Paxalisib Combination Shows Meaningful Activity in Metastatic TNBC

The dual PI3K/mTOR inhibitor paxalisib demonstrated encouraging preliminary clinical activity when combined with pembrolizumab (Keytruda) and chemotherapy for patients with stage IV metastatic triple-negative breast cancer (TNBC), according to a press release from the developer, Kazia Therapeutics.¹

The update from the ongoing phase 1b trial (ACTRN12624001340527) revealed that 3 patients treated with paxalisib-based regimens experienced meaningful clinical responses.

Main Data

At the time of the data update, 3 patients with metastatic TNBC demonstrated clinical responses. Within the formal phase 1b trial, 2 of 2 evaluable patients achieved a partial response (PR). Another patient, treated under an expanded access program, achieved a confirmed complete metabolic response.

Investigators observed these responses in patients presenting with visceral disease and multi-organ metastases. The reported median time on treatment for these patients was approximately 6.1 months, and all 3 patients remained on therapy at the time of the clinical update.

"While these observations represent a preliminary read from ongoing studies, the consistency and depth of responses we are seeing including tumor regression across multiple metastatic sites and a complete metabolic response are highly encouraging," said John Friend, MD, chief executive officer of Kazia Therapeutics, in the press release.¹ "Confirmed complete responses in metastatic [TNBC] are exceedingly rare, particularly in patients who have already progressed on standard therapies. These early data reinforce our belief that paxalisib has the potential to meaningfully enhance the activity of existing immunotherapy-based regimens, and we look forward to generating additional clinical and translational insights throughout the year."

Trial Details

This multi-center, open-label, randomized phase 1b study was initiated in June 2025 to evaluate the safety, tolerability, and preliminary activity of paxalisib in patients with advanced breast cancer. The trial evaluated paxalisib in combination with 2 different regimens: pembrolizumab plus chemotherapy or the PARP inhibitor olaparib (Lynparza) for patients with BRCA mutations.

Patients in the pembrolizumab cohort received a 30 mg daily dose of paxalisib. The trial aimed to determine if the addition of a PI3K/mTOR inhibitor could reverse immunotherapy resistance by remodeling the tumor microenvironment and increasing T-cell infiltration. Developers plan to activate additional clinical sites in 2026 with a goal of enrolling 12 patients with TNBC by the end of that year.

Patient Characteristics

Patients eligible for the pembrolizumab-containing cohort were required to have a PD-L1 combined positive score of 10 or higher and stage IV metastatic TNBC. One responder was a 61-year-old woman with metastatic disease localized to the left upper lobe of the lung and given paxalisib plus pembrolizumab and chemotherapy. After 9 cycles, serial imaging showed continued tumor reduction during each assessment with a partial response by iRECIST criteria.

A 47-year-old woman who had extensive metastatic TNBC including the lung, liver, bone, and lymph nodes was given the study regimen. After 3 cycles of treatment, imaging showed a partial response that included complete resolution of a target lung lesion.

A 44-year-old woman with metastatic TNBC who had previously received pembrolizumab plus chemotherapy had disease progression that included bone and lung metastases. She began retreatment in June 2025, and by November, PET/CT imaging showed no evidence of active malignancy, which is consistent with a complete metabolic response.

Main End Points

The primary end points of the phase 1b study included the assessment of safety and tolerability.² Secondary and exploratory end points focused on preliminary clinical activity, including objective response rates and the impact of the regimen on circulating tumor cell (CTC) counts, CTC clusters, and immune cell populations such as CD8 T cells.

Safety

Paxalisib at the 30 mg daily dose demonstrated a generally favorable safety and tolerability profile when used in combination with pembrolizumab and chemotherapy. Approximately 75% of the reported adverse events (AEs) were assessed by investigators as unlikely to be related to paxalisib.

The AEs specifically attributed to paxalisib were primarily mild to moderate in severity. Reported drug-related toxicities included 1 case of grade 1 hyperglycemia, which did not require medical intervention. While 2 serious AEs were reported during the study, both were deemed unrelated to the study drug.

References

1. Kazia Therapeutics reports encouraging preliminary clinical responses in ongoing phase 1b study of paxalisib in late-stage metastatic triple-negative breast cancer. News release. Kazia Therapeutics Limited. January 27, 2026. Accessed January 27, 2026. https://tinyurl.com/4793yrtx
2. Australian New Zealand Clinical Trials Registry. ACTRN12624001340527. Updated January 16, 2026. Accessed January 27, 2026. https://tinyurl.com/527r767f