Open-Label, Randomized, Multicenter, Phase III Study Comparing Oral Paclitaxel Plus Encequidar Versus Intravenous Paclitaxel in Patients With Metastatic Breast Cancer

Abstract

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 (funded by Athenex, Inc; ClinicalTrials.gov identifier: NCT02594371).

FIG 1.

Oraxol study CONSORT diagram. IV, intravenous; oPac + E, oral paclitaxel plus encequidar.

FIG 2.

Confirmed tumor response in clinically relevant subgroups. Others category includes patients with receptor status unknown for one or more receptors.

FIG 3.

Kaplan-Meier curve for (A) PFS and (B) OS. (A) oPac + E: median estimate 8.4, range 0-35.7, censored summary 125 of 265 (47%); IVpac: median estimate 7.4, range 0-33.1, censored summary 49 of 137 (36%); HR (95.5% CI) 0.768 (0.584 to 1.01), P = .046. (B) oPac + E: median estimate 22.7, range 0.3-49.4, event summary 154 of 265 (58%), censored summary 111 of 265 (42%), alive 107 of 265 (40%), and discontinued 4 of 265 (2%); IVpac: median estimate 16.5, range 0.3-45.3, event summary 89 of 137 (65%), censored summary 48 of 137 (35%), alive 46 of 137 (34%), and discontinued 2 of 137 (1%); HR (95.5% CI) 0.794 (0.607 to 1.037). + = censored; HR estimated with the Cox proportional hazards model at a significance level of 0.045. HR, hazard ratio; IV, intravenous; IVpac, intravenous paclitaxel; oPac + E, oral paclitaxel plus encequidar; OS, overall survival; PFS, progression-free survival.