Chemo- versus endocrine therapy in combination with dual HER2-targeted therapy of Herceptin® (trastuzumab) and Perjeta® (pertuzumab) plus Kisqali® (ribociclib) in patients with HER2 positive and hormone-receptor positive metastatic breast cancer.

Especially for diseases that are not curable such as metastatic breast cancer (MBC), the maintenance of quality of life is one of the main aims of treatments. Adverse events are well-known side effects of any cytostatic treatment and impact the patients' quality of life. Therefore, new treatment options are developed that should stop or at least slow down metastatic spread of cancer without causing negative side effects in terms of high-grade adverse events. For patients with hormone-receptor positive and HER2 positive MBC the combination of HER2-targeted therapy with endocrine therapy has already been proven to be an effective and in many cases valuable alternative to the combination of HER2-targeted therapy with chemotherapy. The high relevance of HER2-neu-targeted/endocrine treatment combinations derives from the fact that potential chemotherapy-related toxicity can be avoided, which in turn positively affects quality of life. Clinical trials suggest an additional benefit when a CDK4/6 inhibitor is added to the combination of endocrine therapy and anti HER2 treatment. DETECT V is a randomized phase III study comparing the safety and efficacy of trastuzumab plus pertuzumab and the CDK 4/6 inhibitor ribociclib in combination with either endocrine therapy or chemotherapy.

Inclusion criteria:

• Signed, written informed consent in study participation

• The primary tumor and/or biopsies from metastatic sites or locoregional recurrences have been confirmed as HER2-positive (FISH-positive or IHC 3+) and hormone receptor positive breast cancer by histopathology according to local testing

• Metastatic breast cancer or locally advanced BC, which cannot be treated by surgery or radiotherapy only

• Pre- and postmenopausal women are allowed

• No more than two prior chemotherapies for metastatic disease

• No more than two prior anti-HER2 therapies for metastatic disease

• Pertuzumab retreatment is allowed if prior pertuzumab treatment was finished 12 months before

• At least one measurable lesion assessable using standard techniques by Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1)

• Tumor evaluation according to RECIST version 1.1 has been performed within 4 weeks before randomization based on local assessment

• Age ≥ 18 years

• Standard 12-lead ECG values assessed by the local laboratory:

  • QTcF interval at screening < 450 msec (using Fridericia's correction)
  • Resting heart rate 50-90 bpm

• Left ventricular cardiac ejection fraction (LVEF) ≥ 50% at baseline (as measured by echocardiogram)

• ECOG Score ≤ 2

• Adequate organ function within 14 days before randomization, evidenced by the following laboratory results below:

  • absolute neutrophil count ≥ 1500 cells/µL,
  • platelet count ≥ 100000 cells/µL,
  • hemoglobin ≥ 9 g/dL,
  • ALT (SGPT) ≤ 2.0 × ULN (≤ 3.0 × ULN in case of liver metastases)
  • AST (SGOT) ≤ 2.0 × ULN (≤ 3.0 × ULN in case of liver metastases)
  • bilirubin ≤ 1.5 × ULN (with the exception of Gilbert's syndrome)
  • creatinine ≤ 2.0 mg/dl or 177µmol/L INR ≤ 1,5

• Patients must have the following laboratory values within normal limits or corrected to within normal limits with supplemets before the first dose of study medication:

  • Sodium
  • Potassium
  • Total calcium

• In case of patients of child bearing potential:

Negative serum pregnancy test at baseline (within 7 days prior to randomization) and agreement to remain abstinent (if it is in line with the preferred and usual lifestyle) or use single or combined non-hormonal contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 7 months after the last dose of study treatment

Exclusion criteria:

Patients will be excluded from the study for any of the following reasons:

• History of hypersensitivity reactions attributed to trastuzumab, pertuzumab, ribociclib or to other components of drug formulation

• Mandatory need for cytostatic treatment at time of study entry based on clinical judgment and national/international treatment guidelines

• Known CNS metastases

• Any concurrent severe, uncontrolled systemic disease, social or psychiatric condition that might interfere with the planned treatment and with the patient's adherence to the protocol

• Progression on prior Pertuzumab therapy

• Treatment with Pertuzumab within the last 12 months

• Prior treatment with any mTOR- or CDK4/6-inhibitor

• Treatment with any other investigational agents during trial

• Known hypersensitivity to lecithin (soya) or peanuts

• Life expectancy < 6 months

• Patients with pre-existing grade ≥2 peripheral neuropathy are excluded from taxane-based chemotherapy

• History of serious cardiac disease, including but not confined to:

  • history of documented heart failure or systolic dysfunction (LVEF < 50%)
  • high-risk uncontrolled arrhythmias i.e., atrial tachycardia with a heart rate ≥100/min at rest, significant ventricular arrhythmia (ventricular tachycardia) or higher-grade AV-block (second degree AV-block Type 2 [Mobitz 2] or third degree AV-block)
  • angina pectoris requiring anti-anginal medication
  • clinically significant valvular heart disease
  • evidence of transmural infarction on ECG
  • poorly controlled hypertension (e.g., systolic >180 mm Hg or diastolic >100 mm Hg)
  • any other cardiac condition, which in the opinion of the treating physician would make this protocol unreasonably hazardous for the patient

• Dyspnea at rest or other diseases that require continuous oxygen therapy

• Patients with poorly controlled diabetes or with evidence of clinically significant diabetic vascular complications

• Patients with known infection with HIV, hepatitis B virus, or hepatitis C virus

• Male patients

• Pregnant, lactating or women of childbearing potential without a negative pregnancy test (serum) within 7 days prior to randomization, irrespective of the method of contraception used

• Medical or psychological conditions that would not permit the subject to complete the study or sign informed consent

• Participation in another clinical study within the 30 days before registration

• Legal incapacity or limited legal capacity