Phase II study of trastuzumab-pkrb plus gedatolisib in patients with HER2-positive metastatic breast cancer who progressed after two or more HER2-directed therapies

초록

Background: To evaluate the activity and safety of trastuzumab-pkrb plus gedatolisib in patients with treatment-refractory human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) harboring phosphatidylinositol 3-kinase (PI3K) pathway alterations. Patients and methods: In this multicenter, single-arm phase II study, eligible patients had HER2-positive MBC with PI3K pathway aberrations identified by tumor or circulating cell-free DNA and had progressed after at least two prior HER2-directed therapies. Patients received trastuzumab-pkrb (8 mg/kg loading dose, then 6 mg/kg IV every 3 weeks) plus gedatolisib (180 mg IV on days 1, 8 and 15 of each 21-day cycle). The primary endpoint was objective response rate (ORR), 90% power with one-sided 5% type I error, assuming a 25% target for the combination therapy. The trial closed early after 44 patients due to changes in regulatory sponsorship. Results: PI3K pathway alterations included PIK3CA kinase domain mutations (59%), helical domain mutations (25%), and PTEN deletions (5%). The ORR was 43.2% [95% confidence interval (CI) 28.3%-59.0%], with two complete and 17 partial responses. Disease control rate was 86.4%. Median progression-free survival (PFS) was 6.01 months (95% CI 5.03-7.69), and median overall survival (OS) was 24.74 months (95% CI 17.28-NA) after 32.05 months of follow-up. Oral mucositis (90.9%; 15.9% grade ≥3) and hyperglycemia (25.0%; 2.3% grade 3) were most frequent, and no treatment-related deaths occurred. Early circulating tumor DNA dynamics predicted PFS and OS. Conclusion: Trastuzumab-pkrb plus gedatolisib demonstrated a 43.2% response rate and manageable toxicity, supporting dual HER2/PI3K pathway targeting in heavily pretreated HER2-positive MBC. © 2026 The Author(s)

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