Trastuzumab and pertuzumab based regimen are the standard of care for patients with human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer (MBC), significantly improving survival outcomes. However, an unmet medical need remain for patients with disease refractoriness and recurrence. Interestingly, HER2 over-expression is associated with upregulation of vascular endothelial growth factor (VEGF) in cancer cells in vitro and in vivo. Preclinical studies indicated that VEGF expression is positively regulated by HER2 signaling. In the clinical setting, HER2 over-expression correlated significantly with VEGF over- expression in samples from patients with breast cancer. There is, therefore, a biologic rationale for targeting both HER2 and VEGF pathways in patients with HER2-positive breast cancer.

PURPOSE: The hypothesis that justifies this research is that the addition of Thero2-01S22 as add-on therapy on top of first line anti-HER2 targeted treatment will improve the efficacy of anti-HER2 targeted containing regimen at the metastatic setting for breast cancer.

This study is a two-part, multicenter, randomized, double-blind, placebo-controlled, Phase III trial.

Part 1 will confirm the recommended Phase III dose of Thero2-01S22 when administered as add-on therapy on top of first line anti-HER2 targeted treatment of patients with metastatic breast, with the aim to obtain about 15 evaluable participants in Thero2-01S22 group and 15 in the placebo group.

Part 2 will assess the efficacy of Thero2-01S22 treatment at the recommended dose when administered as add-on therapy on top of first line anti-HER2 targeted treatment of patients with metastatic breast. Approximately 290 participants will be randomized to receive Thero2-01S22 or Thero2-01S22 matching-placebo in combination with trastuzumab and pertuzumab.

Participants in both Part 1 and Part 2 will receive induction therapy according to local practice with a taxane (docetaxel, paclitaxel, or nab-paclitaxel) or vinorelbine for 4 to 6 cycles in combination with pertuzumab and trastuzumab.

Inclusion Criteria:

1. Women aged > 18
2. Metastatic setting of an histologically confirmed adenocarcinoma of the breast
3. Performance status = 0, 1 or 2
4. Metastatic disease requiring the initiation of an anti HER2 containing regimen
5. First line treatment for metastatic disease
6. Standard treatment including Trastuzumab and Pertuzumab in first line
7. Patients for whom a 3-month life expectancy is anticipated
8. Baseline LVEF value > 50%, measured cardiac MRI or by echocardiography (Simpson's method) or MUGA scan within 12 weeks before initiation of the treatment. According to HERCEPTIN SPCs.
9. Overexpression of HER2 in the invasive component of the primary tumor (3+ by ICH or 2+ with confirmation of positivity by FISH or CISH)
10. Informed consent form signed

Exclusion Criteria:

1. Patients not eligible for anti-HER2 therapy
2. Patients previously treated at the metastatic setting by systemic treatment
3. Serious cardiac illness or medical conditions disallowing administration of anti-HER2 therapy. According to HERCEPTIN and PERJETA SPCs.
4. Known hypersensitivity to trastuzumab, pertuzumab, Thero2-01S22, murine proteins or to any of the excipients.
5. Uncontrolled central nervous system metastatic lesion
6. Patients who, for social, geographic or psychological reasons, cannot be adequately followed up and/or are incapable of undergoing regular controls
7. Pregnant or breastfeeding women