Sequential use of PI3K/AKT/mTOR pathway inhibitors alpelisib and everolimus in patients with hormone receptor-positive metastatic breast cancer

Everolimus, an mTOR inhibitor, is FDA-approved with endocrine therapy (ET) for hormone receptor-positive (HR+)/HER2- MBC regardless of PI3K/AKT/mTOR pathway mutation status. Alpelisib, a PI3K inhibitor, is FDA-approved with fulvestrant for PIK3CA- mutant HR+/HER2- MBC. The efficacy and safety of sequential treatment with these pathway inhibitors is not well described. This single-center observational study identified patients with PIK3CA -mutant HR+/HER2- MBC treated with everolimus and alpelisib sequentially from 2012 to 2023. We abstracted patient, tumor, and treatment information from medical records. Patients treated first with everolimus then alpelisib were categorized as Group 1 and those treated first with alpelisib then everolimus as Group 2. Median time to treatment failure on 1st pathway inhibitor (TTF1) and TTF on 2nd pathway inhibitor (TTF2) were computed using the Kaplan-Meier method. 115 patients were included, with 63 (55%) in Group 1 and 52 (45%) in Group 2. Median age was 61 and 53% of patients had visceral disease. Patients received a median 3 prior lines of metastatic treatment (interquartile range IQR 2–4.5) and 71% received prior CDK4/6 inhibitor; more patients in Group 2 received prior CDK4/6 inhibitor than Group 1 (87 vs. 59%, p = 0.001). In Group 1, 50 (79%) patients discontinued everolimus for progression and 13 (21%) for toxicity. In Group 2, 33 (63%) patients discontinued alpelisib for progression and 19 (37%) for toxicity. Median TTF1 was 9.2 months (95%CI 5.5–12) in Group 1 and 9.7 months (95%CI 7.1–14) in Group 2 ( p = 0.5, Fig. 1, left). In patients who received prior CDK4/6 inhibitor, median TTF1 was 4.3 months (95%CI 3.2–11) in Group 1 and 8.7 months (95%CI 6.4–12) in Group 2 (p = 0.02). In univariable Cox proportional hazards analyses, factors associated with worse TTF1 included prior CDK4/6 inhibitor use and more prior lines of treatment; these remained significant in multivariable analyses. After adjusting for prior CDK4/6 inhibitor use and prior total/intervening lines of therapy, TTF1 was not significantly different between groups (p = 0.2), nor was TTF2 (p = 0.1). Presence of GATA3 mutation was significantly associated with poorer alpelisib-specific TTF ( p = 0.016). Prior CDK4/6 inhibitor use was associated with worse TTF1 and TTF2. There were no significant differences in TTF1 nor in TTF2 between Groups 1 and 2 after adjusting for clinical predictors. Given the recent approvals of capivasertib and inavolisib, prospective studies testing optimal sequencing of pathway agents with integration of biomarker analysis are needed.