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 ).

Reply to Z.R. McCaw et al

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We appreciate the comments from McCaw et al 1 regarding the statistical analysis of end points in our study. 2 The primary end point of the study was response rate, but we agree that the estimate of absolute value by median improvement in progression-free survival using Kaplan-Meier can be misleading and may underestimate the true value of new treatment approaches.Using a time-based (t-year) approach to estimate benefit in mean event-free (survival) time to summarize the survival curve is interesting and may provide clinically meaningful results. The t-year mean survival time is the area under the Kaplan-Meier curve.

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“…We appreciate the comments from McCaw et al 1 regarding the statistical analysis of end points in our study. 2 The primary end point of the study was response rate, but we agree that the estimate of absolute value by median improvement in progression-free survival using Kaplan-Meier can be misleading and may underestimate the true value of new treatment approaches.…”

Assessing the Clinical Utility of Oral Paclitaxel Plus Encequidar Versus Intravenous Paclitaxel in Patients With Metastatic Breast Cancer

“…For the present case, the 36-month mean survival time can be used to quantify the treatment effect. With reconstructed data from Figure 3A, 1 the expected 36-month survival times are 12.3 months with oPac + E and 9.5 with IVpac. That is, on average, future patients treated with oPac + E and followed for 36 months are expected to survive progression-free for 12.3 months.…”

“…2,3 Furthermore, the validity of the HR depends on a proportional hazards assumption. 4 From Figure 3A, 1 the Kaplan-Meier curves suggest that the proportional hazards assumption was likely not met. For this case, the observed HR estimates an uninterpretable population quantity that involves the censoring distributions.…”

“…Rugo et al 1 conducted an important clinical trial comparing oral paclitaxel plus encequidar (oPac 1 E) with intravenous paclitaxel (IVpac) for treating patients with metastatic breast cancer. The key secondary end points were progression-free survival (PFS) and overall survival.…”