Paxalisib with Trastuzumab for HER2-Positive Metastatic Breast Cancer with Active Brain Metastases: A Phase II Trial with Integrated Plasma and CSF ctDNA Analyses.
Elia Segui, Jorge Gomez Tejeda Zañudo, Noah Graham et al.
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In 30 seconds
This phase II trial evaluated brain-penetrant paxalisib plus trastuzumab in patients with active or progressive HER2-positive breast cancer brain metastases, including heavily pretreated patients; leptomeningeal disease was excluded. The recommended phase II dose was paxalisib 30 mg daily with trastuzumab. Among 12 patients treated at that dose, there were no confirmed CNS responses (CNS ORR, 0%; 95% CI, 0%-26.5%), and the study closed for futility. Exploratory paired liquid-biopsy analyses found higher tumor fraction in CSF than plasma, with CSF changes paralleling CNS tumor burden.
Key findings
- At the recommended dose, no confirmed CNS responses occurred among 12 patients (CNS ORR, 0%; 95% CI, 0%-26.5%).
- Median overall survival was 16.5 months.
- Paxalisib 30 mg daily plus trastuzumab was feasible, with a safety profile consistent with PI3K/mTOR inhibition.
- CSF ctDNA tumor fraction was higher than plasma tumor fraction, and longitudinal CSF changes paralleled CNS tumor burden.
Why it matters
The trial found minimal CNS antitumor activity for this combination in a heavily pretreated HER2-positive brain-metastasis population, despite its biological rationale and brain penetration. Its exploratory liquid-biopsy results also suggest that CSF ctDNA may reflect intracranial tumor genomics and changes in burden more closely than plasma, informing translational assessment in this setting.
What to keep in mind
The study was a phase II trial with only 12 patients treated at the recommended dose; leptomeningeal disease was excluded. The ctDNA findings were exploratory.