Inetetamab combined with pyrotinib for neoadjuvant treatment of HER2-positive locally advanced breast cancer (neoPICD): A prospective, multicenter, single-arm phase II trial.

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Background: Neoadjuvant docetaxel plus carboplatin with trastuzumab and pertuzumab (TCbHP) is the standard regimen for HER2-positive breast cancer, yet 22%–25% of patients develop resistance to monoclonal antibody–based anti-HER2 therapy. Inetetamab, an anti-HER2 monoclonal antibody with enhanced antibody-dependent cellular cytotoxicity, and pyrotinib, an oral irreversible pan-HER tyrosine kinase inhibitor targeting HER1/2/4, are effective in advanced HER2-positive breast cancer, but their combined neoadjuvant use remains underexplored. We conducted a prospective, single-arm trial (NCT06234137) to evaluate inetetamab, pyrotinib, and chemotherapy in HER2-positive locally advanced breast cancer with high tumor burden. Methods: Patients with non-metastatic, HER2-positive stage II–III primary breast cancer eligible for neoadjuvant therapy were enrolled. The primary endpoint was total pathological complete response (tpCR); secondary endpoints included objective response rate, safety, immunogenicity, and survival outcomes. Sample size was determined using Simon’s two-stage design (null tpCR 45% vs alternative 60%, one-sided α = 0.05, power = 90%). Neoadjuvant therapy comprised inetetamab (8 mg/kg loading then 6 mg/kg IV q3w ×6), pyrotinib (400 mg orally once daily for 18 weeks), and docetaxel (75 mg/m²) plus carboplatin (AUC 6) q3w ×6; treatment continued until completion, progression, or unacceptable toxicity, with surgery 2–4 weeks later and continuation of anti-HER2 therapy to complete one year. Results: Between December 2021 and October 2025, 124 patients were enrolled across seven centers, with 108 evaluable for efficacy. Total pathological complete response (tpCR; ypT0/is, ypN0) occurred in 65 patients (60.2%, 95% CI 50.8–69.6), while breast pathological complete response (bpCR; ypT0/is) was 65.7% (95% CI 56.6–74.8). The objective response rate was 92.6% (95% CI 87.6–97.6), and disease control rate was 100%. Hormone receptor (HR)–negative disease achieved higher tpCR and bpCR rates than HR-positive disease (tpCR: 73.3% vs 43.8%; bpCR: 76.7% vs 52.1%). Multivariate analysis identified HR status as an independent predictor of efficacy (p < 0.05); favorable responses were also associated with premenopausal status, smaller tumor size, earlier nodal stage, lower disease stage, higher Ki-67 index, and higher histological grade. Conclusions: Neoadjuvant inetetamab plus pyrotinib and chemotherapy may provide substantial benefit in HER2-positive locally advanced breast cancer, particularly in HR-negative disease and high proliferative features. Research Sponsor: Special Funding Project for Characteristic Directional S-Disciplines of the First Affiliated Hospital of Wenzhou Medical University (wyyy-2025S01). Clinical trial information: NCT06234137 .