Translational and Real-World Evidence of Trastuzumab Biosimilar CT-P6 Plus Pertuzumab in Neoadjuvant HER2-Positive Early Breast Cancer

Background Data on neoadjuvant treatment with trastuzumab biosimilars, particularly CT-P6, in combination with pertuzumab, are limited. This study evaluates the efficacy, tolerability, and immunogenicity of CT-P6 plus pertuzumab and chemotherapy, according to routine clinical practice, in the neoadjuvant setting for HER2-positive early breast cancer, while integrating translational biomarker analyses and exploratory predictors of pathologic complete response (pCR). Methods Prospective, multicenter, observational study in 102 patients with HER2-positive early breast cancer. Patients received hospital-preferred neoadjuvant regimens protocol, with (scheme 1 and 3) or without anthracyclines (scheme 2). The primary endpoint was pCR in breast tissue and axilla. Translational endpoints included soluble HER2, anti-trastuzumab CT-P6 antibodies, and exploratory response prediction models validated using machine learning approaches. Results Overall, pCR was achieved in 60.40% of patients in the breast and 80.20% in the axilla, with no significant differences between anthracycline-based and non-anthracycline-based regimens. Soluble HER2 and anti-trastuzumab CT-P6 antibodies were not significantly associated with pCR. Treatment was well tolerated; the most relevant Grade 3–4 treatment-related adverse events were diarrhea (2.25%) and asthenia (0.50%). No immunogenicity or clinically relevant cardiotoxicity was observed. Conclusions Trastuzumab CT-P6 combined with pertuzumab and chemotherapy can be used in neoadjuvant treatment for HER2-positive early breast cancer, showing pCR rates comparable to the reference trastuzumab and without evidence of immunogenicity. Exploratory analyses of soluble HER2 and anti-trastuzumab CT-P6 antibodies did not show predictive value for pCR, although this possibility cannot be excluded. Their systematic assessment nevertheless contributes to the translational understanding of biosimilar integration into curative regimens. Trial registration: The study has been registered in Clinicaltrials.gov (https://clinicaltrials.gov/study/NCT06907082).