Paxalisib with Trastuzumab for HER2-Positive Metastatic Breast Cancer with Active Brain Metastases: A Phase II Trial with Integrated Plasma and CSF ctDNA Analyses.

PURPOSE: HER2+ breast cancer brain metastases (BCBM) frequently harbor PI3K/AKT/mTOR alterations. Preclinical HER2+ BCBM models demonstrated durable tumor regression with dual PI3K and mTOR inhibition. Our phase II trial evaluated paxalisib, a brain-penetrant dual PI3K/mTOR inhibitor, combined with trastuzumab.

PATIENTS AND

METHODS

Eligible patients had active/progressive HER2+ BCBM and could have received prior therapies; leptomeningeal disease was excluded. The trial included a safety run-in to determine the recommended phase II dose (RP2D), followed by expansion cohorts. The primary endpoint was confirmed central nervous system (CNS) objective response rate (ORR) per Response Assessment in Neuro-Oncology Brain Metastases criteria at the RP2D. Paired plasma and cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) was analyzed using ultra-low-pass whole-genome sequencing and whole-exome sequencing.

RESULTS

Seventeen patients were treated (median age 44 years; median 5 prior therapy lines). Paxalisib 30 mg daily plus trastuzumab was established as the RP2D. Among 12 patients treated at the RP2D, no confirmed CNS responses occurred (CNS ORR, 0%; 95% CI, 0.0-26.5%), and the study closed for futility. Median overall survival was 16.5 months. Treatment was feasible, with a safety profile consistent with PI3K/mTOR inhibition. Exploratory ctDNA analyses showed higher tumor fraction in CSF than plasma, with longitudinal changes in CSF tumor fraction paralleling CNS tumor burden.

CONCLUSIONS

Paxalisib combined with trastuzumab was feasible but did not meet the primary endpoint of CNS ORR in heavily pretreated HER2+ BCBM. Exploratory findings suggest that CSF-derived ctDNA may better capture tumor genomics and treatment response than plasma ctDNA in HER2+ BCBM.  .