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
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。
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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