晚期乳腺癌口服与静注紫杉醇比较

　　紫杉醇是最有效的乳腺癌化疗药物之一。不过，静脉注射紫杉醇可并发神经病变，并且需要皮质激素和抗组胺药预防过敏反应，而口服紫杉醇后可被肠道细胞跨膜转运糖蛋白泵主动排出，吸收率极低。恩塞奎达是一种新型高度选择性跨膜转运糖蛋白泵抑制剂，可显著提高紫杉醇口服吸收率。

　　2022年7月20日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表美国旧金山加利福尼亚大学海伦迪勒家族综合癌症中心、洪都拉斯DEMEDICA综合肿瘤中心、危地马拉美洲癌症中心、多明尼加圣多明哥临床研究中心、危地马拉拉美医疗中心、洪都拉斯EXCEL医疗中心、危地马拉克萨尔特南戈医疗中心、阿根廷罗萨里奥肿瘤研究所、阿根廷别德玛临床研究中心的KX-ORAX-001研究报告，对晚期乳腺癌患者口服紫杉醇＋恩塞奎达与静脉注射紫杉醇的有效性和安全性进行了比较。

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

　　该国际多中心非盲随机对照三期临床研究于2015年12月～2019年2月从拉丁美洲加勒比地区10个国家41家医院入组晚期乳腺癌距末次紫杉类化疗至少1年且器官功能正常女性患者402例，按2∶1的比例随机分为两组：其中265例每周连续3天口服紫杉醇205mg/m²＋恩塞奎达甲磺酸甲酯一水合物15mg，其余137例每3周静脉注射紫杉醇175mg/m²，两组患者人口统计学特征和既往治疗分布平衡。主要终点为根据实体肿瘤缓解评价标准1.1版确认的放射影像缓解率，由位于美国的盲法独立审核中心评定。次要终点包括无进展生存和总生存。

　　结果，口服紫杉醇＋恩塞奎达与静脉注射紫杉醇相比：

• 确认缓解率：36%比23%（P=0.01）
• 无进展生存：中位8.4个月比7.4个月（风险比：0.768，95.5%置信区间：0.584～1.01，P=0.046）
• 总生存：中位22.7个月和16.5个月（风险比：0.794，95.5%置信区间：0.607～1.037，P=0.08）
• 3～4级不良反应发生率：55%比53%
• ＞2级神经病变发生率：2%比15%
• 各级脱发发生率：49%比62%
• 恶心、呕吐、腹泻和中性粒细胞减少发生率及严重程度较高，尤其肝酶升高患者
• 谨慎选择患者、加用粒细胞生长刺激因子、减少剂量可以成功控制中性粒细胞减少
• 研究期间死亡发生率：8%比9%
• 治疗相关死亡发生率：3%比0%

　　亚组分析表明，无论年龄、体力状态评分、内脏转移、既往紫杉类或蒽环类化疗、乳腺癌受体亚型如何，口服紫杉醇＋恩塞奎达都优于静脉注射紫杉醇。

　　因此，该研究结果表明，对于晚期乳腺癌患者，口服紫杉醇＋恩塞奎达与静脉注射紫杉醇相比，确认缓解率显著较高，无进展生存和总生存改善，神经病变和脱发发生率较低且严重程度较低，可以作为每3周静脉注射紫杉醇的替代治疗选择之一。不过，口服紫杉醇＋恩塞奎达与静脉注射紫杉醇相比，恶心、呕吐、腹泻等消化道反应和中性粒细胞减少发生率及严重程度较高，尤其对于治疗前肝酶升高患者，容易发生早期中性粒细胞减少和严重感染，谨慎选择患者、加用粒细胞生长刺激因子、减少剂量可以成功控制中性粒细胞减少。

相关链接

• 柳叶刀编辑点评圣安东尼奥乳腺癌论坛

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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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