Pyrotinib Maleate, CDK4/6 Inhibitor and Letrozole in Combination for Stage II-III TPBC: a Phase II Trial

The emergence of CDK4/6 inhibitors has brought hope to breast cancer patients resistant to endocrine therapy. In the mouse model, pyrotinib maleate combined with CDK4/6 inhibitor exhibits higher anti-tumor activity than any anti-tumor drug alone. Moreover, the toxicity of the combined therapy does not increase compared with monotherapy. This provides a good preclinical model for the treatment of breast cancer by pyrotinib maleate combined with CDK4/6 inhibitor. Based on above, it is hypothesized that pyrotinib maleate, CDK4/6 inhibitor SHR6390 and aromatase inhibitor letrozole in combination can provide a better neoadjuvant strategy for stage II-III triple-positive breast cancer.

This single-center, single-arm, open-label trial will include 89 patients with stage II-III triple-positive breast cancer (Simon's two-stage design). After providing written informed consent, the participants will undergo combined treatment of pyrotinib maleate, CDK4/6 inhibitor SHR6390, and letrozole. The effectiveness of the combined treatment will be evaluated by MRI every two treatment cycles. If the disease progresses, the participant will withdraw from the trial. If the combined treatment has identified effectiveness, the participant will undergo surgical treatment within 4 weeks (over 2 weeks) after termination of the neoadjuvant treatment. The patients will be followed up for 5 years.

Eligibility Criteria:
Inclusion Criteria:

* (1)Women aged \> 18 years and ≤ 80 years meeting one of the following conditions;

  1. Those previously receiving ovariectomy, or aged ≥ 60 years
  2. Those aged \< 60 years who have had 12 consecutive months of amenorrhoea without any pathological or physical causes, and have postmenopausal E2 and follicle stimulating hormone (FSH) levels
  3. Premenopausal or perimenopausal women who are willing to receive LHRH agonist treatment during the study period
* (2) Women who have breast cancer histopathologically confirmed by positive estrogen receptor (ER; ≥ 10%), positive progesterone receptor (PR; ≥ 1%), and positive human epidermal growth factor receptor 2 (HER2) according to the 2018 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) human epidermal growth factor receptor 2 (HER2) guideline. ER, PR and HER2 will be assessed by immunohistochemistry (IHC) on harvested tissue. ER, PR and HER2 will be considered positive if the IHC result is positive (score 3+), or the IHC result is positive (2+) and in situ hybridization (ISH) amplification rate (≥ 2.0);
* (3) Women having stage II-III breast cancer diagnosed based on AJCC cancer staging system (8th edition) who will be admitted because of breast cancer for the first time;
* (4) Karnofsky Performance Status (KPS) Scale score ≥ 70;
* (5) The functional level of organs must meet the following requirements:

  a) Bone marrow function i) Absolute neutrophil count ≥ 1.5 × 109/L (no use of growth factor within 14 days) ii) Platelet count ≥ 100 × 109/L (no corrective treatment within 7 days) iii) Hemoglobin level ≥ 100 g/L (no corrective treatment within 7 days) b) Liver and kidney function i) Total bilirubin ≤1 upper limit of normal value (ULN) ii) Alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 3 × ULN (ALT and AST ≤ 5 × ULN in patients with liver metastasis) iii) Blood urea nitrogen (BUN) and creatinine ≤ 1.5 × ULN and creatinine clearance ≥ 50 mL/min (Cockcroft-Gault formula); c) Color Doppler echocardiography: Left ventricular ejection fraction ≥ 50% d) 12-lead electrocardiography: QTc interval ≤ 480 ms
* (6) Women who can undergo a biopsy;
* (7) Volunteers to participate in the study, provision of signed informed consent, good compliance and willingness to cooperate with follow-ups

Exclusion Criteria:

* (1) Women who have received any form of anti-tumor treatment - (chemotherapy, radiotherapy, molecular targeted therapy, or endocrine therapy);
* (2) Those who have received other anti-tumor drug treatments concurrently;
* (3) Those who have bilateral breast cancer, inflammatory breast cancer or occult breast cancer;
* (4) Those who have stage IV breast cancer;
* (5) Those who have breast cancer not histopathologically confirmed;
* (6) Those who have other malignant tumors (with the exception of healed cervical carcinoma in situ) occurring in the past 5 years;
* (7) Those who have severe dysfunction of the heart, liver, kidney, and other major organs;
* (8) There are multiple factors that affect drug administration and absorption, such as inability to swallow, chronic diarrhea, and intestinal obstruction;
* (9) Those who have participated in other clinical drug trials in the past 4 weeks;
* (10) Those who are known to have a history of allergy to the component of study drugs; those who have a history of immunodeficiency, including positive detection of human immunodeficiency virus, hepatitis C virus, active hepatitis B or other acquired, congenital immunodeficiency diseases, or organ transplantation;
* (11) Those who had suffered from any heart disease, including arrhythmia which requires drug treatment or is of clinical significance; myocardial infarction; heart failure; and any other heart disease judged by the investigator as unsuitable for this trial;
* (12) Pregnant and lactating women; fertile women who provide positive results of baseline pregnancy test; women of childbearing age who are unwilling to take effective contraceptive measures during the whole study period;
* (13) If the accompanying diseases (including, but not limited to, severe hypertension, severe diabetes, and active infection, which cannot be controlled by drugs) that would be a potential hazard to participant's health, or affect the completion of the study as per investigator's judgement;
* (14) A clear history of neurological or psychiatric disorders, including epilepsy or dementia;
* (15) Upon the suggestion of the investigators for other reasons