Targeted maintenance therapy with trastuzumab/pertuzumab (PHESGO) for inoperable HER2-positive breast cancer following initial treatment with trastuzumab deruxtecan

HER2-positive breast cancer is an aggressive form of breast cancer in which the HER2 receptor (human epidermal growth factor receptor 2) is overexpressed on the surface of the cancer cells. In about 15–20% of breast cancer patients, this growth-promoting receptor is overexpressed; this is referred to as HER2-positive breast cancer. This characteristic also makes HER2 an ideal target for modern cancer therapies. Drugs such as trastuzumab, pertuzumab, or trastuzumab deruxtecan recognize the HER2 receptor and specifically target the cancer cells, while largely sparing healthy tissue. The HER2 receptor thus serves as a “target” (therapeutic entry point) for so-called targeted therapies, which can effectively slow the progression of the disease. The current standard treatment for HER2-positive breast cancer depends on the stage of the disease. In advanced, metastatic breast cancer, targeted antibodies are used in combination with chemotherapy, supplemented as needed by trastuzumab deruxtecan (T-DXd). T-DXd is a so-called antibody-drug conjugate; the antibody trastuzumab specifically recognizes HER2-positive cancer cells, binds to them, and delivers a cytotoxic agent (deruxtecan) directly into the cancer cell. Once inside, the drug is released and selectively destroys the affected cells, while sparing healthy tissue as much as possible. PHESGO is a fixed-dose combination of the two antibodies trastuzumab and pertuzumab. Unlike conventional infusions, PHESGO is administered as an injection under the skin (subcutaneously). Both active ingredients block the HER2 receptor in different ways, thereby inhibiting the growth and division of tumor cells. PHESGO is frequently used as maintenance therapy to delay the progression of the disease following successful initial treatment. Subcutaneous administration simplifies treatment and shortens the duration of hospital stays.

The goal of this Phase 2 study is to investigate the efficacy of treatment with T-DXd followed by PHESGO as maintenance therapy. The primary endpoint—that is, the main focus—of the study is the proportion of patients showing no disease progression after one year and the overall survival (OS) rate after three years. To this end, all patients will first receive 6 cycles of T-DXd as an infusion every 3 weeks. This is followed by maintenance therapy with PHESGO administered as a subcutaneous injection. Initially, a higher starting dose (1,200 mg pertuzumab/600 mg trastuzumab) is administered, followed by a standard dose (600 mg pertuzumab/600 mg trastuzumab) every 3 weeks. Treatment will continue until disease progression, death, discontinuation of study treatment for another reason, or for up to 3 years after the start of T-DXd treatment, whichever occurs first. After the study ends, all patients will undergo a safety evaluation to monitor for toxicity and changes in concomitant medications.

Eligible participants include women and men aged 18 years or older with HER2-positive, inoperable, locally advanced, or metastatic breast cancer. No prior systemic treatment with chemotherapy or HER2-targeted therapy is permitted. Prior anti-hormone therapy is permitted. Patients may have already received prior treatment if at least 12 months have passed since its completion. Patients with untreated or symptomatic brain metastases are excluded.