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 (p