Efficacy and safety results of a prospective phase II study (IPUtrial) of inetetamab and pyrotinib in combination with utidelone for first- or second-line treatment of HER2-positive metastatic breast cancer.

1050 Background: Despite standard anti-HER2 regimens with chemotherapy, therapeutic challenges persist in HER2-positive metastatic breast cancer (MBC). Inetetamab (anti-HER2 monoclonal antibody) and pyrotinib (tyrosine kinase inhibitor) demonstrate established efficacy in advanced disease. Utidelone, a novel epothilone analog, exhibits antitumor activity with a differentiated safety profile. This phase II study assessed the triplet combination in first- or second-line HER2-positive MBC. Methods: This multicenter single-arm phase II trial enrolled HER2-positive MBC patients for first- or second-line therapy. Patients who have previously used trastuzumab must meet the followings: for first-line treatment, neoadjuvant therapy was effective, and relapse occurred over 1 year after the end of adjuvant therapy; for second-line treatment, progressed in previous adjuvant/neoadjuvant therapy or progressed within 1 year of completion of trastuzumab therapy; disease progression occurred after 6 months of treatment with trastuzumab in advanced setting. Patients with stable brain metastases were enrolled with or without prior local treatment. ECOG PS 0-1, and measurable disease (RECIST v1.1). Eligible patients received inetetamab (8 mg/kg cycle 1, then 6 mg/kg, IV, day 1), pyrotinib (400 mg, PO, daily), and utidelone (30 mg/m², IV, days 1-5) every 21 days until progression or intolerance. Primary endpoint was investigator-assessed ORR. Secondary endpoints included PFS, OS, and safety. Results: By data cutoff (December 31, 2025), the recruitment has been completed. 94 patients were enrolled. Median treatment cycles were 11 (range 4-57). 56 (65.9%) and 29 (34.1%) patients were in first- and second-line settings, respectively. 85 patients were evaluable for response with 6 CR, 64 PR and 7 SD. The ORR was 82.4% (95% CI, 72.6%-89.8%). Median PFS was 13.1 months (95% CI, 10.420-15.780). Median OS was not reached. The OS rate of 12-month, 26-month and 35-month was 94.6% (95% CI, 89.5%-99.7%), 85.2% (95% CI, 76.6%-93.8%) and 78.5% (95% CI, 67.7%-89.3%), respectively. Predominant Grade ≥3 TRAEs were diarrhea (28.2%) and peripheral neuropathy (4.7%). Other Grade ≥3 TRAEs included nausea (3.5%), transaminitis (2.4%) and neutropenia (1.2%). Treatment discontinuations due to TRAEs occurred in 6 patients (6.6%). No treatment-related deaths occurred. Conclusions: The regimen demonstrated clinically meaningful activity of this triplet regimen for the first/second-line treatment of HER2-positive MBC, evidenced by high ORR (82.4%), durable median PFS (13.1 months), with encouraging 35-month OS rate (78.5%). Predominant toxicities (diarrhea, neuropathy) were controllable through supportive measures and dose adjustments. These data support phase III evaluation of this combination strategy.