Phase I Study of Everolimus, Letrozole, and Trastuzumab in Patients with Hormone Receptor-positive Metastatic Breast Cancer or Other Solid Tumors.
Phase I Study of Everolimus, Letrozole, and Trastuzumab in Patients with Hormone Receptor-positive Metastatic Breast Cancer or Other Solid Tumors.
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依维莫司、来曲唑和曲妥珠单抗在激素受体阳性转移性乳腺癌或其他实体瘤患者中的I期研究
DOI：
10.1158/1078-0432.ccr-20-2878
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发表时间：
2021-03-01
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已证实依维莫司与来曲唑或曲妥珠单抗的双联体对HER 2阳性乳腺癌具有活性，表明三联组合可具有协同抗癌活性。这项首次人体剂量递增研究（NCT 02152943）入组激素受体阳性、HER 2阳性患者（定义为扩增、过表达或突变）治疗难治性晚期癌症接受递增剂量（3+3设计）每日口服来曲唑（第1-21天）、每日口服依维莫司（第1-21天）和每21天静脉内曲妥珠单抗（第1天），以确定剂量限制性毒性（DLT）和最大耐受剂量或推荐的II期剂量（RP 2D）。共入组了32例激素受体阳性、HER 2阳性（扩增，n=27;过表达，n=1;突变，n=4）晚期乳腺癌（n=26）或其他癌症（n=6）患者。最常见的≥ 3级不良事件包括高血糖症（n=4）、贫血（n=3）、血小板减少症（n= 2）和粘膜炎（n=2）。DLT包括3级粘膜炎和4级中性粒细胞减少症，曲妥珠单抗在第1周期第1天以8 mg/kg负荷剂量给药，随后在后续周期第1天以6 mg/kg维持剂量给药，加上每日10 mg依维莫司和每日2.5 mg来曲唑，每21天一次，被宣布为RP 2D。5例乳腺癌患者（4例HER 2扩增，1例HER 2突变）有部分缓解。基线时循环无细胞DNA中的HER 2扩增与较短的无进展生存期和总生存期相关（P<0.05）。依维莫司、来曲唑和曲妥珠单抗在重度激素受体和HER 2阳性晚期癌症患者中具有良好的安全性特征，并显示出令人鼓舞的抗癌活性信号。依维莫司、来曲唑和曲妥珠单抗的组合耐受性良好，并且对激素受体阳性、HER 2阳性晚期癌症，特别是乳腺癌具有令人鼓舞的活性。基线时循环无细胞DNA中的HER 2扩增与较短的无进展生存期和总生存期相关。
Doublets of everolimus with letrozole or trastuzumab have demonstrated activity against HER2-positive breast cancer, suggesting that the triple combination can have synergistic anticancer activity. This first-in-human dose escalation study (NCT02152943) enrolled patients with hormone receptor–positive, HER2-positive (defined by amplification, overexpression or mutation) treatment-refractory advanced cancers to receive escalating doses (3+3 design) of daily oral letrozole (days 1-21), daily oral everolimus (days 1-21) and intravenous trastuzmab (day 1) every 21 days to determine dose-limiting toxicities (DLTs) and maximum tolerated dose or recommended phase 2 dose (RP2D). Total of 32 patients with hormone receptor–positive, HER2-positive (amplification, n=27; overexpression, n=1; mutation, n=4) advanced breast cancer (n=26) or other cancers (n=6) were enrolled. The most frequent grade ≥ 3 adverse events included hyperglycemia (n=4), anemia (n=3), thrombocytopenia (n= 2) and mucositis (n=2). DLTs included grade 3 mucositis and grade 4 neutropenia, and trastuzumab given as an 8-mg/kg loading dose on day 1 of cycle 1 followed by a 6-mg/kg maintenance dose on day 1 of subsequent cycles plus 10 mg everolimus daily and 2.5 mg letrozole daily every 21 days was declared as RP2D. Five breast cancer patients (4 with HER2 amplification and 1 with HER2 mutation) had partial responses. HER2 amplification in circulating cell-free DNA at baseline was associated with shorter progression-free and overall survival durations (P<0.05). Everolimus, letrozole, and trastuzumab has a favorable safety profile and elicits encouraging signals of anticancer activity in patients with heavily pretreated hormone receptor– and HER2-positive advanced cancers. The combination of everolimus, letrozole, and trastuzumab is well tolerated and has encouraging activity against hormone receptor–positive, HER2-positive advanced cancers, especially breast cancer. HER2 amplification in circulating cell-free DNA at baseline is associated with shorter progression-free and overall survival.