuit of a standard approval. Other clinical trials involving paxalisib are ongoing in advanced breast cancer, brain metastases, diffuse midline gliomas, and primary central nervous system lymphoma, with several of these trials having reported encouraging interim data. Paxalisib was granted Orphan Drug Designation for glioblastoma by the U.S. Food and Drug Administration (FDA) in February 2018, and Fast Track Designation (FTD) for glioblastoma in August 2020. Paxalisib was also granted FTD in July 2023 for the treatment of solid tumor brain metastases harboring PI3K pathway mutations in combination with radiation therapy. Additionally, paxalisib was granted Rare Pediatric Disease Designation and Orphan Drug Designation by the FDA for diffuse intrinsic pontine glioma in August 2020 and for atypical teratoid/rhabdoid tumors in June 2022 and July 2022, respectively. Kazia is also developing EVT801, a small molecule inhibitor of VEGFR3, which was licensed from Evotec SE in April 2021. In addition to its clinical-stage programs, Kazia is advancing NDL2, a potentially first-in-class intracellular PD-L1 protein degrader program targeting a newly identified mechanism of immunotherapy resistance and metastatic progression, as well as MSETC, a potentially first-in-class SETDB1 inhibitor program intended to restore immune signaling in tumors that have become resistant to immunotherapy, including checkpoint inhibitors. Both programs are currently in preclinical development. For more information, please visit www.kaziatx.com or follow us on X @KaziaTx.
Forward-Looking Statements
This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. These forward-looking statements include, but are not limited to, statements regarding: the potential therapeutic benefit of paxalisib in HR+/HER2- breast cancer; the significance of preclinical findings, including benchmarking studies relative to other PI3K/mTOR inhibitors; the Company's plan to expand the ongoing TNBC clinical trial into HR+/HER2- advanced breast cancer; the expected timing of site activation, first patient enrollment and full enrollment; anticipated clinical updates and full data readout timelines; the Company's biomarker program and anticipated future disclosures; and the sufficiency of the Company's capital to fund the program. Forward-looking statements are generally identified by words such as "anticipates," "believes," "expects," "intends," "plans," "may," "will," "could," "should," "estimates," "projects," "potential," and similar expressions. These forward-looking statements are based on management's current expectations and assumptions as of the date of this press release and are subject to significant risks, uncertainties, and other factors that could cause actual results to differ materially from those expressed or implied. Such risks and uncertainties include, but are not limited to: the preliminary and preclinical nature of the data described, which may not predict clinical outcomes in humans; the ability to successfully amend the existing trial protocol and activate new sites; risks associated with the conduct, timing and enrollment of clinical trials; regulatory review and approval processes; reliance on third-party collaborators and trial sites; the Company's ability to obtain, maintain and protect its intellectual property; the Company's future capital needs and ability to fund planned operations; general economic and market conditions; and the Company's ability to maintain compliance with NASDAQ listing requirements.
For a more complete discussion of risks and uncertainties, please refer to the Company's filings with the SEC, including the "Risk Factors" section of the Company's most recent Annual Report on Form 20-F. The Company undertakes no obligation to update or revise any forward-looking statements, whether as a result of new information, future events, or otherwise, except as required by law. All forward-looking statements are qualified in their entirety by this cautionary statement.
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SOURCE Kazia Therapeutics Limited