Neoadjuvant pyrotinib, trastuzumab, and docetaxel for HER2-positive breast cancer (PHEDRA): a double-blind, randomized phase 3 trial

Jiong Wu, Zefei Jiang, Zhenzhen Liu, Benlong Yang, Hongjian Yang, Jinhai Tang, Kun Wang, Yunjiang Liu, Haibo Wang, Peifen Fu, Shuqun Zhang, Qiang Liu, Shusen Wang, Jian Huang, Chuan Wang, Shu Wang, Yongsheng Wang, Linlin Zhen, Xiaoyu Zhu, Fei Wu, Xiang Lin, Jianjun Zou, Jiong Wu, Zefei Jiang, Zhenzhen Liu, Benlong Yang, Hongjian Yang, Jinhai Tang, Kun Wang, Yunjiang Liu, Haibo Wang, Peifen Fu, Shuqun Zhang, Qiang Liu, Shusen Wang, Jian Huang, Chuan Wang, Shu Wang, Yongsheng Wang, Linlin Zhen, Xiaoyu Zhu, Fei Wu, Xiang Lin, Jianjun Zou

Abstract

Background: Pyrotinib (an irreversible pan-ErbB inhibitor) plus capecitabine has survival benefits and acceptable tolerability in patients with HER2-positive metastatic breast cancer. We further assessed addition of pyrotinib to trastuzumab and docetaxel in the neoadjuvant setting.

Methods: In this multicenter, double-blind, phase 3 study (PHEDRA), treatment-naive women with HER2-positive early or locally advanced breast cancer were randomly assigned (1:1) to receive four neoadjuvant cycles of oral pyrotinib or placebo (400 mg) once daily, plus intravenous trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg) and docetaxel (100 mg/m2) every 3 weeks. The primary endpoint was the total pathological complete response (tpCR; ypT0/is and ypN0) rate per independent central review.

Results: Between Jul 23, 2018, and Jan 8, 2021, 355 patients were randomly assigned, 178 to the pyrotinib group and 177 to the placebo group. The majority of patients completed four cycles of neoadjuvant treatment as planned (92.7% and 97.7% in the pyrotinib and placebo groups, respectively). The tpCR rate was 41.0% (95% CI 34.0 to 48.4) in the pyrotinib group compared with 22.0% (95% CI 16.6 to 28.7) in the placebo group (difference, 19.0% [95% CI 9.5 to 28.4]; one-sided P < 0.0001). The objective response rate per investigator was 91.6% (95% CI 86.6 to 94.8) in the pyrotinib group and 81.9% (95% CI 75.6 to 86.9) in the placebo group after the neoadjuvant treatment, resulting in an increase of 9.7% (95% CI 2.7 to 16.6). The most common grade 3 or worse adverse events were diarrhea (79 [44.4%] in the pyrotinib group and nine [5.1%] in the placebo group), neutropenia (33 [18.5%] and 36 [20.3%]), and decreased white blood cell count (29 [16.3%] and 24 [13.6%]). No deaths were reported during neoadjuvant treatment.

Conclusions: The primary endpoint of the study was met. Neoadjuvant pyrotinib, trastuzumab, and docetaxel significantly improved the tpCR rate compared with placebo, trastuzumab, and docetaxel, with manageable toxicity, providing a new option for HER2-positive early or locally advanced breast cancer.

Trial registration: ClinicalTrials.gov, NCT03588091.

Keywords: Breast cancer; HER2; Neoadjuvant treatment; Phase 3; Pyrotinib.

Conflict of interest statement

XZ, FW, XL, and JZ reported being employed by Hengrui when conducting this study. No other disclosures were reported.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Trial profile
Fig. 2
Fig. 2
Total pathological complete response (tpCR) rate and breast pathological complete response (bpCR) rate. A Per independent central review; B per local pathology review. Patients with missing or unevaluable pCR status were considered non-responders. Error bars show 95% CIs for the pCR rate in each group, which were calculated using the Wilson method. Comparison between groups was done using the Cochran-Mantel-Haenszel test stratified by the randomization strata, and the 95% CI for the between-group difference was calculated using the Wald method
Fig. 3
Fig. 3
Subgroup analysis of total pathological complete response (tpCR) per independent central review. Differences between pyrotinib and placebo groups in each subgroup were shown, with the 95% CI being calculated using the Wald method. ER estrogen receptor, PR progesterone receptor

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