紫杉醇是最有效的乳腺癌化療藥物之一。不過,,靜脈注射紫杉醇可并發(fā)神經(jīng)病變,,并且需要皮質(zhì)激素和抗組胺藥預(yù)防過敏反應(yīng),而口服紫杉醇后可被腸道細胞跨膜轉(zhuǎn)運糖蛋白泵主動排出,,吸收率極低,。恩塞奎達是一種新型高度選擇性跨膜轉(zhuǎn)運糖蛋白泵抑制劑,可顯著提高紫杉醇口服吸收率,。 2022年7月20日,,美國臨床腫瘤學(xué)會《臨床腫瘤學(xué)雜志》在線發(fā)表美國舊金山加利福尼亞大學(xué)海倫迪勒家族綜合癌癥中心、洪都拉斯DEMEDICA綜合腫瘤中心,、危地馬拉美洲癌癥中心,、多明尼加圣多明哥臨床研究中心、危地馬拉拉美醫(yī)療中心,、洪都拉斯EXCEL醫(yī)療中心,、危地馬拉克薩爾特南戈醫(yī)療中心、阿根廷羅薩里奧腫瘤研究所,、阿根廷別德瑪臨床研究中心的KX-ORAX-001研究報告,,對晚期乳腺癌患者口服紫杉醇+恩塞奎達與靜脈注射紫杉醇的有效性和安全性進行了比較。 KX-ORAX-001 (NCT02594371): An Open-Label, Randomized, Multicenter, Phase 3 Study to Determine the Safety, Tolerability, and Tumor Response of Oraxol and Its Comparability to IV Taxol or Generic IV Paclitaxel in Subjects With Metastatic Breast Cancer 該國際多中心非盲隨機對照三期臨床研究于2015年12月~2019年2月從拉丁美洲加勒比地區(qū)10個國家41家醫(yī)院入組晚期乳腺癌距末次紫杉類化療至少1年且器官功能正常女性患者402例,,按2∶1的比例隨機分為兩組:其中265例每周連續(xù)3天口服紫杉醇205mg/m2+恩塞奎達甲磺酸甲酯一水合物15mg,,其余137例每3周靜脈注射紫杉醇175mg/m2,兩組患者人口統(tǒng)計學(xué)特征和既往治療分布平衡,。主要終點為根據(jù)實體腫瘤緩解評價標(biāo)準(zhǔn)1.1版確認的放射影像緩解率,,由位于美國的盲法獨立審核中心評定。次要終點包括無進展生存和總生存,。 結(jié)果,,口服紫杉醇+恩塞奎達與靜脈注射紫杉醇相比:- 無進展生存:中位8.4個月比7.4個月(風(fēng)險比:0.768,95.5%置信區(qū)間:0.584~1.01,,P=0.046)
- 總生存:中位22.7個月和16.5個月(風(fēng)險比:0.794,,95.5%置信區(qū)間:0.607~1.037,P=0.08)
- 3~4級不良反應(yīng)發(fā)生率:55%比53%
- >2級神經(jīng)病變發(fā)生率:2%比15%
- 惡心,、嘔吐,、腹瀉和中性粒細胞減少發(fā)生率及嚴重程度較高,尤其肝酶升高患者
- 謹慎選擇患者,、加用粒細胞生長刺激因子,、減少劑量可以成功控制中性粒細胞減少
- 治療相關(guān)死亡發(fā)生率:3%比0%
亞組分析表明,無論年齡,、體力狀態(tài)評分,、內(nèi)臟轉(zhuǎn)移,、既往紫杉類或蒽環(huán)類化療、乳腺癌受體亞型如何,,口服紫杉醇+恩塞奎達都優(yōu)于靜脈注射紫杉醇,。 因此,該研究結(jié)果表明,,對于晚期乳腺癌患者,,口服紫杉醇+恩塞奎達與靜脈注射紫杉醇相比,確認緩解率顯著較高,,無進展生存和總生存改善,,神經(jīng)病變和脫發(fā)發(fā)生率較低且嚴重程度較低,可以作為每3周靜脈注射紫杉醇的替代治療選擇之一,。不過,,口服紫杉醇+恩塞奎達與靜脈注射紫杉醇相比,惡心,、嘔吐,、腹瀉等消化道反應(yīng)和中性粒細胞減少發(fā)生率及嚴重程度較高,尤其對于治療前肝酶升高患者,,容易發(fā)生早期中性粒細胞減少和嚴重感染,,謹慎選擇患者、加用粒細胞生長刺激因子,、減少劑量可以成功控制中性粒細胞減少,。?? J Clin Oncol. 2022 Jul 20:JCO2102953.Open-Label, Randomized, Multicenter, Phase III Study Comparing Oral Paclitaxel Plus Encequidar Versus Intravenous Paclitaxel in Patients With Metastatic Breast Cancer. Rugo HS, Umanzor GA, Barrios FJ, Vasallo RH, Chivalan MA, Bejarano S, Ramírez JR, Fein L, Kowalyszyn RD, Kramer ED, Wang H, Kwan MR, Cutler DL; Oraxol Study Consortium Investigators. University of California San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; Centro Oncológico Integral with DEMEDICA, San Pedro Sula, Honduras; American Cancer Center, Guatemala City, Guatemala; Clinical Research RD, Santo Domingo, Dominican Republic; CELAN Clínica Médica, Guatemala City, Guatemala; Excel Medica, San Pedro Sula, Honduras; Sanatorio Centro Regional de Sub-Especialidades Médicas (CRESEM), Quetzaltenango, Guatemala; Instituto de Oncología de Rosario, Rosario, Argentina; Centro de Investigaciones Clínicas, Clínica Viedma, Viedma, Argentina; Athenex, Inc, Buffalo, NY. PURPOSE: Intravenous paclitaxel (IVpac) is complicated by neuropathy and requires premedication to prevent hypersensitivity-type reactions. Paclitaxel is poorly absorbed orally; encequidar (E), a novel P-glycoprotein pump inhibitor, allows oral absorption. METHODS: A phase III open-label study comparing oral paclitaxel plus E (oPac + E) 205 mg/m2 paclitaxel plus 15 mg E methanesulfonate monohydrate 3 consecutive days per week versus IVpac 175 mg/m2 once every 3 weeks was performed. Women with metastatic breast cancer and adequate organ function, at least 1 year from last taxane, were randomly assigned 2:1 to oPac + E versus IVpac. The primary end point was confirmed radiographic response using RECIST 1.1, assessed by blinded independent central review. Secondary end points included progression-free survival (PFS) and overall survival (OS). RESULTS: Four hundred two patients from Latin America were enrolled (265 oPac + E, 137 IVpac); demographics and prior therapies were balanced. The confirmed response (intent-to-treat) was 36% for oPac + E versus 23% for IVpac (P = .01). The PFS was 8.4 versus 7.4 months, respectively (hazard ratio, 0.768; 95.5% CI, 0.584 to 1.01; P = .046), and the OS was 22.7 versus 16.5 months, respectively (hazard ratio, 0.794; 95.5% CI, 0.607 to 1.037; P = .08). Grade 3-4 adverse reactions were 55% with oPac + E and 53% with IVpac. oPac + E had lower incidence and severity of neuropathy (2% v 15% > grade 2) and alopecia (49% v 62% all grades) than IVpac but more nausea, vomiting, diarrhea, and neutropenic complications, particularly in patients with elevated liver enzymes. On-study deaths (8% oPac + E v 9% IVpac) were treatment-related in 3% and 0%, respectively. CONCLUSION: oPac + E increased the confirmed tumor response versus IVpac, with trends in PFS and OS. Neuropathy was less frequent and severe with oPac + E; neutropenic serious infections were increased. Elevated liver enzymes at baseline predispose oPac + E patients to early neutropenia and serious infections. KEY OBJECTIVE: Potential benefits make oral administration of paclitaxel appealing, including home administration, lack of need for intravenous (IV) access, and as oral paclitaxel (oPac) does not contain Cremophor EL, lack of hypersensitivity reactions or need for corticosteroid and antihistamine prophylaxis. KNOWLEDGE GENERATED: Overall tumor response in the intent-to-treat population and in clinically important subgroups was generally consistent and favored oPac plus encequidar over IV paclitaxel by at least 10% in most clinically important subgroups. Careful patient selection, use of growth factors, and dose reductions allow successful management of neutropenia. RELEVANCE: The study demonstrates that oPac can provide an alternative treatment option to every 3-week paclitaxel with lower rates and severity of neuropathy for patients with advanced or metastatic breast cancer. FUNDING: Athenex, Inc. ClinicalTrials.gov identifier: NCT02594371 PMID: 35858154 DOI: 10.1200/JCO.21.02953
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