在 PIK3CA 突变 HR /HER2-  晚期乳腺癌 (ABC) (SOLAR-1) 患者中，Alpelisib 加氟维司群与氟维司群相比具有显着的无进展生存获益。高血糖是 PI3Kα 抑制的一种靶向不良反应，可能导致剂量调整，从而可能影响 alpelisib 的疗效。我们报告了关于使用钠葡萄糖协同转运蛋白 2 抑制剂 (SGLT2i) 改善 PI3Kα 抑制剂相关高血糖的临床前模型和两项临床试验（SOLAR-1 和 BYLieve）的数据。健康布朗挪威 (BN)、轻度糖尿病 Zucker 糖尿病脂肪 (ZDF) ，和 Rat1-myr-p110α/HBRX3077 荷瘤裸鼠用 alpelisib 治疗，分析二甲双胍和达格列净 (SGLT2i) 的葡萄糖和胰岛素对照以及 alpelisib 的疗效。在两项试验中，对接受 SGLT2i 联合 alpelisib 治疗的患者 (n = 19) 和未接受 SGLT2i 治疗的倾向评分匹配队列 (n = 74) 之间的高血糖不良事件 (AE) 进行了比较。接受 alpelisib 治疗的 BN 和 ZDF 大鼠中达格列净和二甲双胍正常化血糖和胰岛素水平降低。当二甲双胍和达格列净与阿培利西一起给药时，没有观察到酮症或药物相互作用的迹象。当与达格列净一起用于荷瘤大鼠时，Alpelisib 的抗肿瘤功效得以维持。与未接受 SGLT2i 的匹配患者组相比，接受 SGLT2i 的患者发生 3 级高血糖 AE 和导致 alpelisib 剂量调整、中断或停药的高血糖 AE 的发生率分别降低 4.9 倍和 6.4 倍，并且发生风险相对降低。这些 AE（70.6% 和 35.7%）。这些数据表明，添加 SGLT2i 可以有效管理高血糖，从而减少 PIK3CA 突变 HR /HER2- ABC 患者的 alpelisib 剂量调整和停药次数（SOLAR-1：NCT02437318；BYLieve：NCT03056755） ).© 2024。作者。

Alpelisib plus fulvestrant demonstrated a significant progression-free survival benefit versus fulvestrant in patients with PIK3CA-mutated HR+ /HER2- advanced breast cancer (ABC) (SOLAR-1). Hyperglycemia, an on-target adverse effect of PI3Kα inhibition, can lead to dose modifications, potentially impacting alpelisib efficacy. We report data from preclinical models and two clinical trials (SOLAR-1 and BYLieve) on Sodium glucose cotransporter 2 inhibitor (SGLT2i) use to improve PI3Kα inhibitor-associated hyperglycemia.Healthy Brown Norway (BN), mild diabetic Zucker diabetic fatty (ZDF), and Rat1-myr-p110α/HBRX3077 tumor-bearing nude rats treated with alpelisib were analyzed for glucose and insulin control with metformin and dapagliflozin (SGLT2i) and alpelisib efficacy. Hyperglycemia adverse events (AEs) were compared between patients receiving SGLT2i with alpelisib (n = 19) and a propensity score-matched cohort not receiving SGLT2i (n = 74) in both trials.Dapagliflozin and metformin in BN and ZDF rats treated with alpelisib normalized blood glucose and reduced insulin levels. No signs of ketosis or drug-drug interaction were observed when metformin and dapagliflozin was administered with alpelisib. Alpelisib antitumor efficacy was maintained when used with dapagliflozin in tumor-bearing rats. Compared with a matched set of patients without SGLT2i, patients receiving SGLT2i had 4.9 and 6.4 times lower rates of grade ≥ 3 hyperglycemia AEs and hyperglycemia AEs resulting in alpelisib dose adjustments, interruptions, or withdrawals, respectively, and a relative reduction in risk of experiencing these AEs (70.6% and 35.7%).These data suggest adding an SGLT2i can effectively manage hyperglycemia, resulting in fewer alpelisib dose modifications and discontinuations in patients with PIK3CA-mutated HR+ /HER2- ABC (SOLAR-1: NCT02437318; BYLieve: NCT03056755).© 2024. The Author(s).