Abstract PO1-27-05: De-escalated neoadjuvant weekly nab-paclitaxel with trastuzumab and pertuzumab in HER2-positive early breast cancer (HELEN-006):a randomized,phase 3 trial

Abstract Background: Chemotherapy de-escalation is currently under investigation as a treatment approach for HER2-positive early-stage breast cancer(EBC). We conducted a phase 3 clinical trial to evaluate the effectiveness of a weekly regimen of nab-paclitaxel monotherapy in combination with dual HER2 blockade for HER2-positive EBC. Methods: We conducted a multicenter, randomized, open-label Phase 3 trial at six hospitals in China. Eligible participants were women aged 18-70 with locally confirmed, HER2-positive, stage II-III, invasive, operable breast cancer and an Eastern Cooperative Oncology Group performance status of 0 or 1. Participants were randomly assigned (1:1) using central block randomization, with block sizes of four, stratified by hormone receptor status, tumor stage, and node status. They were assigned to receive either intravenous nab-paclitaxel (125mg/m2 on days 1, 8, and 15) for six 3-week cycles (group A), or intravenous docetaxel (75mg/m² on day 1) and carboplatin (area under the concentration-time curve 6mg/mL per min on day 1) for six 3-week cycles (group B). Both groups received concurrent trastuzumab (8mg/m2 loading dose, 6mg/m2 maintenance dose on day 1) and pertuzumab (intravenous 840mg loading dose, 420mg maintenance dose on day 1). The primary endpoint was the proportion of patients achieving a pathological complete response(pCR) in the breast and axilla (ypT0/is ypN0) as determined by a local pathologist after surgery, assessed using a modified intention-to-treat analysis. To test for non-inferiority, we used a closed test procedure, considering the nab-paclitaxel group non-inferior to the docetaxel plus carboplatin group if the lower 95% confidence interval(CI) for the odds ratio (OR) was above 0.802, which accounted for a 5.5% non-inferiority margin (10% of the 55% pCR rate for docetaxel plus carboplatin and dual HER2 blockade regimen). We planned to test for superiority only if the non-inferiority test was positive, using an alpha value of 0.05. Safety was assessed in all patients who received the study drug. The trial is registered with ClinicalTrials.gov, with the registration number NCT04547907. Findings: Between September 10, 2020, and March 1, 2023, we randomly assigned 689 women, of whom 669 started treatment (332 with nab-paclitaxel and 337 with docetaxel plus carboplatin). The nab-paclitaxel group had a higher proportion of patients achieving a pCR (220 66.3%, 95% CI 61.2-71.4) compared to the docetaxel plus carboplatin group (194 57.6%, 52.3-62.9). The OR for pCR was 1.448 (95% CI 1.058-1.981), indicating a statistically significant difference (unadjusted p=0.021). Overall, 228 (34.1%) patients were noted to have at least one grade 3 or 4 event, 100(30.1%) in the nab-paclitaxel group and 128 (38.0%) in the docetaxel plus carboplatin group (P=0·032). The most common grade 3 or 4 events overall were nausea (9814.6% of 669 patients), diarrhea (80 12.0%), and neuropathy (51 7.6%).However, no treatment-associated deaths were identified. Conclusions: In neoadjuvant treatment of HER2-positive EBC, 18 weeks of nab-paclitaxel monotherapy combined with dual HER2 blockade has shown significantly higher pCR rates and improved tolerability compared to the standard docetaxel plus carboplatin and dual HER2 blockade regimen. These findings could potentially reshape preferences for neoadjuvant therapy in HER2-positive EBC. Patient Characteristics pCR by clinical-pathological variables Abbreviation:Nab-PHP,nanoparticle albumin-bound paclitaxel plus trastuzumab and pertuzumab; TCbHP,docetaxel plus carboplatin ,trastuzumab and pertuzumab; HR,hormone receptor; IHC,immunohistochemistry. *estrogen and/or progesterone receptor positive is classified as hormone receptor positive;estrogen and progesterone receptor negative is classified as hormone receptor negative Adverse events Abbreviation:Nab-PHP,nanoparticle albumin-bound paclitaxel plus trastuzumab and pertuzumab; TCbHP,docetaxel plus carboplatin ,trastuzumab and pertuzumab;ALT,alanine aminotransferase;AST,aspartate transaminase. Citation Format: Zhenzhen Liu, Xiuchun Chen, Jianghua Qiao, Jiao Dechuang, Chengzheng Wang, Xianfu Sun, Zhenduo Lu, Lianfang Li, Chongjian Zhang, Min Yan, Ya Wei, Chen Bo, Yueqing Feng, Miao Deng, Mingde Ma. De-escalated neoadjuvant weekly nab-paclitaxel with trastuzumab and pertuzumab in HER2-positive early breast cancer (HELEN-006):a randomized,phase 3 trial abstract. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-27-05.