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Everolimus versus alpelisib in advanced hormone receptor-positive HER2-negative breast cancer: targeting different nodes of the PI3K/AKT/mTORC1 pathway with different clinical implications
Breast Cancer Research ( IF 6.1 ) Pub Date : 2020-04-06 , DOI: 10.1186/s13058-020-01271-0
Claudio Vernieri , Francesca Corti , Federico Nichetti , Francesca Ligorio , Sara Manglaviti , Emma Zattarin , Carmen G. Rea , Giuseppe Capri , Giulia V. Bianchi , Filippo de Braud

The PI3K/AKT/mTORC1 axis is implicated in hormone receptor-positive HER2-negative metastatic breast cancer (HR+ HER2− mBC) resistance to anti-estrogen treatments. Based on results of the BOLERO-2 trial, the mTORC1 inhibitor everolimus in combination with the steroidal aromatase inhibitor (AI) exemestane has become a standard treatment for patients with HR+ HER2− mBC resistant to prior non-steroidal AI therapy. In the recent SOLAR-1 trial, the inhibitor of the PI3K alpha subunit (p110α) alpelisib in combination with fulvestrant prolonged progression-free survival (PFS) when compared to fulvestrant alone in patients with PIK3CA-mutated HR+ HER2− mBC that progressed after/on previous AI treatment. Therefore, two different molecules targeting the PI3K/AKT/mTORC1 axis, namely everolimus and alpelisib, are available for patients progressing on/after previous AI treatment, but it is unclear how to optimize their use in the clinical practice. Here, we reviewed the available clinical evidence deriving from the BOLERO-2 and SOLAR-1 trials to compare efficacy and safety profiles of everolimus and alpelisib in advanced HR+ HER2− BC treatment. Adding either compound to standard endocrine therapy provided similar absolute and relative PFS advantage. In the SOLAR-1 trial, a 76% incidence of grade (G) 3 or 4 (G3/G4) adverse events was reported, while G3/G4 toxicities occurred in 42% of patients in the BOLERO-2 trial. While alpelisib was only effective in patients with PIK3CA-mutated neoplasms, retrospective analyses indicate that everolimus improves exemestane efficacy independently of PIK3CA mutational status. Based on the available efficacy and safety data, the “new” alpelisib may be burdened by higher incidence of severe adverse events, higher costs, and anticancer efficacy that is limited to PIK3CA-mutated tumors when compared to the “old” everolimus. Therefore, the everolimus-exemestane combination remains an effective and reasonably well-tolerated therapeutic option for HR+ HER2− mBC patients progressing after/on previous AI treatment, independently of PIK3CA mutational status.

中文翻译:

依维莫司与alpelisib在晚期激素受体阳性HER2阴性乳腺癌中的应用:针对PI3K / AKT / mTORC1途径的不同结节,具有不同的临床意义

PI3K / AKT / mTORC1轴与激素受体阳性的HER2阴性转移性乳腺癌(HR + HER2-mBC)对抗雌激素治疗的耐药性有关。根据BOLERO-2试验的结果,mTORC1抑制剂依维莫司与类固醇芳香化酶抑制剂(AI)依西美坦合用已成为对先前非类固醇AI治疗耐药的HR + HER2-mBC患者的标准治疗方法。在最近的SOLAR-1试验中,PI3K突变型HR + HER2-mBC患者在//后发展,PI3Kα亚基(p110α)alpelisib的抑制剂与氟维司群联合使用的长效无进展生存期(PFS)与仅氟维司群相比以前的AI治疗。因此,靶向PI3K / AKT / mTORC1轴的两种不同分子,即依维莫司和alpelisib,在先前的AI治疗中/之后接受治疗的患者均可使用,但尚不清楚如何在临床实践中优化使用。在这里,我们回顾了来自BOLERO-2和SOLAR-1试验的可用临床证据,以比较依维莫司和alpelisib在晚期HR + HER2-BC治疗中的疗效和安全性。在标准的内分泌治疗中添加任何一种化合物都可提供相似的绝对和相对PFS优势。在SOLAR-1试验中,据报道发生了76%的3级或4级(G3 / G4)不良事件,而BOLERO-2试验中42%的患者发生了G3 / G4毒性。尽管alpelisib仅在PIK3CA突变的肿瘤患者中有效,但回顾性分析表明依维莫司可独立于PIK3CA突变状态而改善依西美坦的疗效。根据现有的疗效和安全性数据,与“旧的”依维莫司相比,“新的” alpelisib可能会受到严重不良事件发生率更高,费用更高以及抗癌功效的限制,而这些副作用仅限于PIK3CA突变的肿瘤。因此,依维莫司-依西美坦联合治疗对先前接受AI治疗后/进展的HR + HER2-mBC患者仍然有效且耐受性良好,与PIK3CA突变状态无关。
更新日期:2020-04-22
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