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.