Abstract PS3-12-25: First Preclinical Evaluation of Inavolisib-Based Combinatorial Strategies in PIK3CA-Mutant Breast Cancer Brain Metastasis Models

Abstract Introduction: Brain metastases are a major cause of mortality in breast cancer, particularly in HER2-positive and triple-negative breast cancer (TNBC) subtypes. Due to the restrictive nature of the blood–brain barrier (BBB), conventional anti-tumor agents often show limited efficacy in the central nervous system. Moreover, PIK3CA mutations, common in breast cancer, activate the PI3K–AKT–mTOR pathway, promoting tumor proliferation, invasion, and therapeutic resistance. However, how to effectively treat PIK3CA-mutant breast cancer brain metastases (BCBM) remains a critical clinical challenge. Here, we report the first preclinical evaluation of Inavolisib, a selective PI3Kα inhibitor, in intracranial animal models and patient-derived xenografts (PDX) of BCBM harboring PIK3CA mutations across HER2-positive and TNBC subtypes. Methods: We developed the world’s first intracranial BCBM mouse models and PDX models with confirmed PIK3CA mutations, using direct intracranial injection of tumor cells derived from HER2+ and TNBC subtypes. These models were used to assess the anti-tumor efficacy of Inavolisib monotherapy and its combinations with clinically relevant agents. For TNBC models, combinations included PD-1 antibody and albumin-bound paclitaxel. For HER2-positive models, Inavolisib was combined with Trastuzumab + Pertuzumab, T-DXd (Trastuzumab deruxtecan), or Tucatinib. Tumor size and survival were measured, and all findings were validated in corresponding PIK3CA-mutant PDX models. Dose-response and toxicity profiles were also evaluated. Results: In TNBC brain metastasis models, Inavolisib monotherapy had limited efficacy. However, the combination of Inavolisib with anti–PD-1 antibody led to significant tumor volume reduction and prolonged survival, demonstrating synergistic intracranial activity. In HER2-positive BCBM models, Inavolisib + Trastuzumab + Pertuzumab and Inavolisib + T-DXd both resulted in marked suppression of brain tumor growth and significant extension of survival. Conversely, combination with HER2-TKI Tucatinib showed minimal additional benefit. These results were consistently reproduced in PIK3CA-mutant PDX models. Notably, T-DXd-based regimens demonstrated a clear dose–response relationship and maintained a favorable safety profile. Conclusion: This study provides the first preclinical evidence of Inavolisib-based combination strategies in PIK3CA-mutant breast cancer brain metastases, using both novel intracranial animal models and PDX systems. Our results suggest that: Inavolisib combined with PD-1 antibody is a promising regimen for TNBC with brain metastases; Inavolisib + T-DXd or Trastuzumab + Pertuzumab shows potent activity in HER2-positive BCBM. These findings highlight the potential of PI3K-targeted combinatorial strategies for overcoming the BBB challenge in breast cancer brain metastases and provide a strong rationale for clinical translation. Citation Format: Z. Jianli, B. Gao, L. Ding, D. Bi, T. Chen, Z. Wu, D. Huang, Y. Wang. First Preclinical Evaluation of Inavolisib-Based Combinatorial Strategies in PIK3CA-Mutant Breast Cancer Brain Metastasis Models abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-12-25.