Abstract PD8-08: Pyrotinib in combination with trastuzumab and docetaxel as neoadjuvant treatment for HER2-positive early or locally advanced breast cancer (PHEDRA): A randomized, double-blind, multicenter, phase 3 study

Abstract Background: Pyrotinib (an irreversible pan-ErbB inhibitor) plus capecitabine have shown clinically and statistically meaningful progression free survival and overall survival benefits and acceptable tolerability in patients with HER2-positive metastatic breast cancer in phase 3 study. We compared the efficacy and safety of adding pyrotinib to trastuzumab and docetaxel vs placebo, trastuzumab and docetaxel as neoadjuvant treatment in women with HER2-positive early or locally advanced breast cancer (ABC) in this randomized, double-blind, multicenter, phase 3 study. Methods: Treatment naive patients with HER2-positive early or locally ABC (T2-3, N0-3, M0) were randomly assigned (1:1) to pyrotinib arm receiving 4 neoadjuvant cycles of pyrotinib (400 mg po qd, d1-21, q3w), trastuzumab (8 mg/kg iv, cycle 1 d1, then 6 mg/kg d1 q3w) and placebo arm with docetaxel (100 mg/m2 iv d1, q3w) or placebo, trastuzumab and docetaxel. Randomization was done via a centralized interactive web-response system and stratified by primary tumor size (>2 cm and ≤5cm, or >5cm) and hormone receptor status (ER positive and/or PR positive, or negative for both). After surgery, patients received 3 cycles of intravenous fluorouracil, epirubicin, and cyclophosphamide followed by anti-cancer treatment (anti-HER2 therapy, radiotherapy, or endocrine therapy) at physicians’ discretion in accordance with clinical practice guidelines. The primary endpoint was total pCR rate (tpCR; defined as absence of any residual invasive cancer in the breast and lymph nodes [ypT0/is, ypN0]), assessed by an independent review committee (IRC). This study is registered with ClinicalTrials.gov, number NCT03588091. The data cutoff date was April 30, 2021. Results: Between July 23, 2018 and January 8, 2021, a total of 355 patients were randomized (pyrotinib arm, n=178; and placebo arm, n=177; mean [SD] age, 48.8 [9.4] years). Baseline demographics and disease characteristics were well balanced. In the full analysis set, IRC-assessed tpCR rates were 41.0% (73 of 178) in the pyrotinib arm and 22.0% (39 of 177) in the placebo arm (difference, 19.0% [95% CI, 9.5%-28.4%]; one-sided P<0.0001). The local pathologist-assessed tpCR rates were 44.4% (79 of 178) and 24.3% (43 of 177) in the pyrotinib arm and the placebo arm, respectively. Incidence of grade ≥3 adverse events (AEs) was 71.3% (127 of 178) in the pyrotinib arm and 37.3% (66 of 177) in the placebo arm. Of the most-common grade ≥3 AEs (≥5% of patients in either arm), the incidences of diarrhea (79 of 178 [44.4%] vs 9 of 177 [5.1%]), decreased WBC count (29 of 178 [16.3%] vs 24 of 177 [13.6%]), vomiting (23 of 178 [12.9%] vs 2 of 177 [1.1%]), anemia (11 of 178 [6.2%] vs 2 of 177 [1.1%]), and hypokalemia (9 of 178 [5.1%] vs 0) were higher in the pyrotinib arm compared with the placebo arm. Grade 3 diarrhea occurred mainly during the first treatment cycle and decreased in the second cycle and thereafter. No grade 4 or 5 diarrheas occurred. The median duration per grade 3 episode was 2.0 days and median cumulative duration of grade 3 episodes was 4.0 days. Only 1 patient (1 of 178 [0.6%]) in the pyrotinb arm experienced diarrhea-related discontinuation. Serious AEs were reported in 14.6% of patients (26 of 178) in the pyrotinib arm and 6.8% of patients (12 of 177) in the placebo arm. Conclusions: Pyrotinib, trastuzumab, and docetaxel as neoadjuvant treatment achieved a statistically significant and clinically meaningful improvement in IRC-assessed tpCR rate for patients with HER2-positive early or locally ABC compared with placebo, trastuzumab, and docetaxel, with an acceptable and manageable safety profile. These findings support pyrotinib, trastuzumab, and docetaxel as a new neoadjuvant treatment option in this patient population. Citation Format: Jiong Wu, Zhenzhen Liu, Hongjian Yang, Jinhai Tang, Kun Wang, Yunjiang Liu, Haibo Wang, Peifen Fu, Shuqun Zhang, Qiang Liu, Zefei Jiang, Shusen Wang, Jian Huang, Chuan Wang, Shu Wang, Yongsheng Wang, Linlin Zhen, Xiaoyu Zhu, Fei Wu, Tao Zhang, Jianjun Zou. Pyrotinib in combination with trastuzumab and docetaxel as neoadjuvant treatment for HER2-positive early or locally advanced breast cancer (PHEDRA): A randomized, double-blind, multicenter, phase 3 study [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 PD8-08.