Study of Inavolisib in Combination with Ribociclib and Fulvestrant in Patients with Advanced, Hormone Receptor-Positive, and HER2-Negative Breast Cancer

Breast cancer develops when cells in the breast tissue—usually in the milk ducts or lobules—grow uncontrollably. The disease is considered locally advanced if the tumor is large, has invaded adjacent tissue such as the skin or muscles, or has extensively affected surrounding lymph nodes, without showing signs of metastasis to distant organs. Metastatic means that the cancer has formed metastases in other organs of the body. In a hormone receptor-positive tumor, the cancer cells have binding sites (receptors) for the sex hormones estrogen and/or progesterone, through which these hormones can stimulate tumor growth. HER2, on the other hand, is a receptor for growth signals on the cell surface that is present in greatly increased quantities in some types of cancer. HER2-negative means that HER2 is not present in increased quantities on the cancer cells. If the tumor continues to grow despite anti-hormone therapy, this is referred to as endocrine resistance. Fulvestrant is part of anti-hormone therapy. It binds to the estrogen receptor, blocks it, and causes the receptor to be broken down, thereby interrupting the signal from the hormone estrogen in cancer cells that express this receptor. It is usually administered as an injection into a muscle (intramuscularly). Ribociclib is a CDK4/6 inhibitor that blocks two proteins, CDK4 and CDK6, which drive the cell cycle and trigger cell division, thereby slowing the division of cancer cells. Inavolisib specifically targets PI3K-alpha, a protein in the so-called PI3K signaling pathway, through which cells receive signals to grow and survive and which can be permanently active in cancer cells. Inavolisib is already approved as a combination therapy for the treatment of certain patients with PIK3CA-mutated, estrogen receptor-positive, HER2-negative, locally advanced or metastatic breast cancer, provided the disease has recurred during or within twelve months after completion of adjuvant anti-hormone therapy. Inavolisib is not yet approved for breast cancer without a PIK3CA mutation, as is being investigated in this study. The goal of this Phase 2 study is to investigate whether adding inavolisib to standard therapy can increase the treatment response rate. To this end, patients will be randomly assigned to two treatment groups. The treatment arm receives inavolisib along with ribociclib and fulvestrant, while the control arm receives a placebo instead of inavolisib, along with ribociclib and fulvestrant. The study is double-blind, which means that neither the patients nor the study physicians know who is receiving inavolisib and who is receiving the placebo. Patients aged 18 and older with locally advanced or metastatic, hormone receptor-positive, HER2-negative breast cancer that can no longer be treated with curative surgery or radiation therapy are eligible to participate. The disease must have progressed during adjuvant anti-hormone therapy or within twelve months thereafter, without prior drug therapy for the advanced breast cancer. In addition, a tissue analysis must confirm the absence of a PIK3CA mutation and the loss of chromosome 8p.