Study design and patients
The PHEDRA study was a multicenter, double-blind, randomized, placebo-controlled, phase 3 study done at 17 hospitals in China (NCT03588091). Eligible patients were treatment-naive women aged 18 to 75 years with pathologically confirmed HER2-positive, early (T2 to 3, N0 to 1, M0) or locally advanced (T2 to 3, N2 to 3, M0) breast cancer with primary tumor larger than 2 cm in diameter. HER2 positivity was determined locally and defined as 3+ staining intensity by immunohistochemistry or HER2 gene amplification by fluorescence in situ hybridization according to the 2013 American Society of Clinical Oncology/College of American Pathologists guidelines . Other main inclusion criteria included Eastern Cooperative Oncology Group performance status of 0 or 1, known estrogen receptor (ER) and progesterone receptor (PR) status, and adequate hepatic, renal, bone marrow, and cardiac function based on laboratory assessments. For adequate cardiac function, baseline left ventricular ejection fraction (LVEF) of 55% or more as measured by echocardiography and Fridericia-corrected QT (QTcF) interval of less than 470 ms was required. Key exclusion criteria included metastatic disease (stage IV), inflammatory breast cancer, other malignancies, prior anti-cancer therapy or radiotherapy for any malignancy (except cured cervical carcinoma in situ, basal cell carcinoma, or squamous cell carcinoma), impaired cardiac function, uncontrolled hypertension, pregnancy, and refusal to use contraception.
The study protocol and all amendments were approved by the Ethics Committee of each study site. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. All patients provided written informed consent.
Randomization and masking
Patients were randomly assigned (1:1) to receive either pyrotinib, trastuzumab, plus docetaxel (pyrotinib group) or placebo, trastuzumab, plus docetaxel (placebo group). A stratified, permuted block randomization with a block size of four was performed, with stratification by primary tumor size (>2 cm and ≤5 cm versus >5 cm) and hormone receptor status (ER and/or PR positive versus ER and PR negative, the positivity cutoff for both was ≥1%). All investigators, patients, and the funder of the study were masked to treatment allocation.
Patients received oral pyrotinib 400 mg once daily or matched placebo in combination with intravenous trastuzumab (8 mg/kg loading dose, 6 mg/kg maintenance dose) and docetaxel (100 mg/m2) on day 1 of each 21-day cycle for four cycles, followed by surgery within 14 days (Additional file 1: Fig. S1). Thereafter, patients were given adjuvant therapy with three cycles of FEC (fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2; all given intravenously every 3 weeks) and subsequent anti-cancer treatments at physicians’ discretion in accordance with clinical practice guidelines.
Primary prophylaxis for diarrhea was not prespecified. Based on the results of the interim analysis, the independent data monitoring committee (IDMC) recommended the implementation of proactive diarrhea management (PDM). Primary prophylaxis of neutropenia using a single, 6 mg fixed dose of mecapegfilgrastim on day 2 of each cycle was prespecified. Other granulocyte colony-stimulating factors were permitted if mecapegfilgrastim was intolerable or unavailable at the local study center.
To assess the tumor response to neoadjuvant therapy, patients underwent mammography, ultrasounds, and MRI at baseline and after completion of the neoadjuvant therapy (before surgery). Objective responses were assessed by investigators according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Pathological response was assessed by local pathology review and masked independent central review using tumor tissue resection specimens obtained at surgery.
Laboratory assessments and vital signs were done at baseline, at each cycle during neoadjuvant therapy, before surgery, and at each cycle during adjuvant therapy. Cardiac monitoring was done with echocardiography at baseline, at every two cycles during neoadjuvant therapy, and on the day before adjuvant therapy and with 12-lead electrocardiograms at baseline, at every two cycles during neoadjuvant therapy, and before surgery. Adverse events were monitored continuously until 28 days after the last dose of FEC treatment and graded according to the Common Terminology Criteria for Adverse Events, version 4.03.
The primary endpoint was the rate of total pathological complete response (tpCR), defined as the absence of any residual invasive cancer on hematoxylin and eosin staining of the resected breast specimen and all sampled ipsilateral lymph nodes (ypT0/is, ypN0) after neoadjuvant therapy and surgery, as assessed by independent central review. Protocol-defined secondary endpoints were tpCR rate per local pathology review, ORR (defined as the proportion of patients who had a best overall response of complete or partial response during neoadjuvant therapy), EFS (defined as the time from randomization to the first documentation of progressing disease while on study therapy, postoperative disease recurrence, or death from any cause), disease-free survival (DFS, time from surgery to the first documentation of postoperative disease recurrence or death from any cause), distant disease-free survival (DDFS, defined as the time from surgery to the first documentation of postoperative distant metastasis or death from any cause), and safety. Disease recurrence in EFS and DFS definitions referred to breast cancer recurrence, occurrence of second primary breast cancer, and occurrence of any other cancer. Exploratory endpoints included breast pathological complete response (bpCR) rate per local pathology review and independent central review. Results for EFS, DFS, and DDFS are not included in this report as the data are not mature.
With 294 patients, the study had 85% power to detect an increase of 18% in tpCR rate (from 30% in the placebo group to 48% in the pyrotinib group), at a one-sided α level of 0.025, considering that 10% of enrolled patients would be unevaluable for pathological response assessment. Comparison between groups was done using the Cochran-Mantel-Haenszel test stratified by the randomization strata. One prespecified interim analysis was planned when pathological responses were available for 158 patients. As of Aug 30, 2019, the pathological responses were assessable in 159 patients, and interim analysis was done by an independent statistics team from KNOWLANDS MedPharm Consulting (Shanghai, China). The IDMC reviewed the results on Nov 6, 2019, and recommended continuing the trial with an increased sample size of 354 patients for final analysis (the criteria for IDMC recommendation described in Additional file 1: Supplementary Methods). Considering the sample size was increased, the Cui, Hung, and Wang method was used in the primary analysis for the tpCR rate in order to control the type I error . A one-sided P value was reported, and the value of less than 0.025 was considered significant.
Efficacy analyses were done in the full-analysis set, including all patients who underwent randomization and received at least one dose of study treatment, with patients analyzed according to their randomized assignment. Safety analyses were done in all patients who received at least one dose of study treatment, with patients included according to their actual treatment. The 95% CIs for the pCR rate were calculated using the Wilson method. The 95% CI for the between-group difference was calculated using the Wald method. Patients without a recorded assessment of pCR were regarded as non-responders. Prespecified subgroup analyses of the tpCR rate per independent central review were also done. Statistical analyses were conducted using SAS version 9.4 and sample size re-estimation was done using East version 6.5.