晚期乳腺癌：氟维司群的追兵来了！
选择性雌激素受体调节剂他莫西芬等内分泌治疗是雌激素受体阳性HER2阴性晚期乳腺癌的主要治疗方法。不过，大多数晚期乳腺癌内分泌治疗后出现耐药、复发、转移，主要原因可能为雌激素受体基因α（ESR1）突变。氟维司群是目前唯一上市的选择性雌激素受体降解剂，与雌激素受体的亲和力是他莫西芬的100倍，主要用于他莫昔芬等内分泌治疗失败后雌激素受体阳性HER2阴性晚期乳腺癌绝经后女性，被认为是目前唯一对他莫昔芬治疗失败后仍然有效的雌激素受体抑制剂。不过，由于氟维司群专利过期，而且口服或静脉注射无效，只能注射，故面临着前有埋伏、后有追兵的局面。前有埋伏：正大天晴的第一个氟维司群仿制药晴可依已于2020年获得美国、德国、中国批准上市。后有追兵：由卫材发现并由雷迪厄斯和武田开发的新一代选择性雌激素受体降解剂艾拉司群口服有效，可免受皮肉之苦，而且比氟维司群容易穿过血脑屏障，对乳腺癌脑转移也有效。
2021年1月29日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表哈佛大学麻省总医院、德克萨斯大学健康科学中心、德克萨斯圣安东尼奥肿瘤医院、底特律芭芭拉安卡曼诺斯癌症中心、德克萨斯泰勒肿瘤医院、拉斐特地平线肿瘤中心、德克萨斯贝勒查尔斯萨蒙斯癌症中心、俄亥俄州立大学综合癌症中心、德克萨斯大学MD安德森癌症中心、弗吉尼亚诺福克肿瘤医院、雷迪厄斯制药、科罗拉多大学奥罗拉医学院的RAD1901-005研究报告，探讨了艾拉司群治疗雌激素受体阳性HER2阴性晚期乳腺癌患者的剂量、有效性和安全性。
RAD1901-005 (NCT02338349): A Phase I, Multicenter, Open-Label, Multi-Part, Dose-escalation Study of RAD1901 in Postmenopausal Women With Advanced Estrogen Receptor Positive and HER2-Negative Breast Cancer
该多中心非盲一期临床研究于2015年4月～2019年10月从美国11家医院入组雌激素受体阳性HER2阴性晚期乳腺癌内分泌治疗失败的绝经后女性57例。主要目标为确定艾拉司群的最大耐受剂量和二期临床研究推荐剂量。该研究原先设计为两步：第一步为艾拉司群胶囊剂量递增，第二步为艾拉司群胶囊推荐剂量扩大患者人数。随后追加两步：第三步为艾拉司群片剂推荐剂量，第四步为艾拉司群片剂推荐剂量用于难治患者，例如CDK4/6抑制剂和氟维司群≥二线治疗失败。第一步确定的艾拉司群推荐剂量为每天1次口服400毫克，直至疾病进展或无法耐受。
结果，50例患者服用了推荐剂量，中位年龄63岁，既往抗癌治疗中位三线，其中：
CDK4/6抑制剂失败：26例（52%）
氟维司群失败：26例（52%）
循环肿瘤基因ESR1突变：25例（50%）
未发生剂量受限毒性反应。大多数不良事件严重程度为1～2级。
推荐剂量发生率最高的不良事件：
恶心：24例（33.3%）
血甘油三酯增加：6例（25.0%）
血磷减少：6例（25.0%）
31例患者的缓解率可评估，客观缓解率为19.4%（6例）
20例氟维司群失败患者：15.0%（3例）
18例CDK4/6抑制剂失败患者：16.7%（3例）
15例ESR1突变患者：33.3%（5例）
47例患者的获益率可评估，临床获益率为42.6%（20例）
23例ESR1突变患者：56.5%（13例）
23例CDK4/6抑制剂失败患者：30.4%（7例）
艾拉司群临床获益与ESR1突变等位基因百分比成反比。
因此，该研究结果表明，对于雌激素受体阳性HER2阴性晚期乳腺癌内分泌治疗失败的绝经后女性，每天1次口服艾拉司群400毫克的安全性可接受，单药具有抗癌活性并确认部分缓解。值得注意的是，对于ESR1突变、CDK4/6抑制剂和氟维司群治疗失败的患者也可见缓解。据悉，艾拉司群＋标准内分泌治疗的三期临床研究正在进行，代号：祖母绿，预计将于2021年初步完成、2022年全部完成。
RAD1901-308 (NCT03778931): Phase 3 Trial of Elacestrant vs. Standard of Care for the Treatment of Patients With ER+/HER2- Advanced Breast Cancer (EMERALD)
J Clin Oncol. 2021 Jan 29. Online ahead of print.
Phase I Study of Elacestrant (RAD1901), a Novel Selective Estrogen Receptor Degrader, in ER-Positive, HER2-Negative Advanced Breast Cancer.
Bardia A, Kaklamani V, Wilks S, Weise A, Richards D, Harb W, Osborne C, Wesolowski R, Karuturi M, Conkling P, Bagley RG, Wang Y, Conlan MG, Kabos P.
Massachusetts General Hospital Cancer Center, Boston, MA; University of Texas Health Sciences Center, Houston, TX; Texas Oncology-San Antonio, San Antonio, TX; Barbara Ann Karmanos Cancer Center, Detroit, MI; Texas Oncology-Tyler, Tyler, TX; Horizon Oncology Center, Lafayette, IN; Texas Oncology-Baylor Charles A. Sammons Cancer Center, Dallas, TX; Ohio State University Comprehensive Cancer Center, Columbus, OH; MD Anderson Cancer Center, Houston, TX; US Oncology Research, Virginia Oncology Associates, Norfolk, VA; Radius Health, Inc., Waltham, MA; University of Colorado, Aurora, CO.
PURPOSE: This phase I study (RAD1901-005; NCT02338349) evaluated elacestrant, an investigational oral selective estrogen receptor degrader (SERD), in heavily pretreated women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer, including those with estrogen receptor gene alpha (ESR1) mutation. The primary objective was to determine the maximum tolerated dose and/or recommended phase II dose (RP2D).
METHODS: The study consisted of a 3 + 3 design (elacestrant capsules) followed by expansion at RP2D (400-mg capsules, then 400-mg tablets) for the evaluation of safety and antitumor activity. Elacestrant was taken once daily until progression or intolerability.
RESULTS: Of 57 postmenopausal women enrolled, 50 received RP2D (400 mg once daily): median age, 63 years; median three prior anticancer therapies, including cyclin-dependent kinase 4,6 inhibitors (CDK4/6i; 52%), SERD (52%), and ESR1 mutation (circulating tumor DNA; 50%). No dose-limiting toxicities occurred; the most common adverse events at RP2D (400-mg tablet; n = 24) were nausea (33.3%) and increased blood triglycerides and decreased blood phosphorus (25.0% each). Most adverse events were grade 1-2 in severity. The objective response rate was 19.4% (n = 31 evaluable patients receiving RP2D), 15.0% in patients with prior SERD, 16.7% in patients with prior CDK4/6i, and 33.3% in patients with ESR1 mutation (n = 5/15). The clinical benefit rate (24-week) was 42.6% overall (n = 47 patients receiving RP2D), 56.5% (n = 23, ESR1 mutation), and 30.4% (n = 23, prior CDK4/6i). Elacestrant clinical benefit was associated with decline in ESR1 mutant allele fraction.
CONCLUSION: Elacestrant 400 mg orally once daily has an acceptable safety profile and demonstrated single-agent activity with confirmed partial responses in heavily pretreated patients with estrogen receptor-positive metastatic breast cancer. Notably, responses were observed in patients with ESR1 mutation as well as those with prior CDK4/6i and prior SERD. A phase III trial investigating elacestrant versus standard endocrine therapy is ongoing.
PMID: 33513026
DOI: 10.1200/JCO.20.02272