Gedatolisib在HR阳性/HER2阴性晚期乳腺癌CDK4/6抑制后的应用：药理学、III期证据及治疗定位。
完整摘要 · 中文译文
引言：CDK4/6抑制剂治疗后出现疾病进展，仍是激素受体阳性、HER2阴性晚期乳腺癌治疗中的一项挑战。Gedatolisib是一种经FDA批准的泛I类PI3K/mTORC1/2抑制剂，为未检测到PIK3CA突变（PIK3CA mutation）的疾病提供了一种治疗策略。 涵盖领域：本综述批判性评估了gedatolisib的药理学、临床证据、安全性、生物标志物及治疗定位。检索了PubMed/MEDLINE、出版商平台、ClinicalTrials.gov、监管来源及肿瘤学会议记录，检索时间截至2026年7月，并更新至2026年9月。在III期VIKTORIA-1研究中，gedatolisib-氟维司群-帕博西尼组与氟维司群组相比，中位无进展生存期（progression-free survival）为9.3个月对比2.0个月（风险比 0.24）；gedatolisib-氟维司群组与氟维司群组相比，中位无进展生存期为7.4个月对比2.0个月（风险比 0.33）。实验性治疗方案未在有统计学功效的分析中进行直接比较。口腔炎、代谢毒性、帕博西尼相关的中性粒细胞减少症以及每周静脉给药，均使治疗实施复杂化。 专家意见：Gedatolisib扩展了CDK4/6抑制剂治疗后的可选方案，但最佳定位需要个体化的患者选择，且不能假定三联方案具有优效性。成熟的生存结局、经过验证的预测性生物标志物、比较性序贯治疗证据以及VIKTORIA-2研究的结果，将决定其长期临床价值。
完整摘要 · 英文原文
INTRODUCTION: Progression following CDK4/6 inhibition remains a therapeutic challenge in hormone receptor-positive, HER2-negative advanced breast cancer. Gedatolisib, an FDA-approved pan-class I PI3K/mTORC1/2 inhibitor, introduces a treatment strategy for disease without a detected PIK3CA mutation. AREAS COVERED: This review critically evaluates gedatolisib pharmacology, clinical evidence, safety, biomarkers, and therapeutic positioning. PubMed/MEDLINE, publisher platforms, ClinicalTrials.gov, regulatory sources, and oncology conference records were searched through July 2026, with updates through September 2026. In phase III VIKTORIA-1, median progression-free survival was 9.3 versus 2.0 months with gedatolisib-fulvestrant-palbociclib versus fulvestrant (hazard ratio 0.24) and 7.4 versus 2.0 months with gedatolisib-fulvestrant versus fulvestrant (hazard ratio 0.33). Experimental regimens were not directly compared in a powered analysis. Stomatitis, metabolic toxicity, palbociclib-associated neutropenia, and weekly intravenous administration complicate treatment delivery. EXPERT OPINION: Gedatolisib expands post-CDK4/6 treatment options, but optimal positioning requires individualized patient selection without assuming triplet superiority. Mature survival outcomes, validated predictive biomarkers, comparative sequencing evidence, and VIKTORIA-2 findings will determine its long-term clinical value.