In HER2-positive metastatic breast cancer, trastuzumab based treatment is the standard of care as long as there are no contraindications to trastuzumab. Frequently, trastuzumab is being combined with taxanes in the first-line setting. However, since therapy with trastuzumab is active even in the absence of chemotherapy in HER2-positive MBC, the optimal treatment strategy either in combination or in sequence with chemotherapy is still under debate. This randomized phase II trial is studying a new strategy for the treatment of metastatic breast cancer with HER2-positive. First-line treatment consists of trastuzumab and pertuzumab, a treatment without chemotherapy. In case of disease progression, chemotherapy with T-DM1 is then performed as second-line treatment. Third-line and further line therapies are performed according to the physician's discretion. If this new therapeutic strategy is as effective and better tolerated than the conventional strategy, this would mean a serious breakthrough in the treatment of HER2-positive metastatic breast cancer.

OBJECTIVES:

Primary

-To evaluate the efficacy in terms of overall survival (OS) at 24 months of a chemotherapy-free dual HER2-inhibition with trastuzumab and pertuzumab (first-line) followed by T-DM1 (second-line) and of a chemotherapy-containing dual HER2-inhibition with trastuzumab and pertuzumab (first-line) followed by T-DM1 (second-line) in patients with HER2-positive metastatic breast cancer.

Secondary

• To evaluate other efficacy parameter
• To evaluate the safety and tolerability profile of the two treatment strategies
• To evaluate the Quality of Life (QoL)
• To learn how patients are treated after trial treatment

OUTLINE: This is a multicenter study. Patients are stratified according to hormone receptor status (positive vs negative), prior trastuzumab (never or >12 months vs ≤12 months after last infusion), visceral metastases (present vs absent) and site. Patients are randomized to 1 of 2 treatment arms.

SELECTION OF PATIENTS (MOST IMPORTANT CRITERIA)

Inclusion criteria for first-line therapy

• Histologically confirmed breast cancer with distant metastases

Note:

1. A biopsy from the primary tumor or a metastasis can be used for diagnosis.

2. Patients with non-measurable lesions are eligible.

3. Patients with inoperable, locally advanced breast cancer with lymph node metastases other than ipsilateral locoregional (axillary, infraclavicular, parasternal) or other distant metastases are eligible.

4. Patients with bone metastases with or without bone targeted therapy (bisphosphonates, denosumab) are eligible.

5. Patients with de-novo Stage IV disease are eligible.

   • HER2-positive tumor according to central pathology testing for HER2

Note:

1. A formalin-fixed paraffin-embedded (FFPE) biopsy from the primary tumor or a metastasis has to be used for HER2 status determination. If a biopsy is available from a metastasis, the HER2 testing should be performed using the metastasis.

2. Fine needle aspiration is not acceptable for HER 2 testing. • Women aged ≥18 years

   • WHO performance status 0 to 2

   • Left Ventricular Ejection Fraction (LVEF) ≥50% as determined by either ECHO or MUGA
   • Adequate organ function, evidenced by the following laboratory results:

   Neutrophils >1.5x109/L, platelets >100x109/L, hemoglobin ≥90g/L, total bilirubin ≤1.5xULN (unless the patients has documented Gilbert's disease), AST ≤3xULN, ALT ≤3xULN, AP ≤2.5xULN (except in patients with bone metastases: AP ≤5xULN), creatinine ≤1.5xULN

   Exclusion criteria for first-line therapy

   • Prior chemotherapy for inoperable locally advanced or metastatic breast cancer

   Note:

   Prior neoadjuvant/adjuvant chemotherapy is allowed if doses for anthracyclines have not exceeded 720mg/m2 and 240mg/m2 for epirubicin and doxorubicin, respectively.

   - Re-exposure to paclitaxel is permitted, if the last dose of taxane was given at least 1 year before randomization.

   - Re-exposure to vinorelbine is permitted, if the last dose of vinorelbine was given at least 1 year before randomization.

   • Prior anti-HER2 treatment for metastatic or inoperable breast cancer

   Note:

   Prior neoadjuvant/adjuvant anti-HER2 treatment with trastuzumab and/or lapatinib is allowed.

   • More than one endocrine treatment line for metastatic or inoperable breast cancer exceeding a duration of 1 month

   Note:

1. Adjuvant endocrine treatment is not counted as one line.

2. Patients progressing on endocrine treatment: this specific endocrine treatment must have been stopped at least 2 weeks prior to randomization.

   • Prior treatment with pertuzumab and/or T-DM1

   • Known leptomeningeal or CNS metastases

   Note:

   A brain MRI or CT scan is mandatory in case of clinical suspicion of CNS metastases.

   • Single bone metastasis treated with radiotherapy (if the bone metastasis is the only tumor lesion)

   Inclusion criteria for second-line therapy • At least one dose of trial therapy in the first-line treatment phase of this trial

   • • Proven disease progression on first-line therapy or radiotherapy of a bone metastasis

   Notes:

   First new parenchymal CNS metastases only do not count as progression requiring the initiation of second line trial treatment. Radiotherapy of a single area only for pain control is allowed and will not count as PD.

   • Adequate organ function, evidenced by the following laboratory results: Neutrophils >1.5x109/L, platelets >100x109/L, hemoglobin ≥90g/L, total bilirubin ≤1.5xULN (unless the patients has documented Gilbert's disease), AST ≤3xULN, AP ≤2.5xULN (except in patients with bone metastases: AP ≤5xULN), creatinine ≤1.5ULN

   • LVEF ≥50% as determined by either ECHO or MUGA

   • QoL questionnaire has been completed.

   Exclusion criteria for second-line therapy

   • Termination of first-line therapy with trastuzumab/pertuzumab due to unacceptable toxicity without objective evidence of disease progression

   • CNS metastases that are untreated, symptomatic, or require therapy to control symptoms, as well as a history of radiation, surgery, or other therapy, including steroids, to control symptoms from CNS metastases within 2 months (60 days) before registration

   • Peripheral neuropathy of CTCAE grade ≥3

   • Interstitial lung disease (ILD) or pneumonitis grade ≥3
   • Any other adverse event which has not recovered to CTCAE grade ≤1 (except alopecia)