Abstract OT1-12-06: Neoadjuvant pyrotinib versus pertuzumab in combination with trastuzumab and nab-Paclitaxel for patients with HER2-positive early or locally advanced breast cancer (Pyramid): A randomized, multicenter, open-label, phase 2 trial

Abstract

Abstract Background: Pyrotinib is an irreversible pan-ErbB receptor tyrosine kinase inhibitor targeting human epidermal growth factor receptor 1 (HER1), HER2, and HER4. Exploratory studies of neoadjuvant pyrotinib combined with trastuzumab-based standard chemotherapy for HER2-positive (HER2+) early or locally advanced breast cancer (BC) showed promising pathological complete response (pCR) rates of 51.6%-71%, with a manageable toxicity profile. We are to further investigate this combination strategy versus standard therapy in a randomized trial. Trial design: Pyramid is a randomized, multicenter, open-label, two-stage adaptive enrichment phase 2 trial to evaluate the efficacy and safety of pyrotinib plus trastuzumab and nab-Paclitaxel versus pertuzumab plus trastuzumab and nab-Paclitaxel as neoadjuvant treatment in patients with HER2+ early or locally advanced BC (NCT04900311). Eligible patients will be randomized 1:1 to receive four 21-day cycles of pyrotinib (400 mg, po, qd) or pertuzumab (840 mg loading dose, 420 mg maintenance doses, i.v., day 1) with trastuzumab (8 mg/kg loading dose, 6 mg/kg maintenance doses, i.v., day 1) and nab-Paclitaxel (260 mg/m2, day 1 or 125 mg/m2, i.v., day 1/8/15). After completion of neoadjuvant treatment, patients will undergo surgery, followed by standard EC regime for 4 cycles. Subsequent adjuvant therapy will be decided by investigators. Randomization was stratified by hormone receptor (HR) status (ER and/or PR positive vs. negative) and primary tumor size (2<T≤5 cm vs. T>5 cm). There will be two stage of this trial, and population may be enriched to HR-positive based on the results of interim analysis at Stage I. Eligibility criteria: Key inclusion criteria include female, treatment-naïve, histologically confirmed HER2+ invasive BC (cT2-4/cN0-3/cM0), the diameter of primary tumor > 2 cm, known HR status (ER and PR). Specific aims: Primary endpoint is total pathologic complete response (tpCR) rate per central review assessment. Secondary endpoints include invasive disease-free survival, event-free survival, objective response rate, breast-conserving surgery rate, safety. Exploratory endpoint is to investigate the possible predictive biomarkers of efficacy. Statistical methods: A sample size of 220 patients per arm is calculated to provide a power of 80% with a significance level of 0.1 (one-sided) to detect an estimated increase in the tpCR rate from 39% in the pertuzumab group to 49% in the pyrotinib group. Considering a dropout rate of 10%, 490 patients (245 per arm) will be required to be enrolled. A two-stage adaptive enrichment design will be used. The trial will enroll 186 patients at Stage I and an interim analysis will be conducted by an independent data monitoring committee (IDMC) when the pathologic response has been evaluated in at least 132 patients (including at least 66 HR-positive patients) at Stage I. Then, one of five options might be adapted at Stage II depending on the results, including: i. Continue study as planned in whole population; ii. Re-estimate sample size in whole population; iii. Enrich to HR-positive population with pre-defined sample size; iv. Enrich to HR-positive population and re-estimate sample size; v. Early termination. The Clopper-Pearson method will be used to calculate a 95% confidence interval (CI) for the tpCR rate. The CMH chi-square test will be used to compare the tpCR rate between groups and 95% CIs for the difference will be estimated using the Miettinen-Nurminen method. Present accrual and target accrual: Target enrollment will be 490 patients at approximately 20 sites in China. As of June 24, 2021, 4 patients have been enrolled. Contact information: Jin Zhang, MD, Email: zhangjin@tjmuch.com. Citation Format: Jin Zhang, Qiang Liu, Hongchuan Jiang, Jianguo Zhang, Jianghua Ou, Dedian Chen, Fuguo Tian, Yongqing Li, Xiaoming Cheng, Zhong Ouyang. Neoadjuvant pyrotinib versus pertuzumab in combination with trastuzumab and nab-Paclitaxel for patients with HER2-positive early or locally advanced breast cancer (Pyramid): A randomized, multicenter, open-label, phase 2 trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-12-06.