Palbociclib, Fulvestrant, Trastuzumab, and Pyrotinib for Patients with Advanced Breast Cancer with Brain Metastases: A Prospective Multicenter Phase 2 Trial

Abstract Background : Patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-positive (HER2+) advanced breast cancer (ABC) face a high risk of brain metastases (BMs), yet prospective systemic‑treatment evidence for this subgroup is limited. We conducted a multicenter, single-arm, phase 2 trial evaluating a chemotherapy-sparing regimen of palbociclib, fulvestrant, trastuzumab, and pyrotinib in patients with HR+/HER2+ ABC and measurable BMs. The interim analysis suggested preliminary intracranial activity with manageable toxicity.Methods: Eligible patients had HR+/HER2+ ABC with measurable BMs and no prior local treatment to the target lesion. The regimen was administered until progression, unacceptable toxicity, or death. The primary endpoint was confirmed central nervous system objective response rate (CNS-ORR). Secondary endpoints included overall ORR, progression-free survival (PFS), CNS-PFS, overall survival (OS), and safety. We present the final analysis for 32 enrolled patients. Results: From Dec 2020 to Feb 2026, 32 patients were enrolled. For 29 response‑evaluable patients, confirmed CNS‑ORR was 58.6% (95%CI 40.7‑74.5) and overall ORR 62.1% (95%CI 44.0‑77.3). With median follow‑up of 32.5 months, median CNS-PFS was 9.6 months (95% CI: 5.3–13.9), and median overall PFS was 12.3 months (95% CI: 6.8–17.7). OS remained immature (5 deaths; 24‑month‑OS rate 80.7%). Post‑hoc analyses suggested numerically better PFS/CNS‑PFS in chemotherapy‑naïve patients, whereas prior trastuzumab did not impair efficacy. Frequent grade ≥3 adverse events comprised diarrhea (37.5%), neutropenia (28.1%) and leukopenia (15.6%), with no treatment‑related deaths. Conclusions: The chemotherapy-sparing quadruple regimen showed promising intracranial activity, systemic disease control, and manageable toxicity in HR+/HER2+ ABC patients with BMs.