Enhanced efficacy of inavolisib combined with anti-PD-1 or anti-HER2 antibody in treating brain metastases from breast cancer.

1108 Background: The PI3K/AKT/mTOR signaling pathway is a crucial regulatory pathway involved in cell proliferation, survival, migration, and metabolism. This dysregulation can occur through various mechanisms, such as PIK3CA gene mutations and PTEN gene loss. The research of PI3K inhibitors has made significant progress in the treatment of ER-positive and HER2-negative breast cancer. Alpelisib is the only approved PI3K inhibitor for treating PIK3CA mutation-positive breast cancer. The SOLAR-1 trial demonstrated that Alpelisib combined with endocrine therapy significantly prolongs progression-free survival in these patients. However, despite improving PFS, the side effects of PI3K inhibitors pose limitations on their widespread application. Consequently, researchers are exploring next-generation PI3K inhibitors with improved safety and efficacy. Inavolisib is a novel, highly selective PI3Kα inhibitor that shows better tolerability and safety compared to existing PI3K inhibitors and has demonstrated promising antitumor effects in clinical trials. Building on this, our study aims to identify the optimal treatment regimen combining Inavolisib with various breast cancer therapies to effectively target brain metastases. Methods: We established a brain metastasis model in C57BL/6 mice by intracardiac injection of control (triple-negative) and hHER2+ Py8119 breast cancer cells. In addition to the Inavolisib monotherapy and vehicle control groups, Inavolisib was combined with a PD-1 antibody or albumin-bound paclitaxel in the triple-negative model. In the HER2+ model, Inavolisib was combined with Tucatinib, trastuzumab, or SHR-A1811 (an ADC drug targeting HER2). We monitored changes in body weight and survival rates in each group and assessed brain metastasis using IVIS small animal in vivo imaging. Results: In the triple-negative model, Inavolisib monotherapy or its combination with albumin-bound paclitaxel reduced intracranial tumor size but did not significantly extend mouse survival. Conversely, the combination of Inavolisib and PD-1 antibody significantly prolonged overall survival in triple-negative breast cancer mice. In the HER2+ breast cancer model, all three combination therapies reduced tumor burden and extended survival compared to monotherapy. However, overall, the combination with trastuzumab achieved unexpectedly good results, which were comparable to SHR-A1811 and superior to Tucatinib. Conclusions: Our findings suggest that the combination of the PI3K inhibitor Inavolisib with anti-PD-1 or anti-HER2 antibody therapy may offer an effective strategy for treating brain metastases in breast cancer. This discovery provides new insights and possibilities for improving treatment options in breast cancer brain metastasis. Further research is needed to validate the efficacy and safety of this combination therapy.