Kazia Therapeutics Announces Transformative Preclinical Data Demonstrating Paxalisib's Potential to Overcome Immunotherapy Resistance in Triple-Negative Breast Cancer (TNBC)

Rhea-AI Summary

Kazia Therapeutics (NASDAQ: KZIA) has unveiled groundbreaking preclinical research published in Molecular Cancer Therapeutics demonstrating that its lead drug paxalisib shows promise in treating triple-negative breast cancer (TNBC). The study, conducted at QIMR Berghofer Medical Research Institute, revealed that paxalisib can effectively reprogram the tumor microenvironment and enhance immune response when combined with immunotherapy. Key findings show that paxalisib's dual targeting of PI3K and mTOR inhibits cancer cell growth, increases T cell infiltration, and demonstrates synergistic antitumor activity when combined with KEYTRUDA, leading to tumor regression in preclinical models. The company has already initiated a Phase 1b clinical trial testing paxalisib in combination with checkpoint inhibitors and chemotherapy for advanced breast cancer, with the first patient dosed.

Positive

• Preclinical data shows paxalisib's dual targeting mechanism effectively inhibits cancer cell proliferation and migration
• Demonstrated synergistic antitumor activity when combined with KEYTRUDA, leading to tumor regression and prolonged survival
• Successfully launched Phase 1b clinical trial with first patient already dosed
• Potential expansion of paxalisib's application beyond brain cancers to solid tumors

Negative

• Results are only preclinical and need to be validated in human trials
• No efficacy data available yet from the Phase 1b trial
• Potential competition from existing TNBC treatments and other compounds in development

Insights

Oncology Research Scientist

Kazia's paxalisib shows significant potential to enhance immunotherapy in triple-negative breast cancer through compelling preclinical synergy with checkpoint inhibitors.

The preclinical data for paxalisib represents a potentially important advancement in the TNBC treatment landscape. The dual PI3K/mTOR inhibition mechanism demonstrated superiority over PI3K inhibition alone in controlling cancer cell proliferation and migration. This pharmacological distinction is crucial, as previous single-pathway PI3K inhibitors have shown limited clinical utility in breast cancer.

The study's finding that paxalisib remodels the tumor microenvironment to increase both CD4+ and CD8+ T cell infiltration and activation addresses a fundamental challenge in TNBC treatment. Many TNBC tumors exhibit an immunosuppressive microenvironment that limits checkpoint inhibitor efficacy. By enhancing T cell activity, paxalisib potentially converts "cold" tumors to "hot" ones - a key prerequisite for immunotherapy response.

Most compelling is the synergistic antitumor activity observed when combining paxalisib with pembrolizumab (Keytruda), resulting in robust tumor regression and prolonged survival in preclinical models. This synergy provides strong mechanistic rationale for the company's recently launched Phase 1b clinical trial.

The extension of paxalisib development beyond brain cancers into TNBC represents strategic portfolio expansion, targeting an indication with significant unmet need. The $53 billion immunotherapy market stands to benefit substantially from agents that can overcome resistance mechanisms. While promising, investors should recognize that translation from preclinical to clinical success remains a significant hurdle, with the Phase 1b trial results becoming the next critical milestone for validating this approach.

SYDNEY, June 11, 2025 /PRNewswire/ -- Kazia Therapeutics Limited (NASDAQ: KZIA), a clinical-stage biotechnology company pioneering next-generation oncology therapeutics, today announced the publication of transformative preclinical research in the journal Molecular Cancer Therapeutics, a journal of the American Association for Cancer Research that underscores the powerful potential of its lead asset, paxalisib, in reshaping the treatment landscape for triple-negative breast cancer (TNBC), one of the most aggressive and treatment-resistant cancer subtypes.

The preclinical program was conducted by Professor Sudha Rao at the renowned QIMR Berghofer Medical Research Institute, revealing how paxalisib can reprogram the tumor microenvironment and enhance immune response, showing substantial synergy with immune checkpoint inhibitors. The data provide strong scientific and translational rationale for continued development of paxalisib as part of immunotherapy-based regimens.

Key Findings

• Dual targeting of PI3K and mTOR but not PI3K alone inhibits cancer cell proliferation and migration in vitro.
• Paxalisib remodels the TNBC tumor microenvironment, increasing CD4+ and CD8+ T cell infiltration and activation
• The combination of paxalisib with KEYTRUDA® (pembrolizumab) demonstrated synergistic antitumor activity in advanced breast cancer, resulting in robust tumor regression and prolonged survival in preclinical models
• The data validate a mechanistic rationale for ongoing clinical exploration of paxalisib in combination with checkpoint inhibitors and PARP inhibitors

"This landmark study offers a mechanistic and translational foundation for our newly launched Phase 1b clinical trial of paxalisib in advanced breast cancer," said Dr. John Friend, CEO of Kazia. "It not only extends the therapeutic potential of paxalisib beyond brain cancers but also positions it at the forefront of innovative immunotherapy combinations in solid tumors."

The publication, "Combination of the PI3K/mTOR inhibitor paxalisib with immune checkpoint inhibitors enhances antitumor activity in preclinical models of triple-negative breast cancer," is available online at https://aacrjournals.org/mct/article/doi/10.1158/1535-7163.MCT-24-0693/762929/Depleting-the-action-of-EZH2-through-PI3K-mTOR.

Clinical Milestone
Kazia recently announced that the first patient has been dosed in the Phase 1b trial evaluating paxalisib in combination with checkpoint inhibitors and chemotherapy in advanced breast cancer, marking a critical step toward clinical translation of these findings.

For investor and media, please contact Alex Star, Managing Director LifeSci Advisors LLC

About Kazia Therapeutics Limited
Kazia Therapeutics Limited (NASDAQ: KZIA) is an oncology-focused drug development company, based in Sydney, Australia. Our lead program is paxalisib, an investigational brain penetrant inhibitor of the PI3K / Akt / mTOR pathway, which is being developed to treat multiple forms of brain cancer. Licensed from Genentech in late 2016, paxalisib is or has been the subject of ten clinical trials in this disease. 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 brain metastases, diffuse midline gliomas, and primary CNS lymphoma, with several of these trials having reported encouraging interim data. Paxalisib was granted Orphan Drug Designation for glioblastoma by the FDA in February 2018, and Fast Track Designation (FTD) for glioblastoma by the FDA in August 2020. Paxalisib was also granted FTD in July 2023 for the treatment of solid tumour brain metastases harboring PI3K pathway mutations in combination with radiation therapy. In addition, 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 tumours 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. Preclinical data has shown EVT801 to be active against a broad range of tumour types and has provided evidence of synergy with immuno-oncology agents. A Phase I study has been completed and preliminary data was presented at 15th Biennial Ovarian Cancer Research Symposium in September 2024. For more information, please visit www.kaziatherapeutics.com or follow us on X @KaziaTx.

Forward-Looking Statements
This announcement may contain forward-looking statements, which can generally be identified as such by the use of words such as "may," "will," "estimate," "future," "forward," "anticipate," or other similar words. Any statement describing Kazia's future plans, strategies, intentions, expectations, objectives, goals or prospects, and other statements that are not historical facts, are also forward looking statements, including, but not limited to, statements regarding: the timing for results and data related to Kazia's clinical and preclinical trials, Kazia's strategy and plans with respect to its programs, including paxalisib and EVT801, the potential results of its Phase 1b clinical trial evaluating paxalisib in combination with olaparib or KEYTRUDA® (pembrolizumab), developed by Merck & Co., Inc. for patients with advanced breast cancer, the potential benefits of paxalisib as an investigational PI3K/mTOR inhibitor, timing for any regulatory submissions or discussions with regulatory agencies, the potential market opportunity for paxalisib and Kazia's intent and efforts to regain and/or maintain compliance with the applicable Nasdaq continued listing requirements and standards. Such statements are based on Kazia's current expectations and projections about future events and future trends affecting its business and are subject to certain risks and uncertainties that could cause actual results to differ materially from those anticipated in the forward-looking statements, including risks and uncertainties: associated with clinical and preclinical trials and product development, related to regulatory approvals, related to the impact of global economic conditions, and related to Kazia's ability to regain and/or maintain compliance with the applicable Nasdaq continued listing requirements and standards. These and other risks and uncertainties are described more fully in Kazia's Annual Report, filed on form 20-F with the SEC, and in subsequent filings with the United States Securities and Exchange Commission. Kazia undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise, except as required under applicable law. You should not place undue reliance on these forward-looking statements, which apply only as of the date of this announcement.

This announcement was authorized for release by Dr. John Friend, CEO.

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SOURCE Kazia Therapeutics Limited

FAQ

What are the key findings of KZIA's preclinical study for paxalisib in TNBC?

The study showed paxalisib's dual targeting of PI3K and mTOR inhibits cancer cell growth, increases T cell infiltration, and demonstrates synergistic antitumor activity with KEYTRUDA, resulting in tumor regression in preclinical models.

What is the current development stage of Kazia's paxalisib for breast cancer treatment?

Kazia has initiated a Phase 1b clinical trial testing paxalisib in combination with checkpoint inhibitors and chemotherapy for advanced breast cancer, with the first patient already dosed.

How does paxalisib work in treating triple-negative breast cancer?

Paxalisib works by dual targeting PI3K and mTOR pathways, reprogramming the tumor microenvironment, and enhancing immune response when combined with immunotherapy.

What potential markets could paxalisib target according to the KZIA announcement?

Beyond its current focus on brain cancers, paxalisib shows potential for treating solid tumors, particularly triple-negative breast cancer (TNBC) when combined with immunotherapy.

Who conducted the preclinical research for Kazia's paxalisib?

The preclinical research was conducted by Professor Sudha Rao at the QIMR Berghofer Medical Research Institute.