The present study is a multicenter, randomized, open-label, phase II study in HR+/HER2- metastatic breast cancer patients who have not received any prior systemic anti-cancer therapy for advanced disease (first-line setting). Eligible patients will be randomized in a 2:1 ratio to either of these groups: pyrotinib+ trastuzumab + an AI (Group A) or trastuzumab + an AI (Group B). The schematic overview of the study design is shown in Fig. 1.
Study objectives
The primary objective of the study is to evaluate whether the combination of pyrotinib, trastuzumab and AI (Group A) will be superior to trastusumab plus AI (Group B). The primary endpoint is PFS, defined as the time from randomization to the first radiographically documented progression of disease or death from any cause, whichever will occur first. Disease progression will be evaluated according to the Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) [17]. The secondary endpoints are overall survival (OS), objective response rate (ORR), duration of response (DoR), time to response (TTR), clinical benefit response (CBR), quality of life (QoL), safety, and tolerability. The exploratory endpoint is second progression-free survival (PFS2), defined as the time from randomization to second progression or death from any cause. PFS2 will be only recorded in crossover patients. Additional biomarker analyses are planned and regarded as exploratory analyses. Patients will be required to provide additional informed consent for those procedures. This study does not hypothesize about biomarkers or include any adjustment for type I errors. The aim is to highlight biomarkers or combinations of markers that may be predictive for efficacy or AEs.
Inclusion criteria
To be eligible for inclusion in the trial, patients must provide written informed consent before the commencement of any study-related procedures. All patients must be above 18 years old with an Eastern Cooperative Oncology Group performance status 0–2 and a life expectancy of not less than 12 weeks. Eligible patients should be postmenopausal (fulfilling one or more National Comprehensive Cancer Network guideline criteria) or pre-menopausal with ovarian ablation or suppression. Furthermore, all participants should have pathological confirmed HR+/HER2+ metastatic or inoperable LABC with at least one measurable lesion evaluable according to RECIST 1.1. Also eligible are patients with asymptomatic brain metastases or stable brain metastases after local therapy (provided there is no clinical indication for immediate local re-treatment, as judged by the investigators).
Patients should have adequate bone marrow and organ function as defined by the following laboratory values at screening: neutrophil count ≥1.5 × 109/L; platelet count ≥90 × 109/L; hemoglobin ≥90 g/L; total bilirubin ≤1.5 × upper limit of normal (ULN); alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 2 × ULN (ALT and AST ≤ 5 × ULN for liver metastases); creatinine ≤1.5 × ULN; left ventricular ejection fraction (LVEF) ≥ 50%.
Exclusion criteria
The exclusion criteria are listed as follows: previous systemic non-hormonal anti-cancer therapy in the metastatic or advanced breast cancer setting; previous treatment with pertuzumab or T-DM1 in neoadjuvant or adjuvant treatment; extensive symptomatic visceral disease, severe organ dysfunction or disease considered by the investigator to be rapidly progressing or life-threatening, with a clinical indication for chemotherapy; the patient received the same AI as advised by the investigator within 7 days before randomization; uncontrolled central nervous system symptoms; disease-free interval from completion of adjuvant/neoadjuvant systemic non-hormonal treatment to recurrence less than 6 months; other malignancies within the last 3 years, except for carcinoma in situ of the cervix or basal cell carcinoma; major surgical procedure or significant traumatic injury within 28 days prior to the study treatment or anticipation of major surgery during the study period; inability to swallow or other factors that affect treatment administration; known hypersensitivity to any of the study drugs; a history of chronic heart failure of any New York Heart Association criteria, or serious cardiac arrhythmia requiring treatment (with the exception of atrial fibrillation and paroxysmal supraventricular tachycardia); a history of myocardial infarction within 6 months of randomization; a history of LVEF reduction to below 50% during or after prior trastuzumab neo-adjuvant or adjuvant therapy; pregnant or lactating women; QT interval > 470 ms; serious concomitant diseases (including severe hypertension, severe diabetes, active infection, thyroid disease, etc.) that are harmful to the patient’s safety or affect the patient’s completion of the study; the patient is assessed by the investigators to be unable or unwilling to comply with the requirements of the protocol.
Interventions
Eligible patients will be randomized in 2:1 ratio to either Group A or Group B. A stratified randomization will be used to control confounding variables and balance the baseline characteristics between the different treatments. Patients will be stratified by the time since prior ET (< 12 months/≥ 12 months/no prior ET) and location of metastatic lesions (visceral versus non-visceral).
Patients randomized to Group A will receive pyrotinib + trastuzumab + AI and patients randomized to Group B will receive trastuzumab + AI. In each group, trastuzumab will be administered every 3 weeks intravenously (8 mg/kg loading doses followed by 6 mg/kg maintenance doses). Pyrotinib will be administered 400 mg orally daily. For ET, all pre- and perimenopausal women will receive ovarian ablation or suppression. The AI is to be determined by investigators before randomization. The available options for AI could be either anastrozole, letrozole, or exemestane (1 mg/2.5 mg/25 mg, once daily, oral). Patients will continue to receive the assigned medication until objective disease progression, symptomatic deterioration, or unacceptable toxicity (at the discretion of the treating physician), death or withdrawal of consent, whichever occurs first. The imaging evaluation will be performed according to the RECIST 1.1. The patients in Group B will be eligible for crossover to Group A in case of disease progression.
Patients will be screened at baseline for eligibility. And providing signing informed consent, baseline measurements will be obtained. Survival status will be followed every 12 weeks regardless of treatment discontinuation until death, lost to follow-up, or withdrawal of consent to survival follow-up. Survival information can be obtained via phone, and information will be documented in the relevant case report form. Any post-study cancer treatment will be recorded. All patients will be followed for safety up to 28 days after the last dose of study treatment (pyrotinib/trastuzumab/AIs). For patients who discontinue due to reasons other than progressive disease (PD), death, lost to follow-up or withdrawal of consent to efficacy follow-up, tumor assessments and patient-reported outcomes must continue to be acquired every 6 weeks until PD, death, lost to follow-up, or withdrawal of consent to efficacy follow-up. Group B patients who choose to cross over after first objective progression will have their progression status recorded every 6 weeks to assess time to the second PD.
Schedule of enrollment, interventions, and assessments are shown in the supplementary material.
Statistics: sample size and power calculation
The primary objective of this study is to compare the PFS between the two groups. The hypothesis is based on hazard ratio (HR): H0: HR = 1; Ha: HR ≠ 1. In the case of 2:1 allocation, a sample of 180 evaluable patients with 144 events is expected to provide 80% power (significance level 0.05) to detect an improvement in median PFS, from 8.0 months with trastuzumab plus an AI to 13.0 months when adding pyrotinib [PASS 15]. Taking the withdrawal rate as approximately 10%, the sample size will be 198 patients.
Statistics: analyses
Efficacy analyses
The difference in PFS (primary endpoint) will be estimated using the full analysis set (FAS) in a stratified log-rank test accounting for all stratification factors and a Cox proportional hazards model to explore baseline factors that may affect PFS. Secondary objectives include comparisons of OS, ORR, TTR, DoR, CBR, QoL, and safety. A stratified log-rank test (using the same stratification factors as for the PFS analysis) will be used to compare OS, TTR and DoR between the two groups. Kaplan-Meier curves, median PFS/OS, TTR, and DoR HR with appropriate confidence intervals will be reported. Exploratory analyses will be conducted for PFS2.
A 95% CI for ORR/CBR will be provided. The comparison for response rates between the two groups will be assessed using the Cochran-Mantel-Haenszel test with the same stratification factors as for the PFS analyses. Analyses of ORR/CBR will be performed on the FAS population.
Safety analyses
The type, grade and frequency of AEs will be recorded. AEs and abnormal findings in laboratory tests will be listed with the relationship to the study treatments. The AE summary tables for crossover patients will include all AEs that occurred after the start of crossover treatment until the end of the 30-day follow-up period.