Abstract PS1-11-21: Sequencing PIK3CA, AKT and mTOR Inhibitors in HR+/HER2- Metastatic Breast Cancer: A Real-World Retrospective Analysis

Abstract Background The PI3K/AKT/mTOR signaling pathway is a well-established therapeutic target in hormone receptor-positive, HER2-negative metastatic breast cancer (HR+/HER2- MBC). Approved agents—everolimus (mTOR inhibitor), alpelisib (PIK3CA inhibitor), and capivasertib (AKT inhibitor)—have demonstrated median progression-free survival (mPFS) ranging from 5.5 to 7.3 months in patients previously treated with CDK4/6 inhibitors. Most clinical trials leading to the approval of PIK3CA and AKT inhibitors excluded patients with prior exposure to PIK3CA, AKT, or mTOR inhibitors. Despite lack of prospective evidence, these targeted drugs are prescribed sequentially in real-world settings. Methods We identified 72 HR+/HER2- MBC patients with PI3K/AKT/PTEN pathway alterations treated with everolimus, alpelisib, or capivasertib between January 2019 and January 2025. Of these, 30 (42%) received ≥2 pathway inhibitors sequentially (Cohort A), 28 (39%) received alpelisib alone (Cohort B), and 14 (19%) received capivasertib alone (Cohort C). Clinical data including age, measurable vs. non-measurable disease, disease site, reason for discontinuation (progression vs. toxicity), PIK3CA mutation subtype (helical vs. kinase domain), ESR1 mutation status, and prior therapy lines were collected. mPFS was defined as time from treatment start to radiographic progression or death, with censoring at last follow-up. PFS1 and PFS2 were measured independently for patients in Cohort A, and PFS1+2 was calculated to reflect cumulative disease control. ANOVA, log-rank, univariate analysis, and McNemar tests were used for survival comparisons. Results The median age of our patient population was 63 years; 23% were Hispanic. Number of prior lines of therapy in the metastatic setting was similar in all cohorts. All patients had prior CDK4/6 inhibitor exposure. mPFS1+2 was 14.0 months in Cohort A (95% CI: 9-28), compared with 7.0 months in Cohort B (95% CI: 5-8) and 6.0 months in Cohort C (95% CI: 3-8), with a hazard ratio of 0.428 for patients who received ≥2 versus a single agent (p0.0001, log-rank). PIK3CA helical versus kinase domain mutations (44% vs 56%) and ESR1 co-mutation status (present in 63%) were not significantly associated with PFS in any cohort. AKT/PTEN co-alterations (16%, 15%, 35% in Cohorts A, B, and C) showed no significant impact. In patients with measurable disease, PFS1+2 in Cohort A was 16.3 months vs. PFS of 7.2 months and 7.0 months in Cohorts B and C, respectively (p=0.003642, ANOVA). Among those with non-measurable disease, median PFS did not differ significantly across cohorts. Within Cohort A, no significant difference in combined PFS was noted between patients with measurable vs. non-measurable disease (18.3 vs. 21.8 months, p=0.66) or in patients with ESR1 mutations (p=0.265). Interestingly, no association was found between progression or toxicity on the first drug and outcomes on the second drug within Cohort A (p=0.366). Conclusions In this real-world, post-CDK4/6i cohort of HR+/HER2- MBC patients, sequential use of PI3K/AKT/mTOR pathway inhibitors was associated with significantly longer disease control compared to single-agent use. Notably, measurable disease status and mutation profiles (e.g., ESR1, PIK3CA subtype) did not predict benefit from sequential therapy. Furthermore, toxicity from one agent did not preclude benefit from subsequent agents. Our findings support the consideration of sequencing pathway inhibitors regardless of tolerance to the first agent. These results reinforce sequential PI3K/AKT/mTOR inhibition as a viable strategy in modern metastatic breast cancer care, though prospective studies are needed to validate this approach in pretreated populations. Citation Format: K. Pal, J. Thomas, N. Sadeghi, S. Kanjwal, H. McArthur, S. Reddy, G. Delgado Ramos, S. Syed, C. Ahn, N. Unni. Sequencing PIK3CA, AKT and mTOR Inhibitors in HR+/HER2- Metastatic Breast Cancer: A Real-World Retrospective Analysis 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 PS1-11-21.