2024年12月10日，第47屆圣安東尼奧乳腺癌研討會(huì)在德克薩斯州第二大城市圣安東尼奧開(kāi)幕，這是全球最大的乳腺癌研究會(huì)議，預(yù)計(jì)將有來(lái)自102多個(gè)國(guó)家和地區(qū)的1.1萬(wàn)多位臨床工作者、研究者和患者參加。 2024年12月11日，國(guó)際四大醫(yī)學(xué)期刊之一、創(chuàng)刊212周年的美國(guó)麻省醫(yī)學(xué)會(huì)《新英格蘭醫(yī)學(xué)雜志》首頁(yè)頭條和第47屆圣安東尼奧乳腺癌研討會(huì)首場(chǎng)全體大會(huì)首位報(bào)告者同時(shí)公布美國(guó)、比利時(shí)、阿根廷、韓國(guó)、日本、西班牙、德國(guó)、意大利、澳大利亞、墨西哥、巴西、法國(guó)、中國(guó)哈爾濱醫(yī)科大學(xué)附屬腫瘤醫(yī)院張清媛等29位學(xué)者代表EMBER-3研究協(xié)作組起草的研究結(jié)果，首次對(duì)英魯奈司群±阿貝西利或者標(biāo)準(zhǔn)內(nèi)分泌單藥治療晚期乳腺癌內(nèi)分泌治療耐藥患者的有效性和安全性進(jìn)行比較。  - NCT04975308: A Study of Imlunestrant, Investigator's Choice of Endocrine Therapy, and Imlunestrant Plus Abemaciclib in Participants With ER+, HER2- Advanced Breast Cancer (EMBER-3)
- Official Title: A Phase 3, Randomized, Open-Label Study of Imlunestrant, Investigator's Choice of Endocrine Therapy, and Imlunestrant Plus Abemaciclib in Patients With Estrogen Receptor Positive, HER2 Negative Locally Advanced or Metastatic Breast Cancer Previously Treated With Endocrine Therapy
- GS1-01: Imlunestrant, an Oral Selective Estrogen Receptor Degrader (SERD), as Monotherapy and Combined with Abemaciclib, for Patients with ER+, HER2- Advanced Breast Cancer (ABC), Pretreated with Endocrine Therapy (ET): Results of the Phase 3 EMBER-3 trial.
英魯奈司群是可滲透血腦屏障、可口服的新一代選擇性雌激素受體降解劑，即使對(duì)于雌激素受體α編碼基因ESR1發(fā)生突變的乳腺癌也能發(fā)揮持續(xù)抑制作用。 該國(guó)際多中心非盲隨機(jī)對(duì)照三期臨床研究于2021年10月至2023年11月從全球22個(gè)國(guó)家和地區(qū)195個(gè)研究中心入組雌激素受體陽(yáng)性HER2陰性晚期乳腺癌芳香化酶抑制劑單獨(dú)或聯(lián)合CDK4/6抑制劑治療期間或之后出現(xiàn)復(fù)發(fā)或進(jìn)展患者874例（中位年齡61歲，范圍27至89歲，55.5%有內(nèi)臟轉(zhuǎn)移，59.8%用過(guò)CDK4/6抑制劑治療；其中256例ESR1突變，占38.7%，這些患者與全部患者相比，基線(xiàn)特征大致相似，但是PI3K通路突變、肝轉(zhuǎn)移、用過(guò)CDK4/6抑制劑治療患者比例略高，分別占50.4%、40.6%、69.5%）按1∶1∶1的比例隨機(jī)分為三組：- 標(biāo)準(zhǔn)單藥內(nèi)分泌治療：330例（其中氟維司群292例）
主要終點(diǎn)為ESR1突變患者和無(wú)論是否突變患者英魯奈司群與標(biāo)準(zhǔn)治療相比、同時(shí)隨機(jī)入組全部患者英魯奈司群＋阿貝西利與英魯奈司群相比，研究者評(píng)定的無(wú)進(jìn)展生存。如若生存曲線(xiàn)不平行且比例風(fēng)險(xiǎn)假設(shè)不成立，則進(jìn)行受限平均生存分析（截至特定時(shí)間點(diǎn)的生存曲線(xiàn)下面積）。關(guān)鍵次要終點(diǎn)為總生存。其他次要終點(diǎn)包括通過(guò)盲法獨(dú)立集中復(fù)核評(píng)定的無(wú)進(jìn)展生存、總緩解率和安全性。 結(jié)果，對(duì)于256例ESR1突變患者，英魯奈司群與標(biāo)準(zhǔn)治療相比：- 中位無(wú)進(jìn)展生存：5.5個(gè)月比3.8個(gè)月
- 由于存在非比例風(fēng)險(xiǎn)證據(jù)，估計(jì)受限平均生存19.4個(gè)月
- 中位無(wú)進(jìn)展生存：7.9個(gè)月比5.4個(gè)月（95%置信區(qū)間：6.8～9.1、4.6～6.2）
- 受限平均生存相差：2.6個(gè)月（95%置信區(qū)間：1.2～3.9，P<0.001）
- 18個(gè)月估計(jì)總生存率：77.0%比58.6%（95%置信區(qū)間：67.4～84.1、47.2～68.3）
- 死亡風(fēng)險(xiǎn)比：0.55（95%置信區(qū)間：0.35～0.86，P=0.008，未低于預(yù)設(shè)2.2×10-10）
對(duì)于661例無(wú)論是否突變患者，英魯奈司群與標(biāo)準(zhǔn)治療相比：- 中位無(wú)進(jìn)展生存：5.6個(gè)月比5.5個(gè)月
- 進(jìn)展或死亡風(fēng)險(xiǎn)比：0.87（95%置信區(qū)間：0.72～1.04，P=0.12）
- 18個(gè)月估計(jì)總生存率：78.6%比71.8%（95%置信區(qū)間：72.6～83.5、65.4～77.2）
- 死亡風(fēng)險(xiǎn)比：0.69（95%置信區(qū)間：0.50～0.96，未進(jìn)行統(tǒng)計(jì)學(xué)檢驗(yàn)）
對(duì)于426例同時(shí)隨機(jī)入組全部患者，英魯奈司群＋阿貝西利與英魯奈司群相比：- 中位無(wú)進(jìn)展生存：9.4個(gè)月比5.5個(gè)月
- 進(jìn)展或死亡風(fēng)險(xiǎn)比：0.57（95%置信區(qū)間：0.44～0.73，P<0.001）
對(duì)于279例用過(guò)CDK4/6抑制劑的同時(shí)隨機(jī)入組患者，英魯奈司群＋阿貝西利與英魯奈司群相比：- 中位無(wú)進(jìn)展生存：9.1個(gè)月比3.7個(gè)月
- 進(jìn)展或死亡風(fēng)險(xiǎn)比：0.51（95%置信區(qū)間：0.38～0.68，未進(jìn)行統(tǒng)計(jì)學(xué)檢驗(yàn)）
英魯奈司群、標(biāo)準(zhǔn)治療、英魯奈司群＋阿貝西利相比，≥3級(jí)不良事件發(fā)生率分別為17.1%、20.7%、48.6%。 因此，該研究令人燒腦的設(shè)計(jì)和結(jié)果表明，對(duì)于雌激素受體陽(yáng)性HER2陰性晚期乳腺癌，英魯奈司群與氟維司群等標(biāo)準(zhǔn)單藥內(nèi)分泌治療相比，ESR1突變患者無(wú)進(jìn)展生存顯著較長(zhǎng)。英魯奈司群＋阿貝西利與英魯奈司群相比，無(wú)論ESR1是否突變，無(wú)進(jìn)展生存顯著較長(zhǎng)。 阿貝西利等CDK4/6抑制劑一直是芳香化酶抑制劑標(biāo)準(zhǔn)內(nèi)分泌治療的重要補(bǔ)充，如果出現(xiàn)進(jìn)展，CDK4/6抑制劑聯(lián)合選擇性雌激素受體降解劑可能獲益。不過(guò)，由于氟維司群等現(xiàn)有選擇性雌激素受體降解劑的局限性，包括口服生物利用度低、需要每月肌肉注射，以及對(duì)出現(xiàn)ESR1突變患者療效有限，正在開(kāi)發(fā)的英魯奈司群等新一代選擇性雌激素受體降解劑可以通過(guò)口服簡(jiǎn)化給藥提高療效和患者體驗(yàn)，而且40%～50%的內(nèi)分泌治療進(jìn)展患者可出現(xiàn)ESR1突變。 這些有希望的結(jié)果意味著，對(duì)于許多乳腺癌復(fù)發(fā)伴ESR1突變患者而言，英魯奈司群可能是另一種單藥選擇。此外，英魯奈司群＋阿貝西利與英魯奈司群相比，中位無(wú)進(jìn)展生存分別為9.4個(gè)月和5.5個(gè)月，疾病進(jìn)展或死亡風(fēng)險(xiǎn)降低43%。對(duì)于全部患者都觀(guān)察到這兩種藥物聯(lián)合的獲益，無(wú)論是否ESR1突變或PI3K通路突變患者以及是否用過(guò)CDK4/6抑制劑治療，而且這兩種藥物都可口服。 由于目前大多數(shù)符合二線(xiàn)治療條件的患者之前都用過(guò)CDK4/6抑制劑治療，而且許多目前可用的二線(xiàn)治療需要進(jìn)行生物標(biāo)志物選擇，因此這些結(jié)果對(duì)臨床相關(guān)亞組的一致性令人放心。 英魯奈司群無(wú)論作為單藥治療還是聯(lián)合治療，安全性和耐受性都良好，不良事件通常級(jí)別較低而且可控，并且沒(méi)有其他口服選擇性雌激素受體降解劑特有的眼部或心臟安全問(wèn)題。該聯(lián)合的安全性與已知的氟維司群＋阿貝西利安全性一致，停藥率相對(duì)較低，僅6.3%，與現(xiàn)有的聯(lián)合方案相比更為有利。此外，根據(jù)該研究患者報(bào)告結(jié)局?jǐn)?shù)據(jù)，72%的氟維司群治療患者報(bào)告注射部位疼痛、腫脹或發(fā)紅。 總而言之，這些數(shù)據(jù)對(duì)于患者而言值得期待，表明英魯奈司群單藥治療或聯(lián)合阿貝西利有望成為雌激素受體陽(yáng)性HER2陰性晚期乳腺癌內(nèi)分泌治療進(jìn)展后患者全口服靶向治療新選擇。N Engl J Med. 2024 Dec 11. IF: 96.2 Imlunestrant with or without Abemaciclib in Advanced Breast Cancer. Jhaveri KL, Neven P, Casalnuovo ML, Kim SB, Tokunaga E, Aftimos P, Saura C, O'Shaughnessy J, Harbeck N, Carey LA, Curigliano G, Llombart-Cussac A, Lim E, García Tinoco ML, Sohn J, Mattar A, Zhang Q, Huang CS, Hung CC, Martinez Rodriguez JL, Ruíz Borrego M, Nakamura R, Pradhan KR, Cramer von Laue C, Barrett E, Cao S, Wang XA, Smyth LM, Bidard FC; EMBER-3 Study Group. Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York; University Hospitals Leuven, Leuven, Belgium; Hospital María Curie, Buenos Aires; Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea; National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan; Institut Jules Bordet, Hopital Universitaire de Bruxelles, Brussels; Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona; Baylor University Medical Center, Texas Oncology, U.S. Oncology, Dallas; the Breast Center, Comprehensive Cancer Center Munich, Ludwig Maximilians University Munich University Hospital, Munich, Germany; the University of North Carolina at Chapel Hill, Chapel Hill; the University of Milan, Milan; the European Institute of Oncology, IRCCS, Milan; Hospital Arnau de Vilanova, Valencia, Spain; Garvan Institute of Medical Research and University of New South Wales, Sydney; Hospital de Oncología, Centro Médico Nacional Siglo XXI, Mexico City; Yonsei University College of Medicine, Seoul, South Korea; Women's Health Hospital, Sao Paulo; Harbin Medical University Cancer Hospital, Harbin, China; National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei; Taichung Veterans General Hospital, Taichung, Taiwan; Filios Alta Medicina, Monterrey, Mexico; Hospital Universitario Virgen del Rocío, Seville, Spain; Chiba Cancer Center Hospital, Chiba, Japan; Eli Lilly, Indianapolis; Institut Curie and University of Versailles Saint-Quentin-en-Yvelines-Paris-Saclay University, Paris. BACKGROUND: Imlunestrant is a next-generation, brain-penetrant, oral selective estrogen-receptor (ER) degrader that delivers continuous ER inhibition, even in cancers with mutations in the gene encoding ERα (ESR1). METHODS: In a phase 3, open-label trial, we enrolled patients with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer that recurred or progressed during or after aromatase inhibitor therapy, administered alone or with a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor. Patients were assigned in a 1:1:1 ratio to receive imlunestrant, standard endocrine monotherapy, or imlunestrant-abemaciclib. Primary end points were investigator-assessed progression-free survival with imlunestrant as compared with standard therapy among patients with ESR1 mutations and among all patients and with imlunestrant-abemaciclib as compared with imlunestrant among all patients who had undergone randomization concurrently. RESULTS: Overall, 874 patients underwent randomization, with 331 assigned to imlunestrant, 330 to standard therapy, and 213 to imlunestrant-abemaciclib. Among 256 patients with ESR1 mutations, the median progression-free survival was 5.5 months with imlunestrant and 3.8 months with standard therapy. The estimated restricted mean survival time at 19.4 months was 7.9 months (95% confidence interval [CI], 6.8 to 9.1) with imlunestrant and 5.4 months (95% CI, 4.6 to 6.2) with standard therapy (difference, 2.6 months; 95% CI, 1.2 to 3.9; P<0.001). In the overall population, the median progression-free survival was 5.6 months with imlunestrant and 5.5 months with standard therapy (hazard ratio for progression or death, 0.87; 95% CI, 0.72 to 1.04; P = 0.12). Among 426 patients in the comparison of imlunestrant-abemaciclib with imlunestrant, the median progression-free survival was 9.4 months and 5.5 months, respectively (hazard ratio, 0.57; 95% CI, 0.44 to 0.73; P<0.001). The incidence of grade 3 or higher adverse events was 17.1% with imlunestrant, 20.7% with standard therapy, and 48.6% with imlunestrant-abemaciclib. CONCLUSIONS: Among patients with ER-positive, HER2-negative advanced breast cancer, treatment with imlunestrant led to significantly longer progression-free survival than standard therapy among those with ESR1 mutations but not in the overall population. Imlunestrant-abemaciclib significantly improved progression-free survival as compared with imlunestrant, regardless of ESR1-mutation status. Funded by Eli Lilly EMBER-3 ClinicalTrials.gov number, NCT04975308. PMID: 39660834 DOI: 10.1056/NEJMoa2410858
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