A Study of Neoadjuvant Combination Therapy with the PI3K Inhibitor Inavolisib in Early-Stage, PIK3CA-Mutated Breast Cancer

Breast cancer (mammary carcinoma) is a malignant disease of the mammary gland tissue characterized by the uncontrolled proliferation of mammary gland cells. Treatment depends, among other factors, on whether the cancer cells have hormone receptors on their surface (estrogen receptor, progesterone receptor) and whether the HER2 receptor is overexpressed (HER2-positive). In some patients with breast cancer, the cancer cells have a PIK3CA mutation. This genetic alteration leads to a change in the function of certain enzymes (phosphoinositide-3-kinases, or PI3K for short), which are normally responsible for cell division and cell growth. The mutation accelerates the growth of cancer cells and may impair the response to anti-hormone therapy. Inavolisib is a so-called PI3K inhibitor that specifically blocks the signaling pathway activated by the PIK3CA mutation in cancer cells, thereby inhibiting tumor growth. In this study, the drug is being used as neoadjuvant therapy. This means that drug treatment takes place before the tumor is surgically removed. The goal of this therapy is to shrink the tumor and thereby create better conditions for surgery. The study drug can be combined with ribociclib and letrozole. Ribociclib belongs to the class of CDK4/6 inhibitors and slows down the division of cancer cells. Letrozole is an aromatase inhibitor that blocks estrogen production in the body, thereby suppressing the hormone-dependent growth of cancer cells. All three drugs are taken as tablets.

The goal of this Phase 2 study is to investigate the safety and efficacy of neoadjuvant treatment with the new drug inavolisib in combination with ribociclib and letrozole. As part of the study, patients will be randomly assigned to one of three treatment arms, which differ in when the triple combination of inavolisib, ribociclib, and letrozole is initiated. In Arm A, patients receive all three drugs from the start; in Arm B, treatment begins with only Inavolisib and Letrozole, with Ribociclib added starting in the second cycle; and in Arm C, treatment begins with Ribociclib and Letrozole, with Inavolisib added starting in the second cycle. Treatment consists of a total of six cycles prior to the planned breast surgery (approximately 6 months). The study is open-label, meaning that both the patients and the study physicians know which treatment is being administered. After treatment, follow-up observation continues for approximately 30 days.

Women aged 18 and older with untreated, early-stage, hormone receptor-positive, HER2-negative breast cancer in which a PIK3CA mutation has been detected are eligible to participate in the study. Surgical removal of the tumor must be planned following treatment (provided the tumor is operable). Patients must not have type 1 diabetes mellitus or type 2 diabetes mellitus requiring treatment.