Paxalisib produced clinical benefit across all six evaluable patients with Stage IV triple-negative breast cancer (TNBC) in an ongoing Phase Ib study. The molecule is a PI3K/mTOR inhibitor being developed by Australia-based Kazia Therapeutics Limited (Nasdaq: KZIA). Five of the six patients achieved an objective response — defined as a 30% or greater reduction in tumor burden — including one complete metabolic response and four partial responses, for an objective response rate of 83%. The sixth patient achieved stable disease. No paxalisib-related serious adverse events were observed, and no grade 3 or higher hyperglycemia, stomatitis, or mucositis occurred, toxicities that frequently limit PI3K/mTOR pathway inhibitors.
Paxalisib inhibits both PI3K and mTOR, disrupting downstream signaling that drives tumor cell proliferation and, the company asserts, suppressing immune evasion mechanisms that render TNBC refractory to checkpoint inhibitor therapy. The trial evaluates paxalisib in combination with Merck's Keytruda (pembrolizumab) and chemotherapy in patients with advanced metastatic TNBC.
The clinical responses were accompanied by exploratory translational findings. Across all six patients, terminally exhausted CD8+ T cells — a dysfunctional cytotoxic T-cell population that has lost anti-tumor activity — declined by a median of 51% within approximately three weeks of treatment, while total CD8+ T cell counts remained unchanged. Kazia said the finding may indicate a shift away from terminal T-cell exhaustion, while total CD8+ T-cell counts remained stable. Circulating tumor cell (CTC) clusters, which are associated with metastatic seeding, fell by a median of 83% within six to seven weeks. The company said blood-based multimodal protein, RNA, and plasma profiling showed increases in immune cell populations associated with anti-tumor activity alongside evidence of PI3K-AKT pathway target engagement.
The most striking individual outcome involved a 44-year-old woman with Stage IV TNBC who achieved a complete metabolic response with no evidence of disease since November 2025 — a response that has remained durable through the most recent assessment. Responses were observed across lung, liver, bone, lymph node, and central nervous system target lesions, with responses emerging as early as approximately three months post-randomization.