A network meta-analysis of efficacy and safety of neoadjuvant anti-HER2 treatments in HER2-positive early breast cancer.

Abstract

e12636 Background: Neoadjuvant treatment options for HER2-positive early breast cancer are continuously evolving, including chemotherapy combined with either single or dual HER2-targeted antibodies or HER2-targeted antibody–drug conjugate (ADC), leading to improved pCR rates and long-term survival outcomes. However, the relative efficacy and safety of these regimens still need to be further clarified. This study aims to compare the efficacy and safety of single versus dual HER2-targeted antibodies and ADCs, as well as to conduct comparative analysis across these regimens. Methods: PubMed, EMBASE, Cochrane Library, and Web of Science were systematically searched for phase III randomized controlled trials (RCTs). Eligible RCTs must include at least two of the following interventions as neoadjuvant therapy: TH, THP, TCbHP, AC-THP, T-DM1+P, or T-DXd-THP. Outcomes were pCR, event-free survival (EFS), and grade ≥3 or severe adverse events. Data were extracted independently by two reviewers; risk of bias was assessed using Cochrane RoB 2. A Bayesian network meta-analysis with fix-effects model estimated odds ratio (OR), hazard ratio (HR), and treatment rankings using SUCRA. Results: Six phase III RCTs comprised of 3,287 patients with HER2-positive early breast cancer were included in our study. The results showed a superior pCR rate of regimens incorporating dual HER2-targeted antibodies or ADCs, including T-DXd-THP (OR 3.07, 95% CI 1.42–6.75), THP (OR 2.34, 95% CI 1.39–4.05), and TCbHP (OR 2.05, 95% CI 1.16–3.70), comparing to TH in the overall population. The SUCRA analysis showed that T-DXd-THP ranked highest for pCR rate (0.95), indicating the greatest probability of being the most effective regimen, followed by THP (0.77), TCbHP (0.55). In HR-negative patients, T-DXd-THP (OR 5.17, 95% CI 1.13–24.09) and THP (OR 3.85, 95% CI 1.79–8.91) had a significant pCR rate benefit comparing to TH, with T-DXd-THP ranked highest in SUCRA (0.93). Additionally, T-DXd-THP (OR 3.52, 95% CI 1.13–11.29) demonstrated a significant pCR rate improvement compared to TCbHP. In terms of EFS, T-DXd-THP showed a consistent trend towards improved outcomes compared with other dual HER2-targeted therapies, in line with its highest SUCRA ranking (0.95). Compared to TH, both AC-THP and TCbHP showed a higher risk of grade≥3 anemia, grade≥3 neutropenia, and serious adverse events (SAEs). Notably, T-DXd-THP demonstrated a lower risk of grade≥3 anemia and grade≥3 neutropenia compared to TCbHP or AC-THP. TCbHP showed a higher risk of grade≥3 vomiting compared to THP (OR 7.69, 95% CI 2.88–27.09). Conclusions: Neoadjuvant therapies with dual HER2-targeted antibodies or ADCs provide superior pCR rates compared to single anti-HER2 antibodies for HER2-positive early breast cancer. T-DXd-THP demonstrated the greatest therapeutic effectiveness among all regimens while maintaining a well-balanced safety profile.